Methods and compositions for treating a subject with 15-hydroxyprostaglandin dehydrogenase inhibitors

Abstract

Provided herein are compositions and methods for reducing levels of at least one biomarker in a subject. The at least one biomarker may include p75ECD, PGE-MUM, or both. In some cases, the compositions and methods provided herein involve administering to a subject an amount of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor effective to reduce levels of the at least one biomarker in the subject.

Description

METHODS AND COMPOSITIONS FOR TREATING A SUBJECT WITH 15- HYDROXYPROSTAGLANDIN DEHYDROGENASE INHIBITORS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 520,592, filed on August 18, 2023, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] The p75 neurotrophin receptor (p75NTR) is implicated in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) disease. In ALS, elevation of the p75 extracellular domain (p75ECD) in urine is a biomarker for disease. Urinary Prostaglandin E-metabolite (PGE-MUM, also known as PGE-M) is a metabolite of Prostaglandin E2 that is a biomarker for disease, and elevated levels of PGE-MUM are associated with increased risk for ALS. INCORPORATION BY REFERENCE

[0003] 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

[0004] There is an unmet need for compositions and methods for reducing levels of biomarkers (e.g., associated with a disease or condition) in a subject. This disclosure meets this unmet need by providing compositions and methods for reducing levels of biomarkers (e.g., p75ECD, PGE-MUM) associated with a disease or condition using 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors.

[0005] In one aspect, a method for reducing levels of p75ECD, PGE-MUM, or both in a subject is provided, the method comprising: administering to the subject an amount of a 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor effective to reduce levels of p75ECD, PGE-MUM, or both, in the subject.

[0006] In another aspect, a method for treating a subject with a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor is provided, the method comprising: (a) identifying the subject as having elevated levels of p75ECD, PGE-MUM, or both, relative to a control or levels of p75ECD or PGE-MUM that exceed a predetermined threshold; and (b) administering the 15-PGDH inhibitor to the subject to reduce the levels of p75ECD, PGE- MUM, or both, in the subject. In some cases, the method further comprises prior to the administering, measuring the levels of p75ECD, PGE-MUM, or both, in the subject.

[0007] In another aspect, a method for selecting a subject for treatment with a 15- hydroxyprostaglandin (15-PGDH) inhibitor is provided, the method comprising: (a) providing or obtaining a biological sample obtained from the subject; (b) measuring a level of p75ECD, PGE-MUM, or both in the biological sample; and (c) identifying the subject as a candidate for treatment with the 15-PGDH inhibitor when the levels of p75ECD, PGE-MUM, or both, in the biological sample exceeds a predetermined threshold. In some cases, the method further comprises, administering the 15-PGDH inhibitor to the subject.

[0008] In some cases, the subject has a disease or condition associated with elevated levels of p75ECD. In some cases, the disease or condition associated with elevated levels of p75ECD is a neurodegenerative disorder. In some cases, the neurodegenerative disorder is In some cases, the subject has a disease or condition associated with elevated levels of PGE-MUM. In some cases, the administering is selected from the group consisting of: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra- arterial administration, intradermal administration, subcutaneous administration, and any combination thereof. In some cases, the administering is selected from the group consisting of: acute administration, chronic administration, intermittent administration, and continuous administration. In some cases, the 15-PGDH inhibitor is administered to the subject in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, diluent, and / or carrier. In some cases, the subject in need thereof is a human. In some cases, the biological sample is whole blood, plasma, or serum. In some cases, the biological sample is urine. In some cases, the 15-PGDH inhibitor is selected from the group consisting of: a small molecule, an antibody or fragment thereof, a peptide inhibitor, an aptamer, an oligonucleotide inhibitor, and any combination thereof. In some cases, the 15-PGDH inhibitor is a compound of Formula I: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 R1is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo or thio; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R11is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 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 the compound of Formula I is not,.

[0009] In some cases, compound is a compound of Formula Ia:Formula Ia or a pharmaceutically acceptable salt thereof.

[0010] In some cases, the compound is a compound of Formula Ib:Formula Ib or a pharmaceutically acceptable salt thereof.

[0011] In some cases, 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; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo or thio; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl;each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; provided that the compound of Formula II is not,,, , ,Formula IIa or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0013] In some cases, the compound is a compound of Formula IIb:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0014] In some cases, the compound is a compound of Formula IIc:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0015] In some cases, the compound is a compound of Formula IId:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0016] In some cases, the compound is a compound of Formula IIe:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0017] In some cases, the compound is a compound of Formula IIf:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0018] In some cases, the compound is a compound of Formula IIg:Formula IIg or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0019] In some cases, the compound is a compound of Formula IIh:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0020] In some cases, the compound is a compound of Formula IIi:Formula IIi or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

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

[0022] In some cases, the compound is a compound of Formula IIn:Formula IIn or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0023] In some cases, the compound is a compound of Formula IIp:Formula IIp or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0024] In some cases, the 15-PGDH inhibitor is a compound of Formula III:Formula IIIor 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; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo or thio; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, 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, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R63- 10cycloalkyl, and any remaining R6NR9R10, OR11, C(O)R11, C(O)OR11, C(O)NR9R10, SOR12, SO2R12, SO2NR9R10, NR13C(O)R11, NR13C(O)NR9R10, NR13SO2R11, NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl,C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R8is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R83-10cycloalkyl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

[0025] In some cases, the compound is a compound of Formula IIIa:Formula IIIa or a pharmaceutically acceptable salt thereof.

[0026] In some cases, the compound is a compound of Formula IIIb:Formula IIIb or a pharmaceutically acceptable salt thereof, wherein: each R14is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0027] In some cases, the compound is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof.

[0028] In some cases, the compound is a compound of Formula IIId:Formula IIId or a pharmaceutically acceptable salt thereof, wherein: each R14is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0029] In some cases, the 15-PGDH inhibitor is a compound of Formula IIk: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; R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; each R4is independently selected from H and halo; R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R11is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; andp is 0, 1, or 2.

[0030] In some cases, the 15-PGDH inhibitor is a compound of Formula IIm:Formula IIm or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, 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.

[0031] In some cases, the 15-PGDH inhibitor is a compound of Formula IIq:Formula IIq or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4intervening atoms to form a C3-10cycloalkyl, and any remaining R4selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, 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.

[0032] In some cases, the 15-PGDH inhibitor is a compound of Formula IIIc:Formula IIIc 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; R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, 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, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; orR4and R5are 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R6R6m halo, NR9R10, OR11, C(O)R11, C(O)OR11, C(O)NR9R10, SOR12, SO2R12, SO2NR9R10, NR13C(O)R11, NR13C(O)NR9R10, NR13SO2R11, NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7and R8is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0033] In some cases, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0034] In some cases, the 15-PGDH inhibitor is a compound selected from the group consisting of:; ;;;;

[0035] In some cases, the 15-PGDH inhibitor is a compound selected from the group consisting of:.

[0036] In some instances, the 15-PGDH inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt thereof:Formula IV, wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2or N; R1is H, halogen, -CN, OR10, C(O)R10, C(O)OR10, NR8R9, C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C cycloalkyl; each R2is independently H, halogen, OR10, C(O)R10, C(O)OR10, -CN, C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9; R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C2-C alkenyl, substituted or unsubstituted C1-C aminoalkyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8- membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C heterocycloalkyl; XAis -NR5R5or -OR5; wherein each R5is independently H or C1-C6alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C6heterocycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is optionally substituted with one or more Ra;each R10is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R12is 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-C8cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is optionally substituted with one or more Ra; each Rais 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.

[0037] In some instances, ring Q is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 N atoms. In some instances, ring Q is a phenyl, pyrimidinyl, or pyridinyl. In some instances, when Q is phenyl then one of R3is not H.

[0038] In some instances,wherein, X1, X2, X3and X4are each independently N or CR3; each R3is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted orunsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9; each R8and R9is 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-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais 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.

[0039] In some instances, X1, X2, X3and X4are each CR3. In some instances, X1is N; and X2, X3, and X4are each CR3. In some instances, X1and X2are each N; and X3and X4areeach CR3. In some instances, X1and X3are each N; and X2and X4are each CR3. In some instances, X1and X4are each N; and X2and X3are each CR3. In some instances, X1, X2, and X3are each N; and X4is CR3. In some instances, X1, X2, and X4are each N; and X3is CR3.

[0040] In some instances, each R3is independently selected from H, halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some instances, each R3is independently selected from H, halogen, C(O)OR10, C(O)NR8R9, and substituted or unsubstituted 5-membered heteroaryl.

[0041] In some instances, the compound has the structure of Formula V, or a pharmaceutically acceptable salt thereof:Formula V, wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1is H, halogen, -CN, OR10, C(O)R10, C(O)OR10, NR8R9, C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C cycloalkyl; each R2is independently H, halogen, OR10, C(O)R10, C(O)OR10, -CN, C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C8cycloalkyl; R3a, R3b, and R3care 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-Cheterocycloalkyl, 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9; R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C2-C alkenyl, substituted or unsubstituted C1-C aminoalkyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is 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-C alkyl, substituted C1-C haloalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C heterocycloalkyl; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl; each R8and R9is 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-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais 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.

[0042] In some instances, XAis NR5R5. In some instances, XAis OR5. In some instances, Y is CR2. In some instances, Y is N.

[0043] In some instances, the compound of Formula V has the structure of Formula VIa, or a pharmaceutically acceptable salt thereof:Formula VIa.

[0044] In some instances, the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:Formula VIb.

[0045] In some instances, Z is N. In some instances, Z is CR1. In some instances, Z is CH.

[0046] In some instances, the compound of Formula V has the structure of Formula VIIa, or a pharmaceutically acceptable salt thereof:.

[0047] In some instances, the compound of Formula V has the structure of Formula VIIb, or a pharmaceutically acceptable salt thereof:.

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

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

[0050] In some instances, X1is N. In some instances, R3bis H; and R3cis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9.

[0051] In some instances, R3bis H; and R3cis selected from halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

[0052] In some instances, R3cis H; and R3bis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9.

[0053] In some instances, R3cis H; and R3bis selected from halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1-Calkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

[0054] In some instances, X1is CR3a. In some instances, R3aand R3bare independently H or halogen; and R3cis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, - SR8, C(O)R10, C(O)OR10, or C(O)NR8R9.

[0055] In some instances, R3cis selected from H, halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5- membered heteroaryl.

[0056] In some instances, R3cis C(O)OR10, C(O)NR8R9, or substituted or unsubstituted 5- membered heteroaryl. In some instances, R3aand R3bare each H.

[0057] In some instances, R3aand R3care independently H or halogen; and R3bis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9.

[0058] In some instances, R3bis selected from H, halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5- membered heteroaryl.

[0059] In some instances, R3bis C(O)OR10, C(O)NR8R9, or substituted or unsubstituted 5- membered heteroaryl.

[0060] In some instances, R3aand R3care each H. In some instances, R3band R3care each H or halogen; and R3ais 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9.

[0061] In some instances, R3ais selected from H, halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5- membered heteroaryl.

[0062] In some instances, R3ais C(O)OR10, C(O)NR8R9, or substituted or unsubstituted 5- membered heteroaryl. In some instances, R3band R3care each H. In some instances, each R2is H. In some instances, R5aand one of R6combine together with the atom(s) to which they are attached to form a C3-C6cycloalkyl. In some instances, R5ais H. In some instances, R5is H.

[0063] In some instances, R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C aminoalkyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C heterocycloalkyl, each of which is substituted with one or more R6. In some instances, R4is substituted or unsubstituted C1-C alkyl or substituted or unsubstituted C1-C heteroalkyl, each of which is substituted with one or more R6. In some instances, R4is substituted or unsubstituted C3-C8 cycloalkyl or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6.

[0064] In some instances, R4is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl. In some instances, each R6is independently halogen, NR8R9, OR10, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl,substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C heterocycloalkyl. In some instances, each R6is independently halogen, OR10, C1-C alkyl, C1-C haloalkyl, or C3-C8 cycloalkyl. In some instances, each R6is independently -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0065] In some instances, the compound is selected from Table 4, or a pharmaceutically acceptable salt thereof.

[0066] In some instances, the subject has a disease or condition associated with elevated levels of PGE-MUM. In some instances, the disease or condition associated with elevated levels of PGE-MUM is associated with muscle damage, injury, or atrophy. In some instances, the disease or condition associated with muscle damage, injury, or atrophy comprises acute muscle injury or trauma, soft tissue hand injury, muscular dystrophy, 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, mvotubular myopathy (MM), myasthenia gravis (MG), congestive heart failure, periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, cardiac cachexia, or stress induced urinary incontinence. In some instances, the disease or condition associated with elevated levels of PGE-MUM is a neuromuscular disease. In some instances, the neuromuscular disease is spinal muscular atrophy. In some instances, administering to a subject with spinal muscular atrophy an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor reduces PGE-MUM levels in the subject. In some instances, administering to a subject with spinal muscular atrophy an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor improves one or more spinal muscular atrophy disease symptoms in the subject.

[0067] In some instances, the subject is an aged subject. In some instances, the subject is at least 60 years of age. In some instances, the disease or condition associated with elevated levels of PGE-MUM is a condition associated with aging. In some instances, the condition associated with aging is sarcopenia. In some instances, administering to a subject with sarcopenia an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor reduces PGE- MUM levels in the subject. In some instances, administering to a subject with sarcopenia an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor improves one or more sarcopenia symptom in the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0068] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0069] Figs.1A-1F show the effects of orally-administered MF-300 on urinary PGE-MUM levels. Fig.1A shows an overview of the experimental timeline for assessing the effects of daily, orally administered MF-300 (30 mg / kg or 60 mg / kg) on urinary PGE-MUM levels in male CD rats. Fig.1B shows a schematic illustrating a mechanism through which MF-300 affects PGE-MUM levels by inhibiting 15-PGDH and biological localization of significant levels of PGE2 and metabolites. Fig.1C shows the baseline levels of urinary PGE-MUM normalized to creatinine for the CD rat cohorts administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300. Fig.1D shows the day 6 levels of urinary PGE-MUM normalized to creatinine for the CD rat cohorts administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF- 300. Fig.1E shows levels of MF-300 in CD rats over a 24-hour time course after single or 7 daily doses of 30 mg / kg MF-300. Fig.1F shows changes from baseline levels of PGE-MUM for CD rats administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300.

[0070] Figs.2A-2C shows an experiment to achieve steady state MF-300 levels in CD rats. Fig.2A shows an overview of the experimental timeline for assessing the effects of daily, orally administered MF-300 (30 mg / kg or 60 mg / kg) in male CD rats over 14 days. Fig.2B shows urine levels of PGE2, PGE-MUM, and a ratio of PGE2 / PGE-MUM over 14 days for CD rats administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300. Fig.2C shows a comparison of the effects of a ratio of urinary PGE-MUM to creatinine at baseline (day zero), day 7, and day 13 for CD rats administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300.

[0071] Figs.3A-3B show the effects of MF-300 in a spinal muscular atrophy (SMA) disease model ( 7 mice, also Delta 7 mice plus SMN-C3). Fig.3A shows a schematic representation of a mechanism by which MF-300 reduces levels of PGE2 metabolites by blocking 15-PGDH. Fig.3B shows urine levels of PGE2, PGE-MUM, and a ratio of PGE2 / PGE-MUM days for WT mice, Delta 7 mice administered vehicle, or Delta 7 mice administered 30 mg / kg of MF-300 every other day.

[0072] Fig.4 shows the effects of MF-300 in adult and aged C57BL / 6 mice administered vehicle, 10 mg / kg MF-300, 30 mg / kg MF-300, or 60 mg / kg MF-300.DETAILED DESCRIPTION OF THE DISCLOSURE

[0073] Provided herein are methods and compositions for reducing at least one biomarker in a subject. The at least one biomarker may include a biomarker that is associated with a disease or a condition. Further provided herein are methods and compositions for identifying a subject as a candidate for treatment with a therapeutic, such as a 15-PGDH inhibitor. In some cases, the subject has elevated levels of at least one biomarker relative to a control subject or a control population. In some cases, the subject has elevated levels of at least one biomarker relative to a subject that does not have the disease or condition associated with the at least one biomarker. In some cases, the subject has elevated levels of at least one biomarker relative to a predetermined threshold. In some cases, the at least one biomarker includes p75ECD. In some cases, the p75ECD includes or may be the extracellular domain (ECD) of p75ECD. In some cases, the at least one biomarker includes PGE-MUM. PGE- MUM may also be referred to as PGE-M. In some cases, the at least one biomarker includes both p75ECD and PGE-MUM. In some cases, the methods and compositions provided herein involve administering a 15-PGDH inhibitor to a subject that has elevated levels of at least one biomarker including p75ECD and / or PGE-MUM. In some cases, the methods and compositions provided herein involve measuring levels of at least one biomarker in the subject (e.g., in a biological sample from the subject) including p75ECD and / or PGE-MUM. In some cases, the methods and compositions provided herein involve selecting or identifying a subject as eligible or a candidate for treatment with a 15-PGDH inhibitor by identifying the subject as having elevated levels of at least one biomarker including p75ECD and / or PGE- MUM.

[0074] In one aspect, provided herein are methods for reducing levels of p75ECD, PGE- MUM, or both in a subject. In some cases, the method comprises administering to the subject an amount of a 15-PGDH inhibitor effective to reduce levels of p75ECD, PGE-MUM, or both, in the subject.

[0075] In another aspect, provided herein are methods for treating a subject with a 15-PGDH inhibitor. In some cases, the method comprises identifying the subject as having elevated levels of p75ECD, PGE-MUM, or both, relative to a control, or levels of p75ECD, PGE- MUM, or both, that exceed a predetermined threshold. In some cases, the method further comprises administering the 15-PGDH inhibitor to the subject to reduce the levels of p75ECD, PGE-MUM, or both, in the subject (e.g., when the levels of p75ECD, PGE-MUM, or both are elevated in the subject).

[0076] In yet another aspect, provided herein are methods for selecting a subject for treatment with a 15-PGDH inhibitor. In some cases, the method comprises providing or obtaining a biological sample obtained from the subject. In some cases, the method further comprises measuring a level of p75ECD, PGE-MUM, or both, in the biological sample. In some cases, the method further comprises identifying the subject as a candidate for treatment with the 15-PGDH inhibitor when the levels of p75ECD, PGE-MUM, or both, in the biological sample exceeds a predetermined threshold or exceeds a level of a control. In some cases, the method further comprises, after identifying the subject as a candidate or as eligible for treatment with the 15-PGDH inhibitor, administering the 15-PGDH inhibitor to the subject.

[0077] In some cases, the methods provided herein involve administering a composition of the disclosure, such as a 15-PGDH inhibitor, to the subject (e.g., having elevated levels of the biomarker(s) (e.g., p75ECD, PGE-MUM). In some cases, the elevated levels of the biomarker(s) (e.g., p75ECD, PGE-MUM) are associated with increased levels or increased activity of 15-PGDH. In some cases, the levels of the biomarker(s) (e.g., p75ECD, PGE- MUM) can be decreased or reduced by inhibiting the function of 15-PGDH or by reducing expression or amounts of 15-PGDH in the subject.

[0078] In some cases, the methods provided herein involve identifying a subject as having elevated levels of at least one biomarker, such as elevated levels of p75ECD, PGE-MUM, or both. In some cases, the at least one biomarker (e.g., p75ECD, PGE-MUM) is elevated relative to a control, such as a control subject or a control population. In some cases, the at least one biomarker (e.g., p75ECD, PGE-MUM) is elevated relative to a predetermined threshold. In some cases, the at least one biomarker (e.g., p75ECD, PGE-MUM) is elevated relative to a subject that does not have a disease or condition associated with the at least one biomarker.

[0079] In some cases, identifying the subject as having elevated levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) may involve obtaining or providing a biological sample from the subject or that has been obtained from the subject. The biological sample can be tested for the presence or absence of the at least one biomarker (e.g., p75ECD, PGE- MUM). Levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) can be measured in the biological sample, providing an indication that the levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) is elevated in the subject. Any method of testing or measuring a biological sample for a biomarker can be used, such as, but not limited to, Western blotting,enzyme-linked immunosorbent assay (ELISA), colorimetric protein assays, polymerase chain reaction (PCR), sequencing, and the like.

[0080] In some cases, the biological sample is a body fluid. herein refers to any fluid from the body of an animal. Examples of body fluids include, but are not limited to, plasma, serum, blood, lymphatic fluid, cerebrospinal fluid, synovial fluid, urine, saliva, mucous, phlegm, and sputum. A body fluid sample may be collected by any suitable method. In some cases, the biological sample is a blood sample. A blood sample may include whole blood, or a component thereof, such as plasma or serum. In some cases, the biological sample is urine.

[0081] When it is determined that the subject has elevated levels of at least one biomarker (e.g., p75ECD, PGE-MUM), the subject is selected for treatment with a 15-PGDH inhibitor. The 15-PGDH inhibitor may be administered to the subject as many times as necessary to reduce the levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) in the subject. In some cases, the levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) can be used to determine whether a subject is responding positively to treatment with a 15-PGDH inhibitor. For example, when the levels of the at least one biomarker (e.g., p75ECD, PGE- MUM) are reduced with the 15-PGDH inhibitor, the subject is identified as responding positively to the 15-PGDH inhibitor. In other examples, when the levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) are not reduced with the 15-PGDH inhibitor, the subject may be identified as requiring additional treatment with the 15-PGDH inhibitor. In other examples, when the levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) are not reduced with the 15-PGDH inhibitor, the subject may be identified as requiring additional treatment with a therapeutic other than 15-PGDH inhibitor.

[0082] In some cases, the subject may have a disease or a condition associated with the at least one biomarker or elevated levels of the at least one biomarker. In some cases, the subject has a disease or a condition associated with elevated levels of p75ECD. In some cases, the subject has a disease or a condition associated with elevated levels of PGE-MUM. In some cases, the subject has a disease or a condition associated with elevated levels of both p75ECD and PGE-MUM. The disease or condition can be any disease or condition associated with the at least one biomarker or elevated levels of the at least one biomarker. In some cases, the disease or condition associated with the at least one biomarker or elevated levels of the at least one biomarker (or one or more symptoms thereof) can be treated by administering to the subject a 15-PGDH inhibitor.

[0083] In some cases, the disease or condition may be a neurodegenerative disease. In some cases, the neurodegenerative disease is associated with elevated levels of p75ECD (e.g., in the urine). In some cases, the neurodegenerative disease is amyotrophic lateral sclerosis ase. In some cases, thereof) can be treated by administering to the subject a 15-PGDH inhibitor.

[0084] In some instances, the subject has a disease or condition associated with elevated levels of PGE-MUM. In some instances, the disease or condition associated with elevated levels of PGE-MUM is associated with muscle damage, injury, or atrophy. In some instances, the disease or condition associated with muscle damage, injury, or atrophy comprises acute muscle injury or trauma, soft tissue hand injury, muscular dystrophy, 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, mvotubular myopathy (MM), myasthenia gravis (MG), congestive heart failure, periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, cardiac cachexia, or stress induced urinary incontinence. In some instances, the disease or condition associated with elevated levels of PGE-MUM is a neuromuscular disease. In some instances, the neuromuscular disease is spinal muscular atrophy. In some instances, administering to a subject with spinal muscular atrophy an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor reduces PGE-MUM levels in the subject. In some instances, administering to a subject with spinal muscular atrophy an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor improves one or more spinal muscular atrophy disease symptoms in the subject. Spinal muscular atrophy symptoms may include muscle weakness, muscle atrophy, muscle tremors, or muscle twitching.

[0085] In some instances, the subject is an aged subject. In some instances, the subject is at least 60 years of age. In some instances, the disease or condition associated with elevated levels of PGE-MUM is a condition associated with aging. In some instances, the condition associated with aging is sarcopenia. In some instances, administering to a subject with sarcopenia an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor reduces PGE- MUM levels in the subject. In some instances, administering to a subject with sarcopenia an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor improves one or more sarcopenia symptom in the subject. Sarcopenia symptoms may include muscle weakness,muscle atrophy, decreased muscle size, decreased hand grip strength, loss of stamina, or impaired motor function.

[0086] The 15-PGDH inhibitor may be administered to the subject in an amount that is effective to reduce the levels of the biomarker(s) (e.g., p75ECD, PGE-MUM) in the subject. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises about 1 mg / kg (or about 1MPK), about 3 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, or about 100 mg / kg. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises at least about 1 mg / kg (also referred to as at least about 1MPK), at least about 3 mg / kg, at least about 10 mg / kg, at least about 20 mg / kg, at least about 30 mg / kg, at least about 40 mg / kg, at least about 50 mg / kg, at least about 60 mg / kg, at least about 70 mg / kg, at least about 80 mg / kg, at least about 90 mg / kg, or at least about 100 mg / kg. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises less than about 1 mg / kg (also referred to as less than about 1MPK), less than about 3 mg / kg, less than about 10 mg / kg, less than about 20 mg / kg, less than about 30 mg / kg, less than about 40 mg / kg, less than about 50 mg / kg, less than about 60 mg / kg, less than about 70 mg / kg, less than about 80 mg / kg, less than about 90 mg / kg, or less than about 100 mg / kg. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises about 0.1MPK, about 0.2MPK, about 0.3MPK, about 0.4MPK, about 0.5MPK, about 0.6MPK, about 0.7MPK, about 0.8MPK, about 0.9MPK, about 1MPK, about 1.1MPK, about 1.2MPK, about 1.3MPK, about 1.4MPK, about 1.5MPK, about 1.6MPK, about 1.7MPK, about 1.8MPK, about 1.9MPK, about 2MPK, about 2.1MPK, about 2.2MPK, about 2.3MPK, about 2.4MPK, about 2.5MPK, about 2.6MPK, about 2.7MPK, about 2.8MPK, about 2.9MPK, about 3MPK, about 3.1MPK, about 3.2MPK, about 3.3MPK, about 3.4MPK, about 3.5MPK, about 3.6MPK, about 3.7MPK, about 3.8MPK, about 3.9MPK, about 4MPK, about 4.1MPK, about 4.2MPK, about 4.3MPK, about 4.4MPK, about 4.5MPK, about 4.6MPK, about 4.7MPK, about 4.8MPK, about 4.9MPK, about 5MPK, about 5.1MPK, about 5.2MPK, about 5.3MPK, about 5.4MPK, about 5.5MPK, about 5.6MPK, about 5.7MPK, about 5.8MPK, about 5.9MPK, or about 6MPK. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises at least about 0.1MPK, at least about 0.2MPK, at least about 0.3MPK, at least about 0.4MPK, at least about 0.5MPK, at least about 0.6MPK, at least about 0.7MPK, at least about 0.8MPK, at least about 0.9MPK, at least about 1MPK, at least about 1.1MPK, at least about 1.2MPK, at least about 1.3MPK, at least about 1.4MPK, at least about 1.5MPK, at least about 1.6MPK, at least about1.7MPK, at least about 1.8MPK, at least about 1.9MPK, at least about 2MPK, at least about 2.1MPK, at least about 2.2MPK, at least about 2.3MPK, at least about 2.4MPK, at least about 2.5MPK, at least about 2.6MPK, at least about 2.7MPK, at least about 2.8MPK, at least about 2.9MPK, at least about 3MPK, at least about 3.1MPK, at least about 3.2MPK, at least about 3.3MPK, at least about 3.4MPK, at least about 3.5MPK, at least about 3.6MPK, at least about 3.7MPK, at least about 3.8MPK, at least about 3.9MPK, at least about 4MPK, at least about 4.1MPK, at least about 4.2MPK, at least about 4.3MPK, at least about 4.4MPK, at least about 4.5MPK, at least about 4.6MPK, at least about 4.7MPK, at least about 4.8MPK, at least about 4.9MPK, at least about 5MPK, at least about 5.1MPK, at least about 5.2MPK, at least about 5.3MPK, at least about 5.4MPK, at least about 5.5MPK, at least about 5.6MPK, at least about 5.7MPK, at least about 5.8MPK, at least about 5.9MPK, or at least about 6MPK. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises less than about 0.1MPK, less than about 0.2MPK, less than about 0.3MPK, less than about 0.4MPK, less than about 0.5MPK, less than about 0.6MPK, less than about 0.7MPK, less than about 0.8MPK, less than about 0.9MPK, less than about 1MPK, less than about 1.1MPK, less than about 1.2MPK, less than about 1.3MPK, less than about 1.4MPK, less than about 1.5MPK, less than about 1.6MPK, less than about 1.7MPK, less than about 1.8MPK, less than about 1.9MPK, less than about 2MPK, less than about 2.1MPK, less than about 2.2MPK, less than about 2.3MPK, less than about 2.4MPK, less than about 2.5MPK, less than about 2.6MPK, less than about 2.7MPK, less than about 2.8MPK, less than about 2.9MPK, less than about 3MPK, less than about 3.1MPK, less than about 3.2MPK, less than about 3.3MPK, less than about 3.4MPK, less than about 3.5MPK, less than about 3.6MPK, less than about 3.7MPK, less than about 3.8MPK, less than about 3.9MPK, less than about 4MPK, less than about 4.1MPK, less than about 4.2MPK, less than about 4.3MPK, less than about 4.4MPK, less than about 4.5MPK, less than about 4.6MPK, less than about 4.7MPK, less than about 4.8MPK, less than about 4.9MPK, less than about 5MPK, less than about 5.1MPK, less than about 5.2MPK, less than about 5.3MPK, less than about 5.4MPK, less than about 5.5MPK, less than about 5.6MPK, less than about 5.7MPK, less than about 5.8MPK, less than about 5.9MPK, or less than about 6MPK. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises between 0.5MPK to 5MPK, 0.6MPK to 5MPK, 0.7MPK to 5MPK, 0.8MPK to 5MPK, 0.9MPK to 5MPK, 1MPK to 5MPK, 1.1MPK to 5MPK, 1.2MPK to 5MPK, 1.3MPK to 5MPK, 1.4MPK to 5MPK, 1.5MPK to 5MPK, 1.6MPK to 5MPK, 1.7MPK to 5MPK, 1.8MPK to 5MPK, 1.9MPK to 5MPK, 2MPK to 5MPK, 2.1MPK to5MPK, 2.2MPK to 5MPK, 2.3MPK to 5MPK, 2.4MPK to 5MPK, 2.5MPK to 5MPK, 2.6MPK to 5MPK, 2.7MPK to 5MPK, 2.8MPK to 5MPK, 2.9MPK to 5MPK, 3MPK to 5MPK, 3.1MPK to 5MPK, 3.2MPK to 5MPK, 3.3MPK to 5MPK, 3.4MPK to 5MPK, 3.5MPK to 5MPK, 3.6MPK to 5MPK, 3.7MPK to 5MPK, 3.8MPK to 5MPK, 3.9MPK to 5MPK, 4MPK to 5MPK, 4.1MPK to 5MPK, 4.2MPK to 5MPK, 4.3MPK to 5MPK, 4.4MPK to 5MPK, 4.5MPK to 5MPK, 4.6MPK to 5MPK, 4.7MPK to 5MPK, 4.8MPK to 5MPK, or 4.9MPK to 5MPK.

[0087] The 15-PGDH inhibitor can be administered to the subject by any suitable administration route. In some cases, the 15-PGDH inhibitor is administered to the subject by one or more of oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra-arterial administration, intradermal administration, or subcutaneous administration.

[0088] In some embodiments, the 15-PGDH inhibitor may be administered to the subject by acute administration, chronic administration, intermittent administration, or continuous administration. In some embodiments, the 15-PGDH inhibitor is administered to the subject in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, diluent, and / or carrier. In some cases, the subject is a mammal. In some cases, the subject is a human.

[0089] In some cases, the 15-PGDH inhibitor is selected from the group consisting of: a small molecule, an antibody or fragment thereof, a peptide inhibitor, an aptamer, an oligonucleotide inhibitor, and any combination thereof.

[0090] In some cases, the 15-PGDH inhibitor is a small molecule. In some cases, the small molecule is an orally bioavailable small molecule.

[0091] 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 R1is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo or thio; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; each R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; each R11is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 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,.

[0092] 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.

[0093] 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.

[0094] In some embodiments, each R1is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R1is 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 R1is 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 R1is independently selected from halo, NR6R7, OR8, C(O)R8, and C(O)OR8.

[0095] In some embodiments, R2is H and R3is CF3. In some embodiments, R2and R3are taken together to form oxo. In some embodiments, R2and R3are taken together to form thio.

[0096] In some embodiments, each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is 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 R4is 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 R4is independently selected from halo, NR6R7, OR8, C(O)R8, and C(O)OR8.

[0097] In some embodiments, each R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R5is 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 R5is 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 R5is independently selected from halo, NR6R7, OR8, C(O)R8, and C(O)OR8.

[0098] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, and C1-6alkyl.

[0099] In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H, and C1-6alkyl.

[0100] In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0101] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0102] In some embodiments, each R11is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is 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 R11is 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 R11is independently selected from halo, NR6R7, OR8, C(O)R8, and C(O)OR8.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] In some embodiments, the compound is a compound of Formula Ia:Formula Ia or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the compound is a compound of Formula Ib:Formula Ib or a pharmaceutically acceptable salt thereof.

[0108] 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; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo or thio; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4intervening atoms to form a C3-10cycloalkyl, and any remaining R4selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;,.

[0109] 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.

[0110] 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.

[0111] In some embodiments, R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C6-10aryl, and 5- to 10-memberedheteroaryl; 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl 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, R1is selected from C6-10aryl 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.

[0112] In some embodiments, R2is H and R3is CF3. In some embodiments, R2and R3are taken together to form oxo. In some embodiments, R2and R3are taken together to form thio.

[0113] In some embodiments, each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is 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, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, each R4is 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 R4is independently selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, and C(O)NR6R7. In some embodiments, each R4is halo. In some embodiments, each R4is fluoro.

[0114] In some embodiments, two R4they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remainingR4NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R4atoms to form a C3-10cycloalkyl, and any remaining R4halo, NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R4to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4NR6R7, 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 R4atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4NR6R7, OR8, C(O)R8, C(O)OR8, and C(O)NR6R7. In some embodiments, two R4carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4R4atoms to form a C3-10cycloalkyl, and any remaining R4fluoro.

[0115] In some embodiments, each R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R5is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R5is 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 R5is independently selected from H, halo, NR6R7, OR8, C(O)R8, C(O)OR8, and C(O)NR6R7. In some embodiments, each R5is independently selected from H and halo.

[0116] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0117] In some embodiments, each R8is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H and C1-6alkyl.

[0118] In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0119] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0120] 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.

[0121] 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.

[0122] In some embodiments, the compound is a compound of Formula IIa:Formula IIa 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 IIb:Formula IIb or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0125] 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.

[0126] In some embodiments, the compound is a compound of Formula IIc:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0127] 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.

[0128] In some embodiments, compound is a compound of Formula IId: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 IIe:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0131] 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.

[0132] In some embodiments, the compound is a compound of Formula IIf:Formula IIf or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0133] 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.

[0134] In some embodiments, the compound is a compound of Formula IIg:Formula IIg or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0135] 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.

[0136] In some embodiments, the compound is a compound of Formula IIh:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0137] 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.

[0138] In some embodiments, the compound is a compound of Formula IIi:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0139] 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.

[0140] In some embodiments, the compound is a compound of Formula IIj:Formula IIj 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 IIn:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0143] 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.

[0144] In some embodiments, the compound is a compound of Formula IIp:Formula IIp or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0145] 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.

[0146] In some embodiments, 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; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo or thio; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R6is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R63-10cycloalkyl, and any remaining R6NR9R10, OR11, C(O)R11, C(O)OR11, C(O)NR9R10, SOR12, SO2R12, SO2NR9R10, NR13C(O)R11, NR13C(O)NR9R10, NR13SO2R11, NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R8is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R83-10cycloalkyl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

[0147] 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.

[0148] 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.

[0149] In some embodiments, R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R1is selected from C3-10cycloalkyl, C6-10aryl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl 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, R1is selected from C6-10aryl and 5- to 10-memberedheteroaryl; 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.

[0150] In some embodiments, R2is H and R3is CF3. In some embodiments, R2and R3are taken together to form oxo. In some embodiments, R2and R3are taken together to form thio.

[0151] In some embodiments, R4and R5are independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are 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, and NR13SO2NR9R10. In some embodiments, R4and R5are 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.

[0152] In some embodiments, R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are 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, R4and R5are 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.

[0153] In some embodiments, each R6is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R6is 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, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, each R6is 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 R6is independently selected from halo, NR9R10, OR11, C(O)R11, C(O)OR11, and C(O)NR9R10.

[0154] In some embodiments, two R6to form oxo, thio, or C3-10cycloalkyl, and any remaining R6lected from halo, NR9R10, OR11, C(O)R11, C(O)OR11, C(O)NR9R10, SOR12, SO2R12, SO2NR9R10, NR13C(O)R11, NR13C(O)NR9R10, NR13SO2R11, NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R6same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6NR9R10, OR11, C(O)R11, C(O)OR11, C(O)NR9R10, SOR12, SO2R12, SO2NR9R10, NR13C(O)R11, NR13C(O)NR9R10, NR13SO2R11, NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R6together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6NR9R10, 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 R6thio, or C3-10cycloalkyl, and any remaining R6NR9R10, OR11, C(O)R11, C(O)OR11, and C(O)NR9R10.

[0155] In some embodiments, each R7is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, each R7is 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, C1-6alkyl, C1- 6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R7is 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, and NR13SO2NR9R10. In some embodiments, each R7is independently selected from H, halo, NR9R10, OR11, C(O)R11, C(O)OR11, and C(O)NR9R10.

[0156] In some embodiments, each R8is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, each R8is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is 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, and NR13SO2NR9R10. In some embodiments, each R8is independently selected from H, halo, NR9R10, OR11, C(O)R11, C(O)OR11, and C(O)NR9R10.

[0157] In some embodiments, two R83-10cycloalkyl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, two R83- 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R8a 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, and NR13SO2NR9R10. In some embodiments, two R8together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, NR9R10, OR11, C(O)R11, C(O)OR11, and C(O)NR9R10.

[0158] In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H and C1-6alkyl.

[0159] In some embodiments, each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R11is independently selected from H and C1-6alkyl.

[0160] In some embodiments, each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R12is independently selected from C1-6alkyl.

[0161] In some embodiments, each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R13is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R13is independently selected from H and C1-6alkyl.

[0162] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0163] 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.

[0164] In some embodiments, the compound is a compound of Formula IIIa:Formula IIIa or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the compound is a compound of Formula IIIb:Formula IIIb or a pharmaceutically acceptable salt thereof, wherein: each R14is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0166] In some embodiments, each R14is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R14is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R14is 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 R14is independently selected from halo, NR9R10, OR11, C(O)R11, C(O)OR11, and C(O)NR9R10. In some embodiments, each R14is independently halo. In some embodiments, each R14is independently fluoro.

[0167] 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.

[0168] In some embodiments, the compound is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the compound is a compound of Formula IIId:or a pharmaceutically acceptable salt thereof, wherein: each R14is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0170] In some embodiments, each R14is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R14is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R14is 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 R14is independently selected from halo, NR9R10, OR11, C(O)R11, C(O)OR11, and C(O)NR9R10. In some embodiments, each R14is independently halo. In some embodiments, each R14is independently fluoro.

[0171] 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.

[0172] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIk:Formula IIk 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; R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; each R4is independently selected from H and halo;R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6is 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, C1- 6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R11is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; and p is 0, 1, or 2.

[0173] 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 CR6and the rest are N. In some embodiments, two of T, U, and Y are CR6and the rest are N. In some embodiments, T, U, and Y are N. In some embodiments, T, U, and Y are CR6.

[0174] In some embodiments, R1is selected from C6-10aryl 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, NR11SO2R9, NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl 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, NR11SO2R9, NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl isoptionally 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, and NR11SO2NR7R8. In some embodiments, R1is selected from C6-10aryl 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.

[0175] In some embodiments, R2is H and R3is CF3. In some embodiments, R2and R3are taken together to form oxo.

[0176] In some embodiments, each R4is independently selected from H and halo. In some embodiments, each R4is independently selected from H and fluoro. In some embodiments, each R4is H. In some embodiments, each R4is fluoro. In some embodiments, one R4is H and one R4is fluoro.

[0177] In some embodiments, R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R5is 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, R5is selected from halo, NR7R8, OR9, C(O)R9, C(O)OR9, and C(O)NR7R8.

[0178] In some embodiments, R6is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R6is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6is 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, and NR11SO2NR7R8. In someembodiments, R6is selected from H, halo, NR7R8, OR9, C(O)R9, C(O)OR9, and C(O)NR7R8.

[0179] In some embodiments, R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl. In some embodiments, R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R7and R8are independently selected at each occurrence from H and C1-6alkyl.

[0180] In some embodiments, each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R9is independently selected from H and C1-6alkyl.

[0181] In some embodiments, each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from C1-6alkyl.

[0182] In some embodiments, each R11is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-6cycloalkyl. In some embodiments, each R11is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R11is independently selected from H and C1-6alkyl.

[0183] 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.

[0184] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIm:Formula IIm or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;R2is H and R3is CF3; or R2and R3are taken together to form oxo; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4intervening atoms to form a C3-10cycloalkyl, and any remaining R4selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, 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.

[0185] In some embodiments, R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl 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, R1is selected from C6-10aryl 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.

[0186] In some embodiments, R2is H and R3is CF3. In some embodiments, R2and R3are taken together to form oxo.

[0187] In some embodiments, each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R4is 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 R4is independently selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, and C(O)NR6R7. In some embodiments, each R4is independently selected from halo. In some embodiments, each R4is fluoro.

[0188] In some embodiments, two R4ether with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R4atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In someembodiments, two R4and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4independently 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 R4which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4NR6R7, OR8, C(O)R8, C(O)OR8, and C(O)NR6R7.

[0189] In some embodiments, R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10- membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R5is 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, R5is selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, and C(O)NR6R7.

[0190] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0191] In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H and C1-6alkyl.

[0192] In some embodiments, each R9is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0193] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIq:Formula IIq or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4hich they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, 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.

[0198] In some embodiments, R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl 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, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionallysubstituted with 1 to 3 substituents independently selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, and C(O)NR6R7.

[0199] In some embodiments, R2is H and R3is CF3. In some embodiments, R2and R3are taken together to form oxo.

[0200] In some embodiments, each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R4is 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 R4is independently selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, and C(O)NR6R7. In some embodiments, each R4is independently selected from halo. In some embodiments, each R4is fluoro.

[0201] In some embodiments, two R4they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4ependently 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R4atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R4attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4independently 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 R4which they are attached and any intervening atoms to form a C3-10cycloalkyl, and anyremaining R4NR6R7, OR8, C(O)R8, C(O)OR8, and C(O)NR6R7.

[0202] In some embodiments, R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10- membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R5is 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, R5is selected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, and C(O)NR6R7.

[0203] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0204] In some embodiments, each R8is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H and C1-6alkyl.

[0205] In some embodiments, each R9is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0206] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIIc:Formula IIIc 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; R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R6R6NR9R10, OR11, C(O)R11, C(O)OR11, C(O)NR9R10, SOR12, SO2R12, SO2NR9R10, NR13C(O)R11, NR13C(O)NR9R10, NR13SO2R11, NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7and R8is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0211] 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.

[0212] 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.

[0213] In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituentsindependently 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl 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, R1is selected from C6-10aryl 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.

[0214] In some embodiments, R2is H and R3is CF3. In some embodiments, R2and R3are taken together to form oxo.

[0215] In some embodiments, R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are 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, and NR13SO2NR9R10. In some embodiments, R4and R5are 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.

[0216] In some embodiments, R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are 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, R4and R5are 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.

[0217] In some embodiments, each R6is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R6is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R6is 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 R6is independently selected from halo, NR9R10, OR11, C(O)R11, C(O)OR11, and C(O)NR9R10.

[0218] In some embodiments, two R6to form oxo, and any remaining R6NR9R10, OR11, C(O)R11, C(O)OR11, C(O)NR9R10, SOR12, SO2R12, SO2NR9R10, NR13C(O)R11, NR13C(O)NR9R10, NR13SO2R11, NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R6together to form oxo, and any remaining R6NR9R10, OR11, C(O)R11, C(O)OR11, C(O)NR9R10, SOR12, SO2R12, SO2NR9R10, NR13C(O)R11, NR13C(O)NR9R10, NR13SO2R11, NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R6atom are taken together to form oxo, and any remaining R6independently 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 R6together to form oxo, and any remaining R6NR9R10, OR11, C(O)R11, C(O)OR11, and C(O)NR9R10.

[0219] In some embodiments, each R7and R8is 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, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R7and R8is 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, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R7and R8is 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, andNR13SO2NR9R10. In some embodiments, each R7and R8is independently selected from halo, NR9R10, OR11, C(O)R11, C(O)OR11, and C(O)NR9R10.

[0220] In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H and C1-6alkyl.

[0221] In some embodiments, each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R11is independently selected from H and C1-6alkyl.

[0222] In some embodiments, each R12is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R12is independently selected from C1-6alkyl.

[0223] In some embodiments, each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R13is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R13is independently selected from H and C1-6alkyl.

[0224] 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.

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

[0226] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:; ;;;;

[0227] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:;

[0228] In some cases, the solubility and hPGDH IC50 of the inhibitors are characterized as shown in Tables 1 and 2. Table 1: Characteristics of PGDH Inhibitors with a 6-5 ring core.Table 2: Characteristics of PGDH Inhibitors with a phenyl core.

[0229] Provided in Table 3 are analytical data for some of the inhibitors described herein. Table 3: Analytical data for select inhibitors

[0230] In some embodiments, the 15-PGDH inhibitor is a compound of having the structure of Formula IV, or a pharmaceutically acceptable salt thereof:Formula IV, wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2or N; R1is H, halogen, -CN, OR10, C(O)R10, C(O)OR10, NR8R9, C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C cycloalkyl;each R2is independently H, halogen, OR10, C(O)R10, C(O)OR10, -CN, C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3- C8 cycloalkyl; each R3is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9; R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C2-C alkenyl, substituted or unsubstituted C1-C aminoalkyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C heterocycloalkyl; XAis -NR5R5or -OR5; wherein each R5is independently H or C1-C6alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C6heterocycloalkyl;each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; each R10is 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-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, 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 Ra; each R11is independently selected from substituted or unsubstituted C1-C6alkyl, 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-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, 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 Ra; each Rais 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.

[0231] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula IV, or a pharmaceutically acceptable salt thereof:Formula IV,wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2of N; R1is H, halogen, -CN, OR10, C(O)R10, C(O)OR10, NR8R9, C(O)NR8R9, -NR8C(O)R9substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C cycloalkyl; R2is H, halogen, OR10, C(O)R10, C(O)OR10, -CN, C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C8cycloalkyl; each R3is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl; R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C2-C alkenyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl; substituted or unsubstituted C3-C8cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently H, halogen, CN,-NO2, NR8R9, -OH, OR10, -SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, -NR8C(O)R9, C1-C alkyl, C1-C haloalkyl, C1-C hydroxyalkyl, C3-C8cycloalkyl, phenyl, or 5- to 8- membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a C3- C6cycloalkyl ring; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a C3- C6 cycloalkyl ring; each R8and R9is independently selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, and C4-C10 heterocycloalkyl;each R10is independently selected from H, C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C1- C6haloalkyl, C3-C8cycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl; each R11is 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 R12is independently selected from H, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, and C3-C8 cycloalkyl; and p is 1, 2, 3, or 4.

[0232] 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, benzotriazole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyridine, or tetrazolo pyridine. In some embodiments, ring Q is [1,2,4]triazolo[1,5-a]pyridine.

[0233] 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.

[0234] In some embodiments, ring Q is phenyl, pyridine, or triazolopyridine.

[0235] In some embodiments,, wherein, X1, X2, X3and X4are each independently N or CR3; each R3is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, 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-C10cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, 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 Ra; each R11is 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-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, 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 Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, 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 Ra; and each Rais 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.

[0236] In some embodiments, X1, X2, X3and X4are each CR3.

[0237] In some embodiments, X1is N; and X2, X3, and X4are each CR3.

[0238] In some embodiments, X1and X2are each N; and X3and X4are each CR3.

[0239] In some embodiments, X1and X3are each N; and X2and X4are each CR3.

[0240] In some embodiments, X1and X4are each N; and X2and X3are each CR3.

[0241] In some embodiments, X1, X2, and X3are each N; and X4is CR3.

[0242] In some embodiments, X1, X2, and X4are each N; and X3is CR3.

[0243] In some embodiments, each R3is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each R3is independently selected from H, halogen, C(O)R10, C(O)OR10, C(O)NR8R9, NR12C(O)R10, NR12C(O)OR10, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each R3is 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 R3is independently selected from H, halogen, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.

[0244] In some embodiments, each R3is independently selected from H or halogen. In some embodiments, each R3is independently substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, each R3is independently a substituted or unsubstituted 5-membered heteroaryl.

[0245] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula V, or a pharmaceutically acceptable salt thereof:Formula V, wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N;R1is H, halogen, -CN, OR10, C(O)R10, C(O)OR10, NR8R9, C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C cycloalkyl; each R2is independently H, halogen, OR10, C(O)R10, C(O)OR10, -CN, C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3- C8cycloalkyl; R3a, R3b, and R3care 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9; R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C2-C alkenyl, substituted or unsubstituted C1-C aminoalkyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C heterocycloalkyl; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl;each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; each R10is 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-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, 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 Ra; each R11is independently selected from substituted or unsubstituted C1-C6alkyl, 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-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, 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 Ra; and each Rais 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

[0246] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula V, or a pharmaceutically acceptable salt thereof:Formula V, wherein,Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1is H; each R2is independently H or C1-C alkyl; R3a, R3b, and R3care 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-C alkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl, each of which is substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9; R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C heterocycloalkyl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C heterocycloalkyl; XAis -OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; each R10is 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-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, 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 Ra; each R11is 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-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, 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 Ra; and each Rais 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.

[0247] In some embodiments, XAis NR5R5. In some embodiments, XAis OR5.

[0248] In some embodiments, Y is N. In some embodiments, Y is CR2.

[0249] In some embodiments, the compound of Formula V has the structure of Formula VIa, or a pharmaceutically acceptable salt thereof:Formula VIa.

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

[0251] In some embodiments, Z is N. In some embodiments, Z is CR1. In some embodiments, Z is CH.

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

[0253] In some embodiments, the compound of Formula V has the structure of Formula VIIb, or a pharmaceutically acceptable salt thereof:Formula (IVb).

[0254] In some embodiments, the compound of Formula V has the structure of Formula VIIc, or a pharmaceutically acceptable salt thereof:Formula VIIc.

[0255] In some embodiments, the compound of Formula V has the structure of Formula VIId, or a pharmaceutically acceptable salt thereof:Formula VIId.

[0256] In some embodiments, R1is H, halogen, OR10, C(O)R10, C(O)OR10, or substituted or unsubstituted C1-C alkyl. In some embodiments, R1is H.

[0257] In some embodiments, each R2is independently H, halogen, OR10, C(O)R10, C(O)OR10, or substituted or unsubstituted C1-C alkyl. In some embodiments, each R2is independently H or C1-C alkyl.

[0258] In some embodiments, each R2is H.

[0259] In some embodiments, X1is CR3a. In some embodiments, X1is N.

[0260] In some embodiments, R3a, R3b, and R3care 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3a, R3b, and R3care 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10- membered heteroaryl. In some embodiments, R3a, R3b, and R3care 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, R3a, R3b, and R3care each independently selected from H, halogen, C(O)R10, C(O)NR8R9, and substituted or unsubstituted 5- membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, OR10, -S8, C(O)OR10, C(O)NR8R9, SOR11, SO2R11,NR12C(O)R10, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, C(O)R10, C(O)NR8R9, C3-C6heterocycloalkyl, and 5- membered heteroaryl.

[0261] In some embodiments, R3a, R3b, and R3care 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-C6alkyl substituted with -C(O)OH.

[0262] In some embodiments, R3aand R3bare each H or halogen; and R3cis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis 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, R3aand R3bare each H or halogen; and R3cis selected from NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from substituted or unsubstituted C1-C6alkyl, C(O)R10, C(O)NR8R9, C3-C6 heterocycloalkyl, and 5- membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis a substituted or unsubstituted 5- membered heteroaryl.

[0263] In some embodiments, R3ais halogen and R3bis H. In some embodiments, R3ais -Cl or -F; and R3bis H. In some embodiments, R3bis halogen and R3ais H. In some embodiments, R3bis -Cl or -F; and R3ais H.

[0264] In some embodiments, R3aand R3bare each H.

[0265] In some embodiments, R3aand R3care independently H or halogen; and R3bis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3care each H; and R3bis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3care each H; and R3bis 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, R3aand R3care each H; and R3bis 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, R3aand R3care each H or halogen; and R3bis selected from substituted or unsubstituted C1-C6 alkyl, C(O)R10, C(O)NR8R9, C3-C6heterocycloalkyl, and 5- membered heteroaryl.

[0266] In some embodiments, R3aand R3care each H or halogen; and R3bis selected from C(O)R10, C(O)OR10and substituted or unsubstituted 5-membered heteroaryl.

[0267] In some embodiments, R3ais halogen and R3cis H. In some embodiments, R3ais H and R3bis halogen. In some embodiments, R3ais -Cl or -F; and R3cis H. In some embodiments, R3cis -Cl or -F; and R3ais H.

[0268] In some embodiments, R3aand R3care each H.

[0269] In some embodiments, each R3, R3a, R3b, and R3care each independently a 5- membered heteroaryl selected from pyrrole, triazole, tetrazole, oxazole, diazole, oxadiazole, thiadiazole, and furanyl. In some embodiments, each R3, R3a, R3b, and R3care each independently a 5-membered heteroaryl selected from pyrrole, triazole, and tetrazole. In some embodiments, each R3, R3a, R3b, and R3care each independently a 5-membered heteroaryl selected from triazole and tetrazole.

[0270] In some embodiments, each R3, R3a, R3b, or R3cis independently selected from the group consisting,

[0271] In some embodiments, each R3, R3a, R3b, or R3cis independently selected from the, , , , . In some embodiments, each R3, R3a, R3b, or R3cis independently selected from the group consisting of, ,. In some embodiments, each R3, R3a, R3b, or R3cis independently selected from the group consisting

[0272] In some embodiments, R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C2-C alkenyl, substituted or unsubstituted C1-C aminoalkyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6. In some embodiment, R4is substituted or unsubstituted C1- C alkyl, substituted or unsubstituted C1-C aminoalkyl, substituted or unsubstituted C1-C heteroalkyl, or substituted or unsubstituted C1-C hydroxyalkyl. In some embodiments, R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C1-C hydroxyalkyl.

[0273] In some embodiment, R4is substituted or unsubstituted C1-C alkyl or substituted or unsubstituted C1-C heteroalkyl. In some embodiment, R4is substituted or unsubstituted C1- C alkyl. In some embodiments, the alkyl is a straight chain or branched alkyl. In some embodiment, R4is substituted or unsubstituted C1-C 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, R4is substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), substituted or unsubstituted -CH2CH2-O-(C1-C4 haloalkyl), -CH2-O- (C1-C4haloalkyl), -CH2CH2-O-(C3-C6cycloalkyl), -CH2-O-(C3-C6cycloalkyl), -CH2CH2-O- (C3-C6heterocycloalkyl), or -CH2-O-(C3-C6heterocycloalkyl). In some embodiment, R4is substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), substituted or unsubstituted -CH2CH2-O-(C1-C4haloalkyl), or -CH2-O-(C1-C4haloalkyl). In someembodiments, R4is -CH2CH2-O-(C3-C6cycloalkyl), -CH2-O-(C3-C6cycloalkyl), -CH2CH2- O-(C3-C6heterocycloalkyl), or -CH2-O-(C3-C6heterocycloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-C6 cycloalkyl). In some embodiments, R4is -CH2-O-(C3-C6 cycloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R4is -CH2-O-(C3-C6heterocycloalkyl).

[0274] In some embodiments, R4is substituted or unsubstituted C1-C alkyl, which is substituted with one or more halogen, -OR10, C1-C8 alkyl, or C3-C6 cycloalkyl.

[0275] In some embodiments, R4is substituted or unsubstituted C3-C8cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6. In some embodiments, R4is C3-C8 cycloalkyl. In some embodiments, R4is monocyclic, polycyclic, spirocyclic, or bridged cycloalkyl. In some embodiments, R4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R4is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R4is cyclopropyl. In some embodiments, R4is cyclobutyl. In some embodiments, R4is cyclopentyl. In some embodiments, R4is cyclohexyl. In some embodiments, R4is.

[0276] In some embodiments, R4is substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6. In some embodiments, R4is monocyclic, polycyclic, spirocyclic, or bridged heterocycloalkyl. In some embodiments, R4is a 4- membered heterocycloalkyl. In some embodiments, R4is a 5-membered heterocycloalkyl. In some embodiments, R4is a 6-membered cycloalkyl. In some embodiments, R4is a 7- membered cycloalkyl. In some embodiments, R4is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine. In some embodiments, R4is tetrahydrofuran or tetrahydropyran.

[0277] In some embodiments, each R6is independently halogen, -CN,-NO2, NR8R9, -OR10, -SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, -NR8C(O)R9, C1-C alkyl, C1- C haloalkyl, C1-C hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl. In some embodiments, each R6is independently halogen, -NR8R9, - OR10, C(O)R10, C(O)OR10, C(O)NR8R9, -NR8C(O)R9, C1-C alkyl, C1-C haloalkyl, C1-C hydroxyalkyl, or C3-C8 cycloalkyl. In some embodiments, each R6is independently halogen, -NR8R9, -OR10, C(O)OR10, C(O)NR8R9, C1-C alkyl, or C3-C8cycloalkyl. In some embodiments, each R6is independently halogen, -NR8R9, -OR10, or C3-C8cycloalkyl. In some embodiments, each R6is independently -NR8R9or -OR10. In some embodiments, eachR6is independently C3-C8cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, spirocyclic or bridged cycloalkyl. In some embodiments, each R6is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R6is independently halogen. In some embodiments, each R6is independently H, Cl, F, or Br. In some embodiments, each R6is independently F. In some embodiments, each R6is 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 R6is independently F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R6is independently F, -OH, -CH3, or -CF3. In some embodiments, each R6is independently F. In some embodiments, each R6is independently -OH. In some embodiments, each R6is independently -CF3. In some embodiments, each R6is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R6is independently cyclopropyl. In some embodiments, each R6is cyclobutyl.

[0278] In some embodiments, two R6combine 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 R6combine together with the atom(s) to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl or cyclobutyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclobutyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a C3-C6 heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a 4 membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a 5 membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a 6-membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a pyran, piperazine, piperidine, or morpholine.

[0279] In some embodiments, R4is -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.

[0280] In some embodiments, each R5is independently C1-C6 alkyl. In some embodiments, each R5is independently -CH2CH3 or -CH3. In some embodiments, each R5is independently -CH2CH3. In some embodiments, each R5is independently -CH3. In some embodiments, each R5is independently H.

[0281] In some embodiments, R5ais CH3. In some embodiments, R5ais H.

[0282] In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a C3-C6cycloalkyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclopentyl or cyclohexyl. Insome embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclopentyl.

[0283] In some embodiments, each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, 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-C10heterocycloalkyl, each of which is substituted with one or more Ra. In some embodiments, each R8and R9is independently selected at each occurrence from H, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C10 cycloalkyl. In some embodiments, each R8and R9is independently selected at each occurrence from H, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C10cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R8and R9is independently selected at each occurrence from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0284] In some embodiments, each R10is 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-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra. In some embodiments, each R10is independently selected from H, C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R10is independently selected from H, C1-C6 alkyl, C3- C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R10is independently selected from H and C1-C6alkyl. In some embodiments, each R10is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0285] In some embodiments, each R11is independently selected from substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, 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-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra. In some embodiments, each R11is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6haloalkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from C1-C6alkyl, C1-C6heteroalkyl, and C1-C6 haloalkyl. In some embodiments, each R11is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0286] In some embodiments, each R12is 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-C10heterocycloalkyl, each of which is substituted with one or more Ra. In some embodiments, each R12is independently selected from H, straight or branched chain C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R12is independently selected from H, straight or branched chain C1-C6alkyl. In some embodiments, each R12is independently selected from C3-C10cycloalkyl and C3-C10 heterocycloalkyl.

[0287] In some embodiments, each Rais independently selected from halogen, -OH, -CH3, - CF3, -OCH3, -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 Rais independently selected from -F, -Cl, -Br, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, each Rais independently selected from -F, -OH, -CH3, -CF3, or - C(O)OH.

[0288] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. I 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.

[0289] In some embodiments, the PDGH inhibitor is a compound described in Table 4, or a pharmaceutically acceptable salt thereof..EXAMPLES

[0290] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. Example 1: Effects of orally-administered MF-300 on urinary PGE-MUM levels in CD rats.

[0291] The effect of daily, orally administered MF-300 (30 mg / kg or 60 mg / kg) on urinary PGE-MUM levels within cohorts of male CD (Sprague-Dawley) rats was assessed. Briefly, 8-week-old male CD rats had baseline plasma and urine levels of PGE2, 15-K-PGE2, 13,14- dihydro-15-keto-PGE2, and PGE-MUM assessed using liquid chromatography tandem mass spectrometry (LC-MS / MS). Cohorts of rats then received either daily oral administration of vehicle (Veh; 10% 2-Hydroxypropyl-beta-cyclodextrin) or daily oral administration of MF- 300 (30 mg / kg or 60 mg / kg) for 7 days. An additional urine analysis was performed on day 6, an additional plasma analysis was performed on day 7 prior to dose administration, and a final plasma analysis and muscle analysis was performed on day 7 after dose administration. All urine samples were collected between 8am-9am on the baseline measurement day and day 6, and PGE-MUM levels were normalized to creatinine. An overview of the experimental timeline for assessing the effects of MF-300 on urinary PGE-MUM levels in CD rats is shown in Fig.1A. A schematic showing the mechanism by which MF-300 inhibits 15-PGDH (and thus inhibits the first step in PGE-MUM production from PGE2) is and biological localization of PGE2 and metabolites is shown in Fig.1B. There were no significant differences in levels of urinary PGE-MUM normalized to creatinine during the baseline measurement for the rat cohorts administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF- 300 as shown in Fig.1C. There were significantly lower levels of urinary PGE-MUM normalized to creatinine on day 6 for the rats orally administered 30 mg / kg or 60 mg / kg of MF-300 compared to the rats orally administered vehicle as shown in Fig.1D. Plasma levels of MF-300 after a single dose or seven daily doses were also measured over 24 hours in rats, as shown in Fig.1E. Changes from baseline levels of PGE-MUM for CD rats administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300 were also measured as shown in Fig.1F.

[0292] An additional experiment was performed to achieve steady state MF-300 plasma levels in adult CD rats, an experimental overview of which is shown in Fig.2A. Over the 14 day time course, CD rats were administered either vehicle (Veh; 10% 2-Hydroxypropyl-beta-cyclodextrin), 30 mg / kg of MF-300, or 60 mg / kg of MF-300. Urine levels of PGE2, PGE- MUM, and a ratio of PGE2 / PGE-MUM was assessed over 14 days for CD rats administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300, and MF-300 was found to increase the ratio of PGE2 / PGE-MUM levels as shown in Fig.2B. A decrease in PGE-MUM levels in CD rats administered 30 mg / kg MF-300 or 60 mg / kg MF-300 relative to CD rats administered vehicle was also found, as shown in Fig.2C. Example 2: Effects of MF-300 on PGE-MUM levels in SMN 7 mice.

[0293] The effect of administration of MF-300 in cohorts of in a spinal muscular atrophy (SMA) disease model ( 7 mice, also SMN-C3), was assessed. A schematic is shown in Fig.3A representing that MF-300 blocks 15-PGDH to reduce levels of PGE2 metabolites. Urine levels of PGE2, PGE-MUM, and a ratio of PGE2 / PGE-MUM days for WT mice, Delta 7 mice administered vehicle, or Delta 7 mice administered 30 mg / kg of MF-300 every other day was assessed and MF-300 treatment was shown to increase PGE2 levels and the ratio of PGE2 to PGE-MUM and to decrease PGE-MUM levels in Delta 7 mice administered 30 mg / kg of MF-300 relative to Delta 7 mice administered vehicle as shown in Fig.3B. Example 3: Effects of MF-300 on PGE-MUM levels in aged mice.

[0294] The effect of administration of MF-300 in cohorts of aged mice was assessed. Briefly, mice were male C57Bl / 6J mice that were either adults (12-15 months of age) or aged (23 months of age) and were administered vehicle or 10 mg / kg MF-300, 30 mg / kg MF-300, or 60 mg / kg of MF-300. Administration of 10 mg / kg of MF-300 in aged mice reduced PGE- MUM levels relative to PGE-MUM levels in aged mice administered vehicle after 12 weeks as shown in Fig.4. Example 4: The effects of orally-administered MF-300 on P75ECD expression.

[0295] A biological sample is obtained from a subject. The biological sample is tested for the presence of the biomarker p75ECD. The subject is found to have elevated levels of p75ECD. A 15-PGDH inhibitor is administered to the subject. The subject is again tested for the presence of the biomarker p75ECD after treatment with the 15-PGDH inhibitor and it is found that the subject has reduced levels of p75ECD as compared to prior to the treatment.

[0296] While preferred embodiments of the present invention 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 invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention 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 for reducing levels of p75ECD, PGE-MUM, or both in a subject, the method comprising: administering to the subject an amount of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor effective to reduce levels of p75ECD, PGE-MUM, or both, in the subject.

2. A method for treating a subject with a 15-hydroxyprostaglandin dehydrogenase (15- PGDH) inhibitor, the method comprising: (a) identifying the subject as having elevated levels of p75ECD, PGE-MUM, or both, relative to a control or levels of p75ECD or PGE-MUM that exceed a predetermined threshold; and (b) administering the 15-PGDH inhibitor to the subject to reduce the levels of p75ECD, PGE-MUM, or both, in the subject.

3. The method of claim 1 or 2, further comprising, prior to the administering, measuring the levels of p75ECD, PGE-MUM, or both, in the subject.

4. A method for selecting a subject for treatment with a 15-hydroxyprostaglandin (15- PGDH) inhibitor, the method comprising: (a) providing or obtaining a biological sample obtained from the subject; (b) measuring a level of p75ECD, PGE-MUM, or both in the biological sample; and (c) identifying the subject as a candidate for treatment with the 15-PGDH inhibitor when the levels of p75ECD, PGE-MUM, or both, in the biological sample exceeds a predetermined threshold.

5. The method of claim 4, further comprising, administering the 15-PGDH inhibitor to the subject.

6. The method of any one of claims 1-5, wherein the subject has a disease or condition associated with elevated levels of p75ECD.

7. The method of claim 6, wherein the disease or condition associated with elevated levels of p75ECD is a neurodegenerative disorder.

8. The method of claim 7, wherein the neurodegenerative disorder is amyotrophic lateral 9. The method of claim 8, wherein the neurodegenerative disorder is amyotrophic lateral sclerosis.

10. The method of any one of claims 1-3 or 5-9, wherein the administering is selected from the group consisting of: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra-arterial administration, intradermal administration, subcutaneous administration, and any combination thereof.

11. The method of any one of claims 1-3 or 5-10, wherein the administering is selected from the group consisting of: acute administration, chronic administration, intermittent administration, and continuous administration.

12. The method of any one of claims 1-3 or 5-11, wherein the 15-PGDH inhibitor is administered to the subject in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, diluent, and / or carrier.

13. The method of any one of claims 1-12, wherein the subject in need thereof is a human.

14. The method of any one of claims 4-13, wherein the biological sample is whole blood, plasma, or serum.

15. The method of any one of claims 4-13, wherein the biological sample is urine.

16. The method of any one of claims 1-15, wherein the 15-PGDH inhibitor is selected from the group consisting of: a small molecule, an antibody or fragment thereof, a peptide inhibitor, an aptamer, an oligonucleotide inhibitor, and any combination thereof.

17. The method of any one of claims 1-16, wherein the 15-PGDH inhibitor is a compound of Formula I: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 R1is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo or thio; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; each R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; each R11is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 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;.

18. The method of claim 17, wherein the compound is a compound of Formula Ia:Formula Ia or a pharmaceutically acceptable salt thereof.

19. The method of claim 17, wherein the compound is a compound of Formula Ib:Formula Ib or a pharmaceutically acceptable salt thereof.

20. The method of any one of claims 1-16, wherein 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; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo or thio;each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or two R4intervening atoms to form a C3-10cycloalkyl, and any remaining R4independently 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; each R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;Formula IIaor a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

22. The method of claim 20, wherein the compound is a compound of Formula IIb:Formula IIb or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

23. The method of claim 20, wherein the compound is a compound of Formula IIc:Formula IIc or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

24. The method of claim 20, wherein the compound is a compound of Formula IId:Formula IId or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

25. The method of claim 20, wherein the compound is a compound of Formula IIe:Formula IIe or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

26. The method of claim 20, wherein the compound is a compound of Formula IIf:Formula IIf or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

27. The method of claim 20, wherein the compound is a compound of Formula IIg:Formula IIg or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

28. The method of claim 20, wherein the compound is a compound of Formula IIh:Formula IIh or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

29. The method of claim 20, wherein the compound is a compound of Formula IIi:Formula IIi or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

30. The method of claim 20, wherein the compound is a compound of Formula IIj:Formula IIj or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

31. The method of claim 20, wherein the compound is a compound of Formula IIn:Formula IIn or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

32. The method of claim 20, wherein the compound is a compound of Formula IIp:Formula IIp or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

33. The method of any one of claims 1-16, 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;R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo or thio; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is 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, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; ortwo R63-10cycloalkyl, and any remaining R6NR9R10, OR11, C(O)R11, C(O)OR11, C(O)NR9R10, SOR12, SO2R12, SO2NR9R10, NR13C(O)R11, NR13C(O)NR9R10, NR13SO2R11, NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7is 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, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R8is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R83-10cycloalkyl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

34. The method of claim 33, wherein the compound is a compound of Formula IIIa:Formula IIIa or a pharmaceutically acceptable salt thereof.

35. The method of claim 33, wherein the compound is a compound of Formula IIIb:Formula IIIb or a pharmaceutically acceptable salt thereof, wherein: each R14is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

36. The method of claim 33, wherein the compound is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof.

37. The method of claim 33, wherein the compound is a compound of Formula IIId:Formula IIId or a pharmaceutically acceptable salt thereof, wherein: each R14is 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, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

38. The method of any one of claims 1-16, wherein the 15-PGDH inhibitor is a compound of Formula IIk:Formula IIk 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; R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; each R4is independently selected from H and halo; R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R11is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 6cycloalkyl; and p is 0, 1, or 2.

39. The method of any one of claims 1-16, wherein the 15-PGDH inhibitor is a compound of Formula IIm:Formula IIm or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4intervening atoms to form a C3-10cycloalkyl, and any remaining R4independently 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, 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.

40. The method of any one of claims 1-16, wherein the 15-PGDH inhibitor is a compound of Formula IIq:Formula IIq or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independentlyselected from halo, NR6R7, OR8, C(O)R8, C(O)OR8, C(O)NR6R7, SOR9, SO2R9, SO2NR6R7, NR10C(O)R8, NR10C(O)NR6R7, NR10SO2R8, NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; each R4is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4intervening atoms to form a C3-10cycloalkyl, and any remaining R4independently 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, 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.

41. The method of any one of claims 1-16, wherein the 15-PGDH inhibitor is a compound of Formula IIIc:Formula IIIc 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; R1is selected from C6-10aryl 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is CF3; or R2and R3are taken together to form oxo; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is 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, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R6remaining R6NR9R10, OR11, C(O)R11, C(O)OR11, C(O)NR9R10, SOR12, SO2R12, SO2NR9R10, NR13C(O)R11, NR13C(O)NR9R10, NR13SO2R11, NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7and R8is 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, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; and n is 0, 1, 2, 3, or 4.

42. The method of any one of claims 1-16, wherein the 15-PGDH inhibitor is a compound selected from the group consisting of:; ;43. The method of any one of claims 1-16, wherein the 15-PGDH inhibitor is a compound selected from the group consisting of:; ; ;;;;44. The method of any one of claims 1-16, wherein the 15-PGDH inhibitor is a compound selected from the group consisting of: ;.

45. The method of any one of claims 1-44, wherein the wherein the 15-PGDH inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt thereof:Formula IV, wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2or N; R1is H, halogen, -CN, OR10, C(O)R10, C(O)OR10, NR8R9, C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C cycloalkyl; each R2is independently H, halogen, OR10, C(O)R10, C(O)OR10, -CN, C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9; R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C2-C alkenyl, substituted or unsubstituted C1-C aminoalkyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8- membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C heterocycloalkyl; XAis -NR5R5or -OR5; wherein each R5is independently H or C1-C6alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C6heterocycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is optionally substituted with one or more Ra;each R10is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R12is 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-C8cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is optionally substituted with one or more Ra; each Rais 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.

46. The method of claim 45, wherein ring Q is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 N atoms.

47. The method of claim 45, wherein ring Q is a phenyl, pyrimidinyl, or pyridinyl.

48. The method of claim 45 or 47, wherein when Q is phenyl then one of R3is not H.

49. The method of claim 45, whereinwherein, X1, X2, X3and X4are each independently N or CR3; each R3is 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 orunsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; each R10is 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-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 Ra; each R11is 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-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais 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.

50. The method of claim 49, wherein X1, X2, X3and X4are each CR3.

51. The method of claim 49, wherein X1is N; and X2, X3, and X4are each CR3.

52. The method of claim 49, wherein X1and X2are each N; and X3and X4are each CR3.

53. The method of claim 49, wherein X1and X3are each N; and X2and X4are each CR3.

54. The method of claim 49, wherein X1and X4are each N; and X2and X3are each CR3.

55. The method of claim 49, wherein X1, X2, and X3are each N; and X4is CR3.

56. The method of claim 49, wherein X1, X2, and X4are each N; and X3is CR3.

57. The method of any one of claims 45-56, wherein each R3is independently selected from H, halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

58. The method of claim 57, wherein each R3is independently selected from H, halogen, C(O)OR10, C(O)NR8R9, and substituted or unsubstituted 5-membered heteroaryl.

59. The method of claim 45, wherein the compound has the structure of Formula V, or a pharmaceutically acceptable salt thereof:Formula V, wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1is H, halogen, -CN, OR10, C(O)R10, C(O)OR10, NR8R9, C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C cycloalkyl; each R2is independently H, halogen, OR10, C(O)R10, C(O)OR10, -CN, C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C alkyl, or substituted or unsubstituted C3-C8cycloalkyl; R3a, R3b, and R3care 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9; R4is substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C2-C alkenyl, substituted or unsubstituted C1-C aminoalkyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is 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-C alkyl, substituted C1-C haloalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C heterocycloalkyl; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl; each R8and R9is 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-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted orunsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; each R10is 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-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 Ra; each R11is 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-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais 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.

60. The method of any one of claims 45-59, wherein XAis NR5R5.

61. The method of any one of claims 45-59, wherein XAis OR5.

62. The method of any one of claims 45-61, wherein Y is CR2.

63. The method of any one of claims 45-61, wherein Y is N.

64. The method of claim 59, wherein the compound of Formula V has the structure of Formula VIa, or a pharmaceutically acceptable salt thereof:Formula VIa.

65. The method of claim 59, wherein the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:Formula VIb.

66. The method of any one of claims 45-65, wherein Z is N.

67. The method of any one of claims 45-65, wherein Z is CR1.

68. The method of any one of claims 45-65, wherein Z is CH.

69. The method of claim 59, wherein the compound of Formula V has the structure of Formula VIIa, or a pharmaceutically acceptable salt thereof:Formula VIIa.

70. The method of claim 59, wherein the compound of Formula V has the structure of Formula VIIb, or a pharmaceutically acceptable salt thereof:Formula VIIb.

71. The method of claim 59, wherein the compound of Formula V has the structure of Formula VIIc, or a pharmaceutically acceptable salt thereof:.

72. The method of claim 59, wherein the compound of Formula V has the structure of Formula VIId, or a pharmaceutically acceptable salt thereof:Formula VIId. . The method of any one of claims 59-72, wherein X1is N.

74. The method of any one of claims 59-73, wherein R3bis H; and R3cis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9.

75. The method of claim 74, wherein R3bis H; and R3cis selected from halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

76. The method of any one of claims 59-73, wherein R3cis H; and R3bis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, -SR8, C(O)R10, C(O)OR10, or C(O)NR8R9.

77. The method of claim 76, wherein R3cis H; and R3bis selected from halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

78. The method of any one of claims 59-72, wherein X1is CR3a.

79. The method of any one of claims 59-72 or 78, wherein R3aand R3bare independently H or halogen; and R3cis 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, - SR8, C(O)R10, C(O)OR10, or C(O)NR8R9.

80. The method of claim 79, wherein R3cis selected from H, halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1- C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

81. The method of claim 80, wherein R3cis C(O)OR10, C(O)NR8R9, or substituted or unsubstituted 5-membered heteroaryl.

82. The method of any one of claims 79-81, wherein R3aand R3bare each H.

83. The method of any one of claims 59-72 or 78, wherein R3aand R3care independently H or halogen; and R3bis 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-C alkyl,substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, - SR8, C(O)R10, C(O)OR10, or C(O)NR8R9.

84. The method of claim 83, wherein R3bis selected from H, halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1- C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

85. The method of claim 83, wherein R3bis C(O)OR10, C(O)NR8R9, or substituted or unsubstituted 5-membered heteroaryl.

86. The method of any one of claims 83-85, wherein R3aand R3care each H.

87. The method of any one of claims 59-72 or 78, wherein R3band R3care each H or halogen; and R3ais 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-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C 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 R13is independently halogen, CN, -NO2, NR8R9, OR10, - SR8, C(O)R10, C(O)OR10, or C(O)NR8R9.

88. The method of claim 87, wherein R3ais selected from H, halogen, NR8R9, OR10, SR8, C(O)R10, C(O)OR10, C(O)NR8R9, SOR11, SO2R11, substituted or unsubstituted C1- C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C3-C ycloalkyl, substituted or unsubstituted C3-C heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

89. The method of claim 87, wherein R3ais C(O)OR10, C(O)NR8R9, or substituted or unsubstituted 5-membered heteroaryl.

90. The method of any one of claims 87-89, wherein R3band R3care each H.

91. The method of any one of claims 45-90, wherein each R2is H.

92. The method of any one of claims 45-91, wherein R5aand one of R6combine together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl.

93. The method of any one of claims 45-91, wherein R5ais H.

94. The method of any one of claims 45-93, wherein R5is H.

95. The method of any one of claims 45-94, wherein R4is substituted or unsubstituted C1- C alkyl, substituted or unsubstituted C1-C aminoalkyl, substituted or unsubstituted C1-C heteroalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3- C8 cycloalkyl, or substituted or unsubstituted C3-C heterocycloalkyl, each of which is substituted with one or more R6.

96. The method of claim 95, wherein R4is substituted or unsubstituted C1-C alkyl or substituted or unsubstituted C1-C heteroalkyl, each of which is substituted with one or more R6.

97. The method of any one of claims 45-94, wherein R4is substituted or unsubstituted C3- C8cycloalkyl or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6.

98. The method of claim 97, wherein R4is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl.

99. The method of any one of claims 45-98, wherein each R6is independently halogen, NR8R9, OR10, substituted or unsubstituted C1-C alkyl, substituted or unsubstituted C1-C haloalkyl, substituted or unsubstituted C1-C hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C heterocycloalkyl.

100. The method of claim 99, wherein each R6is independently halogen, OR10, C1-C alkyl, C1-C haloalkyl, or C3-C8cycloalkyl.

101. The method of claim 99 or 100, wherein each R6is independently -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

102. The method of any one of claims 45-101, wherein the compound is selected from Table 4, or a pharmaceutically acceptable salt thereof.

103. The method of any one of claims 1-102, wherein the subject has a disease or condition associated with elevated levels of PGE-MUM.

104. The method of claim 103, wherein the disease or condition associated with elevated levels of PGE-MUM is associated with muscle damage, injury, or atrophy.

105. The method of claim 104, wherein the disease or condition associated with muscle damage, injury, or atrophy comprises acute muscle injury or trauma, soft tissue hand injury, muscular dystrophy, 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, mvotubular myopathy (MM), myasthenia gravis (MG), congestive heart failure, periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, cardiac cachexia, or stress induced urinary incontinence.

106. The method of any one of claims 103-105, wherein the disease or condition associated with elevated levels of PGE-MUM is a neuromuscular disease.

107. The method of claim 106, wherein the neuromuscular disease is spinal muscular atrophy.

108. The method of claim 107, wherein administering to a subject with spinal muscular atrophy an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor reduces PGE- MUM levels in the subject.

109. The method of claim 107 or 108, wherein administering to a subject with spinal muscular atrophy an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor improves one or more spinal muscular atrophy disease symptoms in the subject.

110. The method of claim any one of claims 1-109, wherein the subject is an aged subject.

111. The method of claim 110, wherein the subject is at least 60 years of age.

112. The method of any one of claims 1-111, wherein the disease or condition associated with elevated levels of PGE-MUM is a condition associated with aging.

113. The method of claim 112, wherein the condition associated with aging is sarcopenia.

114. The method of claim 113, wherein administering to a subject with sarcopenia an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor reduces PGE-MUM levels in the subject.

115. The method of claim 113 or 114, wherein administering to a subject with sarcopenia an amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor improves one or more sarcopenia symptom in the subject.

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