Methods and compositions for treating a target with a 15-hydroxyprostaglandin dehydrogenase inhibitor

Abstract

This specification provides compositions and methods for reducing the level 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 include administering to a subject an amount effective in reducing the level of at least one biomarker in the subject, which is a 15-hydroxyprostaglandin dehydrogenase inhibitor (15-PGDH).

Description

[Technical Field]

[0001] cross reference This application claims the benefits of U.S. Provisional Patent Application No. 63 / 520,592, filed on 18 August 2023, which is incorporated herein by reference in whole. [Background technology]

[0002] The p75 neurotrophin receptor (p75NTR) is involved in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In ALS, elevated levels of the urinary p75 extracellular domain (p75ECD) are a biomarker of the disease. Urinary prostaglandin E metabolite (PGE-MUM, also known as PGE-M) is a metabolite of prostaglandin E2, which is a biomarker of the disease, and elevated levels of PGE-MUM are associated with an increased risk of ALS.

[0003] Reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is shown to be specifically and individually referenced. If any publication or patent or patent application referenced herein conflicts with any disclosure contained herein, this specification is intended to supersede and / or take precedence over any such conflicting material. [Overview of the project]

[0004] The need for compositions and methods to reduce the levels of biomarkers (e.g., disease or disease-related) in a subject remains unmet. This disclosure satisfies this unmet need by providing compositions and methods for reducing the levels of disease or disease-related biomarkers (e.g., p75ECD, PGE-MUM) using 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors.

[0005] One embodiment provides a method for reducing the levels of p75ECD, PGE-MUM, or both in a subject, comprising the step of administering to the subject an amount effective in reducing the levels of p75ECD, PGE-MUM, or both in the subject, to a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor.

[0006] In another embodiment, a method is provided for treating a subject with a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor, comprising the steps of (a) identifying the subject as having elevated levels of p75ECD, PGE-MUM, or both, compared to a control or a predetermined threshold level of p75ECD or PGE-MUM, and (b) administering the 15-PGDH inhibitor to the subject to reduce the levels of p75ECD, PGE-MUM, or both in the subject. Optionally, the method further comprises measuring the levels of p75ECD, PGE-MUM, or both in the subject prior to the administration step.

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

[0008] In some cases, the subject suffers from a disease or disorder associated with an elevated level of p75ECD. In some cases, the disease or disorder associated with an elevated level of p75ECD is a neurodegenerative disorder. In some cases, the neurodegenerative disorder is amyotrophic lateral sclerosis or Alzheimer's disease. In some cases, the subject suffers from a disease or disorder associated with an elevated level of PGE-MUM. In some cases, the administering step is selected from the group consisting of oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intraarterial administration, intradermal administration, subcutaneous administration, and any combination thereof. In some cases, the administering step 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 small molecules, antibodies or fragments thereof, peptide inhibitors, aptamers, oligonucleotide inhibitors, and any combination thereof. In some cases, the 15-PGDH inhibitor is of formula I

[0009]

化

[0010] [ka] This assumes that this is not the case.

[0011] In some cases, the compound is of formula Ia

[0012] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0013] In some cases, the compound is of formula Ib

[0014] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0015] In some cases, 15-PGDH inhibitors are used in formula II

[0016] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, T, U, W, X, and Y are independent of N and CR. 5 Selected from, S, V, and Z are independently selected from N and C. R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl are halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5-10 membered heteroaryl groups, R 2 H is R 3 -CF 3 And, or R 2 and R 3 They combine to form an oxo or thio, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R's 4They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 5 These are H, Hal, and -NR, respectively, and are independent of each other. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 10 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. However, the compound of formula II is

[0017] [ka]

[0018] [ka]

[0019] [ka] This assumes that this is not the case.

[0020] In some cases, the compound is formula IIa

[0021] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, or 2.

[0022] In some cases, the compound is formula IIb

[0023] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, or 2.

[0024] In some cases, the compound is of formula IIc

[0025] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, 4, or 5.

[0026] In some cases, the compound is of formula IId

[0027] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0028] In some cases, the compound is of formula IIe

[0029] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0030] In some cases, the compound is of formula IIf

[0031] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, or 3.

[0032] In some cases, the compound is formula IIg

[0033] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0034] In some cases, the compound is of formula IIh

[0035] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, or 3.

[0036] In some cases, the compound is formula IIi

[0037] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0038] In some cases, the compound is of formula IIj

[0039] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, or 3.

[0040] In some cases, the compound is of formula IIn

[0041] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, or 3.

[0042] In some cases, the compound is of formula IIp

[0043] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0044] In some cases, 15-PGDH inhibitors are used in formula III

[0045] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, X is independent of N and CR. 7 Selected from, Y is O, S, SO2, and C(R 8 ) Selected from 2, R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl are halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Optionally substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls, R 2 H is R 3 -CF 3 And, or R 2 and R 3 They combine to form an oxo or thio, R 4 and R 5 Independently, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyls, alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 They are optionally substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls, or R 4 and R 5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Forming 3-10 member heterocycloalkyls by optionally substituting with 1-3 substituents independently selected from aryls and 5-10 member heteroaryls, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11-C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R atoms bonded to the same carbon atom 6 These are combined as oxo, thio, or C 3-10 Form a cycloalkyl group, and all remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 7 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 8 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R's 8 They are united as Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 C is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. 3-10 Forming a cycloalkyl group, R 9 and R 10 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, R 11 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 12 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 13 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, m is either 1 or 2. n is 0, 1, 2, 3, or 4.

[0046] In some cases, the compound is formula IIIa

[0047] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0048] In some cases, the compound is formula IIIb

[0049] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, R 14 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, p is 0, 1, 2, or 3.

[0050] In some cases, the compound is of formula IIIc

[0051] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0052] In some cases, the compound is formula IIId

[0053] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, R 14 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10, -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, p is 0, 1, 2, or 3.

[0054] In some cases, 15-PGDH inhibitors are formulated with formula IIk

[0055] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, T, U, and Y are independent of N and CR. 6 Selected from, provided that when U is N, at least one of T and Y is N, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5-10 membered heteroaryl groups, R 2 H is R 3 -CF 3 And, or R 2 and R 3 They combine to form an oxo, R 4 These are independently selected from H and Halo, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 7 and R 8 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, R 9 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 10 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 11 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, p is 0, 1, or 2.

[0056] In some cases, 15-PGDH inhibitors are formulated with formula IIm

[0057] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5-10 membered heteroaryl groups, R 2 H is R 3 -CF 3 And, or R 2 and R 3 They combine to form an oxo, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R's 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10Selected from aryls and 5-10 member heteroaryls, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 10 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. p is 0, 1, 2, or 3.

[0058] In some cases, 15-PGDH inhibitors are used in formula IIq.

[0059] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10optionally substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl, R 2 is H, and R 3 is -CF 3 or alternatively R 2 and R 3 together form oxo, R 4 each R is independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or alternatively two R 4 together with the carbon atom to which they are bonded and any intervening atoms form C 3-10 cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9, -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C3-10 selected from cycloalkyl, R 8 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, R 9 are each independently C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, R 10 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 selected from cycloalkyl, n is 1, 2, 3, or 4, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, p is 0, 1, 2, or 3.

[0060] Optionally, the 15-PGDH inhibitor is of formula IIIc

[0061]

Chemical Formula

[0062] In some cases, 15-PGDH inhibitors are used.

[0063] [ka] It is a compound selected from the group consisting of the following.

[0064] In some cases, 15-PGDH inhibitors are used.

[0065] [ka]

[0066] [ka]

[0067] [ka]

[0068] [ka]

[0069] [ka]

[0070] [ka]

[0071]

Chemical

[0072]

Chemical

[0073]

Chemical

[0074]

Chemical

[0075]

Chemical

[0076]

Chemical

[0077] Optionally, the 15-PGDH inhibitor is

[0078]

Chemical

[0079] In some examples, the 15-PGDH inhibitor is a compound of formula IV

[0080]

Chemical

[0081] In some cases, ring Q is a six-membered monocyclic heteroaryl containing one, two, or three nitrogen atoms. In some cases, ring Q is phenyl, pyrimidinyl, or pyridinyl. In some cases, when Q is phenyl, R3 One of them is not H.

[0082] In some examples,

[0083] [ka] teeth,

[0084] [ka] And in the formula, X 1 , X 2 , X 3 , and X 4 These are, independently, N or CR 3 And, R 3 These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups, each of which has one or more R groups.13 Replaced by, R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, R 8 and R 9 These are, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R 10 These are, independently, 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, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 11 These are, independently, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 12 These are, independently, 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-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R a Each of these is independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0085] In some examples, X 1 , X 2 , X 3 , and X 4 These are CR 3 In some cases, X 1 is N, and X 2 , X 3 , and X 4 These are CR 3 In some cases, X 1 and X 2 These are N and X 3 and X 4 These are CR 3 In some cases, X 1 and X 3 These are N and X 2 and X 4 These are CR 3 In some cases, X 1 and X 4 These are N and X 2 and X 3 These are CR 3In some cases, X 1 , X 2 , and X 3 These are N and X 4 CR 3 In some cases, X 1 , X 2 , and X 4 These are N and X 3 CR 3 That is the case.

[0086] In some examples, R 3a These are H, halogen, and -NR, respectively, independently. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 The following are selected: substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups. In some examples, R 3 These are H, halogen, and -C(O)OR, respectively, independently. 10 -C(O)NR 8 R 9 , and selected from substituted or unsubstituted 5-membered heteroaryls.

[0087] In some cases, the compound is of formula V

[0088] [ka] Having the structure of, or a pharmaceutically acceptable salt thereof, in the formula, Z is CR 1 or N, X 1 is N or CR 3a And, Y is CR 2or N, R 1 H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, R 2 These are H, halogen, and -OR, respectively, independently. 10 , -C(O)R 10 , -C(O)OR 10 -CN, -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, R 3a , R 3b , and R 3c These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups, each of which has one or more R groups. 13 Replaced by, R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C2-C8 alkenyl groups, substituted or unsubstituted C1-C8 aminoalkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups, each of which contains one or more R groups. 6 Replaced by, R 6 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 8 C(O)R 9, substituted or unsubstituted C1-C6 alkyl, substituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-8 member heteroaryl, Or two R's 6 These atoms, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl groups. X A , NR 5 R 5 OR 5 And, R 5 Each of these is independently H or C1-C6 alkyl, R 5a is H or CH3, Or R 5a and one R 6 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C6 cycloalkyl groups. R 8 and R 9 These are, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R 10 These are, independently, 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, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 11 These are, independently, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 12 These are, independently, 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-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R a Each of these is independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0089] In some examples, X A , NR 5 R 5 In some cases, X A is OR 5 In some cases, Y is CR 2 In some cases, Y is N.

[0090] In some cases, the compound of formula V is of formula VIa

[0091] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0092] In some cases, the compound of formula V is of formula VIb

[0093] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0094] In some cases, Z is N. In some cases, Z is CR. 1 In some cases, Z is CH.

[0095] In some cases, the compound of formula V is formula VIIa

[0096] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0097] In some cases, the compound of formula V is formula VIIb

[0098] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0099] In some cases, the compound of formula V is formula VIIc

[0100] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0101] In some cases, the compound of formula V is of formula VIId

[0102] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0103] In some examples, X 1 It is N. In some cases, R 3b H is R 3c These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups, each of which has one or more R groups. 13 Replaced with R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10, or -C(O)NR 8 R 9 That is the case.

[0104] In some examples, R 3b H is R 3c Halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 The following are selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

[0105] In some examples, R 3c H is R 3b These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups, each of which has one or more R groups. 13 Replaced with R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 That is the case.

[0106] In some examples, R 3c H is R 3b Halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 The following are selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

[0107] In some examples, X 1 CR 3a In some cases, R 3a and R 3b R is independently H or halogen, 3c These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups, each of which has one or more R groups. 13 Replaced with R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 That is the case.

[0108] In some examples, R 3c H, halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11The following are selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

[0109] In some examples, R 3c is -C(O)OR 10 -C(O)NR 8 R 9 , or a substituted or unsubstituted 5-membered heteroaryl. In some examples, R 3a and R 3b These are H, respectively.

[0110] In some examples, R 3a and R 3c R is independently H or halogen, 3b These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups, each of which has one or more R groups.13 Replaced with R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 That is the case.

[0111] In some examples, R 3b H, halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 The following are selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

[0112] In some examples, R 3b is -C(O)OR 10 -C(O)NR 8 R 9 , or a substituted or unsubstituted 5-membered heteroaryl.

[0113] In some examples, R 3a and R 3c These are H, respectively. In some examples, R 3b and R 3c These are H or halogen, respectively, and R 3a These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups, each of which has one or more R groups. 13 Replaced with R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 That is the case.

[0114] In some examples, R 3a H, halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11The following are selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

[0115] In some examples, R 3a is -C(O)OR 10 -C(O)NR 8 R 9 , or a substituted or unsubstituted 5-membered heteroaryl. In some examples, R 3b and R 3c These are H, respectively. In some examples, R 2 These are H, respectively. In some examples, R 5a and R 6 One of them, together with the atom to which they bond, forms a C3-C6 cycloalkyl group. In some examples, R 5a is H. In some cases, R 5 H is H.

[0116] In some examples, R 4 These are substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which contains one or more R 6 It is replaced by R 4 These are substituted or unsubstituted C1-C8 alkyl groups or substituted or unsubstituted C1-C8 heteroalkyl groups, each comprising one or more R groups. 6 It is replaced by R 4 These are substituted or unsubstituted C3-C8 cycloalkyl or 4-8 member heterocycloalkyl groups, each containing one or more R 6 It will be replaced by this.

[0117] In some examples, R 4These are cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl. In some cases, R 6 These are, independently, halogen and -NR. 8 R 9 , -OR 10 These are substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C1-C6 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups. In some examples, R 6 These are, independently, halogen, -OR 10 These are C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl. In some examples, R 6 These are, independently, -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0118] In some cases, the compound is selected from Table 4 or its pharmaceutically acceptable salts.

[0119] In some cases, subjects have a disease or illness associated with elevated PGE-MUM levels. In some cases, the disease or illness associated with elevated PGE-MUM levels is associated with muscle injury, injury, or atrophy. In some cases, the disease or illness associated with muscle injury, injury, or atrophy includes acute muscle injury or trauma, soft tissue injury of the hand, muscular dystrophy, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), hereditary myopathy, myotonic muscular dystrophy (MDD), mitochondrial myopathy, myotubular 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 cases, the disease or condition associated with elevated PGE-MUM levels is a neuromuscular disorder. In some cases, the neuromuscular disorder is spinal muscular atrophy. In some cases, administration of a certain amount of 15-hydroxyprostaglandin dehydrogenase inhibitor to subjects with spinal muscular atrophy reduces PGE-MUM levels in those subjects. In some cases, administration of a certain amount of 15-hydroxyprostaglandin dehydrogenase inhibitor to subjects with spinal muscular atrophy improves one or more symptoms of spinal muscular atrophy in those subjects.

[0120] In some cases, the subjects are elderly. In some cases, the subjects are at least 60 years old. In some cases, the disease or illness associated with elevated PGE-MUM levels is an age-related disease. In some cases, the age-related disease is sarcopenia. In some cases, administration of a certain amount of 15-hydroxyprostaglandin dehydrogenase inhibitor to subjects with sarcopenia reduces PGE-MUM levels in the subjects. In some cases, administration of a certain amount of 15-hydroxyprostaglandin dehydrogenase inhibitor to subjects with sarcopenia improves one or more sarcopenic symptoms in the subjects. [Brief explanation of the drawing]

[0121] Novel features of the present invention are specifically stated in the appended claims. The features and advantages of the present invention will be better understood by referring to the following detailed description, which specifies exemplary embodiments in which the principles of the present invention are utilized, and to the accompanying drawings.

[0122] [Figure 1A] This figure shows the effect of orally administered MF-300 on urinary PGE-MUM levels. Figure 1A outlines the experimental timeline evaluating the effect of daily oral administration of MF-300 (30 mg / kg or 60 mg / kg) on ​​urinary PGE-MUM levels in male CD rats. [Figure 1B] This figure shows the effect of orally administered MF-300 on urinary PGE-MUM levels. Figure 1B shows a schematic diagram illustrating the mechanism by which MF-300 affects PGE-MUM levels by inhibiting the biological localization of 15-PGDH and significant levels of PGE2 and its metabolites. [Figure 1C] This figure shows the effect of orally administered MF-300 on urinary PGE-MUM levels. Figure 1C shows baseline levels of urinary PGE-MUM normalized to creatinine for CD rat cohorts administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300. [Figure 1D] This figure shows the effect of orally administered MF-300 on urinary PGE-MUM levels. Figure 1D shows creatinine-normalized urinary PGE-MUM levels on day 6 for CD rat cohorts administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300. [Figure 1E] This figure shows the effect of orally administered MF-300 on urinary PGE-MUM levels. Figure 1E shows the levels of MF-300 in CD rats over a 24-hour time course after a single or seven daily doses of 30 mg / kg MF-300. [Figure 1F]This figure shows the effect of orally administered MF-300 on urinary PGE-MUM levels. Figure 1F shows the change from baseline levels of PGE-MUM in CD rats administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300. [Figure 2A] This figure shows an experiment to achieve steady-state MF-300 levels in C. difficile rats. Figure 2A outlines the experimental timeline for evaluating the effect of daily oral administration of MF-300 (30 mg / kg or 60 mg / kg) over 14 days on male C. difficile rats. [Figure 2B] This figure shows experiments to achieve steady-state MF-300 levels in C. difficile rats. Figure 2B shows urinary levels of PGE2, PGE-MUM, and PGE2 / PGE-MUM ratio over 14 days in C. difficile rats administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300. [Figure 2C] This figure shows experiments to achieve steady-state MF-300 levels in C. difficile rats. Figure 2C shows a comparison of the effects of the urinary PGE-MUM to creatinine ratio at baseline (day 0), day 7, and day 13 in C. difficile rats administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300. [Figure 3A] This figure shows the effects of MF-300 in a spinal muscular atrophy (SMA) disease model (SMNΔ7 mouse, also known as "Delta 7 mouse" + SMN-C3). Figure 3A shows a schematic diagram of the mechanism by which MF-300 reduces the level of the PGE2 metabolite by inhibiting 15-PGDH. [Figure 3B]This figure shows the effects of MF-300 in a spinal muscular atrophy (SMA) disease model (SMNΔ7 mouse, also known as "Delta 7 mouse" + SMN-C3). Figure 3B shows the urinary levels of PGE2, PGE-MUM, and the PGE2 / PGE-MUM ratio over several days in WT mice, Delta 7 mice administered with vehicle, or Delta 7 mice administered 30 mg / kg of MF-300 every other day. [Figure 4] This figure shows the effects of MF-300 on adult and aged C57BL / 6 mice administered with a vehicle, 10 mg / kg MF-300, 30 mg / kg MF-300, or 60 mg / kg MF-300. [Modes for carrying out the invention]

[0123] This specification provides methods and compositions for reducing at least one biomarker in a subject. The at least one biomarker may include a biomarker associated with a disease or illness. Furthermore, this specification provides methods and compositions for identifying a subject as a candidate for treatment with a therapeutic agent such as a 15-PGDH inhibitor. In some cases, the subject has elevated levels of at least one biomarker compared to a control subject or control population. In some cases, the subject has elevated levels of at least one biomarker compared to a disease or illness-free subject associated with at least one biomarker. In some cases, the subject has elevated levels of at least one biomarker compared to a predetermined threshold. In some cases, the at least one biomarker includes p75ECD. In some cases, p75ECD includes or may include 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, at least one biomarker comprises both p75ECD and PGE-MUM. In some cases, the methods and compositions provided herein include administering a 15-PGDH inhibitor to a subject with elevated levels of at least one biomarker, including p75ECD and / or PGE-MUM. In some cases, the methods and compositions provided herein include measuring the level of at least one biomarker (including p75ECD and / or PGE-MUM) in a subject (e.g., in a biological sample derived from the subject). In some cases, the methods and compositions provided herein include 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.

[0124] One embodiment of this specification provides a method for reducing the levels of p75ECD, PGE-MUM, or both in a subject. The method may include administering a 15-PGDH inhibitor to the subject in an amount effective in reducing the levels of p75ECD, PGE-MUM, or both in the subject.

[0125] In another aspect of this specification, a method is provided for treating a subject with a 15-PGDH inhibitor. Optionally, the method includes identifying a subject as having elevated levels of p75ECD, PGE-MUM, or both, compared to a control or a predetermined threshold level of p75ECD, PGE-MUM, or both. Optionally, the method further includes administering a 15-PGDH inhibitor to the subject (for example, if the subject has elevated levels of p75ECD, PGE-MUM, or both) to reduce the levels of p75ECD, PGE-MUM, or both in the subject.

[0126] In another aspect of this specification, a method is provided for selecting a subject for treatment with a 15-PGDH inhibitor. The method may include the step of providing or obtaining a biological sample obtained from the subject. The method may further include the step of measuring the levels of p75ECD, PGE-MUM, or both, in the biological sample. The method may further include the step of identifying the subject as a candidate for treatment with a 15-PGDH inhibitor if the levels of p75ECD, PGE-MUM, or both, in the biological sample exceed a predetermined threshold or a control level. The method may further include administering the 15-PGDH inhibitor to the subject after identifying the subject as a candidate or eligible for treatment with a 15-PGDH inhibitor.

[0127] In some cases, the methods provided herein include administering a composition of the disclosure, such as a 15-PGDH inhibitor, to a subject (for example, one in which levels of a biomarker (e.g., p75ECD, PGE-MUM) are elevated). In some cases, the elevated levels of the biomarker (e.g., p75ECD, PGE-MUM) are associated with elevated levels or increased activity of 15-PGDH. In some cases, the levels of the biomarker (e.g., p75ECD, PGE-MUM) can be decreased or reduced by inhibiting the function of 15-PGDH in the subject, or by reducing the expression or amount of 15-PGDH.

[0128] In some cases, the methods provided herein include the step of identifying a subject as having elevated levels of at least one biomarker, e.g., elevated levels of p75ECD, PGE-MUM, or both. In some cases, at least one biomarker (e.g., p75ECD, PGE-MUM) is elevated compared to a control, e.g., a control subject or control population. In some cases, at least one biomarker (e.g., p75ECD, PGE-MUM) is elevated compared to a predetermined threshold. In some cases, at least one biomarker (e.g., p75ECD, PGE-MUM) is elevated compared to a subject without the disease or illness associated with at least one biomarker.

[0129] Depending on the circumstances, the step of identifying a subject as having elevated levels of at least one biomarker (e.g., p75ECD, PGE-MUM) may include obtaining or providing a biological sample of the subject or a biological sample obtained from the subject. The biological sample can be tested for the presence or absence of at least one biomarker (e.g., p75ECD, PGE-MUM). Measuring the level of at least one biomarker (e.g., p75ECD, PGE-MUM) in the biological sample can provide an indicator that the level of at least one biomarker (e.g., p75ECD, PGE-MUM) is elevated in the subject. Any method for testing or measuring the biological sample for biomarkers, such as but not limited to, Western blotting, enzyme-linked immunosorbent assay (ELISA), colorimetric protein assay, polymerase chain reaction (PCR), sequencing, etc., can be used.

[0130] In some cases, the biological sample is a body fluid. As used herein, the term “body fluid” refers to any fluid in the body of an animal. Examples of body fluids include, but are not limited to, plasma, serum, blood, lymph, cerebrospinal fluid, synovial fluid, urine, saliva, mucus, phlegm, and sputum. Body fluid samples may be collected by any suitable method. In some cases, the biological sample is a blood sample. A blood sample may contain whole blood or its components, such as plasma or serum. In some cases, the biological sample is urine.

[0131] If the level of at least one biomarker (e.g., p75ECD, PGE-MUM) in a subject is determined to be elevated, the subject is selected for treatment with a 15-PGDH inhibitor. The 15-PGDH inhibitor may be administered to the subject in the number of doses necessary to reduce the level of at least one biomarker (e.g., p75ECD, PGE-MUM) in the subject. In some cases, the level of at least one biomarker (e.g., p75ECD, PGE-MUM) can be used to determine whether the subject's response to treatment with the 15-PGDH inhibitor is positive. For example, if the level of at least one biomarker (e.g., p75ECD, PGE-MUM) is reduced by the 15-PGDH inhibitor, the subject's response to the 15-PGDH inhibitor is identified as positive. In other cases, if the level of at least one biomarker (e.g., p75ECD, PGE-MUM) is not reduced by the 15-PGDH inhibitor, the subject may be identified as requiring further treatment with the 15-PGDH inhibitor. In other cases, if the level of at least one biomarker (e.g., p75ECD, PGE-MUM) is not reduced by a 15-PGDH inhibitor, the patient may be identified as requiring further treatment with a non-15-PGDH inhibitor.

[0132] In some cases, the subjects may have a disease or illness associated with at least one biomarker, or may have elevated levels of at least one biomarker. In some cases, the subjects may have a disease or illness associated with elevated levels of p75ECD. In some cases, the subjects may have a disease or illness associated with elevated levels of PGE-MUM. In some cases, the subjects may have a disease or illness associated with elevated levels of both p75ECD and PGE-MUM. This disease or illness may be any disease or illness associated with at least one biomarker, or elevated levels of at least one biomarker. In some cases, a disease or illness (or one or more symptoms thereof) associated with at least one biomarker or elevated levels of at least one biomarker can be treated by administering a 15-PGDH inhibitor to the subjects.

[0133] In some cases, the disease or illness may be a neurodegenerative disease. In some cases, the neurodegenerative disease may be associated with elevated levels of p75ECD (e.g., in urine). In some cases, the neurodegenerative disease may be amyotrophic lateral sclerosis (ALS). In some cases, the neurodegenerative disease may be Alzheimer's disease. In some cases, the neurodegenerative disease (e.g., ALS, Alzheimer's disease) (or one or more of its symptoms) may be treated by administering a 15-PGDH inhibitor to the subject.

[0134] In some cases, subjects have a disease or illness associated with elevated PGE-MUM levels. In some cases, the disease or illness associated with elevated PGE-MUM levels is associated with muscle injury, injury, or atrophy. In some cases, the disease or illness associated with muscle injury, injury, or atrophy includes acute muscle injury or trauma, soft tissue injury of the hand, muscular dystrophy, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), hereditary myopathy, myotonic muscular dystrophy (MDD), mitochondrial myopathy, myotubular 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 cases, the disease or condition associated with elevated PGE-MUM levels is a neuromuscular disease. In some cases, the neuromuscular disease is spinal muscular atrophy. In some cases, administration of a certain amount of 15-hydroxyprostaglandin dehydrogenase inhibitor to subjects with spinal muscular atrophy reduces PGE-MUM levels in those subjects. In some cases, administration of a certain amount of 15-hydroxyprostaglandin dehydrogenase inhibitor to subjects with spinal muscular atrophy improves one or more symptoms of spinal muscular atrophy in those subjects. Symptoms of spinal muscular atrophy may include muscle weakness, muscle atrophy, muscle tremor, or muscle spasms.

[0135] In some cases, the subjects are elderly. In some cases, the subjects are at least 60 years old. In some cases, the disease or illness associated with elevated PGE-MUM levels is an age-related illness. In some cases, the age-related illness is sarcopenia. In some cases, administration of a certain amount of 15-hydroxyprostaglandin dehydrogenase inhibitor to subjects with sarcopenia reduces PGE-MUM levels in the subjects. In some cases, administration of a certain amount of 15-hydroxyprostaglandin dehydrogenase inhibitor to subjects with sarcopenia improves one or more sarcopenic symptoms in the subjects. Symptoms of sarcopenia may include muscle weakness, muscle atrophy, decreased muscle size, decreased grip strength, loss of stamina, or motor dysfunction.

[0136] 15-PGDH inhibitors can be administered to a subject in a dose effective in reducing the level of a biomarker (e.g., p75ECD, PGE-MUM) in the subject. In some embodiments, effective doses of 15-PGDH inhibitors include approximately 1 mg / kg (or approximately 1 MPK), approximately 3 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 40 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, or approximately 100 mg / kg. In some embodiments, the effective dose of the 15-PGDH inhibitor includes at least about 1 mg / kg (also referred to as at least about 1 MPK), 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 includes less than about 1 mg / kg (also referred to as less than about 1 MPK), 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 is approximately 0.1 MPK, 0.2 MPK, 0.3 MPK, 0.4 MPK, 0.5 MPK, 0.6 MPK, 0.7 MPK, 0.8 MPK, 0.9 MPK, 1 MPK, 1.1 MPK, 1.2 MPK, 1.3 MPK, 1.4 MPK, 1.5 MPK, 1.6 MPK, 1.7 MPK, 1.8 MPK, 1.9 MPK, 2 MPK, 2.1 MPK, 2.2 MPK, 2.3 MPK, 2.4 MPK, 2.5 MPK, 2.6 MPK, 2.7 MPK, 2.8 MPK, and 2.9 MPK. This includes MPK, approximately 3 MPK, approximately 3.1 MPK, approximately 3.2 MPK, approximately 3.3 MPK, approximately 3.4 MPK, approximately 3.5 MPK, approximately 3.6 MPK, approximately 3.7 MPK, approximately 3.8 MPK, approximately 3.9 MPK, approximately 4 MPK, approximately 4.1 MPK, approximately 4.2 MPK, approximately 4.3 MPK, approximately 4.4 MPK, approximately 4.5 MPK, approximately 4.6 MPK, approximately 4.7 MPK, approximately 4.8 MPK, approximately 4.9 MPK, approximately 5 MPK, approximately 5.1 MPK, approximately 5.2 MPK, approximately 5.3 MPK, approximately 5.4 MPK, approximately 5.5 MPK, approximately 5.6 MPK, approximately 5.7 MPK, approximately 5.8 MPK, approximately 5.9 MPK, or approximately 6 MPK.In some embodiments, the effective dose of the 15-PGDH inhibitor is at least about 0.1 MPK, at least about 0.2 MPK, at least about 0.3 MPK, at least about 0.4 MPK, at least about 0.5 MPK, at least about 0.6 MPK, at least about 0.7 MPK, at least about 0.8 MPK, at least about 0.9 MPK, at least about 1 MPK, at least about 1.1 MPK, at least about 1.2 MPK, at least about 1.3 MPK, at least about 1.4 MPK, at least about 1.5 MPK, at least about 1.6 MPK, at least about 1.7 MPK, at least about 1.8 MPK, at least about 1.9 MPK, at least about 2 MPK, at least about 2.1 MPK, at least about 2.2 MPK, at least about 2.3 MPK, at least about 2.4 MPK, at least about 2.5 MPK, at least about 2.6 MPK, at least about 2.7 MPK, at least about 2.8 MPK, at least about 2.9 MPK, and a small amount. It includes at least approximately 3 MPK, at least approximately 3.1 MPK, at least approximately 3.2 MPK, at least approximately 3.3 MPK, at least approximately 3.4 MPK, at least approximately 3.5 MPK, at least approximately 3.6 MPK, at least approximately 3.7 MPK, at least approximately 3.8 MPK, at least approximately 3.9 MPK, at least approximately 4 MPK, at least approximately 4.1 MPK, at least approximately 4.2 MPK, at least approximately 4.3 MPK, at least approximately 4.4 MPK, at least approximately 4.5 MPK, at least approximately 4.6 MPK, at least approximately 4.7 MPK, at least approximately 4.8 MPK, at least approximately 4.9 MPK, at least approximately 5 MPK, at least approximately 5.1 MPK, at least approximately 5.2 MPK, at least approximately 5.3 MPK, at least approximately 5.4 MPK, at least approximately 5.5 MPK, at least approximately 5.6 MPK, at least approximately 5.7 MPK, at least approximately 5.8 MPK, at least approximately 5.9 MPK, or at least approximately 6 MPK.In some embodiments, the effective dose of the 15-PGDH inhibitor is approximately less than 0.1 MPK, less than 0.2 MPK, less than 0.3 MPK, less than 0.4 MPK, less than 0.5 MPK, less than 0.6 MPK, less than 0.7 MPK, less than 0.8 MPK, less than 0.9 MPK, less than 1 MPK, less than 1.1 MPK, less than 1.2 MPK, less than 1.3 MPK, less than 1.4 MPK, less than 1.5 MPK, less than 1.6 MPK, less than 1.7 MPK, less than 1.8 MPK, less than 1.9 MPK, less than 2 MPK, less than 2.1 MPK, less than 2.2 MPK, less than 2.3 MPK, less than 2.4 MPK, less than 2.5 MPK, less than 2.6 MPK, less than 2.7 MPK, less than 2.8 MPK, less than 2.9 MPK. This includes amounts less than approximately 3 MPK, less than approximately 3.1 MPK, less than approximately 3.2 MPK, less than approximately 3.3 MPK, less than approximately 3.4 MPK, less than approximately 3.5 MPK, less than approximately 3.6 MPK, less than approximately 3.7 MPK, less than approximately 3.8 MPK, less than approximately 3.9 MPK, less than approximately 4 MPK, less than approximately 4.1 MPK, less than approximately 4.2 MPK, less than approximately 4.3 MPK, less than approximately 4.4 MPK, less than approximately 4.5 MPK, less than approximately 4.6 MPK, less than approximately 4.7 MPK, less than approximately 4.8 MPK, less than approximately 4.9 MPK, less than approximately 5 MPK, less than approximately 5.1 MPK, less than approximately 5.2 MPK, less than approximately 5.3 MPK, less than approximately 5.4 MPK, less than approximately 5.5 MPK, less than approximately 5.6 MPK, less than approximately 5.7 MPK, less than approximately 5.8 MPK, less than approximately 5.9 MPK, or less than approximately 6 MPK.In some embodiments, the effective dose of the 15-PGDH inhibitor is 0.5 MPK-5 MPK, 0.6 MPK-5 MPK, 0.7 MPK-5 MPK, 0.8 MPK-5 MPK, 0.9 MPK-5 MPK, 1 MPK-5 MPK, 1.1 MPK-5 MPK, 1.2 MPK-5 MPK, 1.3 MPK-5 MPK, 1.4 MPK-5 MPK, 1.5 MPK-5 MPK, 1.6 MPK-5 MPK, 1.7 MPK-5 MPK, 1.8 MPK-5 MPK, 1.9 MPK-5 MPK, 2 MPK-5 MPK, 2.1 MPK-5 MPK, 2.2 MPK-5 MPK, 2.3 MPK-5 MPK, 2.4 MPK-5 MPK, 2.5 MPK-5 MPK, 2.6 MPK-5 MPK. This includes PK, 2.7MPK~5MPK, 2.8MPK~5MPK, 2.9MPK~5MPK, 3MPK~5MPK, 3.1MPK~5MPK, 3.2MPK~5MPK, 3.3MPK~5MPK, 3.4MPK~5MPK, 3.5MPK~5MPK, 3.6MPK~5MPK, 3.7MPK~5MPK, 3.8MPK~5MPK, 3.9MPK~5MPK, 4MPK~5MPK, 4.1MPK~5MPK, 4.2MPK~5MPK, 4.3MPK~5MPK, 4.4MPK~5MPK, 4.5MPK~5MPK, 4.6MPK~5MPK, 4.7MPK~5MPK, 4.8MPK~5MPK, or between 4.9MPK~5MPK.

[0137] 15-PGDH inhibitors can be administered to subjects by any preferred route of administration. Depending on the case, 15-PGDH inhibitors may be administered to subjects by one or more of the following methods: oral, intramuscular, intrathecal, intravenous, intraperitoneal, intra-arterial, intradermal, or subcutaneous.

[0138] In some embodiments, the 15-PGDH inhibitor may be administered to the subject by acute, chronic, intermittent, or continuous administration. In some embodiments, the 15-PGDH inhibitor is administered to the subject in a pharmaceutical formulation comprising pharmaceutically acceptable excipients, diluents, and / or carriers. In some embodiments, the subject is a mammal. In some cases, the subject is a human.

[0139] Depending on the circumstances, 15-PGDH inhibitors may be selected from the group consisting of small molecules, antibodies or their fragments, peptide inhibitors, aptamers, oligonucleotide inhibitors, and any combination thereof.

[0140] In some cases, 15-PGDH inhibitors are small molecules. In some cases, these small molecules are orally bioavailable.

[0141] In some embodiments, the 15-PGDH inhibitor is of formula I

[0142] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, -SO2CH2-, Y is independent of N and CR. 11 Selected from, R 1 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C6-10 Selected from aryls and 5-10 member heteroaryls, R 2 H is R 3 -CF 3 And, or R 2 and R 3 They combine to form an oxo or thio, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 5 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 10 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, R 11 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, n is 0, 1, 2, 3, 4, or 5. m is 0, 1, 2, 3, or 4. p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. However, the compound of formula I is

[0143] [ka] This assumes that this is not the case.

[0144] 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-.

[0145] In some embodiments, Y is independently N and CR 11 Selected from. In some embodiments, Y is N. In some embodiments, Y is CR. 11 In some embodiments, one Y is N and the other Y is CR. 11 That is the case.

[0146] In some embodiments, R 1 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 1 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 1 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 1 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 Selected from.

[0147] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2 and R 3 These combine to form an oxo. In some embodiments, R 2 and R 3 They combine to form thio.

[0148] In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8-C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 , -NR10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 Selected from.

[0149] In some embodiments, R 5 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 5 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8, -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 5 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 5 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 Selected from.

[0150] In some embodiments, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 6 and R7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 6 and R 7 These are H and C, each appearing independently. 1-6 Selected from alkyl groups.

[0151] In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0152] In some embodiments, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C3-10 Selected from cycloalkyl. In some embodiments, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 9 Each of them is independent of C 1-6 Selected from alkyl groups.

[0153] In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0154] In some embodiments, R 11 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 11 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 11 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 11 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 Selected from.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] In some embodiments, the compound is of formula Ia

[0159] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0160] In one embodiment, the compound is of formula Ib

[0161] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the 15-PGDH inhibitor is of formula II

[0163] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, T, U, W, X, and Y are independent of N and CR. 5 Selected from, S, V, and Z are independently selected from N and C. R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl are halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5-10 membered heteroaryl groups, R 2 H is R 3 -CF 3 And, or R 2 and R 3They combine to form an oxo or thio, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R's 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8, -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 5 These are H, Hal, and -NR, respectively, and are independent of each other. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 10 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. However, the compound of formula II is

[0164] [ka]

[0165] [ka]

[0166] [ka] This assumes that this is not the case.

[0167] In some embodiments, T, U, W, X, and Y are independently N and CR. 5 Selected from: In some embodiments, at least one of T, U, W, X, and Y is N, and the rest are CR 5 In some embodiments, at least two of T, U, W, X, and Y are N, and the rest are CR. 5 In some embodiments, at least three of T, U, W, X, and Y are N, and the rest are CR. 5In some embodiments, at least four of T, U, W, X, and Y are N, and the rest are CR. 5 In some embodiments, T, U, W, X, and Y are CR 5 In some embodiments, T, U, W, X, and Y are N.

[0168] 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.

[0169] In some embodiments, R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl are halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C3-10 It is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alkyl, aryl, or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 It is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 It is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 It is optionally substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7It is optionally replaced by 1 to 3 substituents that are independently selected from the original molecule.

[0170] In some embodiments, R 2 H is R 3 -CF 3 In some embodiments, R 2 and R 3 These combine to form an oxo. In some embodiments, R 2 and R 3 They combine to form thio.

[0171] In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from. In some embodiments, R 4 Each of these is a halo. In some embodiments, R 4 These are all fluoro.

[0172] In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R4 These are independently selected from the halo. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is fluoro.

[0173] In some embodiments, R 5 These are H, Hal, and -NR, respectively, and are independent of each other. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 5 These are H, Hal, and -NR, respectively, and are independent of each other. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8, -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 5 These are H, Hal, and -NR, respectively, and are independent of each other. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 5 These are H, Hal, and -NR, respectively, and are independent of each other. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from. In some embodiments, R 5 These are independently selected from H and Halo.

[0174] In some embodiments, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 6 and R 7 These are H and C, independently, each time they appear. 1-6 Selected from alkyl groups.

[0175] In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0176] In some embodiments, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 9 Each of them is independent of C1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 9 Each of them is independent of C 1-6 Selected from alkyl groups.

[0177] In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0178] In some embodiments, n is 0, 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.

[0179] 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.

[0180] In some embodiments, the compound is of formula IIa

[0181] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, or 2.

[0182] 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.

[0183] In some embodiments, the compound is formula IIb

[0184] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, or 2.

[0185] 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.

[0186] In some embodiments, the compound is of formula IIc

[0187] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, 4, or 5.

[0188] 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.

[0189] In some embodiments, the compound is formula IId

[0190] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0191] 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.

[0192] In some embodiments, the compound is of formula IIe

[0193] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0194] 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.

[0195] In some embodiments, the compound is of formula IIf

[0196] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, or 3.

[0197] 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.

[0198] In some embodiments, the compound is formula IIg

[0199] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0200] 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.

[0201] In some embodiments, the compound is of formula IIh

[0202] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, or 3.

[0203] 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.

[0204] In some embodiments, the compound is formula IIi

[0205] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0206] 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.

[0207] In some embodiments, the compound is of formula IIj

[0208] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, or 3.

[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 compound is of formula IIn

[0211] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, or 3.

[0212] 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.

[0213] In some embodiments, the compound is of formula IIp

[0214] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0215] 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.

[0216] In some embodiments, the 15-PGDH inhibitor is of formula III

[0217] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, X is independent of N and CR. 7 Selected from, Y is O, S, SO2, and C(R 8 ) Selected from 2, R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl are halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Optionally substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls, R 2 H is R 3 -CF 3 And, or R 2 and R 3 They combine to form an oxo or thio, R 4 and R 5 Independently, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyls, alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 They are optionally substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls, or R 4 and R5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Forming 3-10 member heterocycloalkyls by optionally substituting with 1-3 substituents independently selected from aryls and 5-10 member heteroaryls, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R atoms bonded to the same carbon atom 6 These are combined as oxo, thio, or C 3-10 Form a cycloalkyl group, and all remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 7 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 8 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R's 8 They are united as Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 C is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. 3-10 Forming a cycloalkyl group, R 9 and R 10 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, R 11 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 12 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 13 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6Haloalkyl and C 3-10 Selected from cycloalkyl groups, m is either 1 or 2. n is 0, 1, 2, 3, or 4.

[0218] In some embodiments, X is independently N and CR 7 Selected from. In some embodiments, at least one X is N and the rest are CR 7 In some embodiments, at least two X's are N, and the rest are CR. 7 In some embodiments, X is N. In some embodiments, X is CR. 7 That is the case.

[0219] In some embodiments, Y is O, S, SO2, and C(R 8 )2 is selected. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R 8 )2.

[0220] In some embodiments, R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl are halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 It is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 1 C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, cycloalkyls, aryls, or heteroaryls are halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 It is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 9 R 10 , -OR11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 It is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6It is optionally substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 It is optionally substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 It is optionally replaced by 1 to 3 substituents that are independently selected from the original molecule.

[0221] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2 and R 3 These combine to form an oxo. In some embodiments, R 2 and R 3 They combine to form thio.

[0222] In some embodiments, R 4 and R 5 Independently, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyls, alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 It is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 4 and R 5 Independently, C 3-10 Selected from cycloalkyls, each cycloalkyl is independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 It is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 4 and R 5 Independently, C 3-10 Selected from cycloalkyls, each cycloalkyl is independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is optionally substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 4 and R 5 Independently, C 3-10 Selected from cycloalkyls, each cycloalkyl is independently halo, -NR9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 It is optionally substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 4 and R 5 Independently, C 3-10 Selected from cycloalkyls, each cycloalkyl is independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 It is optionally replaced by 1 to 3 substituents that are independently selected from the original molecule.

[0223] In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 A 3- to 10-membered heterocycloalkyl is formed by optionally substituting with 1 to 3 substituents independently selected from aryl and 5- to 10-membered heteroaryls. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 A 3-10 member heterocycloalkyl group is formed by optionally substituting 1-3 substituents independently selected from the haloalkyl group. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 A 3- to 10-membered heterocycloalkyl group is formed by optionally substituting with 1 to 3 substituents independently selected from the group. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 They form 3-10 member heterocycloalkyl groups, optionally substituted with 1-3 substituents independently selected from the original group.

[0224] In some embodiments, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R10 Selected from. In some embodiments, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0225] In some embodiments, two R atoms bonded to the same carbon atom 6 These are combined as oxo, thio, or C 3-10 Form a cycloalkyl group, and all remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls. In some embodiments, two Rs bonded to the same carbon atom. 6 These are combined as oxo, thio, or C 3-10 Form a cycloalkyl group, and all remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, two R atoms bonded to the same carbon atom. 6 These are combined as oxo, thio, or C 3-10 Form a cycloalkyl group, and all remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, two R atoms bonded to the same carbon atom 6 These are combined as oxo, thio, or C 3-10 Form a cycloalkyl group, and all remaining R 6 It is independently, Halo, -NR9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0226] In some embodiments, R 7 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 7 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 7 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, R 7 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0227] In some embodiments, R 8 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12, -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 8 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 8 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, R 8 These are H, Hal, and -NR, respectively, and are independent of each other. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0228] In some embodiments, two R 8 They are united as Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10C is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. 3-10 Forms a cycloalkyl group. In some embodiments, two R 8 They are united as Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 C is optionally substituted with 1 to 3 substituents independently selected from the haloalkyl group. 3-10 Forms a cycloalkyl group. In some embodiments, two R 8 They are united as Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R10 C is optionally substituted with 1 to 3 substituents independently selected from the original C 3-10 Forms a cycloalkyl group. In some embodiments, two R 8 They are united as Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 C is optionally substituted with 1 to 3 substituents independently selected from the original C 3-10 It forms a cycloalkyl group.

[0229] In some embodiments, R 9 and R 10 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 9 and R 10 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 9 and R 10 These are H and C, independently, each time they appear. 1-6 Selected from alkyl groups.

[0230] In some embodiments, R 11 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 11 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6Selected from haloalkyls. In some embodiments, R 11 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0231] In some embodiments, R 12 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 12 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 12 Each of them is independent of C 1-6 Selected from alkyl groups.

[0232] In some embodiments, R 13 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 13 These are H and C, respectively, independently. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 13 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0233] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0234] 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.

[0235] In some embodiments, the compound is of formula IIIa

[0236] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, the compound is of formula IIIb

[0238] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, R 14 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, p is 0, 1, 2, or 3.

[0239] In some embodiments, R 14 These are, independently, Halo and -NR.9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 14 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 14 These are, independently, Halo and -NR.9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, R 14 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from. In some embodiments, R 14 Each of these is an independent halo. In some embodiments, R 14 Each of these is independently fluoro.

[0240] 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.

[0241] In some embodiments, the compound is of formula IIIc

[0242] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, the compound is formula IIId

[0244] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, R 14 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, p is 0, 1, 2, or 3.

[0245] In some embodiments, R 14 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 14 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 14 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, R 14 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from. In some embodiments, R 14 Each of these is an independent halo. In some embodiments, R 14 Each of these is independently fluoro.

[0246] 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.

[0247] In some embodiments, the 15-PGDH inhibitor is of formula IIk

[0248] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, T, U, and Y are independent of N and CR. 6 Selected from, provided that when U is N, at least one of T and Y is N, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5-10 membered heteroaryl groups, R 2 H is R 3 -CF 3 And, or R 2 and R 3 They combine to form an oxo, R 4 These are independently selected from H and Halo, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 7 and R 8 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, R 9 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 10 Each of them is independent of C1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 11 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, p is 0, 1, or 2.

[0249] In some embodiments, T, U, and Y are independently N and CR. 6 Selected from, 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 CR 6 In some embodiments, two of T, U, and Y are N, and the rest are CR. 6 In some embodiments, one of T, U, and Y is CR. 6 And the rest is N. In some embodiments, two of T, U, and Y are CR 6 And the rest is N. In some embodiments, T, U, and Y are N. In some embodiments, T, U, and Y are CR 6 That is the case.

[0250] In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 It is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is optionally substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9-C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , and -NR 11 SO2NR 7 R 8 It is optionally substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , and -C(O)NR 7 R 8 It is optionally replaced by 1 to 3 substituents that are independently selected from the original molecule.

[0251] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2 and R 3 These combine to form an oxo.

[0252] In some embodiments, R 4 These are independently selected from H and halo. In some embodiments, R 4 Each is independently selected from H and fluoro. In some embodiments, R 4 These are H, respectively. In some embodiments, R 4 Each of these is fluoro. In some embodiments, one R 4 H is one R 4 It is fluoro.

[0253] In some embodiments, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6Selected from haloalkyls. In some embodiments, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , and -NR 11 SO2NR 7 R 8 Selected from. In some embodiments, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , and -C(O)NR 7 R 8 Selected from.

[0254] In some embodiments, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , and -NR 11 SO2NR7 R 8 Selected from. In some embodiments, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , and -C(O)NR 7 R 8 Selected from.

[0255] In some embodiments, R 7 and R 8 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl. In some embodiments, R 7 and R 8 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 7 and R 8 These are H and C, independently, each time they appear. 1-6 Selected from alkyl groups.

[0256] In some embodiments, R 9 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 9 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 9 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0257] In some embodiments, R 10 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 10 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 10 Each of them is independent of C 1-6 Selected from alkyl groups.

[0258] In some embodiments, R 11 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl. In some embodiments, R 11 These are H and C, respectively, independently. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 11 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0259] 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.

[0260] In some embodiments, the 15-PGDH inhibitor is of formula IIm

[0261] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, R 1 C 6-10Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5-10 membered heteroaryl groups, R 2 H is R 3 -CF 3 And, or R 2 and R 3 They combine to form an oxo, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R's 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 10 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. p is 0, 1, 2, or 3.

[0262] In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 It is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is optionally substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 It is optionally substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 It is optionally replaced by 1 to 3 substituents that are independently selected from the original molecule.

[0263] In some embodiments, R2 H is R 3 is -CF3. In some embodiments, R 2 and R 3 These combine to form an oxo.

[0264] In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from. In some embodiments, R 4 Each is independently selected from the halos. In some embodiments, R 4 These are all fluoro.

[0265] In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8, -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6Selected from haloalkyls. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from.

[0266] In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from.

[0267] In some embodiments, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Selected from haloalkyls. In some embodiments, R 6 and R 7 These are H and C, independently, each time they appear. 1-6 Selected from alkyl groups.

[0268] In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 8 These are H and C, respectively, independently.1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0269] In some embodiments, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Selected from haloalkyls. In some embodiments, R 9 Each of them is independent of C 1-6 Selected from alkyl groups.

[0270] In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0271] In some embodiments, n is 0, 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.

[0272] 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.

[0273] 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.

[0274] In some embodiments, the 15-PGDH inhibitor is a compound of formula IIq.

[0275] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5-10 membered heteroaryl groups, R 2 H is R 3 -CF 3 And, or R 2 and R 3 They combine to form an oxo, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R's 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8-C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 Each instance of these appears independently, with H and C.1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 10 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. p is 0, 1, 2, or 3.

[0276] In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 It is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is optionally substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 It is optionally substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 It is optionally replaced by 1 to 3 substituents that are independently selected from the original molecule.

[0277] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2 and R 3 These combine to form an oxo.

[0278] In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 4 These are, independently, Halo and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from. In some embodiments, R 4 Each is independently selected from the halos. In some embodiments, R 4 These are all fluoro.

[0279] In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10Selected from aryls and 5-10 member heteroaryls. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, two R 4 They bond together with the carbon atoms and any intervening atoms, forming a single unit with C 3-10 Form a cycloalkyl group, and all remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from.

[0280] In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from.

[0281] In some embodiments, R 6 and R 7Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 6 and R 7 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Selected from haloalkyls. In some embodiments, R 6 and R 7 These are H and C, independently, each time they appear. 1-6 Selected from alkyl groups.

[0282] In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 8 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0283] In some embodiments, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 9 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6Selected from haloalkyls. In some embodiments, R 9 Each of them is independent of C 1-6 Selected from alkyl groups.

[0284] In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 10 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0285] In some embodiments, n is 0, 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.

[0286] 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.

[0287] 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.

[0288] In some embodiments, the 15-PGDH inhibitor is of formula IIIc

[0289] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, X is independent of N and CR. 7 Selected from, Y is O, S, SO2, and C(R 8 ) Selected from 2, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5-10 membered heteroaryl groups, R 2 H is R 3 -CF 3 And, or R 2 and R 3 They combine to form an oxo, R 4 and R 5 Independently, C 1-6 Alkyl, C 1-6Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyls, alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 They are optionally substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls, or R 4 and R 5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Forming 3-10 member heterocycloalkyls by optionally substituting with 1-3 substituents independently selected from aryls and 5-10 member heteroaryls, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R atoms bonded to the same carbon atom 6 They combine to form an oxo, and all the remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10-SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 7 and R 8 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 9 and R 10Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, R 11 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 12 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 13 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, n is 0, 1, 2, 3, or 4.

[0290] In some embodiments, X is independently N and CR 7 Selected from. In some embodiments, at least one X is N and the rest are CR 7 In some embodiments, at least two X's are N, and the rest are CR. 7 In some embodiments, X is N. In some embodiments, X is CR. 7 That is the case.

[0291] In some embodiments, Y is O, S, SO2, and C(R 8 )2 is selected. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R 8 )2.

[0292] In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 It is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is optionally substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 It is optionally substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the aryl or heteroaryl is halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 It is optionally replaced by 1 to 3 substituents that are independently selected from the original molecule.

[0293] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2and R 3 These combine to form an oxo.

[0294] In some embodiments, R 4 and R 5 Independently, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyls, alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 It is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 4 and R 5 Independently, C 3-10 Selected from cycloalkyls, each cycloalkyl is independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10-SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 It is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 4 and R 5 Independently, C 3-10 Selected from cycloalkyls, each cycloalkyl is independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is optionally substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 4 and R 5Independently, C 3-10 Selected from cycloalkyls, each cycloalkyl is independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 It is optionally substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 4 and R 5 Independently, C 3-10 Selected from cycloalkyls, each cycloalkyl is independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 It is optionally replaced by 1 to 3 substituents that are independently selected from the original molecule.

[0295] In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10, -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 A 3- to 10-membered heterocycloalkyl is formed by optionally substituting with 1 to 3 substituents independently selected from aryl and 5- to 10-membered heteroaryls. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 A 3-10 member heterocycloalkyl group is formed by optionally substituting 1-3 substituents independently selected from the haloalkyl group. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 A 3- to 10-membered heterocycloalkyl group is formed by optionally substituting with 1 to 3 substituents independently selected from the group. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they bond, form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 They form 3-10 member heterocycloalkyl groups, optionally substituted with 1-3 substituents independently selected from the original group.

[0296] In some embodiments, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, R 6 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0297] In some embodiments, two R atoms bonded to the same carbon atom 6 They combine to form an oxo, and all the remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls. In some embodiments, two Rs bonded to the same carbon atom. 6 They combine to form an oxo, and all the remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, two R atoms bonded to the same carbon atom. 6 They combine to form an oxo, and all the remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, two R atoms bonded to the same carbon atom 6 They combine to form an oxo, and all the remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR 11 , -C(O)R11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0298] In some embodiments, R 7 and R 8 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 7 and R 8 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 7 and R 8 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, R 7 and R 8 These are, independently, Halo and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0299] In some embodiments, R 9 and R 10 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 9 and R10 Each instance of these appears independently, with H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 9 and R 10 These are H and C, independently, each time they appear. 1-6 Selected from alkyl groups.

[0300] In some embodiments, R 11 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 11 These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 11 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0301] In some embodiments, R 12 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 12 Each of them is independent of C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 12 Each of them is independent of C 1-6 Selected from alkyl groups.

[0302] In some embodiments, R 13These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 13 These are H and C, respectively, independently. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 13 These are H and C, respectively, independently. 1-6 Selected from alkyl groups.

[0303] 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.

[0304] In some embodiments, the 15-PGDH inhibitor is

[0305] [ka] It is a compound selected from the group consisting of the following.

[0306] In some embodiments, the 15-PGDH inhibitor is

[0307] [ka]

[0308] [ka]

[0309] [ka]

[0310] [ka]

[0311]

Chem.

[0312]

Chem.

[0313]

Chem.

[0314]

Chem.

[0315]

Chem.

[0316]

Chem.

[0317]

Chem.

[0318] In some embodiments, the 15-PGDH inhibitor is

[0319]

Chem.

[0320] Optionally, the inhibitor solubility and hPGDH IC 50 are characterized as shown in Tables 1 and 2.

[0321] [Table 1-1]

[0322] [Table 1-2]

[0323] [Table 1-3]

[0324] [Table 1-4]

[0325] [Table 1-5]

[0326] [Table 1-6]

[0327] [Table 1-7]

[0328] [Table 2-1]

[0329] [Table 2-2]

[0330] Table 3 shows analytical data for some of the inhibitors described in the present specification.

[0331] [Table 3-1]

[0332] Table 3-2

[0333] Table 3-3

[0334] Table 3-4

[0335] Table 3-5

[0336] Table 3-6

[0337] Table 3-7

[0338] Table 3-8

[0339] Table 3-9

[0340] Table 3-10

[0341] Table 3-11

[0342] Table 3-12

[0343] Table 3-13

[0344] Table 3-14

[0345] Table 3-15

[0346] Table 3-16

[0347] Table 3-17

[0348] Table 3-18

[0349] Table 3-19

[0350] Table 3-20

[0351] Table 3-21

[0352] Table 3-22

[0353] Table 3-23

[0354] Table 3-24

[0355] Table 3-25

[0356] Table 3-26

[0357] Table 3-27

[0358] Table 3-28

[0359] Table 3-29

[0360] Table 3-30

[0361] Table 3-31

[0362] Table 3-32

[0363] Table 3-33

[0364] Table 3-34

[0365] Table 3-35

[0366] Table 3-36

[0367] Table 3-37

[0368] Table 3-38

[0369] Table 3-39

[0370] Table 3-40

[0371] Table 3-41

[0372] Table 3-42

[0373] Table 3-43

[0374] Table 3-44

[0375] Table 3-45

[0376] Table 3-46

[0377] Table 3-47

[0378] Table 3-48

[0379] Table 3-49

[0380] Table 3-50

[0381] Table 3-51

[0382] Table 3-52

[0383] [Table 3-53]

[0384] In some embodiments, the 15-PGDH inhibitor is of formula IV

[0385] [ka] A compound having the structure or a pharmaceutically acceptable salt thereof, wherein, Ring Q is a phenyl or 5-10 membered heteroaryl. Z is CR 1 or N, Y is CR 2 or N, R 1 H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, R 2 These are H, halogen, and -OR, respectively, independently. 10 , -C(O)R 10 , -C(O)OR 10 -CN, -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, R 3 These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 , -SR8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups, each of which has one or more R groups. 13 Replaced by, R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C2-C8 alkenyl groups, substituted or unsubstituted C1-C8 aminoalkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups, each of which contains one or more R groups. 6 Replaced by, R 6These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-8 member heteroaryl, Or two R's 6 These atoms, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl groups. X A -NR 5 R 5 OR 5 And, R 5 Each of these is independently H or C1-C6 alkyl, R 5a is H or CH3, Or R 5a and one R 6 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl groups. R 8 and R 9 These are, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10Cycloalkyl and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R 10 These are, independently, 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, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 11 These are, independently, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 12 These are, independently, 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-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R aEach of these is independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3. p is 1, 2, 3, or 4.

[0386] In some embodiments, the 15-PGDH inhibitor is of formula IV

[0387] [ka] A compound having the structure or a pharmaceutically acceptable salt thereof, wherein, Ring Q is a phenyl or 5-10 membered heteroaryl. Z is CR 1 or N, Y is CR 2 or N, R 1 H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, R 2 H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 -CN, -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , or substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, R 3These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups. R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C2-C8 alkenyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups, each of which contains one or more R groups. 6 Replaced by, R 6 These are H, halogen, CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 -OH, -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR8 C(O)R 9 These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, phenyl, or 5-8 member heteroaryl compounds. Or two R's 6 These atoms, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl ring. X A , NR 5 R 5 OR 5 And, R 5 Each of these is independently H or C1-C6 alkyl, R 5a is H or CH3, Or R 5a and one R 6 These atoms, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl ring. R 8 and R 9 These are, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, and C4-C 10 Selected from heterocycloalkyl groups, R 10 These are, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from aryls and 5-10 member heteroaryls, R 11 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from aryls and 5-10 member heteroaryls, R 12 Each of these is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl. p is 1, 2, 3, or 4.

[0388] In some embodiments, ring Q is a 5- to 10-membered heteroaryl compound containing one, two, three, or four heteroatoms selected from N, O, and S. In some embodiments, ring Q is a 5- to 8-membered heteroaryl compound containing one, two, three, or four heteroatoms selected from N, O, and S. In some embodiments, ring Q is a 5- to 8-membered heteroaryl compound containing one, two, three, or four heteroatoms selected from N and O. In some embodiments, ring Q is a monocyclic, bicyclic, or polycyclic heteroaryl compound. In some embodiments, ring Q is a bicyclic heteroaryl compound containing one, two, three, or four heteroatoms selected from N and O. In some embodiments, ring Q is indole, benzimidazole, benzotriazole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyridine, or tetrazolopyridine. In some embodiments, ring Q is [1,2,4]triazolo[1,5-a]pyridine.

[0389] In some embodiments, ring Q is a six-membered monocyclic heteroaryl containing one, two, or three nitrogen atoms. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is 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.

[0390] In some embodiments, ring Q is phenyl, pyridine, or triazolopyridine.

[0391] In some embodiments,

[0392] [ka] teeth,

[0393] [ka] And in the formula, X 1 , X 2 , X 3 , and X 4 These are, independently, N or CR 3 And, R 3 These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups, each of which has one or more R groups. 13 Replaced by, R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, R 8 and R 9 These are, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R 10 These are, independently, 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, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 11 These are, independently, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 12 These are, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R a Each of these is independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0394] In some embodiments, X 1 , X 2 , X 3 , and X 4 These are CR 3 That is the case.

[0395] In some embodiments, X 1 is N, and X 2 , X 3 , and X 4 These are CR 3 That is the case.

[0396] In some embodiments, X 1 and X 2 These are N and X 3 and X 4 These are CR 3 That is the case.

[0397] In some embodiments, X 1 and X 3 These are N and X 2 and X 4 These are CR 3 That is the case.

[0398] In some embodiments, X 1 and X 4 These are N and X 2 and X 3 These are CR 3 That is the case.

[0399] In some embodiments, X 1 , X 2 , and X 3 These are N and X 4 CR 3 That is the case.

[0400] In some embodiments, X 1 , X 2 , and X 4 These are N and X 3 CR 3 That is the case.

[0401] In some embodiments, R 3 These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl. In some embodiments, R 3 These are H, halogen, and -C(O)R, respectively, independently. 10 , -C(O)OR 10 -C(O)NR 8 R 9, -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3 These are H, halogen, and -C(O)R, respectively, independently. 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3 Each of these is independently selected from H, halogens, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 6-membered heteroaryls.

[0402] In some embodiments, R 3 Each is independently selected from H and halogens. In some embodiments, R 3 These are, independently, a substituted or unsubstituted phenyl and a substituted or unsubstituted 5-6 member heteroaryl. In some embodiments, R 3 Each of these is independently a substituted or unsubstituted five-membered heteroaryl.

[0403] In some embodiments, the 15-PGDH inhibitor is of formula V

[0404] [ka] A compound having the structure or a pharmaceutically acceptable salt thereof, wherein, Z is CR 1 or N, X 1 is N or CR 3a And, Y is CR 2 or N, R 1 H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, R 2 These are H, halogen, and -OR, respectively, independently. 10 , -C(O)R 10 , -C(O)OR 10 -CN, -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, R 3a , R 3b , and R 3c These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups, each of which has one or more R groups. 13 Replaced by, R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C2-C8 alkenyl groups, substituted or unsubstituted C1-C8 aminoalkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups, each of which contains one or more R groups. 6 Replaced by, R 6 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 8 C(O)R 9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-8 member heteroaryl, Or two R's 6 These atoms, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl groups. X A , NR 5 R 5 OR 5 And, R 5 Each of these is independently H or C1-C6 alkyl, R 5a is H or CH3, Or R 5a and one R 6 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C6 cycloalkyl groups. R 8 and R 9 These are, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R 10 These are, independently, 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, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 11 These are, independently, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 12 These are, independently, 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-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R a Each of these is independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0405] In some embodiments, the 15-PGDH inhibitor is of formula V

[0406] [ka] A compound having the structure or a pharmaceutically acceptable salt thereof, wherein, Z is CR 1or N, X 1 is N or CR 3a And, Y is CR 2 or N, R 1 H is, R 2 Each of these is independently H or C1-C6 alkyl, R 3a , R 3b , and R 3c These are H, halogen, and -OR, respectively, independently. 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups, each of which has one or more R 13 Replaced by, R 13 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups, each of which contains one or more R groups. 6 Replaced by, R6 These are, independently, halogen, CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, Or two R's 6 These atoms, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl groups. X A is, -OR 5 And, R 5 Each of these is independently H or C1-C6 alkyl, R 5a is H or CH3, Or R 5a and one R 6 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C6 cycloalkyl groups. R 8 and R 9 These are, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R 10 These are, independently, 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, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 11 These are, independently, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, R 12 These are, independently, 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-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a Replaced by, R a Each of these is independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0407] In some embodiments, X A , NR 5 R 5 In some embodiments, X A is OR 5 That is the case.

[0408] In some embodiments, Y is N. In some embodiments, Y is CR 2 That is the case.

[0409] In some embodiments, the compound of formula V is of formula VIa

[0410] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0411] In some embodiments, the compound of formula V is of formula VIb

[0412] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0413] In some embodiments, Z is N. In some embodiments, Z is CR. 1 In some embodiments, Z is CH.

[0414] In some embodiments, the compound of formula V is of formula VIIa

[0415] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0416] In some embodiments, the compound of formula V is of formula VIIb

[0417] [ka] has a structure, or a pharmaceutically acceptable salt thereof.

[0418] In some embodiments, the compound of formula V is formula VIIc

[0419]

Chemical Formula

[0420] In some embodiments, the compound of formula V is formula VIId

[0421]

Chemical Formula

[0422] In some embodiments, R 1 is H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 , or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 1 is H.

[0423] In some embodiments, R 2 are each independently H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 , or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 2 are each independently H or C1-C6 alkyl.

[0424] In some embodiments, R 2 are each H.

[0425] In some embodiments, X 1 is CR 3a . In some embodiments, X 1 is N.

[0426] In some embodiments, R 3a , R 3b , and R 3c These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 -S8, -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl. In some embodiments, R 3a , R 3b , and R 3c These are H, halogen, and -C(O)R, respectively, independently. 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a , R 3b , and R 3cThese are H, halogen, and -C(O)R, respectively, independently. 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3a , R 3b , and R 3c These are H, halogen, and -C(O)R, respectively, independently. 10 -C(O)NR 8 R 9 , and selected from substituted or unsubstituted 5-membered heteroaryls. In some embodiments, R 3a , R 3b , and R 3c These are H, halogen, and -OR, respectively, independently. 10 -S8, -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 12 C(O)R 10 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 3a , R 3b , and R 3c These are, independently, H, halogen, substituted or unsubstituted C1-C6 alkyl, and -C(O)R. 10 -C(O)NR 8 R 9 Selected from C3-C6 heterocycloalkyls and 5-membered heteroaryls.

[0427] In some embodiments, R 3a , R 3b , and R 3cEach of these is independently selected from H, halogen, -C(O)OH, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, triazole, tetrazole, pyrrolidine, morpholine, or C1-C6 alkyl substituted with -C(O)OH.

[0428] In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl. In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c is halogen, -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR10 , -NR 12 C(O)NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c is halogen, -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c These are substituted or unsubstituted C1-C6 alkyl groups, -C(O)R 10 -C(O)NR 8 R 9 Selected from C3-C6 heterocycloalkyls and 5-membered heteroaryls. In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c It is a substituted or unsubstituted five-membered heteroaryl compound.

[0429] In some embodiments, R 3a is a halogen, and R 3b is H. In some embodiments, R 3a is -Cl or -F, and R3b is H. In some embodiments, R 3b is a halogen, and R 3a is H. In some embodiments, R 3b is -Cl or -F, and R 3a H is H.

[0430] In some embodiments, R 3a and R 3b These are H, respectively.

[0431] In some embodiments, R 3a and R 3c R is independently H or halogen, 3b These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl. In some embodiments, R 3a and R 3c These are H and R respectively. 3b is halogen, -C(O)R 10 , -C(O)OR 10 -C(O)NR8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3c These are H and R respectively. 3b is halogen, -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3a and R 3c These are H and R respectively. 3b is -C(O)R 10 , -C(O)OR 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3a and R 3c These are H or halogen, respectively, and R 3b These are substituted or unsubstituted C1-C6 alkyl groups, -C(O)R 10 -C(O)NR 8 R 9 Selected from C3-C6 heterocycloalkyls and 5-membered heteroaryls.

[0432] In some embodiments, R 3a and R 3c These are H or halogen, respectively, and R 3b is -C(O)R 10, -C(O)OR 10 , and selected from substituted or unsubstituted 5-membered heteroaryls.

[0433] In some embodiments, R 3a is a halogen, and R 3c is H. In some embodiments, R 3a H is R 3b is a halogen. In some embodiments, R 3a is -Cl or -F, and R 3c is H. In some embodiments, R 3c is -Cl or -F, and R 3a H is H.

[0434] In some embodiments, R 3a and R 3c These are H, respectively.

[0435] In some embodiments, R 3 , R 3a , R 3b , and R 3c Each of these is independently a five-membered heteroaryl selected from pyrrole, triazole, tetrazole, oxazole, diazole, oxadiazole, thiadiazole, and furanil. In some embodiments, R 3 , R 3a , R 3b , and R 3c Each is independently a five-membered heteroaryl selected from pyrrole, triazole, and tetrazole. In some embodiments, R 3 , R 3a , R 3b , and R 3c These are, independently, five-membered heteroaryl compounds selected from triazoles and tetrazoles.

[0436] In some embodiments, R 3 , R 3a , R 3b , and R 3c Each of them operates independently.

[0437] [ka] It is selected from the group consisting of the following.

[0438] In some embodiments, R 3 , R 3a , R 3b , and R 3c Each of them operates independently.

[0439] [ka] Selected from the group consisting of R 3 , R 3a , R 3b , and R 3c Each of them operates independently.

[0440] [ka] Selected from the group consisting of R 3 , R 3a , R 3b , and R 3c Each of them operates independently.

[0441] [ka] It is selected from the group consisting of the following.

[0442] In some embodiments, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C2-C8 alkenyl groups, substituted or unsubstituted C1-C8 aminoalkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups, each of which contains one or more R groups. 6 It is replaced by R. In some embodiments, 4is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or a substituted or unsubstituted C1-C8 hydroxyalkyl. In some embodiments, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, or substituted or unsubstituted C1-C8 hydroxyalkyl groups.

[0443] In some embodiments, R 4 is a substituted or unsubstituted C1-C8 alkyl or a substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments, R 4 is a substituted or unsubstituted C1-C8 alkyl group. In some embodiments, the alkyl group is a linear or branched alkyl group. In some embodiments, R 4 is a substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments, the heteroalkyl is an alkyl chain in which one or more carbon atoms are substituted with O atoms or N atoms. In some embodiments, R 4 is a substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), substituted or unsubstituted -CH2CH2-O-(C1-C4 haloalkyl), -CH2-O-(C1-C4 haloalkyl), -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2-O-(C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R 4 R is a substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), substituted or unsubstituted -CH2CH2-O-(C1-C4 haloalkyl), or -CH2-O-(C1-C4 haloalkyl). In some embodiments, R 4is -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2-O-(C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R 4 is -CH2CH2-O-(C3-C6 cycloalkyl). In some embodiments, R 4 is -CH2-O-(C3-C6 cycloalkyl). In some embodiments, R 4 is -CH2CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R 4 It is -CH2-O-(C3-C6 heterocycloalkyl).

[0444] In some embodiments, R 4 is one or more halogens, -OR 10 It is a substituted or unsubstituted C1-C8 alkyl group, which is either substituted with a C1-C8 alkyl group or a C3-C6 cycloalkyl group.

[0445] In some embodiments, R 4 These are substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which contains one or more R 6 It is replaced by R. In some embodiments, 4 is a C3-C8 cycloalkyl group. In some embodiments, R 4 R is a monocyclic, polycyclic, spirocyclic, or crosslinked cycloalkyl group. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R 4 is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is cyclobutyl. In some embodiments, R 4 is cyclopentyl. In some embodiments, R 4is cyclohexyl. In some embodiments, R 4 teeth,

[0446] [ka] That is the case.

[0447] In some embodiments, R 4 These are substituted or unsubstituted C3-C8 heterocycloalkyl groups, each containing one or more R 6 It is replaced by R. In some embodiments, 4 R is a monocyclic, polycyclic, spirocyclic, or cross-linked heterocycloalkyl. In some embodiments, R 4 is a 4-membered heterocycloalkyl. In some embodiments, R 4 is a 5-membered heterocycloalkyl. In some embodiments, R 4 is a 6-membered cycloalkyl group. In some embodiments, R 4 is a 7-membered cycloalkyl group. In some embodiments, R 4 is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine. In some embodiments, R 4 It is tetrahydrofuran or tetrahydropyran.

[0448] In some embodiments, R 6 These are, independently, halogen, -CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 8 C(O)R 9, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or 5-8 member heteroaryl. In some embodiments, R 6 These are, independently, halogen and -NR. 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C8 cycloalkyl. In some embodiments, R 6 These are, independently, halogen and -NR. 8 R 9 , -OR 10 , -C(O)OR 10 -C(O)NR 8 R 9 , C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, R 6 These are, independently, halogen and -NR. 8 R 9 , -OR 10 , or C3-C8 cycloalkyl. In some embodiments, R 6 These are, independently, -NR 8 R 9 OR 10 In some embodiments, R 6 Each is independently a C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, spirocyclic, or crosslinked cycloalkyl. In some embodiments, R 6 These are, independently, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 6 These are each halogens independently. In some embodiments, R 6 These are, independently, H, Cl, F, or Br. In some embodiments, R 6Each of these is independently F. In some embodiments, R 6 These are, 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, R 6 These are, independently, F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 6 These are, independently, F, -OH, -CH3, or -CF3. In some embodiments, R 6 Each of these is independently F. In some embodiments, R 6 Each of these is independently -OH. In some embodiments, R 6 Each of these is independently -CF3. In some embodiments, R 6 These are, independently, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 6 Each is independently cyclopropyl. In some embodiments, R 6 These are cyclobutyl compounds, respectively.

[0449] In some embodiments, two R 6 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl. In some embodiments, two R 6 These, together with the atoms to which they bond, form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R 6 These, together with the atoms to which they bond, form cyclopropyl or cyclobutyl. In some embodiments, two R 6 These, together with the atom to which they bond, form a cyclopropyl group. In some embodiments, two R 6These, together with the atoms to which they bond, form cyclobutyl. In some embodiments, two R 6 These, together with the atom to which they bond, form a cyclopropyl group. In some embodiments, two R 6 These, together with the atom to which they bond, form a cyclohexyl. In some embodiments, two R 6 These, together with the atoms to which they bond, form a C3-C6 heterocycloalkyl group. In some embodiments, two R 6 These, together with the atom to which they bond, form a four-membered heterocycloalkyl group. In some embodiments, two R 6 These, together with the atoms to which they bond, form a five-membered heterocycloalkyl group. In some embodiments, two R 6 These, together with the atoms to which they bond, form a six-membered heterocycloalkyl group. In some embodiments, two R 6 These atoms, together with the atoms they bond to, form pyran, piperazine, piperidine, or morpholine.

[0450] In some embodiments, R 4 -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, substituted or unsubstituted oxetane, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted tetrahydropyran,

[0451] [ka] That is the case.

[0452] In some embodiments, R 5 Each of these is independently a C1-C6 alkyl group. In some embodiments, R 5These are independently -CH2CH3 or -CH3. In some embodiments, R 5 Each of these is independently -CH2CH3. In some embodiments, R 5 Each of these is independently -CH3. In some embodiments, R 5 Each of these is independently H.

[0453] In some embodiments, R 5a This is CH3. In some embodiments, R 5a H is H.

[0454] In some embodiments, R 5a and one R 6 These, together with the atoms to which they bond, form a C3-C6 cycloalkyl group. In some embodiments, R 5a and one R 6 These, together with the atoms to which they bond, form cyclopentyl or cyclohexyl. In some embodiments, R 5a and one R 6 These, together with the atoms to which they bond, form a cyclohexyl. In some embodiments, R 5a and one R 6 These atoms, together with the atoms they bond to, form cyclopentyl.

[0455] In some embodiments, R 8 and R 9 These are, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a It is replaced by R. In some embodiments, 8 and R 9Each of these independently, upon appearance, is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Selected from cycloalkyl. In some embodiments, R 8 and R 9 Each of these elements appears independently as follows: H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups. In some embodiments, R 8 and R 9 Each of these appears independently, C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups.

[0456] In some embodiments, R 10 These are, independently, 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, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a It is replaced by R. In some embodiments, 10 These are, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C6-C 10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 10 These are, independently, H, C1-C6 alkyl, and C3-C 10 Cycloalkyl and C3-C 10Selected from heterocycloalkyl groups. In some embodiments, R 10 Each is independently selected from H and C1-C6 alkyl groups. In some embodiments, R 10 These are, independently, C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups.

[0457] In some embodiments, R 11 These are, independently, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a It is replaced by R. In some embodiments, 11 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C6-C 10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 11 Each of these is independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl. In some embodiments, R 11 These are, independently, C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups.

[0458] In some embodiments, R 12These are, independently, 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-C 10 Selected from heterocycloalkyl groups, these each contain one or more R groups. a It is replaced by R. In some embodiments, 12 These are, independently, H, linear or branched C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups. In some embodiments, R 12 Each is independently selected from H, a linear or branched C1-C6 alkyl group. In some embodiments, R 12 These are, independently, C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups.

[0459] In some embodiments, R a Each is 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, R a Each is independently selected from -F, -Cl, -Br, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, R a Each of these is independently selected from -F, -OH, -CH3, -CF3, or -C(O)OH.

[0460] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. In 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.

[0461] In some embodiments, the PDGH inhibitor is one of the compounds listed in Table 4 or a pharmaceutically acceptable salt thereof.

[0462] [Table 4-1]

[0463] [Table 4-2]

[0464] [Table 4-3]

[0465] [Table 4-4]

[0466] [Table 4-5]

[0467] [Table 4-6]

[0468] [Table 4-7]

[0469] [Table 4-8]

[0470] Table 4-9

[0471] Table 4-10

[0472] Table 4-11

[0473] Table 4-12

[0474] Table 4-13

[0475] Table 4-14

[0476] Table 4-15

[0477] Table 4-16

[0478] Table 4-17

[0479] Table 4-18

[0480] [Table 4-19]

[0481] [Table 4-20]

[0482] [Table 4-21]

[0483] [Table 4-22]

[0484] [Table 4-23]

[0485] [Table 4-24]

[0486] [Table 4-25]

[0487] [Table 4-26]

[0488] [Table 4-27]

[0489] [Table 4-28] [Examples]

[0490] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[0491] Example 1: Effect of oral administration of MF-300 on urinary PGE-MUM levels in CD rats The effect of daily oral administration of MF-300 (30 mg / kg or 60 mg / kg) on ​​urinary PGE-MUM levels in a cohort of male CD (Sprague-Dawley) rats was evaluated. Briefly, baseline plasma and urinary levels of PGE2, 15-K-PGE2, 13,14-dihydro-15-keto-PGE2, and PGE-MUM in 8-week-old male CD rats were assessed using liquid chromatography-tandem mass spectrometry (LC-MS / MS). The rat cohort was then administered either daily orally with a vehicle (Veh, 10% 2-hydroxypropyl-beta-cyclodextrin) or daily orally with MF-300 (30 mg / kg or 60 mg / kg) for 7 days. Additional urine analysis was performed on day 6, additional plasma analysis was performed on day 7 prior to dose administration, and final plasma and muscle analysis was performed on day 7 post-dose administration. All urine samples were collected between 8:00 AM and 9:00 AM on the baseline measurement day and day 6, and PGE-MUM levels were normalized to creatinine. A schematic of the experimental timeline for evaluating the effect of MF-300 on urinary PGE-MUM levels in CD rats is shown in Figure 1A. A schematic diagram showing the mechanism by which MF-300 inhibits 15-PGDH (and thus inhibits the first step in PGE-MUM production from PGE2), as well as the biological localization of PGE2 and its metabolites, is shown in Figure 1B. As shown in Figure 1C, no significant differences were observed in urinary PGE-MUM levels normalized to creatinine during baseline measurements in rat cohorts administered vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300. As shown in Figure 1D, rats orally administered 30 mg / kg or 60 mg / kg of MF-300 had significantly lower levels of urinary PGE-MUM normalized to creatinine on day 6 compared with rats orally administered a vehicle. Plasma levels of MF-300 after a single dose or seven doses per day were also measured over 24 hours, as shown in Figure 1E.The change from baseline levels of PGE-MUM in CD rats administered with vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300 was also measured, as shown in Figure 1F.

[0492] Additional experiments were conducted in adult C. difficile rats to achieve steady-state plasma levels of MF-300, and a summary of these experiments is shown in Figure 2A. Over a 14-day period, C. difficile rats were administered either a vehicle (Veh, 10% 2-hydroxypropyl-beta-cyclodextrin), 30 mg / kg MF-300, or 60 mg / kg MF-300. Urinary levels of PGE2 and PGE-MUM, and the PGE2 / PGE-MUM ratio were evaluated over 14 days in C. difficile rats administered the vehicle, 30 mg / kg MF-300, or 60 mg / kg MF-300, and MF-300 was found to increase the PGE2 / PGE-MUM level ratio, as shown in Figure 2B. As shown in Figure 2C, PGE-MUM levels were also lower in CD rats administered 30 mg / kg MF-300 or 60 mg / kg MF-300 compared to CD rats administered the vehicle.

[0493] Example 2: Effect of MF-300 on PGE-MUM levels in SMNΔ7 mice The effects of MF-300 administration were evaluated in a cohort of spinal muscular atrophy (SMA) disease models (SMNΔ7 mice, also known as "Delta 7 mice" + SMN-C3). A schematic diagram illustrating that MF-300 inhibits 15-PGDH and reduces the level of the PGE2 metabolite is shown in Figure 3A. Urinary levels of PGE2 and PGE2-PGE-MUM, and the PGE2 / PGE-MUM ratio were evaluated over several days in WT mice, vehicle-treated Delta 7 mice, or Delta 7 mice administered 30 mg / kg of MF-300 every other day. As shown in Figure 3B, MF-300 treatment increased PGE2 levels and the PGE2-to-PGE-MUM ratio, and decreased PGE-MUM levels in Delta 7 mice administered 30 mg / kg of MF-300 compared to vehicle-treated Delta 7 mice.

[0494] Example 3: Effect of MF-300 on PGE-MUM levels in aged mice The effects of MF-300 administration were evaluated in a cohort of aged mice. Briefly, the mice were adult (12-15 months old) or aged (23 months old) male C57Bl / 6J mice, which were administered either a vehicle or 10 mg / kg MF-300, 30 mg / kg MF-300, or 60 mg / kg MF-300. As shown in Figure 4, administration of 10 mg / kg MF-300 to aged mice resulted in a decrease in PGE-MUM levels after 12 weeks compared to aged mice administered with a vehicle.

[0495] Example 4: Effect of oral administration of MF-300 on P75ECD expression A biological sample is obtained from the subject. The biological sample is tested for the presence of the biomarker p75ECD. The subject is found to have an elevated level of p75ECD. The subject is administered a 15-PGDH inhibitor. After treatment with the 15-PGDH inhibitor, the subject is tested again for the presence of the biomarker p75ECD, and a decrease in the subject's p75ECD level is observed compared to before treatment.

[0496] Preferred embodiments of the present invention have been shown and described herein, but it will be obvious to those skilled in the art that such embodiments are provided merely as examples. Numerous variations, modifications, and substitutions will be conceivable to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be adopted in the practice of the present invention. The following claims define the scope of the present invention, and the methods and structures within these claims, as well as their equivalents, are intended to be encompassed by the claims.

Claims

1. A method for reducing the levels of p75ECD, PGE-MUM, or both in a subject, comprising the step of administering to the subject an amount effective in reducing the levels of p75ECD, PGE-MUM, or both in the subject, which is a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor.

2. A method for treating a subject with a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor, (a) A step of identifying a subject in which the level of p75ECD, PGE-MUM, or both has increased compared to a control or a level of p75ECD or PGE-MUM that exceeds a predetermined threshold, (b) A step of administering the 15-PGDH inhibitor to the subject to reduce the levels of p75ECD, PGE-MUM, or both in the subject. A method that includes this.

3. The method according to claim 1 or 2, further comprising the step of measuring the levels of p75ECD, PGE-MUM, or both in the subject before the administration step.

4. A method for selecting subjects for treatment with a 15-hydroxyprostaglandin (15-PGDH) inhibitor, (a) A step of providing or obtaining a biological sample obtained from the subject, (b) A step of measuring the levels of p75ECD, PGE-MUM, or both in the biological sample, (c) When the levels of p75ECD, PGE-MUM, or both in the biological sample exceed a predetermined threshold, the step of identifying the subject as a candidate for treatment with the 15-PGDH inhibitor. A method that includes this.

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

6. The method according to any one of claims 1 to 5, wherein the subject is suffering from a disease or illness associated with an increase in the level of p75ECD.

7. The method according to claim 6, wherein the disease or illness associated with the elevation of the p75ECD level is a neurodegenerative disorder.

8. The method according to claim 7, wherein the neurodegenerative disorder is amyotrophic lateral sclerosis or Alzheimer's disease.

9. The method according to claim 8, wherein the neurodegenerative disorder is amyotrophic lateral sclerosis.

10. The method according to any one of claims 1 to 3 or 5 to 9, wherein the administration step 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 according to any one of claims 1 to 3 or 5 to 10, wherein the administration step is selected from the group consisting of acute administration, chronic administration, intermittent administration, and continuous administration.

12. The method according to any one of claims 1 to 3 or 5 to 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 according to any one of claims 1 to 12, wherein the required subject is a human being.

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

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

16. The method according to any one of claims 1 to 15, wherein the 15-PGDH inhibitor is selected from the group consisting of small molecules, antibodies or fragments thereof, peptide inhibitors, aptamers, oligonucleotide inhibitors, and any combination thereof.

17. The aforementioned 15-PGDH inhibitor, Formula I 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, X is -OCH ２ -, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH ２ -, -S(O)CH ２ -, -SO ２ CH ２ - Selected from, Y is independent of N and CR １１ Selected from, R １ are each independently selected from halo, -NR ６ R ７ , -OR ８ , -C(O)OR ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ alkyl, C １－６ heteroalkyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, R ２ H is R ３ Ha-CF ３ And, or R ２ and R ３ They combine to form an oxo or thio, R ４ These are, independently, Halo and -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ５ are each independently selected from halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ alkyl, C １－６ heteroalkyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, R ６ and R ７ Each of these appears independently, with H and C. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, R ８ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ９ Each of them is independent of C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R １０ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, R １１ These are, independently, Halo and -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, n is 0, 1, 2, 3, 4, or 5. m is 0, 1, 2, 3, or 4. p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. However, the compound of formula I is 【Chemistry 2】 The method according to any one of claims 1 to 16, provided that it is not the case.

18. The aforementioned compound is, Formula Ia 【Transformation 3】 The method according to claim 17, wherein the compound is or a pharmaceutically acceptable salt thereof.

19. The aforementioned compound is, Formula Ib 【Chemistry 4】 The method according to claim 17, wherein the compound is or a pharmaceutically acceptable salt thereof.

20. The aforementioned 15-PGDH inhibitor, Formula II 【Transformation 5】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, T, U, W, X, and Y are independent of N and CR. ５ Selected from, S, V, and Z are independently selected from N and C. R １ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl is halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5- to 10-membered heteroaryl groups, R ２ H is R ３ Ha-CF ３ And, or R ２ and R ３ They combine to form an oxo or thio, R ４ These are, independently, Halo and -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's ４ They bond together with the carbon atoms and any intervening atoms, forming a single unit with C ３－１０ Forms a cycloalkyl group, and all remaining R ４ It is independently, Halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ５ These are H, Halogen, and -NR, respectively, independently. ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ６ and R ７ Each of these appears independently, with H and C. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, R ８ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ９ Each of them is independent of C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R １０ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. However, the compound of formula II is 【Transformation 6】 【Transformation 7】 【Transformation 8】 The method according to any one of claims 1 to 16, provided that it is not the case.

21. The aforementioned compound is, Formula IIa 【Chemistry 9】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

22. The aforementioned compound is, Formula IIb 【Chemistry 10】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

23. The aforementioned compound is, Formula IIc 【Chemistry 11】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

24. The aforementioned compound is, Formula IId 【Chemistry 12】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

25. The aforementioned compound is, Formula IIe 【Chemistry 13】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

26. The aforementioned compound is, formula IIf 【Chemistry 14】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

27. The aforementioned compound is formula IIg 【Chemistry 15】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

28. The aforementioned compound is, Formula IIh 【Chemistry 16】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

29. The aforementioned compound is, Formula III 【Chemistry 17】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

30. The aforementioned compound is, Formula IIj [Chemistry 18] The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

31. The aforementioned compound is, Formula I In 【Chemistry 19】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

32. The aforementioned compound is, Formula IIp 【Chemistry 20】 The method according to claim 20, wherein the compound or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

33. The aforementioned 15-PGDH inhibitor is, Formula III 【Chemistry 21】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, X is independent of N and CR ７ Selected from, Y is O, S, SO ２ , and C(R ８ ) ２ Selected from, R １ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl is halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls, R ２ H is R ３ Ha-CF ３ And, or R ２ and R ３ They combine to form an oxo or thio, R ４ and R ５ Independently, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyls, alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ They are optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls, or R ４ and R ５ These, together with the nitrogen atom to which they bond, form a halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Forming 3- to 10-membered heterocycloalkyls by optionally substituting with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls, R ６ These are, independently, Halo and -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's bonded to the same carbon atom ６ These are combined as oxo, thio, or C ３－１０ Forms a cycloalkyl group, and all remaining R ６ It is independently, Halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ７ These are H, Halogen, and -NR, respectively, independently. ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ８ These are H, Halogen, and -NR, respectively, independently. ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's ８ They are united as Halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ C is optionally substituted with 1 to 3 substituents independently selected from aryl and 5- to 10-membered heteroaryl groups. ３－１０ Forming a cycloalkyl group, R ９ and R １０ Each of these appears independently, with H and C. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, R １１ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R １２ Each of them is independent of C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R １３ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, m is either 1 or 2. The method according to any one of claims 1 to 16, wherein n is 0, 1, 2, 3, or 4.

34. The aforementioned compound is, Formula IIIa 【Chemistry 22】 The method according to claim 33, wherein the compound is a pharmaceutically acceptable salt thereof.

35. The aforementioned compound is, Formula IIIb 【Chemistry 23】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, R １４ These are, independently, Halo and -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, The method according to claim 33, wherein p is 0, 1, 2, or 3.

36. The aforementioned compound is, Formula IIIc 【Chemistry 24】 The method according to claim 33, wherein the compound is a pharmaceutically acceptable salt thereof.

37. The aforementioned compound is, Formula IIId 【Chemistry 25】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, R １４ These are, independently, Halo and -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, The method according to claim 33, wherein p is 0, 1, 2, or 3.

38. The aforementioned 15-PGDH inhibitor, formula IIk 【Chemistry 26】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, T, U, and Y are independent of N and CR ６ Selected from, provided that when U is N, at least one of T and Y is N, R １ C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, the aryl or heteroaryl is halo, -NR ７ R ８ , -OR ９ , -C(O)R ９ , -C(O)OR ９ , -C(O)NR ７ R ８ , -SOR １０ , -SO ２ R １０ , -SO ２ NR ７ R ８ , -NR １１ C(O)R ９ , -NR １１ C(O)NR ７ R ８ , -NR １１ SO ２ R ９ , -NR １１ SO ２ NR ７ R ８ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5- to 10-membered heteroaryl groups, R ２ H is R ３ Ha-CF ３ And, or R ２ and R ３ They combine to form an oxo, R ４ These are independently selected from H and Halo, R ５ Hello, -NR ７ R ８ , -OR ９ , -C(O)R ９ , -C(O)OR ９ , -C(O)NR ７ R ８ , -SOR １０ , -SO ２ R １０ , -SO ２ NR ７ R ８ , -NR １１ C(O)R ９ , -NR １１ C(O)NR ７ R ８ , -NR １１ SO ２ R ９ , -NR １１ SO ２ NR ７ R ８ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ６ H, Halo, -NR ７ R ８ , -OR ９ , -C(O)R ９ , -C(O)OR ９ , -C(O)NR ７ R ８ , -SOR １０ , -SO ２ R １０ , -SO ２ NR ７ R ８ , -NR １１ C(O)R ９ , -NR １１ C(O)NR ７ R ８ , -NR １１ SO ２ R ９ , -NR １１ SO ２ NR ７ R ８ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ７ and R ８ Each of these appears independently, with H and C. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－６ Selected from cycloalkyl groups, R ９ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R １０ Each of them is independent of C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R １１ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Haloalkyl and C ３－６ Selected from cycloalkyl groups, The method according to any one of claims 1 to 16, wherein p is 0, 1, or 2.

39. The aforementioned 15-PGDH inhibitor, formula IIm 【Chemistry 27】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, R １ C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, the aryl or heteroaryl is halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5- to 10-membered heteroaryl groups, R ２ H is R ３ Ha-CF ３ And, or R ２ and R ３ They combine to form an oxo, R ４ These are, independently, Halo and -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's ４ They bond together with the carbon atoms and any intervening atoms, forming a single unit with C ３－１０ Forms a cycloalkyl group, and all remaining R ４ It is independently, Halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ５ is selected from halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ alkyl, C １－６ heteroalkyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 3 to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5 to 10-membered heteroaryl, R ６ and R ７ Each of these appears independently, with H and C. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, R ８ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ９ Each of them is independent of C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R １０ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The method according to any one of claims 1 to 16, wherein p is 0, 1, 2, or 3.

40. The aforementioned 15-PGDH inhibitor, formula IIq 【Chemistry 28】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, R １ is selected from C ６－１０ aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is substituted with halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ alkyl, C １－６ heteroalkyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, and 5- to 10-membered heteroaryl, and is optionally substituted with 1 to 3 substituents independently selected from the foregoing, R ２ H is R ３ Ha-CF ３ And, or R ２ and R ３ They combine to form an oxo, R ４ These are, independently, Halo and -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's ４ They bond together with the carbon atoms and any intervening atoms, forming a single unit with C ３－１０ Forms a cycloalkyl group, and all remaining R ４ It is independently, Halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ５ Hello, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ６ and R ７ Each of these appears independently, with H and C. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, R ８ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ９ Each of them is independent of C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R １０ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The method according to any one of claims 1 to 16, wherein p is 0, 1, 2, or 3.

41. The aforementioned 15-PGDH inhibitor is, Formula IIIc 【Chemistry 29】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, X is independent of N and CR ７ Selected from, Y is O, S, SO ２ , and C(R ８ ) ２ Selected from, R １ C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, the aryl or heteroaryl is halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl groups and 5- to 10-membered heteroaryl groups, R ２ H is R ３ Ha-CF ３ And, or R ２ and R ３ They combine to form an oxo, R ４ and R ５ Independently, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－６ Selected from cycloalkyls, alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ They are optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls, or R ４ and R ５ These, together with the nitrogen atom to which they bond, form a halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Forming 3- to 10-membered heterocycloalkyls by optionally substituting with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls, R ６ These are, independently, Halo and -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's bonded to the same carbon atom ６ They combine to form an oxo, and all the remaining R ６ It is independently, Halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ７ and R ８ These are, independently, Halo and -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ９ and R １０ Each of these appears independently, with H and C. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－６ Selected from cycloalkyl groups, R １１ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R １２ Each of them is independent of C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R １３ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Haloalkyl and C ３－６ Selected from cycloalkyl groups, The method according to any one of claims 1 to 16, wherein n is 0, 1, 2, 3, or 4.

42. The aforementioned 15-PGDH inhibitor 【Transformation 30】 The method according to any one of claims 1 to 16, wherein the compound is selected from the group consisting of the following.

43. The aforementioned 15-PGDH inhibitor 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 The method according to any one of claims 1 to 16, wherein the compound is selected from the group consisting of the following.

44. The aforementioned 15-PGDH inhibitor 【Chemistry 43】 The method according to any one of claims 1 to 16, wherein the compound is selected from the group consisting of the following.

45. The aforementioned 15-PGDH inhibitor is, Formula IV 【Chemistry 44】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, Ring Q is phenyl or a 5-10 membered heteroaryl. Z is CR １ or N, Y is CR ２ or N, R １ H, halogen, -CN, -OR １０ , -C(O)R １０ , -C(O)OR １０ , -NR ８ R ９ , -C(O)NR ８ R ９ , -NR ８ C(O)R ９ , substitution or non-substitution of C １ -C ６ Alkyl, or substituted or unsubstituted C ３ -C ８ It is a cycloalkyl, R ２ These are H, halogen, and -OR, respectively, independently. １０ , -C(O)R １０ , -C(O)OR １０ , -CN, -C(O)NR ８ R ９ , -NR ８ C(O)R ９ , substitution or non-substitution of C １ -C ６ Alkyl, or substituted or unsubstituted C ３ -C ８ It is a cycloalkyl, R ３ These are H, halogen, -CN, and -NO, respectively, independently. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ Replaced by, R １３ These are, independently, halogen, CN, and -NOx. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ And, R ４ C is either substituted or non-substituted. １ -C ８ Alkyl, substituted, or unsubstituted C ２ -C ８ Alkenyl, substituted or unsubstituted C １ -C ８ aminoalkyl, substituted or unsubstituted C １ -C ８ Heteroalkyl, substituted or unsubstituted C １ -C ８ Hydroxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, or substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ These are heterocycloalkyl groups, each consisting of one or more R ６ Replaced by, R ６ These are, independently, halogen, CN, and -NOx. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -NR ８ C(O)R ９ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C １ -C ６ Hydroxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl, Or two R's ６ These atoms, together with the atoms to which they bond, form a substituted or unsubstituted C ３ -C ６ Cycloalkyl or substituted or unsubstituted C ３ -C ８ Forms heterocycloalkyl groups, X Ａ -NR ５ R ５ OR ５ And, R ５ These are, independently, H or C １ -C ６ It is alkyl, R ５ａ is H or CH ３ And, Or R ５ａ and one R ６ These atoms, together with the atoms to which they bond, form a substituted or unsubstituted C ３ -C ６ Cycloalkyl or substituted or unsubstituted C ３ -C ６ Forms heterocycloalkyl groups, R ８ and R ９ These are, independently, H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C ２ -C ６ Alkynyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyl groups, each of which has one or more R ａ Replaced by optional selection, R １０ These are, independently, H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by optional selection, R １１ These are, independently, substitute or non-substitute C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by optional selection, R １２ These are, independently, H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyl groups, each of which has one or more R ａ Replaced by optional selection, R ａ These are, independently, halogen, -OH, and -CH. ３ , -CF ３ , -OCH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -C(O)OH, -C(O)OCH ３ , -C(O)NH ２ , -C(O)NHCH ３ , -C(O)N(CH ３ ) ２ , -NHC(O)OH, -OC(O)NH ２ , and -NHC(O)CH ３ Selected from, The method according to any one of claims 1 to 44, wherein p is 1, 2, 3, or 4.

46. The method according to claim 45, wherein ring Q is a six-membered monocyclic heteroaryl containing one, two, or three N atoms.

47. The method according to claim 45, wherein ring Q is phenyl, pyrimidinyl, or pyridinyl.

48. When Q is phenyl, R ３ The method according to claim 45 or 47, wherein one of them is not H. [Request Item 49] [Chemistry 45] teeth, 【Chemistry 46】 And in the formula, X １ , X ２ , X ３ , and X ４ These are, independently, N or CR ３ And, R ３ These are H, halogen, -CN, and -NO, respectively, independently. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ Replaced by, R １３ These are, independently, halogen, CN, and -NOx. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ And, R ８ and R ９ These are, independently, H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C ２ -C ６ Alkynyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyl groups, each of which has one or more R ａ Replaced by, R １０ These are, independently, H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by, R １１ These are, independently, substitute or non-substitute C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by, R １２ These are, independently, H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyl groups, each of which has one or more R ａ Replaced by, R ａ These are, independently, halogen, -OH, and -CH. ３ , -CF ３ , -OCH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -C(O)OH, -C(O)OCH ３ , -C(O)NH ２ , -C(O)NHCH ３ , -C(O)N(CH ３ ) ２ , -NHC(O)OH, -OC(O)NH ２ , and -NHC(O)CH ３ The method according to claim 45, selected from the following.

50. X １ , X ２ , X ３ , and X ４ However, each CR ３ The method according to claim 49.

51. X １ N is X ２ , X ３ , and X ４ However, each CR ３ The method according to claim 49.

52. X １ and X ２ Each of these is N, and X ３ and X ４ Each of them is CR ３ The method according to claim 49.

53. X １ and X ３ Each of these is N, and X ２ and X ４ Each of them is CR ３ The method according to claim 49.

54. X １ and X ４ Each of these is N, and X ２ and X ３ Each of them is CR ３ The method according to claim 49.

55. X １ , X ２ , and X ３ However, each of them is N, and X ４ CR ３ The method according to claim 49.

56. X １ , X ２ , and X ４ However, each of them is N, and X ３ CR ３ The method according to claim 49.

57. R ３ However, each is independent of H, halogen, and -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ The method according to any one of claims 45 to 56, selected from heterocycloalkyls and substituted or unsubstituted five-membered heteroaryls.

58. R ３ However, each is independent of H, halogen, -C(O)OR １０ , -C(O)NR ８ R ９ The method according to claim 57, wherein the five-membered heteroaryl is selected from, and substituted or unsubstituted.

59. The aforementioned compound is, Formula V 【Chemistry 47】 Having the structure of, or a pharmaceutically acceptable salt thereof, in the formula, Z is CR １ or N, X １ is N or CR ３ａ And, Y is CR ２ or N, R １ H, halogen, -CN, -OR １０ , -C(O)R １０ , -C(O)OR １０ , -NR ８ R ９ , -C(O)NR ８ R ９ , -NR ８ C(O)R ９ , substitution or non-substitution of C １ -C ６ Alkyl, or substituted or unsubstituted C ３ -C ８ It is a cycloalkyl, R ２ These are H, halogen, and -OR, respectively, independently. １０ , -C(O)R １０ , -C(O)OR １０ , -CN, -C(O)NR ８ R ９ , -NR ８ C(O)R ９ , substitution or non-substitution of C １ -C ６ Alkyl, or substituted or unsubstituted C ３ -C ８ It is a cycloalkyl, R ３ａ , R ３ｂ , and R ３ｃ These are H, halogen, -CN, and -NO, respectively, independently. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ Replaced by, R １３ These are, independently, halogen, CN, and -NOx. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ And, R ４ C is either substituted or non-substituted. １ -C ８ Alkyl, substituted, or unsubstituted C ２ -C ８ Alkenyl, substituted or unsubstituted C １ -C ８ aminoalkyl, substituted or unsubstituted C １ -C ８ Heteroalkyl, substituted or unsubstituted C １ -C ８ Hydroxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, or substituted or unsubstituted C ３ -C ８ These are heterocycloalkyl groups, each consisting of one or more R ６ Replaced by, R ６ These are, independently, halogen, CN, and -NOx. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -NR ８ C(O)R ９ , substitution or non-substitution of C １ -C ６ Alkyl, substituted C １ -C ６ Haloalkyl, substituted or unsubstituted C １ -C ６ Hydroxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl, Or two R's ６ These atoms, together with the atoms to which they bond, form a substituted or unsubstituted C ３ -C ６ Cycloalkyl or substituted or unsubstituted C ３ -C ８ Forms heterocycloalkyl groups, X Ａ NR ５ R ５ OR ５ And, R ５ These are, independently, H or C １ -C ６ It is alkyl, R ５ａ is H or CH ３ And, Or R ５ａ and one R ６ These atoms, together with the atoms to which they bond, form a substituted or unsubstituted C ３ -C ６ Forming a cycloalkyl group, R ８ and R ９ These are, independently, H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C ２ -C ６ Alkynyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyl groups, each of which has one or more R ａ Replaced by, R １０ These are, independently, H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by, R １１ These are, independently, substitute or non-substitute C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by, R １２ These are, independently, H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyl groups, each of which has one or more R ａ Replaced by, R ａ These are, independently, halogen, -OH, and -CH. ３ , -CF ３ , -OCH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -C(O)OH, -C(O)OCH ３ , -C(O)NH ２ , -C(O)NHCH ３ , -C(O)N(CH ３ ) ２ , -NHC(O)OH, -OC(O)NH ２ , and -NHC(O)CH ３ The method according to claim 45, selected from the following.

60. X Ａ NR ５ R ５ The method according to any one of claims 45 to 59.

61. X Ａ OR ５ The method according to any one of claims 45 to 59.

62. Y is CR ２ The method according to any one of claims 45 to 61.

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

64. The compound of formula V is, formula VIa 【Chemistry 48】 The method according to claim 59, having the structure of or a pharmaceutically acceptable salt thereof.

65. The compound of formula V is, 【Chemistry 49】 The method according to claim 59, having the structure of or a pharmaceutically acceptable salt thereof.

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

67. Z is CR １ The method according to any one of claims 45 to 65.

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

69. The compound of formula V is, formula VIIa [Transformation 50] The method according to claim 59, having the structure of or a pharmaceutically acceptable salt thereof.

70. The compound of formula V is, formula VIIb 【Chemistry 51】 The method according to claim 59, having the structure of or a pharmaceutically acceptable salt thereof.

71. The compound of formula V is, formula VIIc 【Chemistry 52】 The method according to claim 59, having the structure of or a pharmaceutically acceptable salt thereof.

72. The compound of formula V is, formula VIId 【Chemistry 53】 The method according to claim 59, having the structure of or a pharmaceutically acceptable salt thereof.

73. X １ The method according to any one of claims 59 to 72, wherein N.

74. R ３ｂ H is R ３ｃ However, halogen, -CN, -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ Replaced with R １３ These are, independently, halogen, CN, and -NOx. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ The method according to any one of claims 59 to 73.

75. R ３ｂ H is R ３ｃ However, halogen, -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ The method according to claim 74, selected from heterocycloalkyls and substituted or unsubstituted five-membered heteroaryls.

76. R ３ｃ H is R ３ｂ However, halogen, -CN, -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ Replaced with R １３ These are, independently, halogen, CN, and -NOx. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ The method according to any one of claims 59 to 73.

77. R ３ｃ H is R ３ｂ However, halogen, -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ The method according to claim 76, selected from heterocycloalkyls and substituted or unsubstituted five-membered heteroaryls.

78. X １ CR ３ａ The method according to any one of claims 59 to 72.

79. R ３ａ and R ３ｂ However, independently, H or halogen, R ３ｃ However, halogen, -CN, -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ Replaced with R １３ These are, independently, halogen, CN, and -NOx. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ The method according to any one of claims 59 to 72 or 78.

80. R ３ｃ However, H, halogen, -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ The method according to claim 79, selected from heterocycloalkyls and substituted or unsubstituted five-membered heteroaryls.

81. R ３ｃ However, -C(O)OR １０ , -C(O)NR ８ R ９ The method according to claim 80, wherein the heteroaryl group is either substituted or unsubstituted, or a 5-membered heteroaryl group.

82. R ３ａ and R ３ｂ The method according to any one of claims 79 to 81, wherein each of them is H.

83. R ３ａ and R ３ｃ However, independently, H or halogen, R ３ｂ However, halogen, -CN, -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ Replaced with R １３ These are, independently, halogen, CN, and -NOx. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ The method according to any one of claims 59 to 72 or 78.

84. R ３ｂ However, H, halogen, -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ The method according to claim 83, selected from heterocycloalkyls and substituted or unsubstituted five-membered heteroaryls.

85. R ３ｂ However, -C(O)OR １０ , -C(O)NR ８ R ９ The method according to claim 83, wherein the heteroaryl group is either substituted or unsubstituted, or a 5-membered heteroaryl group.

86. R ３ａ and R ３ｃ The method according to any one of claims 83 to 85, wherein each of them is H.

87. R ３ｂ and R ３ｃ However, each is either H or halogen, and R ３ａ However, halogen, -CN, -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ Replaced with R １３ These are, independently, halogen, CN, and -NOx. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ The method according to any one of claims 59 to 72 or 78.

88. R ３ａ However, H, halogen, -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ The method according to claim 87, selected from heterocycloalkyls and substituted or unsubstituted five-membered heteroaryls.

89. R ３ａ However, -C(O)OR １０ , -C(O)NR ８ R ９ The method according to claim 87, wherein the heteroaryl group is either substituted or unsubstituted, or a 5-membered heteroaryl group.

90. R ３ｂ and R ３ｃ The method according to any one of claims 87 to 89, wherein each of them is H.

91. R ２ The method according to any one of claims 45 to 90, wherein each of them is H.

92. R ５ａ and R ６ One of them, together with the atom to which they are bonded, C ３ -C ６ The method according to any one of claims 45 to 91, for forming a cycloalkyl group.

93. R ５ａ The method according to any one of claims 45 to 91, wherein is H.

94. R ５ The method according to any one of claims 45 to 93, wherein is H.

95. R ４ However, C is either substituted or non-substituted. １ -C ８ Alkyl, substituted, or unsubstituted C １ -C ８ aminoalkyl, substituted or unsubstituted C １ -C ８ Heteroalkyl, substituted or unsubstituted C １ -C ８ Hydroxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, or substituted or unsubstituted C ３ -C ８ These are heterocycloalkyl groups, each consisting of one or more R ６ The method according to any one of claims 45 to 94, which is replaced by

96. R ４ However, C is either substituted or non-substituted. １ -C ８ Alkyl, substituted, or unsubstituted C １ -C ８ These are heteroalkyl groups, and each of them contains one or more R ６ The method according to claim 95, which is replaced by

97. R ４ However, C is either substituted or non-substituted. ３ -C ８ These are cycloalkyl or 4- to 8-membered heterocycloalkyl groups, each consisting of one or more R groups. ６ The method according to any one of claims 45 to 94, which is replaced by

98. R ４ The method according to claim 97, wherein the substance is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl.

99. R ６ However, each is independent of halogen and -NR ８ R ９ , -OR １０ , substitution or non-substitution of C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted or unsubstituted C １ -C ６ Hydroxyalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, or substituted or unsubstituted C ３ -C ８ The method according to any one of claims 45 to 98, wherein the material is a heterocycloalkyl.

100. R ６ However, each is independent of halogen, -OR １０ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C ３ -C ８ The method according to claim 99, wherein the material is cycloalkyl.

101. R ６ The method according to claim 99 or 100, wherein each is independently -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

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

103. The method according to any one of claims 1 to 102, wherein the subject is suffering from a disease or illness associated with elevated levels of PGE-MUM.

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

105. The method according to claim 104, wherein the disease or illness relating to muscle injury, injury, or atrophy includes acute muscle injury or trauma, soft tissue injury of the hand, muscular dystrophy, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), hereditary myopathy, myotonic muscular dystrophy (MDD), mitochondrial myopathy, myotubular 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 according to any one of claims 103 to 105, wherein the disease or illness associated with the elevation of PGE-MUM levels is a neuromuscular disease.

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

108. The method according to claim 107, wherein administering a certain amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject suffering from spinal muscular atrophy reduces the PGE-MUM level in the subject.

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

110. The method according to any one of claims 1 to 109, wherein the subject is an elderly subject.

111. The method according to claim 110, wherein the subject is at least 60 years old.

112. The method according to any one of claims 1 to 111, wherein the disease or illness associated with an increase in PGE-MUM levels is an age-related disease.

113. The method according to claim 112, wherein the age-related disease is sarcopenia.

114. The method according to claim 113, wherein administering a certain amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject suffering from sarcopenia reduces the PGE-MUM level in the subject.

115. The method according to claim 113 or 114, wherein administering a certain amount of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject suffering from sarcopenia improves one or more sarcopenic symptoms in the subject.

Images