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

Abstract

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

Description

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

[0002] The p75 neurotrophic factor receptor (p75NTR) is associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In ALS, elevated levels of the p75 extracellular domain (p75ECD) in urine 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 PGE-MUM levels are associated with an increased risk of ALS.

[0003] By incorporating references All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference. In the event that any publication or patent or patent application incorporated by reference contradicts the disclosure contained herein, this specification is intended to substitute for and / or give precedence to any such contradictory material. Summary of the Invention

[0004] There is an unmet need for compositions and methods for reducing the levels of biomarkers (e.g., those related to a disease or condition) in subjects. This disclosure addresses this unmet need by providing compositions and methods for reducing the levels of disease- or condition-related biomarkers (e.g., p75ECD, PGE-MUM) using a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor.

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

[0006] In another aspect, a method is provided for treating a subject with a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor, the method comprising: (a) identifying an elevation in the subject's p75ECD, PGE-MUM, or both levels relative to a control or exceeding a predetermined threshold for p75ECD or PGE-MUM levels; and (b) administering the 15-PGDH inhibitor to the subject to reduce the subject's p75ECD, PGE-MUM, or both levels. In some cases, the method further includes measuring the subject's p75ECD, PGE-MUM, or both levels prior to the administration.

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

[0008] In some cases, the subject has a disease or condition associated with elevated p75ECD levels. In some cases, the disease or condition associated with elevated p75ECD levels is a neurodegenerative disease. In some cases, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS) or Alzheimer's disease. In some cases, the subject has a disease or condition associated with elevated PGE-MUM levels. In some cases, the administration is selected from the group consisting of: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, arterial administration, intradermal administration, subcutaneous administration, and any combination thereof. In some cases, the administration 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 pharmaceutically acceptable excipients, diluents, and / or carriers. In some cases, the subject in need 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 a compound of formula I:

[0009] Formula I Or its pharmaceutically acceptable salt, wherein: X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, -SO2CH2-; Each Y is independently selected from N and CR 11 ; Each R 1 Independently selected from halogen groups, -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 groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxidized or thiolated compounds; Each R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from 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 groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 11 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The condition is that the compound of formula I is not , , or .

[0010] In some cases, the compound is a compound of formula Ia:

[0011] Formula Ia Or its pharmaceutically acceptable salt.

[0012] In some cases, the compound is a compound of formula Ib:

[0013] Formula Ib Or its pharmaceutically acceptable salt.

[0014] In some cases, the 15-PGDH inhibitor is a compound of formula II:

[0015] Formula II Or its pharmaceutically acceptable salt, wherein: T, U, W, X, and Y are independently selected from N and CR. 5 ; S, V, and Z are independently selected from N and C; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the alkyl group, the cycloalkyl group, the aryl group, or the heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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, C1-6 Haloalkyl, C 3-10 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxidized or thiolated compounds; Each R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from 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 groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The condition is that the compound of formula II is not , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0016] In some cases, the compound is a compound of formula IIa:

[0017] Formula IIa Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

[0018] In some cases, the compound is a compound of formula IIb:

[0019] Formula IIb Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

[0020] In some cases, the compound is a compound of formula IIc:

[0021] Formula IIc Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4 or 5.

[0022] In some cases, the compound is a compound of formula IId:

[0023] Formula IId Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0024] In some cases, the compound is a compound of formula IIe:

[0025] Formula IIe Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0026] In some cases, the compound is a compound of formula IIf:

[0027] Formula IIf Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0028] In some cases, the compound is a compound of formula IIg:

[0029] Formula IIg Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0030] In some cases, the compound is a compound of formula IIh:

[0031] Formula IIh Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0032] In some cases, the compound is a compound of formula IIi:

[0033] Formula IIi Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0034] In some cases, the compound is a compound of formula IIj:

[0035] Formula IIj Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0036] In some cases, the compound is a compound of formula IIn:

[0037] Formula IIn Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0038] In some cases, the compound is a compound of formula IIp:

[0039] Formula IIp Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0040] In some cases, the 15-PGDH inhibitor is a compound of formula III:

[0041] Formula III Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the alkyl group, the cycloalkyl group, the aryl group, or the heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution of aryl and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxidized or thiolated compounds; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl; wherein each alkyl group, heteroalkyl group, haloalkyl group, and cycloalkyl group is independently and optionally composed of 1 to 3 independently selected from a halogen group, -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 1-6Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Substitution of aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atom to which they are attached, they form groups optionally composed of one to three independent groups selected from halogen groups, -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 3- to 10-membered heterocyclic alkyl groups substituted with aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -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 R10 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 heteroaryl groups; or Two R atoms attached to the same carbon atom 6 Together they form oxidized, thiolated, or C-shaped compounds. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 Independently selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 8 Independently selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 8 They can be formed together by 1 to 3 independently selected halogen groups, -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 -NR13 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- to 10-membered heterocycloalkyl, C 6-10 C-substituted with aryl and 5 to 10 heteroaryl groups 3-10 cycloalkyl; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 11 Independently selected from H and 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 groups; Each R 12 Selected independently from 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 groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3 or 4.

[0042] In some cases, the compound is a compound of formula IIIa:

[0043] Formula IIIa Or its pharmaceutically acceptable salt.

[0044] In some cases, the compound is a compound of formula IIIb:

[0045] Formula IIIb Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -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 Aryl and 5- to 10-membered heteroaryl groups; and p is 0, 1, 2 or 3.

[0046] In some cases, the compound is a compound of formula IIIc:

[0047] Formula IIIc Or its pharmaceutically acceptable salt.

[0048] In some cases, the compound is a compound of formula IIId:

[0049] Formula IIId Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -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 Aryl and 5- to 10-membered heteroaryl groups; and p is 0, 1, 2 or 3.

[0050] In some cases, the 15-PGDH inhibitor is a compound of formula IIk:

[0051] Formula IIk Or its pharmaceutically acceptable salt, wherein: T, U, and Y are independently selected from N and CR. 6 The condition is that when U is N, at least one of T and Y is N; R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxygen; Each R 4 Independently selected from H and halogen groups; R 5 Selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 Selected from H, halogen, -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)R9 -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 7 and R 8 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; Each R 9 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; and p is 0, 1, or 2.

[0052] In some cases, the 15-PGDH inhibitor is a compound of formula IIm:

[0053] Formula IIm Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -NR 6 R7 -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 3-6 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxygen; Each R 4 Independently selected from halogen groups, -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 3-10cycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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 groups; R 5 Selected from halogen groups, -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 1-6Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and 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 groups; Each R 9 Selected independently from 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 groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2 or 3.

[0054] In some cases, the 15-PGDH inhibitor is a compound of formula IIq:

[0055] Formula IIq Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxygen; Each R 4 Independently selected from halogen groups, -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 heteroaryl groups; or Two Rs 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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 groups; R 5 Selected from halogen groups, -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 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and 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 groups; Each R 9 Selected independently from 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 groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2 or 3.

[0056] In some cases, the 15-PGDH inhibitor is a compound of formula IIIc:

[0057] Formula IIIc Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR12 -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 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxygen; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 Cycloalkyl; wherein each alkyl group, heteroalkyl group, haloalkyl group, and cycloalkyl group is independently and optionally composed of 1 to 3 independently selected from a halogen group, -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, C3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Substitution of aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atom to which they are attached, they form groups optionally composed of one to three independent groups selected from halogen groups, -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, C 6-10 3- to 10-membered heterocyclic alkyl groups substituted with aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -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 R10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms attached to the same carbon atom 6 Together they form an oxygen atom, and any remaining R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 and R 8 Independently selected from halogen groups, -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 -NR13 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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; and n is 0, 1, 2, 3 or 4.

[0058] In some cases, the 15-PGDH inhibitor is a compound selected from the group consisting of: ; ; ; ; ; ; ; ; ; ; ; ; ;and .

[0059] In some cases, the 15-PGDH inhibitor is a compound selected from the group consisting of: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;and .

[0060] In some cases, the 15-PGDH inhibitor is a compound selected from the group consisting of: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;and .

[0061] In some cases, the 15-PGDH inhibitor is a compound of formula IV, or a pharmaceutically acceptable salt thereof:

[0062] Formula IV, in, Ring Q is phenyl or a 5- to 10-membered heteroaryl group; Z is CR 1 Or N; Y is CR 2 Or N; R 1 It is 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 groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is 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 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 3 Independently selected from H, halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C8 heterocycloalkyl, wherein each is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -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- to 8-membered heteroaryl. Or two Rs 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A Yes -NR 5 R 5 or -OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; or R 5a And an R 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is optionally surrounded by one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, wherein each is optionally substituted by one or more R a replace; Each R 11Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, wherein each is optionally substituted by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is optionally surrounded by one or more R groups. a replace; Each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3 or 4.

[0063] In some cases, ring Q is a six-membered monocyclic heteroaryl group containing one, two, or three nitrogen atoms. In some cases, ring Q is phenyl, pyrimidinyl, or pyridinyl. In some cases, when Q is phenyl, then R... 3 One of them is not H.

[0064] In some cases, yes

[0065] in, X 1 X 2 X 3 and X 4 Each is independently N or CR 3 ; Each R 3 Independently selected from H, halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 replace; Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a Replace; and Each R a It is independently selected from halogens, -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.

[0066] In some cases, X 1 X 2 X 3 and X 4 Each is CR 3 In some cases, X 1 It is N; and X 2 X 3 and X 4 Each is CR 3 In some cases, X 1 and X 2 Each is N; and X 3 and X 4 Each is CR 3 In some cases, X 1 and X 3 Each is N; and X 2 and X 4 Each is CR 3 In some cases, X1 and X 4 Each is N; and X 2 and X 3 Each is CR 3 In some cases, X 1 X 2 and X 3 Each is N; and X 4 It is CR 3 In some cases, X 1 X 2 and X 4 Each is N; and X 3 It is CR 3 .

[0067] In some cases, each R 3 Independently selected from 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 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 cases, each R 3 Independently selected from H, halogens, -C(O)OR 10 -C(O)NR 8 R 9 And substituted or unsubstituted 5-membered heteroaryl groups.

[0068] In some cases, the compound has the structure of formula V, or a pharmaceutically acceptable salt thereof:

[0069] Formula V, in, Z is CR 1 Or N; X 1 Is it N or CR? 3a ; Y is CR 2 Or N; R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is 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 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; R 3a R 3b and R 3c Each is independently selected from H, halogen, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; among them Each R 13Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, wherein each is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -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- to 8-membered heteroaryl. Or two Rs 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A It is NR 5 R 5 OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; or R 5a And an R 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl groups; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a Replace; and Each R a It is independently selected from halogens, -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.

[0070] In some cases, X A It is NR 5 R 5 In some cases, X A OR 5 In some cases, Y is CR. 2 In some cases, Y is N.

[0071] In some cases, compounds of formula V have the structure of formula VIa, or a pharmaceutically acceptable salt thereof:

[0072] Formula VIa.

[0073] In some cases, compounds of formula V have the structure of formula VIb, or a pharmaceutically acceptable salt thereof:

[0074] Formula VIb.

[0075] In some cases, Z is N. In other cases, Z is CR. 1 In some cases, Z is CH.

[0076] In some cases, compounds of formula V have the structure of formula VIIa, or a pharmaceutically acceptable salt thereof:

[0077] Formula VIIa.

[0078] In some cases, compounds of formula V have the structure of formula VIIb, or a pharmaceutically acceptable salt thereof:

[0079] Equation VIIb.

[0080] In some cases, compounds of formula V have the structure of formula VIIc, or a pharmaceutically acceptable salt thereof:

[0081] Formula VIIc.

[0082] In some cases, compounds of formula V have the structure of formula VIId, or a pharmaceutically acceptable salt thereof:

[0083] Formula VIId.

[0084] In some cases, X 1 It is N. In some cases, R3b It is H; and R 3c Selected from halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

[0085] In some cases, R 3b It is H; and R 3c Selected from halogens, -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 11Substituted 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.

[0086] In some cases, R 3c It is H; and R 3b Selected from halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

[0087] In some cases, R 3c It is H; and R 3b Selected from halogens, -NR 8 R 9 -OR 10 -SR8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 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.

[0088] In some cases, X 1 It is CR 3a In some cases, R 3a and R 3b It is independently H or halogen; and R 3c Selected from halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10-C(O)OR 10 or -C(O)NR 8 R 9 .

[0089] In some cases, R 3c Selected from H, halogens, -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 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.

[0090] In some cases, R 3c It is -C(O)OR 10 -C(O)NR 8 R 9 A 5-membered heteroaryl group, either substituted or unsubstituted. In some cases, R 3a and R 3b Each is H.

[0091] In some cases, R 3a and R 3c It is independently H or halogen; and R 3b Selected from halogens, -CN, -NO2, -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 -NR12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

[0092] In some cases, R 3b Selected from H, halogens, -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 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.

[0093] In some cases, R 3b It is -C(O)OR 10 -C(O)NR 8 R 9 A 5-membered heteroaryl group, either substituted or unsubstituted.

[0094] In some cases, R 3a and R 3c Each is H. In some cases, R 3b and R 3c Each is either H or halogen; and R 3a Selected from halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

[0095] In some cases, R 3a Selected from H, halogens, -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 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.

[0096] In some cases, R 3a It is -C(O)OR 10-C(O)NR 8 R 9 A 5-membered heteroaryl group, either substituted or unsubstituted. In some cases, R 3b and R 3c Each is H. In some cases, each R 2 It is H. In some cases, R 5a And an R 6 They combine with the atoms to which they are attached to form C3-C6 cycloalkyl groups. In some cases, R 5a It is H. In some cases, R 5 It's H.

[0097] In some cases, R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, wherein each is substituted or unsubstituted by one or more R 6 Replacement. In some cases, R 4 It is a substituted or unsubstituted C1-C8 alkyl or a substituted or unsubstituted C1-C8 heteroalkyl, wherein each is substituted by one or more R 6 Replacement. In some cases, R 4 It is a substituted or unsubstituted C3-C8 cycloalkyl or a 4- to 8-membered heterocycloalkyl, wherein each is substituted by one or more R 6 replace.

[0098] In some cases, R 4 It is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl. In some cases, each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 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 heterocyclic alkyl. In some cases, each R 6 Independently, it is halogen, -OR 10 C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl. In some cases, each R 6 Independently, it is -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0099] In some cases, the compounds are selected from Table 4, or pharmaceutically acceptable salts thereof.

[0100] In some cases, the subjects had a disease or condition associated with elevated PGE-MUM levels. In some cases, the disease or condition associated with elevated PGE-MUM levels was related to muscle damage, injury, or atrophy. In some cases, the diseases or conditions associated with muscle damage, injury, or atrophy include acute muscle injury or trauma, soft tissue hand injury, muscular dystrophy, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), 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 dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject with spinal muscular atrophy can reduce the subject's PGE-MUM levels. In some cases, administration of a dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject with spinal muscular atrophy can improve the subject's symptoms of one or more spinal muscular atrophy conditions.

[0101] In some cases, the subject is an elderly subject. In some cases, the subject is at least 60 years old. In some cases, the disease or condition associated with elevated PGE-MUM levels is an age-related condition. In some cases, the age-related condition is sarcopenia. In some cases, administration of a dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject with sarcopenia can reduce the subject's PGE-MUM levels. In some cases, administration of a dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject with sarcopenia can improve one or more sarcopenia symptoms in the subject. Attached Figure Description

[0102] The novel features of the invention are specifically set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description of illustrative embodiments, which utilize the principles of the invention and are illustrated in the accompanying drawings: Figures 1A-1F This study demonstrates the effect of orally administered MF-300 on urinary PGE-MUM levels. Figure 1A This provides an overview of the experimental timeline used to assess the effects 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 A schematic diagram showing the mechanism by which MF-300 affects PGE-MUM levels by inhibiting 15-PGDH and the biolocation of a large number of PGE2 and its metabolites. Figure 1C This shows the baseline urinary PGE-MUM levels (normalized to creatinine) in CD rat groups that were administered the cauterizer, 30 mg / kg MF-300, or 60 mg / kg MF-300. Figure 1D This shows the urinary PGE-MUM levels (normalized to creatinine) on day 6 in CD rat groups that were administered the cauterizer, 30 mg / kg MF-300, or 60 mg / kg MF-300. Figure 1E The MF-300 levels in CD rats were shown over a 24-hour timeframe following a single dose or seven daily doses of 30 mg / kg MF-300. Figure 1F This shows the changes in PGE-MUM levels relative to baseline in CD rats that were administered the causative agent, 30 mg / kg MF-300, or 60 mg / kg MF-300.

[0103] Figures 2A-2C Experiments demonstrating the achievement of steady-state MF-300 levels in CD rats. Figure 2A This shows an overview of the experimental timeline used to evaluate the effects of daily oral administration of MF-300 (30 mg / kg or 60 mg / kg) over 14 days in male CD rats. Figure 2B The study showed the urinary PGE2 and PGE-MUM levels and the PGE2 / PGE-MUM ratio in CD rats that were administered a causative agent, 30 mg / kg MF-300, or 60 mg / kg MF-300 over 14 days. Figure 2C The effects of urinary PGE-MUM to creatinine ratio on baseline (day 0), day 7, and day 13 were compared in CD rats administered the mordant, 30 mg / kg MF-300, or 60 mg / kg MF-300.

[0104] Figures 3A-3B MF-300 was demonstrated in a spinal muscular atrophy (SMA) disease model (SMN). The role of 7 mice, also known as "Delta7 mice" (with SMN-C3). Figure 3A A schematic diagram showing the mechanism by which MF-300 reduces PGE2 metabolite levels by blocking 15-PGDH. Figure 3B The study showed the urinary PGE2 and PGE-MUM levels and the number of days with the PGE2 / PGE-MUM ratio in WT mice, Delta 7 mice treated with the cauterizer, or Delta 7 mice treated with 30 mg / kg MF-300 every other day.

[0105] Figure 4 The effects of MF-300 were demonstrated in adult and aged C57BL / 6 mice administered with a mediator, 10 mg / kg MF-300, 30 mg / kg MF-300, or 60 mg / kg MF-300. Detailed Implementation

[0106] This document 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 condition. This document also provides methods and compositions for identifying whether a subject is a candidate for treatment with a therapeutic agent, such as a 15-PGDH inhibitor. In some cases, the level of at least one biomarker in a subject is elevated relative to a control subject or control population. In some cases, the level of at least one biomarker in a subject is elevated relative to a subject who does not have a disease or condition associated with at least one biomarker. In some cases, the level of at least one biomarker in a subject is elevated relative to a predetermined threshold. In some cases, at least one biomarker includes p75ECD. In some cases, p75ECD includes or may be the extracellular domain (ECD) of p75ECD. In some cases, at least one biomarker includes PGE-MUM. PGE-MUM may also be referred to as PGE-M. In some cases, at least one biomarker includes both p75ECD and PGE-MUM. In some cases, the methods and compositions provided herein involve administering a 15-PGDH inhibitor to a subject with elevated levels of at least one biomarker, including p75ECD and / or PGE-MUM. In some cases, the methods and compositions provided herein involve measuring the levels of at least one biomarker (including p75ECD and / or PGE-MUM) in a subject (e.g., a biological sample from the subject). In some cases, the methods and compositions provided herein involve selecting or identifying a subject as eligible for treatment with or a candidate for treatment with a 15-PGDH inhibitor by identifying elevated levels of at least one biomarker (including p75ECD and / or PGE-MUM) in the subject.

[0107] In one aspect, this article provides methods for reducing p75ECD, PGE-MUM, or both levels in a subject. In some cases, the method involves administering a 15-PGDH inhibitor to the subject in an amount that effectively reduces the subject's p75ECD, PGE-MUM, or both levels.

[0108] On the other hand, this article provides methods for treating subjects with a 15-PGDH inhibitor. In some cases, the method includes identifying an elevation in the subject's p75ECD, PGE-MUM, or both levels relative to a control or exceeding a predetermined threshold. In some cases, the method also includes administering a 15-PGDH inhibitor to the subject to reduce their p75ECD, PGE-MUM, or both levels (e.g., when the subject's p75ECD, PGE-MUM, or both levels are elevated).

[0109] In another aspect, this article provides methods for selecting subjects to receive 15-PGDH inhibitor treatment. In some cases, the method includes providing or obtaining a biological sample from the subject. In some cases, the method also includes measuring the levels of p75ECD, PGE-MUM, or both in the biological sample. In some cases, the method also includes identifying the subject as a candidate for 15-PGDH inhibitor treatment when the levels of p75ECD, PGE-MUM, or both in the biological sample exceed a predetermined threshold or control level. In some cases, the method also includes administering a 15-PGDH inhibitor to the subject after identifying the subject as a candidate or suitable recipient for 15-PGDH inhibitor treatment.

[0110] In some cases, the methods provided herein involve administering the compositions of the invention, such as 15-PGDH inhibitors, to subjects (e.g., subjects with elevated levels of biomarkers, such as p75ECD, PGE-MUM). In some cases, elevated levels of biomarkers (e.g., p75ECD, PGE-MUM) are associated with elevated levels or enhanced activity of 15-PGDH. In some cases, the levels of biomarkers (e.g., p75ECD, PGE-MUM) can be reduced or decreased by inhibiting the function of 15-PGDH or by reducing the expression or content of 15-PGDH in subjects.

[0111] In some cases, the methods provided herein involve identifying elevated levels of at least one biomarker in a subject, such as p75ECD, PGE-MUM, or both. In some cases, the 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, the at least one biomarker (e.g., p75ECD, PGE-MUM) is elevated compared to a predetermined threshold level. In some cases, the at least one biomarker (e.g., p75ECD, PGE-MUM) is elevated compared to subjects who do not have a disease or condition associated with the at least one biomarker.

[0112] In some cases, identifying elevated levels of at least one biomarker (e.g., p75ECD, PGE-MUM) in a subject may involve obtaining or providing a biological sample from or already obtained from the subject. The presence of at least one biomarker (e.g., p75ECD, PGE-MUM) can be detected in the biological sample. The level of said at least one biomarker (e.g., p75ECD, PGE-MUM) can be measured in the biological sample, thereby indicating elevated levels of said at least one biomarker (e.g., p75ECD, PGE-MUM) in the subject. Any method can be used to detect or measure the biomarker in the biological sample, such as, but not limited to, Western blotting, enzyme-linked immunosorbent assay (ELISA), colorimetric protein assay, polymerase chain reaction (PCR), sequencing, etc.

[0113] In some cases, the biological sample is a body fluid. As used herein, the term "body fluid" refers to any fluid within an animal's body. Examples of body fluids include, but are not limited to, plasma, serum, blood, lymph, cerebrospinal fluid, synovial fluid, urine, saliva, mucus, sputum, and expectorant. Body fluid samples can be collected by any suitable method. In some cases, the biological sample is a blood sample. Blood samples may include whole blood or components thereof, such as plasma or serum. In some cases, the biological sample is urine.

[0114] When a subject is found to have elevated levels of at least one biomarker (e.g., p75ECD, PGE-MUM), that subject is selected for 15-PGDH inhibitor treatment. The 15-PGDH inhibitor may be administered to the subject multiple times as needed to lower the levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) in their body. In some cases, the levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) can be used to determine whether a subject has responded well to 15-PGDH inhibitor treatment. For example, when the levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) decrease due to the 15-PGDH inhibitor, the subject may be identified as having responded well to the 15-PGDH inhibitor. In other examples, when the levels of the at least one biomarker (e.g., p75ECD, PGE-MUM) do not decrease due to the 15-PGDH inhibitor, the subject may be identified as requiring further 15-PGDH inhibitor treatment. In other examples, when the level of at least one biomarker (e.g., p75ECD, PGE-MUM) does not decrease due to the 15-PGDH inhibitor, the subject may be identified as requiring further treatment in addition to the 15-PGDH inhibitor.

[0115] In some cases, the subject may have a disease or condition associated with the at least one biomarker or an elevated level thereof. In some cases, the subject may have a disease or condition associated with elevated p75ECD levels. In some cases, the subject may have a disease or condition associated with elevated PGE-MUM levels. In some cases, the subject may have a disease or condition associated with elevated levels of both p75ECD and PGE-MUM. The disease or condition may be any disease or condition associated with the at least one biomarker or an elevated level thereof. In some cases, administering a 15-PGDH inhibitor to the subject may treat a disease or condition associated with the at least one biomarker or an elevated level thereof (or one or more symptoms thereof).

[0116] In some cases, the disease or condition is a neurodegenerative disorder. In some cases, the neurodegenerative disorder is associated with elevated p75ECD levels (e.g., in urine). In some cases, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS). In some cases, the neurodegenerative disorder is Alzheimer's disease. In some cases, a neurodegenerative disorder (e.g., ALS, Alzheimer's disease) or one or more symptoms thereof can be treated by administering a 15-PGDH inhibitor to the subject.

[0117] In some cases, the subjects had a disease or condition associated with elevated PGE-MUM levels. In some cases, the disease or condition associated with elevated PGE-MUM levels was related to muscle damage, injury, or atrophy. In some cases, the diseases or conditions associated with muscle damage, injury, or atrophy include acute muscle injury or trauma, soft tissue hand injury, muscular dystrophy, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), 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 dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject with spinal muscular atrophy can reduce the subject's PGE-MUM levels. In some cases, administration of a dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject with spinal muscular atrophy can improve one or more symptoms of spinal muscular atrophy. Symptoms of spinal muscular atrophy may include muscle weakness, muscle atrophy, muscle tremors, or muscle spasms.

[0118] In some cases, the subject is an elderly subject. In some cases, the subject is at least 60 years old. In some cases, the disease or condition associated with elevated PGE-MUM levels is an age-related condition. In some cases, the age-related condition is sarcopenia. In some cases, administration of a dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject with sarcopenia can reduce the subject's PGE-MUM levels. In some cases, administration of a dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject with sarcopenia can improve one or more sarcopenia symptoms in the subject. Sarcopenia symptoms may include muscle weakness, muscle atrophy, decreased muscle volume, decreased grip strength, loss of endurance, or impaired motor function.

[0119] A 15-PGDH inhibitor may be administered to the subject to reduce the levels of biomarkers (e.g., p75ECD, PGE-MUM) in their body. In some embodiments, effective doses of the 15-PGDH inhibitor include about 1 mg / kg (or about 1 MPK), about 3 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, or about 100 mg / kg. In some embodiments, an effective dose of a 15-PGDH inhibitor includes at least about 1 mg / kg (also known 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, an effective dose of a 15-PGDH inhibitor includes less than about 1 mg / kg (also known 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 implementations, effective doses of the 15-PGDH inhibitor include approximately 0.1 MPK, approximately 0.2 MPK, approximately 0.3 MPK, approximately 0.4 MPK, approximately 0.5 MPK, approximately 0.6 MPK, approximately 0.7 MPK, approximately 0.8 MPK, approximately 0.9 MPK, approximately 1 MPK, approximately 1.1 MPK, approximately 1.2 MPK, approximately 1.3 MPK, approximately 1.4 MPK, approximately 1.5 MPK, approximately 1.6 MPK, approximately 1.7 MPK, approximately 1.8 MPK, approximately 1.9 MPK, approximately 2 MPK, approximately 2.1 MPK, approximately 2.2 MPK, approximately 2.3 MPK, approximately 2.4 MPK, approximately 2.5 MPK, approximately 2.6 MPK, approximately 2.7 MPK, approximately 2.8 MPK, and approximately... 2.9 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 implementations, the effective dose of the 15-PGDH inhibitor includes 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, and at least about 2. 9MPK, at least about 3MPK, at least about 3.1MPK, at least about 3.2MPK, at least about 3.3MPK, at least about 3.4MPK, at least about 3.5MPK, at least about 3.6MPK, at least about 3.7MPK, at least about 3.8MPK, at least about 3.9MPK, at least about 4MPK, at least about 4.1MPK, at least about 4.2MPK, at least about 4.3MPK, at least about 4.4MPK, at least about 4.5MPK, at least about 4.6MPK, at least about 4.7MPK, at least about 4.8MPK, at least about 4.9MPK, at least about 5MPK, at least about 5.1MPK, at least about 5.2MPK, at least about 5.3MPK, at least about 5.4MPK, at least about 5.5MPK, at least about 5.6MPK, at least about 5.7MPK, at least about 5.8MPK, at least about 5.9MPK, or at least about 6MPK.In some implementations, effective doses of the 15-PGDH inhibitor include less than about 0.1 MPK, less than about 0.2 MPK, less than about 0.3 MPK, less than about 0.4 MPK, less than about 0.5 MPK, less than about 0.6 MPK, less than about 0.7 MPK, less than about 0.8 MPK, less than about 0.9 MPK, less than about 1 MPK, less than about 1.1 MPK, less than about 1.2 MPK, less than about 1.3 MPK, less than about 1.4 MPK, less than about 1.5 MPK, less than about 1.6 MPK, less than about 1.7 MPK, less than about 1.8 MPK, less than about 1.9 MPK, less than about 2 MPK, less than about 2.1 MPK, less than about 2.2 MPK, less than about 2.3 MPK, less than about 2.4 MPK, less than about 2.5 MPK, less than about 2.6 MPK, less than about 2.7 MPK, less than about 2.8 MPK, and less than about 2. 9 MPK, less than about 3 MPK, less than about 3.1 MPK, less than about 3.2 MPK, less than about 3.3 MPK, less than about 3.4 MPK, less than about 3.5 MPK, less than about 3.6 MPK, less than about 3.7 MPK, less than about 3.8 MPK, less than about 3.9 MPK, less than about 4 MPK, less than about 4.1 MPK, less than about 4.2 MPK, less than about 4.3 MPK, less than about 4.4 MPK, less than about 4.5 MPK, less than about 4.6 MPK, less than about 4.7 MPK, less than about 4.8 MPK, less than about 4.9 MPK, less than about 5 MPK, less than about 5.1 MPK, less than about 5.2 MPK, less than about 5.3 MPK, less than about 5.4 MPK, less than about 5.5 MPK, less than about 5.6 MPK, less than about 5.7 MPK, less than about 5.8 MPK, less than about 5.9 MPK, or less than about 6 MPK.In some implementations, effective doses of the 15-PGDH inhibitor include 0.5 MPK to 5 MPK, 0.6 MPK to 5 MPK, 0.7 MPK to 5 MPK, 0.8 MPK to 5 MPK, 0.9 MPK to 5 MPK, 1 MPK to 5 MPK, 1.1 MPK to 5 MPK, 1.2 MPK to 5 MPK, 1.3 MPK to 5 MPK, 1.4 MPK to 5 MPK, 1.5 MPK to 5 MPK, 1.6 MPK to 5 MPK, 1.7 MPK to 5 MPK, 1.8 MPK to 5 MPK, 1.9 MPK to 5 MPK, 2 MPK to 5 MPK, 2.1 MPK to 5 MPK, 2.2 MPK to 5 MPK, 2.3 MPK to 5 MPK, 2.4 MPK to 5 MPK, 2.5 MPK to 5 MPK, 2.6 MPK to 5 MPK, and so on. K to 5MPK, 2.7MPK to 5MPK, 2.8MPK to 5MPK, 2.9MPK to 5MPK, 3MPK to 5MPK, 3.1MPK to 5MPK, 3.2MPK to 5MPK, 3.3MPK to 5MPK, 3.4MPK to 5MPK, 3.5MPK to 5MPK, 3.6MPK to 5MPK, 3.7MPK to 5MPK, 3.8MPK to 5MPK, 3.9MPK to 5MPK, 4MPK to 5MPK, 4.1MPK to 5MPK, 4.2MPK to 5MPK, 4.3MPK to 5MPK, 4.4MPK to 5MPK, 4.5MPK to 5MPK, 4.6MPK to 5MPK, 4.7MPK to 5MPK, 4.8MPK to 5MPK, or 4.9MPK to 5MPK.

[0120] 15-PGDH inhibitors can be administered to subjects via any suitable route of administration. In some cases, 15-PGDH inhibitors can be administered to subjects via one or more oral, intramuscular, intrathecal, intravenous, intraperitoneal, intra-arterial, intradermal, or subcutaneous routes of administration.

[0121] In some embodiments, the 15-PGDH inhibitor may be administered to the subject via 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 cases, the subject is a mammal. In some cases, the subject is a human.

[0122] 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.

[0123] In some cases, the 15-PGDH inhibitor is a small molecule. In some cases, the small molecule is an orally bioavailable small molecule.

[0124] In some embodiments, the 15-PGDH inhibitor is a compound of formula I:

[0125] Formula I Or its pharmaceutically acceptable salt, wherein: X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, -SO2CH2-; Each Y is independently selected from N and CR 11 ; Each R 1 Independently selected from halogen groups, -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 groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxidized or thiolated compounds; Each R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and 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 groups; Each R 9 Selected independently from 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 groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 11 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The condition is that the compound of formula I is not , , or .

[0126] 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-.

[0127] In some implementations, each Y is independently selected from N and CR. 11 In some implementations, each Y is N. In some implementations, each Y is CR. 11 In some implementations, one Y is N, and the other Y is CR. 11 .

[0128] In some implementations, each R 1 Independently selected from halogen groups, -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, C 6-10 Aryl and 5- to 10-membered heteroaryl; in some embodiments, each R 1 Independently selected from halogen groups, -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 In some implementations, each R 1 Independently selected from halogen groups, -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 In some implementations, each R 1 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 and -C(O)OR 8 .

[0129] In some implementation schemes, R 2 It is H, and R 3 It is -CF3. In some implementations, R 2 and R 3Together they form an oxygen atom. In some implementations, R 2 and R 3 Together they form thiolated compounds.

[0130] In some implementations, each R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 4 Independently selected from halogen groups, -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 In some implementations, each R 4Independently selected from halogen groups, -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 In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 and -C(O)OR 8 .

[0131] In some implementations, each R 5 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 5 Independently selected from halogen groups, -NR 6R 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 In some implementations, each R 5 Independently selected from halogen groups, -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 In some implementations, each R 5 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 and -C(O)OR 8 .

[0132] In some implementation schemes, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C.1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0133] In some implementations, each R 8 Independently selected from H and 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 groups. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R 8 Independently selected from H and C 1-6 alkyl.

[0134] In some implementations, each R 9 Selected independently from 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 groups. In some embodiments, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R 9 Selected independently from C 1-6 alkyl.

[0135] In some implementations, each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C3-10 Cycloalkyl. In some embodiments, each R 10 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 10 Independently selected from H and C 1-6 alkyl.

[0136] In some implementations, each R 11 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 11 Independently selected from halogen groups, -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 In some implementations, each R 11 Independently selected from halogen groups, -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 In some implementations, each R 11 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 and -C(O)OR 8 .

[0137] 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.

[0138] 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.

[0139] In some implementations, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4. In some implementations, p is 5. In some implementations, p is 6. In some implementations, p is 7. In some implementations, p is 8. In some implementations, p is 9. In some implementations, p is 10.

[0140] In some embodiments, the compound is a compound of formula Ia:

[0141] Formula Ia Or its pharmaceutically acceptable salt.

[0142] In some embodiments, the compound is a compound of formula Ib:

[0143] Formula Ib Or its pharmaceutically acceptable salt.

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

[0145] Formula II Or its pharmaceutically acceptable salt, wherein: T, U, W, X, and Y are independently selected from N and CR. 5 ; S, V, and Z are independently selected from N and C; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the alkyl group, the cycloalkyl group, the aryl group, or the heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxidized or thiolated compounds; Each R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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)NR6 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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and 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 groups; Each R 9 Selected independently from 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 groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The condition is that the compound of formula II is not , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0146] In some implementations, T, U, W, X, and Y are independently selected from N and CR. 5 In some implementations, at least one of T, U, W, X, and Y is N, and the remainder is CR. 5 In some implementations, at least two of T, U, W, X, and Y are N, and the remainder are CR. 5 In some implementations, at least three of T, U, W, X, and Y are N, and the remainder are CR. 5In some implementations, at least four of T, U, W, X, and Y are N, and the remainder are CR. 5 In some implementations, T, U, W, X, and Y are CR 5 In some implementations, T, U, W, X, and Y are N.

[0147] 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 remainder is C. In some embodiments, at least two of S, V, and Z are N, and the remainder is C. In some embodiments, S, V, and Z are N. In some embodiments, S, V, and Z are C.

[0148] In some implementation schemes, R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the alkyl group, the cycloalkyl group, the aryl group, or the heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with cycloalkyl groups and 5 to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 6-10Aryl and 5 to 10 heteroaryl groups; wherein the alkyl, the aryl, or the heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with cycloalkyl groups and 5 to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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, C3-6 Substitution with cycloalkyl groups and 5 to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 In some implementations, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 Substituents are substituted.

[0149] In some implementation schemes, R 2 It is H, and R 3 It is -CF3. In some implementations, R 2 and R 3 Together they form an oxygen atom. In some implementations, R 2 and R 3 Together they form thiolated compounds.

[0150] In some implementations, each R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 4 Independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, each R... 4 Independently selected from halogen groups, -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 In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 In some implementations, each R 4 It is a halogen group. In some implementations, each R 4 It's fluorine.

[0151] In some implementations, two R 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, the two R groups... 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, the two R groups... 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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 In some implementations, two Rs4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 In some implementations, two Rs 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 The groups are independently selected from halogen groups. In some embodiments, the two R groups are... 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 It's fluorine.

[0152] In some implementations, each R 5 Independently selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 5 Independently selected from H, halogen, -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 Halogenated alkyl groups. In some embodiments, each R... 5 Independently selected from H, halogen, -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 In some implementations, each R 5 Independently selected from H, halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 In some implementations, each R 5 It is independently selected from H and halogen groups.

[0153] In some implementation schemes, R6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0154] In some implementations, each R 8 Independently selected from H and 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 groups. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 8 Independently selected from H and C 1-6 alkyl.

[0155] In some implementations, each R 9 Selected independently from 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 groups. In some embodiments, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C1-6 Halogenated alkyl groups. In some embodiments, each R... 9 Selected independently from C 1-6 alkyl.

[0156] In some implementations, each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, each R 10 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 10 Independently selected from H and C 1-6 alkyl.

[0157] In some implementations, n is 1, 2, 3, or 4. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0158] In some implementations, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is 5. In some implementations, m is 6. In some implementations, m is 7. In some implementations, m is 8. In some implementations, m is 9. In some implementations, m is 10.

[0159] In some embodiments, the compound is a compound of formula IIa:

[0160] Formula IIa Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

[0161] 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.

[0162] In some embodiments, the compound is a compound of formula IIb:

[0163] Formula IIb Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

[0164] 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.

[0165] In some embodiments, the compound is a compound of formula IIc:

[0166] Formula IIc Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4 or 5.

[0167] In some implementations, p is 0, 1, 2, 3, 4, or 5. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4. In some implementations, p is 5.

[0168] In some embodiments, the compound is a compound of formula IId:

[0169] Formula IId Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0170] In some implementations, p is 0, 1, 2, 3, or 4. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

[0171] In some embodiments, the compound is a compound of formula IIe:

[0172] Formula IIe Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0173] In some implementations, p is 0, 1, 2, 3, or 4. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

[0174] In some embodiments, the compound is a compound of formula IIf:

[0175] Formula IIf Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0176] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0177] In some embodiments, the compound is a compound of formula IIg:

[0178] Formula IIg Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0179] In some implementations, p is 0, 1, 2, 3, or 4. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

[0180] In some embodiments, the compound is a compound of formula IIh:

[0181] Formula IIh Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0182] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0183] In some embodiments, the compound is a compound of formula IIi:

[0184] Formula IIi Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0185] In some implementations, p is 0, 1, 2, 3, or 4. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

[0186] In some embodiments, the compound is a compound of formula IIj:

[0187] Formula IIj Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0188] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0189] In some embodiments, the compound is a compound of formula IIn:

[0190] Formula IIn Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0191] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0192] In some embodiments, the compound is a compound of formula IIp:

[0193] Formula IIp Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0194] In some implementations, p is 0, 1, 2, 3, or 4. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

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

[0196] Formula III Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the alkyl group, the cycloalkyl group, the aryl group, or the heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution of aryl and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxidized or thiolated compounds; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl; wherein each alkyl group, heteroalkyl group, haloalkyl group, and cycloalkyl group is independently and optionally composed of 1 to 3 independently selected from a halogen group, -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- to 10-membered heterocycloalkyl, C 6-10 Substitution of aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atom to which they are attached, they form groups optionally composed of one to three independent groups selected from halogen groups, -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 3- to 10-membered heterocyclic alkyl groups substituted with aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -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, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms attached to the same carbon atom 6 Together they form oxidized, thiolated, or C-shaped compounds. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 Independently selected from H, halogen, -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 9R 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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 8 Independently selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 8 They can be formed together by 1 to 3 independently selected halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R12 -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- to 10-membered heterocycloalkyl, C 6-10 C-substituted with aryl and 5 to 10 heteroaryl groups 3-10 cycloalkyl; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 11 Independently selected from H and 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 groups; Each R 12 Selected independently from 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 groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; m is 1 or 2; and n can be 0, 1, 2, 3, or 4.

[0197] In some implementations, each X is independently selected from N and CR. 7 In some implementations, at least one X is N, and the remainder is CR. 7In some implementations, at least two X's are N, and the remainder are CR's. 7 In some implementations, each X is N. In some implementations, each X is CR. 7 .

[0198] In some implementations, Y is selected from O, S, SO2, and C(R) 8 2. In some implementations, Y is O. In some implementations, Y is S. In some implementations, Y is SO2. In some implementations, Y is C(R) 8 )2.

[0199] In some implementation schemes, R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the alkyl group, the cycloalkyl group, the aryl group, or the heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein the cycloalkyl, the aryl, or the heteroaryl is optionally composed of 1 to 3 independently selected from halogen, -NR 9 R10 -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 Substitution with aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 6-10Aryl and 5- to 10-membered heteroaryl substituents; in some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substituents of haloalkyl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substituents are substituted. In some embodiments, R 1 Selected from C6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 Substituents are substituted.

[0200] In some implementation schemes, R 2 It is H, and R 3 It is -CF3. In some implementations, R 2 and R 3 Together they form an oxygen atom. In some implementations, R 2 and R 3 Together they form thiolated compounds.

[0201] In some implementation schemes, R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl; wherein each alkyl group, heteroalkyl group, haloalkyl group, and cycloalkyl group is independently and optionally composed of 1 to 3 independently selected from a halogen group, -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- to 10-membered heterocycloalkyl, C 6-10Substitution with aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is optionally composed of 1 to 3 independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Substitution with aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 SO2NR9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Substituents of haloalkyl groups. In some embodiments, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substituents are substituted. In some embodiments, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is optionally composed of 1 to 3 independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 Substituents are substituted.

[0202] In some implementation schemes, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form groups optionally composed of one to three independent groups selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R12 -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 3- to 10-membered heterocyclic alkyl groups substituted with aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form groups optionally composed of one to three independent groups selected from halogen groups, -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 The alkyl group is a 3- to 10-membered heterocyclic alkyl group substituted with a haloalkyl group. In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form groups optionally composed of one to three independent groups selected from halogen groups, -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 and -NR 13 SO2NR 9 R 10 The substituent is a 3- to 10-membered heterocyclic alkyl group. In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form groups optionally composed of one to three independent groups selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 Substituents are substituted 3 to 10-membered heterocyclic alkyl groups.

[0203] In some implementations, each R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 6 Independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, each R... 6 Independently selected from halogen groups, -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 In some implementations, each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR9 R 10 .

[0204] In some implementations, two R atoms attached to the same carbon atom 6 Together they form oxidized, thiolated, or C-shaped compounds. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, two R groups attached to the same carbon atom... 6 Together they form oxidized, thiolated, or C-shaped compounds. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, two R groups attached to the same carbon atom... 6 Together they form oxidized, thiolated, or C-shaped compounds. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -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 In some implementations, two R atoms attached to the same carbon atom... 6 Together they form oxidized, thiolated, or C-shaped compounds. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0205] In some implementations, each R 7 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R12 -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 7 Independently selected from H, halogen, -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 Halogenated alkyl groups. In some embodiments, each R... 7 Independently selected from H, halogen, -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 In some implementations, each R 7 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0206] In some implementations, each R 8 Independently selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 8 Independently selected from H, halogen, -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 and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 8 Independently selected from H, halogen, -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 In some implementations, each R 8 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0207] In some implementations, two R 8 Together they form C 3-10 Cycloalkyl group, which may optionally be composed of 1 to 3 groups independently selected from halogen groups, -NR 9 R10 -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- to 10-membered heterocycloalkyl, C 6-10 The aryl group is substituted with substituents of 5 to 10 heteroaryl groups. In some embodiments, the two R groups are... 8 Together they form C 3-10 Cycloalkyl group, which may optionally be composed of 1 to 3 groups independently selected from halogen groups, -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 The alkyl halogroups are substituted. In some embodiments, the two R groups are substituted. 8 Together they form C 3-10Cycloalkyl group, which may optionally be composed of 1 to 3 groups independently selected from halogen groups, -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 The substituents are substituted. In some embodiments, the two R groups are substituted. 8 Together they form C 3-10 Cycloalkyl group, which may optionally be composed of 1 to 3 groups independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 Substitution is performed using substituents.

[0208] In some implementation schemes, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0209] In some implementations, each R 11 Independently selected from H and C 1-6 Alkyl, C1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 11 Independently selected from H and C 1-6 alkyl.

[0210] In some implementations, each R 12 Selected independently from 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 groups. In some embodiments, each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 12 Selected independently from C 1-6 alkyl.

[0211] In some implementations, each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, each R 13 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 13 Independently selected from H and C 1-6 alkyl.

[0212] In some implementations, m is 1 or 2. In some implementations, m is 1. In some implementations, m is 2.

[0213] In some implementations, n is 0, 1, 2, 3, or 4. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0214] In some embodiments, the compound is a compound of formula IIIa:

[0215] Formula IIIa Or its pharmaceutically acceptable salt.

[0216] In some embodiments, the compound is a compound of formula IIIb:

[0217] Formula IIIb Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -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 Aryl and 5- to 10-membered heteroaryl groups; p is 0, 1, 2 or 3.

[0218] In some implementations, each R 14 Independently selected from halogen groups, -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 Aryl groups, and 5- to 10-membered heteroaryl groups. In some embodiments, each R 14 Independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, each R... 14 Independently selected from halogen groups, -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 In some implementations, each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 In some implementations, each R 14 It can be halogen independently. In some implementations, each R... 14 It can be fluorine on its own.

[0219] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0220] In some embodiments, the compound is a compound of formula IIIc.

[0221]

[0222] Formula IIIc Or its pharmaceutically acceptable salt.

[0223] In some embodiments, the compound is a compound of formula IIId.

[0224]

[0225] Formula IIId Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -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 -NR13 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 Aryl groups, and 5- to 10-membered heteroaryl groups; p is 0, 1, 2 or 3.

[0226] In some implementations, each R 14 Independently selected from halogen groups, -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 Aryl groups, and 5- to 10-membered heteroaryl groups. In some embodiments, each R 14 Independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, each R... 14 Independently selected from halogen groups, -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 In some implementations, each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 In some implementations, each R 14 It can be halogen independently. In some implementations, each R... 14 It can be fluorine on its own.

[0227] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0228] In some implementations, the 15-PGDH inhibitor is a compound of formula IIk.

[0229]

[0230] Formula IIk Or its pharmaceutically acceptable salt, wherein: T, U, and Y are independently selected from N and CR. 6 However, when U is N, at least one of T and Y is N; R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl, wherein the aryl or heteroaryl may optionally be composed of 1 to 3 independently selected from halogen, -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 groups and 5- to 10-membered heteroaryl groups are substituted; R 2 It is H and R 3 It is -CF3; or R 2 and R 3 Together they form oxygen; Each R 4 Independently selected from H and halogens; R 5 Selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl groups, and 5 to 10 heteroaryl groups.

[0231] R 6 Selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 7 and R 8 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; Each R 9 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; p is 0, 1, or 2.

[0232] In some embodiments, T, U, and Y are independently selected from N and CR each time they occur. 6 However, 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 remainder is CR. 6 In some embodiments, two of T, U, and Y are N, and the remainder 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 remainder is N. In some embodiments, T, U, and Y are all N. In some embodiments, T, U, and Y are all CR. 6 .

[0233] In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group may optionally be composed of 1 to 3 independently selected halogen groups, -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 -NR11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Substitution with cycloalkyl groups and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group may optionally be composed of 1 to 3 independently selected halogen groups, -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 Substituents of haloalkyl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group may optionally be composed of 1 to 3 independently selected halogen groups, -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)NR7 R 8 -NR 11 SO2R 9 and -NR 11 SO2NR 7 R 8 Substituents are substituted. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group may optionally be composed of 1 to 3 independently selected halogen groups, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 and -C(O)NR 7 R 8 Substituents are substituted.

[0234] In some embodiments, R 2 It is H, R 3 It is -CF3. In some embodiments, R 2 and R 3 Together they form oxygen.

[0235] In some embodiments, each R 4 Independently selected from H and halogens. In some implementations, each R... 4 Independently selected from H and fluorine. In some embodiments, each R 4 It is H. In some implementations, each R 4 It is fluorine. In some implementations, an R 4 It's H, and another R. 4 It's fluorine.

[0236] In some implementation schemes, R 5 Selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 5 Selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, R 5 Selected from halogen groups, -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 8In some implementations, R 5 Selected from halogen groups, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 and -C(O)NR 7 R 8 .

[0237] In some implementation schemes, R 6 Selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 6 Selected from H, halogen, -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 -NR11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 6 Selected from H, halogen, -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 In some implementations, R 6 Selected from H, halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 and -C(O)NR 7 R 8 .

[0238] In some implementation schemes, R 7 and R 8 Selected independently from H and C in each location 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 Cycloalkyl. In some embodiments, R 7 and R 8 Selected independently from H and C in each location 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 7 and R 8 Selected independently from H and C in each place 1-6 alkyl.

[0239] In some implementations, each R 9 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 9 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 9 Independently selected from H and C 1-6 alkyl.

[0240] In some implementations, each R 10 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 10 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 10 Selected independently from C 1-6 alkyl.

[0241] In some implementations, each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 Cycloalkyl. In some embodiments, each R 11 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 11 Independently selected from H and C 1-6 alkyl.

[0242] 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.

[0243] In some implementations, the 15-PGDH inhibitor is a compound of formula IIm:

[0244] Formula IIm Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; Each R 4 Independently selected from halogen groups, -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, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms to which they are attached and the atoms spaced in between, they form C 3-10 cycloalkyl, and any remaining R 4 Each is independently selected from halogen groups, -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 heteroaryl compounds.

[0245] R 5 Selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl compounds.

[0246] R 6 and R 7 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl.

[0247] Each R 8 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl compounds.

[0248] Each R 9 Each was independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl compounds.

[0249] Each R 10 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl.

[0250] n is 1, 2, 3 or 4.

[0251] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0252] p is 0, 1, 2 or 3.

[0253] In some implementation schemes, R 1 Selected from C 6-10Aryl and 5 to 10 heteroaryl groups, wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with cycloalkyl groups and 5 to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups, wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 1-6Substituents of haloalkyl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups, wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substituents are substituted. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups, wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 Substituents are substituted.

[0254] In some implementation schemes, R 2 It is H and R 3 It is -CF3. In some implementations, R 2 and R 3 Together they form an oxygen group.

[0255] In some implementations, each R 4 Each is independently selected from halogen groups, -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, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 4 Each is independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, each R... 4 Each is independently selected from halogen groups, -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 and -NR 10 SO2NR 6 R 7 In some implementations, each R 4 Each is independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 In some implementations, each R 4 Each is independently selected from halogens. In some implementations, each R... 4 It's fluorine.

[0256] In some implementations, two R 4 Together with the carbon atoms to which they are attached and the atoms spaced in between, they form C 3-10 cycloalkyl, and any remaining R 4 Each is independently selected from halogen groups, -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 groups. In some embodiments, the two R groups... 4Together with the carbon atoms to which they are attached and any atoms in between, they form C 3-10 cycloalkyl, and any remaining R 4 Each is independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, the two R groups... 4 Together with the carbon atoms to which they are attached and any atoms in between, they form C 3-10 cycloalkyl, and any remaining R 4 Each is independently selected from halogen groups, -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 In some implementations, two Rs 4 Together with the carbon atoms to which they are attached and any atoms in between, they form C3-10 cycloalkyl, and any remaining R 4 Each is independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0257] In some implementation schemes, R 5 Selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 5 Selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, R 5 Selected from halogen groups, -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 In some implementations, R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0258] In some implementation schemes, R 6 and R 7 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, R 6 and R 7 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups. In some embodiments, R 6 and R 7 Each is independently selected from H and C. 1-6alkyl.

[0259] In some implementations, each R 8 Each is independently selected from H and 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 groups. In some embodiments, each R 8 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 8 Each is independently selected from H and C. 1-6 alkyl.

[0260] In some implementations, each R 9 Each was independently selected from 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 groups. In some embodiments, each R 9 Each was independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups. In some embodiments, each R... 9 Each was independently selected from C 1-6 alkyl.

[0261] In some implementations, each R 10 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, each R 10 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 10 Independently selected from H and C 1-6 alkyl.

[0262] In some implementations, n is 1, 2, 3, or 4. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0263] In some implementations, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is 5. In some implementations, m is 6. In some implementations, m is 7. In some implementations, m is 8. In some implementations, m is 9. In some implementations, m is 10.

[0264] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0265] In some implementations, the 15-PGDH inhibitor is a compound of formula IIq:

[0266] Formula IIq Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution of cycloalkyl groups and 5- to 10-membered heteroaryl groups; R 2 It is H and R 3 It is -CF3; or R 2 and R 3 Together they form oxygen; Each R 4 Independently selected from halogen groups, -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 heteroaryl groups; or Two Rs 4 Together with the carbon atoms to which they are attached and the atoms spaced in between, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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 R7 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 groups; R 5 Selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and 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 groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 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.

[0267] In some implementation schemes, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substituents in cycloalkyl groups and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 6R 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 Substituents in the haloalkyl group. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substituents are substituted in R. In some embodiments, R... 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 Substituents in the group.

[0268] In some implementation schemes, R 2 It is H and R 3 It is -CF3. In some implementations, R 2 and R3 Together they form oxygen.

[0269] In some implementations, each R 4 Independently selected from halogen groups, -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 groups. In some embodiments, each R 4 Independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, each R...4 Independently selected from halogen groups, -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 In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 In some implementations, each R 4 The halogen is selected independently. In some implementations, each R... 4 It's fluorine.

[0270] In some implementations, two R 4 Together with the carbon atoms to which they are attached and any atoms in between, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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 groups. In some embodiments, the two R groups... 4 Together with the carbon atoms to which they are attached and any atoms in between, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, the two R groups... 4 Together with the carbon atoms to which they are attached and any atoms in between, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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 10C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, two Rs 4 Together with the carbon atoms to which they are attached and any atoms in between, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0271] In some implementation schemes, R 5 Optional from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 5 Optional from halogen groups, -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 Halogenated alkyl groups. In some embodiments, R 5 Optional from halogen groups, -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 In some implementations, R 5 Optional from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0272] In some implementation schemes, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0273] In some implementations, each R 8 Independently selected from H and 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 groups. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 8 Independently selected from H and C 1-6 alkyl.

[0274] In some implementations, each R 9 Selected independently from 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 groups. In some embodiments, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 9 Selected independently from C 1-6 alkyl.

[0275] In some implementations, each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, each R 10 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 10 Independently selected from H and C1-6 alkyl.

[0276] In some implementations, n is 1, 2, 3, or 4. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0277] In some implementations, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is 5. In some implementations, m is 6. In some implementations, m is 7. In some implementations, m is 8. In some implementations, m is 9. In some implementations, m is 10.

[0278] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0279] In some implementations, the 15-PGDH inhibitor is a compound of formula IIIc:

[0280] Formula IIIc Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 -NR13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 Cycloalkyl; wherein each alkyl group, heteroalkyl group, haloalkyl group, and cycloalkyl group is optionally composed of 1 to 3 independently selected from a halogen group, -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- to 10-membered heterocycloalkyl, C 6-10 Substitution of aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atom to which they are attached, they form 3 to 10-membered heterocyclic alkyl groups, which are optionally composed of 1 to 3 independently selected halogen groups, -NR groups, etc. 9R 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, C 6-10 The aryl group and 5 to 10 heteroaryl group are substituted with 1 to 3 substituents.

[0281] Each R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms attached to the same carbon atom 6 Together they form an oxo group, and any remaining R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl compounds.

[0282] Each R 7 and R 8 Independently selected from halogen groups, -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, C1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl compounds.

[0283] R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 Cycloalkyl.

[0284] Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl compounds.

[0285] Each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl compounds.

[0286] Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; n can be 0, 1, 2, 3, or 4.

[0287] In some implementations, each X is independently selected from N and CR. 7 In some implementations, at least one X is N, and the remainder is CR. 7 In some implementations, at least two X's are N, and the remainder are CR's. 7 In some implementations, each X is N. In some implementations, each X is CR. 7 .

[0288] In some implementations, Y is selected from O, S, SO2, and C(R) 8 2. In some implementations, Y is O. In some implementations, Y is S. In some implementations, Y is SO2. In some implementations, Y is C(R) 8 )2.

[0289] In some implementation schemes, R 1Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected halogen groups, -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 Substitution with cycloalkyl groups and 5 to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected halogen groups, -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 1-6Substituents of haloalkyl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected halogen groups, -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 Substituents are substituted. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 Substituents are substituted.

[0290] In some implementation schemes, R 2 It is H, R 3 It is -CF3. In some implementations, R 2 and R 3 Together they form an oxygen group.

[0291] In some implementation schemes, R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl; wherein each alkyl group, heteroalkyl group, haloalkyl group, and cycloalkyl group is optionally composed of 1 to 3 independently selected from a halogen group, -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- to 10-membered heterocycloalkyl, C 6-10 Substitution with aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Each was independently selected from C 3-10 Cycloalkyl; wherein each cycloalkyl group is optionally composed of 1 to 3 independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10Substitution with aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Each was independently selected from C 3-10 Cycloalkyl; wherein each cycloalkyl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substituents of haloalkyl groups. In some embodiments, R 4 and R 5 Each was independently selected from C 3-10 Cycloalkyl; wherein each cycloalkyl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substituents are substituted. In some embodiments, R4 and R 5 Each was independently selected from C 3-10 Cycloalkyl; wherein each cycloalkyl group is optionally composed of 1 to 3 independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 Substituents are substituted.

[0292] In some implementation schemes, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form a 3- to 10-membered heterocyclic alkyl group, which is optionally composed of 1 to 3 independently selected halogen groups, -NR groups, etc. 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 Substitution with aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form a 3- to 10-membered heterocyclic alkyl group, which is optionally composed of 1 to 3 independently selected halogen groups, -NR groups, etc. 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR12 -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 Substituents of haloalkyl groups. In some embodiments, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form a 3- to 10-membered heterocyclic alkyl group, which is optionally composed of 1 to 3 independently selected halogen groups, -NR groups, etc. 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 Substituents are substituted. In some embodiments, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form a 3- to 10-membered heterocyclic alkyl group, which is optionally composed of 1 to 3 independently selected halogen groups, -NR groups, etc. 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 Substituents are substituted.

[0293] In some implementations, each R6 Each is independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 6 Each is independently selected from halogen groups, -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 Halogenated alkyl groups. In some embodiments, each R... 6 Each is independently selected from halogen groups, -NR 9 R10 -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 In some implementations, each R 6 Each is independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0294] In some implementations, two R atoms attached to the same carbon atom 6 Together they form an oxo group, and any remaining R 6 Each can be independently selected from halogen groups and -NR groups. 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, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, two R groups attached to the same carbon atom... 6 Together they form an oxo group, and any remaining R 6 Each can be independently selected from halogen groups and -NR groups. 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 Halogenated alkyl groups. In some embodiments, two R groups attached to the same carbon atom... 6 Together they form an oxo group, and any remaining R 6 Each can be independently selected from halogen groups and -NR groups. 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 In some implementations, two R atoms attached to the same carbon atom... 6 Together they form an oxo group, and any remaining R 6 Each can be independently selected from halogen groups and -NR groups. 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 、 and -C(O)NR 9 R 10 .

[0295] In some implementations, each R 7 and R 8 Each can be independently selected from halogen groups and -NR groups. 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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 7 and R 8 Each can be independently selected from halogen groups and -NR groups. 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 and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 7 and R 8 Each can be independently selected from halogen groups and -NR groups. 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 In some implementations, each R 7 and R 8 Each can be independently selected from halogen groups and -NR groups. 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0296] In some implementation schemes, R 9 and R 10 Each occurrence can be independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, R 9 and R10 Each occurrence can be independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 9 and R 10 Each occurrence can be independently selected from H and C. 1-6 alkyl.

[0297] In some implementations, each R 11 Each can be independently selected from H and 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 groups. In some embodiments, each R 11 Each can be independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 11 Each can be independently selected from H and C. 1-6 alkyl.

[0298] In some implementations, each R 12 Selected independently from 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 groups. In some embodiments, each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R 12 Selected independently from C 1-6 alkyl.

[0299] In some implementations, each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl. In some embodiments, each R 13 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R 13 Independently selected from H and C 1-6 alkyl.

[0300] In some implementations, n is 0, 1, 2, 3, or 4. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0301] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of: ; ; ; ; ; ; ; ; ; ; ; ; ;as well as .

[0302] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;as well as .

[0303] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;as well as .

[0304] In some cases, the solubility of the inhibitor and hPGDH IC 50 The characteristics are shown in Table 1 and Table 2.

[0305] Table 1: Characteristics of PGDH inhibitors with a 6-5 ring backbone.

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313] Table 2: Properties of PGDH inhibitors with a phenyl backbone

[0314]

[0315] Table 3 provides analytical data for some of the inhibitors described in this paper.

[0316] Table 3: Analytical data of some inhibitors

[0317] In some implementations, the 15-PGDH inhibitor is a compound having the general formula IV, or a pharmaceutically acceptable salt thereof:

[0318] Formula IV, in, Ring Q is phenyl or 5- to 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 groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is 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 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 3 Independently selected from H, halogens, -CN, -NO2, -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 9substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 The C1-C8 alkyl group (substituted or unsubstituted), C2-C8 alkenyl group (substituted or unsubstituted), C1-C8 aminoalkyl group (substituted or unsubstituted), C1-C8 heteroalkyl group (substituted or unsubstituted), C1-C8 hydroxyalkyl group (substituted or unsubstituted), C3-C8 cycloalkyl group (substituted or unsubstituted), or C3-C8 heterocycloalkyl group (substituted or unsubstituted), each of which may be expressed by one or more R groups. 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -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- to 8-membered heteroaryl. Or two Rs 6 Together with the atoms to which they are attached, they form substituted or unsubstituted C3-C6 cycloalkyl groups or substituted or unsubstituted C3-C8 heterocycloalkyl groups; X A For -NR 5 R 5 or -OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5a And an R 6 Together with the atoms to which they are attached, they form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which can be derived from one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which can be substituted by one or more R a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which can be substituted by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which can be derived from one or more R groups. a replace; Each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3 or 4.

[0319] In some implementations, the 15-PGDH inhibitor is a compound having the general formula IV, or a pharmaceutically acceptable salt thereof:

[0320] Formula IV, in, Ring Q is phenyl or 5- to 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 groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; 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; Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -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 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl; R 4 The substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl; substituted or unsubstituted C3-C8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein each is substituted with one or more R 6 Replace; among them Each R 6 Independently, it is H, halogen, CN, -NO2, -NR 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 -NR 8 C(O)R 9 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, phenyl or 5 to 8 heteroaryl; Or two Rs 6 Together with the atoms to which they are attached, they form a C3-C6 cycloalkane ring; X A For NR 5 R 5 OR 5 ;in Each R5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; or R 5a With an R 6 Together with the atoms it is attached to, it forms a C3-C6 cycloalkane ring; Each R 8 and R 9 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl and C4-C 10 Heterocyclic alkyl groups; Each R 10 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 Aryl groups, and 5- to 10-membered heteroaryl groups; Each R 11 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 Aryl groups, and 5- to 10-membered heteroaryl groups; Each R 12 It 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.

[0321] In some embodiments, ring Q is a 5- to 10-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is a 5- to 8-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is a 5- to 8-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is a monocyclic, bicyclic, or polycyclic heteroaryl group. In some embodiments, ring Q is a bicyclic heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is indole, benzimidazole, benzotriazole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyridine, or tetrazolopyridine. In some embodiments, ring Q is [1,2,4]triazolo[1,5-a]pyridine.

[0322] In some embodiments, ring Q is a 6-membered monocyclic heteroaryl group containing 1, 2, or 3 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.

[0323] In some implementations, ring Q is phenyl, pyridine, or triazolidine.

[0324] In some implementation schemes, for , in, X 1 X 2 X 3 and X 4 Each is independently N or CR 3 ; Each R 3 Independently selected from H, halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 replace; Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, wherein each is substituted by one or more R a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, wherein each is substituted by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a replace; Each R aIt is independently selected from halogens, -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.

[0325] In some implementation schemes, X 1 X 2 X 3 and X 4 All are CR 3 .

[0326] In some implementation schemes, X 1 Let N be the number of elements; and X be the number of elements. 2 X 3 and X 4 All are CR 3 .

[0327] In some implementation schemes, X 1 and X 2 Both are N; and X 3 and X 4 All are CR 3 .

[0328] In some implementation schemes, X 1 and X 3 Both are N; and X 2 and X 4 All are CR 3 .

[0329] In some implementation schemes, X 1 and X 4 Both are N; and X 2 and X 3 All are CR 3 .

[0330] In some implementation schemes, X 1 X 2 and X 3 Both are N; and X 4 For CR 3 .

[0331] In some implementation schemes, X 1 X 2 and X 4 Both are N; and X 3 For CR 3 .

[0332] In some implementations, each R 3Independently selected from H, halogens, -CN, -NO2, -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 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- to 10-membered heteroaryl groups. In some embodiments, each R 3 Independently selected from H, halogens, -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 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, each R 3 Independently selected from H, halogens, -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 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, each R3 It is independently selected from H, halogen, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.

[0333] In some implementations, each R 3 Independently selected from H or halogen. In some embodiments, each R 3 Independently, it is a substituted or unsubstituted phenyl group, and a substituted or unsubstituted 5- to 6-membered heteroaryl group. In some embodiments, each R 3 Independently substituted or unsubstituted 5-membered heteroaryl group.

[0334] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of formula V, or a pharmaceutically acceptable salt thereof:

[0335] Formula V, in, Z is CR 1 Or N; X 1 For N or CR 3a ; 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 groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is 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 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; R 3a R 3b and R 3c Each is independently selected from H, halogen, -CN, -NO2, -NR 8 R 9 -OR10 -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; among them Each R 13 Independently halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 The substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, wherein each is substituted by one or more R 6 Replace; among them Each R 6 Independently halogen, CN, -NO2, -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 -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- to 8-membered heteroaryl. Or two Rs 6 Together with the atoms to which they are attached, they form substituted or unsubstituted C3-C6 cycloalkyl groups or substituted or unsubstituted C3-C8 heterocycloalkyl groups; X A For NR 5 R 5 OR 5 ;in Each R 5 Independently H or C1-C6 alkyl; R 5a It is H or CH3; or R 5a With an R 6 Together with the atoms to which they are attached, they form substituted or unsubstituted C3-C6 cycloalkyl groups; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R a replace; Each R 11Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a replace; Each R a It is independently selected from halogens, -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.

[0336] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of formula V, or a pharmaceutically acceptable salt thereof:

[0337] Formula V, in, Z is CR 1 Or N; X 1 For N or CR 3a ; Y is CR 2 Or N; R 1 For H; Each R 2 It is independently an H or C1-C6 alkyl group; R 3a R 3b and R 3c Each is independently selected from H, halogen, -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 heterocyclic alkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups, wherein each is separated by one or more R groups. 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 The substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, wherein each is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -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 Rs 6 Together with the atoms to which they are attached, they form substituted or unsubstituted C3-C6 cycloalkyl groups or substituted or unsubstituted C3-C8 heterocycloalkyl groups; X A For -OR 5 ;in Each R5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; or R 5a With an R 6 Together with the atoms to which they are attached, they form substituted or unsubstituted C3-C6 cycloalkyl groups; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a replace; Each R aIt is independently selected from halogens, -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.

[0338] In some implementation schemes, X A For NR 5 R 5 In some implementations, X A OR 5 .

[0339] In some implementations, Y is N. In some implementations, Y is CR. 2 .

[0340] In some embodiments, the compound of formula V has a structure of formula VIa, or a pharmaceutically acceptable salt thereof:

[0341] Formula VIa.

[0342] In some embodiments, the compound of formula V has the structure of formula VIb, or a pharmaceutically acceptable salt thereof:

[0343] Formula VIb.

[0344] In some implementations, Z is N. In some implementations, Z is CR. 1 In some implementations, Z stands for CH.

[0345] In some embodiments, the compound of formula V has the structure of formula VIIa, or a pharmaceutically acceptable salt thereof:

[0346] Formula VIIa.

[0347] In some embodiments, the compound of formula V has the structure of formula VIIb, or a pharmaceutically acceptable salt thereof:

[0348] Formula (IVb).

[0349] In some embodiments, the compound of formula V has the structure of formula VIIc, or a pharmaceutically acceptable salt thereof:

[0350] Formula VIIc.

[0351] In some embodiments, the compound of formula V has the structure of formula VIId, or a pharmaceutically acceptable salt thereof:

[0352] Formula VIId.

[0353] In some implementation schemes, R 1 H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 Or substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, R 1 For H.

[0354] In some implementations, each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 Or substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, each R 2 It is independently H or C1-C6 alkyl.

[0355] In some implementations, each R 2 For H.

[0356] In some implementation schemes, X 1 For CR 3a In some implementations, X 1 Let N be the number of elements in the array.

[0357] In some implementation schemes, R 3a R 3b and R 3c Each is independently selected from H, halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -S 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 R9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 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- to 10-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogens, and -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 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 3c Each is independently selected from H, halogens, and -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 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogens, and -C(O)R. 10 -C(O)NR 8 R 9 And substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogen, -OR 10 -S 8 -C(O)OR 10 -C(O)NR 8 R 9 -SOR11 -SO2R 11 -NR 12 C(O)R 10 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 Each is independently selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, -C(O)R 10 -C(O)NR 8 R 9 C3-C6 heterocyclic alkyl groups and 5-membered heteroaryl groups.

[0358] In some implementation schemes, R 3a R 3b and R 3c Each is independently selected from H, halogen, -C(O)OH, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, triazole, tetraazole, pyrrolidine, morpholine or C1-C6 alkyl substituted with -C(O)OH.

[0359] In some implementation schemes, R 3a and R 3b Each is either H or halogen; and R 3c Selected from halogens, -CN, -NO2, -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 9Substituted 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- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c Selected from halogens, -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 -NR 12 C(O)NR 8 R 9 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 Each is either H or halogen; and R 3c Selected from halogens, -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 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c Selected from -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c Selected from substituted or unsubstituted C1-C6 alkyl groups, -C(O)R 10 -C(O)NR 8 R 9 C3-C6 heterocyclic alkyl groups, and 5-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3cIt is a substituted or unsubstituted 5-membered heteroaryl group.

[0360] In some implementation schemes, R 3a It is halogen and R 3b For H. In some implementations, R 3a It is -Cl or -F; and R 3b For H. In some implementations, R 3b It is halogen and R 3a For H. In some implementations, R 3b It is -Cl or -F; and R 3a For H.

[0361] In some implementation schemes, R 3a and R 3b Each is represented by H.

[0362] In some implementation schemes, R 3a and R 3c Each is independently either H or halogen; and R 3b Selected from halogens, -CN, -NO2, -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 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- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is H; and R 3b Selected from halogens, -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 -NR 12 C(O)NR 8 R 9 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 Each is H; and R 3b Selected from halogens, -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 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is H; and R 3b Selected from -C(O)R 10 -C(O)OR 10 -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is either H or halogen; and R 3b Selected from substituted or unsubstituted C1-C6 alkyl groups, -C(O)R 10 -C(O)NR 8 R 9 C3-C6 heterocyclic alkyl groups and 5-membered heteroaryl groups.

[0363] In some implementation schemes, R 3a and R 3c Each is either H or halogen; and R 3b Selected from -C(O)R 10 -C(O)OR 10 And substituted or unsubstituted 5-membered heteroaryl groups.

[0364] In some implementation schemes, R 3a For halogens, R 3c For H. In some implementations, R 3aFor H, R 3b It is a halogen. In some implementations, R 3a For -Cl or -F, R 3c For H. In some implementations, R 3c For -Cl or -F, R 3a For H.

[0365] In some implementation schemes, R 3a and R 3c Each is H.

[0366] In some implementations, each R 3 R 3a R 3b and R 3c Each is independently a 5-membered heteroaryl group selected from pyrrole, triazole, tetraazole, oxazole, diazole, oxadiazole, thiadiazole, and furanyl. In some embodiments, each R 3 R 3a R 3b and R 3c Each is independently a 5-membered heteroaryl group selected from pyrrole, triazole, and tetraazole. In some embodiments, each R 3 R 3a R 3b and R 3c Each is independently a 5-membered heteroaryl group selected from triazole and tetraazole.

[0367] In some implementations, each R 3 R 3a R 3b or R 3c Each group is independently selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0368] In some implementations, each R 3 R 3a R 3b or R 3c Each group is independently selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , In some implementations, each R 3 R 3a R 3b or R 3c Each group is independently selected from the following groups: , , , , , , , , , , , , , , , and In some implementations, each R 3 R 3a R 3b or R 3c Each group is independently selected from the following groups: , or .

[0369] In some implementation schemes, R 4 The substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or 4- to 8-membered heterocyclic alkyl, and each is substituted or unsubstituted by one or more R 6 Replacement. In some implementations, R 4 The substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, or substituted or unsubstituted C1-C8 hydroxyalkyl. In some embodiments, R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or a substituted or unsubstituted C1-C8 hydroxyalkyl.

[0370] In some implementation schemes, R 4 It is a substituted or unsubstituted C1-C8 alkyl or a substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments, R 4 The alkyl group may be substituted or unsubstituted C1-C8 alkyl. In some embodiments, the alkyl group is a straight-chain or branched alkyl group. In some embodiments, R... 4The heteroalkyl group may be substituted or unsubstituted C1-C8. In some embodiments, the heteroalkyl group is an alkyl chain in which one or more carbon atoms are substituted by O or N atoms. In some embodiments, R 4 The 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 heterocyclic alkyl), or -CH2-O- (C3-C6 heterocyclic alkyl). In some embodiments, R 4 The 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) may be used. In some embodiments, R... 4 It is -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2-O-(C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R 4 It is -CH2CH2-O- (C3-C6 cycloalkyl). In some embodiments, R 4 It is -CH2-O-(C3-C6 cycloalkyl). In some embodiments, R 4 It is -CH2CH2-O- (C3-C6 heterocyclic alkyl). In some embodiments, R 4 It is -CH2-O-(C3-C6 heterocyclic alkyl).

[0371] In some implementation schemes, R 4 It is a substituted or unsubstituted C1-C8 alkyl group, and the alkyl group is reacted with one or more halogens, -OR 10 C1-C8 alkyl or C3-C6 cycloalkyl substitution.

[0372] In some implementation schemes, R 4 The substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl, each being substituted with one or more R 6 Replacement. In some implementations, R 4 It is a C3-C8 cycloalkyl group. In some embodiments, R 4 It can be a monocyclic, polycyclic, spirocyclic, or bridged cycloalkyl group. In some embodiments, R 4 It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R4 It is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 4 It is cyclopropyl. In some embodiments, R 4 It is cyclobutyl. In some embodiments, R 4 It is cyclopentyl. In some embodiments, R 4 It is cyclohexyl. In some implementations, R 4 for or .

[0373] In some implementation schemes, R 4 It is a substituted or unsubstituted C3-C8 heterocyclic alkyl group, and each is separated by one or more R 6 Replacement. In some implementations, R 4 It is a monocyclic, polycyclic, spirocyclic, or bridged heterocyclic alkyl group. In some embodiments, R 4 It is a 4-membered heterocyclic alkyl group. In some embodiments, R 4 It is a 5-membered heterocyclic alkyl group. In some embodiments, R 4 It is a 6-membered cycloalkyl group. In some embodiments, R 4 It is a 7-membered cycloalkyl group. In some embodiments, R 4 It is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine. In some embodiments, R 4 It is tetrahydrofuran or tetrahydropyran.

[0374] In some implementations, each R 6 Each is independently a halogen, -CN, -NO2, or -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- to 8-membered heteroaryl. In some embodiments, each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R9 -NR 8 C(O)R 9 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C8 cycloalkyl. In some embodiments, each R 6 Independently, it is halogen, -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, each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 Or C3-C8 cycloalkyl. In some embodiments, each R 6 Independently is -NR 8 R 9 or -OR 10 In some implementations, each R 6 Independently, it is a C3-C8 cycloalkyl group. In some embodiments, the cycloalkyl group is a monocyclic, spirocyclic, or bridged cycloalkyl group. In some embodiments, each R... 6 Independently, it is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R... 6 It is halogen independently. In some implementations, each R... 6 It can be H, Cl, F, or Br independently. In some implementations, each R... 6 Independently, it is F. In some implementations, each R... 6 Independently, it is F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH3CH3), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, piperidine, piperazine, oxane, tetrahydrofuran, or tetrahydropyran. In some embodiments, each R 6 Independently, it is F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R 6 Independently, it is F, -OH, -CH3, or -CF3. In some embodiments, each R 6 Independently, it is F. In some implementations, each R... 6 Independently, it is -OH. In some implementations, each R... 6 Independently, it is -CF3. In some implementations, each R 6It is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R 6 Independently, it is cyclopropyl. In some embodiments, each R... 6 It is cyclobutyl.

[0375] In some implementations, two R 6 Together with the atoms to which they are attached, they form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocyclic cycloalkyl. In some embodiments, the two R... 6 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. In some embodiments, the two R groups... 6 Together with the atoms to which they are attached, they form cyclopropyl or cyclobutyl groups. In some embodiments, the two R groups... 6 Together with the atoms to which they are attached, they form cyclopropyl groups. In some embodiments, the two R groups... 6 Together with the atoms to which they are attached, they form a cyclobutyl group. In some embodiments, the two R groups... 6 Together with the atoms to which they are attached, they form cyclopropyl groups. In some embodiments, the two R groups... 6 Together with the atoms to which they are attached, they form a cyclohexyl group. In some implementations, the two R groups... 6 Together with the atoms to which they are attached, they form C3-C6 heterocyclic cycloalkyl groups. In some embodiments, the two R... 6 Together with the atoms to which they are attached, they form a four-membered heterocyclic cycloalkyl group. In some embodiments, the two R groups... 6 Together with the atoms to which they are attached, they form a 5-membered heterocyclic cycloalkyl group. In some embodiments, the two R groups... 6 Together with the atoms to which they are attached, they form a 6-membered heterocyclic cycloalkyl group. In some embodiments, the two R groups... 6 Together with the atoms to which they are attached, they form pyran, piperazine, piperidine, or morpholine.

[0376] In some implementation schemes, 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 oxane, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted tetrahydropyran, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0377] In some embodiments, each R 5 Independently, it is a C1-C6 alkyl group. In some embodiments, each R... 5 Independently, it is -CH2CH3 or -CH3. In some implementations, each R 5 Independently, it is -CH2CH3. In some implementations, each R 5 Independently, it is -CH3. In some implementations, each R 5 H stands alone.

[0378] In some implementation schemes, R 5a For CH3. In some implementations, R 5a For H.

[0379] In some implementation schemes, R 5a With an R 6 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl groups. In some embodiments, R 5a With an R 6 Together with the atoms to which they are attached, they form cyclopentyl or cyclohexyl groups. In some embodiments, R... 5a With an R 6 Together with the atoms to which they are attached, they form a cyclohexyl group. In some implementations, R 5a With an R6 Together with the atoms to which they are attached, they form cyclopentyl groups.

[0380] In some implementations, each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic cycloalkyl groups, wherein each is composed of one or more R groups. a Replacement. In some implementations, each R 8 and R 9 Each is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl. In some embodiments, each R 8 and R 9 Each is independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl groups, and C3-C 10 Heterocyclic cycloalkyl. In some embodiments, each R 8 and R 9 Selected independently from C3-C in each location 10 cycloalkyl and C3-C 10 Heterocyclic cycloalkyl groups.

[0381] In some implementations, each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic cycloalkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a Replacement. In some implementations, each R 10 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C3-C 10 Heterocyclic cycloalkyl, C6-C 10Aryl groups, and 5- to 10-membered heteroaryl groups. In some embodiments, each R 10 Independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl groups, and C3-C 10 Heterocyclic cycloalkyl. In some embodiments, each R 10 Independently selected from H and C1-C6 alkyl groups. In some embodiments, each R 10 Independently selected from C3-C 10 cycloalkyl and C3-C 10 Heterocyclic cycloalkyl groups.

[0382] In some implementations, each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic cycloalkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a Replacement. In some implementations, each R 11 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C3-C 10 Heterocyclic cycloalkyl, C6-C 10 Aryl groups, and 5- to 10-membered heteroaryl groups. In some embodiments, each R 11 Independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl. In some embodiments, each R 11 Independently selected from C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups.

[0383] In some implementations, each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a Replacement. In some implementations, each R 12 Independently selected from H, straight-chain or branched C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl and C3-C10 Heterocyclic alkyl groups. In some embodiments, each R 12 Independently selected from H, straight-chain or branched C1-C6 alkyl groups. In some embodiments, each R 12 Independently selected from C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups.

[0384] In some implementations, each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3. In some embodiments, each R a Independently selected from -F, -Cl, -Br, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, each R a It is independently selected from -F, -OH, -CH3, -CF3 or -C(O)OH.

[0385] In some implementations, p is 1, 2, 3, or 4. In some implementations, p is 2 or 3. In some implementations, p is 3. In some implementations, p is 5. In some implementations, p is 4. In some implementations, p is 3. In some implementations, p is 2. In some implementations, p is 1.

[0386] In some implementations, the PDGH inhibitor is a compound described in Table 4, or a pharmaceutically acceptable salt thereof.

[0387] Table 4. 15-PGDH Inhibitors

[0388] Example The following examples are included for illustrative purposes only, and are not intended to limit the scope of the invention.

[0389] Example 1: Effect of oral administration of MF-300 on the level of PGE-MUM in the urine of CD rats.

[0390] The effects of daily oral administration of MF-300 (30 mg / kg or 60 mg / kg) on ​​urinary PGE-MUM levels in male Sprague-Dawley (CD) rats were evaluated. Briefly, baseline plasma and urinary levels of PGE2, 15-K-PGE2, 13,14-dihydro-15-one-PGE2, and PGE-MUM in 8-week-old male CD rats were detected using liquid chromatography-tandem mass spectrometry (LC-MS / MS). Rats were then divided into groups and administered either the carrier (carrier; 10% 2-hydroxypropyl-β-cyclodextrin) or MF-300 (30 mg / kg or 60 mg / kg) daily for 7 days. Additional urinary analysis was performed on day 6, additional plasma analysis was performed before administration on day 7, and final plasma and muscle analyses were performed after administration on day 7. All urine samples were collected between 8:00 and 9:00 on baseline day and day 6. PGE-MUM levels were normalized to creatinine. An overview of the experimental timeline assessing the effect of MF-300 on urinary PGE-MUM levels in CD rats can be found in [link to relevant documentation]. Figure 1A A schematic diagram illustrating the mechanism by which MF-300 inhibits 15-PGDH (thus inhibiting the first step in the conversion of PGE2 to PGE-MUM) and the biolocation of PGE2 and its metabolites can be found in [link to diagram]. Figure 1B During the baseline assay, there were no significant differences in urinary PGE-MUM (normalized to creatinine) levels among rats administered the carrier, 30 mg / kg MF-300, or 60 mg / kg MF-300.<t g101988-1> Figure 1C As shown. Compared with the oral carrier group, rats orally administered 30 mg / kg or 60 mg / kg MF-300 showed significantly lower urinary PGE-MUM (normalized to creatinine) levels on day 6, such as... Figure 1D As shown. The plasma levels of MF-300 in rats were also measured within 24 hours after a single administration or continuous daily administration for 7 days, such as... Figure 1E As shown. Changes in baseline PGE-MUM levels in CD rats administered the carrier, 30 mg / kg MF-300, or 60 mg / kg MF-300 were also measured, such as... Figure 1F As shown.

[0391] To achieve stable plasma MF-300 levels in adult CD rats, additional experiments were conducted, the details of which are summarized below. Figure 2AAs shown. During the 14-day experiment, CD rats were administered a carrier (carrier; 10% 2-hydroxypropyl-β-cyclodextrin), 30 mg / kg of MF-300, or 60 mg / kg of MF-300, respectively. The levels of PGE2 and PGE-MUM in urine and the PGE2 / PGE-MUM ratio were assessed in CD rats administered the carrier, 30 mg / kg MF-300, or 60 mg / kg MF-300 over 14 days. The results showed that MF-300 could increase the PGE2 / PGE-MUM ratio, such as... Figure 2B As shown. It was also found that, compared to CD rats administered the carrier, CD rats administered 30 mg / kg MF-300 or 60 mg / kg MF-300 had decreased PGE-MUM levels, such as... Figure 2C As shown.

[0392] Example 2: MF-300 to SMN 7. Effects of PGE-MUM levels in mice.

[0393] The study evaluated the use of spinal muscular atrophy (SMA) disease models (SMN) The effect of administering MF-300 to a population of Delta 7 mice (also known as Delta 7 mice plus SMN-C3) was studied. Figure 3A The diagram illustrates how MF-300 reduces PGE2 metabolite levels by inhibiting 15-PGDH. Urinary PGE2, PGE-MUM, and the PGE2 / PGE-MUM ratio were evaluated in WT mice, Delta 7 mice treated with the carrier, or Delta 7 mice treated with 30 mg / kg MF-300 every other day. Results showed that MF-300 treatment increased PGE2 levels and the PGE2 / PGE-MUM ratio in Delta 7 mice, and decreased PGE-MUM levels in Delta 7 mice treated with 30 mg / kg MF-300 compared to Delta 7 mice treated with the carrier. Figure 3B As shown.

[0394] Example 3: Effect of MF-300 on PGE-MUM levels in aged mice.

[0395] The effects of MF-300 administration in aged mouse populations were evaluated. Briefly, male C57Bl / 6J mice were divided into adult (12-15 months old) and aged (23 months old) groups, and administered the carrier, 10 mg / kg MF-300, 30 mg / kg MF-300, or 60 mg / kg MF-300, respectively. In aged mice, administration of 10 mg / kg MF-300 reduced PGE-MUM levels after 12 weeks, compared to aged mice administered the carrier. Figure 4 As shown.

[0396] Example 4: Effect of oral MF-300 on P75ECD expression.

[0397] Biological samples were obtained from the subjects. The presence of the biomarker p75ECD was detected in the biological samples. Elevated p75ECD levels were found in the subjects. A 15-PGDH inhibitor was administered to the subjects. After treatment with the 15-PGDH inhibitor, the p75ECD biomarker was detected again in the subjects, and their p75ECD levels were found to be lower than before treatment.

[0398] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Various changes, modifications, and substitutions can now be made by those skilled in the art without departing from the invention. It should be understood that various alternative embodiments of the invention can be used in the practice of the invention. The scope of protection of the invention is defined by the following claims, and all methods and structures within the scope of these claims and their equivalents are protected.

Claims

1. A method for reducing the levels of p75ECD, PGE-MUM, or both in a subject, the method comprising: The subject was given an amount of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor that could effectively reduce the subject's p75ECD, PGE-MUM, or both levels.

2. A method of treating a subject with a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor, the method comprising: (a) Identify that the subject’s p75ECD, PGE-MUM or both levels are elevated relative to the control or p75ECD or PGE-MUM levels exceeding a predetermined threshold. as well as (b) Administer the 15-PGDH inhibitor to the subject to reduce the subject's p75ECD, PGE-MUM, or both levels.

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

4. A method for selecting a subject to be treated with a 15-hydroxyprostaglandin (15-PGDH) inhibitor, the method comprising: (a) Providing or obtaining biological samples from the subject; (b) Measure the levels of p75ECD, PGE-MUM, or both in the biological sample; and (c) When the level of p75ECD, PGE-MUM or both of the biological sample exceeds a predetermined threshold, the subject is identified as a candidate for treatment with the 15-PGDH inhibitor.

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

6. The method according to any one of claims 1 to 5, wherein the subject suffers from a disease or condition associated with elevated p75ECD levels.

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

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

9. The method of claim 8, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).

10. The method according to any one of claims 1 to 3 or 5 to 9, wherein the administration is selected from the group consisting of: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, 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 application is selected from the group consisting of: acute application, chronic application, intermittent application, and continuous application.

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 desired 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 method according to any one of claims 1 to 16, wherein the 15-PGDH inhibitor is a compound of formula I: Formula I Or its pharmaceutically acceptable salt, wherein: X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, -SO2CH2-; Each Y is independently selected from N and CR 11 ; Each R 1 Independently selected from halogen groups, -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 groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxidized or thiolated compounds; Each R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and 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 groups; Each R 9 Selected independently from 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 groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 11 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The condition is that the compound of formula I is not , , or .

18. The method of claim 17, wherein the compound is a compound of formula Ia: Formula Ia Or its pharmaceutically acceptable salt.

19. The method of claim 17, wherein the compound is a compound of formula Ib: Formula Ib Or its pharmaceutically acceptable salt.

20. The method according to any one of claims 1 to 16, wherein the 15-PGDH inhibitor is a compound of formula II: Formula II Or its pharmaceutically acceptable salt, wherein: T, U, W, X, and Y are independently selected from N and CR. 5 ; S, V, and Z are independently selected from N and C; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the alkyl group, the cycloalkyl group, the aryl group, or the heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxidized or thiolated compounds; Each R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and 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 groups; Each R 9 Selected independently from 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 groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The condition is that the compound of formula II is not , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

21. The method of claim 20, wherein the compound is a compound of formula IIa: Formula IIa Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

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

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

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

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

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

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

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

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

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

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

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

33. The method according to any one of claims 1 to 16, wherein the 15-PGDH inhibitor is a compound of formula III: Formula III Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the alkyl group, the cycloalkyl group, the aryl group, or the heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution of aryl and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxidized or thiolated compounds; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl; wherein each alkyl group, heteroalkyl group, haloalkyl group, and cycloalkyl group is independently and optionally composed of 1 to 3 independently selected from a halogen group, -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- to 10-membered heterocycloalkyl, C 6-10 Substitution of aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atom to which they are attached, they form groups optionally composed of one to three independent groups selected from halogen groups, -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 3- to 10-membered heterocyclic alkyl groups substituted with aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms attached to the same carbon atom 6 Together they form oxidized, thiolated, or C-shaped compounds. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 Independently selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 8 Independently selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 8 They can be formed together by 1 to 3 independently selected halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 C-substituted with aryl and 5 to 10 heteroaryl groups 3-10 cycloalkyl; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 11 Independently selected from H and 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 groups; Each R 12 Selected independently from 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 groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3 or 4.

34. The method of claim 33, wherein the compound is a compound of formula IIIa: Formula IIIa Or its pharmaceutically acceptable salt.

35. The method of claim 33, wherein the compound is a compound of formula IIIb: Formula IIIb Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -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 Aryl and 5- to 10-membered heteroaryl groups; and p is 0, 1, 2 or 3.

36. The method of claim 33, wherein the compound is a compound of formula IIIc: Formula IIIc Or its pharmaceutically acceptable salt.

37. The method of claim 33, wherein the compound is a compound of formula IIId: Formula IIId Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -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 Aryl and 5- to 10-membered heteroaryl groups; and p is 0, 1, 2 or 3.

38. The method according to any one of claims 1 to 16, wherein the 15-PGDH inhibitor is a compound of formula IIk: Formula IIk Or its pharmaceutically acceptable salt, wherein: T, U, and Y are independently selected from N and CR. 6 The condition is that when U is N, at least one of T and Y is N; R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxygen; Each R 4 Independently selected from H and halogen groups; R 5 Selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 Selected from H, halogen, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 7 and R 8 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; Each R 9 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; and p is 0, 1, or 2.

39. The method according to any one of claims 1 to 16, wherein the 15-PGDH inhibitor is a compound of formula IIm: Formula IIm Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 3-6 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxygen; Each R 4 Independently selected from halogen groups, -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 heteroaryl groups; or Two Rs 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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 groups; R 5 Selected from halogen groups, -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 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and 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 groups; Each R 9 Selected independently from 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 groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2 or 3.

40. The method according to any one of claims 1 to 16, wherein the 15-PGDH inhibitor is a compound of formula IIq: Formula IIq Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxygen; Each R 4 Independently selected from halogen groups, -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 heteroaryl groups; or Two Rs 4 Together with the carbon atoms and any intermediate atoms to which they are attached, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -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 groups; R 5 Selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and 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 groups; Each R 9 Selected independently from 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 groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2 or 3.

41. The method according to any one of claims 1 to 16, wherein the 15-PGDH inhibitor is a compound of formula IIIc: Formula IIIc Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 6-10 Aryl and 5 to 10 heteroaryl groups; wherein the aryl or heteroaryl group is optionally composed of 1 to 3 independently selected from halogen groups, -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 Substitution with cycloalkyl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxygen; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 Cycloalkyl; wherein each alkyl group, heteroalkyl group, haloalkyl group, and cycloalkyl group is independently and optionally composed of 1 to 3 independently selected from a halogen group, -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- to 10-membered heterocycloalkyl, C 6-10 Substitution of aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atom to which they are attached, they form groups optionally composed of one to three independent groups selected from halogen groups, -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, C 6-10 3- to 10-membered heterocyclic alkyl groups substituted with aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms attached to the same carbon atom 6 Together they form an oxygen atom, and any remaining R 6 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 and R 8 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; and n is 0, 1, 2, 3 or 4.

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

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

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

45. The method according to any one of claims 1 to 44, wherein the 15-PGDH inhibitor is a compound of formula IV or a pharmaceutically acceptable salt thereof: Formula IV, in, Ring Q is phenyl or a 5- to 10-membered heteroaryl group; Z is CR 1 Or N; Y is CR 2 Or N; R 1 It is 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 groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is 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 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 3 Independently selected from H, halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C8 heterocycloalkyl, wherein each is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -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- to 8-membered heteroaryl. Or two Rs 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A Yes -NR 5 R 5 or -OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; or R 5a And an R 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is optionally surrounded by one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, wherein each is optionally substituted by one or more R a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, wherein each is optionally substituted by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is optionally surrounded by one or more R groups. a replace; Each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3 or 4.

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

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

48. The method according to claim 45 or 47, wherein when Q is phenyl, then R 3 One of them is not H.

49. The method of claim 45, wherein yes in, X 1 X 2 X 3 and X 4 Each is independently N or CR 3 ; Each R 3 Independently selected from H, halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 replace; Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a Replace; and Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

50. The method of claim 49, wherein X 1 X 2 X 3 and X 4 Each is CR 3 .

51. The method of claim 49, wherein X 1 It is N; and X 2 X 3 and X 4 Each is CR 3 .

52. The method of claim 49, wherein X 1 and X 2 Each is N; and X 3 and X 4 Each is CR 3 .

53. The method of claim 49, wherein X 1 and X 3 Each is N; and X 2 and X 4 Each is CR 3 .

54. The method of claim 49, wherein X 1 and X 4 Each is N; and X 2 and X 3 Each is CR 3 .

55. The method of claim 49, wherein X 1 X 2 and X 3 Each is N; and X 4 It is CR 3 .

56. The method of claim 49, wherein X 1 X 2 and X 4 Each is N; and X 3 It is CR 3 .

57. The method according to any one of claims 45 to 56, wherein each R 3 Independently selected from 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 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.

58. The method of claim 57, wherein each R 3 Independently selected from H, halogens, -C(O)OR 10 -C(O)NR 8 R 9 And substituted or unsubstituted 5-membered heteroaryl groups.

59. The method of claim 45, wherein the compound has the structure of formula V, or a pharmaceutically acceptable salt thereof: Formula V, in, Z is CR 1 Or N; X 1 Is it N or CR? 3a ; Y is CR 2 Or N; R 1 It is 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 groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is 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 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; R 3a R 3b and R 3c Each is independently selected from H, halogen, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, wherein each is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -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- to 8-membered heteroaryl. Or two Rs 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A It is NR 5 R 5 OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; or R 5a And an R 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl groups; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10 heteroaryl groups, each of which is bonded by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, wherein each is composed of one or more R groups. a Replace; and Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

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

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

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

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

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

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

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

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

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

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

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

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

72. The method according to claim 59, wherein the compound of formula V has the structure of formula VIId, or a pharmaceutically acceptable salt thereof: Formula VIId.

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

74. The method according to any one of claims 59 to 73, wherein R 3b It is H; and R 3c Selected from halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

75. The method of claim 74, wherein R 3b It is H; and R 3c Selected from halogens, -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 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.

76. The method according to any one of claims 59 to 73, wherein R 3c It is H; and R 3b Selected from halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

77. The method of claim 76, wherein R 3c It is H; and R 3b Selected from halogens, -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 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.

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

79. The method according to any one of claims 59 to 72 or 78, wherein R 3a and R 3b It is independently H or halogen; and R 3c Selected from 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 -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

80. The method of claim 79, wherein R 3c Selected from H, halogens, -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 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.

81. The method of claim 80, wherein R 3c It is -C(O)OR 10 -C(O)NR 8 R 9 A 5-membered heteroaryl group, either substituted or unsubstituted.

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

83. The method according to any one of claims 59 to 72 or 78, wherein R 3a and R 3c It is independently H or halogen; and R 3b Selected from halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

84. The method of claim 83, wherein R 3b Selected from H, halogens, -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 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.

85. The method of claim 83, wherein R 3b It is -C(O)OR 10 -C(O)NR 8 R 9 A 5-membered heteroaryl group, either substituted or unsubstituted.

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

87. The method according to any one of claims 59 to 72 or 78, wherein R 3b and R 3c Each is either H or halogen; and R 3a Selected from halogens, -CN, -NO2, -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 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

88. The method of claim 87, wherein R 3a Selected from H, halogens, -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 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.

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

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

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

92. The method according to any one of claims 45 to 91, wherein R 5a And an R 6 They combine with the atoms to which they are attached to form C3-C6 cycloalkyl groups.

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

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

95. The method according to any one of claims 45 to 94, wherein R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, wherein each is substituted or unsubstituted by one or more R 6 replace.

96. The method of claim 95, wherein R 4 It is a substituted or unsubstituted C1-C8 alkyl or a substituted or unsubstituted C1-C8 heteroalkyl, wherein each is substituted by one or more R 6 replace.

97. The method according to any one of claims 45 to 94, wherein R 4 It is a substituted or unsubstituted C3-C8 cycloalkyl or a 4- to 8-membered heterocycloalkyl, wherein each is substituted by one or more R 6 replace.

98. The method of claim 97, wherein R 4 It is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl or tetrahydropyranyl.

99. The method according to any one of claims 45 to 98, wherein each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 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.

100. The method of claim 99, wherein each R 6 Independently, it is halogen, -OR 10 C1-C6 alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl.

101. The method according to claim 99 or 100, wherein each R 6 Independently, it is -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 suffers from a disease or condition associated with elevated PGE-MUM levels.

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

105. The method of claim 104, wherein the disease or condition associated with muscle injury, damage, or atrophy includes acute muscle injury or trauma, soft tissue hand injury, muscular dystrophy, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), 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 condition associated with elevated PGE-MUM levels is a neuromuscular disease.

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

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

109. The method according to claim 107 or 108, wherein administering a dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject suffering from spinal muscular atrophy can improve symptoms of one or more spinal muscular atrophy diseases 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 of 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 condition associated with elevated PGE-MUM levels is an age-related condition.

113. The method of claim 112, wherein the age-related condition is sarcopenia.

114. The method of claim 113, wherein administering a dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject with sarcopenia reduces the subject's PGE-MUM level.

115. The method of claim 113 or 114, wherein administering a dose of a 15-hydroxyprostaglandin dehydrogenase inhibitor to a subject suffering from sarcopenia can improve one or more sarcopenia symptoms in the subject.

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