Intermittent dosing methods for treating diseases associated with elevated 15-PGDH levels

Abstract

To reduce toxicity, an intermittent dosing method is provided for treating diseases associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject with a 15-PGDH inhibitor. Furthermore, this specification describes how the plasma concentration of the 15-PGDH inhibitor in the subject corresponds to the EC of the 15-PGDH inhibitor. 50 A method is provided for treating diseases associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject by administering a 15-PGDH inhibitor while maintaining the therapeutic efficacy of the 15-PGDH inhibitor when the level is below a certain threshold.

Description

[Technical Field]

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

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

[0003] However, therapeutic agents such as inhibitors can have drug toxicity, which can lead to adverse effects on the target individual. These therapeutic agents are tested for toxicity before they can be approved for clinical use. Some therapeutic agents may fail to enter clinical trials because they are unsafe or ineffective due to toxicity.

[0004] Reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference. To the extent that any publications and patents or patent applications incorporated by reference conflict with the disclosures contained herein, this Specified is intended to supersede and / or take precedence over any such conflicting material. [Overview of the project]

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

[0006] In one embodiment, a method for treating a disease associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression level in a subject is provided herein, the method comprising administering to the subject an amount of a 15-PGDH inhibitor effective in inhibiting 15-PGDH to a level sufficient to treat the disease, wherein the 15-PGDH inhibitor is administered to the subject at a frequency that shows reduced toxicity to the subject compared to once daily administration of the same amount of the 15-PGDH inhibitor.

[0007] In some cases, the dosing frequency that shows reduced toxicity to the subject is less than once daily. In some cases, the dosing frequency that shows reduced toxicity to the subject is once every two days, once every three days, once every four days, once every five days, once every six days, or once every seven days. In some cases, the dosing frequency that shows reduced toxicity to the subject is less than once every two days, less than once every three days, less than once every four days, less than once every five days, less than once every six days, or less than once every seven days. In some cases, the administration step is such that the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor 50 This includes administering a 15-PGDH inhibitor if the level is less than [a certain level].

[0008] In another aspect, the disclosure provides a method for treating a disease associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject, wherein the method involves reducing the plasma concentration of a 15-PGDH inhibitor in the subject to the EC of the 15-PGDH inhibitor. 50 The procedure includes administering to a subject an amount of a 15-PGDH inhibitor effective in raising the level above a certain threshold, wherein the subject has received at least one dose of the 15-PGDH inhibitor prior to the administration procedure, and the administration procedure is performed when the subject is at an EC level of the 15-PGDH inhibitor. 50 This includes administering a 15-PGDH inhibitor to a patient whose plasma concentration of the 15-PGDH inhibitor is below a certain level.

[0009] In some cases, subjects received at least one dose of a 15-PGDH inhibitor at least 24 hours prior to the administration step. In some cases, subjects received at least one dose of a 15-PGDH inhibitor at least 48 hours prior to the administration step. In some cases, subjects received at least one dose of a 15-PGDH inhibitor at least 72 hours prior to the administration step. In some cases, subjects received at least one dose of a 15-PGDH inhibitor at least 24 hours prior to administration and within 72 hours prior to administration.

[0010] In some embodiments, the administration step involves the plasma concentration of the 15-PGDH inhibitor in the subject being the EC of the 15-PGDH inhibitor. 50 This includes administering a 15-PDGH inhibitor if the amount is at least 2 times, at least 5 times, at least 10 times, at least 50 times, at least 100 times, at least 500 times, at least 1000 times, or more than 1000 times less than the given amount.

[0011] In some cases, the method involves measuring the plasma concentration of the 15-PGDH inhibitor in the subject. 50When it exceeds, it results in a reduction in toxicity to the subject as compared to administering the same amount of a 15-PGDH inhibitor to the subject. In some examples, the method results in a reduction in toxicity to the subject as compared to administering the same amount of a 15-PGDH inhibitor to the subject by once-daily administration.

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

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

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

[0015]

Chemical formula

[0016] [ka] isn't it.

[0017] In some embodiments, the compound is of formula Ia:

[0018] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound is of formula Ib:

[0020] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the 15-PGDH inhibitor is expressed as formula II:

[0022] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, T, U, W, X, and Y are independent of N and CR. 5 Selected from, S, V, and Z are independently selected from N and C. R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, where the alkyl, cycloalkyl, aryl, or heteroaryl is optionally halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo or thio, Each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10Selected from aryls and 5-10 membered heteroaryls, or Two R's 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected independently from aryls and 5-10 member heteroaryls, Each R 5 These are independently H, Halo, and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, Each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 10 H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected independently from cycloalkyl, and n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, However, the above compound of formula II is

[0023] [ka]

[0024] [ka]

[0025] [ka] isn't it.

[0026] In some embodiments, the compound is of formula IIa:

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

[0028] In some embodiments, the compound is of formula IIb:

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

[0030] In some embodiments, the compound is of formula IIc:

[0031] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, 4, or 5.

[0032] In some embodiments, the compound is of formula IId:

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

[0034] In some embodiments, the compound is of formula IIe:

[0035] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0036] In some embodiments, the compound is of formula IIf:

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

[0038] In some embodiments, the compound is of formula IIg:

[0039] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0040] In some embodiments, the compound is of formula IIh:

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

[0042] In some embodiments, the compound is of formula III:

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

[0044] In some embodiments, this compound is derived from formula IIj:

[0045] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, or 3.

[0046] In some embodiments, the compound is of formula IIn:

[0047] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, or 3.

[0048] In some embodiments, the compound is of formula IIp:

[0049] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0050] In some embodiments, the 15-PGDH inhibitor is expressed as formula III:

[0051] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, Each X is independent of N and CR 7 Selected from, Y is O, S, SO2, and C(R 8 ) Selected from 2, R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10Selected from aryls and 5-10 membered heteroaryls, where the alkyl, cycloalkyl, aryl, or heteroaryl is optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo or thio, R 4 and R 5 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyls, where each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently and optionally selected as halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls, or R 4 and R 5 Together with the nitrogen atom to which they are bonded, they form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10Optionally, substituted 3-10 membered heterocycloalkyls are formed with 1-3 substituents independently selected from aryls and 5-10 membered heteroaryls. Each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, or Two R atoms bonded to the same carbon atom 6 They combine to form oxo, thio, or C 3-10 Form a cycloalkyl group, and any remaining R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , NR 13 C(O)NR 9 R10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 7 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 8 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, or Two R's 8 They came together, Hello, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 C is optionally substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls. 3-10 It can form cycloalkyl groups, R 9 and R 10 H and C appear independently at each occurrence. 1-6Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, Each R 11 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 12 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 13 H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected independently from cycloalkyl, m is either 1 or 2. n is 0, 1, 2, 3, or 4.

[0052] In some embodiments, the compound is of formula IIIa:

[0053] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the compound is of formula IIIb:

[0055] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, Each R 14 It is independent, Halo, -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 Selected from aryls and 5-10 member heteroaryls, p is 0, 1, 2, or 3.

[0056] In some embodiments, the compound is of formula IIIc:

[0057] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the compound is formula IIId:

[0059] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, Each R 14 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11-C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, p is 0, 1, 2, or 3.

[0060] In some embodiments, the 15-PGDH inhibitor is expressed as formula IIk:

[0061] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, T, U, and Y are independent of N and CR. 6 The selection is made from, however, if U is N, then at least one of T and Y is N. R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, where the above aryl or heteroaryl is optionally halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R8 , -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 Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo, Each R 4 These are independently selected from H and Halo, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10Selected from aryls and 5-10 member heteroaryls, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 7 and R 8 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, Each R 9 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C6-10 Selected from aryls and 5-10 member heteroaryls, Each R 11 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, p is 0, 1, or 2.

[0062] In some embodiments, the 15-PGDH inhibitor is expressed as formula IIm:

[0063] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, where the above aryl or heteroaryl is optionally halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, R 2 is H and R3 is -CF3 or R 2 and R 3 They come together to form an oxo, Each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R's 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected independently from aryls and 5-10 member heteroaryls, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, Each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 10 H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected independently from 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.

[0064] In some embodiments, the 15-PGDH inhibitor is expressed by formula IIq:

[0065] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, where the above aryl or heteroaryl is optionally halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)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 Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, R 2 is H and R 3 Is it -CF3? R 2 and R 3 They come together to form an oxo, Each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, or Two R's 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 Hello, -NR6 R 7 ,-OR 8 ,-C(O)R 8 ,-C(O)OR 8 ,-C(O)NR 6 R 7 ,-SOR 9 ,-SO2R 9 ,-SO2NR[[ID=?]] 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 5-10 member heteroaryl,independently selected from R 5 is halo,-NR 6 R 7 ,-OR 8 ,-C(O)R 8 ,-C(O)OR 8 ,-C(O)NR 6 R 7 ,-SOR 9 ,-SO2R 9 ,-SO2NR 6 R 7 ,-NR 10 C(O)R 8 ,-NR 10 C(O)NR 6 R 7 ,-NR 10 SO2R 8 ,-NR 10 SO2NR 6 R 7 ,-C 1-6 alkyl,C 1-6 heteroalkyl,C 1-6 haloalkyl,C 3-10 cycloalkyl,3-10 member heterocycloalkyl,C 6-10Selected from aryl and 5- to 10-membered heteroaryl, R 6 and R 7 are, each time they appear, independently H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl, each R 8 is independently H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, each R 9 is independently C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​8 ) Selected from 2, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, where the above aryl or heteroaryl is optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo, R 4 and R 5 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyls, where each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently and optionally selected as halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Substituting with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls, or R 4 and R 5 Together with the nitrogen atom to which they are bonded, they form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10Optionally, substituted 3-10 membered heterocycloalkyls are formed with 1-3 substituents independently selected from aryls and 5-10 membered heteroaryls. Each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, or Two R atoms bonded to the same carbon atom 6 They come together to form an oxo, and any remaining R 6 Hello, -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 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected independently from aryls and 5-10 member heteroaryls, Each R 7 and R 8 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 9 and R 10 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, Each R 11 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryl and 5- to 10-membered heteroaryl, each R 12 is independently selected from C 1-6 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0075] [ka]

[0076] [ka]

[0077] [ka]

[0078] [ka]

[0079] [ka]

[0080] [ka]

[0081] [ka]

[0082] [ka] It is a compound selected from the group consisting of the following:

[0083] In some embodiments, the 15-PGDH inhibitor is

[0084] [ka] It is a compound selected from the group consisting of the following:

[0085] In some embodiments, the 15-PGDH inhibitor is of formula IV

[0086] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, Ring Q is phenyl or a 5-10 membered heteroaryl. Z is CR 1 or N, Y is CR 2 or N, R 1 H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, Each R 2 These are independently 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, or substituted or unsubstituted C3-C8 cycloalkyl, Each R 3 These are independently H, halogen, -CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, each of which has one or more R 13 It is replaced by, here, Each R 13 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, R 4 These are substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 cycloalkyl, each of which has one or more R 6 It is replaced by, here, Each R 6 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8R 9 -SOR 11 , -SO2R 11 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-8 member heteroaryl, Or two R's 6 However, they combine with the atoms to which they are bonded to form substituted or unsubstituted C3-C6 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups. X A -NR 5 R 5 OR 5 And here Each R 5 These are independently H or C1-C6 alkyl groups. R 5a is either H or CH3, Or R 5a and one R 6 These combine with the atoms to which they are bonded to form substituted or unsubstituted C3-C6 cycloalkyl groups, or substituted or unsubstituted C3-C6 heterocycloalkyl groups. Each R 8 and R 9 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which optionally has one or more R a Replaced by, Each R 10These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which can optionally be one or more R a Replaced by, Each R 11 This includes substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, and substituted or unsubstituted C3-C groups. 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Independently selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, Each R 12 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which optionally has one or more R a Replaced by, Each R a These are independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3. p is 1, 2, 3, or 4.

[0087] In some embodiments, ring Q is a six-membered monocyclic heteroaryl containing one, two, or three nitrogen atoms. In some embodiments, ring Q is phenyl, pyrimidinyl, or pyridinyl. In some embodiments, if Q is phenyl, then R 3 One of them is not H.

[0088] In some embodiments,

[0089] [ka] teeth

[0090] [ka] And, During the ceremony, X 1 , X 2 , X 3 , and X 4 These are, independently, N or CR 3 And, Each R 3 These are independently H, halogen, -CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , NR 12 SO2NR 8 R 9Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, each of which has one or more R 13 Replaced by, Each R 13 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, Each R 8 and R 9 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which has one or more R a Replaced by, Each R 10 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, Each R 11This includes substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, and substituted or unsubstituted C3-C groups. 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Independently selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, Each R 12 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which has one or more R a Replaced by, Each R a These are independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0091] In some embodiments, X 1 , X 2 , X 3 , and X 4 These are CR 3 In some embodiments, X 1 is N, and X 2 , X 3 , and X 4 These are CR 3 In some embodiments, X 1 and X 2 These are N and X 3 and X 4 These are CR 3 In some embodiments, X1 and X 3 These are N and X 2 and X 4 These are CR 3 In some embodiments, X 1 and X 4 These are N and X 2 and X 3 These are CR 3 In some embodiments, X 1 , X 2 , and X 3 These are N and X 4 CR 3 In some embodiments, X 1 , X 2 , and X 4 Each of these is N, and X 3 CR 3 In some embodiments, each R 3 These are independently H, halogen, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, each R 3 These are independently H, halogen, -C(O)OR 10 -C(O)NR 8 R 9 , and selected from substituted or unsubstituted 5-membered heteroaryls.

[0092] In some embodiments, the compound is of formula V:

[0093] [ka] Having the structure of, or a pharmaceutically acceptable salt thereof, During the ceremony, Z is CR 1 or N, X 1 is N or CR 3a And, Y is CR 2 or N, R 1 H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, Each R 2 These are independently 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, or substituted or unsubstituted C3-C8 cycloalkyl, R 3a , R 3b , and R 3c These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, each of which has one or more R 13 Replaced by, Here, each R 13 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C2-C8 alkenyl groups, substituted or unsubstituted C1-C8 aminoalkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups, each of which has one or more R groups. 6 It is replaced by, here, Each R 6 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 8C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, substituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-8 member heteroaryl, Or two R's 6 However, they combine with the atoms to which they are bonded to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl groups. X A , NR 5 R 5 OR 5 And here Each R 5 These are independently H or C1-C6 alkyl groups. R 5a is either H or CH3, Or R 5a and one R 6 These combine with the atoms to which they are bonded to form substituted or unsubstituted C3-C6 cycloalkyl groups. Each R 8 and R 9 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which has one or more R a Replaced by, Each R 10 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, Each R 11 These are independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, Each R 12 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which has one or more R a Replaced by, Each R a These are independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0094] In some embodiments, X A is NR 5 R 5 In some embodiments, X A is OR 5 In some embodiments, Y is CR 2 In some embodiments, Y is N.

[0095] In some embodiments, the compound of formula V is:

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

[0097] In some embodiments, the compound of formula V is formula VIb:

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

[0099] In some embodiments, Z is N. In some embodiments, Z is CR 1 In some embodiments, Z is CH.

[0100] In some embodiments, the compound of formula V is formula VIIa:

[0101] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the compound of formula V is represented by formula VIIb.

[0103] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound of formula V is of formula VIIc

[0105] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound of formula V is of formula VIId

[0107] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, X 1 is N. In some embodiments, R 3b H is R 3c These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, each of which has one or more R 13 It is replaced by, here, each R 13 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R10 , -C(O)OR 10 , or -C(O)NR 8 R 9 In some embodiments, R 3b H is R 3c Halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3c H is R 3b These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, each of which has one or more R 13 It is replaced by, here, each R 13 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 In some embodiments, R 3c H is R 3b Halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, X 1 CR 3a In some embodiments, R 3a and R 3b is independently H or halogen, and R 3c These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, each of which has one or more R 13 It is replaced by, here, each R 13 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 In some embodiments, R 3c H, halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3c is -C(O)OR 10 -C(O)NR 8 R9 , or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3a and R 3b These are H, respectively. In some embodiments, R 3a and R 3c is independently H or halogen, and R 3b These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, each of which has one or more R 13 It is replaced by, here, each R 13 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 In some embodiments, R 3b H, halogen, -NR 8R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3b is -C(O)OR 10 -C(O)NR 8 R 9 , or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3a and R 3c These are H, respectively. In some embodiments, R 3b and R 3c These are H or halogen, respectively, and R 3a These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, each of which has one or more R 13 It is replaced by, here, each R 13 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 That is. In one embodiment, R 3a H, halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3a is -C(O)OR 10 -C(O)NR 8 R 9 , or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3b and R 3c These are H, respectively. In some embodiments, each R 2 is H. In some embodiments, R 5a and R 6 One of them combines with the atoms to which they are bonded to form a C3-C6 cycloalkyl group. In some embodiments, R5a is H. In some embodiments, R 5 is H. In some embodiments, R 4 These are substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which has one or more R 6 It is replaced by R 4 is a substituted or unsubstituted C1-C8 alkyl, or a substituted or unsubstituted C1-C8 heteroalkyl, each of which has one or more R 6 It is replaced by R 4 These are substituted or unsubstituted C3-C8 cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups, each of which has one or more R groups. 6 It is replaced by R 4 is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl. In some embodiments, each R 6 These are independently halogen, -NR 8 R 9 , -OR 10 These are substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C1-C6 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups. In some embodiments, each R 6 These are independently halogen, -OR 10 These are C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl. In some embodiments, each R 6 These are independently -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the compound is selected from Table 4 or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the disease is a muscle condition. In some embodiments, the muscle condition is a muscle atrophy, muscle damage, muscle disorder, or muscle injury. In some embodiments, the disease is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), inherited myopathy, myotonic muscular dystrophy. Muscular dystrophy (MDD), oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, congenital myotonia, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysisThe following conditions are selected from the group consisting of paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, stress-induced urinary incontinence, urethral sphincter deficiency, sarcopenia, and any combination thereof.

[0110] In some embodiments, the disease is spinal muscular atrophy (SMA). In some embodiments, the disease is facioscapulohumeral muscular dystrophy (FSHD). In some embodiments, the disease is hair loss. In some embodiments, the disease is inflammation and / or injury of the skin. In some embodiments, the disease is vascular insufficiency. In some embodiments, the disease is congestive heart failure or cardiomyopathy. In some embodiments, the disease is gastrointestinal disease. In some embodiments, the disease is renal dysfunction. In some embodiments, the disease is a neurological disorder, neuropsychiatric disorder, neuronal injury, neurotoxic disorder, neuropathic pain, or neurodegenerative disorder. In some embodiments, the disease is a fibrotic or adhesional disorder, disorder, or disease. In some embodiments, the disease is scar formation. In some embodiments, the disease is fibrosis. In some embodiments, the disease is idiopathic pulmonary fibrosis. In some embodiments, the disease is kidney fibrosis. In some embodiments, the disease is acute kidney injury. In some embodiments, the disease is sarcopenia. In some embodiments, the disease is neuromuscular disease. [Brief explanation of the drawing]

[0111] Novel features of this disclosure are described in detail in the appended claims. A better understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description, which describes exemplary embodiments in which the principles of this disclosure are utilized, and to the appended drawings. [Figure 1] This paper outlines the effects of MF-300 on PGE2 signaling. [Figure 2A] The mechanism of action and pharmacokinetic profile of MF-300 are shown. Figure 2A shows the effect of MF-300 on NADH production in a biochemical 15-PGDH inhibition assay. [Figure 2B] The mechanism of action and pharmacokinetic profile of MF-300 are shown. Figure 2B shows the effect of MF-300 on PGE2 stability in A549 cells. [Figure 2C] The mechanism of action and pharmacokinetic profile of MF-300 are shown. Figure 2C shows the plasma levels of various doses of MF-300 24 hours after administration in mice. [Figure 3A] This shows the effect of intraperitoneal administration of MF-300 in SMNΔ7 mice. Figure 3A shows an outline of the experiment to evaluate the effects of repeated administration of SMN-C3 and MF-300 in SMNΔ7 mice. [Figure 3B] Figure 3B shows the effects of intraperitoneal administration of MF-300 in SMNΔ7 mice. Figure 3B shows the effects of repeated administration of SMN-C3 and MF-300 on isometric plantar flexor force in SMNΔ7 mice. [Figure 3C] Figure 3C shows the effects of intraperitoneal administration of MF-300 in SMNΔ7 mice. The effects of repeated administration of SMN-C3 and MF-300 on isometric plantar flexor maximum force in SMNΔ7 mice. [Figure 3D]Figure 3D shows the effect of intraperitoneal administration of MF-300 in SMNΔ7 mice. The effect of repeated administration of SMN-C3 and MF-300 on isometric ankle plantar flexor maximum force in SMNΔ7 mice is shown as a percentage of the average maximum muscle strength of vehicle-treated animals. [Figure 3E] This shows the effect of intraperitoneal administration of MF-300 in SMNΔ7 mice. Figure 3E shows the level of HPGD expression in the gastrocnemius muscles of SMNΔ7 mice. [Figure 3F] The effects of intraperitoneal administration of MF-300 in SMNΔ7 mice are shown. Figure 3F shows the principal component analysis of the effects of repeated administration of SMN-C3 and MF-300 to the gastrocnemius muscle of SMNΔ7 mice. [Figure 3G] Figure 3G shows the effect of intraperitoneal administration of MF-300 in SMNΔ7 mice. The effect of repeated administration of SMN-C3 and MF-300 on the probability of righting within 30 seconds in SMNΔ7 mice. [Figure 4A] The effects of orally administered MF-300 in SMN1C / C mice are shown. Figure 4A shows an outline of the experiment to evaluate the effects of repeated MF-300 administration in SMN1C / C mice. [Figure 4B] Figure 4B shows the effects of orally administered MF-300 in SMN1C / C mice. Figure 4B shows the effect of repeated MF-300 administration in SMN1C / C mice on the percentage increase in isometric ankle plantarflexion muscle strength and maximal muscle strength compared to vehicle-administered mice. [Figure 4C] Figure 4C shows the effects of orally administered MF-300 in SMN1C / C mice. The effect of repeated MF-300 administration in SMN1C / C mice on the percentage increase in maximal muscle strength compared to vehicle-administered mice normalized to isometric ankle plantarflexion muscle strength and muscle mass. [Figure 4D] Figure 4D shows the effect of orally administered MF-300 in SMN1C / C mice. Figure 4D outlines the experiment and rationale for localizing the effect of MF-300 by treating mice with MF-300 and measuring nerve stimulation and direct muscle-stimulated contractions. [Figure 4E] Figure 4E shows the effect of orally administered MF-300 in SMN1C / C mice. The effect of MF-300 treatment on maximal muscle strength related to sciatic nerve stimulation is shown. [Figure 4F] Figure 4F shows the effect of orally administered MF-300 in SMN1C / C mice. The effect of MF-300 treatment on maximal muscle strength, normalized to muscle weight and related to sciatic nerve stimulation, is shown. [Figure 4G] Figure 4G shows the effect of orally administered MF-300 on maximal muscle strength, which is directly related to muscle stimulation. [Figure 4H] Figure 4H shows the effect of orally administered MF-300 in SMN1C / C mice. Figure 4H shows the effect of MF-300 treatment on maximal muscle strength, which is directly related to muscle stimulation and normalized to muscle weight. [Figure 4I] Figure 4I shows the effect of orally administered MF-300 on maximal muscle strength related to muscle stimulation normalized to nerve stimulation. [Figure 4J] Figure 4J shows the effect of orally administered MF-300 in SMN1C / C mice. Figure 4J shows the effect of MF-300 treatment on maximal muscle strength, expressed as a fold difference, in relation to muscle stimulation normalized to nerve stimulation. [Figure 5A]This shows the effect of orally administered MF-300 in a mouse model of sciatic nerve crush. Figure 5A outlines the experimental timeline for evaluating the effect of MF-300 on isometric ankle plantarflexion muscle strength in a mouse model of sciatic nerve crush. [Figure 5B] This shows the effect of orally administered MF-300 in a mouse model of sciatic nerve compression. Figure 5B shows the baseline maximum muscle strength of surgical sham mice administered with vehicle, and sciatic nerve compression mice administered with either MF-300 or vehicle. [Figure 5C] This shows the effect of orally administered MF-300 in a mouse model of sciatic nerve compression. Figure 5C shows the maximum muscle strength on day 14 for surgical Siamese mice administered with Vehicle, and for sciatic nerve compression mice administered with either MF-300 or Vehicle. [Figure 5D] This shows the effect of orally administered MF-300 in a mouse model of sciatic nerve compression. Figure 5D shows the maximum muscle strength at day 21 for surgical Siamese mice administered with Vehicle, and for sciatic nerve compression mice administered with either MF-300 or Vehicle. [Figure 5E] This shows the effect of orally administered MF-300 in a mouse model of sciatic nerve compression. Figure 5E shows the maximum muscle strength at day 28 for surgical Siamese mice administered with vehicle, and for sciatic nerve compression mice administered with either MF-300 or vehicle. [Figure 5F] This shows the effect of orally administered MF-300 in a mouse model of sciatic nerve compression. Figure 5F shows the maximum muscle strength at day 35 for surgical Siamese mice administered with vehicle, and for sciatic nerve compression mice administered with either MF-300 or vehicle. [Figure 5G] The effects of orally administered MF-300 in a mouse model of sciatic nerve compression are shown. Figure 5G shows the maximum muscle strength normalized by muscle weight at day 35 for surgical Siamese mice administered with vehicle and sciatic nerve compression mice administered with either MF-300 or vehicle. [Figure 5H]This shows the effect of orally administered MF-300 in a mouse model of sciatic nerve compression. Figure 5H shows the muscle mass at the end of the study for surgical Siamese mice administered with vehicle, and for sciatic nerve compression mice administered with either MF-300 or vehicle. [Figure 6A] Figure 6A shows the effects of intermittently administered, orally given MF-300 in SMN1C / C mice. Figure 6A outlines the experimental timeline for evaluating the effect of intermittently administered MF-300 on isometric ankle plantarflexion muscle strength in SMN1C / C mice. [Figure 6B] The effects of intermittently administered, orally given MF-300 in SMN1C / C mice are shown. Figure 6B shows the predicted plasma concentrations of MF-300 in a cohort of mice that received 60 mg / kg of MF-300 daily. [Figure 6C] The effects of intermittently administered, orally given MF-300 in SMN1C / C mice are shown. Figure 6C shows the predicted plasma concentrations of MF-300 in a cohort of mice that received 60 mg / kg of MF-300 every two days. [Figure 6D] Figure 6D shows the effects of intermittently administered, orally given MF-300 in SMN1C / C mice. Figure 6D shows the predicted plasma concentrations of MF-300 in a cohort of mice that received 60 mg / kg of MF-300 every three days. [Figure 6E] Figure 6E shows the effects of intermittently administered, orally administered MF-300 in SMN1C / C mice. It also shows the effect of intermittent MF-300 treatment on maximum isometric plantar flexor force and the percentage increase in maximum muscle strength compared to vehicle-administered cohorts. [Figure 6F]Figure 6F shows the effects of intermittently administered, orally administered MF-300 in SMN1C / C mice. It also shows the effect of intermittent MF-300 treatment on the percentage increase in maximal isometric ankle plantarflexion strength compared to a vehicle-administered cohort normalized to muscle weight. [Figure 7A] Figure 7A shows the effects of intermittently administered MF-300 in SMNΔ7 mice. It outlines the experimental setup for evaluating the effects of SMN-C3 and intermittent MF-300 administration in SMNΔ7 mice. [Figure 7B] The effects of intermittently administered MF-300 in SMNΔ7 mice are shown. Figure 7B shows the predicted plasma concentrations of MF-300 in a cohort of mice that received 30 mg / kg of MF-300 daily. [Figure 7C] The effects of intermittently administered MF-300 in SMNΔ7 mice are shown. Figure 7C shows the predicted plasma concentrations of MF-300 in a cohort of mice that received 30 mg / kg of MF-300 every two days. [Figure 7D] The effects of intermittently administered MF-300 in SMNΔ7 mice are shown. Figure 7D shows the predicted plasma concentrations of MF-300 in a cohort of mice that received 30 mg / kg of MF-300 every 3 days. [Figure 7E] The effects of intermittently administered MF-300 in SMNΔ7 mice are shown. Figure 7E shows the predicted plasma concentrations of MF-300 in a cohort of mice that received daily doses of 10 mg / kg or 30 mg / kg of MF-300. [Figure 7F] The effects of intermittently administered MF-300 in SMNΔ7 mice are shown. Figure 7F shows the predicted plasma concentrations of MF-300 in a cohort of mice that received 10 mg / kg or 30 mg / kg of MF-300 every two days. [Figure 7G] Figure 7G shows the effect of intermittently administered MF-300 on maximum isometric ankle plantarflexion muscle strength in SMNΔ7 mice. [Figure 7H] Figure 7H shows the effect of intermittently administered MF-300 in SMNΔ7 mice. The effect of intermittent administration of MF-300 treatment on the percentage increase in maximum muscle strength from vehicle in SMNΔ7 mice. Detailed description of the invention

[0112] Determining the administration regimen requires a precise balance between drug efficacy and safety, aiming to reduce toxicity and side effects while maintaining the dose at the treatment level. (Half maximal effective concentration or EC) 50 EC refers to the concentration of a drug that induces an intermediate effect or response between the baseline and the maximum possible effect after a specific exposure time. To maintain efficacy, some drugs have a dosing interval at which the EC is adjusted. 50 Maintaining concentrations above a certain level may increase the incidence of undesirable drug toxicity and adverse events. In one embodiment, the present disclosure relates to the plasma concentration of the 15-PGDH inhibitor in a subject being the EC of the 15-PGDH inhibitor. 50 When the dose is below a certain threshold, a method is provided for administering 15-PGDH inhibitors while maintaining the therapeutic efficacy of the inhibitors. In some cases, the methods described herein reduce or avoid the toxicity associated with more frequent administration of 15-PGDH inhibitors.

[0113] This specification provides a method for treating diseases associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity and / or expression levels in a subject. The method may include administering a 15-PGDH inhibitor to a subject at a frequency less than once daily (QD) and / or at a frequency that reduces toxicity compared to once daily (QD). For example, the method may include administering a 15-PGDH inhibitor to a subject (e.g., by oral administration) at a frequency of once every two days (Q2D), once every three days (Q3D), or less than once every three days.

[0114] In some cases, the method is to determine the plasma concentration of the 15-PGDH inhibitor in the subject. 50 If the value is less than the target value, the procedure may include administering a 15-PGDH inhibitor. For example, at some point after administration of a 15-PGDH inhibitor, the plasma concentration of the 15-PGDH inhibitor in the subject is equal to the EC of the 15-PGDH inhibitor. 50 At least one dose of a 15-PGDH inhibitor may be administered or may have been administered in an amount exceeding the EC of the 15-PGDH inhibitor. 50 The method may include administering a subsequent dose of the 15-PGDH inhibitor to the subject if the plasma concentration of the 15-PGDH inhibitor falls below the EC threshold (e.g., at some point after the administration of a previous dose, e.g., more than 24 hours after the administration of a previous dose). The method provided herein maintains the efficacy of the 15-PGDH inhibitor (e.g., to treat a disease) and reduces the risk of toxic side effects to the subject, while ensuring that the plasma concentration of the 15-PGDH inhibitor is below the EC threshold before the subsequent dose. 50 This is based on the finding that 15-PGDH inhibitors can be administered in lower-frequency dosing regimens, allowing for lower levels of dosing.

[0115] This specification provides methods for treating diseases associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject. In some cases, the method includes administering to the subject an amount of a 15-PGDH inhibitor effective in inhibiting 15-PGDH at a level sufficient to treat the disease. In some cases, the 15-PGDH inhibitor is administered to the subject at a dosing frequency that shows reduced toxicity to the subject compared to once daily administration of the same amount of the 15-PGDH inhibitor.

[0116] Furthermore, methods for treating diseases associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject are provided herein. In some cases, the method involves reducing the plasma concentration of a 15-PGDH inhibitor in the subject to the EC of the 15-PGDH inhibitor. 50 The procedure includes administering to a subject an amount of a 15-PGDH inhibitor effective in increasing the level to a certain level. In some cases, the subject has received at least one dose of a 15-PGDH inhibitor prior to the administration. In some cases, the administration is performed when the subject is receiving an EC of the 15-PGDH inhibitor. 50 The procedure includes administering a 15-PGDH inhibitor to a target user when the plasma concentration of the 15-PGDH inhibitor is less than [amount missing].

[0117] In some embodiments, the frequency of administration refers to the frequency with which a therapeutic agent, such as a pharmaceutical, drug, compound, or inhibitor, is administered to or ingested by a subject. In some embodiments, the administration frequencies that demonstrate reduced toxicity to the subject are once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once every seven days, once every eight days, once every nine days, or once every ten days.

[0118] In some embodiments, the administration frequency that demonstrates a reduction in toxicity to the subject is less than once a day. In some embodiments, the administration frequency that demonstrates reduced toxicity to the subject is less than once every two days, less than once every three days, less than once every four days, less than once every five days, less than once every six days, or less than once every seven days.

[0119] In some embodiments, the administration frequencies that demonstrate reduced toxicity to the subject are less than once a day to once every 10 days, less than once a day to once every 9 days, less than once a day to once every 8 days, less than once a day to once every 7 days, less than once a day to once every 6 days, less than once a day to once every 5 days, less than once a day to once every 4 days, less than once a day to once every 3 days, or less than once a day to once every 2 days.

[0120] In some embodiments, the administration frequencies that demonstrate reduced toxicity to the subject are less than once a day to less than once every 10 days, less than once a day to less than once every 9 days, less than once a day to less than once every 8 days, less than once a day to less than once every 7 days, less than once a day to less than once every 6 days, less than once a day to less than once every 5 days, less than once a day to less than once every 4 days, less than once a day to less than once every 3 days, or less than once a day to less than once every 2 days.

[0121] In some examples, EC 50 This is determined using biochemical assays and / or cell-based assays that measure the levels of 15-PGDH activity and / or 15-PGDH substrates such as prostaglandin E2. In some cases, the administration of the 15-PGDH inhibitor determines the plasma concentration of the 15-PGDH inhibitor in the subject, while the EC of the 15-PGDH inhibitor is determined. 50 This includes administering a 15-PGDH inhibitor if the level is less than [a certain level].

[0122] In some cases, administration resulted in plasma concentrations of 15-PGDH inhibitors in the subject, and the EC of 15-PGDH inhibitors. 50 This includes administering a 15-PGDH inhibitor if the level is at least 2 times, at least 5 times, at least 10 times, at least 50 times, at least 100 times, at least 500 times, at least 1000 times, or more than 1000 times lower than the given level.

[0123] In some embodiments, the administration is such that the plasma concentration of the 15-PGDH inhibitor in the subject is equal to the EC of the 15-PGDH inhibitor. 50 If the value is less than the EC2 of the 15-PGDH inhibitor, the administration of a 15-PGDH inhibitor is included. In some embodiments, the plasma concentration of the 15-PGDH inhibitor is the EC2 of the 15-PGDH inhibitor. 50 It is less than at least 2 times, at least 5 times, at least 10 times, at least 50 times, at least 100 times, at least 500 times, at least 1000 times, or more than 1000 times.

[0124] In some embodiments, the plasma concentration of the 15-PGDH inhibitor is the EC of the 15-PGDH inhibitor. 50 It is approximately 2 to 10 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor is the EC of the 15-PGDH inhibitor. 50 It is approximately 2 to 100 times lower than [the other value]. In some embodiments, the plasma concentration of the 15-PGDH inhibitor is [the EC2] of the 15-PGDH inhibitor. 50 It is approximately 10 to 100 times lower than [the other value]. In some embodiments, the plasma concentration of the 15-PGDH inhibitor is [the EC2] of the 15-PGDH inhibitor. 50 It is approximately 2 to 1000 times lower than [the other value]. In some embodiments, the plasma concentration of the 15-PGDH inhibitor is [the EC of the 15-PGDH inhibitor]. 50 It is approximately 10 to 1000 times lower than [the other value]. In some embodiments, the plasma concentration of the 15-PGDH inhibitor is [the EC2] of the 15-PGDH inhibitor. 50 It is approximately 100 to 1000 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor is the EC of the 15-PGDH inhibitor. 50 It is approximately 2 to 100,000 times lower than [the other value]. In some embodiments, the plasma concentration of the 15-PGDH inhibitor is [the EC of the 15-PGDH inhibitor]. 50 It is approximately 10 to 100,000 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor is the EC of the 15-PGDH inhibitor. 50 It is approximately 100 to 100,000 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor is the EC of the 15-PGDH inhibitor. 50It is approximately 1,000 to 100,000 times lower than that.

[0125] In some embodiments, the administration is such that the plasma concentration of the 15-PGDH inhibitor in the subject is equal to the EC of the 15-PGDH inhibitor. 50 This includes administering a 15-PGDH inhibitor if the level is at least 2 times, at least 5 times, at least 10 times, at least 50 times, at least 100 times, at least 500 times, at least 1000 times, or more than 1000 times lower than the given level.

[0126] In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. 50 It is approximately 2 to 10 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. 50 It is approximately 2 to 100 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. 50 It is approximately 10 to 100 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. 50 It is approximately 2 to 1000 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. 50 It is approximately 10 to 1000 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. 50 It is approximately 100 to 1000 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. 50 It is approximately 2 to 100,000 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. 50 It is approximately 10 to 100,000 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. 50It is approximately 100 to 100,000 times lower than that. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. 50 It is approximately 1,000 to 100,000 times lower than that.

[0127] In some cases, subjects received at least one dose of a 15-PGDH inhibitor at least 24 hours, 48 ​​hours, 72 hours, or 96 hours prior to administration. In some cases, subjects received at least one dose of a 15-PGDH inhibitor at least 24 hours prior to administration. In some cases, subjects received at least one dose of a 15-PGDH inhibitor at least 48 hours prior to administration. In some cases, subjects received at least one dose of a 15-PGDH inhibitor at least 72 hours prior to administration. In some cases, subjects received at least one dose of a 15-PGDH inhibitor at least 24 hours prior to administration and within 96 hours prior to administration. In some cases, subjects received at least one dose of a 15-PGDH inhibitor at least 24 hours prior to administration and within 72 hours prior to administration.

[0128] In some cases, the methods described herein involve the plasma concentration of the 15-PGDH inhibitor in the subject, and the EC of the 15-PGDH inhibitor. 50 When the threshold exceeds a certain level, it results in reduced toxicity to the subject compared to administering the same amount of 15-PGDH inhibitor to the subject. In some cases, the method described herein results in reduced toxicity to the subject compared to administering the same amount of 15-PGDH inhibitor to the subject once daily.

[0129] In some embodiments, toxicity reduction includes reduction of neurotoxicity (e.g., reduction of neurological damage). In some embodiments, toxicity reduction includes reduction of muscle degeneration. In some embodiments, toxicity reduction includes reduction of gastrointestinal and / or metabolic disorders. In some embodiments, toxicity reduction includes reduction of inflammation. In some embodiments, toxicity reduction is measured by safety pharmacology, genetic toxicology, acute and subchronic toxicology, absorption, distribution, metabolism and excretion (ADME) studies, reproductive and developmental toxicity, carcinogenicity assessment, or any combination thereof.

[0130] In some embodiments, administration involves administering the 15-PGDH inhibitor to the target by various methods. For example, oral administration, intramuscular administration, intradermal administration, subcutaneous administration, intrathecal administration, intravenous administration, intraperitoneal administration, topical (percutaneous), intravenous infusion, and implantation (e.g., implantation of a sustained-release device such as a polymer implant or mini osmotic pump) can all be appropriate routes of administration. In some embodiments, administration involves administering the 15-PGDH inhibitor to the target by oral administration. In some embodiments, administration involves administering the 15-PGDH inhibitor to the target by intramuscular administration. In some embodiments, administration involves administering the 15-PGDH inhibitor to the target by intraperitoneal injection.

[0131] In some embodiments, the 15-PGDH inhibitor is a small molecule. In some embodiments, the 15-PGDH inhibitor is an orally bioavailable small molecule.

[0132] In some embodiments, the 15-PGDH inhibitor is of formula I:

[0133] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, -SO2CH2-, Each Y is independent of N and CR 11 Selected from, Each R 1 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo or thio, Each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 5 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10Selected from cycloalkyl groups, Each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 10 H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected independently from cycloalkyl, Each R 11 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, 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, However, the above compound of formula I is

[0134] [ka] isn't it.

[0135] 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-.

[0136] In some embodiments, each Y is independently N and CR 11 Selected from. In some embodiments, each Y is N. In some embodiments, each Y is CR 11 In some embodiments, one Y is N and the other Y is CR. 11 That is the case.

[0137] Several embodiments, each R 1 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 1 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 1 It is independent, Halo, -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 SO2R8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 1 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 Selected from.

[0138] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2 and R 3 They come together to form an oxo. In some embodiments, R 2 and R 3 They come together to form thio.

[0139] Several embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 Selected from.

[0140] Several embodiments, each R 5 It is independent, Halo, -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 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 5 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 5 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8, -C(O)OR 8 -C(O)NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 5 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 Selected from.

[0141] In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Selected from alkyl groups.

[0142] Several embodiments, each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 8H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 8 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0143] Several embodiments, each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 9 C is independent 1-6 Selected from alkyl groups.

[0144] Several embodiments, each R 10 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, each R 10 H and C are independent of each other. 1-6 Alkyl, and C 1-6Selected from haloalkyls. In some embodiments, each R 10 H and C 1-6 It is selected independently of alkyl.

[0145] Several embodiments, each R 11 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 11 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 11 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 11 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 Selected from.

[0146] 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.

[0147] 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.

[0148] In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10.

[0149] In some embodiments, the compound is of formula Ia:

[0150] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the compound is of formula Ib

[0152] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the 15-PGDH inhibitor is of formula II

[0154] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, T, U, W, X, and Y are independent of N and CR. 5 Selected from, S, V, and Z are independently selected from N and C. R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, here The above alkyl, cycloalkyl, aryl, or heteroaryl elements may be optionally halo, -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo or thio, Each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, or Two R's 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 5 These are independently H, Halo, and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, Each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 10 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, However, the above compound of formula II is

[0155] [ka]

[0156] [ka]

[0157] [ka] isn't it.

[0158] In some embodiments, T, U, W, X, and Y are independently N and CR. 5 Selected from. In some embodiments, at least one of T, U, W, X, and Y is N, and the rest are CR 5 In some embodiments, at least two of T, U, W, X, and Y are N, and the rest are CR. 5 In some embodiments, at least three of T, U, W, X, and Y are N, and the rest are CR. 5 In some embodiments, at least four of T, U, W, X, and Y are N, and the rest are CR. 5 In some embodiments, T, U, W, X, and Y are CR 5 In some embodiments, T, U, W, X, and Y are N.

[0159] In some embodiments, S, V, and Z are independently selected from N and C. In some embodiments, at least one of S, V, and Z is N and the rest are C. In some embodiments, at least two of S, V, and Z are N and the rest are C. In some embodiments, S, V, and Z are N. In some embodiments, S, V, and Z are C.

[0160] In some embodiments, R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl are optionally halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Substituting with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, in some embodiments, R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 6-10Selected from aryls and 5-10 membered heteroaryls, alkyl, aryl, or heteroaryl is optional, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 It is substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 It is substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 It is substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 It is substituted with 1 to 3 substituents independently selected from the original molecule.

[0161] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2 and R 3They come together to form an oxo. In some embodiments, R 2 and R 3 They come together to form thio.

[0162] Several embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from. In some embodiments, each R 4 is a halo. In some embodiments, each R 4 It is fluoro.

[0163] In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6Selected from haloalkyls. In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from. In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 These are independently selected from the halo. In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is fluoro.

[0164] Several embodiments, each R 5 These are independently H, Halo, and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 5 These are independently H, Halo, and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 5 These are independently H, Halo, and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 5 These are independently H, Halo, and -NR. 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from. In some embodiments, each R 5 These are independently selected from H and halo.

[0165] In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6Selected from haloalkyls. In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Selected from alkyl groups.

[0166] Several embodiments, each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 8 H and C 1-6 It is selected independently of alkyl.

[0167] Several embodiments, each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, and C1-6 Selected from haloalkyls. In some embodiments, each R 9 C 1-6 Selected from alkyl groups.

[0168] Several embodiments, each R 10 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, each R 10 H and C are independent of each other. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 10 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0169] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0170] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

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

[0172] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, or 2.

[0173] 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.

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

[0175] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, or 2.

[0176] 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.

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

[0178] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, 4, or 5.

[0179] In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

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

[0181] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0182] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

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

[0184] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

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

[0186] In some embodiments, the compound is formulated with formula IIf:

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

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

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

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

[0191] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

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

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

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

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

[0196] [ka] A compound of or a pharmaceutically acceptable salt thereof, where p is 0, 1, 2, 3, or 4.

[0197] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0198] In some embodiments, this compound is derived from formula IIj:

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

[0200] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

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

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

[0203] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0204] In some embodiments, the compound is of formula IIp:

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

[0206] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0207] In some embodiments, the 15-PGDH inhibitor is expressed as formula III:

[0208] [ka] A compound of or a pharmaceutically acceptable salt thereof During the ceremony, Each X is independent of N and CR 7 Selected from, Y is O, S, SO2, and C(R 8 ) Selected from 2, R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, the alkyl, cycloalkyl, aryl or heteroaryl may optionally be halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo or thio, R 4 and R 5 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyls, each alkyl, heteroalkyl, haloalkyl, and cycloalkyl can be independently and optionally selected as halo, -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls, or R 4 and R5 Together with the nitrogen atom to which they are bonded, they form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Optionally, substituted 3-10 membered heterocycloalkyls are formed with 1-3 substituents independently selected from aryls and 5-10 membered heteroaryls. Each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Selected from cycloalkyls, 3-10 member heterocycloalkyls, C 6-10 Selected from aryls and 5-10 membered heteroaryls, or Two R atoms bonded to the same carbon atom 6 These combine to form oxo, thio, or C 3-10 Form a cycloalkyl group, and any remaining R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 7 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 8 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Two R's 8 They came together, Hello, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10-SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 C is optionally substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls. 3-10 It can form cycloalkyl groups, R 9 and R 10 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, Each R 11 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 12 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 13 H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10Selected independently from cycloalkyl, m is either 1 or 2. n is 0, 1, 2, 3, or 4.

[0209] In some embodiments, each X is independently N and CR 7 Selected from. In some embodiments, at least one X is N and the rest are CR 7 In some embodiments, at least two X's are N, and the rest are CR. 7 In some embodiments, each X is N. In some embodiments, each X is CR 7 That is the case.

[0210] In some embodiments, Y is O, S, SO2, and C(R 8 )2 is selected. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R 8 )2.

[0211] In some embodiments, R 1 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl are optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 It is substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 1 C 3-10 Cycloalkyl, C 6-10 Selected from aryl and 5-10 membered heteroaryls, cycloalkyl, aryl, or heteroaryl is optional, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 It is substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 9 R 10 , -OR11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 It is substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6It is substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 It is substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 It is substituted with 1 to 3 substituents independently selected from the original molecule.

[0212] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2 and R 3 They come together to form an oxo. In some embodiments, R 2 and R 3 They come together to form thio.

[0213] In some embodiments, R 4 and R 5 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyls, each alkyl, heteroalkyl, haloalkyl, and cycloalkyl can be independently and optionally selected as halo, -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 It is substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 4 and R 5 C 3-10 Selected from cycloalkyls, each cycloalkyl independently and optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 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, 3-10 member heterocycloalkyl, C 6-10 It is substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 4 and R 5 C 3-10 Selected from cycloalkyls, each cycloalkyl independently and optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 4 and R 5 C 3-10 Selected from cycloalkyls, each cycloalkyl independently and optionally halo, -NR9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 It is substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 4 and R 5 C 3-10 Selected from cycloalkyls, each cycloalkyl independently and optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 It is substituted with 1 to 3 substituents independently selected from the original molecule.

[0214] In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, optionally form halos, -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 Forms 3-10 member heterocycloalkyls substituted with 1-3 substituents independently selected from aryls and 5-10 member heteroaryls. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, optionally form halos, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 A 3-10 membered heterocycloalkyl group is formed by substituted with 1-3 substituents independently selected from the haloalkyl group. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, optionally form halos, -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 A 3- to 10-membered heterocycloalkyl group is formed by substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, optionally form halos, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 They form 3-10 member heterocycloalkyl groups substituted with 1-3 substituents independently selected from the original group.

[0215] Several embodiments, each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Selected from cycloalkyls, 3-10 member heterocycloalkyls, C 6-10 These are aryls and 5-10 member heteroaryls. In some embodiments, each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 6 Hello, -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 SO2NR9 R 10 Selected independently from R. In some embodiments, each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0216] In some embodiments, two R atoms bonded to the same carbon atom 6 They combine to form oxo, thio, or C 3-10 Form a cycloalkyl group, and any remaining R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls. In some embodiments, two Rs bonded to the same carbon atom 6 They combine to form oxo, thio, or C 3-10 Form a cycloalkyl group, and any remaining R 6 It is independent, Halo, -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, and C 1-6 Selected from haloalkyls. In some embodiments, two R atoms bonded to the same carbon atom. 6 They combine to form oxo, thio, or C 3-10 Form a cycloalkyl group, and any remaining R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, two R atoms bonded to the same carbon atom 6 They combine to form oxo, thio, or C 3-10 Form a cycloalkyl group, and any remaining R 6Hello, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 It is selected independently of others.

[0217] Several embodiments, each R 7 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 7 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -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, and C 1-6 Selected from haloalkyls. In some embodiments, each R 7 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, each R 7 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0218] Several embodiments, each R 8 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12, -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 8 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 8 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10-SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, each R 8 These are independently H, Halo, and -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0219] In some embodiments, two R 8 These are combined, optional, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10C substituted with 1 to 3 substituents independently selected from aryl and 5-10 membered heteroaryl groups. 3-10 Cycloalkyl can be formed. In some embodiments, two R 8 These are combined, optional, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 C substituted with 1 to 3 substituents independently selected from haloalkyl groups 3-10 Cycloalkyl can be formed. In some embodiments, two R 8 They came together, Hello, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , NR 13 SO2R 11 , and -NR 13 SO2NR 9 R10 C substituted with 1 to 3 substituents independently selected from 3-10 Cycloalkyl can be formed. In some embodiments, two R 8 These are combined, optional, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 C substituted with 1 to 3 substituents independently selected from 3-10 It can form cycloalkyl groups.

[0220] In some embodiments, R 9 and R 10 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 9 and R 10 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 9 and R 10 H and C appear independently at each occurrence. 1-6 Selected from alkyl groups.

[0221] Several embodiments, each R 11 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 11 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6Selected from haloalkyls. In some embodiments, each R 11 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0222] Several embodiments, each R 12 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 12 C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 12 C 1-6 Selected from alkyl groups.

[0223] Several embodiments, each R 13 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, each R 13 H and C are independent of each other. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 13 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0224] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0225] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0226] In some embodiments, the compound is of formula IIIa:

[0227] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the compound is of formula IIIb:

[0229] [ka] A compound of or a pharmaceutically acceptable salt thereof Each R 14 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, p is 0, 1, 2, or 3.

[0230] Several embodiments, each R 14 It is independent, Halo, -NR 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 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 14 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 14 Hello, -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 Selected independently from R. In some embodiments, each R 14 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from. In some embodiments, each R 14 In some embodiments, each R is a halo. 14 It is independently fluoro.

[0231] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0232] In some embodiments, the compound is of formula IIIc:

[0233] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the compound is formula IIId:

[0235] [ka] A compound of or a pharmaceutically acceptable salt thereof Each R 14 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, p is 0, 1, 2, or 3.

[0236] Several embodiments, each R 14 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 14 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 14 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, each R 14 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from. In some embodiments, each R 14 In some embodiments, each R is a halo. 14 It is independently fluoro.

[0237] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0238] In some embodiments, the 15-PGDH inhibitor is expressed as formula IIk:

[0239] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, T, U, and Y are independent of N and CR. 6 The selection is made from, however, if U is N, then at least one of T and Y is N. R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, where the above aryl or heteroaryl is optionally halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo, Each R 4 These are independently selected from H and Halo, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 7 and R 8 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, Each R 9 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 10 C 1-6 Alkyl, C 1-6Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 11 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl groups, p is 0, 1, or 2.

[0240] In some embodiments, T, U, and Y are independently N and CR. 6 The following are selected, however, if U is N, then at least one of T and Y is N. In some embodiments, one of T, U, and Y is N, and the rest are CR 6 In some embodiments, two of T, U, and Y are N, and the rest are CR. 6 In some embodiments, one of T, U, and Y is CR. 6 And the rest is N. In some embodiments, two of T, U, and Y are CR 6 And the rest is N. In some embodiments, T, U, and Y are N. In some embodiments, T, U, and Y are CR 6 That is the case.

[0241] In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9, -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 It is substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , and -NR 11 SO2NR 7 R 8 It is substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , and -C(O)NR 7 R 8 It is substituted with 1 to 3 substituents independently selected from the original molecule.

[0242] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2 and R 3 They come together to form an oxo.

[0243] Several embodiments, each R 4 R is independently selected from H and halo. In some embodiments, each R 4 R is independently selected from H and fluoro. In some embodiments, each R 4 is H. In some embodiments, each R 4 is fluoro. In some embodiments, one R 4 H is one R 4 It is fluoro.

[0244] In some embodiments, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6Selected from haloalkyls. In some embodiments, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , and -NR 11 SO2NR 7 R 8 Selected from. In some embodiments, R 5 Hello, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , and -C(O)NR 7 R 8 Selected from.

[0245] In some embodiments, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 , -SO2R 10 -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , and -NR 11 SO2NR7 R 8 Selected from. In some embodiments, R 6 H, Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 and -C(O)NR 7 R 8 Selected from.

[0246] In some embodiments, R 7 and R 8 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl. In some embodiments, R 7 and R 8 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 7 and R 8 H and C appear independently at each occurrence. 1-6 Selected from alkyl groups.

[0247] Several embodiments, each R 9 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 9 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 9 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0248] Several embodiments, each R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 10 C 1-6 Selected from alkyl groups.

[0249] Several embodiments, each R 11 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyl. In some embodiments, each R 11 H and C are independent of each other. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 11 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0250] 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.

[0251] In some embodiments, the 15-PGDH inhibitor is expressed as formula IIm:

[0252] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, R 1 C 6-10Selected from aryls and 5-10 member heteroaryls, the above aryl or heteroaryl may optionally be halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo, Each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R's 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, Each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 10 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and p is 0, 1, 2, or 3.

[0253] In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the above aryl or heteroaryl may optionally be halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 It is substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the above aryl or heteroaryl may optionally be halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the above aryl or heteroaryl may optionally be halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 It is substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the above aryl or heteroaryl may optionally be halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 It is substituted with 1 to 3 substituents independently selected from the original molecule.

[0254] In some embodiments, R 2H is R 3 is -CF3. In some embodiments, R 2 and R 3 They come together to form an oxo.

[0255] Several embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8, -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from. In some embodiments, each R 4 R is independently selected from the halo. In some embodiments, each R 4 It is fluoro.

[0256] In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independently, Halo, -NR 6 R 7 , -OR 8 , -C(O)R8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6Selected from haloalkyls. In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from.

[0257] In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from.

[0258] In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Selected from haloalkyls. In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Selected from alkyl groups.

[0259] Several embodiments, each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 8H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 8 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0260] Several embodiments, each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Selected from haloalkyls. In some embodiments, each R 9 C 1-6 Selected from alkyl groups.

[0261] Several embodiments, each R 10 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, each R 10 H and C are independent of each other. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 10 H and C are independent of each other. 1-6 Selected from alkyl groups.

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

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

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

[0265] In some embodiments, the 15-PGDH inhibitor is expressed by formula IIq:

[0266] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, where the above aryl or heteroaryl is optionally halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8, -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo, Each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or Two R's 4 They become C together with the carbon atoms to which they are bonded and any intervening atoms. 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 6 and R7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, Each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 10 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and p is 0, 1, 2, or 3.

[0267] In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the above aryl or heteroaryl may optionally be halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 It is substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the above aryl or heteroaryl may optionally be halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the above aryl or heteroaryl may optionally be halo, -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 , and -NR 10 SO2NR 6 R 7 It is substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, the above aryl or heteroaryl may optionally be halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 It is substituted with 1 to 3 substituents independently selected from the original molecule.

[0268] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2 and R 3 They come together to form an oxo.

[0269] Several embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, each R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from. In some embodiments, each R 4 R is independently selected from the halo. In some embodiments, each R 4 It is fluoro.

[0270] In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, two R 4 They become C together with the carbon atoms to which they are bonded and any intervening atoms. 3-10 Form a cycloalkyl group, and any remaining R 4 It is independent, Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7, -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, two R 4 Together with the carbon atoms to which they are bonded and any intervening atoms, C 3-10 Forming a cycloalkyl group, Any remaining R 4 teeth Independent, Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from.

[0271] In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, R 5 Hello, -NR 6 R 7, -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 , -SO2R 9 -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 Selected from. In some embodiments, R 5 Hello, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 Selected from.

[0272] In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Selected from haloalkyls. In some embodiments, R 6 and R 7 H and C appear independently at each occurrence. 1-6 Selected from alkyl groups.

[0273] Several embodiments, each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 8 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 8 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0274] Several embodiments, each R 9 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 9 C 1-6 Alkyl, C1-6 Heteroalkyl, C 1-6 Selected from haloalkyls. In some embodiments, each R 9 C 1-6 Selected from alkyl groups.

[0275] Several embodiments, each R 10 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, each R 10 H and C are independent of each other. 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 10 H and C 1-6 It is selected independently of alkyl.

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

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

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

[0279] In some embodiments, the 15-PGDH inhibitor is expressed as formula IIIc:

[0280] [ka] A compound of or a pharmaceutically acceptable salt thereof, in the formula, Each X is independent of N and CR 7 Selected from, Y is O, S, SO2, and C(R 8 ) Selected from 2, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, where the above aryl or heteroaryl is optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups, R 2 is H and R 3 is -CF3 or R 2 and R 3 They come together to form an oxo, R4 and R 5 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Selected from cycloalkyls, each alkyl, heteroalkyl, haloalkyl, and cycloalkyl can be independently and optionally selected as halo, -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Substituted with 1 to 3 substituents independently selected from aryls and 5-10 membered heteroaryls, or R 4 and R 5 Together with the nitrogen atom to which they are bonded, they form a halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , NR 13 C(O)R 11, -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Optionally, substituted 3-10 membered heterocycloalkyls are formed with 1-3 substituents independently selected from aryls and 5-10 membered heteroaryls. Each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, or Two R atoms bonded to the same carbon atom 6 They come together to form an oxo, and any remaining R 6 It is independently, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11, -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, Each R 7 and R 8 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, R 9 and R 10 is, independently at each occurrence, H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl, selected from each R 11 is independently H, 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, selected from each R 12 is independently 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, selected from each R 13 is H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl, independently selected from n is 0, 1, 2, 3, or 4.

[0281] In some embodiments, each X is independently selected from N and CR 7 In some embodiments, at least one X is N and the remainder are CR 7 In some embodiments, at least two X are N and the remainder are CR 7 In some embodiments, each X is N. In some embodiments, each X is CR 7 In some embodiments, Y is O, S, SO2, and C(R

[0282] In some embodiments, Y is O, S, SO2, and C(R 8)2 is selected. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R 8 )2.

[0283] In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 It is substituted with 1 to 3 substituents independently selected from cycloalkyl and 5-10 membered heteroaryl groups. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 It is substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 1 C 6-10 Selected from aryls and 5-10 member heteroaryls, aryl or heteroaryl is optional, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 It is substituted with 1 to 3 substituents independently selected from the original molecule.

[0284] In some embodiments, R 2 H is R 3 is -CF3. In some embodiments, R 2 and R 3 They come together to form an oxo.

[0285] In some embodiments, R 4 and R 5 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyls, each alkyl, heteroalkyl, haloalkyl, and cycloalkyl can be independently and optionally selected as halo, -NR. 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 It is substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 4 and R 5 C 3-10Selected from cycloalkyls, each cycloalkyl independently and optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 It is substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. In some embodiments, R 4 and R 5 C 3-10 Selected from cycloalkyls, where each cycloalkyl is independently and optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 It is substituted with 1 to 3 substituents independently selected from the haloalkyl group. In some embodiments, R 4 and R 5 C 3-10 Selected from cycloalkyls, each cycloalkyl independently and optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 It is substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 4 and R 5 C 3-10 Selected from cycloalkyls, each cycloalkyl independently and optionally halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 It is substituted with 1 to 3 substituents independently selected from the original molecule.

[0286] In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, optionally form halos, -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 Forms 3-10 member heterocycloalkyls substituted with 1-3 substituents independently selected from aryls and 5-10 member heteroaryls. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, optionally form halos, -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 C1-6 A 3-10 membered heterocycloalkyl group is formed by substituted with 1-3 substituents independently selected from the haloalkyl group. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, optionally form halos, -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 A 3- to 10-membered heterocycloalkyl group is formed by substituted with 1 to 3 substituents independently selected from R. In some embodiments, R 4 and R 5 These, together with the nitrogen atom to which they are bonded, optionally form halos, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 They form 3-10 member heterocycloalkyl groups substituted with 1-3 substituents independently selected from the original group.

[0287] Several embodiments, each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10-SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, each R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0288] In some embodiments, two R atoms bonded to the same carbon atom 6 They come together to form an oxo, and any remaining R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls. In some embodiments, two Rs bonded to the same carbon atom 6 They come together to form an oxo, and any remaining R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, two R atoms bonded to the same carbon atom. 6 They come together to form an oxo, and any remaining R 6 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13SO2NR 9 R 10 Selected from. In some embodiments, two R atoms bonded to the same carbon atom 6 They come together to form an oxo, and any remaining R 6 Hello, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 It is selected independently of others.

[0289] Several embodiments, each R 7 and R 8 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 7 and R 8 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11-C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 7 and R 8 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 , -SO2R 12 -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 Selected from. In some embodiments, each R 7 and R 8 It is independent, Halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Selected from.

[0290] In some embodiments, R 9 and R 10 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Selected from cycloalkyl. In some embodiments, R 9 and R 10 H and C appear independently at each occurrence. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, R 9 and R 10 H and C appear independently at each occurrence. 1-6 Selected from alkyl groups.

[0291] Several embodiments, each R 11 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 11 H and C are independent of each other. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 Selected from haloalkyls. In some embodiments, each R 11 H and C 1-6 It is selected independently of alkyl.

[0292] Several embodiments, each R 12 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 12 C 1-6 Alkyl, C 1-6Heteroalkyl, and C 1-6 is selected from haloalkyl. In some embodiments, each R 12 is independently selected from C 1-6 alkyl.

[0293] In some embodiments, each R 13 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 13 is independently H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 13 is independently H and C 1-6 alkyl.

[0294] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. [[ID=第33]]

[0295] In some embodiments, the 15-PGDH inhibitor is

[0296]

Chemical formula

[0297] In some embodiments, the 15-PGDH inhibitor is

[0298]

Chemical formula

[0299]

Chemical formula

[0300] [ka]

[0301] [ka]

[0302] [ka]

[0303] [ka]

[0304] [ka]

[0305] [ka]

[0306] [ka]

[0307] [ka]

[0308] [ka] It is a compound selected from the group consisting of the following:

[0309] In some embodiments, the 15-PGDH inhibitor is

[0310] [ka] It is a compound selected from the group consisting of the following:

[0311] In some cases, the solubility of the inhibitor and hPGDH IC2 50 It is characterized as shown in Tables 1 and 2.

[0312] [Table 1-1]

[0313] [Table 1-2]

[0314] [Table 1-3]

[0315] [Table 1-4]

[0316] [Table 1-5]

[0317] [Table 1-6]

[0318] [Table 1-7]

[0319] [Table 2-1]

[0320] [Table 2-2]

[0321] Table 3 provides analytical data for some of the inhibitors described herein.

[0322] [Table 3-1]

[0323] [Table 3-2]

[0324] [Table 3-3]

[0325] [Table 3-4]

[0326] [Table 3-5]

[0327] [Table 3-6]

[0328] [Table 3-7]

[0329] [Table 3-8]

[0330] [Table 3-9]

[0331] Table 3-10

[0332] Table 3-11

[0333] Table 3-12

[0334] Table 3-13

[0335] Table 3-14

[0336] Table 3-15

[0337] Table 3-16

[0338] Table 3-17

[0339] Table 3-18

[0340] Table 3-19

[0341] Table 3-20

[0342] Table 3-21

[0343] Table 3-22

[0344] Table 3-23

[0345] Table 3-24

[0346] Table 3-25

[0347] Table 3-26

[0348] Table 3-27

[0349] Table 3-28

[0350] Table 3-29

[0351] Table 3-30

[0352] Table 3-31

[0353] Table 3-32

[0354] Table 3-33

[0355] Table 3-34

[0356] Table 3-35

[0357] Table 3-36

[0358] Table 3-37

[0359] Table 3-38

[0360] Table 3-39

[0361] Table 3-40

[0362] Table 3-41

[0363] Table 3-42

[0364] Table 3-43

[0365] Table 3-44

[0366] Table 3-45

[0367] Table 3-46

[0368] Table 3-47

[0369] Table 3-48

[0370] Table 3-49

[0371] Table 3-50

[0372] Table 3-51

[0373] Table 3-52

[0374] Table 3-53

[0375] Table 3-54

[0376] Table 3-55

[0377] Table 3-56

[0378] Table 3-57

[0379] Table 3-58

[0380] Table 3-59

[0381] Table 3-60

[0382] In some embodiments, the 15-PGDH inhibitor is derived from formula IV:

[0383] [ka] A compound having the structure or a pharmaceutically acceptable salt thereof, During the ceremony, Ring Q is phenyl or a 5-10 membered heteroaryl. Z is CR 1 or N, Y is CR 2 or N, R 1 H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, Each R 2 These are independently 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, or substituted or unsubstituted C3-C8 cycloalkyl, Each R 3 These are independently H, halogen, -CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11, -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, each of which has one or more R 13 It is replaced by, here, Each R 13 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C2-C8 alkenyl groups, substituted or unsubstituted C1-C8 aminoalkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups, each of which has one or more R groups. 6 It is replaced by, here, Each R 6 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10-C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-8 member heteroaryl, Or two R's 6 However, they combine with the atoms to which they are bonded to form substituted or unsubstituted C3-C6 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups. X A -NR 5 R 5 OR 5 And here, Each R 5 These are independently H or C1-C6 alkyl groups. R 5a is either H or CH3, Or R 5a and one R 6 These combine with the atoms to which they are bonded to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl groups. Each R 8 and R 9 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which has one or more R a Replaced by, Each R 10These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, Each R 11 This includes substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, and substituted or unsubstituted C3-C groups. 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Independently selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, Each R 12 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which has one or more R a Replaced by, Each R a These are independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3. p is 1, 2, 3, or 4.

[0384] In some embodiments, the 15-PGDH inhibitor is derived from formula IV:

[0385] [ka] A compound having the structure or a pharmaceutically acceptable salt thereof, During the ceremony, Ring Q is phenyl or a 5-10 membered heteroaryl. Z is CR 1 or N, Y is CR 2 or N, R 1 H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, R 2 H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 -CN, -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , or substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, Each R 3 These are independently H, halogen, -CN, -NO2, and -NR. 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C2-C8 alkenyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups, each of which has one or more R groups. 6 Replaced by, Each R 6 These are independently H, halogen, CN, -NO2, and -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 5-8 membered heteroaryl, Or two R's 6 However, they combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl ring. X A , NR 5 R 5OR 5 And here, Each R 5 These are independently H or C1-C6 alkyl groups. R 5a is either H or CH3, Or R 5a and one R 6 These combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl ring. Each R 8 and R 9 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, and C4-C 10 Selected from heterocycloalkyl groups, Each R 10 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from aryls and 5-10 member heteroaryls, Each R 11 These are independently C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from aryls and 5-10 member heteroaryls, Each R 12 These are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl. p is 1, 2, 3, or 4.

[0386] In some embodiments, ring Q is a 5- to 10-member heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is a 5- to 8-member heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is a 5- to 8-member heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is a monocyclic, bicyclic, or polycyclic heteroaryl. In some embodiments, ring Q is a bicyclic heteroaryl 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.

[0387] In some embodiments, ring Q is a 6-member monocyclic heteroaryl containing 1, 2, or 3 N atoms. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is phenyl, pyrimidine, or pyridine. In some embodiments, ring Q is pyrimidine.

[0388] In some embodiments, ring Q is phenyl, pyridine, or triazolopyridine.

[0389] In some embodiments,

[0390]

Chemical formula

[0391]

Chemical formula

[0392] In some embodiments, X 1 , X 2 , X 3 , and X 4 These are CR 3 That is the case.

[0393] In some embodiments, X 1 is N, and X 2 , X 3 , and X 4 These are CR 3 That is the case.

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

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

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

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

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

[0399] Several embodiments, each R 3 These are independently H, halogen, -CN, -NO2, and -NR. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl. In some embodiments, each R 3 These are independently H, halogen, 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)OR10 Selected from substituted or unsubstituted C1-C6 alkyls, substituted or unsubstituted C1-C6 haloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5-10 member heteroaryls. In some embodiments, each R 3 These are independently H, halogen, 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 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, each R 3 These are independently selected from H, halogens, substituted or unsubstituted phenyls, and substituted or unsubstituted 5-6 member heteroaryls.

[0400] Several embodiments, each R 3 R is independently selected from H or halogen. In some embodiments, each R 3 These are independently substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, each R 3 These are independently substituted or unsubstituted five-membered heteroaryl compounds.

[0401] In some embodiments, the 15-PGDH inhibitor is expressed as formula V:

[0402] [ka] A compound having the structure or a pharmaceutically acceptable salt thereof, During the ceremony, Z is CR 1 or N, X 1 is N or CR 3a And, Y is CR 2 or N, R 1 H, halogen, -CN, -OR10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, Each R 2 These are independently 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, or substituted or unsubstituted C3-C8 cycloalkyl, R 3a , R 3b , and R 3c These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl, each of which has one or more R 13 It is replaced with, here Each R 13 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , or -C(O)NR 8 R 9 And, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C2-C8 alkenyl groups, substituted or unsubstituted C1-C8 aminoalkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted C3-C8 heterocycloalkyl groups, each of which has one or more R groups. 6 It is replaced with, here Each R 6 These are independently halogen, CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 8 C(O)R 9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-8 member heteroaryl, Or two R's 6 However, they combine with the atoms to which they are bonded to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl groups. X A , NR 5 R 5 OR 5 And here Each R 5 These are independently H or C1-C6 alkyl groups. R 5a is either H or CH3, Or R 5a and one R 6 These combine with the atoms to which they are bonded to form substituted or unsubstituted C3-C6 cycloalkyl groups. Each R 8 and R 9 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which has one or more R a Replaced by, Each R 10 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, Each R 11 This includes substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, and substituted or unsubstituted C3-C groups. 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Independently selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a Replaced by, Each R 12 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which has one or more R a Replaced by, and Each R a These are independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0403] In some embodiments, the 15-PGDH inhibitor is expressed as formula V:

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

[0405] In some embodiments, X A is NR 5 R5 In some embodiments, X A is OR 5 That is the case.

[0406] In some embodiments, Y is N. In some embodiments, Y is CR 2 That is the case.

[0407] In some embodiments, the compound of formula V is VIa:

[0408] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

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

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

[0411] In some embodiments, Z is N. In some embodiments, Z is CR 1 In some embodiments, Z is CH.

[0412] In some embodiments, the compound of formula V is formula VIIa:

[0413] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

[0419] [ka] It has the structure of, or a pharmaceutically acceptable salt thereof.

[0420] In some embodiments, 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 H is H.

[0421] Several embodiments, each R 2 These are independently H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 , or substituted or unsubstituted C1-C6 alkyl. In some embodiments, each R 2 These are independently H or C1-C6 alkyl groups.

[0422] Several embodiments, each R 2 H is H.

[0423] In some embodiments, X 1 CR 3a In some embodiments, X 1 It is N.

[0424] In some embodiments, R 3a , R 3b , and R 3c These are H, halogen, -CN, -NO2, and -NR, respectively, and are independent of each other. 8 R 9 , -OR 10 , -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 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl. In some embodiments, R 3a , R 3b , and R 3c These are H, halogen, and -C(O)R, respectively, independently. 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups. In some embodiments, R 3a , R 3b , and R3c These are H, halogen, and -C(O)R, respectively, independently. 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3a , R 3b , and R 3c These are H, halogen, and -C(O)R, respectively, independently. 10 -C(O)NR 8 R 9 , and selected from substituted or unsubstituted 5-membered heteroaryls. In some embodiments, R 3a , R 3b , and R 3c These are H, halogen, and -OR, respectively, independently. 10 , -S 8 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 12 C(O)R 10 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 3a , R 3b , and R 3c These are, independently, H, halogen, substituted or unsubstituted C1-C6 alkyl, and -C(O)R. 10 -C(O)NR 8 R 9 Selected from C3-C6 heterocycloalkyl and 5-membered heteroaryl groups.

[0425] In some embodiments, R 3a , R 3b , and R 3cEach of these is independently selected from H, halogen, -C(O)OH, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, triazole, tetrazole, pyrrolidine, morpholine, or C1-C6 alkyl substituted with -C(O)OH.

[0426] In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl. In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c is halogen, -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR10 , -NR 12 C(O)NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups. In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c is halogen, -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c These are substituted or unsubstituted C1-C6 alkyl groups, -C(O)R 10 -C(O)NR 8 R 9 Selected from C3-C6 heterocycloalkyl and 5-membered heteroaryl. In some embodiments, R 3a and R 3b These are H or halogen, respectively, and R 3c These are substituted or unsubstituted five-membered heteroaryl compounds.

[0427] In some embodiments, R 3a is a halogen, and R 3b is H. In some embodiments, R 3a is -Cl or -F, and R3b is H. In some embodiments, R 3b is a halogen, and R 3a is H. In some embodiments, R 3b is -Cl or -F, and R 3a H is H.

[0428] In some embodiments, R 3a and R 3b These are H, respectively.

[0429] In some embodiments, R 3a and R 3c is independently H or halogen, and R 3b These are halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 -SO2NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-10 member heteroaryl. In some embodiments, R 3a and R 3c These are H and R respectively. 3b is halogen, -C(O)R 10 , -C(O)OR 10-C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5-10 member heteroaryl groups. In some embodiments, R 3a and R 3c These are H and R respectively. 3b is halogen, -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3a and R 3c These are H and R respectively. 3b is -C(O)R 10 , -C(O)OR 10 , -NR 12 C(O)OR 10 Selected from substituted or unsubstituted phenyls and substituted or unsubstituted 5-6 member heteroaryls. In some embodiments, R 3a and R 3c These are H or halogen, respectively, and R 3b These are substituted or unsubstituted C1-C6 alkyl groups, -C(O)R 10 -C(O)NR 8 R 9 Selected from C3-C6 heterocycloalkyl and 5-membered heteroaryl groups.

[0430] In some embodiments, R 3a and R 3c These are H or halogen, respectively, and R 3bis -C(O)R 10 , -C(O)OR 10 , and selected from substituted or unsubstituted 5-membered heteroaryls.

[0431] In some embodiments, R 3a is a halogen, and R 3c is H. In some embodiments, R 3a H is R 3b is a halogen. In some embodiments, R 3a is -Cl or -F, and R 3c is H. In some embodiments, R 3c is -Cl or -F, and R 3a H is H.

[0432] In some embodiments, R 3a and R 3c These are H, respectively.

[0433] Several embodiments, each R 3 , R 3a , R 3b , and R 3c Each of these is independently selected from pyrrole, triazole, tetrazole, oxazole, diazole, oxadiazole, thiadiazole, and furanil, a five-membered heteroaryl. In some embodiments, each R 3 , R 3a , R 3b , and R 3c Each of these is independently a 5-membered heteroaryl selected from pyrrole, triazole, and tetrazole. In some embodiments, each R 3 , R 3a , R 3b , and R 3c These are, independently, five-membered heteroaryl compounds selected from triazoles and tetrazoles.

[0434] Several embodiments, each R 3 , R 3a , R 3b , or R 3c teeth,

[0435] [ka] It is independently selected from the group consisting of [the specified elements].

[0436] Several embodiments, each R 3 , R 3a , R 3b , or R 3c teeth,

[0437] [ka] It is independently selected from the group consisting of. In some embodiments, each R 3 , R 3a , R 3b , or R 3c teeth,

[0438] [ka] It is independently selected from the group consisting of. In some embodiments, each R 3 , R 3a , R 3b , or R 3c teeth,

[0439] [ka] It is independently selected from the group consisting of [the specified elements].

[0440] In some embodiments, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C2-C8 alkenyl groups, substituted or unsubstituted C1-C8 aminoalkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, substituted or unsubstituted C1-C8 hydroxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, or 4- to 8-membered heterocycloalkyl groups, each of which has one or more R groups. 6 It is replaced by R 4is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or a substituted or unsubstituted C1-C8 hydroxyalkyl. In some embodiments, R 4 These are substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C1-C8 heteroalkyl groups, or substituted or unsubstituted C1-C8 hydroxyalkyl groups.

[0441] In some embodiments, R 4 is a substituted or unsubstituted C1-C8 alkyl group, or a substituted or unsubstituted C1-C8 heteroalkyl group. In some embodiments, R 4 is a substituted or unsubstituted C1-C8 alkyl group. In some embodiments, the alkyl group is a linear or branched alkyl group. In some embodiments, R 4 is a substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments, the heteroalkyl is an alkyl chain in which one or more carbon atoms are substituted with O or N atoms. In some embodiments, R 4 is a substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), substituted or unsubstituted -CH2CH2-O-(C1-C4 haloalkyl), -CH2-O-(C1-C4 haloalkyl), -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2-O-(C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R 4 R is a substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), substituted or unsubstituted -CH2CH2-O-(C1-C4 haloalkyl), or -CH2-O-(C1-C4 haloalkyl). In some embodiments, R 4R 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 is -CH2CH2-O-(C3-C6 cycloalkyl). In some embodiments, R 4 is -CH2-O-(C3-C6 cycloalkyl). In some embodiments, R 4 is -CH2CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R 4 It is -CH2-O-(C3-C6 heterocycloalkyl).

[0442] In some embodiments, R 4 is one or more halogens, -OR 10 It is a substituted or unsubstituted C1-C8 alkyl group, which is either substituted with a C1-C8 alkyl group or a C3-C6 cycloalkyl group.

[0443] In some embodiments, R 4 is a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted C3-C8 heterocycloalkyl group, each of which has one or more R 6 It is replaced by R. In some embodiments, 4 is a C3-C8 cycloalkyl group. In some embodiments, R 4 R is monocyclic, polycyclic, spirocyclic, or crosslinked cycloalkyl. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R 4 is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is cyclobutyl. In some embodiments, R 4 R is cyclopentyl. In some embodiments, R4 is cyclohexyl. In some embodiments, R 4 teeth,

[0444] [ka] That is the case.

[0445] In some embodiments, R 4 These are substituted or unsubstituted C3-C8 heterocycloalkyl groups, each of which has one or more R groups. 6 It is replaced by R. In some embodiments, 4 R is monocyclic, polycyclic, spirocyclic, or cross-linked heterocycloalkyl. In some embodiments, R 4 is a 4-membered heterocycloalkyl. In some embodiments, R 4 is a 5-membered heterocycloalkyl. In some embodiments, R 4 is a 6-membered cycloalkyl. In some embodiments, R 4 is a 7-membered cycloalkyl group. In some embodiments, R 4 is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine. In some embodiments, R 4 It is tetrahydrofuran or tetrahydropyran.

[0446] Several embodiments, each R 6 These are independently halogen, -CN, -NO2, and -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 , -SO2R 11 , -NR 8 C(O)R 9These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or 5-8 member heteroaryl. In some embodiments, each R 6 These are independently halogen, -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 -C(O)NR 8 R 9 , -NR 8 C(O)R 9 These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C8 cycloalkyl. In some embodiments, each R 6 These are independently halogen, -NR 8 R 9 , -OR 10 , -C(O)OR 10 -C(O)NR 8 R 9 These are C1-C6 alkyl or C3-C8 cycloalkyl. In some embodiments, each R 6 These are independently halogen, -NR 8 R 9 , -OR 10 , or C3-C8 cycloalkyl. In some embodiments, each R 6 -NR is independent. 8 R 9 OR 10 In some embodiments, each R 6 R is independently a C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, spirocyclic, or cross-linked cycloalkyl. In some embodiments, each R 6 R is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 6 R is independently a halogen. In some embodiments, each R 6 R is independently H, Cl, F, or Br. In some embodiments, each R 6Independently, F. In some embodiments, each R 6 R is independently F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH3CH3), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, piperidine, piperazine, oxetane, tetrahydrofuran, or tetrahydropyran. In some embodiments, each R 6 R is independently F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R 6 R is independently F, -OH, -CH3, or -CF3. In some embodiments, each R 6 Independently, F. In some embodiments, each R 6 In some embodiments, each R is independently -OH. 6 Independently, R is -CF3. In some embodiments, each R 6 R is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R 6 In some embodiments, each R is independently cyclopropyl. 6 It is cyclobutyl.

[0447] In some embodiments, two R 6 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C6 cycloalkyl groups, or substituted or unsubstituted C3-C6 heterocycloalkyl groups. In some embodiments, two R 6 These combine with the atoms to which they are bonded to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R 6 These combine with the atoms to which they are bonded to form cyclopropyl or cyclobutyl. In some embodiments, two R 6 These combine with the atoms to which they are bonded to form a cyclopropyl. In some embodiments, two R6 These combine with the atoms to which they are bonded to form cyclobutyl. In some embodiments, two R 6 These combine with the atoms to which they are bonded to form a cyclopropyl. In some embodiments, two R 6 These combine with the atoms to which they are bonded to form a cyclohexyl. In some embodiments, two R 6 These combine with the atoms to which they are bonded to form a C3-C6 heterocycloalkyl group. In some embodiments, two R 6 These combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl group. In some embodiments, two R 6 These combine with the atoms to which they are bonded to form a 5-membered heterocycloalkyl group. In some embodiments, two R 6 These combine with the atoms to which they are bonded to form a 6-membered heterocycloalkyl group. In some embodiments, two R 6 These combine with the atoms they are bonded to to form pyran, piperazine, piperidine, or morpholine.

[0448] In some embodiments, R 4 -CH3, -CH2CH3, -CH2CH3CH3, -CH2(CH2)2CH3, -CH2(CH2)3CH3, -CH2(CH2)4CH3, -CH2CH2CH(CH3)2, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted oxetane, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted tetrahydropyran,

[0449] [ka] That is the case.

[0450] Several embodiments, each R 5Independently, each R is a C1-C6 alkyl group. In some embodiments, each R 5 Independently, R is either -CH2CH3 or -CH3. In some embodiments, each R 5 Independently, each R is -CH2CH3. In some embodiments, each R 5 Independently, R is -CH3. In some embodiments, each R 5 H is independent of H.

[0451] In some embodiments, R 5a is CH3. In some embodiments, R 5a H is H.

[0452] In some embodiments, R 5a and one R 6 These combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl group. In some embodiments, R 5a and one R 6 These combine with the atoms to which they are bonded to form cyclopentyl or cyclohexyl. In some embodiments, R 5a and one R 6 These combine with the atoms to which they are bonded to form a cyclohexyl. In some embodiments, R 5a and one R 6 These combine with the atoms they are bonded to to form cyclopentyl.

[0453] Several embodiments, each R 8 and R 9 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which has one or more R aIt is replaced by. In some embodiments, each R 8 and R 9 Each instance independently produces H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Selected from cycloalkyl. In some embodiments, each R 8 and R 9 Each instance independently produces H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups. In some embodiments, each R 8 and R 9 Each occurrence is independent of C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups.

[0454] Several embodiments, each R 10 These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a It is replaced by. In some embodiments, each R 10 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C6-C 10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 10 These are independently H, C1-C6 alkyl, and C3-C 10Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups. In some embodiments, each R 10 R is independently selected from H and C1-C6 alkyl groups. In some embodiments, each R 10 It is independent, C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups.

[0455] Several embodiments, each R 11 This includes substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, and substituted or unsubstituted C3-C groups. 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C6-C 10 Independently selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R a It is replaced by. In some embodiments, each R 11 These are independently C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C6-C 10 Selected from aryls and 5-10 member heteroaryls. In some embodiments, each R 11 R is independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl. In some embodiments, each R 11 It is independent, C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups.

[0456] Several embodiments, each R 12These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Selected from heterocycloalkyls, each of which has one or more R a It is replaced by. In some embodiments, each R 12 These are independently H, linear or branched C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups. In some embodiments, each R 12 R is independently selected from H, linear or branched C1-C6 alkyl groups. In some embodiments, each R 12 It is independent, C3-C 10 Cycloalkyl and C3-C 10 Selected from heterocycloalkyl groups.

[0457] Several embodiments, each R a R is independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3. In some embodiments, each R a R is independently selected from -F, -Cl, -Br, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, each R a The group is independently selected from -F, -OH, -CH3, -CF3, or -C(O)OH.

[0458] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. In some embodiments, p is 3. In some embodiments, p is 5. In some embodiments, p is 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.

[0459] In some embodiments, the PDGH inhibitor is a compound listed in Table 4 or a pharmaceutically acceptable salt thereof.

[0460] [Table 4-1]

[0461] [Table 4-2]

[0462] [Table 4-3]

[0463] [Table 4-4]

[0464] [Table 4-5]

[0465] [Table 4-6]

[0466] [Table 4-7]

[0467] [Table 4-8]

[0468] Table 4-9

[0469] Table 4-10

[0470] Table 4-11

[0471] Table 4-12

[0472] Table 4-13

[0473] Table 4-14

[0474] Table 4-15

[0475] Table 4-16

[0476] Table 4-17

[0477] Table 4-18

[0478] Table 4-19

[0479] Table 4-20

[0480] Table 4-21

[0481] Table 4-22

[0482] Table 4-23

[0483] Table 4-24

[0484] Table 4-25

[0485] Table 4-26

[0486] Table 4-27

[0487] Table 4-28

[0488] [Table 4-29]

[0489] [Table 4-30]

[0490] In some embodiments, the disease is a muscle disease. In some embodiments, the disease is spinal muscular atrophy (SMA). In some embodiments, the disease is a disorder. In some embodiments, the disorder is a muscle disease. In some embodiments, a muscle disease is a muscle atrophy, muscle injury, muscle disorder, or muscle trauma. In some embodiments, a muscle disease is associated with a muscle atrophy, muscle injury, or muscle trauma.

[0491] In some embodiments, diseases associated with muscle injury, trauma, or atrophy are selected from the group consisting of acute muscle injury or trauma, soft tissue hand injury, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), 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, stress-induced urinary incontinence, and sarcopenia.

[0492] In some embodiments, muscle injury involves the pectoralis major complex, latissimus dorsi, teres major and subscapularis, brachioradialis, biceps brachii, brachialis, pronator quadratus, pronator teres, flexor carpi radialis, flexor carpi ulnaris, flexor digitorum superficialis, flexor digitorum profundus, flexor pollicis brevis, opponens pollicis, adductor pollicis, and flexor pollicis brevis. The muscles involved in gastrointestinal muscle development include the brevis, iliopsoas, psoas, rectus abdominis, rectus femoris, gluteus maximus, gluteus medius, medial hamstrings, gastrocnemius, lateral hamstring, quadriceps mechanism, adductor longus, adductor brevis, adductor magnus, medial gastrocnemius, lateral gastrocnemius, soleus, tibialis posterior, tibialis anterior, and flexor digitorum longus. Flexor digitorum brevis, flexor hallucis longus, extensor hallucis longus, hand musclesThis includes, but is not limited to, the muscles of the body, including, arm muscles, foot muscles, leg muscles, chest muscles, stomach muscles, back muscles, buttock muscles, shoulder muscles, head and neck muscles, facial muscles, and oculopharyngeal muscles.

[0493] In some embodiments, muscle diseases include musculoskeletal injuries (e.g., fractures, muscle tears, sprains, acute injuries, overuse injuries), post-traumatic injuries of the limbs or face, athletic injuries, post-fractures in the elderly, soft tissue hand injuries, muscle atrophy (e.g., loss of muscle mass), Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreyfus muscular dystrophy, congenital myotonia, and myotonic dystrophy. This may include dystrophy, other muscular dystrophies, muscle wasting diseases such as cancer cachexia, end-stage renal disease (ESRD), acquired immune deficiency syndrome (AIDS), or chronic obstructive pulmonary disease (COPD), post-surgical muscle weakness, post-traumatic muscle weakness, sarcopenia, inactivity (e.g., muscle disuse or immobility), urethral sphincter deficiency, urethral sphincter agenesis, and neuromuscular diseases.

[0494] In some embodiments, muscle diseases include neuromuscular diseases. In some embodiments, neuromuscular diseases include acid maltase deficiency, amyotrophic lateral sclerosis, Andersen-Tawil syndrome, Becker muscular dystrophy, Becker myotonia congenita, Bethlem myopathy, bulbospinal muscular atrophy, carnitine deficiency, carnitine palmityl transferase deficiency, central core disease, central nuclear myopathy, Charcot-Marie-Tooth disease, congenital muscular dystrophy, congenital myasthenic syndromes, and congenital myasthenia gravis. myotonic dystrophy, Cori disease, Debrancher enzyme deficiency, Dejerine-Sottas disease, dermatomyositis, distal muscular dystrophy, Duchenne muscular dystrophy, myotonic dystrophy (dystrophia myotonica), Emery-Dreyfus muscular dystrophy, endocrine myopathies, Eulenburg disease, facioscapulohumeral muscular dystrophy, tibial distal myopathy, Friedreich's ataxiaataxia), Fukuyama congenital muscular dystrophy, glycogenosis type 10, glycogen storage disease type 11, glycogen storage disease type 2, glycogen storage disease type 3, glycogen storage disease type 5, glycogen storage disease type 7, glycogen storage disease type 9, Gowers-Laing distal myopathy, hereditary inclusion-body myopathy. myositis), hyperthyroid myopathy, hypothyroid myopathy, inclusion-body myopathy, inherited myopathies, integrin-deficient congenital muscular dystrophy, spinal-bulbar muscular atrophy. atrophy), spinal-bulbar muscular atrophy, lactate dehydrogenase deficiency, Lambert-Eaton myasthenic syndrome, McArdel disease, merosin-deficient congenital muscular dystrophy, metabolic disorders of muscle, mitochondrial myopathy Miyoshi distal myopathy, motor neuron disease, muscle-eye-brain disease, myasthenia gravis, myoadenylate deaminase deficiency, myofibrillar myopathy, myophosphorylase deficiency, congenital myotonia, myotonic muscular dystrophy, myotubular myopathy, nemaline myopathy, nonaka distal myopathy, oculopharyngeal muscular dystrophy, congenital paramyotonia, Pearson syndrome This includes, but is not limited to, syndrome, periodic paralysis, phosphofructokinase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, phosphorylase deficiency, polymyositis, Pompe disease, progressive external ophthalmoplegia, spinal muscular atrophy, Ullrich congenital muscular dystrophy, Welander distal myopathy, and ZASP-related myopathy.

[0495] In some embodiments, muscle atrophy (e.g., muscle wasting) can be caused by, for example, normal aging (e.g., sarcopenia), genetic abnormalities (e.g., mutations or single nucleotide polymorphisms), malnutrition, poor circulation, loss of hormone support, or lack of exercise (e.g., bed rest, immobilization of limbs in casts, etc.), aging, damage to nerves innervating muscles, poliomyelitis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), heart failure, liver disease, diabetes, obesity, metabolic syndrome, demyelinating diseases (e.g., multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbach disease), etc. It can be caused by conditions such as encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, and Guillain-Barré syndrome, denervation, fatigue, exercise-induced muscle fatigue, frailty, neuromuscular disease, neuromuscular disease, and chronic pain.

[0496] In some embodiments, the disease is hair loss. In some embodiments, the disease is inflammation and / or injury of the skin. In some embodiments, the disease is vascular insufficiency. In some embodiments, the disease is congestive heart failure or cardiomyopathy. In some embodiments, the disease is gastrointestinal disorder. In some embodiments, the disease is renal dysfunction. In some embodiments, the disease is neurological disorder, neuropsychiatric disorder, nerve injury, neurotoxic disorder, neuropathic pain, or neurodegenerative disorder. In some embodiments, the disease is a fibrous or adhesive disorder, disorder, or disease. In some embodiments, the disease is scar formation. In some embodiments, the disease is fibrosis. In some embodiments, the disease is idiopathic pulmonary fibrosis. In some embodiments, the disease is renal fibrosis. In some embodiments, the disease is acute kidney injury. In some embodiments, the disease is sarcopenia. In some embodiments, the disease is neuromuscular disorder. [Examples]

[0497] The following examples are for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0498] Example 1: Effects of 15-PGDH inhibitor (e.g., MF-300) administration on PGE2 signaling. Administration of a 15-PGDH inhibitor (e.g., MF-300) blocks the binding of PGE2 to 15-PGDH in skeletal muscle, resulting in increased stem cell proliferation, increased muscle strength, and improved mitochondrial function. A summary of the effects of a 15-PGDH inhibitor (e.g., MF-300) on the PGE2 signaling pathway is shown in Figure 1.

[0499] Example 2: Mechanism of action and pharmacokinetic profile of MF-300. The mechanism of action and pharmacokinetic profile of the 15-PGDH inhibitor MF-300 were evaluated using biochemical assays, cell-based assays utilizing A549 cells, and single-dose and 24-hour plasma pharmacokinetic analyses in mice. Figure 2A shows the effects of various doses of MF-300 on NADH production in 15-PGDH inhibitory biochemical assays. Figure 2B shows the effects of various doses of MF-300 on PGE2 stability in A549 cells in cell-based assays. Figure 2C shows the effects of 10 mg / kg, 30 mg / kg, and 60 mg / kg doses of MF-300 in circulating mouse plasma over 24 hours.

[0500] Example 3: Effects of intraperitoneal MF-300 administration in SMNΔ7 mice. SMNΔ7 mice were used as a model for severe spinal muscular atrophy (SMA). The SMNΔ7 mouse genome contains a deletion at the endogenous SMN gene locus and two transgenes, with the human SMN2 gene coding region and the mouse SMN gene having a deletion in exon 7 (i.e., SMNΔ7). This combination of genetic alterations results in severe skeletal muscle denervation and muscle weakness, which can be pharmacologically mitigated by SMN-C3, an SMN splice modulator and analogue of risdiplam. The effects of intraperitoneal injection of various doses of MF-300 were evaluated in a cohort of male and female SMNΔ7 mice. In short, on day 1 postnatal, SMNΔ7 mice were intraperitoneally injected with the SMN splice enhancer SMN-C3 (3 mg / kg) daily for 21 days. Subsequently, they were intraperitoneally injected either SMN-C3 (3 mg / kg) alone or in combination with MF-300 (3 mg / kg, 10 mg / kg, or 30 mg / kg; N=10-13 / group) daily for another 28 days. Wild-type mice (WT) were not injected. The mice were then tested for isometric ankle plantar flexion strength, and gastrocnemius muscles were collected for RNA-seq analysis (N=6 / group). RNA-seq analysis was performed using paired-end reads and approximately 30 × 10¹⁶ samples per sample. 6 The procedure was performed using Poly A selection with a read depth of [specified value]. An additional cohort of SMNΔ7 med / med model mice (SMN-C3 1 mg / kg) received daily intraperitoneal injections of SMN-C3 in combination with MF-300 (3 mg / kg or 10 mg / kg) starting from postnatal day 3. Subsequently, on postnatal day 12, their time to right was evaluated, during which 30 seconds were given for recovery.

[0501] Figure 3A outlines the experimental timeline for evaluating the effects of SMN-C3 and various doses of MF-300 on isometric ankle plantar flexion strength in SMNΔ7 mice. Figure 3B shows the effects of repeated treatment with either SMN-C3 alone (vehicle) or SMN-C3 in combination with various doses of MF-300 (3 mg / kg [3 MPK], 10 mg / kg [10 MPK], or 30 mg / kg [30 MPK]) on isometric ankle plantar flexion strength in SMNΔ7 mice. Wild-type mice (WT) were not treated. Figure 3C shows the effect of repeated treatment of SMNΔ7 mice with either SMN-C3 alone (vehicle) or SMN-C3 in combination with various doses of MF-300 (3 mg / kg [3 MPK], 10 mg / kg [10 MPK], or 30 mg / kg [30 MPK]) on the maximum isometric plantarflexion force of SMNΔ7 mice. Wild-type mice (WT) were not treated. Figure 3D shows the effect of repeated treatment with SMN-C3 and various doses of MF-300 (3 mg / kg [3 MPK], 10 mg / kg [10 MPK], or 30 mg / kg [30 MPK]) on the maximum muscle strength of SMNΔ7 mice, expressed as a percentage of the mean maximum muscle strength of the vehicle-treated cohort (SMN-C3 only).

[0502] 15-PGDH is encoded by the Hpgd gene. The level of HPGD expression (expressed as transcripts / million) in the gastrocnemius muscle was investigated between wild-type (WT) mice and SMNΔ7 mice (δ7SMNC3), and the results are shown in Figure 3E. Principal component analysis comparing gene expression in mice exposed to repeated treatment with either SMN-C3 alone (vehicle, SMNΔ7 mice without 15-PGDH inhibitor, Delta7 Veh), no injection (WT mice), or combined administration of SMN-C3 and MF-300 (SMNΔ7 mice with 15-PGDH inhibitor, Delta7 MF-300) is shown in Figure 3F.

[0503] Figure 3G shows the effect of repeated treatment with either SMN-C3 alone (1 mg / kg) (SMN-C3 1mpk(Veh)) or SMN-C3 with various doses of MF-300 (3 mg / kg or 10 mg / kg) (SMN-C3 + MF-300 3mpk, or SMN-C3 + MF-300 10mpk) on the probability of recovery time within 30 seconds in SMNΔ7 mice. WT mice were included for comparison and did not receive any treatment. These results suggest that SMNΔ7 mice treated with a 15-PGDH inhibitor, such as MF-300, recovered upright posture (righting behavior) more effectively than SMNΔ7 mice that did not receive a 15-PGDH inhibitor.

[0504] Overall, these results indicate that in SMNΔ7 mice, administration of a 15-PGDH inhibitor, such as MF-300, significantly increased muscle strength compared to SMNΔ7 mice without 15-PGDH inhibitor treatment.

[0505] Example 4: SMN1 C / C The effects of orally administered MF-300 in mice. The effects of MF-300 administered orally at various doses were observed in SMN1 of SMA. C / C The model was evaluated using SMN1. C / C The genome contains the hybrid mouse SMN gene / human SMN2 gene, as well as the transgenic human SMN2 gene. These animals exhibit a mild atrophy phenotype and are not treated with SMN-C3. Briefly, 6-8 week old male SMN1 C / CMice were administered either daily oral vehicle (Veh) or daily oral MF-300 (10 mg / kg [10 MPK], 30 mg / kg [30 MPK], or 60 mg / kg [60 MPK]) for 4 weeks, and then isometric ankle plantar flexion muscle strength was tested. Further experiments were conducted using mice treated with either vehicle or MF-300 (60 mg / kg) incorporating measurements of nerve and direct muscle-stimulated contractions to localize the effect of MF-300. SMN1 C / C SMN1 in relation to isometric ankle plantarflexion muscle strength in mice C / C Figure 4A outlines the experimental timeline for evaluating the effects of MF-300 at various genotypes and doses.

[0506] Figure 4B shows the effect of repeated treatment with the vehicle or various doses of MF-300 (10 mg / kg, 30 mg / kg, or 60 mg / kg) on ​​the percentage increase in isometric plantar flexion strength and maximum muscle strength from the vehicle at 150 Hz. Figure 4C shows the effect of repeated treatment with the vehicle or various doses of MF-300 (10 mg / kg, 30 mg / kg, or 60 mg / kg) on ​​the percentage increase in isometric plantar flexion strength and maximum muscle strength from the vehicle at 150 Hz, normalized for muscle mass.

[0507] Figure 4D outlines the design and rationale of an experiment in which mice were treated with either a vehicle or MF-300 (60 mg / kg), and measurements of nerve and direct muscle stimulation contraction were incorporated to localize the effect of MF-300.

[0508] Figure 4E shows the effect of vehicle and MF-300 treatment (60 mg / kg) (MF300 60 MPK) on maximal muscle strength related to nerve stimulation. Figure 4F shows the effect of vehicle and MF-300 treatment (60 mg / kg) (MF300 60 MPK) on maximal muscle strength related to nerve stimulation, normalized to muscle mass (MW). Figure 4G shows the effect of vehicle and MF-300 treatment (60 mg / kg) (MF300 60 MPK) on maximal muscle strength related to muscle stimulation. Figure 4H shows the effect of vehicle and MF-300 treatment (60 mg / kg) (MF300 60 MPK) on maximal muscle strength related to muscle stimulation, normalized to muscle mass (MW). Figure 4I shows the effects of vehicle and MF-300 treatment (60 mg / kg) (MF300 60 MPK) on maximal muscle strength related to normalized muscle stimulation in response to nerve stimulation. Figure 4J shows the effects of vehicle and MF-300 treatment (60 mg / kg) (MF300 60 MPK) on maximal muscle strength related to normalized muscle stimulation in response to nerve stimulation and expressed as a fold difference.

[0509] Overall, SMN1 treated with a 15-PGDH inhibitor, such as MF-300. C / C The mice were SMN1 in the vehicle group. C / C Compared to mice, they showed better isometric ankle plantar flexion strength.

[0510] Example 5: Effects of orally administered MF-300 in a mouse model of sciatic nerve compression. The effects of oral administration of Vehicle or MF-300 were evaluated in cohorts of male mice (C57Bl / 6, 10-12 weeks old) exposed to sciatic nerve crush or sham surgery controls. The nerve crush cohort was exposed to 30 seconds of nerve crush, while the sham surgery cohort was not. Sham surgery control mice received Vehicle orally daily for 35 days. The nerve crush cohort received Vehicle or MF-300 (60 mg / kg) orally daily for 35 days. Isometric ankle plantarflexion strength was measured for each cohort at baseline, and then at 14, 21, 28, and 35 days after the start of treatment.

[0511] Figure 5A shows an overview of the experimental timeline for evaluating the effect of MF-300 on isometric ankle plantarflexion muscle strength in a mouse model of sciatic nerve crush. Figure 5B shows the baseline maximum muscle strength of sham mice (Sham) orally administered with the vehicle, sciatic nerve crush mice (Crush-Vehicle) orally administered with the vehicle, and sciatic nerve crush mice (Crush-MF300 60 mpk QD) orally administered with MF-300 (60 mg / kg). Figure 5C shows the maximum muscle strength on day 14 of sham mice (Sham) orally administered with the vehicle, sciatic nerve crush mice (Crush-Vehicle), and sciatic nerve crush mice (Crush-MF300 60 mpk QD) orally administered with MF-300 (60 mg / kg). Figure 5D shows the maximum muscle strength on day 21 of sham mice orally administered with Vehicle, sciatic nerve compression mice orally administered with Vehicle (Crush-Vehicle), and sciatic nerve compression mice orally administered with MF-300 (60 mg / kg) (Crush-MF300 60 mpk QD). Figure 5E shows the maximum muscle strength on day 28 of sham mice orally administered with Vehicle, sciatic nerve compression mice orally administered with Vehicle (Crush-Vehicle), and sciatic nerve compression mice orally administered with MF-300 (60 mg / kg) (Crush-MF300 60 mpk QD). Figure 5F shows the maximum muscle strength at day 35 for sham control mice orally administered with Vehicle, sciatic nerve compression mice orally administered with Vehicle (Crush-Vehicle), and sciatic nerve compression mice orally administered with MF-300 (60 mg / kg) (Crush-MF300 60 mpk QD). Figure 5G shows the maximum muscle strength at day 35, normalized by muscle weight, for sham control mice orally administered with Vehicle (Crush-Vehicle), and sciatic nerve compression mice orally administered with MF-300 (60 mg / kg) (Crush-MF300 60 mpk QD).Figure 5H shows the muscle mass at the end of the study for sham control mice orally administered with Vehicle, sciatic nerve compression mice orally administered with Vehicle (Crush-Vehicle), and sciatic nerve compression mice orally administered with MF-300 (60 mg / kg) (Crush-MF300 60 mpk QD).

[0512] Overall, in a sciatic nerve compression model, mice treated with a 15-PGDH inhibitor, such as MF-300, showed improved isometric ankle plantar flexion strength compared to mice without 15-PGDH inhibitor treatment.

[0513] Example 6: Effects of orally administered MF-300 in a mouse model of sciatic nerve compression. male SMN1 C / C In a cohort of mice, the effects of intermittent oral administration of MF-300, a 15-PGDH inhibitor at a dose of 60 mg / kg, were evaluated. Briefly, the study involved 6-8 week old male SMN1 mice. C / C Mice were administered either daily oral vehicle (Veh) or intermittent oral doses of MF-300 (60 mg / kg daily, every two days, or every three days) for four weeks, and then their isometric ankle plantar flexion strength was tested. Simulations were also performed to predict the plasma concentrations of various doses of MF-300 based on the plasma concentrations of MF-300 24 hours after a single 60 mg / kg dose in mice. SMN1 on isometric ankle plantar flexion strength C / C Figure 6A shows an overview of the experimental timeline for evaluating the effects of intermittent administration of MF-300 in mice. Figure 6B shows the predicted plasma concentrations of MF-300 over 8 days for the cohort administered MF-300 daily (60 mg / kg). Figure 6C shows the predicted plasma concentrations of MF-300 over 8 days for the cohort administered MF-300 every two days (60 mg / kg). Figure 6D shows the predicted plasma concentrations of MF-300 over 8 days for the cohort administered MF-300 every three days (60 mg / kg). The data in Figures 6B-6D represent MF-300 plasma concentrations of 60 mg / kg, administered once daily (QD), with EC (European Epidemic) levels measured before subsequent dose administration.50 While the levels remained above this, with 60 mg / kg administered every two days (Q2D) and every three days (Q3D), the plasma concentration of MF-300 after administration was EC 50 It exceeded that, and then decreased before the administration of the subsequent dose, EC 50 It falls below that.

[0514] Figure 6E shows the effect of treatment with the vehicle or intermittent doses of MF-300 (60 mg / kg, administered daily, every two days, or every three days) on the percentage increase in maximal isometric ankle plantarflexion strength and maximal muscle strength relative to the vehicle at 150 Hz. Figure 6F shows the effect of treatment with the vehicle or intermittent doses of MF-300 (60 mg / kg, administered daily, every two days, or every three days) on the percentage increase in maximal isometric ankle plantarflexion strength and maximal muscle strength relative to the vehicle at 150 Hz, normalized to muscle weight. The data in Figures 6E and 6F show that Q2D administration of a 15-PGDH inhibitor at 60 mg / kg increases maximal isometric ankle plantarflexion strength and maximal muscle strength relative to the vehicle to a similar level as QD administration. The data in Figures 6E and 6F further demonstrate that Q3D administration of the 15-PGDH inhibitor at 60 mg / kg also increases maximal isometric ankle plantarflexion strength and maximal muscle strength relative to the vehicle. This data suggests that with administration less than once daily (e.g., Q2D, Q3D), plasma concentrations of the 15-PGDH inhibitor initially increased in the EC 50 It exceeds, and then, before administering the subsequent dose, EC 50 This demonstrates that the dose may be sufficient to improve muscle function (e.g., muscle strength in subjects with muscle disease).

[0515] Example 7: Effect of intermittently administered MF-300 in SMNΔ7 mice The effects of intermittent intraperitoneal administration of the 15-PGDH inhibitor MF-300 on SMNΔ7 mice were evaluated. Briefly, on postnatal day 1, mice were intraperitoneally injected daily with the SMN splice enhancer SMN-C3 (3 mg / kg) for 21 days, followed by further intraperitoneal injections of either SMN-C3 (3 mg / kg) alone or a combination of SMN-C3 (3 mg / kg) and MF-300 (30 mg / kg) for 28 days, daily, every other day, or every three days. SMNΔ7 mice were compared to wild-type (WT) mice that did not receive injections. The mice were then tested for isometric ankle plantar flexion strength. A summary of the experimental timeline for evaluating the effects of intermittent administration of SMN-C3 and MF-300 on isometric ankle plantar flexion strength in SMNΔ7 mice is shown in Figure 7A. Figure 7B shows the predicted plasma concentration of MF-300 for a daily MF-300 administration cohort (30 mg / kg). Figure 7C shows the predicted plasma concentration of MF-300 for a bi-day MF-300 administration cohort (30 mg / kg). Figure 7D shows the predicted plasma concentration of MF-300 for a 3-day MF-300 administration cohort (30 mg / kg). Figure 7E shows the predicted plasma concentration of MF-300 for a daily MF-300 administration cohort (administered in combination with 10 mg / kg and 30 mg / kg). Figure 7F shows the predicted plasma concentration of MF-300 for a 2-day MF-300 administration cohort (administered in combination with 10 mg / kg and 30 mg / kg). The data in Figures 7B-7D show that the plasma concentration of MF-300 was 30 mg / kg, administered once daily (QD), and EC was administered before the subsequent dose. 50 While the levels remained above this, with 30 mg / kg administered every two days (Q2D) and every three days (Q3D), the plasma concentration of MF-300 after administration was EC 50 It exceeded that, and then decreased before the administration of the subsequent dose, EC 50 The data in Figures 7E and 7F show that the plasma concentration of MF-300 was 10 mg / kg, administered once daily (QD), before the subsequent dose, EC 50 It is predicted that the levels will remain above this, and with a dose of 10 mg / kg every other day (QOD), the plasma concentration of MF-300 will be, after administration, EC50 It is predicted to exceed this, and then, before the administration of the subsequent dose, EC 50 This indicates that it is predicted to fall below [a certain level].

[0516] Figure 7G shows the effect of SMN-C3 treatment, either alone or in combination with intermittent administration of MF-300 (30 mg / kg), on maximal isometric ankle plantarflexion strength. Figure 7H shows the effect of SMN-C3 treatment, either alone or in combination with intermittent administration of MF-300 (30 mg / kg), on the percentage increase in maximal muscle strength from the vehicle at 150 Hz. The data in Figures 7G and 7H show that Q2D administration of a 15-PGDH inhibitor at 30 mg / kg increases maximal isometric ankle plantarflexion strength from the vehicle to a similar level as QD administration. The data in Figures 7G and 7H further demonstrate that Q3D administration of a 15-PGDH inhibitor at 30 mg / kg also increases maximal isometric ankle plantarflexion strength from the vehicle. This data shows that with administration less than once daily (e.g., Q2D, Q3D), plasma concentrations of the 15-PGDH inhibitor initially increase to EC 50 It exceeds, and then, before administering the subsequent dose, EC 50 The dose may be below this level and may be sufficient to improve muscle function (e.g., muscle strength in subjects with muscle diseases).

[0517] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Numerous variations, modifications, and substitutions will be conceivable to those skilled in the art without departing from the present invention. It should be understood that various alternative forms to the embodiments described herein may be adopted. The following claims define the scope of the present invention, and the methods and structures within these claims, as well as their equivalents, are intended to be encompassed thereby.

Claims

1. A method for treating a disease associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression level in a subject, wherein the method is: The step includes administering to the subject an amount of a 15-PGDH inhibitor effective in inhibiting 15-PGDH at a level sufficient to treat the disease, A method comprising administering the 15-PGDH inhibitor to a subject at a frequency that demonstrates a reduction in toxicity to the subject compared to administering the same amount of the 15-PGDH inhibitor once daily.

2. The method according to claim 1, wherein the administration frequency that demonstrates a reduction in toxicity to the subject is less than once a day.

3. The method according to claim 1, wherein the administration frequency that demonstrates a reduction in toxicity to the subject is once every two days, once every three days, once every four days, once every five days, once every six days, or once every seven days.

4. The method according to claim 1, wherein the administration frequency that demonstrates a reduction in toxicity to the subject is less than once every two days, less than once every three days, less than once every four days, less than once every five days, less than once every six days, or less than once every seven days.

5. The administration step is such that the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. ５０ The method according to any one of claims 1 to 4, comprising administering the 15-PGDH inhibitor if the value is less than the specified value.

6. A method for treating a disease associated with an increase in the activity or expression level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject, wherein the method is: The plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. ５０ The step includes administering to the subject an amount of the 15-PGDH inhibitor that is effective in raising the level to a level exceeding the specified level, The subject has been administered at least one dose of the 15-PGDH inhibitor prior to the administration step, The aforementioned administration step is performed when the target is the EC of the 15-PGDH inhibitor. ５０ A method comprising administering the 15-PGDH inhibitor to the subject when the plasma concentration of the 15-PGDH inhibitor is below a certain threshold.

7. The method according to claim 6, wherein the subject is administered at least one dose of the 15-PGDH inhibitor at least 24 hours prior to the administration step.

8. The method according to claim 6 or 7, wherein the subject is administered at least one dose of the 15-PGDH inhibitor 48 hours or more prior to the administration step.

9. The method according to any one of claims 6 to 8, wherein the subject is administered at least one dose of the 15-PGDH inhibitor at least 72 hours prior to the administration step.

10. The method according to any one of claims 6 to 9, wherein the subject is administered at least one dose of the 15-PGDH inhibitor at least 24 hours before the administration step and within 72 hours before the administration.

11. The administration step is such that the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. ５０ The method according to any one of claims 5 to 10, comprising administering the 15-PDGH inhibitor when the amount is at least twice, at least five times, at least ten times, at least fifty times, at least 100 times, at least 500 times, at least 1000 times, or more than 1000 times less than the given amount.

12. The method is such that the plasma concentration of the 15-PGDH inhibitor in the subject is the EC of the 15-PGDH inhibitor. ５０ The method according to any one of claims 5 to 11, which, when the value exceeds the limit, results in a reduction in toxicity to the subject compared to administering the same amount of the 15-PGDH inhibitor to the subject.

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

14. The method according to any one of claims 1 to 13, wherein the reduction of toxicity is selected from the group consisting of a reduction in neurological disorders, a reduction in muscle degeneration, a reduction in gastrointestinal and / or metabolic disorders, a reduction in inflammation, or any combination thereof.

15. The method according to any one of claims 1 to 14, wherein the reduction of toxicity is measured by safety pharmacology, genetic toxicology, acute and subchronic toxicology, absorption, distribution, metabolism and excretion (ADME) studies, reproductive and developmental toxicity, assessment of carcinogenicity, or any combination thereof.

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

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

18. The aforementioned 15-PGDH inhibitor is defined by formula I: 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, X is selected from -OCH ２ -, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH ２ -, -S(O)CH ２ -, -SO ２ CH ２ - and is selected from Each Y independently, N and CR １１ Selected from, Each R １ It became independent, Haro, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ２ H and R ３ ga-CF ３ is, or R ２ and R ３ They come together to form an oxo or thio, Each R ４ It became independent, Haro, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R ５ is independently halo, -NR ６ R ７ -, -OR ８ -, -C(O)R ８ -, -C(O)OR ８ -, -C(O)NR ６ R ７ -, -SOR ９ -, -SO ２ R ９ -, -SO ２ NR ６ R ７ -, -NR １０ C(O)R ８ -, -NR １０ C(O)NR ６ R ７ -, -NR １０ SO ２ R ８ -, -NR １０ SO ２ NR ６ R ７ C １－６ alkyl, C １－６ heteroalkyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and a 5- to 10-membered heteroaryl, and is selected from R ６ and R ７ However, H and C appear independently at each occurrence. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, Each R ８ H and C became independent. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R ９ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R １０ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, Each R １１ It became independent, Haro, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, n is 0, 1, 2, 3, 4, or 5, m is 0, 1, 2, 3, or 4, and also, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, However, the compound of formula I is 【Chemistry 2】 The method according to any one of claims 1 to 17.

19. The aforementioned compound is given by formula Ia: 【Transformation 3】 The method according to claim 18, wherein the compound is or a pharmaceutically acceptable salt thereof.

20. The aforementioned compound is of formula Ib: 【Chemistry 4】 The method according to claim 18, wherein the compound is or a pharmaceutically acceptable salt thereof.

21. The aforementioned 15-PGDH inhibitor is given by formula II: 【Transformation 5】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, T, U, W, X, and Y independently, N and CR ５ Selected from, S, V, and Z are independently selected from N and C. R １ However, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, where alkyl, cycloalkyl, aryl, or heteroaryl is optionally halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups, R ２ H and R ３ ga-CF ３ is, or R ２ and R ３ They come together to form an oxo or thio, Each R ４ It became independent, Haro, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's ４ However, together with the carbon atoms to which they are bonded and any intervening atoms, C ３－１０ Form a cycloalkyl group, and any remaining R ４ It became independent, Haro, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R ５ They became independent, H, Halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ６ and R ７ However, H and C appear independently at each occurrence. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, Each R ８ H and C became independent. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R ９ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R １０ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl, and n is 1, 2, 3, or 4, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, However, the compound of formula II is 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 The method according to any one of claims 1 to 17.

22. The aforementioned compound is given by formula IIa: 【Transformation 7】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, or 2.

23. The aforementioned compound is given by formula IIb: 【Transformation 8】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, or 2.

24. The aforementioned compound is given by formula IIc: 【Chemistry 9】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, 2, 3, 4, or 5.

25. The aforementioned compound is given by formula IId: 【Chemistry 10】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, 2, 3, or 4.

26. The aforementioned compound is given by formula IIe: 【Chemistry 11】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, 2, 3, or 4.

27. The aforementioned compound is given by formula IIf: 【Chemistry 12】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, 2, or 3.

28. The aforementioned compound is of formula IIg: 【Chemistry 13】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, 2, 3, or 4.

29. The aforementioned compound is given by formula IIh: 【Chemistry 14】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, 2, or 3.

30. The aforementioned compound is given by formula III: 【Chemistry 15】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, 2, 3, or 4.

31. The aforementioned compound is given by formula IIj: 【Chemistry 16】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, 2, or 3.

32. The aforementioned compound is of formula I In: 【Chemistry 17】 The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, 2, or 3.

33. The aforementioned compound is given by formula IIp: [Chemistry 18] The method according to claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is p is 0, 1, 2, 3, or 4.

34. The aforementioned 15-PGDH inhibitor is defined by formula III: 【Chemistry 19】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, Each X independently, N and CR ７ Selected from, Y is O, S, SO ２ , and C(R ８ ) ２ Selected from, R １ However, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, where alkyl, cycloalkyl, aryl, or heteroaryl is optionally halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Substituted with 1 to 3 substituents independently selected from aryl and 5- to 10-membered heteroaryl groups, R ２ H and R ３ ga-CF ３ is, or R ２ and R ３ They come together to form an oxo or thio, R ４ and R ５ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyls, where each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently and optionally selected as halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Substituting with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls, or R ４ and R ５ However, together with the nitrogen atom to which they are bonded, they form a halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Optionally, substituted 3- to 10-membered heterocycloalkyls are formed with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. Each R ６ It became independent, Haro, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's bonded to the same carbon atom ６ These combine to form oxo, thio, or C ３－１０ Form a cycloalkyl group, and any remaining R ６ It is independent, halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R ７ They became independent, H, Halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R ８ They became independent, H, Halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's ８ Together, Hello, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ C is optionally substituted with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. ３－１０ It can form cycloalkyl groups, R ９ and R １０ However, H and C appear independently at each occurrence. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, Each R １１ H and C became independent. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R １２ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R １３ However, H, C １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ Selected independently from cycloalkyl, m is either 1 or 2, The method according to any one of claims 1 to 17, wherein n is 0, 1, 2, 3, or 4.

35. The aforementioned compound is of formula IIIa: 【Chemistry 20】 The method according to claim 34, wherein the compound is or a pharmaceutically acceptable salt thereof.

36. The aforementioned compound is given by formula IIIb: 【Chemistry 21】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, Each R １４ It became independent, Haro, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, The method according to claim 34, wherein p is 0, 1, 2, or 3.

37. The aforementioned compound is given by formula IIIc: 【Chemistry 22】 The method according to claim 34, wherein the compound is or a pharmaceutically acceptable salt thereof.

38. The aforementioned compound is given by formula IIId: 【Chemistry 23】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, Each R １４ It became independent, Haro, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, The method according to claim 34, wherein p is 0, 1, 2, or 3.

39. The aforementioned 15-PGDH inhibitor is given by formula IIk: 【Chemistry 24】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, T, U, and Y independently, N and CR ６ It is selected from, however, if U is N, then at least one of T and Y is N. R １ However, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, where the aryl or heteroaryl is optionally a halo, -NR ７ R ８ , -OR ９ , -C(O)R ９ , -C(O)OR ９ , -C(O)NR ７ R ８ , -SOR １０ , -SO ２ R １０ , -SO ２ NR ７ R ８ , -NR １１ C(O)R ９ , -NR １１ C(O)NR ７ R ８ , -NR １１ SO ２ R ９ , -NR １１ SO ２ NR ７ R ８ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups, R ２ H and R ３ ga-CF ３ is, or R ２ and R ３ They come together to form an oxo, Each R ４ These are independently selected from H and Halo, R ５ But, hello, -NR ７ R ８ , -OR ９ , -C(O)R ９ , -C(O)OR ９ , -C(O)NR ７ R ８ , -SOR １０ , -SO ２ R １０ , -SO ２ NR ７ R ８ , -NR １１ C(O)R ９ , -NR １１ C(O)NR ７ R ８ , -NR １１ SO ２ R ９ , -NR １１ SO ２ NR ７ R ８ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ６ However, H, Halo, -NR ７ R ８ , -OR ９ , -C(O)R ９ , -C(O)OR ９ , -C(O)NR ７ R ８ , -SOR １０ , -SO ２ R １０ , -SO ２ NR ７ R ８ , -NR １１ C(O)R ９ , -NR １１ C(O)NR ７ R ８ , -NR １１ SO ２ R ９ , -NR １１ SO ２ NR ７ R ８ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ７ and R ８ However, H and C appear independently at each occurrence. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－６ Selected from cycloalkyl groups, Each R ９ H and C became independent. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R １０ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R １１ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl and C ３－６ Selected from cycloalkyl groups, The method according to any one of claims 1 to 17, wherein p is 0, 1, or 2.

40. The aforementioned 15-PGDH inhibitor is given by formula IIm: 【Chemistry 25】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, R １ However, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, where the aryl or heteroaryl is optionally a halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups, R ２ H and R ３ ga-CF ３ is, or R ２ and R ３ They come together to form an oxo, Each R ４ It became independent, Haro, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's ４ However, together with the carbon atoms to which they are bonded and any intervening atoms, C ３－１０ Form a cycloalkyl group, and any remaining R ４ But, hello, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Independently selected from aryls and 5- to 10-membered heteroaryls, R ５ is halo, -NR ６ R ７ is -OR ８ is -C(O)R ８ is -C(O)OR ８ is -C(O)NR ６ R ７ is -SOR ９ is -SO ２ R ９ is -SO ２ NR ６ R ７ is -NR １０ C(O)R ８ is -NR １０ C(O)NR ６ R ７ is -NR １０ SO ２ R ８ is -NR １０ SO ２ NR ６ R[[ID=5> ７ is C １－６ alkyl, C １－６ is heteroalkyl, C １－６ is haloalkyl, C ３－１０ is cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ is selected from aryl, and 5- to 10-membered heteroaryl, R ６ and R ７ However, H and C appear independently at each occurrence. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, Each R ８ H and C became independent. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R ９ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R １０ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, n is 1, 2, 3, or 4. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and The method according to any one of claims 1 to 17, wherein p is 0, 1, 2, or 3.

41. The aforementioned 15-PGDH inhibitor is given by formula IIq: 【Chemistry 26】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, R １ is C ６－１０ selected from aryl and 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ alkyl, C １－６ heteroalkyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, and independently selected from 1 to 3 substituents selected from 5- to 10-membered heteroaryl, R ２ H and R ３ ga-CF ３ is, or R ２ and R ３ They come together to form an oxo, Each R ４ It became independent, Haro, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's ４ However, together with the carbon atoms to which they are bonded and any intervening atoms, C ３－１０ Form a cycloalkyl group, and any remaining R ４ Hello, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Independently selected from aryls and 5- to 10-membered heteroaryls, R ５ But, hello, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , -C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ６ and R ７ However, H and C appear independently at each occurrence. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－１０ Selected from cycloalkyl groups, Each R ８ H and C became independent. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R ９ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R １０ However, H, C １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ Selected independently from cycloalkyl, n is 1, 2, 3, or 4, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and The method according to any one of claims 1 to 17, wherein p is 0, 1, 2, or 3.

42. The 15-PGDH inhibitor is given by formula IIIc: 【Chemistry 27】 A compound of or a pharmaceutically acceptable salt thereof, in the formula, Each X independently, N and CR ７ Selected from, Y is O, S, SO ２ , and C(R ８ ) ２ Selected from, R １ However, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, where the aryl or heteroaryl is optionally a halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Substituted with 1 to 3 substituents independently selected from cycloalkyl and 5- to 10-membered heteroaryl groups, R ２ H and R ３ ga-CF ３ is, or R ２ and R ３ They come together to form an oxo, R ４ and R ５ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－６ Selected from cycloalkyls, where each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently and optionally selected as halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Substituting with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls, or R ４ and R ５ However, together with the nitrogen atom to which they are bonded, they form a halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Optionally, substituted 3- to 10-membered heterocycloalkyls are formed with 1 to 3 substituents independently selected from aryls and 5- to 10-membered heteroaryls. Each R ６ It became independent, Haro, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or Two R's bonded to the same carbon atom ６ These come together to form an oxo, and any remaining R ６ But, hello, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Independently selected from aryls and 5- to 10-membered heteroaryls, Each R ７ and R ８ It became independent, Haro, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, R ９ and R １０ However, H and C appear independently at each occurrence. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl and C ３－６ Selected from cycloalkyl groups, Each R １１ H and C became independent. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R １２ C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, Each R １３ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl and C ３－６ Selected from cycloalkyl groups, The method according to any one of claims 1 to 17, wherein n is 0, 1, 2, 3, or 4.

43. The aforementioned 15-PGDH inhibitor 【Chemistry 28】 The method according to any one of claims 1 to 17, wherein the compound is selected from the group consisting of the following.

44. The aforementioned 15-PGDH inhibitor 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 【Chemistry 29-5】 【Chemistry 29-6】 【Chemistry 29-7】 【Chemistry 29-8】 【Chemistry 29-9】 [Chemistry 29-10] 【Chemistry 29-11】 [Chemistry 29-12] The method according to any one of claims 1 to 17, wherein the compound is selected from the group consisting of the following.

45. The aforementioned 15-PGDH inhibitor 【Transformation 30】 The method according to any one of claims 1 to 17, wherein the compound is selected from the group consisting of the following.

46. The aforementioned 15-PGDH inhibitor is given by formula IV: 【Chemistry 31】 A compound of or a pharmaceutically acceptable salt thereof During the ceremony, Ring Q is phenyl or a 5-10 member heteroaryl. Z is CR １ or N, Y is CR ２ or N, R １ However, H, halogen, -CN, -OR １０ , -C(O)R １０ , -C(O)OR １０ , -NR ８ R ９ , -C(O)NR ８ R ９ , -NR ８ C(O)R ９ , substitution or non-substitution C １ -C ６ Alkyl, or substituted or unsubstituted C ３ -C ８ It is a cycloalkyl, Each R ２ These are independent of 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 , substitution or non-substitution C １ -C ６ Alkyl, or substituted or unsubstituted C ３ -C ８ It is a cycloalkyl, Each R ３ These are independently H, halogen, -CN, and -NO. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , NR １２ SO ２ NR ８ R ９ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ It is replaced by, here, Each R １３ These are independently halogen, CN, and -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ And, R ４ However, substitution or non-substitution C １ -C ８ Alkyl, substituted, or unsubstituted C ２ -C ８ Alkenyl, substituted or unsubstituted C １ -C ８ Aminoalkyl, substituted, or unsubstituted C １ -C ８ Heteroalkyl, substituted, or unsubstituted C １ -C ８ Hydroxyalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, or substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ They are heterocycloalkyl groups, each of which has one or more R ６ It is replaced by, here, Each R ６ These are independently halogen, CN, and -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -NR ８ C(O)R ９ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C １ -C ６ Hydroxyalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ It is a heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 8-membered heteroaryl. Or two R's ６ However, together with the atoms to which they are bonded, they become substituted or unsubstituted C ３ -C ６ Cycloalkyl, or substituted or unsubstituted C ３ -C ８ Forms heterocycloalkyl groups, X Ａ However, -NR ５ R ５ OR ５ And, Each R ５ H or C １ -C ６ It is alkyl, R ５ａ However, H or CH ３ And, Or R ５ａ and one R ６ However, together with the atoms to which they are bonded, they become substituted or unsubstituted C ３ -C ６ Cycloalkyl, or substituted or unsubstituted C ３ -C ６ Forms heterocycloalkyl groups, Each R ８ and R ９ These independently correspond to H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C ２ -C ６ Alkynyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C １０ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyls, each of which optionally contains one or more R ａ Replaced by, Each R １０ These independently correspond to H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C １０ Cycloalkyl, substituted, or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which optionally contains one or more R ａ Replaced by, Each R １１ However, substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C １０ Cycloalkyl, substituted, or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Independently selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by, Each R １２ These independently correspond to H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyls, each of which optionally contains one or more R ａ Replaced by, Each R ａ These are independently halogen, -OH, and -CH ３ , -CF ３ , -OCH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -C(O)OH, -C(O)OCH ３ , -C(O)NH ２ , -C(O)NHCH ３ , -C(O)N(CH ３ ) ２ , -NHC(O)OH, -OC(O)NH ２ , and -NHC(O)CH ３ Selected from, The method according to any one of claims 1 to 17, wherein p is 1, 2, 3, or 4.

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

48. The method according to claim 46, wherein ring Q is phenyl, pyrimidinyl, or pyridinyl.

49. If Q is phenyl, then R ３ The method according to claim 46 or 48, wherein one of them is not H. 【Request Item 50】 【Chemistry 32】 but, 【Transformation 33】 And, During the ceremony, X １ , X ２ , X ３ , and X ４ However, each independently, N or CR ３ And, Each R ３ These are independently H, halogen, -CN, and -NO. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , NR １２ SO ２ NR ８ R ９ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ Replaced by, Each R １３ These are independently halogen, CN, and -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ And, Each R ８ and R ９ These independently correspond to H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C ２ -C ６ Alkynyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C １０ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyl groups, each of which has one or more R ａ Replaced by, Each R １０ These independently correspond to H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C １０ Cycloalkyl, substituted, or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by, Each R １１ These independently determine whether C is substituted or not. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C １０ Cycloalkyl, substituted, or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by, Each R １２ These independently correspond to H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyl groups, each of which has one or more R ａ Replaced by, Each R ａ These are independently halogen, -OH, and -CH ３ , -CF ３ , -OCH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -C(O)OH, -C(O)OCH ３ , -C(O)NH ２ , -C(O)NHCH ３ , -C(O)N(CH ３ ) ２ , -NHC(O)OH, -OC(O)NH ２ , and -NHC(O)CH ３ The method according to claim 46, selected from the following.

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

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

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

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

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

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

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

58. Each R ３ These are independent of H, halogen, and -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ The method according to any one of claims 46 to 57, selected from heterocycloalkyls and substituted or unsubstituted five-membered heteroaryls.

59. Each R ３ These are independently H, halogen, -C(O)OR １０ , -C(O)NR ８ R ９ The method according to claim 58, and selected from substituted or unsubstituted five-membered heteroaryls.

60. The aforementioned compound is given by formula V: 【Transformation 34】 Having the structure of, or a pharmaceutically acceptable salt thereof, During the ceremony, Z is CR １ or N, X １ However, N or CR ３ａ And, Y is CR ２ or N, R １ However, H, halogen, -CN, -OR １０ , -C(O)R １０ , -C(O)OR １０ , -NR ８ R ９ , -C(O)NR ８ R ９ , -NR ８ C(O)R ９ , substitution or non-substitution C １ -C ６ Alkyl, or substituted or unsubstituted C ３ -C ８ It is a cycloalkyl, Each R ２ These are independent of 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 , substitution or non-substitution C １ -C ６ Alkyl, or substituted or unsubstituted C ３ -C ８ It is a cycloalkyl, R ３ａ , R ３ｂ , and R ３ However, each is independent of H, halogen, -CN, and -NO. ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ It is replaced by, here, Each R １３ These are independently halogen, CN, and -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ And, R ４ However, substitution or non-substitution C １ -C ８ Alkyl, substituted, or unsubstituted C ２ -C ８ Alkenyl, substituted or unsubstituted C １ -C ８ Aminoalkyl, substituted, or unsubstituted C １ -C ８ Heteroalkyl, substituted, or unsubstituted C １ -C ８ Hydroxyalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, or substituted or unsubstituted C ３ -C ８ They are heterocycloalkyl groups, each of which has one or more R ６ It is replaced by, here, Each R ６ These are independently halogen, CN, and -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -NR ８ C(O)R ９ , substitution or non-substitution C １ -C ６ Alkyl, substituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C １ -C ６ Hydroxyalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ It is a heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 8-membered heteroaryl. Or two R's ６ However, when they combine with the atoms to which they are bonded, they form substituted or unsubstituted carbon atoms. ３ -C ６ Cycloalkyl, or substituted or unsubstituted C ３ -C ８ Forms heterocycloalkyl groups, X Ａ However, NR ５ R ５ OR ５ And here, Each R ５ H or C １ -C ６ It is alkyl, R ５ａ However, H or CH ３ Is it, Or R ５ａ and one R ６ However, when they combine with the atoms to which they are bonded, they form substituted or unsubstituted carbon atoms. ３ -C ６ Forming a cycloalkyl group, Each R ８ and R ９ These independently correspond to H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C ２ -C ６ Alkynyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C １０ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyl groups, each of which has one or more R ａ Replaced by, Each R １０ These independently correspond to H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C １０ Cycloalkyl, substituted, or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by, Each R １１ These independently determine whether C is substituted or not. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C １０ Cycloalkyl, substituted, or unsubstituted C ３ -C １０ Heterocycloalkyl, substituted or unsubstituted C ６ -C １０ Selected from aryls and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which has one or more R ａ Replaced by, Each R １２ These independently correspond to H, substituted or unsubstituted C. １ -C ６ Alkyl, substituted, or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl and substituted or unsubstituted C ３ -C １０ Selected from heterocycloalkyl groups, each of which has one or more R ａ Replaced by, Each R ａ These are independently halogen, -OH, and -CH ３ , -CF ３ , -OCH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -C(O)OH, -C(O)OCH ３ , -C(O)NH ２ , -C(O)NHCH ３ , -C(O)N(CH ３ ) ２ , -NHC(O)OH, -OC(O)NH ２ , and -NHC(O)CH ３ The method according to claim 46, selected from the following.

61. X Ａ NR ５ R ５ The method according to any one of claims 46 to 60.

62. X Ａ OR ５ The method according to any one of claims 46 to 60.

63. Y is CR ２ The method according to any one of claims 46 to 62.

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

65. The compound of formula V is of formula VIa: 【Chemistry 35】 The method according to claim 60, having the structure of or a pharmaceutically acceptable salt thereof.

66. The compound of formula V is given by formula VIb: 【Transformation 36】 The method according to claim 60, having the structure or a pharmaceutically acceptable salt thereof.

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

68. Z is CR １ The method according to any one of claims 46 to 66.

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

70. The compound of formula V is of formula VIIa: 【Chemistry 37】 The method according to claim 60, having the structure of or a pharmaceutically acceptable salt thereof.

71. The compound of formula V is, formula VIIb: 【Transformation 38】 The method according to claim 60, having the structure of or a pharmaceutically acceptable salt thereof.

72. The compound of formula V is, formula VIIc: 【Chemistry 39】 The method according to claim 60, having the structure of or a pharmaceutically acceptable salt thereof.

73. The compound of formula V is, formula VIId: 【Chemistry 40】 The method according to claim 60, having the structure of or a pharmaceutically acceptable salt thereof.

74. X １ The method according to any one of claims 60 to 73, wherein N.

75. R ３ｂ H is R ３ｃ However, halogen, -CN, -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ It is replaced by, here, each R １３ These are independently halogen, CN, and -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ The method according to any one of claims 60 to 74.

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

77. R ３ｃ H is R ３ｂ However, halogen, -CN, -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ It is replaced by, here, each R １３ These are independently halogen, CN, and -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ The method according to any one of claims 60 to 74.

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

79. X １ CR ３ａ The method according to any one of claims 60 to 73.

80. R ３ａ and R ３ｂ Independently, H or halogen, and R ３ｃ However, halogen, -CN, -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ It is replaced by, here, each R １３ These are independently halogen, CN, and -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ The method according to any one of claims 60 to 73 or 79.

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

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

83. R ３ａ and R ３ｂ The method according to any one of claims 80 to 82, wherein each of them is H.

84. R ３ａ and R ３ｃ Independently, H or halogen, and R ３ｂ However, halogen, -CN, -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ It is replaced by, here, each R １３ These are independently halogen, CN, and -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ The method according to any one of claims 60 to 73 or 79.

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

86. R ３ｂ However, -C(O)OR １０ , -C(O)NR ８ R ９ The method according to claim 84, wherein the heteroaryl group is either substituted or unsubstituted.

87. R ３ａ and R ３ｃ The method according to any one of claims 84 to 86, wherein each of them is H.

88. R ３ｂ and R ３ｃ However, each is either H or halogen, and R ３ａ However, halogen, -CN, -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , -C(O)NR ８ R ９ , -SOR １１ , -SO ２ R １１ , -SO ２ NR ８ R ９ , -NR １２ C(O)R １０ , -NR １２ C(O)OR １０ , -NR １２ C(O)NR ８ R ９ , -NR １２ SO ２ R １０ , -NR １２ SO ２ NR ８ R ９ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, substituted, or unsubstituted C ３ -C ８ Selected from heterocycloalkyls, substituted or unsubstituted phenyls, and substituted or unsubstituted 5- to 10-membered heteroaryls, each of which contains one or more R １３ It is replaced by, here, each R １３ These are independently halogen, CN, and -NO ２ , -NR ８ R ９ , -OR １０ , -SR ８ , -C(O)R １０ , -C(O)OR １０ , or -C(O)NR ８ R ９ The method according to any one of claims 60 to 73 or 79.

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

90. R ３ａ However, -C(O)OR １０ , -C(O)NR ８ R ９ The method according to claim 88, wherein the heteroaryl group is either substituted or unsubstituted.

91. R ３ｂ and R ３ｃ The method according to any one of claims 88 to 90, wherein each of them is H.

92. Each R ２ The method according to any one of claims 46 to 91, wherein is H.

93. R ５ａ and R ６ One of them combines with the atoms to which they are bonded, C ３ -C ６ The method according to any one of claims 46 to 92, which forms a cycloalkyl group.

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

95. R ５ The method according to any one of claims 46 to 94, wherein is H.

96. R ４ However, substitution or non-substitution C １ -C ８ Alkyl, substituted, or unsubstituted C １ -C ８ Aminoalkyl, substituted, or unsubstituted C １ -C ８ Heteroalkyl, substituted, or unsubstituted C １ -C ８ Hydroxyalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, or substituted or unsubstituted C ３ -C ８ They are heterocycloalkyl groups, each of which has one or more R ６ The method according to any one of claims 46 to 95, which is replaced by

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

98. R ４ However, substitution or non-substitution C ３ -C ８ They are cycloalkyl or 4- to 8-membered heterocycloalkyl, each of which has one or more R ６ The method according to any one of claims 46 to 95, which is replaced by

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

100. Each R ６ These are independent of halogen and -NR ８ R ９ , -OR １０ , substitution or non-substitution C １ -C ６ Alkyl, substituted, or unsubstituted C １ -C ６ Haloalkyl, substituted, or unsubstituted C １ -C ６ Hydroxyalkyl, substituted, or unsubstituted C ３ -C ８ Cycloalkyl, or substituted or unsubstituted C ３ -C ８ The method according to any one of claims 46 to 99, wherein the material is a heterocycloalkyl.

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

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

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

104. The method according to any one of claims 1 to 103, wherein the disease is a muscle disease.

105. The method according to claim 104, wherein the muscle disease is muscle atrophy, muscle injury, muscle disorder, or muscle trauma.

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

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

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

109. The method according to any one of claims 1 to 103, wherein the disease is hair loss.

110. The method according to any one of claims 1 to 103, wherein the disease is inflammation and / or injury of the skin.

111. The method according to any one of claims 1 to 103, wherein the disease is vascular insufficiency.

112. The method according to any one of claims 1 to 103, wherein the disease is congestive heart failure or cardiomyopathy.

113. The method according to any one of claims 1 to 103, wherein the disease is a gastrointestinal disorder.

114. The method according to any one of claims 1 to 103, wherein the disease is renal dysfunction.

115. The method according to any one of claims 1 to 103, wherein the disease is a neurological disorder, neuropsychiatric disorder, nerve injury, neurotoxic disorder, neuropathic pain, or neurodegenerative disorder.

116. The method according to any one of claims 1 to 103, wherein the disease is a fibrous or adhesive disease, disorder, or illness.

117. The method according to any one of claims 1 to 103, wherein the disease is scar formation.

118. The method according to any one of claims 1 to 103, wherein the disease is fibrosis.

119. The method according to any one of claims 1 to 103, wherein the disease is idiopathic pulmonary fibrosis.

120. The method according to any one of claims 1 to 103, wherein the disease is renal fibrosis.

121. The method according to any one of claims 1 to 103, wherein the disease is acute kidney injury.

122. The method according to any one of claims 1 to 103, wherein the disease is sarcopenia.

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

Images