Methods for combination treatment of spinal muscular atrophy

Abstract

Provided are methods of treating spinal muscular atrophy (SMA) using a combination of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor and an agent that increases motor neuron survival (SMN) protein expression. Furthermore, provided herein is a composition, a pharmaceutical formulation, or a kit comprising a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor and an agent that increases the expression of a motor neuron survival (SMN) protein.

Description

Cross-references

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 513,814, filed July 14, 2023, which is incorporated herein by reference in its entirety. Background Technology

[0002] Muscle disorders or conditions can manifest in many forms and can range from relatively mild to extremely severe. They may be hereditary (e.g., muscular dystrophy) or acquired. Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder involving the loss of motor neurons, thus affecting the nervous system and voluntary muscle movement. There is an unmet need for treatments for SMA. Incorporation

[0003] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application has been specifically and individually indicated to be incorporated by reference. To the extent that any publication or patent or patent application incorporated by reference contradicts the disclosure contained in this specification, the specification is intended to supersede and / or take precedence over any such contradictory material. Summary of the Invention

[0004] There is an unmet need for a treatment for spinal muscular atrophy (SMA). This disclosure addresses this unmet need.

[0005] In one aspect, this disclosure provides a method for treating spinal muscular atrophy (SMA), the method comprising: administering to a subject in need of SMA in an amount effective for treating SMA: (i) a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent that increases the expression of survival motor neuron (SMN) protein, thereby treating SMA.

[0006] In some implementations, the SMN protein is selected from: motor neuron survival 1 (SMN1) protein, motor neuron survival 2 (SMN2) protein, and any combination thereof.

[0007] In some embodiments, the agent that increases the expression of SMN protein is an agent that increases the expression of SMN2 protein. In some embodiments, the agent that increases the expression of SMN2 protein is an agent that regulates the splicing of motor neuron survival 2 (SMN2) pre-mRNA. In some embodiments, the agent that regulates the splicing of SMN2 pre-mRNA increases exon 7 inclusion in the SMN2 mRNA transcript. In some embodiments, the agent that regulates the splicing of SMN2 pre-mRNA is selected from: risdiplam, SMN-C2, SMN-C3, SMN-C5, RG-7916, RG7800, SMN-C1, SMN-C8, branaplam, nusinersen, and any combination thereof. In some embodiments, the agent that increases the expression of SMN2 protein is RG3039.

[0008] In some embodiments, the agent that increases the expression of SMN protein is an agent that increases the expression of SMN1 protein. In some embodiments, the agent that increases the expression of SMN1 protein is onasemnogene abeparvovec.

[0009] In some embodiments, the agent for increasing SMN protein expression is selected from: small molecules, antisense oligonucleotides, siRNA, miRNA, shRNA, gene therapy agents, antigen-binding units, peptides, aptamers, and any combination thereof. In some embodiments, the agent for increasing SMN protein expression is a small molecule. In some embodiments, the agent for increasing SMN protein expression is an antisense oligonucleotide. In some embodiments, the agent for increasing SMN protein expression is a gene therapy agent.

[0010] In some implementation schemes, SMA is selected from: SMA type 0, SMA type 1 (Werdnig-Hoffmann disease), SMA type 2 (Dubowitz disease), SMA type 3 (Kugelberg-Welander disease), and SMA type 4.

[0011] In some embodiments, a 15-PGDH inhibitor is administered, along with an agent that increases the expression of SMN protein, or both selected from: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra-arterial injection, intradermal administration, subcutaneous administration, and any combination thereof. In some embodiments, a 15-PGDH inhibitor is administered, along with an agent that increases the expression of SMN protein, or both selected from: acute administration, chronic administration, intermittent administration, and continuous administration.

[0012] In some embodiments, administration includes administering a 15-PGDH inhibitor and an agent that increases SMN protein expression to a subject in need, in the form of a single formulation. In some embodiments, administration includes sequentially administering a 15-PGDH inhibitor and an agent that increases SMN protein expression to a subject in need, in the form of a single formulation. In some embodiments, administration includes administering the 15-PGDH inhibitor to the subject in need prior to administering the agent that increases SMN protein expression. In some embodiments, administration includes administering the agent that increases SMN protein expression to the subject in need prior to administering the 15-PGDH inhibitor.

[0013] In some implementations, 15-PGDH inhibitors, agents that increase the expression of SMN proteins, or both, are administered to the recipient in the form of one or more pharmaceutical formulations, including pharmaceutically acceptable excipients, diluents, and / or carriers.

[0014] In some implementations, an effective therapeutic amount for SMA is an amount that effectively reduces one or more symptoms of SMA. In some implementations, an effective therapeutic amount for SMA is an amount that effectively reduces the severity of SMA.

[0015] In some embodiments, compared to a method comprising administering an agent that increases SMN protein in the absence of a 15-PGDH inhibitor, the method results in the downregulation of one or more genes involved in the myelination pathway. In some embodiments, compared to a method comprising administering an agent that increases SMN protein in the absence of a 15-PGDH inhibitor, the method results in the downregulation of one or more Schwann cell genes. In some embodiments, compared to a method comprising administering an agent that increases SMN protein in the absence of a 15-PGDH inhibitor, the method results in the downregulation of one or more genes selected from: mpz , mbp , ugt8a , mal , pmp22 , pllp , ngfr , kif1a , robo2 , prx , cldn19 , cited2 , nfasc, ncmap, s100b, mag, hgf as well as edn3.

[0016] In some implementations, the target audience is people. In other implementations, the target audience is people aged 75 or younger.

[0017] In some implementations, subjects requiring SMA have elevated 15-PGDH levels prior to administration, compared to control subjects without SMA.

[0018] In some implementations, the 15-PGDH inhibitor is a compound of formula I:

[0019] Or its pharmaceutically acceptable salt, wherein: X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, -SO2CH2-; Each Y is independently selected from N and CR 11 ; Each R 1 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxo or thio groups; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -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 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 11 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The premise is that the compound of formula I is not , , or .

[0020] In some embodiments, the compound is a compound of formula Ia:

[0021] Or its pharmaceutically acceptable salt.

[0022] In some embodiments, the compound is a compound of formula Ib:

[0023] Or its pharmaceutically acceptable salt.

[0024] In some implementations, the 15-PGDH inhibitor is a compound of formula II:

[0025] Or its pharmaceutically acceptable salt, wherein: T, U, W, X, and Y are independently selected from N and CR. 5 ; S, V, and Z are independently selected from N and C; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxo or thio groups; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from H, halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The premise is that the compound of formula II is not .

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

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

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

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

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

[0031] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4 or 5.

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

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

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

[0035] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

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

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

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

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

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

[0041] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

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

[0043] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0044] In some embodiments, the compound is a compound of formula IIj.

[0045] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

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

[0047] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

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

[0049] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

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

[0051] Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxo or thio groups; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl group is independently and optionally substituted by one to three independently selected substituents from the following: halogen, -NR 9 R 10-OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms connected to the same carbon atom 6 Together they form oxo groups, thio groups, or C groups. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 8 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 8 Together they can form C16 groups, optionally substituted by 1 to 3 independent substituents selected from the following. 3-10 Cycloalkyl groups: halogenated, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3 or 4.

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

[0053] Or its pharmaceutically acceptable salt.

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

[0055] Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and p is 0, 1, 2 or 3.

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

[0057] Or its pharmaceutically acceptable salt.

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

[0059] Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and p is 0, 1, 2 or 3.

[0060] In some implementations, the 15-PGDH inhibitor is a compound of formula IIk:

[0061] Or its pharmaceutically acceptable salt, wherein: T, U, and Y are independently selected from N and CR. 6 The premise is that when U is N, at least one of T and Y is N; R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 7 R 8 -OR 9 -C(O)R9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; Each R 4 Independently selected from H and halogen groups; R 5 Selected from halogen groups, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 Selected from H, halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 7 and R 8 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; Each R 9 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 11 Independently selected from H and C 1-6 Alkyl, C1-6 Halogenated alkyl and C 3-6 cycloalkyl; and p is 0, 1, or 2.

[0062] In some implementations, the 15-PGDH inhibitor is a compound of formula IIm:

[0063] Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2 or 3.

[0064] In some implementations, the 15-PGDH inhibitor is a compound of formula IIq:

[0065] Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 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, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2 or 3.

[0066] In some implementations, the 15-PGDH inhibitor is a compound of formula IIIc:

[0067] Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-6 Cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl group is independently and optionally substituted by one to three independently selected substituents from the following: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms connected to the same carbon atom 6 Together they form an oxo group, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 and R 8 Independently selected from halogen groups, -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 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; and n is 0, 1, 2, 3 or 4.

[0068] In some implementations, the 15-PGDH inhibitor is selected from the following compounds: .

[0069] In some implementations, the 15-PGDH inhibitor is selected from the following compounds: .

[0070] In some implementations, the 15-PGDH inhibitor is selected from the following compounds: .

[0071] In some cases, 15-PGDH inhibitors are compounds of formula IV, or pharmaceutically acceptable salts thereof: , in, Ring Q is phenyl or a 5- to 10-membered heteroaryl group; Z is CR 1 Or N; Y is CR 2 Or N; R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 3Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them Each R 6Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl. Or two Rs 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A Yes -NR 5 R 5 or -OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5a And an R 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is optionally surrounded by one or more R groups. a replace; Each R 10Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more R a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is optionally surrounded by one or more R groups. a replace; Each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3 or 4.

[0072] In some cases, ring Q is a six-membered monocyclic heteroaryl group containing one, two, or three nitrogen atoms. In some cases, ring Q is phenyl, pyrimidinyl, or pyridinyl. In some cases, when Q is phenyl, then R... 3 One of them is not H.

[0073] In some cases, yes

[0074] in, X 1 X 2 X 3 and X 4 Each is independently N or CR 3 ; Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 replace; Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; Each R 8 and R 9Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C 1- C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a Replace; and Each R aIt is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

[0075] In some cases, X 1 X 2 X 3 and X 4 Each is CR 3 In some cases, X 1 It is N; and X 2 X 3 and X 4 Each is CR 3 In some cases, X 1 and X 2 Each is N; and X 3 and X 4 Each is CR 3 In some cases, X 1 and X 3 Each is N; and X 2 and X 4 Each is CR 3 In some cases, X 1 and X 4 Each is N; and X 2 and X 3 Each is CR 3 In some cases, X 1 X 2 and X 3 Each is N; and X 4 It is CR 3 In some cases, X 1 X 2 and X 4 Each is N; and X 3 It is CR 3 .

[0076] In some cases, each R 3 Independently selected from H, halogen, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11-SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups. In some cases, each R 3 Independently selected from H, halogens, -C(O)OR 10 -C(O)NR 8 R 9 , and substituted or unsubstituted 5-membered heteroaryl groups.

[0077] In some cases, the compound has the structure of formula V, or a pharmaceutically acceptable salt thereof: , in, Z is CR 1 Or N; X 1 Is it N or CR? 3a ; Y is CR 2 Or N; R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; R 3a R 3b and R 3c Each is independently selected from H, halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -SR8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10-C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl. Or two Rs 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A It is NR 5 R 5 OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5a And an R 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl groups; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C 1- C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a Replace; and Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

[0078] In some cases, X A It is NR 5 R 5 In some cases, X A OR 5 In some cases, Y is CR. 2 In some cases, Y is N.

[0079] In some cases, compounds of formula V have the structure of formula VIa, or a pharmaceutically acceptable salt thereof: .

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

[0081] In some cases, Z is N. In other cases, Z is CR. 1 In some cases, Z is CH.

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

[0083] In some cases, compounds of formula V have the structure of formula VIIb, or a pharmaceutically acceptable salt thereof: .

[0084] In some cases, compounds of formula V have the structure of formula VIIc, or a pharmaceutically acceptable salt thereof: .

[0085] In some cases, compounds of formula V have the structure of formula VIId, or a pharmaceutically acceptable salt thereof: .

[0086] In some cases, X 1 It is N. In some cases, R 3b It is H; and R 3c Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

[0087] In some cases, R 3b It is H; and R 3c Selected from halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

[0088] In some cases, R 3c It is H; and R 3b Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

[0089] In some cases, R 3c It is H; and R 3b Selected from halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

[0090] In some cases, X 1 It is CR 3a In some cases, R 3a and R 3b It is independently H or halogen; and R 3c Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8-C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

[0091] In some cases, R 3c Selected from H, halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

[0092] In some cases, R 3c It is -C(O)OR 10 -C(O)NR 8 R 9 , or substituted or unsubstituted 5-membered heteroaryl groups. In some cases, R 3a and R 3b Each is H.

[0093] In some cases, R 3a and R 3c It is independently H or halogen; and R 3b Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

[0094] In some cases, R 3b Selected from H, halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

[0095] In some cases, R 3b It is -C(O)OR 10 -C(O)NR 8 R 9 , or substituted or unsubstituted 5-membered heteroaryl groups.

[0096] In some cases, R 3a and R 3c Each is H. In some cases, R 3b and R 3c Each is either H or halogen; and R 3a Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

[0097] In some cases, R 3a Selected from H, halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

[0098] In some cases, R 3a It is -C(O)OR 10 -C(O)NR 8 R 9 , or substituted or unsubstituted 5-membered heteroaryl groups. In some cases, R 3b and R 3c Each is H. In some cases, each R 2 It is H. In some cases, R 5a and R 6 One of them combines with one or more atoms to form a C3-C6 cycloalkyl group. In some cases, R 5a It is H. In some cases, R 5 It's H.

[0099] In some cases, R 4It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replacement. In some cases, R 4 It is a substituted or unsubstituted C1-C8 alkyl or a substituted or unsubstituted C1-C8 heteroalkyl, each of which is substituted by one or more R 6 Replacement. In some cases, R 4 It is a substituted or unsubstituted C3-C8 cycloalkyl or a 4- to 8-membered heterocycloalkyl, each of which is substituted by one or more R 6 replace.

[0100] In some cases, R 4 It is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl. In some cases, each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 Substituted or unsubstituted C1-C6 alkyl 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 heterocyclic alkyl groups. In some cases, each R 6 Independently, it is halogen, -OR 10 C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl. In some cases, each R 6 Independently, it is -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0101] In some cases, the compounds are selected from Table 4, or their pharmaceutically acceptable salts.

[0102] In another aspect, this disclosure provides a composition comprising: (i) a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent that increases the expression of SMN protein. In some embodiments, the composition comprises a 15-PGDH inhibitor and an agent that increases the expression of SMN protein in an amount effective for treating spinal muscular atrophy (SMA).

[0103] In one aspect, this disclosure provides a pharmaceutical formulation comprising the composition described herein, and one or more pharmaceutically effective excipients, carriers, and / or diluents.

[0104] In one aspect, this disclosure provides unit doses comprising pharmaceutical formulations as described herein. In another aspect, this disclosure provides a kit comprising: (i) a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent for increasing the expression of SMN protein. In some embodiments, the 15-PGDH inhibitor and the agent for increasing SMN protein expression are in separate containers. In some embodiments, the 15-PGDH inhibitor and the agent for increasing SMN protein expression are in the same container. In some embodiments, the kit further includes instructions for administering the 15-PGDH inhibitor and the agent for increasing SMN protein expression to a subject in need of it. In some embodiments, the subject in need of it has spinal muscular atrophy (SMA). Attached Figure Description

[0105] The novel features of the invention are specifically set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description of illustrative embodiments in which the principles of the invention are utilized, and the accompanying drawings, in which: Figure 1 This study provides an overview of the PGE2 signaling pathway and the effects of 15-PGDH inhibitors on PGE2 signaling.

[0106] Figure 2A-2B The mechanism of action and pharmacokinetic characteristics of the 15-PGDH inhibitor (MF-300) were demonstrated. Figure 2A The effect of MF-300 on NADH production was shown in the biochemical 15-PGDH inhibition assay. Figure 2B The effect of MF-300 on PGE2 stability in A549 cells was demonstrated.

[0107] Figures 3A-3E The effects of intraperitoneal administration of MF-300 on SMNΔ7 mice were shown. Figure 3A An experimental overview is shown to evaluate the effects of repeated administration of SMN-C3 and MF-300 in SMNΔ7 mice. Figure 3B The effects of repeated administration of SMN-C3 and MF-300 on isometric plantar flexor strength were shown in SMNΔ7 mice. Figure 3C The effects of repeated administration of SMN-C3 and MF-300 to SMNΔ7 mice on maximum force of isometric plantar flexors were shown. Figure 3D The effects of repeated administration of SMN-C3 and MF-300 to SMNΔ7 mice on isolength plantar flexor maximal force (expressed as a percentage of the mean maximal force relative to the mediator-treated animals) were shown. Figure 3EThe levels of HPGD expression in the tibialis anterior (TA) muscle obtained from WT mice and Δ7SMA mice are shown (left panel), and the levels of HPGD expression in the gastrocnemius muscle obtained from WT mice and SMNΔ7 mice treated with SMN-C3 are shown (right panel).

[0108] Figures 4A-4B This demonstrates the quality control of RNA seq reads. Figure 4A The sum of the original reads for each sample is displayed. Figure 4B The distribution of read segment counts is shown.

[0109] Figures 5A-5B The data from the RNA-seq analysis are shown. Figure 5A This demonstrates a multidimensional scaling that spans all genes that meet the minimum count threshold. Figure 5B Box plots and one-way ANOVA are shown for MDS1 values ​​by treatment group.

[0110] Figure 6 Venn plots show the genes that were nominally significantly differentially expressed in the SMA+ mediator versus WT and in the SMA+MF-300 versus SMA+ mediator.

[0111] Figure 7 The results of gene set enrichment analysis comparing SMA+ mediators with SMA+MF-300 on the GO biological processes (GP) ontology are shown. The figure shows the thresholds for minimum and maximum normalized enrichment scores (NES). A positive NES score indicates enrichment of SMA+MF relative to SMA+ mediators.

[0112] Figure 8 The changes in the expression of genes associated with myelination were shown.

[0113] Figure 9 The changes in the expression of genes associated with the assembly of mitochondrial respiratory chain complexes were shown.

[0114] Figure 10 The top promoter features are shown to be significantly enriched or depleted in gene subsets that are significantly reduced by the SMA model and significantly increased by MF-300 treatment.

[0115] Figure 11A-11C The expression of Schwann cell markers was shown: Mpb ( Figure 11A ), Mpz ( Figure 11B )and Ncmap ( Figure 11C ).

[0116] Figures 12A-12E Showing Prx ( Figure 12A ) Cited2 ( Figure 12B ) Mal ( Figure 12C ) Cldn19 ( Figure 12D )and Edn ( Figure 12E The level of expression.

[0117] Figures 13A-13C Showing Ngft ( Figure 13A ) Ncam1 ( Figure 13B )and L1cam ( Figure 13C The level of expression.

[0118] Figures 14A-14B Showing S100b ( Figure 14A )and Mag ( Figure 14B The level of expression.

[0119] Figures 15A-15C Showing Pmp22 ( Figure 15A ), Ugt8a ( Figure 15B )and Pllp ( Figure 15C The level of expression.

[0120] Figure 16 Showing Nfasc The expression.

[0121] Figures 17A-17B It shows the expression of axon genes, such as Kif1a ( Figure 17A )and Robo2 ( Figure 17B ) 。

[0122] Figures 18A-18C Showing Pou3f1 ( Figure 18A ) 、Cdkn1c ( Figure 18B ) And Sox 10 ( Figure 18C The expression of ).

[0123] Figure 19 Showing Hpgd The expression of this substance was observed in the healthy sciatic nerve of mice at different developmental stages.

[0124] Figure 20 It shows HpgdExpression in immune cells (IC), epineural cells (EpC), and peripheral nerve cells (PnC) of the sciatic nerve in healthy mice at 60 days of age. 。

[0125] Figures 21A-21B The expression of myelination genes in untreated SMA mice is shown. Figure 21A The expressions for Mbp, Mpz, Ugt8a, and Mal are shown. Figure 21B The expressions for Ncmap, Ngfr, Pllp, Pmp22, Cited2, and Prx are shown. Detailed Implementation

[0126] Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder involving the loss of motor neurons, thus affecting the nervous system and voluntary muscle movement. Chromosome 5-related SMA is the most common form of SMA (types 1-4), and it is caused by the loss of motor neurons 1 or 4. SMN1 Mutations in the survival of genes lead to a deficiency in the survival of motor neurons or the SMN protein. Increased levels of the SMN protein can improve SMA symptoms. SMN2 Genes are SMN1 Neighboring genes of a gene, and SMN2 Genes and SMN1 Gene sharing is 99% identical. Increased expression of SMN proteins comes from any SMN gene (e.g., SMN1 Gene, SMN2 SMN agents or SMN modulators (e.g., those derived from any SMN gene, or both) can improve SMA symptoms. Other agents that increase SMN protein expression include those derived from any SMN gene (e.g., those from any SMN gene, or both). SMN1 Gene, SMN2 Agents of genes (or both) or SMN modulators may be used in methods, compositions, pharmaceutical preparations, unit doses or kits as described herein.

[0127] Prostaglandins are a group of physiologically active lipid compounds with diverse biological effects. Prostaglandin E2 (PGE2), also known as dinoprostone, acts as a lipid mediator that resolves inflammation. PGE2 can be used as an anticoagulant and antithrombotic agent. PGE2 is synthesized from arachidonic acid via cyclooxygenase (COX) and prostaglandin E synthase. Hydroxyprostaglandin dehydrogenases (such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH)) are involved in the inactivation of prostaglandins.

[0128] This article provides a method for treating spinal muscular atrophy (SMA) using a combination of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor and a motor neuron survival (SMN) modulator that increases the expression of SMN protein. In one aspect, this disclosure provides a method for treating spinal muscular atrophy (SMA) comprising: administering to a subject in need of SMA (i) a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor in an amount effective for treating SMA; and (ii) an agent that increases the expression of motor neuron survival (SMN) protein (also referred to as an SMN modulator), thereby treating SMA. In some embodiments, the SMN protein is selected from: motor neuron survival 1 (SMN1) protein, motor neuron survival 2 (SMN2) protein, and any combination thereof.

[0129] In some embodiments, the agent for increasing SMN protein expression is selected from: small molecules, antisense oligonucleotides, siRNA, miRNA, shRNA, gene therapy agents, antigen-binding units, peptides, aptamers, and any combination thereof. In some embodiments, the agent for increasing SMN protein expression is a small molecule. In some embodiments, the agent for increasing SMN protein expression is an antisense oligonucleotide. In some embodiments, the agent for increasing SMN protein expression is a gene therapy agent.

[0130] In some embodiments, the agent that increases SMN protein expression is an agent that increases SMN2 protein expression (SMN2 regulator). Regulation of SMN2 protein expression (e.g., including exon 7 spliced ​​from SMN2 pre-mRNA) can increase SMN protein, thereby improving SMA-related symptoms. In some embodiments, the agent that increases SMN2 protein expression is an agent that regulates the splicing of motor neuron survival 2 (SMN2) pre-mRNA. In some embodiments, the agent that regulates the splicing of SMN2 pre-mRNA increases the inclusion of exon 7 in the SMN2 mRNA transcript. In some embodiments, the agent that regulates the splicing of SMN2 pre-mRNA is selected from: lispiracil, SMN-C2, SMN-C3, SMN-C5, RG-7916, RG7800, SMN-C1, SMN-C8, lispiracil, nusinersen sodium, and any combination thereof. In some embodiments, the agent that increases SMN2 protein expression is RG3039.

[0131] In some embodiments, the agent that increases the expression of SMN protein is an agent that increases the expression of SMN1 protein (SMN1 regulator). In some embodiments, the SMN1 regulator includes gene therapy. Gene therapy can be used to deliver a wild-type copy of the SMN1 transgene located under a synthetic promoter. In some embodiments, gene therapy includes the delivery of a wild-type SMN1 transgene. In some embodiments, the agent that increases the expression of SMN1 protein is onasemnogeneabeparvovec.

[0132] There are four types of SMA. SMA type 1 (also known as Werdnig-Hoffmann disease or infantile SMA) is the most common and severe form of SMA. Patients with SMA type 1 may begin to show symptoms at birth or within the first six months of life. SMA type 2, or Dubowitz disease, is an intermediate form of SMA, and symptoms usually begin between 6 and 18 months of age. SMA type 3 (also known as Kugelberg-Welander disease) is a milder form of SMA, and symptoms usually appear around 18 months of age or in early childhood. SMA type 4 is very rare, and it usually begins in adolescence and causes mild motor impairment. In some implementations, SMA is selected from: SMA type 0, SMA type 1 (Werdnig-Hoffmann disease), SMA type 2 (Dubowitz disease), SMA type 3 (Kugelberg-Welander disease), and SMA type 4.

[0133] In some embodiments, the 15-PGDH inhibitor and the SMN modulator may be administered via the same route of administration. In some embodiments, the 15-PGDH inhibitor and the SMN modulator may be administered via different routes of administration. In some embodiments, the 15-PGDH inhibitor and the SMN modulator may be administered simultaneously. In some embodiments, the 15-PGDH inhibitor and the SMN modulator may be administered separately. In some embodiments, the 15-PGDH inhibitor and the SMN modulator may be administered sequentially; for example, the 15-PGDH inhibitor may be administered before the SMN modulator, or vice versa.

[0134] In some embodiments, the 15-PGDH inhibitor and the SMN modulator may be administered at the same frequency. In some embodiments, the 15-PGDH inhibitor and the SMN modulator may be administered at different frequencies. In some embodiments, the 15-PGDH inhibitor may be administered once daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, or every 10 days. In some embodiments, the 15-PGDH inhibitor may be administered less than once every 2 days, less than once every 3 days, less than once every 4 days, less than once every 5 days, less than once every 6 days, or less than once every 7 days. In some embodiments, the dosing frequency of the 15-PGDH inhibitor is less than once daily to once every 10 days, less than once daily to once every 9 days, less than once daily to once every 8 days, less than once daily to once every 7 days, less than once daily to once every 6 days, less than once daily to once every 5 days, less than once daily to once every 4 days, less than once daily to once every 3 days, or less than once daily to once every 2 days. In some embodiments, the dosing frequency of the 15-PGDH inhibitor is less than once daily to at least once every 10 days, less than once daily to at least once every 9 days, less than once daily to at least once every 8 days, less than once daily to at least once every 7 days, less than once daily to at least once every 6 days, less than once daily to at least once every 5 days, less than once daily to at least once every 4 days, less than once daily to at least once every 3 days, or less than once daily to at least once every 2 days.

[0135] In some embodiments, a 15-PGDH inhibitor is administered, along with an agent that increases the expression of SMN protein, or both selected from: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra-arterial administration, intradermal administration, subcutaneous administration, and any combination thereof. In some embodiments, a 15-PGDH inhibitor is administered, along with an agent that increases the expression of SMN protein, or both selected from: acute administration, chronic administration, intermittent administration, and continuous administration.

[0136] In some embodiments, the 15-PGDH inhibitor and the SMN modulator are administered together. In some embodiments, administration includes administering a single formulation of the 15-PGDH inhibitor and the agent that increases the expression of the SMN protein (SMN modulator) to the subject in need.

[0137] In some embodiments, the 15-PGDH inhibitor and the SMN modulator are administered separately. In some embodiments, administration includes sequentially administering the 15-PGDH inhibitor and the agent that increases SMN protein expression to the subject in need, in separate formulations. In some embodiments, administration includes administering the 15-PGDH inhibitor before administering the agent that increases SMN protein expression to the subject in need. In some embodiments, administration includes administering the agent that increases SMN protein expression before administering the 15-PGDH inhibitor to the subject in need.

[0138] In some implementations, a 15-PGDH inhibitor, an agent that increases the expression of SMN protein, or both, are administered to the recipient in a pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients, diluents, and / or carriers.

[0139] In some embodiments, an effective therapeutic amount for SMA is an amount that effectively reduces one or more symptoms of SMA. In some embodiments, an effective therapeutic amount for SMA is an amount that effectively reduces the severity of SMA. In some embodiments, an effective therapeutic amount for SMA includes an effective dose of a 15-PGDH inhibitor. In some embodiments, an effective dose of a 15-PGDH inhibitor includes about 1 mg / kg (or about 1 MPK), about 3 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, or about 100 mg / kg. In some embodiments, an effective dose of a 15-PGDH inhibitor includes at least about 1 mg / kg (or at least about 1 MPK), at least about 3 mg / kg, at least about 10 mg / kg, at least about 20 mg / kg, at least about 30 mg / kg, at least about 40 mg / kg, at least about 50 mg / kg, at least about 60 mg / kg, at least about 70 mg / kg, at least about 80 mg / kg, at least about 90 mg / kg, or at least about 100 mg / kg. In some embodiments, an effective dose of a 15-PGDH inhibitor includes less than about 1 mg / kg (or 1 MPK), less than about 3 mg / kg, less than about 10 mg / kg, less than about 20 mg / kg, less than about 30 mg / kg, less than about 40 mg / kg, less than about 50 mg / kg, less than about 60 mg / kg, less than about 70 mg / kg, less than about 80 mg / kg, less than about 90 mg / kg, or less than about 100 mg / kg.

[0140] In some implementations, effective doses of the 15-PGDH inhibitor include approximately 0.1 MPK, approximately 0.2 MPK, approximately 0.3 MPK, approximately 0.4 MPK, approximately 0.5 MPK, approximately 0.6 MPK, approximately 0.7 MPK, approximately 0.8 MPK, approximately 0.9 MPK, approximately 1 MPK, approximately 1.1 MPK, approximately 1.2 MPK, approximately 1.3 MPK, approximately 1.4 MPK, approximately 1.5 MPK, approximately 1.6 MPK, approximately 1.7 MPK, approximately 1.8 MPK, approximately 1.9 MPK, approximately 2 MPK, approximately 2.1 MPK, approximately 2.2 MPK, approximately 2.3 MPK, approximately 2.4 MPK, approximately 2.5 MPK, approximately 2.6 MPK, approximately 2.7 MPK, approximately 2.8 MPK, and approximately... 2.9 MPK, approximately 3 MPK, approximately 3.1 MPK, approximately 3.2 MPK, approximately 3.3 MPK, approximately 3.4 MPK, approximately 3.5 MPK, approximately 3.6 MPK, approximately 3.7 MPK, approximately 3.8 MPK, approximately 3.9 MPK, approximately 4 MPK, approximately 4.1 MPK, approximately 4.2 MPK, approximately 4.3 MPK, approximately 4.4 MPK, approximately 4.5 MPK, approximately 4.6 MPK, approximately 4.7 MPK, approximately 4.8 MPK, approximately 4.9 MPK, approximately 5 MPK, approximately 5.1 MPK, approximately 5.2 MPK, approximately 5.3 MPK, approximately 5.4 MPK, approximately 5.5 MPK, approximately 5.6 MPK, approximately 5.7 MPK, approximately 5.8 MPK, approximately 5.9 MPK, or approximately 6 MPK.In some implementations, the effective dose of the 15-PGDH inhibitor includes at least about 0.1 MPK, at least about 0.2 MPK, at least about 0.3 MPK, at least about 0.4 MPK, at least about 0.5 MPK, at least about 0.6 MPK, at least about 0.7 MPK, at least about 0.8 MPK, at least about 0.9 MPK, at least about 1 MPK, at least about 1.1 MPK, at least about 1.2 MPK, at least about 1.3 MPK, at least about 1.4 MPK, at least about 1.5 MPK, at least about 1.6 MPK, at least about 1.7 MPK, at least about 1.8 MPK, at least about 1.9 MPK, at least about 2 MPK, at least about 2.1 MPK, at least about 2.2 MPK, at least about 2.3 MPK, at least about 2.4 MPK, at least about 2.5 MPK, at least about 2.6 MPK, at least about 2.7 MPK, at least about 2.8 MPK, and at least about 2. 9MPK, at least about 3MPK, at least about 3.1MPK, at least about 3.2MPK, at least about 3.3MPK, at least about 3.4MPK, at least about 3.5MPK, at least about 3.6MPK, at least about 3.7MPK, at least about 3.8MPK, at least about 3.9MPK, at least about 4MPK, at least about 4.1MPK, at least about 4.2MPK, at least about 4.3MPK, at least about 4.4MPK, at least about 4.5MPK, at least about 4.6MPK, at least about 4.7MPK, at least about 4.8MPK, at least about 4.9MPK, at least about 5MPK, at least about 5.1MPK, at least about 5.2MPK, at least about 5.3MPK, at least about 5.4MPK, at least about 5.5MPK, at least about 5.6MPK, at least about 5.7MPK, at least about 5.8MPK, at least about 5.9MPK, or at least about 6MPK.In some implementations, effective doses of the 15-PGDH inhibitor include less than about 0.1 MPK, less than about 0.2 MPK, less than about 0.3 MPK, less than about 0.4 MPK, less than about 0.5 MPK, less than about 0.6 MPK, less than about 0.7 MPK, less than about 0.8 MPK, less than about 0.9 MPK, less than about 1 MPK, less than about 1.1 MPK, less than about 1.2 MPK, less than about 1.3 MPK, less than about 1.4 MPK, less than about 1.5 MPK, less than about 1.6 MPK, less than about 1.7 MPK, less than about 1.8 MPK, less than about 1.9 MPK, less than about 2 MPK, less than about 2.1 MPK, less than about 2.2 MPK, less than about 2.3 MPK, less than about 2.4 MPK, less than about 2.5 MPK, less than about 2.6 MPK, less than about 2.7 MPK, less than about 2.8 MPK, and less than about 2. 9 MPK, less than about 3 MPK, less than about 3.1 MPK, less than about 3.2 MPK, less than about 3.3 MPK, less than about 3.4 MPK, less than about 3.5 MPK, less than about 3.6 MPK, less than about 3.7 MPK, less than about 3.8 MPK, less than about 3.9 MPK, less than about 4 MPK, less than about 4.1 MPK, less than about 4.2 MPK, less than about 4.3 MPK, less than about 4.4 MPK, less than about 4.5 MPK, less than about 4.6 MPK, less than about 4.7 MPK, less than about 4.8 MPK, less than about 4.9 MPK, less than about 5 MPK, less than about 5.1 MPK, less than about 5.2 MPK, less than about 5.3 MPK, less than about 5.4 MPK, less than about 5.5 MPK, less than about 5.6 MPK, less than about 5.7 MPK, less than about 5.8 MPK, less than about 5.9 MPK, or less than about 6 MPK.In some implementations, effective doses of the 15-PGDH inhibitor include 0.5 MPK to 5 MPK, 0.6 MPK to 5 MPK, 0.7 MPK to 5 MPK, 0.8 MPK to 5 MPK, 0.9 MPK to 5 MPK, 1 MPK to 5 MPK, 1.1 MPK to 5 MPK, 1.2 MPK to 5 MPK, 1.3 MPK to 5 MPK, 1.4 MPK to 5 MPK, 1.5 MPK to 5 MPK, 1.6 MPK to 5 MPK, 1.7 MPK to 5 MPK, 1.8 MPK to 5 MPK, 1.9 MPK to 5 MPK, 2 MPK to 5 MPK, 2.1 MPK to 5 MPK, 2.2 MPK to 5 MPK, 2.3 MPK to 5 MPK, 2.4 MPK to 5 MPK, 2.5 MPK to 5 MPK, 2.6 MPK to 5 MPK, and so on. K to 5MPK, 2.7MPK to 5MPK, 2.8MPK to 5MPK, 2.9MPK to 5MPK, 3MPK to 5MPK, 3.1MPK to 5MPK, 3.2MPK to 5MPK, 3.3MPK to 5MPK, 3.4MPK to 5MPK, 3.5MPK to 5MPK, 3.6MPK to 5MPK, 3.7MPK to 5MPK, 3.8MPK to 5MPK, 3.9MPK to 5MPK, 4MPK to 5MPK, 4.1MPK to 5MPK, 4.2MPK to 5MPK, 4.3MPK to 5MPK, 4.4MPK to 5MPK, 4.5MPK to 5MPK, 4.6MPK to 5MPK, 4.7MPK to 5MPK, 4.8MPK to 5MPK, or 4.9MPK to 5MPK.

[0141] In some embodiments, an effective treatment for SMA includes an effective dose of an agent that increases the expression of the SMN protein (SMN modulator). In some embodiments, the SMN modulator comprises a small molecule. In some embodiments, the SMN modulator includes liximab, SMN-C2, SMN-C3, SMN-C5, RG-7916, RG7800, SMN-C1, SMN-C8, liximab, nusinersen, or any combination thereof.

[0142] In some embodiments, the effective dose of the agent that increases the expression of SMN protein (SMN modulator) includes about 1 mg / kg (or about 1 MPK), about 3 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, or about 100 mg / kg. In some embodiments, the effective dose of the SMN modulator includes at least about 1 mg / kg (or at least about 1 MPK), at least about 3 mg / kg, at least about 10 mg / kg, at least about 20 mg / kg, at least about 30 mg / kg, at least about 40 mg / kg, at least about 50 mg / kg, at least about 60 mg / kg, at least about 70 mg / kg, at least about 80 mg / kg, at least about 90 mg / kg, or at least about 100 mg / kg. In some implementations, effective doses of the SMN modifier include less than about 1 mg / kg (or 1 MPK), less than about 3 mg / kg, less than about 10 mg / kg, less than about 20 mg / kg, less than about 30 mg / kg, less than about 40 mg / kg, less than about 50 mg / kg, less than about 60 mg / kg, less than about 70 mg / kg, less than about 80 mg / kg, less than about 90 mg / kg, or less than about 100 mg / kg.

[0143] In some embodiments, compared to a method comprising administering an agent that increases SMN protein in the absence of a 15-PGDH inhibitor, the method results in the downregulation of one or more genes involved in the myelination pathway. In some embodiments, compared to a method comprising administering an agent that increases SMN protein in the absence of a 15-PGDH inhibitor, the method results in the downregulation of one or more Schwann cell genes. In some embodiments, compared to a method comprising administering an agent that increases SMN protein in the absence of a 15-PGDH inhibitor, the method results in the downregulation of one or more genes selected from: mpz, mbp, ugt8a, mal, pmp22, pllp, ngfr, kif1a, robo2, prx, cldn19, cited2, nfasc, ncmap, s100b, mag, hgf and edn3.

[0144] In some embodiments, compared to methods comprising administering an agent that increases SMN protein in the absence of a 15-PGDH inhibitor, the method results in the upregulation of one or more genes involved in the mitochondrial pathway. In some embodiments, compared to methods comprising administering an agent that increases SMN protein in the absence of a 15-PGDH inhibitor, the method results in the upregulation of one or more genes selected from: Slc25a33, lyrm7 as well as 1190007I07Rik、Ppargc1a .

[0145] In some implementations, the recipients are persons. In some implementations, the recipients are 75 years of age or younger. In some implementations, the recipients are 80 years of age or younger, 75 years of age or younger, 70 years of age or younger, 65 years of age or younger, 60 years of age or younger, 55 years of age or younger, 50 years of age or younger, 45 years of age or younger, 40 years of age or younger, 35 years of age or younger, 30 years of age or younger, 25 years of age or younger, 20 years of age or younger, 15 years of age or younger, 10 years of age or younger, or 5 years of age or younger. In some implementations, the recipients are at least 3 months old, at least 6 months old, at least 1 year old, at least 2 years old, at least 5 years old, at least 10 years old, at least 18 years old, at least 21 years old, or at least 30 years old. In some implementations, the target group is defined as being between 1 and 75 years old, between 5 and 75 years old, between 10 and 75 years old, between 15 and 75 years old, between 20 and 75 years old, between 25 and 75 years old, between 30 and 75 years old, between 35 and 75 years old, between 40 and 75 years old, between 45 and 75 years old, between 50 and 75 years old, between 55 and 75 years old, between 60 and 75 years old, between 65 and 75 years old, or between 70 and 75 years old.

[0146] In some implementations, subjects requiring SMA have elevated 15-PGDH levels prior to administration, compared to control subjects without SMA.

[0147] In some embodiments, the 15-PGDH inhibitor is a small molecule. In some embodiments, the 15-PGDH inhibitor is an orally bioavailable small molecule.

[0148] In some implementations, the 15-PGDH inhibitor is a compound of formula I:

[0149] Or its pharmaceutically acceptable salt, wherein: X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, -SO2CH2-; Each Y is independently selected from N and CR 11 ; Each R 1 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9-SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxo or thio groups; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from halogen groups, -NR 6 R 7-OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 11 Independently selected from halogen groups, -NR 6 R 7 -OR8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The premise is that the compound of formula I is not , , or .

[0150] 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-.

[0151] In some implementations, each Y is independently selected from N and CR. 11 In some implementations, each Y is N. In some implementations, each Y is CR. 11In some implementations, one Y is N, and the other Y is CR. 11 .

[0152] In some implementations, each R 1 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 1 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 1 Independently selected from halogen groups, -NR 6R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 1 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 and -C(O)OR 8 .

[0153] In some implementation schemes, R 2 It is H, and R 3 It is -CF3. In some implementations, R 2 and R 3 Together they form an oxygen group. In some implementations, R 2 and R 3 Together they form a thio group.

[0154] In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 and -C(O)OR 8 .

[0155] In some implementations, each R 5 Independently selected from halogen groups, -NR6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 5 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 5 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 5 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 and -C(O)OR 8 .

[0156] In some implementation schemes, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0157] In some implementations, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R...8 Independently selected from H and C 1-6 alkyl.

[0158] In some implementations, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 9 Selected independently from C 1-6 alkyl.

[0159] In some implementations, each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, each R 10 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 10 Independently selected from H and C 1-6 alkyl.

[0160] In some implementations, each R 11 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 11 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 11 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 11 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R8 and -C(O)OR 8 .

[0161] In some implementations, n is 0, 1, 2, 3, 4, or 5. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some implementations, n is 5.

[0162] In some implementations, m is 0, 1, 2, 3, or 4. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4.

[0163] In some implementations, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4. In some implementations, p is 5. In some implementations, p is 6. In some implementations, p is 7. In some implementations, p is 8. In some implementations, p is 9. In some implementations, p is 10.

[0164] In some embodiments, the compound is a compound of formula Ia:

[0165] Or its pharmaceutically acceptable salt.

[0166] In some embodiments, the compound is a compound of formula Ib:

[0167] Or its pharmaceutically acceptable salt.

[0168] In some implementations, the 15-PGDH inhibitor is a compound of formula II:

[0169] Or its pharmaceutically acceptable salt, wherein: T, U, W, X, and Y are independently selected from N and CR. 5 ; S, V, and Z are independently selected from N and C; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10Aryl and 5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxo or thio groups; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from H, halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 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, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The premise is that the compound of formula II is not .

[0170] In some implementations, T, U, W, X, and Y are independently selected from N and CR. 5 In some implementations, at least one of T, U, W, X, and Y is N, and the remainder is CR. 5 In some implementations, at least two of T, U, W, X, and Y are N, and the remainder are CR. 5In some implementations, at least three of T, U, W, X, and Y are N, and the remainder are CR. 5 In some implementations, at least four of T, U, W, X, and Y are N, and the remainder are CR. 5 In some implementations, T, U, W, X, and Y are CR 5 In some implementations, T, U, W, X, and Y are N.

[0171] In some embodiments, S, V, and Z are independently selected from N and C. In some embodiments, at least one of S, V, and Z is N, and the remainder is C. In some embodiments, at least two of S, V, and Z are N, and the remainder is C. In some embodiments, S, V, and Z are N. In some embodiments, S, V, and Z are C.

[0172] In some implementation schemes, R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 Haloalkyl, C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said alkyl, aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0173] In some implementation schemes, R 2 It is H, and R 3 It is -CF3. In some implementations, R 2 and R 3 Together they form an oxygen group. In some implementations, R 2 and R 3 Together they form a thio group.

[0174] In some implementations, each R 4 Independently selected from halogen groups, -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 In some implementations, each R 4 It is a halogen group. In some implementations, each R 4 It is fluorine-based.

[0175] In some implementations, two R 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, the two R groups... 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, the two R groups... 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10SO2NR 6 R 7 In some implementations, two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 In some implementations, two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 The groups are independently selected from halogen groups. In some embodiments, the two R groups are... 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 It is fluorine-based.

[0176] In some implementations, each R 5 Independently selected from H, halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 5 Independently selected from H, halogen, -NR6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 5 Independently selected from H, halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 5 Independently selected from H, halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 In some implementations, each R 5It is independently selected from H and halogen groups.

[0177] In some implementation schemes, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0178] In some implementations, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 8 Independently selected from H and C 1-6 alkyl.

[0179] In some implementations, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, each R9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 9 Selected independently from C 1-6 alkyl.

[0180] In some implementations, each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, each R 10 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 10 Independently selected from H and C 1-6 alkyl.

[0181] In some implementations, n is 1, 2, 3, or 4. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0182] In some implementations, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is 5. In some implementations, m is 6. In some implementations, m is 7. In some implementations, m is 8. In some implementations, m is 9. In some implementations, m is 10.

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

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

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

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

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

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

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

[0190] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4 or 5.

[0191] In some implementations, p is 0, 1, 2, 3, 4, or 5. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4. In some implementations, p is 5.

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

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

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

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

[0196] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

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

[0198] In some implementations, the compound is a compound of formula IIf:

[0199] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

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

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

[0202] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0203] In some implementations, p is 0, 1, 2, 3, or 4. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

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

[0205] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

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

[0207] In some embodiments, the compound is a compound of formula IIi:

[0208] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0209] In some implementations, p is 0, 1, 2, 3, or 4. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

[0210] In some embodiments, the compound is a compound of formula IIj:

[0211] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0212] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0213] In some embodiments, the compound is a compound of formula IIn:

[0214] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0215] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

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

[0217] Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0218] In some implementations, p is 0, 1, 2, 3, or 4. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

[0219] In some implementations, the 15-PGDH inhibitor is a compound of formula III:

[0220] Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxo or thio groups; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl group is independently and optionally substituted by one to three independently selected substituents from the following: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or R 4 and R 5Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms connected to the same carbon atom 6 Together they form oxo groups, thio groups, or C groups. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 8 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 8 Together they can form C16 groups, optionally substituted by 1 to 3 independent substituents selected from the following. 3-10 Cycloalkyl groups: halogenated, -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 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3 or 4.

[0221] In some implementations, each X is independently selected from N and CR. 7 In some implementations, at least one X is N, and the rest are CR. 7 In some implementations, at least two X's are N, and the remainder are CR's. 7 In some implementations, each X is N. In some implementations, each X is CR. 7 .

[0222] In some implementations, Y is selected from O, S, SO2, and C(R) 8 2. In some implementations, Y is O. In some implementations, Y is S. In some implementations, Y is SO2. In some implementations, Y is C(R)8 )2.

[0223] In some implementation schemes, R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11-NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0224] In some implementation schemes, R 2 It is H, and R3 It is -CF3. In some implementations, R 2 and R 3 Together they form an oxygen group. In some implementations, R 2 and R 3 Together they form a thio group.

[0225] In some implementation schemes, R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl group is independently and optionally substituted by one to three independently selected substituents from the following: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is independently and optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is independently and optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is independently and optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11-C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is independently and optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0226] In some implementation schemes, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R11 and -NR 13 SO2NR 9 R 10 In some implementations, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0227] In some implementations, each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12-SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0228] In some implementations, two R atoms bonded to the same carbon atom 6 Together they form oxo groups, thio groups, or C groups. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11-C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, two R groups are attached to the same carbon atom. 6 Together they form oxo groups, thio groups, or C groups. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, two R groups attached to the same carbon atom... 6 Together they form oxo groups, thio groups, or C groups. 3-10 cycloalkyl, and any remaining R 6Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, two R atoms bonded to the same carbon atom... 6 Together they form oxo groups, thio groups, or C groups. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0229] In some implementations, each R 7 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 7 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 7 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, each R 7Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0230] In some implementations, each R 8 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 8 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)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 and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 8 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, each R 8 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0231] In some implementations, two R 8 Together they can form C16 groups, optionally substituted by 1 to 3 independent substituents selected from the following. 3-10 Cycloalkyl groups: halogenated, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11-NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, the two R groups... 8 Together they can form C16 groups, optionally substituted by 1 to 3 independent substituents selected from the following. 3-10 Cycloalkyl groups: halogenated, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, the two R groups... 8 Together they can form C16 groups, optionally substituted by 1 to 3 independent substituents selected from the following. 3-10 Cycloalkyl groups: halogenated, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10-NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, two Rs 8 Together they can form C16 groups, optionally substituted by 1 to 3 independent substituents selected from the following. 3-10 Cycloalkyl groups: halogenated, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0232] In some implementation schemes, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0233] In some implementations, each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 11 Independently selected from H and C 1-6 alkyl.

[0234] In some implementations, each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 12 Selected independently from C 1-6 alkyl.

[0235] In some implementations, each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, each R 13 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 13 Independently selected from H and C 1-6 alkyl.

[0236] In some implementations, m is 1 or 2. In some implementations, m is 1. In some implementations, m is 2.

[0237] In some implementations, n is 0, 1, 2, 3, or 4. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0238] In some embodiments, the compound is a compound of formula IIIa:

[0239] Or its pharmaceutically acceptable salt.

[0240] In some embodiments, the compound is a compound of formula IIIb:

[0241] Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and p is 0, 1, 2 or 3.

[0242] In some implementations, each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 14 Independently selected from halogen groups, -NR 9 R10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 In some implementations, each R 14 Independently, it is a halogen group. In some implementations, each R...14 It is a fluorine group on its own.

[0243] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0244] In some embodiments, the compound is a compound of formula IIIc:

[0245] Or its pharmaceutically acceptable salt.

[0246] In some embodiments, the compound is a IIId compound:

[0247] Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and p is 0, 1, 2 or 3.

[0248] In some implementations, each R 14 Independently selected from halogen groups, -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 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 In some implementations, each R 14 Independently, it is a halogen group. In some implementations, each R... 14 It is a fluorine group on its own.

[0249] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0250] In some implementations, the 15-PGDH inhibitor is a compound of formula IIk:

[0251] Or its pharmaceutically acceptable salt, wherein: T, U, and Y are independently selected from N and CR. 6 The premise is that when U is N, at least one of T and Y is N; R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; Each R 4 Independently selected from H and halogen groups; R 5 Selected from halogen groups, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 Selected from H, halogen, -NR 7 R 8 -OR 9 -C(O)R9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 7 and R 8 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; Each R 9 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; and p is 0, 1, or 2.

[0252] In some implementations, T, U, and Y are independently selected from N and CR. 6This is provided that when U is N, at least one of T and Y is N. In some implementations, one of T, U, and Y is N, and the rest are CR. 6 In some implementations, two of T, U, and Y are N, and the rest are CR. 6 In some implementations, one of T, U, and Y is CR. 6 And the rest are N. In some implementations, two of T, U, and Y are CR. 6 And the rest are N. In some implementations, T, U, and Y are N. In some implementations, T, U, and Y are CR. 6 .

[0253] In some implementation schemes, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8-SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 and -NR 11 SO2NR 7 R 8 In some implementations, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 and -C(O)NR 7 R 8 .

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

[0255] In some implementations, each R 4 Independently selected from H and halogen groups. In some embodiments, each R... 4 Independently selected from H and fluorine groups. In some embodiments, each R 4 It is H. In some implementations, each R 4 It is fluorine-based. In some implementations, an R 4 It is H, and an R 4 It is fluorine-based.

[0256] In some implementation schemes, R 5 Selected from halogen groups, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 5 Selected from halogen groups, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 5 Selected from halogen groups, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 and -NR 11 SO2NR 7 R 8 In some implementations, R 5 Selected from halogen groups, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 and -C(O)NR 7 R 8 .

[0257] In some implementation schemes, R 6 Selected from H, halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 6 Selected from H, halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 6 Selected from H, halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 and -NR 11 SO2NR 7 R 8 In some implementations, R 6 Selected from H, halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 and -C(O)NR 7 R 8 .

[0258] In some implementation schemes, R 7 and R 8 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-6 Cycloalkyl. In some embodiments, R 7 and R 8 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 7 and R 8 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0259] In some implementations, each R 9 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 9 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 9 Independently selected from H and C 1-6 alkyl.

[0260] In some implementations, each R 10 Selected independently from C 1-6Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 10 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 10 Selected independently from C 1-6 alkyl.

[0261] In some implementations, each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 Cycloalkyl. In some embodiments, each R 11 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 11 Independently selected from H and C 1-6 alkyl.

[0262] In some implementations, p is 0, 1, or 2. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2.

[0263] In some implementations, the 15-PGDH inhibitor is a compound of formula IIm:

[0264] Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6R 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 groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7-SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 8Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2 or 3.

[0265] In some implementation schemes, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, R 1 Selected from C 6-10Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0266] In some implementation schemes, R 2 It is H, and R 3 It is -CF3. In some implementations, R 2 and R 3 Together they form an oxygen group.

[0267] In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 In some implementations, each R 4 The groups are independently selected from halogen groups. In some implementations, each R... 4 It is fluorine-based.

[0268] In some implementations, two R 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, the two R groups... 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, the two R groups... 4Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0269] In some implementation schemes, R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R7 In some implementations, R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0270] In some implementation schemes, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0271] In some implementations, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 8 Independently selected from H and C 1-6 alkyl.

[0272] In some implementations, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 Halogenated alkyl groups. In some embodiments, each R... 9 Selected independently from C 1-6 alkyl.

[0273] In some implementations, each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, each R 10 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 10 Independently selected from H and C 1-6 alkyl.

[0274] In some implementations, n is 1, 2, 3, or 4. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0275] In some implementations, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is 5. In some implementations, m is 6. In some implementations, m is 7. In some implementations, m is 8. In some implementations, m is 9. In some implementations, m is 10.

[0276] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0277] In some implementations, the 15-PGDH inhibitor is a compound of formula IIq:

[0278] Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2 or 3.

[0279] In some implementation schemes, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0280] In some implementation schemes, R 2 It is H, and R 3 It is -CF3. In some implementations, R 2 and R 3 Together they form an oxygen group.

[0281] In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 4 Independently selected from halogen groups, -NR 6 R7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 In some implementations, each R 4 The groups are independently selected from halogen groups. In some implementations, each R...4 It is fluorine-based.

[0282] In some implementations, two R 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, the two R groups... 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8-NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, the two R groups... 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0283] In some implementation schemes, R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 and -NR 10 SO2NR 6 R 7 In some implementations, R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 and -C(O)NR 6 R 7 .

[0284] In some implementation schemes, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups. In some embodiments, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0285] In some implementations, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 8 Independently selected from H and C 1-6 alkyl.

[0286] In some implementations, each R 9 Selected independently from C 1-6 Alkyl, C 1-6Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups. In some embodiments, each R... 9 Selected independently from C 1-6 alkyl.

[0287] In some implementations, each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, each R 10 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 10 Independently selected from H and C 1-6 alkyl.

[0288] In some implementations, n is 1, 2, 3, or 4. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0289] In some implementations, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is 5. In some implementations, m is 6. In some implementations, m is 7. In some implementations, m is 8. In some implementations, m is 9. In some implementations, m is 10.

[0290] In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0291] In some implementations, the 15-PGDH inhibitor is a compound of formula IIIc:

[0292] Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-6 Cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl group is independently and optionally substituted by one to three independently selected substituents from the following: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms connected to the same carbon atom 6 Together they form an oxo group, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 and R 8 Independently selected from halogen groups, -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 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; and n is 0, 1, 2, 3 or 4.

[0293] In some implementations, each X is independently selected from N and CR.7 In some implementations, at least one X is N, and the rest are CR. 7 In some implementations, at least two X's are N, and the remainder are CR's. 7 In some implementations, each X is N. In some implementations, each X is CR. 7 .

[0294] In some implementations, Y is selected from O, S, SO2, and C(R) 8 2. In some implementations, Y is O. In some implementations, Y is S. In some implementations, Y is SO2. In some implementations, Y is C(R) 8 )2.

[0295] In some implementation schemes, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11-C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0296] In some implementation schemes, R 2 It is H, and R 3 It is -CF3. In some implementations, R 2 and R 3 Together they form an oxygen group.

[0297] In some implementation schemes, R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl group is independently and optionally substituted by one to three independently selected substituents from the following: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is independently and optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12-SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is independently and optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is independently and optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, R 4 and R 5 Selected independently from C 3-10 Cycloalkyl; wherein each cycloalkyl group is independently and optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0298] In some implementation schemes, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11and -NR 13 SO2NR 9 R 10 In some implementations, R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0299] In some implementations, each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0300] In some implementations, two R atoms bonded to the same carbon atom 6 Together they form an oxo group, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)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- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, two R groups are attached to the same carbon atom. 6 Together they form an oxo group, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, two R groups attached to the same carbon atom... 6 Together they form an oxo group, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11-C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, two R atoms bonded to the same carbon atom... 6 Together they form an oxo group, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0301] In some implementations, each R 7 and R 8 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 7 and R 8 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 7 and R 8 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 and -NR 13 SO2NR 9 R 10 In some implementations, each R 7 and R 8 Independently selected from halogen groups, -NR 9 R 10 -OR11 -C(O)R 11 -C(O)OR 11 and -C(O)NR 9 R 10 .

[0302] In some implementation schemes, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0303] In some implementations, each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 11 Independently selected from H and C 1-6 alkyl.

[0304] In some implementations, each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 12 Selected independently from C 1-6 alkyl.

[0305] In some implementations, each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-10 Cycloalkyl. In some embodiments, each R 13 Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 13 Independently selected from H and C 1-6 alkyl.

[0306] In some implementations, n is 0, 1, 2, 3, or 4. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0307] In some implementations, the 15-PGDH inhibitor is selected from the following compounds: .

[0308] In some implementations, the 15-PGDH inhibitor is selected from the following compounds: .

[0309] In some implementations, the 15-PGDH inhibitor is selected from the following compounds: .

[0310] In some cases, the solubility of the inhibitor and hPGDH IC 50 The features are shown in Tables 1 and 2.

[0311] Table 1: Characteristics of PGDH inhibitors with a 6-5 ring core.

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319] Table 2: Characteristics of PGDH inhibitors with a phenyl core.

[0320] Table 3 provides analytical data for some of the inhibitors described in this paper.

[0321] Table 3: Analytical data of the selected inhibitors

[0322] In some implementations, the 15-PGDH inhibitor is a compound having the structure of formula IV, or a pharmaceutically acceptable salt thereof: , in, Ring Q is phenyl or a 5- to 10-membered heteroaryl group; Z is CR 1 Or N; Y is CR 2 Or N; R 1 It is H, halogen, -CN, -OR 10-C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; among them Each R13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl. Or two Rs 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A Yes -NR 5 R 5 or -OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5aAnd an R 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a replace; Each R aIndependently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3 or 4.

[0323] In some implementations, the 15-PGDH inhibitor is a compound having the structure of formula IV, or a pharmaceutically acceptable salt thereof: , in, Ring Q is phenyl or a 5- to 10-membered heteroaryl group; Z is CR 1 Or N; Y is the CR of N 2 ; R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; R 2 It is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 , or substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11-SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a 4- to 8-membered heterocyclic alkyl, each of which is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is H, halogen, CN, -NO2, -NR 8 R 9 -OH, -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, phenyl or 5 to 8 heteroaryl; Or two Rs 6 They combine with one or more atoms to form C3-C6 cyclic alkyl rings; X A It is NR 5 R 5 OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5a And an R 6 They combine with one or more atoms to form C3-C6 cyclic alkyl rings; Each R 8 and R 9 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl and C 4- C 10 Heterocyclic alkyl groups; Each R 10 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups; Each R 11 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups; Each R 12 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; and p is 1, 2, 3 or 4.

[0324] In some embodiments, ring Q is a 5- to 10-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is a 5- to 8-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is a 5- to 8-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is a monocyclic, bicyclic, or polycyclic heteroaryl group. In some embodiments, ring Q is a bicyclic heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is indole, benzimidazole, benzotriazole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyridine, or tetrazolopyridine. In some embodiments, ring Q is [1,2,4]triazolo[1,5-a]pyridine.

[0325] In some embodiments, ring Q is a 6-membered monocyclic heteroaryl group containing 1, 2, or 3 nitrogen atoms. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is phenyl, pyrimidine, or pyridine. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is pyrimidine. In some embodiments, ring Q is pyridine.

[0326] In some implementations, ring Q is phenyl, pyridine, or triazolidine.

[0327] In some implementation schemes, yes , in, X 1 X 2 X 3 and X 4 Each is independently N or CR 3 ; Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 replace; Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C 1- C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10Heterocyclic alkyl groups, each of which is composed of one or more R a Replace; and Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

[0328] In some implementation schemes, X 1 X 2 X 3 and X 4 Each is CR 3 .

[0329] In some implementation schemes, X 1 It is N; and X 2 X 3 and X 4 Each is CR 3 .

[0330] In some implementation schemes, X 1 and X 2 Each is N; and X 3 and X 4 Each is CR 3 .

[0331] In some implementation schemes, X 1 and X 3 Each is N; and X 2 and X 4 Each is CR 3 .

[0332] In some implementation schemes, X 1 and X 4 Each is N; and X 2 and X 3 Each is CR 3 .

[0333] In some implementation schemes, X 1 X 2 and X 3 Each is N; and X 4 It is CR 3 .

[0334] In some implementation schemes, X 1 X 2 and X 4 Each is N; and X 3It is CR 3 .

[0335] In some implementations, each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, each R 3 Independently selected from H, halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, each R 3 Independently selected from H, halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10-NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, each R 3 It is independently selected from H, halogen, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups.

[0336] In some implementations, each R 3 Independently selected from H or halogen. In some embodiments, each R 3 Independently, it is a substituted or unsubstituted phenyl group, and a substituted or unsubstituted 5- to 6-membered heteroaryl group. In some embodiments, each R... 3 It is a substituted or unsubstituted 5-membered heteroaryl group.

[0337] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of formula V, or a pharmaceutically acceptable salt thereof: , in, Z is CR 1 Or N; X 1 Is it N or CR? 3a ; Y is CR 2 Or N; R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; R 3a R 3band R 3c Each is independently selected from H, halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them Each R 6Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl. Or two Rs 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A It is NR 5 R 5 OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5a And an R 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl groups; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a replace; Each R 10Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C 1- C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a Replace; and Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

[0338] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of formula V, or a pharmaceutically acceptable salt thereof: , in, Z is CR 1 Or N; X 1 Is it N or CR? 3a ; Y is CR 2 Or N; R 1 It is H; Each R 2 It is independently an H or C1-C6 alkyl group; R 3a R 3b and R 3c Each is independently selected from H, halogen, -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 heterocyclic alkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups, each of which is construed by one or more R groups. 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl. Or two Rs 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A Yes - OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5a And an R 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl groups; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 11Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a Replace; and Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

[0339] In some implementation schemes, X A It is NR 5 R 5 In some implementations, X A OR 5 .

[0340] In some implementations, Y is N. In some implementations, Y is CR. 2 .

[0341] In some embodiments, the compound of formula V has the structure of formula VIa, or a pharmaceutically acceptable salt thereof: .

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

[0343] In some implementations, Z is N. In some implementations, Z is CR. 1 In some implementations, Z is CH.

[0344] In some embodiments, the compound of formula V has the structure of formula VIIa, or a pharmaceutically acceptable salt thereof: .

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

[0346] In some embodiments, the compound of formula V has the structure of formula VIIc, or a pharmaceutically acceptable salt thereof: .

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

[0348] In some implementation schemes, R 1 It is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 Or substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, R 1 It's H.

[0349] In some implementations, each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 Or substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, each R 2 It is independently H or C1-C6 alkyl.

[0350] In some implementations, each R 2 Both are H.

[0351] In some implementation schemes, X 1 It is CR 3a In some implementations, X 1 It is N.

[0352] In some implementation schemes, R 3a R 3b and R 3c Each is independently selected from H, halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -S 8 -C(O)R 10-C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogens, and -C(O)R. 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogens, and -C(O)R. 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a R 3b and R3c Each is independently selected from H, halogens, and -C(O)R. 10 -C(O)NR 8 R 9 And substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogen, -OR 10 -S 8 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 12 C(O)R 10 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, -C(O)R 10 -C(O)NR 8 R 9 C3-C6 heterocyclic alkyl groups and 5-membered heteroaryl groups.

[0353] In some implementation schemes, R 3a R 3b and R 3c Each is independently selected from H, halogen, -C(O)OH, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, triazole, tetraazole, pyrrolidine, morpholine or C1-C6 alkyl substituted with -C(O)OH.

[0354] In some implementation schemes, R 3a and R 3b Each is either H or halogen; and R 3c Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 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 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c Selected from halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c Selected from halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c Selected from -NR 12 C(O)OR 10substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c Selected from substituted or unsubstituted C1-C6 alkyl groups, -C(O)R 10 -C(O)NR 8 R 9 C3-C6 heterocyclic alkyl groups and 5-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c It is a substituted or unsubstituted 5-membered heteroaryl group.

[0355] In some implementation schemes, R 3a It is halogen, and R 3b It is H. In some implementations, R 3a It is -Cl or -F; and R 3b It is H. In some implementations, R 3b It is halogen and R 3a It is H. In some implementations, R 3b It is -Cl or -F; and R 3a It's H.

[0356] In some implementation schemes, R 3a and R 3b Each is H.

[0357] In some implementation schemes, R 3a and R 3c It is independently H or halogen; and R 3b Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10-NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is H; and R 3b Selected from halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is H; and R 3b Selected from halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is H; and R 3b Selected from -C(O)R 10 -C(O)OR 10 -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is either H or halogen; and R 3b Selected from substituted or unsubstituted C1-C6 alkyl groups, -C(O)R 10-C(O)NR 8 R 9 C3-C6 heterocyclic alkyl groups and 5-membered heteroaryl groups.

[0358] In some implementation schemes, R 3a and R 3c Each is either H or halogen; and R 3b Selected from C(O)R 10 -C(O)OR 10 , and substituted or unsubstituted 5-membered heteroaryl groups.

[0359] In some implementation schemes, R 3a It is halogen and R 3c It is H. In some implementations, R 3a It is H and R 3b It is a halogen. In some implementations, R 3a It is -Cl or -F; and R 3c It is H. In some implementations, R 3c It is -Cl or -F; and R 3a It's H.

[0360] In some implementation schemes, R 3a and R 3c Each is H.

[0361] In some implementations, each R 3 R 3a R 3b and R 3c Each is independently a 5-membered heteroaryl group selected from pyrrole, triazole, tetraazole, oxazole, diazole, oxadiazole, thiadiazole, and furanyl. In some embodiments, each R 3 R 3a R 3b and R 3c Each is independently a 5-membered heteroaryl group selected from pyrrole, triazole, and tetraazole. In some embodiments, each R 3 R 3a R 3b and R 3c Each is independently a 5-membered heteroaryl group selected from triazole and tetraazole.

[0362] In some implementations, each R 3 R 3a R 3b Or R 3c Selected independently from: .

[0363] In some implementations, each R 3 R3a R 3b Or R 3c Selected independently from: In some implementations, each R 3 R 3a R 3b Or R 3c Selected independently from: In some implementations, each R 3 R 3a R 3b Or R 3c Selected independently from: .

[0364] In some implementation schemes, R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a 4- to 8-membered heterocyclic alkyl, each of which is substituted by one or more R 6 Replacement. In some implementations, R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or a substituted or unsubstituted C1-C8 hydroxyalkyl. In some embodiments, R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or a substituted or unsubstituted C1-C8 hydroxyalkyl.

[0365] In some implementation schemes, R 4 It is a substituted or unsubstituted C1-C8 alkyl or a substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments, R 4 It is a substituted or unsubstituted C1-C8 alkyl group. In some embodiments, the alkyl group is a straight-chain or branched alkyl group. In some embodiments, R 4 It is a substituted or unsubstituted C1-C8 heteroalkyl group. In some embodiments, the heteroalkyl group is an alkyl chain in which one or more carbon atoms are substituted with O or N atoms. In some embodiments, R 4It 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 heterocyclic alkyl), or -CH2-O-(C3-C6 heterocyclic alkyl). In some embodiments, R 4 It 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 4 It is -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2-O-(C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R 4 It is -CH2CH2-O- (C3-C6 cycloalkyl). In some embodiments, R 4 It is -CH2-O-(C3-C6 cycloalkyl). In some embodiments, R 4 It is -CH2CH2-O- (C3-C6 heterocyclic alkyl). In some embodiments, R 4 It is -CH2-O-(C3-C6 heterocyclic alkyl).

[0366] In some implementation schemes, R 4 It is a substituted or unsubstituted C1-C8 alkyl group, which is reacted with one or more halogens, -OR 10 C1-C8 alkyl or C3-C6 cycloalkyl substitution.

[0367] In some implementation schemes, R 4 It is a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replacement. In some implementations, R 4 It is a C3-C8 cycloalkyl group. In some embodiments, R 4 It is a monocyclic, polycyclic, spirocyclic, or bridged cycloalkyl group. In some embodiments, R 4 It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R 4 It is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 4 It is cyclopropyl. In some implementations, R4 It is cyclobutyl. In some implementations, R 4 It is cyclopentyl. In some implementations, R 4 It is cyclohexyl. In some implementations, R 4 yes or .

[0368] In some implementation schemes, R 4 It is a substituted or unsubstituted C3-C8 heterocyclic alkyl group, each of which is substituted by one or more R 6 Replacement. In some implementations, R 4 It is a monocyclic, polycyclic, spirocyclic, or bridged heterocyclic alkyl group. In some embodiments, R 4 It is a 4-membered heterocyclic alkyl group. In some embodiments, R 4 It is a 5-membered heterocyclic alkyl group. In some embodiments, R 4 It is a 6-membered cycloalkyl group. In some embodiments, R 4 It is a 7-membered cycloalkyl group. In some embodiments, R 4 It is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine. In some embodiments, R 4 It is tetrahydrofuran or tetrahydropyran.

[0369] In some implementations, each R 6 Independently, it is halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl. In some embodiments, each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 8 C(O)R 9C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C8 cycloalkyl. In some embodiments, each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 -C(O)OR 10 -C(O)NR 8 R 9 C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 Or C3-C8 cycloalkyl. In some embodiments, each R 6 Independently is -NR 8 R 9 or -OR 10 In some implementations, each R 6 Independently, it is a C3-C8 cycloalkyl group. In some embodiments, the cycloalkyl group is monocyclic, spirocyclic, or bridged cycloalkyl. In some embodiments, each R... 6 Independently, it is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R... 6 It is halogen independently. In some implementations, each R... 6 It can be H, Cl, F, or Br independently. In some implementations, each R... 6 Independently, it is F. In some implementations, each R... 6 Independently, it is F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH3CH3), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, piperidine, piperazine, oxetane, tetrahydrofuran, or tetrahydropyran. In some embodiments, each R 6 Independently, it is F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R 6 Independently, it is F, -OH, -CH3, or -CF3. In some embodiments, each R 6 Independently, it is F. In some implementations, each R... 6 Independently, it is -OH. In some implementations, each R... 6 Independently, it is -CF3. In some implementations, each R 6 It is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R 6 Independently, it is cyclopropyl. In some embodiments, each R...6 It is cyclobutyl independently.

[0370] In some implementations, two R 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl. In some embodiments, the two R... 6 They combine with one or more atoms to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. In some embodiments, two R groups... 6 They combine with one or more atoms to form cyclopropyl or cyclobutyl groups. In some embodiments, the two R groups... 6 They bond with one or more atoms to form cyclopropyl groups. In some embodiments, the two R groups... 6 They bond with one or more atoms to form a cyclobutyl group. In some embodiments, the two R atoms... 6 They bond with one or more atoms to form cyclopropyl groups. In some embodiments, the two R groups... 6 They bond with one or more atoms to form a cyclohexyl group. In some implementations, two R atoms... 6 They combine with one or more atoms to form C3-C6 heterocyclic alkyl groups. In some embodiments, the two R atoms... 6 They combine with one or more atoms to form a four-membered heterocyclic alkyl group. In some embodiments, the two R groups... 6 They combine with one or more atoms to form a 5-membered heterocyclic alkyl group. In some embodiments, the two R groups... 6 They combine with one or more atoms to form a 6-membered heterocyclic alkyl group. In some embodiments, the two R groups... 6 They combine with one or more atoms to form pyran, piperazine, piperidine, or morpholine.

[0371] In some implementation schemes, R 4 The following are possible combinations of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutane, tetrahydropyran, and tetrahydropyran. .

[0372] In some implementations, each R 5 Independently, it is a C1-C6 alkyl group. In some embodiments, each R... 5 Independently, it is -CH2CH3 or -CH3. In some implementations, each R 5 Independently, it is -CH2CH3. In some implementations, each R 5 Independently, it is -CH3. In some implementations, each R 5 H stands alone.

[0373] In some implementation schemes, R 5a It is CH3. In some implementations, R 5a It's H.

[0374] In some implementation schemes, R 5a And an R 6 They combine with one or more atoms to form C3-C6 cycloalkyl groups. In some embodiments, R 5a And an R 6 They combine with one or more atoms to form cyclopentyl or cyclohexyl groups. In some embodiments, R 5a And an R 6 They combine with one or more atoms to form a cyclohexyl group. In some implementations, R 5a And an R 6 They combine with one or more atoms to form cyclopentyl groups.

[0375] In some implementations, each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a Replacement. In some implementations, each R 8 and R 9 Each time it appears, it is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl. In some embodiments, each R8 and R 9 Each time it appears, it is independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups. In some embodiments, each R 8 and R 9 Each time it appears, it is independently selected from C3-C. 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups.

[0376] In some implementations, each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a Replacement. In some implementations, each R 10 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C 3- C 10 cycloalkyl, C3-C 10 Heterocyclic alkyl, C 6- C 10 Aryl groups and 5- to 10-membered heteroaryl groups. In some embodiments, each R 10 Independently selected from H, C1-C6 alkyl, C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups. In some embodiments, each R 10 Independently selected from H and C1-C6 alkyl groups. In some embodiments, each R 10 Independently selected from C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups.

[0377] In some implementations, each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a Replacement. In some implementations, each R 11 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C3-C 10 Heterocyclic alkyl, C 6- C 10 Aryl groups and 5- to 10-membered heteroaryl groups. In some embodiments, each R 11 Independently selected from C1-C6 alkyl, C1-C6 heteroalkyl and C 1- C6 haloalkyl. In some embodiments, each R 11 Independently selected from C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups.

[0378] In some implementations, each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a Replacement. In some implementations, each R 12 Independently selected from H, straight-chain or branched C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups. In some embodiments, each R 12 Independently selected from H, straight-chain or branched C1-C6 alkyl groups. In some embodiments, each R 12 Independently selected from C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups.

[0379] In some implementations, each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3. In some embodiments, each R aIndependently selected from -F, -Cl, -Br, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, each R a It is independently selected from -F, -OH, -CH3, -CF3 or -C(O)OH.

[0380] In some implementations, p is 1, 2, 3, or 4. In some implementations, p is 2 or 3. In some implementations, p is 3. In some implementations, p is 5. In some implementations, p is 4. In some implementations, p is 3. In some implementations, p is 2. In some implementations, p is 1.

[0381] In some implementations, the PDGH inhibitor is a compound described in Table 4, or a pharmaceutically acceptable salt thereof.

[0382] Table 4. 15-PGDH Inhibitors

[0383] In another aspect, this disclosure provides a composition comprising: (i) a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent that increases the expression of SMN protein. In some embodiments, the composition comprises a 15-PGDH inhibitor and an agent that increases the expression of SMN protein in an amount effective for treating spinal muscular atrophy (SMA).

[0384] In one aspect, this disclosure provides a pharmaceutical formulation comprising the composition described herein, and one or more pharmaceutically effective excipients, carriers, and / or diluents.

[0385] On the other hand, this disclosure provides unit doses of pharmaceutical preparations comprising those described herein.

[0386] In one aspect, this disclosure provides a kit comprising: (i) a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent for increasing the expression of SMN protein. In some embodiments, the 15-PGDH inhibitor and the agent for increasing SMN protein expression (SMN modulator) are in separate containers. In some embodiments, the 15-PGDH inhibitor and the SMN modulator are mixed together prior to administration. In some embodiments, the 15-PGDH inhibitor and the SMN modulator are mixed separately prior to administration. In some embodiments, the 15-PGDH inhibitor and the SMN modulator are administered together. In some embodiments, the 15-PGDH inhibitor and the SMN modulator are administered separately. In some embodiments, the 15-PGDH inhibitor and the SMN modulator are administered sequentially.

[0387] In some embodiments, the 15-PGDH inhibitor and the agent that increases SMN protein expression are contained in the same container. In some embodiments, the kit also includes instructions for administering the 15-PGDH inhibitor and the agent that increases SMN protein expression to the recipient. In some embodiments, the recipient has spinal muscular atrophy (SMA).

[0388] Any method, composition, pharmaceutical formulation, unit dose, or kit may contain any 15-PGDH inhibitor as described herein.

[0389] Unless otherwise defined, all technical terms, symbols, and other technical and scientific terms or proper nouns used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some instances, terms with their commonly understood meaning are defined herein for clarity and / or ease of reference, and such definitions contained herein should not necessarily be construed as representing a material difference from the commonly understood meaning in the art.

[0390] As used in the specification and claims, the singular forms “a / an” and “the” include plural references unless the context clearly specifies otherwise. For example, the term “a sample” includes multiple samples, including mixtures thereof.

[0391] The chapter titles used in this article are for organizational purposes only and are not to be construed as limiting the subject matter. Example

[0392] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0393] Example 1: Effects of 15-PGDH inhibitor administration on the PGE2 signaling pathway Administration of 15-PGDH inhibitors blocks the binding of 15-PGDH to PGE2, thereby leading to increased stem cell proliferation, increased muscle strength, and improved mitochondrial function in skeletal muscle. Figure 1 This provides an overview of the PGE2 signaling pathway and the effects of 15-PGDH inhibitors on the PGE2 signaling pathway.

[0394] Example 2: Mechanism of action and pharmacokinetic characteristics of a 15-PGDH inhibitor (MF-300).

[0395] The mechanism of action and pharmacokinetic characteristics of the 15-PGDH inhibitor (MF-300) were evaluated using biochemical assays and cell-based assays using A549 cells. Figure 2A The effects of different doses of MF-300 on NADH production were shown in the 15-PGDH inhibition biochemical assay. Figure 2B The effects of different doses of MF-300 on PGE2 stability in A549 cells were shown in a cell-based assay.

[0396] Example 3: Effects of intraperitoneal administration of MF-300 in SMNΔ7 mice.

[0397] The SMN Δ7 mouse model was used as a model of spinal muscular atrophy (SMA), and these mice exhibited a severe phenotype that was modulated by therapeutic administration of the SMN splice enhancer (SMN-C3). The effects of intraperitoneal injection of different doses of MF-300 (a 15-PGDH inhibitor) were evaluated in cohorts of male and female SMNΔ7 mice.

[0398] In summary, WT mice were not given injections starting from day 2 after birth. For SMN Δ7 mice, starting from day 2 after birth, they received daily intraperitoneal injections of the SMN splicing enhancer SMN-C3 (3 mg / kg) for 21 days, followed by an additional 28 days of daily intraperitoneal injections of 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). On day 49, isometric plantar flexor strength was then tested in mice, after which gastrocnemius muscle was harvested (n=6 / group) for RNA-seq. RNA-seq was performed using PolyA selection with paired-end reads and a read depth of approximately 30 x 10⁻⁶. 6 / sample.

[0399] Figure 3A An overview of the experimental timeline used to evaluate the effects of SMN-C3 and different doses of MF-300 on moderate-long plantar flexor strength in SMNΔ7 mice is shown. Figure 3B The effects of repeated treatment with SMN-C3 alone (the medium), no injection (WT), or SMN-C3 with different doses of MF-300 (3 mg / kg [3 MPK], 10 mg / kg [10 MPK], or 30 mg / kg [30 MPK]) on isometric plantar flexor strength were shown. Figure 3C The effects of repeated treatment with SMN-C3 alone (the medium), no injection (WT), or SMN-C3 with different doses of MF-300 (3 mg / kg, 10 mg / kg, or 30 mg / kg) on ​​the maximum force of isometric plantar flexors were shown. Figure 3D The effects of repeated treatment with SMN-C3 and different doses of MF-300 (3 mg / kg [3 MPK], 10 mg / kg [10 MPK], or 30 mg / kg [30 MPK]) on the maximum force as a percentage of the mean maximum force relative to the cohort treated with the medium are shown.

[0400] 15-PGDH was Hpgd Gene encoding. Figure 3E The level of HPGD expression was displayed. Figure 3E The left side shows the expression levels of HPGD in the tibialis anterior (TA) muscle obtained from WT and SMNΔ7 mice. These data were reanalyzed from public data from McCormack, NM et al. 2021, Journal of Cachexia, Sarcopenia, and Muscle. Figure 3EThe right side shows the expression level of HPGD in the gastrocnemius muscle (expressed as TPM) between wild-type mice and SMNΔ7 mice (treated with SMN-C3 only). This result shows... Hpgd Expression is upregulated in the presence of SMN regulation via SMN-C3. 。

[0401] Overall, these results show that the 15-PGDH inhibitor (MF-300) significantly increased potency in SMN Δ7 mice. Figure 3E The results also showed that in SMN Δ7 mice with and without SMN-C3 treatment, Hpgd Gene expression increases.

[0402] Example 4: RNA-seq analysis from WT, SMA mice and SMA MF mice.

[0403] Further RNA-seq analyses were performed from the mice in Example 3 to investigate: i. trait changes driven by the SMA genetic model; ii. identification of changes in the SMA model normalized by MF-300 treatment; and iii. gene signatures generated by MF-300 treatment. RNA-seq analyses were performed from the following skeletal muscle (gastrocnemius muscle): i. wild-type (WT) mice (N=6; 3 males and 3 females), ii. mice carrying the SMA-mimicking targeted mutation (SMNΔ7 mice) treated only with SMN-C3 (and receiving the MF-300 mediator control) (SMA mice) (N=6; 3 males and 3 females), and iii. mice carrying the SMA-mimicking targeted mutation (SMNΔ7 mice) treated with SMN-C3 and MF-300 at 30 mg / kg [30 MPK] (SMA MF mice) (N=5).

[0404] method Comparison and annotation The reads were aligned to the mouse GRCm39 genome build 109 using the Subread package (v2.12.3). Genome features were annotated using the featureCounts function from the Subread package. The mouse GRCm39 build 109 GTF file was used as a reference for annotation. Genome FASTA and GTF references were obtained from the ENSEMBL genome browser FTP.

[0405] Differential expression analysis Differential expression analysis was performed using edgeR (v3.40.2) and limma (v3.54.2) in R (v4.2.2). The mapIds function from the AnnotationDbi package (v.1.60.0) was used to map ENSEMBL gene IDs to gene symbols and Entrez IDs. Read counts were normalized to per million reads, and genes with less than 1 per million reads in at least two samples were filtered, leaving 15,774 genes in the final analysis. Normalization was performed using the M-value truncated mean method implemented as in calcNormFactors from edgeR. Data were modeled, and differential expression was determined using the limma voom pipeline, which generates a linear model with empirical Bayes moderation. Benjamini-Hochberg adjusted p-values ​​(less than 0.05) were used to determine differential expression. Once differentially expressed genes were identified, gene set enrichment analysis was performed using the enrichKEGG function from the clusterProfiler package.

[0406] Pathway enrichment was determined using gene set enrichment analysis and gene set overexpression tests (implemented using the clusterProfiler R package (v4.6.2)). Enrichment was determined for three publicly available gene ontology: GO cellular components, GO biological processes, and GO molecular functions. Significance was defined as pathways enriched with a p-value <0.05 after Benjamini-Hochberg adjustment.

[0407] result Quality control In all samples, >95% of reads mapped to the reference genome, and >85% of the mapped reads were successfully annotated. Read counts across the samples showed good consistency, with only one sample showing a slightly higher raw read count. Figure 4A Furthermore, all samples showed a consistent distribution of reads throughout the gene. Figure 4B ).

[0408] Multidimensional scaling After standardization, multidimensional scaling was performed to look for global trends in transcriptome features. MDS1 explained ~27% of the variance and provided a robust distinction between WT and SMA, which is shown in Figure 5A In the middle. Using MF-300 to process and push the SMA profile in the positive direction along MDS1, making the profile closer to WT ( Figure 5A This trend is in Figure 5B The quantification was achieved, although it did not reach statistical significance (p=0.25).

[0409] Differential expression The differential expression test demonstrated the robustness of the SMA model. However, relatively few changes could be attributed to the MF300 treatment. The total number of differentially expressed genes, thresholded by nominal p-values ​​and q-values ​​corrected for Bejamini-Hochberg false positive rate (FDR), is shown in Tables 1 and 2.

[0410] Table 1: Differentially expressed genes by nominal p-value

[0411] Table 2: Differentially expressed genes by FDR-corrected q values

[0412] No changes withstood FDR correction, which is not necessarily surprising given that 1) muscle tends to be slightly more variable than more homogeneous or RNA-rich tissues such as the liver; and 2) disease models can show variable performance / penetration. Despite the lack of significance from FDR correction, a global trend was observed to move transcriptomic features closer to WT for MF-300 treatment.

[0413] Comparison of gene levels affected by MF-300 To further investigate the opposite changes induced by SMA to those induced by MF-300 treatment, differentially expressed genes were superimposed in two comparisons (SMA-mediated vs. WT and MF-300 SMA vs. SMA-mediated). Of the 2300 genes significantly increased by the SMA model, 151 were significantly decreased by MF-300 treatment. Of the 2245 genes significantly decreased by the SMA model, 26 were significantly increased by MF-300 treatment, such as... Figure 6 The diagram shows Venn plots comparing genes that were nominally significantly differentially expressed in the SMA+ mediator versus WT and in the SMA+MF-300 mediator versus the SMA+ mediator. Of the nominally significant MF-300-induced changes, 56% were directly opposite to those induced by the SMA genetic model.

[0414] Expression characteristics of MF-300 To identify gene expression characteristics in an SMA mouse model treated with MF-300, a gene set enrichment analysis (GSEA) was performed comparing MF-300-treated and vector-treated SMA mice. Due to the limited number of nominally significantly differentially expressed genes in vector-treated SMA compared to MF-300 SMA, relatively fewer significant GSEA hits were observed compared to WT relative to vector-treated SMA.

[0415] Figure 7Gene set enrichment analysis results for the GO biological processes (BP) ontology comparing SMA+ mediators with SMA+ MF-300 are shown. The graphs were thresholded to display minimum and maximum normalized enrichment scores (NES). Positive NES scores indicate enrichment of SMA+ MF-300 relative to SMA+ mediators. This data shows that many gene sets involved in myelination (e.g., neuronal sheathing, axonal sheathing, myelination, myelin assembly, and positive regulation of myelination) were upregulated in the SMN-C3 treatment group and corrected for by combination therapy with MF-300.

[0416] In the BP ontology, MF-300 treatment increases multiple pathways related to mitochondrial structure and function, including mitochondrial gene expression and mitochondrial respiratory chain complex assembly. Multiple pathways related to myelination and axonal sheathing are significantly downregulated.

[0417] also, Figure 8 The changes in the expression of genes involved in myelination are shown when comparing the SMA group with MF-300. Figure 9 The changes in the expression of genes involved in the assembly of the mitochondrial respiratory chain complex are shown when comparing the SMA group with MF-300.

[0418] Figure 10 The top promoter features shown are significantly enriched or depleted in gene subsets that are significantly reduced by the SMA model and significantly increased by MF-300 treatment, indicating that MF-300 treatment increases CREB1 target gene expression and reduces NFKB2.

[0419] Overall, these results show that the genetic traits of SMNΔ7 mice treated with a combination of SMN-C3 and MF-300 shifted towards WT when compared with SMNΔ7 mice treated with SMN-C3 alone. Based on GSEA, myelination and mitochondrial pathways were shown to play a role in the combination therapy of SMN-C3 and MF-300.

[0420] Example 5: RNA-Seq analysis of genes involved in myelination according to Figure 7 The results further investigated the enrichment analysis of gene sets related to myelination, which showed upregulation in SMNΔ7 mice (SMA mice) treated with a mediator receiving only SMN-C3, but downregulation in SMNΔ7 mice treated with a combination of SMN-C3 and MF-300 (SMA+MF-300). These genes showed... Figure 8 Further investigation using RNA-Seq data revealed the genes most frequently upregulated or downregulated during MF-300 treatment, such as... Ugt8a,Mal,Ngfr,Pllp,Mpz,Mbp and Pmp22 This was quantified as counts per million (CPM). The results showed... Figure 11A-18C middle.

[0421] Figure 11A-11C Showing Mbp, Mpz and Ncmap The expression levels of these genes. These genes are Schwann cell markers for myelination.

[0422] Schwann cells serve as supporting cells in the peripheral nervous system and form myelin sheaths on the axons of neurons. Changes in Schwann cell gene expression obtained from RNA-Seq have been reported in cases of sciatic nerve compression (Lutz et al., 2022). Figures 12A-12E Showing Prx, Cited2, Mal, Cldn19 and Edn3 The expression levels of these genes were observed. In a rat model of ischial compression injury obtained from Schwann cells, these genes were upregulated after injury, and were also upregulated in the SMA group.

[0423] Figures 13A-13C Showing Ngfr、Ncam1 and L1cam The expression levels of these genes. These genes are markers of immature / unmyelinated Schwann cells.

[0424] Figures 14A-14B Showing S100b and Mag The expression levels of these genes. These genes are Schwann cell markers.

[0425] Figures 15A-15C Showing Pmp22, Ugt8a and Pllp The expression levels of these genes. These genes are involved in myelin formation.

[0426] Figure 16 The expression of Nfasc is shown. This gene is involved in the organization of axons and Ranvier's nodes on axons during development.

[0427] Figures 17A-17B It showed axonal genes such as Kif1a and Robo2 The expression.

[0428] Figures 18A-18C It showed Schwann cell-related genes such as Pou3f1、Cdkn1c and Sox 10 The expression.

[0429] The functions of some of these genes and the p-values ​​from the RNA-seq analysis are shown in Table 3.

[0430] Overall, these results indicate that the expression levels of many genes involved in Schwann cell biology were upregulated in the SMA group, but combination therapy with MF-300 reduced these expressions back to the levels observed in WT. The potential genetic profile of Schwann cells in Δ7 SMNC3 mice corrected for combination therapy with SMN-C3 and MF-300 is shown in Table 5.

[0431] Table 3: Selected genes from the GO analysis of myelination

[0432] Table 5: Potential Schwann cell genetic characteristics in Δ7 SMNC3 mice

[0433] Example 6: In a healthy sciatic nerve Hpgd Gene expression In this embodiment, the encoding of 15-PGDH was investigated. Hpgd Gene expression. Publicly available RNA-seq data were obtained and analyzed using sciatic nerve atlases available in the public domain from Gerber et al. 2021, eLife.

[0434] like Figure 19 The text appears to be a mix of Chinese characters and symbols, making it difficult to translate accurately. Hpgd Expression of this gene was observed throughout the healthy sciatic nerve at different developmental stages in mice. The Y-axis is shown as the number of reads per million mapped reads (RPKM).

[0435] The expression in the sciatic nerve was also studied. Hpgd target cells 。 like Figure 20 The text appears to be a mix of Chinese characters and symbols, making it difficult to translate accurately. Hpgd It is expressed in immune cells (IC), epineurial cells (EpC), and perineurial cells (PnC) of the sciatic nerve in healthy mice at 60 days of age. Based on EpC, PnC, and IC expression... Hpgd Expression may be widespread in the sciatic nerve. SC - Schwann cells; EpC - epineurial cells; EnC - endoneurial cells; PnC - perineurial cells; IC - immune cells; EC1 - endothelial cells 1; EC2 - endothelial cells 2; Per / VSMC - pericytes and vascular smooth muscle cells; Per / EC - pericytes and endothelial cells. Expression is shown in ln.

[0436] Overall, these results show that various cells found in healthy sciatic nerves, such as immune cells, epineurium cells, and perineurium cells, express 15-PGDH. These cells may be potential targets for 15-PGDH inhibitor therapy.

[0437] Example 7: Expression of myelination genes in untreated SMNΔ7 mice.

[0438] In this embodiment, the expression of myelination genes in untreated SMNΔ7 mice was analyzed.

[0439] like Figures 21A-21B The study showed that genes involved in myelination were upregulated in SMA-affected mice (SMNΔ7 mice) in the absence of SMN upregulatory factors. These data were reanalyzed from publicly available data from McCormack, NM et al. 2021, Journal of Cachexia, Sarcopenia, and Muscle. Overall, data from… Figures 21A-21B Data from previous examples illustrate that myelination is upregulated in SMA disease mice (SMNΔ7 mice).

[0440] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in carrying out the invention. The following claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A method for treating spinal muscular atrophy (SMA), the method comprising: Administer the effective therapeutic dose of the SMA to the recipient. (i) 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; as well as (ii) A drug that increases the expression of the survival motor neuron (SMN) protein. This treats the SMA.

2. The method according to claim 1, wherein the SMN protein is selected from: motor neuron survival 1 (SMN1) protein, motor neuron survival 2 (SMN2) protein, and any combination thereof.

3. The method according to claim 1 or 2, wherein the agent for increasing the expression of SMN protein is an agent for increasing the expression of SMN2 protein.

4. The method of claim 3, wherein the agent that increases the expression of SMN2 protein is an agent that regulates the splicing of pre-mRNA of motor neuron survival 2 (SMN2).

5. The method of claim 4, wherein the agent regulating the splicing of SMN2 pre-mRNA increases exon 7 in the SMN2 mRNA transcript.

6. The method according to claim 4 or 5, wherein the agent regulating the splicing of SMN2 pre-mRNA is selected from: lixithioprine, SMN-C2, SMN-C3, SMN-C5, RG-7916, RG7800, SMN-C1, SMN-C8, lixithioprine, nusinersen sodium, and any combination thereof.

7. The method of claim 3, wherein the agent for increasing the expression of SMN2 protein is RG3039.

8. The method according to claim 1 or 2, wherein the agent for increasing the expression of SMN protein is an agent for increasing the expression of SMN1 protein.

9. The method of claim 8, wherein the agent for increasing the expression of SMN1 protein is onasemnogeneabeparvovec.

10. The method according to any one of claims 1-9, wherein the agent for increasing the expression of SMN protein is selected from: small molecules, antisense oligonucleotides, siRNA, miRNA, shRNA, gene therapy agents, antigen-binding units, peptides, aptamers, and any combination thereof.

11. The method of claim 10, wherein the agent that increases the expression of SMN protein is a small molecule.

12. The method of claim 10, wherein the agent that increases the expression of the SMN protein is an antisense oligonucleotide.

13. The method of claim 10, wherein the agent that increases the expression of the SMN protein is a gene therapy agent.

14. The method according to any one of claims 1-13, wherein the SMA is selected from: SMA type 0, SMA type 1 (Werdnig-Hoffmann disease), SMA type 2 (Dubowitz disease), SMA type 3 (Kugelberg-Welander disease), and SMA type 4.

15. The method according to any one of claims 1-14, wherein the administration of the 15-PGDH inhibitor, the administration of the agent that increases the expression of SMN protein, or both are selected from: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra-arterial administration, intradermal administration, subcutaneous administration, and any combination thereof.

16. The method according to any one of claims 1-15, wherein the administration of the 15-PGDH inhibitor, the administration of the agent that increases the expression of SMN protein, or both are selected from: acute administration, chronic administration, intermittent administration, and continuous administration.

17. The method according to any one of claims 1-16, wherein the administration comprises administering the 15-PGDH inhibitor and the agent that increases the expression of the SMN protein in a single formulation to the subject in need of it.

18. The method according to any one of claims 1-16, wherein the administration comprises sequentially administering the 15-PGDH inhibitor and the agent that increases the expression of the SMN protein to the subject in need of it, in separate formulations.

19. The method according to any one of claims 1-16, wherein the administration comprises administering the 15-PGDH inhibitor prior to administering the agent that increases the expression of the SMN protein to the subject in need of it.

20. The method according to any one of claims 1-16, wherein the administration comprises administering the agent that increases the expression of the SMN protein prior to administering the 15-PGDH inhibitor to the subject in need of it.

21. The method according to any one of claims 1-20, wherein the 15-PGDH inhibitor, the agent that increases the expression of SMN protein, or both are administered to the subject in need of the method in one or more pharmaceutical formulations comprising pharmaceutically acceptable excipients, diluents, and / or carriers.

22. The method according to any one of claims 1-21, wherein the amount effective in treating SMA is an amount that effectively alleviates one or more symptoms of SMA.

23. The method according to any one of claims 1-21, wherein the amount of SMA effectively treated is the amount that effectively reduces the severity of the SMA.

24. The method according to any one of claims 1-23, wherein, compared to a method comprising administering the agent that increases SMN protein in the absence of the 15-PGDH inhibitor, the method results in the downregulation of one or more genes involved in the myelination pathway.

25. The method according to any one of claims 1-24, wherein, compared with a method comprising administering the agent that increases SMN protein in the absence of the 15-PGDH inhibitor, the method results in the downregulation of one or more Schwann cell genes.

26. The method according to any one of claims 1-25, wherein, compared to a method comprising administering the agent that increases SMN protein in the absence of the 15-PGDH inhibitor, the method results in the downregulation of one or more genes selected from: mpz , mbp , ugt8a , mal , pmp22 , pllp , ngfr , kif1a , robo2 , prx , cldn19 , cited2 , nfasc、 ncmap, s100b, mag, hgf and edn3 .

27. The method according to any one of claims 1-26, wherein the object requiring it is a person.

28. The method according to any one of claims 1-27, wherein the subject requiring it is 75 years of age or younger.

29. The method according to any one of claims 1-28, wherein the subject requiring it has an elevated 15-PGDH level prior to the application, compared to a control subject without SMA.

30. The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of formula I: Or its pharmaceutically acceptable salt, wherein: X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, -SO2CH2-; Each Y is independently selected from N and CR 11 ; Each R 1 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxo or thio groups; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 11 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The premise is that the compound of formula I is not , , or .

31. The method according to claim 30, wherein the compound is a compound of formula Ia: Or its pharmaceutically acceptable salt.

32. The method of claim 30, wherein the compound is a compound of formula Ib: Or its pharmaceutically acceptable salt.

33. The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of formula II: Or its pharmaceutically acceptable salt, wherein: T, U, W, X, and Y are independently selected from N and CR. 5 ; S, V, and Z are independently selected from N and C; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxo or thio groups; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 5 Independently selected from H, halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The premise is that the compound of formula II is not .

34. The method according to claim 33, wherein the compound is a compound of formula IIa: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

35. The method of claim 33, wherein the compound is a compound of formula IIb: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

36. The method of claim 33, wherein the compound is a compound of formula IIc: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4 or 5.

37. The method of claim 33, wherein the compound is a compound of formula IId: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

38. The method according to claim 33, wherein the compound is a compound of formula IIe: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

39. The method according to claim 33, wherein the compound is a compound of formula IIf: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

40. The method according to claim 33, wherein the compound is a compound of formula IIg: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

41. The method according to claim 33, wherein the compound is a compound of formula IIh: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

42. The method according to claim 33, wherein the compound is a compound of formula IIi: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

43. The method according to claim 33, wherein the compound is a compound of formula IIj: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

44. The method according to claim 33, wherein the compound is a compound of formula IIn: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

45. The method of claim 33, wherein the compound is a compound of formula IIp: Or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

46. ​​The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of formula III: Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form oxo or thio groups; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 Cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl group is independently and optionally substituted by one to three independently selected substituents from the following: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms connected to the same carbon atom 6 Together they form oxo groups, thio groups, or C groups. 3-10 cycloalkyl, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 8 Independently selected from H, halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 8 Together they can form C16 groups, optionally substituted by 1 to 3 independent substituents selected from the following. 3-10 Cycloalkyl groups: halogenated, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3 or 4.

47. The method of claim 46, wherein the compound is a compound of formula IIIa: Or its pharmaceutically acceptable salt.

48. The method of claim 46, wherein the compound is a compound of formula IIIb: Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and p is 0, 1, 2 or 3.

49. The method of claim 46, wherein the compound is a compound of formula IIIc: Or its pharmaceutically acceptable salt.

50. The method of claim 46, wherein the compound is a compound of formula IIId: Or its pharmaceutically acceptable salt, wherein: Each R 14 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and p is 0, 1, 2 or 3.

51. The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of formula IIk: Or its pharmaceutically acceptable salt, wherein: T, U, and Y are independently selected from N and CR. 6 The premise is that when U is N, at least one of T and Y is N; R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; Each R 4 Independently selected from H and halogen groups; R 5 Selected from halogen groups, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 Selected from H, halogen, -NR 7 R 8 -OR 9 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -SOR 10 -SO2R 10 -SO2NR 7 R 8 -NR 11 C(O)R 9 -NR 11 C(O)NR 7 R 8 -NR 11 SO2R 9 -NR 11 SO2NR 7 R 8 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 7 and R 8 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; Each R 9 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; and p is 0, 1, or 2.

52. The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of formula IIm: Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2 or 3.

53. The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of formula IIq: Or its pharmaceutically acceptable salt, wherein: R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; Each R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two Rs 4 Together with the carbon atoms they are attached to and any intercalated atoms, they form C 3-10 cycloalkyl, and any remaining R 4 Independently selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 5 Selected from halogen groups, -NR 6 R 7 -OR 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 6 R 7 -SOR 9 -SO2R 9 -SO2NR 6 R 7 -NR 10 C(O)R 8 -NR 10 C(O)NR 6 R 7 -NR 10 SO2R 8 -NR 10 SO2NR 6 R 7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; Each R 8 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 9 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 10 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-10 cycloalkyl; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2 or 3.

54. The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of formula IIIc: Or its pharmaceutically acceptable salt, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R). 8 )2; R 1 Selected from C 6-10 Aryl and 5 to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl groups and 5 to 10-membered heteroaryl groups; R 2 It is H, and R 3 It is -CF3; or R 2 and R 3 Together they form an oxygen group; R 4 and R 5 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 Cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl group is independently and optionally substituted by one to three independently selected substituents from the following: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic alkyl groups optionally substituted by 1 to 3 independently selected from the following substituents: halogen, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5 to 10 heteroaryl groups; or Two R atoms connected to the same carbon atom 6 Together they form an oxo group, and any remaining R 6 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 7 and R 8 Independently selected from halogen groups, -NR 9 R 10 -OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 9 R 10 -SOR 12 -SO2R 12 -SO2NR 9 R 10 -NR 13 C(O)R 11 -NR 13 C(O)NR 9 R 10 -NR 13 SO2R 11 -NR 13 SO2NR 9 R 10 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; Each R 11 Independently selected from H and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 12 Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; Each R 13 Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; and n is 0, 1, 2, 3 or 4.

55. The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is selected from the group consisting of: 。 56. The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is selected from the group consisting of: 。 57. The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound selected from the group consisting of: 。 58. The method according to any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of formula IV, or a pharmaceutically acceptable salt thereof: ， in, Ring Q is phenyl or a 5- to 10-membered heteroaryl group; Z is CR 1 Or N; Y is CR 2 Or N; R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl. Or two Rs 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A Yes -NR 5 R 5 or -OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5a And an R 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is optionally surrounded by one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10-membered heteroaryl, each of which is optionally substituted by one or more R a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, and substituted or unsubstituted 5 to 10-membered heteroaryl, each of which is optionally substituted by one or more R a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is optionally surrounded by one or more R groups. a replace; Each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3 or 4.

59. The method of claim 58, wherein ring Q is a 6-membered monocyclic heteroaryl group comprising 1, 2, or 3 N atoms.

60. The method of claim 58, wherein ring Q is phenyl, pyrimidinyl, or pyridinyl.

61. The method according to claim 58 or 60, wherein when Q is phenyl, then R 3 One of them is not H.

62. The method of claim 58, wherein yes in, X 1 X 2 X 3 and X 4 Each is independently N or CR 3 ; Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 replace; Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C 1- C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a Replace; and Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

63. The method of claim 62, wherein X 1 X 2 X 3 and X 4 Each is CR 3 .

64. The method of claim 62, wherein X 1 It is N; and X 2 X 3 and X 4 Each is CR 3 .

65. The method of claim 62, wherein X 1 and X 2 Each is N; and X 3 and X 4 Each is CR 3 .

66. The method of claim 62, wherein X 1 and X 3 Each is N; and X 2 and X 4 Each is CR 3 .

67. The method of claim 62, wherein X 1 and X 4 Each is N; and X 2 and X 3 Each is CR 3 .

68. The method of claim 62, wherein X 1 X 2 and X 3 Each is N; and X 4 It is CR 3 .

69. The method of claim 62, wherein X 1 X 2 and X 4 Each is N; and X 3 It is CR 3 .

70. The method according to any one of claims 58-69, wherein each R 3 Independently selected from H, halogen, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

71. The method of claim 70, wherein each R 3 Independently selected from H, halogens, -C(O)OR 10 -C(O)NR 8 R 9 , and substituted or unsubstituted 5-membered heteroaryl groups.

72. The method of claim 58, wherein the compound has a structure of formula V, or a pharmaceutically acceptable salt thereof: ， in, Z is CR 1 Or N; X 1 Is it N or CR? 3a ; Y is CR 2 Or N; R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; R 3a R 3b and R 3c Each is independently selected from H, halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl. Or two Rs 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A It is NR 5 R 5 OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5a And an R 6 They combine with one or more atoms to form substituted or unsubstituted C3-C6 cycloalkyl groups; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl groups, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C 1- C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is composed of one or more R a Replace; and Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

73. The method according to any one of claims 58-72, wherein X A It is NR 5 R 5 .

74. The method according to any one of claims 58-72, wherein X A Is it OR 5 .

75. The method according to any one of claims 58-74, wherein Y is CR 2 .

76. The method according to any one of claims 58-74, wherein Y is N.

77. The method according to claim 72, wherein the compound of formula V has a structure of formula VIa, or a pharmaceutically acceptable salt thereof: 。 78. The method according to claim 72, wherein the compound of formula V has a structure of formula VIb, or a pharmaceutically acceptable salt thereof: 。 79. The method according to any one of claims 58-78, wherein Z is N.

80. The method according to any one of claims 58-78, wherein Z is CR 1 .

81. The method according to any one of claims 58-78, wherein Z is CH.

82. The method according to claim 72, wherein the compound of formula V has the structure of formula VIIa, or a pharmaceutically acceptable salt thereof: 。 83. The method according to claim 72, wherein the compound of formula V has the structure of formula VIIb, or a pharmaceutically acceptable salt thereof: 。 84. The method according to claim 72, wherein the compound of formula V has the structure of formula VIIc, or a pharmaceutically acceptable salt thereof: 。 85. The method according to claim 72, wherein the compound of formula V has the structure of formula VIId, or a pharmaceutically acceptable salt thereof: 。 86. The method according to any one of claims 72-85, wherein X 1 It is N.

87. The method according to any one of claims 72-86, wherein R 3b It is H; and R 3c Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

88. The method of claim 87, wherein R 3b It is H; and R 3c Selected from halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

89. The method according to any one of claims 72-86, wherein R 3c It is H; and R 3b Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

90. The method of claim 89, wherein R 3c It is H; and R 3b Selected from halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

91. The method according to any one of claims 72-85, wherein X 1 It is CR 3a .

92. The method according to any one of claims 72-85 or 91, wherein R 3a and R 3b It is independently H or halogen; and R 3c Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

93. The method of claim 92, wherein R 3c Selected from H, halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

94. The method of claim 93, wherein R 3c It is -C(O)OR 10 -C(O)NR 8 R 9 A 5-membered heteroaryl group, either substituted or unsubstituted.

95. The method according to any one of claims 92-94, wherein R 3a and R 3b Each is H.

96. The method according to any one of claims 72-85 or 91, wherein R 3a and R 3c It is independently H or halogen; and R 3b Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

97. The method of claim 96, wherein R 3b Selected from H, halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

98. The method of claim 96, wherein R 3b It is -C(O)OR 10 -C(O)NR 8 R 9 , or substituted or unsubstituted 5-membered heteroaryl groups.

99. The method according to any one of claims 96-98, wherein R 3a and R 3c Each is H.

100. The method according to any one of claims 72-85 or 91, wherein R 3b and R 3c Each is either H or halogen; and R 3a Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

101. The method of claim 100, wherein R 3a Selected from H, halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

102. The method of claim 100, wherein R 3a It is -C(O)OR 10 -C(O)NR 8 R 9 , or substituted or unsubstituted 5-membered heteroaryl groups.

103. The method according to any one of claims 100-102, wherein R 3b and R 3c Each is H.

104. The method according to any one of claims 58-103, wherein each R 2 It's H.

105. The method according to any one of claims 58-104, wherein R 5a and R 6 One of them combines with one or more atoms to form a C3-C6 cycloalkyl group.

106. The method according to any one of claims 58-104, wherein R 5a It's H.

107. The method according to any one of claims 58-106, wherein R 5 It's H.

108. The method according to any one of claims 58-107, wherein R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 replace.

109. The method of claim 108, wherein R 4 It is a substituted or unsubstituted C1-C8 alkyl or a substituted or unsubstituted C1-C8 heteroalkyl, each of which is substituted by one or more R 6 replace.

110. The method according to any one of claims 58-107, wherein R 4 It is a substituted or unsubstituted C3-C8 cycloalkyl or a 4- to 8-membered heterocycloalkyl, each of which is substituted by one or more R 6 replace.

111. The method of claim 110, wherein R 4 It is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl or tetrahydropyranyl.

112. The method according to any one of claims 58-111, wherein each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl.

113. The method of claim 112, wherein each R 6 Independently, it is halogen, OR 10 C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl.

114. The method according to claim 112 or 113, wherein each R 6 Independently, it is -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

115. The method according to any one of claims 58-114, wherein the compound is selected from Table 4, or a pharmaceutically acceptable salt thereof.

116. A composition comprising: (i) a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent that increases the expression of SMN protein.

117. The composition of claim 116, wherein the composition comprises the 15-PGDH inhibitor and the agent that increases the expression of SMN protein, the amount of which is effective in treating spinal muscular atrophy (SMA).

118. A pharmaceutical formulation comprising the composition according to claim 116 or 117, and one or more pharmaceutically effective excipients, carriers, and / or diluents.

119. A unit dose comprising the pharmaceutical preparation according to claim 118.

120. A reagent kit comprising: (i) 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; And (ii) agents that increase the expression of SMN protein.

121. The kit of claim 120, wherein the 15-PGDH inhibitor and the agent for increasing SMN protein expression are in separate containers.

122. The kit of claim 120, wherein the 15-PGDH inhibitor and the agent for increasing SMN protein expression are in the same container.

123. The kit according to any one of claims 120-122, further comprising instructions for administering the 15-PGDH inhibitor and the agent for increasing the expression of SMN protein to a subject in need thereof.

124. The kit of claim 123, wherein the subject requiring it has spinal muscular atrophy (SMA).

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