Methods for combination treatment of spinal muscular atrophy

Abstract

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

Description

METHODS FOR COMBINATION TREATMENT OF SPINAL MUSCULAR ATROPHY CROSS-REFERENCE

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

[0002] Muscle disorders or conditions appear in many forms and can range from being relatively mild to extremely severe. Muscle disorders or conditions can be inherited, e.g., muscular dystrophy, or acquired. Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease that involves the loss of motor neurons, thereby affecting nervous system and voluntary muscle movement. There is an unmet need for treatment of SMA. INCORPORATION BY REFERENCE

[0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. SUMMARY

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

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

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

[0007] In some embodiments, the agent that increases expression of SMN protein is an agent that increases expression of SMN2 protein. In some embodiments, the agent that increases expression of SMN2 protein is an agent that modulates splicing of survival motor neuron 2 (SMN2) pre-mRNA. In some embodiments, the agent that modulates splicing of SMN2 pre- mRNA increases exon 7 inclusion in SMN2 mRNA transcripts. In some embodiments, the agent that modulates splicing of SMN2 pre-mRNA is selected from the group consisting of: 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 expression of SMN2 protein is RG3039.

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

[0009] In some embodiments, the agent that increases expression of SMN protein is selected from the group consisting of: a small molecule, an antisense oligonucleotide, an siRNA, a miRNA, an shRNA, a gene therapy agent, an antigen binding unit, a peptide, an aptamer, and any combination thereof. In some embodiments, the agent that increases expression of SMN protein is a small molecule. In some embodiments, the agent that increases expression of SMN protein is an antisense oligonucleotide. In some embodiments, the agent that increases expression of SMN protein is a gene therapy agent.

[0010] In some embodiments, the SMA is selected from the group consisting of: 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, the administering the 15-PGDH inhibitor, the administering the agent that increases expression of SMN protein, or both, is selected from the group consisting of: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra-arterial administration, intradermal administration, subcutaneous administration, and any combination thereof. In some embodiments, the administering the 15-PGDH inhibitor, the administering the agent that increases expression of SMN protein, or both, is selected from the group consisting of: acute administration, chronic administration, intermittent administration, and continuous administration.

[0012] In some embodiments, the administering comprises administering the 15-PGDH inhibitor and the agent that increases expression of SMN protein in a single formulation to the subject in need thereof. In some embodiments, the administering comprises administeringthe 15-PGDH inhibitor and the agent that increases expression of SMN protein sequentially in separate formulations to the subject in need thereof. In some embodiments, the administering comprises administering the 15-PGDH inhibitor before administering the agent that increases expression of SMN protein to the subject in need thereof. In some embodiments, the administering comprises administering the agent that increases expression of SMN protein before administering the 15-PGDH inhibitor to the subject in need thereof.

[0013] In some embodiments, the 15-PGDH inhibitor, the agent that increases expression of SMN protein, or both, are administered to the subject in need thereof in one or more pharmaceutical formulations comprising a pharmaceutically acceptable excipient, diluent, and / or carrier.

[0014] In some embodiments, the amounts effective to treat SMA are amounts effective to ameliorate one or more symptoms of the SMA. In some embodiments, the amounts effective to treat SMA are amounts effective to reduce severity of the SMA.

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

[0016] In some embodiments, the subject in need thereof is a human. In some embodiments, the subject in need thereof is 75 years old or less.

[0017] In some embodiments, the subject in need thereof has elevated 15-PGDH levels prior to the administering, relative to a control subject that does not have SMA.

[0018] In some embodiments, the 15-PGDH inhibitor is a compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof, wherein:X is selected from –OCH2–, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, – SCH2–, –S(O)CH2–, –SO2CH2–; each Y is independently selected from N and CR11; each R1is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; each R5is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl;R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; each R11is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; andp is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;.

[0019] In some embodiments, the compound is a compound of Formula Ia:Formula Ia or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the compound is a compound of Formula Ib:Formula Ib or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the 15-PGDH inhibitor is a compound of Formula II:Formula II or a pharmaceutically acceptable salt thereof, wherein: T, U, W, X, and Y are independently selected from N and CR5; S, V, and Z are independently selected from N and C; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s areindependently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; each R5is independently selected from H, halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

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

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

[0024] In some embodiments, the compound is a compound of Formula IIc:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0025] In some embodiments, the compound is a compound of Formula IId:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0026] In some embodiments, the compound is a compound of Formula IIe:Formula IIe or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0027] In some embodiments, the compound is a compound of Formula IIf:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0028] In some embodiments, the compound is a compound of Formula IIg:Formula IIg or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0029] In some embodiments, the compound is a compound of Formula IIh:Formula IIh or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0030] In some embodiments, the compound is a compound of Formula IIi:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0031] In some embodiments, the compound is a compound of Formula IIj:Formula IIj or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0032] In some embodiments, the compound is a compound of Formula IIn:Formula IIn or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0033] In some embodiments, the compound is a compound of Formula IIp:Formula IIp or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0034] In some embodiments, the 15-PGDH inhibitor is a compound of Formula III:Formula III or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR7; Y is selected from O, S, SO2, and C(R8)2; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3- 10cycloalkyl, and any remaining R6’s are independently selected from halo, – NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R8is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R8’s can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1- 6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

[0035] In some embodiments, the compound is a compound of Formula IIIa:Formula IIIa or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the compound is a compound of Formula IIIb:Formula IIIb or a pharmaceutically acceptable salt thereof, wherein: each R14 is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0037] In some embodiments, the compound is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the compound is a compound of Formula IIId:Formula IIId or a pharmaceutically acceptable salt thereof, wherein: each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0039] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIk:or a pharmaceutically acceptable salt thereof, wherein: T, U, and Y are independently selected from N and CR6, provided that when U is N, at least one of T and Y is N; R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, – SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, – NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from H and halo;R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, – NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6is selected from H, halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, – SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, – NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R11is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 6cycloalkyl; and p is 0, 1, or 2.

[0040] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIm:Formula IIm or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo;each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

[0041] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIq:Formula IIq or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

[0042] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR7; Y is selected from O, S, SO2, and C(R8)2; R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1- 6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 6cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0043] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0044] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:; ;; ;;;;

[0045] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:.

[0046] In some instances, the 15-PGDH inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt thereof:Formula (I), wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2or N; R1is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R2is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, – C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-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 R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; XAis -NR5R5or -OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is optionally substituted with one or more Ra;each R10 is 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-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted orunsubstituted C3-C10 heterocycloalkyl, each of which is optionally substituted with one or more Ra; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

[0047] In some instances, ring Q is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 N atoms. In some instances, ring Q is a phenyl, pyrimidinyl, or pyridinyl. In some instances, when Q is phenyl then one of R3is not H.

[0048] In some instances,wherein, X1, X2, X3and X4are each independently N or CR3; each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, – C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted orunsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0049] In some instances, X1, X2, X3and X4are each CR3. In some instances, X1is N; and X2, X3, and X4are each CR3. In some instances, X1and X2are each N; and X3and X4are each CR3. In some instances, X1and X3are each N; and X2and X4are each CR3. In someinstances, X1 and X4 are each N; and X2 and X3 are each CR3. In some instances, X1, X2, andX3are each N; and X4is CR3. In some instances, X1, X2, and X4are each N; and X3is CR3.

[0050] In some instances, each R3is independently selected from H, halogen, –NR8R9, – OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some instances, each R3is independently selected from H, halogen, –C(O)OR10, –C(O)NR8R9, and substituted or unsubstituted 5-membered heteroaryl.

[0051] In some instances, the compound has the structure of Formula V, or a pharmaceutically acceptable salt thereof:Formula V, wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R2is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, –NR8R9, – OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, – NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted orunsubstituted 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 R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;each R10 is 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-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted orunsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0052] In some instances, XAis NR5R5. In some instances, XAis OR5. In some instances, Y is CR2. In some instances, Y is N.

[0053] In some instances, the compound of Formula V has the structure of Formula VIa, or a pharmaceutically acceptable salt thereof:.

[0054] In some instances, the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:Formula VIb.

[0055] In some instances, Z is N. In some instances, Z is CR1. In some instances, Z is CH.

[0056] In some instances, the compound of Formula V has the structure of Formula VIIa, or a pharmaceutically acceptable salt thereof:Formula VIIa.

[0057] In some instances, the compound of Formula V has the structure of Formula VIIb, or a pharmaceutically acceptable salt thereof:Formula VIIb.

[0058] In some instances, the compound of Formula V has the structure of Formula VIIc, or a pharmaceutically acceptable salt thereof:Formula VIIc.

[0059] In some instances, the compound of Formula V has the structure of Formula VIId, or a pharmaceutically acceptable salt thereof:Formula VIId.

[0060] In some instances, X1is N. In some instances, R3bis H; and R3cis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, – SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, – NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9.

[0061] In some instances, R3bis H; and R3cis selected from halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

[0062] In some instances, R3cis H; and R3bis selected from halogen, -CN, -NO2, –NR8R9, – OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, – NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9.

[0063] In some instances, R3cis H; and R3bis selected from halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted orunsubstituted 5-membered heteroaryl.

[0064] In some instances, X1is CR3a. In some instances, R3aand R3bare independently H or halogen; and R3cis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, – NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, - SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9.

[0065] In some instances, R3cis selected from H, halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl,substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5- membered heteroaryl.

[0066] In some instances, R3cis –C(O)OR10, –C(O)NR8R9, or substituted or unsubstituted 5- membered heteroaryl. In some instances, R3aand R3bare each H.

[0067] In some instances, R3aand R3care independently H or halogen; and R3bis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, – SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, – NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9.

[0068] In some instances, R3bis selected from H, halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5- membered heteroaryl.

[0069] In some instances, R3bis –C(O)OR10, –C(O)NR8R9, or substituted or unsubstituted 5- membered heteroaryl.

[0070] In some instances, R3aand R3care each H. In some instances, R3band R3care each H or halogen; and R3ais selected from halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, – NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, - SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9.

[0071] In some instances, R3ais selected from H, halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5- membered heteroaryl.

[0072] In some instances, R3ais –C(O)OR10, –C(O)NR8R9, or substituted or unsubstituted 5- membered heteroaryl. In some instances, R3band R3care each H. In some instances, each R2is H. In some instances, R5aand one of R6combine together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl. In some instances, R5ais H. In some instances, R5is H.

[0073] In some instances, R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6. In some instances, R4is substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C1-C8 heteroalkyl, each of which is substituted with one or more R6. In some instances, R4is substituted or unsubstituted C3-C8 cycloalkyl or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6.

[0074] In some instances, R4is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl. In some instances, each R6is independently halogen, –NR8R9, –OR10, 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. In some instances, each R6is independently halogen,–OR10, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl. In someinstances, each R6 is independently -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

[0075] In some instances, the compound is selected from Table 4, or a pharmaceutically acceptable salt thereof.

[0076] In another aspect, the present disclosure provides a composition comprising: (i) a 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent that increases expression of SMN protein. In some embodiments, the composition comprises the 15-PGDH inhibitor and the agent that increases expression of SMN protein in amounts effective to treat spinal muscular atrophy (SMA).

[0077] In one aspect, the present disclosure provides a pharmaceutical formulation comprising the composition described herein, and one or more pharmaceutically effective excipients, carriers, and / or diluents.

[0078] In one aspect, the present disclosure provides a unit dose comprising the pharmaceutical formulation as described herein. In another aspect, the present disclosure provides a kit comprising: (i) a 15-hydroxyprostaglandin dehydrogenase (15-PGDH)inhibitor; and (ii) an agent that increases expression of SMN protein. In some embodiments, the 15-PGDH inhibitor and the agent that increases expression of SMN protein are in separate containers. In some embodiments, the 15-PGDH inhibitor and the agent that increases expression of SMN protein are in the same container. In some embodiments, the kit further comprises instructions for administering the 15-PGDH inhibitor and the agent that increases expression of SMN protein to a subject in need thereof. In some embodiments, the subject in need thereof has spinal muscular atrophy (SMA). BRIEF DESCRIPTION OF THE DRAWINGS

[0079] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0080] FIG.1 shows an overview of PGE2 signaling pathway and the effects of 15-PGDH inhibitor on PGE2 signaling.

[0081] FIGS.2A-2B show the mechanism of action and pharmacokinetic profile of 15- PGDH inhibitor, MF-300. Fig.2A shows the effects of MF-300 on NADH production in a biochemical 15-PGDH inhibition assay. Fig.2B shows the effects of MF-300 on PGE2 stability in A549 cells.

[0082] FIGS.3A-3E show the effects of intraperitoneally administered MF-300 in SMNΔ7 mice. FIG.3A shows an experimental overview for assessing the effects of repeated SMN- C3 and MF-300 administration in SMNΔ7 mice. FIG.3B shows the effects of repeated SMN-C3 and MF-300 administration in SMNΔ7 mice on isometric plantar flexor force. FIG. 3C shows the effects of repeated SMN-C3 and MF-300 administration in SMNΔ7 mice on isometric plantar flexor maximum force. FIG.3D shows the effects of repeated SMN-C3 and MF-300 administration in SMNΔ7 mice on isometric plantar flexor maximum force as a percentage relative to the average maximum force of vehicle-treated animals. FIG.3E shows the level of HPGD expression in tibialis anterior muscle (TA muscle) obtained from WT mice and Δ7SMA mice (figure on the left) and gastrocnemius muscles from WT mice and SMNΔ7 mice treated with SMN-C3 (figure on the right).

[0083] FIGS.4A-4B show quality control of RNA seq reads. FIG.4A shows sum of raw reads per sample. FIG.4B shows distribution of read counts.

[0084] FIGS.5A-5B show data from RNA-seq analysis. FIG.5A shows multidimensional scaling across incorporating all genes meeting minimum count threshold. FIG.5B shows boxplot and 1-way ANOVA of MDS1 values by treatment group.

[0085] FIG.6 shows Venn diagram comparing nominally significant differentially expressed genes in SMA+veh vs WT and SMA+MF-300 vs SMA+veh.

[0086] FIG.7 shows gene set enrichment analysis results for GO biological processes (GP) ontology comparing SMA+veh vs SMA+MF-300. Plot is threshold to show minimum and maximum normalized enrichment scores (NES). Positive NES score indicates enrichment in SMA+MF vs SMA+veh.

[0087] FIG.8 shows changes in expression of genes involved with myelination.

[0088] FIG.9 shows changes in expression of genes involved with mitochondrial respiratory chain complex assembly.

[0089] FIG.10 shows top promoter signatures that were significantly enriched or depleted in the subset of genes that were significantly decreased by the SMA model and significantly increased by MF-300 treatment.

[0090] FIGS.11A-11C show expression of Schwann cell markers: Mpb (FIG.11A), Mpz (FIG.11B), and Ncmap (FIG.11C).

[0091] FIGS.12A-12E show expression levels of Prx (FIG.12A), Cited2 (FIG.12B), Mal (FIG.12C), Cldn19(FIG.12D), and Edn (FIG.12E).

[0092] FIGS.13A-13C show expression levels of Ngft (FIG.13A), Ncam1 (FIG.13B), and L1cam (FIG.13C).

[0093] FIGS.14A-14B show expression level of S100b (FIG.14A) and Mag (FIG.14B).

[0094] FIGS.15A-15C show expression level of Pmp22 (FIG.15A), Ugt8a (FIG.15B), and Pllp (FIG.15C).

[0095] FIG.16 shows expression of Nfasc.

[0096] FIGS.17A-17B show expression of axonal genes such as Kif1a (FIG.17A) and Robo2 (FIG.17B).

[0097] FIGS.18A-18C show expression of Pou3f1 (FIG.18A), Cdkn1c (FIG.18B), and Sox 10 (FIG.18C).

[0098] FIG.19 shows the expression of Hpgd, which was observed in healthy sciatic nerve throughout different developmental stages in mice.

[0099] FIG.20 shows that Hpgd is expressed in immune cells (IC), epineural cells (EpC), and perineural cells (PnC) in 60 days postnatal healthy mouse sciatic nerve.

[0100] FIGS.21A-21B shows the expression of myelination gene in untreated SMA mice. FIG.21A shows the expression of Mbp, Mpz, Ugt8a, and Mal. FIG.21B shows the expression of Ncmap, Ngfr, Pllp, Pmp22, Cited2, and Prx. DETAILED DESCRIPTION

[0101] Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease involving the loss of motor neurons, thereby affecting nervous system and voluntary muscle movement. Chromosome 5-related SMA is the most common form of SMA (types 1-4), and this is caused by a mutation in survival of motor neuron 1 or SMN1 gene, leading to deficiency in survival of motor neuron or SMN protein. Increase level of SMN protein can improve symptoms of SMA. SMN2 gene is the neighboring gene of SMN1 gene, and SMN2 gene shares 99% identity to SMN1 gene. SMN agent or SMN modulator that increases expression of SMN protein from any SMN genes, e.g., SMN1 gene, SMN2 gene, or both, can improve symptoms of SMA. Other agent or SMN modulator that increases expression of SMN protein from any SMN genes, e.g., SMN1 gene, SMN2 gene, or both, can be used for methods, compositions, pharmaceutical formulations, unit doses, or kits as described herein.

[0102] Prostaglandins are a group of physiologically active lipid compounds with diverse biological effects. Prostaglandin E2 (PGE2), also known as dinoprostone, plays a role as a lipid mediator that can resolve inflammation. PGE2 can be used as an anticoagulant and antithrombotic agent. PGE2 is synthesized from arachidonic acid by cyclooxygenase (COX) and prostaglandin E synthase enzymes. Hydroxyprostaglandin dehydrogenases, such as 15- hydroxyprostaglandin dehydrogenase (15-PGDH) are involved in the inactivation of prostaglandins.

[0103] Provided herein is a method of treating spinal muscular atrophy (SMA) by using combination treatment of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor, and a survival motor neuron (SMN) modulator that increases the expression of SMN protein. In one aspect, the present disclosure provides a method of treating spinal muscular atrophy (SMA), the method comprising: administering to a subject in need thereof, in amounts effective to treat the SMA, (i) a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent that increases expression of survival motor neuron (SMN) protein (also referred to as SMN modulator), thereby treating the SMA. In some embodiments, the SMN protein is selected from the group consisting of: survival motor neuron 1 (SMN1) protein, survival motor neuron 2 (SMN2) protein, and any combination thereof.

[0104] In some embodiments, the agent that increases expression of SMN protein is selected from the group consisting of: a small molecule, an antisense oligonucleotide, an siRNA, a miRNA, an shRNA, a gene therapy agent, an antigen binding unit, a peptide, an aptamer, and any combination thereof. In some embodiments, the agent that increases expression of SMN protein is a small molecule. In some embodiments, the agent that increases expression of SMN protein is an antisense oligonucleotide. In some embodiments, the agent that increases expression of SMN protein is a gene therapy agent.

[0105] In some embodiments, the agent that increases expression of SMN protein is an agent that increases expression of SMN2 protein (SMN2 modulator). Modulation of the SMN2 protein expression, for example, to include exon 7 from splicing out of SMN2 pre-mRNA, can increase SMN protein, thereby improving symptoms associated with SMA. In some embodiments, the agent that increases expression of SMN2 protein is an agent that modulates splicing of survival motor neuron 2 (SMN2) pre-mRNA. In some embodiments, the agent that modulates splicing of SMN2 pre-mRNA increases exon 7 inclusion in SMN2 mRNA transcripts. In some embodiments, the agent that modulates splicing of SMN2 pre-mRNA is selected from the group consisting of: 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 expression of SMN2 protein is RG3039.

[0106] In some embodiments, the agent that increases expression of SMN protein is an agent that increases expression of SMN1 protein (SMN1 modulator). In some embodiments, the SMN1 modulator comprises a gene therapy. Gene therapy can be utilized to deliver wildtype copy of SMN1 transgene located under synthetic promoter. In some embodiments, the gene therapy comprises delivery of wildtype SMN1 transgene. In some embodiments, the agent that increases expression of SMN1 protein is onasemnogene abeparvovec.

[0107] There are four types of SMA. SMA Type 1, which is also called Werdnig-Hoffmann disease or infantile-onset SMA, is the most common and severe form of SMA. Patients with SMA Type 1 can show symptoms beginning at birth or within the first six months of life. SMA Type 2 or Dubowitz disease is an intermediate form of SMA, and the symptoms typically start between 6 and 18 months of age. SMA Type 3, which is 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 starts in young adulthood, and causes mild motor impairment. In some embodiments, the SMA is selected from the group consisting of: SMA Type 0, SMA Type 1 (Werdnig–Hoffmanndisease), SMA Type 2 (Dubowitz disease), SMA Type 3 (Kugelberg–Welander disease), and SMA Type 4.

[0108] In some embodiments, the administration of the 15-PGDH inhibitor and the SMN modulator can be performed using the same route of administration. In some embodiments, the administration of the 15-PGDH inhibitor and the SMN modulator can be performed using different routes of administration. In some embodiments, the administration of the 15-PGDH inhibitor and the SMN modulator can be performed simultaneously. In some embodiments, the administration of the 15-PGDH inhibitor and the SMN modulator can be performed separately. In some embodiments, the administration of the 15-PGDH inhibitor and the SMN modulator can be performed sequentially, for examples, the 15-PGDH inhibitor can be administered prior to the SMN modulator, or vice-versa.

[0109] In some embodiments, the administration of the 15-PGDH inhibitor and the SMN modulator can be at the same frequency. In some embodiments, the administration of the 15- PGDH inhibitor and the SMN modulator can be at different frequency. In some embodiments, the dosing frequency for administering the 15-PGDH inhibitor is once every day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, or once every 10 days. In some embodiments, the dosing frequency for administering the 15-PGDH inhibitor is 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 for administering the 15-PGDH inhibitor is less than once every day to once every 10 days, less than once every day to once every 9 days, less than once every day to once every 8 days, less than once every day to once every 7 days, less than once every day to once every 6 days, less than once every day to once every 5 days, less than once every day to once every 4 days, less than once every day to once every 3 days, or less than once every day to once every 2 days. In some embodiments, the dosing frequency for administering the 15-PGDH inhibitor is less than once every day to less than once every 10 days, less than once every day to less than once every 9 days, less than once every day to less than once every 8 days, less than once every day to less than once every 7 days, less than once every day to less than once every 6 days, less than once every day to less than once every 5 days, less than once every day to less than once every 4 days, less than once every day to less than once every 3 days, or less than once every day to less than once every 2 days.

[0110] In some embodiments, the administering the 15-PGDH inhibitor, the administering the agent that increases expression of SMN protein, or both, is selected from the groupconsisting of: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra-arterial administration, intradermal administration, subcutaneous administration, and any combination thereof. In some embodiments, the administering the 15-PGDH inhibitor, the administering the agent that increases expression of SMN protein, or both, is selected from the group consisting of: acute administration, chronic administration, intermittent administration, and continuous administration.

[0111] In some embodiments, the 15-PGDH inhibitor and the SMN modulator are administered together. In some embodiments, the administering comprises administering the 15-PGDH inhibitor and the agent that increases expression of SMN protein (SMN modulator) in a single formulation to the subject in need thereof.

[0112] In some embodiments, the 15-PGDH inhibitor and the SMN modulator are administered separately. In some embodiments, the administering comprises administering the 15-PGDH inhibitor and the agent that increases expression of SMN protein sequentially in separate formulations to the subject in need thereof. In some embodiments, the administering comprises administering the 15-PGDH inhibitor before administering the agent that increases expression of SMN protein to the subject in need thereof. In some embodiments, the administering comprises administering the agent that increases expression of SMN protein before administering the 15-PGDH inhibitor to the subject in need thereof.

[0113] In some embodiments, the 15-PGDH inhibitor, the agent that increases expression of SMN protein, or both, are administered to the subject in need thereof in one or more pharmaceutical formulations comprising a pharmaceutically acceptable excipient, diluent, and / or carrier.

[0114] In some embodiments, the amounts effective to treat SMA are amounts effective to ameliorate one or more symptoms of the SMA. In some embodiments, the amounts effective to treat SMA are amounts effective to reduce severity of the SMA. In some embodiments, the amounts effective to treat SMA comprises an effective dose of the 15-PGDH inhibitor. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises about 1 mg / kg (or about 1MPK), about 3 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, or about 100 mg / kg. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises at least about 1 mg / kg (or at least about 1MPK), at least about 3 mg / kg, at least about 10 mg / kg, at least about 20 mg / kg, at least about 30 mg / kg, at least about 40 mg / kg, at least about 50 mg / kg, at least about 60 mg / kg, at least about 70 mg / kg, at least about 80mg / kg, at least about 90 mg / kg, or at least about 100 mg / kg. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises less than about 1 mg / kg (or 1MPK), less than about 3 mg / kg, less than about 10 mg / kg, less than about 20 mg / kg, less than about 30 mg / kg, less than about 40 mg / kg, less than about 50 mg / kg, less than about 60 mg / kg, less than about 70 mg / kg, less than about 80 mg / kg, less than about 90 mg / kg, or less than about 100 mg / kg.

[0115] In some embodiments, the effective dose of the 15-PGDH inhibitor comprises about 0.1MPK, about 0.2MPK, about 0.3MPK, about 0.4MPK, about 0.5MPK, about 0.6MPK, about 0.7MPK, about 0.8MPK, about 0.9MPK, about 1MPK, about 1.1MPK, about 1.2MPK, about 1.3MPK, about 1.4MPK, about 1.5MPK, about 1.6MPK, about 1.7MPK, about 1.8MPK, about 1.9MPK, about 2MPK, about 2.1MPK, about 2.2MPK, about 2.3MPK, about 2.4MPK, about 2.5MPK, about 2.6MPK, about 2.7MPK, about 2.8MPK, about 2.9MPK, about 3MPK, about 3.1MPK, about 3.2MPK, about 3.3MPK, about 3.4MPK, about 3.5MPK, about 3.6MPK, about 3.7MPK, about 3.8MPK, about 3.9MPK, about 4MPK, about 4.1MPK, about 4.2MPK, about 4.3MPK, about 4.4MPK, about 4.5MPK, about 4.6MPK, about 4.7MPK, about 4.8MPK, about 4.9MPK, about 5MPK, about 5.1MPK, about 5.2MPK, about 5.3MPK, about 5.4MPK, about 5.5MPK, about 5.6MPK, about 5.7MPK, about 5.8MPK, about 5.9MPK, or about 6MPK. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises at least about 0.1MPK, at least about 0.2MPK, at least about 0.3MPK, at least about 0.4MPK, at least about 0.5MPK, at least about 0.6MPK, at least about 0.7MPK, at least about 0.8MPK, at least about 0.9MPK, at least about 1MPK, at least about 1.1MPK, at least about 1.2MPK, at least about 1.3MPK, at least about 1.4MPK, at least about 1.5MPK, at least about 1.6MPK, at least about 1.7MPK, at least about 1.8MPK, at least about 1.9MPK, at least about 2MPK, at least about 2.1MPK, at least about 2.2MPK, at least about 2.3MPK, at least about 2.4MPK, at least about 2.5MPK, at least about 2.6MPK, at least about 2.7MPK, at least about 2.8MPK, at least about 2.9MPK, at least about 3MPK, at least about 3.1MPK, at least about 3.2MPK, at least about 3.3MPK, at least about 3.4MPK, at least about 3.5MPK, at least about 3.6MPK, at least about 3.7MPK, at least about 3.8MPK, at least about 3.9MPK, at least about 4MPK, at least about 4.1MPK, at least about 4.2MPK, at least about 4.3MPK, at least about 4.4MPK, at least about 4.5MPK, at least about 4.6MPK, at least about 4.7MPK, at least about 4.8MPK, at least about 4.9MPK, at least about 5MPK, at least about 5.1MPK, at least about 5.2MPK, at least about 5.3MPK, at least about 5.4MPK, at least about 5.5MPK, at least about 5.6MPK, at least about 5.7MPK, at least about 5.8MPK, at least about 5.9MPK, or at least about 6MPK. In some embodiments, the effective dose of the 15-PGDH inhibitorcomprises less than about 0.1MPK, less than about 0.2MPK, less than about 0.3MPK, less than about 0.4MPK, less than about 0.5MPK, less than about 0.6MPK, less than about 0.7MPK, less than about 0.8MPK, less than about 0.9MPK, less than about 1MPK, less than about 1.1MPK, less than about 1.2MPK, less than about 1.3MPK, less than about 1.4MPK, less than about 1.5MPK, less than about 1.6MPK, less than about 1.7MPK, less than about 1.8MPK, less than about 1.9MPK, less than about 2MPK, less than about 2.1MPK, less than about 2.2MPK, less than about 2.3MPK, less than about 2.4MPK, less than about 2.5MPK, less than about 2.6MPK, less than about 2.7MPK, less than about 2.8MPK, less than about 2.9MPK, less than about 3MPK, less than about 3.1MPK, less than about 3.2MPK, less than about 3.3MPK, less than about 3.4MPK, less than about 3.5MPK, less than about 3.6MPK, less than about 3.7MPK, less than about 3.8MPK, less than about 3.9MPK, less than about 4MPK, less than about 4.1MPK, less than about 4.2MPK, less than about 4.3MPK, less than about 4.4MPK, less than about 4.5MPK, less than about 4.6MPK, less than about 4.7MPK, less than about 4.8MPK, less than about 4.9MPK, less than about 5MPK, less than about 5.1MPK, less than about 5.2MPK, less than about 5.3MPK, less than about 5.4MPK, less than about 5.5MPK, less than about 5.6MPK, less than about 5.7MPK, less than about 5.8MPK, less than about 5.9MPK, or less than about 6MPK. In some embodiments, the effective dose of the 15-PGDH inhibitor comprises between 0.5MPK to 5MPK, 0.6MPK to 5MPK, 0.7MPK to 5MPK, 0.8MPK to 5MPK, 0.9MPK to 5MPK, 1MPK to 5MPK, 1.1MPK to 5MPK, 1.2MPK to 5MPK, 1.3MPK to 5MPK, 1.4MPK to 5MPK, 1.5MPK to 5MPK, 1.6MPK to 5MPK, 1.7MPK to 5MPK, 1.8MPK to 5MPK, 1.9MPK to 5MPK, 2MPK to 5MPK, 2.1MPK to 5MPK, 2.2MPK to 5MPK, 2.3MPK to 5MPK, 2.4MPK to 5MPK, 2.5MPK to 5MPK, 2.6MPK to 5MPK, 2.7MPK to 5MPK, 2.8MPK to 5MPK, 2.9MPK to 5MPK, 3MPK to 5MPK, 3.1MPK to 5MPK, 3.2MPK to 5MPK, 3.3MPK to 5MPK, 3.4MPK to 5MPK, 3.5MPK to 5MPK, 3.6MPK to 5MPK, 3.7MPK to 5MPK, 3.8MPK to 5MPK, 3.9MPK to 5MPK, 4MPK to 5MPK, 4.1MPK to 5MPK, 4.2MPK to 5MPK, 4.3MPK to 5MPK, 4.4MPK to 5MPK, 4.5MPK to 5MPK, 4.6MPK to 5MPK, 4.7MPK to 5MPK, 4.8MPK to 5MPK, or 4.9MPK to 5MPK.

[0116] In some embodiments, the amounts effective to treat SMA comprises an effective dose of the agent that increases expression of SMN protein (SMN modulator). In some embodiments, the SMN modulator comprises a small molecule. In some embodiments, the SMN modulator comprises risdiplam, SMN-C2, SMN-C3, SMN-C5, RG-7916, RG7800, SMN-C1, SMN-C8, Branaplam, nusinersen, or any combination thereof.

[0117] In some embodiments, the effective dose of the agent that increases expression of SMN protein (SMN modulator) comprises about 1 mg / kg (or about 1MPK), about 3 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, or about 100 mg / kg. In some embodiments, the effective dose of the SMN modulator comprises at least about 1 mg / kg (or at least about 1MPK), at least about 3 mg / kg, at least about 10 mg / kg, at least about 20 mg / kg, at least about 30 mg / kg, at least about 40 mg / kg, at least about 50 mg / kg, at least about 60 mg / kg, at least about 70 mg / kg, at least about 80 mg / kg, at least about 90 mg / kg, or at least about 100 mg / kg. In some embodiments, the effective dose of the SMN modulator comprises less than about 1 mg / kg (or 1MPK), less than about 3 mg / kg, less than about 10 mg / kg, less than about 20 mg / kg, less than about 30 mg / kg, less than about 40 mg / kg, less than about 50 mg / kg, less than about 60 mg / kg, less than about 70 mg / kg, less than about 80 mg / kg, less than about 90 mg / kg, or less than about 100 mg / kg.

[0118] In some embodiments, the method results in downregulation of one or more genes involved in a myelination pathway, relative to a method comprising administering the agent that increases SMN protein in the absence of the 15-PGDH inhibitor. In some embodiments, the method results in downregulation of one or more Schwann cell genes, relative to a method comprising administering the agent that increases SMN protein in the absence of the 15-PGDH inhibitor. In some embodiments, the method results in downregulation of one or more genes selected from the group consisting of: mpz, mbp, ugt8a, mal, pmp22, pllp, ngfr, kif1a, robo2, prx, cldn19, cited2, nfasc, ncmap, s100b, mag, hgf, and edn3, relative to a method comprising administering the agent that increases SMN protein in the absence of the 15-PGDH inhibitor.

[0119] In some embodiments, the method results in upregulation of one or more genes involved in a mitochondria pathway, relative to a method comprising administering the agent that increases SMN protein in the absence of the 15-PGDH inhibitor. In some embodiments, the method results in upregulation of one or more genes selected from the group consisting of: Slc25a33, lyrm7, and 1190007I07Rik, Ppargc1a relative to a method comprising administering the agent that increases SMN protein in the absence of the 15-PGDH inhibitor.

[0120] In some embodiments, the subject in need thereof is a human. In some embodiments, wherein the subject in need thereof is 75 years old or less. In some embodiments, wherein the subject in need thereof is 80 years old or less, 75 years old or less, 70 years old or less, 65 years old or less, 60 years old or less, 55 years old or less, 50 years old or less, 45 years old or less, 40 years old or less, 35 years old or less, 30 years old or less, 25 years old or less, 20years old or less, 15 years old or less, 10 years old or less, or 5 years old or less. In some embodiments, wherein the subject in need thereof is 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 embodiments, wherein the subject in need thereof is between 1 year old to 75 years old, between 5 years old to 75 years old, between 10 years old to 75 years old, between 15 years old to 75 years old, between 20 years old to 75 years old, between 25 years old to 75 years old, between 30 years old to 75 years old, between 35 years old to 75 years old, between 40 years old to 75 years old, between 45 years old to 75 years old, between 50 years old to 75 years old, between 55 years old to 75 years old, between 60 years old to 75 years old, between 65 years old to 75 years old, or between or 70 years old to 75 years old.

[0121] In some embodiments, the subject in need thereof has elevated 15-PGDH levels prior to the administering, relative to a control subject that does not have SMA.

[0122] In some embodiments, the 15-PGDH inhibitor is a small molecule. In some embodiments, the 15-PGDH inhibitor is an orally bioavailable small molecule.

[0123] In some embodiments, the 15-PGDH inhibitor is a compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof, wherein: X is selected from –OCH2–, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, – SCH2–, –S(O)CH2–, –SO2CH2–; each Y is independently selected from N and CR11; each R1is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; each R5is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; each R11is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;.

[0124] 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–.

[0125] In some embodiments, each Y is independently selected from N and CR11. In some embodiments, each Y is N. In some embodiments, each Y is CR11. In some embodiments, one Y is N and the other Y is CR11.

[0126] In some embodiments, each R1is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R1is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and – NR10SO2NR6R7. In some embodiments, each R1is independently selected from halo, – NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7,–NR10C(O)R8, –NR10C(O)NR6R7, – NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R1is independently selected from halo, –NR6R7, –OR8, –C(O)R8, and –C(O)OR8.

[0127] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo. In some embodiments, R2and R3are taken together to form thio.

[0128] In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7,– NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, and –C(O)OR8.

[0129] In some embodiments, each R5is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R5is independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R5is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7,– NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments,each R5 is independently selected from halo, –NR6R7, –OR8, –C(O)R8, and –C(O)OR8.

[0130] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, and C1-6alkyl.

[0131] In some embodiments, each R8is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H, and C1-6alkyl.

[0132] In some embodiments, each R9is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0133] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0134] In some embodiments, each R11is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R11is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7,– NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R11is independently selected from halo, –NR6R7, –OR8, –C(O)R8, and –C(O)OR8.

[0135] In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0136] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0137] In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10.

[0138] In some embodiments, the compound is a compound of Formula Ia:Formula Ia or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the compound is a compound of Formula Ib:Formula Ib or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the 15-PGDH inhibitor is a compound of Formula II:Formula II or a pharmaceutically acceptable salt thereof, wherein: T, U, W, X, and Y are independently selected from N and CR5; S, V, and Z are independently selected from N and C; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independentlyselected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, – SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R5is independently selected from H, halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;.

[0141] In some embodiments, T, U, W, X, and Y are independently selected from N and CR5. In some embodiments, at least one of T, U, W, X, and Y is N and the rest are CR5. In some embodiments, at least two of T, U, W, X, and Y are N and the rest are CR5. In some embodiments, at least three of T, U, W, X, and Y are N and the rest are CR5. In some embodiments, at least four of T, U, W, X, and Y are N and the rest are CR5. In some embodiments, T, U, W, X, and Y are CR5. In some embodiments, T, U, W, X, and Y are N.

[0142] In some embodiments, S, V, and Z are independently selected from N and C. In some embodiments, at least one of S, V, and Z is N and the rest are C. In some embodiments, at least two of S, V, and Z are N and the rest are C. In some embodiments, S, V, and Z are N. In some embodiments, S, V, and Z are C.

[0143] In some embodiments, R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and – C(O)NR6R7.

[0144] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo. In some embodiments, R2and R3are taken together to form thio.

[0145] In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, each R4is independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7. In some embodiments, each R4is halo. In some embodiments, each R4is fluoro.

[0146] In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-memberedheterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, twoR4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, – NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, – C(O)OR8, and –C(O)NR6R7. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo. In some embodiments, twoR4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are fluoro.

[0147] In some embodiments, each R5is independently selected from H, halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R5is independently selected from H, halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, each R5is independently selected from H, halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, each R5is independently selected from H, halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7. In some embodiments, each R5is independently selected from H and halo.

[0148] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0149] In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H and C1-6alkyl.

[0150] In some embodiments, each R9is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0151] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selectedfrom H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0152] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0153] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0154] In some embodiments, the compound is a compound of Formula IIa:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0155] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0156] In some embodiments, the compound is a compound of Formula IIb:Formula IIb or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0157] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0158] In some embodiments, the compound is a compound of Formula IIc:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0159] In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0160] In some embodiments, compound is a compound of Formula IId:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0161] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0162] In some embodiments, the compound is a compound of Formula IIe:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0163] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0164] In some embodiments, the compound is a compound of Formula IIf:Formula IIf or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0165] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0166] In some embodiments, the compound is a compound of Formula IIg:Formula IIg or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

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

[0168] In some embodiments, the compound is a compound of Formula IIh:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0169] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0170] In some embodiments, the compound is a compound of Formula IIi:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0171] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0172] In some embodiments, the compound is a compound of Formula IIj:Formula IIj or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

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

[0174] In some embodiments, the compound is a compound of Formula IIn:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0175] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0176] In some embodiments, the compound is a compound of Formula IIp:Formula IIp or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0177] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0178] In some embodiments, the 15-PGDH inhibitor is a compound of Formula III:Formula III or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR7; Y is selected from O, S, SO2, and C(R8)2; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3- 10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3- 10cycloalkyl, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R8is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R8’s can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl;each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

[0179] In some embodiments, each X is independently selected from N and CR7. In some embodiments, at least one X is N and the rest are CR7. In some embodiments, at least two X are N and the rest are CR7. In some embodiments, each X is N. In some embodiments, each X is CR7.

[0180] In some embodiments, Y is selected from O, S, SO2, and C(R8)2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R8)2.

[0181] In some embodiments, R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl,C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl.In some embodiments, R1is selected from C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11,–NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and – C(O)NR9R10.

[0182] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo. In some embodiments, R2and R3are taken together to form thio.

[0183] In some embodiments, R4and R5are independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independentlyoptionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, R4and R5are independently selected from C3- 10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, R4and R5are independently selected from C3- 10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and – C(O)NR9R10.

[0184] In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10- membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyloptionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0185] In some embodiments, each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R6is independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, each R6is independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and – C(O)NR9R10.

[0186] In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6’s are independently selected from halo, – NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6’s are independently selected from halo, – NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0187] In some embodiments, each R7is independently selected from H, halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11,–NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, each R7is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R7is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R7is independently selected from H, halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0188] In some embodiments, each R8is independently selected from H, halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, each R8is independently selected from H, halo,–NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R8is independently selected from H, halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0189] In some embodiments, two R8’s can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, two R8’s can be taken together to form a C3- 10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R8’s can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. Insome embodiments, two R8’s can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0190] In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H and C1-6alkyl.

[0191] In some embodiments, each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R11is independently selected from H and C1- 6alkyl.

[0192] In some embodiments, each R12is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R12is independently selected from C1-6alkyl.

[0193] In some embodiments, each R13is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R13is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R13is independently selected from H and C1-6alkyl.

[0194] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0195] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0196] In some embodiments, the compound is a compound of Formula IIIa:Formula IIIa or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the compound is a compound of Formula IIIb:Formula IIIb or a pharmaceutically acceptable salt thereof, wherein: each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0198] In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10. In some embodiments, each R14is independently halo. In some embodiments, each R14is independently fluoro.

[0199] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0200] In some embodiments, the compound is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the compound is a compound of Formula IIId:or a pharmaceutically acceptable salt thereof, wherein: each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0202] In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10. In some embodiments, each R14is independently halo. In some embodiments, each R14is independently fluoro.

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

[0204] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIk:Formula IIk or a pharmaceutically acceptable salt thereof, wherein: T, U, and Y are independently selected from N and CR6, provided that when U is N, at least one of T and Y is N; R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from H and halo; R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, – SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, –NR11SO2NR7R8, C1- 6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6is selected from H, halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, – SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, –NR11SO2NR7R8, C1- 6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R11 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; andp is 0, 1, or 2.

[0205] In some embodiments, T, U, and Y are independently selected from N and CR6, provided that when U is N, at least one of T and Y is N. In some embodiments, one of T, U, and Y is N and the rest are CR6. In some embodiments, two of T, U, and Y are N and the rest are CR6. In some embodiments, one of T, U, and Y is CR6and the rest are N. In some embodiments, two of T, U, and Y are CR6and the rest are N. In some embodiments, T, U, and Y are N. In some embodiments, T, U, and Y are CR6.

[0206] In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, – SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, – NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3substituents independently selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, – C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR7R8, – OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, – NR11C(O)NR7R8, –NR11SO2R9, and –NR11SO2NR7R8. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR7R8, –OR9, – C(O)R9, –C(O)OR9, and –C(O)NR7R8.

[0207] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo.

[0208] In some embodiments, each R4is independently selected from H and halo. In some embodiments, each R4is independently selected from H and fluoro. In some embodiments, each R4is H. In some embodiments, each R4is fluoro. In some embodiments, one R4is H and one R4is fluoro.

[0209] In some embodiments, R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, – NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In someembodiments, R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, – SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, – NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, – SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, and –NR11SO2NR7R8. In some embodiments, R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, and – C(O)NR7R8.

[0210] In some embodiments, R6is selected from H, halo, –NR7R8, –OR9, –C(O)R9, – C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, – NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R6is selected from H, halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, – C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6isselected from H, halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, and –NR11SO2NR7R8. In some embodiments, R6is selected from H, halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, and – C(O)NR7R8.

[0211] In some embodiments, R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl. In some embodiments, R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, R7and R8are independently selected at each occurrence from H and C1-6alkyl.

[0212] In some embodiments, each R9is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R9is independently selected from H and C1-6alkyl.

[0213] In some embodiments, each R10is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from C1-6alkyl.

[0214] In some embodiments, each R11is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-6cycloalkyl. In some embodiments, each R11is independently selectedfrom H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R11 is independentlyselected from H and C1-6alkyl.

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

[0216] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIm:Formula IIm or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, – SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl;each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

[0217] In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, and –C(O)NR6R7.

[0218] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo.

[0219] In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and – NR10SO2NR6R7. In some embodiments, each R4is independently selected from halo, – NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7. In some embodiments, each R4is independently selected from halo. In some embodiments, each R4is fluoro.

[0220] In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, – C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, – NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In someembodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and – NR10SO2NR6R7. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7.

[0221] In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10- membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, – SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and – C(O)NR6R7.

[0222] In some embodiments, R6 and R7 are independently selected at each occurrence fromH, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0223] In some embodiments, each R8is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H and C1-6alkyl.

[0224] In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0225] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selectedfrom H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0226] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0227] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0228] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0229] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIq:Formula IIq or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, – NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6- 10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

[0230] In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, – OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, and –C(O)NR6R7.

[0231] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo.

[0232] In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, – C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and – NR10SO2NR6R7. In some embodiments, each R4is independently selected from halo, – NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7. In some embodiments, each R4is independently selected from halo. In some embodiments, each R4is fluoro.

[0233] In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to10-membered heteroaryl. In some embodiments, two R4’s are taken together with the carbonatoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, – C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, – NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and – NR10SO2NR6R7. In some embodiments, two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and –C(O)NR6R7.

[0234] In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8,–NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10- membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, – SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, and –NR10SO2NR6R7. In some embodiments, R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, and – C(O)NR6R7.

[0235] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0236] In some embodiments, each R8is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8is independently selected from H and C1-6alkyl.

[0237] In some embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. Insome embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0238] In some embodiments, each R10is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10is independently selected from H and C1-6alkyl.

[0239] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0240] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0241] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0242] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR7; Y is selected from O, S, SO2, and C(R8)2; R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3- 6cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0243] In some embodiments, each X is independently selected from N and CR7. In someembodiments, at least one X is N and the rest are CR7. In some embodiments, at least two X are N and the rest are CR7. In some embodiments, each X is N. In some embodiments, each X is CR7.

[0244] In some embodiments, Y is selected from O, S, SO2, and C(R8)2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R8)2.

[0245] In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R1is selected from C6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0246] In some embodiments, R2is H and R3is –CF3. In some embodiments, R2and R3are taken together to form oxo.

[0247] In some embodiments, R4and R5are independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independentlyoptionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, R4and R5are independently selected from C3- 10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, – C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, R4and R5are independently selected from C3- 10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and – C(O)NR9R10.

[0248] In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10- membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyloptionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0249] In some embodiments, each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R6is independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1- 6haloalkyl. In some embodiments, each R6is independently selected from halo, –NR9R10, – OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and – C(O)NR9R10.

[0250] In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and –NR13SO2NR9R10. In some embodiments, two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0251] In some embodiments, each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, – SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, and – NR13SO2NR9R10. In some embodiments, each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, and –C(O)NR9R10.

[0252] In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R9and R10are independently selected at each occurrence from H and C1-6alkyl.

[0253] In some embodiments, each R11is independently selected from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R11is independently selected from H and C1- 6alkyl.

[0254] In some embodiments, each R12is independently selected from C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R12is independently selected from C1-6alkyl.

[0255] In some embodiments, each R13is independently selected from H, C1-6alkyl, C1- 6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R13is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R13is independently selected from H and C1-6alkyl.

[0256] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0257] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of: ;; ; ;;;;

[0259] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0260] In some cases, the solubility and hPGDH IC50 of the inhibitors are characterized as shown in Tables 1 and 2. Table 1: Characteristics of PGDH Inhibitors with a 6-5 ring core.Table 2: Characteristics of PGDH Inhibitors with a phenyl core.

[0261] Provided in Table 3 are analytical data for some of the inhibitors described herein. Table 3: Analytical data for select inhibitors

[0262] In some embodiments, the 15-PGDH inhibitor is a compound of having the structure of Formula IV, or a pharmaceutically acceptable salt thereof:Formula IV, wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2or N;R1is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R2is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3- C8 cycloalkyl; each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, – C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6 is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-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 R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; XAis -NR5R5or -OR5; wherein each R5is independently H or C1-C6alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl;each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

[0263] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula IV, or a pharmaceutically acceptable salt thereof:wherein,ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2of N; R1is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; R2is H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl; substituted or unsubstituted C3-C8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently H, halogen, CN,-NO2, –NR8R9, -OH, –OR10, -SR8, – C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, phenyl, or 5- to 8- membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a C3- C6 cycloalkyl ring; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a C3- C6 cycloalkyl ring; each R8and R9is independently selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, and C4-C10 heterocycloalkyl; each R10is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C3-C8 cycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl;each R11is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; and p is 1, 2, 3, or 4.

[0264] In some embodiments, In some embodiments, ring Q is 5- to 10-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is 5- to 8-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is 5- to 8-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is a monocyclic, bicyclic, or polycyclic heteroaryl. In some embodiments, ring Q is a bicyclic heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is indole, benzimidazole, benzotriazole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyridine, or tetrazolo pyridine. In some embodiments, ring Q is [1,2,4]triazolo[1,5-a]pyridine.

[0265] In some embodiments, ring Q is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 N atoms. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is a phenyl, pyrimidine, or pyridine In some embodiments, ring Q is phenyl. In some embodiments, ring Q is pyrimidine In some embodiments, ring Q is pyridine.

[0266] In some embodiments, ring Q is phenyl, pyridine, or triazolopyridine.

[0267] In some embodiments,, wherein, X1, X2, X3and X4are each independently N or CR3; each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, -SR8, – C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9;each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0268] In some embodiments, X1, X2, X3and X4are each CR3.

[0269] In some embodiments, X1is N; and X2, X3, and X4are each CR3.

[0270] In some embodiments, X1and X2are each N; and X3and X4are each CR3.

[0271] In some embodiments, X1and X3are each N; and X2and X4are each CR3.

[0272] In some embodiments, X1and X4are each N; and X2and X3are each CR3.

[0273] In some embodiments, X1, X2, and X3are each N; and X4is CR3.

[0274] In some embodiments, X1, X2, and X4are each N; and X3is CR3.

[0275] In some embodiments, each R3is independently selected from H, halogen, -CN, - NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, – SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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. In some embodiments, each R3is independently selected from H, halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each R3is independently selected from H, halogen, –C(O)R10, –C(O)OR10, – C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, each R3is independently selected from H, halogen, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.

[0276] In some embodiments, each R3is independently selected from H or halogen. In some embodiments, each R3is independently substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, each R3is independently a substituted or unsubstituted 5-membered heteroaryl.

[0277] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula V, or a pharmaceutically acceptable salt thereof:Formula V, wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R2is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3- C8 cycloalkyl;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, –NR8R9, – OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, – NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-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 R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3

[0278] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula V, or a pharmaceutically acceptable salt thereof:Formula V, wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1is H; each R2is independently H or C1-C6 alkyl;R3a, R3b, and R3care each independently selected from H, halogen, –OR10, –SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl, each of which is substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-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 R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl;XA is -OR5; whereineach R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted orunsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0279] In some embodiments, XAis NR5R5. In some embodiments, XAis OR5.

[0280] In some embodiments, Y is N. In some embodiments, Y is CR2.

[0281] In some embodiments, the compound of Formula V has the structure of Formula VIa, or a pharmaceutically acceptable salt thereof:Formula VIa.

[0282] In some embodiments, the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:Formula VIb.

[0283] In some embodiments, Z is N. In some embodiments, Z is CR1. In some embodiments, Z is CH.

[0284] In some embodiments, the compound of Formula V has the structure of Formula VIIa, or a pharmaceutically acceptable salt thereof:Formula VIIa.

[0285] In some embodiments, the compound of Formula V has the structure of Formula VIIb, or a pharmaceutically acceptable salt thereof:Formula (IVb).

[0286] In some embodiments, the compound of Formula V has the structure of Formula VIIc, or a pharmaceutically acceptable salt thereof:Formula VIIc.

[0287] In some embodiments, the compound of Formula V has the structure of Formula VIId, or a pharmaceutically acceptable salt thereof:Formula VIId.

[0288] In some embodiments, R1is H, halogen, –OR10, –C(O)R10, –C(O)OR10, or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R1is H.

[0289] In some embodiments, each R2is independently H, halogen, –OR10, –C(O)R10, – C(O)OR10, or substituted or unsubstituted C1-C6alkyl. In some embodiments, each R2is independently H or C1-C6 alkyl.

[0290] In some embodiments, each R2is H.

[0291] In some embodiments, X1is CR3a. In some embodiments, X1is N.

[0292] In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, -S8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, – SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, – NR12SO2NR8R9, substituted or unsubstituted C1-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. In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, – NR12C(O)OR10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10- membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, – NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6- membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, –C(O)R10, –C(O)NR8R9, and substituted or unsubstituted 5- membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, –OR10, -S8,–C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11,– NR12C(O)R10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R3a, R3b, and R3care eachindependently selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, –C(O)R10, –C(O)NR8R9, C3-C6 heterocycloalkyl, and 5- membered heteroaryl.

[0293] In some embodiments, R3a, R3b, and R3care each independently selected from H, halogen, –C(O)OH, –C(O)NH2, –C(O)NH(CH3), –C(O)N(CH3)2, triazole, tetrazole, pyrrolidine, morpholine, or C1-C6 alkyl substituted with -C(O)OH.

[0294] In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, – SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, – NR12SO2NR8R9, substituted or unsubstituted C1-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. In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, – NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3bare each H orhalogen; and R3c is selected from –NR12C(O)OR10, substituted or unsubstituted phenyl, andsubstituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from substituted or unsubstituted C1-C6 alkyl, – C(O)R10, –C(O)NR8R9, C3-C6 heterocycloalkyl, and 5- membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis a substituted or unsubstituted 5- membered heteroaryl.

[0295] In some embodiments, R3ais halogen and R3bis H. In some embodiments, R3ais -Cl or -F; and R3bis H. In some embodiments, R3bis halogen and R3ais H. In some embodiments, R3bis -Cl or -F; and R3ais H.

[0296] In some embodiments, R3aand R3bare each H.

[0297] In some embodiments, R3aand R3care independently H or halogen; and R3bis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, – SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, – NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted orunsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3care each H; and R3bis selected from halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3care each H; and R3bis selected from halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, – NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6- membered heteroaryl. In some embodiments, R3aand R3care each H; and R3bis selected from –C(O)R10, –C(O)OR10, –NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3care each H or halogen; and R3bis selected from substituted or unsubstituted C1-C6 alkyl, –C(O)R10, – C(O)NR8R9, C3-C6 heterocycloalkyl, and 5- membered heteroaryl.

[0298] In some embodiments, R3aand R3care each H or halogen; and R3bis selected from – C(O)R10, –C(O)OR10and substituted or unsubstituted 5-membered heteroaryl.

[0299] In some embodiments, R3ais halogen and R3cis H. In some embodiments, R3ais H and R3bis halogen. In some embodiments, R3ais -Cl or -F; and R3cis H. In some embodiments, R3cis -Cl or -F; and R3ais H.

[0300] In some embodiments, R3aand R3care each H.

[0301] In some embodiments, each R3, R3a, R3b, and R3c are each independently a 5-membered heteroaryl selected from pyrrole, triazole, tetrazole, oxazole, diazole, oxadiazole, thiadiazole, and furanyl. In some embodiments, each R3, R3a, R3b, and R3care each independently a 5-membered heteroaryl selected from pyrrole, triazole, and tetrazole. In some embodiments, each R3, R3a, R3b, and R3care each independently a 5-membered heteroaryl selected from triazole and tetrazole.

[0302] In some embodiments, each R3, R3a, R3b, or R3cis independently selected from the

[0303] In some embodiments, each R3, R3a, R3b, or R3cis independently selected from theIn some embodiments, each R3, R3a, R3b, or R3cis independently selected from the group consisting

[0304] In some embodiments, R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6. In some embodiment, R4is substituted or unsubstituted C1- C8 alkyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, or substituted or unsubstituted C1-C8 hydroxyalkyl. In some embodiments, R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 heteroalkyl, or substituted or unsubstituted C1-C8 hydroxyalkyl.

[0305] In some embodiment, R4is substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C1-C8 heteroalkyl. In some embodiment, R4is substituted or unsubstituted C1- C8 alkyl. In some embodiments, the alkyl is a straight chain or branched alkyl. In some embodiment, R4is substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments, the heteroalkyl is an alkyl chain wherein one or more of the carbon atoms is replaced with an O or N atom. In some embodiment, R4is substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), substituted or unsubstituted -CH2CH2-O-(C1-C4 haloalkyl), -CH2-O- (C1-C4 haloalkyl), -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2-O- (C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiment, R4is 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, R4is -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2- O-(C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-C6 cycloalkyl). In some embodiments, R4is -CH2-O-(C3-C6 cycloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R4is -CH2-O-(C3-C6 heterocycloalkyl).

[0306] In some embodiments, R4is substituted or unsubstituted C1-C8 alkyl, which is substituted with one or more halogen, -OR10, C1-C8 alkyl, or C3-C6 cycloalkyl.

[0307] In some embodiments, R4is substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6. In some embodiments, R4is C3-C8 cycloalkyl. In some embodiments, R4is monocyclic, polycyclic, spirocyclic, or bridged cycloalkyl. In some embodiments, R4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R4is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R4is cyclopropyl. In some embodiments, R4is cyclobutyl. In some embodiments, R4is cyclopentyl. In some embodiments, R4is cyclohexyl. In some embodiments, R4is.

[0308] In some embodiments, R4is substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6. In some embodiments, R4is monocyclic, polycyclic, spirocyclic, or bridged heterocycloalkyl. In some embodiments, R4is a 4- membered heterocycloalkyl. In some embodiments, R4is a 5-membered heterocycloalkyl. In some embodiments, R4is a 6-membered cycloalkyl. In some embodiments, R4is a 7- membered cycloalkyl. In some embodiments, R4is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine. In some embodiments, R4is tetrahydrofuran or tetrahydropyran.

[0309] In some embodiments, each R6is independently halogen, -CN,-NO2, –NR8R9, -OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, C1-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 R6is independently halogen, -NR8R9, - OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, -NR8C(O)R9, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C8 cycloalkyl. In some embodiments, each R6is independently halogen, -NR8R9, -OR10,–C(O)OR10, –C(O)NR8R9, C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, each R6is independently halogen, -NR8R9, -OR10, or C3-C8 cycloalkyl. In some embodiments, each R6is independently -NR8R9or -OR10. In some embodiments, each R6is independently C3-C8cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, spirocyclic or bridged cycloalkyl. In some embodiments, each R6is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R6is independently halogen. In some embodiments, each R6is independently H, Cl, F, or Br. In some embodiments, each R6is independently F. In some embodiments, each R6is independently F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH3CH3), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, piperidine, piperazine, oxetane,tetrahydrofuran, or tetrahydropyran. In some embodiments, each R6is independently F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R6is independently F, -OH, -CH3, or -CF3. In some embodiments, each R6is independently F. In some embodiments, each R6is independently -OH. In some embodiments, each R6is independently -CF3. In some embodiments, each R6is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R6is independently cyclopropyl. In some embodiments, each R6is cyclobutyl.

[0310] In some embodiments, two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl or cyclobutyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclobutyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a C3-C6heterocycloalkyl. In some embodiments, two R6 combine together with the atom(s) to whichthey are attached to form a 4 membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a 5 membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a 6-membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a pyran, piperazine, piperidine, or morpholine.

[0311] In some embodiments, R4is -CH3, -CH2CH3, -CH2CH3CH3, -CH2(CH2)2CH3, - CH2(CH2)3CH3, -CH2(CH2)4CH3, -CH2CH2CH(CH3)2, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substitute or unsubstituted oxetane, substituted or ,,.

[0312] In some embodiments, each R5is independently C1-C6 alkyl. In some embodiments, each R5is independently -CH2CH3 or -CH3. In some embodiments, each R5is independently -CH2CH3. In some embodiments, each R5is independently -CH3. In some embodiments, each R5is independently H.

[0313] In some embodiments, R5ais CH3. In some embodiments, R5ais H.

[0314] In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclopentyl or cyclohexyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclopentyl.

[0315] In some embodiments, each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra. In some embodiments, each R8and R9is independently selected at each occurrence from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C10 cycloalkyl. In some embodiments, each R8and R9is independently selected at each occurrence from H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R8and R9is independently selected at each occurrence from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0316] In some embodiments, each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra. In some embodiments, each R10is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R10is independently selected from H, C1-C6 alkyl, C3- C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R10is independently selected from H and C1-C6 alkyl. In some embodiments, each R10is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0317] In some embodiments, each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted orunsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted orunsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra. In some embodiments, each R11is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl. In some embodiments, each R11is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0318] In some embodiments, each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra. In some embodiments, each R12is independently selected from H, straight or branched chain C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, and C3-C10 heterocycloalkyl.In some embodiments, each R12is independently selected from H, straight or branched chain C1-C6 alkyl. In some embodiments, each R12is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0319] In some embodiments, each Rais independently selected from halogen, -OH, -CH3, - CF3, -OCH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3. In some embodiments, each Rais independently selected from -F, -Cl, -Br, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, each Rais independently selected from -F, -OH, -CH3, -CF3, or - C(O)OH.

[0320] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. I some embodiments, p is 3. In some embodiments, p is 5. In some embodiments, p is 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.

[0321] In some embodiments, the PDGH inhibitor is a compound described in Table 4, or a pharmaceutically acceptable salt thereof.

[0322] In another aspect, the present disclosure provides a composition comprising: (i) a 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent that increases expression of SMN protein. In some embodiments, the composition comprises the 15-PGDH inhibitor and the agent that increases expression of SMN protein in amounts effective to treat spinal muscular atrophy (SMA).

[0323] In one aspect, the present disclosure provides a pharmaceutical formulation comprising the composition described herein, and one or more pharmaceutically effective excipients, carriers, and / or diluents.

[0324] In another aspect, the present disclosure provides a unit dose comprising the pharmaceutical formulation described herein.

[0325] In one aspect, the present disclosure provides a kit comprising: (i) a 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent that increases expression of SMN protein. In some embodiments, the 15-PGDH inhibitor and the agent that increases expression of SMN protein (SMN modulator) are in separate containers. In some embodiments, the 15-PGDH inhibitor and the SMN modulator are mixed together prior to the administration. In some embodiments, the 15-PGDH inhibitor and the SMN modulator are mixed separately prior to the 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.

[0326] In some embodiments, the 15-PGDH inhibitor and the agent that increases expression of SMN protein are in the same container. In some embodiments, the kit further comprises instructions for administering the 15-PGDH inhibitor and the agent that increases expression of SMN protein to a subject in need thereof. In some embodiments, the subject in need thereof has spinal muscular atrophy (SMA).

[0327] Any methods, compositions, pharmaceutical formulations, unit doses, or kits, can comprise any of the 15-PGDH inhibitors as described herein.

[0328] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0329] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0330] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.EXAMPLES

[0331] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. Example 1: Effects of 15-PGDH inhibitor administration on PGE2 signaling pathway

[0332] Administration of 15-PGDH inhibitor blocks binding of 15-PGDH to PGE2, which within skeletal muscle results in increased stem cell proliferation, increased muscle force, and improved mitochondrial function. An overview of the PGE2 signaling pathway and the effects of 15-PGDH inhibitor on the PGE2 signaling pathway is shown in FIG.1. Example 2: Mechanism of action and pharmacokinetic profile of 15-PGDH inhibitor, MF-300.

[0333] The mechanism of action and pharmacokinetic profile of 15-PGDH inhibitor, MF- 300, was assessed using biochemical assays and cell-based assays utilizing A549 cells. The effect of administration of various doses of MF-300 on NADH production in a 15-PGDH inhibition biochemical assay is shown in FIG.2A. The effect of administration of various doses of MF-300 on PGE2 stability in A549 cells in a cell-based assay is shown in FIG.2B. Example 3: Effects of intraperitoneal MF-300 administration in SMNΔ7 mice.

[0334] SMN Δ7 Mouse Model is used as model for spinal muscle atrophy (SMA) and these mice show severe phenotype which is modulated by therapeutic administration of the SMN splice enhancer, SMN-C3. The effect of intraperitoneal injections of MF-300, which is a 15- PGDH inhibitor, at various doses within cohorts of male and female SMNΔ7 mice was assessed.

[0335] Briefly, beginning the day after birth, WT mice received no injections. For SMN Δ7 mice, beginning the day after birth, SMN Δ7 mice received daily intraperitoneal injections of the SMN splice enhancer SMN-C3 (3 mg / kg) for 21 days, and then received an additional 28 days of daily intraperitoneal injections of either SMN-C3 (3 mg / kg) alone or SMN-C3 (3mg / kg) in combination with MF-300 (3 mg / kg, 10 mg / kg, or 30 mg / kg; N = 10-13 per group). At day 49, mice were then tested for isometric plantar flexor force, after which gastrocnemius muscles were harvested (N = 6 per group) for RNA-seq. RNA-seq was performed using Poly A selection with paired end reads and a read depth of approximately 30 x 106per sample.

[0336] FIG.3A shows an overview of the experimental timeline for assessing the effects of SMN-C3 and varying doses of MF-300 on isometric plantar flexor force in SMNΔ7 mice.FIG.3B shows the effects of repeated treatment with either SMN-C3 only (vehicle), no injections (WT), or SMN-C3 with varying doses of MF-300 (3 mg / kg [3MPK], 10 mg / kg [10MPK], or 30 mg / kg [30MPK]) on isometric plantar flexor force. FIG.3C shows the effects of repeated treatment with either SMN-C3 only (vehicle), no injections (WT), or SMN-C3 with varying doses of MF-300 (3 mg / kg, 10 mg / kg, or 30 mg / kg) on isometric plantar flexor maximum force. FIG.3D shows the effects of repeated treatment with SMN-C3 and varying doses of MF-300 (3 mg / kg [3MPK], 10 mg / kg [10MPK], or 30 mg / kg [30MPK]) on maximum force shown as a percentage relative to the average maximum force of the vehicle-treated cohorts.

[0337] 15-PGDH is encoded by Hpgd gene. FIG.3E shows the levels of HPGD expression. FIG.3E on the left shows the expression level of HPGD in tibialis anterior muscle (TA muscle) obtained from WT mice and SMNΔ7 mice. This data was reanalyzed from public data from McCormack, N.M. et al.2021, Journal of Cachexia, Sarcopenia, and Muscle. FIG. 3E on the right shows the expression level of HPGD in gastrocnemius muscles (represented as transcripts per million or TPM) between wildtype mice and SMNΔ7 mice treated with SMN-C3 only. This result shows that Hpgd expression is upregulated in the presence of SMN modulation by SMN-C3.

[0338] Overall, these results show that 15-PGDH inhibitor, MF-300, significantly increased force in SMN Δ7 Mice. As shown in FIG.3E, results also show that expression of Hpgd gene is increased in SMN Δ7 Mice with and without SMN-C3 treatment. Example 4: RNA-seq analysis from WT, SMA mice, and SMA MF mice.

[0339] Further RNA-seq analysis from mice in the Example 3 was performed to investigate i. profile changes driven by the SMA genetic model, ii. identify changes in the SMA model which are normalized by MF-300 treatment, and iii. generate a gene signature of MF-300 treatment. RNA-seq analysis was performed on skeletal muscle (gastrocnemius muscles) from i. wild-type (WT) mice (N=6; 3 male and 3 female), ii. mice harboring a targeted mutation to model SMA (SMNΔ7 mice) treated with SMN-C3 only (and receiving vehicle control for MF-300) (SMA mice) (N=6; 3 male and 3 female), and iii. mice harboring a targeted mutation (SMNΔ7 mice) to model SMA treated with SMN-C3 and MF-300 at 30 mg / kg [30MPK] (SMA MF mice) (N=5).

[0340] Methods

[0341] Alignment and annotation

[0342] Reads were aligned to the Mus musculus GRCm39 genome build 109 using the Subread software package (v2.12.3). Annotation to genomic features was performed using the featureCounts function from the Subread software package. The Mus musculus GRCm39 build 109 GTF file was used as a reference for annotation. Genomic fasta and GTF references were obtained from the ENSEMBL genome browser ftp.

[0343] Differential expression analysis

[0344] Differential expression analysis was performed using the edgeR (v3.40.2) and limma (v.3.54.2) in R (v4.2.2). ENSEMBL gene IDs were mapped to gene symbols and Entrez IDs using the mapIds function from the AnnotationDbi package (v.1.60.0). Read counts were normalized to counts per million reads and genes that did not have at least one count per million in at least two samples were filtered, leaving 15,774 genes in the final analysis. Normalization was performed using the trimmed mean of M-values method as implemented in the calcNormFactors from edgeR. Data were modeled and differential expression was determined using the limma voom pipeline to generate linear models with empirical Bayes moderation. Differential expression was determined using a Benjamini-Hochberg adjusted p value less than 0.05. Once differentially expressed genes were determined, gene set enrichment analysis was performed using the enrichKEGG function from the clusterProfiler package.

[0345] Pathway enrichment was determined using gene set enrichment analysis and gene set over-representation tests implemented using the clusterProfiler R package (v4.6.2). Enrichment was determined against three publicly available gene ontologies; GO cellular components, GO biological processes and GO molecular functions. Significance was determined as pathways with Benjamini-Hochberg adjusted enrichment p value < 0.05.

[0346] Results

[0347] Quality Control

[0348] In all samples >95% of reads mapped to the reference genome and >85% of mapped reads were successfully annotated. Read counts across samples showed good consistency with only one sample showing slightly higher raw read counts (FIG.4A) and all samples showing consistent distribution of reads across genes (FIG.4B).

[0349] Multidimensional Scaling

[0350] Following normalization, multidimensional scaling was performed to look for global trends in transcriptome profiles. MDS1 explained ~27% of variance and robustly discriminated between WT and SMA, which is shown in FIG.5A. Treatment with MF-300 pushed the SMA profile in the positive direction along MDS1, bringing the profile closer toWT (FIG.5A). This trend is quantified in FIG.5B although it does not reach statistical significance (p = 0.25).

[0351] Differential Expression

[0352] Differential expression tests showed a robust signature of the SMA model. However, fewer changes could be attributed to MF300 treatment. The overall number of differentially expressed genes thresholded by nominal p-value and by Bejamini-Hochberg false detection rate (FDR)-corrected q-value are presented in Table 1 and Table 2.

[0353] Table 1: Differently expressed genes by nominal p-value

[0354] Table 2: Differently expresses genes by FDR-corrected q-value

[0355] No changes survived FDR correction is not necessarily surprising given that 1) muscle tends to be slightly more variable than more homogenous or RNA-rich tissue like liver and 2) disease models may show variable presentation / penetrance. Despite the lack of FDR-corrected significance, the global trend for MF-300 treatment to move the transcriptional profile closer to WT is observed.

[0356] Gene-Level Comparison of MF-300 Effects

[0357] To further investigate the changes induced by SMA that were opposed by MF-300 treatment, significantly differentially expressed genes across the two comparisons (vehicle SMA vs WT and MF-300 SMA vs vehicle SMA) were overlaid. Among the 2300 genes significantly increased by the SMA model, 151 were significantly decreased by MF-300 treatment. Among the 2245 genes significantly decreased by the SMA model, 26 were significantly increased by MF300 treatment as shown in FIG.6, which shows Venn diagram comparing nominally significant differentially expressed genes in SMA+veh vs WT and SMA+MF-300 vs SMA+veh. Among the nominally significant MF-300-induced changes, 56% directly opposed changes induced by the SMA genetic model.

[0358] Expression Signatures of MF-300

[0359] To identify gene expression signatures of MF-300 treatment in the SMA mouse model, Gene Set Enrichment Analysis (GSEA) was performed comparing MF-300-treated to vehicle-treated SMA mice. Due to the limited number of nominally significant differentially express genes in the vehicle SMA vs MF-300 SMA comparison, relatively fewer significant GSEA hits were observed compared to WT vs vehicle SMA.

[0360] FIG.7 shows gene set enrichment analysis results for GO biological processes (BP) ontology comparing SMA+veh vs SMA+MF-300. Plot is thresholded to show minimum and maximum normalized enrichment scores (NES). Positive NES score indicates enrichment in SMA+MF-300 vs SMA+veh. This data shows that many gene sets involved in myelination (e.g., ensheathment of neurons, axon ensheathment, myelination, myelin assembly, and positive regulation of myelination) are upregulated in SMN-C3 treated group and are corrected by combination treatment with MF-300.

[0361] In the BP ontology, multiple pathways related mitochondrial structure and function were increased by MF-300 treatment, including ‘mitochondrial gene expression’ and ‘mitochondrial respiratory chain complex assembly’. Multiple pathways related to myelination and axon ensheathment were significantly downregulated.

[0362] Furthermore, FIG.8 shows changes in expression of genes involved with myelination when comparing SMA group with MF-300. FIG.9 shows changes in expression of genes involved with mitochondrial respiratory chain complex assembly when comparing SMA group with MF-300.

[0363] FIG.10 shows top promoter signatures that were significantly enriched or depleted in the subset of genes that were significantly decreased by the SMA model and significantly increased by MF-300 treatment, suggesting that MF-300 treatment increased CREB1 target gene expression and reduced NFKB2.

[0364] Overall, these results show genetic profile of SMNΔ7 mice with combination of SMN-C3 and MF-300 treatment shifting toward WT when compared to SMNΔ7 mice that received SMN-C3 treatment alone. Based on GSEA, myelination and mitochondria pathways are shown to play roles in the combination treatment of SMN-C3 and MF-300. Example 5: RNA-Seq analysis on genes involving myelination

[0365] According to results in FIG.7, gene set enrichment analysis of myelination, which was upregulated in SMNΔ7 mice treated with vehicle control which received only SMN-C3 only (SMA mice) but were downregulated in SMNΔ7 mice with combination of SMN-C3 and MF-300 treatment (SMA+MF-300), was further investigated. These genes are shown inFIG.8. Genes that are most upregulated or downregulated upon MF-300 treatments such as Ugt8a, Mal, Ngfr, Pllp, Mpz, Mbp, and Pmp22 were further investigated from the RNA-Seq data, quantified as counts per million (CPM). Results are shown in FIGS.11A-18C.

[0366] FIGS.11A-11C show expression levels of Mbp, Mpz, and Ncmap. These genes are myelinating Schwann cell markers.

[0367] Schwann cells serve as the support cells in the peripheral nerve system and form myelin sheath on the axon of neurons. Upon sciatic nerve crush, changes in Schwann cell gene expression obtained from RNA-Seq has been reported (Lutz et al., 2022). FIGS.12A- 12E show expression levels of Prx, Cited2, Mal, Cldn19, and Edn3. These genes are shown to be upregulated following injury in rat sciatic crush injury model obtained from Schwann cells and also upregulated in SMA group.

[0368] FIGS.13A-13C show expression levels of Ngfr, Ncam1, and L1cam. These genes are immature / non-myelinating Schwann cell markers.

[0369] FIGS.14A-14B show expression level of S100b and Mag. These genes are Schwann cell markers.

[0370] FIGS.15A-15C show expression level of Pmp22, Ugt8a, and Pllp. These genes are involved in myelination.

[0371] FIG.16 shows expression of Nfasc. This gene is involved in organization of the axon and nodes of Ranvier on axons during development.

[0372] FIGS.17A-17B show expression of axonal genes such as Kif1a and Robo2.

[0373] FIGS.18A-18C show expression of Schwann cell associated genes such as Pou3f1, Cdkn1c, and Sox 10.

[0374] Function of some of these genes and p-value from RNA-seq analysis are shown in Table 3.

[0375] Overall, these results show that the expression levels of many genes involved in Schwann cell biology were upregulated in SMA group, but combination treatment with MF- 300 decreased these expressions back to the expression level observed in WT. Potential gene signature of Schwann cells in Δ7 SMNC3 mice that were corrected by combination treatment of SMN-C3 and MF-300 is shown in Table 5.

[0376] Table 3: Selected genes from myelination GO analysis

[0377] Table 5: Potential Schwann cell gene signature in Δ7 SMNC3 miceExample 6: Hpgd gene expression in healthy sciatic nerve

[0378] In this example, expression of Hpgd gene which encodes 15-PGDH was investigated. The publicly available RNA-seq data was obtained, and was analysed using the Sciatic Nerve Atlas available in the public domain from Gerber et al.2021, eLife.

[0379] As shown in FIG.19, the expression of Hpgd was observed in healthy sciatic nerve throughout different developmental stages in mice. Y-axis is shown as Reads Per Kilobase per Million mapped reads (RPKM).

[0380] Target cells in sciatic nerve that express Hpgd were also investigated. As shown in FIG.20, Hpgd is expressed in immune cells (IC), epineural cells (EpC), and perineural cells (PnC) in 60 days postnatal healthy mouse sciatic nerve. Hpgd expression could be broad within sciatic nerve based upon EpC, PnC, and IC expression. 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.

[0381] Overall, this result shows various cells such as immune cells, epineural cells, and perineural cells found in healthy sciatic nerve express 15-PGDH. These cells can potentially be a target for 15-PGDH inhibitor treatment.Example 7: Myelination gene expression in untreated SMNΔ7 mice.

[0382] In this example, myelination gene expression from untreated SMNΔ7 mice was analyzed.

[0383] As shown in FIGS.21A-21B, genes involved in myelination were upregulated in the SMA disease mice (SMNΔ7 mice) in the absence of SMN upregulator. This data was reanalyzed from public data from McCormack, N.M. et al.2021, Journal of Cachexia, Sarcopenia, and Muscle. Overall, data from FIGS.21A-21B and from previous examples demonstrate that myelination were upregulated in the SMA disease mice (SMNΔ7 mice).

[0384] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS What is claimed is:

1. A method of treating spinal muscular atrophy (SMA), the method comprising: administering to a subject in need thereof, in amounts effective to treat the SMA, (i) a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor; and (ii) an agent that increases expression of survival motor neuron (SMN) protein, thereby treating the SMA.

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

3. The method of claim 1 or 2, wherein the agent that increases expression of SMN protein is an agent that increases expression of SMN2 protein.

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

5. The method of claim 4, wherein the agent that modulates splicing of SMN2 pre- mRNA increases exon 7 inclusion in SMN2 mRNA transcripts.

6. The method of claim 4 or 5, wherein the agent that modulates splicing of SMN2 pre- mRNA is selected from the group consisting of: risdiplam, SMN-C2, SMN-C3, SMN-C5, RG-7916, RG7800, SMN-C1, SMN-C8, Branaplam, nusinersen, and any combination thereof.

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

8. The method of claim 1 or 2, wherein the agent that increases expression of SMN protein is an agent that increases expression of SMN1 protein.

9. The method of claim 8, wherein the agent that increases expression of SMN1 protein is onasemnogene abeparvovec.

10. The method of any one of claims 1-9, wherein the agent that increases expression of SMN protein is selected from the group consisting of: a small molecule, an antisense oligonucleotide, an siRNA, a miRNA, an shRNA, a gene therapy agent, an antigen binding unit, a peptide, an aptamer, and any combination thereof.

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

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

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

14. The method of any one of claims 1-13, wherein the SMA is selected from the group consisting of: 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 of any one of claims 1-14, wherein the administering the 15-PGDH inhibitor, the administering the agent that increases expression of SMN protein, or both, is selected from the group consisting of: oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra- arterial administration, intradermal administration, subcutaneous administration, and any combination thereof.

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

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

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

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

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

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

22. The method of any one of claims 1-21, wherein the amounts effective to treat SMA are amounts effective to ameliorate one or more symptoms of the SMA.

23. The method of any one of claims 1-21, wherein the amounts effective to treat SMA are amounts effective to reduce severity of the SMA.

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

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

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

27. The method of any one of claims 1-26, wherein the subject in need thereof is a human.

28. The method of any one of claims 1-27, wherein the subject in need thereof is 75 years old or less.

29. The method of any one of claims 1-28, wherein the subject in need thereof has elevated 15-PGDH levels prior to the administering, relative to a control subject that does not have SMA.

30. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof, wherein:X is selected from –OCH2–, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, – SCH2–, –S(O)CH2–, –SO2CH2–; each Y is independently selected from N and CR11; each R1is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; each R5is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl;each R11is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;.

31. The method of claim 30, wherein the compound is a compound of Formula Ia:Formula Ia or a pharmaceutically acceptable salt thereof.

32. The method of claim 30, wherein the compound is a compound of Formula Ib:Formula Ib or a pharmaceutically acceptable salt thereof.

33. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of Formula II:Formula II or a pharmaceutically acceptable salt thereof, wherein: T, U, W, X, and Y are independently selected from N and CR5; S, V, and Z are independently selected from N and C; R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio;each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; each R5is independently selected from H, halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, – NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;34. The method of claim 33, wherein the compound is a compound of Formula IIa: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: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: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:Formula IId or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

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

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

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

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

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

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

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

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

46. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of Formula III:Formula III or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR7; Y is selected from O, S, SO2, and C(R8)2;R1is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo or thio; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; ortwo R6’s attached to the same carbon atom are taken together to form oxo, thio, or C3- 10cycloalkyl, and any remaining R6’s are independently selected from halo, – NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, – SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, – NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R8is independently selected from H, halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R8’s can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1- 6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

47. The method of claim 46, wherein the compound is a compound of Formula IIIa:Formula IIIa or a pharmaceutically acceptable salt thereof.

48. The method of claim 46, wherein the compound is a compound of Formula IIIb:Formula IIIb or a pharmaceutically acceptable salt thereof, wherein: each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

49. The method of claim 46, wherein the compound is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof.

50. The method of claim 46, wherein the compound is a compound of Formula IIId:Formula IIId or a pharmaceutically acceptable salt thereof, wherein: each R14is independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

51. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of Formula IIk:Formula IIk or a pharmaceutically acceptable salt thereof, wherein: T, U, and Y are independently selected from N and CR6, provided that when U is N, at least one of T and Y is N; R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, – SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, – NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from H and halo; R5is selected from halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, –SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, –NR11SO2R9, – NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6is selected from H, halo, –NR7R8, –OR9, –C(O)R9, –C(O)OR9, –C(O)NR7R8, – SOR10, –SO2R10, –SO2NR7R8, –NR11C(O)R9, –NR11C(O)NR7R8, – NR11SO2R9, –NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; R7and R8are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R9is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R11is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 6cycloalkyl; and p is 0, 1, or 2.

52. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of Formula IIm:Formula IIm or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl;each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

53. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of Formula IIq:Formula IIq or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, – SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; each R4is independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; ortwo R4’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4’s are independently selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, – C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, –NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R5is selected from halo, –NR6R7, –OR8, –C(O)R8, –C(O)OR8, –C(O)NR6R7, –SOR9, –SO2R9, –SO2NR6R7, –NR10C(O)R8, –NR10C(O)NR6R7, –NR10SO2R8, – NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 10cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

54. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof, wherein:each X is independently selected from N and CR7; Y is selected from O, S, SO2, and C(R8)2; R1is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, and 5- to 10-membered heteroaryl; R2is H and R3is –CF3; or R2and R3are taken together to form oxo; R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, – SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, –NR13C(O)NR9R10, – NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R4and R5are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R6is independently selected from halo, –NR9R10, –OR11, –C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or two R6’s attached to the same carbon atom are taken together to form oxo, and any remaining R6’s are independently selected from halo, –NR9R10, –OR11, – C(O)R11, –C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, – NR13C(O)R11, –NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R7and R8is independently selected from halo, –NR9R10, –OR11, –C(O)R11, – C(O)OR11, –C(O)NR9R10, –SOR12, –SO2R12, –SO2NR9R10, –NR13C(O)R11, – NR13C(O)NR9R10, –NR13SO2R11, –NR13SO2NR9R10, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1- 6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- 6cycloalkyl; and n is 0, 1, 2, 3, or 4.

55. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound selected from the group consisting of:; ; ;56. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound selected from the group consisting of:; ;; ; ; ;57. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound selected from the group consisting of: ;.

58. The method of any one of claims 1-29, wherein the 15-PGDH inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt thereof:Formula (I), wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2or N; R1is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R2is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, – C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-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 R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; XAis -NR5R5or -OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C6heterocycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is optionally substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is optionally substituted with one or more Ra;each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

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

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

61. The method of claim 58 or 60, wherein when Q is phenyl then one of R3is not H.

62. The method of claim 58, whereinwherein, X1, X2, X3and X4are each independently N or CR3;each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, – C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, – NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted 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 with one or more R13; each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-memberedheteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; andeach Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

63. The method of claim 62, wherein X1, X2, X3and X4are each CR3.

64. The method of claim 62, wherein X1is N; and X2, X3, and X4are each CR3.

65. The method of claim 62, wherein X1and X2are each N; and X3and X4are each CR3.

66. The method of claim 62, wherein X1and X3are each N; and X2and X4are each CR3.

67. The method of claim 62, wherein X1and X4are each N; and X2and X3are each CR3.

68. The method of claim 62, wherein X1, X2, and X3are each N; and X4is CR3.

69. The method of claim 62, wherein X1, X2, and X4are each N; and X3is CR3.

70. The method of any one of claims 58-69, wherein each R3is independently selected from H, halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, – SO2R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

71. The method of claim 70, wherein each R3is independently selected from H, halogen, –C(O)OR10, –C(O)NR8R9, and substituted or unsubstituted 5-membered heteroaryl.

72. The method of claim 58, wherein the compound has the structure of Formula V, or a pharmaceutically acceptable salt thereof:Formula V, wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;each R2is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, –NR8R9, – OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, – NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted orunsubstituted 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 R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl;each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

73. The method of any one of claims 58-72, wherein XAis NR5R5.

74. The method of any one of claims 58-72, wherein XAis OR5.

75. The method of any one of claims 58-74, wherein Y is CR2.

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

77. The method of claim 72, wherein the compound of Formula V has the structure of Formula VIa, or a pharmaceutically acceptable salt thereof:Formula VIa.

78. The method of claim 72, wherein the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:Formula VIb.

79. The method of any one of claims 58-78, wherein Z is N.

80. The method of any one of claims 58-78, wherein Z is CR1.

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

82. The method of claim 72, wherein the compound of Formula V has the structure of Formula VIIa, or a pharmaceutically acceptable salt thereof:.

83. The method of claim 72, wherein the compound of Formula V has the structure of Formula VIIb, or a pharmaceutically acceptable salt thereof:Formula VIIb.

84. The method of claim 72, wherein the compound of Formula V has the structure of Formula VIIc, or a pharmaceutically acceptable salt thereof:Formula VIIc.

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

86. The method of any one of claims 72-85, wherein X1is N.

87. The method of any one of claims 72-86, wherein R3bis H; and R3cis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, – SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, – NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9.

88. The method of claim 87, wherein R3bis H; and R3cis selected from halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

89. The method of any one of claims 72-86, wherein R3cis H; and R3bis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, – SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, – NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9.

90. The method of claim 89, wherein R3cis H; and R3bis selected from halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

91. The method of any one of claims 72-85, wherein X1is CR3a.

92. The method of any one of claims 72-85 or 91, wherein R3aand R3bare independently H or halogen; and R3cis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, - SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9.

93. The method of claim 92, wherein R3cis selected from H, halogen, –NR8R9, –OR10, – SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1- C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

94. The method of claim 93, wherein R3cis –C(O)OR10, –C(O)NR8R9, or substituted or unsubstituted 5-membered heteroaryl.

95. The method of any one of claims 92-94, wherein R3aand R3bare each H.

96. The method of any one of claims 72-85 or 91, wherein R3aand R3care independently H or halogen; and R3bis selected from halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10,–C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, - SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9.

97. The method of claim 96, wherein R3bis selected from H, halogen, –NR8R9, –OR10, – SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1- C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

98. The method of claim 96, wherein R3bis –C(O)OR10, –C(O)NR8R9, or substituted or unsubstituted 5-membered heteroaryl.

99. The method of any one of claims 96-98, wherein R3aand R3care each H.

100. The method of any one of claims 72-85 or 91, wherein R3band R3care each H or halogen; and R3ais selected from halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, – NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-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 with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, - SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9.

101. The method of claim 100, wherein R3ais selected from H, halogen, –NR8R9, –OR10, – SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1- C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

102. The method of claim 100, wherein R3ais –C(O)OR10, –C(O)NR8R9, or substituted or unsubstituted 5-membered heteroaryl.

103. The method of any one of claims 100-102, wherein R3band R3care each H.

104. The method of any one of claims 58-103, wherein each R2is H.

105. The method of any one of claims 58-104, wherein R5aand one of R6combine together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl.

106. The method of any one of claims 58-104, wherein R5ais H.

107. The method of any one of claims 58-106, wherein R5is H.

108. The method of any one of claims 58-107, wherein R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3- C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6.

109. The method of claim 108, wherein R4is substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C1-C8 heteroalkyl, each of which is substituted with one or more R6.

110. The method of any one of claims 58-107, wherein R4is substituted or unsubstituted C3-C8 cycloalkyl or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6.

111. The method of claim 110, wherein R4is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl.

112. The method of any one of claims 58-111, wherein each R6is independently halogen, – NR8R9, –OR10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl.

113. The method of claim 112, wherein each R6is independently halogen,–OR10, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl.

114. The method of claim 112 or 113, wherein each R6is independently -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

115. The method of 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 expression of SMN protein.

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

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

119. A unit dose comprising the pharmaceutical formulation of claim 118.

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

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

122. The kit of claim120, wherein the 15-PGDH inhibitor and the agent that increases expression of SMN protein are in the same container.

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

124. The kit of claim 123, wherein the subject in need thereof has spinal muscular atrophy (SMA).

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