Compositions and methods for treating obesity and diabetes using 15-PGDH inhibitors

Abstract

Provided herein are methods for treating obesity or diabetes by administering a 15- PGDH inhibitor to a subject. In some cases, the methods provided herein additionally involve administering to a subject an agent selected from the group consisting of: a glucagon- like peptide- 1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor co- agonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co-agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist.

Description

COMPOSITIONS AND METHODS FOR TREATING OBESITY AND DIABETES USING 15-PGDH INHIBITORSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 621,527, filed January 16, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Muscle mass and muscle strength may progressively decrease with aging, and muscle strength diminishes at a faster rate than muscle mass. Approximately 35% of adults over the age of 65 are obese, and pharmacotherapeutic treatments for weight loss and diabetes may reduce muscle mass and lead to muscle weakness. Weight loss may exacerbate progressive muscle weakness and increase the risk of age-related sarcopenia.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 improved methods for treating obesity and diabetes in a subject, which do not involve, or which reverse or slow the concomitant loss of muscle mass or muscle function associated with certain diabetes and obesity medications. This disclosure meets this unmet need.

[0005] In one aspect, provided herein is a method of treating a subject having obesity, the method comprising administering to the subject: (a) an effective amount of an agent selected from the group consisting of a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucosedependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor co-agonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagonreceptor triple agonist, a GLP-1 receptor / GLP-2 receptor co-agonist, a combination of a GLP- 1 receptor agonist and an amylin receptor agonist, and any combination thereof; and (b) an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, thereby treating the subject having obesity.

[0006] In some embodiments, after the administering, the subject experiences increased muscle mass and / or increased muscle function, as compared to a subject treated with the agent in the absence of the 15-PGDH inhibitor.

[0007] In some embodiments, after the administering, the subject experiences a reduction in a loss of muscle mass and / or a loss of muscle function, as compared to a subject treated with the agent in the absence of the 15-PGDH inhibitor.

[0008] In some embodiments, the reduction in the loss of muscle mass and / or loss of muscle function comprises a reduction in a rate of loss of muscle mass and / or loss of muscle function, and / or a reduction in an amount of loss of muscle mass and / or loss of muscle function.

[0009] In some embodiments, the muscle function comprises muscle force, muscle stamina, and / or muscle endurance.

[0010] In some embodiments, the subject has sarcopenic obesity.

[0011] In some embodiments, after the administering, the subject experiences weight loss without a concomitant loss of muscle mass and / or muscle function.

[0012] In some embodiments, the subject has a body mass index of at least 25 kg / m2.

[0013] In some embodiments, the subject has a body mass index of at least 40 kg / m2.

[0014] In some embodiments, the subject is at least 40 years of age.

[0015] In some embodiments, the subject is at least 65 years of age.

[0016] In some embodiments, the 15-PGDH inhibitor and the agent are administered to the subject in a single formulation.

[0017] In some embodiments, the 15-PGDH inhibitor and the agent are administered to the subject in separate formulations.

[0018] In some embodiments, the 15-PGDH inhibitor is administered to the subject once every day, once every 2 days, once every 3 days, or less frequently than once every 3 days.

[0019] In some embodiments, the 15-PGDH inhibitor is administered by oral administration.

[0020] In some embodiments, the agent is administered to the subject once every day, less frequently than once a day, once every week, less frequently than once every week, once every month, or less frequently than once every month.

[0021] In some embodiments, the agent is administered to the subject by oral administration or by subcutaneous administration.

[0022] In another aspect, provided herein is a method of increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in a subject in need thereof, the method comprising: administering to the subject an effective amount of a 15- hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, wherein, prior to the administering, the subject has experienced a decrease in muscle mass and / or muscle function associated with administration of an agent selected from the group consisting of: a glucagon- like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor coagonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co-agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof, thereby increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in the subject.

[0023] In some embodiments, the reducing loss of muscle mass and / or muscle function comprises a reduction in a rate of loss of muscle mass and / or loss of muscle function, and / or a reduction in an amount of loss of muscle mass and / or loss of muscle function.

[0024] In some embodiments, the muscle function comprises muscle force, muscle stamina, and / or muscle endurance.

[0025] In some embodiments, the subject is at least 40 years of age.

[0026] In some embodiments, the subject is at least 65 years of age.

[0027] In some embodiments, the 15-PGDH inhibitor is administered to the subject once every day, once every 2 days, once every 3 days, or less frequently than once every 3 days.

[0028] In some embodiments, the 15-PGDH inhibitor is administered by oral administration.

[0029] In some embodiments, the subject was administered the agent to treat obesity.

[0030] In some embodiments, the subject has, or prior to the administering the 15-PGDH inhibitor had, a body mass index of at least 25 kg / m2.

[0031] In some embodiments, the subject has, or prior to the administering the 15-PGDH inhibitor had, a body mass index of at least 40 kg / m2.

[0032] In some embodiments, the subject has, or prior to the administering the 15-PGDH inhibitor had, a body mass index of less than 25 kg / m2.

[0033] In some embodiments, the subject was administered the agent for cosmetic weight loss.

[0034] In some embodiments, the method further comprises administering the agent to the subject.

[0035] In some embodiments, the 15-PGDH inhibitor and the agent are administered to the subject in a single formulation.

[0036] In some embodiments, the 15-PGDH inhibitor and the agent are administered to the subject in separate formulations.

[0037] In some embodiments, the agent is administered to the subject once every day, less frequently than once every day, once every week, less frequently than once every week, once a month, or less frequently than once a month.

[0038] In some embodiments, the agent is administered to the subject by oral administration or by subcutaneous administration.

[0039] In another aspect, provided herein is a method of treating prediabetes or diabetes mellitus in a subject, the method comprising administering to the subject: (a) an effective amount of an agent selected from the group consisting of: a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor co-agonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co- agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof; and (b) an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, thereby treating prediabetes or diabetes mellitus in the subject.

[0040] In some embodiments, the diabetes mellitus is Type 1 diabetes mellitus.

[0041] In some embodiments, the diabetes mellitus is Type 2 diabetes mellitus.

[0042] In some embodiments, after the administering, the subject experiences increased muscle mass and / or increased muscle function.

[0043] In some embodiments, after the administering, the subject experiences a reduction in a loss of muscle mass and / or a loss of muscle function.

[0044] In some embodiments, the subject experiences a reduction in a rate of loss of muscle mass and / or loss of muscle function, and / or a reduction in an amount of loss of muscle mass and / or loss of muscle function.

[0045] In some embodiments, the muscle function comprises muscle force, muscle stamina, and / or muscle endurance.

[0046] In some embodiments, the subject has obesity.

[0047] In some embodiments, the subject has a body mass index of at least 25 kg / m2.

[0048] In some embodiments, the subject has a body mass index of at least 40 kg / m2.

[0049] In some embodiments, the subject has a body mass index of less than 25 kg / m2.

[0050] In some embodiments, the subject has normal weight type 2 diabetes.

[0051] In some embodiments, after the administering, the subject experiences weight loss without a concomitant loss of muscle mass and / or muscle function.

[0052] In some embodiments, after the administering, the subject has a decrease in Hemoglobin A1C (HbAic) levels, as compared to the subject prior to the administering.

[0053] In some embodiments, after the administering, the subject has a greater decrease in HbAic levels as compared to a subject treated with the agent in the absence of the 15-PGDH inhibitor.

[0054] In some embodiments, after the administering, the subject has a decrease in HbAic levels comparable to or greater than HbAic levels in a subject having type 2 diabetes undergoing aerobic exercise and / or strength training.

[0055] In some embodiments, the 15-PGDH inhibitor and the agent are administered to the subject in a single formulation.

[0056] In some embodiments, the 15-PGDH inhibitor and the agent are administered to the subject in separate formulations.

[0057] In some embodiments, the 15-PGDH inhibitor is administered to the subject once every day, once every 2 days, once every 3 days, or less frequently than once every 3 days.

[0058] In some embodiments, the 15-PGDH inhibitor is administered by oral administration.

[0059] In some embodiments, the agent is administered to the subject once every day, less frequently than once every day, once every week, less frequently than once every week, once every month, or less frequently than once every month.

[0060] In some embodiments, the agent is administered to the subject by oral administration or by subcutaneous administration.

[0061] In some embodiments, the method further comprise administering insulin to the subject.

[0062] In some embodiments, the insulin is selected from the group consisting of: rapidacting insulin, short-acting insulin, intermediate-acting insulin, mixed insulin, and long- acting insulin.

[0063] In some embodiments, the rapid-acting insulin is selected from the group consisting of: insulin aspart, insulin glulisine, and insulin lispro.

[0064] In some embodiments, the long-acting insulin is selected from the group consisting of: insulin detemir, insulin glargine, and insulin degludec.

[0065] In another aspect, provided herein is a method of treating fatty liver disease / nonalcoholic steatohepatitis (NASH) / metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising administering to the subject: (a) an effective amount of an agent selected from the group consisting of: a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor co-agonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co- agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof; and (b) an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor; thereby treating fatty liver disease / NASH / MASH in the subject.

[0066] In some embodiments, the glucagon receptor agonist is selected from the group consisting of: glucagon, diazoxide, and dasi glucagon.

[0067] In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of: exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, orforglipron, danuglipron, and SAR425899.

[0068] In some embodiments, the GIP receptor agonist is ZP6590.

[0069] In some embodiments, the GLP-1 receptor / GIP receptor co-agonist is selected from the group consisting of: tirzepatide and CT-868.

[0070] In some embodiments, the GLP-1 receptor agonist / GIP receptor antagonist is AMG133.

[0071] In some embodiments, the GLP-1 receptor / glucagon receptor co-agonist is selected from the group consisting of: pegapamodutide, BI 456909, BI 456906, mazdutide, pemvidutide, and NN9277.

[0072] In some embodiments, the GLP-1 receptor / GIP receptor / glucagon receptor triple agonist is selected from the group consisting of: retatrutide, NN9423, and efocipegtrutide.

[0073] In some embodiments, the GLP-1 receptor / GLP-2 receptor co-agonist is dapiglutide.

[0074] In some embodiments, the combination of a GLP-1 receptor agonist and an amylin receptor agonist or the GLP-1 receptor / amylin receptor co-agonist is selected from the group consisting of: a combination of cagrilintide + semaglutide, and amy cretin.

[0075] In another aspect, provided herein is a method of increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in a subject, the method comprising: administering to the subject an effective amount of a 15- hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, wherein, prior to the administering, the subject underwent gastric bypass surgery, thereby increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in the subject.

[0076] In some embodiments, prior to the administering, the subject has experienced a decrease in muscle mass and / or muscle function.

[0077] In some embodiments, the reducing loss of muscle mass and / or muscle function comprises reducing a rate of loss of muscle mass and / or loss of muscle function, and / or reducing an amount of loss of muscle mass and / or loss of muscle function.

[0078] In some embodiments, the muscle function comprises muscle force, muscle stamina, and / or muscle endurance.

[0079] In some embodiments, the 15-PGDH inhibitor is administered to the subject once every day, once every 2 days, once every 3 days, or less frequently than once every 3 days.

[0080] In some embodiments, the 15-PGDH inhibitor is administered by oral administration.

[0081] In some embodiments, prior to the gastric bypass surgery, the subject had a body mass index of at least 40 kg / m2.

[0082] In some embodiments, the 15-PGDH inhibitor is a compound of Formula I: 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- wcycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R2is H and R3is -CF3; orR2and 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- wcycloalkyl, 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- wcycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R6and R7are independently selected at each occurrence from H, C1-6alkyl, Ci-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- wcycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- wcycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- wcycloalkyl; 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- wcycloalkyl, 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;

[0083] In some embodiments, the compound is a compound of Formula la:Formula la or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the compound is a compound of Formula lb:or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the 15-PGDH inhibitor is a compound of 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, Ci- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;R2is H and R3is -CF3; orR2and 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- wcycloalkyl, 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-iocycloalkyl, 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-iocycloalkyl, 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- wcycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R6and R7are independently selected at each occurrence from H, C1-6alkyl, Ci- 6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R8is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- wcycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- wcycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- wcycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;BRIEF DESCRIPTION OF THE DRAWINGS

[0086] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0087] FIGs. 1A and IB show an exemplary experimental protocol using aged male mice (26 weeks old) in a diet-induced obesity (DIO) model for testing the effects of combination treatment with a GLP-1 receptor agonist (tirzepatide) and a 15-PGDH inhibitor.

[0088] FIG. 2A shows the effects of tirzepatide treatment (10 nmol / kg) on maximal muscle force in an aged DIO mouse model compared to DIO mice that received v6hicle administration or mice on a control chow diet.

[0089] FIG. 2B shows the effects of tirzepatide treatment (10 nmol / kg) alone or in combination with a 15-PGDH inhibitor (3 mg / kg, 10 mg / kg, or 30 mg / kg) on maximal muscle force in an aged DIO mouse model.

[0090] FIG. 2C shows the results of FIG. 2A and FIG. 2B in a single graph.DETAILED DESCRIPTION

[0091] Sarcopenia is a skeletal muscle disorder which involves progressive and accelerated loss of muscle mass and strength. Sarcopenia is often associated with increased adverse outcomes, for example, frailty, risk of falls, muscle decline, and mortality. Sarcopenia commonly occurs in older people. It has been shown that weight loss may exacerbate progressive muscle weakness and increase the risk of developing sarcopenia. There is currently no FDA approved treatment for sarcopenia. Physical exercise is currently the only protective measure, and the effectiveness of physical exercise declines with age.

[0092] Pharmacotherapeutic weight loss has been shown to reduce muscle mass and may lead to muscle weakness. For example, a dual GIP / GLP-1 receptor co-agonist, tirzepatide, commonly used for the treatment of type II diabetes and for weight loss, has been to shown to cause about a 10% reduction in lean muscle mass.

[0093] Provided herein are compositions and methods for preventing or reducing the loss of muscle function commonly associated with the use of certain diabetes and obesity medications. The methods provided herein generally involve administering a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor to a subject. In some cases, the 15-PGDH inhibitor is co-administered to the subject (e.g., simultaneously, sequentially) with an agent for treating diabetes and / or obesity. In some cases, the 15-PGDH inhibitor is administered to a subject who has previously been administered the agent for treating diabetes and / or obesity (e.g., a subject who has already experienced a loss of muscle function due to the diabetes and / or obesity agent). In some cases, the agent for treating diabetes and / or obesity is selected from the group consisting of: a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor co-agonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co- agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof.

[0094] In one aspect, provided herein is a method treating a subject having obesity, the method comprising administering to the subject: (a) an effective amount of an agent selected from the group consisting of: a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucosedependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor co-agonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co-agonist, a combination of a GLP- 1 receptor agonist and an amylin receptor agonist, and any combination thereof; and (b) an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, thereby treating the subject having obesity.

[0095] In another aspect, provided herein is a method of increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in a subject in need thereof, the method comprising: administering to the subject an effective amount of a 15- hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, wherein, prior to the administering, the subject has experienced a decrease in muscle mass and / or muscle function associated with administration of an agent selected from the group consisting of: a glucagon- like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor co- agonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1receptor / GLP-2 receptor co-agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof, thereby increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in the subject.

[0096] In another aspect, provided herein is a method of increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in a subject, the method comprising: administering to the subject an effective amount of a 15- hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, wherein, prior to the administering, the subject underwent gastric bypass surgery, thereby increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in the subject.

[0097] In another aspect, provided herein is a method of treating prediabetes or diabetes mellitus in a subject, the method comprising administering to the subject: (a) an effective amount of an agent selected from the group consisting of: a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor co-agonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co- agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof; and (b) an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, thereby treating prediabetes or diabetes mellitus in the subject.

[0098] In another aspect, provided herein is a method of treating fatty liver disease / nonalcoholic steatohepatitis (NASH) / metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising administering to the subject: (a) an effective amount of an agent selected from the group consisting of: a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor co-agonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co- agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof; and (b) an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor; thereby treating fatty liver disease / NASH / MASH in the subject.

[0099] In some embodiments, after the administering, the subject experiences increased muscle mass and / or increased muscle function, as compared to a subject treated with the agent in the absence of the 15-PGDH inhibitor. In some embodiments, after the administering, the subject experiences a reduction in a loss of muscle mass and / or a loss of muscle function, as compared to a subject treated with the agent in the absence of the 15- PGDH inhibitor. In some embodiments, the reduction in the loss of muscle mass and / or loss of muscle function comprises a reduction in a rate of loss of muscle mass and / or loss of muscle function, and / or a reduction in an amount of loss of muscle mass and / or loss of muscle function. In some embodiments, the muscle function comprises muscle force, muscle stamina, and / or muscle endurance. In some embodiments, after the administering, the subject experiences weight loss without a concomitant loss of muscle mass and / or muscle function. In some embodiments, a method disclosed herein increases maximal muscle force. For example, FIG. 2B shows an increase in maximal muscle force after administration of a 15- PGDH inhibitor and a dual GIP / GLP-1 receptor co-agonist (e.g., tirzepatide). In some embodiments, assessing muscle function in a subject comprises measuring one or more muscle quality parameters in a subject, wherein the one or more muscle quality parameters comprise maximal muscle force or one or more muscle contractile parameters in response to a stimulus, the one or more muscle contractile parameters in response to a stimulus comprising muscle contraction time, maximal displacement of the muscle contraction, delay time of the muscle contraction, relaxation time of the muscle contraction, sustain time of the muscle contraction, or combinations thereof.

[0100] In some embodiments, the subject has obesity. In some embodiments, the subject has sarcopenic obesity. In some embodiments, the subject was administered the agent to treat obesity.

[0101] In some embodiments, the subject has a body mass index of at least 25 kg / m2. In some embodiments, the subject has a body mass index of at least 40 kg / m2. In some embodiments, the subject has, or prior to the administering the 15-PGDH inhibitor had, a body mass index of less than 25 kg / m2. In some embodiments, prior to the gastric bypass surgery, the subject had a body mass index of at least 40 kg / m2.

[0102] In some embodiments, the subject has diabetes mellitus. In some embodiments, the diabetes mellitus is Type 1 diabetes mellitus. In some embodiments, the diabetes mellitus is Type 2 diabetes mellitus. In some embodiments, the subject has normal weight type 2 diabetes.

[0103] In some embodiments, the method further comprises administering insulin to the subject. In some embodiments, the insulin is selected from the group consisting of: rapidacting insulin, short-acting insulin, intermediate-acting insulin, mixed insulin, and long- acting insulin. In some embodiments, the rapid-acting insulin is selected from the group consisting of: insulin aspart, insulin glulisine, and insulin lispro. In some embodiments, the long-acting insulin is selected from the group consisting of: insulin detemir, insulin glargine, and insulin degludec.

[0104] In some embodiments, the subject was administered the agent for cosmetic weight loss.

[0105] In some embodiments, the subject has a disease or condition associated with reduced muscle quality. In some embodiments, the disease or condition associated with reduced muscle quality is associated with aging. In some embodiments, the disease or condition associated with aging is sarcopenia. In some embodiments, the subject has sarcopenia. In some embodiments, the subject is at least 40 years of age. In some embodiments, the subject is at least 65 years of age. In some embodiments, the subject is over 70 years old. In some embodiments, muscle atrophy (e.g., muscle wasting) can be caused by or associated with, for example, normal aging (e.g., sarcopenia) or diet. In some embodiments, the diet is a high fat diet.

[0106] In some embodiments, a muscle to be assessed can be any muscle of the body, including but not limited to, musculi pectoralis complex, latissimus dorsi, teres major and subscapularis, brachioradialis, biceps, brachialis, pronator quadratus, pronator teres, flexor carpi radialis, flexor carpi ulnaris, flexor digitorum superficialis, flexor digitorum profundus, flexor pollicis brevis, opponens pollicis, adductor pollicis, flexor pollicis brevis, iliopsoas, psoas, rectus abdominis, rectus femoris, gluteus maximus, gluteus medius, medial hamstrings, gastrocnemius, lateral hamstring, quadriceps mechanism, adductor longus, adductor brevis, adductor magnus, gastrocnemius medial, gastrocnemius lateral, soleus, tibialis posterior, tibialis anterior, flexor digitorum longus, flexor digitorum brevis, flexor hallucis longus, extensor hallucis longus, extensor digitorum longus, hand muscles, arm muscles, foot muscles, leg muscles, chest muscles, stomach muscles, back muscles, buttock muscles, shoulder muscles, head and neck muscles, facial muscles, oculopharyngeal muscles, and the like. In some embodiments, the muscle is extensor digitorum longus. In some embodiments, the muscle can be composed of different types of muscle fibers. In some embodiments, the muscle fibers are type I, type IC, type IIC, type IIA, type IIAB, or type IIBmuscle fibers. In some embodiments, these muscle fibers are slow-twitch muscle fibers or fast-twitch muscle fibers. In some embodiments, the muscle comprises fast-twitch muscle fibers. In some embodiments, the fast-twitch muscle fibers can comprise ATPase type II or MHC type II fibers. In some embodiments, the slow-twitch muscle fibers can comprise ATPase type I or MHC type I fibers.

[0107] In some embodiments, the method further comprises administering the agent to the subject. In some embodiments, the 15-PGDH inhibitor and the agent are administered to the subject in a single formulation. In some embodiments, the 15-PGDH inhibitor and the agent are administered to the subject in separate formulations. In some embodiments, the 15-PGDH inhibitor is administered to the subject once every day, once every 2 days, once every 3 days, or less frequently than once every 3 days. In some embodiments, the 15-PGDH inhibitor is administered by oral administration. In some embodiments, the agent is administered to the subject by oral administration or by subcutaneous administration. In some embodiments, the agent is administered to the subject once every day, less frequently than once a day, once every week, less frequently than once every week, once every month, or less frequently than once every month.

[0108] 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 80 mg / kg, at least about 90 mg / kg, or at least about 100 mg / kg. In some embodiments, the effective dose of the 15-PGDH inhibitor 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.

[0109] In some embodiments, the effective dose of the glucagon-like peptide- 1 (GLP-1) receptor agonist, glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, glucagon receptor agonist, GLP-1 receptor / GIP receptor co-agonist, GLP-1 receptor agonist / GIP receptor antagonist, GLP-1 receptor / glucagon receptor co-agonist, GLP-1receptor / GIP receptor / glucagon receptor triple agonist, GLP-1 receptor / GLP-2 receptor coagonist, combination of a GLP-1 receptor agonist or amylin receptor agonist comprises about 1 nmol / kg, about 3 nmol / kg, about 10 nmol / kg, about 20 nmol / kg, about 30 nmol / kg, about 40 nmol / kg, about 50 nmol / kg, about 60 nmol / kg, about 70 nmol / kg, about 80 nmol / kg, about 90 nmol / kg, or about 100 nmol / kg.

[0110] In some embodiments, after the administering, the subject has a decrease in Hemoglobin A1C (HbAic) levels, as compared to the subject prior to the administering. In some embodiments, after the administering, the subject has a greater decrease in HbAic levels as compared to a subject treated with the agent in the absence of the 15-PGDH inhibitor. In some embodiments, after the administering, the subject has a decrease in HbAic levels comparable to or greater than HbAic levels in a subject having type 2 diabetes undergoing aerobic exercise and / or strength training.

[0111] Glucagon-like peptide 1 (GLP-1) is a naturally-occurring incretin hormone released into the circulation by the L cells of the gut in response to ingested nutrients. By binding to its cognate receptor (GLP-1R) GLP-1 is able to promote insulin secretion while suppressing glucagon secretion. GLP-1 decreases the rate of gastric emptying, and reduces appetite, thus resulting in weight loss. In some embodiments, the subject is administered a gastric inhibitory polypeptide (GIP) receptor agonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, an incretin mimetic, or a GLP-1 analog. In some embodiments, the glucagon receptor agonist is selected from the group consisting of: glucagon, diazoxide, and dasi glucagon. In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of: exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, orforglipron, danuglipron, and SAR425899. In some embodiments, the GIP receptor agonist is ZP6590. In some embodiments, the GLP-1 receptor / GIP receptor co-agonist is selected from the group consisting of: tirzepatide and CT-868. In some embodiments, the GLP-1 receptor agonist / GIP receptor antagonist is AMG133. In some embodiments, the GLP-1 receptor / glucagon receptor co-agonist is selected from the group consisting of: pegapamodutide, BI 456909, BI 456906, mazdutide, pemvidutide, and NN9277. In some embodiments, the GLP-1 receptor / GIP receptor / glucagon receptor triple agonist is selected from the group consisting of: retatrutide, NN9423, and efocipegtrutide. In some embodiments, the GLP-1 receptor / GLP-2 receptor co-agonist is dapiglutide. In some embodiments, the combination of a GLP-1 receptor agonist and an amylin receptor agonist or the GLP-1 receptor / amylinreceptor co-agonist is selected from the group consisting of a combination of cagrilintide and semaglutide, and amycretin.

[0112] In some embodiments, administration of the gastric inhibitory polypeptide (GIP) receptor agonist, the glucagon-like peptide-1 (GLP-1) receptor agonist, the incretin mimetic, or the GLP-1 analog to a subject induces a loss of muscle mass and / or a loss of muscle function. In some embodiments, the loss of muscle mass and / or a loss of muscle function induced by administration of the gastric inhibitory polypeptide (GIP) receptor agonist, the glucagon-like peptide-1 (GLP-1) receptor agonist, the incretin mimetic, or the GLP-1 analog to a subject is reduced by co-administration of a 15-PGDH inhibitor. In some embodiments, the loss of muscle mass and / or a loss of muscle function induced by administration of the gastric inhibitory polypeptide (GIP) receptor agonist, the glucagon-like peptide-1 (GLP-1) receptor agonist, the incretin mimetic, or the GLP-1 analog to a subject is prevented by coadministration of a 15-PGDH inhibitor.

[0113] In some embodiments, the administering comprises administering the 15-PGDH inhibitor or agent to the subject by various methods. For example, oral administration, intramuscular administration, intradermal administration, subcutaneous administration, intrathecal administration, intravenous administration, intraperitoneal administration, topical (transdermal), instillation, and implantation (for example, of a slow-release device such as polymeric implant or miniosmotic pump) can all be appropriate routes of administration. In some embodiments, the 15-PGDH inhibitor or agent is administered to the subject in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, diluent, and / or carrier. In some embodiments, the administering comprises administering the 15- PGDH inhibitor or agent to the subject by oral administration. In some embodiments, the administering comprises administering the 15-PGDH inhibitor or agent to the subject by intramuscular administration. In some embodiments, the administering comprises administering the 15-PGDH inhibitor or agent to the subject by intraperitoneal injection.

[0114] In some embodiments, the 15-PGDH inhibitor is a small molecule. In some embodiments, the 15-PGDH inhibitor is a bioavailable small molecule. In some embodiments, the 15-PGDH inhibitor is an orally bioavailable small molecule.

[0115] 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- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R2is H and R3is -CF3; orR2and 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- locycloalkyl, 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- locycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl;R6and R7are independently selected at each occurrence from H, C1-6alkyl, Ci- 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- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- locycloalkyl;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- locycloalkyl, 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;

[0116] 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-

[0117] 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.

[0118] 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, C 1 -6haloalky 1,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.

[0119] 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.

[0120] 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, C 1 -6haloalky 1, C3-iocycloalkyl, 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.

[0121] 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, C 1 -6haloalky 1, C3-iocycloalkyl, 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 R5is independently selected from halo, -NR6R7, -OR8, -C(O)R8, and -C(O)OR8.

[0122] In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-iocycloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, andC1-6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H, and C1-6alkyl.

[0123] In some embodiments, each R8is independently selected from H, C1-6alkyl, Ci- 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, Ci- 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.

[0124] In some embodiments, each R9is independently selected from C1-6alkyl, Ci- 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, Ci- 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.

[0125] In some embodiments, each R10is independently selected from H, C1-6alkyl, Ci- 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.

[0126] 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, C 1 -6haloalky 1, 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] In some embodiments, the compound is a compound of Formula la:

[0131]

[0132] or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the compound is a compound of Formula lb:

[0134] or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the 15-PGDH inhibitor is a compound of 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, C 1 -6haloalky 1, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;R2is H and R3is -CF3; orR2and 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-iocycloalkyl, 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, Ci- 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- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- locycloalkyl, 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;

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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, C 1 -6haloalky 1, 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 Ci- 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.

[0141] 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-membered heterocycloalkyl, 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 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, 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 fluoro.

[0142] 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, C 1 -6haloalky 1, 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 Ci- 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 R5isindependently 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.

[0143] 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.

[0144] In some embodiments, each R8is independently selected from H, C1-6alkyl, Ci- 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, Ci- 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.

[0145] In some embodiments, each R9is independently selected from C1-6alkyl, Ci- 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, Ci- 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.

[0146] In some embodiments, each R10is independently selected from H, C1-6alkyl, Ci- 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.

[0147] 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.

[0148] 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.

[0149] In some embodiments, the compound is a compound of Formula Ila:Formula Ila or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0150] 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.

[0151] In some embodiments, the compound is a compound of Formula lib :Formula lib or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0152] 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.

[0153] In some embodiments, the compound is a compound of Formula lie:Formula lie or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0154] 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.

[0155] In some embodiments, compound is a compound of Formula lid:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0156] 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.

[0157] In some embodiments, the compound is a compound of Formula lie:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0158] 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.

[0159] In some embodiments, the compound is a compound of Formula Ilf:Formula Ilf or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0160] 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.

[0161] In some embodiments, the compound is a compound of Formula Ilg:Formula Ilg or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0162] 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.

[0163] In some embodiments, the compound is a compound of Formula Ilh:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0164] 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.

[0165] In some embodiments, the compound is a compound of Formula Ili:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0166] 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.

[0167] In some embodiments, the compound is a compound of Formula Ilj :Formula Ilj or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0168] 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.

[0169] In some embodiments, the compound is a compound of Formula Iln:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0170] 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.

[0171] In some embodiments, the compound is a compound of Formula lip:Formula Up or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0172] 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.

[0173] 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; orR2and R3are taken together to form oxo or thio;R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3- locycloalkyl; 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, Ci- 6haloalkyl, C3-iocycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; orR4and 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-iocycloalkyl, 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- locycloalkyl, 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-iocycloalkyl, 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-iocycloalkyl, 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-iocycloalkyl 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-iocycloalkyl, 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-iocycloalkyl; each R11is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R13is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-iocycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

[0174] 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.

[0175] 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.

[0176] 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, Ce- waryl, 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 Ci- 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-memberedheteroaryl; 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.

[0177] 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.

[0178] In some embodiments, R4and R5are independently selected from C1-6alkyl, Ci- 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 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, Ci- 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- locycloalkyl; 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-iocycloalkyl; 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- locycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR9R10, -OR11, -C(O)R11, -C(O)OR11, and - C(O)NR9R10.

[0179] 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 heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR9R10, - OR11, -C(O)R11, -C(O)OR11, and -C(O)NR9R10.

[0180] 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 Ci- 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.

[0181] 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, Ce-loaryl, 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.

[0182] 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, Ci- 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, Ci- 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.

[0183] 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, Ci- 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, Ci- 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.

[0184] 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, Ci- 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- locycloalkyl 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, Ci- 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. In some embodiments, two R8’s can be taken together to form a C3-iocycloalkyl optionally 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, R9and R10are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-iocycloalkyl. 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.

[0186] In some embodiments, each R11is independently selected from H, C1-6alkyl, Ci- 6heteroalkyl, C1-6haloalkyl, C3-iocycloalkyl, 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 Ci- ealkyl.

[0187] In some embodiments, each R12is independently selected from C1-6alkyl, Ci- 6heteroalkyl, C1-6haloalkyl, C3-iocycloalkyl, 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.

[0188] In some embodiments, each R13is independently selected from H, C1-6alkyl, Ci- 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.

[0189] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0190] 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.

[0191] In some embodiments, the compound is a compound of Formula Illa:Formula Illa or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the compound is a compound of Formula Illb :Formula Illb 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, Ce- waryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0193] 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.

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

[0195] In some embodiments, the compound is a compound of Formula IIIc:Formula IIIc or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the compound is a compound of Formula Hid:Formula Illd 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, Ce- waryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0197] 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.

[0198] 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.

[0199] In some embodiments, the 15-PGDH inhibitor is a compound of Formula Ilk: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; orR2and 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, CI- ealkyl, 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, CI- ealkyl, 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, Cs- ecycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, Cs- ecycloalkyl, 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.

[0200] 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.

[0201] 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 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, 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.

[0202] In some embodiments, R2is H and R3is -CF3. In some embodiments, R2and R3are taken together to form oxo.

[0203] 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.

[0204] 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- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. 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, 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.

[0205] 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, 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, and -NR11SO2NR7R8. In some embodiments, R6is selected from H, halo, -NR7R8, -OR9, -C(O)R9, -C(O)OR9, and- C(O)NR7R8.

[0206] 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 Ci- 6haloalkyl. In some embodiments, R7and R8are independently selected at each occurrence from H and C1-6alkyl.

[0207] In some embodiments, each R9is independently selected from H, C1-6alkyl, Ci- 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.

[0208] In some embodiments, each R10is independently selected from C1-6alkyl, Ci- 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.

[0209] In some embodiments, each R11is independently selected from H, C1-6alkyl, Ci- 6haloalkyl, and C3-6cycloalkyl. In some embodiments, each R11is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R11is independently selected from H and C1-6alkyl.

[0210] 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.

[0211] In some embodiments, the 15-PGDH inhibitor is a compound of Formula Ilm:Formula Ilm 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; orR2and 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, Ci- 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, Ce- waryl, 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- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-iocycloalkyl; 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.

[0212] 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-iocycloalkyl, 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.

[0213] In some embodiments, R2is H and R3is -CF3. In some embodiments, R2and R3are taken together to form oxo.

[0214] 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, C 1 -6haloalky 1, 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.

[0215] 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-iocycloalkyl, 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-iocycloalkyl, 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-iocycloalkyl, 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.

[0216] 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 -NR10SO2NR6R7In some embodiments, R5is selected from halo, — NR6R7, -OR8, -C(O)R8, -C(O)OR8, and- C(O)NR6R7

[0217] 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, Ci- 6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0218] In some embodiments, each R8is independently selected from H, C1-6alkyl, Ci- 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.

[0219] In some embodiments, each R9is independently selected from C1-6alkyl, Ci- 6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. Insome embodiments, each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, Ci- 6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0220] In some embodiments, each R10is independently selected from H, C1-6alkyl, Ci- 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] In some embodiments, the 15-PGDH inhibitor is a compound of Formula Ilq:Formula Ilq 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; orR2and 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, Ci- 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, Ce- waryl, 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- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-iocycloalkyl; 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.

[0225] 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-iocycloalkyl, 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.

[0226] In some embodiments, R2is H and R3is -CF3. In some embodiments, R2and R3are taken together to form oxo.

[0227] 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, C 1 -6haloalky 1, 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.

[0228] 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-iocycloalkyl, 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-iocycloalkyl, 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-iocycloalkyl, 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-iocycloalkyl, 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.

[0229] 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 -NR10SO2NR6R7In some embodiments, R5is selected from halo, -NR6R7, -OR8, -C(O)R8, -C(O)OR8, and- C(O)NR6R7

[0230] 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, Ci- 6haloalkyl. In some embodiments, R6and R7are independently selected at each occurrence from H and C1-6alkyl.

[0231] In some embodiments, each R8is independently selected from H, C1-6alkyl, Ci- 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.

[0232] In some embodiments, each R9is independently selected from C1-6alkyl, Ci- 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, Ci- 6haloalkyl. In some embodiments, each R9is independently selected from C1-6alkyl.

[0233] In some embodiments, each R10is independently selected from H, C1-6alkyl, Ci- 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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, Ci- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl;R2is H and R3is -CF3; orR2and R3are taken together to form oxo;R4and R5are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and Cs- ecycloalkyl; 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, Ci- 6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl; orR4and 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, Cs- ecycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, Cs- ecycloalkyl, 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] In some embodiments, R2is H and R3is -CF3. In some embodiments, R2and R3are taken together to form oxo.

[0242] In some embodiments, R4and R5are independently selected from C1-6alkyl, Ci- 6heteroalkyl, C1-6haloalkyl, and C3-iocycloalkyl; 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-iocycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4and R5are independently selected from C3-iocycloalkyl; 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, Ci-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- locycloalkyl; 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- locycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR9R10, -OR11, -C(O)R11, -C(O)OR11, and - C(O)NR9R10.

[0243] 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-iocycloalkyl, 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 heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR9R10, - OR11, -C(O)R11, -C(O)OR11, and -C(O)NR9R10.

[0244] 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, Ci-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, Ci-6alkyl, C1-6heteroalkyl, and Ci- 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.

[0245] 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, Ci-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, Ci- 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.

[0246] 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, Ci- 6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R7and R8is independentlyselected 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.

[0247] 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.

[0248] In some embodiments, each R11is independently selected from H, C1-6alkyl, Ci- 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 Ci- ealkyl.

[0249] In some embodiments, each R12is independently selected from C1-6alkyl, Ci- 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.

[0250] In some embodiments, each R13is independently selected from H, C1-6alkyl, Ci- 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.

[0251] 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.

[0252] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0253] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0254] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0255] In some cases, the solubility and hPGDH ICso 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.

[0256] Provided in Table 3 are analytical data for some of the inhibitors described herein.Table 3: Analytical data for select inhibitors-Ill-

[0257] 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 CR1orN;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 Ci-Ce 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- Cs 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 Ci-Ce alkyl, substituted or unsubstituted Ci-Ce 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; whereineach R13is independently halogen, CN, -NO2, — NR8R9, -OR10, -SR8, -C(O)R10, — C(O)OR10, or -C(O)NR8R9;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted Ci-Cs 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 Ci-Ce hydroxy alkyl, 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 Ci-Ce 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, 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(0)0CH3, -C(O)NH2, -C(0)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

[0258] In some embodiments, the 15-PGDH inhibitor is a compound 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 CR1orN;Y is CR2ofN;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9substituted or unsubstituted Ci-Ce 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 Ci-Ce 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 orunsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce 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 Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs 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,-N02, — NR8R9, -OH, —OR10, -SR8, - C(O)R10, -C(O)OR10, -C(O)NR8R9,-SOR11, -SO2R11, -NR8C(O)R9, Ci-C6alkyl, Ci-Ce haloalkyl, Ci-Ce 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- Ce cycloalkyl ring;XAis NR5R5or OR5; wherein each R5is independently H or Ci-Ce alkyl;R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a C3- Ce cycloalkyl ring; each R8and R9is independently selected from H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, and C4-C10 heterocycloalkyl; each R10is independently selected from H, Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce heteroalkyl, Ci- Ce haloalkyl, C3-C8 cycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl; each R11is independently selected from Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from H, Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce haloalkyl, and C3-C8 cycloalkyl; and p is 1, 2, 3, or 4.

[0259] 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 isa 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, benzotri azole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyridine, or tetrazolo pyridine. In some embodiments, ring Q is [l,2,4]triazolo[l,5-a]pyridine.

[0260] 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.

[0261] In some embodiments, ring Q is phenyl, pyridine, or triazolopyridine.

[0262] 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 Ci-Ce 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted orunsubstituted Ce-Cio 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce 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(0)0CH3, -C(O)NH2, -C(0)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0263] In some embodiments, X1, X2, X3and X4are each CR3.

[0264] In some embodiments, X1is N; and X2, X3, and X4are each CR3.

[0265] In some embodiments, X1and X2are each N; and X3and X4are each CR3.

[0266] In some embodiments, X1and X3are each N; and X2and X4are each CR3.

[0267] In some embodiments, X1and X4are each N; and X2and X3are each CR3.

[0268] In some embodiments, X1, X2, and X3are each N; and X4is CR3.

[0269] In some embodiments, X1, X2, and X4are each N; and X3is CR3.

[0270] 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 Ci-Ce 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 Ci-Ce 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.

[0271] 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.

[0272] 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 CR1orN;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 Ci-Ce alkyl, or substituted or unsubstituted Cs-Cs cycloalkyl; each R2is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3- Cs 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 Ci-C6haloalkyl, 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; whereineach R13is independently halogen, CN, -NCh, — NR8R9, -OR10, -SR8, -C(O)R10, — C(O)OR10, or -C(O)NR8R9;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted Ci-Cs 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,-N02, -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 Ci-Ce hydroxy alkyl, 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 Ci-Ce 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce 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(0)0CH3, -C(O)NH2, -C(0)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0273] 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 CR1orN;X1is N or CR3a;Y is CR2or N;R1is H; each R2is independently H or Ci-Ce 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 Ci-Ce alkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl, each of which is substituted with one or more R13; whereineach R13is independently halogen, CN, -NO2, — NR8R9, -OR10, -SR8, -C(O)R10, — C(O)OR10, or -C(O)NR8R9;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs 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 Ci-C6 haloalkyl, substituted or unsubstituted Ci-Ce 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;XAis -OR5; wherein each R5is independently H or Ci-Ce 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl,substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio 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 Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce 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(0)0CH3, -C(O)NH2, -C(0)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0274] In some embodiments, XAis NR5R5. In some embodiments, XAis OR5.

[0275] In some embodiments, Y is N. In some embodiments, Y is CR2.

[0276] In some embodiments, the compound of Formula V has the structure of Formula Via, or a pharmaceutically acceptable salt thereof:Formula Via.

[0277] In some embodiments, the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:Formula VIb.

[0278] In some embodiments, Z is N. In some embodiments, Z is CR1. In some embodiments, Z is CH.

[0279] In some embodiments, the compound of Formula V has the structure of Formula Vila, or a pharmaceutically acceptable salt thereof:Formula Vila.

[0280] In some embodiments, the compound of Formula V has the structure of FormulaVllb, or a pharmaceutically acceptable salt thereof:Formula (IVb).

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

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

[0283] In some embodiments, R1is H, halogen, -OR10, -C(O)R10, -C(O)OR10, or substituted or unsubstituted Ci-Ce alkyl. In some embodiments, R1is H.

[0284] In some embodiments, each R2is independently H, halogen, -OR10, — C(O)R10, - C(O)OR10, or substituted or unsubstituted Ci-Ce alkyl. In some embodiments, each R2is independently H or Ci-Ce alkyl.

[0285] In some embodiments, each R2is H.

[0286] In some embodiments, X1is CR3a. In some embodiments, X1is N.

[0287] 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 Ci-Ce alkyl, substituted or unsubstituted Ci-Ce 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 Ci-Ce alkyl, substituted or unsubstituted Ci-Ce 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 Ci-Ce 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 each independently selected from H, halogen, substituted or unsubstituted Ci-Ce alkyl, -C(O)R10, -C(O)NR8R9, C3-C6 heterocycloalkyl, and 5- membered heteroaryl.

[0288] 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 Ci-Ce alkyl substituted with -C(O)OH.

[0289] 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 Ci-Ce alkyl, substituted or unsubstituted Ci-Ce 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 Ci-Ce 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 or halogen; and R3cis selected from -NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis selected from substituted or unsubstituted Ci-Ce 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.

[0290] 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.

[0291] In some embodiments, R3aand R3bare each H.

[0292] 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 Ci-Ce 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 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 Ci-Ce alkyl, substituted orunsubstituted Ci-Cehaloalkyl, 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 Ci-Ce alkyl, -C(O)R10, - C(O)NR8R9, C3-C6 heterocycloalkyl, and 5- membered heteroaryl.

[0293] 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.

[0294] 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.

[0295] In some embodiments, R3aand R3care each H.

[0296] In some embodiments, each R3, R3a, R3b, and R3care 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.

[0297] In some embodiments, each R3, R3a, R3b, or R3cis independently selected from the

[0298] In some embodiments, each R3, R3a, R3b, or R3cis independently selected from the5 5, in some embodiments, each R3, R3a,R3b, or R3Cis independently selected from the group consisting of,In some embodiments, each R3, R3a, R3b, or R3cis independently selected from the group consisting

[0299] In some embodiments, R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs 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 Ci- Cs alkyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, or substituted or unsubstituted Ci-Cs hydroxy alkyl. In some embodiments, R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted Ci-Cs heteroalkyl, or substituted or unsubstituted Ci-Cs hydroxy alkyl.

[0300] In some embodiment, R4is substituted or unsubstituted Ci-Cs alkyl or substituted or unsubstituted Ci-Cs heteroalkyl. In some embodiment, R4is substituted or unsubstituted Ci- Cs alkyl. In some embodiments, the alkyl is a straight chain or branched alkyl. In some embodiment, R4is substituted or unsubstituted Ci-Cs 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-(Ci-C4 alkyl), -CH2-O-(Ci-C4alkyl), substituted or unsubstituted -CH2CH2-O-(Ci-C4 haloalkyl), -CH2-O- (C1-C4 haloalkyl), -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6cycloalkyl), -CH2CH2-O- (C3-C6 heterocycloalkyl), or -CH2-O-(C3-Ce heterocycloalkyl). In some embodiment, R4is substituted or unsubstituted -CH2CH2-O-(Ci-C4 alkyl), -CH2-O-(Ci-C4 alkyl), substituted or unsubstituted -CH2CH2-O-(Ci-C4 haloalkyl), or -CH2-O-(Ci-C4 haloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-Ce cycloalkyl), -CH2-O-(C3-Ce cycloalkyl), -CH2CH2- O-(C3-Ce heterocycloalkyl), or -CH2-O-(C3-Ce heterocycloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-C6 cycloalkyl). In some embodiments, R4is -CH2-O-(C3-Ce cycloalkyl).In some embodiments, R4is -CH2CH2-O-(C3-Ce heterocycloalkyl). In some embodiments, R4is -CH2-O-(C3-C6heterocycloalkyl).

[0301] In some embodiments, R4is substituted or unsubstituted Ci-Cs alkyl, which is substituted with one or more halogen, -OR10, Ci-Cs alkyl, or C3-C6 cycloalkyl.

[0302] 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

[0303] 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.

[0304] In some embodiments, each R6is independently halogen, -CN,-NCh, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SOR11, -SO2R11, -NR8C(O)R9, Ci-C6alkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, 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, CI-C6alkyl, Ci-Cehaloalkyl, Ci-C6hydroxyalkyl, 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-C8 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, spirocyclic or bridged cycloalkyl. In some embodiments, each R6is independentlycyclopropyl, 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.

[0305] In some embodiments, two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-Ce cycloalkyl or substituted or unsubstituted C3-Ce 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-Ce heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they 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.

[0306] In some embodiments, R4is -CH3, -CH2CH3, -CH2CH3CH3, -CH2(CH2)2CH3, - CH2(CH2)3CH3, -CH2(CH2)4CH3, -CH2CH2CH(CH3)2, substituted or unsubstitutedcyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substitute or unsubstituted oxetane, substituted or

[0307] In some embodiments, each R5is independently Ci-Ce 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.

[0308] In some embodiments, R5ais CH3. In some embodiments, R5ais H.

[0309] 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.

[0310] In some embodiments, each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C 10 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, Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, and C3-C10 cycloalkyl. In some embodiments, each R8and R9is independently selected at each occurrence from H, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R8and R9is independently selected at each occurrence from C3-C 10 cycloalkyl and C3-C10 heterocycloalkyl.

[0311] In some embodiments, each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R10is independently selected from H, Ci-Ce alkyl, C3- C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R10is independently selected from H and Ci-Ce alkyl. In some embodiments, each R10is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0312] In some embodiments, each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio 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 Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from Ci-Ce alkyl, Ci-Ceheteroalkyl, and Ci-Ce haloalkyl. In some embodiments, each R11is independently selected from C3-C 10 cycloalkyl and C3-C10 heterocycloalkyl.

[0313] In some embodiments, each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce 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 Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R12is independently selected from H, straight or branched chain Ci-Ce alkyl. In some embodiments, each R12is independently selected from C3-C10 cycloalkyl and C3-C 10 heterocycloalkyl.

[0314] 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.

[0315] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. 1 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.

[0316] In some embodiments, the PGDH inhibitor is a compound described in Table 4, or a pharmaceutically acceptable salt thereof.EXAMPLES

[0317] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.Example 1: Effects of tirzepatide and a 15-PGDH inhibitor DIO aged miceThe effect of administration of tirzepatide and a 15-PGDH inhibitor in cohorts of diet- induced obesity (DIO) aged mice was assessed. Briefly, mice were aged (26 weeks) male C57B1 / 6J mice. The aged mice were exposed to a DIO procedure in which they were placed on a high fat diet for 20 days or kept on a control chow diet. Every 48 hours, mice were administered, alone or in combination, either v6hicle, a 15-PGDH inhibitor (10 mg / kg, 30 mg / kg, or 60 mg / kg), or tirzepatide (10 nmol / kg), an experimental timeline of which is shown in FIG. 1A, and with an alternative exemplary experimental timeline shown in FIG. IB. FIG. 2A shows the effects of tirzepatide treatment (10 nmol / kg) on maximal muscle force in an aged DIO mouse model compared to DIO mice that received v6hicle administration or mice on a control chow diet, and demonstrates that DIO-mice treated with tirzepatide showed a decrease in maximal muscle relative to DIO-mice treated with v6hicle alone. FIG. 2B shows the effects of tirzepatide treatment (10 nmol / kg) alone or in combination with a 15- PGDH inhibitor (3 mg / kg, 10 mg / kg, or 30 mg / kg) on maximal muscle force in an aged DIOmouse model and demonstrates that co-administration with the 15-PGDH inhibitor increased maximal mouse force in DIO-mice compared to DIO-mice administered tirzepatide alone. FIG. 2C shows the data of FIG. 2A and FIG. 2B in a single graph.

[0318] While preferred embodiments of the present disclosure 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 disclosure. It should be understood that various alternatives to the embodiments described herein may be employed. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a subject having obesity, the method comprising administering to the subject:(a) an effective amount of an agent selected from the group consisting of: a glucagon- like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor coagonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co-agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof; and(b) an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, thereby treating the subject having obesity.

2. The method of claim 1, wherein, after the administering, the subject experiences increased muscle mass and / or increased muscle function, as compared to a subject treated with the agent in the absence of the 15-PGDH inhibitor.

3. The method of claim 1, wherein, after the administering, the subject experiences a reduction in a loss of muscle mass and / or a loss of muscle function, as compared to a subject treated with the agent in the absence of the 15-PGDH inhibitor.

4. The method of claim 3, wherein the reduction in the loss of muscle mass and / or loss of muscle function comprises a reduction in a rate of loss of muscle mass and / or loss of muscle function, and / or a reduction in an amount of loss of muscle mass and / or loss of muscle function.

5. The method of any one of claims 2-4, wherein the muscle function comprises muscle force, muscle stamina, and / or muscle endurance.

6. The method of any one of claims 1-5, wherein the subject has sarcopenic obesity.

7. The method of any one of claims 1-6, wherein, after the administering, the subject experiences weight loss without a concomitant loss of muscle mass and / or muscle function.

8. The method of any one of claims 1-7, wherein the subject has a body mass index of at least 25 kg / m2.

9. The method of any one of claims 1-8, wherein the subject has a body mass index of at least 40 kg / m2.

10. The method of any one of claims 1-9, wherein the subject is at least 40 years of age.

11. The method of any one of claims 1-10, wherein the subject is at least 65 years of age.

12. The method of any one of claims 1-11, wherein the 15-PGDH inhibitor and the agent are administered to the subject in a single formulation.

13. The method of any one of claims 1-11, wherein the 15-PGDH inhibitor and the agent are administered to the subject in separate formulations.

14. The method of any one of claims 1-13, wherein the 15-PGDH inhibitor is administered to the subject once every day, once every 2 days, once every 3 days, or less frequently than once every 3 days.

15. The method of any one of claims 1-14, wherein the 15-PGDH inhibitor is administered by oral administration.

16. The method of any one of claims 1-15, wherein the agent is administered to the subject once every day, less frequently than once a day, once every week, less frequently than once every week, once every month, or less frequently than once every month.

17. The method of any one of claims 1-16, wherein the agent is administered to the subject by oral administration or by subcutaneous administration.

18. A method of increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in a subject in need thereof, the method comprising: administering to the subject an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, wherein, prior to the administering, the subject has experienced a decrease in muscle mass and / or muscle function associated with administration of an agent selected from the group consisting of: a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependentinsulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor co-agonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co-agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof, thereby increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in the subject.

19. The method of claim 18, wherein the reducing loss of muscle mass and / or muscle function comprises a reduction in a rate of loss of muscle mass and / or loss of muscle function, and / or a reduction in an amount of loss of muscle mass and / or loss of muscle function.

20. The method of claim 18 or 19, wherein the muscle function comprises muscle force, muscle stamina, and / or muscle endurance.

21. The method of any one of claims 18-20, wherein the subject is at least 40 years of age.

22. The method of any one of claims 18-21, wherein the subject is at least 65 years of age.

23. The method of any one of claims 18-22, wherein the 15-PGDH inhibitor is administered to the subject once every day, once every 2 days, once every 3 days, or less frequently than once every 3 days.

24. The method of any one of claims 18-23, wherein the 15-PGDH inhibitor is administered by oral administration.

25. The method of any one of claims 18-24, wherein the subject was administered the agent to treat obesity.

26. The method of claim 25, wherein the subject has, or prior to the administering the 15- PGDH inhibitor had, a body mass index of at least 25 kg / m2.

27. The method of claim 25 or 26, wherein the subject has, or prior to the administering the 15-PGDH inhibitor had, a body mass index of at least 40 kg / m2.

28. The method of any one of claims 18-24, wherein the subject has, or prior to the administering the 15-PGDH inhibitor had, a body mass index of less than 25 kg / m2.

29. The method of any one of claims 18-28, wherein the subject was administered the agent for cosmetic weight loss.

30. The method of any one of claims 18-29, further comprising administering the agent to the subject.

31. The method of claim 30, wherein the 15-PGDH inhibitor and the agent are administered to the subject in a single formulation.

32. The method of claim 30, wherein the 15-PGDH inhibitor and the agent are administered to the subject in separate formulations.

33. The method of any one of claims 30-32, wherein the agent is administered to the subject once every day, less frequently than once every day, once every week, less frequently than once every week, once a month, or less frequently than once a month.

34. The method of any one of claims 30-33, wherein the agent is administered to the subject by oral administration or by subcutaneous administration.

35. A method of treating prediabetes or diabetes mellitus in a subject, the method comprising administering to the subject:(a) an effective amount of an agent selected from the group consisting of: a glucagon- like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor coagonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co-agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof; and(b) an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor; thereby treating prediabetes or diabetes mellitus in the subject.

36. The method of claim 35, wherein the diabetes mellitus is Type 1 diabetes mellitus.

37. The method of claim 35, wherein the diabetes mellitus is Type 2 diabetes mellitus.

38. The method of any one of claims 35-37, wherein, after the administering, the subject experiences increased muscle mass and / or increased muscle function.

39. The method of any one of claims 35-37, wherein, after the administering, the subject experiences a reduction in a loss of muscle mass and / or a loss of muscle function.

40. The method of claim 39, wherein the subject experiences a reduction in a rate of loss of muscle mass and / or loss of muscle function, and / or a reduction in an amount of loss of muscle mass and / or loss of muscle function.

41. The method of any one of claims 38-40, wherein the muscle function comprises muscle force, muscle stamina, and / or muscle endurance.

42. The method of any one of claims 35-41, wherein the subject has obesity.

43. The method of any one of claims 35-42, wherein the subject has a body mass index of at least 25 kg / m2.

44. The method of any one of claims 35-43, wherein the subject has a body mass index of at least 40 kg / m2.

45. The method of any one of claims 35-41, wherein the subject has a body mass index of less than 25 kg / m2.

46. The method of any one of claims 35-41 or 45, wherein the subject has normal weight type 2 diabetes.

47. The method of any one of claims 35-46, wherein, after the administering, the subject experiences weight loss without a concomitant loss of muscle mass and / or muscle function.

48. The method of any one of claims 35-47, wherein, after the administering, the subject has a decrease in Hemoglobin A1C (HbAic) levels, as compared to the subject prior to the administering.

49. The method of any one of claims 35-48, wherein, after the administering, the subject has a greater decrease in HbAic levels as compared to a subject treated with the agent in the absence of the 15-PGDH inhibitor.

50. The method of any one of claims 35-49, wherein, after the administering, the subject has a decrease in HbAic levels comparable to or greater than HbAic levels in a subject having type 2 diabetes undergoing aerobic exercise and / or strength training.

51. The method of any one of claims 35-50, wherein the 15-PGDH inhibitor and the agent are administered to the subject in a single formulation.

52. The method of any one of claims 35-50, wherein the 15-PGDH inhibitor and the agent are administered to the subject in separate formulations.

53. The method of any one of claims 35-52, wherein the 15-PGDH inhibitor is administered to the subject once every day, once every 2 days, once every 3 days, or less frequently than once every 3 days.

54. The method of any one of claims 35-53, wherein the 15-PGDH inhibitor is administered by oral administration.

55. The method of any one of claims 35-54, wherein the agent is administered to the subject once every day, less frequently than once every day, once every week, less frequently than once every week, once every month, or less frequently than once every month.

56. The method of any one of claims 35-55, wherein the agent is administered to the subject by oral administration or by subcutaneous administration.

57. The method of any one of claims 35-56, further comprising administering insulin to the subject.

58. The method of claim 57, wherein the insulin is selected from the group consisting of: rapid-acting insulin, short-acting insulin, intermediate-acting insulin, mixed insulin, and long- acting insulin.

59. The method of claim 58, wherein the rapid-acting insulin is selected from the group consisting of: insulin aspart, insulin glulisine, and insulin lispro.

60. The method of claim 58, wherein the long-acting insulin is selected from the group consisting of: insulin detemir, insulin glargine, and insulin degludec.

61. A method of treating fatty liver disease / nonalcoholic steatohepatitis (NASH) / metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising administering to the subject:(a) an effective amount of an agent selected from the group consisting of: a glucagon- like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a glucagon receptor agonist, a GLP-1 receptor / GIP receptor coagonist, a GLP-1 receptor agonist / GIP receptor antagonist, a GLP-1 receptor / glucagon receptor co-agonist, a GLP-1 receptor / GIP receptor / glucagon receptor triple agonist, a GLP-1 receptor / GLP-2 receptor co-agonist, a combination of a GLP-1 receptor agonist and an amylin receptor agonist, and any combination thereof; and(b) an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor; thereby treating fatty liver disease / NASH / MASH in the subject.

62. The method of any one of claims 1-61, wherein the glucagon receptor agonist is selected from the group consisting of: glucagon, diazoxide, and dasiglucagon.

63. The method of any one of claims 1-62, wherein the GLP-1 receptor agonist is selected from the group consisting of: exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, orforglipron, danuglipron, and SAR425899.

64. The method of any one of claims 1-63, wherein the GIP receptor agonist is ZP6590.

65. The method of any one of claims 1-64, wherein the GLP-1 receptor / GIP receptor co- agonist is selected from the group consisting of: tirzepatide and CT-868.

66. The method of any one of claims 1-65, wherein the GLP-1 receptor agonist / GIP receptor antagonist is AMG133.

67. The method of any one of claims 1-66, wherein the GLP-1 receptor / glucagon receptor co-agonist is selected from the group consisting of: pegapamodutide, BI 456909, BI 456906, mazdutide, pemvidutide, and NN9277.

68. The method of any one of claims 1-67, wherein the GLP-1 receptor / GIP receptor / glucagon receptor triple agonist is selected from the group consisting of: retatrutide, NN9423, and efocipegtrutide.

69. The method of any one of claims 1-68, wherein the GLP-1 receptor / GLP-2 receptor co-agonist is dapiglutide.

70. The method of any one of claims 1-69, wherein the combination of a GLP-1 receptor agonist and an amylin receptor agonist or the GLP-1 receptor / amylin receptor co-agonist is selected from the group consisting of: a combination of cagrilintide + semaglutide, and amycretin.

71. A method of increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in a subject, the method comprising: administering to the subject an effective amount of a 15-hydroxyprostaglandin d6hydrogenase (15-PGDH) inhibitor, wherein, prior to the administering, the subject underwent gastric bypass surgery, thereby increasing muscle mass and / or muscle function, or reducing loss of muscle mass and / or muscle function, in the subject.

72. The method of claim 71, wherein, prior to the administering, the subject has experienced a decrease in muscle mass and / or muscle function.

73. The method of claim 72, wherein the reducing loss of muscle mass and / or muscle function comprises reducing a rate of loss of muscle mass and / or loss of muscle function, and / or reducing an amount of loss of muscle mass and / or loss of muscle function.

74. The method of any one of claims 71-73, wherein the muscle function comprises muscle force, muscle stamina, and / or muscle endurance.

75. The method of any one of claims 71-74, wherein the 15-PGDH inhibitor is administered to the subject once every day, once every 2 days, once every 3 days, or less frequently than once every 3 days.

76. The method of any one of claims 71-75, wherein the 15-PGDH inhibitor is administered by oral administration.

77. The method of any one of claims 71-76, wherein prior to the gastric bypass surgery, the subject had a body mass index of at least 40 kg / m2.

78. The method of any one of claims 1-77, 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- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R2is H and R3is -CF3; orR2and 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- locycloalkyl, 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- locycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10- membered heteroaryl;R6and R7are independently selected at each occurrence from H, C1-6alkyl, Ci- 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- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3- locycloalkyl; 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- locycloalkyl, 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; provided that said compound of Formula I is not79. The method of any one of claims 1-77, wherein the compound is a compound of Formula la:Formula la or a pharmaceutically acceptable salt thereof.

80. The method of any one of claims 1-77, wherein the 15-PGDH inhibitor is a compound of Formula lb:Formula lb or a pharmaceutically acceptable salt thereof.

81. The method of any one of claims 1-77, 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, C 1 -6haloalky 1, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;R2is H and R3is -CF3; orR2and 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-iocycloalkyl, 3- to 10-membered heterocycloalkyl, 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, Ci- 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- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R9is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3- locycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; each R10is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-iocycloalkyl; and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

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