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WO2025006810A1 - Méthodes de dosage intermittent pour le traitement d'un état associé à une augmentation de 15-pgdh - Google Patents

Méthodes de dosage intermittent pour le traitement d'un état associé à une augmentation de 15-pgdh Download PDF

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Publication number
WO2025006810A1
WO2025006810A1 PCT/US2024/035916 US2024035916W WO2025006810A1 WO 2025006810 A1 WO2025006810 A1 WO 2025006810A1 US 2024035916 W US2024035916 W US 2024035916W WO 2025006810 A1 WO2025006810 A1 WO 2025006810A1
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substituted
unsubstituted
alkyl
cycloalkyl
haloalkyl
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Annie M. CLARK
Didier Bagnol
Micah WEBSTER
Alexander CASDIN
Bruce Fahr
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Epirium Bio Inc
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Epirium Bio Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • Prostaglandins are a group of physiologically active lipid compounds with diverse biological effects. Treatment of conditions, diseases, or disorders may require activation of prostaglandins, or inhibition of inactivation of prostaglandins. Hydroxyprostaglandin dehydrogenases, such as 15 -hydroxyprostaglandin dehydrogenase (15-PGDH) are involved in the inactivation of prostaglandins. As such, conditions, diseases, or disorders associated with prostaglandins can be prevented, treated and/or managed using inhibitors of hydroxyprostaglandin dehydrogenase, such as inhibitors of 15-PGDH.
  • hydroxyprostaglandin dehydrogenase such as inhibitors of 15-PGDH.
  • therapeutic agents such as inhibitors can have drug toxicity, which can lead to adverse effects on a subject.
  • these therapeutic agents In order for these therapeutic agents to be approved for clinical application, they are tested for toxicity.
  • Several therapeutic agents entering clinical trials can fail because they are unsafe or ineffective due to toxicity.
  • a method of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject comprising: administering a 15-PGDH inhibitor to the subject in an amount effective to inhibit 15-PGDH at a level sufficient to treat the condition, wherein the 15-PGDH inhibitor is administered to the subject at a dosing frequency that exhibits reduced toxicity to the subject as compared to a once every day dosing frequency of the 15-PGDH inhibitor at the same amount.
  • 15-PGDH 15-hydroxyprostaglandin dehydrogenase
  • the dosing frequency that exhibits reduced toxicity to the subject is less than once every day. In some instances, the dosing frequency that exhibits reduced toxicity to the subject is once every 2 days, once every 3 days, once every 4 days, once every 5 days, one every 6 days, or once every 7 days. In some instances, the dosing frequency that exhibits reduced toxicity to the subject is less than once every 2 days, less than once every 3 days, less than once every 4 days, less than once every 5 days, less than once every 6 days, or less than once every 7 days. In some instances, the administering comprises administering the 15-PGDH inhibitor when a plasma concentration of the 15-PGDH inhibitor in the subject is below the ECso of the 15-PGDH inhibitor.
  • the present disclosure provides a method of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject, the method comprising: administering a 15-PGDH inhibitor to the subject at an amount effective to increase a plasma concentration of the 15-PGDH inhibitor in the subject to a level above the ECso of the 15-PGDH inhibitor, where the subject has received at least one dose of the 15-PGDH inhibitor prior to the administering, and where the administering comprises administering the 15-PGDH inhibitor to the subject when the subject has a plasma concentration of the 15-PGDH inhibitor that is below the EC50 of the 15-PGDH inhibitor.
  • 15-PGDH 15-hydroxyprostaglandin dehydrogenase
  • the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 48 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15- PGDH inhibitor greater than 72 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15 -PGDH inhibitor greater than 24 hours and less than 72 hours prior to the administering.
  • the administering comprises administering the 15-PDGH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject is at least 2- fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000-fold, or greater than 1000-fold lower than the ECso of the 15-PGDH inhibitor.
  • the method results in reduced toxicity to the subject as compared to administering the same amount of the 15-PGDH inhibitor to the subject when the plasma concentration of the 15-PGDH inhibitor in the subject is above the ECso of the 15-PGDH inhibitor. In some instances, the method results in reduced toxicity to the subject as compared to administering the same amount of the 15-PGDH inhibitor to the subject by once a day administration.
  • the reduced toxicity is selected from the group consisting of: reduced neurological disorders, reduced muscle degeneration, reduced gastrointestinal and/or metabolic distress, reduced inflammation, or any combination thereof.
  • the reduced toxicity is measured by: safety pharmacology, genetic toxicology, acute and subchronic toxicology, absorption, distribution, metabolism, and excretion (ADME) studies, reproductive and developmental toxicity, an evaluation of carcinogenic potential, or any combination thereof.
  • the administering comprises administering the 15-PGDH inhibitor to the subject by oral administration.
  • the 15-PGDH inhibitor is a small molecule.
  • the 15-PGDH inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:
  • X is selected from -OCH 2 - -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH 2 -, -S(O)CH 2 -, -SO 2 CH 2 -; each Y is independently selected from N and CR 11 ; each R 1 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 . 1
  • R 2 is H and R 3 is -CF 3 ; or
  • R 2 and R 3 are taken together to form oxo or thio; each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • each R 5 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 . 1 0 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10- membered heteroaryl;
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, and C 3 - 10 cycloalkyl; each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3 . 1 0 cycloalkyl; each R 11 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • n 0, 1, 2, 3, 4, or 5
  • m 0, 1, 2, 3, or 4
  • p 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • the compound is a compound of Formula la: or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula lb: or a pharmaceutically acceptable salt thereof.
  • 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 CR 5 ;
  • S, V, and Z are independently selected from N and C;
  • R 1 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycl
  • R 2 is H and R 3 is -CF 3 ; or
  • R 2 and R 3 are taken together to form oxo or thio; each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • R 4 ’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3 - 10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • each R 5 is independently selected from H, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;
  • the compound is a compound of Formula lib : or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.
  • the compound is a compound of Formula lie: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.
  • the compound is a compound of Formula lid:
  • the compound is a compound of Formula lie: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.
  • the compound is a compound of Formula Ilf: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.
  • the compound is a compound of Formula Ilg: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.
  • the compound is a compound of Formula Ilh: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.
  • the compound is a compound of Formula Ili : or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.
  • the compound is a compound of Formula Ilj : or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.
  • the compound is a compound of Formula Iln:
  • the compound is a compound of Formula lip: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.
  • the 15-PGDH inhibitor is a compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR 7 ;
  • Y is selected from O, S, SO 2 , and C(R 8 )2;
  • R 1 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , - SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 1 0
  • R 2 is H and R 3 is -CF 3 ; or R 2 and R 3 are taken together to form oxo or thio;
  • R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , - SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 1 0 cycloalkyl, 3- to
  • R 4 and R 5 are 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, -NR 9 R 10 , -OR 11 , -C(O)R 11 , - C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 6 is independently selected from halo, -NR 9 R 10 , -OR 11
  • R 9 and R 10 are independently selected at each occurrence from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 12 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 1 0 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3 - 1 0 cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.
  • the compound is a compound of Formula Illa: or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula Illb :
  • each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , - C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.
  • the compound is a compound of Formula IIIc: or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula Hid: or a pharmaceutically acceptable salt thereof, wherein: each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , - C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.
  • 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 CR 6 , provided that when U is N, at least one of T and Y is N;
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , - SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , -NR 11 SO 2 NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 . 6cycloalkyl, and 5- to 10-membered heteroaryl;
  • R 2 is H and R 3 is -CF 3 ; or
  • R 2 and R 3 are taken together to form oxo; each R 4 is independently selected from H and halo;
  • R 5 is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , - NR 11 SO 2 NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;
  • R 6 is selected from H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , - SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , - NR 11 SO 2 R 9 , -NR 11 SO 2 NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • R 7 and R 8 are independently selected at each occurrence from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; each R 9 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 10 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 6cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3 - 6cycloalkyl; and p is 0,
  • the 15-PGDH inhibitor is a compound of Formula Ilm: or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl;
  • R 2 is H and R 3 is -CF 3 ; or
  • R 2 and R 3 are taken together to form oxo; each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 1 0 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or two R 4 ’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, and C 3 - 10 cycloalkyl; each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3 .
  • 1 0 cycloalkyl n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.
  • the 15-PGDH inhibitor is a compound of Formula Ilq: or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, and 5- to 10-membered heteroaryl;
  • R 2 is H and R 3 is -CF 3 ; or R 2 and R 3 are taken together to form oxo; each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • R 4 ’ S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3 - 10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 . 1 0 cycloalkyl, C 6-10 aryl,
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, and C 3 - 10 cycloalkyl; each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3 .
  • 1 0 cycloalkyl n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.
  • the 15-PGDH inhibitor is a compound of Formula IIIc: or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR 7 ;
  • Y is selected from O, S, SO 2 , and C(R 8 )2;
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , - SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 6cycloalkyl, and 5- to 10-membered heteroaryl;
  • R 2 is H and R 3 is -CF 3 ; or
  • R 2 and R 3 are taken together to form oxo
  • R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , - SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 6cycloalkyl, 3- to 10-membere
  • R 4 and R 5 are 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, -NR 9 R 10 , -OR 11 , -C(O)R 11 , - C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 6 is independently selected from halo, -NR 9 R 10 , -OR 11
  • R 9 and R 10 are independently selected at each occurrence from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 12 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 6cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3 - 6cycloalkyl; and n is 0, 1, 2, 3, or 4.
  • the 15-PGDH inhibitor is a compound selected from the group consisting of:
  • the 15-PGDH inhibitor is a compound selected from the group consisting of:
  • the 15-PGDH inhibitor is a compound selected from the group consisting of:
  • the 15-PGDH inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt thereof:
  • ring Q is phenyl or 5- to 10-membered heteroaryl
  • Z is CR 1 or N
  • Y is CR 2 or N
  • R 1 is H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , - NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; each R 2 is independently H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -CN, -C(O)NR 8 R 9 , - NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; each R 3 is independently selected from H, halogen, -CN, -NO 2 , -NR 8 R 9 ,
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 1 -C 8 aminoalkyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, substituted or unsubstituted C 1 -C 8 hydroxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, each of which is substituted with one or more R 6 ; wherein each R 6 is independently halogen, CN, -NO 2 , -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , - C(O)OR 10 , -C(O)NR 8 R 9
  • X A is -NR 5 R 5 or -OR 5 ; wherein each R 5 is independently H or C 1 -C 6 alkyl;
  • R 5a is H or CH 3 ; or R 5a and one R 6 combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 3 -C 6 heterocycloalkyl; each R 8 and R 9 is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, and substituted or unsubstituted C 3 -C 10 heterocycloalkyl, each of which is optionally substituted with one or more R a
  • ring Q is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 N atoms.
  • ring Q is a phenyl, pyrimidinyl, or pyridinyl.
  • X 1 , X 2 , X 3 and X 4 are each independently N or CR 3 ; each R 3 is independently selected from H, halogen, -CN, -NO 2 , -NR 8 R 9 , -OR 10 , -SR 8 , - C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 8 R 9 , -NR 12 C(O)R 10 , - NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO 2 R 10 , -NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or
  • X 1 , X 2 , X 3 and X 4 are each CR 3 .
  • X 1 is N; and X 2 , X 3 , and X 4 are each CR 3 .
  • X 1 and X 2 are each N; and X 3 and X 4 are each CR 3 .
  • X 1 and X 3 are each N; and X 2 and X 4 are each CR 3 .
  • X 1 and X 4 are each N; and X 2 and X 3 are each CR 3 .
  • X 1 , X 2 , and X 3 are each N; and X 4 is CR 3 .
  • X 1 , X 2 , and X 4 are each N; and X 3 is CR 3 .
  • each R 3 is independently selected from H, halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • each R 3 is independently selected from H, halogen, -C(O)OR 10 , -C(O)NR 8 R 9 , and substituted or unsubstituted 5-membered heteroaryl.
  • the compound has the structure of Formula V, or a pharmaceutically acceptable salt thereof: wherein,
  • Z is CR 1 or N
  • X 1 is N or CR 3a ;
  • Y is CR 2 or N
  • R 1 is H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , - NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; each R 2 is independently H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -CN, -C(O)NR 8 R 9 , - NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
  • R 3a , R 3b , and R 3c are each independently selected from H, halogen, -CN, -NO 2 , -NR 8 R 9 , - OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 8 R 9 , - NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO 2 R 10 , -NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocyclo
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 1 -C 8 aminoalkyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, substituted or unsubstituted C 1 -C 8 hydroxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalkyl, each of which is substituted with one or more R 6 ; wherein each R 6 is independently halogen, CN,-N02, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , - C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -NR 8 C(O
  • X A is NR 5 R 5 or OR 5 ; wherein each R 5 is independently H or C 1 -C 6 alkyl;
  • R 5a is H or CH 3 ; or R 5a and one R 6 combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C 3 -C 6 cycloalkyl; each R 8 and R 9 is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, and substituted or unsubstituted C 3 -C 10 heterocycloalkyl, each of which is substituted with one or more R a ; each R 10 is independently selected from H, substituted or unsubstituted C 1 -
  • X A is NR 5 R 5 . In some embodiments, X A is OR 5 . In some embodiments, Yis CR 2 . In some embodiments, Y is N.
  • the compound of Formula V has the structure of Formula Via, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:
  • Z is N. In some embodiments, Z is CR 1 . In some embodiments, Z is CH.
  • the compound of Formula V has the structure of Formula Vila, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula V has the structure of Formula Vllb, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula V has the structure of Formula Vile, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula V has the structure of Formula Vlld, or a pharmaceutically acceptable salt thereof: [0055]
  • X 1 is N.
  • R 3b is H; and R 3c is selected from halogen, -CN, -NO 2 , -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , - SOR 11 , -SO 2 R 11 , -SO 2 NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , - NR 12 SO 2 R 10 , -NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 haloal
  • R 3b is H; and R 3c is selected from halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • R 3c is H; and R 3b is selected from halogen, -CN, -NO 2 , -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 8 R 9 , -NR 12 C(O)R 10 , - NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO 2 R 10 , -NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl,
  • R 3c is H; and R 3b is selected from halogen, -NR 8 R 9 , - OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • R 3c is selected from H, halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • R 3c is -C(O)OR 10 , - C(O)NR 8 R 9 , or substituted or unsubstituted 5-membered heteroaryl.
  • R 3a and R 3b are each H.
  • R 3a is selected from H, halogen, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • R 3a is -C(O)OR 10 , - C(O)NR 8 R 9 , or substituted or unsubstituted 5-membered heteroaryl.
  • R 3b and R 3c are each H.
  • each R 2 is H.
  • R 5a and one of R 6 combine together with the atom(s) to which they are attached to form a C 3 -C 6 cycloalkyl.
  • R 5a is H.
  • R 5 is H.
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted Ci- Cs aminoalkyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, substituted or unsubstituted C 1- C 8 hydroxy alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalkyl, each of which is substituted with one or more R 6 .
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl or substituted or unsubstituted C 1 -C 8 heteroalkyl, each of which is substituted with one or more R 6 .
  • R 4 is substituted or unsubstituted C 3 -C 8 cycloalkyl or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R 6 .
  • R 4 is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl.
  • each R 6 is independently halogen, -NR 8 R 9 , -OR 10 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted C 1 -C 6 hydroxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalkyl.
  • each R 6 is independently halogen, -OR 10 , C 1 -C 6 alkyl, C 1- C 6 haloalkyl, or C 3 -C 8 cycloalkyl.
  • each R 6 is independently -F, -CH 3 , -CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the compound is selected from Table 4, or a pharmaceutically acceptable salt thereof.
  • the condition is a muscle condition.
  • the muscle condition is muscle atrophy, muscle damage, a muscle disorder, or muscle injury.
  • the condition is selected from the group consisting of: Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), an inherited myopathy, myotonic muscular dystrophy (MDD), oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery -Dreifuss muscular dystrophy, myotonia congenita, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysis, polymyositis, rhabdomyolysis, der
  • the condition is spinal muscular atrophy (SMA). In some instances, the condition is facioscapulohumeral muscular dystrophy (FSHD). In some embodiments, the condition is hair loss. In some embodiments, the condition is skin inflammation and/or damage. In some embodiments, the condition is vascular insufficiency. In some embodiments, the condition is congestive heart failure or cardiomyopathy. In some embodiments, the condition is a gastrointestinal disease. In some embodiments, the condition is renal dysfunction. In some embodiments, the condition is a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder.
  • SMA spinal muscular atrophy
  • FSHD facioscapulohumeral muscular dystrophy
  • the condition is hair loss.
  • the condition is skin inflammation and/or damage.
  • the condition is vascular insufficiency.
  • the condition is congestive heart failure or cardiomyopathy.
  • the condition is a gastrointestinal disease
  • the condition is a fibrotic or adhesion disease, disorder, or condition. In some embodiments, the condition is scar formation. In some embodiments, the condition is fibrosis. In some embodiments, the condition is idiopathic pulmonary fibrosis. In some embodiments, the condition is kidney fibrosis. In some embodiments, the condition is acute kidney injury. In some embodiments, the condition is sarcopenia. In some embodiments, the condition is a neuromuscular disease.
  • Fig. 1 shows an overview of the effects of MF-300 on PGE2 signaling.
  • Figs. 2A-2C show the mechanism of action and pharmacokinetic profile of MF-300.
  • Fig. 2A shows the effects of MF-300 on NADH production in a biochemical 15-PGDH inhibition assay.
  • Fig. 2B shows the effects of MF-300 on PGE2 stability in A549 cells.
  • Fig. 2C shows the plasma levels of varying doses of MF-300 twenty-four hours after administration in mice.
  • Figs. 3A-3G show the effects of intraperitoneally administered MF-300 in SMNA7 mice.
  • Fig. 3A shows an experimental overview for assessing the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice.
  • Fig. 3B shows the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice on isometric plantar flexor force.
  • Fig. 3C shows the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice on isometric plantar flexor maximum force.
  • Fig. 3A-3G show the effects of intraperitoneally administered MF-300 in SMNA7 mice.
  • Fig. 3A shows an experimental overview for assessing the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice.
  • Fig. 3B shows the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice on isometric plantar flexor force
  • FIG. 3D shows the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice on isometric plantar flexor maximum force as a percentage relative to the average maximum force of vehicle-treated animals.
  • Fig. 3E shows the level of HPGD expression in gastrocnemius muscles from SMNA7 mice.
  • Fig. 3F shows a principal component analysis of the effects of repeated SMN-C3 and MF-300 administration in gastrocnemius muscles of SMNA7 mice.
  • Fig. 3G shows the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice on the probability of righting within 30 seconds.
  • Figs. 4A-4J show the effects of orally administered MF-300 in SMN1 C/C mice.
  • Fig. 4A shows an experimental overview for assessing the effects of repeated MF-300 administration in SMN1 C/C mice.
  • Fig. 4B shows the effects of repeated MF-300 administration in SMN1 C/C mice on isometric plantar flexor force and percent increase in maximum force relative to vehicle-administered mice.
  • Fig. 4C shows the effects of repeated MF-300 administration in SMN1 C/C mice on isometric plantar flexor force and percent increase in maximum force relative to vehicle-administered mice normalized to muscle mass.
  • Fig. 4D shows an overview and rationale for experiments in which mice were treated with MF-300 and nerve and direct muscle-stimulated contractions measured to localize the effects of MF-300.
  • Fig. 4A shows an experimental overview for assessing the effects of repeated MF-300 administration in SMN1 C/C mice.
  • Fig. 4B shows the effects of repeated MF-300 administration in SMN1 C/C mice on isometric plant
  • FIG. 4E shows the effects of MF-300 treatment on maximal force associated with sciatic nerve stimulation.
  • Fig. 4F shows the effects of MF-300 treatment on maximal force associated with sciatic nerve stimulation and normalized to muscle weight.
  • Fig. 4G shows the effects of MF-300 treatment on maximal force associated with direct muscle stimulation.
  • Fig- 411 shows the effects of MF-300 treatment on maximal force associated with direct muscle stimulation and normalized to muscle weight.
  • Fig. 41 shows the effects of MF-300 treatment on maximal force associated with normalized muscle stimulation to nerve stimulation.
  • Fig- 4 J shows the effects of MF-300 treatment on maximal force associated with normalized muscle stimulation to nerve stimulation and represented as fold difference.
  • Figs. 5A-5H show the effects of orally administered MF-300 in a sciatic nerve crush mouse model.
  • Fig. 5A shows an overview of the experimental timeline for assessing effects of MF-300 in a sciatic nerve crush mouse model on isometric plantar flexor force.
  • Fig. 5B shows the maximum force at baseline for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle.
  • Fig. 5C shows the maximum force on day 14 for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle.
  • Fig. 5D shows the maximum force on day 21 for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle.
  • Fig. 5A shows an overview of the experimental timeline for assessing effects of MF-300 in a sciatic nerve crush mouse model on isometric plantar flexor force.
  • Fig. 5B shows the maximum force at baseline for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300
  • 5E shows the maximum force on day 28 for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle.
  • Fig. 5F shows the maximum force on day 35 for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle.
  • Fig. 5G shows the maximum force normalized by muscle weight on day 35 for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle.
  • Fig. 5H shows muscle mass at the end of testing for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle.
  • Figs. 6A-6F show the effects of intermittently dosed, orally administered MF-300 in SMN1 C/C mice.
  • Fig. 6A shows an overview of the experimental timeline for assessing the effects of intermittently dosed MF-300 on isometric plantar flexor force in SMN1 C/C mice.
  • Fig. 6B shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 60 mg/kg MF-300 administration every day.
  • Fig. 6C shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 60 mg/kg MF-300 administration every 2 days.
  • Fig. 6D shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 60 mg/kg MF-300 administration every 3 days.
  • Fig. 6E shows the effect of intermittent doses of MF-300 treatment on maximum isometric plantar flexor force and percent increase in maximum force relative to vehicle-administered cohorts.
  • Fig. 6F shows the effect of intermittent doses of MF-300 treatment on maximum isometric plantar flexor force and percent increase in maximum force relative to vehicle-administered cohorts normalized to muscle weight.
  • Figs. 7A-7H show the effects of intermittently administered MF-300 in SMNA7 mice.
  • Fig. 7A shows an experimental overview for assessing the effects of SMN-C3 and intermittent MF-300 administration in SMNA7 mice.
  • Fig. 7B shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 30 mg/kg MF-300 administration every day.
  • Fig. 7C shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 30 mg/kg MF-300 administration every two days.
  • Fig. 7D shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 30 mg/kg MF-300 administration every three days.
  • Fig. 7A-7H show the effects of intermittently administered MF-300 in SMNA7 mice.
  • Fig. 7A shows an experimental overview for assessing the effects of SMN-C3 and intermittent MF-300 administration in SMNA7 mice.
  • Fig. 7B shows the predicted plasma concentrations of
  • Fig. 7E shows the predicted plasma concentrations of MF- 300 in cohorts of mice that received 10 mg/kg or 30 mg/kg MF-300 administration every day.
  • Fig. 7F shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 10 mg/kg or 30 mg/kg MF-300 administration every two days.
  • Fig. 7G shows the effect of intermittent doses of MF-300 treatment on maximum isometric plantar flexor force in SMNA7 mice.
  • Fig. 7H shows the effect of intermittent doses of MF-300 treatment on percent increase in maximum force from vehicle in SMNA7 mice.
  • EC50 Half maximal effective concentration refers to the concentration of a drug that induces an effect or a response halfway between the baseline and the maximum possible effect after a certain exposure time.
  • some drugs require maintaining the concentration above the EC50 throughout the dosing interval, which may increase incidents associated with unwanted drug toxicity and side effects.
  • the present disclosure provides methods for administering a 15-PGDH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject falls below the EC50 of the 15-PGDH inhibitor, while maintaining therapeutic efficacy of the 15-PGDH inhibitor. In some instances, the methods described herein reduce or avoid the toxicity associated with more frequent dosing of the 15-PGDH inhibitor.
  • the methods may involve the administration of a 15-PGDH inhibitor to a subject at a dosing frequency that is less than a once a day (QD) dosing frequency and/or at a frequency that reduces toxicity as compared to a once a day (QD) dosing frequency.
  • QD once a day
  • QD once a day
  • the methods may involve administering to a subject (e.g., by oral administration) a 15-PGDH inhibitor at a once every 2 days (Q2D) dosing frequency, a once every 3 days (Q3D) dosing frequency, or less than a once every 3 days dosing frequency.
  • a 15-PGDH inhibitor at a once every 2 days (Q2D) dosing frequency, a once every 3 days (Q3D) dosing frequency, or less than a once every 3 days dosing frequency.
  • the methods may involve administering a 15-PGDH inhibitor to a subject when a plasma concentration of the 15-PGDH inhibitor in the subject is less than the EC50 of the 15-PGDH inhibitor.
  • a subject may receive or may have received at least one dose of a 15-PGDH inhibitor at an amount such that a plasma concentration of the 15-PGDH inhibitor in the subject is above the EC50 of the 15-PGDH inhibitor at some time point after the 15-PGDH inhibitor is administered.
  • the method comprises administering a 15-PGDH inhibitor to the subject at an amount effective to increase a plasma concentration of the 15-PGDH inhibitor in the subject to a level above the EC50 of the 15-PGDH inhibitor.
  • the subject has received at least one dose of the 15-PGDH inhibitor prior to the administering.
  • the administering comprises administering the 15-PGDH inhibitor to the subject when the subject has a plasma concentration of the 15-PGDH inhibitor that is below the EC50 of the 15-PGDH inhibitor.
  • the dosing frequency that exhibits reduced toxicity to the subject is less than once every day. In some embodiments, the dosing frequency that exhibits reduced toxicity to the subject is less than once every 2 days, less than once every 3 days, less than once every 4 days, less than once every 5 days, less than once every 6 days, or less than once every 7 days.
  • the dosing frequency that exhibits reduced toxicity to the subject is less than once every day to once every 10 days, less than once every day to once every 9 days, less than once every day to once every 8 days, less than once every day to once every 7 days, less than once every day to once every 6 days, less than once every day to once every 5 days, less than once every day to once every 4 days, less than once every day to once every 3 days, or less than once every day to once every 2 days.
  • the dosing frequency that exhibits reduced toxicity to the subject is less than once every day to less than once every 10 days, less than once every day to less than once every 9 days, less than once every day to less than once every 8 days, less than once every day to less than once every 7 days, less than once every day to less than once every 6 days, less than once every day to less than once every 5 days, less than once every day to less than once every 4 days, less than once every day to less than once every 3 days, or less than once every day to less than once every 2 days.
  • the ECso is determined using biochemical assays and/or cell-based assays that measure 15-PGDH activity and/or levels of 15-PGDH substrate, such as prostaglandin E2.
  • the administering comprises administering the 15- PGDH inhibitor when a plasma concentration of the 15-PGDH inhibitor in the subject is below the ECso of the 15-PGDH inhibitor.
  • the administering comprises administering the 15-PGDH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject is at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000- fold, or greater than 1000-fold lower than the ECso of the 15-PGDH inhibitor.
  • the administering comprises administering the 15-PGDH inhibitor when the a plasma concentration of the 15-PGDH inhibitor in the subject is below the ECso of the 15-PGDH inhibitor.
  • the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by at least 2-fold, by at least 5-fold, by at least 10-fold, by at least 50-fold, by at least 100-fold, by at least 500-fold, by at least 1000-fold, or greater than 1000-fold.
  • the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 2-fold to about 10-fold than the EC50 of the 15- PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 2-fold to about 100-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15- PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 10-fold to about 100-fold than the EC50 of the 15-PGDH inhibitor.
  • the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 2-fold to about 1000-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 10-fold to about 1000-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 100-fold to about 1000-fold than the EC50 of the 15-PGDH inhibitor.
  • the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 2-fold to about lOOOOO-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 10-fold to about 1 OOOOO-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 100-fold to about 1 OOOOO-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 1000-fold to about 1 OOOOO-fold than the EC50 of the 15- PGDH inhibitor.
  • the administering comprises administering the 15-PGDH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject is at least 2- fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000-fold, or greater than 1000-fold lower than the EC50 of the 15-PGDH inhibitor.
  • the plasma concentration of the 15-PGDH inhibitor in the subject is about 2-fold to about 10-fold lower than the EC50 of the 15-PGDH inhibitor.
  • the plasma concentration of the 15-PGDH inhibitor in the subject is about 2-fold to about 100-fold lower than the EC50 of the 15-PGDH inhibitor.
  • the plasma concentration of the 15-PGDH inhibitor in the subject is about 10- fold to about 100-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 2-fold to about 1000-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 10-fold to about 1000-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 100-fold to about 1000-fold lower than the EC50 of the 15-PGDH inhibitor.
  • the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours, greater than 48 hours, greater than 72 hours, or greater than 96 hours, prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 48 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 72 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours and less than 96 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours and less than 72 hours prior to the administering.
  • the method described herein results in reduced toxicity to the subject as compared to administering the same amount of the 15-PGDH inhibitor to the subject when the plasma concentration of the 15-PGDH inhibitor in the subject is above the EC50 of the 15-PGDH inhibitor. In some instances, the method described herein results in reduced toxicity to the subject as compared to administering the same amount of the 15- PGDH inhibitor to the subject by once a day administration.
  • the administering comprises administering the 15-PGDH inhibitor to the subject by various methods.
  • 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.
  • the administering comprises administering the 15-PGDH inhibitor to the subject by oral administration.
  • the administering comprises administering the 15-PGDH inhibitor to the subject by intramuscular administration.
  • the administering comprises administering the 15-PGDH inhibitor to the subject by intraperitoneal injection.
  • the 15-PGDH inhibitor is a small molecule. In some embodiments, the 15-PGDH inhibitor is an orally bioavailable small molecule.
  • the 15-PGDH inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:
  • R 2 is H and R 3 is -CF 3 ; or
  • R 2 and R 3 are taken together to form oxo or thio; each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • each R 5 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 . 1 0 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10- membered heteroaryl;
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, and C 3 - 10 cycloalkyl; each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3 . 1 0 cycloalkyl; each R 11 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 .
  • X is selected from -OCH 2 -, -C(O)NH- -NHC(O)-, - C(O)NMe-, -NMeC(O)-, -SCH 2 -, -S(O)CH 2 - and -SO 2 CH 2 -.
  • X is -OCH 2 -.
  • X is -C(O)NH-
  • X is -NHC(O)-.
  • X is -C(O)NMe-
  • X is -NMeC(O)-.
  • X is -SCH 2 -.
  • X is -S(O)CH 2 -
  • X is -SO 2 CH 2 -.
  • each Y is independently selected from N and CR 11 . In some embodiments, each Y is N. In some embodiments, each Y is CR 11 . In some embodiments, one Y is N and the other Y is CR 11 .
  • each R 1 is independently selected from halo, -NR 6 R 7 , -OR 8 , - C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 1 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and - NR 10 SO 2 NR 6 R 7 .
  • each R 1 is independently selected from halo, - NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 ,-NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , - NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7 .
  • each R 1 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 .
  • R 2 is H and R 3 is -CF 3 .
  • R 2 and R 3 are taken together to form oxo.
  • R 2 and R 3 are taken together to form thio.
  • each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , - C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10
  • each R 4 is independently selected from halo, -NR 6 R 7 , - OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7 .
  • each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 ,- NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7
  • each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 .
  • each R 5 is independently selected from halo, -NR 6 R 7 , -OR 8 , - C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 5 is independently selected from halo, -NR 6 R 7 , - OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7 .
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 6 and R 7 are independently selected at each occurrence from H, and C 1-6 alkyl.
  • each R 8 is independently selected from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 8 is independently selected from H, and C 1-6 alkyl.
  • each R 9 is independently selected from C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl.
  • each R 11 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 11 is independently selected from halo, -NR 6 R 7 , - OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7 .
  • each R 11 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 ,- NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7
  • each R 11 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 .
  • 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.
  • 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.
  • 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.
  • the compound is a compound of Formula la:
  • the compound is a compound of Formula lb:
  • 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 CR 5 ;
  • S, V, and Z are independently selected from N and C;
  • R 1 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , - C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalky
  • R 2 is H and R 3 is -CF 3 ; or
  • R 2 and R 3 are taken together to form oxo or thio; each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or two R 4 ’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 1 0 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 1 0 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; and n is 1, 2, 3, or 4; and m is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • T, U, W, X, and Y are independently selected from N and CR 5 .
  • at least one of T, U, W, X, and Y is N and the rest are CR 5 .
  • at least two of T, U, W, X, and Y are N and the rest are CR 5 .
  • at least three of T, U, W, X, and Y are N and the rest are CR 5 .
  • at least four of T, U, W, X, and Y are N and the rest are CR 5 .
  • T, U, W, X, and Y are CR 5 .
  • T, U, W, X, and Y are N.
  • 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.
  • R 1 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C
  • R 1 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10- membered heteroaryl.
  • R 1 is selected from C 6-10 aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10- membered heteroaryl.
  • R 1 is selected from C 6-10 aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7 .
  • R 1 is selected from C 6-10 aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and - C(O)NR 6 R 7 .
  • R 2 is H and R 3 is -CF 3 .
  • R 2 and R 3 are taken together to form oxo.
  • R 2 and R 3 are taken together to form thio.
  • each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , - C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10
  • each R 4 is independently selected from halo, -NR 6 R 7 , - OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1- 6 haloalkyl.
  • each R 4 is independently selected from halo, -NR 6 R 7 , - OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7 .
  • each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 .
  • each R 4 is halo.
  • each R 4 is fluoro.
  • R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’S are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • two R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7 .
  • two R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , - C(O)OR 8 , and -C(O)NR 6 R 7 .
  • two R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo.
  • two R 4 ’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are fluoro.
  • each R 5 is independently selected from H, halo, -NR 6 R 7 , - OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 5 is independently selected from H, halo, -NR 6 R 7 , - OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1- 6 haloalkyl.
  • each R 5 is independently selected from H, halo, -NR 6 R 7 , - OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7 .
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 6 and R 7 are independently selected at each occurrence from H and C 1-6 alkyl.
  • each R 8 is independently selected from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 8 is independently selected from H and C 1-6 alkyl.
  • each R 9 is independently selected from C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl.
  • each R 10 is independently selected from H, C 1-6 alkyl, C 1- 6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 10 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 10 is independently selected from H and C 1-6 alkyl.
  • 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.
  • 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.
  • p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.
  • the compound is a compound of Formula lib : or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.
  • p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.
  • the compound is a compound of Formula lie: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.
  • 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.
  • compound is a compound of Formula lid:
  • 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.
  • the compound is a compound of Formula lie: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.
  • 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.
  • the compound is a compound of Formula Ilf: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.
  • 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. [0132] In some embodiments, the compound is a compound of Formula Ilg: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.
  • 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.
  • the compound is a compound of Formula Ilh: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.
  • 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.
  • the compound is a compound of Formula Ili: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.
  • p is 0, 1, 2, 3, or 4.
  • p is 0.
  • p is 1.
  • p is 2.
  • p is 3.
  • p is 4.
  • the compound is a compound of Formula Ilj : or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.
  • 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.
  • the compound is a compound of Formula Iln: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.
  • 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.
  • the compound is a compound of Formula lip: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.
  • p is 0, 1, 2, 3, or 4.
  • p is 0.
  • p is 1.
  • p is 2.
  • p is 3.
  • p is 4.
  • the 15-PGDH inhibitor is a compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR 7 ;
  • Y is selected from O, S, SO 2 , and C(R 8 )2;
  • R 1 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , - C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalky
  • R 2 is H and R 3 is -CF 3 ; or
  • R 2 and R 3 are taken together to form oxo or thio;
  • R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3 - 10 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membere
  • R 4 and R 5 are 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, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , - SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , - NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 6 is independently selected from halo, -NR 9 R 10 , -OR 11
  • R 9 and R 10 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 12 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.
  • each X is independently selected from N and CR 7 . In some embodiments, at least one X is N and the rest are CR 7 . In some embodiments, at least two X are N and the rest are CR 7 . In some embodiments, each X is N. In some embodiments, each X is CR 7 .
  • Y is selected from O, S, SO 2 , and C(R 8 )2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO 2 . In some embodiments, Y is C(R 8 )2.
  • R 1 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , - SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1 -ehaloalky 1, C
  • R 1 is selected from C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , - C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6 - waryl, and 5- to 10-membered heteroaryl.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , - C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1- 6 haloalkyl.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , - SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and - NR 13 SO 2 NR 9 R 10 .
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and - C(O)NR 9 R 10 .
  • R 2 is H and R 3 is -CF 3 .
  • R 2 and R 3 are taken together to form oxo.
  • R 2 and R 3 are taken together to form thio.
  • R 4 and R 5 are independently selected from C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , - SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR
  • R 4 and R 5 are independently selected from C 3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10- membered heteroaryl.
  • R 4 and R 5 are independently selected from C 3 - 10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , - C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 4 and R 5 are independently selected from C 3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , - SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and - NR 13 SO 2 NR 9 R 10 .
  • R 4 and R 5 are independently selected from C 3 - 10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and - C(O)NR 9 R 10 .
  • R 4 and R 5 are 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, -NR 9 R 10 , -OR 11 , -C(O)R 11 , - C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • R 4 and R 5 are 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, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , - SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 4 and R 5 are 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, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , - SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and - NR 13 SO 2 NR 9 R 10 .
  • R 4 and R 5 are 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, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 .
  • each R 6 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 6 is independently selected from halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1- 6 haloalkyl.
  • each R 6 is independently selected from halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and -NR 13 SO 2 NR 9 R 10 .
  • each R 6 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and - C(O)NR 9 R 10 .
  • R 6 ’s attached to the same carbon atom are taken together to form oxo, thio, or C 3-10 cycloalkyl, and any remaining R 6 ’s are independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , - SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1 -ehaloalky 1, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6 - loaryl, and 5- to 10-membered heteroaryl.
  • R 6 ’s attached to the same carbon atom are taken together to form oxo, thio, or C 3-10 cycloalkyl, and any remaining R 6 ’S are independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , - C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 6 ’s attached to the same carbon atom are taken together to form oxo, thio, or C 3-10 cycloalkyl, and any remaining R 6 ’s are independently selected from halo, - NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(0)OR", -C(0)NR 9 R I O , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , - NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and -NR 13 SO 2 NR 9 R 10 .
  • R 6 ’s attached to the same carbon atom are taken together to form oxo, thio, or C 3-10 cycloalkyl, and any remaining R 6 ’s are independently selected from halo, - NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 .
  • each R 7 is independently selected from H, halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(0)OR", -C(0)NR 9 R I O , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10- membered heteroaryl.
  • each R 7 is independently selected from H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , - NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1- 6 heteroalkyl, and C 1-6 haloalkyl.
  • each R 7 is independently selected from H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR", -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , - SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and -NR 13 SO 2 NR 9 R 10 .
  • each R 7 is independently selected from H, halo, -NR 9 R 10 , -OR 11 , - C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 .
  • each R 8 is independently selected from H, halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(0)OR", -C(0)NR 9 R I O , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10- membered heteroaryl.
  • each R 8 is independently selected from H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , - NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1- 6 heteroalkyl, and C 1-6 haloalkyl.
  • each R 8 is independently selected from H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR", -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -
  • two R 8 ’s can be taken together to form a C 3-10 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10- membered heteroaryl.
  • two R 8 ’s can be taken together to form a C 3 - 10 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , - NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1- 6 heteroalkyl, and C 1-6 haloalkyl.
  • two R 8 ’s can be taken together to form a C 3-10 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , - SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and -NR 13 SO 2 NR 9 R 10 .
  • two R 8 ’s can be taken together to form a C 3-10 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , - C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 .
  • R 9 and R 10 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, R 9 and R 10 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 9 and R 10 are independently selected at each occurrence from H and C 1-6 alkyl.
  • each R 12 is independently selected from C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 12 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 12 is independently selected from C 1-6 alkyl. [0159] In some embodiments, each R 13 is independently selected from H, C 1-6 alkyl, C 1- 6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 13 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 13 is independently selected from H and C 1-6 alkyl.
  • 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.
  • the compound is a compound of Formula Illa: or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula Illb : or a pharmaceutically acceptable salt thereof, wherein: each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , - C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6 - waryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.
  • each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , - C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , and -NR 13 SO 2 NR 9 R 10 .
  • each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 . In some embodiments, each R 14 is independently halo. In some embodiments, each R 14 is independently fluoro.
  • 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.
  • the compound is a compound of Formula IIIc: or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula Hid: or a pharmaceutically acceptable salt thereof, wherein: each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , - C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6 - waryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.
  • each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , - NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , - C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , and -NR 13 SO 2 NR 9 R 10 .
  • each R 14 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 . In some embodiments, each R 14 is independently halo. In some embodiments, each R 14 is independently fluoro.
  • 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.
  • 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 CR 6 , provided that when U is N, at least one of T and Y is N;
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , - NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , -NR 11 SO 2 NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 5- to 10-membered heteroaryl;
  • R 2 is H and R 3 is -CF 3 ; or R 2 and R 3 are taken together to form oxo; each R 4 is independently selected from H and halo;
  • R 5 is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , - SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , -NR 11 SO 2 NR 7 R 8 , C 1- ealkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;
  • R 6 is selected from H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , - SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , -NR 11 SO 2 NR 7 R 8 , C 1- ealkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;
  • R 7 and R 8 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; each R 9 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 10 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; and p is 0, 1, or 2.
  • T, U, and Y are independently selected from N and CR 6 , 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 CR 6 . In some embodiments, two of T, U, and Y are N and the rest are CR 6 . In some embodiments, one of T, U, and Y is CR 6 and the rest are N. In some embodiments, two of T, U, and Y are CR 6 and the rest are N. In some embodiments, T, U, and Y are N. In some embodiments, T, U, and Y are CR 6 .
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , - SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , - NR 11 SO 2 NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 5- to 10- membered heteroaryl.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 7 R 8 , - OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , - NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , and -NR 11 SO 2 NR 7 R 8 .
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 7 R 8 , -OR 9 , - C(O)R 9 , -C(O)OR 9 , and-C(O)NR 7 R 8 .
  • R 2 is H and R 3 is -CF 3 . In some embodiments, R 2 and R 3 are taken together to form oxo.
  • each R 4 is independently selected from H and halo. In some embodiments, each R 4 is independently selected from H and fluoro. In some embodiments, each R 4 is H. In some embodiments, each R 4 is fluoro. In some embodiments, one R 4 is H and one R 4 is fluoro.
  • R 5 is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , - NR 11 SO 2 R 9 , -NR 11 SO 2 NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • R 5 is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , - SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , - NR 11 SO 2 NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 5 is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO 2 R 10 , - SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , and -NR 11 SO 2 NR 7 R 8 .
  • R 5 is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , and - C(O)NR 7 R 8 .
  • R 6 is selected from H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , - C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , - NR 11 SO 2 R 9 , -NR 11 SO 2 NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • R 6 is selected from H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , - C(O)NR 7 R 8 , -SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , -NR 11 SO 2 NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 6 is selected from H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO 2 R 9 , and -NR 11 SO 2 NR 7 R 8 .
  • R 6 is selected from H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , and- C(O)NR 7 R 8 .
  • R 7 and R 8 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl. In some embodiments, R 7 and R 8 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1- 6 haloalkyl. In some embodiments, R 7 and R 8 are independently selected at each occurrence from H and C 1-6 alkyl.
  • each R 10 is independently selected from C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 10 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 10 is independently selected from C 1-6 alkyl. [0180] In some embodiments, each R 11 is independently selected from H, C 1-6 alkyl, C 1- 6 haloalkyl, and C 3-6 cycloalkyl. In some embodiments, each R 11 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 11 is independently selected from H and C 1-6 alkyl.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , - NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl;
  • R 2 and R 3 are taken together to form oxo; each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or two R 4 ’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1 -ehaloalky 1, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6 - waryl, and 5- to 10-membered heteroaryl;
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10- membered heteroaryl.
  • R 1 is selected from C 6-10 aryl and 5- to 10- membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , - OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7 .
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , - C(O)R 8 , -C(O)OR 8 , and-C(O)NR 6 R 7 .
  • R 2 is H and R 3 is -CF 3 . In some embodiments, R 2 and R 3 are taken together to form oxo.
  • each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , - C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and - NR 10 SO 2 NR 6 R 7 .
  • each R 4 is independently selected from halo, - NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 . In some embodiments, each R 4 is independently selected from halo. In some embodiments, each R 4 is fluoro.
  • two R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’S are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , - C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , - NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • two R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and - NR 10 SO 2 NR 6 R 7 .
  • two R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 .
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10- membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , - SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and - C(O)NR 6 R 7
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl. In some embodiments, R 6 and R 7 are independently selected at each occurrence from H and C 1-6 alkyl.
  • each R 8 is independently selected from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 8 is independently selected from H and C 1-6 alkyl.
  • each R 9 is independently selected from C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl.
  • each R 10 is independently selected from H, C 1-6 alkyl, C 1- 6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 10 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 10 is independently selected from H and C 1-6 alkyl.
  • 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.
  • 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.
  • 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.
  • the 15-PGDH inhibitor is a compound of Formula Ilq: or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , - NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl;
  • R 2 is H and R 3 is -CF 3 ; or
  • R 2 and R 3 are taken together to form oxo; each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or two R 4 ’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C i -ehaloalky 1, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6 - waryl, and 5- to 10-membered heteroaryl;
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10- membered heteroaryl.
  • R 1 is selected from C 6-10 aryl and 5- to 10- membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , - OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7 .
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 6 R 7 , -OR 8 , - C(O)R 8 , -C(O)OR 8 , and-C(O)NR 6 R 7 .
  • R 2 is H and R 3 is -CF 3 . In some embodiments, R 2 and R 3 are taken together to form oxo.
  • each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , - C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , - NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and - NR 10 SO 2 NR 6 R 7 .
  • each R 4 is independently selected from halo, - NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 . In some embodiments, each R 4 is independently selected from halo. In some embodiments, each R 4 is fluoro.
  • two R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’S are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , - C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , - NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • two R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and - NR 10 SO 2 NR 6 R 7 .
  • two R 4 ’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C 3-10 cycloalkyl, and any remaining R 4 ’s are independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 .
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10- membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , - SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , - NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , - SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , and -NR 10 SO 2 NR 6 R 7
  • R 5 is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and - C(O)NR 6 R 7
  • R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl. In some embodiments, R 6 and R 7 are independently selected at each occurrence from H and C 1-6 alkyl.
  • each R 9 is independently selected from C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl.
  • each R 10 is independently selected from H, C 1-6 alkyl, C 1- 6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 10 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 10 is independently selected from H and C 1-6 alkyl. [0205] 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.
  • 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.
  • 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.
  • the 15-PGDH inhibitor is a compound of Formula IIIc: or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR 7 ;
  • Y is selected from O, S, SO 2 , and C(R 8 )2;
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , - NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 5- to 10-membered heteroaryl;
  • R 2 is H and R 3 is -CF 3 ; or
  • R 2 and R 3 are taken together to form oxo
  • R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3 - 6 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membere
  • R 9 and R 10 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 12 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; and n is 0, 1, 2, 3, or 4.
  • each X is independently selected from N and CR 7 . In some embodiments, at least one X is N and the rest are CR 7 . In some embodiments, at least two X are N and the rest are CR 7 . In some embodiments, each X is N. In some embodiments, each X is CR 7 .
  • Y is selected from O, S, SO 2 , and C(R 8 )2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO 2 . In some embodiments, Y is C(R 8 )2.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , - SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , - NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 5- to 10- membered heteroaryl.
  • R 1 is selected from C 6-10 aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , - C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , - SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and -NR 13 SO 2 NR 9 R 10 .
  • R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and-C(O)NR 9 R 10 .
  • R 2 is H and R 3 is -CF 3 . In some embodiments, R 2 and R 3 are taken together to form oxo.
  • R 4 and R 5 are independently selected from C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , - SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl; wherein each alkyl,
  • R 4 and R 5 are independently selected from C 3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10- membered heteroaryl.
  • R 4 and R 5 are independently selected from C 3 - 10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , - C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , - NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 4 and R 5 are independently selected from C 3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , - SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and - NR 13 SO 2 NR 9 R 10 .
  • R 4 and R 5 are independently selected from C 3 - 10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and - C(O)NR 9 R 10 .
  • R 4 and R 5 are 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, -NR 9 R 10 , -OR 11 , -C(O)R 11 , - C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • R 4 and R 5 are 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, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , - SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 4 and R 5 are 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, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , - SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and - NR 13 SO 2 NR 9 R 10 .
  • R 4 and R 5 are 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, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 .
  • each R 6 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 6 is independently selected from halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1- 6 haloalkyl.
  • each R 6 is independently selected from halo, -NR 9 R 10 , - OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and -NR 13 SO 2 NR 9 R 10 .
  • each R 6 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and - C(O)NR 9 R 10 .
  • R 6 ’s attached to the same carbon atom are taken together to form oxo, and any remaining R 6 ’s are independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , - NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • R 6 ’s attached to the same carbon atom are taken together to form oxo, and any remaining R 6 ’s are independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , - NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1- 6 heteroalkyl, and C 1-6 haloalkyl.
  • R 6 ’s attached to the same carbon atom are taken together to form oxo, and any remaining R 6 ’s are independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , - SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and -NR 13 SO 2 NR 9 R 10 .
  • R 6 ’s attached to the same carbon atom are taken together to form oxo, and any remaining R 6 ’s are independently selected from halo, -NR 9 R 10 , -OR 11 , - C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 .
  • each R 7 and R 8 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , - NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.
  • each R 7 and R 8 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , - SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , -NR 13 SO 2 NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl.
  • each R 7 and R 8 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , - SOR 12 , -SO 2 R 12 , -SO 2 NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO 2 R 11 , and - NR 13 SO 2 NR 9 R 10 .
  • each R 7 and R 8 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and-C(O)NR 9 R 10 .
  • R 9 and R 10 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, R 9 and R 10 are independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 9 and R 10 are independently selected at each occurrence from H and C 1-6 alkyl.
  • each R 11 is independently selected from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 11 is independently selected from H and C 1- ealkyl.
  • each R 12 is independently selected from C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 12 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 12 is independently selected from C 1-6 alkyl. [0221] In some embodiments, each R 13 is independently selected from H, C 1-6 alkyl, C 1- 6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 13 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 13 is independently selected from H and C 1-6 alkyl.
  • 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.
  • the 15-PGDH inhibitor is a compound selected from the group consisting of:
  • the 15-PGDH inhibitor is a compound selected from the group consisting of: -801-
  • the 15-PGDH inhibitor is a compound selected from the group consisting of:
  • solubility and hPGDH ICso of the inhibitors are characterized as shown in Tables 1 and 2.
  • Table 2 Characteristics of PGDH Inhibitors with a phenyl core.
  • the 15-PGDH inhibitor is a compound of having the structure of Formula IV, or a pharmaceutically acceptable salt thereof: wherein, ring Q is phenyl or 5- to 10-membered heteroaryl;
  • Z is CR 1 or N
  • Y is CR 2 or N
  • R 1 is H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; each R 2 is independently H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -CN, -C(O)NR 8 R 9 , - NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 - Cs cycloalkyl; each R 3 is independently selected from H, halogen, -CN, -NO 2 , -NR 8 R 9 , -
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 1 -C 8 aminoalkyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, substituted or unsubstituted C 1- Q hydroxy alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalkyl, each of which is substituted with one or more R 6 ; wherein each R 6 is independently halogen, CN, -NO 2 , -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , - C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -NR 8 C(O)
  • X A is -NR 5 R 5 or -OR 5 ; wherein each R 5 is independently H or C 1 -C 6 alkyl;
  • R 5a is H or CH 3 ; or R 5a and one R 6 combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 3 -C 6 heterocycloalkyl; each R 8 and R 9 is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, and substituted or unsubstituted C 3 -C 10 heterocycloalkyl, each of which is substituted with one or more R a ;
  • the 15-PGDH inhibitor is a compound having the structure of Formula IV, or a pharmaceutically acceptable salt thereof: wherein, ring Q is phenyl or 5- to 10-membered heteroaryl;
  • Z is CR 1 or N
  • Y is CR 2 of N
  • R 1 is H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , -NR 8 C(O)R 9 substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
  • R 2 is H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -CN, -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , or substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; each R 3 is independently selected from H, halogen, -CN, -NO 2 , -NR 8 R 9 , -OR 10 , -C(O)R 10 , - C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 8 R 9 , -NR 12 C(O)R 10 , - NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO 2 R 10 , -NR 12
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, substituted or unsubstituted C 1 -C 8 hydroxyalkyl; substituted or unsubstituted C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R 6 ; wherein each R 6 is independently H, halogen, CN,-N02, -NR 8 R 9 , -OH, -OR 10 , -SR 8 , - C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -NR 8 C(O)R 9 , Ci-C 6 alkyl, C 1- C 6 haloalky
  • X A is NR 5 R 5 or OR 5 ; wherein each R 5 is independently H or C 1 -C 6 alkyl;
  • R 5a is H or CH 3 ; or R 5a and one R 6 combine together with the atom(s) to which they are attached to form a C 3 - C 6 cycloalkyl ring; each R 8 and R 9 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1- C 6 heteroalkyl, C 1- C 6 haloalkyl, C 3 -C 10 cycloalkyl, and C4-C 10 heterocycloalkyl; each R 10 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1- C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; each R 11 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkeny
  • ring Q is 5- to 10-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is 5- to 8-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is 5- to 8-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is a monocyclic, bicyclic, or polycyclic heteroaryl. In some embodiments, ring Q is a bicyclic heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N and O.
  • 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.
  • ring Q is phenyl, pyridine, or triazolopyridine.
  • X 1 , X 2 , X 3 and X 4 are each independently N or CR 3 ; each R 3 is independently selected from H, halogen, -CN, -NO 2 , -NR 8 R 9 , -OR 10 , -SR 8 , - C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 8 R 9 , -NR 12 C(O)R 10 , - NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO 2 R 10 , -NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or
  • X 1 , X 2 , X 3 and X 4 are each CR 3 .
  • X 1 is N; and X 2 , X 3 , and X 4 are each CR 3 .
  • X 1 and X 2 are each N; and X 3 and X 4 are each CR 3 .
  • X 1 and X 3 are each N; and X 2 and X 4 are each CR 3 .
  • X 1 and X 4 are each N; and X 2 and X 3 are each CR 3 .
  • X 1 , X 2 , and X 3 are each N; and X 4 is CR 3 .
  • each R 3 is independently selected from H, halogen, -CN, - NO 2 , -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , - SO 2 NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO 2 R 10 , - NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalky
  • each R 3 is independently selected from H, halogen, -C(O)R 10 , -C(O)OR 10 , - C(O)NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.
  • each R 3 is independently selected from H, halogen, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.
  • each R 3 is independently selected from H or halogen. In some embodiments, each R 3 is independently substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, each R 3 is independently a substituted or unsubstituted 5-membered heteroaryl.
  • the 15-PGDH inhibitor is a compound having the structure of Formula V, or a pharmaceutically acceptable salt thereof: wherein,
  • Z is CR 1 or N
  • X 1 is N or CR 3a ;
  • Y is CR 2 or N
  • R 1 is H, halogen, -CN, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; each R 2 is independently H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -CN, -C(O)NR 8 R 9 , - NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 - Cs cycloalkyl;
  • R 3a , R 3b , and R 3c are each independently selected from H, halogen, -CN, -NO 2 , -NR 8 R 9 , - OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 8 R 9 , - NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO 2 R 10 , -NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocyclo
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 1 -C 8 aminoalkyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, substituted or unsubstituted C 1- Q hydroxy alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalkyl, each of which is substituted with one or more R 6 ; wherein each R 6 is independently halogen, CN,-N02, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , - C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -NR 8 C(O)R 9
  • X A is NR 5 R 5 or OR 5 ; wherein each R 5 is independently H or C 1 -C 6 alkyl;
  • Z is CR 1 or N
  • X 1 is N or CR 3a ;
  • R 1 is H; each R 2 is independently H or C 1 -C 6 alkyl;
  • R 3a , R 3b , and R 3c are each independently selected from H, halogen, -OR 10 , -SR 8 , -C(O)R 10 , - C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 8 R 9 , -NR 12 C(O)R 10 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl, each of which is substituted with one or more R 13 ; wherein each R 13 is independently halogen, CN, -NO 2 , -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , - C(O)OR 10 , or -C(O)NR 8 R 9 ;
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, substituted or unsubstituted C 1 -C 8 hydroxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalkyl, each of which is substituted with one or more R 6 ; wherein each R 6 is independently halogen, CN,-N02, -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , - C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 halo
  • X A is -OR 5 ; wherein each R 5 is independently H or C 1 -C 6 alkyl;
  • R 5a is H or CH 3 ; or R 5a and one R 6 combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C 3 -C 6 cycloalkyl; each R 8 and R 9 is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, and substituted or unsubstituted C 3 -C 10 heterocycloalkyl, each of which is substituted with one or more R a ; each R 10 is independently selected from H, substituted or unsubstituted C 1 -
  • X A is NR 5 R 5 . In some embodiments, X A is OR 5 .
  • Y is N. In some embodiments, Y is CR 2 .
  • the compound of Formula V has the structure of Formula Via, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:
  • Z is N. In some embodiments, Z is CR 1 . In some embodiments, Z is CH.
  • the compound of Formula V has the structure of Formula Vila, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula V has the structure of Formula Vllb, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula V has the structure of Formula Vile, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula V has the structure of Formula Vlld, or a pharmaceutically acceptable salt thereof: [0254]
  • R 1 is H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 , or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, R 1 is H.
  • each R 2 is independently H, halogen, -OR 10 , -C(O)R 10 , - C(O)OR 10 , or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 2 is independently H or C 1 -C 6 alkyl.
  • each R 2 is H.
  • X 1 is CR 3a . In some embodiments, X 1 is N.
  • R 3a , R 3b , and R 3c are each independently selected from H, halogen, -CN, -NO 2 , -NR 8 R 9 , -OR 10 , -S 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , - SO 2 R 11 , -SO 2 NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO 2 R 10 , - NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8
  • R 3a , R 3b , and R 3c are each independently selected from H, halogen, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , - NR 12 C(O)OR 10 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10- membered heteroaryl.
  • R 3a , R 3b , and R 3c are each independently selected from H, halogen, -OR 10 , -S 8 ,-C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 ,- NR 12 C(O)R 10 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • R 3a , R 3b , and R 3c are each independently selected from H, halogen, substituted or unsubstituted C 1 -C 6 alkyl, -C(O)R 10 , -C(O)NR 8 R 9 , C 3 -C 6 heterocycloalkyl, and 5- membered heteroaryl.
  • R 3a , R 3b , and R 3c are each independently selected from H, halogen, -C(O)OH, -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , triazole, tetrazole, pyrrolidine, morpholine, or C 1 -C 6 alkyl substituted with -C(O)OH.
  • R 3a and R 3b are each H or halogen; and R 3c is selected from halogen, -CN, -NO 2 , -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , - SO 2 R 11 , -SO 2 NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO 2 R 10 , - NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl
  • R 3a and R 3b are each H or halogen; and R 3c is selected from halogen, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , - NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl.
  • R 3a and R 3b are each H or halogen; and R 3c is selected from halogen, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , - NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.
  • R 3a and R 3b are each H or halogen; and R 3c is selected from -NR 12 C(O)OR 10 , substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.
  • R 3a and R 3b are each H or halogen; and R 3c is selected from substituted or unsubstituted C 1 -C 6 alkyl, - C(O)R 10 , -C(O)NR 8 R 9 , C 3 -C 6 heterocycloalkyl, and 5- membered heteroaryl.
  • R 3a and R 3b are each H or halogen; and R 3c is a substituted or unsubstituted 5- membered heteroaryl.
  • R 3a is halogen and R 3b is H. In some embodiments, R 3a is -Cl or -F; and R 3b is H. In some embodiments, R 3b is halogen and R 3a is H. In some embodiments, R 3b is -Cl or -F; and R 3a is H.
  • R 3a and R 3b are each H.
  • R 3a and R 3c are independently H or halogen; and R 3b is selected from halogen, -CN, -NO 2 , -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , - SOR 11 , -SO 2 R 11 , -SO 2 NR 8 R 9 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , - NR 12 SO 2 R 10 , -NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 --C 8 cycloalky
  • R 3a and R 3c are each H; and R 3b is selected from halogen, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , - NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl.
  • R 3a and R 3c are each H; and R 3b is selected from halogen, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , - NR 12 C(O)OR 10 , substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6- membered heteroaryl.
  • R 3a and R 3c are each H; and R 3b is selected from -C(O)R 10 , -C(O)OR 10 , -NR 12 C(O)OR 10 , substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.
  • R 3a and R 3c are each H or halogen; and R 3b is selected from substituted or unsubstituted C 1 -C 6 alkyl, -C(O)R 10 , - C(O)NR 8 R 9 , C 3 -C 6 heterocycloalkyl, and 5- membered heteroaryl.
  • R 3a and R 3c are each H or halogen; and R 3b is selected from - C(O)R 10 , -C(O)OR 10 and substituted or unsubstituted 5-membered heteroaryl.
  • R 3a is halogen and R 3c is H. In some embodiments, R 3a is H and R 3b is halogen. In some embodiments, R 3a is -Cl or -F; and R 3c is H. In some embodiments, R 3c is -Cl or -F; and R 3a is H.
  • R 3a and R 3c are each H.
  • each R 3 , R 3a , R 3b , and R 3c are each independently a 5- membered heteroaryl selected from pyrrole, triazole, tetrazole, oxazole, diazole, oxadiazole, thiadiazole, and furanyl.
  • each R 3 , R 3a , R 3b , and R 3c are each independently a 5-membered heteroaryl selected from pyrrole, triazole, and tetrazole.
  • each R 3 , R 3a , R 3b , and R 3c are each independently a 5-membered heteroaryl selected from triazole and tetrazole.
  • each R 3 , R 3a , R 3b , or R 3c is independently selected from the
  • each R 3 , R 3a , R 3b , or R 3c is independently selected from the
  • each R 3 , R 3a , R 3b , or R 3c is independently selected from the group consisting [0270]
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 1 -C 8 aminoalkyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, substituted or unsubstituted C 1- Q hydroxy alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R 6 .
  • R 4 is substituted or unsubstituted Ci- C 8 alkyl, substituted or unsubstituted C 1 -C 8 aminoalkyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, or substituted or unsubstituted C 1 -C 8 hydroxy alkyl. In some embodiments, R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 heteroalkyl, or substituted or unsubstituted C 1 -C 8 hydroxy alkyl.
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl or substituted or unsubstituted C 1 -C 8 heteroalkyl. In some embodiment, R 4 is substituted or unsubstituted Ci- Cs alkyl. In some embodiments, the alkyl is a straight chain or branched alkyl. In some embodiment, R 4 is substituted or unsubstituted C 1 -C 8 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.
  • R 4 is substituted or unsubstituted -CH 2 CH 2 -O-(C 1 -C 4 alkyl), -CH 2 -O-(CI-C 4 alkyl), substituted or unsubstituted -CH 2 CH 2 -O-(C 1 -C 4 haloalkyl), -CH 2 -O- (C1-C4 haloalkyl), -CH 2 CH 2 -O-(C 3 -C 6 cycloalkyl), -CH 2 -O-(C 3 -C 6 cycloalkyl), -CH 2 CH 2 -O- (C 3 -C 6 heterocycloalkyl), or -CH 2 -O-(C 3 -C 6 heterocycloalkyl).
  • R 4 is substituted or unsubstituted -CH 2 CH 2 -O-(C 1 -C 4 alkyl), -CH 2 -O-(C 1 -C 4 alkyl), substituted or unsubstituted -CH 2 CH 2 -O-(C 1 -C 4 haloalkyl), or -CH 2 -O-(C 1 -C 4 haloalkyl).
  • R 4 is -CH 2 CH 2 -O-(C 3 -C 6 cycloalkyl), -CH 2 -O-(C 3 -C 6 cycloalkyl), -CH 2 CH 2 - O-(C 3 -C 6 heterocycloalkyl), or -CH 2 -O-(C 3 -C 6 heterocycloalkyl).
  • R 4 is -CH 2 CH 2 -O-(C 3 -C 6 cycloalkyl).
  • R 4 is -CH 2 -O-(C 3 -C 6 cycloalkyl).
  • R 4 is -CH 2 CH 2 -O-(C 3 -C 6 heterocycloalkyl).
  • R 4 is -CH 2 -O-(C 3 -C 6 heterocycloalkyl).
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl, which is substituted with one or more halogen, -OR 10 , C 1 -C 8 alkyl, or C 3 -C 6 cycloalkyl.
  • R 4 is substituted or unsubstituted C 3 -C 8 cycloalkyl or substituted or unsubstituted C 3 -C 8 heterocycloalkyl, each of which is substituted with one or more R 6 .
  • R 4 is C 3 -C 8 cycloalkyl.
  • R 4 is monocyclic, polycyclic, spirocyclic, or bridged cycloalkyl.
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 4 is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is cyclobutyl. In some embodiments, R 4 is cyclopentyl. In some embodiments, R 4 is cyclohexyl. In some embodiments, R 4 is
  • R 4 is substituted or unsubstituted C 3 -C 8 heterocycloalkyl, each of which is substituted with one or more R 6 .
  • R 4 is monocyclic, polycyclic, spirocyclic, or bridged heterocycloalkyl.
  • R 4 is a 4- membered heterocycloalkyl.
  • R 4 is a 5-membered heterocycloalkyl.
  • R 4 is a 6-membered cycloalkyl.
  • R 4 is a 7- membered cycloalkyl.
  • R 4 is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine.
  • R 4 is tetrahydrofuran or tetrahydropyran.
  • each R 6 is independently halogen, -CN,-NO 2 , -NR 8 R 9 , -OR 10 , -SR 8 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO 2 R 11 , -NR 8 C(O)R 9 , Ci-C 6 alkyl, C 1- C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl.
  • each R 6 is independently halogen, -NR 8 R 9 , - OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , CI-C 6 alkyl, Ci-C 6 haloalky 1, Ci-C 6 hydroxyalkyl, or C 3 -C 8 cycloalkyl.
  • each R 6 is independently halogen, -NR 8 R 9 , -OR 10 ,-C(O)OR 10 , -C(O)NR 8 R 9 , CI-C 6 alkyl, or C 3 -C 8 cycloalkyl.
  • each R 6 is independently halogen, -NR 8 R 9 , -OR 10 , or C 3 -C 8 cycloalkyl. In some embodiments, each R 6 is independently -NR 8 R 9 or -OR 10 . In some embodiments, each R 6 is independently C 3 -C 8 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, spirocyclic or bridged cycloalkyl. In some embodiments, each R 6 is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 6 is independently halogen.
  • each R 6 is independently H, Cl, F, or Br. In some embodiments, each R 6 is independently F. In some embodiments, each R 6 is independently F, -OH, -CH 3 , -CF 3 , -N(CH 3 ) 2 , -NH(CH 3 ), -NH(CH 3 CH 3 ), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, piperidine, piperazine, oxetane, tetrahydrofuran, or tetrahydropyran.
  • each R 6 is independently F, -OH, -CH 3 , -CF 3 , -N(CH 3 ) 2 , -NH(CH 3 ), -NH(CH 2 CH 3 ), cyclopropyl, cyclobutyl, or cyclopentyl.
  • each R 6 is independently F, -OH, -CH 3 , or -CF 3 .
  • each R 6 is independently F.
  • each R 6 is independently -OH.
  • each R 6 is independently -CF 3 .
  • each R 6 is independently cyclopropyl, cyclobutyl, or cyclopentyl.
  • each R 6 is independently cyclopropyl.
  • each R 6 is cyclobutyl.
  • two R 6 combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 3 -C 6 heterocycloalkyl. In some embodiments, two R 6 combine together with the atom(s) to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R 6 combine together with the atom(s) to which they are attached to form a cyclopropyl or cyclobutyl.
  • two R 6 combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R 6 combine together with the atom(s) to which they are attached to form a cyclobutyl. In some embodiments, two R 6 combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R 6 combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, two R 6 combine together with the atom(s) to which they are attached to form a C 3 -C 6 heterocycloalkyl.
  • two R 6 combine together with the atom(s) to which they are attached to form a 4 membered heterocycloalkyl. In some embodiments, two R 6 combine together with the atom(s) to which they are attached to form a 5 membered heterocycloalkyl. In some embodiments, two R 6 combine together with the atom(s) to which they are attached to form a 6-membered heterocycloalkyl. In some embodiments, two R 6 combine together with the atom(s) to which they are attached to form a pyran, piperazine, piperidine, or morpholine.
  • R 4 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 3 CH 3 , -CH 2 (CH 2 ) 2 CH 3 , - CH 2 (CH 2 ) 3 CH 3 , -CH 2 (CH 2 ) 4 CH 3 , -CH 2 CH 2 CH(CH 3 ) 2 , substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substitute or unsubstituted oxetane, substituted or
  • each R 5 is independently C 1 -C 6 alkyl. In some embodiments, each R 5 is independently -CH 2 CH 3 or -CH 3 . In some embodiments, each R 5 is independently -CH 2 CH 3 . In some embodiments, each R 5 is independently -CH 3 . In some embodiments, each R 5 is independently H.
  • R 5a is CH 3 . In some embodiments, R 5a is H.
  • R 5a and one R 6 combine together with the atom(s) to which they are attached to form a C 3 -C 6 cycloalkyl. In some embodiments, R 5a and one R 6 combine together with the atom(s) to which they are attached to form a cyclopentyl or cyclohexyl. In some embodiments, R 5a and one R 6 combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, R 5a and one R 6 combine together with the atom(s) to which they are attached to form a cyclopentyl.
  • each R 8 and R 9 is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, and substituted or unsubstituted C 3 -C 10 heterocycloalkyl, each of which is substituted with one or more R a .
  • each R 8 and R 9 is independently selected at each occurrence from H, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1- C 6 haloalkyl, and C 3 -C 10 cycloalkyl. In some embodiments, each R 8 and R 9 is independently selected at each occurrence from H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, and C 3 -C 10 heterocycloalkyl. In some embodiments, each R 8 and R 9 is independently selected at each occurrence from C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl.
  • each R 10 is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 3 -C 10 heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R a .
  • each R 10 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl.
  • each R 10 is independently selected from H, C 1 -C 6 alkyl, C 3 - C 10 cycloalkyl, and C 3 -C 10 heterocycloalkyl.
  • each R 10 is independently selected from H and C 1 -C 6 alkyl.
  • each R 10 is independently selected from C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl.
  • each R 11 is independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 1 -C 6 heteroalkyl substituted or unsubstituted, C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 3 -C 10 heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R a .
  • each R 11 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl.
  • each R 11 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, and C 1- C 6 haloalkyl.
  • each R 11 is independently selected from C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl.
  • each R 12 is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 1- C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, and substituted or unsubstituted C 3 -C 10 heterocycloalkyl, each of which is substituted with one or more R a .
  • each R 12 is independently selected from H, straight or branched chain C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 1- C 6 haloalkyl, C 3 -C 10 cycloalkyl, and C 3 -C 10 heterocycloalkyl. In some embodiments, each R 12 is independently selected from H, straight or branched chain C 1- C 6 alkyl. In some embodiments, each R 12 is independently selected from C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl.
  • each R a is independently selected from halogen, -OH, -CH 3 , - CF 3 , -0CH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)NH 2 , -C(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -NHC(O)OH, -OC(O)NH 2 , and -NHC(O)CH 3 .
  • each R a is independently selected from -F, -Cl, -Br, -OH, -CH 3 , -CF 3 , -OCH 3 , -C(O)OH, -C(O)NH 2 , and -NHC(O)CH 3 .
  • each R a is independently selected from -F, -OH, -CH 3 , -CF 3 , or - C(O)OH.
  • 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.
  • the PDGH inhibitor is a compound described in Table 4, or a pharmaceutically acceptable salt thereof.
  • the condition is a muscle condition.
  • the condition is spinal muscular atrophy (SMA).
  • the condition is a disease.
  • the disease is a muscle disease.
  • the muscle condition is muscle atrophy, muscle damage, muscle disorder, or muscle injury.
  • the muscle disease is associated with muscle atrophy, muscle damage, or muscle injury.
  • the condition associated with muscle damage, injury, or atrophy is selected from the group consisting of acute muscle injury or trauma, soft tissue hand injury, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), inherited myopathies, myotonic muscular dystrophy (MDD), mitochondrial myopathies, myotubular myopathy (MM), myasthenia gravis (MG), congestive heart failure, periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, cardiac cachexia, stress induced urinary incontinence, and sarcopenia.
  • DMD Duchenne muscular dystrophy
  • ALS amyotrophic lateral sclerosis
  • DD distal muscular dystrophy
  • MDD inherited myopathies
  • MM myotubular myopathy
  • the muscle condition comprises a neuromuscular disease.
  • the neuromuscular diseases include, but are not limited to, acid maltase deficiency, amyotrophic lateral sclerosis, Andersen-Tawil syndrome, Becker muscular dystrophy, Becker myotonia congenita, Bethlem myopathy, bulbospinal muscular atrophy, carnitine deficiency, carnitine palmityl transferase deficiency, central core disease, centronuclear myopathy, Charcot-Marie-Tooth disease, congenital muscular dystrophy, congenital myasthenic syndromes, congenital myotonic dystrophy, Cori disease, Debrancher enzyme deficiency, Dejerine-Sottas disease, dermatomyositis, distal muscular dystrophy, Duchenne muscular dystrophy, dystrophia myotonica, Emery-Dreifuss muscular dystrophy, endocrine myopathie
  • Muscle atrophy e.g., muscle wasting
  • normal aging e.g., sarcopenia
  • genetic abnormalities e.g., mutations or single nucleotide polymorphisms
  • poor nourishment e.g., poor circulation
  • loss of hormonal support e.g., bedrest, immobilization of a limb in a cast, etc.
  • aging damage to the nerve innervating the muscle
  • poliomyelitis e.g., amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease)
  • heart failure e.g., multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, and Guillian-Barre syndrome
  • denervation fatigue, exercise
  • the condition is idiopathic pulmonary fibrosis. In some embodiments, the condition is kidney fibrosis. In some embodiments, the condition is acute kidney injury. In some embodiments, the condition is sarcopenia. In some embodiments, the condition is a neuromuscular disease.
  • Example 1 Effects of 15-PGDH inhibitor (e.g., MF-300) administration on PGE2 signaling.
  • 15-PGDH inhibitor e.g., MF-300
  • a 15-PGDH inhibitor e.g., MF-300
  • 15-PGDH inhibitor blocks binding of PGE2 to 15- PGDH, which within skeletal muscle results in increased stem cell proliferation, increased muscle force, and improved mitochondrial function.
  • a 15- PGDH inhibitor e.g., MF-300
  • FIG. 1 An overview of the effects of a 15- PGDH inhibitor (e.g., MF-300) on the PGE2 signaling pathway is shown in Fig. 1.
  • Example 2 Mechanism of action and pharmacokinetic profile of MF-300.
  • a 15-PGDH inhibitor MF- 300
  • the mechanism of action and pharmacokinetic profile of a 15-PGDH inhibitor, MF- 300 was assessed using biochemical assays, cell-based assays utilizing A549 cells, and single-dose, 24-hour plasma pharmacokinetic analysis in mice.
  • the effect of administration of various doses of MF-300 on NADH production in a 15-PGDH inhibition biochemical assay is shown in Fig. 2A.
  • the effect of administration of various doses of MF-300 on PGE2 stability in A549 cells in a cell -based assay is shown in Fig. 2B.
  • the effect of administration of 10 mg/kg, 30 mg/kg, and 60 mg/kg doses of MF-300 over 24-hours in circulating plasma of mice is shown in Fig. 2C.
  • Example 3 Effects of intraperitoneal MF-300 administration in SMNA7 mice.
  • SMNA7 mice are used as a model for severe spinal muscle atrophy (SMA).
  • SMA severe spinal muscle atrophy
  • the SMNA7 mouse genome contains a deletion in the endogenous SMN gene locus and two transgenes, the human SMN2 gene coding region and the murine SMN gene deleted for exon 7 (i.e., SMNA7).
  • This combination of genetic alterations leads to severe skeletal muscle denervation and weakness that can be mitigated pharmacologically by the SMN splice modulator, SMN-C3, an analogue of Risdiplam.
  • SMN-C3 an analogue of Risdiplam.
  • the effect of intraperitoneal injections of MF-300 at various doses within cohorts of male and female SMNA7 mice was assessed.
  • RNA-seq analysis was performed using Poly A selection with paired end reads and a read depth of approximately 30 x 10 6 per sample.
  • An additional cohort of SMNA7 med/med model mice (SMN-C3 1 mg/kg) received daily intraperitoneal injections of SMN-C3 and SMN-C3 combined with MF-300 (3 mg/kg or 10 mg/kg) beginning on postnatal day 3 and then assessed for their time-to-right on postnatal day 12, during which they were given 30 seconds to right.
  • FIG. 3A An overview of the experimental timeline for assessing the effects of SMN-C3 and varying doses of MF-300 on isometric plantar flexor force in SMNA7 mice is shown in Fig. 3A.
  • the effects of repeated treatment with either SMN-C3 only (vehicle), or SMN-C3 with varying doses of MF-300 (3 mg/kg [3MPK], 10 mg/kg [10MPK], or 30 mg/kg [30MPK]) on isometric plantar flexor force of SMNA7 mice is shown in Fig. 3B. Wildtype mice (WT) received no treatment.
  • SMNA7 mice with either SMN- C3 only (vehicle), or SMN-C3 with varying doses of MF-300 (3 mg/kg [3MPK], 10 mg/kg [10MPK], or 30 mg/kg [30MPK]) on isometric plantar flexor maximum force of SMNA7 mice is shown in Fig. 3C.
  • Wildtype mice (WT) received no treatment.
  • 15-PGDH is encoded by Hpgd gene.
  • the levels of HPGD expression in gastrocnemius muscles (represented as transcripts per million) between wildtype (WT) and SMNA7 mice (57 SMNC3) were investigated, and result is shown in Fig. 3E.
  • a principal component analysis comparing gene expression in mice exposed to repeated treatment with either SMN-C3 only (vehicle; SMNA7 mice without 15-PGDH inhibitor; Delta 7 Veh;), no injections (WT mice), or the combined doses of SMN-C3 with MF-300 (SMNA7 mice with 15-PGDH inhibitor; Delta7 MF-300) is shown in Fig. 3F.
  • Example 4 Effects of orally-administered MF-300 in SMN1 C/C mice.
  • mice treated with either vehicle or MF-300 60 mg/kg incorporating measurements of nerve and direct muscle-stimulated contractions to localize the effects of MF-300.
  • An overview of the experimental timeline for assessing the effects of the SMN1 C/C genotype and varying doses of MF-300 on isometric plantar flexor force in SMN1 C/C mice is shown in Fig. 4A.
  • Fig. 4B The effects of repeated treatment with vehicle or varying doses of MF-300 (10 mg/kg, 30 mg/kg, or 60 mg/kg) on isometric plantar flexor force and percent increase in maximum force from vehicle at 150 Hz is shown in Fig. 4B.
  • Fig. 4C The effects of repeated treatment with vehicle or varying doses of MF-300 (10 mg/kg, 30 mg/kg, or 60 mg/kg) on isometric plantar flexor force and percent increase in maximum force from vehicle at 150 Hz normalized to muscle mass is shown in Fig. 4C.
  • mice were treated with either vehicle or MF-300 (60 mg/kg) and incorporating measurements of nerve and direct muscle-stimulated contractions to localize the effects of MF-300 is shown in Fig.
  • Fig. 4E The effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force associated with nerve stimulation is shown in Fig. 4E.
  • the effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force associated with muscle stimulation is shown in Fig. 4G.
  • Fig. 4H The effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force normalized to muscle weight (MW) and associated with muscle stimulation is shown in Fig. 4H.
  • MF300 60MPK The effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force associated with normalized muscle stimulation to nerve stimulation is shown in Fig. 41.
  • MF300 60MPK The effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force associated with normalized muscle stimulation to nerve stimulation and represented as fold difference is shown in Fig. 4J.
  • SMN1 C/C mice administered with 15-PGDH inhibitor e.g., MF-300
  • 15-PGDH inhibitor e.g., MF-300
  • Example 5 Effects of orally administered MF-300 in a sciatic nerve crush mouse model.
  • FIG. 5A An overview of the experimental timeline for assessing the effects of MF-300 on isometric plantar flexor force in a sciatic nerve crush mouse model is shown in Fig. 5A.
  • the maximum force at baseline for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5B.
  • the maximum force on day 14 for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5C.
  • the maximum force on day 21 for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5D.
  • the maximum force on day 28 for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5E.
  • the maximum force on day 35 for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5F.
  • FIG. 5G The maximum force normalized by muscle weight on day 35 for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5G.
  • the muscle mass at the end of testing for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5H.
  • mice that received 15-PGDH inhibitor e.g., MF-300, showed improvement on isometric plantar flexor force when compared to mice without 15-PGDH inhibitor treatment.
  • Example 6 Effects of orally-administered MF-300 in a sciatic nerve crush mouse model.
  • the effect of intermittently dosed, orally administered MF-300, a 15-PGDH inhibitor, at 60 mg/kg within cohorts of male SMN1 C/C mice was assessed. Briefly, 6-8-week-old male SMN1 C/C mice received either daily oral vehicle administration (Veh) or intermittent doses of oral MF-300 administration (60 mg/kg, given either daily, every 2 days, or every 3 days) for four weeks and were then tested for isometric plantar flexor force.
  • Veh daily oral vehicle administration
  • intermittent doses of oral MF-300 administration 60 mg/kg, given either daily, every 2 days, or every 3 days
  • FIG. 6A The predicted plasma concentrations of MF-300 for the daily MF-300 administration cohort (60 mg/kg) across 8 days is shown in Fig. 6B.
  • Fig. 6D The predicted plasma concentrations of MF-300 for the cohort given MF-300 administration every 3 days (60 mg/kg) across 8 days is shown in Fig. 6D.
  • the data in Figs. 6B-6D demonstrate that the plasma concentration of MF-300 remains above the ECso prior to administration of the subsequent dose with once a day dosing (QD) at 60 mg/kg, whereas with once every 2 days (Q2D) and once every 3 days (Q3D) dosing at 60 mg/kg, the plasma concentration of MF-300 is above the ECso after dosing and then drops below the ECso before administration of the subsequent dose.
  • QD once a day dosing
  • Q2D once every 2 days
  • Q3D once every 3 days
  • Example 7 Effects of intermittently administered MF-300 in SMNA7 mice
  • mice received daily intraperitoneal injections of the SMN splice enhancer SMN-C3 (3 mg/kg) for 21 days, and then received an additional 28 days of intraperitoneal injections of either SMN- C3 (3 mg/kg) alone or SMN-C3 (3mg /kg) in combination with MF-300 (30 mg/kg) administered either daily, every two days, or every three days.
  • SMNA7 mice were compared to wildtype (WT) mice that did not receive injections. Mice were then tested for isometric plantar flexor force.
  • Fig. 7A An overview of the experimental timeline for assessing the effects of SMN-C3 and intermittent doses of MF-300 on isometric plantar flexor force in SMNA7 mice is shown in Fig. 7A.
  • the predicted plasma concentrations of MF-300 for the daily MF-300 administration cohort (30 mg/kg) is shown in Fig. 7B.
  • the predicted plasma concentrations of MF-300 for the every two days MF-300 administration cohort (30 mg/kg) is shown in Fig. 7C.
  • the predicted plasma concentrations of MF-300 for the every three days MF-300 administration cohort (30 mg/kg) is shown in Fig. 7D.
  • the predicted plasma concentrations of MF-300 for the daily MF-300 administration cohort (10 mg/kg overlaid with 30 mg/kg) is shown in Fig. 7E.
  • the predicted plasma concentrations of MF-300 for the two days MF-300 administration cohorts (10 mg/kg overlaid with 30 mg/kg) is shown in Fig. 7F.
  • 7E and 7F show that the plasma concentration of MF-300 is predicted to remain above the EC50 prior to administration of the subsequent dose with once a day dosing (QD) at 10 mg/kg, whereas with once every other day dosing (QOD) at 10 mg/kg, the plasma concentration of MF-300 is predicted to be above the EC50 after dosing and then predicted to drop below the EC50 prior to administration of the subsequent dose.
  • QD once a day dosing
  • QOD once every other day dosing

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Abstract

L'invention concerne des méthodes de dosage intermittent pour traiter un état associé à une augmentation de l'activité ou des niveaux d'expression de la 15-hydroxyprostaglandine déshydrogénase (15-PGDH) chez un sujet avec un inhibiteur de 15-PGDH pour réduire la toxicité. En outre, la présente invention concerne des méthodes de traitement d'un état associé à une augmentation de l'activité ou des niveaux d'expression de la 15-hydroxyprostaglandine déshydrogénase (15-PGDH) chez un sujet par l'administration d'un inhibiteur de la 15-PGDH lorsque la concentration plasmatique de l'inhibiteur de la 15-PGDH chez le sujet est inférieure à la CE50 de l'inhibiteur de la 15-PGDH, tout en conservant l'efficacité thérapeutique de l'inhibiteur de la 15-PGDH.
PCT/US2024/035916 2023-06-28 2024-06-27 Méthodes de dosage intermittent pour le traitement d'un état associé à une augmentation de 15-pgdh Pending WO2025006810A1 (fr)

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US63/510,874 2023-06-28
US202363588989P 2023-10-09 2023-10-09
US63/588,989 2023-10-09

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016144958A1 (fr) * 2015-03-08 2016-09-15 Case Western Reserve University Inhibiteurs de l'activité de la déshydrogénase à chaîne courte pour le traitement de la fibrose
WO2020106998A1 (fr) * 2018-11-21 2020-05-28 Case Western Reserve University Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte
WO2020252146A1 (fr) * 2019-06-11 2020-12-17 The Board Of Trustees Of The Leland Stanford Junior University Méthodes de rajeunissement de tissus âgés par l'inhibition de la 15-hydroxyprostaglandine déshydrogénase (15-pgdh)
WO2021151014A1 (fr) * 2020-01-23 2021-07-29 Myoforte Therapeutics, Inc. Inhibiteurs pgdh et leurs procédés de fabrication et d'utilisation
WO2021236779A1 (fr) * 2020-05-20 2021-11-25 Rodeo Therapeutics Corporation Compositions et procédés pour moduler l'activité de la déshydrogénase à chaîne courte
WO2021252936A1 (fr) * 2020-06-11 2021-12-16 The Board Of Trustees Of The Leland Stanford Junior University Rajeunissement de tissus et d'organes âgés par l'inhibition de l'enzyme dégradant pge2, 15-pgdh
WO2022082009A1 (fr) * 2020-10-15 2022-04-21 Epirium Bio Inc. Formulations inhalées d'inhibiteurs de pgdh et leurs procédés d'utilisation
WO2022087631A1 (fr) * 2020-10-23 2022-04-28 The Board Of Trustees Of The Leland Stanford Junior University Élévation de la biogenèse et de la fonction mitochondriales par inhibition de l'enzyme de dégradation des prostaglandines 15-pgdh
WO2023070008A1 (fr) * 2021-10-19 2023-04-27 The Board Of Trustees Of The Leland Stanford Junior University Procédés et compositions pour améliorer la morphologie et la fonction de la jonction neuromusculaire

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016144958A1 (fr) * 2015-03-08 2016-09-15 Case Western Reserve University Inhibiteurs de l'activité de la déshydrogénase à chaîne courte pour le traitement de la fibrose
WO2020106998A1 (fr) * 2018-11-21 2020-05-28 Case Western Reserve University Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte
WO2020252146A1 (fr) * 2019-06-11 2020-12-17 The Board Of Trustees Of The Leland Stanford Junior University Méthodes de rajeunissement de tissus âgés par l'inhibition de la 15-hydroxyprostaglandine déshydrogénase (15-pgdh)
WO2021151014A1 (fr) * 2020-01-23 2021-07-29 Myoforte Therapeutics, Inc. Inhibiteurs pgdh et leurs procédés de fabrication et d'utilisation
WO2021236779A1 (fr) * 2020-05-20 2021-11-25 Rodeo Therapeutics Corporation Compositions et procédés pour moduler l'activité de la déshydrogénase à chaîne courte
WO2021252936A1 (fr) * 2020-06-11 2021-12-16 The Board Of Trustees Of The Leland Stanford Junior University Rajeunissement de tissus et d'organes âgés par l'inhibition de l'enzyme dégradant pge2, 15-pgdh
WO2022082009A1 (fr) * 2020-10-15 2022-04-21 Epirium Bio Inc. Formulations inhalées d'inhibiteurs de pgdh et leurs procédés d'utilisation
WO2022087631A1 (fr) * 2020-10-23 2022-04-28 The Board Of Trustees Of The Leland Stanford Junior University Élévation de la biogenèse et de la fonction mitochondriales par inhibition de l'enzyme de dégradation des prostaglandines 15-pgdh
WO2023070008A1 (fr) * 2021-10-19 2023-04-27 The Board Of Trustees Of The Leland Stanford Junior University Procédés et compositions pour améliorer la morphologie et la fonction de la jonction neuromusculaire

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