Compositions and methods for reducing reactive microglia using 15-PGDH inhibitors

Abstract

Provided herein are methods for reducing reactive microglia in a subject. Further provided herein are methods for treating a neurological disease, disorder, or condition in a subject. In some cases, the methods involve administering a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to the subject. In some cases, the 15-PGDH inhibitor can penetrate the blood-brain barrier.

Description

Attorney Docket No. : 55773-741.601COMPOSITIONS AND METHODS FOR REDUCING REACTIVE MICROGLIA USING 15-PGDH INHIBITORSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 723,087, filed on November 20, 2024, and U.S. Provisional Application Serial No. 63 / 768,725, filed on March 7, 2025, each of which is incorporated by reference herein in its entirety.BACKGROUND

[0002] Neuroinflammation is a condition associated with an inflammatory response in the nervous system. Neuroinflammation in response to stimuli, e.g., infection, damage, and / or injury can be beneficial and adaptive. However, chronic neuroinflammation can have negative impacts to the brain structure and functions, thereby affecting learning ability, memory, physical regulation and / or behavioral regulation.INCORPORATION BY REFERENCE

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

[0004] There is an unmet need for compositions and methods for treating a subject having a neurological disease, disorder, or condition and / or elevated levels of reactive glia cells, e.g., microglia. This disclosure meets this unmet need.

[0005] In one aspect, a method of reducing a level of reactive microglia in the central nervous system (CNS) of a subject is provided, the method comprising: administering a 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to the subject in an amount effective to reduce the level of reactive microglia in the CNS.Attorney Docket No. : 55773-741.601

[0006] In some cases, the subject has microgliosis. In some cases, the subject has neuroinflammation, neurodegeneration, or both. In some cases, the subject has peripheral inflammation. In some cases, the subject has a viral infection. In some cases, the viral infection is an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In some cases, the subject has inflammation due to aging (inflammaging).

[0007] In another aspect, a method of treating a subject having a neurological disorder, condition, or disease is provided, the method comprising: administering an amount of a 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to the subject in an amount effective to treat the neurological disorder, condition, or disease.

[0008] In some cases, the subject has levels of reactive microglia in the central nervous system (CNS). In some cases, the subject has elevated levels of reactive microglia in the CNS. In some cases, the levels of reactive microglia in the CNS are reduced after the administering. In some cases, the levels of reactive microglia in the CNS are reduced by at least about 5% after the administering. In some cases, a level of total microglia is unchanged after the administering. In some cases, the reactive microglia express CD68. In some cases, the CNS comprises brain tissue. In some cases, the brain tissue comprises grey matter. In some cases, the brain tissue comprises white matter. In some cases, the brain tissue comprises the cingulum, the corpus callosum, deep motor cortex, dentate gyrus, or any combination thereof. In some cases, the subject has a neurodegenerative disease, disorder, or condition. In some cases, the subject has neuroinflammation or a neuroinflammatory disease, disorder, or condition. In some cases, the subject has peripheral inflammation. In some cases, the subject has spinal muscular atrophy (SMA). In some cases, the subject has a synucleinopathy. In some cases, the synucleinopathy is selected from the group consisting of: Parkinson’s disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). In some cases, the subject has Alzheimer’s disease. In some cases, the subject has a psychiatric condition. In some cases, the psychiatric condition is schizophrenia. In some cases, the subject has epilepsy. In some cases, the subject has experienced a stroke. In some cases, the subject has amyotrophic lateral sclerosis (ALS). In some cases, the subject has elevated spinal fluid levels of at least one inflammatory molecule selected from the group consisting of: IL-lbeta, IL-4, IL-6, IL-8, IL-10, IL-11, IL-12, TNF-alpha, IFN-gamma, GM- CSF, CCL11, and TGF-beta. In some cases, the 15-PGDH inhibitor is a small molecule compound. In some cases, the 15-PGDH inhibitor exhibits at least about a 5% blood / plasmaAttorney Docket No. : 55773-741.601 ratio 2 hours after the administering. In some cases, the 15-PGDH inhibitor exhibits at least about a 10% blood / plasma ratio 2 hours after the administering. In some cases, the 15-PGDH inhibitor exhibits from about a 5% to about a 75% blood / plasma ratio 2 hours after the administering. In some cases, the 15-PGDH inhibitor exhibits at least about a 5% blood / plasma ratio 8 hours after the administering. In some cases, the 15-PGDH inhibitor exhibits at least about a 10% blood / plasma ratio 8 hours after the administering. In some cases, the 15-PGDH inhibitor exhibits from about a 5% to about a 75% blood / plasma ratio 8 hours after the administering. In some cases, the 15-PGDH inhibitor exhibits at least about a 5% blood / plasma ratio 24 hours after the administering. In some cases, the 15-PGDH inhibitor exhibits at least about a 10% blood / plasma ratio 24 hours after the administering. In some cases, the 15-PGDH inhibitor exhibits from about a 5% to about a 75% blood / plasma ratio 24 hours after the administering. In some cases, the administering comprises systemic administration. In some cases, the administering comprises oral administration.

[0009] In some cases, the 15-PGDH inhibitor is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I), wherein:Ring Q is Ce-Cio aryl or 5- to 10-membered heteroaryl;L is -C(O)-, -S-, -S(O)-, or -S(O)2-;R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR10C(O)R10, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; each R3is independently selected from H, halogen, -CN, -NR8R9, -OR10, CN, - C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -NR12C(O)R10, - NR12C(O)OR10, -NR12C(O)NR8R9, -OC(O)NR8R9, -NRI2SO2R'°, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl,Attorney Docket No. : 55773-741.601 substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each or which is substituted or unsubstituted with one or more R14;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs heteroalkyl, or substituted or unsubstituted Ci-Cs heteroalkyl, wherein each is substituted or unsubstituted with one or more R14;whereinW is -CR6R6- , -C(O)R10-, -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; n and m are each independently 0, 1, 2, or 3; q is 0, 1, 2, 3, 4, 5, or 6; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, - C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted orAttorney Docket No. : 55773-741.601 unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, or -C(O)NR8R9; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

[0010] In some cases, the compound having the structure of Formula (I) has the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:wherein:X1is N, NR3a, or CR3a;X2is N or CR3b;X3is N, NR3C, or CR3c;Attorney Docket No. : 55773-741.601R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR10C(O)R10, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;R3a, R3b, and R3care each independently H, halogen, -CN, -NR8R9, -OR10, CN, - C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -NR12C(O)R10, - NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, -OC(O)NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or R3aand R3btogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl; or R3band R3ctogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl;W is -CR6R6- , -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, - C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted C2-Ce alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; n and m are each independently 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, 5, or 6.

[0011] In some cases, the compound having the structure of Formula (I) has the structure of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof:Formula (lb), wherein:Attorney Docket No. : 55773-741.601Ring A is a 5-membered heteroaryl optionally comprising 1 or 2 N atoms;R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR10C(O)R10, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;W is -CR6R6- , -C(O)R10-, -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, - C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted C2-G> alkenyl, substituted or unsubstituted C2-Ce alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted orAttorney Docket No. : 55773-741.601 unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;R15is H, halogen, -NR8R9, -substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; n and m are each independently 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, 5, or 6.

[0012] In some cases, the 15-PGDH inhibitor is a compound having the structure of Formula (II), or a pharmaceutically accpetable salt of solvate thereof:Formula (II), wherein:Ring Q is Ce aryl or 5- to 10-membered heteroaryl;L is -C(O)-, -S-, -S(O)-, -S(O)2-, or -S(O2)NH-;A1is N or CR1and A2is N or CR2, provided that at least one of A1or A2is N;A3is N or CR7;R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3is independently selected from H, halogen, -CN, -NR8R9, -OR10, CN, - C(O)R10, -C(O)OR10, -C(O)NR8R9, -NR12C(O)OR9, -SOR11, -SO2R11, -SO2NR8R9, - NR12C(O)R10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted orAttorney Docket No. : 55773-741.601 unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted or unsubstituted with one or more R14;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs heteroalkyl;whereinW is -CR6R6- , -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; n and m are each independently 0, 1, 2, or 3; q is 0, 1, 2, 3, 4, 5, or 6; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, - C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted orAttorney Docket No. : 55773-741.601 unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, or -C(O)NR8R9; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

[0013] In some cases, the compound having the structure of Formula (II) has the structure of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof:wherein:A3is N or CR7;Attorney Docket No. : 55773-741.601R2is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3- Cs cycloalkyl;X1is N, NR3a, or CR3a;X3is N, NR3C, or CR3c;R3a, R3b, and R3care each independently H, halogen, -CN, -NR8R9, -OR10, CN, - C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -NR12C(O)R10, - NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, -OC(O)NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or R3aand R3btogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl; or R3band R3ctogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl;W is -CR6R6- , -C(O)R10-, -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, - C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted C2-Ce alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; n and m are each independently 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, 5, or 6.

[0014] In some cases, the 15-PGDH inhibitor is a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:Formula (III), wherein:Z is CR1or N;Attorney Docket No. : 55773-741.601X1is N or CR3a;Y is CR7or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R2is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, - NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SOR11, -SO2R11, - SO2NR8R9, -NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, - NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci- Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3- Cs heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R14;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs hydroxy alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NC>2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted Ci-Ce hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl;XAis NR5R5or OR5; wherein each R5is independently H or Ci-Ce alkyl;R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl;Attorney Docket No. : 55773-741.601R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, or -C(O)NR8R9; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0015] In some cases, the compound having the structure of Formula (III) has the structure of Formula (Illa), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No. : 55773-741.601Formula (Illa), wherein:Z is CR1or N;X1is N or CR3a;Y is CR2or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R2is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, - NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SOR11, -SO2R11, - SO2NR8R9, -NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, - NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci- Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3- Cs heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R14; whereinR4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs hydroxy alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NC>2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted Ci-Ce hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstitutedAttorney Docket No. : 55773-741.601C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; each R5is independently H or Ci-Ce alkyl;R5ais H or CH3;R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, or -C(O)NR8R9; andAttorney Docket No. : 55773-741.601 each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0016] In some cases, the 15-PGDH inhibitor is a compound having the structure ofFormula (IV), or a pharmaceutically acceptable salt thereof:Formula (IV), wherein,L1is -S(O)- or S(O)2-; Z is CR1or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;X1is N or CR3a;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, - NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SOR11, -SO2R11, - SO2NR8R9, -NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, - NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci- Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3- Cs heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs haloalkyl, substituted or unsubstituted Ci-Cs hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6;Attorney Docket No. : 55773-741.601, whereinX is CH or N;W is CR6R6, -NR6a-, or -O-; each R6is independently H, halogen, CN,-NC>2, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, C1-C6 alkyl, Ci-C6haloalkyl, Ci-Ce hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or 5- to 8- membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl;R6ais H or C1-C3 alkyl; m and n are each independently 0, 1, or 2; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted orAttorney Docket No. : 55773-741.601 unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0017] In some cases, the 15-PGDH inhibitor is a compound having the structure of Formula (V), or a pharmaceutically acceptable salt thereof:Formula (V), wherein:L1is -S(O)- or -S(O)2-;Z is CR1or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, - NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;X1is N or CR3a;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, - NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SOR11, -SO2R11, - SO2NR8R9, -NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, - NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci- Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3- Cs heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R13is independently H, halogen, -CN, -NO2, -NR8R9, -OR10, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C3-C6 heterocycloalkyl, each of which is substituted with one or more R13a; or two R13combine together with the atoms to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted heterocycloalkyl, each of which is substituted with one or more R13a, wherein each R13ais independently halogen, -CN, -NO2, -NR8R9, -OR10, alkyl, or haloalkyl;R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci- Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, - NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and v is 0-20.

[0018] In some cases, the 15-PGDH inhibitor is selected from any compound listed inTable 1

[0019] In some cases, the 15-PGDH inhibitor is selected from the group consisting of:Attorney Docket No. : 55773-741.601Attorney Docket No. : 55773-741.601BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0021] FIG. 1A shows a representative image indicating the localization of neuroanatomical regions of interest, which includes the cingulum, corpus callosum, deep motor cortex, and dentate gyrus.Attorney Docket No. : 55773-741.601

[0022] FIG. IB shows the number of CD68 / Ibal cells per mm3in the cingulum of A7 female mice and non-SMA control female mice that received either vehicle or 15-PGDH inhibitor administration.

[0023] FIG. 1C shows the number of CD68 / Ibal cells per mm3in the corpus callosum of A7 female mice and non-SMA control female mice that received either vehicle or 15-PGDH inhibitor administration.

[0024] FIG. ID shows the number of CD68 / Ibal cells per mm3in the dentate gyrus of A7 female mice and non-SMA control female mice that received either vehicle or 15-PGDH inhibitor administration.

[0025] FIG. IE shows the number of CD68 / Ibal cells per mm3in the deep motor cortex of A7 female mice and non-SMA control female mice that received either vehicle or 15-PGDH inhibitor administration.

[0026] FIG. IF shows the number of Iba+ cells per mm3in the deep motor cortex of A7 female mice and non-SMA control female mice that received either vehicle or 15-PGDH inhibitor administration.

[0027] FIGS. 2A-2C show the number of Olig2+ASPA+ mature myelination oligodendrocytes in deep motor cortex, cingulum, and corpus callosum of A7 mice that received either vehicle or 15-PGDH inhibitor administration.

[0028] FIGS. 3A-3C show the number of PDGFRa+ oligodendrocyte progenitor cells (OPCs) in deep motor cortex, cingulum, and corpus callosum of A7 mice that received either vehicle or 15-PGDH inhibitor administration.DETAILED DESCRIPTION

[0029] Microgliosis is the reactive proliferation of microglial cells in response to pathological conditions in the brain. Activated microglia have been implicated in neuroinflammatory and neurodegenerative diseases. Neuroinflammation is a condition associated with an inflammation response in the nervous system and this can have negative impacts on brain structure and functions. The blood-brain barrier is a selective semipermeable membrane that protects the brain from harmful agents, e.g., pathogens or substances, that circulate in the blood from contacting organs of the central nervous system (CNS). The blood-brain barrier also excludes more than 98% of small molecule drugs from access to the brain. Accordingly, small molecule compounds that cross the blood-brainAttorney Docket No. : 55773-741.601 barrier may be beneficial for use as drugs to treat brain indications, such as neuroinflammation.

[0030] The present disclosure is based on the discovery that 15 -hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors that can penetrate the blood-brain barrier and access the CNS can reduce the levels of reactive microglia.

[0031] Provided herein are methods for reducing the levels of reactive microglia (e.g., CD68- positive microglia) in a tissue or organ of the CNS (e.g., brain) of a subject. In some cases, the subject has microgliosis, an increase in the number of reactive microglia in the brain in response to a pathological condition. In some cases, the subject has a neuroinflammatory and / or neurodegenerative disease, disorder, or condition. In some cases, the methods involve administering to the subject a 15-PGDH inhibitor. In some cases, the 15-PGDH inhibitor is blood-brain barrier penetrant such that the 15-PGDH inhibitor can cross the blood-brain barrier and affect the reactive microglia present in the CNS. The blood-brain barrier penetration of the 15-PGDH inhibitor can be measured by measuring the levels of the compound that is present in the brain tissue at a time point after administration of the 15- PGDH inhibitor. The disclosure herein provides 15-PGDH inhibitors that can be used to practice the methods of the disclosure.

[0032] In some cases, the methods provided herein increase the numbers of mature myelinating oligodendrocytes in a tissue or organ of the CNS of a subject. In some cases, the mature myelinating oligodendrocytes are Olig2+ASPA+ oligodendrocytes. In some cases, the methods provided herein do not affect (increase or decrease) the numbers of oligodendrocyte progenitor cells (OPCs). In some cases, the OPCs are PDGFRa+ OPCs.

[0033] In one aspect, provided herein are methods for reducing levels of reactive microglia in the CNS of a subject. In some cases, the method comprises administering a 15- hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to the subject in an amount effective to reduce the levels of reactive microglia in the CNS.

[0034] In some instances, the subject has neuroinflammation. In some embodiments, the neuroinflammation refers to an inflammatory response in the nervous system that is mediated by non-neuronal cells, such as glia cells, due to infection, damage, or injury, thereby disturbing homeostasis of the nervous system. In some embodiments, the neuroinflammation refers to an inflammation response mediated by non-neuronal cells, e.g., oligodendrocytes, astrocytes, ependymal cells, microglia, and / or endothelial cells in the CNS. In someAttorney Docket No. : 55773-741.601 embodiments, the neuroinflammation refers to an inflammation response mediated by microglia in the CNS.

[0035] In various aspects, provided herein are methods of treating a subject having a neurological disease, disorder, or condition. In some cases, the method comprises administering al5-PGDH inhibitor to the subject in an amount effective to treat the neurological disease, disorder, or condition.

[0036] In some embodiments, the subject has neuroinflammation. In some cases, the neuroinflammation is associated with a disease or a condition. In some embodiments, the disease or condition comprises a neurodegenerative disease or condition. In some embodiments, the neurodegenerative disease or condition comprises a synucleinopathy, such as Parkinson’s disease, dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). In some embodiments, the neurodegenerative disease or condition comprises Alzheimer’s disease, Parkinson’s disease, multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), progressive supranuclear palsy (DLB), corticobasal degeneration (CBD), dementia with Lewy bodies (DLB), or Huntington’s disease.

[0037] In some embodiments, reactive microglia refer to microglia cells that undergo morphological, molecular, and / or functional remodeling in response to stimuli or challenges. In some embodiments, the stimuli or challenges comprise abnormal misfolding of proteins, e.g., amyloid P (AP) or a-synuclein. In some embodiments, the stimuli or challenges comprise abnormal accumulation and / or deposition of proteins, e.g., amyloid P (AP) or a- synuclein. In some embodiments, the stimuli or challenges comprise infection, damage, and / or injury to organs in the nervous system. In some embodiments, the stimuli or challenges comprise degenerating neurons in the nervous system. In some instances, the subject has elevated levels of reactive microglia in the central nervous system (CNS). In some instances, the subject has microgliosis. In some instances, the elevated levels of reactive microglia in the CNS are reduced after the administering. In some cases, the reactive microglia are CD68-positive microglia.

[0038] In some embodiments, the levels of reactive microglia in the CNS are reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% after administering. In someAttorney Docket No. : 55773-741.601 embodiments, the levels of reactive microglia in the CNS are reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% after administering. In some instances, the levels of reactive microglia in the CNS are reduced by at least about 5% after the administering. In some embodiments, the levels of reactive microglia in the CNS are reduced by at most about 5%, at most about 10%, at most about 15%, at most about 20%, at most about 25%, at most about 30%, at most about 35%, at most about 40%, at most about 45%, at most about 50%, at most about 55%, at most about 60%, at most about 65%, at most about 70%, at most about 75%, at most about 80%, at most about 85%, at most about 90%, at most about 95%, or at most about 100% after administering. In some embodiments, the levels of reactive microglia in the CNS are reduced by from about 5% to about 75%, from about 10% to about 75%, from about 15% to about 75%, from about 20% to about 75%, from about 25% to about 75%, from about 30% to about 75%, from about 35% to about 75%, from about 40% to about 75%, from about 45% to about 75%, from about 50% to about 75%, from about 55% to about 75%, from about 60% to about 75%, from about 65% to about 75%, or from about 70% to about 75% after administering.

[0039] In some instances, a level of total microglia is unchanged after the administering. Microglia can be detected using a pan-microglia marker, such as Ibal . In some cases, treatment with the 15-PGDH inhibitor reduces the number of reactive microglia in the brain without affecting total numbers of microglia. In some cases, the number of reactive microglia relative to total microglia is represented as a ratio between the number of CD68- positive reactive microglia and the total number of Ibal -positive microglia.

[0040] Other biomarkers of microglia can be used, including, but not limited to, fractalkine receptor (CX3CR1), receptor of the colony-stimulating factor-1 (CSF1R), integrin CD1 lb, surface glycoproteins F4 / 80, CD68, ionized calcium-binding adaptor molecule 1 (Ibal), or pan-hematopoietic CD45. In some instances, the reactive microglia express CD68.

[0041] In some instances, the methods provided herein reduce levels of reactive microglia in the CNS. In some cases, the CNS comprises brain tissue. In some instances, the brain tissue comprises grey matter. In some instances, the brain tissue comprises white matter. In someAttorney Docket No. : 55773-741.601 instances, the brain tissue comprises the cingulum, the corpus callosum, deep motor cortex, dentate gyrus, or any combination thereof. In some embodiments, the subject is a human.

[0042] In some instances, a level of mature myelinating oligodendrocytes is increased after the administering. Mature myelinating oligodendrocytes can be detected by detecting coexpression of the oligodendroglial lineage marker Olig2 and the mature oligodendrocyte marker ASPA. In some cases, a level of oligodendrocyte progenitor cells (OPCs) is not affected after the administering. OPCs can be detected by detecting expression of the OPC marker PDGFRa.

[0043] In some instances, the methods provided herein increase levels of mature myelinating oligodendrocytes in the CNS. In some cases, the CNS comprises brain tissue. In some instances, the brain tissue comprises grey matter. In some instances, the brain tissue comprises white matter. In some instances, the brain tissue comprises the cingulum, the corpus callosum, deep motor cortex, dentate gyrus, or any combination thereof. In some embodiments, the subject is a human.

[0044] In some embodiments, the subject has neuroinflammation. In some embodiments, the neuroinflammation is associated with a disease or a condition. In some embodiments, the disease or condition comprises a neurodegenerative disease or condition. In some instances, the subject has a neurodegenerative disease or condition. In some embodiments, the neurodegenerative disease or condition comprises a synucleinopathy. In some embodiments, the neurodegenerative disease or condition comprises Alzheimer’s disease, Parkinson’s disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies or Huntington’s disease.

[0045] In some instances, the subject has a synucleinopathy. In some embodiments, the synucleinopathy (also called a-Synucleinopathy) refers to a neurodegenerative disease or condition characterized by abnormal accumulation of aggregates and / or misfolded protein, e.g., alpha-synuclein protein, in cells such as neurons, nerve fibers, or glia cells, of nervous system. In some embodiments, the synucleinopathy comprises Parkinson’s disease, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or pure autonomic failure (PAF). In some instances, the synucleinopathy is selected from the group consisting of: Parkinson’s disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). In some embodiments, the subject has shared clinical features and / or symptoms of parkinsonism,Attorney Docket No. : 55773-741.601 impaired cognition, sleep disorders, or visual hallucinations. Due to interaction between the synuclein and tau proteins, in some embodiments, the synucleinopathy is overlapped with tauopathy.

[0046] In some instances, the subject has Alzheimer’s disease. In some embodiments, the Alzheimer’s disease comprises Alzheimer's Disease with Amygdalar Restricted Lewy Bodies (AD / ALB). In some embodiments, the Alzheimer’s disease exhibits a-synuclein positive Lewy pathology.

[0047] In some instances, the subject has a psychiatric condition. In some instances, the psychiatric condition is schizophrenia.

[0048] In some instances, the subject has epilepsy. In some instances, the subject has experienced a stroke. In some instances, the subject has amyotrophic lateral sclerosis (ALS). In some instances, the subject has spinal muscular atrophy (SMA).

[0049] In some instance, the subject has a viral infection. In some cases, the viral infection is an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0050] In some cases, the subject has inflammation due to aging (inflammaging).

[0051] In some cases, the subject has peripheral inflammation.

[0052] In some instances, the subject has elevated levels of at least one neuroinflammation biomarker. In some embodiments, the at least one neuroinflammation biomarker comprises nitric oxide (NO), cyclooxygenase-2 (COX-2), reactive oxygen species (ROS), IL-lbeta, IL- 4, IL-6, IL-8, IL-10, IL-11, IL-12, TNF-alpha, IFN-gamma, GM-CSF, CCL11, or TGF-beta. In some embodiments, the at least one neuroinflammation biomarker in a subject is determined by an appropriate method on a biological sample collected from the subject. In some embodiments, the methods include, but are not limited to, a nucleotide-based assay, a protein-based assay, Polymerase Chain Reaction (PCR), DNA microarray, Mass Spectrometry (MS), Single Nucleotide Polymorphism (SNP) assay, denaturing high- performance liquid chromatography (DHPLC), Restriction Fragment Length Polymorphism (RFLP) assay, RNA-seq, DNA-seq, next generation DNA sequencing, sequencing, whole exome sequencing, fluorescent in situ hybridization (FISH), DNA microarray analysis, RNA microarray analysis, mass spectrometry, western blot, immunoblot, or enzyme-linked immunosorbent assay (ELISA). In some instances, the subject has elevated spinal fluid levels of at least one inflammatory molecule selected from the group consisting of: IL-lbeta, IL-4, IL-6, IL-8, IL-10, IL-11, IL-12, TNF-alpha, IFN-gamma, GM-CSF, CCL11, and TGF-beta.Attorney Docket No. : 55773-741.601

[0053] In some instances, the 15-PGDH inhibitor is a small molecule compound. In some embodiments, the 15-PGDH inhibitor is any of the compounds provided herein.

[0054] In some embodiments, the 15-PGDH inhibitor can penetrate the blood-brain barrier (BBB). In some embodiments, brain-to-plasma concentration ratio (brain / plasma ratio) is utilized as an indicator of a compound’s ability to penetrate the BBB. In some embodiments, the 15-PGDH inhibitor exhibits about a 5% brain / plasma ratio, about a 10% brain / plasma ratio, about a 15% brain / plasma ratio, about a 20% brain / plasma ratio, about a 25% brain / plasma ratio, about a 30% brain / plasma ratio, about a 35% brain / plasma ratio, about a 40% brain / plasma ratio, about a 45% brain / plasma ratio, about a 50% brain / plasma ratio, about a 55% brain / plasma ratio, about a 60% brain / plasma ratio, about a 65% brain / plasma ratio, about a 70% brain / plasma ratio, or about a 75% brain / plasma ratio 2 hours after the administering. In some embodiments, the 15-PGDH inhibitor exhibits at least about a 5% brain / plasma ratio, at least about a 10% brain / plasma ratio, at least about a 15% brain / plasma ratio, at least about a 20% brain / plasma ratio, at least about a 25% brain / plasma ratio, at least about a 30% brain / plasma ratio, at least about a 35% brain / plasma ratio, at least about a 40% brain / plasma ratio, at least about a 45% brain / plasma ratio, at least about a 50% brain / plasma ratio, at least about a 55% brain / plasma ratio, at least about a 60% brain / plasma ratio, at least about a 65% brain / plasma ratio, at least about a 70% brain / plasma ratio, or at least about a 75% brain / plasma ratio 2 hours after the administering. In some instances, the 15-PGDH inhibitor exhibits at least about a 5% brain / plasma ratio 2 hours after the administering. In some instances, the 15-PGDH inhibitor exhibits at least about a 10% brain / plasma ratio 2 hours after the administering. In some embodiments, the 15-PGDH inhibitor exhibits at most about a 5% brain / plasma ratio, at most about a 10% brain / plasma ratio, at most about a 15% brain / plasma ratio, at most about a 20% brain / plasma ratio, at most about a 25% brain / plasma ratio, at most about a 30% brain / plasma ratio, at most about a 35% brain / plasma ratio, at most about a 40% brain / plasma ratio, at most about a 45% brain / plasma ratio, at most about a 50% brain / plasma ratio, at most about a 55% brain / plasma ratio, at most about a 60% brain / plasma ratio, at most about a 65% brain / plasma ratio, at most about a 70% brain / plasma ratio, or at most about a 75% brain / plasma ratio 2 hours after the administering. In some embodiments, the 15-PGDH inhibitor exhibits from about a 5% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 10% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 15% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 20%Attorney Docket No. : 55773-741.601 brain / plasma ratio to about a 75% brain / plasma ratio, from about a 25% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 30% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 35% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 40% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 45% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 50% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 55% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 60% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 65% brain / plasma ratio to about a 75% brain / plasma ratio, or from about a 70% brain / plasma ratio to about a 75% brain / plasma ratio 2 hours after the administering.

[0055] In some embodiments, the 15-PGDH inhibitor exhibits about a 5% brain / plasma ratio, about a 10% brain / plasma ratio, about a 15% brain / plasma ratio, about a 20% brain / plasma ratio, about a 25% brain / plasma ratio, about a 30% brain / plasma ratio, about a 35% brain / plasma ratio, about a 40% brain / plasma ratio, about a 45% brain / plasma ratio, about a 50% brain / plasma ratio, about a 55% brain / plasma ratio, about a 60% brain / plasma ratio, about a 65% brain / plasma ratio, about a 70% brain / plasma ratio, or about a 75% brain / plasma ratio 8 hours after the administering. In some embodiments, the 15-PGDH inhibitor exhibits at least about a 5% brain / plasma ratio, at least about a 10% brain / plasma ratio, at least about a 15% brain / plasma ratio, at least about a 20% brain / plasma ratio, at least about a 25% brain / plasma ratio, at least about a 30% brain / plasma ratio, at least about a 35% brain / plasma ratio, at least about a 40% brain / plasma ratio, at least about a 45% brain / plasma ratio, at least about a 50% brain / plasma ratio, at least about a 55% brain / plasma ratio, at least about a 60% brain / plasma ratio, at least about a 65% brain / plasma ratio, at least about a 70% brain / plasma ratio, or at least about a 75% brain / plasma ratio 8 hours after the administering. In some instances, the 15-PGDH inhibitor exhibits at least about a 5% brain / plasma ratio 8 hours after the administering. In some instances, the 15-PGDH inhibitor exhibits at least about a 10% brain / plasma ratio 8 hours after the administering. In some embodiments, the 15-PGDH inhibitor exhibits at most about a 5% brain / plasma ratio, at most about a 10% brain / plasma ratio, at most about a 15% brain / plasma ratio, at most about a 20% brain / plasma ratio, at most about a 25% brain / plasma ratio, at most about a 30% brain / plasma ratio, at most about a 35% brain / plasma ratio, at most about a 40% brain / plasma ratio, at most about a 45% brain / plasma ratio, at most about a 50% brain / plasma ratio, at most about a 55% brain / plasma ratio, at most about a 60% brain / plasma ratio, at most about a 65% brain / plasma ratio, at most about a 70%Attorney Docket No. : 55773-741.601 brain / plasma ratio, or at most about a 75% brain / plasma ratio 8 hours after the administering. In some embodiments, the 15-PGDH inhibitor exhibits from about a 5% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 10% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 15% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 20% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 25% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 30% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 35% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 40% ratio brain / plasma to about a 75% brain / plasma ratio, from about a 45% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 50% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 55% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 60% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 65% brain / plasma ratio to about a 75% brain / plasma ratio, or from about a 70% brain / plasma ratio to about a 75% brain / plasma ratio 8 hours after the administering.

[0056] In some embodiments, the 15-PGDH inhibitor exhibits about a 5% brain / plasma ratio, about a 10% brain / plasma ratio, about a 15% brain / plasma ratio, about a 20% brain / plasma ratio, about a 25% brain / plasma ratio, about a 30% brain / plasma ratio, about a 35% brain / plasma ratio, about a 40% brain / plasma ratio, about a 45% brain / plasma ratio, about a 50% brain / plasma ratio, about a 55% brain / plasma ratio, about a 60% brain / plasma ratio, about a 65% brain / plasma ratio, about a 70% brain / plasma ratio, or about a 75% brain / plasma ratio 24 hours after the administering. In some embodiments, the 15-PGDH inhibitor exhibits at least about a 5% brain / plasma ratio, at least about a 10% brain / plasma ratio, at least about a 15% brain / plasma ratio, at least about a 20% brain / plasma ratio, at least about a 25% brain / plasma ratio, at least about a 30% brain / plasma ratio, at least about a 35% brain / plasma ratio, at least about a 40% brain / plasma ratio, at least about a 45% brain / plasma ratio, at least about a 50% brain / plasma ratio, at least about a 55% brain / plasma ratio, at least about a 60% brain / plasma ratio, at least about a 65% brain / plasma ratio, at least about a 70% brain / plasma ratio, or at least about a 75% brain / plasma ratio 24 hours after the administering. In some instances, the 15-PGDH inhibitor exhibits at least about a 5% brain / plasma ratio 24 hours after the administering. In some instances, the 15-PGDH inhibitor exhibits at least about a 10% brain / plasma ratio 24 hours after the administering. In some embodiments, the 15- PGDH inhibitor exhibits at most about a 5% brain / plasma ratio, at most about a 10%Attorney Docket No. : 55773-741.601 brain / plasma ratio, at most about a 15% brain / plasma ratio, at most about a 20% brain / plasma ratio, at most about a 25% brain / plasma ratio, at most about a 30% brain / plasma ratio, at most about a 35% brain / plasma ratio, at most about a 40% brain / plasma ratio, at most about a 45% brain / plasma ratio, at most about a 50% brain / plasma ratio, at most about a 55% brain / plasma ratio, at most about a 60% brain / plasma ratio, at most about a 65% brain / plasma ratio, at most about a 70% brain / plasma ratio, or at most about a 75% brain / plasma ratio 24 hours after the administering. In some embodiments, the 15-PGDH inhibitor exhibits from about a 5% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 10% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 15% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 20% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 25% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 30% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 35% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 40% ratio brain / plasma to about a 75% brain / plasma ratio, from about a 45% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 50% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 55% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 60% brain / plasma ratio to about a 75% brain / plasma ratio, from about a 65% brain / plasma ratio to about a 75% brain / plasma ratio, or from about a 70% brain / plasma ratio to about a 75% brain / plasma ratio 24 hours after the administering.

[0057] In some embodiments, the administering comprises parenteral administration, intravenous administration, subcutaneous administration, intraperitoneal administration, intramuscular administration, intra-arterial administration, intravascular administration, intracardiac administration, intrathecal administration, intranasal administration, intradermal administration, intravitreal administration, transmucosal injection, oral administration, administration as a suppository, or topical administration. In some instances, the administering comprises systemic administration. In some instances, the administering comprises oral administration.

[0058] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No. : 55773-741.601Formula (I), wherein:Ring Q is Ce-Cio aryl or 5- to 10-membered heteroaryl;L is -C(O)-, -S-, -S(O)-, or -S(O)2-;R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, - C(O)NR8R9, -NR10C(O)R10, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; each R3is independently selected from H, halogen, -CN, -NR8R9, -OR10, CN, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -NR12C(O)R10, - NR12C(O)OR10, -NR12C(O)NR8R9, -OC(O)NR8R9, -NRI2SO2R'°, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each or which is substituted or unsubstituted with one or more R14;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-Cx alkenyl, substituted or unsubstituted Ci-Cs heteroalkyl, or substituted or unsubstituted Ci-Cs heteroalkyl, wherein each is substituted or unsubstituted with one or more R14;W is -CR6R6- , -C(O)R10-, -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;Attorney Docket No. : 55773-741.601 each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, - C(O)NR8R9, -SOR11, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3- Ce cycloalkyl or C3-C8 heterocycloalkyl ring; n and m are each independently 0, 1, 2, or 3; q is 0, 1, 2, 3, 4, 5, or 6; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, or -C(O)NR8R9; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

[0059] In some embodiments of Formula (I), ring Q is Ce-Cio aryl. In some embodiments of Formula (I), Ring Q is a 5- to 10-membered heteroaryl. In some embodiments of Formula (I), ring Q is phenyl or pyridyl. In some embodiments of Formula (I), ring Q is phenyl.

[0060] In some embodiments of Formula (I), L is -C(O)-. In some embodiments of Formula (I), L is -S-, -S(O)-, or -S(O)2-. In some embodiments of Formula (I), L is -S(O)- or -S(O)2-.

[0061] In some embodiments of Formula (I), R4is substituted or unsubstituted Ci-Cs alkyl or substituted or unsubstituted C2-C8 alkenyl, wherein each is substituted or unsubstituted with one or more R14. In some embodiments of Formula (I), R4is substituted or unsubstituted Ci- Cx alkyl, which is substituted or unsubstituted with one or more R14.

[0062] In some embodiments of Formula

[0063] In some embodiments, the compound of Formula (I) has the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:Formula (la), wherein:X1is N, NR3a, or CR3a;X2is N or CR3b;X3is N, NR3C, or CR3c;Attorney Docket No. : 55773-741.601R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, - C(O)NR8R9, -NR10C(O)R10, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;R3a, R3b, and R3care each independently H, halogen, -CN, -NR8R9, -OR10, CN, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -NR12C(O)R10, - NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, -OC(O)NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or R3aand R3btogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl; or R3band R3ctogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl;W is -CR6R6- , -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, - C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted C2-Ce alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; n and m are each independently 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, 5, or 6.

[0064] In some embodiments of Formula (la), X1is N, X2is CR3b, and X3is CR3c. In some embodiments of Formula (la), X1is CR3a, X2is N, and X3is CR3c. In some embodiments of Formula (la), X1is CR3a, X2is CR3b, and X3is N. In some embodiments of Formula (la), X1is CR3a, X2is CR3b, and X3is CR3c.

[0065] In some embodiments of Formula (la), at least one of X1, X2, or X3is not carbon.

[0066] In some embodiments of Formula (la), R3cis H; and R3aand R3btogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl. In some embodiments of Formula (la), R3ais H; and R3band R3ctogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl.Attorney Docket No. : 55773-741.601

[0067] In some embodiments, the compound of Formula (I) has the structure of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof:Formula (lb), wherein:Ring A is a 5-membered heteroaryl optionally comprising 1 or 2 N atoms;R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, - C(O)NR8R9, -NR10C(O)R10, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;W is -CR6R6- , -C(O)R10-, -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, - C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;R15is H, halogen, -NR8R9, -substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; n and m are each independently 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, 5, or 6.

[0068] In some embodiments of Formula (Ic), R15is H, halogen, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl. In some embodiments of Formula (Ic), R15is substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl. In some embodiments of Formula (Ic), R15is H.

[0069] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula (II), or a pharmaceutically accpetable salt of solvate thereof:Attorney Docket No. : 55773-741.601Formula (II), wherein:Ring Q is Ce aryl or 5- to 10-membered heteroaryl;L is -C(O)-, -S-, -S(O)-, -S(O)2-, or -S(O2)NH-;A1is N or CR1and A2is N or CR2, provided that at least one of A1or A2is N;A3is N or CR7;R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, - C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3is independently selected from H, halogen, -CN, -NR8R9, -OR10, CN, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -NR12C(O)OR9, -SOR11, -SO2R11, -SO2NR8R9, -NR12C(O)R10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted or unsubstituted with one or more R14;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-Cx alkenyl, substituted or unsubstituted Ci-Cs heteroalkyl;whereinW is -CR6R6- , -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, - C(O)NR8R9, -SOR11, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;Attorney Docket No. : 55773-741.601 or two R6can join together with the atom(s) to which they are attached to form a C3- Ce cycloalkyl or C3-C8 heterocycloalkyl ring; n and m are each independently 0, 1, 2, or 3; q is 0, 1, 2, 3, 4, 5, or 6; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, or -C(O)NR8R9;Attorney Docket No. : 55773-741.601 each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

[0070] In some embodiments of Formula (II), A1is N and A2is N. In some embodiments of Formula (II), A1is N and A2CR2. In some embodiments of Formula (II), A1is CR1and A2is N.

[0071] In some embodiments of Formula (II), ring Q is Ce-Cio aryl. In some embodiments of Formula (II), Ring Q is a 5- to 10-membered heteroaryl. In some embodiments of Formula (II), ring Q is phenyl or pyridyl. In some embodiments of Formula (II), ring Q is phenyl.

[0072] In some embodiments of Formula (II), L is -C(O)-. In some embodiments of Formula (II), L is -S-, -S(O)-, or -S(O)2-. In some embodiments of Formula (II), L is -S(O)- or -S(O)2-

[0073] In some embodiments of Formula (II), R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-Cs alkenyl, substituted or unsubstituted Ci-Cs heteroalkyl, or substituted or unsubstituted Ci-Cs heteroalkyl. In some embodiments of Formula (II), R4is substituted or unsubstituted Ci-Cs alkyl.

[0074] In some embodiments of Formula (

[0075] In some embodiments, the compound of Formula (II) has the structure of Formula (Ila), or a pharmaceutically accpetable salt of solvate thereof:Formula (Ila), wherein:A3is N or CR7;Attorney Docket No. : 55773-741.601R2is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;X1is N, NR3a, or CR3a;X3is N, NR3C, or CR3c;R3a, R3b, and R3care each independently H, halogen, -CN, -NR8R9, -OR10, CN, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -NR12C(O)R10, - NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, -OC(O)NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or R3aand R3btogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl; or R3band R3ctogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl;W is -CR6R6- , -C(O)R10-, -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, - C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted C2-Ce alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; n and m are each independently 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, 5, or 6.

[0076] In some embodiments of Formula (II) or (Ila), A3is N. In some embodiments of Formula (II) or (Ila), A3is CH.

[0077] In some embodiments of Formula (Ila), X1is N. In some embodiments of Formula (Ila), CR3a.

[0078] In some embodiments of Formula (Ila), X3is N. In some embodiments of Formula (Ila), CR3C.

[0079] In some embodiments of Formula (Ila), R3cis H; and R3aand R3btogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl. In some embodiments of Formula (Ila), R3ais H; and R3band R3ctogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl.Attorney Docket No. : 55773-741.601

[0080] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:Formula (III), wherein:Z is CR1or N;X1is N or CR3a;Y is CR7or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R2is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, -NR8R9, - OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, - NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R14;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs hydroxy alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NC>2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted Ci-Ce hydroxyalkyl, substituted or unsubstituted C3-C8Attorney Docket No. : 55773-741.601 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl;XAis NR5R5or OR5; wherein each R5is independently H or Ci-Ce alkyl;R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl;R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, or -C(O)NR8R9; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0081] In some embodiments of Formula (III), Y is N. In some embodiments of Formula (III), Y is CH.

[0082] In some embodiments of Formula (III), XAis NR5R5. In some embodiments of Formula (III), XAis OR5. In some embodiments of Formula (III), XAis -OH.

[0083] In some embodiments, the compound of Formula (III) has the structure of Formula (Illa), or a pharmaceutically acceptable salt or solvate thereof:Formula (Illa), wherein:Z is CR1or N;X1is N or CR3a;Y is CR2or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R2is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, -NR8R9, - OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, - NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8Attorney Docket No. : 55773-741.601 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R14; wherein R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NC>2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted Ci-Ce hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; each R5is independently H or Ci-Ce alkyl;R5ais H or CH3;R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, or -C(O)NR8R9; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0084] In some embodiments of Formula (III) or (Illa), Z is CR1. In some embodiments of Formula (III) or (Illa), Z is CH. In some embodiments of Formula (III) or (Illa), Z is N.

[0085] In some embodiments of Formula (III) or (Illa), X1is N. In some embodiments of Formula (III) or (Illa), CR3a.

[0086] In some embodiments of Formula (III) or (Illa), R4is substituted or unsubstituted Ci- Cx alkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6. In some embodiments of Formula (III) or (Illa), R4is substituted or unsubstituted Ci-Cs alkyl or substituted or unsubstituted Ci-Cs heteroalkyl. In some embodiments, R4is substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl.

[0087] In some embodiments of Formula (III) or (Illa), R4is -CH3, -CH2CH3, -CH2CH3CH3, -CH2(CH2)2CH3, -CH2(CH2)3CH3, -CH2(CH2)4CH3, -CH2CH2CH(CH3)2, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substitute or unsubstituted oxetane, substituted or unsubstituted tetrahydropyran, substituted or unsubstitutedAttorney Docket No. : 55773-741.601

[0088] In some embodiments, the 15-PGDH inhibitor is a compound having the structure ofFormula (IV), or a pharmaceutically acceptable salt thereof:Formula (IV), wherein,L1is -S(O)- or -S(O)2-;Z is CR1or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;X1is N or CR3a;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -Attorney Docket No. : 55773-741.601NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-Cx alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs haloalkyl, substituted or unsubstituted Ci- Cs hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6;whereinX is CH or N;W is CR6R6, -NR6a-, or -O-; each R6is independently H, halogen, CN,-NO2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, C1-C6 alkyl, Ci-C6haloalkyl, Ci-Ce hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a C3- Ce cycloalkyl or C3-C6 heterocycloalkyl;R6ais H or C1-C3 alkyl; m and n are each independently 0, 1, or 2; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted C2-Ce alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

[0089] In some embodiments of Formula (I), (la), (lb), (II), (Ila), or (VI), W is -CR6R6- , -O-, or -NR6a-. In some embodiments of Formula (I), (la), (lb), (II), (Ila), or (VI), W is -CR6R6- .

[0090] In some embodiments of Formula (I), (la), (lb), (II), (Ila), or (VI), n and m are each independently 0, 1, or 2. In some embodiments of Formula (I), (la), (lb), (II), (Ila), or (VI), n and m are each independently 0 or 1. In some embodiments of Formula (I), (la), (lb), (II), (Ila), or (VI), n and m are each independently 2.

[0091] In some embodiments of Formula (I), (la), (lb), (II), (Ila), or (VI), q is 0, 1, or 2.

[0092] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (III), (Illa), or (VI), each R6is independently H, halogen, -NR8R9, -OR10, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments of Formula (I), (la), (lb), (II), (Ila), (III), (Illa), or (VI), each R6is independently H, halogen, - Ci-Ce alkyl. In some embodiments of Formula (I), (la), (lb), (II), (Ila), (III), (Illa), or (VI), each R6is independently H or halogen. In some embodiments of Formula (I), (la), (lb), (II), (Ila), (III), (Illa), or (VI), each R6is independently F, -OH, -CH3,Attorney Docket No. : 55773-741.601 or -CF3. In some embodiments of Formula (I), (la), (lb), (II), (Ila), (III), (Illa), or (VI), each R6is -F.

[0093] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (III), (Illa), or (VI), two R6combine together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In some embodiments of Formula (I), (la), (lb), (II), (Ila), (III), (Illa), or (VI), two R6combine together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl.

[0094] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula (V), or a pharmaceutically acceptable salt thereof:Formula (V), wherein:L1is -S(O)- or -S(O)2-;Z is CR1or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;X1is N or CR3a;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, -NR8R9, - OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, - NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R13is independently H, halogen, -CN, -NO2, -NR8R9, -OR10, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted orAttorney Docket No. : 55773-741.601 unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C3-C6 heterocycloalkyl, each of which is substituted with one or more R13a; or two R13combine together with the atoms to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted heterocycloalkyl, each of which is substituted with one or more R13a, wherein each R13ais independently halogen, - CN, -NO2, -NRsRg, -OR10, alkyl, or haloalkyl;R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; andAttorney Docket No. : 55773-741.601 v is 0-20.

[0095] In some embodiments of Formula (V), each R13is independently H, halogen, -NR8R9, -OR10, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C3-C6 heterocycloalkyl, each of which is substituted with one or more R13a. In some embodiments of Formula (V), each R13is independently H, -OR10, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

[0096] In some embodiments of Formula (V), two R13combine together with the atoms to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted heterocycloalkyl, each of which is substituted with one or more R13a.

[0097] In some embodiments of Formula (V), v is 0-10. In some embodiments of Formula (V), v is 1-8. In some embodiments of Formula (V), v is 1-6.

[0098] In some embodiments of Formula (IV) or (V), L1is -S(O)-. In some embodiments of Formula (VI) or (V), L1is -S(O)2-.

[0099] In some embodiments of Formula (IV) or (V), Z is CR1. n some embodiments of Formula (IV) or (V), Z is CH. n some embodiments of Formula (IV) or (V), Z is N.

[0100] In some embodiments of Formula (IV) or (V), X1is N. In some embodiments of Formula (IV) or (V), X1is CR3a.

[0101] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), (IV), or (V), R1is H or substituted or unsubstituted Ci-Ce alkyl. In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), (IV), or (V), R1is H.

[0102] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), or (Illa), R2is H or substituted or unsubstituted Ci-Ce alkyl. In some embodiments of Formula (I), (la), (lb), (II), (Ila), (Hb), (III), or (Illa), R2is H.

[0103] In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NR8R9, -OR10, - C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -NR12C(O)R10, - NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments of Formula (la), (lb), (Ila), (Hb), (III), (Illa), (IV), or (V), R3a, R3b, and R3care each independentlyAttorney Docket No. : 55773-741.601 selected from H, halogen, -CN, -C(O)R10, -C(O)OR10, -C(O)NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3a, R3b, and R3care each independently selected from H, halogen, - CF3, -CN, -C(O)OR10, -C(O)NR8R9, and 5- membered heteroaryl. In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3a, R3b, and R3care each independently selected from H, halogen, -CN, -CF3, -C(O)OH, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, triazole, tetrazole, pyrrolidine, morpholine, or Ci-Ce alkyl substituted with - C(O)OH. In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3a, R3b, and R3care each independently selected from H, halogen, -CN, -CF3, -C(O)OH, triazole, tetrazole, or Ci-Ce alkyl substituted with -C(O)OH.

[0104] In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3aand R3bare each H or halogen; and R3cis selected from halogen, -CN, -C(O)R10, -C(O)OR10, -C(O)NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5- to 10-membered heteroaryl.

[0105] In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3aand R3bare each H or halogen; and R3cis selected from halogen, -C(O)R10, -C(O)OR10, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3aand R3bare each H or halogen; and R3cis a substituted or unsubstituted 5-membered heteroaryl.

[0106] In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3aand R3Care each H or halogen; and R3bis selected from halogen, -C(O)R10, -C(O)OR10, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3aand R3care each H or halogen; and R3bis a substituted or unsubstituted 5-membered heteroaryl.

[0107] In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3band R3Care each H or halogen; and R3ais selected from halogen, -C(O)R10, -C(O)OR10, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments of Formula (la), (lb), (Ila), (lib), (III), (Illa), (IV), or (V), R3band R3care each H or halogen; and R3ais a substituted or unsubstituted 5-membered heteroaryl.Attorney Docket No. : 55773-741.601

[0108] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), (IV), or (V), each R3, R3a, R3b, and R3care each independently H or a 5-membered heteroaryl selected from pyrrole, triazole, tetrazole, oxazole, diazole, oxadiazole, thiadiazole, and furanyl. In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), (IV), or (V), each R3, R3a, R3b, and R3care each independently H or a 5-membered heteroaryl selected from pyrrole, triazole, and tetrazole.

[0109] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), (IV), or (V), each R3, R3a, R3b, or R3cis independently selected from the group consisting of H,, . In some embodiments of Formula (I), (la),(lb), (II), (Ila), (lib), (III), (Illa), (IV), or (V), each R3, R3a, R3b, or R3cis independentlyAttorney Docket No. : 55773-741.601 selected from the group consisting of H,, , , orinsome embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), (IV), or (V), each R3, R3a, R3b, or R3cis independently

[0110] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), (IV), or (V), R7is H or substituted or unsubstituted Ci-Ce alkyl. In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), (IV), or (V), R7is H.[OHl] In some embodiments, each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra. In some embodiments, each R8and R9is independently selected at each occurrence from H, Ci- Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, and C3-C 10 heterocycloalkyl.

[0112] In some embodiments, each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra. In some embodiments, each R10is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R10is independently selected from H and Ci- Ce alkyl.

[0113] In some embodiments, each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra. In some embodiments, each R11is independently selected from Ci-Ce alkyl, Ci-Ce heteroalkyl, and Ci-Ce haloalkyl. InAttorney Docket No. : 55773-741.601 some embodiments, each R11is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0114] In some embodiments, each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra. In some embodiments, each R12is independently selected from H, straight or branched chain Ci-Ce alkyl. In some embodiments, each R12is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0115] In some embodiments, each Rais independently selected from halogen, -OH, -CH3, - CF3, -0CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3. In some embodiments, each Rais independently selected from -F, -Cl, -Br, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, each Rais independently selected from -F, -OH, -CH3, -CF3, or - C(O)OH.

[0116] In some embodiments, the 15-PDGH inhibitor is a compound described in Table 1, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, any compounds described herein can be useful for forming a composition. In some embodiments, the composition comprising the compounds described herein can be used to reduce a level of reactive microglia in the CNS. In some embodiments, the composition can be used to treat a neurological disease, disorder, or condition in a subject.

[0118] Provided in some embodiments herein is a pharmaceutical composition comprising a compound provided herein, or pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

[0119] The pharmaceutically acceptable excipients in the pharmaceutical composition described herein can be any suitable pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient is sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the sodium lauryl sulfate is Kolliphore SLS fine, the partially pre-gelatinizedAttorney Docket No. : 55773-741.601 maize starch is Starch 1500, the microcrystalline cellulose is Avicel PH 101, the sodium starch glycolate is type A, the hydroxypropyl cellulose LF is Klucel HPC LF, and the colloidal silicon dioxide is Aerosil Pharma 200.

[0120] Provided herein is a pharmaceutical composition comprising a compound described herein, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.DEFINITIONS

[0121] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0122] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0123] As used herein, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof. Another example, "an element" means one element or more than one element. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related termsAttorney Docket No. : 55773-741.601 such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may “consist of’ or “consist essentially of’ the described features.

[0124] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0125] The terms “subject,” “individual,” or “patient” are often used interchangeably herein. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.

[0126] As used herein, the term “about” can mean plus or minus less than 1 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, or greater than 30 percent, depending upon the situation and knowledge by one skilled in the art.

[0127] The term “effective amount” or “therapeutically effective amount” may generally refer to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment. The term may also apply to a dose that will induce a particular response in target cells.

[0128] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of one or more symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes, but is not limited to, delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminatingAttorney Docket No. : 55773-741.601 the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[0129] A “therapeutic effect” may encompass a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0130] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0131] “ oxo” refers to =0.

[0132] “Carboxyl” refers to -COOH.

[0133] “Cyano” refers to -CN.

[0134] “Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl-2-propyl, 2 -m ethyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2- dimethyl-1 -propyl, 2 -m ethyl- 1 -pentyl, 3 -methyl- 1 -pentyl, 4-m ethyl- 1 -pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2- ethyl-1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” or “Ci-ealkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci- loalkyl. In some embodiments, the alkyl is a Ci-ealkyl. In some embodiments, the alkyl is a Ci-salkyl. In some embodiments, the alkyl is a C alkyl. In some embodiments, the alkyl is a Ci-salkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, andAttorney Docket No. : 55773-741.601 the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, - C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0135] “Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1 -propenyl (- CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or - NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0136] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -Attorney Docket No. : 55773-741.601NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0137] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0138] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, - C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0139] “Aryl” refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system can contain only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, / .< ., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6- membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene,Attorney Docket No. : 55773-741.601 naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0140] “Carbocycle” refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle may be optionally substituted.

[0141] “Cycloalkyl” refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3 - to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6- membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fullyAttorney Docket No. : 55773-741.601 saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0142] “Cycloalkenyl” refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0143] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0144] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, di chloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2- fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalom ethane (e.g., tri chloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-Attorney Docket No. : 55773-741.601 halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3- trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., l-chloro,2-fluoroethane.

[0145] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.

[0146] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0147] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0148] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, - N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, - CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, - CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -Attorney Docket No. : 55773-741.601CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0149] “Heterocycloalkyl” refers to a 3 - to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (C2- C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl,Attorney Docket No. : 55773-741.601 trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1- dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l- yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6- membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 6- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6- membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0150] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatomsAttorney Docket No. : 55773-741.601 selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4- benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1- oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinol inyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.Attorney Docket No. : 55773-741.601

[0151] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, / .< ., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0152] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0153] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted(protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, suchAttorney Docket No. : 55773-741.601 as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0154] “ Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0155] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.

[0156] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layerAttorney Docket No. : 55773-741.601 chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.

[0157] When stereochemistry is not specified, certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration. In addition, such certain small molecules include Z- and / :- forms (or cis- and trans- forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds. Where certain small molecules described herein exist in various tautomeric forms, the term “certain small molecule” is intended to include all tautomeric forms of the certain small molecule.

[0158] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases fromAttorney Docket No. : 55773-741.601 which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0159] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;(15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0160] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.EXAMPLES

[0161] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.Example 1: Effects of a 15-PGDH inhibitor on microglia activity in A 7 mice

[0162] The effects of administering a 15-PGDH inhibitor on microglial activity in female mice was determined. Mice were selected for cohorts that either exhibited a mouse model of spinal muscular atrophy (SMA; A7 mice) or were non-SMA control mice. The A7 mice andAttorney Docket No. : 55773-741.601 non-SMA control mice received intraperitoneal or subcutaneous administration of SMN-C3 (a SMN2 splicing modulator) and nusinersen (which modulates alternative splicing of the SMN2 gene), and either vehicle or a 15-PGDH inhibitor (15-PGDHi). After treatment with either the 15-PGDH inhibitor or vehicle, the A7 mice and non-SMA control mice were sacrificed and expression of the microglial markers Ibal (a microglia marker) and CD68 (a reactive microglia marker) were quantified in neural regions of interest. As shown in FIG. 1A, the neural regions of interest that were assessed included the cingulum, corpus callosum, deep motor cortex, and dentate gyrus. As shown in FIG. IB, the number of reactive microglia in response to treatment with a 15-PGDH inhibitor was assessed in the cingulum of A7 female mice and non-SMA control female mice by quantifying the number of CD68 / Ibal cells per mm3in the cingulum. As shown in FIG. 1C, the number of reactive microglia in response to treatment with a 15-PGDH inhibitor was assessed in the corpus callosum of A7 female mice and non-SMA control female mice by quantifying the number of CD68 / Ibal cells per mm3in the corpus callosum. As shown in FIG. ID, the number of reactive microglia in response to treatment with a 15-PGDH inhibitor was assessed in the dentate gyrus of A7 female mice and non-SMA control female mice by quantifying the number of CD68 / Ibal cells per mm3in the dentate gyrus. As shown in FIG. IE, the number of reactive microglia in response to treatment with a 15-PGDH inhibitor was assessed in the deep motor cortex of A7 female mice and non-SMA control female mice by quantifying the number of CD68 / Ibal cells per mm3in the deep motor cortex. As shown in FIG. IF, changes in overall levels of Ibal+ microglia in response to treatment with a 15-PGDH inhibitor was assessed in the deep motor cortex of A7 female mice and non-SMA control female mice by quantifying the number Ibal+ cells per mm3in the deep motor cortex and indicated that there were no changes in overall levels of bal+ microglia.Example 2: Effects of a 15-PGDH inhibitor on oligodendrocyte populations in A7 mice

[0163] The effects of administering a 15-PGDH inhibitor on oligodendrocyte populations in mice was determined. A mouse model of spinal muscular atrophy (SMA; A7 mice) and non- SMA control mice were used. A7 mice received intraperitoneal administration of SMN-C3 (3 mg / kg) and subcutaneous administration of nusinersen (100 mg / kg) at post-natal day (PND) 4 and PND6. A7 and non-SMA control mice received intraperitoneal administration of a 15-PGDH inhibitor or vehicle control once daily from PND60 to PND90. At PND90, mice were sacrificed. Levels of oligodendrocyte progenitor cells (OPCs) in deep motor-n -Attorney Docket No. : 55773-741.601 cortex, cingulum, and corpus callosum were assessed by identifying cells that expressed the OPC marker PDGFRa. Levels of mature myelinating oligodendrocytes in deep motor cortex, cingulum, and corpus callosum were assessed by identifying cells that co-expressed the oligodendroglial lineage marker Olig2 and the mature oligodendrocyte marker ASPA.

[0164] As shown in FIGS. 2A-2C, the levels of Olig2+ASPA+ mature myelinating oligodendrocytes were decreased in SMA A7-vehicle treated mice in deep motor cortex, cingulum, and corpus callosum, and 15-PGDH inhibition increased the number of Olig2+ ASPA2+ mature oligodendrocytes in SMA A7 mice compared to SMA A7 mice treated with vehicle. As shown in FIGS. 3A-3C, 15-PGDH inhibition did not affect the number of PDGRFA+ OPCs in deep motor cortex, cingulum, and corpus callosum.Example 3: Blood-brain barrier penetrant 15-PGDH inhibitors

[0165] 15-PGDH inhibitor compound levels were measured in the brain and in blood plasma of mice at 2 hours and at 8 hours after administration of the compound. After sacrifice, the brains were removed, washed, weighed and homogenized. The brain concentrations were expressed as a weight percent (ng test article per gram tissue), whereas the plasma concentrations were expressed as nanograms / milliliter. The 2 hour and the 8 hour brain / plasma ratios were both obtained and the arithmetic average was calculated. The average brain / plasma ratio is provided in Table 1 below.Table 1. 15-PGDH inhibitorsAttorney Docket No. : 55773-741.601Attorney Docket No. : 55773-741.601Attorney Docket No. : 55773-741.601Attorney Docket No. : 55773-741.601Attorney Docket No. : 55773-741.601

[0166] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

Attorney Docket No. : 55773-741.601CLAIMSWhat is Claimed is:

1. A method of reducing a level of reactive microglia in the central nervous system (CNS) of a subject, the method comprising: administering a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to the subject in an amount effective to reduce the level of reactive microglia in the CNS.

2. The method of claim 1, wherein the subject has microgliosis.

3. The method of claim 1 or 2, wherein the subject has neuroinflammation, neurodegeneration, or both.

4. The method of claim 1 or 2, wherein the subject has peripheral inflammation.

5. The method of claim 1, wherein the subject has a viral infection.

6. The method of claim 5, wherein the viral infection is an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

7. The method of claim 1, wherein the subject has inflammation due to aging (inflammaging).

8. A method of treating a subject having a neurological disorder, condition, or disease, the method comprising: administering an amount of a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to the subject in an amount effective to treat the neurological disorder, condition, or disease.

9. The method of claim 8, wherein the subject has levels of reactive microglia in the central nervous system (CNS).

10. The method of claim 8 or 9, wherein the subject has elevated levels of reactive microglia in the CNS.

11. The method of any one of claims 1-10, wherein the levels of reactive microglia in the CNS are reduced after the administering.

12. The method of any one of claims 1-11, wherein the levels of reactive microglia in the CNS are reduced by at least about 5% after the administering.

13. The method of any one of claims 1-12, wherein a level of total microglia is unchanged after the administering.

14. The method of any one of claims 1-7 or 9-13, wherein the reactive microglia express CD68.Attorney Docket No. : 55773-741.60115. The method of any one of claims 1-7 or 9-14, wherein the CNS comprises brain tissue.

16. The method of claim 15, wherein the brain tissue comprises grey matter.

17. The method of claim 15 or 16, wherein the brain tissue comprises white matter.

18. The method of claim 15, wherein the brain tissue comprises the cingulum, the corpus callosum, deep motor cortex, dentate gyrus, or any combination thereof.

19. The method of any one of claims 8-18, wherein the subject has a neurodegenerative disease, disorder, or condition.

20. The method of any one of claims 8-19, wherein the subject has neuroinflammation or a neuroinflammatory disease, disorder, or condition.

21. The method of any one of claims 8-20, wherein the subject has peripheral inflammation.

22. The method of any one of claims 1-4 or 8-21, wherein the subject has spinal muscular atrophy (SMA).

23. The method of any one of claims 1-4 or 8-21, wherein the subject has a synucleinopathy.

24. The method of claim 23, wherein the synucleinopathy is selected from the group consisting of: Parkinson’s disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).

25. The method of any one of claims 1-4 or 8-21, wherein the subject has Alzheimer’s disease.

26. The method of any one of claims 1-4 or 8-21, wherein the subject has a psychiatric condition.

27. The method of claim 26, wherein the psychiatric condition is schizophrenia.

28. The method of any one of claims 1-4 or 8-21, wherein the subject has epilepsy.

29. The method of any one of claims 1-4 or 8-21, wherein the subject has experienced a stroke.

30. The method of any one of claims 1-4 or 8-21, wherein the subject has amyotrophic lateral sclerosis (ALS).

31. The method of any one of claims 1-30, wherein the subject has elevated spinal fluid levels of at least one inflammatory molecule selected from the group consisting of: IL-lbeta,Attorney Docket No. : 55773-741.601IL-4, IL-6, IL-8, IL-10, IL-11, IL-12, TNF-alpha, IFN-gamma, GM-CSF, CCL11, and TGF- beta.

32. The method of any one of claims 1-31, wherein the 15-PGDH inhibitor is a small molecule compound.

33. The method of any one of claims 1-32, wherein the 15-PGDH inhibitor exhibits at least about a 5% blood / plasma ratio 2 hours after the administering.

34. The method of any one of claims 1-33, wherein the 15-PGDH inhibitor exhibits at least about a 10% blood / plasma ratio 2 hours after the administering.

35. The method of any one of claims 1-34, wherein the 15-PGDH inhibitor exhibits from about a 5% to about a 75% blood / plasma ratio 2 hours after the administering.

36. The method of any one of claims 1-35, wherein the 15-PGDH inhibitor exhibits at least about a 5% blood / plasma ratio 8 hours after the administering.

37. The method of any one of claims 1-36, wherein the 15-PGDH inhibitor exhibits at least about a 10% blood / plasma ratio 8 hours after the administering.

38. The method of any one of claims 1-37, wherein the 15-PGDH inhibitor exhibits from about a 5% to about a 75% blood / plasma ratio 8 hours after the administering.

39. The method of any one of claims 1-38, wherein the 15-PGDH inhibitor exhibits at least about a 5% blood / plasma ratio 24 hours after the administering.

40. The method of any one of claims 1-39, wherein the 15-PGDH inhibitor exhibits at least about a 10% blood / plasma ratio 24 hours after the administering.

41. The method of any one of claims 1-40, wherein the 15-PGDH inhibitor exhibits from about a 5% to about a 75% blood / plasma ratio 24 hours after the administering.

42. The method of any one of claims 1-41, wherein the administering comprises systemic administration.

43. The method of any one of claims 1-41, wherein the administering comprises oral administration.

44. The method of any one of claims 1-43, wherein the 15-PGDH inhibitor is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No. : 55773-741.601Formula (I), wherein:Ring Q is Ce-Cio aryl or 5- to 10-membered heteroaryl;L is -C(O)-, -S-, -S(O)-, or -S(O)2-;R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, - C(O)NR8R9, -NR10C(O)R10, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; each R3is independently selected from H, halogen, -CN, -NR8R9, -OR10, CN, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -NR12C(O)R10, - NR12C(O)OR10, -NR12C(O)NR8R9, -OC(O)NR8R9, -NRI2SO2R'°, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each or which is substituted or unsubstituted with one or more R14;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-Cx alkenyl, substituted or unsubstituted Ci-Cs heteroalkyl, or substituted or unsubstituted Ci-Cs heteroalkyl, wherein each is substituted or unsubstituted with one or more R14;whereinW is -CR6R6- , -C(O)R10-, -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;Attorney Docket No. : 55773-741.601 each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, - C(O)NR8R9, -SOR11, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3- Ce cycloalkyl or C3-C8 heterocycloalkyl ring; n and m are each independently 0, 1, 2, or 3; q is 0, 1, 2, 3, 4, 5, or 6; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, or -C(O)NR8R9; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

45. The method of claim 44, wherein the compound having the structure of Formula (I) has the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:wherein:X1is N, NR3a, or CR3a;X2is N or CR3b;X3is N, NR3C, or CR3c;R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, - C(O)NR8R9, -NR10C(O)R10, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;R3a, R3b, and R3care each independently H, halogen, -CN, -NR8R9, -OR10, CN, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -NR12C(O)R10, - NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, -OC(O)NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl;Attorney Docket No. : 55773-741.601 or R3aand R3btogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl; or R3band R3ctogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl;W is -CR6R6- , -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, - C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; n and m are each independently 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, 5, or 6.

46. The method of claim 44, wherein the compound having the structure of Formula (I) has the structure of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof:Formula (lb), wherein:Ring A is a 5-membered heteroaryl optionally comprising 1 or 2 N atoms;R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, - C(O)NR8R9, -NR10C(O)R10, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;W is -CR6R6- , -C(O)R10-, -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, - C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;Attorney Docket No. : 55773-741.601 or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra;R15is H, halogen, -NR8R9, -substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3;Attorney Docket No. : 55773-741.601 n and m are each independently 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, 5, or 6.

47. The method of any one of claims 1-43, wherein the 15-PGDH inhibitor is a compound having the structure of Formula (II), or a pharmaceutically accpetable salt of solvate thereof:Formula (II), wherein:Ring Q is Ce aryl or 5- to 10-membered heteroaryl;L is -C(O)-, -S-, -S(O)-, -S(O)2-, or -S(O2)NH-;A1is N or CR1and A2is N or CR2, provided that at least one of A1or A2is N;A3is N or CR7;R1and R2are each independently H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, - C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3is independently selected from H, halogen, -CN, -NR8R9, -OR10, CN, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -NR12C(O)OR9, -SOR11, -SO2R11, -SO2NR8R9, -NR12C(O)R10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted or unsubstituted with one or more R14;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-Cx alkenyl, substituted or unsubstituted Ci-Cs heteroalkyl;whereinW is -CR6R6- , -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;Attorney Docket No. : 55773-741.601R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, - C(O)NR8R9, -SOR11, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3- Ce cycloalkyl or C3-C8 heterocycloalkyl ring; n and m are each independently 0, 1, 2, or 3; q is 0, 1, 2, 3, 4, 5, or 6; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl,Attorney Docket No. : 55773-741.601 substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, or -C(O)NR8R9; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and p is 1, 2, 3, or 4.

48. The method of claim 47, wherein the compound having the structure of Formula (II) has the structure of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof:wherein:A3is N or CR7;R2is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;X1is N, NR3a, or CR3a;X3is N, NR3C, or CR3c;R3a, R3b, and R3care each independently H, halogen, -CN, -NR8R9, -OR10, CN, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, -NR12C(O)R10, - NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, -OC(O)NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted Ce aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl;Attorney Docket No. : 55773-741.601 or R3aand R3btogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl; or R3band R3ctogether with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl;W is -CR6R6- , -C(O)R10-, -O-, -S-, -NR6a-, -S(O)2-, or -C(O)-;R6ais H or substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6is independently H, halogen, CN, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, - C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, -SR8, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; or two R6can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; each R7is independently H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, - NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra;Attorney Docket No. : 55773-741.601 each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; n and m are each independently 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, 5, or 6.

49. The method of any one of claims 1-43, wherein the 15-PGDH inhibitor is a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:Formula (III), wherein:Z is CR1or N;X1is N or CR3a;Y is CR7or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R2is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, -NR8R9, - OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2RU, -SO2NR8R9, - NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8Attorney Docket No. : 55773-741.601 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R14;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NC>2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted Ci-Ce hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl;XAis NR5R5or OR5; wherein each R5is independently H or Ci-Ce alkyl;R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl;R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted orAttorney Docket No. : 55773-741.601 unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, or -C(O)NR8R9; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

50. The method of claim 49, wherein the compound having the structure of Formula (III) has the structure of Formula (Illa), or a pharmaceutically acceptable salt or solvate thereof:Formula (Illa), wherein:Z is CR1or N;X1is N or CR3a;Y is CR2or N;Attorney Docket No. : 55773-741.601R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R2is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, -NR8R9, - OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, - NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R14; whereinR4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs hydroxy alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently halogen, CN,-NC>2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted Ci-Ce hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; each R5is independently H or Ci-Ce alkyl;R5ais H or CH3;R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-CeAttorney Docket No. : 55773-741.601 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R14is independently halogen, CN, -NO2, -NR8R9, -OR10, -SR8, -C(O)R10, -C(O)OR10, or -C(O)NR8R9; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

51. The method of any one of claims 1-43, wherein the 15-PGDH inhibitor is a compound having the structure of Formula (IV), or a pharmaceutically acceptable salt thereof:Formula (IV), wherein,Attorney Docket No. : 55773-741.601L1is -S(O)- or -S(O)2-;Z is CR1or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;X1is N or CR3a;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, -NR8R9, - OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, - NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra;R4is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted Ci-Cs aminoalkyl, substituted or unsubstituted Ci-Cs heteroalkyl, substituted or unsubstituted Ci-Cs haloalkyl, substituted or unsubstituted Ci- Cs hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6;whereinX is CH or N;W is CR6R6, -NR6a-, or -O-; each R6is independently H, halogen, CN,-NC>2, -NR8R9, -OR10, -SR8, -C(O)R10, - C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -NR8C(O)R9, C1-C6 alkyl, Ci-C6haloalkyl, Ci-Ce hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a C3- Ce cycloalkyl or C3-C6 heterocycloalkyl;R6ais H or C1-C3 alkyl; m and n are each independently 0, 1, or 2; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;Attorney Docket No. : 55773-741.601R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3.

52. The method of any one of claims 1-43, wherein the 15-PGDH inhibitor is a compound having the structure of Formula (V), or a pharmaceutically acceptable salt thereof:Attorney Docket No. : 55773-741.601Formula (V), wherein:L1is -S(O)- or -S(O)2-;Z is CR1or N;R1is H, halogen, -CN, -OR10, -C(O)R10, -C(O)OR10, -NR8R9, -C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;X1is N or CR3a;R3a, R3b, and R3care each independently selected from H, halogen, -CN, -NO2, -NR8R9, - OR10, -SR8, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -SORn, -SO2R11, -SO2NR8R9, - NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, -NR12SO2R10, -NR12SO2NR8R9, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R13is independently H, halogen, -CN, -NO2, -NR8R9, -OR10, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C3-C6 heterocycloalkyl, each of which is substituted with one or more R13a; or two R13combine together with the atoms to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted heterocycloalkyl, each of which is substituted with one or more R13a, wherein each R13ais independently halogen, - CN, -NO2, -NR8R9, -OR10, alkyl, or haloalkyl;R7is H, halogen, -OR10, -C(O)R10, -C(O)OR10, -CN, -C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl,Attorney Docket No. : 55773-741.601 substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce heteroalkyl substituted or unsubstituted, Ci-Ce haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, - N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, - NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and v is 0-20.

53. The method of any one of claims 1-43, wherein the 15-PGDH inhibitor is selected from any compound listed in Table 1.

54. The method of any one of claims 1-43, wherein the 15-PGDH inhibitor is selected from the group consisting of:Attorney Docket No. : 55773-741.601Attorney Docket No. : 55773-741.601

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