PGDH inhibitors and methods of making and using

Abstract

Disclosed herein are 15-hydroxyprostaglandin dehydrogenase (PGDH) inhibitor compounds. Such compounds may be administered to subjects that may benefit from modulation of prostaglandin levels for the treatment of muscle disorders.

Description

WSGR Docket No.55773-740.601 PGDH INHIBITORS AND METHODS OF MAKING AND USING CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 675,202, filed July 24,2024, which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION

[0002] Prostaglandins are a group of physiologically active lipid compounds with diverse biologicaleffects including vasodilation, inhibition of platelet aggregation, bronchodilation, bronchoconstriction, immune responses, contraction and relaxation of gastrointestinal smooth muscles, gastric acid secretion, gastric mucus secretion, uterus contraction, lipolysis inhibition, neurotransmission, clotting, hyperalgesia, and pyrexia.

[0003] Treatment of diseases or disorders may require activation of prostaglandins, or inhibition ofinactivation of prostaglandins. Hydroxyprostaglandin dehydrogenases, such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) are involved in the inactivation of prostaglandins. As such, diseases / disorders associated with prostaglandins can be prevented, treated and / or managed using inhibitors of hydroxyprostaglandin dehydrogenase such as inhibitors of 15-PGDH. SUMMARY OF THE INVENTION

[0004] In an aspect provided herein is a compound of Formula (II), or a pharmaceutically acceptable saltthereof:Formula (II), wherein: Z is CR1or N; X1is N or CR3a; Y is CR2or N;R1 is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9, substituted orunsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;each R2 is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, -NR8C(O)R9,substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C3-C8cycloalkyl; - 1 -WSGR Docket No.55773-740.601 R3a, R3b, and R3care each independently H, halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9; R4is substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C2-C8alkenyl, substituted or unsubstituted C1-C8aminoalkyl, substituted or unsubstituted C1-C8heteroalkyl, substituted or unsubstituted C1-C8hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C8heterocycloalkyl, each of which is optionally substituted with one or more R6; wherein each R6 is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, 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-C6cycloalkyl or substituted or unsubstituted C3-C8heterocycloalkyl; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is optionally substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or - 2 -WSGR Docket No.55773-740.601 unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is optionally 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.

[0005] In an aspect, provided herein is a compounds of Formula (V), or a pharmaceutically acceptablesalt thereof:Formula (V), wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; L is C1-C3alkylene; Q1is -O- or -S-; R1is H; each R2is independently H or C1-C6alkyl;R3a, R3b, and R3c are each independently H, halogen, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl, - 3 -WSGR Docket No.55773-740.601 wherein each alkyl, or heteroaryl is optionally substituted with one or more R13; each of which is substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9; R4ais substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8heterocycloalkyl, each of which is optionally substituted with one or more R6; wherein each R6 is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C8heterocycloalkyl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C8heterocycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is optionally substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is optionally substituted with one or more Ra; and - 4 -WSGR Docket No.55773-740.601 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.

[0006] In some embodiments, the compounds of Formula (V) has the structure of Formula (Va), or apharmaceutically acceptable salt thereof:Formula (Va).

[0007] In some embodiments, the compounds of Formula (V) has the structure of Formula (VIa) orFormula (VIb), or a pharmaceutically acceptable salt thereof:

[0008] In another aspect, provided herein is a pharmaceutical composition comprising a compounddescribed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient

[0009] In another aspect, provided herein is a method of promoting and / or stimulation skin pigmentation,comprising administering one or more of the compositions described herein to a subject in need thereof.

[0010] In another aspect, provided herein is a method of inhibiting hair loss, comprising administeringone or more of the compositions described herein to a subject in need thereof.

[0011] method of preventing and / or treating skin inflammation and / or damage, comprising administeringone or more of the compositions described herein to a subject in need thereof.

[0012] In another aspect, provided herein is a method of preventing and / or treating vascularinsufficiency, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0013] In another aspect, provided herein is a method of preventing, treating, minimizing and / orreversing congestive heart failure, cardiomyopathy, comprising administering one or more of the compositions described herein to a subject in need thereof. - 5 -WSGR Docket No.55773-740.601

[0014] In another aspect, provided herein is a method of reducing cardiac ejection fraction, comprisingadministering one or more of the compositions described herein to a subject in need thereof.

[0015] In another aspect, provided herein is a method of preventing and / or treating a gastrointestinaldisease, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0016] In another aspect, provided herein is a method of preventing and / or treating renal dysfunction,comprising administering one or more of the compositions described herein to a subject in need thereof.

[0017] In another aspect, provided herein is a method of stimulation bone resorption and bone formation,comprising administering one or more of the compositions described herein to a subject in need thereof.

[0018] In another aspect, provided herein is a method of stimulating tissue regeneration by stimulating,comprising administering one or more of the compositions described herein to a subject in need thereof.

[0019] In another aspect, provided herein is a method of modulating cervical ripening, comprisingadministering one or more of the compositions described herein to a subject in need thereof.

[0020] In another aspect, provided herein is a method of promoting neuroprotection and / or stimulatingneuronal regeneration, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0021] In another aspect, provided herein is a method of treating and / or preventing a neurologicaldisorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0022] In another aspect, provided herein is a method of treating and / or preventing fibrotic or adhesiondisease, disorder, or condition, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0023] In another aspect, provided herein is a method of reducing and / or preventing scar formation,comprising administering one or more of the compositions described herein to a subject in need thereof.

[0024] In another aspect, provided herein is a method of treating and / or preventing muscle disorder,muscle injury and / or muscle atrophy, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0025] In another aspect, provided herein is a method of treating and / or preventing fibrosis, comprisingadministering one or more of the compositions described herein to a subject in need thereof.

[0026] In another aspect, provided herein is a method of treating and / or preventing idiopathic pulmonaryfibrosis, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0027] In another aspect, provided herein is a method of treating and / or preventing kidney fibrosis,comprising administering one or more of the compositions described herein to a subject in need thereof. - 6 -WSGR Docket No.55773-740.601

[0028] In another aspect, provided herein is a method of stimulating muscle regeneration, comprisingadministering one or more of said compositions described herein to a subject in need thereof.

[0029] In another aspect, provided herein is a method of promoting organ fitness, comprisingadministering one or more of said compositions described herein to a subject in need thereof.

[0030] In another aspect, provided herein is a method of promoting wound healing, comprisingadministering one or more of said compositions described herein to a subject in need thereof.

[0031] In another aspect, provided herein is a method of treating acute kidney injury, comprisingadministering one or more of said compositions described herein to a subject in need thereof.

[0032] In another aspect, provided herein is a method of treating sarcopenia, comprising administeringone or more of said compositions described herein to a subject in need thereof.

[0033] In another aspect, provided herein is a method of treating a neuromuscular disease, comprisingadministering one or more of said compositions of any of the preceding claims to a subject in need thereof. INCORPORATION BY REFERENCE

[0034] All publications, patents, and patent applications mentioned in this specification are hereinincorporated 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. DETAILED DESCRIPTION OF THE INVENTION

[0035] While various embodiments of the invention have been shown and described herein, it will beobvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may 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. Definitions

[0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaningas is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0037] Unless the context requires otherwise, throughout the specification and claims which follow, theword “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in anopen, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are forconvenience only and do not interpret the scope or meaning of the claimed invention.

[0038] Reference throughout this specification to “some embodiments” or “an embodiment” meansthat a particular feature, structure, or characteristic described in connection with the embodiment isincluded in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in anembodiment” in various places throughout this specification are not necessarily all referring to the same- 7 -WSGR Docket No.55773-740.601 embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or”unless the content clearly dictates otherwise.

[0039] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0040] “oxo” refers to =O.

[0041] “Carboxyl” refers to -COOH.

[0042] “Cyano” refers to -CN.

[0043] “Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical havingfrom 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-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-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, anumerical range such as “C1-C6 alkyl” or “C1-6alkyl”, means that the alkyl group may consist of 1 carbonatom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” where no numerical range is designated.In some embodiments, the alkyl is a C1-10alkyl. In some embodiments, the alkyl is a C1-6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. 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, and 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.

[0044] “Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one ormore 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 andthe like. Whenever It appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, meansthat the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where nonumerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group - 8 -WSGR Docket No.55773-740.601 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.

[0045] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one ormore 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 carbonatoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of theterm “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in thespecification, 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 -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0046] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwisespecifically 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.

[0047] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unlessstated 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.

[0048] “Aryl” refers to a radical derived from an aromatic monocyclic or aromatic multicyclichydrocarbon 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, i.e., it - 9 -WSGR Docket No.55773-740.601 contains a cyclic, delocalized (4n+2) p–electron system in accordance with the Hückel 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, 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.

[0049] “Carbocycle” refers to a saturated, unsaturated or aromatic rings in which each atom of the ringis 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.

[0050] “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-C15fully saturated cycloalkyl or C3-C15cycloalkenyl), from three to ten carbon atoms (C3-C10fully saturated cycloalkyl or C3-C10cycloalkenyl), from three to eight carbon atoms (C3-C8fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6cycloalkenyl), from three to five carbon atoms (C3-C5fully saturated cycloalkyl or C3- C5cycloalkenyl), or three to four carbon atoms (C3-C4fully saturated cycloalkyl or C3-C4cycloalkenyl). 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 - 10 -WSGR Docket No.55773-740.601 cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6- membered fully 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, norbornyl, 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.

[0051] “Cycloalkenyl” refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbonradical 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.

[0052] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen isfluoro or chloro. In some embodiments, halogen is fluoro.

[0053] As used herein, the term “haloalkyl” or “haloalkane” refers to an alkyl radical, as definedabove, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl,bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substitutedalkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane,iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-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., 1-chloro,2-fluoroethane. - 11 -WSGR Docket No.55773-740.601

[0054] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or morefluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like.

[0055] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or morehydroxyls. 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.

[0056] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or moreamines. 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.

[0057] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl areselected 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 C1-C6heteroalkyl 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, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0058] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radicalcomprising 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 - 12 -WSGR Docket No.55773-740.601 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 quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15fully saturated heterocycloalkyl or C2-C15heterocycloalkenyl), from two to ten carbon atoms (C2-C10fully saturated heterocycloalkyl or C2-C10heterocycloalkenyl), from two to eight carbon atoms (C2-C8fully saturated heterocycloalkyl or C2-C8heterocycloalkenyl), from two to seven carbon atoms (C2-C7fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to six carbon atoms (C2-C6fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to five carbon atoms (C2-C5fully saturated heterocycloalkyl or C2-C5heterocycloalkenyl), or two to four carbon atoms (C2-C4fully saturated heterocycloalkyl or C2-C4heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]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, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo- thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3- dioxol-4-yl, and 2-oxo-1,3-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, - 13 -WSGR Docket No.55773-740.601 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.

[0059] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteencarbon 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 heteroatoms 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 quaternized. 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, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4- benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-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-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, 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, - 14 -WSGR Docket No.55773-740.601 ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0060] The term “substituted” refers to moieties having substituents replacing a hydrogen on one ormore 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 accordancewith permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., 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 broadaspect, 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.

[0061] The term “one or more” when referring to an optional substituent means that the subject groupis 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.

[0062] The compounds described herein may exhibit their natural isotopic abundance, or one or more ofthe 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, denoted1H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such 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.

[0063] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” areisomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair ofstereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair ofenantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where- 15 -WSGR Docket No.55773-740.601appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetricatoms 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 I- 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 I- 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.

[0064] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may existin 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.

[0065] Isolation and purification of the chemical entities and intermediates described herein can beeffected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer 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.

[0066] When stereochemistry is not specified, certain small molecules described herein include, but arenot 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 E- forms (or - 16 -WSGR Docket No.55773-740.601 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.

[0067] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety oforganic 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 from 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.

[0068] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” asused herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid orsolid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in thesense 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.

[0069] The term “effective amount” or “therapeutically effective amount” refers to that amount of acompound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the - 17 -WSGR Docket No.55773-740.601 intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that may induce a particular response in target cells, e.g., reduction of platelet adhesion and / or cell migration. The specific dose may vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0070] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desiredresults with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit can include, for example, 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. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0071] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or aprophylactic 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.

[0072] The term “co-administration,” “administered in combination with,” and their grammaticalequivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the subject at the same time. Co- administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0073] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compoundhaving the ability to inhibit a biological function (e.g., activity, expression, binding, protein-proteininteraction) of a target protein or enzyme. Accordingly, the terms “antagonist” and “inhibitor” are definedin the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. - 18 -WSGR Docket No.55773-740.601

[0074] Whenever a protein is referred to herein, it will be understood that a single protein can be referredto by different names. For example, “15-PGDH”, “PGDH”, and “hPGDH” all refer to the same protein,15-hydroxyprostaglandin dehydrogenase. COMPOUNDS

[0075] Provided herein are compounds and methods of inhibiting 15-hydroxyprostaglandindehydrogenase (15-PGDH).

[0076] In one aspect, provided herein is a compound having the structure of Formula (I), or apharmaceutically acceptable salt thereof:Formula (I), wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2or N;R1 is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9, substituted orunsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;each R2 is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, -NR8C(O)R9,substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8aminoalkyl, substituted or unsubstituted C1-C8heteroalkyl, substituted or unsubstituted C1-C8hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or - 19 -WSGR Docket No.55773-740.601 unsubstituted C3-C8 heterocycloalkyl, each of which is optionally substituted with one or more R6; wherein each R6 is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, 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-C6cycloalkyl or substituted or unsubstituted C3-C8heterocycloalkyl; XAis -NR5R5or -OR5; wherein each R5is independently H or C1-C6alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C6heterocycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is optionally substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is optionally substituted with one or more Ra; - 20 -WSGR Docket No.55773-740.601 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.

[0077] In one aspect, provided herein is a compound having the structure of Formula (I), or apharmaceutically acceptable salt thereof:Formula (I), wherein, ring Q is phenyl or 5- to 10-membered heteroaryl; Z is CR1or N; Y is CR2of N;R1 is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9 substituted orunsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;R2 is H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, -NR8C(O)R9, or substituted orunsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;each R3 is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10- membered heteroaryl; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl; substituted or unsubstituted C3-C8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6is independently H, halogen, CN,-NO2, –NR8R9, -OH, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6hydroxyalkyl, C3-C8cycloalkyl, phenyl, or 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a C3-C6cycloalkyl ring; XAis NR5R5or OR5; wherein - 21 -WSGR Docket No.55773-740.601 each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl ring; each R8and R9is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6haloalkyl, C3-C10cycloalkyl, and C4-C10heterocycloalkyl; each R10is independently selected from H, C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl; each R11is independently selected from C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3- C8cycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl; each R12is independently selected from H, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, and C3-C8cycloalkyl; and p is 1, 2, 3, or 4.

[0078] In some embodiments, ring Q is 5- to 10-membered heteroaryl, comprising 1, 2, 3, or 4heteroatoms selected from N, O, and S. In some embodiments, ring Q is 5- to 8-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is 5- to 8- membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is a monocyclic, bicyclic, or polycyclic heteroaryl. In some embodiments, ring Q is a bicyclic heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is indole, benzimidazole, benzotriazole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyridine, or tetrazolo pyridine. In some embodiments, ring Q is [1,2,4]triazolo[1,5-a]pyridine.

[0079] In some embodiments, ring Q is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 Natoms. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is a phenyl, pyrimidine, or pyridine In some embodiments, ring Q is phenyl. In some embodiments, ring Q is pyrimidine In some embodiments, ring Q is pyridine.

[0080] In some embodiments, ring Q is phenyl, pyridine, or triazolopyridine.

[0081] In some embodiments,wherein, X1, X2, X3and X4are each independently N or CR3; each R3is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted - 22 -WSGR Docket No.55773-740.601 or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R13; each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl substituted or unsubstituted, C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, - C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and - NHC(O)CH3.

[0082] In some embodiments, X1, X2, X3 and X4 are each CR3.

[0083] In some embodiments, X1 is N; and X2, X3, and X4 are each CR3.

[0084] In some embodiments, X1 and X2 are each N; and X3 and X4 are each CR3.

[0085] In some embodiments, X1 and X3 are each N; and X2 and X4 are each CR3.

[0086] In some embodiments, X1 and X4 are each N; and X2 and X3 are each CR3.

[0087] In some embodiments, X1, X2, and X3 are each N; and X4 is CR3.

[0088] In some embodiments, X1, X2, and X4 are each N; and X3 is CR3.

[0089] In some embodiments, each R3 is independently selected from H, halogen, -CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 - 23 -WSGR Docket No.55773-740.601 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each R3is independently selectedfrom H, halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, substituted orunsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each R3isindependently selected from H, halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, each R3is independently selected from H, halogen, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.

[0090] In some embodiments, each R3 is independently selected from H or halogen. In someembodiments, each R3is independently substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, each R3is independently a substituted or unsubstituted 5-membered heteroaryl.

[0091] In another aspect, provided herein is a compound having the structure of Formula (II), or apharmaceutically acceptable salt thereof:Formula (II), wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N;R1 is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9, substituted orunsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;each R2 is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, -NR8C(O)R9,substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; R3a, R3b, and R3care each independently H, halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or - 24 -WSGR Docket No.55773-740.601 unsubstituted 5- to 10-membered heteroaryl, wherein each alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8aminoalkyl, substituted or unsubstituted C1-C8heteroalkyl, substituted or unsubstituted C1-C8hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C8heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6 is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, 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-C6cycloalkyl or substituted or unsubstituted C3-C8heterocycloalkyl; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; - 25 -WSGR Docket No.55773-740.601 each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, - C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and - NHC(O)CH3.

[0092] In another aspect, provided herein is a compound having the structure of Formula (II), or apharmaceutically acceptable salt thereof:Formula (II), wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1is H; each R2is independently H or C1-C6alkyl;R3a, R3b, and R3c are each independently H, halogen, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, each of which is substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6 is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl; - 26 -WSGR Docket No.55773-740.601 or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; XAis -OR5; wherein each R5is independently H or C1-C6 alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl substituted or unsubstituted, C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and each Rais independently selected from halogen, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, - C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and - NHC(O)CH3.

[0093] In some embodiments, XA is NR5R5. In some embodiments, XA is OR5.

[0094] In some embodiments, Y is N. In some embodiments, Y is CR2.

[0095] In some embodiments, the compound of Formula (II) has the structure of Formula (III), or apharmaceutically acceptable salt thereof: - 27 -WSGR Docket No.55773-740.601Formula (IIIa).

[0096] In some embodiments, the compound of Formula (II) has the structure of Formula (IIIb), or apharmaceutically acceptable salt thereof:Formula (IIIb).

[0097] In some embodiments, Z is N. In some embodiments, Z is CR1. In some embodiments, Z is CH.

[0098] In some embodiments, the compound of Formula (II) has the structure of Formula (IVa), or apharmaceutically acceptable salt thereof:Formula (IVa).

[0099] In some embodiments, the compound of Formula (II) has the structure of Formula (IVb), or apharmaceutically acceptable salt thereof:Formula (IVb). - 28 -WSGR Docket No.55773-740.601

[0100] In some embodiments, the compound of Formula (II) has the structure of Formula (IVc), or apharmaceutically acceptable salt thereof:Formula (IVc).

[0101] In some embodiments, the compound of Formula (II) has the structure of Formula (IVd), or apharmaceutically acceptable salt thereof:Formula (IVd).

[0102] In another aspect, provided herein is a compounds of Formula (V), or a pharmaceuticallyacceptable salt thereof:Formula (V), wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; L is C1-C3alkylene; Q1is -O- or -S-; R1is H; each R2is independently H or C1-C6alkyl; - 29 -WSGR Docket No.55773-740.601R3a, R3b, and R3c are each independently selected from H, halogen, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl, each of which is substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9; R4ais substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C8heterocycloalkyl, each of which is substituted with one or more R6; wherein each R6 is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C8heterocycloalkyl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C8heterocycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is substituted with one or more Ra; and - 30 -WSGR Docket No.55773-740.601 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.

[0103] In some embodiments, provided herein is a compound of Formula (Va), or a pharmaceuticallyacceptable salt thereof:Formula (Va), wherein, Z is CH or N; X1is N or CR3a; Y is CH or N; Q1is -O- or -S-;R3a, R3b, and R3c are each independently H, halogen, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, each of which is optionally substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9; R4ais substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C8heterocycloalkyl, each of which is optionally substituted with one or more R6; wherein each R6 is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C8heterocycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is optionally substituted with one or more Ra; - 31 -WSGR Docket No.55773-740.601 each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl substituted or unsubstituted, C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is optionally 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.

[0104] In some embodiments, the compound of Formula (Va) has the structure of Formula (VIa), or apharmaceutically acceptable salt thereof:Formula (VIa).

[0105] In some embodiments, the compound of Formula (Va) has the structure of Formula (VIb), or apharmaceutically acceptable salt thereof:- 32 -WSGR Docket No.55773-740.601

[0106] In some embodiments, Q1 is O. In some embodiments, Q1 is S.

[0107] In some embodiments, R1 is H, halogen, –OR10, –C(O)R10, –C(O)OR10, or substituted orunsubstituted C1-C6 alkyl. In some embodiments, R1is H.

[0108] In some embodiments, each R2 is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, orsubstituted or unsubstituted C1-C6 alkyl. In some embodiments, each R2is independently H or C1-C6 alkyl. In some embodiments, each R2is H.

[0109] In some embodiments, X1 is CR3a. In some embodiments, X1 is N.

[0110] In some embodiments, R3a, R3b, and R3c are each independently H, halogen, -CN, -NO2, –NR8R9,–OR10, -S8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3a, R3b, and R3care eachindependently H, halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10,substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl. In someembodiments, R3a, R3b, and R3c are each independently H, halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently H, halogen, – C(O)R10, –C(O)NR8R9, or substituted or unsubstituted 5- membered heteroaryl. In some embodiments,R3a, R3b, and R3c are each independently H, halogen, –OR10, -S8,–C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11,–NR12C(O)R10, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, or substituted or unsubstituted 5- membered heteroaryl. In some embodiments, R3a, R3b, and R3care each independently H, halogen, substituted or unsubstituted C1-C6 alkyl, –C(O)R10, –C(O)NR8R9, C3-C6 heterocycloalkyl, or 5-membered heteroaryl.

[0111] In some embodiments, R3a, R3b, and R3c are each independently H, halogen, –C(O)OH, –C(O)NH2, –C(O)NH(CH3), –C(O)N(CH3)2, triazole, tetrazole, pyrrolidine, morpholine, or C1-C6 alkyl substituted with -C(O)OH.

[0112] In some embodiments, R3a and R3b are each H or halogen; and R3c is halogen, -CN, -NO2, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen;and R3c is halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –- 33 -WSGR Docket No.55773-740.601 NR12C(O)NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl. In someembodiments, R3a and R3b are each H or halogen; and R3c is halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9,–NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis – NR12C(O)OR10, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis substituted or unsubstituted C1-C6alkyl, –C(O)R10, –C(O)NR8R9, C3-C6heterocycloalkyl, or 5-membered heteroaryl. In some embodiments, R3aand R3bare each H or halogen; and R3cis a substituted or unsubstituted 5- membered heteroaryl.

[0113] In some embodiments, R3a is halogen and R3b is H. In some embodiments, R3a is -Cl or -F; and R3bis H. In some embodiments, R3bis halogen and R3ais H. In some embodiments, R3bis -Cl or -F; and R3ais H.

[0114] In some embodiments, R3a and R3b are each H.

[0115] In some embodiments, R3a and R3c are independently H or halogen; and R3b is halogen, -CN, -NO2, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R3aand R3care each H;and R3b is halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl. In someembodiments, R3a and R3c are each H; and R3b is halogen, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –NR12C(O)R10, –NR12C(O)OR10, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3care each H; and R3bis –C(O)R10, –C(O)OR10, –NR12C(O)OR10, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R3aand R3care each H or halogen; and R3bis substituted or unsubstituted C1-C6 alkyl, –C(O)R10, –C(O)NR8R9, C3-C6 heterocycloalkyl, or 5-membered heteroaryl. In some embodiments, R3aand R3care each H or halogen; and R3bis –C(O)R10, –C(O)OR10, or substituted or unsubstituted 5-membered heteroaryl.

[0116] In some embodiments, R3a is halogen and R3c is H. In some embodiments, R3a is H and R3b ishalogen. In some embodiments, R3ais -Cl or -F; and R3cis H. In some embodiments, R3cis -Cl or -F; and R3ais H.

[0117] In some embodiments, R3a and R3c are each H.- 34 -WSGR Docket No.55773-740.601

[0118] In some embodiments, each R3, R3a, R3b, and R3c are each independently a 5-membered heteroarylselected from pyrrole, triazole, tetrazole, oxazole, diazole, oxadiazole, thiadiazole, and furanyl. In some embodiments, each R3, R3a, R3b, and R3care each independently a 5-membered heteroaryl selected from pyrrole, triazole, and tetrazole. In some embodiments, each R3, R3a, R3b, and R3care each independently a 5-membered heteroaryl selected from triazole and tetrazole.

[0119] In some embodiments, each R3, R3a, R3b, or R3c is independently selected from the group

[0120] In some embodiments, each R3, R3a, R3b, or R3c is independently selected from the groupconsisting- 35 -WSGR Docket No.55773-740.601

[0121] In some embodiments, each R3, R3a, R3b, or R3c is independently selected from,

[0122] In some embodiments, R4 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstitutedC2-C8alkenyl, substituted or unsubstituted C1-C8aminoalkyl, substituted or unsubstituted C1-C8heteroalkyl, substituted or unsubstituted C1-C8hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R6. In some embodiment, R4is substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C1-C8aminoalkyl, substituted or unsubstituted C1-C8heteroalkyl, or substituted or unsubstituted C1-C8hydroxyalkyl. In some embodiments, R4is substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C1-C8heteroalkyl, or substituted or unsubstituted C1-C8hydroxyalkyl.

[0123] In some embodiment, R4 is substituted or unsubstituted C1-C8 alkyl or substituted or unsubstitutedC1-C8heteroalkyl. In some embodiment, R4is substituted or unsubstituted C1-C8alkyl. In some embodiments, the alkyl is a straight chain or branched alkyl. In some embodiment, R4is substituted or - 36 -WSGR Docket No.55773-740.601 unsubstituted C1-C8 heteroalkyl. In some embodiments, the heteroalkyl is an alkyl chain wherein one or more of the carbon atoms is replaced with an O or N atom. In some embodiment, R4is substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), substituted or unsubstituted -CH2CH2-O- (C1-C4 haloalkyl), -CH2-O-(C1-C4 haloalkyl), -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2-O-(C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiment, R4is substituted or unsubstituted -CH2CH2-O-(C1-C4alkyl), -CH2-O-(C1-C4alkyl), substituted or unsubstituted -CH2CH2-O-(C1-C4haloalkyl), or -CH2-O-(C1-C4haloalkyl). In some embodiments, R4is -CH2CH2-O- (C3-C6cycloalkyl), -CH2-O-(C3-C6cycloalkyl), -CH2CH2-O-(C3-C6heterocycloalkyl), or -CH2-O-(C3-C6heterocycloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-C6cycloalkyl). In some embodiments, R4is -CH2-O-(C3-C6cycloalkyl). In some embodiments, R4is -CH2CH2-O-(C3-C6heterocycloalkyl). In some embodiments, R4is -CH2-O-(C3-C6heterocycloalkyl).

[0124] In some embodiments, R4 is substituted or unsubstituted C1-C8 alkyl, which is substituted with oneor more halogen, -OR10, C1-C8alkyl, or C3-C6cycloalkyl.

[0125] In some embodiments, R4 is substituted or unsubstituted C3-C8 cycloalkyl or substituted orunsubstituted C3-C8heterocycloalkyl, each of which is substituted with one or more R6. In some embodiments, R4is C3-C8cycloalkyl. In some embodiments, R4is monocyclic, polycyclic, spirocyclic, or bridged cycloalkyl. In some embodiments, R4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R4is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R4is cyclopropyl. In some embodiments, R4is cyclobutyl. In some embodiments, R4is cyclopentyl. In some embodiments, R4is cyclohexyl. In some embodiments, R4is.

[0126] In some embodiments, R4 is substituted or unsubstituted C3-C8 heterocycloalkyl, each of which issubstituted with one or more R6. In some embodiments, R4is monocyclic, polycyclic, spirocyclic, or bridged heterocycloalkyl. In some embodiments, R4is a 4-membered heterocycloalkyl. In some embodiments, R4is a 5-membered heterocycloalkyl. In some embodiments, R4is a 6-membered cycloalkyl. In some embodiments, R4is a 7-membered cycloalkyl. In some embodiments, R4is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine. In some embodiments, R4is tetrahydrofuran or tetrahydropyran.

[0127] In some embodiments, each R6 is independently halogen, -CN,-NO2, –NR8R9, -OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl. In someembodiments, each R6 is independently halogen, -NR8R9, -OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, -NR8C(O)R9, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, or C3-C8cycloalkyl. In some embodiments,each R6 is independently halogen, -NR8R9, -OR10,–C(O)OR10, –C(O)NR8R9, C1-C6 alkyl, or C3-C8cycloalkyl. In some embodiments, each R6is independently halogen, -NR8R9, -OR10, or C3-C8 cycloalkyl. - 37 -WSGR Docket No.55773-740.601 In some embodiments, each R6is independently -NR8R9or -OR10. In some embodiments, each R6is independently C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, spirocyclic or bridged cycloalkyl. In some embodiments, each R6is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R6is independently halogen. In some embodiments, each R6is independently H, Cl, F, or Br. In some embodiments, each R6is independently F. In some embodiments, each R6is independently F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH3CH3), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, piperidine, piperazine, oxetane, tetrahydrofuran, or tetrahydropyran. In some embodiments, each R6is independently F, -OH, -CH3, -CF3, -N(CH3)2, - NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R6is independently F, -OH, -CH3, or -CF3. In some embodiments, each R6is independently F. In some embodiments, each R6is independently -OH. In some embodiments, each R6is independently -CF3. In some embodiments, each R6is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R6is independently cyclopropyl. In some embodiments, each R6is cyclobutyl.

[0128] In some embodiments, two R6 combine together with the atom(s) to which they are attached toform a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C6heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl or cyclobutyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclobutyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a C3-C6 heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a 4 membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a 5 membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a 6-membered heterocycloalkyl. In some embodiments, two R6combine together with the atom(s) to which they are attached to form a pyran, piperazine, piperidine, or morpholine.

[0129] In some embodiments, R4 is -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 unsubstituted- 38 -WSGR Docket No.55773-740.601

[0130] In some embodiments, R4a is -CH3, -CH2CH3, -CH2CH3CH3, -CH2(CH2)2CH3, -CH2(CH2)3CH3, -CH2(CH2)4CH3, -CH2CH2CH(CH3)2, -CH(CH3)2, -C(CH3)3, 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 unsubstituted tetrahydropyran.

[0131] In some embodiments, R4a is -CH3, -CH2CH3, -CH2CH3CH3, -CH2(CH2)2CH3, -CH2(CH2)3CH3, -embodiments, R4ais -CH2CH3, -C(CH3)3, or. In some embodiments, R4ais -CH2CH3. In some embodiments, R4ais -CH2CH3CH3. In some embodiments, R4ais -C(CH3)3. In some embodiments, R4ais. - 39 -WSGR Docket No.55773-740.601

[0132] In some embodiments, each R5 is independently C1-C6 alkyl. In some embodiments, each R5 isindependently -CH2CH3 or -CH3. In some embodiments, each R5is independently -CH2CH3. In some embodiments, each R5is independently -CH3. In some embodiments, each R5is independently H.

[0133] In some embodiments, R5a is CH3. In some embodiments, R5a is H.

[0134] In some embodiments, R5a and one R6 combine together with the atom(s) to which they areattached to form a C3-C6cycloalkyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclopentyl or cyclohexyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, R5aand one R6combine together with the atom(s) to which they are attached to form a cyclopentyl.

[0135] In some embodiments, each R8 and R9 is independently selected from H, substituted orunsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra. In some embodiments, each R8and R9is independently selected at each occurrence from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, and C3-C10cycloalkyl. In some embodiments, each R8and R9is independently selected at each occurrence from H, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C10cycloalkyl, and C3-C10heterocycloalkyl. In some embodiments, each R8and R9is independently selected at each occurrence from C3-C10cycloalkyl and C3-C10heterocycloalkyl.

[0136] In some embodiments, each R10 is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra. In some embodiments, each R10is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R10is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, and C3-C10 heterocycloalkyl. In some embodiments, each R10is independently selected from H and C1-C6 alkyl. In some embodiments, each R10is independently selected from C3-C10 cycloalkyl and C3- C10 heterocycloalkyl.

[0137] In some embodiments, each R11 is independently selected from substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more Ra. In some - 40 -WSGR Docket No.55773-740.601 embodiments, each R11is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11is independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl. In some embodiments, each R11is independently selected from C3-C10 cycloalkyl and C3-C10 heterocycloalkyl.

[0138] In some embodiments, each R12 is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is substituted with one or more Ra. In some embodiments, each R12is independently selected from H, straight or branched chain C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C3-C10cycloalkyl, and C3-C10heterocycloalkyl. In some embodiments, each R12is independently selected from H, straight or branched chain C1-C6alkyl. In some embodiments, each R12is independently selected from C3-C10cycloalkyl and C3-C10heterocycloalkyl.

[0139] In some embodiments, each Ra is independently selected from halogen, -OH, -CH3, -CF3, -OCH3,-C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and - NHC(O)CH3. In some embodiments, each Rais independently selected from -F, -Cl, -Br, -OH, -CH3, - CF3, -OCH3, -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, each Rais independently selected from -F, -OH, -CH3, -CF3, or -C(O)OH.

[0140] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. I some embodiments, pis 3. In some embodiments, p is 5. In some embodiments, p is 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.

[0141] In some embodiments, the PDGH inhibitor is a compound described in Table 1, or apharmaceutically acceptable salt thereof. - 41 -WSGR Docket No.55773-740.601 Table 1. Compounds of the disclosure.- 42 -WSGR Docket No.55773-740.601- 43 -WSGR Docket No.55773-740.601- 44 -WSGR Docket No.55773-740.601- 45 -WSGR Docket No.55773-740.601- 46 -WSGR Docket No.55773-740.601- 47 -WSGR Docket No.55773-740.601METHODS OF USE

[0142] In one aspect, provided herein are methods for treating various disorders in a subject in needthereof, comprising administering to said subject a compound described herein. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein may be used for the prevention or treatment of a disease or a disorder that is associated with hydroxyprostaglandin dehydrogenase (such as 15-PGDH) and / or decreased levels of prostaglandins. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein may be used for the prevention or treatment of a disease or a disorder in which it is desirable to increase prostaglandin levels in the subject having said disease or disorder.

[0143] In some embodiments, the methods for treating the disorders comprises administering to saidsubject a 15-PGDH inhibitor. In some embodiments, a compound described herein is the 15-PGDH inhibitor. In some embodiments, a compound of Formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (IVc), or (IVd), is the 15-PGDH inhibitor. In some embodiments, the methods comprise administering a therapeutically effective amount of a compound described herein. In some embodiments, the methods comprise administering a therapeutically effective amount of a compound of Formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (IVc), or (IVd). In some embodiments, the compound described herein is a 15-PGDH inhibitor. In some embodiments, the compound of Formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (IVc), or (IVd), is a 15-PGDH inhibitor. In some embodiments, the administration takes place in vitro. In other embodiments, the administration takes place in vivo.

[0144] As used herein, a therapeutically effective amount of a 15-PGDH inhibitor refers to an amountsufficient to effect the intended application, including but not limited to, disease treatment, as defined herein. Also contemplated in the subject methods is the use of a sub-therapeutic amount of a 15-PGDH inhibitor for treating an intended disease condition.

[0145] The amount of the 15-PGDH inhibitor administered may vary depending upon the intendedapplication (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. - 48 -WSGR Docket No.55773-740.601

[0146] Measuring inhibition of biological effects of 15-PGDH can comprise performing an assay on abiological sample, such as a sample from a subject. Any of a variety of samples may be selected, depending on the assay. Examples of samples include, but are not limited to, blood samples (e.g., blood plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0147] A subject being treated with a 15-PGDH inhibitor may be monitored to determine theeffectiveness of treatment, and the treatment regimen may be adjusted based on the subject’sphysiological response to treatment. For example, if inhibition of a biological effect of 15-PGDH is above or below a threshold, the dosing amount or frequency may be decreased or increased, respectively. The methods can further comprise continuing the therapy if the therapy is determined to be efficacious. The methods can comprise maintaining, tapering, reducing, or stopping the administered amount of a compound in the therapy if the therapy is determined to be efficacious. The methods can comprise increasing the administered amount of a compound in the therapy if it is determined not to be efficacious. Alternatively, the methods can comprise stopping therapy if it is determined not to be efficacious. In some embodiments, treatment with a 15-PGDH inhibitor is discontinued if inhibition of the biological effect is above or below a threshold, such as in a lack of response or an adverse reaction. The biological effect may be a change in any of a variety of physiological indicators.

[0148] In general, a 15-PGDH inhibitor is a compound that inhibits one or more biological effects of 15-PGDH. Such biological effects may be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.

[0149] In some other embodiments, the subject methods are useful for treating a disease conditionassociated with 15-PGDH. Any disease condition that results directly or indirectly from an abnormal activity or expression level of 15-PGDH can be an intended disease condition.

[0150] In one aspect, provided herein is a method of promoting and / or stimulation skin pigmentation,comprising administering one or more of the compositions described herein to a subject in need thereof. Inhibitors of 15-PGDH are known to promote skin pigmentation (Markowitz et. al., WO 2015 / 065716). The hydroxyprostaglandin dehydrogenase inhibitors described herein can be used for promoting and / or inducing and / or stimulating pigmentation of the skin and / or skin appendages, and / or as an agent for preventing and / or limiting depigmentation and / or whitening of the skin and / or skin appendages, in particular as an agent for preventing and / or limiting canities. In some embodiments, the 15-PGDH inhibitors provided herein can be applied to skin of a subject, e.g., in a topical application, to promote and / or stimulate pigmentation of the skin and / or hair growth, inhibit hair loss, and / or treat skin damage or inflammation, such as skin damage caused by physical or chemical irritants and / or UV-exposure.

[0151] In another aspect, provided herein is a method of inhibiting hair loss, comprising administeringone or more of the compositions described herein to a subject in need thereof. It is known that prostaglandins play an important role in hair growth. Prostaglandins such as prostaglandin A1, F2a and E2 - 49 -WSGR Docket No.55773-740.601 are stored in hair follicles or adjacent skin environments and have been shown to be essential in maintaining and increasing hair density (Colombe L et. al, 2007, Exp. Dermatol, 16(9), 762-9). It has been reported that 15-PGDH, which is involved in the degradation of prostaglandins is present in the hair follicle dermal papillae, inactivates prostaglandins, especially, PGF2a and PGE2, to cause scalp damage and alopecia (Michelet J F et. al., 2008, Exp. Dermatol, 17(10), 821-8). Thus, the hydroxyprostaglandin dehydrogenase inhibitors described herein that have a suppressive or inhibitory activity against 15-PGDH can improve scalp damage, prevent alopecia and promote hair growth and be used in a pharmaceutical composition for the prevention of alopecia and the promotion of hair growth.

[0152] In another aspect, provided herein is a method of preventing and / or treating skin inflammationand / or damage, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0153] In another aspect, provided herein is a method of preventing and / or treating vascularinsufficiency, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins including prostaglandin homologues produced in the body have been known to maintain the proper action of the blood vessel wall, especially to contribute to vasodilation for blood flow, preventing platelet aggregation and modulating the proliferation of smooth muscle that surrounds blood vessel walls (Yan. Cheng et. al., 2006, J. Clin., Invest). In addition, the inhibition of prostaglandins production or the loss of their activity causes the degeneration of the endothelium in the blood vessel walls, platelet aggregation and the dysfunction of cellular mechanism in the smooth muscle. Among others, the production of prostaglandins in blood vessels was shown to be decreased in hypertensionpatients, including pulmonary artery hypertension. The 15-PGDH inhibitors described herein can be usedin a pharmaceutical composition for the prevention or the treatment of cardiovascular disease and / or diseases of vascular insufficiency, such as Raynaud’s disease, Buerger’s disease, diabetic neuropathy, and pulmonary artery hypertension.

[0154] In another aspect, provided herein is a method of preventing, treating, minimizing and / orreversing congestive heart failure, cardiomyopathy, comprising administering one or more of the compositions described herein to a subject in need thereof. In another aspect, provided herein is a method of reducing cardiac ejection fraction, comprising administering one or more of the compositions described herein to a subject in need thereof. It has been shown that administration of a 15-PGDH inhibitor can be used to treat, prevent, minimize, and / or reverse congestive heart failure, cardiomyopathy, and / or reduction of cardiac ejection fraction (Markowitz et. al., WO2018 / 187810). As such, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be administered to a subject in need to treat, prevent, minimize and / or reverse congestive heart failure, cardiomyopathy, and / or reduction of cardiac ejection fraction.

[0155] In another aspect, provided herein is a method of preventing and / or treating a gastrointestinaldisease, comprising administering one or more of the compositions described herein to a subject in need - 50 -WSGR Docket No.55773-740.601 thereof. Prostaglandins are essential for maintaining the mechanism for protecting and defending gastric mucus membrane (Wallace J L., 2008, Physiol Rev., 88(4), 1547-65, S. J. Konturek et al., 2005, Journalof Physiology and Pharmacology, 56(5)).The inhibitors of hydroxyprostaglandin dehydrogenase describedherein show a suppressive or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect gastric mucus membranes. As such, the hydroxyprostaglandin dehydrogenase inhibitors can be effective for the prevention or the treatment of gastrointestinal diseases, inter alia, gastritis and gastric ulcer. In addition, the hydroxyprostaglandin dehydrogenase inhibitors provided herein may be used to prevent and / or treat other forms of intestinal injury including toxicity from radiation and / or chemotherapy, and chemotherapy-induced mucositis.

[0156] Additionally, it has been shown that administration of 15-PGDH inhibitors, alone or incombination with corticosteroids and / or TNF inhibitors can treat intestinal, gastrointestinal, or bowel disorders such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatorybowel disease, and Crohn’s disease (Markowitz et. al., WO 2018 / 102552). As such, thehydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat and / or prevent treat intestinal, gastrointestinal, or bowel disorders such as oral ulcers, gum disease, gastritis, colitis, ulcerativecolitis, gastric ulcers, inflammatory bowel disease, and Crohn’s disease.

[0157] In another aspect, provided herein is a method of preventing and / or treating renal dysfunction,comprising administering one or more of the compositions described herein to a subject in need thereof. In the kidney, prostaglandins modulate renal blood flow and may serve to regulate urine formation by both renovascular and tubular effects. In clinical studies, inhibitors of prostaglandin have been used to improve creatinine clearance in patients with chronic renal disease, to prevent graft rejection and cyclosporine toxicity in renal transplant patients, to reduce the urinary albumin excretion rate and N- acetyl-beta-D-glucosaminidase levels in patients with diabetic nephropathy (Porter, Am., 1989, J. Cardiol., 64: 22E-26E). Furthermore, it has been reported that prostaglandins serve as vasodilators in the kidney, and, thus, the inhibition of prostaglandin production in the kidney results in renal dysfunction (Hao. C M, 2008, Annu Rev Physiol, 70, 357.about.77). The hydroxyprostaglandin dehydrogenase inhibitors described herein have a suppressive or inhibitory activity against 15-PGDH that degrades prostaglandins and can be used for the prevention and / or treatment of renal diseases that are associated with renal dysfunction.

[0158] In another aspect, provided herein is a method of stimulation bone resorption and bone formation,comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins have been shown to stimulate bone resorption and bone formation to increase the volume and the strength of the bone (H. Kawaguchi et. al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculoskeletal Res., 1, 1992, 8692). Furthermore, inhibition of 15-PGDH increases callus size and mineralization after bone fracture (Collier et. al., ORS 2017 Annual Meeting Paper No.0190). Considering that 15-PGDH inhibits the activities of prostaglandins as mentioned in the above, the - 51 -WSGR Docket No.55773-740.601 inhibition of 15-PGDH activity may lead to the promotion of bone resorption and bone formation that are inhibited by 15-PGDH. Thus, the inhibitors of hydroxyprostaglandin dehydrogenase described herein can be effective for the promotion of bone resorption and bone formation by inhibiting 15-PGDH activity. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can also be used to increase bone density, treat osteoporosis, promote healing of fractures, promote healing after bone surgery or joint replacement, and / or to promote healing of bone to bone implants, bone to artificial implants, dental implants, and bone grafts.

[0159] In another aspect, provided herein is a method of stimulating tissue regeneration by stimulating,comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin PGE2 supports expansion of several types of tissue stem cells. Inhibition of 15- hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs. Studies show that inhibition of 15-PGDH increases prostaglandin PGE2 levels in bone marrow and other tissues; accelerates hematopoietic recovery following a bone marrow transplant; promotes tissue regeneration of colon and liver injury (Zhang, Y. et. al. Science 2015, 348 (6240)). The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for tissue regeneration by supporting the expansion of tissue stem cells.

[0160] In another aspect, provided herein is a method of modulating cervical ripening, comprisingadministering one or more of the compositions described herein to a subject in need thereof. Prostaglandin E2 (PGE2) is a known cervical ripening agent that mediates EP2-receptor- signaling pathways in human cervical stromal cells; targets its own synthesis by increasing COX-2 and PTGES expression; and decreases its metabolism by loss of its degradative enzyme 15-PGDH (Word et. Al., WO2019010482) Downregulation of 15-PGDH was also found to be crucial for PGE2-induced cervical ripening and preterm birth. Modulation of 15-PDGH activity can be used to modulate cervical ripening; and induce or prevent preterm labor. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to induce cervical ripening and labor, alone or in combination with another labor inducing agent.

[0161] In another aspect, provided herein is a method of promoting neuroprotection and / or stimulatingneuronal regeneration, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins, via their specific G protein coupled receptors, have a variety ofphysiological functions in the central nervous system. The major prostaglandin, prostaglandin E2 (PGE2)can activate receptor types EP1, 2, 3, and 4. Activation of EP2 and EP4 receptors can regulate adenylatecyclase and the generation of 3, 5′-cyclic adenosine monophosphate (cAMP), whereas the activation ofEP1 and EP3 receptors can regulate Ca2+ signaling. Studies show that the EP1 and EP2 receptors are expressed in neurons and microglia as well as neurons of the cerebral cortex, striatum, and hippocampus. In addition, activation of the EP2 receptor by PGE2 is involved in long-term synaptic plasticity and cognitive function (Chemtob et al. Semin Perinatol.1994 Feb; 18(1):23-9; Yang et al., J Neurochem.2009 Jan; 108(1):295-304). Studies also show that following activation, different PGE2 receptors can contribute - 52 -WSGR Docket No.55773-740.601 or protect against N-methyl-D-aspartate (NMDA) neurotoxicity and ischemic stroke (Ahmad et al., Exp Transl Stroke Med.2010 Jul 8; 2(1):12). Other studies show that activation of the EP2 receptors protectedneurons from amyloid β-peptide neurotoxicity in vitro (Echeverria et al., Eur J Neurosci.2005 Nov;22(9):2199-206). Several studies suggest that the mechanism by which PGE2 affords neuroprotection isthrough EP2 or EP4 receptors, as they both increases cAMP, followed by a protein kinase A (PKA)- dependent pathway (Echeverria et al. Eur J Neurosci.2005 Nov; 22(9):2199-206; McCullough et al., J Neurosci.2004 Jan 7; 24(1):257-68). Stimulation of these receptors with PGE2 by administration of a compound that inhibits, reduces, and / or antagonizes 15-PGDH activity, such as the hydroxyprostaglandin dehydrogenase inhibitors that can inhibit 15-PGDH described herein, can promote neuroprotection in a subject from axonal degeneration, neuronal cell death, and / or glia cell damage after injury, augment neuronal signaling underlying learning and memory, stimulate neuronal regeneration after injury, and / or treat diseases, disorders, and / or conditions of the nervous system.

[0162] In another aspect, provided herein is a method of treating and / or preventing a neurologicaldisorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder, comprising administering one or more of the compositions described herein to a subject in need thereof. In some embodiments, the disease, disorder, and / or condition of the nervous system, which can be treated with hydroxyprostaglandin dehydrogenase inhibitors provided herein, can include at least one of a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder. For example, the neurological disorder can include at least one of traumatic or toxic injuries to peripheral or cranial nerves, spinal cord or brain, such as traumatic brain injury, stroke, cerebral aneurism, and spinal cord injury. The neurological disorder can also include at least one of Alzheimer’s disease, dementias related to Alzheimer’s disease, Parkinson’s, Lewy diffuse body diseases, senile dementia, Huntington’s disease, Gilles de Ia Tourette’s syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Jakob- Creutzfieldt disease.

[0163] In some embodiments, the neural injury can be caused by or associated with at least one ofepilepsy, cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic disorders, urinary bladder disorders, abnormal metabolic states, disorders of the muscular system, infectious and parasitic diseases, neoplasms, endocrine diseases, nutritional and metabolic diseases, immunological diseases, diseases of the blood and blood-forming organs, mental disorders, diseases of the nervous system, diseases of the sense organs, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the genitourinary system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, congenital anomalies, or conditions originating in the perinatal period.

[0164] In certain embodiments, the hydroxyprostaglandin dehydrogenase inhibitors can be administeredto a subject or neurons of the subject to promote the survival, growth, development and / or function of the - 53 -WSGR Docket No.55773-740.601 neurons, particularly, the central nervous system (CNS), brain, cerebral, and hippocampal neurons. In certain embodiments, the hydroxyprostaglandin dehydrogenase inhibitors can be used stimulatehippocampal neurogenesis, for the treatment of neuropsychiatric and neurodegenerative diseases,including (but not limited to) schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson’s disease, Alzheimer’s disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington’s disease, stroke, radiation therapy, chronic stress, and abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine.

[0165] In another aspect, provided herein is a method of treating and / or preventing fibrotic or adhesiondisease, disorder or condition, comprising administering one or more of the compositions described herein to a subject in need thereof. It has been shown that inhibitors of short-chain dehydrogenase activity, such as 15-PGDH inhibitors, can be administered to a subject in need thereof to decrease fibrotic symptoms, such as collagen deposition, collagen accumulation, collagen fiber formation, inflammatory cytokine expression, and inflammatory cell infiltration, and treat and / or prevent various fibrotic diseases, disorders, and conditions characterized, in whole or in part, by the excess production of fibrous material, including excess production of fibrotic material within the extracellular matrix, or the replacement of normal tissue elements by abnormal, non-functional, and / or excessive accumulation of matrix-associated components (Markowitz et. al., WO2016 / 144958).

[0166] Fibrotic diseases, disorders and conditions characterized, in whole or in part, by excess productionof fibrotic material can include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma(including morphea, generalized morphea, or linear scleroderma), sclerodermatousgraft- vs-host-disease„ kidney fibrosis (including glomerular sclerosis, renal tubulointerstitial fibrosis,progressive renal disease or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g. pulmonary fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, and chemotherapy / radiation induced pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn’s disease, nodular fasciitis, eosinophilic fasciitis, general fibrosis syndrome characterized by replacement of normal muscle tissue by fibrous tissue in varying degrees, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure; myelofibrosis (bone marrow fibrosis), drug induced ergotism, myelodysplastic syndrome, myeloproliferative syndrome, collagenous colitis, acute fibrosis, organ specific fibrosis, and the like. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent a fibrotic disease, disorder or condition.

[0167] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat orprevent kidney fibrosis, including kidney fibrosis resulting from dialysis following kidney failure, catheter placement, a nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end stage renal disease or renal failure, or combinations thereof. - 54 -WSGR Docket No.55773-740.601

[0168] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat orprevent liver fibrosis, including liver fibrosis resulting from a chronic liver disease, viral induced hepatic cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH associated cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, auto-immune hepatitis, cystic fibrosis, alpha- 1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxins, or combinations thereof.

[0169] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat orprevent heart fibrosis such as cardiac fibrosis, endomyocardial fibrosis, idiopathic pulmonary fibrosis, and kidney fibrosis.

[0170] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat orprevent systemic sclerosis.

[0171] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat orprevent fibrotic diseases, disorders or conditions caused by post-surgical adhesion formation.

[0172] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce inintensity, severity, or frequency, and / or delay onset of one or more symptoms or features of a fibrotic disease, disorder or condition, or other related diseases, disorders or conditions.

[0173] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to decrease orreduce collagen secretion, or collagen deposition, or collagen fiber accumulation, in a tissue or organ, such as the lung, the liver, the intestines, the colon, the skin or the heart, or a combination thereof.

[0174] Studies have shown that 15-PGDH inhibition ameliorates inflammatory pathology and fibrosis inpulmonary fibrosis (Smith et. al., bioRxiv 2019.12.16.878215; Barnthaler et. al., J. Allergy Clin. Immunol.2019, 145 (3), 818-833). In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be used to treat or prevent lung fibrosis, including pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker’s pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitides, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

[0175] In another aspect, provided herein is a method of reducing and / or preventing scar formation,comprising administering one or more of the compositions described herein to a subject in need thereof. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can used for reducing or preventing scar formation in a subject. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent scar formation on skin or scleroderma. - 55 -WSGR Docket No.55773-740.601

[0176] In another aspect, provided herein is a method of treating and / or preventing muscle disorder,muscle injury and / or muscle atrophy, comprising administering one or more of the compositions described herein to a subject in need thereof. Studies have shown that inhibition of PGE2 degrading enzymes such as 15-PGDH, enable muscle regeneration and muscle repair after injury (Ho et al., PNAS 2017; Dong et al., Stem cell research and therapy 2020). The inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat muscle disorder, muscle injury and / or muscle atrophy in a subject. In some cases, said subject suffering from a muscle disorder, muscle injury and / or muscle atrophy may have Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FHMD), amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), an inherited myopathy, myotonic muscular dystrophy (MDD), oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, myotonia congenita, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, stress induced urinary incontinence, urethral sphincter deficiency, sarcopenia, or a combination thereof.

[0177] In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein canbe used to treat sarcopenia. In another embodiment, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat diaphragmatic atrophy or limb muscle atrophy due to the use of a mechanical ventilator. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat genetic disorders or neuromuscular disorders such as Spinal Muscular Atrophy (SMA). In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat ptosis, rotator cuff muscle atrophy, immobilization related muscle atrophy, surgical procedure related muscle atrophy, sarcopenia, or a combination thereof. PHARMACEUTICAL COMPOSITIONS

[0178] The inhibitors of hydroxyprostaglandin dehydrogenase can be formulated into pharmaceuticalcompositions to treat diseases and disorders described herein. In some embodiments, a pharmaceutical composition may comprise a therapeutically effective amount of one or more inhibitors of hydroxyprostaglandin dehydrogenase having the structure of Formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (IVc), (IVd), (V), (Va), (VIa), or (VIb), or a pharmaceutically acceptable salt thereof.

[0179] The pharmaceutical composition described herein may be administered in such oral dosage formsas tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, micronized compositions, granules, elixirs, tinctures, suspensions, ointments, vapors, liposomal particles, nanoparticles, syrups and emulsions. In some embodiments, the pharmaceutical composition may also be administered in intravenous (bolus or infusion), subcutaneous injection, suppository, intraperitoneal, topical (e.g., dermal epidermal, transdermal), ophthalmic, such as, ocular eyedrop, - 56 -WSGR Docket No.55773-740.601 intranasally, subcutaneous, inhalation, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0180] In some embodiments, a compound provided herein can be administered as part of a therapeuticregimen that comprises administering one or more second agents (e.g., 1, 2, 3, 4, 5, or more second agents), either simultaneously or sequentially with the compound provided herein. When administered sequentially, the compound provided herein may be administered before or after the one or more second agents. When administered simultaneously, the compound provided herein and the one or more second agents may be administered by the same route (e.g., injections to the same location; tablets taken orally at the same time), by a different route (e.g., a tablet taken orally while receiving an intravenous infusion), or as part of the same combination (e.g., a solution comprising a compound provided herein and one or more second agents).

[0181] A combination treatment according to the disclosure may be effective over a wide dosage range.For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the agent selected, the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. EXAMPLES Synthesis and Characterization of Compounds

[0182] The following examples are offered to illustrate, but not to limit the claimed invention. Thefollowing examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0183] The following synthetic schemes are provided for purposes of illustration, not limitation. Thefollowing examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0184] The compounds and salts of Formulas (I), (II), (IIIa), (IIIb), (IVa), (IVb), (IVc), (IVd), (V), (Va),(VIa), and (VIb) can be synthesized according to one or more illustrative schemes herein and / ortechniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in the synthesis schemes below, the steps in some cases may be - 57 -WSGR Docket No.55773-740.601 performed in a different order than the order shown below. Numberings or R groups in each scheme do not necessarily correspond to that of the claims or other schemes or tables herein.

[0185] Described herein are exemplary synthesis schemes that can be used to synthesize the inhibitorsdescribed herein.Example 1. Representative Procedure A for Synthesis of pyrazolo-pyridine alcohols

[0186] Scheme 1.

[0187] Step 1. To a solution of 2-isopropoxyacetic acid (2.00 g, 16.9 mmol, 1.00 eq.) and N-methoxymethanamine (1.24 g, 20.3 mmol, 1.20 eq.) in DCM (8 mL) was added DIEA (9.85 g, 76.2 mmol, 13.3 mL, 4.50 eq.), HOBt (4.58 g, 33.9 mmol, 2.00 eq.) and EDCI (6.49 g, 33.9 mmol, 2.00 eq.). The mixture was stirred at 25 °C for 2 hours. The mixture was poured into water (50 mL) and extracted with EA (20 mL × 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, then the mixture was filtered concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 0 / 1) to provide the desired product 2-isopropoxy-N-methoxy-N- methyl-acetamide (2.10 g, 13.0 mmol, 77% yield) as a yellow liquid.

[0188] 1H NMR (400 MHz, chloroform-d) δ = 4.22 (s, 2H), 3.73 – 3.67 (m, 1H), 3.67 (s, 3H), 3.16 (s,3H), 1.19 (d, J = 6.1 Hz, 6H).

[0189] Step 2. To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (2.00 g, 10.1 mmol, 1.00 eq.) inTHF (20.0 mL) was slowly added NaH (485 mg, 12.1 mmol, 60% purity, 1.20 eq.) at 0 °C. After 30 minutes, TIPSCl (2.14 g, 11.1 mmol, 2.38 mL, 1.10 eq.) was added to the reaction mixture, and the - 58 -WSGR Docket No.55773-740.601 mixture was stirred at 0 °C for 30 mins. The mixture was poured into saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, then filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to petroleum ether / ethyl acetate = 10 / 1) to give (5-bromopyrazolo[3,4-b]pyridine-1-yl)-triisopropyl-silane (3.4 g, 8.64 mmol, 85% yield, 90% purity) as a yellow oil.

[0190] 1H NMR (400 MHz, DMSO-d6) δ = 8.59 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.37 (s,1H), 1.85 (quin, J = 7.6 Hz, 3H), 1.05 (d, J = 7.6 Hz, 18H).

[0191] Step 3. To a solution of (5-bromopyrazolo[3,4-b]pyridine-1-yl)-triisopropyl-silane (3.66 g, 10.3mmol, 1.00 eq.) in THF (15 mL) was added n-BuLi (2.50 M, 20.7 mL, 5.00 eq.) at -78 °C, and the reaction stirred for 2 hrs.2-Isopropoxy-N-methoxy-N-methyl-acetamide (2.00 g, 12.4 mmol, 1.20 eq.) was added to the reaction mixture, and the mixture was warmed and stirred at 25 °C for 2 hours. The mixture was poured into saturated aqueous solution of ammonium chloride (50 mL) at 0 °C, then extracted with EA (20 mL×3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, then the mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 0 / 1) to provide 2-isopropoxy-1-(1- triisopropylsilylpyrazolo [3,4-b]pyridine-5-yl)pyridine (1.30 g, 3.46 mmol, 33% yield) as a yellow oil.

[0192] LCMS [ESI, M+1]: 376.2. 1H NMR (400 MHz, chloroform-d) δ = 9.12 (d, J = 2.0 Hz, 1H), 8.72(d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 4.73 (s, 2H), 3.79 – 3.69 (m, 1H), 1.46 – 1.40 (m, 3H), 1.13 (d, J = 7.6 Hz, 18H), 0.91 (t, J = 7.2 Hz, 6H).

[0193] Step 4. To a solution of 2-isopropoxy-1-(1-triisopropylsilylpyrazolo[3,4-b] pyridine-5-yl)pyridine(1.00 g, 2.66 mmol, 1.00 eq.) in THF (10 mL) was added TBAF (1.00 M, 3.20 mL, 1.20 eq.). The mixture was stirred at 25 °C for 1 hr. The mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and the mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 0 / 1) to obtain 2-isopropoxy -1-(1H-pyrazolo[3,4-b]pyridine-5-yl)pyridine (210 mg, 900 µmol, 34% yield, 94% purity) as a yellow solid. LCMS [ESI, M+1]: 220.0.

[0194] Step 5. To a solution of 2-isopropoxy-1-(1H-pyrazolo[3,4-b]pyridine-5-yl)pyridine (190 mg, 867μmol, 1.00 eq.) in MeOH (2 mL) was added NaBH4 (32.8 mg, 867 μmol, 1.00 eq.) at 0 °C. The mixturewas stirred at 25 °C for 1 hr. The mixture was poured into saturated NHCl4 aqueous solution (100 mL) and extracted with EA (30 mL × 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, then the mixture was filtered and concentrated to provide 2-isopropoxy-1-(1H-pyrazolo[3,4-b]- 59 -yridine-5-yl)ethanol (180 mg, 692 μmol, 80% yield, 85% purity) was obtained as a yellow oil.LCMS [ESI, M+1]: 222.1.

[0195] Step 6. A mixture of 2-isopropoxy-1-(1H-pyrazolo[3,4-b]pyridine-5-yl)ethanol (160 mg, 723μmol, 1.00 eq.), 3-(3-iodophenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (257 mg, 723 μmol, 1.00 eq.), CuI- 59 -WSGR Docket No.55773-740.601(68.9 mg, 362 μmol, 0.50 eq.), K3PO4 (307 mg, 1.45 mmol, 2.00 eq.) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (206 mg, 1.45 mmol, 2.00 eq.) in DMA (1.5 mL) was degassed and purged with N2 (15 psi) three times, and the mixture was stirred at 90 °C for 3 hrs under N2 (15 psi) atmosphere. The mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, then the mixture was filtered, and the filtrate concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 0 / 1) to provide 2-isopropoxy -1-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridine-5-yl]ethanol (280 mg, 562 μmol, 78% yield, 90% purity) as a yellowoil. LCMS [ESI, M+1]: 449.3.

[0196] Step 7. To a solution of 2-isopropoxy-1-[1-[3-(4-tetrahydropyran -2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridine-5-yl]ethanol (260 mg, 580 μmol, 1.00 eq.) in MeOH (2.5 mL) wasadded TsOH•H2O (165 mg, 870 μmol, 1.50 eq.). The mixture was stirred at 50 °C for 1 hr. Themixture was poured into saturated NaHCO3aqueous solution (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then the mixture was filtered, and the filtrate concentrated. The residue was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2-I / i-PrOH(0.1% NH3H2O)]; B%:55%, isocratic elution mode).

[0197] Compound A (64.7 mg, 174 μmol, 37% yield, 98% purity) was obtained as a white solid. LCMS[ESI, M+1]: 365.2. 1H NMR (400 MHz, DMSO-d6) δ = 14.56 – 13.73 (m, 1H), 9.00 (t, J = 1.6 Hz, 1H),8.71 (d, J = 2.0 Hz, 1H), 8.60 – 8.45 (m, 2H), 8.44 – 8.38 (m, 1H), 8.33 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 5.60 (br d, J = 4.0 Hz, 1H), 5.00 – 4.73 (m, 1H), 3.62 – 3.54 (m, 2H), 3.54 – 3.49 (m, 1H), 1.05 (dd, J = 6.0, 14.8 Hz, 6H).

[0198] Compound B (72.1 mg, 194 μmol, 42% yield, 98% purity) was obtained as a white solid. LCMS[ESI, M+1]: 365.1. 1H NMR (400 MHz, DMSO-d6) δ = 14.58 – 13.87 (m, 1H), 9.00 (s, 1H), 8.71 (d, J =2.0 Hz, 1H), 8.49 (s, 2H), 8.41 (br d, J = 7.2 Hz, 1H), 8.33 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 5.60 (br d, J = 4.4 Hz, 1H), 4.92 – 4.86 (m, 1H), 3.63 – 3.54 (m, 2H), 3.54 – 3.49 (m, 1H), 1.05 (dd, J = 6.0, 14.8 Hz, 6H). - 60 -WSGR Docket No.55773-740.601 Example 2: Representative Synthesis of Thioethers: Compounds 1A, 1B, 1C, and 1D

[0199] Scheme 2.

[0200] Step 1. To a solution of tetrahydrothiophene-2-carboxylic acid (4.00 g, 30.2 mmol, 1.00 eq.) inpyridine (20 mL) was added 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1- amine;hydrochloride (11.6 g, 60.5 mmol, 2.00 eq.) and N-methoxymethanamine (3.54 g, 36.3 mmol, 1.20 eq., HCl), and the mixture was stirred at 25 °C for 2 hrs. To the mixture was added HCl (1N) to adjust to pH = 3, then the mixture was extracted with EA (30 mL × 3), and the organic phase was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 1 / 1) to give N-methoxy-N-methyl-tetrahydrothiophene-2-carboxamide (3.00 g, 15.4 mmol, 90% yield, 90% purity) as a yellow oil.

[0201] 1H NMR (400 MHz, chloroform-d) δ = 4.25 (br s, 1H), 3.74 (s, 3H), 3.21 (s, 3H), 3.02 - 2.92(m, 1H), 2.91 - 2.82 (m, 1H), 2.45 - 2.35 (m, 1H), 2.27 (tt, J = 6.4, 13.2 Hz, 1H), 2.06 (quind, J = 6.0, 12.4 Hz, 1H), 1.92 (dtd, J = 6.0, 7.2, 12.8 Hz, 1H).

[0202] Step 2. To a solution of (5-bromopyrazolo[3,4-b]pyridin-1-yl)-triisopropyl-silane (3.37 g, 9.51mmol, 1.00 eq.) in THF (60 mL) at -78 °C was added n-BuLi (2.5 M, 5.71 mL, 1.50 eq.) under N2, and the mixture was stirred at -78 °C for 30 min. N-methoxy-N-methyl-tetrahydrothiophene-2-carboxamide (2.00 - 61 -WSGR Docket No.55773-740.601 g, 11.41 mmol, 1.20 eq.) in THF (20 mL) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 hr under N2 (15 psi). The reaction was quenched with H2O (50 mL) at 0 °C, then extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give tetrahydrothiophen-2-yl-(1- triisopropylsilylpyrazolo[3,4-b]pyridin-5-yl)methanone (4.00 g, crude) as a yellow oil.

[0203] Step 3. To a solution of tetrahydrothiophen-2-yl-(1-triisopropylsilylpyrazolo [3,4-b]pyridin-5-yl)methanone (3.50 g, 8.98 mmol, 1.00 eq.) in MeOH (40 mL) was added CsF (6.82 g, 44.9 mmol, 5.00 eq.). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was diluted with EA (50 mL), washed with brine (50 mL × 4), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 1 / 1) to give 1H-pyrazolo[3,4-b]pyridin-5-yl(tetrahydrothiophen-2- yl)methanone (1.10 g, 3.58 mmol, 40% yield, 76% purity) as a yellow oil. LCMS [ESI, M+1]: m / z = 234.1.

[0204] Step 4. To a solution of 1H-pyrazolo[3,4-b]pyridin-5-yl(tetrahydrothiophen-2-yl) methanone(1.00 g, 4.29 mmol, 1.00 eq.) in THF (10.0 mL) was added NaBH4(194 mg, 5.14 mmol, 1.20 eq.) at 0 °C. The mixture was stirred at 20 °C for 1 hr. The reaction was quenched with acetone (50 mL) at 0 °C, then extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (50 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1H-pyrazolo[3,4-b]pyridin-5-yl (tetrahydrothiophen-2-yl)methanol (1.00 g, 3.57 mmol, 83% yield, 84% purity) as a yellow oil. LCMS [ESI, M+1]: m / z = 236.2.

[0205] Step 5. A mixture of 1H-pyrazolo[3,4-b]pyridin-5-yl(tetrahydrothiophen-2-yl) methanol (900mg, 3.82 mmol, 1.00 eq.), methyl 4-iodobenzoate (1.10 g, 4.21 mmol, 1.10 eq.), CuI (364 mg, 1.91 mmol, 0.50 eq.), N1,N2-dimethylcyclohexane-1,2-diamine (1.09 g, 7.65 mmol, 2.00 eq.) and K3PO4(811 mg, 3.82 mmol, 1.00 eq.) in DMAC (10.0 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90 °C for 2 hrs under N2 atmosphere (15 psi). The reaction mixture was diluted with H2O (50 mL) and EA (50 mL), then quenched by addition of NH3•H2O (5 mL, 25% purity) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 1 / 1) to give methyl 4-[5- [hydroxy(tetrahydrothiophen-2-yl)methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (650 mg, 1.72 mmol, 45% yield, 98% purity) as a white solid.

[0206] LCMS [ESI, M+1]: m / z = 370.0. 1H NMR (400 MHz, DMSO-d6) δ = 8.75 (d, J = 2.0 Hz, 1H),8.56 (d, J = 8.8 Hz, 2H), 8.54 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 8.8 Hz, 2H), 5.82 (d, J = 5.2 Hz, 1H), 4.71 (dd, J = 5.2, 7.6 Hz, 1H), 3.88 (s, 3H), 3.77 - 3.64 (m, 1H), 2.77 (dd, J = 5.2, 7.6 Hz, 2H), 2.04 - 1.99 (m, 1H), 1.81 - 1.67 (m, 1H), 1.66 - 1.50 (m, 2H). - 62 -WSGR Docket No.55773-740.601

[0207] Step 6. Intermediates A-D: The diastereomeric intermediate was further separated by SFC(column: DAICEL CHIRALPAK IC (250 mm × 30 mm,10 um); mobile phase: [CO2-ACN / MeOH (0.1% NH3•H2O)]; B%:35%, isocratic elution mode) and further separated by SFC (column: DAICELCHIRALPAK AD (250mm × 30mm,10um); mobile phase: [CO2-ACN / i-PrOH (0.1% NH3•H2O)];B%:55%, isocratic elution mode) to give methyl 4-[5-[(R)-hydroxy-[(2R)-tetrahydrothiophen-2-yl]methyl] pyrazolo[3,4-b]pyridin-1-yl]benzoate (Intermediate A, 55.0 mg, 141 μmol, 10 % yield, 95%purity) as a white solid, methyl 4-[5-[(S)-hydroxy-[(2S)-tetrahydrothiophen-2-yl]methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (Intermediate B, 55.0 mg, 142 μmol, 10% yield, 96% purity) as a white solid,methyl 4-[5-[(R)-hydroxy-[(2S)-tetrahydrothiophen-2-yl]methyl]pyrazolo[3,4-b]pyridin-1-yl] benzoate(Intermediate C, 150 mg, 397 μmol, 30% yield, 98% purity) as a white solid, and methyl 4-[5-[(S)-hydroxy-[(2R)-tetrahydrothiophen-2-yl]methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (Intermediate D,150 mg, 401 μmol, 30% yield, 99% purity) as a white solid. Intermediate A: LCMS [ESI, M+1]: m / z =370.2. Intermediate B: LCMS [ESI, M+1]: m / z = 370.2. Intermediate C: LCMS [ESI, M+1]: m / z = 370.2. Intermediate D: LCMS [ESI, M+1]: m / z = 370.2.

[0208] Compound 1A: To a solution of Intermediate A, methyl 4-[5-[(R)-hydroxy-[(2R)-tetrahydrothiophen-2-yl] methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate, (45.0 mg, 121 μmol, 1.00 eq.) inTHF (1.00 mL) was added LiOH•H2O (25.5 mg, 609 μmol, 5.00 eq.) in H2O (1.00 mL). The mixture wasstirred at 30 °C for 1 hr. The mixture was diluted with H2O (5 mL) and extracted with EA (5 mL × 2). ThepH of the water phase was adjusted to 1 with HCl at 0 ℃ and white solid formed, which was filtered togive Compound 1A (30.0 mg, 79.8 μmol, 65% yield, 94% purity) as a white solid. LCMS [ESI, M+1]:m / z = 356.2. 1H NMR (400 MHz, DMSO-d6) δ = 12.98 (br s, 1H), 8.72 (d, J = 1.6 Hz, 1H), 8.56 - 8.50(m, 3H), 8.34 (d, J = 1.2 Hz, 1H), 8.14 (br d, J = 8.8 Hz, 2H), 5.86 (br s, 1H), 4.63 (br d, J = 8.8 Hz, 1H), 3.78 - 3.63 (m, 1H), 2.80 - 2.62 (m, 2H), 2.14 - 2.03 (m, 1H), 1.97 (dt, J = 5.2, 10.0 Hz, 2H), 1.93 - 1.82 (m, 1H).

[0209] Compound 1B: To a solution of Intermediate B, methyl 4-[5-[(S)-hydroxy-[(2S)-tetrahydrothiophen-2-yl] methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate, (40.0 mg, 108 μmol, 1.00 eq.) inTHF (1.00 mL) was added LiOH•H2O (22.7 mg, 541 μmol, 5.00 eq.) in H2O (1.00 mL). The mixture wasstirred at 30 °C for 1 hr. The mixture was diluted with H2O (5 mL) and extracted with EA (5 mL × 2). ThepH of the water phase was adjusted to 1 with HCl at 0 ℃ and a white solid formed, which was collectedto give Compound 1B (17.0 mg, 47.35 μmol, 43% yield, 99% purity) as a white solid. LCMS [ESI, M+1]:m / z = 356.2. 1H NMR (400 MHz, DMSO-d6) δ = 13.01 (br s, 1H), 8.72 (d, J = 1.6 Hz, 1H), 8.57 - 8.49(m, 3H), 8.34 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 8.8 Hz, 2H), 5.86 (br d, J = 3.6 Hz, 1H), 4.73 - 4.52 (m, 1H), 3.80 - 3.64 (m, 1H), 2.80 - 2.64 (m, 2H), 2.08 (br t, J = 6.4 Hz, 1H), 1.97 (td, J = 5.2, 15.2 Hz, 2H), 1.92 - 1.83 (m, 1H).

[0210] Compound 1C: To a solution of Intermediate C, methyl 4-[5-[(R)-hydroxy-[(2S)-tetrahydrothiophen-2-yl] methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate, (140 mg, 378 μmol, 1.00 eq.) in- 63 -WSGR Docket No.55773-740.601THF (2.00 mL) was added LiOH•H2O (79.5 mg, 1.89 mmol, 5.00 eq.) in H2O (2.00 mL). The mixture wasstirred at 30 °C for 1 hr, then diluted with H2O (5 mL) and extracted with EA (5 mL × 2). The pH of thewater phase was adjusted to 1 with HCl at 0 ℃ and white solid formed, which was collected to giveCompound 1C (116 mg, 323 μmol, 85% yield, 99% purity) as a white solid. LCMS [ESI, M+1]: m / z =356.2. 1H NMR (400 MHz, DMSO-d6) δ = 13.01 (br s, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.56 - 8.50 (m, 3H),8.36 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 8.8 Hz, 2H), 5.83 (br d, J = 4.4 Hz, 1H), 4.71 (br dd, J = 2.8, 7.6 Hz, 1H), 3.77 - 3.61 (m, 1H), 2.77 (dd, J = 5.2, 7.6 Hz, 2H), 2.08 - 1.93 (m, 1H), 1.81 - 1.66 (m, 1H), 1.65 - 1.48 (m, 2H).

[0211] Compound 1D: To a solution of Intermediate D, methyl 4-[5-[(S)-hydroxy-[(2R)-tetrahydrothiophen-2-yl] methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate, (140 mg, 378 μmol, 1.00 eq.) inTHF (1.50 mL) was added LiOH•H2O (79.51 mg, 1.89 mmol, 5.00 eq.) in H2O (1.50 mL). The mixturewas stirred at 20 °C for 2 hrs, then diluted with H2O (5 mL) and extracted with EA (5 mL × 2). The pH ofthe water phase was adjusted to 1 with HCl at 0 ℃ and white solid formed, which was collected to giveCompound 1D (115 mg, 317 μmol, 83% yield, 98% purity) as a white solid. LCMS [ESI, M+1]: m / z =356.2. 1H NMR (400 MHz, DMSO-d6) δ = 12.99 (br s, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.57 - 8.48 (m, 3H),8.36 (d, J = 1.6 Hz, 1H), 8.18 - 8.11 (m, 2H), 5.82 (br d, J = 4.8 Hz, 1H), 4.71 (dd, J = 4.8, 7.6 Hz, 1H), 3.78 - 3.64 (m, 1H), 2.77 (dd, J = 5.2, 7.6 Hz, 2H), 2.07 - 1.94 (m, 1H), 1.81 - 1.67 (m, 1H), 1.66 - 1.48 (m, 2H). - 64 -WSGR Docket No.55773-740.601 Example 3: Representative Procedure for Pyrrolopyridines: Compounds 17A and 17B

[0212] Scheme 3.

[0213] Step 1. A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (10 g, 2.54 mol, 1.0 eq.) and 2-(cyclobutoxy)-N-methoxy-N-methyl-acetamide (10.5 g, 3.05 mol, 1.2 eq.) in THF (100 mL) was degassed and purged with N2 three times, then n-BuLi (2.5 M, 25.4 mL, 1.5 eq.) was added into the mixture at-40 °C and the mixture was stirred at -40 °C for 1.5 hrs. The reaction was quenched with saturated NH4Cl (50 mL) at 0 °C, then extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1) to give 2-(cyclobutoxy)-1-(1H-pyrrolo[2,3-b]pyridin-5-yl) ethanone (4 g, 8.12 mol, 68.0% yield, 84% purity) as a yellow solid. LCMS [ESI, M-155]: 231.2.

[0214] Step 2. To a solution of 2-(cyclobutoxy)-1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone (4.0 g, 8.69mmol, 1.0 eq.) in THF (40 mL) was added NaBH4(1.36 g, 18.0 mmol, 2.07 eq.). The mixture was stirred at 20 °C for 1 hr, then quenched with saturated NH4Cl (50 mL) at 0 °C. The mixture was extracted with - 65 -WSGR Docket No.55773-740.601 EA (3 × 50 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / ) to give 2-(cyclobutoxy)-1-(1H- pyrrolo[2,3-b] pyridin-5-yl)ethanol (2 g, 8.61 mmol, 46.1% yield, 93% purity) as a white solid. LCMS [ESI, M+1]: 233.0.

[0215] Step 4. Intermediates A and B: 2-(cyclobutoxy)-1-(1H-pyrrolo[2,3-b]pyridin-5-yl) ethanol (2.0g, 8.61 mmol, 1.0 eq) was separated by SFC (column: DAICEL CHIRALPAK IK (250 mm * 30 mm, 10 um); mobile phase: [CO2-i-PrOH (0.1%NH3•H2O)]; B%: 30%, isocratic elution mode) to give (1R)-2- (cyclobutoxy)-1-(1H-pyrrolo[2,3-b]pyridin-5-yl) ethanol (1 g, 4.26 mmol, 49.5% yield, 99% purity) as a white solid and (1S)-2-(cyclobutoxy)-1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethanol (1 g, 4.26 mmol, 49.5% yield, 99% purity) as a yellow gum. LCMS [ESI, M+1]: 233.0.

[0216] Compound 17A: A mixture of 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole (200 mg, 699 μmol,1.0 eq.), (1R)-2-(cyclobutoxy)-1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethanol (162 mg, 699 μmol, 1.0 eq.), CuI(66.6 mg, 350 μmol, 0.5 eq.), K3PO4 (445 mg, 2.10 mmol, 3.0 eq.) and N1,N2-dimethylcyclohexane-1,2-diamine (199 mg, 1.40 mmol, 2.0 eq) in DMA (2 mL) was degassed and purged with N2three times, then the mixture was stirred at 90 °C for 1 hr under N2atmosphere (15 psi). The reaction mixture was diluted with H2O (3 mL), then extracted with EtOAc (5 mL × 2). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (TFA)-ACN]; gradient: 38%-68% B over 14 min) to give Compound 17A (105.89 mg, 266 μmol, 38% yield, 98% purity) as an off-white solid.

[0217] LCMS [ESI, M+1]: 391.2. 1H NMR (400 MHz, DMSO-d6) δ = 8.34 (d, J = 2.0 Hz, 1H), 8.26 -8.21 (m, 2H), 8.18 - 8.13 (m, 2H), 8.08 (d, J = 3.6 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 4.83 (t, J = 6.0 Hz, 1H), 3.93 (quin, J = 7.6 Hz, 1H), 3.55 - 3.33 (m, 2H), 2.69 (s, 3H), 2.18 - 2.05 (m, 2H), 1.86 - 1.70 (m, 2H), 1.58 (q, J = 9.6 Hz, 1H), 1.47 - 1.34 (m, 1H).

[0218] Compound 17B: A mixture of 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole (200 mg, 699 μmol,1.0 eq.), (1S)-2-(cyclobutoxy)-1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethanol (162 mg, 699 μmol, 1.0 eq.), CuI(66.6 mg, 350 μmol, 0.5 eq.), K3PO4 (445 mg, 2.10 mmol, 3.0 eq.) and N1,N2-dimethylcyclohexane-1,2-diamine (199 mg, 1.40 mmol, 2.0 eq.) in DMA (2 mL) was degassed and purged with N2 three times, then the mixture was stirred at 90 °C for 1 hr under N2 atmosphere. The reaction mixture was diluted with H2O (3 mL), then extracted with EA (5 mL × 2). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (TFA)-ACN]; gradient: 38%-68% B over 14 min) to give Compound 17B (93.26 mg, 234 μmol, 33% yield, 98%purity) as an off-white solid. - 66 -WSGR Docket No.55773-740.601

[0219] LCMS [ESI, M+1]: 391.2. 1H NMR (400 MHz, DMSO-d6) δ = 8.34 (d, J = 2.0 Hz, 1H), 8.26 -8.20 (m, 2H), 8.18 - 8.13 (m, 2H), 8.08 (d, J = 4.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 6.78 (d, J = 4.0 Hz, 1H), 4.83 (t, J = 6.0 Hz, 1H), 3.99 - 3.88 (m, 1H), 3.59 - 3.30 (m, 2H), 2.69 (s, 3H), 2.18 - 2.03 (m, 2H), 1.88 - 1.70 (m, 2H), 1.65 - 1.53 (m, 1H), 1.48 - 1.33 (m, 1H).

[0220] The compounds of the disclosure can be made by the methods of Examples 1-3.Table 2.- 67 -WSGR Docket No.55773-740.601- 68 -WSGR Docket No.55773-740.601- 69 -WSGR Docket No.55773-740.601- 70 -WSGR Docket No.55773-740.601- 71 -WSGR Docket No.55773-740.601BIOLOGICAL EXAMPLES

[0221] Example B-1. hPGDH Inhibitor Screening Biochemical Assay

[0222] A hydroxyprostaglandin dehydrogenase inhibition screening biochemical assay can be performedto assess the synthesized inhibitors provided herein.

[0223] The in vitro biochemical assay can be performed in white, 384 plates in total 20 µl reactionvolume consisting of 10 nM of 15-PGDH / HPGD (R&D System# 5660-DH), 15 μM Prostaglandin E2(Sigma, Cat # P5640-10MG) and 0.25 mM β-Nicotinamide adenine dinucleotide sodium salt (Sigma,Cat# N0632-5G) made in reaction buffer (50 mM Tris-HCl, pH 7.5, 0.01% Tween 20) at 10-point dose response curve for test / tool compounds. Briefly, 5 µl (4x) of compounds solution and 5 µl (final concentration, 10 nM) of enzyme solution is added to white 384 well plates and incubated for 10 mins at37 °C. 5 µl (4X) of Prostaglandin E2 and 5 µl (4X) of β-Nicotinamide adenine dinucleotide sodium salt isadded to the wells and incubated for 10 mins at room temperature. Fluorescence is recorded at ex / em = 340 nm / 485 nm. The percentage (%) inhibition of enzyme activity is determined relative to positive control (1% DMSO) and IC50was calculated using GraphPad prism software (four parameter-variableslope equation). Exemplary data are shown in Table 3, wherein A < 0.1 µM; 0.1 µM ≤ B < 2.5 µM; 2.5µM ≤ C.Table 3. hPGDH inhibition potency.- 72 -WSGR Docket No.55773-740.601

[0224] It is understood that the examples and embodiments described herein are for illustrative purposesonly and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. - 73 -

Claims

WSGR Docket No.55773-740.601 CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (II), or a pharmaceutically acceptable salt thereof:Formula (II), wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; R1 is H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, –C(O)NR8R9, -NR8C(O)R9, substitutedor unsubstituted C1-C6alkyl, or substituted or unsubstituted C3-C8cycloalkyl; each R2 is independently H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, -NR8C(O)R9,substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C3-C8cycloalkyl; R3a, R3b, and R3care each independently H, halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9; R4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 aminoalkyl, substituted or unsubstituted C1-C8 heteroalkyl, substituted or unsubstituted C1-C8 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, wherein each of which is optionally substituted with one or more R6; wherein each R6 is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl,substituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted - 74 -WSGR Docket No.55773-740.601 or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; XAis NR5R5or OR5; wherein each R5is independently H or C1-C6alkyl; R5ais H or CH3; or R5aand one R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, wherein each of which is optionally substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each of which is optionally substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl substituted or unsubstituted, C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, wherein each of which is optionally substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, wherein 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.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein XA is -OH.

3. A compound of Formula (V), or a pharmaceutically acceptable salt thereof:- 75 -WSGR Docket No.55773-740.601Formula (V), wherein, Z is CR1or N; X1is N or CR3a; Y is CR2or N; L is C1-C3 alkylene; Q1is -O- or -S-; R1is H; each R2is independently H or C1-C6 alkyl;R3a, R3b, and R3c are each independently H, halogen, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5- membered heteroaryl, wherein each alkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or – C(O)NR8R9; R4ais substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8heterocycloalkyl, each of which is optionally substituted with one or more R6; wherein each R6 is independently halogen, CN,-NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6hydroxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted C3-C8heterocycloalkyl; or two R6combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C3-C8heterocycloalkyl; each R8and R9is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6haloalkyl, - 76 -WSGR Docket No.55773-740.601 substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C3-C10 heterocycloalkyl, each of which is optionally substituted with one or more Ra; each R10is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R11is independently selected from substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6heteroalkyl substituted or unsubstituted, C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Ra; each R12is independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, and substituted or unsubstituted C3-C10heterocycloalkyl, each of which is optionally 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.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein L is -CH2- or -CH2CH2-.

5. The compound of claim 3, wherein the compound of Formula (V) has the structure of Formula(Va), or a pharmaceutically acceptable salt thereof:Formula (Va).

6. The compound of claim 3, wherein the compound of Formula (V) has the structure of Formula(VIa) or Formula (VIb), or a pharmaceutically acceptable salt thereof: - 77 -WSGR Docket No.55773-740.601Formula (VIb).

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Yis CH.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Yis N.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein Zis N.

10. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Zis CH.

11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein X1is N.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, whereinR3b is H; and R3c is halogen, -CN, -NO2, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9,–NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R13; wherein each R13is independently halogen, CN, -NO2, –NR8R9, –OR10, -SR8, – C(O)R10, –C(O)OR10, or –C(O)NR8R9.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R3c is halogen,–NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted orunsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.

14. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, whereinX1is CR3a.

15. The compound of any one of claims 1-10 or 14, or a pharmaceutically acceptable salt thereof,wherein R3aand R3bare each independently H or halogen; and R3cis 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 - 78 -WSGR Docket No.55773-740.601 or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R13; wherein each R13is independently halogen, CN, - NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R3c is H,halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11,substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.

17. The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, wherein R3c is –C(O)OR10, –C(O)NR8R9, or substituted or unsubstituted 5-membered heteroaryl.

18. The compound of any one of claims 15-17, or a pharmaceutically acceptable salt thereof, whereinR3aand R3bare each H.

19. The compound of any one of claims 1-10 or 15, or a pharmaceutically acceptable salt thereof,wherein R3aand R3care each independently H or halogen; and R3bis halogen, -CN, -NO2, – NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, –NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R13; wherein each R13is independently halogen, CN, - NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R3b is H,halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11,substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.

21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein R3b is –C(O)OR10, –C(O)NR8R9, or substituted or unsubstituted 5-membered heteroaryl.

22. The compound of any one of claims 19-21, or a pharmaceutically acceptable salt thereof, whereinR3aand R3care each H.

23. The compound of any one of claims 1-10 or 15, or a pharmaceutically acceptable salt thereof,wherein R3band R3care each independently H or halogen; and R3ais 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 - 79 -WSGR Docket No.55773-740.601 or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R13; wherein each R13is independently halogen, CN, - NO2, –NR8R9, –OR10, -SR8, –C(O)R10, –C(O)OR10, or –C(O)NR8R9.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R3a is H,halogen, –NR8R9, –OR10, –SR8, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11,substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.

25. The compound of claim 23 or 24, or a pharmaceutically acceptable salt thereof, wherein R3a is –C(O)OR10, –C(O)NR8R9, or substituted or unsubstituted 5-membered heteroaryl.

26. The compound of any one of claims 23-25, or a pharmaceutically acceptable salt thereof, whereinR3band R3care each H.

27. The compound of any one of claims 5-10, or a pharmaceutically acceptable salt thereof, whereinR3ais H, -Cl, -F, -OH, or -CF3; R3bis H, -CN, -OCH3, -CF3, -OCF3, -C(O)OH, 5-membered heterocycloalkyl, or 5-membered heteroaryl optionally substituted with 1, 2, or 3 substituents selected from -CH3; and R3cis H or 5-membered heteroaryl optionally substituted with 1, 2, or 3 substituents selected from -CH3; wherein at least one of R3a, R3b, or R3cis not H.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, whereinR3ais H, -Cl, -F, -OH, or -CF3; R3bis H; and R3cis pyrrole, pyrazole, or triazole.

29. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein R3c is30. The compound of any one of claims 27-29, or a pharmaceutically acceptable salt thereof, whereinR3ais H.

31. The compound of any one of claims 27-29, or a pharmaceutically acceptable salt thereof, whereinR3ais -Cl, -F, or -CF3.

32. The compound of claim 27, or a pharmaceutically acceptable salt thereof, whereinR3ais H; - 80 -WSGR Docket No.55773-740.601 R3bis -C(O)OH, 5-membered heterocycloalkyl, or 5-membered heteroaryl optionally substituted with 1, 2, or 3 substituents selected from -CH3; and R3cis H.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein R3b is -C(O)OH.

34. The compound of any one of claims 5-33, or a pharmaceutically acceptable salt thereof, whereinQ1is O.

35. The compound of any one of claims 5-33, or a pharmaceutically acceptable salt thereof, whereinQ1is S.

36. The compound of any one of claims 5-33, or a pharmaceutically acceptable salt thereof, whereinR4ais substituted or unsubstituted C1-C8alkyl.

37. The compound of any one of claims 5-33, or a pharmaceutically acceptable salt thereof, whereinR4ais substituted or unsubstituted C3-C8cycloalkyl.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R4a iscyclobutyl or cyclopropyl.

39. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising a compound of any one of claims 1-39, or apharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

41. A method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in needthereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 40.

42. A method of promoting and / or stimulating skin pigmentation, comprising administering one ormore of said compositions of any of the preceding claims to a subject in need thereof.

43. A method of inhibiting hair loss, comprising administering one or more of said compositions ofany of the preceding claims to a subject in need thereof.

44. A method of preventing and / or treating skin inflammation and / or damage, comprisingadministering one or more of said compositions of any of the preceding claims to a subject in need thereof.

45. A method of preventing and / or treating vascular insufficiency, comprising administering one ormore of said compositions of any of the preceding claims to a subject in need thereof.

46. A method of preventing, treating, minimizing and / or reversing congestive heart failure orcardiomyopathy, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof.

47. A method of reducing cardiac ejection fraction, comprising administering one or more of saidcompositions of any of the preceding claims to a subject in need thereof. - 81 -WSGR Docket No.55773-740.60148. A method of preventing and / or treating a gastrointestinal disease, comprising administering oneor more of said compositions of any of the preceding claims to a subject in need thereof.

49. A method of preventing and / or treating renal dysfunction, comprising administering one or moreof said compositions of any of the preceding claims to a subject in need thereof.

50. A method of stimulating bone resorption and bone formation, comprising administering one ormore of said compositions of any of the preceding claims to a subject in need thereof.

51. A method of stimulating tissue regeneration by stimulating, comprising administering one ormore of said compositions of any of the preceding claims to a subject in need thereof.

52. A method of modulating cervical ripening, comprising administering one or more of saidcompositions of any of the preceding claims to a subject in need thereof.

53. A method of promoting neuroprotection and / or stimulating neuronal regeneration, comprisingadministering one or more of said compositions of any of the preceding claims to a subject in need thereof.

54. A method of treating and / or preventing a neurological disorder, a neuropsychiatric disorder, aneural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof.

55. A method of treating and / or preventing fibrotic or adhesion disease, disorder, or condition,comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof.

56. A method of reducing and / or preventing scar formation, comprising administering one or more ofsaid compositions of any of the preceding claims to a subject in need thereof.

57. A method of treating and / or preventing muscle disorder, muscle injury and / or muscle atrophy,comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof.

58. A method of treating and / or preventing fibrosis, comprising administering one or more of saidcompositions of any of the preceding claims to a subject in need thereof.

59. A method of treating and / or preventing idiopathic pulmonary fibrosis, comprising administeringone or more of said compositions of any of the preceding claims to a subject in need thereof.

60. A method of treating and / or preventing kidney fibrosis, comprising administering one or more ofsaid compositions of any of the preceding claims to a subject in need thereof.

61. A method of stimulating muscle regeneration, comprising administering one or more of saidcompositions of any of the preceding claims to a subject in need thereof.

62. A method of promoting organ fitness, comprising administering one or more of said compositionsof any of the preceding claims to a subject in need thereof. - 82 -WSGR Docket No.55773-740.60163. A method of promoting wound healing, comprising administering one or more of saidcompositions of any of the preceding claims to a subject in need thereof.

64. A method of treating acute kidney injury, comprising administering one or more of saidcompositions of any of the preceding claims to a subject in need thereof.

65. A method of treating sarcopenia, comprising administering one or more of said compositions ofany of the preceding claims to a subject in need thereof.

66. A method of treating a neuromuscular disease, comprising administering one or more of saidcompositions of any of the preceding claims to a subject in need thereof. - 83 -

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