WO2024254601A1 - Hpgd inhibitors and uses thereof - Google Patents

Hpgd inhibitors and uses thereof Download PDF

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WO2024254601A1
WO2024254601A1 PCT/US2024/033275 US2024033275W WO2024254601A1 WO 2024254601 A1 WO2024254601 A1 WO 2024254601A1 US 2024033275 W US2024033275 W US 2024033275W WO 2024254601 A1 WO2024254601 A1 WO 2024254601A1
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compound
ring
nitrogen
sulfur
oxygen
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Neelu Kaila
Leela DODDA
Sebastien Campos
Silvana Marcel LEIT DE MORADEI
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Nimbus Discovery Inc
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Nimbus Discovery Inc
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • HPGD INHIBITORS AND USES THEREOF RELATED APPLICATIONS [0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63/507,390, filed June 9, 2023; the contents of each of which is incorporated by reference.
  • TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to compounds and methods useful for inhibiting hydroxyprostaglandin dehydrogenase 15-(NAD), also called 15-hydroxyprostaglandin dehydrogenase [NAD+] (HPGD).
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
  • Prostaglandins are bioactive lipid signaling mediators that are generated through sequential oxygenation of arachidonic acid present in plasma membranes by cyclooxygenases (COX enzymes) and specific prostaglandin synthases.
  • COX enzymes cyclooxygenases
  • prostaglandins can also be metabolically inactivated by the enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH or HPGD), which mediates the oxidation of prostanoid 15-hydroxyl groups to ketones, abrogating the binding to prostaglandin receptors. Therefore, COX enzymes and HPGD regulate the homeostatic balance of various prostaglandin levels in nucleated cells.
  • Prostaglandin E2 is the most abundant prostaglandin molecule in human cells and plays important roles in immune cell function and in potentiating tissue regeneration through the expansion of several types on tissue stem cells, including hematopoietic and colonic stem cells. Supplied exogenously, PGE2 has been shown to expand hematopoietic stem cell numbers in mice and zebrafish as well as human colonic stem cells in culture.
  • PGE2 is also able to enhance the engraftment of murine bone marrow stem cells when injected back into recipient animals and HPGD knockout mice, characterized by increased PGE2, demonstrating increased tissue regenerative capacity.
  • COX inhibitors exacerbated disease and colon injury, while disease severity was improved by providing exogenous PGE2.
  • HPGD inhibition was shown to accelerate bone marrow transplantation and promote tissue regeneration in mouse models of colonic necrosis and liver injury.
  • HPGD inhibition provides a valuable therapeutic opportunity for restoring tissue capacity and function in a wide variety of clinical indications.
  • the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, X 1 , L 1 , L 2 , R x , R y , R z , x, y, and z are as defined below and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula II: II or a pharmaceutically acceptable salt thereof, each of Ring A, Ring B, X 1 , L 1 , R x , R y , R z , x, y, and z are as defined below and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula III: or a pharmaceutically acceptable salt thereof, each of Ring A, Ring B, L 1 , L 2 , R x , R y , R z , x, y, and z are as defined below and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula IV: or a pharmaceutically acceptable salt thereof, each of Ring A, Ring B, X 1 , L 1 , L 2 , R x , R y , R z , x, y, and z are as defined below and described in embodiments herein, both singly and in combination.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV and a pharmaceutically acceptable carrier, adjuvant, or diluent.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV and a pharmaceutically acceptable carrier, adjuvant, or diluent.
  • the present invention provides a method of treating an HPGD- mediated disorder, disease, or condition in a patient, comprising administering to said patient a compound herein, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition herein. 2.
  • Compounds and Definitions [0015] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
  • aliphatic or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bridged bicyclic refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • alkyl refers to a C 1-12 straight or branched saturated aliphatic group. In certain instances, alkyl refers to a C 1-8 straight or branched saturated aliphatic group or a C 1-6 straight or branched saturated aliphatic group.
  • lower alkyl refers to a C 1-4 straight or branched alkyl group.
  • Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl (also referred to interchangeably herein as 2-propyl, iPr, i Pr and i-Pr), butyl, isobutyl (also referred to interchangeably herein as 2-butyl, iBu, i Bu and i-Bu) and tert-butyl (also referred to interchangeably herein as 2-methyl-2-butyl, tBu, t Bu and t-Bu).
  • alkenyl refers to a C 2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond.
  • alkenyl refers to a C 2-8 or a C 1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond.
  • lower alkenyl refers to a C 2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond.
  • Alkenyl groups include both cis (Z) and trans (E) regioisomers.
  • alkynyl refers to a C 2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. In certain instances, alkynyl refers to a C 2-8 or a C 1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. The term “lower alkynyl” refers to a C 2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond.
  • Exemplary lower alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, and 3-butynyl.
  • haloalkyl refers to a straight or branched alkyl group that is substituted with one or more halogen atoms.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 ) n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, triazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl), 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—,” as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, indolizinyl, isoindolin-1-only, 1,2-dihydro-3H- pyrrolo[3,4-c]pyridin-3-onyl, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-only, imidazo[1,2- a]pyridyl, imidazo[1,5-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2- a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinn
  • heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • Suitable monovalent substituents on R° are independently halogen, —(CH 2 ) 0–2 R ⁇ , –(haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(OR ⁇ ) 2 ; –O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , –(CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH, –(CH 2 ) 0–2 NH 2 , – (CH 2 ) 0
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2– 3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, –R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R ⁇ , –NR ⁇ 2, –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , –C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above,
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, –R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers and R a (or M) and S a (or P) atropisomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • Ring B of a provided compound may be substituted with one or more deuterium atoms.
  • an “HPGD inhibitor” is a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of HPGD. Inhibition using the HPGD inhibitor does not necessarily indicate a total elimination of the HPGD activity. Instead, the activity could decrease by a statistically significant amount including, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95% or 100% of the activity of HPGD compared to an appropriate control. In some embodiments, the HPGD inhibitor reduces, inhibits, or otherwise diminishes the dehydrogenase activity of HPGD.
  • the presently disclosed compounds bind directly to HPGD and inhibit its activity.
  • “Selectivity” and “selective” as used herein is a relative measure of the tendency for a compound to preferentially (e.g., in a statistically significant manner) associate with one target as opposed to another target (or group of targets).
  • the presently disclosed compounds reduce, inhibit, or otherwise diminishes the activity of HPGD greater than that of another target.
  • a selective HPGD inhibitor reduces at least one biological activity of HPGD by an amount that is statistically greater than the inhibitory effect of any other protein.
  • the activity of a selective inhibitor is reported as EC50, IC50, KD or Ki.
  • the activity of a selective inhibitor (measured as any one of EC 50 , IC 50 , K D or K i ) for HPGD is about 10 fold greater than the corresponding inhibitory activity for another target. In other embodiments the activity of the selective inhibitor for HPGD is at least about 15 fold greater, 20 fold greater, 25 fold greater, 30 fold greater, 40 fold greater or 50 fold greater than the corresponding inhibitory activity for another target.
  • the presently disclosed compounds may or may not be selective HPGD inhibitors.
  • a compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents. One of ordinary skill in the art will recognize that a detectable moiety may be attached to a provided compound via a suitable substituent.
  • suitable substituent refers to a moiety that is capable of covalent attachment to a detectable moiety.
  • moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that such moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry.
  • such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst.
  • Methods of using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed.2002, 41:2596-99 and Sun et al., Bioconjugate Chem., 2006, 17:52-57.
  • the term “detectable moiety” is used interchangeably with the term “label” and relates to any moiety capable of being detected, e.g., primary labels and secondary labels.
  • Secondary labels such as radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications. Detectable moieties also include luminescent and phosphorescent groups.
  • the term “secondary label” as used herein refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal.
  • the secondary intermediate may include streptavidin-enzyme conjugates.
  • antigen labels secondary intermediates may include antibody-enzyme conjugates.
  • fluorescent label refers to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength.
  • fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy 3 , Cy5, Cy 3 .5, Cy5.5), Dansyl, Dapoxyl,
  • mass-tag refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques.
  • mass-tags include electrophore release tags such as N-[3-[4’-[(p- Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4’-[2,3,5,6- Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives.
  • mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition.
  • nucleotides dideoxynucleotides
  • oligonucleotides of varying length and base composition oligopeptides, oligosaccharides
  • other synthetic polymers of varying length and monomer composition.
  • a large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change in a HPGD activity between a sample comprising a compound of the present invention, or composition thereof, and a HPGD, and an equivalent sample comprising an HPGD, in the absence of said compound, or composition thereof.
  • the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: Ring A is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) and phenyl, wherein Ring A is substituted with y instances of R y ; Ring B is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered
  • each R x , R y , and R z is independently halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , - S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)C(NR 2 , -N(R)S(O) 2 NR 2 , - N(R)S(O) 2 R, an optionally substituted saturated or unsaturated C 1-6 aliphatic group, an optional
  • the present invention provides a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: Ring A is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) and phenyl, wherein Ring A is substituted with y instances of R y ; Ring B is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring
  • the present invention provides a compound of Formula III: III or a pharmaceutically acceptable salt thereof, wherein: Ring A is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur), a 5- or 6-membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or phenyl, wherein Ring A is substituted with y instances of R y ; Ring B is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaro
  • a structure depicted a includes for example, structures Formula IV [0057]
  • the present invention provides a compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein: Ring A is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur), a 5- or 6-membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or phenyl, wherein Ring A is substituted with y instances of R y ;
  • Ring B is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected
  • Ring A is a cyclic group selected from 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur), a 5- or 6-membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or phenyl, wherein Ring A is substituted with y instances of R y .
  • Ring A is phenyl, wherein Ring A is substituted with y instances of R y .
  • Ring A is a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur), wherein Ring A is substituted with y instances of R y .
  • Ring A is a 5- or 6-membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein Ring A is substituted with y instances of R y .
  • Ring A is a 5-7 membered saturated or partially unsaturated monocyclic heterocyclic ring (having a single nitrogen), wherein Ring A is substituted with y instances of R y .
  • Ring A is a 6 membered saturated monocyclic heterocyclic ring (having a single nitrogen) optionally substituted with 0, 1, 2, 3, or 4 halo. [0061] In some embodiments, Ring A is F . [0062] In some embodiments, Ring A is selected from those depicted in Table 1, below.
  • Ring B is selected from a cyclic group selected from 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with z instances of R z .
  • Ring B is a is a cyclic group selected from a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with z instances of R z .
  • Ring B is a cyclic group selected from a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Ring B is substituted with z instances of R z .
  • Ring B is a cyclic group selected from an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with z instances of R z .
  • Ring B is a cyclic group selected from an 8-10 membered bicyclic heteroaromatic ring (having 1-3 nitrogen atoms), wherein Ring B is substituted with z instances of R z .
  • Ring B is selected from those depicted in Table 1, below.
  • X 1 is N or C. In some embodiments, X 1 is N. In some embodiments, X 1 is C.
  • each L 1 and L 2 is independently a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-.
  • each L 1 and L 2 is independently a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-.
  • each L 1 and L 2 is independently a covalent bond.
  • L 1 is a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, or -N(R)C(O)O-.
  • each L 1 and L 2 is independently selected from those depicted in Table 1, below.
  • L 1 is a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-, -S(O) 2 -, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, or - N(R)C(O)O-.
  • L 1 is a covalent bond.
  • L 1 is a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-.
  • L 1 is selected from those depicted in Table 1, below.
  • L 2 is a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)- , -S(O) 2 -, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, or -N(R)C(O)O-.
  • L 2 is a covalent bond.
  • L 2 is a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-.
  • L 2 is selected from those depicted in Table 1, below.
  • each R x , R y , and R z is independently halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , - C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)
  • each R x , R y , and R z is independently halogen, –CN, –NO 2 , - OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , - C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, an optionally substituted saturated or unsaturated C 1-6 aliphatic group.
  • each R x , R y , and R z is independently selected from those depicted in Table 1, below.
  • each R x is independently halogen, –CN, –NO 2 , -OR, -SR, - NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, - OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)C(NR 2 , - N(R
  • each R x is independently halogen, –CN, –NO 2 , -OR, -SR, - NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, - OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)C(NR 2 , - N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, an optionally substituted saturated or unsaturated C 1-6 aliphatic group.
  • each R x is independently selected from those depicted in Table 1, below.
  • each R y is independently halogen, –CN, –NO 2 , -OR, -SR, - NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, - OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR 2 , -N(R)C(NR 2 , - N(
  • each R y is independently halogen, –CN, –NO 2 , -OR, -SR, - NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, - OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)C(NR 2 , - N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, an optionally substituted saturated or unsaturated C 1-6 aliphatic group.
  • each R y is independently selected from those depicted in Table 1, below.
  • each R z is independently halogen, –CN, –NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)S(O) 2 NR 2 , - N(R)S(O) 2 R, an optionally substituted saturated or uns
  • each R z is independently halogen, –CN, –NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)S(O) 2 NR 2 , - N(R)S(O) 2 R, an optionally substituted saturated or unsaturated C 1-6 aliphatic group.
  • each R z is independently selected from those depicted in Table 1, below.
  • each Cy is independently an optionally substituted and cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • Cy is an optionally substituted and cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • Cy is phenyl.
  • Cy is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • Cy is a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • each Cy is independently selected from those depicted in Table 1, below.
  • each R is independently hydrogen, halogen, or an optionally substituted C 1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R is H.
  • R is halogen, or an optionally substituted C 1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R is halogen. In some embodiments, R is an optionally substituted C 1-6 aliphatic group. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • each R is independently selected from those depicted in Table 1, below.
  • x is 0, 1, 2, 3, or 4.
  • x is 0.
  • x is 1.
  • x is 2.
  • x is 3.
  • x is 4.
  • x is selected from those depicted in Table 1, below.
  • y is 0, 1, 2, 3, or 4. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. [00101] In some embodiments, y is selected from those depicted in Table 1, below. [00102] As described generally above, z is 0, 1, 2, 3, or 4. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. [00103] In some embodiments, z is selected from those depicted in Table 1, below.
  • x, y, and z are 0. In some embodiments, x and y are 0. In some embodiments, x and z are 0. In some embodiments, y and z are 0. [00105] In some embodiments, z is 1 and R 1 is methyl. [00106] In one aspect, the compound of Formula I is a compound of Formula Ia:
  • the compound of Formula I is a compound of Formula Ia-1: Ia-1 or a pharmaceutically acceptable salt thereof, wherein Ring B, R x , R z , X 1 , x, and z are as defined and described in embodiments herein, both singly and in combination.
  • x is 0.
  • x is 1 and R x is methyl.
  • X 1 is C.
  • X 1 is N.
  • Ring [00108] In one aspect, the compound of Formula I is a compound of Formula Ia-2, Ia-3, or Ia- 4:
  • the compound of Formula II is a compound of Formula IIa, or IIb: IIa IIb or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R x , R y , R z , X 1 , x, y, and z are as defined and described in embodiments herein, both singly and in combination.
  • the compound of Formula II is a compound of Formula IIa-1, IIb-1, or IIa-2: IIa-2 or a pharmaceutically acceptable salt thereof, wherein Ring B, R, R x , R z , X 1 , x, and z are as defined and described in embodiments herein, both singly and in combination. Table 1. Selected Compounds
  • the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1, above. [00112] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound disclosed herein (described in embodiments herein, both singly and in combination), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. For example, in some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV as defined above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV as defined above, together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention provides a compound of Formula I, Formula II, Formula III or Formula IV as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.
  • the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for inhibiting HPGD as described herein and/or in a method for treating a HPGD-dependent disorder as described herein.
  • the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for inhibiting HPGD as described herein.
  • the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for treating a HPGD-dependent disorder as described herein.
  • the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for modulating HPGD as described herein and/or in a method for treating a HPGD-dependent disorder as described herein.
  • the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for modulating HPGD as described herein.
  • the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for treating a HPGD-dependent disorder as described herein. 4.
  • a compound described herein such as a compound of Formula I, Formula II, Formula III or Formula IV
  • pharmaceutical compositions described herein for use in a method for treating a HPGD-dependent disorder as described herein. 4.
  • PG protecting group
  • LG leaving group
  • LG includes, but is not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.
  • oxygen protecting group includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
  • Suitable hydroxyl protecting groups include, but are not limited to, esters and ethers.
  • ethers include allyl ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p- chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6- trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p- methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2- methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, and 2- and 4-picolyl.
  • Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like.
  • Examples of such groups include t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
  • compositions of the present invention are generally prepared according to any one of the schemes in Example 1. 5. Uses, Formulation and Administration Pharmaceutically acceptable compositions [00121] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit HPGD, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.
  • the term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of HPGD, or a mutant thereof.
  • the subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of compounds of the invention.
  • Metabolites include compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • the compound of the invention is a base
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • a compound of the invention can be in the form of a “prodrug,” which includes compounds with moieties which can be metabolized in vivo.
  • the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) “Pharmaceutical Salts,” J. Pharm. Sci. 66:1-19).
  • the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid.
  • prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions of this invention may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
  • Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 and 100 mg/kg, 0.01 and 50 mg/kg, or 1 and 25 mg/kg, body weight/day of the compound can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated.
  • the compounds and compositions described herein are generally useful for the inhibition of the activity of HPGD.
  • the presently disclosed compounds find use in inhibiting the enzyme HPGD.
  • the subject matter disclosed herein is directed to a method of inhibiting HPGD, the method comprising contacting HPGD with an effective amount of a compound of the invention or a pharmaceutical composition described herein.
  • the presently disclosed compounds can be used in a method for inhibiting HPGD. Such methods comprise contacting HPGD with an effective amount of a presently disclosed compound.
  • contact is intended bringing the compound within close enough proximity to an isolated HPGD enzyme or a cell expressing HPGD such that the compound is able to bind to and inhibit the HPGD.
  • the compound can be contacted with HPGD in vitro or in vivo via administration of the compound to a subject.
  • a method of inhibiting HPGD in a biological sample is provided herein.
  • the method comprises contacting the sample with a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • a pharmaceutical sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • the present disclosure provides methods of inhibiting HPGD in a patient.
  • the method comprises administering to a patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • a compound disclosed herein such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1
  • a pharmaceutical composition disclosed herein such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • HPGD-dependent disorder is a pathological condition in which HPGD activity is necessary for the genesis or maintenance of the pathological condition.
  • the method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • a compound disclosed herein such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle such as a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions that are potent inhibitors of HPGD and can be used in novel approaches to treat diseases or disorders such as wounds, bone formation, bone regrowth, hair loss, inflammatory bowel disease, liver disease, bone marrow transplantation, and muscle atrophy.
  • the compounds and compositions provided herein can be used in methods of modulating the prostaglandin system.
  • the present invention provides a compound or pharmaceutically acceptable salt thereof or composition described herein for use in a method of treating wounds, bone formation, bone regrowth, hair loss, inflammatory bowel disease, liver disease, bone marrow transplantation, and muscle atrophy.
  • HPGD inhibitors for use as therapeutic active substances.
  • HPGD inhibitor for use in treating or preventing a disease or condition associated with HPGD activity is provided. Also, an HPGD inhibitor for use in treating wounds is provided. Further provided is the use of a HPGD inhibitor in the manufacture of a medicament for treating or preventing a disease or condition associated with HPGD activity. Also provided is the use of a HPGD inhibitor in the manufacture of a medicament for treating wounds. [00159] Accordingly, in some embodiments, the HPGD-mediated disorder is a wound. In one aspect, provided herein is a method of treating a wound in a patient.
  • the method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • the wound is selected from a vascular wound, a neuropathic wound, moisture associated dermatitis, a skin tear, or an ulcer. Assessment of treated wounds is known in those having skill in the art.
  • a method of treating hair loss in a patient is provided herein.
  • the method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • the hair loss comprises one or more of Androgenetic Alopecia, Telogen Effluvium, Anagen Effluvium, Alopecia Areata, Tinea Capitis, Cicatricial Alopecia, Hair Shaft Abnormalities, and Hypotrichosis.
  • a method of transplanting bone marrow in a patient in need thereof comprising administering to the patient a compound of Formula I, Formula II, Formula III, or Formula IV, or a compound of Table 1, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1, or a pharmaceutically acceptable salt thereof, herein.
  • a method of regenerating tissue on existing tissue comprising contacting the existing tissue with a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1 herein.
  • the tissue is colon tissue or liver tissue.
  • the method is in vitro.
  • the method is in vivo.
  • the method is ex vivo.
  • provided herein is a method of treating inflammatory bowel disease in a patient.
  • the method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • a compound disclosed herein such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • a compound disclosed herein such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • a compound disclosed herein such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle such as a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intratumorally, or intranasally.
  • the HPGD inhibitor is administered continuously. In other embodiments, the HPGD inhibitor is administered intermittently.
  • treatment of a subject with an effective amount of a HPGD inhibitor can include a single treatment or can include a series of treatments.
  • doses of the active compound depends upon a number of factors within the knowledge of the ordinarily skilled physician or veterinarian.
  • the dose(s) of the active compound will vary, for example, depending upon the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination.
  • the effective dosage of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays.
  • the compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of between about 0.001 ⁇ g/kg and about 1000 mg/kg, including but not limited to about 0.001 ⁇ g/kg, 0.01 ⁇ g/kg, 0.05 ⁇ g/kg, 0.1 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 10 ⁇ g/kg, 25 ⁇ g/kg, 50 ⁇ g/kg, 100 ⁇ g/kg, 250 ⁇ g/kg, 500 ⁇ g/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, 300 mg/kg, 750 mg/kg, and 1000 mg/kg.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • administration includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal.
  • the term “effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result.
  • An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • the phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.
  • the phrase “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.
  • additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as “appropriate for the disease, or condition, being treated.”
  • a provided combination, or composition thereof is administered in combination with another therapeutic agent.
  • Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition.
  • the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention provides a composition comprising a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1, or a compound of Table 1 and one or more additional therapeutic agents.
  • the therapeutic agent may be administered together with a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1, or may be administered prior to or following administration of a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1. Suitable therapeutic agents are described in further detail below.
  • a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1 may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent.
  • a compound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.
  • the present invention provides a method of treating a wound comprising administering to a patient in need thereof a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1 and one or more additional therapeutic agents selected from acetaminophen, salicylic acid, 2-octyl cyanoacrylate, Alevicyn ®, Artiss ®, becaplermin, Betaine/polyhexanide, cadexomer iodine, collagenase, Dermabond ®, Eletone ® cream, Episalvan ®, Evicel ®, fibrin sealant, Filsuvez ®, hypochlorous acid topical, Lodosorb ®, NexoBrid ®, Oleogel-S10, petrolatum & mineral oil topical, Prontosan ®, proteolytic enzymes, Regranex gel ®, Santyl, TachoSil ®, Tisseel VH ®, Tropazone ®,
  • the present invention provides a method of treating hair loss comprising administering to a patient in need thereof a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1 and one or more additional therapeutic agents selected from minoxidil, finasteride, spironolactone, dutasteride, an anti-androgen, a corticosteroid, and combinations thereof.
  • additional therapeutic agents selected from minoxidil, finasteride, spironolactone, dutasteride, an anti-androgen, a corticosteroid, and combinations thereof.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle e.g., a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.
  • that additional therapeutic agent and the compound of this invention may act synergistically.
  • the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent.
  • a dosage of between 0.01 – 1,000 ⁇ g/kg body weight/day of the additional therapeutic agent can be administered.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Patients using stents or other implantable devices wound formation or worsening. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising an HPGD inhibitor disclosed herein. Implantable devices coated with a compound of this invention are another embodiment of the present invention. EXEMPLIFICATION [00190] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures.
  • TFA trifluoracetic acid sat: saturated TIPS: triisopropylsilyl SEMCl: chloromethyl-2-
  • THF tetrahydrofuran trimethylsilylethyl ether
  • THP tetrahydropyran
  • SFC supercritical fluid chromatography
  • TLC thin layer chromatography
  • SOCl 2 sulfur dichloride
  • TMEDA tetramethylethylenediamine tBuOK: potassium tert-butoxide
  • T 3 P propylphosphonic anhydride TBAB: tetrabutylammonium bromide
  • pTSA para-toluenesulfonic acid
  • TBAC 3,3-dimethylbutanoyl chloride
  • TsCl p-toluenesulfonyl chloride
  • TBAI tetrabutylammonium iodide wt: weight
  • TBD Triazabicyclodecene (1,3,4,6,
  • the crude product was re-purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 . H 2 O), Mobile Phase B: CH 3 CN; Flow rate: 60 mL/min; Gradient: 22% to 52% B in 8 min, hold 52% B in 3 min; Wave Length: 254/210 nm; RT1(min): 7.21). The product-containing fractions were concentrated under vacuum to remove most of the solvent.
  • the residue was purified firstly by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (10 mmol/L NH 4 HCO 3 ) and B: CH 3 CN; Gradient: 0% to 34% B in 10 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford the crude product (16 mg). The crude product was further purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .
  • the filtrate was poured into water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 10 mmol/L NH 4 HCO 3 ) and B: CH 3 CN; Gradient: 5% to 95% B in 30 min; Detector: 254/220 nm).
  • the mixture was purified by Prep-HPLC (Column: XBridge BEH C18 OBD Prep Column, 19x250 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 38% to 68% B in 6 min, 68% B; Wave Length: 254 nm; RT1(min): 5.73).
  • the resulting mixture was purified by Prep-HPLC (Column: YMC-Actus Triart C18, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: CH 3 CN; Flow rate: 60 mL/min; Gradient: 43% to 73% B in 8 min, 73% B; Wave Length: 254/210 nm).
  • the resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere.
  • the reaction mixture was allowed to cool down to room temperature.
  • the resulting mixture was diluted with water and extracted with EtOAc (3 x 100 mL).
  • the combined organic layers were washed with H 2 O (3 x 100 mL), dried over anhydrous Na2SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting mixture was stirred for 4 h at 60 °C.
  • the mixture was cooled to room temperature and diluted with water (60 mL).
  • the resulting mixture was extracted with EtOAc (3 x 60 mL).
  • the combined organic layers were washed with H 2 O (10 mL), dried over anhydrous Na2SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 38% B in 9 min, 38% B; Wave Length: 254/220 nm; RT1(min): 8.02).
  • Example 2 HPGD inhibition activity
  • Compounds to be tested were prepared by serial dilution in DMSO:H 2 O (1:3). The diluted compound solution (0.2 ⁇ L) was added to a 384-well assay plate and was centrifuged at 1000 RPM for 1 minute.
  • HPGD protein H2-Q266 HPGD, 10 ⁇ L
  • 1x assay buffer 50mM Bicine pH 7.5, 100 mM NaCl, 0.1% Pluronic F127, 0.5 mM EGTA, 0.005% BSG, 0.5 mM TCEP
  • HPGD IC50 results for compounds of the invention are reported in Table 4.
  • the letter codes for IC50 include: A ( ⁇ 0.5 nM), B (0.5 – 5 nM), C (>5 – 10 nM), and D ( ⁇ 10 nM). Table 4.
  • Antczak M.; Zhang, Y.; Wang, C.; Doran, J.; Naidoo, J.; Voruganti, S.; Williams, N. S.; Markowitz, S. D.; Ready, J. M. Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair, J. Med. Chem.2017, 60, 3979-4001 11. Hu, B.; Toda, K.; Wang, X.; Antczak, M.

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Abstract

The present invention provides compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), compositions thereof and methods of using the same for the inhibition of HPGD and the treatment of HPGD-mediated disorders.

Description

HPGD INHIBITORS AND USES THEREOF RELATED APPLICATIONS [0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63/507,390, filed June 9, 2023; the contents of each of which is incorporated by reference. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to compounds and methods useful for inhibiting hydroxyprostaglandin dehydrogenase 15-(NAD), also called 15-hydroxyprostaglandin dehydrogenase [NAD+] (HPGD). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION [0003] Prostaglandins (PGs) are bioactive lipid signaling mediators that are generated through sequential oxygenation of arachidonic acid present in plasma membranes by cyclooxygenases (COX enzymes) and specific prostaglandin synthases. In contrast, prostaglandins can also be metabolically inactivated by the enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH or HPGD), which mediates the oxidation of prostanoid 15-hydroxyl groups to ketones, abrogating the binding to prostaglandin receptors. Therefore, COX enzymes and HPGD regulate the homeostatic balance of various prostaglandin levels in nucleated cells. This balance has been demonstrated through the characterization of genetic knockouts and pharmacological inhibition, reducing prostaglandin levels through COX inhibition and increasing prostaglandin levels upon HPGD inhibition. [0004] Prostaglandin E2 (PGE2) is the most abundant prostaglandin molecule in human cells and plays important roles in immune cell function and in potentiating tissue regeneration through the expansion of several types on tissue stem cells, including hematopoietic and colonic stem cells. Supplied exogenously, PGE2 has been shown to expand hematopoietic stem cell numbers in mice and zebrafish as well as human colonic stem cells in culture. PGE2 is also able to enhance the engraftment of murine bone marrow stem cells when injected back into recipient animals and HPGD knockout mice, characterized by increased PGE2, demonstrating increased tissue regenerative capacity. In a mouse model of colitis, COX inhibitors exacerbated disease and colon injury, while disease severity was improved by providing exogenous PGE2. Alternatively, HPGD inhibition was shown to accelerate bone marrow transplantation and promote tissue regeneration in mouse models of colonic necrosis and liver injury. Thus, HPGD inhibition provides a valuable therapeutic opportunity for restoring tissue capacity and function in a wide variety of clinical indications. [0005] There is thus a need for new HPGD inhibitors. The present disclosure satisfies this need and provides other, related, advantages. SUMMARY OF THE INVENTION [0006] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of HPGD. In certain embodiments, the invention provides for compounds of the formulae presented herein. [0007] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with HPGD. Such diseases, disorders, or conditions include those described herein. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention: [0008] In one aspect, the present invention provides a compound of Formula I:
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, X1, L1, L2, Rx, Ry, Rz, x, y, and z are as defined below and described in embodiments herein, both singly and in combination. [0009] In one aspect, the present invention provides a compound of Formula II:
Figure imgf000005_0001
II or a pharmaceutically acceptable salt thereof, each of Ring A, Ring B, X1, L1, Rx, Ry, Rz, x, y, and z are as defined below and described in embodiments herein, both singly and in combination. [0010] In one aspect, the present invention provides a compound of Formula III:
Figure imgf000005_0002
or a pharmaceutically acceptable salt thereof, each of Ring A, Ring B, L1, L2, Rx, Ry, Rz, x, y, and z are as defined below and described in embodiments herein, both singly and in combination. [0011] In one aspect, the present invention provides a compound of Formula IV:
Figure imgf000005_0003
or a pharmaceutically acceptable salt thereof, each of Ring A, Ring B, X1, L1, L2, Rx, Ry, Rz, x, y, and z are as defined below and described in embodiments herein, both singly and in combination. [0012] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV and a pharmaceutically acceptable carrier, adjuvant, or diluent. [0013] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV and a pharmaceutically acceptable carrier, adjuvant, or diluent. [0014] In some embodiments, the present invention provides a method of treating an HPGD- mediated disorder, disease, or condition in a patient, comprising administering to said patient a compound herein, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition herein. 2. Compounds and Definitions: [0015] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001. [0016] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0017] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. The term “alkyl” refers to a C1-12 straight or branched saturated aliphatic group. In certain instances, alkyl refers to a C1-8 straight or branched saturated aliphatic group or a C1-6 straight or branched saturated aliphatic group. The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. [0018] Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl (also referred to interchangeably herein as 2-propyl, iPr, iPr and i-Pr), butyl, isobutyl (also referred to interchangeably herein as 2-butyl, iBu, iBu and i-Bu) and tert-butyl (also referred to interchangeably herein as 2-methyl-2-butyl, tBu, tBu and t-Bu). [0019] The term “alkenyl” refers to a C2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. In certain instances, alkenyl refers to a C2-8 or a C1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. The term “lower alkenyl” refers to a C2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. Alkenyl groups include both cis (Z) and trans (E) regioisomers. Exemplary lower alkenyl groups are vinyl, allyl, 2-propenyl, and butenyl isomers (- CH2CH2CH=CH2, - CH2CH=CHCH3 and -CH=CH=CH2CH3). [0020] The term “alkynyl” refers to a C2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. In certain instances, alkynyl refers to a C2-8 or a C1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. The term “lower alkynyl” refers to a C2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. Exemplary lower alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, and 3-butynyl. [0021] The term “haloalkyl” refers to a straight or branched alkyl group that is substituted with one or more halogen atoms. The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0022] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)). [0023] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0024] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [0025] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0026] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0027] The term “halogen” means F, Cl, Br, or I. [0028] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. [0029] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, triazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl), 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–,” as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, indolizinyl, isoindolin-1-only, 1,2-dihydro-3H- pyrrolo[3,4-c]pyridin-3-onyl, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-only, imidazo[1,2- a]pyridyl, imidazo[1,5-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2- a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [0030] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N–substituted pyrrolidinyl). [0031] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. [0032] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [0033] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0034] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro; –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; – N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; –N(R°)N(R°)C(O)NR°2; – N(R°)N(R°)C(O)OR°; –N(R°)C(NR°)N(R°)2; –(CH2)0–4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; – (CH2)0–4C(O)SR°; –(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR°; –(CH2)0–4 SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, –(CH2)0–4OC(O)NR°2; – C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°; –(CH2)0–4SSR°; –(CH2)0– 4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; –S(O)2NR°2; –(CH2)0–4S(O)R°; – N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; –(CH2)0–4P(O)2R°; –(CH2)0– 4P(O)R°2; –(CH2)0–4OP(O)R°2; –(CH2)0–4OP(O)(OR°)2; –SiR°3; –(C1–4 straight or branched alkylene)O–N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0– 1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [0035] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2; –O(haloR●), –CN, –N3, –(CH2)0–2 C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR●, –(CH2)0–2NR● 2, –NO2, –SiR● 3, –OSiR● 3, -C(O)SR●, –(C1–4 straight or branched alkylene)C(O)OR●, or –SSR● wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S. [0036] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R* 2))2–3O–, or –S(C(R* 2))2–3S–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR* 2)2– 3O–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0037] Suitable substituents on the aliphatic group of R* include halogen, –R●, -(haloR●), -OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR● 2, or –NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0038] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR† 2, –C(S)NR† 2, –C(NH)NR† 2, or –N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0039] Suitable substituents on the aliphatic group of R† are independently halogen, –R●, -(haloR●), –OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR● 2, or –NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0040] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [0041] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [0042] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers and Ra (or M) and Sa (or P) atropisomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, Ring B of a provided compound may be substituted with one or more deuterium atoms. [0043] The structures as drawn represent relative configurations, unless labeled as absolute configurations. The invention contemplates individual enantiomers and racemic mixtures. [0044] As used herein, an “HPGD inhibitor” is a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of HPGD. Inhibition using the HPGD inhibitor does not necessarily indicate a total elimination of the HPGD activity. Instead, the activity could decrease by a statistically significant amount including, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95% or 100% of the activity of HPGD compared to an appropriate control. In some embodiments, the HPGD inhibitor reduces, inhibits, or otherwise diminishes the dehydrogenase activity of HPGD. The presently disclosed compounds bind directly to HPGD and inhibit its activity. [0045] “Selectivity” and “selective” as used herein is a relative measure of the tendency for a compound to preferentially (e.g., in a statistically significant manner) associate with one target as opposed to another target (or group of targets). In some embodiments, the presently disclosed compounds reduce, inhibit, or otherwise diminishes the activity of HPGD greater than that of another target. For example, a selective HPGD inhibitor reduces at least one biological activity of HPGD by an amount that is statistically greater than the inhibitory effect of any other protein. In some embodiments, the activity of a selective inhibitor is reported as EC50, IC50, KD or Ki. In some embodiments, the activity of a selective inhibitor (measured as any one of EC50, IC50, KD or Ki) for HPGD is about 10 fold greater than the corresponding inhibitory activity for another target. In other embodiments the activity of the selective inhibitor for HPGD is at least about 15 fold greater, 20 fold greater, 25 fold greater, 30 fold greater, 40 fold greater or 50 fold greater than the corresponding inhibitory activity for another target. The presently disclosed compounds may or may not be selective HPGD inhibitors. [0046] A compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents. One of ordinary skill in the art will recognize that a detectable moiety may be attached to a provided compound via a suitable substituent. As used herein, the term “suitable substituent” refers to a moiety that is capable of covalent attachment to a detectable moiety. Such moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that such moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed.2002, 41:2596-99 and Sun et al., Bioconjugate Chem., 2006, 17:52-57. [0047] As used herein, the term “detectable moiety” is used interchangeably with the term “label” and relates to any moiety capable of being detected, e.g., primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium, 32P, 33P, 35S, or 14C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications. Detectable moieties also include luminescent and phosphorescent groups. [0048] The term “secondary label” as used herein refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal. For biotin, the secondary intermediate may include streptavidin-enzyme conjugates. For antigen labels, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of nonradiative fluorescent resonance energy transfer (FRET), and the second group produces the detected signal. [0049] The terms “fluorescent label”, “fluorescent dye,” and “fluorophore” as used herein refer to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800), JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone- fluorescein, Tetramethyl-rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X. [0050] The term “mass-tag” as used herein refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass-tags include electrophore release tags such as N-[3-[4’-[(p- Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4’-[2,3,5,6- Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives. The synthesis and utility of these mass-tags is described in United States Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass- tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition. A large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags. [0051] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in a HPGD activity between a sample comprising a compound of the present invention, or composition thereof, and a HPGD, and an equivalent sample comprising an HPGD, in the absence of said compound, or composition thereof. 3. Description of Exemplary Embodiments: Formula I [0052] As described above, in certain embodiments, the present invention provides a compound of Formula I:
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) and phenyl, wherein Ring A is substituted with y instances of Ry; Ring B is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Ring B is substituted with z instances of Rz; X1 is N or C; each L1 and L2 is independently a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, - C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-. each Rx, Ry, and Rz is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, - S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted and cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R is independently hydrogen, halogen, or an optionally substituted C1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, or 4.
Figure imgf000019_0002
Formula II [0054] As described above, in certain embodiments, the present invention provides a compound of Formula II:
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) and phenyl, wherein Ring A is substituted with y instances of Ry; Ring B is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Ring B is substituted with z instances of Rz; X1 is N or C; L1 is a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, - S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, or -N(R)C(O)O-; each Rx, Ry, and Rz is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, - S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted and cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R is independently hydrogen, halogen, or an optionally substituted C1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, or 4. Formula III [0055] As described above, in certain embodiments, the present invention provides a compound of Formula III:
Figure imgf000021_0001
III or a pharmaceutically acceptable salt thereof, wherein: Ring A is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur), a 5- or 6-membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or phenyl, wherein Ring A is substituted with y instances of Ry; Ring B is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with z instances of Rz; each L1 and L2 is independently a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, - C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-; each Rx, Ry, and Rz is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, - S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted and cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R is independently hydrogen, halogen, or an optionally substituted C1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, or 4.
[0056] As described herein, a structure depicted a
Figure imgf000023_0001
includes for example, structures
Figure imgf000023_0002
Formula IV [0057] As described above, in certain embodiments, the present invention provides a compound of Formula IV:
Figure imgf000023_0003
or a pharmaceutically acceptable salt thereof, wherein: Ring A is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur), a 5- or 6-membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or phenyl, wherein Ring A is substituted with y instances of Ry; Ring B is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with z instances of Rz; X1 is N, or C; each L1 and L2 is independently a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, - C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-; each Rx, Ry, and Rz is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, - S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted and cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R is independently hydrogen, halogen, or an optionally substituted C1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, or 4. [0058] As described herein, a structure depicted a
Figure imgf000025_0001
includes for example, structures
Figure imgf000025_0002
[0059] As defined generally above, Ring A is a cyclic group selected from 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur), a 5- or 6-membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or phenyl, wherein Ring A is substituted with y instances of Ry. [0060] In some embodiments, Ring A is phenyl, wherein Ring A is substituted with y instances of Ry. In some embodiments Ring A is a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur), wherein Ring A is substituted with y instances of Ry. In some embodiments, Ring A is a 5- or 6-membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein Ring A is substituted with y instances of Ry. In some embodiments, Ring A is a 5-7 membered saturated or partially unsaturated monocyclic heterocyclic ring (having a single nitrogen), wherein Ring A is substituted with y instances of Ry. In some embodiments, Ring A is a 6 membered saturated monocyclic heterocyclic ring (having a single nitrogen) optionally substituted with 0, 1, 2, 3, or 4 halo.
Figure imgf000025_0003
[0061] In some embodiments, Ring A is F . [0062] In some embodiments, Ring A is selected from those depicted in Table 1, below. [0063] As defined generally above, Ring B is selected from a cyclic group selected from 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with z instances of Rz. [0064] In some embodiments, Ring B is a is a cyclic group selected from a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with z instances of Rz. In some embodiments, Ring B is a cyclic group selected from a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Ring B is substituted with z instances of Rz. In some embodiments, Ring B is a cyclic group selected from an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with z instances of Rz. In some embodiments, Ring B is a cyclic group selected from an 8-10 membered bicyclic heteroaromatic ring (having 1-3 nitrogen atoms), wherein Ring B is substituted with z instances of Rz.
Figure imgf000026_0001
[0066] In some embodiments, Ring B is selected from those depicted in Table 1, below. [0067] As defined generally above, X1 is N or C. In some embodiments, X1 is N. In some embodiments, X1 is C. [0068] As defined generally above, each L1 and L2 is independently a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-. [0069] In some embodiments, each L1 and L2 is independently a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-. [0070] In some embodiments, each L1 and L2 is independently a covalent bond. In some embodiments, L1 is a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, or -N(R)C(O)O-. [0071] In some embodiments, each L1 and L2 is independently selected from those depicted in Table 1, below. [0072] In some embodiments, L1 is a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, or - N(R)C(O)O-. [0073] In some embodiments, L1 is a covalent bond. In some embodiments, L1 is a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-. [0074] In some embodiments, L1 is selected from those depicted in Table 1, below. [0075] In some embodiments, L2 is a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)- , -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, or -N(R)C(O)O-. [0076] In some embodiments, L2 is a covalent bond. In some embodiments, L2 is a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, - C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, - OC(O)N(R)-, or -N(R)C(O)O-. [0077] In some embodiments, L2 is selected from those depicted in Table 1, below. [0078] As defined generally above, each Rx, Ry, and Rz is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, - C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, - N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy. [0079] In some embodiments, each Rx, Ry, and Rz, is independently halogen, –CN, –NO2, - OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, - C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, - N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group. [0080] In some embodiments, each Rx, Ry, and Rz is independently selected from those depicted in Table 1, below. [0081] In some embodiments, each Rx, is independently halogen, –CN, –NO2, -OR, -SR, - NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, - N(R)S(O)2NR2, -N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy. [0082] In some embodiments, each Rx, is independently halogen, –CN, –NO2, -OR, -SR, - NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, - N(R)S(O)2NR2, -N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group. [0083] In some embodiments, each Rx is independently selected from those depicted in Table 1, below. [0084] In some embodiments, each Ry, is independently halogen, –CN, –NO2, -OR, -SR, - NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, - N(R)S(O)2NR2, -N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy. [0085] In some embodiments, each Ry, is independently halogen, –CN, –NO2, -OR, -SR, - NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, - N(R)S(O)2NR2, -N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group. [0086] In some embodiments, each Ry is independently selected from those depicted in Table 1, below. [0087] In some embodiments, each Rz, is independently halogen, –CN, –NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy. [0088] In some embodiments, each Rz, is independently halogen, –CN, –NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group. [0089] In some embodiments, each Rz is independently selected from those depicted in Table 1, below. [0090] As defined generally above, each Cy is independently an optionally substituted and cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0091] In some embodiments, Cy is an optionally substituted and cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Cy is phenyl. In some embodiments, Cy is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy is a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0092] In some embodiments, each Cy is independently selected from those depicted in Table 1, below. [0093] As described generally above, each R is independently hydrogen, halogen, or an optionally substituted C1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0094] In some embodiments, R is H. In some embodiments, R is halogen, or an optionally substituted C1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0095] In some embodiments, R is halogen. In some embodiments, R is an optionally substituted C1-6 aliphatic group. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0096] In some embodiments, two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0097] In some embodiments, each R is independently selected from those depicted in Table 1, below. [0098] As described generally above, x is 0, 1, 2, 3, or 4. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. [0099] In some embodiments, x is selected from those depicted in Table 1, below. [00100] As described generally above, y is 0, 1, 2, 3, or 4. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. [00101] In some embodiments, y is selected from those depicted in Table 1, below. [00102] As described generally above, z is 0, 1, 2, 3, or 4. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. [00103] In some embodiments, z is selected from those depicted in Table 1, below. [00104] In some embodiments, x, y, and z are 0. In some embodiments, x and y are 0. In some embodiments, x and z are 0. In some embodiments, y and z are 0. [00105] In some embodiments, z is 1 and R1 is methyl. [00106] In one aspect, the compound of Formula I is a compound of Formula Ia:
Figure imgf000032_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, Rx, Ry, Rz, X1, x, y, and z are as defined and described in embodiments herein, both singly and in combination. [00107] In one aspect, the compound of Formula I is a compound of Formula Ia-1:
Figure imgf000032_0002
Ia-1 or a pharmaceutically acceptable salt thereof, wherein Ring B, Rx, Rz, X1, x, and z are as defined and described in embodiments herein, both singly and in combination. In some embodiments, x is 0. In some embodiments, x is 1 and Rx is methyl. In some embodiments, X1 is C. In some embodiments, X1 is N. In some embodiments, Ring
Figure imgf000032_0003
[00108] In one aspect, the compound of Formula I is a compound of Formula Ia-2, Ia-3, or Ia- 4:
Figure imgf000032_0004
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Rx, Ry, X1, x, and y are as defined and described in embodiments herein, both singly and in combination. [00109] In one aspect, the compound of Formula II is a compound of Formula IIa, or IIb:
Figure imgf000033_0002
IIa IIb or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, Rx, Ry, Rz, X1, x, y, and z are as defined and described in embodiments herein, both singly and in combination. [00110] In one aspect, the compound of Formula II is a compound of Formula IIa-1, IIb-1, or IIa-2:
Figure imgf000033_0003
IIa-2 or a pharmaceutically acceptable salt thereof, wherein Ring B, R, Rx, Rz, X1, x, and z are as defined and described in embodiments herein, both singly and in combination. Table 1. Selected Compounds
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
[00111] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1, above. [00112] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound disclosed herein (described in embodiments herein, both singly and in combination), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. For example, in some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV as defined above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV as defined above, together with a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, together with a pharmaceutically acceptable carrier, excipient, or diluent. [00113] In some embodiments, the present invention provides a compound of Formula I, Formula II, Formula III or Formula IV as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament. [00114] In some embodiments, the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for inhibiting HPGD as described herein and/or in a method for treating a HPGD-dependent disorder as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for inhibiting HPGD as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for treating a HPGD-dependent disorder as described herein. [00115] In some embodiments, the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for modulating HPGD as described herein and/or in a method for treating a HPGD-dependent disorder as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for modulating HPGD as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of Formula I, Formula II, Formula III or Formula IV), or pharmaceutical compositions described herein, for use in a method for treating a HPGD-dependent disorder as described herein. 4. General Methods of Providing the Present Compounds [00116] In the Example 1 below, where a particular protecting group (“PG”), leaving group (“LG”), or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5th Edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999. [00117] As used herein, the phrase “leaving group” (LG) includes, but is not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like. [00118] As used herein, the phrase “oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters and ethers. Examples of such ethers include allyl ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p- chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6- trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p- methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2- methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, and 2- and 4-picolyl. [00119] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like. [00120] In certain embodiments, compounds of the present invention are generally prepared according to any one of the schemes in Example 1. 5. Uses, Formulation and Administration Pharmaceutically acceptable compositions [00121] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit HPGD, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. [00122] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human. [00123] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. [00124] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. [00125] As used herein, the term “active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of HPGD, or a mutant thereof. [00126] The subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of compounds of the invention. Metabolites include compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof. If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. [00127] A compound of the invention can be in the form of a “prodrug,” which includes compounds with moieties which can be metabolized in vivo. Generally, the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) “Pharmaceutical Salts,” J. Pharm. Sci. 66:1-19). The prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Prodrugs which are converted to active forms through other mechanisms in vivo are also included. In aspects, the compounds of the invention are prodrugs of any of the formulae herein. [00128] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [00129] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. [00130] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00131] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [00132] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. [00133] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [00134] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. [00135] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [00136] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. [00137] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. [00138] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00139] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food. [00140] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. [00141] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00142] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00143] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00144] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00145] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 and 100 mg/kg, 0.01 and 50 mg/kg, or 1 and 25 mg/kg, body weight/day of the compound can be administered to a patient receiving these compositions. [00146] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition. [00147] Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. Uses of Compounds and Pharmaceutically Acceptable Compositions [00148] The compounds and compositions described herein are generally useful for the inhibition of the activity of HPGD. [00149] The presently disclosed compounds find use in inhibiting the enzyme HPGD. In one embodiment, the subject matter disclosed herein is directed to a method of inhibiting HPGD, the method comprising contacting HPGD with an effective amount of a compound of the invention or a pharmaceutical composition described herein. [00150] The presently disclosed compounds can be used in a method for inhibiting HPGD. Such methods comprise contacting HPGD with an effective amount of a presently disclosed compound. By “contact” is intended bringing the compound within close enough proximity to an isolated HPGD enzyme or a cell expressing HPGD such that the compound is able to bind to and inhibit the HPGD. The compound can be contacted with HPGD in vitro or in vivo via administration of the compound to a subject. [00151] In one aspect, provided herein is a method of inhibiting HPGD in a biological sample. The method comprises contacting the sample with a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. [00152] The present disclosure provides methods of inhibiting HPGD in a patient. The method comprises administering to a patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). [00153] Any method known in the art to measure the dehydrogenase activity of HPGD may be used to determine if HPGD has been inhibited, including in vitro kinase assays, immunoblots with antibodies specific for targets of HPGD, or the measurement of a downstream biological effect of HPGD activity (i.e., prostaglandin levels). [00154] The presently disclosed compounds can be used to treat an HPGD-dependent disorder. As used herein, an “HPGD-dependent disorder” is a pathological condition in which HPGD activity is necessary for the genesis or maintenance of the pathological condition. [00155] Accordingly, in one aspect, provided herein is a method of treating an HPGD-mediated disorder, disease, or condition in a patient. The method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). [00156] Provided herein are compounds and pharmaceutical compositions that inhibit the HPGD enzyme, as well as methods of treatment using such compounds and pharmaceutical compositions. The compounds and compositions can be used in methods of modulating the immune system, for treatment of diseases, and for treatment of cells in vivo, in vitro, or ex vivo. [00157] Provided herein are compounds and compositions that are potent inhibitors of HPGD and can be used in novel approaches to treat diseases or disorders such as wounds, bone formation, bone regrowth, hair loss, inflammatory bowel disease, liver disease, bone marrow transplantation, and muscle atrophy. In some embodiments, the compounds and compositions provided herein can be used in methods of modulating the prostaglandin system. In some embodiments, the present invention provides a compound or pharmaceutically acceptable salt thereof or composition described herein for use in a method of treating wounds, bone formation, bone regrowth, hair loss, inflammatory bowel disease, liver disease, bone marrow transplantation, and muscle atrophy. [00158] Additionally, provided are HPGD inhibitors for use as therapeutic active substances. A HPGD inhibitor for use in treating or preventing a disease or condition associated with HPGD activity is provided. Also, an HPGD inhibitor for use in treating wounds is provided. Further provided is the use of a HPGD inhibitor in the manufacture of a medicament for treating or preventing a disease or condition associated with HPGD activity. Also provided is the use of a HPGD inhibitor in the manufacture of a medicament for treating wounds. [00159] Accordingly, in some embodiments, the HPGD-mediated disorder is a wound. In one aspect, provided herein is a method of treating a wound in a patient. The method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). In some embodiments, the wound is selected from a vascular wound, a neuropathic wound, moisture associated dermatitis, a skin tear, or an ulcer. Assessment of treated wounds is known in those having skill in the art. [00160] In one aspect, provided herein is a method of treating hair loss in a patient. The method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). In some embodiments, the hair loss comprises one or more of Androgenetic Alopecia, Telogen Effluvium, Anagen Effluvium, Alopecia Areata, Tinea Capitis, Cicatricial Alopecia, Hair Shaft Abnormalities, and Hypotrichosis. [00161] In one aspect, provided herein is a method of transplanting bone marrow in a patient in need thereof is provided, comprising administering to the patient a compound of Formula I, Formula II, Formula III, or Formula IV, or a compound of Table 1, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1, or a pharmaceutically acceptable salt thereof, herein. [00162] In one aspect, provided herein is a method of regenerating tissue on existing tissue is provided, comprising contacting the existing tissue with a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1 herein. In some embodiments, the tissue is colon tissue or liver tissue. In some embodiments, the method is in vitro. In some embodiments, the method is in vivo. In some embodiments, the method is ex vivo. [00163] In one aspect, provided herein is a method of treating inflammatory bowel disease in a patient. The method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). [00164] In one aspect, provided herein is a method of treating liver disease disease in a patient. The method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). [00165] In one aspect, provided herein is a method of treating muscle atrophy in a patient. The method comprises administering to said patient a compound disclosed herein (such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). [00166] Presently disclosed compounds may be administered in any suitable manner known in the art. In some embodiments, the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intratumorally, or intranasally. [00167] In some embodiments, the HPGD inhibitor is administered continuously. In other embodiments, the HPGD inhibitor is administered intermittently. Moreover, treatment of a subject with an effective amount of a HPGD inhibitor can include a single treatment or can include a series of treatments. [00168] It is understood that appropriate doses of the active compound depends upon a number of factors within the knowledge of the ordinarily skilled physician or veterinarian. The dose(s) of the active compound will vary, for example, depending upon the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination. [00169] It will also be appreciated that the effective dosage of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays. [00170] In some embodiments, the compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of between about 0.001 μg/kg and about 1000 mg/kg, including but not limited to about 0.001 μg/kg, 0.01 μg/kg, 0.05 μg/kg, 0.1 μg/kg, 0.5 μg/kg, 1 μg/kg, 10 μg/kg, 25 μg/kg, 50 μg/kg, 100 μg/kg, 250 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, 300 mg/kg, 750 mg/kg, and 1000 mg/kg. [00171] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. [00172] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease. [00173] The term “administration" or “administering” includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal. [00174] The term “effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. [00175] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes. [00176] The phrase “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. [00177] The term “subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human. Combination Therapies [00178] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent. [00179] Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. [00180] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. [00181] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. [00182] In one embodiment, the present invention provides a composition comprising a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1, or a compound of Table 1 and one or more additional therapeutic agents. The therapeutic agent may be administered together with a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1, or may be administered prior to or following administration of a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1. Suitable therapeutic agents are described in further detail below. In certain embodiments, a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1 may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a compound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent. [00183] In another embodiment, the present invention provides a method of treating a wound comprising administering to a patient in need thereof a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1 and one or more additional therapeutic agents selected from acetaminophen, salicylic acid, 2-octyl cyanoacrylate, Alevicyn ®, Artiss ®, becaplermin, Betaine/polyhexanide, cadexomer iodine, collagenase, Dermabond ®, Eletone ® cream, Episalvan ®, Evicel ®, fibrin sealant, Filsuvez ®, hypochlorous acid topical, Lodosorb ®, NexoBrid ®, Oleogel-S10, petrolatum & mineral oil topical, Prontosan ®, proteolytic enzymes, Regranex gel ®, Santyl, TachoSil ®, Tisseel VH ®, Tropazone ®, and combinations thereof. [00184] In another embodiment, the present invention provides a method of treating hair loss comprising administering to a patient in need thereof a compound of Formula I, Formula II, Formula III or Formula IV, or a compound of Table 1 and one or more additional therapeutic agents selected from minoxidil, finasteride, spironolactone, dutasteride, an anti-androgen, a corticosteroid, and combinations thereof. [00185] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. [00186] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered. [00187] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 μg/kg body weight/day of the additional therapeutic agent can be administered. [00188] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. [00189] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Patients using stents or other implantable devices wound formation or worsening. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising an HPGD inhibitor disclosed herein. Implantable devices coated with a compound of this invention are another embodiment of the present invention. EXEMPLIFICATION [00190] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Additional compounds of the invention were prepared by methods substantially similar to those described herein in the Examples and methods known to one skilled in the art. Abbreviations Ac: acetyl AcOK: potassium acetate AcOH: acetic acid Ac2O: acetic anhydride ACN: acetonitrile DHP: dihydropyran Ad: adamantly DIBAL-H: diisobutylaluminum hydride AIBN: 2,2'-azo bisisobutyronitrile DIPA: diisopropylamine Anhyd: anhydrous DIPEA or DIEA: N,N- Aq: aqueous diisopropylethylamine B2Pin2: bis (pinacolato)diboron- DMA: N,N-dimethylacetamide 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- DME: 1,2-dimethoxyethane dioxaborolane) DMAP: 4-dimethylaminopyridine BINAP: 2,2'-bis(diphenylphosphino)- DMF: N,N-dimethylformamide 1,1'-binaphthyl DMP: Dess-Martin periodinane BH3: borane DMSO: dimethyl sulfoxide Bn: benzyl DPPA: diphenylphosphoryl azide Boc: tert-butoxycarbonyl dppf: 1,1’- Boc2O: di-tert-butyl dicarbonate bis(diphenylphosphino)ferrocene BPO: benzoyl peroxide EDC or EDCI: 1-(3- BTC: Bis(trichloromethyl)carbonate or dimethylaminopropyl)-3- triphosgene ethylcarbodiimide hydrochloride nBuOH: n-butanol ee: enantiomeric excess CDI: carbonyldiimidazole ESI: electrospray ionization COD: cyclooctadiene EA: ethyl acetate Cy: cyclohexyl EtOAc: ethyl acetate d: days EtOH: ethanol DABCO: 1,4-diazobicyclo[2.2.2]octane FA: formic acid DAST: diethylaminosulfur trifluoride h or hrs: hours dba: dibenzylideneacetone HATU: N,N,N’,N’-tetramethyl-O-(7- DBU: 1,8-diazobicyclo[5.4.0]undec-7- azabenzotriazol-1-yl)uronium ene hexafluorophosphate DCE: 1,2-dichloroethane HCl: hydrochloric acid DCM: dichloromethane HPLC: high performance liquid DEA: diethylamine chromatography HOAc: acetic acid NFSI: N-fluorobenzenesulfonimide IBX: 2-iodoxybenzoic acid NMI: N-methylimidazole IPA: isopropyl alcohol NMO: N-methylmorpholine N-oxide KHMDS: potassium NMP: N-methylpyrrolidine hexamethyldisilazide NMR: Nuclear Magnetic Resonance K2CO3: potassium carbonate °C: degrees Celsius LAH: lithium aluminum hydride o/n: overnight LDA: lithium diisopropylamide Palladacycle G2 (Pd G2): [2-(2'-amino- m-CPBA: meta-chloroperbenzoic acid 1,1'-biphenyl)]palladium chloride M: molar Palladacycle G3 (Pd G3): [2-(2'-amino- MeCN: acetonitrile 1,1'-biphenyl)]palladium MeOH: methanol methanesulfonate Me2S: dimethyl sulfide Pd/C: palladium on Carbon MeONa: sodium methylate Pd(dba)2: palladium MeI: iodomethane bis(dibenzylideneacetone) min: minutes Pd(dtdpf)Cl2: [1,1’-Bis(di-tert- mL: milliliters butylphosphino)ferrocene]dichloro mM: millimolar palladium mmol: millimoles Pd(OAc)2: palladium acetate MPa: mega pascal Pd-PEPPSI-IPent: Dichloro[1,3-bis(2,6- MOMCl: methyl chloromethyl ether Di-3-pentylphenyl)imidazol-2-ylidene](3- MsCl: methanesulfonyl chloride chloropyridyl)palladium(II) MTBE: methyl tert-butyl ether Pd(PPh3)2Cl2: palladium nBuLi: n-butyllithium (bis(triphenylphosphine) dichloride NaNO2: sodium nitrite Pd(PPh3)4: palladium NaOH: sodium hydroxide tetrakis(triphenylphosphine) Na2SO4: sodium sulfate PBS: phosphate buffered saline NBS: N-bromosuccinimide PE: petroleum ether NCS: N-chlorosuccinimide PhMe: toluene NIS: N-iodosuccinimide POCl3: phosphorus oxychloride PPh3: triphenylphosphine TCFH: N,N,N′,N′- PyBOP: (61enzotriazole-1- tetramethylchloroformamidinium yloxy)tripyrrolidinophosphonium hexafluorophosphate hexafluorophosphate TEA: triethylamine Rel: relative Tf: trifluoromethanesulfonate RuPhos: 2-Dicyclohexylphosphino-2′,6′- TfAA, TFMSA or Tf2O: diisopropoxybiphenyl trifluoromethanesulfonic anhydride R.T. or rt: room temperature TFA: trifluoracetic acid sat: saturated TIPS: triisopropylsilyl SEMCl: chloromethyl-2- THF: tetrahydrofuran trimethylsilylethyl ether THP: tetrahydropyran SFC: supercritical fluid chromatography TLC: thin layer chromatography SOCl2: sulfur dichloride TMEDA: tetramethylethylenediamine tBuOK: potassium tert-butoxide T3P: propylphosphonic anhydride TBAB: tetrabutylammonium bromide pTSA: para-toluenesulfonic acid TBAC: 3,3-dimethylbutanoyl chloride TsCl: p-toluenesulfonyl chloride TBAI: tetrabutylammonium iodide wt: weight TBD: Triazabicyclodecene (1,3,4,6,7,8- Xantphos: 4,5-bis(diphenylphosphino)- Hexahydro-2H-pyrimido[1,2- 9,9-dimethylxanthene a]pyrimidine) XPhos: 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl Example 1 - General Synthetic Methods Synthesis of 7-iodo-2-methyl- [1,2,4] triazolo[4,3-a] pyridin-3-one (Intermediate A)
Figure imgf000063_0001
[00191] To a stirred solution of 2-fluoro-4-iodopyridine (50 g, 224 mmol, 1.0 equiv) in EtOH (300 mL) was added hydrazine hydrate (125 mL, 80% in water) at room temperature. The resulting mixture was stirred at 80 °C for 1 h, and then was allowed to cool down to 0 °C. The precipitated solids were collected by filtration and washed with EtOH to afford (2Z)-2-hydrazinylidene-4-iodo- 1H-pyridine (Int A.1, 25 g, 47% yield) as an off white solid. MS (ES): m/z 236 [M+H]+. Synthesis of Int A.2. [00192] A mixture of Int A.1 (13.8 g, 58.7 mmol, 1.0 equiv) and CDI (15.0 g, 92.5 mmol, 1.58 equiv) in CH3CN (200 mL) was stirred for 2 h at 60 °C. The mixture was allowed to cool down to 0 °C. The precipitated solids were collected by filtration and washed with CH3CN to afford 7- iodo-2H- [1,2,4] triazolo[4,3-a] pyridin-3-one (Int A.2, 14.9 g, 97% yield) as an off white solid. MS (ES): m/z 262 [M+H]+. Synthesis of Int A. [00193] To a mixture of Int A.2 (13.2 g, 50.6 mmol, 1.0 equiv), Cs2CO3 (33.0 g, 101 mmol, 2.0 equiv) and DMF (200 mL) was added CH3I (21.5 g, 152 mmol, 3.00 equiv) at room temperature. The resulting mixture stirred for 1 h at room temperature, and then was diluted with water (100 mL). The reaction mixture was sonication with an ultrasonic cleaner. The solids were collected by filtration, washed with water and dried to afford 7-iodo-2-methyl- [1,2,4] triazolo[4,3-a] pyridin- 3-one (Int A, 7 g, 50% yield) as a light brown solid. MS (ES): m/z 276 [M+H]+. Synthesis of 7-bromo-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Intermediate B)
Figure imgf000064_0001
Synthesis of Int B. [00194] Int B was synthesized from 7-bromo-2H- [1,2,4] triazolo[4,3-a] pyridin-3-one and CH3I using an analogous procedure to that described for Int A. MS (ES): m/z 228/230 [M+H]+. Synthesis of 7-(7-(4,4-difluoropiperidine-1-carbonyl)-2H-chromen-4-yl)-2-methyl-
Figure imgf000065_0001
Synthesis of 3.1. [00195] To a mixture of 7-bromo-2,3-dihydro-1-benzopyran-4-one (1.50 g, 6.61 mmol, 1.0 equiv), Ac2O (1.01 g, 9.91 mmol, 1.5 equiv), DIEA (1.28 g, 9.91 mmol, 1.5 equiv), HCOOLi (514 mg, 9.89 mmol, 1.5 equiv), dppf (182 mg, 0.33 mmol, 0.05 equiv) and DMF (15 mL) was added Pd(OAc)2 (74 mg, 0.33 mmol, 0.05 equiv) at room temperature. The mixture was degassed three times with vacuum and nitrogen, and then was stirred for 16 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, filtered and the filtrate was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 8 mmol/L NH4HCO3) and B: CH3CN; Gradient: 0% to 70% B in 50 min; Detector, UV 254 nm) to afford 4-oxo-2,3-dihydro-1-benzopyran-7-carboxylic acid (3.1, 1.2 g, 94% yield) as a little yellow solid. MS (ES): m/z 191 [M-H]-. Synthesis of 3.2. [00196] To a stirred mixture of 3.1 (320 mg, 1.665 mmol, 1.0 equiv) and 4,4-difluoropiperidine (201 mg, 1.65 mmol, 1.0 equiv) in acetonitrile (3 mL) were added 1-methylimidazole (NMI, 410 mg, 4.99 mmol, 3.0 equiv) and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCHF, 560 mg, 2.00 mmol, 1.2 equiv) at room temperature. The mixture was stirred for 30 min at room temperature. The resulting mixture was filtered, the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 8 mmol/L NH4HCO3) and B: acetonitrile; Gradient: 0% to 100% B in 40 min; Detector: UV 254 nm) to afford 7-(4,4-difluoropiperidine-1-carbonyl)-2,3-dihydro-1-benzopyran-4-one (3.2, 110 mg, 22% yield) as a brown solid. MS (ES): m/z 296 [M+H]+. Synthesis of 3.3. [00197] 3.2 (400 mg, 1.35 mmol, 1.0 equiv) was added to a solution of 4-toluenesulfonyl hydrazide (252 mg, 1.35 mmol, 1.0 equiv) in methanol (8 mL). After stirring for 16 h at 80 °C, the resulting mixture was allowed to cool down to room temperature. The solids were collected by filtration and washed with CH3CN to afford N'-[(4E)-7-(4,4-difluoropiperidine-1-carbonyl)-2,3- dihydro-1-benzopyran-4-ylidene]-4-methylbenzenesulfonohydrazide (3.3, 560 mg, 89% yield) as a light yellow solid. MS (ES): m/z 464 [M+H]+. Synthesis of I-1. [00198] To a mixture of 3.3 (50 mg, 0.108 mmol, 1.0 equiv), Int B (30 mg, 0.130 mmol, 1.2 equiv), Cs2CO3 (70 mg, 0.216 mmol, 2.0 equiv) and dioxane (5 mL) were added (Ph2P)2-ferrocene (6 mg, 0.011 mmol, 0.1 equiv) and PdCl2(CH3CN)2 (8 mg, 0.022 mmol, 0.2 equiv) at room temperature. The mixture was degassed three times with vacuum and nitrogen and then was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was cooled to room temperature, filtered, the filter cake was washed with dioxane. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 3/1) to afford a crude product. The crude product was further purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 30% to 40% B in 8 min, 40% B; Wave Length: 254/220 nm). The product-containing fractions were collected, combined and concentrated under vacuum to remove most of the solvent. The residue was lyophilized to afford 7-[7-(4,4-difluoropiperidine-1-carbonyl)-2H-chromen-4-yl]-2-methyl- [1,2,4]triazolo[4,3-a]pyridin-3-one (I-1, 20 mg, 43% yield) as a yellow solid. MS (ES): m/z 427 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 7.89 (d, J=7.5 Hz, 1H), 7.21 (s, 1H), 7.10 - 6.97 (m, 3H), 6.53 (d, J = 7.2 Hz, 1H), 6.22 (t, J = 3.3 Hz, 1H), 4.89 (d, J = 3.6 Hz, 2H), 3.80 - 3.39 (m, 7H), 2.11 - 1.99 (m, 4H). Synthesis of 7-[7-(4,4-difluoropiperidine-1-carbonyl)-3-methyl-2H-chromen-4-yl]-2-
Figure imgf000067_0001
Synthesis of 4.1. [00199] A mixture of 4-bromo-2-hydroxybenzaldehyde (4.0 g, 19.9 mmol, 1.0 equiv) and Cs2CO3 (19.5 g, 59.7 mmol, 3.0 equiv) in acetonitrile (60 mL) was stirred for 30 min at room temperature. Then, allyl bromide (4.81 g, 39.8 mmol, 2.0 equiv) was added to the above mixture. The resulting mixture was stirred at 60 °C for 3 h. The mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (0.05% FA) and B: acetonitrile; Gradient: 50% to 81%B in 8 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford 4-bromo-2-(prop-2-en-1-yloxy)benzaldehyde (4.1, 4.40 g, 92% yield) as a white solid. MS (ES): m/z 241/243 [M+H]+. Synthesis of 4.2. [00200] To a solution of 4.1 (2.00 g, 8.29 mmol, 1.0 equiv) in THF (20 mL) was added 3-(2,4,6- trimethylphenyl)-4H,5H,6H,7H,8H-3lambda5-cyclohepta[d][1,3]thiazol-3-ylium perchlorate (617 mg, 1.66 mmol, 0.2 equiv). The mixture was degassed three times with vacuum and nitrogen. DBU (505 mg, 3.32 mmol, 0.4 equiv) was added to the above mixture. After stirring overnight at 80 °C under nitrogen atmosphere, the mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with petroleum ether /ethyl acetate= 5/1). The collected fractions were concentrated under vacuum to afford 7-bromo-3-methyl-2,3-dihydro-1-benzopyran-4-one (4.2, 1.35 g, 67% yield) as a yellow solid. MS (ES): m/z 241/243 [M+H]+. Synthesis of 4.3. [00201] To a mixture of 4.2 (1.35 g, 5.60 mmol, 1.0 equiv), dppf (155 mg, 0.280 mmol, 0.05 equiv), lithium formate (436 mg, 8.40 mmol, 1.5 equiv), Ac2O (858 mg, 8.40 mmol, 1.5 equiv), DIEA (1.09 g, 8.40 mmol, 1.5 equiv) and DMF (15 mL) was added Pd(OAc)2 (63 mg, 0.28 mmol, 0.05 equiv) at room temperature. The mixture was degassed three times with nitrogen and vacuum. After stirring overnight at 100 °C under nitrogen atmosphere, the mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (0.05% FA) and B: acetonitrile; Gradient: 0% to 34%B in 10 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford 3-methyl-4-oxo-2,3-dihydro-1-benzopyran-7-carboxylic acid (4.3, 680 mg, 59% yield) as a light brown solid. MS (ES): m/z 205 [M-H]-. Synthesis of 4.4. [00202] To a stirred mixture of 4.3 (680 mg, 3.30 mmol, 1.0 equiv), 4,4-difluoropiperidine (399 mg, 3.30 mmol, 1.0 equiv) and NMI (1.08 g, 13.2 mmol, 4.0 equiv) in acetonitrile (6 mL) was added TCFH (1.85 g, 6.60 mmol, 2.0 equiv). After stirring at room temperature for 2 h, the mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (6 mmol/L NH4HCO3) and B: acetonitrile; Gradient: 0% to 52%B in 11 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford 7-(4,4-difluoropiperidine-1-carbonyl)-3-methyl-2,3- dihydro-1-benzopyran-4-one (4.4, 830 mg, 81% yield) as a brown oil. MS (ES): m/z 310 [M+H]+. Synthesis of 4.5. [00203] To a solution of 4-toluenesulfonyl hydrazide (500 mg, 2.68 mmol, 1.0 equiv) in MeOH (5 mL) was added a solution of 4.4 (830 mg, 2.68 mmol, 1.0 equiv) in MeOH (16 mL) at room temperature. After stirring at 80 °C overnight, the mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with MeOH. The filtrate was concentrated under reduce pressure and purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (0.05% FA) and B: acetonitrile; Gradient: 0% to 58% B in 13 min; Detector: UV 254/220 nm). The collected fraction and were concentrated under vacuum, and combined with the precipitated solids to afford N'-[(4E)-7-(4,4-difluoropiperidine-1- carbonyl)-3-methyl-2,3-dihydro-1-benzopyran-4-ylidene]-4-methylbenzenesulfonohydrazide (4.5, 890 mg, 69% yield) as an off-white solid. MS (ES): m/z 478 [M+H]+. Synthesis of I-9. [00204] To a mixture of 4.5 (350 mg, 0.73 mmol, 1.0 equiv), Int A (202 mg, 0.73 mmol, 1.0 equiv), t-BuOLi (141 mg, 2.20 mmol, 3.0 equiv) and 1,4-dioxane (5 mL) were added XPhos (280 mg, 0.59 mmol, 0.8 equiv) and Pd2(dba)3 (268 mg, 0.29 mmol, 0.40 equiv) at room temperature. The mixture was degassed three times with vacuum and nitrogen. After stirring overnight at 80 °C under a nitrogen atmosphere, the mixture was allowed to cool down to room temperature. The mixture was then filtered, the filter cake was washed with MeOH and the filtrate was concentrated under reduced pressure. The residue was purified firstly by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (6 mmol/L NH4HCO3) and B: CH3CN; Gradient: 0% to 42% B in 9 min; Detector: UV 254/220 nm). The product containing fractions were concentrated under vacuum to give 50 mg crude product. The crude product was re-purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3 + 0.1% NH3 .H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 22% to 52% B in 8 min, hold 52% B in 3 min; Wave Length: 254/210 nm; RT1(min): 7.21). The product-containing fractions were concentrated under vacuum to remove most of the solvent. The residue was then lyophilized overnight to afford 7-[7-(4,4-difluoropiperidine-1- carbonyl)-3-methyl-2H-chromen-4-yl]-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-one (I-9, 21 mg, 6% yield) as a light yellow solid. MS (ES): m/z 441 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.93 - 7.91 (m, 1H), 7.11 (s, 1H), 6.90 - 6.87 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H), 6.38 - 6.36 (m, 1H), 4.83 (s, 2H), 3.80 - 3.42 (m, 7H), 2.12-1.99 (m, 4H), 1.72 (s, 3H). Synthesis of 7-[7-(4,4-difluoropiperidine-1-carbonyl)-2H-pyrano[3,2-b]pyridin-4-yl]-2- methyl-[1,2,4]triazolo[4,3-a]pyridin-3-one (I-14)
Figure imgf000070_0001
Synthesis of 15.1. [00205] To a stirred mixture of methyl 5-hydroxypyridine-3-carboxylate (7.00 g, 45.7 mmol, 1.0 equiv) in water (5 mL) was added NaOCl aqueous (37 mL, chlorinity 8%) dropwise at 10 °C. The reaction mixture was stirred at 10 °C for 1 h until the mixture turned to clear.4 M HCl (20 mL, aqueous) was then added dropwise and the mixture was stirred for another 1 h at 10 °C. The solids were collected by filtration and washed with water. The solid was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (0.05% FA) and B: CH3CN; Gradient: 0% to 31% B in 10 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford methyl 6-chloro-5-hydroxypyridine-3-carboxylate (15.1, 3.0 g, 35% yield) as an off-white solid. MS (ES): m/z 186/188 [M-H]-. Synthesis of 15.2. [00206] A mixture of 15.1 (3.8 g, 20.6 mmol, 1.0 equiv) and Cs2CO3 (19.8 g, 60.8 mmol, 3.0 equiv) in CH3CN (75 mL) was stirred for 30 min at room temperature.4-Bromo-1-butene (5.47 g, 40.5 mmol, 2.0 equiv) was then added and the resulting mixture was stirred at 60 °C for 4 h. The mixture was allowed to cool down to room temperature, was then filtered, the filter cake was washed with CH3CN. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (0.05% FA) and B: CH3CN; Gradient: 30% to 75% B in 10 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford methyl 5-(but-3-en-1-yloxy)-6- chloropyridine-3-carboxylate (15.2, 4.20 g, 82% yield) as a yellow oil. MS (ES): m/z 242/244 [M+H]+. Synthesis of 15.3. [00207] A mixture of PPh3 (1.30 g, 4.97 mmol, 0.3 equiv), KOAc (8.12 g, 82.8 mmol, 5.0 equiv), 3,3-dimethylbutanoyl chloride (4.46 g, 33.1 mmol, 2.0 equiv) and Pd(OAc)2 (372 mg, 1.66 mmol, 0.1 equiv) was degassed three times with vacuum and nitrogen. A solution of 15.2 (4.00 g, 16.6 mmol, 1.0 equiv) in anhydrous DMF (40 mL) was added. The mixture was degassed three times with vacuum and nitrogen nitrogen, and then was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature and diluted with water (250 mL), then extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (0.05% FA) and B: CH3CN; Gradient: 10% to 56% B in 10 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford methyl 4-methylidene-2H,3H-pyrano[3,2- b]pyridine-7-carboxylate (15.3, 2.50 g, 74% yield) as a reddish brown solid. MS (ES): m/z 206 [M+H]+. Synthesis of 15.4. [00208] A mixture of 15.3 (540 mg, 2.63 mmol, 1.0 equiv) and 1,3,4,6,7,8-Hexahydro-2H- pyrimido[1,2-a]pyrimidine (366 mg, 2.63 mmol, 1.0 equiv) in 4,4-difluoropiperidine (1.5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate = 3/2). The desired fractions were concentrated under vacuum to afford 4,4-difluoro-1-{4- methylidene-2H,3H-pyrano[3,2-b]pyridine-7-carbonyl}piperidine (15.4, 410 mg, 53% yield) as a light yellow oil. MS (ES): m/z 295 [M+H]+. Synthesis of 15.5. [00209] To a solution of 15.4 (410 mg, 1.39 mmol, 1.0 equiv) in 1,4-dioxane (4.92 mL) was added a solution of K2OsO4 .2H2O (51 mg, 0.14 mmol, 0.1 equiv) and 2-hydroxypropane-1,2,3- tricarboxylic acid (535 mg, 2.79 mmol, 2.0 equiv) in H2O (0.82 mL), followed by the addition of 4-methylmorpholine N-oxide (490 mg, 4.18 mmol, 3.0 equiv). The mixture was stirred at room temperature until the starting material was consumed completely, and then NaIO4 (596 mg, 2.79 mmol, 2.0 equiv) was added, and stirred at room temperature until the intermediate was converted to the desired product. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (0.05% FA) and B: CH3CN; Gradient: 0% to 34% B in 10 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford 7-(4,4-difluoropiperidine-1-carbonyl)-2H,3H-pyrano[3,2- b]pyridin-4-one (15.5, 230 mg, 56% yield) as a brown oil. MS (ES): m/z 297 [M+H]+. Synthesis of 15.6. [00210] To a solution of 4-toluenesulfonyl hydrazide (217 mg, 1.16 mmol, 1.5 equiv) in MeOH (1 mL) was added a solution of 15.5 (230 mg, 0.78 mmol, 1.0 equiv) in MeOH (3 mL) at room temperature. The resulting mixture was stirred for 3 h at 80 °C. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1). The desired fractions were concentrated under vacuum to afford N'-[(4E)-7-(4,4-difluoropiperidine-1-carbonyl)-2H,3H- pyrano[3,2-b]pyridin-4-ylidene]-4-methylbenzenesulfonohydrazide (15.6, 250 mg, 69% yield) as a white solid. MS (ES): m/z 465 [M+H]+. Synthesis of I-14. [00211] To a mixture of 15.6 (230 mg, 0.50 mmol, 1.0 equiv) and Int A (163 mg, 0.59 mmol, 1.2 equiv) in 1,4-dioxane (4.7 mL) was added K3PO4 (210 mg, 0.99 mmol, 2.0 equiv) and Pd(PCy3)2Cl2 (37mg, 0.05 mmol, 0.1 equiv) at room temperature. The mixture was degassed three times with vacuum and nitrogen. After stirring for 5 h at 90 °C under a nitrogen atmosphere, the mixture was allowed to cool down to room temperature, filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified firstly by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (10 mmol/L NH4HCO3) and B: CH3CN; Gradient: 0% to 34% B in 10 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford the crude product (16 mg). The crude product was further purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3 + 0.1% NH3 .H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 17% to 47% B in 7 min, hold 47% B in 3 min; Wave Length: 210/254 nm; RT1(min): 6.23). The product-containing fraction was collected and concentrated under vacuum to remove most of solvent, and then lyophilized overnight to afford 7- [7-(4,4-difluoropiperidine-1-carbonyl)-2H-pyrano[3,2-b]pyridin-4-yl]-2-methyl- [1,2,4]triazolo[4,3-a]pyridin-3-one (I-14, 8.9 mg, 4% yield) as a light yellow solid. MS (ES): m/z 428 [M+H]+ .1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.61 - 6.59 (m, 1H), 5.05 (d, J = 3.6 Hz, 2H), 3.80-3.60 (m, 2H), 3.55 (s, 3H), 3.50 - 3.33 (m, 2H), 2.12-1.99 (m, 4H). Synthesis of 1-[4-(4,4-difluoropiperidine-1-carbonyl) phenyl]-2,3-dihydroindole-5- carbonitrile (I-18)
Figure imgf000074_0001
Synthesis of 8.1. [00212] To a stirred mixture of 4-bromobenzoic acid (5.00 g, 24.9 mmol, 1.0 equiv) and 4,4- difluoropiperidine (3.01 g, 24.9 mmol, 1.0 equiv) in acetonitrile (50 mL) were added NMI (4.08 g, 49.8 mmol, 2.0 equiv) and TCFH (14.0 g, 49.8 mmol, 2.0 equiv) in portions at room temperature. After stirring overnight at room temperature, the resulting mixture was poured into water (250 mL), extracted with DCM (3 x 200 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford 1-(4-bromo-3- methylbenzoyl)-4,4-difluoropiperidine (8.1, 5.0 g, 66% yield) as a white solid. MS (ES): m/z 304/306 [M+H]+. Synthesis of I-18. [00213] To a mixture of 8.1 (200 mg, 0.66 mmol, 1.0 equiv), 2,3-dihydro-1H-indole-5- carbonitrile (94 mg, 0.66 mmol, 1.0 equiv), Cs2CO3 (428 mg, 1.32 mmol, 2.0 equiv) and 1,4- dioxane (3 mL) was added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (55 mg, 0.07 mmol, 0.1 equiv) at room temperature. The mixture was degassed three times with nitrogen and vacuum. After stirring at 90 °C for 2 h under nitrogen atmosphere, the mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with acetonitrile, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN; Gradient: 5% to 100% B in 25 min; Detector, UV 254/220 nm). The product-containing fractions were collected and concentrated under vacuum to remove most of the solvent, and then lyophilized overnight to afford 1-[4-(4,4-difluoropiperidine-1- carbonyl) phenyl]-2,3-dihydroindole-5-carbonitrile (I-18, 30 mg, 12% yield) as a white solid. MS (ES): m/z 368 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.56 - 7.49 (m, 4H), 7.35 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.0 Hz, 1H), 4.10 (t, J = 8.4 Hz, 2H), 3.70 - 5.58 (m, 4H), 3.16 (t, J = 8.4 Hz, 2H), 2.09 - 2.01 (m,4H). Synthesis of 1-methyl-3-(1,2-oxazol-4-yl)-4-{[4-(piperidine-1- carbonyl)phenyl]methoxy}pyridin-2-one (I-20)
Figure imgf000075_0001
Synthesis of 12.1. [00214] To a stirred mixture of p-hydroxymethyl benzoic acid (20.0 g, 131 mmol, 1.0 equiv), NMI (43.2 g, 526 mmol, 4.0 equiv) and piperidine (13.4 g, 158 mmol, 1.2 equiv) in acetonitrile (200 mL) was added TCFH (73.8 g, 263 mmol, 2.0 equiv) in portions at room temperature. After stirring for 4 h at room temperature, the reaction was poured into water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford [4- (piperidine-1-carbonyl) phenyl] methanol (12.1, 20 g, 69% yield) as a yellow solid. MS (ES): m/z 220[M+H]+. Synthesis of 12.2 and 12.2A. [00215] To a stirred solution of TEA (18.5 g, 182 mmol, 2.0 equiv) and 12.1 (20.0 g, 91.2 mmol, 1.0 equiv) in DCM (200 mL) was added TsCl (26.1 g, 137 mmol, 1.5 equiv) in portions at room temperature. After stirring for 2 h at room temperature, the resulting mixture was concentrated under vacuum, the residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate 3/1) to afford [4-(piperidine-1-carbonyl) phenyl] methyl 4- methylbenzenesulfonate (12.2, 10.0 g, 29% yield) as a white solid and 1-[4-(chloromethyl) benzoyl] piperidine (12.2A, 8.4 g, 39% yield) as a white solid.12.2: MS (ES): m/z 374 [M+H]+. 12.2A: MS (ES): m/z 238/240 [M+H]+. Synthesis of 12.3. [00216] To a stirred mixture of 4-hydroxy-1-methylpyridin-2-one (500 mg, 4.00 mmol, 1.0 equiv) and 12.2 (1.49 g, 4.00 mmol, 1.0 equiv) in CH3CN (10 mL) was added Cs2CO3 (2.60 g, 8.00 mmol, 2.0 equiv) at room temperature. After stirring at 60ºC for 1 h, the mixture was allowed to cool down to room temperature. The mixture was filtered, the filter cake was washed with CH3CN, the filtrate was concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (containing 0.05% FA) and B: CH3CN; Gradient: 0% to 35% B in 12 min; Detector: 254/220 nm). The desired fractions were concentrated under vacuum to afford 1-methyl-4-{[4-(piperidine-1- carbonyl)phenyl]methoxy}pyridin-2-one (12.3, 420 mg, 32% yield) as a light yellow solid. MS (ES): m/z 327 [M+H]+. Synthesis of 12.4. [00217] To a stirred mixture of 12.3 (400 mg, 1.23 mmol, 1.0 equiv) in acetonitrile (4 mL) was added NIS (414 mg, 1.84 mmol, 1.5 equiv) at room temperature. After stirring at room temperature for 1.5 h, the resulting mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (containing 0.05% FA) and B: CH3CN; Gradient: 0% to 45% B in 13 min; Detector: 254/220 nm). The desired fractions were concentrated under vacuum to afford 3-iodo-1-methyl-4-{[4-(piperidine-1- carbonyl)phenyl]methoxy}pyridin-2-one (12.4, 440 mg, 79% yield) as a yellow oil. MS (ES): m/z 453 [M+H]+. Synthesis of I-20. [00218] To a mixture of 12.4 (250 mg, 0.55 mmol, 1.0 equiv), 1,2-oxazol-4-ylboronic acid (125 mg, 1.11 mmol, 2.0 equiv) and K2CO3 (229 mg, 1.66 mmol, 3.0 equiv) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2CH2Cl2 (45 mg, 0.055 mmol, 0.1 equiv) at room temperature. The mixture was degassed three times with nitrogen and vacuum. After stirring for 4 h at 90 °C under a nitrogen atmosphere, the resulting mixture was allowed to cool down to room temperature. The mixture was poured into water (20 mL), extracted with DCM (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (containing 0.05% FA) and B: CH3CN; Gradient: 0% to 42% B in 12 min; Detector: 254/220 nm) to afford 140 mg crude product, which was further purified by Prep-HPLC (Column: SunFire Prep C18 OBD Column, 19 x 150 mm, 5 μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min; Gradient: 40% to 60% B in 5.8 min, hold 60% B in 5 min; Wave Length: 254/210 nm; RT1(min): 5.58). The product-containing fractions were collected and concentrated under vacuum to remove most of the solvent, and then lyophilized overnight to afford 1-methyl-3-(1,2-oxazol-4-yl)-4-{[4-(piperidine-1-carbonyl)phenyl]methoxy}pyridin-2-one (I-20, 71 mg, 32% yield) as a white solid. MS (ES): m/z 394 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.14 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 6.50 (d, J = 7.6 Hz, 1H), 5.44 (s, 2H), 3.59 - 3.55 (m, 2H), 3.48 (s, 3H), 3.28 -3.24 (m, 2H), 1.61 - 1.46 (m, 6H). Synthesis of 7-{[4-(4,4-difluoropiperidine-1-carbonyl)phenyl](methyl)amino}-2-methyl- [1,2,4]triazolo[4,3-a]pyridin-3-one (I-3)
Figure imgf000078_0001
Synthesis of 17.1. [00219] To a stirred solution of N-methyl-4-aminobenzoate (200 mg, 1.32 mmol, 1.0 equiv) and 4,4-difluoropiperidine (192 mg, 1.59 mmol, 1.2 equiv) in DMF (6 mL) was added HATU (1.00 g, 2.65 mmol, 2.0 equiv) and DIEA (683 mg, 5.29 mmol, 4.0 equiv) at room temperature. After stirring for 20 h at room temperature, the resulting mixture was poured into water (20 mL), extracted with ethyl acetate (5 x 20 mL), the combined organic layer was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Prep-TLC (petroleum ether /ethyl acetate = 1:1) to afford 4-(4,4- difluoropiperidine-1-carbonyl)-N-methylaniline (17.1, 150 mg, 44% yield) as a yellow oil. MS (ES): m/z 255 [M+H]+. Synthesis of I-3. [00220] To a stirred solution of 17.1 (100 mg, 0.39 mmol, 1.0 equiv) and Int B (90 mg, 0.39 mmol, 1.0 equiv) in toluene (5 mL) was added Pd2(dba)3 (36 mg, 0.04 mmol, 0.1 equiv), Xantphos (45 mg, 0.08 mmol, 0.2 equiv) and t-BuONa (75 mg, 0.79 mmol, 2.0 equiv) at room temperature. The resulting mixture was degassed three times with nitrogen/vacuum, and then was stirred for 2 h at 90 °C. The resulting mixture was allowed to cool down to room temperature, filtered and concentrated under vacuum. The residue was purified by Prep-TLC (petroleum ether / ethyl acetate = 1:1) to afford a crude product, which was further purified by Prep-HPLC (Column: XBridge BEH C18 OBD Prep Column, 19 x 250 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3) and B: acetonitrile; Flow rate: 25 mL/min; Gradient: 53% to 65% B in 6 min, 65% B; Wave Length: 254 nm). The product-containing fractions were combined and evaporated partially in vacuum and lyophilized overnight to afford 7-{[4-(4,4-difluoropiperidine-1- carbonyl)phenyl](methyl)amino}-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-one (I-3, 35 mg, 22% yield) as a white solid. MS (ES): m/z 402 [M+H]+.
Figure imgf000079_0001
(400 MHz, DMSO-d6) δ 7.62 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.27 (s, 1H), 6.15 (d, J = 7.6 Hz, 1H), 3.80 - 3.49 (m, 4H), 3.44 (s, 3H), 3.33 (s, 3H), 2.11 - 1.98 (m, 4H). Synthesis of 5-(2-{[4-(piperidine-1-carbonyl) phenyl] methoxy} phenyl) pyrimidin-2- amine (I-46)
Figure imgf000079_0002
Synthesis of 18.1. [00221] To a stirred mixture of 12.2A (7.00 g, 29.5 mmol, 1.0 equiv) and 2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (7.78 g, 35.3 mmol, 1.2 equiv) in DMSO (70 mL) were added NaI (441 mg, 2.95 mmol, 0.1 equiv) and Cs2CO3 (19.2 g, 58.9 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred overnight at 60 °C. The resulting mixture was filtered; the filter cake was washed with ethyl acetate. The filtrate was poured into water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN; Gradient: 5% to 95% B in 30 min; Detector: 254/220 nm). The product-containing fractions were combined and concentrated under vacuum to afford (2-((4-(piperidine-1-carbonyl)benzyl)oxy)phenyl)boronic acid (18.1, 4.0 g, 32% yield) as a white solid. MS (ES): m/z 340 [M+H]+. Synthesis of I-46. [00222] To a mixture of 18.1 (300 mg, 0.88 mmol, 1.0 equiv), 5-bromopyrimidin-2-amine (154 mg, 0.88 mmol, 1.0 equiv), Na2CO3 (281 mg, 2.65 mmol, 3.0 equiv), dioxane (5 mL) and water (0.5 mL) was added Pd(dppf)Cl2 CH2Cl2 (72 mg, 0.09 mmol, 0.1 equiv) at room temperature. The mixture was degassed three times with nitrogen and vacuum. After stirring at 90 °C for 2 h under nitrogen atmosphere, the mixture was allowed to cool down to room temperature. The resulting mixture was poured into water (20 mL), the organics were extracted with DCM (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN; Gradient: 5% to 95% B in 30 min; Detector: 254/220 nm). The desired fractions were concentrated under vacuum to remove most of the solvent, and then lyophilized for overnight to afford 5-(2-{[4-(piperidine-1- carbonyl) phenyl] methoxy} phenyl) pyrimidin-2-amine (I-46, 40 mg, 12% yield) as a white solid. MS (ES): m/z 389 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 2H), 7.55 - 7.53 (m, 2H), 7.47 - 7.31 (m, 4H), 7.27-7.19 (m, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.70 (s, 2H), 5.18 (s, 2H), 3.63 - 3.51 (m, 2H), 3.29 - 3.21 (m, 2H), 1.61 - 1.47 (m, 6H). [00223] The following compounds were synthesized from 18.1 using the analogous procedure as described for compound I-46.
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0002
Synthesis of 4-[6-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,5-a]pyridin-1- yl]benzonitrile (I-35)
Figure imgf000086_0001
[00224] A solution of methyl imidazo[1,5-a]pyridine-6-carboxylate (500 mg, 2.84 mmol, 1.0 equiv) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (790 mg, 5.68 mmol, 2.0 equiv) in 4,4- difluoropiperidine (6.25 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (0.05% FA) and B: ACN; Gradient: 0% to 24%B in 8 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford 4,4-difluoro-1-{imidazo[1,5-a]pyridine-6-carbonyl}piperidine (20.1, 680 mg, 90% yield) as a black oil. MS (ES): m/z 266 [M+H]+. Synthesis of 20.2. [00225] A solution of 20.1 (200 mg, 0.754 mmol, 1.0 equiv) and N-iodosuccinimide (187 mg, 0.829 mmol, 1.1 equiv) in DMF (4.0 mL) was stirred for 1 h at room temperature. The mixture was diluted with water (0.2 mL) and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (0.05% FA) and B: CH3CN; Gradient: 0% to 51%B in 20 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford 4,4-difluoro-1-{1-iodoimidazo[1,5- a]pyridine-6-carbonyl}piperidine (20.2, 110 mg, 37% yield) as a yellow oil. MS (ES): m/z 392 [M+H]+. Synthesis of I-35. [00226] To a mixture of 20.2 (90 mg, 0.230 mmol, 1.0 equiv) and 4-cyanophenylboronic acid (108 mg, 0.736 mmol, 3.2 equiv) in 1,4-dioxane (1.8 mL) and H2O (0.18 mL) were added Cs2CO3 (127 mg, 0.391 mmol, 1.7 equiv). Pd(dppf)Cl2 .CH2Cl2 (19 mg, 0.023 mmol, 0.1 equiv) was finally added to the above reaction mixture. The mixture was degassed three times with vacuum and nitrogen. After stirring for 3 h at 90 °C under a nitrogen atmosphere, the mixture was allowed to cool down to room temperature and filtered. The filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (6 mmol/L NH4HCO3) and B: CH3CN; Gradient: 0% to 37%B in 15 min; Detector: UV 254/220 nm). The desired fractions were concentrated under vacuum to afford crude product (58 mg). This crude product was further purified by Prep-HPLC (Column: SunFire Prep C18 OBD Column, 19 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 60% B in 5.3 min, hold 60% B in 3 min; Wave Length: 210/254 nm). The product- containing fractions were combined and concentrated under vacuum to remove most of the solvent, and then lyophilized overnight to afford 4-[6-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,5- a]pyridin-1-yl]benzonitrile (I-35, 11 mg, 13% yield) as a yellow solid. MS (ES): m/z 367 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.61 (s, 1H), 8.15 – 8.10 (m, 3H), 7.88 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 9.2 Hz, 1H), 3.68 – 3.64 (m, 4H), 2.13 – 2.08 (m, 4H). Synthesis of 4-[7-(4,4-difluoropiperidine-1-carbonyl) imidazo[1,2-b] pyridazin-3-yl] benzonitrile (I-52)
Figure imgf000088_0001
Synthesis of 21.1. [00227] To a stirred mixture of diphenylmethanimine (26.8 g, 148 mmol, 1.0 equiv) in dioxane (220 mL) were added 3,5-dichloropyridazine (22.0 g, 148 mmol, 1.0 equiv), Cs2CO3 (145 g, 443 mmol, 3.0 equiv), XantPhos (8.60 g, 14.8 mmol, 0.1 equiv) and Pd2(dba)3 (6.80 g, 7.38 mmol, 0.05 equiv) at room temperature. The resulting mixture was degassed three times with nitrogen and vacuum. The mixture was stirred for 16 h at 90 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature, filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford N-(5-chloropyridazin-3-yl)-1,1-diphenylmethanimine (21.1, 15.4 g, 35% yield) as an off-white solid. MS (ES): m/z 294 [M+H]+. Synthesis of 21.2. [00228] To a stirred mixture of 21.1 (15.9 g, 54.0 mmol, 1.0 equiv) in tetrahydrofuran (252 mL) was added aqueous HCl (126 mL, 2M) dropwise at room temperature. After stirring for 2 h at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 8mmol/L NH4HCO3) and B: CH3CN; Gradient: 0% to 100% B in 40 min; Detector, UV 254 nm) to afford 5-chloropyridazin-3-amine (21.2, 6.87 g, 98% yield) as a brown solid. MS (ES): m/z 130 [M+H] +. Synthesis of 21.3. [00229] Chloroacetaldehyde (50.0 g, 636 mmol, 12.0 equiv) was added to a mixture of 21.2 (6.90 g, 53.0 mmol, 1.0 equiv) and isopropanol (69.0 mL) at room temperature. The mixture was degassed three times with nitrogen and vacuum, and then was stirred for 16 h at 80 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature, then was poured into aqueous K2CO3 (100 mL, 2M) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford 7- chloroimidazo[1,2-b] pyridazine (21.3, 3.3 g, 41% yield) as a brown yellow solid. MS (ES): m/z 154 [M+H]+. Synthesis of 21.4. [00230] To a stirred mixture of 21.3 (1.50 g, 9.77 mmol, 1.0 equiv) in dimethylformamide (15 mL) was added N-iodosuccinimide (3.30 g, 14.7 mmol, 1.5 equiv) in portions at room temperature. The mixture was stirred for 1 h at 80 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was poured into water (100 mL), extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford 7-chloro-3-iodoimidazo[1,2-b] pyridazine (21.4, 2.70 g, 98% yield) as a brown yellow solid. MS (ES): m/z 280 [M+H]+. Synthesis of 21.5. [00231] Pd(dppf)Cl2 (1.40 g, 1.93 mmol, 0.2 equiv) was added to a mixture of 21.4 (2.70 g, 9.63 mmol, 1.0 equiv), 4-cyanophenylboronic acid (2.10 g, 14.4 mmol, 1.5 equiv), potassium acetate (2.80 g, 28.9 mmol, 3.0 equiv) in dioxane (54 mL) and water (5.4 mL) at room temperature. The mixture was degassed three times with nitrogen and vacuum, and then was stirred for 16 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was poured into water (200 mL), extracted with EtOAc (3 x 100 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford 4-{7-chloroimidazo[1,2-b] pyridazin-3-yl} benzonitrile (21.5, 1.06 g, 43% yield) as a brown yellow solid. MS (ES): m/z 255 [M+H]+. Synthesis of 21.6. [00232] To a mixture of 21.5 (500 mg, 1.96 mmol, 1.0 equiv), oxalic acid (265 mg, 2.94 mmol, 1.5 equiv), Ac2O (301 mg, 2.95 mmol, 1.5 equiv), DIEA (381 mg, 2.95 mmol, 1.5 equiv) in DMF (10 mL) were added XantPhos (57 mg, 0.10 mmol, 0.05 equiv) and Pd(OAc)2 (22 mg, 0.10 mmol, 0.05 equiv) at room temperature. The mixture was degassed three times with nitrogen and vacuum, and then was stirred for 16 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was filtered, the filtrate was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 8mmol/L NH4HCO3) and B: ACN; Gradient: 0% to 100% B in 40 min; Detector: UV 254 nm) to afford 3- (4-cyanophenyl) imidazo[1,2-b] pyridazine-7-carboxylic acid (21.6, 430 mg, 83% yield) as a green solid. MS (ES): m/z 265 [M+H]+. Synthesis of I-52. [00233] To a stirred mixture of 21.6 (250 mg, 0.95 mmol, 1.0 equiv) and 4,4-difluoropiperidine (115 mg, 0.95 mmol, 1.0 equiv) in acetonitrile (5 mL) were added NMI (548 mg, 6.67 mmol, 7.05 equiv) and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH, 319 mg, 1.14 mmol, 1.2 equiv) in portions at room temperature. The mixture was stirred for 30 min at room temperature. The mixture was purified by Prep-HPLC (Column: XBridge BEH C18 OBD Prep Column, 19x250 mm, 5μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 38% to 68% B in 6 min, 68% B; Wave Length: 254 nm; RT1(min): 5.73). The product-containing fractions were combined and concentrated under vacuum to remove most of the solvent, and then lyophilized overnight to afford 4-[7-(4,4- difluoropiperidine-1-carbonyl) imidazo[1,2-b] pyridazin-3-yl] benzonitrile (I-52, 12 mg, 3.4% yield) as an off-white solid. MS (ES): m/z 368 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 2.1 Hz, 1H), 8.62 (s, 1H), 8.46 – 8.44 (m, 3H), 8.03 – 8.01 (m, 2H), 3.85-3.55 (m, 4H), 2.15-2.08 (m, 4H). Synthesis of 4-[5-(4-fluoropiperidine-1-carbonyl)-2-methyl-3-oxopyrazolo[3,4-
Figure imgf000091_0001
[00234] To a stirred mixture of 5-bromo-2-chloropyridine-3-carboxylic acid (5.00 g, 21.1 mmol, 1.0 equiv) and 4-hydrazinylbenzonitrile (2.82 g, 21.2 mmol, 1.0 equiv) in CH3CN (100 mL) was added NMI (6.94 g, 84.6 mmol, 4.0 equiv) and TCFH (11.9 g, 42.3 mmol, 2.0 equiv) in portions at room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated under vacuum, and then was diluted by water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified via reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN; Gradient: 5% to 95% B in 30 min; Detector: 254/220 nm). The product-containing fractions were combined and concentrated under vacuum to afford 5- bromo-2-chloro-N'-(4-cyanophenyl)pyridine-3-carbohydrazide (22.1, 3.20 g, 43% yield) as a white solid. MS (ES): m/z 351/353 [M+H]+. Synthesis of 22.2. [00235] To a stirred mixture of 22.1 (3.10 g, 8.82 mmol, 1.0 equiv) and K2CO3 (2.44 g, 17.6 mmol, 2.0 equiv) in DMSO (50 mL) were added L-proline (101 mg, 0.88 mmol, 0.1 equiv) and CuI (168 mg, 0.88 mmol, 0.1 equiv) at room temperature. The mixture was degassed three times with nitrogen and vacuum. After stirring at 90 °C overnight under nitrogen atmosphere, the mixture was allowed to cool down to room temperature. The resulting mixture was filtered, and the filter cake was washed with CH3CN. The filtrate was concentrated under reduced pressure to remove most of the solvent. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN; Gradient: 5% to 100% B in 25 min; Detector: UV 254 nm) to afford 4-{5-bromo-3-oxo-2H- pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (22.2, 500 mg, 18% yield) as a yellow solid. MS (ES): m/z 315/317 [M+H]+. Synthesis of 22.3. [00236] To a stirred mixture of 22.2 (480 mg, 1.52 mmol, 1.0 equiv) and K2CO3 (421 mg, 3.05 mmol, 2.0 equiv) in DMF (5 mL) was added CH3I (432 mg, 3.05 mmol, 2.0 equiv) at room temperature. After stirring for 1 h at room temperature, the resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to remove most of the solvent. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN; Gradient: 5% to 100% B in 25 min; Detector: UV 254 nm) to afford 4-{5-bromo-2-methyl-3- oxopyrazolo[3,4-b]pyridin-1-yl}benzonitrile (22.3, 230 mg, 46% yield) as a yellow solid. MS (ES): m/z 329/331 [M+H]+. Synthesis of 22.4. [00237] To a mixture of 22.3 (220 mg, 0.67 mmol, 1.0 equiv), DIEA (130 mg, 1.00 mmol, 1.5 equiv), Ac2O (102 mg, 1.0 mmol, 1.5 equiv) and oxalic acid (52 mg, 1.00 mmol, 1.5 equiv) in DMF (4 mL) were added Dppf (18 mg, 0.033 mmol, 0.05 equiv) and Pd(OAc)2 (8 mg, 0.033 mmol, 0.05 equiv) at room temperature. The mixture was degassed three times with nitrogen and vacuum. After stirring at 100 °C overnight under nitrogen atmosphere, the resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to remove most of the solvent. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN; Gradient: 0% to 100% B in 25 min; Detector: UV 254 nm) to afford 1-(4-cyanophenyl)-2-methyl- 3-oxopyrazolo[3,4-b]pyridine-5-carboxylic acid (22.4, 54 mg, 27% yield) as a yellow solid. MS (ES): m/z 295 [M+H]+. Synthesis of I-33. [00238] To a stirred mixture of 22.4 (50 mg, 0.17 mmol, 1.0 equiv) and 4-fluoropiperidine (21 mg, 0.20 mmol, 1.2 equiv) in CH3CN (2 mL) were added NMI (56 mg, 0.68 mmol, 4.0 equiv) and TCFH (95 mg, 0.34 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was purified by Prep-HPLC (Column: YMC-Actus Triart C18, 30 x 150 mm, 5μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 43% to 73% B in 8 min, 73% B; Wave Length: 254/210 nm). The product-containing fractions were combined and concentrated under vacuum to remove most of the solvent, and then lyophilized for overnight to afford 4-[5-(4-fluoropiperidine-1- carbonyl)-2-methyl-3-oxopyrazolo[3,4-b]pyridin-1-yl]benzonitrile (I-33, 19 mg, 29% yield) as a white solid. MS (ES): m/z 380 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 1.6 Hz, 1H), 8.53 (d, J = 8.8 Hz, 2H), 8.38 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 8.8 Hz, 2H), 5.01 - 4.87 (m, 1H), 4.19 (s, 3H), 3.80 – 3.33 (m, 4H), 2.08 - 1.79 (m, 4H). Synthesis of 7-(2-(4,4-difluoropiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-
Figure imgf000094_0001
Synthesis of 23.1. [00239] To a stirred mixture of tert-butyl 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.00 g, 3.20 mmol, 1.0 equiv) and bis(pinacolato)diboron (1.63 g, 6.40 mmol, 2.0 equiv) in dioxane (20 mL) was added AcOK (0.94 g, 9.61 mmol, 3.0 equiv) and Pd(dppf)Cl2.CH2Cl2 (0.26 g, 0.32 mmol, 0.1 equiv) at room temperature. The mixture was degassed three times with nitrogen and vacuum. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H2O (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 10:1) to afford tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H- isoquinoline-2-carboxylate (23.1, 1.20g, 93% yield) as a white solid. MS (ES): m/z 360 [M+H]+. Synthesis of 23.2. [00240] To a stirred mixture of 23.1 (432 mg, 1.20 mmol, 1.0 equiv) and Int.B (301 mg, 1.32 mmol, 1.1 equiv) in DMF (2 mL) was added Cs2CO3 (940 mg, 2.88 mmol, 2.4 equiv) and BINAP (75 mg, 0.12 mmol, 0.10 equiv) at room temperature. To the above mixture was added Pd2(dba)3 (55 mg, 0.06 mmol, 0.05 equiv) at room temperature. The mixture was degassed three times with nitrogen and vacuum. The resulting mixture was stirred for additional 2 h at 100 °C. The reaction mixture was allowed to cool down to room temperature and concentrated. The residue was purified by reversed-phase flash chromatography (Column: C18 silica gel; Mobile phase, A: water (10 mmol/L NH4HCO3) and B: MeCN; Gradient: 30% to 60% B in 20 min; Detector: UV 254 nm) to afford tert-butyl 5-{2-methyl-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-7-yl}-3,4-dihydro-1H- isoquinoline-2-carboxylate (23.2, 220 mg, 46% yield) as a dark red solid. MS (ES): m/z 381 [M+H]+. Synthesis of 23.3. [00241] To a stirred solution of 23.2 (207 mg, 0.54 mmol, 1.0 equiv) in DCM (1.5 mL) was added a solution of HCl in dioxane (0.5 mL, 4.0 M) dropwise at 0 °C. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was concentrated under vacuum to afford 2-methyl-7-(1,2,3,4-tetrahydroisoquinolin-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3- one, hydrochloride acid salt (23.3, 174 mg, crude) as a white solid, which was used without purification in the next step. MS (ES): m/z 281 [M+H]+. Synthesis of I-36. [00242] To a stirred solution of 23.3 (50 mg, 0.18 mmol, 1.0 equiv) and 4,4-difluoropiperidine (32 mg, 0.27 mmol, 1.5 equiv) in THF (4 mL) was added TEA (54 mg, 0.53 mmol, 3.0 equiv) at room temperature. To the above mixture was added triphosgene (26 mg, 0.09 mmol, 0.5 equiv) at room temperature. The mixture was degassed three times with nitrogen and vacuum. The resulting mixture was stirred for additional 4 h at 60 °C. The mixture was allowed to cool down to room temperature, filtered and the filtrate was purified by reverse phase chromatography (Column: XBridge Prep OBD C18 Column, 30 x150 mm, 5μm; Mobile Phase A: water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 33% B to 46% B in 9 min; Wave Length: 254/220 nm; RT1(min): 8.2) to afford 7-[2-(4,4-difluoropiperidine- 1-carbonyl)-3,4-dihydro-1H-isoquinolin-5-yl]-2-methyl-[1,2,4]triazolo [4,3-a]pyridin-3-one (I- 36, 11 mg, 14% yield) as a white solid. MS (ES): m/z 428 [M+H]+.1H NMR (300 MHz, Methanol- d4) δ 7.85 (m, 1H), 7.35 – 7.16 (m, 3H), 7.08 (t, J = 1.3 Hz, 1H), 6.67 (m, 1H), 4.55 (s, 2H), 3.66 (s, 3H), 3.55 – 3.46 (m, 2H), 3.45 – 3.41 (m, 4H), 2.85 (t, J = 5.8 Hz, 2H), 2.03 (m, 4H). Synthesis of 4-[6-(4-fluoropiperidine-1-carbonyl)-1-methyl-2-oxoimidazo[4,5-b] pyridin-3-yl] benzonitrile (I-34)
Figure imgf000096_0001
Synthesis of 24.1. [00243] To a solution of methyl 6-chloro-5-nitropyridine-3-carboxylate (600 mg, 2.77 mmol, 1.0 equiv) and p-aminobenzonitrile (360 mg, 3.05 mmol, 1.1 equiv) in MeCN (10 mL) was added NaOH (122 mg, 3.05 mmol, 1.10 equiv) at room temperature. The mixture was stirred for 1 h at 100 °C. The mixture was allowed to cool down to room temperature and then concentrated under vacuum. The residue was purified by prep-TLC (DCM/MeOH=10/1) to afford methyl 6-[(4- cyanophenyl) amino]-5-nitropyridine-3-carboxylate (24.1, 280 mg, 34% yield) as a white solid. MS (ES): m/z 299 [M+H]+. Synthesis of 24.2. [00244] To a solution of 24.1 (280 mg, 0.94 mmol, 1.0 equiv) in MeOH (20 mL) was added Pd/C (50 mg, 10% on carbon) under a nitrogen atmosphere. The mixture was hydrogenated under 30 psi of hydrogen pressure at room temperature for 12 h, then filtered through a Celite pad and washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure. The residue was used in the next step directly without further purification. MS (ES): m/z 267 [M+H]+. Synthesis of 24.3. [00245] To a stirred mixture of 24.2 (230 mg) in MeCN (10 mL) was added CDI (556 mg, 3.43 mmol) in portions at room temperature. The resulting mixture was stirred for 12 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (DCM/MeOH=10/1) to afford methyl 3-(4-cyanophenyl)-2-oxo-1H-imidazo[4,5-b] pyridine-6-carboxylate (24.3, 200 mg, 72% over 2 steps) as a yellow solid. MS (ES): m/z 295 [M+H]+. Synthesis of 24.4. [00246] To a stirred mixture of 24.3 (195 mg, 0.66 mmol, 1.0 equiv) and CH3I (282 mg, 1.99 mmol, 3.0 equiv) in DMF (15 mL) was added K2CO3 (275 mg, 1.99 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 4 h at 60 °C. The mixture was cooled to room temperature and diluted with water (60 mL). The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with H2O (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Column: C18 silica gel; Mobile phase, A: water (10 mmol/L NH4HCO3) and B: CH3CN; Gradient: 30% to 60% B in 15 min; Detector: UV 254 nm) to afford methyl 3-(4-cyanophenyl)-1-methyl-2-oxoimidazo[4,5-b] pyridine-6-carboxylate (24.4, 160 mg, 78% yield) as a yellow solid. MS (ES): m/z 309 [M+H]+. Synthesis of 24.5. [00247] A mixture of 24.4 (155 mg, 0.51 mmol, 1.0 equiv) in THF (5 mL) and aqueous NaOH (4 mL, 10 M) was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Column: C18 silica gel; Mobile phase, A: water (10 mmol/L NH4HCO3) and B: CH3CN; Gradient: 20% to 30% B in 15 min; Detector: UV 254 nm) to afford 3-(4-cyanophenyl)-1-methyl-2-oxoimidazo[4,5-b] pyridine-6-carboxylic acid (24.5, 145 mg, 98% yield) as a yellow solid. MS (ES): m/z 295 [M+H]+. Synthesis of I-34. [00248] To a stirred mixture of 24.5 (100 mg, 0.34 mmol, 1.0 equiv) and 4-fluoropiperidine (53 mg, 0.51 mmol, 1.5 equiv) in DMF (10 mL) was added HATU (194 mg, 0.51 mmol, 1.5 equiv) and DIEA (88 mg, 0.68 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature and then was concentrated under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5μm; Mobile Phase A: water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 38% B in 9 min, 38% B; Wave Length: 254/220 nm; RT1(min): 8.02). The product-containing fractions were combined and concentrated under vacuum to remove most of solvent, and then lyophilized overnight to afford 4-[6-(4-fluoropiperidine-1-carbonyl)-1- methyl-2-oxoimidazo[4,5-b] pyridin-3-yl] benzonitrile (I-34, 12 mg, 9% yield) as a white solid. MS (ES): m/z 380 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.19 - 7.96 (m, 5H), 7.76 (d, J = 1.9 Hz, 1H), 4.94 (d, J = 47.7 Hz, 1H), 3.69 (t, J = 50.7 Hz, 4H), 3.47 (s, 3H), 1.95 (s, 2H), 1.77 (s, 2H). [00249] Compounds were characterized by LCMS using a binary gradient on a Shimadzu LCMS‐2020. The LCMS results can be found in Table 2. Table 2. HPLC Methods
Figure imgf000098_0001
Figure imgf000099_0001
Table 3. HPLC Data
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0002
Example 2 - HPGD inhibition activity [00250] Compounds to be tested were prepared by serial dilution in DMSO:H2O (1:3). The diluted compound solution (0.2 μL) was added to a 384-well assay plate and was centrifuged at 1000 RPM for 1 minute. HPGD protein (H2-Q266 HPGD, 10 μL) in 1x assay buffer (50mM Bicine pH 7.5, 100 mM NaCl, 0.1% Pluronic F127, 0.5 mM EGTA, 0.005% BSG, 0.5 mM TCEP) was added to the assay plate and centrifuged at 1000 RPM for 1 minute. After incubating the plate at 25 °C for 30 minutes, the substate mixture solution (10 μL) was added to initiate the reaction. The final reagent concentration in 20.2 µL was 0.5 nM protein, 50 μM NAD, 2 μM PGE2, and 1% DMSO. The plate was incubated at 25°C for 25 min and the Ex355/Em460 was recorded on an EnVision plate reader. The results of the HPGD biochemical assays can be found in Table 4, below. [00251] HPGD IC50 results for compounds of the invention are reported in Table 4. The letter codes for IC50 include: A (<0.5 nM), B (0.5 – 5 nM), C (>5 – 10 nM), and D (≥10 nM). Table 4. HPGD inhibition activity
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
References 1. WO2020145250. 2. Abad-Zapatero, C.; Metz, J. T.; Ligand efficiency indices as guideposts for drug discovery, Drug Discovery Today 2005, 10, 464-469 3. WO2020160151. 4. Böhm, H.-J.; Flohr, A.; Stah, M. Scaffold hopping, Drug Discovery Today: Technologies 2004, 1, 217-224 5. Kaplan, J.; Verheijen, J.C.; Brooijmans, N.; Toral-Barza, L.; Hollander, I.; Yu, K.; Zask, A. Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4- d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR), Bioorg Med Chem Lett 2010, 20, 640-643 6. Barton, N.; Convery, M.; Cooper, A. W. J.; Down, K.; Hamblin, N.; Inglis, G.; Peace, S.; Rowedder, J.; Rowland, P.; Taylor, J. A.; Wellaway, N. Discovery of Potent, Efficient, and Selective Inhibitors of Phosphoinositide 3-Kinase δ through a Deconstruction and Regrowth Approach, J. Med. Chem.2018, 61, 24, 11061–11073 7. drughunter.com/first-disclosures-from-esmc-ifmc-nice-2022/ 8. Pilka, E.S.; Guo, K.; Kavanagh, K.; Von Delft, F.; Arrowsmith, C.; Weigelt, J.; Edwards, A.; Sundstrom, M.; Oppermann, U; High-Affinity Inhibitors of Human NAD+-Dependent 15- Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships, PLoS 2010, 5, e13719 9. Duveau, D. Y.; Yasgar, A.; Wang, Y.; Hu, X.; Kouznetsova, J.; Brimacombe, K. R.; Jadhav, A.; Simeonov, A.; Thomas, C. J.; Maloney, D. J. Structure−activity relationship studies and biological characterization of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase inhibitors, Bioorg. Med Chem Lett 2014, 24, 630–635 10. Antczak, M.; Zhang, Y.; Wang, C.; Doran, J.; Naidoo, J.; Voruganti, S.; Williams, N. S.; Markowitz, S. D.; Ready, J. M. Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair, J. Med. Chem.2017, 60, 3979-4001 11. Hu, B.; Toda, K.; Wang, X.; Antczak, M. I.; Smith, J.; Geboers, S.; Nishikawa, G.; Li, H.; Dawson, D.; Fink, S.; Desai, A. B.; Williams, N. S.; Markowitz, S. D.; Ready, J. M. Orally Bioavailable Quinoxaline Inhibitors of 15-Prostaglandin Dehydrogenase (15-PGDH) Promote Tissue Repair and Regeneration, J. Med. Chem. 12. Niesen, F. H.; Schultz, L.; Jadhav, A.; Bhatia, C.; Guo, K.; Maloney, D. J.; Pilka, E. S.; Wang, M.; Oppermann, U.; Heightman, T. D.; Simeonov, A. High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships, PLoS ONE, 2010, 5, e13719.

Claims

CLAIMS We claim: 1. A compound of Formula Ia:
Figure imgf000110_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) and phenyl, wherein Ring A is substituted with y instances of Ry; Ring B is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Ring B is substituted with z instances of Rz; X1 is N or C; each Rx, Ry, and Rz is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, - S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted and cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R is independently hydrogen, halogen, or an optionally substituted C1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, or 4. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5-7 membered saturated or partially unsaturated monocyclic heterocyclic ring (having a single nitrogen), wherein Ring A is substituted with y instances of Ry. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring
Figure imgf000111_0001
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof,
Figure imgf000112_0001
. 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X1 is CH. 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein z is 0. 7. The compound of any one of claims 1-6, wherein the compound is of Formula Ia-1:
Figure imgf000112_0002
Ia-1 or a pharmaceutically acceptable salt thereof. 8. The compound of any one of claims 1-7, wherein x is 0. 9. The compound of any one of claims 1-7, wherein x is 1 and R1 is methyl. 10. The compound of any one of claims 1-9, of Formula Ia-2, Ia-3, or Ia-4:
Figure imgf000113_0001
Ia-4 or a pharmaceutically acceptable salt thereof. 11. A compound of Formula II:
Figure imgf000113_0002
II or a pharmaceutically acceptable salt thereof, wherein: Ring A is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) or phenyl, wherein Ring A is substituted with y instances of Ry; Ring B is a cyclic group selected from a 5-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with z instances of Rz; X1 is N or C; L1 is a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced by - Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, or -N(R)C(O)O-; each Rx, Ry, and Rz is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, - S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, an optionally substituted saturated or unsaturated C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted and cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R is independently hydrogen, halogen, or an optionally substituted C1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), two R groups on the same nitrogen atom or carbon atom are taken together with the nitrogen atom or carbon atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, heterocyclyl, or heteroaryl ring (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); x is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2, 3, or 4. 12. The compound of claim 11, wherein Ring A is 6 membered saturated monocyclic heterocyclic ring (having a single nitrogen) optionally substituted with 0, 1, 2, 3, or 4 halogens.
Figure imgf000115_0001
13. The compound of claim 11 or claim 12, wherein Ring A is F . 14. The compound of any one of claims 11-13, wherein Ring B is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Ring B is substituted with z instances of Rz. 15. The compound of any one of claims 11-14, wherein Ring
Figure imgf000115_0002
Figure imgf000115_0003
1 The compound of any one of claims 11-15, wherein Ring
Figure imgf000116_0001
. 17. The compound of any one of claims 11-16, wherein X1 is C. 18. The compound of any one of claims 11-16, wherein X1 is N. 19. The compound of any one of claims 11-18, wherein x is 0. 20. The compound of claim 11, wherein the compound of Formula II is a compound of Formula IIa-1, IIb-1, or IIa-2:
Figure imgf000116_0002
IIa-2 or a pharmaceutically acceptable salt thereof. 21. The compound of claim 1 or claim 11, wherein the compound is selected from those in Table 1, or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a compound of any one of claims 1-21 and a pharmaceutically acceptable carrier, adjuvant, or diluent. 23. A method of treating an HPGD-mediated disorder, disease, or condition in a patient, comprising administering to said patient a compound of any one of claims 1-21, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22. 24. The method of claim 23, wherein the HPGD-mediated disorder, disease, or condition is selected from a wound, bone formation, bone regrowth, hair loss, inflammatory bowel disease, liver disease, bone marrow transplantation, and muscle atrophy. 25. The method of claim 24, wherein the wound is selected from a vascular wound, a neuropathic wound, moisture associated dermatitis, a skin tear, or an ulcer. 26. The method of claim 24, wherein the HPGD-mediated disorder, disease, or condition comprises hair loss. 27. The method of claim 26, wherein the hair loss comprises Androgenetic Alopecia, Telogen Effluvium, Anagen Effluvium, Alopecia Areata, Tinea Capitis, Cicatricial Alopecia, Hair Shaft Abnormalities, or Hypotrichosis. 28. A method of transplanting bone marrow in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-21, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22. 29. A method of regenerating tissue on existing tissue comprising contacting the existing tissue with a compound of any one of claims 1-21, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22. 30. The method of claim 29, wherein the tissue is colon tissue or liver tissue.
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