WO2016086008A1 - Small molecule aldehyde dehydrogenase inhibitors and methods of use thereof - Google Patents

Abstract

Described herein are compounds, salts and solvates of the formula (I). Certain compounds of formula (I) are potent and selective inhibitors of aldehyde dehydrogenases (ALDH), a family of enzymes that play a critical role in detoxification of various cytotoxic xenogenic and biogenic aldehydes. As such, compounds of formula (I) are useful for treating disorders in which ALDH inhibition is needed, including cancer, inflammatory disorders, and obesity. The disclosure also includes compositions, and methods for inhibiting aldehyde dehydrogenases (ALDH).

Description

SMALL MOLECULE ALDEHYDE DEHYDROGENASE

INHIBITORS AND METHODS OF USE THEREOF

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. Provisional Application Ser. No. 62/084,830, filed November 26, 2014, which is hereby incorporated by reference in its entirety.

GOVERNMENT SUPPORT

[0002] This invention was made with government support under grant numbers MH084681, R24AA022057, and ROIEYOI 1490 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

[0003] Aldehyde dehydrogenases (ALDH) constitute a family of enzymes that play a critical role in oxidizing various cytotoxic xenogenic and biogenic aldehydes. There are at least 19

members/isozymes of the ALDH family, where the various isozymes may exhibit different substrate specificity and/or cellular location relative to other members of the family.

[0004] Increased expression of various ALDH isozymes have been reported in various human cancers and are associated with cancer relapse. Family member ALDH1 Al is a cancer stem cell marker, and its expression correlates with poor prognosis in a number of malignancies. In addition, ALDH1A1 appears to be an important factor in tumor aggressiveness. In addition, tumors and cancer stem cells resistant to chemotherapy and radiation are associated with high expression of ALDH1A1. Although the majority of the research community has considered ALDH1A1 as a marker of cancer stem cells and a predictor of the prognosis, this enzyme plays an important role in the biology of tumors and cancer stem cells. Initial evidence using non-specific ALDH inhibitors and siRNA confirms the involvement of ALDH1A1 in the first line of targets for targeted drug development in order to enhance the efficacy of chemotherapy and radiation.

[0005] ALDH1A1 has also been shown to play a role metabolism and obesity. ALDH1A1 is expressed predominantly in white adipose tissues in mice and humans. White adipose tissue selective ALDH1A1 knockdown in obese mice limited weight gain and improved glucose homeostasis.

ALDH1A1 inhibitors are therefore desirable as anti-obesity agents.

[0006] Therefore, this disclosure provides compounds and compositions that inhibit aldehyde dehydrogenases, such as aldehyde dehydrogenase 1A1, for use for the treatment of various conditions, such as cancer, inflammation, or obesity. SUMMARY

[0007] The disclosure provides compounds of formula (I), and the pharmaceutically acceptable salts and solvates thereof,

' wherein

Within formula I the variables carry the following definitions.

[0008] R¹ and R² are inde endentl selected from the rou consistin of h dro en Me and Et

[0009] R is selected from the group consisting of ,

; wherein b, d, and e are each an independent integer from 1 to 2; f is an integer from 0 to 4; g is an integer from 0 to 3, h is an integer from 1 to 3.

[0010] R s ndependently selected from a group cons st ng of C₍i_₄₎alkyl, (C₍₃.₇₎Cycloalkyl,

[0011] R⁵ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, Me, CF₃, Et, CN, OMe, and OEt.

[0012] R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F, C₍i_₄₎alkyl,

[0013] R⁸ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, C(i-₃₎alkyl, and CF₃.

[0014] R⁹ and R¹⁰ are independently selected from the group consisting of Me and Et, or, alternatively, R⁹ and R¹⁰ are taken together with the nitrogen atom to which they are bound to form pyrrolidin-l-yl, piperidin-l-yl, morpholin-l-yl, or 4-C i.₃₎alkyl-piperazin-l-yl.

[0015] A is selected from the group consisting of

, and

wherein X-Y is

or ; wherein m and n are each an independent integer from 0

H > to 2, or X-Y is H

[0016] Z is selected from the group consisting of

_

(C=0)NHC₍₁_₄₎alkyl, -(C=0)NHC₍₃_₅₎Cycloalkyl, H° R^{1 1} , K* R°^{1 1} , ^ , ° ^

independently selected from the group consisting of-C₍₁.₄₎alkyl, -C₍₃.₅₎Cycloalkyl, -CH₂OH, -

^■N

f

CH₂OC₍₁.2₎alkyl, -NHC₍₁.₃₎alkyl, -NHC₍₃.₅₎cycloalkyl, and Me , each of which R¹¹ is optionally substituted; wherein R¹² is one or more substituents independently selected from the group consisting of hydrogen, F, CI, and Me.

[0017] L is selected from the group consisting of \— -O , -OC₍₃_5)Cycloalkyl, -0-CH₂-C₍₃_

₅₎cycloalkyl,

[0018] R¹³ is 0 or one or more substituents independently selected at each occurrence from the group consisting of hydrogen, F, CI, and Me.

1⁴ is selected from the group consisting of C₍i_₄)alkyl, (C(₃.₆)Cycloalkyl)C(o-2)alkyl,

[0020] R is hydrogen or cyano; R and R are independently chosen from hydrogen, C₍i_₃)alkyl, and cyclopropyl.

[0021] R¹⁸ and R¹⁹ are independently selected from the group consisting of hydrogen, C₍i_₄)alkyl, (C₍₃.

₆₎cycloalkyl)C₍o-2)alkyl,

or

R¹⁸ and R¹⁹ can be joined to form a 3- to 6-membered carbocyclic ring, e.g. a C₍₃.₆)Cycloalkyl or C₍₃. 6)Cycloalkenyl ring. In certain embodiments R¹⁸ and R¹⁹ are independently selected from the group consisting of hydrogen, C(i_₄)alkyl, and (C(₃_6)Cycloalkyl)C(₀-2)alkyl, or R¹⁸ and R¹⁹ are joined to form a 3- to 6- membered cycloalkyl ring.

[0022] In certain embodiments, the disclosure relates to a method of treating an disorder in which ALDHlAl inhibition alleviates symptoms (i.e. an ALDHlAl disorder), comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0023] In certain embodiments, the disclosure relates to any of the methods described herein, wherein the ALDHlAl disorder is selected from the group consisting of cancer, inflammation or a disease or disorder associated with inflammation, and obesity. DETAILED DESCRIPTION

Terminology

[0024] In order for the present disclosure to be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0025] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0026] The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and/or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and/or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and/or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0027] "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0028] As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non- limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and/or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0029] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. [0030] In the claims, as well as in the specification above, all transitional phrases such as

"comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," or the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. The open-end phrases such as "comprising" include and encompass the close-ended phrases. Comprising may be amended to the more limiting phrases "consisting essentially of of "consisting of as needed.

[0031] The definition of each expression, e.g., alkyl, m, n, or the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0032] It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.

[0033] The term "substituted" is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein below. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. "H-" is not considered a substituent.

[0034] The term "saturated," as used herein, pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.

[0035] The term "unsaturated," as used herein, pertains to compounds and/or groups which have at least one carbon-carbon double bond or carbon-carbon triple bond.

[0036] The term "aliphatic," as used herein, pertains to compounds and/or groups which are linear or branched, but not cyclic (also known as "acyclic" or "open-chain" groups).

[0037] Compounds of Formula I include compounds of the formula having isotopic substitutions at any position. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ⁿC, ¹³C, and ¹⁴C. Compounds of Formula I also require enrichment of deuteration (substitution of a hydrogen atom with deuterium) at identified positions.

[0038] The term "cyclic," as used herein, pertains to compounds and/or groups which have one ring, or two or more rings (e.g., spiro, fused, bridged). [0039] "Cyclolalkyl" is a saturated carbocyclic ring having the indicated number of carbon ring atoms, for example C₍₃.₆₎Cycloalkyl is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. Likewise "cycloalkenyl" is an unsaturated carbocyclic group having the indicated number of carbon ring atoms and at least one C=C double bond in the ring.

[0040] The term "aromatic" refers to a planar or polycyclic structure characterized by a cyclically conjugated molecular moiety containing 4n+2 electrons, wherein n is the absolute value of an integer. Aromatic molecules containing fused, or joined, rings also are referred to as bicyclic aromatic rings. For example, bicyclic aromatic rings containing heteroatoms in a hydrocarbon ring structure are referred to as bicyclic heteroaryl rings.

[0041] The term "hydrocarbon" as used herein refers to an organic compound consisting entirely of hydrogen and carbon.

[0042] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986- 87, inside cover.

[0043] The term "heteroatom" as used herein is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

[0044] The term "alkyl" means a branched or unbranched aliphatic radical containing the indicated number of carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, 2-methylcyclopentyl, and 1-cyclohexylethyl.

[0045] The term "substituted alkyl" means a branched or unbranched aliphatic hydrocarbon radical containing the indicated number of carbon atoms, substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfonyl, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, fluoroalkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfinyl, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl,

fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,

haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluoroalkylsulfonyloxy, alkenylsulfonyloxy,

alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy, alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl and silyloxy.

[0046] The term "carbocyclyl" as used herein means monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbons containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g. phenyl). Examples of carbocyclyl groups include 1- cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and 2- cyclopentenylmethyl.

[0047] The term "heterocycloalkyl," means a saturated ring group usually having 4- to 7-ring atoms with 1 or 2 ring atoms independently chosen from N, O, and S: Examples of heterocycloalkyl groups includes azepines, azetidinyl, morpholinyl, pyranyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl.

[0048] The term "aryl," as used herein means a phenyl group, naphthyl or anthracenyl group. The aryl groups of the present disclosure can be optionally substituted with 1, 2, 3, 4 or 5 substituents.

[0049] The term "halo" or "halogen" means -CI, -Br, -I or -F.

[0050] The term "haloalkyl" means an alkyl group, as defined herein, wherein at least one hydrogen is replaced with a halogen, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3- fluoropentyl.

[0051] The term "hydroxyl" as used herein means an -OH group.

[0052] The term "alkoxy" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The terms "alkenyloxy," "alkynyloxy," "carbocyclyloxy," and "heterocyclyloxy" are likewise defined.

[0053] The term "haloalkoxy" as used herein means an alkoxy group, as defined herein, wherein at least one hydrogen is replaced with a halogen, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

[0054] The term "alkoxycarbonyl" as used herein means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

[0055] "Mono- or di-alkylcarboxamide" means a carboxamide functional group, -NHC(=0)- attached to the group it substitutes in either orientation, -NHC(=0)- or -(C=0)NH-, substituted with one or two independently chosen alkyl groups. [0056] The term "alkylcarbonyloxy" as used herein means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert- butylcarbonyloxy.

[0057] The term "amino" as used herein refers to -NH₂ and substituted derivatives thereof wherein one or both of the hydrogens are independently replaced with substituents selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarnbonyl, heteroaralkylcarbonyl and the sulfonyl and sulfinyl groups defined above; or when both hydrogens together are replaced with an alkylene group (to form a ring which contains the nitrogen). Representative examples include, but are not limited to methylamino, acetylamino, and dimethylamino.

[0058] The term "amido" as used herein means an amino group, as defined herein, appended to the parent molecular moiety through a carbonyl.

[0059] The term "cyano" as used herein means a -C≡N group.

[0060] The term "nitro" as used herein means a -N0₂ group.

[0061] The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.

[0062] As used herein, the term "aldehyde dehydrogenase" or "ALDH" refers to an enzyme that oxidizes an aldehyde (e.g., a xenogenic aldehyde, a biogenic aldehyde, or an aldehyde produced from a compound that is ingested, inhaled, or absorbed) to its corresponding acid in an NAD⁺-dependent or an NADP⁺-dependent reaction. For example, ALDH oxidizes aldehydes derived from the breakdown of compounds, e.g., toxic compounds that are ingested, that are absorbed, that are inhaled, that are produced as a result of oxidative stress, or that are produced during normal metabolism, e.g., conversion of retinaldehyde to retinoic acid. An example of a biogenic aldehyde is acetaldehyde produced as a product of alcohol dehydrogenase activity on ingested ethanol. An aldehyde dehydrogenase can also exhibit esterase activity and/or reductase activity.

[0063] The term "ALDH" encompasses ALDH found in the cytosol, in the mitochondria, microsome, or other cellular compartment. The term "ALDH" encompasses ALDH found primarily in one or a few tissues, e.g., cornea, saliva, liver, etc., or in stem cells and embryos. The term "ALDH" encompasses any of the known ALDH isozymes, including ALDH1, ALDH2, ALDH3, ALDH4, ALDH5, etc. [0064] As used herein, "ALDHl " refers to a cytosolic aldehyde dehydrogenase that oxidizes an aldehyde (e.g., a xenogenic aldehyde, a biogenic aldehyde, or an aldehyde produced from a compound that is ingested, inhaled, or absorbed) to its corresponding acid in an NAD⁺-dependent reaction.

[0065] The term "ALDHl " encompasses ALDHl from various species. Amino acid sequences of ALDHl from various species are publicly available. See, e.g., GenBank Accession Nos. AAC51652 (Homo sapiens ALDHl); NP__₀oo68o (Homo sapiens ALDHl); AAH61526 (Rattus norvegicus ALDHl); AAI05194 (Bos taurus ALDHl); and NP..₀₃605i (Mus musculus ALDHl). The term

"ALDHl " as used herein also encompasses fragments, fusion proteins, and variants (e.g., variants having one or more amino acid substitutions, addition, deletions, and/or insertions) that retain ALDHl enzymatic activity. The term "ALDHl " encompasses an aldehyde dehydrogenase that oxidizes aromatic aldehydes, including those of the retinaldehyde, naphthaldehyde, phenanthrenealdehyde, and coumarinaldehyde series, as well as complex polyaromatic aldehydes. The term "ALDHl " encompasses a cytosolic aldehyde dehydrogenase.

[0066] The term "ALDHl " encompasses an enzymatically active polypeptide having at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4 of U.S. Patent Application Publication No. 2013/0267501, which is hereby incorporated by reference in its entirety.

[0067] As used herein, the term "administering" means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering.

[0068] As used throughout this application, the term "pharmaceutically effective amount of a compound for pharmaceutical use" shall mean an amount of compound that exhibits the intended pharmaceutical or therapeutic or diagnostic effect when administered. Examples of methods of administration include, but are not limited to, oral administration (e.g., ingestion, buccal or sublingual administration), anal or rectal administration, topical application, aerosol application, inhalation, intraperitoneal administration, intravenous administration, transdermal administration, intradermal administration, subdermal administration, intramuscular administration, intrauterine administration, vaginal administration, administration into a body cavity, surgical administration, administration into the lumen or parenchyma of an organ, and parenteral administration. The compositions can be administered in any form by any means. Examples of forms of administration include, but are not limited to, injections, solutions, creams, gels, implants, ointments, emulsions, suspensions, microspheres, powders, particles, microparticles, nanoparticles, liposomes, pastes, patches, capsules, suppositories, tablets, transdermal delivery devices, sprays, suppositories, aerosols, or other means familiar to one of ordinary skill in the art. In some embodiments, the compositions can be combined with other components. Examples include, but are not limited to, coatings, depots, matrices for time release and osmotic pump components. [0069] The term "solvate" refers to the compound formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates. "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts may include: (i) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, or the like; or (ii) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, or the like.

[0070] In some embodiments, the one or more compounds, or compositions of the present disclosure, are administered to persons or animals to provide substances in any dose range that will produce desired physiological or pharmacological results. Dosage will depend upon the substance or substances administered, the therapeutic endpoint desired, the diagnostic endpoint desired, the desired effective concentration at the site of action or in a body fluid, and the type of administration.

Information regarding appropriate doses of substances are known to persons of ordinary skill in the art and may be found in references such as L.S. Goodman and A. Oilman, eds, The Pharmacological Basis of Therapeutics, Macmillan Publishing, New York, and Katzung, Basic & Clinical

Pharmacology, Appleton & Lang, Norwalk, Conn. (6.sup.th Ed. 1995). In some embodiments, the compounds and compositions of the present disclosure may be administered to a subject. Suitable subjects include a cell, population of cells, tissue or organism. In certain embodiments, the subject is a mammal such as a human. The compounds may be administered in vitro or in vivo.

[0071] The disclosure includes methods in which one or more compounds are an admixture or otherwise combined with one or more compounds and may be in the presence or absence of commonly used excipients (or "pharmaceutically acceptable carriers"); for example, but not limited to: i) diluents and carriers such as starch, mannitol, lactose, dextrose, sucrose, sorbitol, cellulose, or the like; ii) binders such as starch paste, gelatin, magnesium aluminum silicate, methylcellulose, alginates, gelatin, sodium carboxymethyl-cellulose, polyvinylpyrrolidone or the like; iii) lubricants such as stearic acid, talcum, silica, polyethylene glycol, polypropylene glycol or the like; iv) absorbents, colorants, sweeteners or the like; v) disintegrates, (e.g., calcium carbonate and sodium bicarbonate) such as effervescent mixtures or the like; vi) excipients (e.g. cyclodextrins or the like); vii) surface active agents (e.g., cetyl alcohol, glycerol monostearate), adsorptive carriers (e.g., kaolin and bentonite), emulsifiers or the like. Examples of carriers include, without limitation, any liquids, liquid crystals, solids or semi-solids, such as water or saline, gels, creams, salves, solvents, diluents, fluid ointment bases, ointments, pastes, implants, liposomes, micelles, giant micelles, or the like, which are suitable for use in the compositions.

[0072] Furthermore, the disclosure includes compositions prepared using conventional mixing, granulating, or coating methods and may contain 0.01 to 90% of the active ingredients. In some embodiments, the one or more compounds are for pharmaceutical use or for diagnostic use. Such methods can be used, for example, to prepare a bio-enhanced pharmaceutical composition in which the solubility of the compound(s) is (are) enhanced. In some embodiments, the resulting compositions contain a pharmaceutically effective amount of a compound for pharmaceutical or diagnostic use. The resulting compositions (formulations) may be presented in unit dosage form and may be prepared by methods known in the art of pharmacy. All methodology includes the act of bringing the active ingredient(s) into association with the carrier which constitutes one or more ingredients. Therefore, compositions (formulations) are prepared by blending active ingredient(s) with a liquid carrier or a finely divided solid carrier, and/or both, and then, if needed, shaping the product into a desired formulation.

[0073] "Therapeutically effective amount" or "effective amount" refers to the amount of a compound that, when administered to a subject for treating or diagnosing or monitoring a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The "therapeutically effective amount" can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.

[0074] "Treating" or "treatment" of any disease or disorder refers to arresting or ameliorating a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the development of a disease, disorder or at least one of the clinical symptoms of the disease or disorder, or reducing the risk of developing a disease or disorder or at least one of the clinical symptoms of a disease or disorder. "Treating" or "treatment" also refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, or inhibiting at least one physical parameter which may not be discernible to the subject. Further, "treating" or "treatment" refers to monitoring, delaying or preventing the onset or reoccurrence of the disease or disorder or at least symptoms thereof in a subject which may be exposed to or predisposed to or may have previously suffered from a disease or disorder even though that subject does not yet experience or display symptoms of the disease or disorder.

[0075] Typical compositions of the disclosure contain compound from about 90 to about 80% by weight, from about 80 to about 70% by weight, from about 70 to about 60% by weight, from about 60 to about 50% by weight, from about 50 to about 40% by weight, from about 40 to about 30% by weight, from about 30 to 20% by weight, from about 20 to about 10% by weight, from about 10 to about 4% by weight, from about 4.0% to about 2.0% by weight, from about 2.0% to about 1.0% by weight, and even from about 1.0% to about 0.01 % by weight. The effective amount of compounds or compositions of the disclosure may range from about 0.1 to 100 milligrams (mg) per kilogram (kg) of subject weight. In certain embodiments, the compounds or compositions of the disclosure are administered at from about 0.0001 mg/kg to 0.1 mg/kg (e.g. diagnostic monitoring), or from 0.1 mg/kg to 2 mg/kg, or from about 2 mg/kg to 5 mg/kg; in other embodiments, from about 5 mg/kg to 10 mg/kg, from about 10 mg/kg to 20 mg/kg, from about 20 mg/kg to 30 mg/kg, from about 30 mg/kg to 40 mg/kg, from about 40 mg/kg to 50 mg/kg, from about 50 mg/kg to 75 mg/kg or from about 75 mg/kg to 100 mg/kg.

[0076] As used herein, the term "subject" means a human or non-human animal selected for treatment or therapy.

[0077] As used herein, the phrase "subject suspected of having" means a subject exhibiting one or more clinical indicators of a disease or condition.

[0078] It should be understood that the ingredients particularly mentioned above are merely examples and that some embodiments of formulations comprising the compositions of the present disclosure include other suitable components and agents. The invention further includes packages, vessels, or any other type of container that contain a compound of the present invention.

Overview

[0079] In certain embodiments, the disclosure relates to compounds of formula I. In certain embodiments, these compounds inhibit an aldehyde dehydrogenase, such as aldehyde dehydrogenase 1A1. In certain embodiments, the compounds demonstrate low-nM inhibition and excellent selectivity. In certain embodiments, the disclosure relates to a method of treating cancer, inflammation, or obesity comprising administering to a subject in need thereof an effective amount of a compound of formula I.

[0080] In certain embodiments, compounds of formula (I) may be prepared according to the process outlined in Scheme 1, below, wherein the details of R¹, R², R³, A, X, Y, Z, m, and n are described herein.

Scheme 1

[0081] In certain embodiments, a suitably substituted compound of formula (Va), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound R^3_LG¹ , wherein the LG¹ is suitably selected leaving group such as CI, Br, I, -0-methanesulfonyl,-0- benzenesulfonyl, -0-/?-toluenesulfonyl, a known compound or compound prepared by known methods, in the presence of a suitably selected base such as Na₂C0₃, K₂C0₃, Cs₂C0₃, and the like, in the presence of a suitably selected solvent such as DMF, MeCN, acetone, and the like, under thermal or microwave irradiation conditions to yield a compound of formula (Vb).

[0082] Alternatively, in certain embodiments, a suitably substituted compound of formula (Va) is reacted with a suitably substituted compound R^3_LG¹ under known Mitsunobu conditions, wherein the LG¹ is -OH, a known compound or compound prepared by known methods, in the presence of a suitable organophosphine such as triphenylphosphine and the like, in the presence of a suitably selected activation agent such as DEAD, DIAD, di-tert-butyl azodicarboxylate and the like, in the presence of a suitable solvent such as THF and the like, to yield a compound of formula (Vb). Η

[0083] In certain embodiments, the compound of formula (Vb) is further reacted with

known compound or compound prepared by known methods, wherein X-Y is

and PG¹ is suitably selected protecting group, preferably t-butyoxycarbonyl (Boc) group, in the presence of suitably selected base such as NaH, ( -Pr)₂NEt, and the like, in the presence of a suitably selected solvent such as DMF and the like, to yield an intermediate, which is further deprotected by suitably selected deprotection conditions, such as TFA or HC1, for example, if PG¹ is Boc group, in the presence of suitable solvent such as 1,4-dioxane, to yield a compound of formula (Vc).

[0084] In certain embodiments, a compound of formula (Vd) is reacted with R³~LG¹ _{; a} known compound or compound prepared by known methods, in the presence of suitably selected LG¹, base, and solvent, described herein, to yield an intermediate, which is further oxidized with a suitable oxidative reagent such as Dess-Martin periodinane in the presence of a suitably selected solvent, such as CH₂C1₂ and the like, to yield a compound of formula (Ve).

[0085] In certain embodiments, a compound of formula (Ve) is further reacted with

, a known compound or compound prepared by known methods, under reductive animation conditions, wherein PG¹ is a suitably selected protecting group, preferably a i-butyoxycarbonyl (Boc) group, in the presence of a suitably selected reducing agent such as sodium triacetoxyborohydride

(NaBH(OAc)₃) and the like, a suitable solvent such as CH₂C1₂ and the like, to yield an intermediate, which is further deprotected by suitably selected deprotection conditions, such as TFA or HC1, for example, if PG¹ is a Boc group, in the presence of a suitable solvent such as 1,4-dioxane, to yield a

H >

compound of formula (Vc), wherein X-Y is H ^ .

[0086] In certain embodiments, a compound of formula (Vc) is reacted with Z— LG² _{; a} known compound or compound prepared by known methods, wherein Z— LG² i_s a suitably substituted acyl chloride, a suitably substituted sulfonyl chloride, a suitably substituted ketene, and the like, in the presence of suitable base such as triethyl amine, ( -Pr)₂NEt and the like, in the presence of a suitable solvent such as CH₂C1₂ and the like, to yield a compound of formula (I).

[0087] In certain embodiments, a compound of formula (Vc) is reacted with Z— LG² _; wherein Z^— LG² is a suitably substituted carboxylic acid, and the like, in the presence of a suitable coupling reagent such as EDC, HATU and the like, in the presence of suitable base such as ( -Pr)₂NEt, and the like, in the presence of a suitably selected solvent such as CH₂C1₂, DMF, and the like, to yield the compound of formula (I).

[0088] In certain embodiments, a compound of formula (Vc) is reacted with Z— LG² _{; a} known compound or compound prepared by known methods, wherein Z— LG² i_s a suitably substituted heteroaryl-halide and the like, preferably the halide is CI, in the presence of suitable base such as (i- Pr)₂NEt, and the like, in the presence of a suitably selected solvent such as DMF, and the like, to yield a compound of formula (I).

[0089] In certain embodiments, a compound of formula (Vc) is reacted with Z— LG² _{; a} known compound or compound prepared by known methods, under Pd-catalyzed cross-coupling conditions, wherein Z— LG² i_s a suitably substituted heteroaryl-halide, wherein the halide is I, Br, CI and the like, in the presence of a Pd-catalyst, such as Pd₂(dba)₃, Pd(OAc)₂, and the like, in the presence of a suitable organophosphine ligand such as XPhos, Xantphos, BINAP, and the like, in the presence of a suitable base such as LHMTS, Cs₂C0₃, i-BuONa and the like, in the presence of a suitably selected solvent such as THF, toluene, 1 ,4-dioxane and the like, to yield a compound of formula (I).

[0090] In certain embodiments, compounds of formula (I) wherein A is

may be prepared according to the process outlined in Scheme 2, below.

2. cross-coupling

Scheme 2 [0091] In certain embodiments, a suitably substituted compound of formula (Vb) is reacted with a suitably substituted compound \-= , a known compound or compound prepared by

known methods, wherein G is

presence of suitable base such as K₂C0₃, Cs₂C0₃ and the like, in the presence of a suitably selected solvent such as DMF and the like, under thermal or microwave irradiation conditions to yield a compound of formula (I).

[0092] In certain embodiments, a suitably substituted compound of formula (Vb) is reacted with a suitably substituted compound _{; a} known compound or compound prepared by known methods, wherein the g

yield an ester intermediate, which can be hydrolyzed under known basic hydrolysis conditions, such as LiOH(aq), NaOH(aq) and the like. In certain embodiments, the resulting carboxylic acid may be reacted with an amine such as (Me)₂NH, H₂N-C(i_3₎alkyl, H₂N-C₍₃_5₎Cycloalkyl and the like, in the presence of a suitable coupling reagent such as EDC, HATU and the like, in the presence of a suitable base such as (i-Pr)₂NEt, and the like, in the presence of a suitably selected solvent such as CH₂C1₂, DMF, and the like, to yield a compound of formula (I).

[0093] In certain embodiments, a suitably substituted compound of formula (Vb) is reacted with a

suitably substituted compound , a known compound or compound prepared by known methods, wherein PG¹ is a suitably selected protecting group, preferably i-butyoxycarbonyl (Boc) group, in the presence of a suitable base such as K₂C0₃, Cs₂C0₃ and the like, in the presence of a suitably selected solvent such as DMF and the like, under thermal or microwave irradiation conditions to yield a intermediate. In certain embodiments, the resulting intermediate can be deprotected by suitably selected deprotection conditions, such as TFA or HC1, for example, if PG¹ is Boc, followed by acylation with C₍₁.₃₎alkyl-C(=0)OH, C₍₁_₃₎alkyl-C(=0)Cl, C₍₃.₅₎cycloalkyl-C(=0)OH, C(₃_5₎Cycloalkyl-C(=0)Cl, and the like to yield a compound of formula (I).

[0094] In certain embodiments, a suitably substituted compound of formula (Vb) is reacted with a suitably substituted compound \-= , a known compound or compound prepared by known methods, wherein J is Br, I and the like, in the presence of a suitable base such as K₂C0₃, Cs₂C0₃ and the like, in the presence of a suitably selected solvent such as DMF and the like, under thermal or microwave irradiation conditions to yield an intermediate. In certain embodiments, the resulting intermediate can be reacted with, for example, a heteroaryl-boronic acid, a heteroaryl- boronic ester, a heteroaryl-tributyltin and the like, in the presence of a Pd-catalyst, such as Pd(Ph₃)₄, PdCl₂dppf and the like, in the presence of suitable base such as K₂C0₃, (i-Pr)₂NEt and the like, in the presence of a suitably selected solvent such as 1 ,4-dioxane/H₂0, DMF and the like, to yield a compound of formula (I).

[0095] I the intermediate can be further reacted with, for example,

, , and the like, wherein LG¹ is a suitably selected leaving group such as CI, Br, I, -0-methanesulfonyl,-0-benzenesulfonyl, -0-/?-toluenesulfonyl, a known compound or compound prepared by known methods, in the presence of a suitably selected base such as Na₂C0₃, K₂C0₃, Cs₂C0₃, and the like, in the presence of a suitably selected solvent such as DMF, MeCN, acetone, and the like, under thermal or microwave irradiation condition to yield a compound of formula (I).

Chemical Description

[0096] In addition to the compounds, salts and solvates of formula I provided in the SUMMARY section the disclosure also includes compounds, salts, and solvates of formula I, and its subformulae, in which any of the following conditions. Any variable definition, e.g. the definitions of A, R¹, R², and R³, can be combined with any other variable definition so long as a stable compound results.

[0097] The disclosure includes a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,

(')

Wherein

R¹ and R² are independently chosen from C(i.₄₎alkyl.

R³ is

(i) C₍₂-₈₎alkyl, (C(i.₄₎alkoxy)C(i-4₎alkyl, or (C(i_4₎alkylamino)C(i.4₎alkyl, each of which is optionally substituted with halogen, hydroxyl, cyano, amino, oxo, C₍₃_6₎Cyclohexyl and 4- to 6- membered heterocyloalkyl having 1 to 2 independently chosen O, N, and S atoms; or

(ii) (phenyl)C₍o-₂₎alkyl, (pyridyl)C₍o-₂₎alkyl, (thiazolyl)C₍₀-₂₎alkyl, (naphthyl)C₍₀-₂₎alkyl, (C₍₃. ₆₎Cycloalkyl)C(o-₂₎alkyl, (morpholinyl)C₍i_₄₎aikyl, (pyranyl)C₍i_₄₎alkyl, (piperazinyl)C₍i_₄₎alkly cyclohexyl fused with a spiro 3-7 membered cycloalkyl, cycloalkenyl, or heterocyloalkyl ring, the heterocycloalkyl ring having 1 or two heteroatoms independently chosen from O and N, pyranyl, piperazinyl, thiopyranyl, thiopyran-1,1, -dioxide -4-yl, each of which (ii) is optionally substituted with one or more substituents chosen from halogen, hydroxyl, cyano, amino, Q^alkyl, C₍i_₄₎alkoxy, (mono- and di-C(i.₄₎alkylamino)C(₀-2₎alkyl, C₍i.₂₎haloalkyl, and C₍i.₂₎haloalkoxy, and optionally substituted with one substituent chosen from (C₍₃.₆₎Cycloalkyl)C(o-2₎alkyl, and (phenyl)C₍₀-2₎alkyl.

[0098] A is here m and n are each an integer from 0 to 2.

Z is -(C=0)OC₍₁_₄₎alkyl, -(C=0)OC₍₃-5₎Cycloalkyl, -(C=0)NHC₍₁_₄₎alkyl, -(C=0)NHC₍₃-

₅₎Cycloalkyl, -(C=0)R 11 , -S0₂R11 , pyndyl substituted with R 12 , or pyrmidinyl substituted with R 12.

R¹¹ is C₍₁_₄₎alkyl, -C₍₃-₅₎cycloalkyl, -CH₂OH, -CH₂OC₍₁_₂₎alkyl, -NHC₍₁_₃₎alkyl,

-NHC(₃_5₎Cycloalkyl, and Me .

[0099] R¹² is one or more substituents independently chosen from hydrogen, F, CI, and Me.

[0100] L is

(a) -O-oxetanyl, -OC₍₃_₅₎cycloalkyl, -0-CH₂-C₍₃_₅₎cycloalkyl, -(C=0)alkyl, -(C=0)C₍₃_ ₅₎Cycloalkyl, (mono- or di-C(i. ₎alkylcarboxamide, -(C=0)NHC₍₃.5₎Cycloalkyl, or -NH(C=0)C₍₃.5. _jcycloalkyl, each of which (a) is optionally substituted with hydroxyl, halogen, and -OMe, or

(b) pyrrolidone-l-yl, pyrazolyl, methyl-pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, oxazolyl, imidazolyl, each of which is optionally substituted with F, CI, or Me.

[0101] In certain embodiments one or more of the following conditions are met.

(a) R¹ and R² are both methyl.

(b) R³ is (phenyl)C₍₀-₂₎alkyl or (phenyl)C₍₀-₂₎alkyl,, substituted with 0, 1, or 2 substituents independently chosen from F, CI, CN, Me, -OMe, and CF₃.

(c) R³ is isopentyl, 4-methyl-pentyl, isobutyl, 3-methylbutyl, or 3,3-dimethylbutyl.

(d) R³ is C(₃_6₎Cycloaikyl)C₍o-₂₎aikyl or (pyranyl)C₍₀-₂₎alkyl.

(e) A is

-(C=0)cyclopropyl, -(C=0)0 C₍₁_

₃₎alkyl,

-(C=0)NH C₍₁_₃₎alkyl.

(f) Z is - -(C=0)cyclopropyl.

(g) A is

and L is oxaol-2-yl or thiazolyl.

(h) L is -(C=0)NHC₍₁_₄₎alkyl. [0102] The disclosure includes compounds, salts, and solvates of formula I as shown in the

SUMMARY section and also includes additional compounds, salts, and solvates in which the following conditions are met.

selected from the group consisting of OC₍₃_₅₎cycloalkyl ^ _( =0)NHC₍₁_₄₎alkyl,

[0103] L is selected from the group consisting of v—0 _; OC₍₃_5₎Cycloalkyl, -0-CH₂

O

C(₃_₅)Cycloalkyl Me ^*^* ^H

[0104] j) R¹ and R² are independently Me or Et.

[0105] (fjtAij is an integer from 0 to 3; g is an integer from 1 to 2; h is an integer from 1 to 2.

[0106] R⁵ is independently selected at each occurrence from the group consisting of

hydrogen, F, CI, Me, CF₃, Et, and OMe.

[0107] R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F, C₍i_

₄₎alkyl, C₍i.₄₎alkoxy, CF₃, and (C₍₃.₆₎Cycloalkyl)C(o-2₎alkyl.

[0108] R⁸ is independently selected at each occurrence from the group consisting of

hydrogen, CI, and Me.

[0109] R¹² is one or more substituents independently selected at each occurrence from the group consisting of hydrogen, CI, and Me. [0110] R is one or more substituents independently selected at each occurrence from the group consisting of hydrogen, CI, and Me.

[0111] (k) R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F,

Me, Et, and CF₃.

[0112] R⁸ is independently chosen at each occurrence from hydrogen and Me.

[0113] R¹² is hydrogen or Me.

[0114] R¹³ is hydro gen or Me.

[0115] (1) R¹ and R² are Me.

[01

17] R⁴ is independently selected from a group consisting of

C₍₃_₇₎Cycloalkyl,

[01

, and

[0120] R⁹ and R¹⁰ are independently selected from the group consisting of Me and Et, or, alternatively, R⁹ and R¹⁰ are taken together with the nitrogen atom to which they are bound to form pyrrolidin-l-yl, piperidin-l -yl, or morpholin-l-yl.

[01

[01

(n) R is selected from the group consisting of

, and

[0123] R is independently selected from a group consisting of C₍i_₄₎alkyl, C₍₃.₆₎Cycloalkyl,

[0124] R⁵ is independently selected at each occurrence from the group consisting of

hydrogen, F, CI, Me, CF₃, and OMe. [0125] R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F, Me, and Et.

[0126] R⁹ and R¹⁰ are Me, or, alternatively, R⁹ and R¹⁰ are taken together with the nitrogen atom to which they are bound to form pyrrolidin-l-yl, piperidin-l-yl, or morpholin-l-yl.

[0127] Z is selected from the group consisting of H° OC₍₃_₅₎cycloalkyl _^ _(_C=0)NHC₍₁_

V

[0128] L is selected from the group consisting of -a , -OC₍3-5₎Cycloalkyl, -0-CH_: _₃₎alkyl

C₍₃-₅₎cycloalkyl,

fj c₍₁

[0130] In formula la , lb, Ic, and Id Z is selected from the group consisting of H° OC₍₃_₅₎cycloalk l _^ _(c=0)NHC₍₁_₄₎alkyl,

R¹² is hydrogen or Me.

[0132] f is an integer from 1 to 3; g is an integer from 1 to 2, h is an integer from 1 to 2.

Et

[0133] R is selected from the group consisting of C₍i_₄₎alkyl, C₍₃.₇₎Cycloalkyl, Et ,

[0134] R⁵ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, Me, CF₃, and OMe.

[0135] R⁶ and R⁷ are independently selected from the group consisting of hydrogen, C(i.₄. jalkyl,

C₍₁.₂₎alkoxy, CF₃, CN, (C₍₃-6₎Cycloalkyl)C₍o-2₎alkyl,

[0136] R⁸ is hydrogen, C₍₁.₃₎alkyl, F, or CI.

[0137] (o) The disclosure also includes compounds, solvates, and salts of formula la, lb, Ic, and Id, in which

[0140] R is independently selected at each occurrence from the group consisting of C₍i_

₄₎alkyl, C₍₃.₇₎Cycloalkyl,

[0141] R⁵ is independently selected at each occurrence from the group consisting of

hydrogen, F, CI, Me, CF₃, and OMe.

[0142] R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F, Me,

. In certain embodiments (o), R⁶ and R⁷ are hydrogen, F, Me, Et, and CN.

[0143] (p) In certain embodiments (o),

R¹¹ is indep from the group consisting of C₍i_₄₎alkyl, C₍₃_5₎Cycloalkyl,

-NHC(i-₃₎aikyl, and

[0144] R⁴ is independently selected from a group consisting of

C₍₃.₇₎Cycloalkyl,

and

[0145] (q) The disclosure includes compounds, salts, and solvates of Formula (I-A-1)

[0146] In Formula I-A-1, Z is selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl.

[0147] (r) In Formula I-A-1, Z is optionally substituted pyridinyl.

compounds, salts, and solvates of formula I-A-2,

[0149] In Formula I-A-2, Z is selected from the group consisting of

optionally substituted C₍i_₃₎alkoxy, C₍₃_5₎Cycloalkyl, C₍i_5₎aminoalkyl, C₍₃_5₎Cycloalkyloxy; C₍₃. 5₎Cycloalkylamino, and 5- or and 5- or 6-membered heteroaryl, provided that Z is not OEt or furanyl

(t) Z is substituted alkoxy, C₍₃.₅₎Cycloalkyl,

C₍i.₃₎aminoalkyl, or .

(u) This disclosure includes compounds, salts and solvates of Formula I-A-3

[0150] Z is selected from the group consisting of:

a) optionally substituted branched C₍₃_5₎alkyl;

b) optionally substituted C₍i_₃₎alkoxy; optionally substituted C₍i_₃₎alkoxymethyl;

c) optionally substituted C₍i_5₎alkylamino having only one nitrogen; and

d) C(₃_5₎Cycloalkyl; C₍₃_5₎Cycloalkyloxy; C₍₃.5₎Cycloalkylamino, and C₍₃.

5₎Cycloalkylmethyl.

[0151] (v) In certain embodiments (u) Z is selected from the group consisting of C(i.₃₎alkyl,

C(i.₃₎alkoxy, and C(i.₃₎alkylamino having only one nitrogen.

[0152] (w) This disclosure includes compounds, salts and solvates of Formula I-A-4

[0153] Z is selected from the group consisting of:

a) optionally substituted C(i.₃₎alkyl; branched C₍₃.5₎alkyl;

b) optionally substituted C₍i.₃₎alkoxy; optionally substituted C₍i.₃₎alkoxymethyl;

c) optionally substituted C₍i_5₎alkylamino having only one nitrogen;

d) C₍₃_5₎Cycloalkyl; C₍₃.₅₎Cycloalkyloxy; C₍₃_5₎Cycloalkylamino, and C₍₃.

)Cycloalkylmethyl; and

e) Me .

[0154] (x) This disclosure includes compounds, salts, and solvates of Formula I-A-5

Z¹ is selected from the group consisting of:

optionally substituted C(i.₃₎alkyl; branched C₍₃.5₎alkyl;

optionally substituted C(i.₃₎alkoxymethyl;

optionally substituted 5- or 6-membered heteroaryl; and d) optionally substituted C₍₃.₆₎Cycloalkyl.

[0156] (y) This disclosure includes compounds, salts, and solvates of formula I-A-6, -7, and

-8

[0157] In I-A-6, -7, and -8, Z¹ is selected from the group consisting of:

a) optionally substituted C(i-₃₎aikyl; branched C(₃_5₎alkyl;

b) optionally substituted C(i_₃₎alkoxy; optionally substituted C(i_₃₎alkoxymethyl;

c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C₍₃.₆₎Cycloalkyl.

[015 s compounds, salts, and solvates of formula I-B-1

(I-B-1)

[0159] In formula I-B-1, Z¹ is selected from the group consisting of:

a) optionally substituted C₍i.₃₎alkyl; branched C₍₃.₅₎alkyl;

b) optionally substituted C₍i.₃₎alkoxymethyl;

c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C₍₃.6₎Cycloalkyl.

[0160] (aa) This disclosure includes compounds, salts, and solvates of formula I-B-2

[0161] In formula I-B-2, Z¹ is selected from the group consisting of:

a) optionally substituted

branched C₍₃_5₎alkyl;

b) optionally substituted C₍i_₃₎alkoxy; optionally substituted C₍i_₃₎alkoxymethyl; c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C(₃.6₎Cycloalkyl.

es compounds, salts, and solvates of I-B-3,

[0163] In formula I-B-3, Z¹ is selected from the group consisting of:

a) optionally substituted C(i.₃₎alkyl; branched C₍₃.5₎alkyl;

b) optionally substituted C(i.₃₎alkoxy; optionally substituted C(i.₃₎alkoxymethyl; c) optionally substituted C(i_5₎alkylamino having only one nitrogen; and d) C₍₃_5₎Cycloalkyl; C₍₃.₅₎Cycloalkyloxy; C₍₃_5₎Cycloalkylamino, and C₍₃.

)Cycloalkylmethyl.

[0164] (cc) This disclosure includes compounds, salts, and solvates of formula I-B-4

[0165] In formula I-B-4, Z¹ is selected from the group consisting of:

a) optionally substituted C₍i.₃₎alkyl; branched C₍₃.₅₎alkyl;

b) optionally substituted C₍i.₃₎alkoxy; optionally substituted C₍i.₃₎alkoxymethyl; c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C₍₃.₆₎Cycloalkyl.

[0166] (dd) This disclosure includes compounds, salts, and solvates of formula I-D-2

[016

-D-2, R³ is selected from the group consisting of

f is an integer from 1 to 3; g and h are each an independently integer from 1 to 2.

[0168] (ee) This disclosure includes, compounds, salts, and solvates, of formula I-C-1

[0169] In formula I-C-1 R³ is selected from the group consisting of:

a) hydrogen;

b) optionally substituted C₍i_₃₎alkyl; optionally substituted branched C(₃_5₎alkyl; and c) optionally substituted aryl or arylalkyl; optionally substituted 5- or 6-membered heteroaryl or 5- or 6-membered heteroarylalkyl;

d) optionally substituted C(3_₇₎Cycloalkyl; and

e) optionally substituted Cp^heterocycloalkyl or heterocycloalkyl. [0170] (ff) In certain embodiments of formula I ; -C-1, R³ is

[0171] (gg) This disclosure includes compounds, salts and solvates of formula I-C-2

[0172] In formula I-C-2 e is an integer from 0-2; and

R⁵ is independently chosen at each occurrence from the group consisting of:

a) optionally substituted

optionally substituted branched C₍₃_₅₎alkyl;

b) C₍i.₃₎alkoxy

c) halo and haloalkyl

d) cyano; and

e) optionally substituted aryl or heteroaryl fused at ortho and meta positions to form a biaryl with the phenylmethyl group linked to R⁵.

[0173] s, salts, and solvates of formula I-D-1

In I-D-1 :

I ^ rty f

f is an integer from 1 to 3. [0175] g and h are each an independently integer from 1 to 2.

[0176] (ii) This disclosure includes compounds, salts, and solvates of formula I-C-3

[0177] In formula I-C-3, R^3a is selected from the group consisting of:

a) hydrogen;

b) optionally substituted

optionally substituted branched C₍₃_5₎alkyl;

c) optionally substituted aryl or arylalkyl; optionally substituted 5- or 6-membered heteroaryl or 5- or 6-membered heteroarylalkyl;

d) optionally substituted C₍₃.₇₎Cycloalkyl; and

e) optionally substituted C₍₃.₇₎he lkyl or heterocycloalkyl.

[0178] (jj) In certain embodiments (ii) R^3a is

.

, salts, and solvates of formula I-C-4,

e is an integer from 0-2.

[0180] R⁵ is independently selected at each occurrence from the group consisting of:

a) optionally substituted

b) C₍i.₃₎alkoxy;

c) halo and haloalkyl;

d) cyano; and

e) optionally substituted aryl or heteroaryl fused at ortho and meta positions to form a biaryl with the phenylmethyl group linked to R⁵.

[0181] In certain embodiments, the disclosure relates to a compound depicted in TABLE 4, or a pharmaceutical acceptable salt or solvate thereof: [A2] [0182] In certain embodiments, the disclosure relates to any of the compounds described herein, wherein the compound is depicted in TABLE 1.

[0183] In certain embodiments, the disclosure relates to any of the compounds described herein, provided the compound is NOT compound 1, compound 2, compound 3, compound 137, or compound 140.

Pharmaceutical Compositions

[0184] In certain embodiments, the disclosure relates to a pharmaceutical composition comprising any one of the aforementioned compounds, and a pharmaceutically acceptable carrier.

[0185] In certain embodiments, the disclosure relates to a pharmaceutical composition made by mixing any of the compositions described herein and a pharmaceutically acceptable carrier.

[0186] In certain embodiments, the disclosure relates to any one of the aforementioned compositions, wherein the compound is present in an amount of at least 1.0% by weight.

[0187] In certain embodiments, the disclosure relates to any one of the aforementioned compositions, wherein the compound is present in an amount of from about 1.0% to about 10.0% by weight.

[0188] In certain embodiments, the disclosure relates to any one of the aforementioned compositions, wherein the compound is present in an amount of from about 10.0% to about 75.0% by weight.

[0189] In certain embodiments, the disclosure relates to any one of the aforementioned compositions, wherein the compound is present in an amount of from about 75.0% to about 99% by weight.

Methods and Processes

[0190] In certain embodiments, the disclosure relates to a method of treating an ALDHlAl disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0191] In certain embodiments, the disclosure relates to a method of treating an ALDHlAl disorder, comprising administering to a subject in need thereof a therapeutically effective amount of compound 1, compound 2, compound 3, compound 137, or compound 140.

[0192] In certain embodiments, the disclosure relates to any of the methods described herein, wherein the ALDHlAl disorder is selected from the group consisting of cancer, inflammation or a disease or disorder associated with inflammation, and obesity.

[0193] In certain embodiments, the disclosure relates to any of the methods described herein, wherein the ALDHlAl disorder is selected from the group consisting of colon cancer, pancreatic cancer, nasopharyngeal carcinoma, thyroid cancer, prostate cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, and breast cancer.

[0194] In certain embodiments, the disclosure relates to any of the methods described herein, wherein the ALDHlAl disorder is selected from the group consisting of atherosclerosis, ischaemic heart disease, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and interstitial cystitis.

[0195] In certain embodiments, the disclosure relates to a method of preventing or treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of any one of the compounds described herein. In certain embodiments, the methods are useful for treating a wide variety of cancers, including carcinomas, sarcomas, leukemias, and lymphomas. Thus, the subject can have a cancer such as a carcinoma, a sarcoma, a leukemia, or a lymphoma. In some embodiments, the individual has lung cancer resulting from prolonged exposure to cigarette smoke.

[0196] Carcinomas that can be treated using a subject method include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), bladder carcinoma, including transitional cell carcinoma (a malignant neoplasm of the bladder), bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, renal cell carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelieal carcinoma, and nasopharyngeal carcinoma, etc.

[0197] Specifically, the disclosure relates to the treatment, detection, or prognosis associated with a patient suffering from a head and neck squamous cell carcinoma (HNSCC), which are the most frequent malignancies of the upper aerodigestive tract. ALDH1 -positive HNSCC patients have worse prognosis, which was associated with common clinicopathological features and poor prognostic factors. When isolated from HNSCC patients, ALDH1 -positive cells (HNSCC- ALDH 1 + cells) display radioresistance and represent a reservoir for generating tumors.

[0198] ALDHlAl is also hypothesized to be a marker for normal and malignant human colonic stem cells (CSCs). In addition, ALDHlAl may be used to track CSC overpopulation during colon tumorigenesis. Moreover, higher numbers of ALDHlAl -expressing cells in an adenoma is associated with a higher risk for metachronous adenoma, independent of adenoma size or histopathology.

However, cytoplasmic and stromal expression of ALDHlAl is not significantly associated with prognosis either in colon cancer or in rectal cancer. Furthermore, cytoplasmic expression of

ALDHlAl does not predict therapeutic vulnerability to palliative chemotherapy in patients with metastatic diseases. Interestingly, nuclear expression of ALDHlAl is observed in a small subgroup of patients with colon and rectal cancer. In patients with colon cancer, nuclear expression is significantly associated with shortened overall survival. Besides nuclear localization, ALDHlAl is present in the secretome of metastatic colon cancer cells. While not wishing to be bound by any particular theory, it is possible that extracellular ALDHlAl protects the CSC against the hostile environment in the extracellular space, e.g. chemotherapeutic agents or oxidative conditions.

[0199] In addition, non-small cell lung cancers (NSCLC) express very high levels of ALDHlAl in comparison with SCLC; the elevated expression of ALDHlAl may be associated with malignant transformation to adenocarcinoma.

[0200] In papillary thyroid carcinoma (PTC), ALDHlAl does not appear to be a marker for CSC, but it expression occurs in high levels in PTC. High ALDHlAl expression in PTC is associated with a reduced lymph node recurrence -free survival (LN-RFS) and distant recurrence -free survival (DRFS) in PTC patients, relative to patients having low ALDHlAl expression. Multivariate analysis confirmed that ALDHlAl expression was an independent prognostic factor for LN-RFS and DRFS in PTC patients.

[0201] In addition, ALDHlAl is up-regulated in clonal sub-populations of pancreatic cancer cell line, MiaPaCa-2. ALDHlAl expression is highest in more highly-invading pancreatic cancer cells lines and data suggest that ALDHlAl may be promote pancreatic cancer metastasis. Analysis of human tissue sections revealed ALDHlAl to be abundantly expressed in the pancreatic cancer tissue. Moreover, high expression of ALDHlAl in these cancers is found to be significantly associated with proliferation of the tumor cells. Cell populations with high ALDH activity are much more efficient at promoting tumor-initiation and have enhanced tumorigenic potential than cells that are high in CD 133 expression (CD133(+)) and with low ALDH activity. Although CD133(+) cells may alone possess tumorigenic potential, they are significantly less tumorigenic than cells with high ALDH expression. In addition, high levels of ALDHlAl expression contribute to the intrinsic and acquired resistance of in human pancreatic adenocarcinoma (MiaPaCa-2) cells to gemcitabine. Knock-down of ALDHlAl expression with siRNA along with gemcitabine treatment results in a significant decrease in cell viability and an increase in apoptotic cell death in the gemcitabine -resistant MiaPaCa-2 (MiaPaCa- 2/GR) cells. Additional studies showed that a combination treatment (dasatinib and gemcitabine) results in inhibition of cell proliferation and decreased survival of MiaPaCa-2/P (parental) and MIA PaCa-2/GR by reducing ALDHlAl expression in ALDHlAl -enriched pancreatic cancer MiaPaCa-2 cells. In addition, using adoptive therapy with ALDHlAl -specific CD8(+) T cells eliminated ALDH enzymatically-active (or ALDH bright) cells, inhibited pancreatic tumor growth and metastases, or prolonged survival of xenograft-bearing immunodeficient mice. While not wishing to be bound by any particular theory, the available data strongly support the potential of ALDHlAl -based immunotherapy to selectively target CSCs in human cancer.

[0202] The association between ALDHlAl expression and clinicopathological/prognostic parameters in breast cancer patients has also been evaluated. Through overall and subcategory analyses using data froml5 publications that included 921 ALDHlAl -positive cases and 2353 controls, ALDHlAl was proposed to be a biomarker that predicts tumor progression and poor survival of breast cancer patients.ALDHlAl has also been suggested as being predictive for the prognosis of triple-negative breast cancer (TNBC), a subtype of breast cancer characterized by poor outcomes. In addition, the ALDHlAl phenotype is an independent predictor of early tumor relapse (i.e., incidence of early local recurrence and distant metastasis) of invasive ductal carcinoma.

ALDHlAl expression has been shown to be associated with severity of breast cancer. More specifically, tumors associated with advanced stage, were node-positive, or of larger size are found to have higher ALDHlAl expression in the tumor tissue. ALDHlAl expression is also correlated with worse disease-free survival and overall survival in patients who had been treated with neoadjuvant chemotherapy. B RCA 1 -related breast cancers show more frequent epithelial and stromal

(peritumoral) ALDHlAl expression leading to the suggestion that ALDHlAl may be a diagnostic marker and a therapeutic target of BRCA1 -related breast cancer. Using ellipticine, an inhibitor of ALDHlAl as a model, molecular simulation and docking studies revealed that amino acids present in the active site of human ALDHlAl, viz. Asn-117, Asn-121, Glu-249, Cys-302 and Gln-350, interact with ellipticine. At high concentrations (3 mM), ellipticine decreased the expression of ALDH1A1- positive breast cancer stem cells (BCSCs) in the SUM159 cell line. Ellipticine also reduced the formation of mammospheresby MCF7 and SUM159 breast cancer cell lines. Interestingly, when treated with a combination of ellipticine and paclitaxel, the percentage of ALDHlAl -positive BCSCs was decreased significantly in vitro.

[0203] Ovarian CSCs may be identified by their expression of ALDHlAl. High ALDH1 expression is significantly associated with poor clinical outcomes in serous ovarian cancer patients (P=0.0036). More recent data indicate that there is a link between ALDH1 and EGFR expression in high-grade serous ovarian carcinoma (HGSC). Immunopositivity for both ALDH1 and EGFR identifies a subgroup of highly aggressive, poor-prognosis cancers. In addition, ALDH enzymatically-active (or ALDH bright) tumor cells exhibit CSC properties and are resistant to chemotherapy. Finally, inhibition of ALDHlAl results in disruption of ovarian cancer cell spheroid formation and cell viability.

[0204] ALDHlAl is also a marker for malignant prostate stem cells and predictor of prostate cancer (PCa) patient outcome. ALDHlAl -expressing PCa cells exhibit high clonogenic and tumorigenic capacities. In addition, xenograft experiments showed that PCa in mice resemble histopathologic characteristics and heterogeneity of the parental PCa cells in humans. While ALDHlAl -expressing cells are sparse in normal human prostate tissues and limited to the basal component in normal prostates, in tumor specimens, increased ALDHlAl expression is found not only in secretory type cancer epithelial cells but also in neuroendocrine tumor populations. Finally, high ALDHlAl expression in PCa correlates positively with Gleason score (P=0.01) and pathologic stage (P=0.01), and is inversely associated with overall survival and cancer-specific survival of PCa patients (P=0.00093 and 0.00017, respectively). ALDHlAl is also a valuable biomarker for prognosis. The crucial role of ALDHlAl enzymatic activity in CSC maintenance was demonstrated by DEAB (an ALDH inhibitor) induced repression of sphere formation by RWPE-2, CWR-Rl and DU-145 PCa cell lines.

[0205] In addition, ALDHlAl has been recently suggested to be a novel CSC marker and a valuable predictor of poor survival and enhanced invasiveness and metastatic ability in nasopharyngeal carcinoma (NPC). Furthermore, ALDHlAl expression in the invasive front (which underlies the biological aggressiveness and epithelial-mesenchymal transition (EMT) in human malignances) links closely with EMT characteristics and tumor aggressiveness, confirming the prognostic value of ALDHlAl as a marker in NPC patients. Finally, ALDHlAl expression is high in spindle cells (cells that are prominently found in the invasive tumor front and the surrounding stroma) and may be responsible for the aggressive patterns and unfavorable prognosis in NPC patients.

[0206] Sarcomas that can be treated using a subject method include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,

lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[0207] Other solid tumors that can be treated using a subject method include, but are not limited to, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma,

hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.

[0208] Leukemias that can be treated using a subject method include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of multipotential hematopoietic stem cells); b) acute myelogenous leukemias (neoplastic transformation of a multipotential hematopoietic stem cell or a hematopoietic cell of restricted lineage potential; c) chronic lymphocytic leukemias (CLL; clonal proliferation of immunologically immature and functionally incompetent small lymphocytes), including B-cell CLL, T-cell CLL prolymphocytic leukemia, and hairy cell leukemia; and d) acute lymphoblastic leukemias (characterized by accumulation of lymphoblasts). Lymphomas that can be treated using a subject method include, but are not limited to, B-cell lymphomas (e.g., Burkitt's lymphoma); Hodgkin's lymphoma; or the like.

[0209] In certain embodiments, the disclosure relates to a method of preventing or treating a disease associated with chronic free radicals in a subject in need thereof comprising administering a therapeutically effective amount of any one of the compounds described herein. Chronic free radical- associated disorders that are amenable to treatment with a subject method include neurodegenerative diseases such as Parkinson's Disease and Alzheimer's Disease; amyotrophic lateral sclerosis (ALS); peripheral artery disease, or the like. In some embodiments, a chronic free radical-associated disease is treated by chronic (e.g., daily) treatment with a compound.

[0210] In certain embodiments, the disclosure relates to a method of preventing or treating a cardiovascular disorder in a subject in need thereof comprising administering a therapeutically effective amount of any one of the compounds described herein. In certain embodiments, cardiovascular disorders include angina, heart failure, insensitivity to nitroglycerin in angina and heart failure, hypertension, and heart disease.

[0211] In certain embodiments, the disclosure relates to a method of preventing or treating diabetes in a subject in need thereof comprising administering a therapeutically effective amount of any one of the compounds described herein. Subjects suitable for treatment with the inventive methods include individuals having Type 1 or Type 2 diabetes. Subjects suitable for treatment include individuals who have been diagnosed with Type 1 diabetes mellitus, where such individuals include those having a fasting blood glucose level greater than about 126 mg/dL. Such individuals include those having blood glucose levels of greater than about 200 mg/dL following a two-hour glucose tolerance test (75 g anhydrous glucose orally). Subjects suitable for treatment include individuals who have been diagnosed with Type 2 diabetes; individuals who have not yet been diagnosed with Type 2 diabetes, but who are at risk of developing Type 2 diabetes, e.g., individuals having a body mass index (weight in kilograms divided by height (in meters) squared) greater than 25, e.g., individuals having a body mass index from about 25 to about 27, from about 27 to about 30, or greater than 30.

[0212] In certain embodiments, the disclosure relates to a method of preventing or treating obesity in a subject in need thereof comprising administering a therapeutically effective amount of any one of the compounds described herein. ALDH1A1 has been implicated in obesity. More specifically, Aldhlal -deficient mice are protected from diet-induced obesity and diabetes. In addition Aldhlal- deficient mice display significantly decreased fasting glucose concentrations compared with WT controls as a result of attenuated hepatic glucose production. The same study also showed that Aldhlal deficiency resulted in increased AMP-activated protein kinase a activity, decreased expression of lipogenic targets of AMP-activated protein kinase a and significantly attenuated hepatic triacylglycerol synthesis.

[0213] In certain embodiments, the disclosure relates to a method of preventing or treating inflammation or a disease or disorder associated with inflammation in a subject in need thereof comprising administering a therapeutically effective amount of any one of the compounds described herein. Examples of diseases or disorders associated with inflammation include: cancer (described herein), atherosclerosis, ischaemic heart disease, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and interstitial cystitis.

[0214] Specifically, ALDH1A1 significantly induced in CD14(+) macrophages from the intestinal mucosa of patients with Crohn's disease (CD) than from controls and this is associated with generation of retinoic acid, which in turn may increase the inflammatory phenotype of these cells. Therefore inhibition of ALDH1A1 may reduce the generation of RA by CD14(+) macrophages, offering a new therapeutic options for patients with CD. [0215] In certain embodiments, the disclosure relates to any one of the aforementioned methods, wherein the subject is a mammal.

[0216] In certain embodiments, the disclosure relates to any one of the aforementioned methods, wherein the subject is a human.

[0217] In certain embodiments, the disclosure relates to a process for making a pharmaceutical composition comprising mixing any of the compounds described herein and a pharmaceutically acceptable carrier.

Combination Therapy

[0218] The compounds of the disclosure can be combined with other therapeutic agents. The compound and other therapeutic agent may be administered simultaneously or sequentially. When the other therapeutic agents are administered simultaneously they can be administered in the same or separate formulations, but are administered at the same time. The other therapeutic agents are administered sequentially with one another and with the compounds, when the administration of the other therapeutic agents and the compounds is temporally separated. The separation in time between the administration of these compounds may be a matter of minutes or it may be longer. In some instances the compounds are administered with multiple therapeutic agents, i.e., 2, 3, 4 or even more different agents.

Pharmaceutical Compositions

[0219] While it is possible for compounds of the present disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, the present disclosure provides a pharmaceutical formulation comprising a compound or a pharmaceutically acceptable salt, prodrug or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients can be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions of the present disclosure can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes, for example.

[0220] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route depends upon for example the condition and disorder of the recipient. The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art. All methods include the step of bringing into association a compound of the present disclosure or a pharmaceutically acceptable salt, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0221] The compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.

Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

[0222] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which can contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0223] In addition to the formulations described previously, the compounds of the present disclosure can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

EXAMPLES

[0224] This invention is further illustrated by the following examples, which should not be construed as limiting. General Methods for Examples 1-49

[0225] All air or moisture sensitive reactions were performed under positive pressure of nitrogen with oven-dried glassware. Chemical reagents and anhydrous solvents were obtained from commercial sources and used as-is. Preparative purification was performed on a Waters semi- preparative HPLC. The column used was a Phenomenex Luna CI 8 (5 micron, 30 x 75 mm) at a flow rate of 45 mL/min. The mobile phase consisted of acetonitrile and water (each containing 0.1% trifluoroacetic acid). A gradient of 10% to 50% acetonitrile over 8 minutes was used during the purification. Fraction collection was triggered by UV detection (220 nm). Analytical analysis for purity was determined by two different methods denoted as Final QC Methods 1 and 2. Method 1 : Analysis was performed on an Agilent 1290 Infinity Series HPLC. UHPLC Long Gradient Equivalent 4% to 100% acetonitrile (0.05% trifluoroacetic acid) in water over 3 minutes run time of 4.5 minutes with a flow rate of 0.8 mL/min. A Phenomenex Luna CI 8 column (3 micron, 3 x 75 mm) was used at a temperature of 50 °C. Method 2: analysis was performed on an Agilent 1260 with a 7 minute gradient of 4% to 100% acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) over 8 minute run time at a flow rate of 1 mL/min. A Phenomenex Luna CI 8 column (3 micron, 3 x 75 mm) was used at a temperature of 50 °C. Purity determination was performed using an Agilent Diode Array Detector for both Method 1 and Method 2. Mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization in the positive mode. All of the analogs for assay have purity greater than 95% based on both analytical methods. H spectra were recorded on Varian 400 (100) and 600 MHz spectrometers. High resolution mass spectrometry was recorded on Agilent 6210 Time-of-Flight LC/MS system.

[0226] In addition to the compounds in Examples 1A-49A, other compounds of the disclosure were similarly prepared according to the procedures as described in the general synthesis schemes and examples. TABLE 1 lists some additional compounds of formula (I).

Example 1. 8-((l-(Cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-7-(3-methylbenzyl)- lH-purine-2.6(3H.7H)-dione. TFA (Cpd. 17)

STEP 1: 8-chloro-l,3-dimethyl-7-(3-methylbenzyl)-lH-purine-2,6(3H,7H)-dione

[0227] To a mixture of 8-chloro-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (2.146 g, 10 mmol) and K₂C0₃ (2.073 g, 15.00 mmol) was added N,N-Dimethylformamide (Volume: 12 mL). The mixture was stirred at rt for 5 min and l-(bromomethyl)-3-methylbenzene (2.221 g, 12.00 mmol) was added. The mixture was stirred at rt for 30 min and was heated at 60°C for 2 h. The mixture was then dropped into vigorously stirred H₂0 (250 mL). The resulting solid was filtered, washed with H₂0 (30 mL x 2), hexane (5 mL x 2), and then dried to give 8-chloro-l,3-dimethyl-7-(3-methylbenzyl)-lH- purine-2,6(3H,7H)-dione (3.12 g, 9.79 mmol, 98 % yield). H NMR (400 MHz, Chloroform-d) δ 7.23 (dd, = 8.2, 7.4 Hz, 1H), 7.17-7.09 (m, 3H), 5.51 (s, 2H), 3.55 (s, 3H), 3.40 (s, 3H), 2.33 (s, 3H); LC- MS (Method 1): t_R= 3.40 min, m/z (M+H)⁺ = 319.

STEP 2: i-butyl 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8- yl)oxy)piperidine- 1 -carboxylate

[0228] To a solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (403 mg, 2.000 mmol) in DMF (Volume: 4 mL) under N₂ at rt was added NaH (72.0 mg, 3.00 mmol). After 5 min stirring, 8-chloro- l,3-dimethyl-7-(3-methylbenzyl)-lH-purine-2,6(3H,7H)-dione (638 mg, 2 mmol) was added. The mixture was then stirred at rt for 30 min and was poured into EtOAc/H₂0 (10 niL/10 mL). The aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic layer was dried (Na₂S0₄) and filtered. After removal of solvent, the crude product was purified by silica gel chromatography using 20-60-80% EtOAc/hexane as the eluent to give i-butyl 4-((l,3-dimethyl-7-(3-methylbenzyl)- 2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl)oxy)piperidine-l -carboxylate (857 mg, 1.772 mmol, 89 % yield). H NMR (400 MHz, Chloroform-d) δ 7.23-7.11 (m, 3H), 7.08 (ddq, = 7.3, 1.6, 0.8 Hz, 1H), 5.25 (s, 2H), 5.17 (dt, = 7.4, 3.7 Hz, 1H), 3.57 (ddd, = 13.6, 7.6, 3.9 Hz, 2H), 3.49 (s, 3H), 3.40 (s, 3H), 3.39-3.30 (m, 2H), 2.31 (d, = 0.8 Hz, 3H), 1.97 (m, 2H), 1.79 (m, 2H), 1.47 (s, 9H).

STEP 3: 1.3-dimethyl-7-(3-methylbenzyl)-8-(piperidin-4-yloxy)-lH-purine-2.6(3H.7H)-dione. HC1

[0229] To a solution of i-butyl 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahydro- lH-purin- 8 -yl)oxy)piperidine-l -carboxylate (945 mg, 1.954 mmol) in 1,4-Dioxane (Volume: 2 mL) was added HC1 (4 M in dioxane, 4 mL). The mixture was stirred at rt for overnight and the mixture was concentrated to remove all the solvent. Then the product was dried in vacuo to give 1,3-dimethyl- 7-(3-methylbenzyl)-8-(piperidin-4-yloxy)-lH-purine-2,6(3H,7H)-dione, HC1 (796 mg, 1.896 mmol, 97 % yield). The material was used without further purification. LC-MS (Method 1): ¾ = 2.70 min (100%, UV: 254 nm), m/z (M+H)⁺ = 384.

STEP 4: 8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-7-(3-methylbenzyl)-lH- purine-2,6(3H,7H)-dione, TFA (Cpd. 17)

[0230] To a solution of l,3-dimethyl-7-(3-methylbenzyl)-8-(piperidin-4-yloxy)-lH-purine- 2,6(3H,7H)-dione, HC1 (42.0 mg, 0.1 mmol) in CH₂C1₂ (Volume: 2 mL) was added Et₃N (0.070 mL, 0.5 mmol) and then cyclopropanecarbonyl chloride (21.0 mg, 0.2 mmol) dropwise. The mixture was stirred at rt for 30 min. MeOH (0.2 mL) was added and stirred for another 30 min. The mixture was concentrated, dissolved in DMSO (2 mL), filtered through a filter, and then submitted for purification to give 8-((l-(cyclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-7-(3-methylbenzyl)-lH-purine- 2,6(3H,7H)-dione, TFA (25.5 mg, 0.045 mmol, 45.1 % yield). H NMR (400 MHz, DMSO-d6) δ 7.20 (t, = 7.5 Hz, 1H), 7.14-7.03 (m, 3H), 5.22 (s, 2H), 5.19 (dd, / = 6.8, 3.4 Hz, 1H), 3.66-3.40 (m, 4H), 3.36 (s, 3H), 3.20 (s, 3H), 2.24 (s, 3H), 1.96 (m, 3H), 1.69 (m, 2H), 0.78-0.59 (m, 4H); LC-MS (Method 2): t_R = 5.15 min, m/z (M+H)⁺ = 452; HRMS calculated for C₂₄H₂₉N₅0₄Na (M+Na)⁺ :

474.2112, found: 474.2123.

Example 2. 8-((l-(Cvclopropanecarbonyl)piperidin-4-yl)oxy)-7-isopentyl-l,3-dimethyl-lH- TFA (Cpd. 48)

STEP 1: 8-chloro-7-isopentyl-l,3-dimethyl-lH-purine-2,6(3HJH)-dione

[0231] To a mixture of 8-chloro-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (4.29 g, 20 mmol) and K₂C0₃ (3.46 g, 25.00 mmol) was added N,N-Dimethylformamide (Volume: 25 mL). The mixture was stirred at rt for 5 min and l-bromo-3-methylbutane (3.78 g, 25.00 mmol) was added. The mixture was stirred at rt for 30 min and was heated at 60°C for overnight. The mixture was dropped into vigorously stirred H₂0 (500 mL). The resulting solid was filtered, washed with H₂0 (30 mL x 2) and then dried to give 8-chloro-7-isopentyl-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (5.39 g, 18.93 mmol, 95 % yield). H NMR (400 MHz, Chloroform-d) δ 4.38-4.25 (m, 2H), 3.54 (s, 3H), 3.40 (s, 3H), 1.70 (tdd, = 6.9, 4.3, 2.5 Hz, 3H), 1.04-0.93 (m, 6H); LC-MS (Method 1): t_R = 3.44 min, m/z (M+H)⁺ = 285.

STEP 2: f-butyl 4-((7-isopentyl-l,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8- yl)oxy)piperidine- 1 -carboxylate

[0232] To a solution of i-butyl 4-hydroxypiperidine-l -carboxylate (403 mg, 2.000 mmol) in DMF (Volume: 4 mL) under N₂ at rt was added NaH (72.0 mg, 3.00 mmol). After 5 min stirring, 8-chloro- 7-isopentyl-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (569 mg, 2 mmol) was added. The mixture was then stirred at rt for 1 h and was poured into EtOAc/H₂0 (30 inL/30 mL). The aqueous layer was extracted with EtOAc (10 mL x 2). The combined organic layer was dried (Na₂S0₄) and filtered. After removal of solvent, the crude product was purified by silica gel chromatography using 20-40- 50% EtOAc/hexane as the eluent to give i-butyl 4-((7-isopentyl-l ,3-dimethyl-2,6-dioxo-2,3,6,7- tetrahydro-lH-purin-8-yl)oxy)piperidine-l-carboxylate (725 mg, 1.613 mmol, 81 % yield). H NMR (400 MHz, Chloroform-d) δ 5.16 (dq, / = 7.6, 3.8 Hz, 1H), 4.09 (dd, / = 8.0, 6.5 Hz, 2H), 3.79-3.63 (m, 2H), 3.50 (s, 3H), 3.38 (s, 3H), 3.38-3.29 (m, 2H), 2.03 (ddt, / = 13.9, 7.2, 3.7 Hz, 2H), 1.81 (dp, / = 13.0, 3.9 Hz, 2H), 1.69-1.61 (m, 2H), 1.58 (s, 1H), 1.48 (s, 9H), 0.95 (d, / = 6.4 Hz, 6H); LC-MS (Method 1): t_R = 3.81 min, m/z (M+H)⁺ = 450.

STEP 3: 7-isopentyl-l ,3-dimethyl-8-(piperidin-4-yloxy)-lH-purine-2,6(3H,7H)-dione, HCl

[0233] To a solution of i-butyl 4-((7-isopentyl-l ,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin- 8-yl)oxy)piperidine-l-carboxylate, HCl (700 mg, 1.440 mmol) in 1 ,4-Dioxane (Volume: 5 mL) was added HCl (4M in 1 ,4-dioxane, 5 mL). The mixture was stirred at rt for 4 h. The mixture was dilute with hexane (20 mL) and the solid was filtered. The solid is slightly hydroscopic and was transferred into a vial quickly and dried in vacuo to give 7-isopentyl-l ,3-dimethyl-8-(piperidin-4-yloxy)-lH- purine-2,6(3H,7H)-dione, HCl (502 mg, 1.301 mmol, 90 % yield). This material was used without further purification. H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H, including salt NH), 5.19 (tt, / = 7.2, 3.5 Hz, 1H), 4.05 (t, J = 7.1 Hz, 2H), 3.35 (s, 3H), 3.19 (s, 3H), 2.26-1.90 (m, 4H), 1.57 (dt, / = 7.6, 6.5 Hz, 2H), 1.47 (m, 1H), 0.89 (d, = 6.5 Hz, 6H) (The 4 protons on piperidine ring adjacent NH are broad.); LC-MS (Method 1): f_R = 2.64 min, m/z (M+H)⁺ = 350.

STEP 4: 8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-7-isopentyl-l ,3-dimethyl-lH-purine- 2,6(3H,7H)-dione, TFA (Cpd. 48)

[0234] To a solution of 7-isopentyl-l ,3-dimethyl-8-(piperidin-4-yloxy)-lH-purine-2,6(3H,7H)-dione, HCl (38.6 mg, 0.1 mmol) in CH₂C1₂ (Volume: 2 mL) was added Et₃N (0.070 mL, 0.5 mmol) and then cyclopropanecarbonyl chloride (21.0 mg, 0.2 mmol) dropwise. The mixture was stirred at rt for 30 min. MeOH (0.2 mL) was added and stirred for another 30 min. The mixture was concentrated, dissolved in DMSO (2 mL), filtered through a filter, and then submitted for purification to give 8-((l - (cyclopropanecarbonyl)piperidin-4-yl)oxy)-7-isopentyl-l ,3-dimethyl-lH-purine-2,6(3H,7H)-dione, TFA (21.2 mg, 0.040 mmol, 39.9 % yield). H NMR (400 MHz, DMSO-d6) δ 5.20 (dt, / = 7.4, 3.7 Hz, 1H), 4.04 (t, J = 7.1 Hz, 2H), 3.86 (br s, 1H), 3.68 (br s, 2H), 3.45 (br s, 1H), 3.36 (s, 3H), 3.19 (s, 3H), 2.13-1.86 (m, 3H), 1.87-1.61 (m, 2H), 1.61-1.52 (m, 2H), 1.53-1.38 (m, 1H), 0.88 (d, / = 6.5 Hz, 6H), 0.76-0.62 (m, 4H); LC-MS (Method 2): t_R = 5.22 min (100%, UV: 254 nm), m/z (M+H)⁺ = 418. Example 3. 7-Benzyl-8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-lH-purine- -dione (Cpd. 62)

STEP 1: 7-benzyl-8-chloro-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione

[0235] To a mixture of 8-chloro-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (4.29 g, 20 mmol) and K₂C0₃ (4.15 g, 30.0 mmol) was added N,N-Dimethylformamide (Volume: 25 mL). The mixture was stirred at rt for 5 min and (bromomethyl)benzene (4.10 g, 24.00 mmol) was added. The mixture was stirred at rt for 30 min and was heated at 60 °C for 1 h. The mixture was dropped into vigorously stirred H₂0 (500 mL). The resulting solid was filtered, washed with H₂0 (30 mL x 3), hexane (5 mL x 2), and then dried to give 7-benzyl-8-chloro-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (6.06 g, 19.89 mmol, 99 % yield) The material was used without further purification. ¾ NMR (400 MHz,

Chloroform-d) δ 7.43-7.28 (m, 5H), 5.55 (s, 2H), 3.55 (s, 3H), 3.41 (s, 3H); LC-MS (Method 1): t_R = 3.28 min, m/z (M+H)⁺ = 305.

STEP 2: f-butyl 4-((7-benzyl-l,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8- yl)oxy)piperidine- 1 -carboxylate

[0236] To a solution of i-butyl 4-hydroxypiperidine-l -carboxylate (2.62 g, 13.00 mmol) in DMF (Volume: 25 mL) under N₂ at rt was added NaH (0.480 g, 20.00 mmol). After 5 min stirring, 7- benzyl-8-chloro-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (3.05 g, 10 mmol) was added. The mixture was then stirred at rt for 2 h and was poured into H₂0 (500 mL). The solid was filtered and washed with H₂0 (20 mL x 3) and then dried to give i-butyl 4-((7-benzyl-l,3-dimethyl-2,6-dioxo- 2,3,6,7-tetrahydro-lH-purin-8-yl)oxy)piperidine-l-carboxylate (4.5 g, 9.58 mmol, 96 % yield). This material was used without further purification. LC-MS (Method 1): t_R = 3.64 min, m/z (M+H)⁺ = 470.

STEP 3: 7-benzyl-l,3-dimethyl-8-(piperidin-4-yloxy)-lH-purine-2,6(3H,7H)-dione, HC1

[0237] To a solution of i-butyl 4-((7-benzyl-l,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8- yl)oxy)piperidine-l -carboxylate (1567 mg, 3.34 mmol) in 1,4-Dioxane (Volume: 5 mL) was added HC1 (4 M in 1,4-dioxane, 5 mL). The mixture was stirred at rt for 3 h. The mixture was concentrated and dried in vacuo to give 7-benzyl-l,3-dimethyl-8-(piperidin-4-yloxy)-lH-purine-2,6(3H,7H)-dione, HC1 (1364 mg, 3.36 mmol, > 99 % yield). The material was used for next step without further purification. Η NMR (400 MHz, DMSO-d6) δ 8.79 (s, 2H), 7.41-7.21 (m, 5H), 5.28 (s, 2H), 5.20 (dt, / = 6.8, 3.4 Hz, 1H), 3.36 (s, 3H), 3.20 (s, 3H), 3.09 (t, / = 6.0 Hz, 4H), 2.19-2.04 (m, 2H), 2.01-1.84 (m, 2H); LC-MS (Method 1): f_R = 2.62 min, mJz (M+H)⁺ = 370.

STEP 4: 7-benzyl-8-((l -(cvclopropanecarbonyl)piperidin-4-yl)oxy)-l ,3-dimethyl-lH-purine- 2,6(3H,7H)-dione (Cpd. 62)

[0238] To a solution of 7-benzyl-l ,3-dimethyl-8-(piperidin-4-yloxy)-lH-purine-2,6(3H,7H)-dione, HC1 (0.609 g, 1.5 mmol) in CH₂C1₂ (Volume: 5 mL) was added Et₃N (1.254 mL, 9.00 mmol) and then cyclopropanecarbonyl chloride (0.314 g, 3.00 mmol) dropwise. The mixture was stirred at rt for 30 min. The mixture was poured into EtOAc/H₂0/Na₂C0₃(aq) (50 mL/25 inL/25 mL). The organic layer was washed with H₂0 (50 mL), dried (Na₂S0₄) and filtered. After removal of solvent, the product was dried to give 7-benzyl-8-((l -(cyclopropanecarbonyl)piperidin-4-yl)oxy)-l ,3-dimethyl- lH-purine-2,6(3H,7H)-dione (630 mg, 96%). H NMR (400 MHz, DMSO-d6) δ 7.46-7.11 (m, 5H), 5.26 (s, 2H), 5.20 (dt, / = 7.0, 3.4 Hz, 1H), 3.67 (s, 2H), 3.48 (s, 2H), 3.36 (s, 3H), 3.20 (s, 3H), 1.96 (m, 3H), 1.68 (m, 2H), 0.76-0.60 (m, 4H); LC-MS (Method 1): f_R = 3.24 min, mJz (M+H)⁺ = 438; HRMS calculated for C₂₃H₂₇N₅0₄Na (M+Na)⁺ : 460.1955, found: 460.1977.

Example 4. 7-(2-Cvclohexylethyl)-8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-

STEP 1 : 8-((l-(cyclopropanecarbonyl)piperidin-4-yl)oxy)-l ,3-dimethyl-lH-purine-2,6(3H,7H)-dione

[0239] In a 2-neck flask was placed 7-benzyl-8-((l-(cyclopropanecarbonyl)piperidin-4-yl)oxy)-l ,3- dimethyl-lH-purine-2,6(3H,7H)-dione (1.750 g, 4 mmol) and Pd(OH)₂ (0.562 g, 0.800 mmol). Then, EtOH (Volume: 40 mL, Ratio: 2.000)/EtOAc (Volume: 20 mL, Ratio: 1.000) was added. The air was removed and refilled with H₂ (3 times). The mixture was heated to 70 °C for 24 h under H₂ balloon. After cooling to rt, the mixture was filtered through celite and eluted with CH₂C1₂. The filtrate was concentrated and the solid was triturated with 2% EtOAc/hexane and then dried in vacuo to give 8- ((1 -(cyclopropanecarbonyl)piperidin-4-yl)oxy)- 1 ,3 -dimethyl- 1 H-purine-2,6(3H,7H)-dione ( 1.043 g,

3.00 mmol, 75 % yield). H NMR (400 MHz, Chloroform-d) δ 11.15 (s, 1H), 5.26 (dt, / = 7.2, 3.6 Hz, 1H), 3.90 ( br s, 2H), 3.75-3.57 (m, 2H), 3.55 (s, 3H), 3.43 (s, 3H), 2.08 (br s, 2H), 1.90 (br s, 2H), 1.81-1.73 (m, 1H), 1.00 (dt, / = 4.7, 3.1 Hz, 2H), 0.79 (dt, / = 8.0, 3.3 Hz, 2H); LC-MS (Method 2): f_R = 3.51 min, m/z (M+H)⁺ = 348; HRMS calculated for C₁₆H₂₂N₅0₄ (M+H)⁺ : 348.1666, found: 348.1677.

STEP 2: 7-(2-cvclohexylethyl)-8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-lH- purine-2,6(3H,7H)-dione, TFA (Cpd. 114)

[0240] In a microwave tube was placed 8-((l-(cyclopropanecarbonyl)piperidin-4-yl)oxy)-l,3- dimethyl-lH-purine-2,6(3H,7H)-dione (20.84 mg, 0.06 mmol), 2-cyclohexylethanol (23.08 mg, 0.180 mmol). The tube was sealed and the air was removed and then refilled with N₂. Then, (E)-di-tert-butyl diazene-l,2-dicarboxylate (41.4 mg, 0.180 mmol) and Ph₃P (47.2 mg, 0.180 mmol) in THF (Volume: 1 inL) was added and the mixture was stirred at rt for 3 h. The mixture was concentrated, re-dissolved in DMF, filtered through a filter, and then submitted for purification to give 7-(2-cyclohexylethyl)-8- ((1 -(cyclopropanecarbonyl)piperidin-4-yl)oxy)- 1 ,3 -dimethyl- 1 H-purine-2,6(3H,7H)-dione, TFA (14.7 mg, 0.026 mmol, 42.9 % yield). H NMR (400 MHz, DMSO-d6) δ 5.20 (dt, / = 7.4, 3.7 Hz, 1H), 4.04 (t, = 7.0 Hz, 2H), 3.95-3.39 (m, 4H), 3.36 (s, 3H), 3.19 (s, 3H), 2.19-1.45 (m, 12H), 1.25-1.02 (m, 4H), 0.89 (m, 2H), 0.76-0.63 (m, 4H); LC-MS (Method 2): t_R= 5.99 min, m/z (M+H)⁺ = 458.

Example 5. 7-(2-Chlorobenzyl)-8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl- -purine-2,6(3H,7H)-dione, TFA (Cpd. 105)

[0241] To a mixture of 8-((l-(cyclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-lH-purine- 2,6(3H,7H)-dione (20.84 mg, 0.06 mmol) and K₂C0₃ (16.58 mg, 0.120 mmol) was added N,N- Dimethylformamide (Volume: 1 inL). The mixture was stirred at rt for 5 min and l-(bromomethyl)-2- chlorobenzene (37.0 mg, 0.180 mmol) was added. The mixture was heated at 60°C for 2 h. The mixture was filtered through a filter and submitted for purification to give 7-(2-chlorobenzyl)-8-((l- (cyclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione, TFA (8.2 mg, 0.014 mmol, 23.32 % yield). H NMR (400 MHz, DMSO-d6) δ 7.49 (dd, = 7.5, 1.8 Hz, 1H), 7.40- 7.20 (m, 2H), 6.93 (dd, = 7.4, 1.9 Hz, 1H), 5.39 (s, 2H), 5.20 (dt, / = 7.1, 3.5 Hz, 1H), 3.43 (m, 7H), 3.18 (s, 3H), 2.09-1.42 (m, 5H), 0.67 (m, 4H). LC-MS (Method 2): t_R = 5.19 min, m/z (M+H)⁺ = 472. Example 6. 8-((4-(Cvclopropanecarbonyl)piperazin-l-yl)methyl)-7-isopentyl-l,3-dimethyl-lH-

STEP 1: 8-(hvdroxymethyl)-1.3-dimethyl-lH-purine-2.6(3H.7H)-dione

[0242] To a mixture of 5,6-diamino-1 -dimethylpyrimidine-2,4(lH,3H)-dione (6.81 g, 40 mmol) and 2-hydroxy acetic acid (7.61 g, 100 mmol) (can add some dioxane (15 mL) to help mixing better) was heated at 100 °C. The mixture will melt and then become solid out again. The mixture was heated for 3 h. After cooling to rt, ice water (15 mL) was added and the solid was filtered and washed with ice water (2 mL x 3). The solid was dried in vacuo to give mixture of 2 regioisomers (2 crops, 4.45g, 49%). This material was used without further purification. LC-MS (Method 1): t_R = 0.56 and 0.69 min (53% and 47%, UV: 254 nm), m/z (M+H)⁺ = 229.

[0243] To a suspension of N-(6-amino-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)-2- hydroxyacetamide (4.56 g, 20 mmol) (mixture of 2 regio-ismoers) in Water (Volume: 30 mL) was added NaOH (25 mmol, 1000 mg). The mixture was heated to 100 °C for 2 h. After cooling to rt, AcOH (30 mmol) was added (pH is ca. 6-6.5). The mixture was stand at 0 °C for 3-4 h (or overnight). The resulting solid was filtered and washed with small amount of ice water (2 mL x 3). The solid was dried in vacuo to give 8-(hydroxymethyl)-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (3.45 g, 16.41 mmol, 82 % yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4.37 (s, 2H), 3.37 (s, 3H), 3.18 (s, 3H) (NH, OH not shown); LC-MS (Method 1): t_R = 1.98 min, m/z (M+H)⁺ = 211.

STEP 2: 8-(hydroxymethyl)-7-isopentyl-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione

[0244] To a mixture of 8-(hydroxymethyl)-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (1.051 g, 5 mmol) and K₂C0₃ (2.073 g, 15.00 mmol) was added N,N-dimethylformamide (Volume: 15 mL). The mixture was stirred at rt for 5 min and l-bromo-3-methyibutane (2.398 mL, 20.00 mmol) was added. The mixture was heat at 60 °C for overnight and was poured into EtOAc/H₂0 (80 mL/80 mL). The organic layer was washed with H₂0 (80 mL), dried (Na₂S0₄), and then filtered. After removal of solvent, the product was purified by silica gel chromatography using 80-100% EtOAc/hexane as the eluent to give 8-(hydroxymethyl)-7-isopentyl-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (1.21 g, 4.32 mmol, 86 % yield). H NMR (400 MHz, Chloroform-d) δ 4.75 (dd, = 6.0, 0.9 Hz, 2H), 4.39-4.23 (m, 2H), 3.56 (d, = 0.9 Hz, 3H), 3.41 (d, = 0.8 Hz, 3H), 2.71 (td, = 6.1, 3.1 Hz, 1H), 1.80-1.62 (m, 3H), 1.06-0.92 (m, 6H); LC-MS (Method 1): f_R = 2.76 min, m/z (M+H)⁺ = 281. STEP 3: 7 sopentyl-l,3-dimethyl-2,6-dioxo-2,3,6J-tetrahvdro-lH-purine-8-carbaldehyde

[0245] To a solution of 8-(hydroxymethyl)-7 sopentyl-1 -dimethyl-lH-purine-2,6(3H,7H)-dione (1550 mg, 5.53 mmol) in DCM (Volume: 15 mL) was added Dess-Martin Periodinane (3283 mg, 7.74 mmol) at 0 °C. After 10 min, the mixture was stirred at rt for 2 h. The mixture was concentrated and the residue was purified by silica gel chromatography using 30-60% EtOAc/hexane as the eluent to give 7-isopentyl-l,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purine-8-carbaldehyde (1160 mg, 4.17 mmol, 75 % yield). H NMR (400 MHz, Chloroform-d) δ 9.91 (s, 1H), 4.94^1.61 (m, 2H), 3.62 (s, 3H), 3.44 (s, 3H), 1.87-1.61 (m, 3H), 1.00 (d, / = 6.2 Hz, 6H); LC-MS (Method 1): f_R = 3.30 min, mJz (M+H)⁺ = 279.

STEP 4: 8-((4-(cyclopropanecarbonyl)piperazin-l-yl)methyl)-7-isopentyl-l,3-dimethyl-lH-purine- 2.6(3H.7H)-dione (Cpd. 59)

[0246] To a mixture of 7-isopentyl-l,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purine-8- carbaldehyde (195 mg, 0.7 mmol) and cyclopropyl(piperazin-l-yl)methanone, HC1 (267 mg, 1.400 mmol) was added CH₂C1₂ (Volume: 6 mL) and then Et₃N (0.293 mL, 2.100 mmol) at rt. The mixture was stirred for 3-5 min and sodium triacetoxyborohydride (297 mg, 1.400 mmol) was added. The mixture was stirred at rt for 4 h and was poured into CH₂Cl₂/Na₂C0_3(aq) (5 mL/5 mL). The aqueous layer was extracted with CH₂C1₂ (5 mL x 2). The combined organic layer was dried (Na₂S0₄) and filtered. After removal of solvent, the crude product was purified by silica gel chromatography using 0-5% MeOH/EtOAc as the eluent to give 8-((4-(cyclopropanecarbonyl)piperazin-l-yl)methyl)-7- isopentyl-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (251 mg, 0.603 mmol, 86 % yield). H NMR (400 MHz, DMSO-d6) δ 4.30 (dd, / = 9.7, 5.6 Hz, 2H), 3.70 (s, 2H), 3.63 (s, 2H), 3.43 (s, 2H), 3.39 (s, 3H), 3.21 (s, 3H), 2.41 (m, 4H), 1.93 (m, 1H), 1.68 (m, 3H), 0.94 (d, / = 5.9 Hz, 6H), 0.68 (tt, / = 7.9, 2.9 Hz, 4H); LC-MS (Method 1): f_R = 2.82 min, mJz (M+H)⁺ = 417.

Example 7. Ethyl 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahvdro-lH-purin-8- yl)methyl)piperazine-l-carboxylate (Cpd. 1)

[0247] The title compound was prepared following the similar procedure as described in Example 6A. H NMR (400 MHz, Chloroform-d) δ 7.24-7.15 (m, 1H), 7.12-7.04 (m, 1H), 6.92 (ddd, / = 7.6, 1.9, 0.9 Hz, 2H), 5.73 (s, 2H), 4.13 (q, J = 1.1 Hz, 2H), 3.59 (s, 3H), 3.54 (s, 2H), 3.41 (s, 7H), 2.39 (t, / = 5.2 Hz, 4H), 2.31 (s, 3H), 1.25 (t, / = 7.1 Hz, 3H); LC-MS (Method 1): f_R = 2.80 min, mJz (M+H)⁺ = 455.

Example 8. Ethyl 4-((7-isopentyl-l,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahvdro-lH-purin-8- yl)methyl)piperazine-l-carboxylate, TFA (Cpd. 2)

[0248] The title compound was prepared following the similar procedure as described in Example 6A. H NMR (400 MHz, DMSO-d6) δ 4.37-4.26 (m, 2H), 4.16 (s, 2H), 4.04 (q, / = 7.1 Hz, 2H), 3.42 (s, 7H), 3.22 (s, 3H), 2.96 (d, / = 67.5 Hz, 4H), 1.72-1.52 (m, 3H), 1.17 (t, J = 7.1 Hz, 3H), 0.93 (d, / = 6.1 Hz, 6H); LC-MS (Method 2): f_R = 4.20 min, mJz (M+H)⁺ = 421 ; HRMS calculated for

C₂oH3₂N₆0₄Na (M+Na)⁺ : 443.2377, found: 443.2398.

Example 9. Ethyl 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahvdro-lH-purin-8- yl)amino)piperidine-l-carboxylate (Cpd. 4)

[0249] To a solution of l ,3-dimethyl-7-(3-methylbenzyl)-8-(piperidin-4-ylamino)-lH-purine- 2,6(3H,7H)-dione, HC1 (84 mg, 0.2 mmol) in CH₂C1₂ (Volume: 1 mL) was added Et₃N (0.139 mL, 1.000 mmol) and then ethyl carbonochloridate (21.70 mg, 0.2 mmol) at rt. The mixture was stirred at rt for 10 min. The mixture was concentrated and the residue was purified by silica gel

chromatography using 30-70% EtOAc/hexane as the eluent to give ethyl 4-((l ,3-dimethyl-7-(3- methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl)amino)piperidine-l-carboxylate (79 mg, 0.174 mmol, 87 % yield). H NMR (400 MHz, Chloroform-d) δ 7.24 (d, / = 7.2 Hz, 1H), 7.13 (d, / = 7.6 Hz, 1H), 7.05-6.98 (m, 2H), 5.33 (s, 2H), 4.11 (q, / = 7.1 Hz, 2H), 3.92 (d, / = 10.9 Hz, 3H), 3.56 (s, 3H), 3.40 (s, 3H), 2.98 (t, / = 2.8 Hz, 2H), 2.33 (s, 3H), 1.93 (dd, / = 12.9, 3.5 Hz, 2H), 1.32-1.09 (m, 5H). (NH not shown); LC-MS (Method 1): f_R = 3.25 min, mJz (M+H)⁺ = 455; HRMS calculated for C₂₃H₃oN₆0₄Na (M+Na)⁺ : 477.2221 , found: 477.2242. Example 10. Ethyl 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahvdro-lH-purin- 8-yl)oxy)piperidine-l-carboxylate, TFA (Cpd. 5)

[0250] The title compound was prepared following the similar procedure as described in Example 1A. H NMR (400 MHz, DMSO-d6) δ 7.20 (t, / = 7.6 Hz, 1H), 7.15-7.00 (m, 3H), 5.21 (s, 2H), 5.15 (dt, / = 6.8, 3.4 Hz, 1H), 4.02 (q, / = 7.0 Hz, 2H), 3.45-3.32 (m, 7H), 3.20 (s, 3H), 2.24 (s, 3H), 1.89 (ddt, / = 16.3, 8.0, 4.1 Hz, 2H), 1.68 (ddd, / = 14.1, 7.1, 4.6 Hz, 2H), 1.16 (t, / = 7.1 Hz, 3H); LC-MS (Method 1): t_R = 3.56 min, m/z (M+H)⁺ = 456.

Example 11. 4-((l,3-Dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahvdro-lH-purin-8- yl)oxy)-N-ethylpiperidine-l-carboxamide, TFA (Cpd. 7)

[0251] To a solution of l,3-dimethyl-7-(3-methylbenzyl)-8-(piperidin-4-yloxy)-lH-purine- 2,6(3H,7H)-dione, HC1 (42.0 mg, 0.1 mmol) in CH₂C1₂ (Volume: 1 mL) under N₂ at rt was added Et₃N (0.028 mL, 0.2 mmol) and then isocyanatoethane (35.5 mg, 0.5 mmol). The mixture was then stirred at rt for 30 min and was concentrated. The crude mixture was dissolved in DMSO, filtered through filter, and was submitted for purification to give 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6- dioxo-2,3,6,7 etrahydro-lH^urin-8-yl)oxy)-N-ethylpiperidine-l-carboxamide, TFA (17.1 mg, 0.030 mmol, 30.1 % yield). H NMR (400 MHz, DMSO-d6) δ 7.20 (t, = 7.5 Hz, 1H), 7.13-6.99 (m, 3H), 6.48 (t, = 5.4 Hz, 1H), 5.20 (s, 2H), 5.13 (dt, / = 7.2, 3.6 Hz, 1H), 3.35 (s, 5H), 3.25 (ddd, / = 13.4, 7.2, 3.9 Hz, 2H), 3.20 (s, 3H), 3.02 (qd, = 7.1, 5.2 Hz, 2H), 2.24 (s, 3H), 1.94-1.76 (m, 2H), 1.60 (ddt, / = 13.9, 7.4, 3.6 Hz, 2H), 0.99 (t, = 7.1 Hz, 3H); LC-MS (Method 2): f_R= 4.85 min, m/z (M+H)⁺ = 455; HRMS calculated for Czs^NsC^ (M+H)⁺ : 455.2401, found: 455.2412. Example 12. 8-((l-Acetylpiperidin-4-yl)oxy)-l,3-dimethyl-7-(3-methylbenzyl)-lH-purine- 2,6(3H,7H)-dione, TFA (Cpd. 9)

[0252] The title compound was prepared following the similar procedure as described in Example 1A. H NMR (400 MHz, DMSO-d6) δ 7.20 (t, = 7.4 Hz, 1H), 7.08 (m, 3H), 5.28-5.08 (m, 3H), 3.41 (m, 4H), 3.36 (s, 3H), 3.20 (s, 3H), 2.24 (s, 3H), 2.04-1.79 (m, 5H), 1.78-1.54 (m, 2H); LC-MS (Method 2): f_R = 4.72 min, mJz (M+H)⁺ = 426.

Example 13. l,3-Dimethyl-7-(3-methylbenzyl)-8-((l-propionylpiperidin-4-yl)oxy)-lH-purine- 2,6(3H,7H)-dione, TFA (Cpd. 12)

[0253] The title compound was prepared following the similar procedure as described in Example 1A. H NMR (400 MHz, DMSO-d6) δ 7.20 (t, = 7.6 Hz, 1H), 7.13-7.02 (m, 3H), 5.21 (s, 2H), 5.17 (dq, = 6.9, 3.5 Hz, 1H), 3.44 (m, 4H), 3.36 (s, 3H), 3.20 (s, 3H), 2.30 (q, = 7.4 Hz, 2H), 2.23 (s, 3H), 2.00-1.78 (m, 2H), 1.77-1.54 (m, 2H), 0.96 (t, = 7.4 Hz, 3H); LC-MS (Method 2): f_R = 4.99 min, mJz (M+H)⁺ = 440.

Example 14. 8-((l-butyrylpiperidin-4-yl)oxy)-l,3-dimethyl-7-(3-methylbenzyl)-lH-purine- 2,6(3H,7H)-dione, TFA (Cpd. 13)

[0254] The title compound was prepared following the similar procedure as described in Example 1A. H NMR (400 MHz, DMSO-d6) δ 7.20 (t, / = 7.5 Hz, 1H), 7.13-7.02 (m, 3H), 5.21 (s, 2H), 5.17 (dt, / = 6.8, 3.4 Hz, 1H), 3.45 (m, 4H), 3.36 (s, 3H), 3.20 (s, 3H), 2.30-2.20 (m, 5H), 2.00-1.78 (m, 2H), 1.78-1.55 (m, 2H), 1.49 (h, / = 7.4 Hz, 2H), 0.87 (t, / = 7.4 Hz, 3H); LC-MS (Method 2): t_R = 5.29 min, m/z (M+H)⁺ = 454; HRMS calculated for CzAiNsC Na (M+Na)⁺ : 476.2268, found: 476.2290.

Example 15. l,3-Dimethyl-7-(3-methylbenzyl)-8-((l-(3-methylbutanoyl)piperidin-4-yl)oxy)-lH- purine-2,6(3HJH)-dione, TFA (Cpd. 15)

[0255] The title compound was prepared following the similar procedure as described in Example 1A. H NMR (400 MHz, DMSO-d6) δ 7.20 (t, / = 7.5 Hz, 1H), 7.13-7.02 (m, 3H), 5.21 (s, 2H), 5.18 (dq, / = 6.8, 3.4 Hz, 1H), 3.57-3.38 (m, 4H), 3.36 (s, 3H), 3.20 (s, 3H), 2.23 (d, / = 0.8 Hz, 3H), 2.21- 2.11 (m, 2H), 2.03-1.77 (m, 3H), 1.76-1.53 (m, 2H), 0.93-0.80 (m, 6H); LC-MS (Method 2): f_R = 5.56 min, m/z (M+H)⁺ = 468; HRMS calculated for C₂₅H₃₄N₅O₄ (M+H)⁺ : 468.2605, found: 468.2608. Example 16. 8-((l-Isobutyrylpiperidin-4-yl)oxy)-l,3-dimethyl-7-(3-methylbenzyl)-lH-purine- 2,6(3H,7H)-dione, TFA (Cpd. 14)

[0256] The title compound was prepared following the similar procedure as described in Example 1A. H NMR (400 MHz, DMSO-d6) δ 7.20 (t, / = 7.5 Hz, IH), 7.14-7.02 (m, 3H), 5.24-5.21 (m, 2H), 5.18 (dq, / = 6.8, 3.4 Hz, IH), 3.56-3.38 (m, 4H), 3.36 (s, 3H), 3.20 (s, 3H), 2.85 (p, / = 6.7 Hz, IH), 2.23 (s, 3H), 1.89 (d, / = 28.3 Hz, 2H), 1.77-1.55 (m, 2H), 0.97 (d, / = 6.7 Hz, 6H); LC-MS (Method 2): t_R = 5.29 min, m/z (M+H)⁺ = 454; HRMS calculated for C₂₄H₃₂N₅O₄ (M+H)⁺ : 454.2449, found: 454.2452.

Example 17. 8-((l-(Cvclopropylsulfonyl)piperidin-4-yl)oxy)-l,3-dimethyl-7-(3-methylbenzyl)- lH-purine-2,6(3H,7H)-dione, TFA (Cpd. 87)

[0257] The title compound was prepared following the similar procedure as described in Example 1 A with corresponding cycloporpanesulfonyl chloride. H NMR (400 MHz, DMSO-d6) δ 7.21 (t, = 7.9 Hz, IH), 7.11-7.01 (m, 3H), 5.22 (s, 2H), 5.18-5.09 (m, IH), 3.36 (s, 3H), 3.26-3.14 (m, 7H), 2.55- 2.50 (m, IH), 2.24 (s, 3H), 2.01 (tt, / = 8.0, 4.0 Hz, 2H), 1.84 (dq, / = 10.9, 3.0 Hz, 2H), 1.00-0.83 (m, 4H); LC-MS (Method 2): f_R= 5.46 min, m/z (M+H)⁺ = 488; HRMS calculated for C₂3H₂₉N₅0₅SNa (M+Na)⁺ : 510.1782, found: 510.1803. Example 18. l,3-Dimethyl-7-(3-methylbenzyl)-8-((l-(4-methylpyrimidin-2-yl)piperidin-4- yl)oxy)-lH-purine-2,6(3H,7H)-dione, TFA (Cpd. 19)

[0258] In a microwave tube was placed l,3-dimethyl-7-(3-methylbenzyl)-8-(piperidin-4-yloxy)-lH- purine-2,6(3H,7H)-dione, HCl (63.0 mg, 0.15 mmol), 2-chloro-4-methylpyrimidine (38.6 mg, 0.300 mmol) and K₂C0₃ (83 mg, 0.600 mmol). Then, DMF (Volume: 1 mL) was added sequentially. The mixture was heated at 160 °C under microwave irradiation for 1 h. The mixture was filtered and submitted for purification to give l,3-dimethyl-7-(3-methylbenzyl)-8-((l-(4-methylpyrimidin-2- yl)piperidin-4-yl)oxy)-lH-purine-2,6(3H,7H)-dione, TFA (41.3 mg, 0.070 mmol, 46.7 % yield). H NMR (400 MHz, DMSO-d6) δ 8.20 (d, = 5.0 Hz, 1H), 7.18 (t, = 7.6 Hz, 1H), 7.11 (t, = 1.7 Hz, 1H), 7.05 (dt, = 7.0, 1.4 Hz, 2H), 6.52 (dd, / = 5.0, 1.3 Hz, 1H), 5.26-5.22 (m, 1H), 5.21 (s, 2H), 3.77 (m, 4H), 3.37 (s, 3H), 3.20 (s, 3H), 2.27 (s, 3H), 2.19 (s, 3H), 2.02-1.87 (m, 2H), 1.77-1.62 (m, 2H); LC-MS (Method 2): t_R = 5.15 min, m/z (M+H)⁺ = 476; HRMS calculated for C25H30N7O3 (M+H)⁺ : 476.2405, found: 476.2424.

Example 19. l,3-Dimethyl-7-(3-methylbenzyl)-8-((l-(5-methylthiazol-2-yl)piperidin-4-yl)oxy)- lH-purine-2.6(3H.7H)-dione. TFA (Cpd. 30)

[0259] The title compound was prepared following the similar procedure as described in Example 18A. H NMR (400 MHz, DMSO-d6) δ 7.17 (dd, = 8.1, 7.1 Hz, 1H), 7.10 (s, 1H), 7.05 (dd, = 7.6, 1.7 Hz, 2H), 6.85 (s, 1H), 5.22 (s, 3H), 3.46-3.27 (m, 7H), 3.20 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 2.08-1.92 (m, 2Η), 1.82 (d, / = 8.9 Hz, 2H); LC-MS (Method 2): f_R = 4.48 min, mJz (M+H)⁺ = 481; HRMS calculated for C₂₄H₂₈N₆0₃SNa (M+Na)⁺ : 503.1836, found: 503.1848.

Example 20. Ethyl 4-((7-isopentyl-l,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahvdro-lH-purin-8- yl)oxy)piperidine-l-carboxylate, TFA (Cpd. 32)

[0260] The title compound was prepared following the similar procedure as described in Example 2A. H NMR (400 MHz, DMSO-d6) δ 5.15 (dt, / = 7.4, 3.7 Hz, 1H), 4.08-3.96 (m, 4H), 3.63-3.50 (m, 2H), 3.44-3.33 (m, 5H), 3.19 (s, 3H), 1.98 (ddt, / = 11.6, 7.4, 3.8 Hz, 2H), 1.76-1.64 (m, 2H), 1.61-1.52 (m, 2H), 1.51-1.40 (m, 1H), 1.17 (t, / = 7.1 Hz, 3H), 0.88 (d, / = 6.5 Hz, 6H); LC-MS (Method 2): f_R = 5.81 min, mJz (M+H)⁺ = 422; HRMS calculated for C₂oH3₂N₅0₅ (M+H)⁺ : 422.2398, found: 422.2403.

Example 21. 8-((l-(Cvclopropanecarbonyl)azetidin-3-yl)oxy)-7-isopentyl-l,3-dimethyl-lH- TFA (Cpd. 96)

[0261] The title compound was prepared following the similar procedure as described in Example 2A. ^:H NMR (400 MHz, DMSO-d6) δ 5.52-5.40 (m, 1H), 4.68 (dd, / = 10.1, 6.5 Hz, 1H), 4.34-4.20 (m, 2H), 4.12-3.99 (m, 2H), 3.96-3.83 (m, 1H), 3.35 (s, 3H), 3.19 (s, 3H), 1.66-1.41 (m, 4H), 0.89 (d, / = 6.5 Hz, 6H), 0.76-0.64 (m, 4H); LC-MS (Method 2): t_R = 4.86 min, m/z (M+H)⁺ = 390; HRMS calculated for C₁₉H₂₈N₅0₄ (M+H)⁺ : 390.2136, found: 390.2148. Example 22. 8-((l-(Cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-7-phenethyl-lH-

[0262] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 7.27-7.13 (m, 3H), 7.09-7.03 (m, 2H), 4.96 (dt, / = 7.1 , 3.5 Hz, 1H), 4.22 (t, / = 6.7 Hz, 2H), 3.43 (br s, 4H), 3.35 (s, 3H), 3.23 (s, 3H), 2.99 (t, / = 6.7 Hz, 2H), 1.95 (tt, / = 7.3, 5.1 Hz, 1H), 1.78 (m, 2H), 1.45 (m, 2H), 0.70 (t, / = 6.4 Hz, 4H); LC-MS (Method 2): f_R = 5.08 min, mJz (M+H)⁺ = 452; HRMS calculated for C₂₄H₃₀N₅O₄ (M+H)⁺ : 452.2292, found: 452.2275.

Example 23. 8-((l-(Cvclopropanecarbonyl)piperidin-4-yl)oxy)-7-(3-methoxybenzyl)-l,3-

[0263] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 7.24 (dd, / = 8.3, 7.5 Hz, 1H), 6.89 (t, / = 2.0 Hz, 1H), 6.85 (d, J = 2. \ Hz, 1H), 6.83 (d, = 2.1 Hz, 1H), 5.28-5.13 (m, 3H), 3.69 (s, 5H), 3.49 (s, 2H), 3.36 (s, 3H), 3.20 (s, 3H), 2.09-1.48 (m, 5H), 0.77-0.59 (m, 4H); LC-MS (Method 2): f_R = 4.94 min, mJz (M+H)⁺ = 468; HRMS calculated for C₂₄H₃₀N₅O₅ (M+H)⁺ : 468.2241 , found: 468.2257. Example 24. 8-((l-(Cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-7-(3-

[0264] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 7.74 (s, IH), 7.70-7.63 (m, IH), 7.59 (d, / = 4.7 Hz, 2H), 5.37 (s, 2H), 5.22 (dt, / = 7.6, 3.6 Hz, IH), 3.68 (s, 2H), 3.48 (s, 2H), 3.37 (s, 3H), 3.21 (s, 3H), 2.08-1.46 (m, 5H), 0.68 (d, / = 8.7 Hz, 4H); LC-MS (Method 2): t_R = 5.45 min, m/z (M+H)⁺ = 506 HRMS calculated for C₂₃H₂₇N₅O₄F₃ (M+H)⁺ : 506.2010, found: 506.2001.

Example 25. 7-(3-Chlorobenzyl)-8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl- lH-purine-2,6(3H,7H)-dione, TFA (Cpd. 78)

[0265] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 7.42-7.35 (m, 3H), 7.26-7.21 (m, IH), 5.27 (s, 2H), 5.21 (m, IH), 3.69 (br s, 2H), 3.49 (br s, 2H), 3.36 (s, 3H), 3.20 (s, 3H), 1.97-1.60 (m, 5H), 0.78-0.60 (m, 4H); LC-MS (Method 2): f_R= 5.30 min, m/z (M+H)⁺ = 472; HRMS calculated for C₂₃H₂₇C1N₅0₄ (M+H)⁺ : 472.1746, found: 472.1769. Example 26. 7-(4-chlorobenzyl)-8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl- -purine-2,6(3H,7H)-dione, TFA (Cpd. Ill)

[0266] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 7.43-7.37 (m, 2H), 7.35-7.29 (m, 2H), 5.25 (s, 2H), 5.21 (dq, / = 7.1, 3.5 Hz, 1H), 3.83-3.42 (m, 4H), 3.36 (s, 3H), 3.20 (s, 3H), 2.00-1.65 (m, 5H), 0.74-0.62 (m, 4H); LC-MS (Method 2): t_R = 5.33 min, m/z (M+H)⁺ = 472; HRMS calculated for C₂₃H₂₇N₅O₄CI (M+H)⁺ : 472.1746, found: 472.1762.

Example 27. 8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-7-(3-fluorobenzyl)-l,3-dimethyl- -purine-2.6(3H.7H)-dione. TFA (Cpd. 104)

[0267] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 7.39 (q, = 7.6 Hz, 1H), 7.13 (dd, / = 8.0, 5.2 Hz, 3H), 5.28 (s, 2H), 5.22 (dq, = 7.2, 3.8 Hz, 1H), 3.58 (m, 4H), 3.37 (s, 3H), 3.21 (s, 3H), 2.15-1.54 (m, 5H), 0.70 (m, 4H); LC-MS (Method 2): f_R= 5.03 min, m/z (M+H)⁺ = 456; HRMS calculated for

C₂₃H₂₇N₅0₄F (M+H)⁺ : 456.2042, found: 456.2046. Example 28. 8-((l-(Cvclopropanecarbonyl)piperidin-4-yl)oxy)-7-(2-fluorobenzyl)-l,3-dimethyl- -purine-2,6(3H,7H)-dione, TFA (Cpd. 112)

[0268] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 7.39-7.28 (m, 1H), 7.26-7.08 (m, 3H), 5.34 (s, 2H), 5.20 (dt, / = 6.8, 3.4 Hz, 1H), 3.66-3.40 (m, 4H), 3.37 (s, 3H), 3.19 (s, 3H), 1.99-1.92 (m, 5H), 0.76-0.55 (m, 4H); LC-MS (Method 2): f_R = 4.94 min, mJz (M+H)⁺ = 456; HRMS calculated for C₂3H₂₇N₅0₄F (M+H)⁺ : 456.2042, found: 456.2044.

Example 29. 8-((l-(Cvclopropanecarbonyl)piperidin-4-yl)oxy)-7-(2-fluoro-3-methylbenzyl)-l,3- dimethyl-lH-purine-2.6(3H.7H)-dione. TFA (Cpd. 109)

[0269] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 7.20 (ddd, / = 8.4, 7.1 , 1.8 Hz, 1H), 7.02 (t, / = 7.5 Hz, 1H), 6.98 (ddd, / = 8.6, 7.1 , 2.0 Hz, 1H), 5.33 (s, 2H), 5.19 (dt, / = 6.7, 3.4 Hz, 1H), 3.75-3.40 (m, 4H), 3.37 (s, 3H), 3.19 (s, 3H), 2.20 (d, / = 2.2 Hz, 3H), 2.02-1.51 (m, 5H), 0.69 (t, / = 5.8 Hz, 4H); LC- MS (Method 2): t_R = 5.24 min, m/z (M+H)⁺ = 470; HRMS calculated for C₂₄H₂₉N₅O₄F (M+H)⁺ : 470.2198, found: 470.2218. Example 30. 8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-7-(naphthalen-l-

[0270] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 8.22 (d, / = 8.0 Hz, 1H), 8.04-7.91 (m, 1H), 7.85 (d, / = 8.3 Hz, 1H), 7.65-7.50 (m, 2H), 7.41 (t, / = 7.7 Hz, 1H), 7.01 (d, / = 7.2 Hz, 1H), 5.80 (s, 2H), 5.18 (dt, / = 7.9, 3.7 Hz, 1H), 3.71-3.25 (m, 7H), 3.18 (d, / = 1.7 Hz, 3H), 2.07-1.36 (m, 5H), 0.64 (d, / = 8.2 Hz, 4H); LC-MS (Method 2): f_R = 5.40 min, mJz (M+H)⁺ = 488; HRMS calculated for C27H30N5O4 (M+H)⁺ : 488.2292, found: 488.2298.

Example 31. 8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-7-isobutyl-l,3-dimethyl-lH-

[0271] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 5.21 (dt, / = 7.4, 3.6 Hz, 1H), 3.86 (br s, 1H), 3.82 (d, / = 7.3 Hz, 2H), 3.67 (br s, 2H), 3.47 (br s, 1H), 3.37 (s, 3H), 3.19 (s, 3H), 2.16-1.86 (m, 4H), 1.95-1.67 (m, 2H), 0.84 (d, / = 6.7 Hz, 6H), 0.76-0.62 (m, 4H); LC-MS (Method 2): f_R = 4.89 min, mJz (M+H)⁺ = 404; HRMS calculated for C20H30N5O4 (M+H)⁺ : 404.2292, found: 404.2298. Example 32. 8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-l,3-dimethyl-7-(4-methylpentyl)- e, TFA (Cpd. 75)

[0272] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 5.21 (dt, / = 7.2, 3.6 Hz, 1H), 4.00 (t, / = 7.0 Hz, 2H), 3.85 (s, 1H), 3.67 (s, 2H), 3.48 (s, 1H), 3.36 (s, 3H), 3.19 (s, 3H), 2.13-1.86 (m, 3H), 1.85-1.60 (m, 4H), 1.57-1.43 (m, 1H), 1.16-1.04 (m, 2H), 0.81 (d, / = 6.6 Hz, 6H), 0.74-0.63 (m, 4H); LC-MS (Method 2): f_R = 5.58 min, mJz (M+H)⁺ = 432; HRMS calculated for C₂₂H₃₄N₅O₄ (M+H)⁺ : 432.2605, found: 432.2621.

Example 33. 8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-7-(3,3-dimethylbutyl)-l,3-

[0273] The title compound was prepared following the similar procedure as described in Example 5A. H NMR (400 MHz, DMSO-d6) δ 5.20 (dt, / = 7.2, 3.6 Hz, 1H), 4.11-3.98 (m, 2H), 3.90-3.42 (m, 4H), 3.36 (s, 3H), 3.19 (s, 3H), 2.10-1.65 (m, 5H), 1.62-1.48 (m, 2H), 0.92 (s, 9H), 0.74-0.66 (m, 4H); LC-MS (Method 2): t_R = 5.48 min, m/z (M+H)⁺ = 432. Example 34. 8-((l-(cvclopropanecarbonyl)piperidin-4-yl)oxy)-7-(2-cvclopropylethyl)-l,3-

[0274] The title compound was prepared following the similar procedure as described in Example

5A. H NMR (400 MHz, Chloroform-d) δ 5.26 (dt, / = 7.6, 3.8 Hz, 1H), 4.18 (t, / = 6.9 Hz, 2H), 3.93 (ddd, / = 11.7, 7.4, 3.8 Hz, 2H), 3.60 (ddd, / = 13.6, 7.7, 3.2 Hz, 2H), 3.54 3.49 (m, 3H), 3.38 (d, / = 0.6 Hz, 3H), 2.17-1.62 (m, 7H), 1.05-0.93 (m, 2H), 0.82-0.71 (m, 2H), 0.70-0.56 (m, 1H), 0.42-0.35 (m, 2H), 0.01-0.06 (m, 2H); LC-MS (Method 1): t_R = 3.22 min, m/z (M+H)⁺ = 416; HRMS calculated for C₂₁H₃₀N₅O₄ (M+H)⁺ : 416.2292, found: 416.2310.

Example 35. 7-Benzyl-8-((4-(cvclopropanecarbonyl)piperazin-l-yl)methyl)-l,3-dimethyl-lH-

[0275] The title compound was prepared following the similar procedure as described in Example 6A. H NMR (400 MHz, DMSO-i/₆) δ 7.37-7.23 (m, 3H), 7.21-7.15 (m, 2H), 5.67 (s, 2H), 3.45 (s, 3H), 3.21 (s, 3H), 2.01-1.84 (m, 1H), 0.70 (dd, / = 6.2, 3.7 Hz, 4H) (peaks of NCH₂ and piperazine ring are very broad); LC-MS (Method 2): t_R = 3.76 min, m/z (M+H)⁺ = 437. Example 36. 7-Benzyl-8-((4-isobutyrylpiperazin-l-yl)methyl)-l,3-dimethyl-lH-purine- -dione, TFA (Cpd. 119)

[0276] The title compound was prepared following the similar procedure as described in Example 6A. H NMR (400 MHz, DMSO-i/₆) δ 7.37-7.22 (m, 3H), 7.21-7.14 (m, 2H), 5.67 (s, 2H), 3.44 (s, 3H), 3.21 (s, 3H), 2.44 (p, / = 1.9 Hz, 1H), 0.96 (d, / = 6.7 Hz, 6H). (peaks of NCH₂ and piperazine ring are very broad); LC-MS (Method 2): t_R = 3.90 min, m/z (M+H)⁺ = 439.

Example 37. 8-((4-(Cvclopropanecarbonyl)piperazin-l-yl)methyl)-7-(2-fluorobenzyl)-l,3-

[0277] The title compound was prepared following the similar procedure as described in Example 6A. H NMR (400 MHz, DMSO-i/₆) δ 7.32 (t, J = 1.1 Hz, 1H), 7.23 (dd, = 10.7, 8.1 Hz, 1H), 7.10 (t, = 7.5 Hz, 1H), 6.89 (td, = 7.9, 1.6 Hz, 1H), 5.69 (s, 2H), 4.20-3.3 (br s, 10H), 3.45 (s, 3H), 3.19 (s, 3H), 1.89 (s, 1H), 0.67 (d, = 7.5 Hz, 4H); LC-MS (Method 2): t_R = 3.84 min, m/z (M+H)⁺ = 455; HRMS calculated for CziHzsNsOsF (M+H)⁺ : 455.2201, found: 455.2189. Example 38. 7-(2-Chlorobenzyl)-8-((4-(cvclopropanecarbonyl)piperazin-l-yl)methyl)-l,3-

[0278] The title compound was prepared following the similar procedure as described in Example 6A. 'H NMR (400 MHz, DMS 0-d₆) δ 7.51 (d, = 7.9 Hz, IH), 7.30 (t, = 7.6 Hz, IH), 7.21 (t, = 7.6 Hz, IH), 6.62 (s, IH), 5.68 (s, 2H), 4.00-3.20 (m, 13H), 3.18 (s, 3H), 1.86 (s, IH), 0.66 (br s, 4H); LC-MS (Method 2): t_R= 4.11 min, m/z (M+H)⁺ = 471.

Example 39. 8-((4-(Cvclopropanecarbonyl)piperazin-l-yl)methyl)-7-(3-fluorobenzyl)-l,3-

[0279] The title compound was prepared following the similar procedure as described in Example 6A. H NMR (400 MHz, DMSO-i/₆) δ 7.37 (td, = 7.9, 6.1 Hz, IH), 7.10 (td, / = 8.7, 2.6 Hz, IH), 7.07-6.97 (m, 2H), 5.66 (s, 2H), 4.36-3.50 (m, 10H), 3.44 (s, 3H), 3.21 (s, 3H), 1.92 (m, IH), 0.68 (d, = 8.1 Hz, 4H); LC-MS (Method 2): t_R = 3.90 min, m/z (M+H)⁺ = 455. Example 40. 8-((4-(Cyclopropanecarbonyl)piperazin-l-yl)methyl)-l,3-dimethyl-7-(4-

[0280] The title compound was prepared following the similar procedure as described in Example

6A. H NMR (400 MHz, DMSO-i/₆) δ 4.28 (t, 7 = 7.7 Hz, 2H), 3.42 (s, 3H), 3.23 (s, 3H), 2.04 - 1.88 (m, 1H), 1.74 (q, 7 = 7.9 Hz, 2H), 1.53 (dt, 7 = 13.3, 6.6 Hz, 1H), 1.29 - 1.10 (m, 2H), 0.86 (d, 7 = 6.5 Hz, 6H), 0.77 - 0.63 (m, 4H). (peaks of NCH₂ and piperazine ring are very broad.); LC-MS (Method 2): f_R= 4.21 min, mJz (M+H)⁺ = 431.

Example 41. 8-((4-Isobutyrylpiperazin-l-yl)methyl)-7-isopentyl-l,3-dimethyl-lH-purine- (Cpd. 55)

[0281] The title compound was prepared following the similar procedure as described in Example 6A. H NMR (400 MHz, DMSO-i/₆) δ 4.31 (dd, 7 = 9.3, 6.3 Hz, 2H), 3.84 (m, 10H), 3.42 (s, 3H), 3.22 (s, 3H), 2.86 (p, 7 = 6.7 Hz, 1H), 1.72-1.53 (m, 3H), 0.98 (d, 7 = 6.7 Hz, 6H), 0.93 (d, 7 = 6.1 Hz, 6H). (peaks of NCH₂ and piperazine ring are very broad); LC-MS (Method 2): ¾= 4.06 min, m/z (M+H)⁺ = 419. Example 42. N-Ethyl-4-((7-isopentyl-l,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahvdro-lH-purin-8- yl)methyl)piperazine-l-carboxamide, TFA (Cpd. 125)

[0282] The title compound was prepared following the similar procedure as described in Example 6A. H NMR (400 MHz, DMSO-i/₆) δ 6.59 (s, 1H), 4.31 (t, / = 7.8 Hz, 2H), 3.42 (s, 3H), 3.22 (s, 3H), 3.02 (dt, / = 12.2, 6.0 Hz, 2H), 1.70-1.51 (m, 3H), 0.99 (t, / = 7.2 Hz, 3H), 0.93 (d, / = 6.1 Hz, 6H). (peaks of NCH₂ and piperazine ring are broad); LC-MS (Method 2): t_R= 3.62 min, m/z (M+H)⁺ = 420.

Example 43. 8-((4-(cvclopropanecarbonyl)-l,4-diazepan-l-yl)methyl)-7-isopentyl-l,3-dimethyl- -purine-2,6(3H,7H)-dione, TFA (Cpd. 122)

[0283] The title compound was prepared following the similar procedure as described in Example 6A. H NMR (400 MHz, DMSO-i/₆) δ 4.38-4.26 (m, 2H), 3.44 (s, 3H), 3.23 (s, 3H), 1.96-1.81 (m, 1H), 1.63 (dq, / = 20.9, 8.7, 7.6 Hz, 3H), 0.96-0.90 (m, 6H), 0.81-0.61 (m, 4H). (peaks of NCH2 and homopiperazine (12 H) are very broad); LC-MS (Method 2): t_R = 3.73 min, m/z (M+H)⁺ = 431 ;

HRMS calculated for C₂₂H₃₄N₆0₃Na (M+Na)⁺ : 453.2585, found: 453.2598. Example 44. 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahvdro-lH-purin-8- yl)oxy)-N-methylbenzamide, TFA (Cpd. 21)

STEP 1: methyl 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6 ,7-tetrahydro-lH-purin-8- yl)oxy)benzoate

[0284] In a microwave tube was placed 8-chloro-l,3-dimethyl-7-(3-methylbenzyl)-lH-purine- 2,6(3H,7H)-dione (319 mg, 1 mmol), methyl 4-hydroxybenzoate (183 mg, 1.200 mmol) and K₂C0₃ (207 mg, 1.500 mmol). Then, DMF (Volume: 3 mL) was added sequentially. The mixture was heated at 160 °C under microwave irradiation for 1 h. The mixture was poured into stirred H₂0 (60 mL) and the solid was filtered. The solid was then dissolved in CH₂C1₂ and was purified by silica gel chromatography using 50-100% EtOAc/hexane as the eluent to give methyl 4-((l,3-dimethyl-7-(3- methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl)oxy)benzoate (361 mg, 0.831 mmol, 83 % yield). H NMR (400 MHz, Chloroform-d) δ 8.14-8.03 (m, 2H), 7.35-7.28 (m, 2H), 7.23-7.20 (m, 3H), 7.13-7.07 (m, 1H), 5.43 (s, 2H), 3.93 (s, 3H), 3.45 (s, 3H), 3.42 (s, 3H), 2.30 (d, = 0.8 Hz, 3H); LC-MS (Method 2): f_R= 6.03 min, mJz (M+H)⁺ = 435.

STEP 2: 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8- yl)oxy)benzoic acid

[0285] To a solution of methyl 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahydro- lH-purin-8-yl)oxy)benzoate (148 mg, 0.34 mmol) in THF (Volume: 4 mL, Ratio: 8.00)/MeOH (Volume: 0.5 mL, Ratio: 1.000) was added LiOH(aq) (1.5 N, 2 mL). The mixture was stirred at 50 °C for 3 h and HCl_(aq) (1 N, 4 mL) was added. Then hexane (10 mL) was added and the solid was filtered, washed with H₂0 (2 mL x2), 5% Et₂0/hexane (2 mL x 2), and then dried to give 4-((l,3-dimethyl-7- (3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl)oxy)benzoic acid (69 mg, 0.164 mmol, 48.3 % yield). H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.04-7.94 (m, 2H), 7.44-7.34 (m, 2H), 7.22 (t, = 7.6 Hz, 1H), 7.15-7.03 (m, 3H), 5.39 (s, 2H), 3.29 (s, 3H), 3.22 (s, 3H), 2.24 (s, 3H); LC-MS (Method 2): t_R= 5.08 min, m/z (M+H)⁺ = 421.

STEP 3: 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl)oxy)-N- methylbenzamide, TFA (Cpd. 21)

[0286] To a mixture of 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin- 8-yl)oxy)benzoic acid (42.0 mg, 0.1 mmol) and HATU (95 mg, 0.250 mmol) was added DMF (Volume: 1 mL), methanamine (62.1 mg, 2.000 mmol)(2M in THF, 1 mL), and then Hunig's Base (0.087 mL, 0.500 mmol). The mixture was stirred at rt for 2 h. The mixture was filtered through a filter and submit for purification to give 4-((l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7- tetrahydro-lH-purin-8-yl)oxy)-N-methylbenzamide, TFA (25 mg, 0.046 mmol, 45.7 % yield). H NMR (400 MHz, DMSO-d6) δ 8.45 (q, = 4.5 Hz, 1H), 7.93-7.82 (m, 2H), 7.40-7.33 (m, 2H), 7.22 (t, = 7.5 Hz, 1H), 7.18-7.04 (m, 3H), 5.39 (s, 2H), 3.28 (s, 3H), 3.22 (s, 3H), 2.77 (d, = 4.5 Hz, 3H), 2.24 (s, 3H); LC-MS (Method 2): t_R = 4.87 min, m/z (M+H)⁺ = 434; HRMS calculated for C₂₃H₂₄N₅O₄ (M+H)⁺ : 434.1823, found: 434.1834.

Example 45. l,3-dimethyl-7-(3-methylbenzyl)-8-((4-(thiazol-2-yl)piperazin-l-yl)methyl)-lH- e (Cpd. 10)

[0287] To l,3-dimethyl-7-(3-methylbenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purine-8-carbaldehyde (31.2 mg, 0.1 mmol) and 2-(piperazin-l-yl)thiazole, HQ (41.1 mg, 0.200 mmol) was added CH₂C1₂ (Volume: 2 mL) and then Et₃N (0.028 mL, 0.2 mmol) at rt. The mixture was stirred for 3-5 min and sodium triacetoxyborohydride (127 mg, 0.600 mmol) was added. The mixture was stirred at rt for 3 h and was poured into CH₂Cl₂/Na₂C0₃(aq) (3 mL/3 mL). The aqueous layer was extracted with CH₂C1₂ (3 mL x 2). The combined organic layer was dried (Na₂S0₄) and filtered. After removal of solvent, the crude product was purified by silica gel chromatography using 50-100% EtOAc/hexane as the eluent to give l,3-dimethyl-7-(3-methylbenzyl)-8-((4-(thiazol-2-yl)piperazin-l-yl)methyl)-lH-purine- 2,6(3H,7H)-dione (28 mg, 0.057 mmol, 57.1 % yield). H NMR (400 MHz, Chloroform-if) δ 7.23 - 7.16 (m, 2H), 7.09 (d, = 7.8 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.59 (d, = 3.7 Hz, 1H), 5.76 (s, 2H), 3.60 (d, = 4.2 Hz, 5H), 3.47 (s, 4H), 3.42 (d, = 1.3 Hz, 3H), 2.57 (s, 4H), 2.31 (d, = 4.3 Hz, 3H); MS (M+H)⁺= 466. Example 46. 7-isopentyl-l,3-dimethyl-8-(4-(l-methyl-lH-pyrazol-4-yl)phenoxy)-lH-purine- 23)

STEP 1: 8-(4-bromophenoxy)-7-isopentyl-1 -dimethyl-lH-purine-2,6(3H,7H)-dione

[0288] In a microwave tube was placed 8-chloro-7-isopentyl-l ,3-dimethyl-lH-purine-2,6(3H,7H)- dione (569 mg, 2 mmol), 4-bromophenol (433 mg, 2.500 mmol) and K₂C0₃ (346 mg, 2.500 mmol). Then, DMF (Volume: 3 mL) was added sequentially. The mixture was heated at 150 °C under microwave irradiation for 1 h. The mixture was poured into stirred H₂0 (40 mL) and the solid was filtered. The solid was then dissolved in CH₂C1₂ and was purified by silica gel chromatography using 20-40% EtOAc/hexane as the eluent to give 8-(4-bromophenoxy)-7-isopentyl-l,3-dimethyl-lH- purine-2,6(3H,7H)-dione (774 mg, 1.837 mmol, 92 % yield).

STEP 2: 7-isopentyl- 1 ,3-dimethyl-8 -( 4-( 1 -methyl- 1 H-pyrazol-4-yl)phenoxy)- 1 H-purine-2,6(3H,7H)- dione, TFA (Cpd. 23)

[0289] In a 2-neck flask was placed (1 -methyl- lH-pyrazol-4-yl)boronic acid (25.2 mg, 0.200 mmol), (1 -methyl- lH-pyrazol-4-yl)boronic acid (25.2 mg, 0.200 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (8.17 mg, 10.00 μιηοΐ), and K₂C0₃ (69.1 mg, 0.500 mmol). The air was removed and refilled with N₂ (2-3 times). Then 1,4-Dioxane (Volume: 1.5 mL) and Water (Volume: 0.5 mL) were added and was stirred at 90 °C for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer was dried (Na₂S0₄) and filtered. After removal of solvent, the product was dissolved in DMSO, filtered through a filter, and submitted for purification to give 7- isopentyl-l,3-dimethyl-8-(4-(l-methyl-lH-pyrazol-4-yl)phenoxy)-lH-purine-2,6(3H,7H)-dione, TFA (19.1 mg, 0.036 mmol, 35.6% yield). H NMR (400 MHz, DMSO-i/₆) δ 8.13 (s, 1H), 7.85 (s, 1H), 7.65 - 7.58 (m, 2H), 7.35 - 7.27 (m, 2H), 4.20 (t, / = 7.3 Hz, 2H), 3.85 (s, 3H), 3.27 (s, 3H), 3.22 (s, 3H), 1.67 (q, / = 7.0 Hz, 2H), 1.57 (dt, / = 13.2, 6.6 Hz, 1H), 0.91 (d, / = 6.5 Hz, 6H); MS (M+H)⁺= 423. Example 47. 7-isopentyl-l,3-dimethyl-8-(4-(thiazol-2-yl)phenoxy)-lH-purine-2,6(3H,7H)-dione,

[0290] In a microwave tube was placed 8-(4-bromophenoxy)-7-isopentyl-l,3-dimethyl-lH-purine- 2,6(3H,7H)-dione (42.1 mg, 0.1 mmol) and Pd(Ph₃P)₄ (11.56 mg, 10.00 μιηοΐ). The air was removed and refilled with N₂ (2-3 times). Then DMF (Volume: 1), 2-(tributylstannyl)thiazole (112 mg, 0.300 mmol), and Hunig's Base (87 μΐ_^, 0.500 mmol) were added and the mixture was stirred at 150 °C for 1 h under microwave irradiation. The mixture was filtered through a filter and submitted for purification to give 7-isopentyl-l ,3-dimethyl-8-(4-(thiazol-2-yl)phenoxy)-lH-purine-2,6(3H,7H)- dione, TFA (23.6 mg, 0.044 mmol, 43.7 % yield).MS (M+H)⁺= 426.

Example 48. 7-isopentyl-l,3-dimethyl-8-(4-(2-oxopyrrolidin-l-yl)phenoxy)-lH-purine- d. 37)

[0291] In a microwave tube was placed 8-chloro-7-isopentyl-l ,3-dimethyl-lH-purine-2,6(3H,7H)- dione (42.7 mg, 0.15 mmol), l-(4-hydroxyphenyl)pyrrolidin-2-one (53.2 mg, 0.300 mmol) and K₂C0₃ (83 mg, 0.600 mmol). Then, DMF (Volume: 1 inL) was added sequentially. The mixture was heated at 150 °C under microwave irradiation for 1 h. The mixture was filtered through a filter and submitted for purification to give 7-isopentyl-l,3-dimethyl-8-(4-(2-oxopyrrolidin-l-yl)phenoxy)-lH-purine- 2,6(3H,7H)-dione, TFA (37.4 mg, 0.069 mmol, 46.2 % yield). MS (M+H)⁺= 426 Example 49. 7-isopentyl-l,3-dimethyl-8-(4-(oxetan-3-yloxy)phenoxy)-lH-purine-2,6(3H,7H)- dione, TFA (Cpd. 91)

STEP 1: 8-(4-hydroxyphenoxy)-7-isopentyl-1 -dimethyl-lH^urine-2,6(3H H)-dione

[0292] To a solution of 4-((tert-butyldimethylsilyl)oxy)phenol (224 mg, 1.000 mmol) and 8-chloro- 7-isopentyl-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (285 mg, 1 mmol) in DMF (Volume: 2mL) under N₂ at rt was added NaH (48.0 mg, 2.000 mmol). The mixture was then stirred at rt for 2 h and was poured into EtOAc/NH4Cl(aq) (20 mL/20 mL). The organic layer was washed with NH₄Cl(aq) (20 mL), H₂0 (20 mL), dried (Na₂S0₄), and then filtered. After removal of solvent, the product was purified by silica gel chromatography using 40-70% EtOAc/hexane as the eluent to give 8-(4- hydroxyphenoxy)-7-isopentyl-l,3-dimethyl-lH-purine-2,6(3H,7H)-dione (349 mg, 0.925 mmol, 93 % yield). MS (M+H)⁺= 359.

STEP 2: 7-isopentyl-l,3-dimethyl-8-(4-(oxetan-3-yloxy)phenoxy)-lH-purine-2,6(3HJH)-dione, TFA (Cpd. 91)

[0293] To a mixture of 8-(4-hydroxyphenoxy)-7-isopentyl-l,3-dimethyl-lH-purine-2,6(3H,7H)- dione (35.8 mg, 0.1 mmol) and K₂C0₃ (27.6 mg, 0.200 mmol) was added N,N-Dimethylformamide (Volume: 1). The mixture was stirred at rt for 5 min and oxetan-3-yl 4-methylbenzenesulfonate (45.7 mg, 0.200 mmol) was added. The mixture was sealed and heated at 120 °C for overnight. The mixture was filtered through a filter and submitted for purification to give 7-isopentyl-l,3-dimethyl-8-(4- (oxetan-3-yloxy)phenoxy)-lH-purine-2,6(3H,7H)-dione, TFA (8.7 mg, 0.016 mmol, 16.46 % yield). MS (M+H)⁺= 415.

[0294] Table 1 provides compounds of the disclosure. Any compounds for which a synthesis is not specifically provided can be made by the methods given in Examples 1-49, using minor variations in reagents and reaction conditions that will be readily apparent to those of ordinary skill in the art of organic chemical synthesis.

ABLE 1.

No. Structure Compound name

ABLE 1.

No. Structure Compound name

13 8-((l-butyrylpiperidin-4-yl)oxy)-l,3-dimethyl-7-(3- methylbenzyl)-lH-purine-2,6(3H,7H)-dione, TFA

14 8-(( 1 -isobutyrylpiperidin-4-yl)oxy)- 1 ,3 -dimethyl-7-(3 - methylbenzyl)-lH-purine-2,6(3H,7H)-dione, TFA

l,3-dimethyl-7-(3-methylbenzyl)-8-((l-(3-

15 methylbutanoyl)piperidin-4-yl)oxy)-lH-purine- 2,6(3H,7H)-dione, TFA

8-(( 1 -(cyclopentanecarbonyl)piperidin-4-yl)oxy)- 1,3- dimethyl-7-(3-methylbenzyl)-lH-purine-2,6(3H,7H)- dione, TFA

16 H NMR (400 MHz, DMSO-i/₆) δ 7.20 (t, / = 7.5 Hz,

1H), 7.13 - 7.03 (m, 3H), 5.22 (d, / = 2.0 Hz, 2H), 5.21

- 5.14 (m, 1H), 3.57 - 3.37 (m, 4H), 3.36 (s, 3H), 3.20 (s, 3H), 2.95 (td, / = 6.9, 3.2 Hz, 1H), 2.23 (s, 3H), 2.01

- 1.42 (m, 12H); MS (M+H)⁺= 480

ABLE 1.

o. Structure Compound name

8-((l -(cyclopropanecarbonyl)piperidin-4-yl)oxy)-l ,3- dimethyl-7-(2-methylbenzyl)-lH-purine-2,6(3H,7H)-

74 dione, TFA

MS (M+H)⁺= 452

8-((l -(cyclopropanecarbonyl)piperidin-4-yl)oxy)-l ,3-

75 dimethyl-7-(4-methylpentyl)-lH-purine-2,6(3H,7H)- dione, TFA

8-((l -(cyclopropanecarbonyl)piperidin-4-yl)oxy)-l ,3-

76 dimethyl-7-phenethyl-lH-purine-2,6(3H,7H)-dione,

TFA

8-((l -(cyclopropanecarbonyl)piperidin-4-yl)oxy)-l ,3- dimethyl-7-(4-methylbenzyl)-lH-purine-2,6(3H,7H)- dione, TFA

77 H NMR (400 MHz, DMSO-i/₆) δ 7.23 - 7.16 (m, 2H),

7.12 (d, / = 7.9 Hz, 2H), 5.20 (d, / = 6.4 Hz, 3H), 3.75- 3.49 (m, 4H), 3.35 (s, 3H), 3.20 (s, 3H), 2.24 (s, 3H), 2.08 - 1.51 (m, 5H), 0.75 - 0.61 (m, 4H); MS (M+H)⁺= 452

Example 50. ALDH1A1 Enzymatic Assay (in vitro assay)

[0295] 3 μΐ, of ALDHl Al enzyme (final concentration 20 nM) or assay buffer (100 mM HEPES pH 7.5 with 0.01% Tween 20) were dispensed into a 1,536-well solid-bottom black plate (Greiner Bio One, Monroe, NC) followed by pin-tool transfer (23 nL) of candidate inhibitors (final concentration range 968 pM to 57.2 μΜ) and control (Bay 11-7085, final concentration range 1.31 nM to 2.86 μΜ). Samples were incubated (RT, protected from light) for 15 minutes followed by a 1 μΕ substrate addition of NAD⁺ and Propionaldehyde (final concentrations of 1 mM and 80 μΜ, respectively). Plates were centrifuged at 1,000 rpm for 15 seconds, then read in kinetic mode on a ViewLux High- throughput CCD imager (Perkin-Elmer) equipped with standard UV fluorescence optics (340 nm excitation, 450 nm emission) for 10 minutes. The change in fluorescence intensity over the 10-minute reaction period was normalized against no-inhibitor and no-enzyme controls and the resulting percent inhibition data were fitted for biological activity.

TABLE 2: Biological Activity for Compounds of Formula (I) (data based on fl2)

Inhibitory Inhibitory Inhibitory

Cpd. ID Cpd. ID Cpd. ID

activity activity activity

13 ++ 68 ++ 123 ++

14 69 ++ 124

15 ++ 70 + 125 ++++

16 ++ 71 + 126 +++

17 72 127

18 ++ 73 ++ 128 ++

19 + 74 +++ 129 ++++

20 75 130

21 76 131

22 ++ 77 +++ 132 ++++

23 ++ 78 +++ 133 ++++

24 ++ 79 ++ 134 ++++

25 ++ 80 ++ 135 ++++

26 + 81 ++ 136 ++++

27 ++ 82 + 137 +++

28 83 138

29 ++ 84 ++ 139 ++

30 ++ 85 + 140 +++

31 ++ 86 ++++ 141 +

32 ++++ 87 ++++ 142 +

33 ++ 88 ++++ 143 ++

34 + 89 ++ 144 +

35 +++ 90 ++ 145 ++

36 + 91 ++ 146 +

37 ++ 92 ++ 147 ++

38 ++ 93 + 148 +

39 + 94 ++ 149 ++

40 + 95 ++ 150 +

41 + 96 +++ 151 +

42 ++ 97 + 152 +

43 ++++ 98 ++ 153 +

44 ++ 99 + 154 +

45 100 + 155

46 101 156 Inhibitory Inhibitory Inhibitory

Cpd. ID Cpd. ID Cpd. ID

activity activity activity

47 ++ 102 ++

48 ++++ 103 ++++

49 ++++ 104 ++++

50 ++++ 105 ++++

51 ++++ 106 ++

52 ++ 107 +

53 + 108 ++++

54 ++ 109 ++++

55 ++++ 110 ++++

++++ represents IC₅₀ < 0.5 μΜ;

+++ represents 0.5 μΜ < IC₅₀ < 1.0 μΜ;

++ represents 1.0 μΜ < IC₅₀ < 10 μΜ;

+ represents IC₅₀ > 10 μΜ.

Example 51. ALDH1B1, ALDH2, and ALDH3A1 Enzymatic Assays

[0296] 3 μL of enzyme (final concentration 10 nM, 20 nM, and 10 nM for ALDH1B 1, ALDH2, and ALDH3A1, respectively) or assay buffer (100 mM HEPES pH 7.5 with 0.01% Tween 20) were dispensed into a 1,536-well solid-bottom black plate (Greiner Bio One, Monroe, NC) followed by pin- tool transfer (23 nL) of candidate inhibitors (final concentration range 968 pM to 57.2 μΜ) and control (Bay 11-7085, final concentration range 1.31 nM to 2.86 μΜ). Samples were incubated (RT, protected from light) for 15 minutes followed by a 1 μΕ substrate addition of NAD⁺ and

Propionaldehyde (final concentrations of 1 mM and 80 μΜ, respectively, for ALDH1B1, and ALDH2; or NAD⁺ and benzaldehyde at 1 mM and 200 μΜ, respectively, for ALDH3A1). Plates were centrifuged at 1,000 rpm for 15 seconds, then read in kinetic mode on a ViewLux High-throughput CCD imager (Perkin-Elmer) equipped with standard UV fluorescence optics (340 nm excitation, 450 nm emission) for 10 minutes (ALDH1B1, ALDH2) or 4 minutes (ALDH3A1). The change in fluorescence intensity over the 4 or 10-minute reaction period was normalized against no-inhibitor and no-enzyme controls and the resulting percent inhibition data were fitted for biological activity.

Example 52. 15-Hydroxyprostaglandin dehydrogenase (HPGD) enzymatic assay

[0297] 3 μΕ of enzyme (final concentration 20 nM) or buffer were dispensed into a 1,536-well solid- bottom black plate (Greiner Bio One, Monroe, NC) followed by pin-tool transfer (23 nL) of compound (final concentration range 324 pM to 57.2 μΜ) and control (GW5074, final concentration range 78.4 nM to 57.2 μΜ). Samples were incubated (RT, protected from light) for 15 minutes followed by a 1 μΕ substrate addition of nicotinamide adenine dinucleotide (NAD⁺) and Prostaglandin E₂ (final concentrations of 1 mM and 30 μΜ, respectively). Plates were centrifuged at 1,000 rpm for 15 seconds, then read in kinetic mode on a ViewLux High-throughput CCD imager (PerkinElmer, Waltham, MA) equipped with standard UV fluorescence optics (340 nm excitation, 450 nm emission) for 2 minutes at 30 second intervals. Data were normalized (Read 2_{2 m}i_n - Read l_{0 m}i_n) against no- enzyme (positive) and enzyme-containing (neutral) wells.

Example 53. Type-4 hydroxysteroid dehydrogenase (HSD17g4) enzymatic assay

[0298] Briefly, 3 μΐ_^ of enzyme (final concentration 100 nM) or buffer were dispensed into a 1 ,536- well solid-bottom black plate followed by pin-tool transfer (23 nL) of compound (final concentration range 324 pM to 57.2 μΜ) and control (NCGC00097840-01 , final concentration range 5.23 nM to 11.4 μΜ). Samples were incubated (RT, protected from light) for 15 minutes followed by a 1 substrate addition of NAD⁺ and Estradiol (final concentrations of 1 mM and 50 μΜ, respectively, in 15% DMSO). Plates were centrifuged at 1,000 rpm for 15 seconds, then read immediately on a ViewLux High-throughput CCD imager equipped with standard UV fluorescence optics (340 nm excitation, 450 nm emission), incubated for 1 hour (RT, protected from light) followed by a second read. Data were normalized (Read 2i _bom- Read lo _hour) against no-enzyme (positive) and enzyme- containing (neutral) wells. For more information, see PubChem Assay ID 893

[http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=893].

The activities of certain compounds of the disclosure at the ALDH1A1 , ALDH1B 1 , ALDH3A1 , ALDH2, HPGD, and Η8ϋ17β4 enzymes are provided in TABLE II.

[0299] TABLE 3 tabulates the selectivity of various compounds against other ALDH isozymes and dehydrogenases. ++++ represents IC₅₀ < 0.5 μΜ; +++ represents 0.5 μΜ < IC₅₀≤ 1.0 μΜ; ++ represents 1.0 μΜ < IC₅₀ < 10 μΜ; + represents IC₅₀ > 10 μΜ.

TABLE 3

hALDHlAl hALDHlB l hALDH3Al hALDH2 HPGD HSD17 4

Cpd. ID

ic₅₀ ic₅₀ ic₅₀ ic₅₀ ic₅₀ ic₅₀

1 ++++ + + ++ + +

2 ++++ + + + + +

5 ++++ + ++ ++ + +

32 ++++ + + + + +

21 ++++ + + ++ + +

20 ++++ + ++ ++ + +

17 ₊₊₊₊ + + + + +

48 ++++ + + ++ + +

58 ++++ + + ++ + +

118 ++++ + + + + +

59 ₊₊₊₊ + + + + +

Claims

We claim:

1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,

(I)

wherein

R¹ and R² are independently chosen from

R³ is

(i) C(₂-8₎alkyl, (C(i.₄₎alkoxy)C(i-4₎alkyl, or (mono- or di-C(i- ₎alkylairrino)C(i- ₎aikyl, each of which is optionally substituted with halogen, hydroxyl, cyano, amino, oxo, C(₃_6₎Cyclohexyl and 4- to 6-membered heterocyloalkyl having 1 to 2 independently chosen O, N, and S atoms; or

(ii) (phenyl)C₍o-2₎alkyl, (pyridyl)C₍₀-₂₎alkyl, (thiazolyl)C₍₀-₂₎alkyl, (naphthyl)C₍₀-₂₎alkyl, (C₍₃.

₆₎cycloalkyl)C(o-2₎alkyl, (mo holinyl)C(l.4₎alkyl, (pyranyl)C₍i_₄₎alkyl, (piperazinyl)C₍i_₄₎alkyl, cyclohexyl fused with a spiro 3-7 membered cycloalkyl, cycloalkenyl, or heterocyloalkyl ring, the heterocycloalkyl ring having 1 or two heteroatoms independently chosen from O and N, pyranyl, piperazinyl, thiopyranyl, thiopyran- 1,1, -dioxide -4-yl, each of which (ii) is optionally substituted with one or more substituents chosen from halogen, hydroxyl, cyano, amino, Q^alkyl, C₍i_₄₎alkoxy, (mono- and di-C(i.₄₎alkylamino)C₍₀-2₎alkyl, C₍i_₂₎haloalkyl, and C(i_₂₎haloalkoxy, and optionally substituted with one substituent chosen from (C₍₃. Cycloalkyl)C₍o-2₎alkyl, and (phenyl)C₍₀-2₎alkyl; ere m and n are each an integer from 0 to 2 and

Z is -(C=0)OC₍₁_₄₎alkyl, -(C=0)OC₍₃-₅₎cycloalkyl, -(C=0)NHC₍₁_₄₎alkyl, -(C=0)NHC₍₃_₅₎cycloalkyl,

-(C=0)Rⁿ, -S0₂Rⁿ, pyridyl substituted with R¹², or pyrmidinyl substituted with R¹²;

R¹¹ is C₍₁_₄₎alkyl, -C₍₃_₅₎cycloalkyl, -CH₂OH, -CH₂OC₍₁_₂₎alkyl, -NHC₍₁_₃₎alkyl, -NHC₍₃_₅₎cycloalkyl,

R¹² is one or more substituents independently chosen from hydrogen, F, CI, and Me;

L is

(a) -O-oxetanyl, -OC₍₃.₅₎Cycloalkyl, -0-CH₂-C₍₃.5₎Cycloalkyl, -(C=0)alkyl, -(C=0)C₍₃.₅₎Cycloalkyl,

(mono- or di-C(i.₄₎alkylcarboxamide, -(C=0)NHC₍₃_5₎Cycloalkyl, or -NH(C=0)C₍₃.₅.

jcycloalkyl, each of which (a) is optionally substituted with hydroxyl, halogen, and -OMe, or

(b) pyrrolidone-l-yl, pyrazolyl, methyl-pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, oxazolyl,

imidazolyl, each of which is optionally substituted with F, CI, or Me. d of formula (I), or a pharmaceutically acceptable salt or solvate thereof,

(I)

wherein

1 and R² are independently selected from the group consisting of hydrogen, Me, and Et;

wherein b, d, and e are each an independent integer from 1 to 2; f is an integer from 0 to 4; g is an integer from 0 to 3, h is an integer from 1 to 3; Et

R⁴ is independently selected from a group consisting of (C₍3_₇₎Cycloalkyl, Et _;

R⁵ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, Me,

CF₃, Et, CN, OMe, and OEt;

R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F,

C₍i_

_;)alkoxy, CF₃, CN, (C₍₃-6₎Cycloalkyl)C₍₀-2₎alkyl,

R⁸ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, C₍i_ 3₎alkyl, and CF₃;

R⁹ and R¹⁰ are independently selected from the group consisting of Me and Et, or, alternatively, R and R¹⁰ are taken together with the nitrogen atom to which they are bound to form pyrrolidin- 1-yl, piperidin-l-yl, morpholin-l- l, or 4-C₍i.₃₎alkyl-piperazin-l-yl; and

A is selected from the group consisting of

, and ;

wherein X-Y is ; wherein m and n are each an independent integer

R¹¹ is independently selected from the group consisting of-C(i.₄ alkyl, -C₍₃_₅₎Cycloalkyl,

-CH₂OH, -CH₂OC₍₁.2₎alkyl, -NHC₍₁.₃₎alkyl, -NHC₍₃-5₎Cycloalkyl, and Me , each of which R¹¹ is optionally substituted; wherein R¹² is one or more substituents independently selected from the group consisting of hydrogen, F, CI, and Me;

L is selected from the group consisting of \-Ό , -OC(₃_5₎Cycloalkyl, -0-CH₂-C(₃.5₎Cycloalkyl,

R¹³ is one or more substituents independently selected at each occurrence from the group consisting of hydrogen, F, CI, and Me;

selected from the group consisting of

(C₍₃.₆₎Cycloalkyl)C₍₀-₂₎alkyl,

R¹⁵ is hydrogen or cyano; R^lb and R¹ ' are independently chosen from hydrogen, C(i.₃₎alkyl, and cyclopropyl; and ¹⁸ and R¹⁹ are independently selected from the group consisting of hydrogen, Q^alkyl, (C₍₃.

R¹⁸ and R¹⁹ can be joined to form a 3- to 6-membered carbocyclic ring.

3. The compound, salt, or solvate of claim 2, wherein

Z is selected from the group consisting of OC_(3-5)cycloalkyl _^ .(_C=0)NHC₍₁_₄₎alkyl, -(C=0)NHC_c

, R¹² , R¹² ,

Υ

L is selected from the group consisting of °ν- 0 _; OC₍₃_5₎Cycloalkyl, -0-CH₂-C(₃.5₎Cycloalk l,

4. The compound, salt, or solvate of claim 3, wherein

R¹ and R² are independently selected from the group consisting of Me and Et;

f is an integer from 0 to 3;

g is an integer from 1 to 2;

h is an integer from 1 to 2;

R⁵ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, Me, CF₃, Et, and OMe;

R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F, C₍i_₄₎alkyl, C₍i_ 4₎alkoxy, CF₃, and (C₍₃.₆₎Cycloalkyl)C₍o-2₎alkyl ; ^--WO 2016/086008 PCT/US2015/062467 (NIH0104PCT)

R is independently selected at each occurrence from the group consisting of hydrogen, CI, and Me; R¹² is one or more substituents independently selected at each occurrence from the group consisting of hydrogen, CI, and Me;

R¹³ is one or more substituents independently selected at each occurrence from the group consisting of hydrogen, CI, and Me.

5. The compound, salt, or solvate of claim 4, wherein

R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F, Me, Et, and

CF₃;

R is independently chosen at each occurrence from hydrogen and Me;

R¹² is hydrogen or Me; and

R¹³ is hydrogen or Me.

6. The compound, salt, or solvate of claim 5, wherein

R¹ and ² are Me;

R¹ is se

R⁴ is ind

ependently selected from a group consisting of C .₄₁alkyl, C₍₃.₇₎cycloa] lkyl,

L is selected from the group consisting of , -OC₍3-5₎Cycloalkyl, -0-CH₂-C₍₃-₅₎Cycloalkyl,

a

nd

7. The compound, salt, or solvate of claim 6, wherein

selected from the group consisting

R⁹ and R¹⁰ are independently selected from the group consisting of Me and Et, or, alternatively, R and R¹⁰ are taken together with the nitrogen atom to which they are bound to form pyrrolidin- 1-yl, piperidin-l-yl, or morpholin-l -yl; and

selected from the group co -(C=0)NHC,

₅₎Cycloalkyl, R ,

d 8. The compound, salt, or solvate of claim 7, wherein

R³ is se

R⁴ is ind , and

R is independently selected at each occurrence from the group consisting of hydrogen, F, CI, Me, CF₃, and OMe;

R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F, Me, Et, CN,

R⁹ and R¹⁰ are Me, or, alternatively, R⁹ and R¹⁰ are taken together with the nitrogen atom to which they are bound to form pyrrolidin-l-yl, piperidin-l -yl, or morpholin-l-yl; and

Z is sele ,

L is selected from the group consisting of - 0 _; -OC₍₃_₅₎Cycloalkyl, -0-CH₂-C₍₃.₅₎Cycloalk l,

A compound, salt, or solvate of Claim 1 , of formula la, or a pharmaceutically acceptable salt H .0

R 1 1

R is hydrogen or Me;

R³ is se

f is an integer from 1 to 3; g is an integer from 1 to 2, h is an integer from 1 to 2; R⁵ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, CF₃, and OMe; and

R⁶ and R⁷ are independently selected from the group consisting of hydrogen, C₍i_₄₎alkyl, -6₎Cycloalkyl)C₍₀-2₎alkyl,

R s y rogen, ₍i.₃₎a y , , or .

The compound, salt, or solvate of Claim 9, wherein

is s

R⁴ is independently selected at each occurrence from the group consisting of

C₍₃.

₇₎Cycloalkyl,

R⁵ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, Me, CF₃, and OMe; R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F, Me, Et, CN,

The compound, salt, or solvate of Claim 10, wherein

R is independently selected from the group consisting of C₍₃_5₎Cycloalkyl,

R⁴ is ting of C₍₃.₇₎Cycloalkyl, and

12. A compound of Claim 1 of formula lb, or a pharmaceutically acceptable salt or solvate thereof,

wherein

.0 selected from the group consisting of OcC(₃_₅) cCyeclooa*lky,l

H° R

R¹² is hydrogen or Me; and

R³ is selected from the group consisting of

,

f is an integer from 1 to 3; g is an integer from 1 to 2, h is an integer from 1 to 2;

R⁴ is in

R⁵ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, Me, CF₃, and OMe; and

R⁶ and R⁷ are independently selected from the group consisting of hydrogen,

-₆₎cycloalkyl)C₍o-2₎alkyl,

13. The compound, salt or solvate of Claim 12, wherein

Me

— |— OMe

R⁴ is independently selected at each occurrence from the group consisting of C^alkyl, Me

R⁵ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, Me, CF₃, and OMe;

R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F, Me, Et, CN,

14. The compound, salt, or solvate, of claim 13, wherein

R¹¹ is independently selecte the group consisting of Chalky!, C₍₃.₅₎cycloalkyl,

-NHC₍i.₃ alkyl, and

; and

R⁴ is independently selected from a group consisting of C₍i_₄₎alkyl, Cp^cycloalkyl, and

15. The compound, salt, or solvate of Claim 1 of formula Ic, or a pharmaceutically acceptable salt or solvate thereof,

wherein lected from the group consisting of H_o O_cC(₃_₅) _cCy_dcl_oa .0 se oa_il_kky_il

R

R

f is an integer from 1 to 3; g is an integer from 1 to 2, h is an integer from 1 to 2;

Me — |— OMe

R⁴ is independently selected from the group consisting of C(i_₄₎alkyl, C(3_₇₎Cycloalkyl, Me _; and

R⁵ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, Me, CF₃, and OMe; and

R⁶ and R⁷ are independently selected from the group consisting of hydrogen, F, Me, Et, CN,

, and V E-^WO 2016/086008 PCT/US2015/062467

(NIH0104PCT)

A compound of Claim 1 of formula Id, or a pharmaceutically acceptable salt or solvate thereof,

wherein

selected from the

R^{1 1} , and

R ^" is hydrogen or Me

selected from the

group consisting of

f is an integer from 1 to 3; g is an integer from 1 to 2, h is an integer from 1 to 2;

R⁴ is selected at each occurrence from a group consisting of

and

R⁵ is independently selected at each occurrence from the group consisting of hydrogen, F, CI, Me, CF₃, and OMe; and R⁶ and R⁷ are inde endently selected from the group consisting of hydrogen, F, Me, Et, CN,

, or a pharmaceutically acceptable salt or solvate thereof,

wherein Z is selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl.

18. The compound, salt, or solvate of Claim 17, wherein Z is optionally substituted pyridinyl.

19. The compound, salt, or solvate of formula I-A-2,

wherein Z is selected from the group consisting of C(i_₅₎alkyl, optionally substituted C₍i_₃₎alkoxy, C₍₃.

5₎Cycloalkyl, C₍i_5₎aminoalkyl, C₍₃_5₎Cycloalkyloxy; C₍₃.5₎Cycloalkylamino, and 5- or 6- membered heteroaryl, provided that Z is not OEt or furanyl.

20. The compound, salt, or solvate ein Z is substituted alkoxy, C₍₃.5₎Cycloalkyl,

C(i_₄₎alkyl, C(i.₃₎aminoalkyl, or

21. A compound of formula I-A-3, or a pharmaceutically acceptable salt or solvate thereof, wherein is selected from the group consisting of:

a) optionally substituted

branched C₍₃_₅₎alkyl;

b) optionally substituted C₍i_₃₎alkoxy; optionally substituted C₍i_₃₎alkoxymethyl;

c) optionally substituted C₍i_₅₎alkylamino having only one nitrogen; and

d) C₍₃_₅₎Cycloalkyl; C₍₃_₅₎Cycloalkyloxy; C₍₃.₅₎Cycloalkylamino, and C₍₃_₅₎Cycloalkylmethyl.

22. The compound, salt, or solvate of claim 21 , wherein Z is selected from the group consisting C₍i.₃₎alkyl, C₍i.₃₎alkoxy, and C₍i.₃₎alkylamino having only one nitrogen.

23. A compound of formula I-A-4, or a pharmaceutically acceptable salt or solvate thereof,

wherein Z is selected from the group consisting of:

a) optionally substituted C₍i.₃₎alkyl; branched C₍₃.₅₎alkyl;

b) optionally substituted C₍i.₃₎alkoxy; optionally substituted C₍i.₃₎alkoxymethyl;

c) optionally substituted C₍i_₅₎alkylamino having only one nitrogen;

oalkyl; C₍₃.₅₎Cycloalkyloxy; C₍₃_₅₎Cycloalkylamino, and C₍₃.₅₎Cycloalkylmethyl; and

24. A compound of formula I-A-5, or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is selected from the group consisting of:

a) optionally substituted C₍i-₃₎aikyl; branched C₍₃_₅₎alkyl;

b) optionally substituted C₍i_₃₎alkoxymethyl;

c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C₍₃.₆₎Cycloalkyl.

25. A compound of formula I-A-6, or a pharmaceutically acceptable salt or solvate thereof,

wherein Z¹ is selected from the group consisting of:

a) optionally substituted

branched C₍₃_₅₎alkyl;

b) optionally substituted C₍i.₃₎alkoxy; optionally substituted C₍i.₃₎alkoxymethyl;

c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C₍₃.₆₎Cycloalkyl. 7, or a pharmaceutically acceptable salt or solvate thereof,

wherein Z¹ is selected from the group consisting of:

a) optionally substituted C₍i.₃₎alkyl; branched C₍₃.₅₎alkyl; b) optionally substituted C₍i_₃)alkoxy; optionally substituted C₍i.₃)alkoxymethyl;

c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C(₃.₆)Cycloalkyl. or a pharmaceutically acceptable salt or solvate thereof,

wherein Z¹ is selected from the group consisting of:

a) optionally substituted

branched C₍₃_5)alkyl;

b) optionally substituted C₍i.₃₎alkoxy; optionally substituted C₍i.₃₎alkoxymethyl;

c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C₍₃.₆)Cycloalkyl. - l , or a pharmaceutically acceptable salt or solvate thereof,

I-B-l)

wherein Z¹ is selected from the group consisting of:

a) optionally substituted C₍i.₃₎alkyl; branched C₍₃.5)alkyl;

b) optionally substituted C₍i.₃₎alkoxymethyl;

c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C₍₃.6)Cycloalkyl.

29. A compound of formula I-B-2, or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is selected from the group consisting of:

a) optionally substituted

branched C₍₃_5)alkyl;

b) optionally substituted C₍i_₃)alkoxy; optionally substituted C₍i_₃)alkoxymethyl;

c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C(₃.6)Cycloalkyl. -3, or a pharmaceutically acceptable salt or solvate thereof,

I-B-3)

wherein Z¹ is selected from the group consisting of:

a) optionally substituted C₍i.₃₎alkyl; branched C₍₃.5)alkyl;

b) optionally substituted C₍i.₃₎alkoxy; optionally substituted C₍i.₃₎alkoxymethyl;

c) optionally substituted C₍i_5)alkylamino having only one nitrogen; and

d) C₍₃_5)Cycloalkyl; C(₃.₅)Cycloalkyloxy; C₍₃_5)Cycloalkylamino, and C₍₃_5)Cycloalkylmethyl. -4, or a pharmaceutically acceptable salt or solvate thereof,

(I-B-4)

wherein Z¹ is selected from the group consisting of:

a) optionally substituted C₍i.₃₎alkyl; branched C(₃.₅)alkyl; b) optionally substituted C₍i_₃₎alkoxy; optionally substituted C₍i.₃₎alkoxymethyl;

c) optionally substituted 5- or 6-membered heteroaryl; and

d) optionally substituted C₍₃.₆₎Cycloalkyl.

32. A compound Claim 1 of formula I-D-2, or a pharmaceutically acceptable salt or solvate thereof,

(I-D-2)

wherein

selected from the group consisting of

f is an integer from 1 to 3; and

g and h are each an independently integer from 1 to 2. or a pharmaceutically acceptable salt or solvate thereof,

R³ is selected from the group consisting of:

a) hydrogen; b) optionally substituted C^^alkyl; optionally substituted branched C₍₃_5₎alkyl; c) optionally substituted aryl or arylalkyl; optionally substituted 5- or 6-membered heteroaryl or 5- or 6-membered heteroarylalkyl;

d) optionally substituted C₍₃.₇₎Cycloalkyl; and

e) optionally substituted C₍₃.₇₎heterocycloalkyl or heterocycloalkyl.

34. The compound of claim 33, wherein R³ is

A compound of formula I-C-2, or a pharmaceutically acceptable salt or solvate thereof,

wherein

e is an integer from 0-2;

R⁵ is independently chosen at each occurrence from the group consisting of:

a) optionally substituted C(i-₃₎aikyl; optionally substituted branched C(₃_5₎alkyl;

b) C₍i-₃₎alkoxy;

c) halo and haloalkyl;

d) cyano; and

e) optionally substituted aryl or heteroaryl fused at ortho and meta positions to form a biaryl with the phenylmethyl group linked to R⁵.

36. A compound of Claim 1, of formula I-D-1, or a pharmaceutically acceptable salt or solvate thereof, wherein

(I-D-1) selected from the group consisting of

f is an integer from 1 to 3; and

g and h are each an independently integer from 1 to 2. or a pharmaceutically acceptable salt or solvate thereof,

wherein R^3a is selected from the group consisting of:

a) hydrogen;

b) optionally substituted

optionally substituted branched C₍₃_5₎alkyl;

c) optionally substituted aryl or arylalkyl; optionally substituted 5- or 6-membered heteroaryl or 5- or 6-membered heteroarylalkyl;

d) optionally substituted C₍₃.₇₎Cycloalkyl; and

e) optionally substituted C₍₃.₇₎heterocycloalkyl or heterocycloalkyl.

The compound, salt, or solvate of claim 37, wherein R^;

39. A compound of formula I-C-4, or a pharmaceutically acceptable salt or solvate thereof, e is an integer from 0-2; and

R⁵ for is independently selected at each occurrence from the group consisting of:

a) optionally substituted

optionally substituted branched C₍₃_5₎alkyl;

b) C₍i.₃₎alkoxy;

c) halo and haloalkyl;

d) cyano; and

e) optionally substituted aryl or heteroaryl fused at ortho and meta positions to form a biaryl with the phenylmethyl group linked to R⁵.

40. A compound depicted in TABLE 4, or a pharmaceutical acceptable salt or solvate thereof:

TABLE 4

41. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of claims 1-40. 42. A process for making a pharmaceutical composition comprising mixing a compound of any of claims 1-33 and a pharmaceutically acceptable carrier.

43. A method of treating an ALDH1A1 disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of claims 1-40.

44. A method of treating an ALDH1A1 disorder, comprising administering to a subject in need thereof a therapeutically effective amount of compound 1, compound 2, compound 3, compound 137, or compound 140.

45. The method of claim 52 or claim 53, wherein the ALDH1A1 disorder is selected from the group consisting of cancer, inflammation or a disease or disorder associated with inflammation, and obesity.

46. The method of claim 52 or claim 53, wherein the ALDH1A1 disorder is selected from the group consisting of colon cancer, pancreatic cancer, nasopharyngeal carcinoma, thyroid cancer, prostate cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, and breast cancer.

47. The method of claim 52 or claim 53, wherein the ALDH1A1 disorder is selected from the group consisting of atherosclerosis, ischaemic heart disease, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and interstitial cystitis.

48. The method of any one of claims 52-56, wherein the subject is a mammal.

49. The method of any one of claims 52-56, wherein the subject is a human.