WO2018095260A1

WO2018095260A1 - Dihydroxyphenyl Sulfonylisoindoline Derivatives

Info

Publication number: WO2018095260A1
Application number: PCT/CN2017/111273
Authority: WO
Inventors: Xiangbing QI; Mingliang LOU; Enlong WU; Peihao Chen; Qingcui WU
Original assignee: National Institute of Biological Sciences Beijin
Current assignee: National Institute of Biological Sciences Beijin
Priority date: 2016-11-28
Filing date: 2017-11-16
Publication date: 2018-05-31
Anticipated expiration: 2019-05-28

Abstract

Provided are compounds that are inhibitors of pyruvate dehydrogenase kinase (PDK), and pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition.

Description

Dihydroxyphenyl Sulfonylisoindoline Derivatives

Inventors: Xiangbing Qi, Mingliang Lou, Enlong Wu, Peihao Chen and Qingcui Wu, all of Beijing, CN

Assignee: National Institute of Biological Sciences, Beijing

Priority Claim: PCT/CN2016/107397; Filed: Nov 28, 2016; Sub No. 94691

Introduction

We disclose novel pyruvate dehydrogenase kinase (PDK) inhibitors that can be used to improve glucose metabolism, correct metabolic dysfunction in vivo, and provide therapeutics for treating obesity and type 2 diabetes. Related compounds are disclosed in WO2015089360.

Summary of the Invention

The invention provides dihydroxyphenyl sulfonylisoindoline compounds of formula I:

wherein:

L is an optionally substituted, optionally hetero-, C1-C18 hydrocarbyl;

R is an optionally substituted, optionally hetero-, C1-C18 hydrocarbyl;

or a corresponding sulfinyl, or a stereoisomer, hydride, salt or acetate thereof, wherein the corresponding sulfinyl is:

The invention includes embodiments of the compound, including the sulfonyl, corresponding sulfinyl, or a stereoisomer, hydride, salt or acetate thereof, such as wherein:

L is an optionally substituted, optionally hetero-, C1-C18 alkyl, or an optionally substituted, optionally hetero-, C2-C18 alkenyl or alkynyl, or an optionally substituted, optionally hetero-, C2-C18 aryl;

L is an optionally substituted, optionally hetero-, C1-C18 alky;

L is optionally substituted, diamino-C2-C18 hydrocarbyl;

L is an optionally substituted, diamino-, C1-C18 alkyl, or an optionally substituted, diamino-, C2-C18 alkenyl or alkynyl, or an optionally substituted, diamino-, C2-C18 aryl;

L is an optionally substituted, diamino-, C1-C18 alky; or

L is selected from:

R is an optionally substituted, optionally hetero-, C1-C18 alkyl, or an optionally substituted, optionally hetero-, C2-C18 alkenyl or alkynyl, or an optionally substituted, optionally hetero-, C2-C18 aryl;

R is an optionally substituted, optionally hetero-, C1-C18 alky;

R is an optionally substituted C1-C4 alky; or

R is acetimidyl, propionamide, acetimidamide, 1-hydroxyethyl, hydroxymethyl, butylamine, or guanidine.

The invention includes embodiments that is a disclosed or a following structure:

again, inclusive of a corresponding sulfinyl, or a stereoisomer, hydride, salt or acetate thereof.

In embodiments, the compound is the corresponding sulfinyl of a disclosed sulfonyl, or a following structure or a stereoisomer, hydride, salt or acetate thereof:

In embodiments the compound is an inhibitor of a human pyruvate dehydrogenase kinase, preferably preferentially liver targeting, or an obesity or type 2 diabetes drug.

In embodiments the invention provides a pharmaceutical composition comprising a disclosed compound or composition in unit dosage form, and/or coformulated or copackaged or coadministered with a different obesity or type 2 diabetes drugs.

The invention also provides methods of using a disclosed compound or composition comprising administering it to a person determined to be in need thereof, and optionally, detecting a resultant therapeutic effect, and may also optionally include the antecedent step of determining that the person, particularly diagnosing and applicable disease or condition (herein) , or use thereof in the manufacture of a medicament.

The invention encompasses all combination of the particular embodiments recited herein, as if each combination had been laboriously recited.

Description of Particular Embodiments of the Invention

The following descriptions of particular embodiments and examples are provided by way of illustration and not by way of limitation. Those skilled in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results.

Unless contraindicated or noted otherwise, in these descriptions and throughout this specification, the terms “a” and “an” mean one or more, the term “or” means and/or and polynucleotide sequences are understood to encompass opposite strands as well as alternative backbones described herein. Furthermore, genuses are recited as shorthand for a recitation of all members of the genus; for example, the recitation of (C1-C3) alkyl is shorthand for a recitation of all C1-C3 alkyls: methyl, ethyl and propyl, including isomers thereof.

A hydrocarbyl group is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which comprises 1-15 carbon atoms and optionally includes one or more heteroatoms in its carbon skeleton.

The term "heteroatom" as used herein generally means any atom other than carbon or hydrogen. Preferred heteroatoms include oxygen (O) , phosphorus (P) , sulfur (S) , nitrogen (N) , and halogens, and preferred heteroatom functional groups are haloformyl, hydroxyl, aldehyde, amine, azo, carboxyl, cyanyl, thocyanyl, carbonyl, halo, hydroperoxyl, imine, aldimine, isocyanide, iscyante, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, and sulfhydryl.

The term "alkyl, " by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (i.e. C1-C8 means one to eight carbons) . Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.

The term "alkenyl" , by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono-or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) and higher homologs and isomers thereof.

The term "alkynyl" , by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono-or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1-and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.

The term "alkylene" by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH₂-CH₂-CH₂-CH₂-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

The terms "alkoxy, " "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

The term "heteroalkyl, " by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, P, Si and S, wherein the nitrogen, sulfur, and phosphorous atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom (s) O, N, P and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include -CH₂-CH₂-O-CH₃, -CH₂-CH₂-NH-CH₃, -CH₂-CH₂-N (CH₃) -CH₃, -CH₂-S-CH₂-CH₃, -CH₂-CH₂, -S (O) -CH₃, -CH₂-CH₂-S (O) ₂-CH₃, -CH=CH-O-CH₃, - Si (CH₃) ₃, -CH₂-CH=N-OCH₃, and -CH=CH-N (CH3) -CH₃. Up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃ and -CH₂-O-Si (CH₃) ₃.

Similarly, the term "heteroalkylene, " by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH₂-CH₂-S-CH₂-CH₂-and -CH₂-S-CH₂-CH₂-NH-CH₂-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.

The terms "cycloalkyl" and "heterocycloalkyl" , by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl" , respectively. Accordingly, a cycloalkyl group has the number of carbon atoms designated (i.e., C3-C8 means three to eight carbons) and may also have one or two double bonds. A heterocycloalkyl group consists of the number of carbon atoms designated and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1- (1, 2, 5, 6-tetrahydropyrid-yl) , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The terms "halo" and "halogen, " by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl, " are meant to include alkyl substituted with halogen atoms, which can be the same or different, in a number ranging from one to (2m'+1) , where m'is the total number of carbon atoms in the alkyl group. For example, the term "halo (C1-C4) alkyl" is mean to include trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m'+1) halogen atoms, where m'is the total number of carbon atoms in the alkyl group) . The term "perhaloalkyl" means, unless otherwise stated, alkyl substituted with (2m'+1) halogen atoms, where m'is the total number of carbon atoms in the alkyl group. For example the term "perhalo (C1-C4) alkyl" is meant to include trifluoromethyl, pentachloroethyl, 1, 1, 1-trifluoro-2-bromo-2-chloroethyl and the like.

The term "acyl" refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like.

The term "aryl" means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl and 1, 2, 3, 4-tetrahydronaphthalene.

The term heteroaryl, "refers to aryl groups (or rings) that contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.

For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like) .

Each of the above terms (e.g., "alkyl, " "heteroalkyl, " "aryl" and "heteroaryl" ) is meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) can be a variety of groups selected from: -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R'", -OC (O) R', -C (O) R', -CO₂R', -CONR'R", -OC (O) NR'R", -NR"C (O) R', -NR'-C (O) NR"R'", -NR'-SO₂NR'", -NR"CO₂R', -NH-C (NH₂) =NH, -NR'C (NH₂) =NH, -NH-C (NH₂) =NR', -S (O) R', -SO₂R', -SO₂NR'R", -NR"SO₂R, -CN and -NO₂, in a number ranging from zero to three, with those groups having zero, one or two substituents being particularly preferred. R', R"and R'"each independently refer to hydrogen, unsubstituted (C1-C8) alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl- (C1-C4) alkyl groups. When R'and R"are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-or 7-membered ring. For example, -NR'R"is meant to include 1-pyrrolidinyl and 4-morpholinyl. Typically, an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl (e.g., -CF₃ and -CH₂CF₃) .

Preferred substituents for the alkyl and heteroalkyl radicals are selected from: -OR', =O, -NR'R", -SR', halogen, -SiR'R"R'", -OC (O) R', -C (O) R', -CO₂R', -CONR'R", -OC (O) NR'R", -NR"C (O) R', -NR"CO₂R', -NR'-SO₂NR"R'", -S (O) R', -SO₂R', -SO₂NR'R", -NR"SO₂R, -CN and -NO₂, where R'and R"are as defined above. Further preferred substituents are selected from: -OR', =O, -NR'R", halogen, -OC (O) R', -CO₂R', -CONR'R", -OC (O) NR'R", -NR"C (O) R', -NR"CO₂R', -NR'-SO₂NR"R'", -SO₂R', -SO₂NR'R", -NR"SO₂R, -CN and -NO₂.

Similarly, substituents for the aryl and heteroaryl groups are varied and selected from: halogen, -OR', -OC (O) R', -NR'R", -SR', -R', -CN, -NO₂, -CO₂R', -CONR'R", -C (O) R', -OC (O) NR'R", -NR"C (O) R', -NR"CO₂R', -NR'-C (O) NR"R'", -NR'-SO₂NR"R'", -NH-C (NH₂) =NH, -NR'C (NH₂) =NH, -NH-C (NH₂) =NR', -S (O) R', -SO₂R', -SO₂NR'R", -NR"SO₂R, -N₃, -CH (Ph) ₂, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R"and R'"are independently selected from hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) - (C1-C4) alkyl and (unsubstituted aryl) oxy- (C1-C4) alkyl. When the aryl group is 1, 2, 3, 4-tetrahydronaphthalene, it may be substituted with a substituted or unsubstituted (C3-C7) spirocycloalkyl group. The (C3-C7) spirocycloalkyl group may be substituted in the same manner as defined herein for "cycloalkyl" . Typically, an aryl or heteroaryl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention. In one embodiment of the invention, an aryl or heteroaryl group will be unsubstituted or monosubstituted. In another embodiment, an aryl or heteroaryl group will be unsubstituted.

Preferred substituents for aryl and heteroaryl groups are selected from: halogen, -OR', -OC (O) R', -NR'R", -SR', -R', -CN, -NO₂, -CO₂R', -CONR'R", -C (O) R', -OC (O) NR'R", -NR"C (O) R', -S (O) R', -SO₂R', -SO₂NR'R", -NR"SO₂R, -N₃, -CH (Ph) ₂, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, where R'and R"are as defined above. Further preferred substituents are selected from: halogen, -OR', -OC (O) R', -NR'R", -R', -CN, -NO₂, -CO₂R', -CONR'R", -NR"C (O) R', -SO₂R', -SO₂NR'R", -NR"SO₂R, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl.

The substituent -CO₂H, as used herein, includes bioisosteric replacements therefor; see, e.g., The Practice of Medicinal Chemistry; Wermuth, C. G., Ed. ; Academic Press: New York, 1996; p. 203.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C (O) - (CH₂) q-U-, wherein T and U are independently -NH-, -O-, -CH₂-or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A- (CH₂) r-B-, wherein A and B are independently -CH₂-, -O-, -NH-, -S-, -S (O) -, -S (O) ₂-, -S (O) ₂NR'-or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CH₂) s-X- (CH₂) t--, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, -S (O) -, -S (O) ₂-, or -S (O) ₂NR'-. The substituent R'in -NR'-and -S (O) ₂NR'-is selected from hydrogen or unsubstituted (C1-C6) alkyl.

Preferred substituents are disclosed herein and exemplified in the tables, structures, examples, and claims, and may be applied across different compounds of the invention, i.e. substituents of any given compound may be combinatorially used with other compounds.

In particular embodiments applicable substituents are independently substituted or unsubstituted heteroatom, substituted or unsubstituted, optionally heteroatom C1-C6 alkyl, substituted or unsubstituted, optionally heteroatom C2-C6 alkenyl, substituted or unsubstituted, optionally heteroatom C2-C6 alkynyl, or substituted or unsubstituted, optionally heteroatom C6-C14 aryl, wherein each heteroatom is independently oxygen, phosphorus, sulfur or nitrogen.

In more particular embodiments, applicable substituents are independently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, amine, azo, halogens, carbamoyl, carbonyl, carboxamido, carboxyl, cyanyl, ester, halo, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl or trifluromethyl ether (OCF₃) .

The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.

In addition to salt forms, the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be more bioavailable by oral administration than the parent drug. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (the "prodrug" ) , but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound of the invention.

Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention.

Some of the subject compounds possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and specifically designated or depicted chirality is preferred and in many cases critical for optimal activity; however all such isomers are all intended to be encompassed within the scope of the invention.

The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, for example tritium (³H) , iodine-125 (¹²⁵I) or carbon-14 (¹⁴C) . All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.

The term "therapeutically effective amount" refers to the amount of the subject compound that will elicit, to some significant extent, the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, such as when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

The invention also provides pharmaceutical compositions comprising the subject compounds and a pharmaceutically acceptable excipient, particularly such compositions comprising a unit dosage of the subject compounds, particularly such compositions copackaged with instructions describing use of the composition to treat an applicable disease or condition (herein) .

The compositions for administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, losenges or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50%by weight or preferably from about 1 to about 40%by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

Suitable excipients or carriers and methods for preparing administrable compositions are known or apparent to those skilled in the art and are described in more detail in such publications as Remington's Pharmaceutical Science, Mack Publishing Co, NJ (1991) . In addition, the compounds may be advantageously used in conjunction with other therapeutic agents as described herein or otherwise known in the art, particularly other anti-diabetes or anti-obesity agents. Hence the compositions may be administered separately, jointly, or combined in a single dosage unit.

The amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc. Generally, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg, according to the particular application. In a particular embodiment, unit dosage forms are packaged in a multipack adapted for sequential use, such as blisterpack, comprising sheets of at least 6, 9 or 12 unit dosage forms. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

The compounds can be administered by a variety of methods including, but not limited to, parenteral, topical, oral, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.

The therapeutics of the invention can be administered in a therapeutically effective dosage and amount, in the process of a therapeutically effective protocol for treatment of the patient. For more potent compounds, microgram (μg) amounts per kilogram of patient may be sufficient, for example, in the range of about 1, 10 or 100 μg/kg to about 0.01, 0.1, 1, 10, or 100 mg/kg of patient weight though optimal dosages are compound specific, and generally empirically determined for each compound.

In general, routine experimentation in clinical trials will determine specific ranges for optimal therapeutic effect, for each therapeutic, each administrative protocol, and administration to specific patients will also be adjusted to within effective and safe ranges depending on the patient condition and responsiveness to initial administrations. However, the ultimate administration protocol will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as compounds potency, severity of the disease being treated. For example, a dosage regimen of the compounds can be oral administration of from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.

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

Representative Compounds

All reactions were carried out under an atmosphere of nitrogen in flame-dried glassware with magnetic stirring unless otherwise indicated. Commercially obtained reagents were used as received. Solvents were dried by passage through an activated alumina column under argon. Liquids and solutions were transferred via syringe. All reactions were monitored by thin-layer chromatography with E. Merck silica gel 60 F254 pre-coated plates (0.25 mm) . Structures of the target compounds in this work were assigned by use of NMR spectroscopy and MS spectrometry. The purities of all compounds were >95%as determined on Waters HPLC (Column: X Bridge C18, Eluents: 0.1%NH₄HCO₃/H₂O and CH₃CN) with 2998PDA and 3100MS detectors, using ESI as ionization. Pre-HPLC is used to separate and refine high-purity target compounds. ¹H and ¹³C NMR spectra were recorded on Varian Inova-400 or 500 spectrometers. Data for ¹H NMR spectra are reported relative to CDCl₃ (7.26 ppm) , CD₃OD (3.31 ppm) , or DMSO-d6 (2.50 ppm) as an internal standard and are reported as follows: chemical shift (δ ppm) , multiplicity (s= singlet, d = doublet, t = triplet, q = quartet, sept = septet, m = multiplet, br = broad) , coupling constant J (Hz) , and integration. Data for ¹³C NMR spectra are reported relative to CDCl₃ (77.23 ppm) , CD₃OD (49.00 ppm) or DMSO-d6 (39.52 ppm) as an internal standard and are reported in terms of chemical shift (δ ppm) .

Representative synthetic procedures; Synthesis of common intermediate:

5-Bromoisobenzofuran-1, 3-dione (2) . To a solution of phthalic anhydride (1) (22 g, 148.5 mmol, 1.0 equiv) in water (150 mL) was added NaOH (12 g, 300.0 mmol, 2.0 equiv) and neat Br₂ (8.5 mL, 165.9 mmol, 1.1 equiv) slowly and the mixture was stirred at 90 ℃ for 12 h. After that the reaction mixture was cooled to 0 ℃ and filtered to give a light yellow solid. The solid was washed with cold water (50 mL) , dissolved in SOCl₂ (60 mL) and the mixture was heated to reflux for 5 h. The reaction mixture was concentrated to give a residue, to which DCM (200 mL) was added and the mixture was stirred at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated to give 5-bromoisobenzofuran-1, 3-dione (2) (20 g, 71%yield) as a yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.16-8.17 (m, 1H) , 8.06-8.07 (m, 1H) , 7.89-7.90 (m, 1H) .

5-Bromoisoindoline-1, 3-dione (3) . A mixture of 5-bromoisobenzofuran-1, 3-dione (2) (13.2 g, 58.1 mmol) and formamide (20 mL) was stirred at 200 ℃ for 2 h. After cooling to room temperature, the reaction mixture was poured into water and stirred for 1.5 h. The mixture was filtered and the solid was dried to give 5-bromoisoindoline-1, 3-dione (3) (11 g, 81 %yield) . ¹H-NMR (400 MHz, CDCl₃) δ 11.44 (s, 1H) , 7.95-7.99 (m, 2H) , 7.70-7.72 (m, 1H) .

5-Bromoisoindoline (4) . To a solution of 5-bromoisoindoline-1, 3-dione (3) (25 g, 110.6 mmol, 1.0 equiv) in THF (60 mL) was added BF₃ (30 g, 442.4 mmol, 4.0 equiv) dropwise at 0 ℃. The mixture was stirred at 0 ℃ for 1.5 h and BH₃ (650 ml, 1.0 M, 6.0 equiv) was added dropwise at 0 ℃. Then the mixture was heated to 80℃ for 20 h and quenched by addition of methanol (100 mL) dropwise for 1 h at 0℃. The mixture was concentrated to give a crude product of 5-bromoisoindoline (4) (22 g) , which was used for next step directly.

Potassium 2, 4-dimethoxybenzenesulfonate (6) . To 1, 3-dimethoxybenzene (5) (85 g, 615.2 mmol) in a triple-necked flask equipped with a thermometer, a dropping funnel and a magnetic stirring system was added sulfuric acid (50 mL) dropwise at 0 ℃. The mixture was then brought to room temperature and left to stand for 1.5 h. The mixture set solid and was poured into the saturated solution of potassium carbonate (750 mL) , then left to stand overnight. The mixture was filtered and the solid was dried in vacuo to give potassium 2, 4-dimethoxybenzenesulfonate (6) (100 g, 63%yield) . ¹H-NMR (400 MHz, D₂O) δ 7.73 (d, J = 8.80 Hz, 1H) , 6.70 (s, 1H) , 6.58-6.61 (m, 1H) , 3.92 (s, 3H) , 3.89 (s, 3H) .

2, 4-Dimethoxybenzenesulfonyl chloride (7) . To a solution of potassium 2, 4-dimethoxybenzenesulfonate (6) (26 g, 101.4 mmol, 1.0 equiv) in DMF (105 mL) was added SOCl₂ (15.4 g, 129.6 mmol, 1.2 equiv) dropwise at 0 ℃. The mixture was warmed to room temperature and stirred for 16 h. Then the reaction mixture was poured into ice. The precipitate was filtered and dried in vacuo to give 2, 4-dimethoxybenzenesulfonyl chloride (7) (22 g, 92%yield) . ¹H-NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 8.80 Hz, 1H) , 6.54-6.57 (m, 2H) , 4.02 (s, 3H) , 3.90 (s, 3H) .

5-Bromo-2- ( (2, 4-dimethoxyphenyl) sulfonyl) isoindoline (8) . To a mixture of 5-bromoisoindoline (4) (22 g crude material, 111.6 mmol, 1.0 equiv) and triethylamine (50 mL) in acetonitrile (500 mL) was added 2, 4-dimethoxybenzenesulfonyl chloride (7) (27.6 g, 117.1 mmol, 1.05 equiv) in portions. The mixture was stirred at 25℃ for 48 h. Then the reaction mixture was concentrated to give a residue, to which ethyl acetate (1000 mL) was added and the mixture was washed with 1N HCl (100 mL × 2) . The organic layer was concentrated to give a residue, to which EtOAc (50 mL) was added and the mixture was stirred for 1 h. The mixture was filtered to give a white solid , which was dried in vacuo to give 5-bromo-1- (2, 4-dimethoxybenzenesulfonyl) isoindoline (8) (27 g, 60%yield) . ¹H-NMR (400 MHz, CDCl₃) δ 7.92 (d, J = 8.80 Hz, 1H) , 7.33-7.38 (m, 2H) , 7.06 (d, J = 8.80 Hz, 1H) , 6.40-6.44 (m, 2H) , 4.73 (s, 2H) , 4.66 (s, 2H) , 3.90 (s, 3H) , 3.73 (s, 3H) .

4- ( (5-bromoisoindolin-2-yl) sulfonyl) benzene-1, 3-diol (9) . To a solution of 5-bromo-1- (2, 4-dimethoxybenzenesulfonyl) isoindoline (8) (30 g, 75.3 mmol, 1.0 equiv) in a mixture of DCM (300 mL) and cyclohexene (60 mL) was added BBr₃ (113.2 g, 451.7 mmol, 6.0 equiv) dropwise at 0℃. The mixture was stirred at room temperature for 12 h and quenched by addition of methanol (100 mL) dropwise at 0℃. Then the mixture was concentrated to give a residue, which was dissolved in EtOAc (600 mL) , washed with water (100 mL × 2) and brine (150 mL) . The organic layer was concentrated to give a residue, which was dissolved in DCM (80 mL) and the mixture was stirred for 2 h. The mixture was filtered to give a compound, which was dried in vacuo to give 4- ( (5-bromoisoindolin-2-yl) sulfonyl) benzene-1, 3-diol (9) (10.4 g, 37%yield) . ¹H-NMR (400 MHz, CDCl₃) δ 10.51 (s, 1H) , 10.20 (s, 1H) , 7.48-7.51 (m, 2H) , 7.40 (d, J = 8.80 Hz, 1H) , 7.20 (d, J = 8.80 Hz, 1H) , 6.27-6.29 (m, 2H) , 4.58 (s, 2H) , 4.52 (s, 2H) .

2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) -5-bromoisoindoline (10) . To a mixture of 4- ( (5-bromoisoindolin-2-yl) sulfonyl) benzene-1, 3-diol (9) (41 g, 110.8 mmol, 1.0 equiv) and K₂CO₃ (61.1 g, 443.2 mmol, 4.0 equiv) in DMF (500 mL) was added benzyl bromide (94.7 g, 553.7 mmol, 5.0 equiv) dropwise at room temperature. The mixture was stirred at room temperature for 48 h. Water (1500 mL) was added to the mixture and the mixture was stirred for 2 h. Then the mixture was filtered to give a solid, which was dried in vacuo to give 2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) -5-bromoisoindoline (10) (65 g, 98%yield) . ¹H-NMR (400 MHz, CDCl₃) δ 7.93 (d, J = 8.80 Hz, 1H) , 7.26-7.39 (m, 11H) , 7.04 (s, 1H) , 6.82 (d, J = 8.80 Hz, 1H) , 6.55-6.61 (m, 2H) , 5.05 (s, 2H) , 4.96 (s, 2H) , 4.53 (s, 2H) , 4.48 (s, 2H) .

General synthesis of PS derivatives

General Procedure A: Step 1. To a mixture of 2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) -5-bromoisoindoline (10) (3.2 g, 5.8 mmol, 1.0 equiv) , tert-butyl 4-aminopiperidine-1-carboxylate (1.2 g, 11.6 mmol, 2.0 equiv) , BINAP (364 mg, 0.6 mmol, 0.1 equiv) , NaOtBu (1.1 g, 11.7 mmol, 2.0 equiv) in toluene (50 mL) was added Pd₂ (dba) ₃ (531.7 mg, 0.6 mmol, 0.1 equiv) . The mixture was bubbled with Ar₂ for 5 min and then stirred at 110℃ for 18 h. After the reaction mixture cooled to room temperature, water (50 mL) was added and the mixture was extracted with EtOAc (100 mL × 2) . The combined organic layer was concentrated to give a residue, which was purified by column chromatography to obtain the coupled product tert-butyl 4- ( (2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) isoindolin-5-yl) amino) piperidine-1-carboxylate (11) .

Step 2. To a solution of tert-butyl 4- ( (2- ( (2, 4-bis (benzyloxy)

phenyl) sulfonyl) isoindolin-5-yl) amino) piperidine-1-carboxylate (11) (1.8 mmol, 1.0 equiv) in DMF (20 mL) was added K₂CO₃ (5.4 mmol, 3.0 equiv) and benzyl bromide (5.4 mmol, 3.0 equiv) . The mixture was stirred at room temperature for 24 h. Water (100 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (50 mL × 3) . The combined organic layer was concentrated to give a residue, which was purified by column chromatography to obtain target product tert-butyl 4- (benzyl (2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) isoindoline-5-yl) amino) piperidine-1-carboxylate (12) .

Step 3. A solution of tert-butyl 4- (benzyl (2- ( (2, 4-bis (benzyloxy)

phenyl) sulfonyl) isoindolin-5-yl) amino) piperidine-1-carboxylate (12) (2.3 mmol, 1.0 equiv) in a mixture of aqueous HCl (12N, 50 mL) and MeOH (100 mL) was stirred at room temperature for 24 h. The mixture was concentrated to give a residue. Water was added to the residue and the mixture was basified with K₂CO₃ to pH=10. The mixture was extracted with DCM (30 mL × 2) . The combined organic layer was concentrated to give N-benzyl-2- ( (2, 4-bis(benzyloxy) phenyl) sulfonyl) -N- (piperidin-4-yl) isoindolin-5-amine (13) .

General Procedure B: Step 1. To a solution of N-benzyl-2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) -N- (piperidin-4-yl) isoindolin-5-amine (13) (2.3 mmol, 1.0 equiv) in DMF (20 mL) was added K₂CO₃ (4.6 mmol, 2.0 equiv) and 3-chloropropane-1, 2-diol (2.3 mmol, 1.0 equiv) . The mixture was stirred at room temperature for 24h. Then the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3) . The combined organic layer was concentrated to give a residue, which was purified through column to get 3- (4- (benzyl (2- ( (2, 4-bis (benzyloxy) phenyl)

sulfonyl) isoindolin-5-yl) amino) piperidin-1-yl) propane-1, 2-diol (14) .

Step 2. To a solution of 3- (4- (benzyl (2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) isoindolin-5-yl) amino) piperidin-1-yl) propane-1, 2-diol (14) (0.2 mmol, 1.0 equiv) in MeOH (5 mL) was added Pd/C (0.02 mmol, 0.1 equiv) and the mixture was stirred at room temperature under H₂ atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified by pre-HPLC to obtain the final product PS-038.

PS-038. Follow general procedure B (Scheme 3) . 5.0 mg, 7.2%yield for five steps. LCMS [M + H] ⁺ m/z 464.42. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 8.80 Hz, 1H) , 6.95 (d, J = 8.40 Hz, 1H) , 6.59 (d, J = 8.40 Hz, 1H) , 6.52 (s, 1H) , 6.27-6.30 (m, 2H) , 4.54 (s, 2H) , 4.50 (s, 2H) , 3.87-3.96 (m, 2H) , 3.51-3.54 (m, 2H) , 3.42-3.44 (m, 2H) , 2.84-2.94 (m, 4H) , 2.10-2.18 (m, 2H) , 1.62-1.71 (m, 2H) .

General Procedure C: Step 1. To a mixture of N-benzyl-2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) -N- (piperidin-4-yl) isoindolin-5-amine (13) (0.2 mmol, 1.0 equiv) , (3R, 5R) -3, 4, 5-trihydroxycyclohexane-1-carboxylic acid (0.3 mmol, 1.5 equiv) , HATU (0.4 mmol, 2.0 equiv) in DMF (5 mL) was added DIEA (0.4 mmol, 2.0 equiv) . The mixture was stirred at room temperature for 12 h. Water (15 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (15 mL × 3) . The combined organic layer was concentrated to give a residue, which was purified by column chromatography to obtain (4- (benzyl (2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) isoindolin-5-yl) amino) piperidin-1-yl) ( (3R, 5R) -3, 4, 5-trihydroxycyclohexyl) methanone (15) .

Step 2. To a solution of (4- (benzyl (2- ( (2, 4-bis (benzyloxy)

phenyl) sulfonyl) isoindolin-5-yl) amino) piperidin-1-yl) ( (3R, 5R) -3, 4, 5-trihydroxycyclohexyl) methanone (15) (0.2 mmol, 1.0 equiv) in MeOH (5 mL) was added Pd/C (0.02 mmol, 0.1 equiv) and the mixture was stirred at room temperature under H₂ atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified by pre-HPLC to obtain the final product PS-039.

PS-039. Follow general procedure C (Scheme 4) . 2.3 mg, 2.8%yield for five steps. LCMS [M + H] ⁺ m/z 548.48. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 8.80 Hz, 1H) , 6.95 (d, J = 8.40 Hz, 1H) , 6.59 (d, J = 8.40 Hz, 1H) , 6.52 (s, 1H) , 6.27 (d, J = 8.80 Hz, 1H) , 6.26 (s, 1H) , 4.54 (s, 2H) , 4.49 (s, 2H) , 4.38-4.40 (m, 1H) , 3.87-3.96 (m, 2H) , 3.82-3.85 (m, 1H) , 3.68-3.70 (m, 1H) , 3.51-3.54 (m, 1H) , 3.38-3.40 (m, 1H) , 3.08-3.10 (m, 1H) , 2.84-2.90 (m, 1H) , 1.90-2.10 (m, 2H) , 1.50-1.62 (m, 3H) , 1.25-1.37 (m, 3H) .

PS-044. Follow general procedure C (Scheme 4) . 2 mg, 1.2%yield for five steps. LCMS [M + H] ⁺ m/z 518.26. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 8.80 Hz, 1H) , 6.94 (d, J = 8.40 Hz, 1H) , 6.57 (d, J = 8.40 Hz, 1H) , 6.53 (s, 1H) , 6.37 (d, J = 8.80 Hz, 1H) , 6.33 (s, 1H) , 4.57 (s, 2H) , 4.51 (s, 2H) , 4.46-4.48 (m, 1H) , 4.38-4.40 (m, 1H) , 3.99-4.02 (m, 2H) , 3.51-3.54 (m, 1H) , 2.95-3.24 (m, 1H) , 2.34-2.42 (m, 2H) , 2.03-2.05 (m, 2H) , 1.25-1.38 (m, 4H) .

PS-045. Follow general procedure C (Scheme 4) . 7 mg, 4.6%yield for five steps. LCMS [M + H] ⁺ m/z 491.27. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 8.80 Hz, 1H) , 6.94 (d, J = 8.40 Hz, 1H) , 6.57 (d, J = 8.40 Hz, 1H) , 6.52 (s, 1H) , 6.37 (d, J = 8.80 Hz, 1H) , 6.32 (s, 1H) , 4.56 (s, 2H) , 4.50 (s, 2H) , 4.38-4.42 (m, 1H) , 4.01-4.04 (m, 1H) , 3.78-3.80 (m, 2H) , 3.49-3.51 (m, 1H) , 3.29-3.31 (m, 1H) , 2.93-2.99 (m, 1H) , 1.99-2.04 (m, 2H) , 1.35-1.41 (m, 2H) , 1.16-1.18 (m, 3H) .

PS-046. Follow general procedure C (Scheme 4) . 7 mg, 4.6%yield for five steps. LCMS [M + H] ⁺ m/z 504.23. ¹H NMR (400 MHz, CD₃OD) δ 7.55 (d, J = 8.80 Hz, 1H) , 6.91 (d, J = 8.40 Hz, 1H) , 6.51 (d, J = 8.40 Hz, 1H) , 6.36 (s, 1H) , 6.32 (d, J = 8.80 Hz, 1H) , 6.30 (s, 1H) , 4.55 (s, 2H) , 4.48 (s, 2H) , 4.32-4.36 (m, 1H) , 4.20-4.23 (m, 1H) , 3.98-4.02 (m, 1H) , 3.48-3.52 (m, 1H) , 3.20-3.24 (m, 1H) , 2.85-2.90 (m, 1H) , 2.52-2.56 (m, 1H) , 2.38-2.41 (m, 1H) , 1.96-2.02 (m, 2H) , 1.24-1.40 (m, 2H) .

PS-047. Follow general procedure C (Scheme 4) . 5 mg, 3.4%yield for five steps. LCMS [M + H] ⁺ m/z 477.24. ¹H NMR (400 MHz, CD₃OD) δ 7.56 (d, J = 8.80 Hz, 1H) , 6.94 (d, J = 8.40 Hz, 1H) , 6.58 (d, J = 8.40 Hz, 1H) , 6.52 (s, 1H) , 6.36 (d, J = 8.80 Hz, 1H) , 6.32 (s, 1H) , 4.57 (s, 2H) , 4.51 (s, 2H) , 4.39-4.42 (m, 1H) , 3.96-4.02 (m, 2H) , 3.61-3.63 (m, 1H) , 3.50-3.55 (m, 2H) , 3.24-3.27 (m, 1H) , 2.92-2.96 (m, 1H) , 1.98-2.05 (m, 2H) , 1.28-1.41 (m, 2H) .

PS-053. Follow general procedure C (Scheme 4) . 1 mg, 0.6%yield for five steps. LCMS [M + H] ⁺ m/z 518.40. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 8.80 Hz, 1H) , 6.94 (d, J = 8.40 Hz, 1H) , 6.58 (d, J = 8.40 Hz, 1H) , 6.52 (s, 1H) , 6.33 (d, J = 8.80 Hz, 1H) , 6.29 (s, 1H) , 4.57 (s, 2H) , 4.51 (s, 2H) , 4.38-4.42 (m, 1H) , 3.95-3.98 (m, 2H) , 3.52-3.56 (m, 1H) , 3.22-3.26 (m, 1H) , 2.84-2.89 (m, 1H) , 2.61-2.64 (m, 1H) , 2.42-2.45 (m, 1H) , 2.16-2.19 (m, 2H) , 1.92-2.04 (m, 4H) , 1.60-1.65 (m, 2H) , 1.30-1.42 (m, 2H) .

PS-059. Follow general procedure C (Scheme 4) . 2 mg, 1.2%yield for five steps. LCMS [M + H] ⁺ m/z 546.40. ¹H NMR (400 MHz, CD₃OD) δ 7.54-7.58 (m, 1H) , 6.98-7.02 (m, 1H) , 6.59-6.63 (m, 2H) , 6.36-6.41 (m, 2H) , 4.56 (s, 2H) , 4.52 (s, 2H) , 4.40-4.42 (m, 1H) , 4.01-4.05 (m, 1H) , 3.81-3.90 (m, 1H) , 3.54-3.58 (m, 2H) , 3.18-3.22 (m, 1H) , 2.00-2.36 (m, 4H) , 1.65-1.85 (m, 4H) , 1.25-1.30 (m, 2H) .

PS-070. Follow procedure C (Scheme 4) but use THF instead of methanol as solvent in step 2.4.0 mg, 2.1%yield for five steps. LCMS [M + H] ⁺ m/z 618.58. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (d, J = 8.40 Hz, 1H) , 6.96 (d, J = 8.40 Hz, 1H) , 6.54-6.61 (m, 2H) , 6.35-6.40 (m, 2H) , 4.57 (s, 2H) , 4.52 (s, 2H) , 4.44-4.48 (m, 1H) , 4.34-4.38 (m, 1H) , 4.18-4.22 (m, 1H) , 3.94-3.99 (m, 1H) , 3.58-3.61 (m, 3H) , 3.20-3.22 (m, 2H) , 2.97-3.00 (m, 1H) , 2.77-2.86 (m, 2H) , 2.03-2.13 (m, 2H) , 1.60-1.80 (m, 4H) , 1.25-1.40 (m, 2H) , 0.92-0.98 (m, 4H) .

General Procedure D: Step 1: To a mixture of 1- (2, 4-dibenzyloxybenzenesulfonyl) -5-bromoisoindoline (10) (110 mg, 0.2 mmol, 1.0 equiv) , piperazine (0.4 mmol, 2.0 equiv) , BINAP (12.5 mg, 0.02 mmol, 0.1 equiv) , NaOtBu (40 mg, 0.4 mmol, 2.0 equiv) in toluene (5 mL) was added Pd₂ (dba) ₃ (18 mg, 0.02 mmol, 0.1 equiv) . The mixture was bubbled with Ar₂ for 5 min and then stirred at 110℃ for 18 h. After the reaction mixture cooled to room temperature, water (5 mL) was added and the mixture was extracted with EtOAc (10 mL × 2) . The combined organic layer was concentrated to give a residue, which was purified by column chromatography to obtain 2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) -5- (piperazin-1-yl) isoindoline (16) .

Step 2. To a mixture of 2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) -

5- (piperazin-1-yl) isoindoline (16) (0.2 mmol, 1.0 equiv) , carboxyl acid contained substrate (0.3 mmol, 1.5 equiv) , HATU (0.4 mmol, 2.0 equiv) in DMF (5 mL) was added DIEA (0.4 mmol, 2.0 equiv) . The mixture was stirred at room temperature for 12 h. Water (15 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (15 mL × 3) . The combined organic layer was concentrated to give a residue, which was purified by column chromatography to obtain (S) -3-amino-4- (4- (2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) isoindolin-5-yl) piperazin-1-yl) -4-oxobutanamide (17) .

Step 3: To a solution of (S) -3-amino-4- (4- (2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) isoindolin-5-yl) piperazin-1-yl) -4-oxobutanamide (17) (0.2 mmol, 1.0 equiv) in MeOH (5 mL) was added Pd/C (0.02 mmol, 0.1 equiv) and the mixture was stirred at room temperature under H₂ atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified by pre-HPLC to obtain PS-073.

PS-073. Follow general procedure D (Scheme 5) . 3.5 mg, 9.3%yield for three steps. LCMS [M + H] ⁺ m/z 490.51. ¹H NMR (400 MHz, CD₃OD) δ 7.63 (d, J = 8.80 Hz, 1H) , 7.19 (d, J = 8.40 Hz, 1H) , 6.96 (d, J = 8.40 Hz, 1H) , 6.89 (s, 1H) , 6.41 (d, J = 8.80 Hz, 1H) , 6.36 (s, 1H) , 4.66 (s, 2H) , 4.61 (s, 2H) , 4.28-4.30 (m, 1H) , 3.76-3.82 (m, 4H) , 3.16-3.21 (m, 4H) , 2.60-2.63 (m, 1H) , 2.42-2.45 (m, 1H) .

PS-074. Follow general procedure D (Scheme 5) . 8.1 mg, 8.0%yield for three steps. LCMS [M + H] ⁺ m/z 504.51. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (d, J = 8.80 Hz, 1H) , 7.04 (d, J = 8.40 Hz, 1H) , 6.64-6.70 (m, 2H) , 6.39 (d, J = 8.80 Hz, 1H) , 6.36 (s, 1H) , 4.60 (s, 2H) , 4.56 (s, 2H) , 4.02-4.10 (m, 1H) , 3.60-3.80 (m, 4H) , 3.40-3.60 (m, 4H) , 2.38-2.50 (m, 1H) , 1.90-2.20 (m, 3H) .

PS-075. Follow general procedure D (Scheme 5) . 4.0 mg, 4.0%yield for three steps. LCMS [M + H] ⁺ m/z 504.51. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (d, J = 8.80 Hz, 1H) , 7.10 (d, J = 8.00 Hz, 1H) , 6.90 (d, J = 8.80 Hz, 1H) , 6.86 (s, 1H) , 6.37 (d, J = 8.80 Hz, 1H) , 6.32 (s, 1H) , 4.62 (s, 2H) , 4.58 (s, 2H) , 4.07-4.10 (m, 1H) , 3.70-3.80 (m, 4H) , 3.10-3.18 (m, 4H) , 2.30-2.42 (m, 2H) , 1.98-2.02 (m, 1H) , 1.78-1.81 (m, 1H) .

PS-076. Follow general procedure C (Scheme 4) . 4.0 mg, 2.7%yield for five steps. LCMS [M + H] ⁺ m/z 490.53. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (d, J = 8.80 Hz, 1H) , 6.96 (d, J = 8.40 Hz, 1H) , 6.51-6.58 (m, 2H) , 6.33-6.38 (m, 2H) , 4.58 (s, 2H) , 4.52 (s, 2H) , 4.05-4.15 (m, 1H) , 3.92-3.96 (m, 1H) , 3.58-3.61 (m, 3H) , 3.41-2.46 (m, 1H) , 2.45-2.70 (m, 1H) , 1.90-2.30 (m, 3H) .

PS-077. Follow general procedure C (Scheme 4) . 8 mg, 4.7%yield for five steps. LCMS [M + H] ⁺ m/z 594.57. ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (d, J = 5.60 Hz, 1H) , 7.38 (s, 1H) , 7.15-7.28 (m, 3H) , 6.96 (d, J = 8.80 Hz, 1H) , 6.84 (s, 1H) , 6.69 (s, 1H) , 6.55 (d, J = 8.40 Hz, 1H) , 6.29-6.32 (m, 2H) , 4.36-4.47 (m, 6H) , 4.00-4.06 (m, 3H) , 3.03-3.15 (m, 1H) , 2.62-2.68 (m, 1H) , 2.49-2.51 (m, 1H) , 2.27-2.31 (m, 1H) , 2.09-2.20 (m, 1H) , 1.57-1.74 (m, 3H) , 1.35-1.40 (m, 1H) .

PS-079. Follow general procedure C (Scheme 4) . 4 mg, 5.6%yield for five steps. LCMS [M + H] ⁺ m/z 476.52. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (d, J = 8.80 Hz, 1H) , 6.98 (d, J = 8.40 Hz, 1H) , 6.50 (d, J = 8.40 Hz, 1H) , 6.33-6.40 (m, 2H) , 6.32 (s, 1H) , 4.62-4.64 (m, 1H) , 4.58 (s, 2H) , 4.53 (s, 2H) , 4.26-4.32 (m, 2H) , 4.04-4.06 (m, 1H) , 3.74-3.78 (m, 2H) , 2.54-2.59 (m, 1H) , 2.40-2.44 (m, 1H) .

PS-080. Follow general procedure C (Scheme 4) . 6 mg, 5.6%yield for five steps. LCMS [M + H] ⁺ m/z 490.53. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (d, J = 8.80 Hz, 1H) , 6.96 (d, J = 8.40 Hz, 1H) , 6.57 (d, J = 8.40 Hz, 1H) , 6.51 (s, 1H) , 6.37 (d, J = 8.80 Hz, 1H) , 6.33 (s, 1H) , 4.58 (s, 2H) , 4.52 (s, 2H) , 4.00-4.11 (m, 2H) , 3.92-3.98 (m, 1H) , 3.58-3.75 (m, 2H) , 3.47-3.52 (m, 1H) , 2.59-2.65 (m, 1H) , 2.40-2.46 (m, 1H) , 2.16-2.30 (m, 1H) , 1.92-2.01 (m, 1H) .

PS-081. Follow general procedure D (Scheme 5) . 2.6 mg, 3.6%yield for three steps. LCMS [M + H] ⁺ m/z 478.52. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 8.80 Hz, 1H) , 6.93 (d, J = 8.40 Hz, 1H) , 6.54 (d, J = 8.40 Hz, 1H) , 6.49 (s, 1H) , 6.37 (d, J = 8.80 Hz, 1H) , 6.33 (s, 1H) , 4.57 (s, 2H) , 4.51 (s, 2H) , 3.63 (dd, J = 7.6, 5.2 Hz, 1H) , 3.40 (t, J = 13.6 Hz, 2H) , 3.10 (t, J = 6.4 Hz, 2H) , 2.61 (dd, J = 15.2, 5.2 Hz, 1H) , 2.46 (dd, J = 15.2, 7.6 Hz, 1H) , 1.79 (dd, J = 13.6, 6.4 Hz, 2H) .

PS-082. Follow general procedure D (Scheme 5) . 1.2 mg, 1.7%yield for three steps. LCMS [M + H] ⁺ m/z 464.53. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 8.80 Hz, 1H) , 6.93 (d, J = 8.40 Hz, 1H) , 6.54 (d, J = 8.40 Hz, 1H) , 6.49 (s, 1H) , 6.37 (d, J = 8.80 Hz, 1H) , 6.33 (s, 1H) , 4.57 (s, 2H) , 4.51 (s, 2H) , 3.62-3.65 (m, 1H) , 3.39-3.42 (m, 2H) , 3.20-3.23 (m, 2H) , 2.60-2.63 (m, 1H) , 2.50-2.53 (m, 1H) .

PS-083. Follow general procedure D (Scheme 5) . 5.2 mg, 16.0%yield for three steps. LCMS [M + H] ⁺ m/z 492.56. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 8.40 Hz, 1H) , 6.93 (d, J = 8.40 Hz, 1H) , 6.53 (d, J = 8.40 Hz, 1H) , 6.46 (s, 1H) , 6.37 (d, J = 8.40 Hz, 1H) , 6.33 (s, 1H) , 4.57 (s, 2H) , 4.50 (s, 2H) , 3.65-3.68 (m, 1H) , 3.15-3.22 (m, 2H) , 2.90-3.02 (m, 2H) , 2.61 (dd, J = 15.6, 5.6 Hz, 1H) , 2.47 (dd, J = 15.2, 7.6 Hz, 1H) , 1.95-2.00 (m, 1H) , 0.96 (d, J = 6.4 Hz, 3H) .

PS-084. Follow general procedure D (Scheme 5) . 2.0 mg, 6.7%yield for three steps. LCMS [M + H] ⁺ m/z 506.48. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 8.80 Hz, 1H) , 6.91 (d, J = 8.00 Hz, 1H) , 6.58 (d, J = 8.00 Hz, 1H) , 6.51 (s, 1H) , 6.37 (d, J = 8.80 Hz, 1H) , 6.33 (s, 1H) , 4.56 (s, 2H) , 4.50 (s, 2H) , 3.67 (dd, J = 7.6, 5.6 Hz, 1H) , 3.15-3.20 (m, 2H) , 2.89 (s, 2H) , 2.61 (dd, J = 15.6, 5.6 Hz, 1H) , 2.47 (dd, J = 15.6, 7.6 Hz, 1H) , 0.95 (s, 6H) .

General Procedure E: Step 1: To the solution of 1, 3-dibromobutane (18) (900 mg, 4.2 mmol, 1.0 equiv) in 30 ml of DMF was added Bn₂NH (1.24 g, 6.3 mmol, 1.5 equiv) , K₂CO₃ (871 mg, 6.3 mmol, 1.5 equiv) and KI (70 mg, 0.4 mmol, 0.1 equiv) . The mixture was stirred at 80℃ for 20 h. Then the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure to give a residue which was purified through column chromatography to obtain N, N-dibenzyl-3-bromobutan-1-amine (19) .

Step 2: To the solution of N, N-dibenzyl-3-bromobutan-1-amine (19) (869 mg, 2.6 mmol, 1.0 equiv) in 15 ml of DMF was added NaN₃ (340 g, 5.2 mmol, 2.0 equiv) . The mixture was stirred at 80℃ for 5 h. Then the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure to give the crude target product 3-azido-N, N-dibenzylbutan-1-amine (20) which was used directly for next step.

Step 3: To the solution of 3-azido-N, N-dibenzylbutan-1-amine (20) (2.6 mmol, 1.0 equiv) in 15 ml of THF was added PPh₃ (1.0 g, 3.9 mmol, 1.5 equiv) . The mixture was stirred at room temperature for 15 min. Then 1 ml of water was added to the reaction mixture and the pH of the reaction mixture was adjusted to 7 with 1N aqueous solution of HCl. Then the mixture was stirred at 50℃ for 12 h. After completion of the reaction, the reaction mixture was poured into saturated NaHCO₃ aqueous solution and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure to give a residue which was purified through column chromatography to obtain N1, N1-dibenzylbutane-1, 3-diamine (21) .

Step 4: To a mixture of 1- (2, 4-dibenzyloxybenzenesulfonyl) -5-bromoisoindoline (x) (550 mg, 1.0 mmol, 1.0 equiv) , N1, N1-dibenzylbutane-1, 3-diamine (21) (530 mg, 2.0 mmol, 2.0 equiv) , BINAP (62 mg, 0.1 mmol, 0.1 equiv) , NaOtBu (192 mg, 2.0 mmol, 2.0 equiv) in toluene (15 mL) was added Pd₂ (dba) ₃ (104 mg, 0.1 mmol, 0.1 equiv) . The mixture was bubbled with Ar₂ for 5 min and then stirred at 110℃ for 18 h. After the reaction mixture cooled to room temperature, water (5 mL) was added and the mixture was extracted with EtOAc (10 mL × 2) . The combined organic layer was concentrated to give a residue, which was purified by column chromatography to obtain N1, N1-dibenzyl-N3- (2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) isoindolin-5-yl) butane-1, 3-diamine (22) .

Step 5: To a solution of N1, N1-dibenzyl-N3- (2- ( (2, 4-bis (benzyloxy) phenyl) sulfonyl) isoindolin-5-yl) butane-1, 3-diamine (22) (213 mg, 0.29 mmol, 1.0 equiv) in MeOH (5 mL) was added Pd/C (21.3 mg, 0.1 equiv) and the mixture was stirred at room temperature under H₂ atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified by column chromatography to give target product 4- ( (5- ( (4-aminobutan-2-yl) amino) isoindolin-2-yl) sulfonyl) benzene-1, 3-diol (23) .

Step 6: To a mixture of 4- ( (5- ( (4-aminobutan-2-yl) amino) isoindolin-2-yl) sulfonyl) benzene-1, 3-diol (23) (50 mg, 0.13 mmol, 1.0 equiv) , ( (benzyloxy) carbonyl) -L-asparagine (46 mg, 0.17 mmol, 1.3 equiv) , HATU (65 mg, 0.17 mmol, 1.3 equiv) in DMF (5 mL) was added DIEA (34 mg, 0.26 mmol, 2.0 equiv) . The mixture was stirred at room temperature for 12 h. Water (15 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (15 mL × 3) . The combined organic layer was concentrated to give a residue, which was purified by column chromatography to obtain benzyl ( (2S) -4-amino-1- ( (3- ( (2- ( (2, 4-dihydroxyphenyl) sulfonyl) isoindolin-5-yl) amino) butyl) amino) -1, 4-dioxobutan-2-yl) carbamate (24) .

Step 7: To a solution of benzyl ( (2S) -4-amino-1- ( (3- ( (2- ( (2, 4-dihydroxyphenyl) sulfonyl) isoindolin-5-yl) amino) butyl) amino) -1, 4-dioxobutan-2-yl) carbamate (24) (15 mg, 0.02 mmol, 1.0 equiv) in MeOH (5 mL) was added Pd/C (1.5 mg, 0.1 equiv) and the mixture was stirred at room temperature under H₂ atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified by pre-HPLC to obtain PS-085. 10.2 mg, 7.0%yield for seven steps. LCMS [M + H] ⁺ m/z 492.15. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 8.40 Hz, 1H) , 6.91 (d, J = 8.40 Hz, 1H) , 6.53 (d, J = 8.40 Hz, 1H) , 6.48 (s, 1H) , 6.37 (d, J = 8.40 Hz, 1H) , 6.34 (s, 1H) , 4.57 (s, 2H) , 4.50 (s, 2H) , 3.68-3.78 (m, 1H) , 3.48-3.53 (m, 1H) , 3.24-3.31 (m, 2H) , 2.50-2.70 (m, 2H) , 1.62-1.76 (m, 2H) , 1.14 (d, J = 6.00 Hz, 3H) .

Biological Activity Data

Assays for inhibition of PDK activity were performed essentially as disclosed by Tso et al. J Biol Chem. 2014 Feb 14; 289 (7) : 4432-43.

Representative Inhibitor Data

*PS85 is estimated.

Beneficial physiological activities of the disclosed inhibitors are demonstrable in animal models, wherein administration of representative inhibitors was found to augment pyruvate dehydrogenase complex activity with reduced phosphorylation in different tissue, and resulted in improved glucose tolerance and reduced hepatic steatosis in diet-induced obesity. Treatments of mice with PDK inhibitors and assays for PDC activity in mouse tissues were performed essentially as disclosed by Tso et al. J Biol Chem. 2014 Feb 14; 289 (7) : 4432-43.

Activity in whole animal assays was confirmed in experiments performed in the laboratory of David Chuang at the University of Texas, Southwestern Medical Center. In a representative demonstration, prolonged treatment (2 weeks) , a representative inhibitor, PS46, was administered by osmotic pumps implanted subcutaneously, as dosages between 35-43 mg/kg, depending on individual animal weight. The physiological effects of the inhibitor on diet-induced obese (DIO) mice were significantly beneficial, selectively augmenting PDC activity in liver, and this liver-specific effect is sufficient to restore hepatic PDC activity in DIO mice to close to the normal level. The phosphorylation level of the E1a subunit was significantly reduced after inhibitor treatment, without affecting the expression of the E1a subunit, or the four PDK isoforms. The inhibitor improved glucose tolerance in DIO mice; for example, glucose uptake and/or consumption were faster in the inhibitor-treated DIO mice than the vehicle controls. Inhibitor treatment also reduces hepatic steatosis (fatty liver) in DIO mice: clearance of lipid (stained by Oil Red O) in liver indicates de novo lipogenesis (fatty acid synthesis) is significantly decreased. Treatment also enhances 5'AMP-activated protein kinase (AMPK) activity through phosphorylation, promoting glucose uptake and fatty acid oxidation, which leads to increased energy expenditure. Moreover, inhibitor treatment increases Protein Kinase B (Akt) activity by phosphorylation, which in turn restores insulin sensitivity in DIO mice.

Claims

A dihydroxyphenyl sulfonylisoindoline compound of formula I:

I,

wherein:

L is an optionally substituted, optionally hetero-, C1-C18 hydrocarbyl;

R is an optionally substituted, optionally hetero-, C1-C18 hydrocarbyl;

or a corresponding sulfinyl, or a stereoisomer, hydride, salt or acetate thereof.
The compound of claim 1 wherein:

L is an optionally substituted, optionally hetero-, C1-C18 alkyl, or an optionally substituted, optionally hetero-, C2-C18 alkenyl or alkynyl, or an optionally substituted, optionally hetero-, C2-C18 aryl;

L is an optionally substituted, optionally hetero-, C1-C18 alky;

L is optionally substituted, diamino-C2-C18 hydrocarbyl;

L is an optionally substituted, diamino-, C1-C18 alkyl, or an optionally substituted, diamino-, C2-C18 alkenyl or alkynyl, or an optionally substituted, diamino-, C2-C18 aryl;

L is an optionally substituted, diamino-, C1-C18 alky; or

L is selected from:
The compound of claim 1 wherein:

R is an optionally substituted, optionally hetero-, C1-C18 alkyl, or an optionally substituted, optionally hetero-, C2-C18 alkenyl or alkynyl, or an optionally substituted, optionally hetero-, C2-C18 aryl;

R is an optionally substituted, optionally hetero-, C1-C18 alky;

R is an optionally substituted C1-C4 alky; or

R is acetimidyl, propionamide, acetimidamide, 1-hydroxyethyl, hydroxymethyl, butylamine, or guanidine.
The compound of claim 1 that is a disclosed compound or a following structure:

or a corresponding sulfinyl, or a stereoisomer, hydride, salt or acetate thereof.
The compound of any of claims 1-10 that is an inhibitor of a human pyruvate dehydrogenase kinase, preferably preferentially liver targeting, or an obesity or type 2 diabetes drug.
A pharmaceutical composition comprising a compound of any of claims 1-5 in unit dosage form.
A pharmaceutical composition comprising a compound of any of claims 1-5 and a different obesity or type 2 diabetes drug
A method of using a compound of any of claims 1-5 or composition thereof comprising administering it to a person determined to be in need thereof, or use thereof in the manufacture of a medicament.
A method of using a compound of any of claims 1-5 or composition thereof comprising administering it to a person determined to be in need thereof and detecting a resultant therapeutic effect.