WO2014086697A1 - Substituted thiazole compounds - Google Patents

Abstract

The invention is concerned with the compounds of formula (I): and pharmaceutically acceptable salts thereof. In addition, the present invention relates to methods of manufacturing and using the compounds of formula (I) as well as pharmaceutical compositions containing such compounds. The compounds of formula (I) are LMP7 inhibitors and may be useful in treating associated inflammatory diseases and disorders such as, for example, rheumatoid arthritis, lupus and irritable bowel disease.

Description

Substituted Thiazole Compounds

Field of the Invention

The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal of an inflammatory disease or disorder, and in particular to substituted thiazole compounds for the treatment of rheumatoid arthritis, lupus and irritable bowel disease (IBD), their manufacture, pharmaceutical compositions containing them and their use as LMP7 inhibitors.

Background of the Invention

LMP7 is an essential component of the immunoproteasome, mainly expressed in immune cells such as T/B lymphocytes and monocytes, as well as non-immune cells that have exposed to inflammatory cytokines, including IFN-γ and TNFa. Immunoproteasome plays an essential role in generation of antigenic peptide repertoire and shaping MHC class I restricted CD8+ T cell response. Moebius J. et al. European Journal of Immunology. 2010; Basler, M. et al. Journal of Immunology. 2004. 3925-34. Emerging data suggested that LMP7 also regulate inflammatory cytokine production and immune cell functions beyond the regulation of MHC class I mediated antigen presentation.

A small molecule LMP7 inhibitor, PR-957, has been shown to potently block Thl/17 differentiation, B cell effector functions and production of inflammatory cytokines (IL-6, TNF-a, IL-23). Muchamuel T. et al. Natural Medicine. 2009. 15, 781-787; Basler M. et al. Journal of Immunology. 2010, 634-41.

In addition, LMP7 blockade with PR-957 has been demonstrated to produce therapeutic benefits in several preclinical autoimmune disease models. First, PR-957 was demonstrated to significantly decrease disease score in mouse CAIA and CIA arthritis models, with hallmarks of significantly reduced inflammation and bone erosion. Muchamuel T. et al. Natural Medicine. 2009. 15, 781-787. In addition, PR-957 reduced plasma cells numbers and levels of anti-dsDNA IgG in MRL/lpr lupus-prone mice model, and prevented disease progression in these mice.

Ichikawa HT, et al. Arthritis & Rheumatism. 2012. 64, 493-503. Furthermore, PR-957 reduced inflammation and tissue destruction in a DSS-induced colitis model in mice. Basler M. et al. Journal of Immunology. 2010, 634-41. Lastly, LMP7 knockout mice had also been shown to be protected from disease in IBD models. Schmidt N. et al. Gut 2010. 896-906.

Taken together, data strongly suggests that LMP7 activity is closely related to the functions of B/T lymphocytes and production of inflammatory cytokines, all of which are clinically validated targets/pathways in the pathogenesis of rheumatoid arthritis, lupus and IBD. Thus, existing data have provided strong rationale for targeting LMP7 for autoimmune disease indications. Due to potential liability with long term usage of a covalent inhibitor in chronic diseases like autoimmunity, a covalent reversible or non-covalent small molecule LMP7 inhibitor is highly desired for autoimmune disease indications.

Summary of the Invention

The invention provides for a compound of formula (I):

wherein: X is naphthalene, methoxy-naphthalene, dihydro-naphthalene, tetrahydro-naphthalene,

methoxy-tetrahydro-naphthalene or quinoline;

R¹ is Ci-7 alkyl, C₃_8 cycloalkyl, heterocycloalkyl, or phenyl optionally substituted with one or two halogen, -S0₂CH₃ or cyano;

R is hydrogen; or R 1 and R 2 together are forming a C₂_₇ alkenylene; or a pharmaceutically acceptable salt or ester thereof.

The invention also provides for pharmaceutical compositions comprising the compounds, methods of using the compounds and methods of preparing the compounds.

All documents cited to or relied upon are expressly incorporated herein by reference. Detailed Description of the Invention

Unless otherwise indicated, the following specific terms and phrases used in the

description and claims are defined as follows:

The term "moiety" refers to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule. For example, the R variables of formula I refer to moieties that are attached to the core structure of formula I by a covalent bond.

In reference to a particular moiety with one or more hydrogen atoms, the term

"substituted" refers to the fact that at least one of the hydrogen atoms of that moiety is replaced by another substituent or moiety. For example, the term "lower alkyl substituted by halogen" refers to the fact that one or more hydrogen atoms of a lower alkyl (as defined below) is replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.).

The term "alkyl" denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. Particular examples of alkyl are iso-butyl and tert-butyl.

The term "alkenyl" denotes a monovalent linear or branched hydrocarbon group of 2 to 7 carbon atoms with at least one double bond. In particular embodimets, alkenyl has 2 to 4 carbon atoms with at least one double bond. Examples of alkenyl include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl, and iso-butenyl.

The term "alkenylene" denotes a linear divalent hydrocarbon chain of 2 to 7 carbon atoms or a branched divalent hydrocarbon chain of 3 to 7 carbon atoms with at least one double bond. Exemplary alkenylene include ethenylene, 2,2-dimethylethenylene, propenylene, 2- methylpropenylene, butenylene, and pentenylene. Particular example of alkenylene is butenylene.

The term "alkoxy" denotes a group of the formula -O-R', wherein R' is an alkyl group. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy. Particular example of alkoxy is methoxy. The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particular embodiments cycloalkyl denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common. Particular cycloalkyl groups are monocyclic. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are

bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl. Particular example of cycloalkyl are

cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "heterocycloalkyl" denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 3 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In particular embodiments, heterocycloalkyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples for monocyclic saturated heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, l,l-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples for bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza- bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. Particular example of heterocycloalkyl are tetrahydrofuranyl, tetrahydropyranyl and tetrahydrothiophenyl.

"Aryl" means a monovalent cyclic aromatic hydrocarbon moiety having a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl,

diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl,

benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl,

ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof, each being optionally substituted. Particular example of aryl is phenyl.

The terms "halo", "halogen" and "halide", which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo. Particular example of halogen is chloro.

Unless otherwise indicated, the term "hydrogen" or "hydro" refers to the moiety of a hydrogen atom (-H) and not H₂.

Unless otherwise indicated, the term "a compound of the formula" or "a compound of formula" or "compounds of the formula" or "compounds of formula" refers to any compound selected from the genus of compounds as defined by the formula (including any

pharmaceutically acceptable salt or ester of any such compound if not otherwise noted). The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. Salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, N-acetylcystein and the like. In addition, salts may be prepared by the addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, and magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N- ethylpiperidine, piperidine, polyamine resins and the like.

The compounds of the present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula I to be used as prodrugs). The compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be effected in the course of the manufacturing process or can take place as a consequence of hygroscopic properties of an initially anhydrous compound of formula I

(hydration).

The term "pharmaceutically acceptable esters" denotes derivatives of the compounds of present invention, in which a carboxy group has been converted to an ester, wherein carboxy group means -C(0)0-. Methyl-, ethyl-, methoxymethyl-, methylthiomethyl-, and

pivaloyloxymethylesters are examples of such suitable esters.

Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers" and fall within the scope of the invention. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more

asymmetric centers that are non-superimposable mirror images of each other are termed

"enantiomers." When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".

The IUPAC lamda convention (W.H. Powell, Pure & Appl. Chem. (1984) 56(6): 769-778) provides a general method for indicating nonstandard valence states of heteroatoms in a molecule. The bonding number "n" of a heteroatom is the sum of the total number of valence bonds to adjacent atoms, if any, and the number of attached hydrogen atoms. The bonding number of a heteroatom is standard when it has the value given in the following table:

n=4: C, Si, Ge, Sn, Pb;

n=3: B, N, P, As, Sb, Bi

n=2: O, S, Se, Te, Po;

n=l; F, CI, Br, I, At.

A non-standard bonding number of a (neutral) heteroatom is indicated by the symbol "λ^η", where "n" is the bonding number. If the locant, the number indicating the position within the molecule, for a heteroatom with a nonstandard bonding number is used, the λ^η symbol is cited immediately after this locant.

The term "a therapeutically effective amount" of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art. The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 0.1 mg to about 5,000 mg, 1 mg to about 1,000 mg, or 1 mg to 100 mg may be appropriate, although the lower and upper limits may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration it may be given as continuous infusion. The term "pharmaceutically acceptable carrier" is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions. Useful pharmaceutical carriers for the preparation of the compositions hereof, can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic with the blood) for injectable solutions. For example, formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution, and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like. Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.

In the practice of the method of the present invention, an effective amount of any one of the compounds of this invention or a combination of any of the compounds of this invention or a pharmaceutically acceptable salt or ester thereof, is administered via any of the usual and acceptable methods known in the art, either singly or in combination. The compounds or compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form of solid, liquid or gaseous dosages, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum. The therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a

biodegradable sustained-release composition for subcutaneous or intramuscular administration. In detail, the present invention provides for compounds of formula (I):

wherein:

X is naphthalene, methoxy-naphthalene, dihydro-naphthalene, tetrahydro-naphthalene,

methoxy-tetrahydro-naphthalene or quinoline;

R¹ is Ci-7 alkyl, C₃-8 cycloalkyl, heterocycloalkyl, or phenyl optionally substituted with one or two halogen, -SO₂CH₃ or cyano;

R is hydrogen; or R 1 and R 2 together are forming a C₂-7 alkenylene; or a pharmaceutically acceptable salt or ester thereof.

In another embodiment, the invention provides for compounds of formula (I) wherein:

X is naphthalene, dihydro-naphthalene, methoxy-naphthalene, tetrahydro-naphthalene, methoxy-tetrahydro-naphthalene or quinoline; and

R¹ is Ci-7 alkyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, benzothiazolyl, furanyl, pyranyl, dioxothiophenyl or phenyl optionally substituted with halogen, -SO₂CH₃ or cyano;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides for compounds of formula (I) wherein X is selected from:

In another embodiment, the invention provides for compounds of formula (I) wherein X is naphthalene, methoxy-naphthalene or tetrahydro-naphthalene.

In another embodiment, the invention provides for compounds of formula (I) wherein X is naphthalene.

In another embodiment, the invention provides for compounds of formula (I) wherein X is dihydro-naphthalene or tetrahydro-naphthalene.

In another embodiment, the invention provides for compounds of formula (I) wherein X is methoxy-naphthalene or methoxy-tetrahydro-naphthalene.

In another embodiment, the invention provides for compounds of formula (I) wherein X is quinoline.

In another embodiment, the invention provides for compounds of formula (I) wherein R¹ is iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, dioxo-tetrahydro-thiophenyl, or phenyl which is optionally substituted with one or two chloro, cyano or -SO₂CH₃.

In another embodiment, the invention provides for compounds of formula (I) wherein R¹ is cyclobutyl, cyclopentyl or phenyl.

In another embodiment, the invention provides for compounds of formula (I) wherein R¹ is Ci_7 alkyl.

In another embodiment, the invention provides for compounds of formula (I) wherein R¹ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In another embodiment, the invention provides for compounds of formula (I) wherein R¹ is tetrahydrofuranyl, tetryhydropyranyl or tetrahydro-dioxo-thiophenyl. In another embodiment, the invention provides for compounds of formula (I) wherein R is phenyl.

In another embodiment, the invention provides for compounds of formula (I) wherein R¹ is phenyl substituted with chloro, -SO₂CH₃ or cyano. In another embodiment, the invention provides for compounds of formula (I) wherein R² is hydrogen.

In another embodiment, the invention provides for compounds of formula (I) wherein R¹ and R together are forming a C2-7 alkenylene.

In another embodiment, the invention provides for compounds of formula (I) wherein R¹ and R² together are forming a butadienylene.

In another embodiment, the invention provides for compounds of formula (I) wherein the compound is:

7-(4-Cyclobutyl-thiazol-2-yl)-5,6-dihydro-naphthalene-2-carboxylic acid;

7-(4-Cyclobutyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Cyclopropyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Cyclopentyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Cyclohexyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-[4-(3-Chloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-[4-(2,6-Dichloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-[4-(2-Chloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-Benzothiazol-2-yl-naphthalene-2-carboxylic acid;

7-(4-Cyclobutyl-thiazol-2-yl)-5-methoxy-naphthalene-2-carboxylic acid;

7-(4-Cyclobutyl-thiazol-2-yl)-6-methoxy-naphthalene-2-carboxylic acid;

7-(4-Isobutyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-[4-(Tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-[4-(Tetrahydro-pyran-4-yl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-[4-(l,l-Dioxo-tetrahydro-^⁶-thiophen-3-yl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-(4-tert-Butyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-[4-(4-Methanesulfonyl-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-[4-(4-Cyano-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-(4-Phenyl-thiazol-2-yl)- 1 ,2,3,4-tetrahydro-naphthalene-2-carboxylic acid;

4-Methoxy-7-(4-phenyl-thiazol-2-yl)- 1 ,2,3,4-tetrahydro-naphthalene-2-carboxylic acid;

3-(4-Cyclobutyl-thiazol-2-yl)-quinoline-6-carboxylic acid; or

6-(4-Phenyl-thiazol-2-yl)-quinoline-3-carboxylic acid. In another embodiment, the invention provides for compounds of formula (I) wherein the compound is:

7-(4-Cyclobutyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Cyclopentyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Cyclobutyl-thiazol-2-yl)-6-methoxy-naphthalene-2-carboxylic acid;

7-(4-Phenyl-thiazol-2-yl)- 1 ,2,3,4-tetrahydro-naphthalene-2-carboxylic acid.

In another embodiment, the invention provides for a pharmaceutical composition, comprising a therapeutically effective amount of a compound according to formula (I) and a pharmaceutically acceptable carrier.

In another embodiment, the invention provides for a compound according to formula (I) for use as a therapeutically active substance.

In another embodiment, the invention provides for the use of a compound according to formula (I) for the treatment or prophylaxis of an inflammatory disease or disorder. In another embodiment, the invention provides for the use of a compound according to formula (I) for the preparation of a medicament for the treatment or prophylaxis of an inflammatory disease or disorder.

In another embodiment, the invention provides for a compound according to formula (I) for the treatment or prophylaxis of an inflammatory disease or disorder. In a particular embodiment, the inflammatory disease or disorder is selected from rheumatoid arthritis, lupus and irritable bowel disease (IBD).

In another embodiment, the invention provides for a method for treating an inflammatory disease or disorder selected from rheumatoid arthritis, lupus and irritable bowel disease (IBD), comprising the step of administering a therapeutically effective amount of a compound according to formula (I) to a subject in need thereof.

In another embodiment, provided is an invention as hereinbefore described. Synthesis

The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser 's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15;

Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplemental; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40.

The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.

The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20 °C.

Compounds of the invention may be made by any number of conventional means. For example, they may be made according to the processes outlined in the Schemes below.

Scheme 1

LiOH

O heat

11

The tetralone 1 can be condensed with carbon disulfide under basic conditions and the reaction quenched with iodomethane to provide dithiane 2. Ketone reduction followed by Lewis acid mediated dehydration and methanolysis gives the ester 3. Saponification gives acid 4 which can be converted to the amide 5 using oxalyl chloride followed by aqueous ammonium hydroxide. Treatment with Lawesson's reagent provides the thioamide 6, which can be reacted with bromide 7 with gentle heating to afford thiazole 8. The bromide functionality of 8 can be carbonylated with molybdenum hexacarbonyl and Herrmann's catalyst in the presence of water to afford acid 9. Alternatively, dihydronaphthalene 8 can be oxidized with DDQ to afford naphthalene 10. Treatment with t-BuLi at low temperature and quenching of the intermediate organolithium with carbon dioxide gives rise to acid 11. Scheme 2

R² = Me

R² = Et

The acid 11 can be also prepared according to Scheme 2. The mono-carboxylic acid 13 can be formed through low temperature transmetallation of 2,7-dibromonaphthalene (12) and quenching of the intermediate organolithium with carbon dioxide. The acid can be then converted to the amide 14 using oxalyl chloride followed by aqueous ammonium hydroxide. Treatment with Lawesson's reagent provides the thioamide 15, which can be reacted with bromide 7 with gentle heating to afford thiazole 10. The bromide functionality of 10 can be carbonylated with molybdenum hexacarbonyl and Herrmann's catalyst in the presence of water or an alcoholic solvent to form acid 11 or ester 16, respectively. In the case that ester 16 can be formed, subsequent hydrolysis with lithium hydroxide provides acid 11. Scheme 3

17 18 19

Br,

O MeOH

R -A

20

Acid chloride 18 can be prepared from acid 17 using oxalyl chloride. Treatment with trimethylsilyldiazomethane results in the in situ formation of diazo ketone 19 which can be quenched with hydrobromic acid in acetic acid to isolate the bromoketone 7 in good yield and purity. Alternatively, ketone 20 can be treated with bromine in methanol to provide bromoketone

7.

Scheme 4

The acid 11 can be also prepared according to Scheme 4. The mono-carboxylic acid 13 can be esterified with acidic methanol to provide 21. The bromide can be converted to the borane pinacol ester 22 using bis(pinacolato)diboron under palladium catalysis. Suzuki coupling with appropriately substituted bromothiazole 23 results in ester 16a. Saponification gives the acid 11.

Alternatively, Suzuki coupling of 22 with 2,4-dibromothiazole (24) provids ester 25 in a regio selective manner. Subsequent Suzuki coupling with appropriately substituted boronic acid results in 16a.

Scheme 5

The acid 11 can be also prepared according to Scheme 5. Bromide 21 can be converted to nitrile 26 with zinc cyanide under palladium catalysis. Treatment with ammonium sulfide gives rise to thioamide 27 which can be reacted with bromide 7 with gentle heating to afford thiazole 16a.

Saponification gives the acid 11.

Scheme 6

31 30

Bromide 3 can be converted to the borane pinacol ester 22 using bis(pinacolato)diboron under palladium catalysis. Suzuki coupling with appropriately substituted bromothiazole 23 results in ester 29. Hydrogenation provids ester 30 which can be hydrolyzed to give acid 31. EXAMPLES

Although certain exemplary embodiments are depicted and described herein, the compounds of the present invention can be prepared using appropriate starting materials according to the methods described generally herein and/or by methods available to one of ordinary skill in the art. All reactions involving air-sensitive reagents were performed under an inert atmosphere. Reagents were used as received from commercial suppliers unless otherwise noted.

Example 1

7-(4-Cyclobutyl-thiazol-2-yl)-5,6-dihydro-naphthalene-2-carboxylic acid

Step 1

To an ice cold solution of potassium tert-butoxide (26.7 g, 0.24 mol) in benzene (170 ml) and DMF (50 ml) was added via dropping funnel a solution of 7-bromo-l-tetralone (22.5 g, 0.10 mol) and carbon disulfide (7.6 g, 0.10 mol) in benzene (50 ml). The rate of addition was controlled to maintain an internal temperature below 20°C. After the addition was complete, the reaction was warmed to room temperature and stirred for 4 h. Methyl iodide (30 g, 0.21 mol) was added dropwise and the mixture was stirred at room temperature overnight then carefully quenched with ice cold water (400 ml). The layers were separated and the organic phase was washed with water (2 x 100 ml). The aqueous washings were back-extracted with diethyl ether (2 x 100 ml). The combined organic layers were dried over MgS0₄ and concentrated. The residue was treated with 2 volumes of diethyl ether and stored in a refrigerator overnight.

Collected 26.1 g (79%) of 2-(bis-methylsulfanyl-methylene)-7-bromo-3,4-dihydro-2H- naphthalen-l-one via filtration as two crops of crystals. Mp = 88°C.

Step 2

To a solution of 2-(bis-methylsulfanyl-methylene)-7-bromo-3,4-dihydro-2H-naphthalen-l-one (50 g, 0.15 mol) in MeOH (1 L) was added sodium borohydride (10 g, 0.26 mol) in portions maintaining the reaction temperature at 30-35°C. The reaction was stirred an additional 30 min then boron trifluoride diethyl etherate (340 ml, 2.75 mol) was added via dropping funnel. After the addition was complete, the reaction was heated at 50°C overnight. The reaction was cooled to room temperature and concentrated to half volume then added dichloromethane (200 ml) and water (1 L). The layers were separated and the aqueous phase was extracted with

dichloromethane (3 x 100 ml). The combined organic layers were dried over MgS0₄ and concentrated. The residue was recrystallized from EtOAc/hexanes (1/20) to afford 31.9 g (80%) of 7-bromo-3,4-dihydro-naphthalene-2-carboxylic acid methyl ester. Mp = 56-57°C.

Step 3

To a round-bottomed flask containing water (20 ml) was added lithium hydroxide (968 mg, 40.4 mmol). Methanol (20 ml) was added followed by slow addition of 7-bromo-3,4-dihydro- naphthalene-2-carboxylic acid methyl ester (2.70 g, 10.1 mmol) dissolved in THF (20 ml), the reaction mixture was stirred at room temperature overnight then the organic solvents were evaporated. The residual suspension was cooled to 0°C and acidified with cone. HC1 to pH=~l. The suspension was extracted with dichloromethane (3 x 100 ml). The organic layers were combined and concentrated. The residue was triturated with a small amount of dichloromethane and hexanes to afford 2.4 g (94%) of 7-bromo-3,4-dihydro-naphthalene-2-carboxylic acid as a light yellow powder. 1H NMR (300 MHz, DMSO-d₆) δ: 12.57 (s, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.39 - 7.47 (m, 2H), 7.17 (d, J = 8.3 Hz, 1H), 2.76 (t, J = 7.9 Hz, 2H), 2.46 (t, J = 7.9 Hz, 2H).

Step 4

In a round-bottomed flask, 7-bromo-3,4-dihydro-naphthalene-2-carboxylic acid (2.39 g, 9.44 mmol) was suspended in 45 ml dichloromethane. Oxalyl chloride (1.45 g, 1.0 ml, 11.4 mmol) was added dropwise at room temperature followed by two drops of DMF. Vigorous gas evolution was observed. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in toluene and again concentrated to a light yellow solid. The residue was suspended in 30 ml diethyl ether and 29% ammonium hydroxide (18.0 g, 20 ml, 149 mmol) was slowly added. The thick light yellow suspension was stirred vigorously at room temperature for 1 h then filtered and washed with water and a small amount of diethyl ether. The solid was dried under high vacuum to provide 2.14 g (90%) of 7-bromo-3,4-dihydro- naphthalene-2-carboxylic acid amide as a light yellow powder.

Step 5

In a 150 ml round-bottomed flask, 7-bromo-3,4-dihydro-naphthalene-2-carboxylic acid amide (2.13 g, 8.45 mmol) was suspended in 38 ml THF. Lawesson's reagent (3.76 g, 9.29 mmol) was added and the reaction mixture was stirred at 50°C for 6.5 h. The reaction mixture was cooled to room temperature and concentrated. The residue was triturated with toluene to afford 1.56 g (69%) of 7-bromo-3,4-dihydro-naphthalene-2-carbothioic acid amide as a yellow powder. 1H NMR (400 MHz, DMSO-d₆) δ: 9.61 (br. s., 1H), 9.17 (br. s., 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 7.8, 2.0 Hz, 1H), 7.15 - 7.21 (m, 2H), 2.73 - 2.80 (m, 2H), 2.60 - 2.66 (m, 2H). Step 6

In a 100 ml round-bottomed flask, 1-cyclobutylethanone (2.65 g, 27.0 mmol) was dissolved in 25 ml methanol. The colorless solution was cooled to 0°C and bromine (4.34 g, 1.4 ml, 27.2 mmol) was added drop wise. The dark red solution was stirred at 0°C for 15 min and at room temperature for 2 h. The reaction mixture was quenched with 20 ml water and 5 ml of 10% Na₂S203 solution then the aqueous layer was extracted twice with 150 ml diethyl ether. The organic layers were washed with 20 ml brine then combined, dried over sodium sulfate, filtered and concentrated to afford 4.45 g (93%) of 2-bromo-l-cyclobutylethanone as a yellow oil which was used without further purification. Step 7

In a 50ml round-bottomed flask, 7-bromo-3,4-dihydro-naphthalene-2-carbothioic acid amide (1.55 g, 5.78 mmol) and 2-bromo-l-cyclobutylethanone (1.23 g, 6.94 mmol) were suspended in 10 ml ethanol. The suspension was heated at reflux for 1.5 h then cooled to room temperature and concentrated. The residue was suspended in water, basified with 29% ammonium hydroxide solution and extracted twice with diethyl ether. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 40 g silica gel with EtOAc/hexanes (gradient: 0-20% EtOAc). All fractions containing product were combined and concentrated. The residue was triturated with petroleum ether to afford 1.60 g (80%) of 2-(7-bromo-3,4-dihydro-naphthalen-2-yl)-4- cyclobutyl-thiazole as a yellow solid. 1H NMR (400 MHz, CDC1₃) δ: 7.36 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.1, 2.0 Hz, 1H), 7.26 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 0.8 Hz, 1H), 3.72 (quin, J = 8.5 Hz, 1H), 2.93 (s, 4H), 2.37 - 2.47 (m, 2H), 2.24 - 2.36 (m, 2H), 2.02 - 2.13 (m, 1H), 1.92 - 2.01 (m, 1H).

Step 8

A microwave vial was charged with 2-(7-bromo-3,4-dihydro-naphthalen-2-yl)-4-cyclobutyl- thiazole (142 mg, 0.41 mmol), sodium carbonate (130 mg, 1.23 mmol), molybdenum

hexacarbonyl (55 mg, 0.21 mmol), Herrmann's catalyst (20 mg, 0.021 mmol), 0.9 ml 1,4-dioxane and 1.8 ml water. The vial was flushed with argon, sealed and heated under microwave irradiation at 165°C for 15 min. After cooling, the reaction mixture was passed through a glass microfiber filter, rinsing with water and EtOAc. The filtrate was acidified with 1M HC1 to pH=~2 and then extracted twice with EtOAc. The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and purified by chromatography over 12g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc). All fractions containing product were combined and concentrated to afford 23 mg (17%) of 7-(4-cyclobutyl-thiazol-2-yl)-5,6-dihydro-naphthalene-2-carboxylic acid as a light yellow powder. LC/MS: (M+H)⁺ = 312; 1H NMR (300 MHz, DMSO-d₆) δ: 12.86 (br. s., 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.76 (dd, J = 7.6, 1.5 Hz, 1H), 7.40 (s, 1H), 7.28 - 7.35 (m, 2H), 3.63 (quin, J = 8.4 Hz, 1H), 2.91 - 3.01 (m, 2H), 2.79 - 2.89 (m, 2H), 2.16 - 2.38 (m, 4H), 1.80 2.07 (m, 2H).

Example 2

7-(4-Cyclobutyl-thiazol-2-yl)-naphthalene-2-carboxylic acid

Step 1

A mixture of 2-(7-bromo-3,4-dihydro-naphthalen-2-yl)-4-cyclobutyl-thiazole (5.0 g, 14.4 mmol) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (9.8 g, 43.2 mmol) in toluene (125 ml) was heated at reflux overnight. The mixture was cooled to room temperature and poured through a short plug of silica gel, eluting with toluene. The eluent was concentrated to afford 3.5 g (72%) of 2-(7-bromo-naphthalen-2-yl)-4-cyclobutyl-thiazole as a tan solid. Mp = 78-79°C.

Step 2

To a viscous solution of 2-(7-bromo-naphthalen-2-yl)-4-cyclobutyl-thiazole (2.6 g, 7.6 mmol) in anhydrous diethyl ether (100 ml) at -78°C was added dropwise t-BuLi (1.7 M in pentane, 6.7 ml, 11.4 mmol). The deep red solution was stirred at -78°C for 15 min then solid C0₂ was added in small portions. The thick cream colored reaction mixture was stirred at -78°C for 15 min then allowed to reach room temperature. Added aqueous IN NaOH and washed with diethyl ether. The aqueous layer was acidified with IN HC1. The resultant solid was collected via filtration, washed with water and dried to afford 2.1 g of 7-(4-cyclobutyl-thiazol-2-yl)-naphthalene-2- carboxylic acid as an off-white solid. Mp = 233-234°C; LC/MS: (M+H)⁺ = 310.

Example 3

7-(4-Phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid

Step 1

In a 100 ml round-bottomed flask, 2,7-dibromonaphthalene (2.00 g, 6.99 mmol) was dissolved in 28 ml THF. The solution was cooled to -76°C and n-butyllithium (1.6 M in hexanes, 4.6 ml, 7.36 mmol) was added drop wise. The reaction mixture was stirred at -76°C for 15 min then C0₂ (gas) was bubbled through the reaction mixture. After 15 min the cold bath was removed and the reaction was allowed to warm to room temperature over 1.5 h with continued C0₂ bubbling. The C0₂ bubbling was discontinued and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and acidified with 1M HC1 until pH=~2 then extracted twice with EtOAc. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane to afford 1.53 g (87%) of 7-bromo-naphthalene-2-carboxylic acid as an off- white powder. ¹H NMR (300 MHz, DMSO-d₆) δ: 13.20 (s, 1H), 8.59 (s, 1H), 8.42 (d, J = 1.5 Hz, 1H), 7.93 - 8.11 (m, 3H), 7.76 (dd, J = 8.7, 1.9 Hz, 1H).

Step 2

To a suspension of 7-bromo-naphthalene-2-carboxylic acid (3.44 g, 13.7 mmol) in MeOH (50 ml) was added sulfuric acid (0.51 ml, 9.6 mmol). The reaction mixture was stirred at reflux for 18 h then cooled to room temperature and concentrated. The residue was dissolved in

dichloromethane and washed with satd. NaHC0₃. The aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried (MgS0₄) and concentrated. The residue was triturated with petroleum ether to obtain 3.56 g (98%) of 7- bromo-naphthalene-2-carboxylic acid methyl ester as an off-white powder. Step 3

A suspension of 7-bromo-naphthalene-2-carboxylic acid methyl ester (3.56 g, 13.4 mmol), bis(pinacolato)diboron (4.09 g, 16.1 mmol), dichloro l,l'-bis(diphenylphosphino)ferrocene palladium(II) (983 mg, 1.34 mmol) and potassium acetate (3.95 g, 40.3 mmol) in 1,4-dioxane (25 ml) was purged with nitrogen for 5 min, then heated at 100°C for 3 h. The reaction mixture was cooled to room temperature and diluted with EtOAc, then washed with water and brine, dried (MgS0₄) and concentrated. The residue was triturated with petroleum ether to obtain 4.2 g of 7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-naphthalene-2-carboxylic acid methyl ester as an off-white powder which was used without further purification. 1H NMR (400 MHz, CDC1₃) δ: 8.65 (s, 1H), 8.47 (s, 1H), 8.09 (dd, J = 8.5, 1.8 Hz, 1H), 7.92 - 7.96 (m, 1H), 7.86 (dd, J = 8.5, 5.0 Hz, 2H), 3.98 (s, 3H), 1.40 (s, 12H).

Step 4

A microwave vial was charged with 7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- naphthalene-2-carboxylic acid methyl ester (80 mg, 0.26 mmol), 2-bromo-4-phenylthiazole (80 mg, 0.33 mmol), tetrakis(triphenylphosphine)palladium (0) (30 mg, 0.026 mmol), sodium carbonate (82 mg, 0.77 mmol), 2.4 ml methanol and 0.8 ml dichloromethane. The vial was flushed with argon, sealed and heated under microwave irradiation at 115°C for 30 min. The reaction mixture was quenched with water and extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with methanol to afford a light yellow powder. The powder was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to afford 77 mg (87%) of 7-(4-phenyl- thiazol-2-yl)-naphthalene-2-carboxylic acid methyl ester as an off-white powder.

Step 5

In a round-bottomed flask, 7-(4-phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid methyl ester (76 mg, 0.22 mmol) was suspended in 0.8 ml THF, 0.8 ml methanol and 0.8 ml water. Lithium hydroxide (25 mg, 1.04 mmol) was added and the pale yellow suspension was stirred at room temperature for 1.5 h, at 50°C for 1.5 h and at room temperature overnight. The reaction mixture was acidified with 1M HC1 to a pH of ~1 and diluted with a small amount of dichloromethane. The resulting suspension was filtered, washed with water and dichloromethane to afford 50 mg (69%) of 7-(4-phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid as an off-white powder.

LC/MS: (M+H)⁺ = 332; 1H NMR (400 MHz, DMSO-d₆) δ: 13.20 (br. s., 1H), 8.78 - 8.86 (m, 2H), 8.34 (dd, J = 8.8, 1.9 Hz, 1H), 8.28 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.08 - 8.14 (m, 3H), 8.05 (dd, J = 8.3, 1.5 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.38 - 7.45 (m, 1H).

Example 4

7-(4-Cyclopropyl-thiazol-2-yl)-naphthalene-2-carboxylic acid

Step 1

A microwave vial was charged with 7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- naphthalene-2-carboxylic acid methyl ester (85 mg, 0.27 mmol), 2-bromo-4-cyclopropylthiazole (68 mg, 0.33 mmol), tetrakis(triphenylphosphine)palladium (0) (31 mg, 0.027 mmol), sodium carbonate (87 mg, 0.82 mmol, 2.4 ml methanol and 0.8 ml dichloromethane. The vial was flushed with argon, sealed and heated under microwave irradiation at 115°C for 30 min. The reaction mixture was filtered, rinsing with dichloromethane and the filtrate was concentrated. The residue was absorbed on silica gel and purified by chromatography over 12g silica gel with EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to afford 86 mg of 7-(4-cyclopropyl-thiazol-2-yl)-naphthalene-2-carboxylic acid methyl ester as a colorless oil. Step 2

In a 25 ml round-bottomed flask, 7-(4-cyclopropyl-thiazol-2-yl)-naphthalene-2-carboxylic acid methyl ester (80 mg, 0.25 mmol) was dissolved in 0.8 ml THF, 0.8 ml methanol and 0.8 ml water. Lithium hydroxide (25 mg, 1.04 mmol) was added and the colorless solution was stirred at room temperature overnight. The reaction mixture was acidified with 1M HC1 to pH=~l and extracted twice with EtOAc. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane/petroleum ether to afford 63 mg (87%) of 7-(4-cyclopropyl-thiazol-2-yl)- naphthalene-2-carboxylic acid as a white powder. LC/MS: (M+H)⁺ = 296; 1H NMR (400 MHz, DMSO-d₆) δ: 13.28 (br. s, 1H), 8.71 (s, 1H), 8.63 (d, J = 1.5 Hz, 1H), 8.14 (dd, J = 8.6, 1.5 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 1.5 Hz, 2H), 7.40 (s, 1H), 2.12 - 2.25 (m, 1H), 0.90 - 1.02 (m, 4H).

Example 5

7-(4-Cyclopentyl-thiazol-2-yl)-naphthalene-2-carboxylic acid

Step 1

In a 25 ml round-bottomed flask, 1-cyclopentylethanone (0.50 g, 4.46 mmol) was dissolved in 4.6 ml methanol. The colorless solution was cooled to 0°C and bromine (0.71 g, 0.23 ml, 4.46 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the dark red solution was stirred at room temperature for 2.5 h. The reaction mixture was quenched with 5 ml water and 2 ml of 10% Na₂S203 solution then the aqueous layer was extracted three times with 50 ml diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 793 mg of 2-bromo-l-(l-bromo-cyclopentyl)-ethanone as a dark brown oil which was used without further purification. Step 2

In a 200 ml round-bottomed flask, 7-bromo-naphthalene-2-carboxylic acid (1.50 g, 5.97 mmol) was suspended in 28 ml dichloromethane. Oxalyl chloride (914 mg, 0.63 ml, 7.2 mmol) was added dropwise at room temperature followed by two drops of DMF. Vigorous gas evolution was observed. The reaction mixture was stirred at room temperature for 2.5 h then concentrated to a light yellow solid. The residue was suspended in 19 ml diethyl ether and 29% ammonium hydroxide (11.7 g, 13 ml, 96.8 mmol) was slowly added. The light yellow suspension was stirred vigorously at room temperature for lh then filtered and washed with water and a small amount of diethyl ether. The solid thus collected was dried under high vacuum to provide 1.41 g (94%) of 7-bromo-naphthalene-2-carboxylic acid amide as an off-white powder. 1H NMR (300 MHz, DMSO-d₆) δ: 8.44 (s, 1H), 8.26 (d, J = 1.9 Hz, 1H), 8.13 (br. s., 1H), 7.90 - 8.05 (m, 3H), 7.72 (dd, J = 8.7, 1.9 Hz, 1H), 7.53 (br. s., 1H).

Step 3

In a 100 ml round-bottomed flask, 7-bromo-naphthalene-2-carboxylic acid amide (1.40 g, 5.6 mmol) was suspended in 25 ml THF. Lawesson's reagent (2.49 g, 6.16 mmol) was added and the reaction mixture was stirred at 50°C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was triturated with toluene to afford 1.20 g (81 ) of 7-bromo-naphthalene-2-carbothioic acid amide as a yellow powder. 1H NMR (400 MHz, DMSO-d₆) δ: 10.03 (br. s., 1H), 9.69 (br. s., 1H), 8.37 (s, 1H), 8.30 (s, 1H), 7.90 - 8.06 (m, 3H), 7.73 (d, J = 8.6 Hz, 1H).

Step 4

In a 10 ml round-bottomed flask, 7-bromo-naphthalene-2-carbothioic acid amide (200 mg, 0.75 mmol) and of 2-bromo-l-(l-bromo-cyclopentyl)-ethanone (359 mg, 1.33 mmol) were suspended in 1.5 ml ethanol. The dark brown suspension was heated at reflux for 3 h then cooled to room temperature and the ethanol was evaporated. The residue was suspended in water, basified with 29% ammonium hydroxide solution and extracted twice with diethyl ether. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane/petroleum ether to afford 96 mg (36%) of 2-(7-bromo-naphthalen-2-yl)-4-cyclopent-l-enyl-thiazole as a light brown powder. LC/MS: (M+H)⁺ = 356/358; 1H NMR (400 MHz, CDC1₃) δ: 8.56 (s, 1H), 8.14 - 8.19 (m, 2H), 7.91 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.63 (dd, J = 8.6, 2.0 Hz, 1H), 7.09 (s, 1H), 6.89 (s, 1H), 2.74 - 2.82 (m, 2H), 2.61 - 2.69 (m, 2H), 2.05 - 2.16 (m, 2H).

Step 5

A microwave vial was charged with 2-(7-bromo-naphthalen-2-yl)-4-cyclopent-l-enyl-thiazole (93 mg, 0.26 mmol), sodium carbonate (83 mg, 0.78 mmol), molybdenum hexacarbonyl (42 mg, 0.16 mmol), Herrmann's catalyst (37 mg, 0.04 mmol), 1.0 ml 1,4-dioxane and 1.0 ml water. The vial was flushed with argon, sealed and heated under microwave irradiation at 165°C for 15 min. After cooling, the reaction mixture was passed through a glass microfiber filter, rinsing with water and EtOAc. The filtrate was acidified with 1M HC1 to pH=~2 and then extracted twice with EtOAc. The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with

dichloromethane/EtOAc to afford 118 mg (purity = 70%) of 7-(4-cyclopent-l-enyl-thiazol-2-yl)- naphthalene-2-carboxylic acid as a light brown powder which was used without further purification. Step 6

In a Parr bottle, 7-(4-cyclopent-l-enyl-thiazol-2-yl)-naphthalene-2-carboxylic acid (purity = 70%, 116 mg, 0.25 mmol) was suspended in 2 ml methanol and 2 ml THF and triethylamine (0.04 ml, 0.29 mmol) and 10% palladium on carbon (wet, 60 mg, 0.56 mmol) were added. The Parr bottle was placed on a parr hydrogenator and three times alternatingly evacuated and flushed with hydrogen. The reaction mixture was shaken overnight at room temperature under 60 psi hydrogen pressure then filtered over Celite and rinsed with methanol/EtOAc. The filtrate was concentrated and the residue was diluted with 2 ml of 1M HC1 and extracted twice with EtOAc. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane to afford 35 mg

(43%) of 7-(4-cyclopentyl-thiazol-2-yl)-naphthalene-2-carboxylic acid as an off-white powder. LC/MS: (M+H)⁺ = 324; 1H NMR (400 MHz, DMSO-d₆) δ: 13.17 (br. s., 1H), 8.75 (s, 1H), 8.68 (s, 1H), 8.20 (dd, J = 8.6, 1.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.02 (dd, J = 8.6, 1.8 Hz, 1H), 7.44 (d, J = 0.8 Hz, 1H), 3.28 (t, J = 7.7 Hz, 1H), 2.01 - 2.12 (m, 2H), 1.62 - 1.87 (m, 6H).

Example 6

7-(4-Cyclohexyl-thiazol-2-yl)-naphthalene-2-carboxylic acid

Prepared according to the procedure outlined in Example 5 substituting 1- cyclohexylethanone for 1-cyclopentylethanone in step 1. LC/MS: (M+H)⁺ = 338; 1H NMR (400 MHz, DMSO-d₆) δ: 13.18 (br. s, 1H), 8.75 (s, 1H), 8.68 (s, 1H), 8.20 (dd, J = 8.8, 2.0 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 8.02 (dd, J = 8.8, 2.0 Hz, 1H), 7.40 (d, J = 0.8 Hz, 1H), 2.76 - 2.85 (m, 1H), 2.04 - 2.12 (m, 2H), 1.69 - 1.86 (m, 3H), 1.37 - 1.55 (m, 4H), 1.21 - 1.33 (m, 1H). Example 7

7-[4-(3-Chloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid

Step 1

In a 10 ml round-bottomed flask, 7-bromo-naphthalene-2-carbothioic acid amide (80 mg, 0.30 mmol) and 2-bromo-l-(3-chloro-phenyl)-ethanone (77 mg, 0.33 mmol) were suspended in 1.2 ml ethanol. The yellow suspension was heated at reflux for 30 min then cooled to room temperature. The reaction was diluted with water and basified with 29% ammonium hydroxide solution then extracted twice with diethyl ether. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane/petroleum ether to afford 83 mg (69%) of 2-(7-bromo- naphthalen-2-yl)-4-(3-chloro-phenyl)-thiazole as an off-white powder. LC/MS: (M+H)⁺ = 402.

Step 2

A microwave vial was charged with 2-(7-bromo-naphthalen-2-yl)-4-(3-chloro-phenyl)-thiazole (80 mg, 0.20 mmol), sodium carbonate (64 mg, 0.60 mmol), molybdenum hexacarbonyl (32 mg, 0.12 mmol), Herrmann's catalyst (28 mg, 0.03 mmol), 1.0 ml 1,4-dioxane and 1.0 ml water. The vial was flushed with argon, sealed and heated under microwave irradiation at 165°C for 15 min. After cooling, the reaction mixture was filtered through a glass microfiber filter and rinsed with water and EtOAc. The filtrate was acidified with 1M HC1 (pH=~l-2) then extracted twice with EtOAc. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and purified by chromatography over 4g silica gel with EtOAc/hexanes (gradient: 0-100% EtOAc). All fractions containing product were combined and concentrated. The residue was triturated with

EtOAc/dichloromethane to afford 21 mg (27%) of 7-[4-(3-Chloro-phenyl)-thiazol-2-yl]- naphthalene-2-carboxylic acid as a pale green powder. LC/MS: (M+H)⁺ = 366/368; 1H NMR

(400 MHz, DMSO-d₆) δ: 13.21 (br. s., 1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.43 (s, 1H), 8.34 (dd, J = 8.6, 1.8 Hz, 1H), 8.15 - 8.23 (m, 2H), 8.03 - 8.14 (m, 3H), 7.45 - 7.58 (m, 2H).

Example 8

7-[4-(2,6-Dichloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid

Prepared according to the procedure outlined in Example 7 substituting 2-bromo-l-(2,6- dichloro-phenyl)-ethanone for 2-bromo-l-(3-chloro-phenyl)-ethanone in step 1. LC/MS: (M+H)⁺ = 400/402; 1H NMR (400 MHz, DMSO-d₆) δ: 13.18 (br. s., 1H), 8.78 (s, 2H), 8.23 (dd, J = 8.6, 1.8 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.05 (dd, J = 8.6, 1.8 Hz, 1H), 7.99 (s, 1H), 7.66 (dd, J = 8.8, 1.0 Hz, 2H), 7.55 (dd, J = 8.8, 7.3 Hz, 1H).

Example 9

7-[4-(2-Chloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid

Step 1

In a 10 ml round-bottomed flask, 7-bromo-naphthalene-2-carbothioic acid amide (100 mg, 0.38 mmol) and 2-bromo-l-(2-chloro-phenyl)-ethanone (105 mg, 0.45 mmol) were suspended in 1.5 ml ethanol. The yellow suspension was heated at reflux for 45 min then cooled to room temperature. The reaction was diluted with water and basified with 29% ammonium hydroxide solution then extracted twice with diethyl ether. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and purified by chromatography over 12g silica gel with EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to afford 141 mg (89%) of 2-(7-bromo-naphthalen-2-yl)-4-(2-chloro-phenyl)-thiazole as a light yellow solid.

Step 2

A microwave vial was charged with 2-(7-bromo-naphthalen-2-yl)-4-(2-chloro-phenyl)-thiazole (136 mg, 0.32 mmol), molybdenum hexacarbonyl (43 mg, 0.16 mmol), Herrmann's catalyst (31 mg, 0.033 mmol), N,N-diisopropylethylamine (0.12 ml, 0.69 mmol), 1.0 ml 1,4-dioxane and 1.0 ml methanol. The vial was flushed with argon, sealed and heated under microwave irradiation at 145°C for 20 min. After cooling, the reaction mixture was filtered, rinsing with dichloromethane and the filtrate was concentrated. The residue was purified by chromatography over 12g silica gel with EtOAc/hexanes (gradient 0-10% EtOAc). All fractions containing product were combined and concentrated to afford 67 mg (55%) of 7-[4-(2-chloro-phenyl)-thiazol-2-yl]- naphthalene-2-carboxylic acid methyl ester as a yellow solid. Step 3

In a 25 ml round-bottomed flask, 7-[4-(2-chloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid methyl ester (62 mg, 0.16 mmol) was dissolved in 0.5 ml THF and 0.5 ml methanol.

Lithium hydroxide (18 mg, 0.75 mmol) and 0.5 ml water were added. The light yellow

suspension was stirred at room temperature overnight. The reaction mixture was acidified with 1M HC1 to pH=~l and diluted with a small amount of dichloromethane. The resulting

suspension was filtered, washing with water and dichloromethane to afford 35 mg (59%) of 7-[4- (2-chloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid as a light yellow powder. LC/MS: (M+H)⁺ = 366/368; 1H NMR (400 MHz, DMSO-d₆) δ: 13.21 (br. s., 1H), 8.81 (d, J = 1.8 Hz, 1H), 8.80 (s, 1H), 8.30 (dd, J = 8.6, 1.8 Hz, 1H), 8.25 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.03 - 8.12 (m, 3H), 7.63 (dd, J = 8.0, 1.4 Hz, 1H), 7.43 - 7.55 (m, 2H).

Example 10

7-Benzothiazol-2-yl-naphthalene-2-carboxylic acid

Step 1

In a 25 ml round-bottomed flask, 7-bromo-naphthalene-2-carboxylic acid methyl ester (84 mg, 0.32 mmol) and 2-(tributylstannyl)benzo[d]thiazole (202 mg, 0.48 mmol) were dissolved in 2.0 ml DMF. The reaction mixture was evacuated and backfilled with argon.

Tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.016 mmol) and copper (I) iodide (13 mg, 0.068 mmol) were added. The reaction mixture was heated at 90°C for lh then cooled to room temperature, quenched with water and extracted twice with diethyl ether. The organic layers were washed twice with water and once with brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 12g silica gel with EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated. The residue was triturated with petroleum ether/dichloromethane to provide 48 mg (47%) of 7-benzothiazol-2-yl-naphthalene-2-carboxylic acid methyl ester as an off-white powder. LC/MS: (M+H)⁺ = 320. Step 2

In a 10 ml round-bottomed flask, 7-benzothiazol-2-yl-naphthalene-2-carboxylic acid methyl ester (46 mg, 0.144 mmol) was dissolved in 0.4 ml THF and 0.4 ml methanol. Lithium hydroxide (15 mg, 0.63 mmol) and 0.4 ml water were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 1M HC1 to pH=~l and diluted with a small amount of dichloromethane. The suspension was filtered and washed with water, dichloromethane and a small amount of EtOAc to afford 34 mg (73%) of 7-benzothiazol-2-yl- naphthalene-2-carboxylic acid as an off-white powder. LC/MS: (M+H)⁺ = 306; ¹H NMR (400 MHz, DMSO-d₆) δ: 13.24 (br. s., 1H), 8.90 (s, 1H), 8.85 (s, 1H), 8.38 (dd, J = 8.6, 1.8 Hz, 1H), 8.21 (t, J = 8.6 Hz, 2H), 8.06 - 8.16 (m, 3H), 7.60 (td, J = 7.7, 1.3 Hz, 1H), 7.49 - 7.54 (m, 1H).

Example 11

7-(4-Cyclobutyl-thiazol-2-yl)-5-methoxy-naphthalene-2-carboxylic acid

Step 1

7-Bromo-4-hydroxy-naphthalene-2-carboxylic acid ethyl ester was prepared according to the procedure found in /. Org. Chem. 1996, 61, 4894. 1H NMR (300 MHz, DMSO-d₆) δ: 10.74 (s, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.03 - 8.11 (m, 2H), 7.68 (dd, J = 8.7, 1.7 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H).

Step 2

In a 10 ml round-bottomed flask, 7-bromo-4-hydroxy-naphthalene-2-carboxylic acid ethyl ester (200 mg, 0.68 mmol) was dissolved in 2.2 ml DMF. Potassium carbonate (234 mg, 1.69 mmol) and iodomethane (136 mg, 0.06 ml, 0.96 mmol) were added. The reaction mixture was stirred at 60°C for 2 h then cooled to room temperature, quenched with water and extracted with diethyl ether. The organic layers were washed twice with water and once with brine then combined, dried over sodium sulfate, filtered and concentrated to afford 224 mg of 7-bromo-4-methoxy- naphthalene-2-carboxylic acid ethyl ester as a light yellow solid. 1H NMR (300 MHz, CDC1₃) δ: 8.15 (d, J = 9.1 Hz, 1H), 8.11 (s, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.64 (dd, J = 9.1, 1.9 Hz, 1H), 7.41 (d, J = 1.1 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 4.06 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H).

Step 3

In a 25 ml round-bottomed flask, 7-bromo-4-methoxy-naphthalene-2-carboxylic acid ethyl ester (222 mg, 0.65 mmol) was dissolved in 1.4 ml THF and 1.4 ml methanol. Lithium hydroxide (70 mg, 2.92 mmol) and 1.4 ml water were added. The light yellow suspension was stirred at room temperature overnight then acidified with 1M HC1 to pH=~l and extracted three times with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 188 mg of 7-bromo-4-methoxy-naphthalene-2-carboxylic acid as an off- white solid. 1H NMR (300 MHz, DMSO-d₆) δ: 13.21 (br. s., 1H), 8.38 (d, J = 1.9 Hz, 1H), 8.18 (s, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.74 (dd, J = 9.1, 1.9 Hz, 1H), 7.38 (d, J = 1.5 Hz, 1H), 4.02 (s, 3H).

Step 4

In a 25ml round-bottomed flask, 7-bromo-4-methoxy-naphthalene-2-carboxylic acid (187 mg, 0.63 mmol) was suspended in 3 ml dichloromethane. Oxalyl chloride (102 mg, 0.07 ml, 0.80 mmol) was added dropwise at room temperature followed by two drops of DMF. Gas evolution observed. The reaction mixture was stirred at room temperature for 2 h then concentrated to a light yellow solid. The residue was suspended in 4 ml diethyl ether and 29% ammonium hydroxide (2.6 ml, 19.4 mmol) was slowly added. The thick, light yellow suspension was stirred vigorously at room temperature for 1 h then filtered and washed with water and diethyl ether. Drying under high vacuum provided 159 mg (90%) of 7-bromo-4-methoxy-naphthalene-2- carboxylic acid amide as an off-white powder. LC/MS: (M+H)⁺ = 280/282.

Step 5

In a 25 ml round-bottomed flask, 7-bromo-4-methoxy-naphthalene-2-carboxylic acid amide (157 mg, 0.56 mmol) was suspended in 3 ml THF. Lawesson's reagent (249 mg, 0.62 mmol) was added and the reaction mixture was stirred at 50°C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was triturated with toluene to afford 109 mg (66%) of 7-bromo-4-methoxy-naphthalene-2-carbothioic acid amide as a yellow powder. 1H NMR (300 MHz, DMSO-d₆) δ: 10.02 (br. s., 1H), 9.65 (br. s., 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.98 (s, 1H), 7.68 (dd, J = 8.7, 1.9 Hz, 1H), 7.43 (s, 1H), 4.01 (s, 3H).

Step 6

In a 10 ml round-bottomed flask, 7-bromo-4-methoxy-naphthalene-2-carbothioic acid amide (108 mg, 0.37 mmol) and 2-bromo-l-cyclobutylethanone (77 mg, 0.44 mmol) were suspended in 1 ml ethanol. The yellow suspension was heated at reflux for 1.5 h and then allowed to cool to room temperature and stirred overnight. The reaction mixture was diluted with water, basified with 29% ammonium hydroxide solution and extracted twice with diethyl ether. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane/petroleum ether to afford 89 mg (65%) of 2-(7-bromo-4-methoxy-naphthalen-2-yl)-4-cyclobutyl-thiazole as a light brown powder. LC/MS: (M+H)⁺ = 374/376. Step 7

A microwave vial was charged with 2-(7-bromo-4-methoxy-naphthalen-2-yl)-4-cyclobutyl- thiazole (88 mg, 0.24 mmol), sodium carbonate (75 mg, 0.71 mmol), molybdenum hexacarbonyl (37 mg, 0.14 mmol), Herrmann's catalyst (33 mg, 0.035 mmol), 1 ml 1,4-dioxane and 1 ml water. The vial was flushed with argon, sealed and heated under microwave irradiation at 165°C for 15 min. After cooling, the reaction mixture was filtered through a glass microfiber filter, rinsing with water and EtOAc. The filtrate was acidified with 1M HC1 (pH=~l-2) and then extracted twice with EtOAc. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with

dichloromethane/petroleum ether to afford 42 mg (50%) of 7-(4-cyclobutyl-thiazol-2-yl)-5- methoxy-naphthalene-2-carboxylic acid as a light yellow powder. LC/MS: (M+H)⁺ = 340; 1H NMR (400 MHz, DMSO-d₆) δ: 13.17 (br. s., 1H), 8.70 (d, J = 1.5 Hz, 1H), 8.27 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.02 (dd, J = 8.6, 1.6 Hz, 1H), 7.58 (d, J = 1.3 Hz, 1H), 7.49 (d, J = 0.8 Hz, 1H), 4.10 (s, 3H), 3.74 (quin, J = 8.5 Hz, 1H), 2.24 - 2.40 (m, 4H), 1.87 - 2.09 (m, 2H).

Example 12

7-(4-Cyclobutyl-thiazol-2-yl)-6-methoxy-naphthalene-2-carboxylic acid

Step 1

6-Bromo-3-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ol was prepared according to the procedure outlined in Example 10, steps 4-6 substituting 7-bromo-3-hydroxy-naphthalene-2-carboxylic acid for 7-bromo-4-methoxy-naphthalene-2-carboxylic acid in step 4. 1H NMR (300 MHz, CDC1₃) δ: 8.10 (s, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.49 (dd, J = 8.7, 1.5 Hz, 1H), 7.38 (s, 1H), 6.93 (s, 1H), 3.74 (t, J = 8.5 Hz, 1H), 2.21 - 2.51 (m, 4H), 1.92 - 2.16 (m, 2H). Step 2

In a 10 ml round-bottomed flask, 6-bromo-3-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ol (80 mg, 0.22 mmol) was dissolved in 0.8 ml DMF. Potassium carbonate (77 mg, 0.56 mmol) was added followed by iodomethane (45 mg, 0.02 ml, 0.32 mmol). The reaction mixture was stirred at 60°C for 2 h then cooled to room temperature, quenched with water and extracted with diethyl ether. The organic layers were washed twice with water and once with brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 12g silica gel with EtOAc/hexanes (gradient: 0-5% EtOAc). All fractions containing product were combined and concentrated to afford 35 mg (42%) of 2-(7-bromo-3-methoxy-naphthalen-2-yl)- 4-cyclobutyl-thiazole as a yellow oil. LC/MS: (M+H)⁺ = 374/376.

Step 3

A microwave vial was charged with 2-(7-bromo-3-methoxy-naphthalen-2-yl)-4-cyclobutyl- thiazole (32 mg, 0.086 mmol), sodium carbonate (28 mg, 0.26 mmol), molybdenum

hexacarbonyl (14 mg, 0.053 mmol), Herrmann's catalyst (12 mg, 0.013 mmol), 1 ml 1,4-dioxane and 1 ml water. The vial was flushed with argon, sealed and heated under microwave irradiation at 165°C for 15 min. The reaction mixture was filtered through a glass microfiber filter, rinsing with water and EtOAc. The filtrate was acidified with 1M HC1 (pH=~l-2) and then extracted twice with EtOAc. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with

dichloromethane/petroleum ether to afford 12 mg (41%) of 7-(4-cyclobutyl-thiazol-2-yl)-6- methoxy-naphthalene-2-carboxylic acid as an off-white powder. LC/MS: (M+H)⁺ = 340; 1H NMR (400 MHz, DMSO-d₆) δ: 12.98 (br. s., 1H), 8.96 (s, 1H), 8.69 (s, 1H), 7.92 - 8.03 (m, 2H), 7.67 (s, 1H), 7.51 (s, 1H), 4.14 (s, 3H), 3.75 (t, J = 8.5 Hz, 1H), 2.27 - 2.42 (m, 4H), 1.87 - 2.11 (m, 2H).

Example 13

7-(4-Isobutyl-thiazol-2-yl)-naphthalene-2-carboxylic acid

Step 1

In a 25 ml round-bottomed flask, 2,4-dibromothiazole (380 mg, 1.56 mmol), 7-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-naphthalene-2-carboxylic acid methyl ester (523 mg, 1.67 mmol) and potassium phosphate tribasic (996 mg, 4.69 mmol) were suspended in 8 ml THF. Xantphos (23 mg, 0.04 mmol) and palladium (II) acetate (9 mg, 0.04 mmol) were added and the reaction mixture was stirred at 60°C overnight. The reaction mixture was cooled to room temperature, quenched with water and extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and purified by chromatography over 24g silica gel with EtOAc/hexanes (gradient: 0-50% EtOAc). All fractions containing product were combined and concentrated to afford 460 mg of 7-(4-bromo-thiazol-2-yl)-naphthalene-2-carboxylic acid methyl ester a yellow solid. NMR analysis indicated an approximate 20% impurity assigned as the boronic ester starting material. LC/MS: (M+H)⁺ = 348/350.

Step 2

A microwave vial was charged with 7-(4-bromo-thiazol-2-yl)-naphthalene-2-carboxylic acid methyl ester (100 mg, 0.29 mmol), 2-methylprop-l-enylboronic acid (35 mg, 0.35 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.029 mmol), sodium carbonate (92 mg, 0.87 mmol), 2.4 ml methanol and 0.8 ml dichloromethane. The vial was flushed with argon, sealed, and heated under microwave irradiation at 115°C for 30 min. After cooling, the reaction mixture was quenched with water and extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 12g silica gel with EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to provide 40 mg (43%) of 7-[4-(2-methyl- propenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid methyl ester as a yellow solid. LC/MS: (M+H)⁺ = 324; 1H NMR (300 MHz, CDC1₃) δ: 8.71 (s, 1H), 8.64 (s, 1H), 8.25 (dd, J = 8.7, 1.9 Hz, 1H), 8.12 (dd, J = 8.7, 1.9 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.09 (s, 1H), 6.51 (s, 1H), 4.01 (s, 3H), 2.18 (s, 3H), 2.01 (s, 3H).

Step 3

In a Parr bottle, 7-[4-(2-methyl-propenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid methyl ester (39 mg, 0.12 mmol) was dissolved in 2 ml methanol and 2 ml THF and 10% palladium on carbon (wet, 22 mg, 0.21 mmol) was added. The bottle was placed on a Parr hydrogenator and three times alternatingly evacuated and flushed with hydrogen. The reaction mixture was shaken overnight at room temperature under 55 psi hydrogen pressure then filtered, rinsed with methanol/EtOAc and concentrated to afford 42 mg of 7-(4-isobutyl-thiazol-2-yl)-naphthalene-2- carboxylic acid methyl ester as a light yellow oil which was used without further purification. Step 4

In a 10 ml round-bottomed flask, 7-(4-isobutyl-thiazol-2-yl)-naphthalene-2-carboxylic acid methyl ester (41 mg, 0.12 mmol) was dissolved in 0.5 ml THF and 0.5 ml methanol. Lithium hydroxide (12 mg, 0.50 mmol) and 0.5 ml water were added and the reaction mixture was stirred at room temperature overnight. The reaction was acidified with 1M HC1 to pH=~l and extracted twice with EtOAc. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with

dichloromethane/petroleum ether to afford 17 mg (48%) of 7-(4-isobutyl-thiazol-2-yl)- naphthalene-2-carboxylic acid as an off-white powder. LC/MS (M+H)⁺ = 312; 1H NMR (400 MHz, DMSO-d₆) δ: 13.16 (br. s., 1H), 8.76 (d, J = 1.5 Hz, 1H), 8.68 (d, J = 1.5 Hz, 1H), 8.20 (dd, J = 8.6, 1.5 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 8.02 (dd, J = 8.6, 1.5 Hz, 1H), 7.43 (s, 1H), 2.68 (d, J = 7.1 Hz, 2H), 2.11 (dt, J = 13.4, 6.6 Hz, 1H), 0.96 (d, J = 6.6 Hz, 6H). Example 14

7-[4-(Tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalene-2-carboxylic acid

Step 1

In a 100 ml round-bottomed flask, tetrahydrofuran-3-carboxylic acid (446 mg, 3.84 mmol) was dissolved in 16 ml dichloromethane. Oxalyl chloride (0.40 ml, 4.57 mmol) was added dropwise at room temperature followed by two drops of DMF. Vigorous gas evolution was observed. The reaction mixture was stirred at room temperature for 3.5 h then concentrated to a yellow oil. The residue was dissolved in 5.6 ml acetonitrile and trimethylsilyldiazomethane (2.0 M in diethyl ether, 5.6 ml, 11.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then cooled to 0°C. Acetic acid (0.2 ml, 3.49 mmol) and then 48% hydrobromic acid (1.6 ml, 14.1 mmol) were sequentially added dropwise. Vigorous gas evolution was observed. After the addition was complete, the ice bath was removed and the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with water and extracted twice with dichloromethane. The organic layers were combined and dried over sodium sulfate then filtered and concentrated to afford 807 mg (98%) of 2-bromo-l-(tetrahydro-furan-3-yl)-ethanone as a light brown oil which was used without further purification. 1H NMR (400 MHz, CDC1₃) δ: 3.91 - 3.96 (m, 1H), 3.88 (s, 2H), 3.72 - 3.87 (m, 3H), 3.49 (qd, J = 7.7, 6.3 Hz, 1H), 2.05 - 2.12 (m, 2H).

Step 2

In a 25 ml round-bottomed flask, 7-bromo-naphthalene-2-carbothioic acid amide (300 mg, 1.13 mmol) and 2-bromo-l-(tetrahydro-furan-3-yl-)ethanone (290 mg, 1.35 mmol) were suspended in 3.4 ml ethanol. The reaction mixture was stirred at 90°C for 2 h then at room temperature for two days. The reaction was diluted with diethyl ether and the suspension was filtered, rinsing with a small amount of diethyl ether. The solid was suspended in water, basified with 29% ammonium hydroxide solution and extracted twice with dichloromethane. The organic layers were combined and dried over sodium sulfate then filtered and concentrated to afford 375 mg (92%) of 2-(7- bromo-naphthalen-2-yl)-4-(tetrahydro-furan-3-yl)-thiazole as a light yellow solid. LC/MS:

(M+H)⁺ = 360/362. Step 3

A microwave vial was charged with 2-(7-bromo-naphthalen-2-yl)-4-(tetrahydro-furan-3-yl)- thiazole (80 mg, 0.22 mmol), sodium carbonate (71 mg, 0.67 mmol), molybdenum hexacarbonyl (36 mg, 0.14 mmol), Herrmann's catalyst (31 mg, 0.033 mmol), 1.0 ml 1,4-dioxane and 1.0 ml water. The vial was flushed with argon, sealed and heated under microwave irradiation at 165°C for 15 min. After cooling, the reaction mixture was filtered through a glass microfiber filter, rinsing with water and EtOAc. The filtrate was acidified with 1M HC1 (pH=~l-2) and then extracted twice with EtOAc. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane/EtOAc to afford 33 mg (43%) of 7-[4-(tetrahydro-furan-3-yl)-thiazol-2-yl]- naphthalene-2-carboxylic acid as an off-white powder. LC/MS: (M-H)^~ = 324; 1H NMR (400 MHz, DMSO-d₆) δ: 13.17 (br. s., 1H), 8.76 (s, 1H), 8.70 (d, J = 1.5 Hz, 1H), 8.21 (dd, J = 8.6, 1.5 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 8.03 (dd, J = 8.6, 2.0 Hz, 1H), 7.57 (d, J = 1.0 Hz, 1H), 4.10 (t, J = 7.5 Hz, 1H), 3.95 (td, J = 8.1, 5.1 Hz, 1H), 3.77 - 3.89 (m, 2H), 3.67 (quin, J = 7.5 Hz, 1H), 2.28 - 2.38 (m, 1H), 2.14 - 2.24 (m, 1H).

Example 15

7-[4-(Tetrahydro-pyran-4-yl)-thiazol-2-yl]-naphthalene-2-carboxylic acid

Prepared according to the procedure outlined in Example 14 substituting tetrahydropyran- 4-carboxylic acid for tetrahydrofuran-3-carboxylic acid in step 1. LC/MS: (M+H)⁺ = 340; 1H

NMR (400 MHz, DMSO-d₆) δ: 13.20 (br. s, 1H), 8.75 (s, 1H), 8.69 (s, 1H), 8.20 (dd, J = 8.6, 1.8 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 8.03 (dd, J = 8.6, 1.8 Hz, 1H), 7.47 (s, 1H), 3.97 (d, J = 11.9 Hz, 2H), 3.49 (t, J = 10.7 Hz, 2H), 3.08 (t, J = 11.1 Hz, 1H), 1.95 - 2.01 (m, 2H), 1.68 - 1.86 (m, 2H). Example 16

7-[4-(l,l-Dioxo-tetrahydro-l ⁶-thiophen-3-yl)-thiazol-2-yl]-naphthalene-2-carboxylic acid

Step 1

In a 50 ml round-bottomed flask, l,l-dioxo-tetrahydro-^⁶-thiophene-3-carboxylic acid (490 mg, 2.98 mmol) was suspended in 13 ml dichloromethane. Oxalyl chloride (0.31 ml, 3.54 mmol) was added dropwise at room temperature followed by two drops of DMF. Vigorous gas evolution was observed. The reaction mixture was stirred at room temperature for 3.5 h then concentrated to a light brown solid. The residue was dissolved in 4.4 ml acetonitrile and

trimethylsilyldiazomethane (2.0 M in diethyl ether, 4.4 ml, 8.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then cooled to 0°C. Acetic acid (0.15 ml, 2.62 mmol) and then 48% hydrobromic acid (1.2 ml, 10.6 mmol) were sequentially added dropwise. Vigorous gas evolution was observed. After the addition was complete, the ice bath was removed and the reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with water and extracted twice with dichloromethane. The organic layers were combined and dried over sodium sulfate then filtered and concentrated to afford 724 mg (91%) of 2-bromo-l-(l,l-dioxo-tetrahydro-^⁶-thiophen-3-yl)-ethanone as a yellow solid. 1H NMR (300 MHz, CDC1₃) δ: 3.90 (d, J = 1.1 Hz, 2H), 3.78 (qd, J = 8.8, 6.8 Hz, 1H), 3.11 - 3.25 (m, 3H), 2.98 - 3.10 (m, 1H), 2.41 - 2.56 (m, 1H), 2.17 - 2.35 (m, 1H).

Step 2

In a 10 ml round-bottomed flask, 7-bromo-naphthalene-2-carbothioic acid amide (100 mg, 0.38 mmol) and 2-bromo-l-(l,l-dioxo-tetrahydro-^⁶-thiophen-3-yl)-ethanone (111 mg, 0.41 mmol) were suspended in 1.6 ml ethanol. The reaction mixture was stirred at 90°C for 1 h then cooled to room temperature and diluted with diethyl ether. The suspension was filtered, rinsed with a small amount of diethyl ether and dried under high vacuum to isolate 145 mg (79%) of 2-(7- bromo-naphthalen-2-yl)-4-(l,l-dioxo-tetrahydro-^⁶-thiophen-3-yl)-thiazole hydrobromide as a light yellow powder.

Step 3

A microwave vial was charged with 2-(7-bromo-naphthalen-2-yl)-4-(l,l-dioxo-tetrahydro-^⁶- thiophen-3-yl)-thiazole hydrobromide (144 mg, 0.29 mmol), molybdenum hexacarbonyl (40 mg, 0.15 mmol), Herrmann's catalyst (28 mg, 0.03 mmol), N,N-diisopropylethylamine (118 mg, 0.16 ml, 0.92 mmol), 1 ml 1,4-dioxane and 1 ml ethanol. The vial was flushed with argon, sealed and heated under microwave irradiation at 155°C for 20 min. After cooling, the reaction mixture was filtered, rinsing with dichloromethane and the filtrate was concentrated. The residue was purified by chromatography over 12g silica gel with EtOAc/hexanes (gradient: 0-40% EtOAc). All fractions containing product were combined and concentrated to give 74 mg (63%) of 7-[4-(l,l- dioxo-tetrahydro-^⁶-thiophen-3-yl)-thiazol-2-yl]-naphthalene-2-carboxylic acid ethyl ester as a light yellow solid. LC/MS (M+H)⁺ = 402. Step 4

In a 25 ml round-bottomed flask, 7-[4-(l,l-dioxo-tetrahydro-^⁶-thiophen-3-yl)-thiazol-2-yl]- naphthalene-2-carboxylic acid ethyl ester (72 mg, 0.18 mmol) was suspended in 1 ml THF and 1 ml methanol. Lithium hydroxide (20 mg, 0.84 mmol) and 1 ml water were added and the reaction mixture was stirred at room temperature overnight. The reaction was acidified with 1M HC1 to pH=~l then diluted with water and extracted twice with EtOAc. The organic layers were washed with water and brine then combined and concentrated. The residue was triturated with dichloromethane to afford 65 mg (97%) of 7-[4-(l,l-dioxo-tetrahydro-^⁶-thiophen-3-yl)- thiazol-2-yl]-naphthalene-2-carboxylic acid as an orange powder. LC/MS (M+H)⁺ = 374; 1H NMR (400 MHz, DMSO-d₆) δ: 13.17 (br. s., 1H), 8.77 (s, 1H), 8.73 (s, 1H), 8.22 (dd, J = 8.6, 1.5 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.04 (dd, J = 8.6, 1.5 Hz, 1H),

7.71 (d, J = 0.8 Hz, 1H), 3.85 - 3.98 (m, 1H), 3.63 (dd, J = 13.6, 7.6 Hz, 1H), 3.36 - 3.45 (m, 2H), 3.18 - 3.30 (m, 1H), 2.56 - 2.65 (m, 1H), 2.31 - 2.46 (m, 1H).

Example 17

7-(4-tert-Butyl-thiazol-2-yl)-naphthalene-2-carboxylic acid

Step 1

A pressure tube was charged with tetrakis(triphenylphosphine)palladium(0) (785 mg, 0.68 mmol) and zinc cyanide (1.2 g, 10.2 mmol) and a solution of 7-bromo-naphthalene-2-carboxylic acid methyl ester (1.8 g, 6.79 mmol) in DMF (12 ml) was added. The tube was purged with argon then sealed and heated at 100°C overnight with stirring. The reaction was cooled to room temperature and water and diethyl ether were added. The aqueous layer was extracted three times with diethyl ether. The combined organics were washed with brine then dried over MgS0₄ and concentrated. The residue was triturated twice with petroleum ether to give 1.25 g of 7-cyano- naphthalene-2-carboxylic acid methyl ester as a white solid. 1H NMR (400 MHz, DMSO-d₆) δ: 8.83 (s, 1H), 8.78 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.18 (s, 2H), 7.95 (dd, J = 8.5, 1.6 Hz, 1H), 3.95 (s, 3H). Step 2

To a solution of 7-cyano-naphthalene-2-carboxylic acid methyl ester (1.25 g, 5.92 mmol) in methanol (25 ml) was added ammonium sulfide (5.9 M, 1.2 ml, 7.1 mmol). The reaction was and stirred at room temperature overnight, heated at 60°C for 4 h and then at 50°C overnight.

Additional ammonium sulfide (5.9 M, 1.2 ml, 7.1 mmol) was added and heating was continued at 50°C for 5 h. the reaction was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate and washed with water (2x) and brine then dried over MgS0₄ and concentrated. The residue was triturated three times with diethyl ether to give 1.0 g (69%) of 7- thiocarbamoyl-naphthalene-2-carboxylic acid methyl ester as a brown solid. 1H NMR (400 MHz, DMSO-d₆) δ: 10.08 (br. s., 1H), 9.73 (br. s., 1H), 8.70 (d, J = 0.8 Hz, 1H), 8.57 (d, J = 1.5 Hz, 1H), 8.17 (dd, J = 8.7, 1.5 Hz, 1H), 8.01 - 8.12 (m, 3H), 3.94 (s, 3H).

Step 3

A microwave vial was charged with 7-thiocarbamoyl-naphthalene-2-carboxylic acid methyl ester (50 mg, 0.20 mmol), l-bromo-3,3-dimethylbutan-2-one (40 mg, 0.22 mmol) and ethanol (2 ml). The vial was sealed and heated in a sand bath at 75°C for 3 h. The reaction was cooled to room temperature and aqueous 1.0 M NaOH (2 mL, 2.00 mmol) was added. The mixture was stirred at room temperature overnight then acidified with 1 N HC1 until a precipitate formed. The slurry was diluted with water and the solids were collected via filtration, rinsed twice with water and dried under high vacuum to give 28 mg (44%) of 7-(4-tert-butyl-thiazol-2-yl)-naphthalene-2- carboxylic acid as a tan powder. LC/MS: (M+H)⁺ = 312; 1H NMR (400 MHz, DMSO-d₆) δ:

13.16 (br. s., 1H), 8.77 (s, 1H), 8.68 (s, 1H), 8.23 (dd, J = 8.8, 1.5 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.42 (s, 1H), 1.40 (s, 9H).

Example 18

7-[4-(4-Methanesulfonyl-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid

Prepared according to the procedure outlined in Example 17, substituting 2-bromo-l-(4- (methylsulfonyl)phenyl)ethanone for l-bromo-3,3-dimethylbutan-2-one in step 3. Isolated 21 mg (25%) of an off-white powder. LC/MS: (M+H)⁺ = 410; 1H NMR (400 MHz, DMSO-d₆) δ: 13.20 (br. s., 1H), 8.86 (s, 1H), 8.82 (s, 1H), 8.56 (s, 1H), 8.39 (d, J = 8.5 Hz, 2H), 8.36 (dd, J = 8.8, 1.8 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.04 - 8.09 (m, 3H), 3.29 (s, 3H). Example 19

7-[4-(4-Cyano-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid

Prepared according to the procedure outlined in Example 17, substituting 4- (2- bromoacetyl)benzonitrile for l-bromo-3,3-dimethylbutan-2-one in step 3. Isolated 32 mg (44%) of an off-white powder. LC/MS: (M+H)⁺ = 357; 1H NMR (DMSO-d₆) δ: 8.90 (s, 1H), 8.86 (s, 1H), 8.57 (s, 1H), 8.30 - 8.40 (m, 3H), 8.20 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H).

Example 20

7-(4-Phenyl-thiazol-2-yl)-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid

Step 1

A 25 ml round-bottomed flask was charged with 7-bromo-3,4-dihydro-naphthalene-2-carboxylic acid methyl ester (600 mg, 2.25 mmol), bis(pinacolato)diboron (684 mg, 2.7 mmol), potassium acetate (661 mg, 6.74 mmol), DPPF (50 mg, 0.09 mmol) and dichloro 1,1'- bis(diphenylphosphino)ferrocene palladium(II) dichloromethane adduct (74 mg, 0.09 mmol). The flask was evacuated and backfilled with argon then 6 ml 1,4-dioxane was added. The reaction mixture was stirred at 90°C overnight and then at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 40g silica gel with EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to afford 232 mg (33%) of 7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,4-dihydro-naphthalene-2- carboxylic acid methyl ester as an off-white solid. 1H NMR (400 MHz, CDC1₃) δ: 7.71 (dd, J = 7.5, 1.1 Hz, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 7.20 (d, J = 7.5 Hz, 1H), 3.83 (s, 3H), 2.87 - 2.93 (m, 2H), 2.56 - 2.70 (m, 2H), 1.37 (s, 12H).

Step 2

A microwave vial was charged with 7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,4- dihydro-naphthalene-2-carboxylic acid methyl ester (100 mg, 0.32 mmol), 2-bromo-4- phenylthiazole (100 mg, 0.42 mmol), tetrakis(triphenylphosphine)palladium (0) (37 mg, 0.03 mmol), sodium carbonate (101 mg, 0.96 mmol), 2.4 ml methanol and 0.8 ml dichloromethane. The vial was flushed with argon, sealed and heated under microwave irradiation at 115°C for 30 min. After cooling, the reaction mixture was quenched with water and extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 12g silica gel with

EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to afford 102 mg (88%) of 7-(4-phenyl-thiazol-2-yl)-3,4-dihydro-naphthalene-2- carboxylic acid methyl ester as an off-white solid. LC/MS: (M+H)⁺ = 348. Step 3

In a Parr bottle, 7-(4-phenyl-thiazol-2-yl)-3,4-dihydro-naphthalene-2-carboxylic acid methyl ester (99 mg, 0.29 mmol) was dissolved in 2.5 ml methanol and 2.5 ml THF and 10% palladium on carbon (wet, 50 mg, 0.47 mmol) was added carefully. The bottle was placed on a Parr hydrogenator and three times alternatingly evacuated and flushed with hydrogen. The reaction mixture was shaken at room temperature under 55 psi hydrogen pressure for 6h then filtered and rinsed with methanol/EtOAc. The filtrate was concentrated to afford 98 mg (98%) of 7-(4- phenyl-thiazol-2-yl)-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester as an off- white solid. LC/MS: (M+H)⁺ = 350.

Step 4

In a round-bottomed flask, 7-(4-phenyl-thiazol-2-yl)-l,2,3,4-tetrahydro-naphthalene-2- carboxylic acid methyl ester (96 mg, 0.28 mmol) was dissolved in 1 ml THF and 1 ml methanol. Lithium hydroxide (30 mg, 1.25 mmol) and 1 ml water were added and the reaction mixture was stirred at room temperature overnight. The reaction was acidified with 1M HC1 to a pH of ~2, diluted with a small amount of water and extracted twice with EtOAc. The organic layers were washed with water and brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane to afford 57 mg (62%) of 7-(4-phenyl-thiazol-2- yl)-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid as a white powder. LC/MS: (M+H)⁺ = 336; 1H NMR (300 MHz, DMSO-d₆) δ: 12.31 (br. s., 1H), 8.12 (s, 1H), 8.00 - 8.07 (m, 2H), 7.70 - 7.79 (m, 2H), 7.42 - 7.51 (m, 2H), 7.31 - 7.40 (m, 1H), 7.22 (d, J = 7.6 Hz, 1H), 2.88 - 3.12 (m, 2H), 2.78 - 2.87 (m, 2H), 2.65 - 2.77 (m, 1H), 2.04 - 2.17 (m, 1H), 1.70 - 1.85 (m, 1H).

Example 21 4-Methoxy-7-(4-phenyl-thiazol-2-yl)-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid

Step 1

7-Methoxy-4-oxo-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester was prepared according to the procedure found in J. Am. Chem. Soc. 2007, 129, 376. 1H NMR (400 MHz, CDC1₃) δ: 8.03 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 8.8, 2.5 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.15 - 3.23 (m, 3H), 2.89 - 2.97 (m, 1H), 2.75 - 2.85 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H).

Step 2

In a 100 ml round-bottomed flask, 7-methoxy-4-oxo-l,2,3,4-tetrahydro-naphthalene-2- carboxylic acid ethyl ester (1.00 g, 4.03 mmol) was dissolved in 16 ml of 1,2-dichloroethane. Aluminum chloride (1.61 g, 12.1 mmol) was added in one portion and the dark green reaction mixture was stirred at room temperature overnight. Additional aluminum chloride (537 mg, 4.03 mmol) was added and the reaction mixture was stirred at room temperature for 5 h. Additional aluminum chloride (537 mg, 4.03 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was carefully quenched by dropwise addition of water (caution: exothermic) and then extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 40g silica gel with EtOAc/hexanes (gradient: 0-40% EtOAc). All fractions containing product were combined and concentrated to afford 656 mg (70%) of 7-hydroxy-4- oxo-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester as a yellow solid. LC/MS:

(M+H)⁺ = 235; 1H NMR (400 MHz, CDC1₃) δ: 8.00 (d, J = 8.6 Hz, 1H), 6.82 (dd, J = 8.6, 2.5 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.32 (br. s., 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.17 - 3.20 (m, 3H), 2.76 - 3.00 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H). Step 3

7-Hydroxy-4-oxo-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (654 mg, 2.79 mmol) was dissolved in 20 ml dichloromethane. The reaction mixture was cooled to 0°C and pyridine (0.32 ml, 3.96 mmol) was added. Then trifluoromethanesulfonic anhydride (0.57 ml, 3.37 mmol) was added dropwise and the reaction mixture was stirred at 0°C for 1 h. The reaction was quenched with saturated NaHC0₃-solution and extracted with dichloromethane. The organic layer was washed with water. The aqueous layers were back-extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to provide 1.03 g of 4-oxo-7-trifluoromethanesulfonyloxy-l,2,3,4-tetrahydro-naphthalene-2- carboxylic acid ethyl ester as a brown solid which was used without further purification.

Step 4

A 25 ml round-bottomed flask was charged with 4-oxo-7-trifluoromethanesulfonyloxy- 1,2,3,4- tetrahydro-naphthalene-2-carboxylic acid ethyl ester (500 mg, 1.3 mmol), bis(pinacolato)diboron (395 mg, 1.56 mmol), potassium acetate (382 mg, 3.89 mmol), DPPF (29 mg, 0.05 mmol) and dichloro l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane adduct (43 mg, 0.05 mmol). The flask was evacuated and backfilled with argon then 6 ml of 1,4-dioxane was added. The reaction mixture was heated at 90°C overnight then cooled to room temperature, quenched with water and extracted three times with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 25g silica gel with EtOAc/hexanes (gradient: 0-20% EtOAc). All fractions containing product were combined and concentrated to afford 466 mg of 4-oxo-7-(4,4,5,5- tetramethyH 1 ,3,2]dioxaborolan-2-yl)- 1 ,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester as a light yellow oil. ¹H NMR (400 MHz, CDC1₃) δ: 8.03 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.14 - 3.32 (m, 3H), 2.79 - 3.02 (m, 2H), 1.38 (s, 12H), 1.27 (t, J = 7.2 Hz, 3H).

Step 5

A microwave vial was charged with 4-oxo-7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (459 mg, 1.2 mmol), 2-bromo-4- phenylthiazole (403 mg, 1.68 mmol), sodium carbonate (382 mg, 3.6 mmol) and

tetrakis(triphenylphosphine)palladium (0) (139 mg, 0.12 mmol). The vial was flushed with argon, sealed and 6 ml 1,4-dioxane and 0.6 ml water were added. The reaction mixture was heated at 100°C in an oil bath for 2 d then cooled to room temperature, quenched with water and extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 25g silica gel with EtOAc/hexanes (gradient: 0-20% EtOAc). All fractions containing product were combined and concentrated to provide 404 mg (89%) of 4-oxo-7-(4-phenyl-thiazol-2-yl)-l,2,3,4-tetrahydro- naphthalene-2-carboxylic acid ethyl ester as a light yellow solid. LC/MS: (M+H)⁺ = 378.

Step 6

In a 50 ml round-bottomed flask, 4-oxo-7-(4-phenyl-thiazol-2-yl)-l,2,3,4-tetrahydro- naphthalene-2-carboxylic acid ethyl ester (392 mg, 1.04 mmol) was suspended in 12 ml THF and 6 ml ethanol and the suspension was cooled to 0°C. Sodium borohydride (118 mg, 3.12 mmol) was added and the reaction mixture was stirred at 0°C for 1.5 h. The reaction was quenched with water and extracted three times with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 12g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc). All fractions containing product were combined and concentrated to afford 284 mg (72%) of cis-4-hydroxy-7-(4-phenyl-thiazol- 2-yl)-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester as a light yellow solid. NMR analysis revealed a single diastereomer. The cis relative stereochemistry was confirmed using NOE experiments. LC/MS (M+H)⁺ = 380; 1H NMR (400 MHz, CDC1₃) δ: 8.00 - 8.05 (m, 2H), 7.87 - 7.95 (m, 2H), 7.68 (d, J = 8.1 Hz, 1H), 7.45 - 7.52 (m, 3H), 7.36 - 7.43 (m, 1H), 4.90 (t, J = 7.1 Hz, 1H), 4.21 (qd, J = 7.1, 1.4 Hz, 2H), 3.13 - 3.21 (m, 2H), 2.92 - 3.02 (m, 1H), 2.48 - 2.57 (m, 1H), 2.01 - 2.13 (m, 1H), 1.32 (t, J = 7.1 Hz, 3H).

Step 7

A microwave vial was charged with cis-4-hydroxy-7-(4-phenyl-thiazol-2-yl)-l,2,3,4-tetrahydro- naphthalene-2-carboxylic acid ethyl ester (100 mg, 0.26 mmol), 1 ml methanol and one drop sulfuric acid (-95%). The vial was flushed with argon, sealed and heated at 90°C in an oil bath overnight. The reaction mixture was cooled to room temperature and quenched with water then extracted with dichloromethane. The organic layer was washed with saturated NaHC0₃-solution. The aqueous layers were extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 112 mg of 4-methoxy-7- (4-phenyl-thiazol-2-yl)-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester as an orange oil which was used without further purification. NMR analysis showed an approximate 2: 1 mixture of diastereomers (unassigned). Step 8

In a 5 ml round-bottomed flask, 4-methoxy-7-(4-phenyl-thiazol-2-yl)-l,2,3,4-tetrahydro- naphthalene-2-carboxylic acid methyl ester (104 mg, 0.23 mmol) was dissolved in 0.8 ml THF and 0.8 ml methanol. Lithium hydroxide (15 mg, 0.63 mmol) and 0.8 ml water were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and acidified to pH=~4 with 1M HC1. The resulting suspension was filtered, washed with water, and a small amount of dichloromethane to isolate 64 mg (75%) of 4-methoxy-7-(4- phenyl-thiazol-2-yl)-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid as an off-white powder and an approximate 2: 1 mixture of diastereomers. LC/MS: (M+H)⁺ = 366; Major diastereomer: 1H NMR (400 MHz, DMSO-d₆) δ: 12.42 (br. s., 1H), 8.19 (s, 1H), 8.06 (dd, J = 8.2, 1.1 Hz, 2H), 7.79 - 7.89 (m, 2H), 7.44 - 7.57 (m, 3H), 7.35 - 7.43 (m, 1H), 4.38 (t, J = 3.4 Hz, 1H), 3.43 (s, 3H), 3.07 - 3.19 (m, 1H), 2.75 - 2.96 (m, 2H), 2.33 - 2.43 (m, 1H), 1.76 - 1.87 (m, 1H); Minor diastereomer: 1H NMR (400 MHz, DMSO-d₆) δ: 12.42 (br. s., 1H), 8.18 (s, 1H), 8.06 (dd, J = 8.2, 1.1 Hz, 2H), 7.79 - 7.89 (m, 2H), 7.44 - 7.57 (m, 3H), 7.35 - 7.43 (m, 1H), 4.53 (dd, J = 9.1, 5.1 Hz, 1H), 3.33 (s, 3H), 2.98 - 3.06 (m, 1H), 2.75 - 2.96 (m, 2H), 2.33 - 2.43 (m, 1H), 1.66 - 1.75 (m, 1H).

Example 22 3-(4-Cyclobutyl-thiazol-2-yl)-quinoline-6-carboxylic acid

Step 1

To a suspension of 6-bromoquinoline-3-carboxylic acid (0.50 g, 1.98 mmol) in dichloromethane (10 ml) was added oxalyl chloride (327 mg, 0.22 ml, 2.58 mmol) followed by DMF (3 drops). Gentle gas evolution was observed. The reaction mixture was stirred at room temperature for 2 h then concentrated to a white solid. The residue was suspended in diethyl ether (10 ml) and 28% ammonium hydroxide (2.0 ml, 16.0 mmol) was added. The mixture was stirred vigorously at room temperature for 2 h then filtered, rinsing with water and diethyl ether. Dried to by air then under high vacuum to afford 457 mg (92%) of 6-bromo-quinoline-3-carboxylic acid amide as a beige solid.

Step 2

To a solution of 6-bromo-quinoline-3-carboxylic acid amide (450 mg, 1.79 mmol) in THF (12 ml) was added Lawesson's reagent (1.09 g, 2.69 mmol). The reaction mixture was heated at 60°C overnight then cooled to room temperature and concentrated. The residue was triturated with toluene/dichloromethane/MeOH. The resultant precipitate was collected via filtration, rinsing with toluene and dried under high vacuum to provide 340 mg (71%) of 6-bromo-quinoline-3- carbothioic acid amide as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ: 10.22 (br. s., 1H), 9.90 (br. s., 1H), 9.31 (d, J = 2.3 Hz, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 1.9 Hz, 1H), 7.91 - 8.03 (m, 2H).

Step 3

A solution of 2-bromo-l-cyclobutylethanone (270 mg, 1.53 mmol) in EtOH (8 ml) was added to 6-bromo-quinoline-3-carbothioic acid amide (340 mg, 1.27 mmol). The reaction mixture was heated at reflux for 30 min during which time a bright yellow precipitate was formed. The reaction was cooled to room temperature and concentrated to dryness. The residue was suspended in diethyl ether/EtOAc and water and 28% ammonium hydroxide (3 mL) were added. The mixture was stirred vigorously for 1 h during which time all solids gradually dissolved. The aqueous layer was extracted twice with EtOAc. The combined organics were dried over MgS0₄ and concentrated. The residue was purified by silica gel chromatography with 50%

EtOAc/hexanes to isolate 340 mg (77%) of 6-bromo-3-(4-cyclobutyl-thiazol-2-yl)-quinoline as a yellow solid. 1H NMR (300 MHz, CDC1₃) δ: 9.49 (d, J = 2.3 Hz, 1H), 8.61 (d, J = 1.9 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.82 (dd, J = 9.1, 1.9 Hz, 1H), 7.05 (s, 1H), 3.78 (quin, J = 8.5 Hz, 1H), 2.31 - 2.49 (m, 4H), 1.96 - 2.19 (m, 2H).

Step 4

A microwave vial was charged with 6-bromo-3-(4-cyclobutyl-thiazol-2-yl)-quinoline (80 mg, 0.23 mmol), molybdenum hexacarbonyl (31 mg, 0.12 mmol), and Herrmann's catalyst (22 mg, 0.023 mmol). Then added 1,4-dioxane (1.0 ml), MeOH (1.0 ml), and N,N-diisopropylethylamine (0.12 ml, 0.70 mmol). The vial was sealed and heated under microwave irradiation at 145°C for 20 min. After cooling the reaction mixture was diluted with dichloromethane, absorbed onto silica gel and purified by silica gel chromatography with 10% to 20% EtOAc/hexanes to afford 36 mg (48%) of 3-(4-cyclobutyl-thiazol-2-yl)-quinoline-6-carboxylic acid methyl ester as a light yellow solid.

Step 5

To a solution of 3-(4-cyclobutyl-thiazol-2-yl)-quinoline-6-carboxylic acid methyl ester (35 mg, 0.11 mmol) in MeOH (2 ml) and THF (1 ml) was added aqueous 10% sodium hydroxide (1 ml, 2.5 mmol). The yellow reaction mixture was heated at 50°C for 1 h then concentrated. The residue was diluted with water, cooled to 0°C and neutralized with cone. HCl followed by 1.0M HCl. The resultant precipitate was collected via filtration rinsing with water and a small amount of Et₂0/MeOH then dried under high vacuum to afford 21 mg (63%) of 3-(4-cyclobutyl-thiazol- 2-yl)-quinoline-6-carboxylic acid as an off-white solid. LC/MS (M+H)⁺ = 311; 1H NMR (300 MHz, DMSO-d₆) δ: 13.34 (br. s., 1H), 9.53 (d, J = 2.3 Hz, 1H), 9.07 (d, J = 1.9 Hz, 1H), 8.82 (s, 1H), 8.24 (dd, J = 8.7, 1.9 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.55 (s, 1H), 3.74 (quin, J = 8.5 Hz, 1H), 2.21 - 2.42 (m, 4H), 1.83 - 2.13 (m, 2H).

Example 23

6-(4-Phenyl-thiazol-2-yl)-quinoline-3-carboxylic acid

Step 1

In a 50 mL round-bottomed flask, 6-bromo-quinoline-3-carboxylic acid (467 mg, 1.85 mmol) and sulfuric acid (0.07 ml) were combined with methanol (25 ml). The reaction was heated at 85°C overnight then cooled to room temperature and partitioned between dichloromethane and sodium bicarbonate. The organic layer was evaporated to afford 420 mg of 6-bromo-quinoline-3- carboxylic acid methyl ester as a white solid.

Step 2

A round-bottomed flask was charged with 6-bromo-quinoline-3-carboxylic acid methyl ester (400 mg, 1.50 mmol), bis(pinacolato)diboron (458 mg, 1.8 mmol), potassium acetate (443 mg, 4.51 mmol) [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 0.06 mmol), l,l'-bis(diphenylphosphino)ferrocene (33 mg, 0.06 mmol) and 1,4-dioxane (40 mL). the reaction was degassed with nitrogen and heated at 90°C for 24 h. After cooling to room temperature the mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgS0₄ and evaporated. The residue was purified by silica gel chromatography with 0% to 20% EtOAc/hexanes to give 400 mg of 6-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-quinoline-3- carboxylic acid methyl ester. LC/MS: (M+H)⁺ = 314.

Step 3

In a 20 mL pear-shaped flask, 6-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-quinoline-3- carboxylic acid methyl ester (400 mg, 1.28 mmol), sodium carbonate (406 mg, 3.83 mmol), 2- bromo-4-phenylthiazole (399 mg, 1.66 mmol) and tetrakis(triphenylphosphine)palladium (0) (148 mg, 0.13 mmol) were combined with 1,4-dioxane. The reaction mixture was heated at 115°C for 24 h then cooled to room temperature and concentrated to dryness. The residue was purified by silica gel chromatography with 30% EtOAc/hexanes to obtain 110 mg (25%) of 6-(4- phenyl-thiazol-2-yl)-quinoline-3-carboxylic acid methyl ester as a white solid.

Step 4

In a round-bottomed flask, 6-(4-phenyl-thiazol-2-yl)-quinoline-3-carboxylic acid methyl ester (110 mg, 0.32 mmol) and sodium hydroxide (64 mg, 1.59 mmol) were combined with THF (2 ml) and methanol (2 ml). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was acidified with IN HC1. The resultant yellow solid was collected via filtration and dried under high vacuum to afford 100 mg (95%) of 6-(4-phenyl-thiazol-2-yl)- quinoline-3-carboxylic acid. LC/MS: (M+H)⁺ = 333; 1H NMR (400 MHz, DMSO-d₆) δ: 9.38 (d, J = 2.0 Hz, 1H), 9.21 (d, J = 2.0 Hz, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.60 (dd, J = 8.8, 2.0 Hz, 1H), 8.32 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.09 - 8.16 (m, 2H), 7.49 - 7.56 (m, 2H), 7.37 - 7.46 (m, 1H). Example 24 Assay Protocols and Results

Cell-Based Proteasome Activity/Selectivity Assay

The Cell-Based Proteasome subunit activity/selectivity assay can be a panel of 5

fluorogenic assays that independently measured the activity o \]5c or β 5i (chymotrypsin-like activity), β 2c/2i (trypsin -I ike ), and β lc or β I i (caspase-like ) protease activity associated with the proteasome complex in cultured cells. Specifically, the following substrates were used for respective subunit activities: β li: (PAL)₂Rhl lO, β l c: (LLE)₂ Rh 1 10. β 2c/2i: (KQL)₂Rhl lO, β 5c: (WLA)₂Rhl 10, β 5i: (ANW)₂Rhl 10. The following procedure can be followed: Cell preparation: Plated 25 μΐ of Ramos cells (2 xl0⁶/ml in DPBS) into half area plate

(PerkinElmer Cat 6005569) to final 5xl0⁴ cells/well. Added 0.5 μΐ of lOOx 4-fold serial diluted test compounds or DMSO to each well. Highest concentration of compound tested can be 20 μΜ, thus compound serial dilution started from 200 mM. Incubated for 30 minutes at 37°C. Then equilibrated at room temperature for 15 minutes. Added 25 μΐ of 2x reaction mix consisting of 0.025% digitonin, 20 μΜ of each substrates and 0.5M sucrose in DPBS. Shaked for one minute @ 700 rpm. Incubated for 120 min at room temperature. Then read the plates with an Envision multilabel plate reader (PerkinElmer) with 500 nm excitation/519 nm emission.

Modified PBMC Proteasome Activity Assay

This cell-based proteasome activity assay can be similar to previous Ramos cell-based assay as of the substrates, but using human PB Cs in the context of complete RP I with 10 % FBS as reaction buffer. This assay can be designed to assess the level of cellular penetration of test compounds in primary human cells. The following procedure can be followed: Fresh isolated PBMC from healthy donor were plated at lxlO⁵ cells/well in 100 μΐ of complete RPMI with 10% FBS in V bottom 96 plates. Added 1 μΐ of 100X 4-fold serial diluted compounds /well and incubated for 1 hr. The highest compound concentration tested can be 20 μΜ (100X working stock start with 2 mM). Spun down the cells @ 2000rpm for 5 min. Removed all supernatant. Then resuspended the cells in 25 μΐ DPBS and transferred the cells to a fresh half-area plate (PerkinElmer Cat 6005569). In the final reaction volume can be 50 μΐ, including 25 μΐ cell suspension, 0.5 μΐ lOOx inhibitor or DMSO, 25 μΐ substrate mix containing 0.025% digitonin, 20 uM substrate (Substrate: (PAL)₂Rhl 10, (LLE)₂ Rhl 10, (KQL)₂Rhl 10, (WLA)₂Rhl 10, or

(ANW)₂Rhl l0)/in 10% FBS and 0.5M sucrose mixture. Shaked for one minute (@ 700 rpm). Incubated for 2 hrs, then read the plates with Envision plate reader using 500 nm excitation/519 nm emission.

PBMC IP- 10 Assay PBMCs were isolated from whole blood as follows: Blood can be collected in a sterile environment in heparinized tubes. Blood can be diluted with an equal volume PBS/2% FCS and 30 ml of this mixture can be added to ACCUSPIN tubes containing 15 ml Histopaque-1077 already centrifuged at 800g for 30 seconds and warmed up at room temperature. The tubes were then centrifuged at 800 g for 20 minutes at room temperature with no brake. The mononuclear band, just above the polyethylene frit, can be removed by Pasteur pipet. These mononuclear cells were can behed three times with sterile PBS, counted, and resuspended in RPMI 1640 supplemented with 10% heat inactivated fetal calf serum, 10 mM HEPES, 1 mM sodium pyruvate, penicillin (50 U/ml), streptomycin (50 μg/ml) and glutamine (2 mM) to approximately 1.5 x 10⁶/ml. Approximately 2 x 10⁵ cells/well were plated in 96 well tissue culture plates (BD Falcon 353072), and preincubated 60 mi/37°C with a titration of compounds, in a final concentration of 1% DMSO. Cells were then stimulated with CpG Type A (Invivogen, Cat # tlrl- 2216; ODN 2216) at a final concentration of 2.5 μΜ. Cells were incubated overnight, and supematants were removed. PBMC viability of cells remaining in the well can be measured with ATPlite luminescence assay (Perkin-Elmer) per the manufacturer's instructions. Luminescence can be measured on the Perkin-Elmer Envision, using the luminescence filter. IP 10 level can be measured with CXCL10/IP10 AlphaLISA kit (Perkin-Elmer) per the manufacturer's instructions, except halving all volumes. Fluorescence can be measured on the Envision Multilabel plate reader, using the AlphaScreen standard settings. Results:

The results of the above assays for representative compounds of the invention are provided in Table 1 below, wherein the Ic50 activity values are in μΜ:

Table 1

Ic50:ramos: Ic50:ramos: Ic50:ramos: Ic50:ramos: Ic50:ramos:

Example

ac(anw)2rll0 rhll0-(wla)2 rhll0-(kql)2 rhll0-(pal)2 rhllO-(lle)2

1 1.035 20 20 20 20

2 0.922 20 20 20 20

3 0.247 20 20 20 20

4 3.368 20 20 20 20

5 0.212 17.488 20 20 20

6 0.539 20 20 20 20

7 0.574 20 20 20 20

8 3.567 20 20 20 20

9 0.332 20 20 20 20 Ic50:ramos: Ic50:ramos: Ic50:ramos: Ic50:ramos: Ic50:ramos:

Example

ac(anw)2rll0 rhll0-(wla)2 rhll0-(kql)2 rhll0-(pal)2 rhllO-(lle)2

10 1.146 20 20 20

11 1.779 20 20 20 20

12 0.359 18.661 20 17.167 20

13 0.599 20 20 20 20

14 1.089 20 20 20 20

15 1.206 20 20 20 20

16 0.962 20 20 20 20

17 2.619 20 20 20 20

18 0.757 20 20 20 20

19 0.733 20 20 20 20

20 0.451 20 20 20 20

21 7.605 20 20 20 20

22 12.49 20 20 20 20

23 8.684 20 20 20 20

It is to be understood that the invention is not limited to the particular embodiments of the invention described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims.

Claims

1. A compound of formula (I):

wherein:

X is naphthalene, methoxy-naphthalene, dihydro-naphthalene, tetrahydro-naphthalene, methoxy-tetrahydro-naphthalene or quinoline;

R¹ is Ci-7 alkyl, C₃_8 cycloalkyl, heterocycloalkyl, or phenyl optionally substituted with one or two halogen, -S0₂CH₃ or cyano;

R is hydrogen; or R 1 and R 2 together are forming a C₂_₇ alkenylene; or a pharmaceutically acceptable salt or ester thereof. 2. The com ound accordin to claim 1 wherein X is selected from:

, and The compound according to claim 1, wherein X is naphthalene, methoxy-naphthalene or tetrahydro-naphthalene.

The compound according to claim 1, wherein R¹ is iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, dioxo- tetrahydro-thiophenyl, or phenyl which is optionally substituted with one or two chloro, cyano or -SO₂CH₃.

The compound according to claim 1, wherein R¹ is cyclobutyl, cyclopentyl or phenyl. The compound according to claim 1, wherein R is hydrogen.

The compound according to claim 1, wherein R 1 and R 2 together are forming butadienylene.

The compound according to claiml, wherein said compound is:

7-(4-Cyclobutyl-thiazol-2-yl)-5,6-dihydro-naphthalene-2-carboxylic acid;

7-(4-Cyclobutyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Cyclopropyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Cyclopentyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Cyclohexyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-[4-(3-Chloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-[4-(2,6-Dichloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-[4-(2-Chloro-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-Benzothiazol-2-yl-naphthalene-2-carboxylic acid;

7-(4-Cyclobutyl-thiazol-2-yl)-5-methoxy-naphthalene-2-carboxylic acid;

7-(4-Cyclobutyl-thiazol-2-yl)-6-methoxy-naphthalene-2-carboxylic acid;

7-(4-Isobutyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-[4-(Tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-[4-(Tetrahydro-pyran-4-yl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-[4-(l,l-Dioxo-tetrahydro-^⁶-thiophen-3-yl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-(4-tert-Butyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-[4-(4-Methanesulfonyl-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-[4-(4-Cyano-phenyl)-thiazol-2-yl]-naphthalene-2-carboxylic acid;

7-(4-Phenyl-thiazol-2-yl)- 1 ,2,3,4-tetrahydro-naphthalene-2-carboxylic acid;

4-Methoxy-7-(4-phenyl-thiazol-2-yl)- 1 ,2,3,4-tetrahydro-naphthalene-2-carboxylic acid; 3-(4-Cyclobutyl-thiazol-2-yl)-quinoline-6-carboxylic acid; or

6-(4-Phenyl-thiazol-2-yl)-quinoline-3-carboxylic acid.

9. The compound according to claiml, wherein said compound is:

7-(4-Cyclobutyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Cyclopentyl-thiazol-2-yl)-naphthalene-2-carboxylic acid;

7-(4-Cyclobutyl-thiazol-2-yl)-6-methoxy-naphthalene-2-carboxylic acid;

7-(4-Phenyl-thiazol-2-yl)- 1 ,2,3,4-tetrahydro-naphthalene-2-carboxylic acid.

10. A pharmaceutical composition, comprising a therapeutically effective amount of a

compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

11. A compound according to any one of claims 1 to 9 for use as a therapeutically active

substance.

12. The use of a compound according to any one of claims 1 to 9 for the treatment or

prophylaxis of an inflammatory disease or disorder.

13. The use of a compound according to any one of claims 1 to 9 for the preparation of a

medicament for the treatment or prophylaxis of an inflammatory disease or disorder.

14. A compound according to any one of claims 1 to 9 for the treatment or prophylaxis of an inflammatory disease or disorder.

15. A method for treating an inflammatory disease or disorder selected from rheumatoid

arthritis, lupus and irritable bowel disease, comprising the step of administering a therapeutically effective amount of a compound according to any one of claims 1 to 9 to a subject in need thereof.

16. The invention as hereinbefore described.