WO2014086701A1 - Substituted thiazole compounds - Google Patents
Substituted thiazole compounds Download PDFInfo
- Publication number
- WO2014086701A1 WO2014086701A1 PCT/EP2013/075208 EP2013075208W WO2014086701A1 WO 2014086701 A1 WO2014086701 A1 WO 2014086701A1 EP 2013075208 W EP2013075208 W EP 2013075208W WO 2014086701 A1 WO2014086701 A1 WO 2014086701A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- thiazol
- naphthalen
- cyclobutyl
- succinamic acid
- mmol
- Prior art date
Links
- 150000003557 thiazoles Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- 208000002551 irritable bowel syndrome Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 206010025135 lupus erythematosus Diseases 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
- -1 dioxotetrahydrothiophenyl Chemical group 0.000 claims description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000003118 aryl group Chemical class 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 10
- 125000001072 heteroaryl group Chemical class 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- WUJIWWQGSSBYCI-UHFFFAOYSA-N 4-[[7-(4-cyclobutyl-1,3-thiazol-2-yl)naphthalen-2-yl]amino]-2-(oxan-4-yl)-4-oxobutanoic acid Chemical compound C1COCCC1C(C(=O)O)CC(=O)NC(C=C1C=2)=CC=C1C=CC=2C(SC=1)=NC=1C1CCC1 WUJIWWQGSSBYCI-UHFFFAOYSA-N 0.000 claims description 7
- LQUGEPUJCKWEMJ-UHFFFAOYSA-N 4-[[7-(4-cyclobutyl-1,3-thiazol-2-yl)naphthalen-2-yl]amino]-2-cyclohexyl-4-oxobutanoic acid Chemical compound C1CCCCC1C(C(=O)O)CC(=O)NC(C=C1C=2)=CC=C1C=CC=2C(SC=1)=NC=1C1CCC1 LQUGEPUJCKWEMJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- 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.
- IBD irritable bowel disease
- 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- ⁇ 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).
- IL-6 IL-6
- TNF-a IL-6
- IL-23 inflammatory cytokines
- LMP7 blockade with PR-957 has been demonstrated to produce therapeutic benefits in several preclinical autoimmune disease models.
- 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.
- 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.
- 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.
- 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.
- X and Y independently of each other, are CH or nitrogen;
- Pv 1 is C3-8 cycloalkyl, heterocycloalkyl, dioxo-substituted heterocycloalkyl, aryl or heteroaryl;
- R 2 is hydrogen, Ci_7 alkyl, C3_s cycloalkyl, heterocycloalkyl, aryl, aryl substituted with Ci_7 alkoxy, benzyl or heteroaryl; 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.
- 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.
- R variables of formula I refer to moieties that are attached to the core structure of formula I by a covalent bond.
- substituted refers to the fact that at least one of the hydrogen atoms of that moiety is replaced by another substituent or moiety.
- 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.).
- alkyl refers to an aliphatic straight-chain or branched-chain saturated hydrocarbon moiety having 1 to 20 carbon atoms. In particular embodiments the alkyl has 1 to 10 carbon atoms.
- lower alkyl refers to an alkyl moiety having 1 to 7 carbon atoms. In particular embodiments the lower alkyl has 1 to 4 carbon atoms and in other particular embodiments the lower alkyl has 1 to 3 carbon atoms. Examples of lower alkyls include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and ieri-butyl. Particular example of C 1-7 alkyl is butyl.
- alkoxy denotes a group of the formula -O-R', wherein R' is an alkyl group.
- alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy. Particular example of C 1-7 alkoxy is methoxy.
- 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,
- ethylenedioxyphenyl and the like, each being optionally substituted.
- aryl is phenyl.
- halo refers to a substituent fluoro, chloro, bromo, or iodo.
- hydro refers to the moiety of a hydrogen atom (-H) and not 3 ⁇ 4.
- 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
- cycloalkyl are cyclobutyl and cyclohexyl.
- 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.
- 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, 1 , 1 -dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl.
- bicyclic saturated heterocycloalkyl examples include 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.
- heterocycloalkyl Particular example of heterocycloalkyl are tetrahydrofuranyl,
- heteroaryl denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
- heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquino
- thiophenyl is synonymous with “thiofuranyl” and “thienyl” and denotes a thiophene substituent.
- 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 “ ⁇ ⁇ ", 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 ⁇ ⁇ symbol is cited immediately after this locant.
- 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
- 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-acetylcy stein and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid
- 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.
- 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-.
- carboxy group means -C(0)0-.
- pivaloyloxymethylesters are examples of such suitable esters.
- 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
- isomers 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
- 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" .
- 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.
- 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.
- 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.
- compositions of the invention 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.
- 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.
- 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.
- a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.
- 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.
- a lipophilic salt such as pamoic acid
- a biodegradable sustained-release composition for subcutaneous or intramuscular administration.
- X and Y independently of each other, are CH or nitrogen;
- R 1 is C3_8 cycloalkyl, heterocycloalkyl, dioxo-substituted heterocycloalkyl, aryl or heteroaryl;
- R 2 is hydrogen, C 1-7 alkyl, C3-8 cycloalkyl, heterocycloalkyl, aryl, aryl substituted with C 1-7 alkoxy, benzyl or heteroaryl; or a pharmaceutically acceptable salt or ester thereof.
- the present invention provides for compounds of formula (I) wherein:
- X and Y independently of each other, are CH or nitrogen;
- R 1 is cyclobutyl, tetrahydrofuranyl, dioxotetrahydrothiophenyl, pyrazinyl or phenyl;
- R 2 is hydrogen, cyclohexyl, tetrahydropyranyl, pyridinyl, Ci_7 alkyl, benzyl, phenyl or phenyl substituted with C 1-7 alkoxy;
- the present invention provides for compounds of formula (I) wherein both X and Y are CH.
- the present invention provides for compounds of formula (I) wherein one of X or Y is CH and the other is nitrogen. In another embodiment, the present invention provides for compounds of formula (I) wherein one of X is CH and Y is nitrogen.
- the present invention provides for compounds of formula (I) wherein R 1 is cyclobutyl or phenyl.
- the present invention provides for compounds of formula (I) wherein R 1 is cyclobutyl.
- the present invention provides for compounds of formula (I) wherein R 1 is phenyl. In another embodiment, the present invention provides for compounds of formula (I) wherein R 1 is tetrahydrofuranyl, dioxotetrahydrothiophenyl or pyrazinyl.
- the present invention provides for compounds of formula (I) wherein R 2 is hydrogen, cyclohexyl, tetrahydropyranyl, pyridinyl, butyl, benzyl, phenyl or phenyl substituted with methoxy.
- the present invention provides for compounds of formula (I) wherein R 2 is cyclohexyl, tetrahydropyranyl or phenyl.
- the present invention provides for compounds of formula (I) wherein R 2 is cyclohexyl. In another embodiment, the present invention provides for compounds of formula (I) wherein R 2 is phenyl.
- the present invention provides for compounds of formula (I) wherein R 2 is pyridinyl or benzyl.
- the present invention provides for compounds of formula (I) wherein R 2 is C 1-7 alkyl.
- the present invention provides for compounds of formula (I) wherein the compound is:
- the present invention provides for compounds of formula (I) wherein the compound is:
- the invention provides for a pharmaceutical composition, comprising a therapeutically effective amount of a compound according to formula (I) and a pharmaceutically acceptable carrier.
- 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.
- 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.
- the inflammatory disease or disorder is selected from from rheumatoid arthritis, lupus and irritable bowel disease (IBD).
- IBD irritable bowel disease
- 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.
- an inflammatory disease or disorder selected from rheumatoid arthritis, lupus and irritable bowel disease (IBD)
- 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 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.
- 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.
- the mono-carboxylic acid 2 can be formed through low temperature transmetallation of 2,7-dibromonaphthalene (1) and quenching of the intermediate organolithium with carbon dioxide.
- the acid can be then converted to the amide 3 using oxalyl chloride followed by aqueous ammonium hydroxide.
- Treatment with Lawesson's reagent provided the thioamide 4, which can be reacted with bromide 5 with gentle heating to afford thiazole 6.
- Palladium catalyzed amination with benzophenone imine and subsequent imine hydrolysis with dilute hydrochloric acid results in the amine 7.
- Mild heating of amine 7 and succinic anhydride 8 in chloroform provides the acid 9 in a regioselective manner.
- Acid chloride 11 can be prepared from acid 10 using oxalyl chloride. Treatment with trimethylsilyldiazomethane results in the in situ formation of diazo ketone 12 which can be quenched with hydrobromic acid in acetic acid to isolate the bromoketone 5 in good yield and purity.
- succinic anhydride 8 In cases where the required succinic anhydride 8 is not commercially available it can be conveniently prepared by heating succinic acid 13 in acetic anhydride at 130°C overnight.
- the amine 7 can be prepared in the following manner.
- the mono-carboxylic acid 2 can be esterified with acidic methanol to provide 14.
- the bromide can be converted to the borane pinacol ester 15 using bis(pinacolato)diboron under palladium catalysis. Suzuki coupling with appropriately substituted bromothiazole 16 results in ester 17. Saponification followed by treatment with diphenylphosphoryl azide (DPP A) in t-BuOH promoted Curtius type rearrangement. Subsequent cleavage of the resultant t-butyl carbamate provides 7.
- DPP A diphenylphosphoryl azide
- the triflate derived from 6-chloroisoquinolin-3-ol (24) can be converted to nitrile 25 using zinc cyanide under palladium catalysis. Palladium catalyzed amidation with tert-butyl carbamate (26) gives rise to 27. The nitrile can be then reacted with ammonium sulfide to provide thioamide 28. Heating with bromide 5 induces cyclization to thiazole 29 with concomitant loss of the tert-butyl carbamate. Mild heating with succinic anhydride 8 in chloroform provides the acid 30 in a regioselective manner.
- 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.
- the yellow reaction mixture was heated at 50°C for 1 h then at 100°C for 1 h during which time a dark maroon color was observed.
- the reaction was cooled to room temperature and diluted with water then extracted with EtOAc.
- the combined organics were washed with sat'd NaHCC>3 and water then dried over MgS0 4 and concentrated.
- the crude residue was absorbed on silica gel and purified by chromatography (20% to 30% EtOAc/hexanes) to isolate 676 mg (85%) of 2-(3,6-dihydro-2H-pyran-4-yl)-succinic acid dimethyl ester as a light yellow oil.
- 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.
- reaction mixture was stirred at 90°C for 6 h then cooled to room temperature overnight, quenched with water and extracted with EtOAc (3x). The combined organics were dried over MgS0 4 and concentrated to an orange oil. The residue was dissolved in THF (5 ml) and 1.0 M aqueous HC1 (1.5 ml) was added. The reaction mixture was stirred at room temperature for 1 h then made basic with 10% aqueous NaOH and extracted with EtOAc (2x). The combined organics were dried over MgS0 4 and concentrated.
- reaction mixture was cooled to room temperature and diluted with EtOAc, then washed with water and brine, dried (MgS0 4 ) 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.
- N-[7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-pyridin-3- yl-succinamic acid benzyl ester 90% pure, 197 mg, 0.32 mmol
- the flask was three times alternatingly evacuated and flushed with argon. 20% Palladium hydroxide on carbon (wet, 45 mg, 0.064 mmol) was carefully added.
- the flask was evacuated and flushed with argon, then evacuated and flushed with hydrogen.
- the reaction mixture was stirred under hydrogen atmosphere (balloon) at room temperature overnight.
- Tetrakis(triphenylphosphine)palladium (0) (389 mg, 0.34 mmol) was added and the solution degassed with argon for 2 min. The vial was sealed and the suspension was heated under microwave irradiation at 110°C for 30 min and then again at 110°C for 60 min. After cooling the reaction was diluted with diethyl ether and washed with water (3x). The aqueous layer was back extracted with diethyl ether. The combined organics were washed with brine, dried over MgS0 4 and concentrated. The residue was triturated 3x with diethyl ether to afford 620 mg (49%) of 6- chloro-isoquinoline-3-carbonitrile as a yellow solid.
- the Cell-Based Proteasome subunit activity/selectivity assay was a panel of 5 fluorogenic assays that independently measured the activity of ⁇ 5 ⁇ or ⁇ 5i (chymotrypsin-like activity), ⁇ 2c/2i (trypsin-like), and ⁇ lc or ⁇ li (caspase-like) protease activity associated with the proteasome complex in cultured cells.
- the following substrates were used for respective subunit activities: ⁇ li: ( PAI .hRh l 10.
- ⁇ lc ( 1.1.1 ⁇ ) Kh l 10.
- This cell-based proteasome activity assay was similar to previous Ramos cell-based assay as of the substrates, but using human PBMCs in the context of complete RPMI with 10 % FBS as reaction buffer. This assay was designed to assess the level of cellular penetration of test compounds in primary human cells. The following procedure was followed: Fresh isolated PBMC from healthy donor were plated at lxl 0 5 cells/well in 100 ⁇ of complete RPMI with 10% FBS in V bottom 96 plates. Added 1 ⁇ of 100X 4-fold serial diluted compounds /well and incubated for 1 hr. The highest compound concentration tested was 20 ⁇ (100X working stock start with 2 mM). Spun down the cells @ 2000rpm for 5 min. Removed all supernatant. Then resuspended the cells in 25 ⁇ DPBS and transferred the cells to a fresh half-area plate
- PBMC IP- 10 Assay PBMCs were isolated from whole blood as follows: Blood was collected in a sterile environment in heparinized tubes. Blood was diluted with an equal volume PBS/2% FCS and 30 ml of this mixture was 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, was removed by Pasteur pipet.
- Ic50:ramos Ic50:ramos: Ic50:ramos: Ic50:ramos:
- Ic50:ramos Ic50:ramos: Ic50:ramos: Ic50:ramos:
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.
Back2round 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):
Pv1 is C3-8 cycloalkyl, heterocycloalkyl, dioxo-substituted heterocycloalkyl, aryl or heteroaryl;
R2 is hydrogen, Ci_7 alkyl, C3_s cycloalkyl, heterocycloalkyl, aryl, aryl substituted with Ci_7 alkoxy, benzyl or heteroaryl; 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. n 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" refers to an aliphatic straight-chain or branched-chain saturated hydrocarbon moiety having 1 to 20 carbon atoms. In particular embodiments the alkyl has 1 to 10 carbon atoms.
The term "lower alkyl" refers to an alkyl moiety having 1 to 7 carbon atoms. In particular embodiments the lower alkyl has 1 to 4 carbon atoms and in other particular embodiments the lower alkyl has 1 to 3 carbon atoms. Examples of lower alkyls include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and ieri-butyl. Particular example of C1-7 alkyl is butyl. 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 C1-7 alkoxy is methoxy.
"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, 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.
Unless otherwise indicated, the term "hydrogen" or "hydro" refers to the moiety of a hydrogen atom (-H) and not ¾.
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 examples of cycloalkyl are cyclobutyl 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, 1 , 1 -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,
tetrahydrothiophenyl, and tetrahydropyranyl.
The term "heteroaryl" denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl. Particular example of heteroaryl are pyridinyl and pyrazinyl.
The term "thiophenyl" is synonymous with "thiofuranyl" and "thienyl" and denotes a thiophene substituent.
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 "λη", 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 λη symbol is cited immediately after this locant.
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-acetylcy stein 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 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.
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).
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 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):
X and Y, independently of each other, are CH or nitrogen; R1 is C3_8 cycloalkyl, heterocycloalkyl, dioxo-substituted heterocycloalkyl, aryl or heteroaryl;
R2 is hydrogen, C1-7 alkyl, C3-8 cycloalkyl, heterocycloalkyl, aryl, aryl substituted with C1-7 alkoxy, benzyl or heteroaryl; or a pharmaceutically acceptable salt or ester thereof.
In another embodiment, the present invention provides for compounds of formula (I) wherein:
X and Y, independently of each other, are CH or nitrogen;
R1 is cyclobutyl, tetrahydrofuranyl, dioxotetrahydrothiophenyl, pyrazinyl or phenyl;
R2 is hydrogen, cyclohexyl, tetrahydropyranyl, pyridinyl, Ci_7 alkyl, benzyl, phenyl or phenyl substituted with C1-7 alkoxy;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides for compounds of formula (I) wherein both X and Y are CH.
In another embodiment, the present invention provides for compounds of formula (I) wherein one of X or Y is CH and the other is nitrogen. In another embodiment, the present invention provides for compounds of formula (I) wherein one of X is CH and Y is nitrogen.
In another embodiment, the present invention provides for compounds of formula (I) wherein R1 is cyclobutyl or phenyl.
In another embodiment, the present invention provides for compounds of formula (I) wherein R1 is cyclobutyl.
In another embodiment, the present invention provides for compounds of formula (I) wherein R1 is phenyl.
In another embodiment, the present invention provides for compounds of formula (I) wherein R1 is tetrahydrofuranyl, dioxotetrahydrothiophenyl or pyrazinyl.
In another embodiment, the present invention provides for compounds of formula (I) wherein R2 is hydrogen, cyclohexyl, tetrahydropyranyl, pyridinyl, butyl, benzyl, phenyl or phenyl substituted with methoxy.
In another embodiment, the present invention provides for compounds of formula (I) wherein R2 is cyclohexyl, tetrahydropyranyl or phenyl.
In another embodiment, the present invention provides for compounds of formula (I) wherein R2 is cyclohexyl. In another embodiment, the present invention provides for compounds of formula (I) wherein R2 is phenyl.
In another embodiment, the present invention provides for compounds of formula (I) wherein R2 is pyridinyl or benzyl.
In another embodiment, the present invention provides for compounds of formula (I) wherein R2 is C1-7 alkyl.
In another embodiment, the present invention provides for compounds of formula (I) wherein the compound is:
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid;
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid;
(R)-N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid;
(S)-N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid;
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-phenyl-succinamic acid;
2-Benzyl-N-[7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid;
2-{ [7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-ylcarbamoyl]-methyl}-hexanoic acid;
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-(4-methoxy-phenyl)-succinamic acid;
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-(tetrahydro-pyran-4-yl)-succinamic acid;
2-Cyclohexyl-N-{7-[4-(tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalen-2-yl}-succinamic acid;
N-{7-[4-(Tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalen-2-yl}-2-(tetrahydro-pyran-4-yl)- succinamic acid;
2-Cyclohexyl-N- { 7-[4-( 1 , 1 -dioxo-tetrahydro- 1 6-thiophen-3-yl)-thiazol-2-yl]-naphthalen-2-yl } - succinamic acid;
N-{7-[4-(l,l-Dioxo-tetrahydro 6-miophen-3-yl) hiazol-2-yl]-naphthalen-2-yl}-2-(tetrahydro- pyran-4-yl)-succinamic acid;
N-[7-(4-Pyrazin-2-yl-thiazol-2-yl)-naphthalen-2-yl]-2-(tetrahydro-pyran-4-yl)-succinamic acid;
2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid;
(R)- 2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid;
(S)- 2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid;
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-pyridin-3-yl-succinamic acid;
2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-quinolin-2-yl]-succinamic acid; or
N-[3-(4-Cyclobutyl-thiazol-2-yl)-isoquinolin-6-yl]-2-cyclohexyl-succinamic acid.
In another embodiment, the present invention provides for compounds of formula (I) wherein the compound is:
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid;
(S)-N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid;
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-phenyl-succinamic acid;
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-(tetrahydro-pyran-4-yl)-succinamic acid; and
2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-quinolin-2-yl]-succinamic 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 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.
The mono-carboxylic acid 2 can be formed through low temperature transmetallation of 2,7-dibromonaphthalene (1) and quenching of the intermediate organolithium with carbon dioxide. The acid can be then converted to the amide 3 using oxalyl chloride followed by aqueous ammonium hydroxide. Treatment with Lawesson's reagent provided the thioamide 4, which can be reacted with bromide 5 with gentle heating to afford thiazole 6. Palladium catalyzed amination with benzophenone imine and subsequent imine hydrolysis with dilute hydrochloric acid results in the amine 7. Mild heating of amine 7 and succinic anhydride 8 in chloroform provides the acid 9 in a regioselective manner.
Scheme 2
R1
Acid chloride 11 can be prepared from acid 10 using oxalyl chloride. Treatment with trimethylsilyldiazomethane results in the in situ formation of diazo ketone 12 which can be quenched with hydrobromic acid in acetic acid to isolate the bromoketone 5 in good yield and purity.
Scheme 3
In cases where the required succinic anhydride 8 is not commercially available it can be conveniently prepared by heating succinic acid 13 in acetic anhydride at 130°C overnight.
Scheme 4
17
Alternatively, the amine 7 can be prepared in the following manner. The mono-carboxylic acid 2 can be esterified with acidic methanol to provide 14. The bromide can be converted to the borane pinacol ester 15 using bis(pinacolato)diboron under palladium catalysis. Suzuki coupling with appropriately substituted bromothiazole 16 results in ester 17. Saponification followed by treatment with diphenylphosphoryl azide (DPP A) in t-BuOH promoted Curtius type rearrangement. Subsequent cleavage of the resultant t-butyl carbamate provides 7.
Scheme 5
23
7-Bromo-lH-quinolin-2-one (18) can be converted to the borane pinacol ester 19 using bis(pinacolato)diboron under palladium catalysis. Suzuki coupling with appropriately substituted bromothiazole 16 results in ester 20. Heating with phosphorous oxychloride provides chloroquinoline 21. Palladium catalyzed amination with benzophenone imine and subsequent imine hydrolysis with dilute hydrochloric acid results in the amine 22. Mild heating of amine 22 and succinic anhydride 8 in chloroform provides the acid 23 in a regioselective manner.
Scheme 6
The triflate derived from 6-chloroisoquinolin-3-ol (24) can be converted to nitrile 25 using zinc cyanide under palladium catalysis. Palladium catalyzed amidation with tert-butyl carbamate (26) gives rise to 27. The nitrile can be then reacted with ammonium sulfide to provide thioamide 28. Heating with bromide 5 induces cyclization to thiazole 29 with concomitant loss of the tert-butyl carbamate. Mild heating with succinic anhydride 8 in chloroform provides the acid 30 in a regioselective manner.
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.
Intermediate 1
7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-ylamine
Step 1
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 dropwise. 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% Na2S2C>3 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- 1-cyclobutylethanone as a yellow oil which was used without further purification.
Step 2
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 dropwise. 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. *H 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 3
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. *H 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 4
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. *H 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 5
In a 50 ml round-bottomed flask, 7-bromo-naphthalene-2-carbothioic acid amide (1.20 g, 4.51 mmol) and 2-bromo-l-cyclobutylethanone (1.00 g, 5.65 mmol) were suspended in 9 ml ethanol. The suspension was heated at reflux for 2 h then cooled to room temperature overnight 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 petroleum ether and a minimal amount of diethyl ether to afford 1.1 g (71 %) of 2-(7-bromo-naphthalen-2-yl)-4-cyclobutyl-thiazole as a light brown solid. LCMS: (M+H)+ = 344/346; *H NMR (300 MHz, CDC13) δ: 8.36 (s, 1H), 8.10 (td, J = 4.2, 1.7 Hz, 2H), 7.86 (d, J = 8.3 Hz, 1H), 7.69 - 7.77 (m, 1H), 7.58 (dd, J = 8.7, 1.9 Hz, 1H), 6.99 (s, 1H), 3.78 (quin, J = 8.5 Hz, 1H), 2.28 - 2.51 (m, 4H), 1.91 - 2.17 (m, 2H).
Step 6
A 25 ml round-bottomed flask was charged with 2-(7-bromo-naphthalen-2-yl)-4-cyclobutyl- thiazole hydrobromide (677 mg, 1.59 mmol), (R)-BINAP (40 mg, 0.064 mmol), sodium tert- butoxide (367 mg, 3.82 mmol) and tris(dibenzylideneacetone)dipalladium (0) (30 mg, 0.033 mmol). Then added 7.5 ml toluene followed by benzophenone imine (335 mg, 0.31 ml, 1.85 mmol). The reaction mixture was stirred at 90°C overnight then cooled to room temperature, quenched with water and extracted twice with diethyl ether. The organic layers were washed with brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 15 ml THF and 5 ml 1M HCl was added. After stirring at room temperature for 3 h, the reaction mixture was basified with 10% aqueous NaOH to pH=~10 and extracted twice with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed over 12g silica gel with
EtOAc/hexanes (gradient: 0-30% EtOAc). All fractions containing product were combined and concentrated. The residue was triturated with a small amount of hexanes/EtOAc (1 :9) to afford 338 mg (76%) of 7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ylamine as a light brown solid. LC/MS: (M+H)+ = 281 ; *H NMR (300 MHz, CDC13) δ: 8.28 (s, 1H), 7.80 - 7.86 (m, 1H), 7.72 - 7.77 (m, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 7.02 (dd, J = 8.7, 2.3 Hz, 1H), 6.96 (s, 1H), 3.81 (quin, J = 8.5 Hz, 1H), 2.28 - 2.57 (m, 4H), 1.91 - 2.20 (m, 2H).
Example 1
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid
In a 10 ml round-bottomed flask, 7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ylamine (30 mg, 0.107 mmol) was dissolved in 1 ml dichloromethane. Triethylamine (0.03 ml, 0.22 mmol) was added followed by succinic anhydride (11 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 2 h, at 50°C for 2h and at room temperature overnight. The reaction mixture was quenched with saturated NH4C1 solution and extracted twice with ethyl acetate. 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 chromatographed over 4 g silica gel with EtOAc/hexanes (gradient: 0-100% EtOAc). All fractions containing product were combined and concentrated to afford 16 mg (34%) of N-[7-(4-cyclobutyl-thiazol-2-yl)- naphthalen-2-yl]-succinamic acid as a light yellow solid. The isolated product contained -20% succinic acid as an impurity as judged by NMR. LC/MS: (M+H)+ = 381 ; *H NMR (400 MHz, DMSO-d6) δ: 12.18 (br. s., 1H), 10.26 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.88 - 7.98 (m, 3H), 7.63 (dd, J = 9.0, 1.9 Hz, 1H), 7.43 (d, J = 0.8 Hz, 1H), 3.66 - 3.77 (m, 1H), 2.62 - 2.69 (m, 2H), 2.55 - 2.61 (m, 2H), 2.26 - 2.38 (m, 4H), 1.98 - 2.07 (m, 1H), 1.88 - 1.97 (m, 1H).
Example 2
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid
Step 1
A partial suspension of 2-cyclohexylsuccinic acid (1.0 g, 4.99 mmol) in acetic anhydride (10 ml, 106 mmol) was heated at 130°C overnight. The reaction was cooled to room temperature, concentrated under reduced pressure, and chased once with toluene. The crude brown oil was triturated with Et20/petroleum ether (1 :5). The resulting precipitate was collected via filtration, rinsed with petroleum ether and dried under high vacuum to afford 808 mg (89%) of 3- cyclohexyldihydrofuran-2,5-dione as a light brown solid.
Step 2
A solution of 7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ylamine (20 mg, 0.07 mmol) and 3- cyclohexyldihydrofuran-2,5-dione (13 mg, 0.07 mmol) in chloroform (1 ml) was heated at 65 °C for 30 min then cooled to room temperature and diluted with dichloromethane. The precipitate was collected via filtration, washed with dichloromethane and dried under high vacuum to afford 16 mg (49%) of N-[7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid as a white powder. LC/MS: (M+H)+ = 463; *H NMR (400 MHz, DMSO-d6) δ: 12.15 (br. s., 1H), 10.28 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.34 (s, 1H), 7.87 - 7.96 (m, 3H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.43 (d, J = 0.8 Hz, 1H), 3.72 (quin, J = 8.5 Hz, 1H), 2.67 - 2.77 (m, 2H), 2.53 - 2.60 (m, 1H), 2.25 - 2.39 (m, 4H), 1.98 - 2.10 (m, 1H), 1.87 - 1.98 (m, 1H), 1.58 - 1.79 (m, 6H), 1.03 - 1.31 (m, 5H).
Examples 3 & 4
(R)-N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid and (S)-N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid
A sample of N-[7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid (268 mg, 0.58 mmol) was subjected to chiral preparative SFC chromatography
[Berger/Waters Multigram II; Chiral Technologies DAICEL IA 3x25 cm column; 60%
MeOH/C02, 60 ml/min, 220 nm] to obtain first 101 mg of (R)-N-[7-(4-cyclobutyl-thiazol-2-yl)- naphthalen-2-yl]-2-cyclohexyl-succinamic acid [LC/MS: (M+H)+ = 463] followed by 91 mg of (S)-N-[7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid [LC/MS: (M+H)+ = 463]. Stereochemical assignments were made based on correlation of biological activity with proposed binding mode as determined by molecular modeling and have not been unequivocally proven.
Example 5
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-phenyl-succinamic acid
A mixture of 7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ylamine (100 mg, 0.36 mmol) and 3-phenyl-dihydro-furan-2,5-dione (69 mg, 0.39 mmol) in chloroform (6 ml) was stirred at 65 °C for 16 h then cooled to room temperature. The precipitate was collected via filtration, washed with dichloromethane and dried. The crude solid was recrystallized from MeOH/EtOH (1 : 1) to obtain 20 mg (12%) of N-[7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-phenyl-succinamic acid as a white powder. LC/MS: (M+H)+ = 457; *H NMR (400 MHz, DMSO-d6) δ: 12.49 (br. s., 1H), 10.33 (br. s., 1H), 8.41 (s, 1H), 8.35 (s, 1H), 7.87 - 8.01 (m, 2H), 7.60 (dd, J = 8.8, 2.0 Hz, 1H), 7.44 (s, 1H), 7.33 - 7.40 (m, 4H), 7.29 (td, J = 5.3, 3.4 Hz, 1H), 4.09 (dd, J = 9.7, 5.4 Hz,
1H), 3.72 (quin, J = 8.5 Hz, 1H), 3.19 (dd, J = 15.9, 9.7 Hz, 1H), 2.79 (dd, J = 15.9, 5.4 Hz, 1H), 2.24 - 2.41 (m, 4H), 1.98 - 2.08 (m, 1H), 1.87 - 1.98 (m, 1H).
Example 6
2-Benzyl-N-[7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid
A mixture of 7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ylamine (100 mg, 0.36 mmol) and 3-benzyldihydrofuran-2,5-dione (81 mg, 0.43 mmol) in chloroform (6 ml) was stirred at 65°C for 1 h then cooled to room temperature. The precipitate was collected via filtration, washed with dichloromethane and dried under high vacuum to obtain 102 mg (61%) of 2-benzyl-N-[7-(4- cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid as an off-white powder . NMR analysis showed presence of -20% of the 1 -benzyl regioisomer. LC/MS: (M+H)+ = 471; *H NMR (400 MHz, DMSO-d6) δ: 12.35 (br. s., 1H), 10.29 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 7.87 - 7.98 (m, 3H), 7.60 (dd, J = 9.0, 1.8 Hz, 1H), 7.43 (s, 1H), 7.18 - 7.37 (m, 5H), 3.72 (quin, J = 8.5 Hz, 1H), 3.13 (dd, J = 8.7, 5.1 Hz, 1H), 2.99 (dd, J = 13.7, 6.7 Hz, 1H), 2.80 - 2.90 (m, 1H), 2.63 - 2.74 (m, 1H), 2.43 - 2.48 (m, 1H), 2.24 - 2.40 (m, 4H), 1.98 - 2.10 (m, 1H), 1.88 - 1.97 (m, 1H).
Example 7
2-{[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-ylcarbamoyl]-methyl}-hexanoic acid
A mixture of 7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ylamine (100 mg, 0.36 mmol) and 3-butyldihydrofuran-2,5-dione (67 mg, 0.43 mmol) in chloroform (6 ml) was stirred at 65 °C for 1 h then cooled to room temperature. The precipitate was collected via filtration, washed with dichloromethane and dried under high vacuum to obtain 92 mg (59%) of 2-{ [7-(4-cyclobutyl- thiazol-2-yl)-naphthalen-2-ylcarbamoyl] -methyl }-hexanoic acid as an off-white powder. LC/MS:
(M+H)+ = 437; *H NMR (400 MHz, DMSO-d6) δ: 12.24 (br. s., 1H), 10.28 (s, 1H), 8.42 (d, J = 1.5 Hz, 1H), 8.35 (s, 1H), 7.88 - 7.97 (m, 3H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.43 (d, J = 0.5 Hz, 1H), 3.72 (quin, J = 8.5 Hz, 1H), 2.67 - 2.86 (m, 2H), 2.50 - 2.57 (m, 1H), 2.27 - 2.40 (m, 4H), 1.98 - 2.09 (m, 1H), 1.87 - 1.97 (m, 1H), 1.46 - 1.66 (m, 2H), 1.26 - 1.36 (m, 4H), 0.84 - 0.92 (m, 3H).
Example 8
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-(4-methoxy-phenyl)-succinamic acid
A partial suspension of 2-(4-methoxyphenyl)succinic acid (0.50 g, 2.23 mmol) in acetic anhydride (5 ml, 53 mmol) was heated at 130°C overnight. The reaction was cooled to room temperature, concentrated under reduced pressure, and chased once with toluene. The resultant maroon-brown oil gradually solidified upon standing to provide 480 mg of 3-(4- methoxyphenyl)dihydrofuran-2,5-dione which was used without further purification.
Step 2
A mixture of 7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ylamine (100 mg, 0.36 mmol) and 3-(4- methoxyphenyl)dihydrofuran-2,5-dione (88 mg, 0.43 mmol) in chloroform (6 ml) was stirred at 65 °C for 18 h. Additional 3-(4-methoxyphenyl)dihydrofuran-2,5-dione (88 mg, 0.43 mmol) was added and stirring was continued at 65 °C for 16 h. The reaction mixture was cooled to room temperature. The precipitate was collected via filtration, rinsed with dichloromethane, and dried. The crude solid was recrystallized from MeOH/EtOH (1:1) to obtain 41 mg (24%) of N-[7-(4- cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-(4-methoxy-phenyl)-succinamic acid as an off-white powder. LC/MS: (M+H)+ = 487; *H NMR (400 MHz, DMSO-d6) δ: 12.39 (br. s., 1H), 10.30 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 7.87 - 8.00 (m, 3H), 7.60 (dd, J = 8.9, 1.9 Hz, 1H), 7.44 (s, 1H), 7.27 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 4.03 (dd, J = 9.7, 5.5 Hz, 1H), 3.74 (s, 3H), 3.72 (quin, J = 8.5 Hz, 1H), 3.15 (dd, J = 15.9, 9.7 Hz, 1H), 2.75 (dd, J = 15.9, 5.5 Hz, 1H), 2.24 - 2.41 (m, 4H), 1.98 - 2.08 (m, 1H), 1.87 - 1.98 (m, 1H).
Example 9
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-(tetrahydro-pyran-4-yl)- succinamic acid
A 50 ml round bottomed flask was charged with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (1.02 g, 4.86 mmol), sodium bicarbonate (146 mg, 1.73 mmol), and chloro(l,5-cyclooctadiene)rhodium (I) dimer (68 mg, 0.14 mmol). Then added 1,4-dioxane (10 ml) and water (1.7 ml). Most solids dissolved into an orange solution. The reaction mixture was stirred at room temperature for 15 min then dimethyl fumarate (500 mg, 3.47 mmol) was added. The yellow reaction mixture was heated at 50°C for 1 h then at 100°C for 1 h during which time a dark maroon color was observed. The reaction was cooled to room temperature and diluted with water then extracted with EtOAc. The combined organics were washed with sat'd NaHCC>3 and water then dried over MgS04 and concentrated. The crude residue was absorbed on silica gel and purified by chromatography (20% to 30% EtOAc/hexanes) to isolate 676 mg (85%) of 2-(3,6-dihydro-2H-pyran-4-yl)-succinic acid dimethyl ester as a light yellow oil. 1H NMR (300 MHz, CDC13) δ: 5.65 (dd, J = 2.6, 1.5 Hz, 1H), 4.07 - 4.20 (m, 2H), 3.73 - 3.82 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 3.50 (dd, J = 9.8, 5.7 Hz, 1H), 2.95 (dd, J = 16.6, 9.8 Hz, 1H), 2.52 (dd, J = 16.6, 5.7 Hz, 1H), 1.97 - 2.24 (m, 2H). Step 2
To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-succinic acid dimethyl ester (670 mg, 2.94 mmol) in MeOH (15 ml) was added 10% palladium on carbon (100 mg, 0.09 mmol). The reaction was stirred under an atmosphere of ¾ (balloon) overnight then filtered over Celite, rinsing with EtOAc. The filtrate was concentrated to a grey oil which was dissolved in
EtOAc/MeOH and filtered through a 0.45 uM fritted disk, rinsing with EtOAc/MeOH. The filtrate was concentrated to afford 650 mg (96%) of 2-(tetrahydro-pyran-4-yl)-succinic acid dimethyl ester as a colorless oil.
Step 3
To a solution of 2-(tetrahydro-pyran-4-yl)-succinic acid dimethyl ester (650 mg, 2.82 mmol) in MeOH (8 ml) was added 10% aqueous sodium hydroxide (8 ml, 20.0 mmol). The reaction
mixture was heated at 50°C for 2 h then cooled to room temperature and concentrated. The aqueous residue was cooled to 0°C and neutralized first with cone. HC1 followed by 1.0 M HC1. The mixture was extracted with Et20/EtOAc (3x). The combined organic s were dried over MgS04 and concentrated to afford 424 mg (74%) of 2-(tetrahydro-pyran-4-yl)-succinic acid as a white solid.
Step 4
A partial suspension of 2-(tetrahydro-2H-pyran-4-yl)succinic acid (420 mg, 2.08 mmol) in acetic anhydride (5 ml, 53 mmol) was heated at 130°C overnight. The reaction was cooled to room temperature, concentrated under reduced pressure, and chased once with toluene to give 404 mg of 3-(tetrahydro-pyran-4-yl)-dihydrofuran-2,5-dione as a brown oil which was used without further purification.
Step 5
A solution of 7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ylamine (91 mg, 0.33 mmol) and 3- (tetrahydro-pyran-4-yl)-dihydrofuran-2,5-dione (60 mg, 0.33 mmol) in chloroform (2 ml) was heated at 65°C for 30 min. A thick precipitate had formed. The reaction was cooled to room temperature and the precipitate was collected via filtration, rinsed with a small amount of CH2Cl2/hexanes and dried under high vacuum to afford 87 mg (58%) of N-[7-(4-cyclobutyl- thiazol-2-yl)-naphthalen-2-yl]-2-(tetrahydro-pyran-4-yl)-succinamic acid as a beige solid.
LC/MS: (M+H)+ = 465; *H NMR (300 MHz, DMSO-d6) δ: 12.25 (br. s., 1H), 10.27 (br. s., 1H), 8.39 (s, 1H), 8.33 (s, 1H), 7.84 - 7.95 (m, 3H), 7.60 (dd, J = 9.1, 1.9 Hz, 1H), 7.41 (s, 1H), 3.82 - 3.90 (m, 2H), 3.69 (quin, J = 8.5 Hz, 1H), 3.21 - 3.29 (m, 2H), 2.54 - 2.77 (m, 3H), 2.22 - 2.38 (m, 4H), 1.74 - 2.07 (m, 3H), 1.46 - 1.57 (m, 2H), 1.26 - 1.42 (m, 2H).
Example 10
2-Cyclohexyl-N-{7-[4-(tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalen-2-yl}- succinamic 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. *H 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.
Step 3
A 10 ml round-bottomed flask was charged with 2-(7-bromo-naphthalen-2-yl)-4-(tetrahydro- furan-3-yl)-thiazole (358 mg, 0.99 mmol), (R)-BINAP (25 mg, 0.04 mmol), sodium tert-butoxide (134 mg, 1.39 mmol) and tris(dibenzylideneacetone)dipalladium (0) (19 mg, 0.02 mmol). Then added 4.6 ml toluene followed by benzophenone imine (205 mg, 0.19 ml, 1.13 mmol). The reaction mixture was stirred at 90°C overnight then cooled to room temperature, quenched with water and extracted twice with diethyl ether. The organic layers were washed with brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 10 ml THF and 3.3 ml 1M HC1 was added. After stirring at room temperature for 3 h, the reaction mixture was basified with 10% aqueous NaOH to pH=~10 and extracted twice with EtOAc. 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: 0-40% EtOAc). All fractions containing product were combined and concentrated to afford 187 mg (64%) of 7-[4-(tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalen-2-ylamine as an orange solid.
Step 4
In a 10 ml round-bottomed flask, 7-[4-(tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalen-2- ylamine (60 mg, 0.20 mmol) and 3-cyclohexyldihydrofuran-2,5-dione (37 mg, 0.20 mmol) were suspended in 2 ml chloroform. The reaction mixture was stirred at 65 °C for 30 min. All solids dissolved and then a new precipitate was formed. The reaction mixture was cooled to room temperature and the precipitate was collected via filtration, rinsed with a small amount of dichloromethane and dried under high vacuum to afford 61 mg (63%) of 2-cyclohexyl-N-{7-[4- (tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalen-2-yl}-succinamic acid as an off-white solid. LC/MS: (M-H)" = 477; *H NMR (400 MHz, DMSO-d6) δ: 12.13 (s, 1H), 10.24 (s, 1H), 8.41 (d, J = 1.5 Hz, 1H), 8.35 (s, 1H), 7.94 (d, J = 1.5 Hz, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.52 (d, J = 0.8 Hz, 1H), 4.09 (t, J = 7.9 Hz, 1H), 3.95 (td, J = 7.9, 5.3 Hz, 1H), 3.76 - 3.88 (m, 2H), 3.65 (quin, J = 7.5 Hz, 1H), 2.66 - 2.74 (m, 2H), 2.53 - 2.59 (m, 1H), 2.27 - 2.38 (m, 1H), 2.13 - 2.24 (m, 1H), 1.56 - 1.78 (m, 6H), 1.02 - 1.32 (m, 5H).
Example 11
N-{7-[4-(Tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalen-2-yl}-2-(tetrahydro-pyran-
4-yl)-succinamic acid
In a 10 ml round-bottomed flask, 7-[4-(tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalen-2- ylamine (60 mg, 0.20 mmol) and 3-(tetrahydro-pyran-4-yl)-dihydrofuran-2,5-dione (38 mg, 0.20 mmol) were suspended in 2 ml chloroform. The reaction mixture was stirred at 65 °C for 1 h. All solids dissolved and then a new precipitate was formed. The reaction mixture was cooled to room temperature and the precipitate was collected via filtration, rinsed with a small amount of dichloromethane and dried under high vacuum to afford 70 mg (68%) of N-{7-[4-(tetrahydro- furan-3-yl)-thiazol-2-yl]-naphthalen-2-yl}-2-(tetrahydro-pyran-4-yl)-succinamic acid as an off- white solid. LC/MS: (M-H)" = 479; *H NMR (400 MHz, DMSO-d6) δ: 12.26 (br. s., 1H), 10.27 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.35 (s, 1H), 7.94 (d, J = 1.0 Hz, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 8.8, 1.8 Hz, 1H), 7.52 (d, J = 0.8 Hz, 1H), 4.09 (t, J = 7.7 Hz, 1H), 3.95 (td, J = 8.1, 5.3 Hz, 1H), 3.76 - 3.91 (m, 4H), 3.65 (quin, J = 7.5 Hz, 1H), 3.25 - 3.32 (m, 2H), 2.67 - 2.79 (m, 2H), 2.57 - 2.65 (m, 1H), 2.27 - 2.38 (m, 1H), 2.15 - 2.24 (m, 1H), 1.84 (br. s., 1H), 1.48 - 1.60 (m, 2H), 1.30 - 1.44 (m, 2H).
Example 12.
2-C clohex l-N-{7-[4-(l,l-dioxo-tetrah dro-lλ6-thiophen-3- l)-thiazol-2- l]- naphthalen-2-yl}-succinamic acid
Step 1
In a 50 ml round-bottomed flask, l,l-dioxo-tetrahydro-l 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-l 6-thiophen-3-yl)-ethanone as a yellow solid. *H 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 25 ml round-bottomed flask, 7-bromo-naphthalene-2-carbothioic acid amide (300 mg, 1.13 mmol) and 2-bromo-l-(l ,l-dioxo-tetrahydro-l 6-thiophen-3-yl)-ethanone (332 mg, 1.24 mmol) were suspended in 4.8 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 435 mg (79%) of 2-(7- bromo-naphthalen-2-yl)-4-(l ,l-dioxo-tetrahydro-l 6-thiophen-3-yl)-thiazole hydrobromide as a light yellow powder.
Ste 3
A 25 ml round-bottomed flask was charged with 2-(7-bromo-naphthalen-2-yl)-4-(l ,l-dioxo- tetrahydro-l 6-thiophen-3-yl)-thiazole hydrobromide (432 mg, 0.88 mmol), (R)-BINAP (23 mg, 0.04 mmol), sodium tert-butoxide (204 mg, 2.12 mmol) and tris(dibenzylideneacetone) dipalladium (0) (17 mg, 0.02 mmol). Then added 4.2 ml toluene followed by benzophenone imine (184 mg, 0.17 ml, 1.01 mmol). The reaction mixture was stirred at 90°C overnight then cooled to room temperature, quenched with water and extracted twice with diethyl ether. The organic layers were washed with brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 9 ml THF and 3 ml 1M HCl was added. After stirring at room temperature for 2.5 h, the reaction mixture was basified with 10% aqueous NaOH to pH=~10 and extracted twice with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was suspended in dichloromethane and water. The suspension was filtered, rinsing with dichloromethane and water. The collected precipitate was dried under high vacuum to afford 232 mg (76%) of 7-[4-(l,l-dioxo-tetrahydro-l 6-thiophen-3- yl)-thiazol-2-yl]-naphthalen-2-ylamine as a light brown solid.
Step 4
In a 10 ml round-bottomed flask, 7-[4-(l ,l-dioxo-tetrahydro-l 6-thiophen-3-yl)-thiazol-2-yl]- naphthalen-2-ylamine (60 mg, 0.17 mmol) and 3-cyclohexyldihydrofuran-2,5-dione (32 mg, 0.17 mmol) were suspended in 1.8 ml chloroform. The reaction mixture was stirred at 65 °C for 2h. The reaction mixture was cooled to room temperature and the precipitate was collected via filtration, rinsed with a small amount of dichloromethane and dried under high vacuum to afford 68 mg (70%) of 2-cyclohexyl-N-{7-[4-(l ,l-dioxo-tetrahydro-R6-thiophen-3-yl)-thiazol-2-yl]- naphthalen-2-yl}-succinamic acid as an off-white solid. LC/MS: (M-H)" = 525; !H NMR (400 MHz, DMSO-d6) δ: 12.16 (br. s., 1H), 10.31 (br. s., 1H), 8.42 (d, J = 1.8 Hz, 1H), 8.38 (s, 1H), 7.95 (d, J = 1.3 Hz, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 0.8 Hz, 1H), 7.62 (dd, J = 8.8, 1.8 Hz, 1H), 3.84 - 3.97 (m, 1H), 3.62 (dd, J = 13.3, 7.7 Hz, 1H), 3.34 - 3.43 (m, 2H), 3.19 - 3.30 (m, 1H), 2.66 - 2.77 (m, 2H), 2.46 - 2.64 (m, 2H), 2.30 - 2.44 (m, 1H), 1.55 - 1.80 (m, 6H), 1.00 - 1.30 (m, 5H).
Example 13
N-{7-[4-(l,l-Dioxo-tetrah dro-lλ6-thiophen-3- l)-thiazol-2- l]-naphthalen-2- l}-2- (tetrahydro-pyran-4-yl)-succinamic acid
In a 10 ml round-bottomed flask, 7-[4-(l ,l-dioxo-tetrahydro-l 6-thiophen-3-yl)-thiazol-2- yl]-naphthalen-2-ylamine (60 mg, 0.17 mmol) and 3-(tetrahydro-pyran-4-yl)-dihydrofuran-2,5- dione (33 mg, 0.17 mmol) were suspended in 1.8 ml chloroform. The reaction mixture was stirred at 65 °C for 2 h. The reaction mixture was cooled to room temperature and the precipitate was collected via filtration, rinsed with a small amount of dichloromethane and dried under high vacuum to afford 72 mg (74%) of N-{7-[4-(l ,l-dioxo-tetrahydro- 6-thiophen-3-yl)-thiazol-2- yl]-naphthalen-2-yl}-2-(tetrahydro-pyran-4-yl)-succinamic acid as a light yellow solid. LC/MS: (M-H)" = 527; *H NMR (400 MHz, DMSO-d6) δ: 12.28 (br. s., 1H), 10.30 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 7.95 (d, J = 1.3 Hz, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 0.8 Hz, 1H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 3.83 - 3.98 (m, 3H), 3.62 (dd, J = 13.3, 7.5 Hz, 1H), 3.17 - 3.46 (m, 5H), 2.67 - 2.78 (m, 2H), 2.55 - 2.65 (m, 2H), 2.30 - 2.44 (m, 1H), 1.78 - 1.88 (m, 1H), 1.48 - 1.60 (m, 2H), 1.27 - 1.45 (m, 2H).
Example 14
N-[7-(4-Pyrazin-2-yl-thiazol-2-yl)-naphthalen-2-yl]-2-(tetrahydro-pyran-4-yl)- succinamic acid
Step 1
To a solution of l-(pyrazin-2-yl)ethanone (200 mg, 1.64 mmol) in acetic acid (3 ml) was added
33% HBr in acetic acid (402 mg, 0.30 ml, 1.64 mmol). Then added pyridinium tribromide (576 mg, 1.8 mmol) in one portion which gradually dissolved to give an orange/brown solution. The reaction was stirred at room temperature for 1 h then poured into Et20 (20 mL) and CH3CN (2 ml). A precipitate was formed. The mixture was stirred vigorously at room temperature for 10 min then the solvent was decanted. The precipitate was rinsed/decanted with 10% CH3CN/Et20 three times at which time the supernatent was clear/colorless. The remaining residue was dried under high vacuum to afford 728 mg of a light brown free flowing powder. NMR analysis indicated an approximate 1: 1 mixture of 2-bromo-l-pyrazin-2-yl-ethanone hydrobromide and pyridine hydrobromide. This material was used in the next step without further purification. Step 2
A suspension of 7-bromo-naphthalene-2-carbothioic acid amide (250 mg, 0.94 mmol) and 2- bromo-l-pyrazin-2-yl-ethanone hydrobromide (60% pure, 530 mg, 1.13 mmol) in EtOH (8 ml) was heated at reflux for 1 h. Most solids dissolved and a new yellow -brown precipitate was formed. The reaction was cooled to room temperature and diluted with Et20 (10 ml). The precipitate was collected via filtration, rinsed with Et20 and dried under high vacuum to afford 304 mg (72%) of 2-[2-(7-bromo-naphthalen-2-yl)-thiazol-4-yl]-pyrazine hydrobromide as a yellow-brown solid.
Step 3
A sample of 2-[2-(7-bromo-naphthalen-2-yl)-thiazol-4-yl]-pyrazine hydrobromide was stirred vigorously with aqueous 10% NaOH and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organics were dried over MgS04 and concentrated to afford 2-[2-(7-bromo-naphthalen-2-yl)-thiazol-4-yl]-pyrazine (free base).
A 10 ml round-bottomed flask was charged with 2-[2-(7-bromo-naphthalen-2-yl)-thiazol- 4-yl]-pyrazine (110 mg, 0.30 mmol), (R)-BINAP (26 mg, 0.04 mmol), sodium tert-butoxide (69 mg, 0.72 mmol) and tris(dibenzylideneacetone)dipalladium (0) (19 mg, 0.02 mmol). Then added toluene (3 ml) followed by benzophenone imine (60 mg, 0.055 ml, 0.33 mmol). The reaction mixture was stirred at 90°C for 6 h then cooled to room temperature overnight, quenched with water and extracted with EtOAc (3x). The combined organics were dried over MgS04 and concentrated to an orange oil. The residue was dissolved in THF (5 ml) and 1.0 M aqueous HC1 (1.5 ml) was added. The reaction mixture was stirred at room temperature for 1 h then made basic with 10% aqueous NaOH and extracted with EtOAc (2x). The combined organics were dried over MgS04 and concentrated. The residue was purified by silica gel chromatography with 50% to 75% EtOAc/hexanes to afford 55 mg (61%) of 7-(4-pyrazin-2-yl-thiazol-2-yl)- naphthalen-2-ylamine as a yellow solid. Step 4
A solution of 7-(4-pyrazin-2-yl-thiazol-2-yl)-naphthalen-2-ylamine (54 mg, 0.18 mmol) and 3-
(tetrahydro-pyran-4-yl)-dihydrofuran-2,5-dione (33 mg, 0.17 mmol) in chloroform (2.5 ml) was heated at 65 °C for 1 h. The reaction mixture was cooled to room temperature and the precipitate was collected via filtration, rinsed with a small amount of dichloromethane/hexanes and dried under high vacuum to afford 70 mg (81%) of N-[7-(4-pyrazin-2-yl-thiazol-2-yl)-naphthalen-2- yl]-2-(tetrahydro-pyran-4-yl)-succinamic acid as a light orange solid. LC/MS (M-H)~ = 487; 1H NMR (300 MHz, DMSO-d6) δ: 12.25 (br. s., 1H), 10.28 (s, 1H), 9.47 (s, 1H), 8.72 (s, 1H), 8.67 (d, J = 1.1 Hz, 1H), 8.45 - 8.57 (m, 3H), 8.06 - 8.12 (m, 1H), 7.96 - 8.02 (m, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 3.82 - 3.92 (m, 2H), 3.21 - 3.29 (m, 2H), 2.56 - 2.80 (m, 3H), 1.76 - 1.87 (m, 1H), 1.46 - 1.58 (m, 2H), 1.26 - 1.44 (m, 2H). Example 15
2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid
Step 1
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. NaHCC>3. 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 2
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 3
A suspension of 7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-naphthalene-2-carboxylic acid methyl ester (4.2 g, 13.5 mmol), 2-bromo-4-phenylthiazole (3.88 g, 16.1 mmol),
tetrakis(triphenylphosphine)palladium (0) (1.55 g, 1.35 mmol) and cesium carbonate (8.77 g, 26.9 mmol) in 1,4-dioxane (25 ml) and water (2.5 ml) was purged with nitrogen for 5 min, then heated at 100°C for 4 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated and the residue was triturated with petroleum ether. The precipitate was collected via filtration and dried under high vacuum to obtain 4.6 g of 7-(4-phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid methyl ester as an off-white powder which was used without further purification.
Step 4
To a suspension of 7-(4-phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid methyl ester (4.6 g, 13.3 mmol) in THF (25 ml), MeOH (25 ml) and water (25 ml) was added LiOH (1.59 g, 66.6 mmol). The reaction mixture was stirred at room temperature for 18 h then concentrated. The residue was diluted with water and extracted with Et20 (discarded). The aqueous layer was acidified with IN HC1. The resultant precipitate was collected via filtration, washed with water and Et20 and dried to afford 3.16 g (71%) of 7-(4-phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid as an off-white powder.
Step 5
In a microwave vial, a suspension of 7-(4-phenyl-thiazol-2-yl)-naphthalene-2-carboxylic acid (250 mg, 0.75 mmol) and triethylamine (0.21 ml, 1.51 mmol) in t-butanol (2 ml) was purged with nitrogen for 5 min, then diphenylphosphoryl azide (415 mg, 0.33 ml, 1.51 mmol) was added. The vial was sealed and heated under microwave irradiation at 120°C for 30 min. Additional diphenylphosphoryl azide (200 mg, 0.15 ml, 0.75 mmol) and triethylamine (0.10 ml, 0.75 mmol) were added and the reaction was again heated under microwave irradiation at 120°C for 30 min. After cooling, the residue partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organics were washed with satd. NaHCC>3 and brine, then dried (MgS04) and concentrated. The crude residue was purified by chromatography (silica gel, gradient 0 to 30% EtOAc/hexanes) to provide 125 mg (41%) of [7-(4-phenyl-thiazol-2-yl)- naphthalen-2-yl]-carbamic acid tert-butyl ester as a viscous oil. LC/MS: (M+H)+ = 403.
Step 6
To a mixture of [7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-carbamic acid tert-butyl ester (125 mg, 0.31 mmol) in dichloromethane (5 ml) was added HC1 (4M in 1,4-dioxane, 0.12 ml, 0.48
mmol). The reaction mixture was stirred at room temperature for 6 h then made basic with aqueous IN NaOH and extracted with dichloromethane. The organic layer was dried (MgS04) and concentrated to afford 78 mg (83%) of 7-(4-phenyl-thiazol-2-yl)-naphthalen-2-ylamine as an off-white solid. Step 7
A mixture of 7-(4-phenyl-thiazol-2-yl)-naphthalen-2-ylamine (78 mg, 0.26 mmol) and 3- cyclohexyldihydrofuran-2,5-dione (71 mg, 0.39 mmol) in chloroform (10 ml) was heated at 70°C for 20 h then cooled to room temperature. The precipitate was filtered, washed with
dichloromethane and dried under high vacuum to obtain 116 mg (93%) of 2-cyclohexyl-N-[7-(4- phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid as a white powder. LC/MS: (M+H)+ =
485; *H NMR (400 MHz, DMSO-d6) δ: 12.15 (br. s., 1H), 10.29 (br. s., 1H), 8.44 - 8.50 (m, 2H), 8.24 (s, 1H), 8.10 - 8.15 (m, 2H), 8.06 (dd, J = 8.5, 2.0 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.64 (dd, J = 9.0, 2.0 Hz, 1H), 7.48 - 7.55 (m, 2H), 7.37 - 7.44 (m, 1H), 2.66 - 2.79 (m, 2H), 2.53 - 2.62 (m, 1H), 1.55 - 1.81 (m, 6H), 1.01 - 1.33 (m, 5H).
Examples 16 & 17
(R)- 2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid and (S)- 2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid
A sample of 2-cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid (58 mg, 0.12 mmol) was subjected to chiral preparative SFC chromatography [Berger/Waters Multigram II; Chiral Technologies DAICEL IA 3x25 cm column; 60% MeOH/C02, 60 ml/min, 220 nm] to obtain 18 mg of (R)- 2-cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]- succinamic acid [LC/MS: (M+H)+ = 485] and 14 mg of (S)-2-cyclohexyl-N-[7-(4-phenyl- thiazol-2-yl)-naphthalen-2-yl]-succinamic acid [LC/MS: (M+H)+ = 485]. Stereochemical assignments were made based on correlation of biological activity with proposed binding mode as determined by molecular modeling and have not been unequivocally proven.
Example 18
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-pyridin-3-yl-succinamic acid
Step 1
In a 250 ml round-bottomed flask, 3-pyridylacetic acid (400 mg, 2.92 mmol) was suspended in 35 ml dichloromethane. The suspension was cooled to 0°C and triethylamine (0.87 ml, 6.24 mmol) and 4-dimethylaminopyridine (52 mg, 0.43 mmol) were added which caused all solids to dissolve. Then a solution of benzyl chloroformate (0.50 ml, 3.5 mmol) in 5 ml dichloromethane was added dropwise. The reaction mixture was stirred at 0°C for 1 h and at room temperature for 2 h. The reaction was quenched with saturated NaHCCb-solution and extracted with
dichloromethane. The organic layer was washed with saturated NaHCC solution. The combined aqueous layers were extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate, then filtered and concentrated. The residue was purified by chromatography over 25g silica gel with EtOAc/hexanes (gradient: 0-50% EtOAc). All fractions containing product were combined and concentrated to afford 370 mg (56%) of pyridin-3-yl- acetic acid benzyl ester as a light yellow oil. *H NMR (400 MHz, CDC13) δ: 8.53 - 8.59 (m, 2H), 7.65 - 7.72 (m, 1H), 7.29 - 7.43 (m, 6H), 5.17 (s, 2H), 3.71 (s, 2H).
Step 2
In a 50 ml round-bottomed flask, pyridin-3-yl-acetic acid benzyl ester (367 mg, 1.61 mmol) was dissolved in 6.5 ml THF. The pale yellow solution was cooled to -76°C and lithium
bis(trimethylsilyl)amide (1.0M in THF, 1.8 ml, 1.8 mmol) was added dropwise. The mixture was stirred at -76°C for 30 min then tert-butyl bromoacetate (0.26 ml, 1.76 mmol) was added dropwise. The mixture was stirred at -76°C for 30 min then warmed to room temperature and stirred for 2.5 h. The reaction was quenched with saturated NH4CI- solution and extracted twice with EtOAc. The organic layers were washed with water and brine then combined and dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 25g silica gel with EtOAc/hexanes (gradient: 0-40% EtOAc). All fractions containing product were combined and concentrated to give 330 mg (60%) of 2-pyridin-3-yl-succinic acid 1 -benzyl ester 4-tert-butyl ester as a yellow oil. *H NMR (300 MHz, CDC13) δ: 8.58 (d, J = 2.0 Hz, 1H), 8.55 (dd, J = 4.8, 1.5 Hz, 1H), 7.65 (dt, J = 8.0, 2.0 Hz, 1H), 7.23 - 7.35 (m, 6H), 5.15 (dd, J = 14.1,
2.8 Hz, 2H), 4.14 (dd, J = 9.2, 6.3 Hz, 1H), 3.14 (dd, J = 16.5, 9.2 Hz, 1H), 2.68 (dd, J = 16.5, 6.3 Hz, 1H), 1.39 (s, 9H).
Step 3
In a 10 ml round-bottomed flask, 2-pyridin-3-yl-succinic acid 1-benzyl ester 4-tert-butyl ester (150 mg, 0.44 mmol) was dissolved in 1.5 ml dichloromethane. Trifluoroacetic acid (1.26 g, 0.85 ml, 11.0 mmol) was slowly added and the reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated and the residue was dried under high vacuum to afford 2-pyridin- 3-yl-succinic acid 1-benzyl ester trifluoroacetate as a light yellow oil which was used without further purification. Step 4
In a 10 ml round-bottomed flask, 2-pyridin-3-yl-succinic acid 1-benzyl ester trifluoroacetate (65% pure, 258 mg, 0.42 mmol) was dissolved in 2.2 ml DMF and N,N-diisopropylethylamine (0.65 ml, 3.72 mmol) was added. Then 7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-ylamine (100 mg, 0.34 mmol) and HATU (142 mg, 0.37 mmol) were sequentially added. The reaction mixture was stirred at room temperature overnight then 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: 0-80% EtOAc). All fractions containing product were combined and concentrated to provide 202 mg of N-[7-(4-cyclobutyl- thiazol-2-yl)-naphthalen-2-yl]-2-pyridin-3-yl-succinamic acid benzyl ester as a pale green oil.
Step 5
In a 25 ml round-bottomed flask, N-[7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-pyridin-3- yl-succinamic acid benzyl ester (90% pure, 197 mg, 0.32 mmol) was dissolved in 3 ml methanol and 3 ml THF. The flask was three times alternatingly evacuated and flushed with argon. 20% Palladium hydroxide on carbon (wet, 45 mg, 0.064 mmol) was carefully added. The flask was evacuated and flushed with argon, then evacuated and flushed with hydrogen. The reaction mixture was stirred under hydrogen atmosphere (balloon) at room temperature overnight.
Additional 20% palladium hydroxide on carbon (wet, 45 mg, 0.064 mmol) was carefully added. The flask was again evacuated and flushed with argon, then evacuated and flushed with hydrogen. The reaction mixture was stirred under hydrogen atmosphere (balloon) at room temperature for 5 h then filtered over Celite, rinsing with dichloromethane/methanol. The filtrate was concentrated. The residue was triturated with dichloromethane to afford 94 mg (60%) of N- [7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-pyridin-3-yl-succinamic acid as an off-white powder. LC/MS: (M-H)" = 456; *H NMR (400 MHz, DMSO-d6) δ: 12.67 (br. s, 1H), 10.32 (s, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.49 (dd, J = 4.8, 1.5 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 8.35 (s, 1H), 7.88 - 7.99 (m, 3H), 7.77 (dt, J = 7.8, 2.1 Hz, 1H), 7.59 (dd, J = 8.8, 2.0 Hz, 1H), 7.43 (d, J = 0.8 Hz, 1H), 7.38 - 7.42 (m, 1H), 4.16 (dd, J = 8.8, 6.1 Hz, 1H), 3.71 (quin, J = 8.5 Hz, 1H),
3.21 (dd, J = 15.9, 8.8 Hz, 1H), 2.87 (dd, J = 15.9, 6.1 Hz, 1H), 2.25 - 2.40 (m, 4H), 1.98 - 2.09 (m, 1H), 1.88 - 1.97 (m, 1H).
Example 19
2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-quinolin-2-yl]-succinamic acid
Step 1
A 50 ml round-bottomed flask was charged with 7-bromo-lH-quinolin-2-one (0.50 g, 2.23 mmol), bis(pinacolato)diboron (680 mg, 2.68 mmol), DPPF (50 mg, 0.09 mmol), dichloro 1,1'- bis(diphenylphosphino)ferrocene palladium(II) dichloromethane adduct (73 mg, 0.09 mmol), and potassium acetate (657 mg, 6.69 mmol). Then 1,4-dioxane (8 ml) was added and the reaction mixture was degassed with bubbling nitrogen for 15 min. The mixture was heated at 90°C overnight then cooled to room temperature, quenched with water and extracted with EtOAc (3x). The combined organic layers were dried over MgS04 and concentrated. The dark residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to isolate 488 mg (81%) of 7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-quinolin-2-one as an orange- brown solid. *H NMR (300 MHz, CDC13) δ: 10.58 (br. s., 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.71 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 9.6 Hz, 1H), 1.38 (s, 12H).
Step 2
A microwave vial was charged with 2-bromo-4-phenylthiazole (472 mg, 1.97 mmol), 7-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-quinolin-2-one (485 mg, 1.79 mmol), sodium carbonate (569 mg, 5.37 mmol), and tetrakis(triphenylphosphine)palladium (0) (62 mg, 0.05 mmol). Then added MeOH (7 ml) and CH2CI2 (2.5 ml). The vial was sealed and heated in a microwave reactor at 115°C for 30 min then quenched with water and extracted with
CH2Cl2/MeOH. The combined organics were dried over MgS04 and concentrated. The dark residue was absorbed onto silica gel and purified by chromatography with 50% to 100%
EtOAc/hexanes to afford 260 mg (48%) of 7-(4-phenyl-thiazol-2-yl)-lH-quinolin-2-one as a pale yellow solid. *H NMR (300 MHz, CDC13) δ: 10.45 (br. s., 1H), 8.00 - 8.06 (m, 2H), 7.97 (s, 1H), 7.90 (dd, J = 8.3, 1.7 Hz, 1H), 7.83 (d, J = 9.8 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.58 (s, 1H), 7.45 - 7.53 (m, 2H), 7.40 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 9.8 Hz, 1H).
Ste 3
A suspension of 7-(4-phenyl-thiazol-2-yl)-lH-quinolin-2-one (260 mg, 0.85 mmol) in phosphoryl trichloride (3.5 ml, 37.5 mmol) was heated to 110°C. All solids gradually dissolved to give a yellow solution. Heating was continued for 1 h then the reaction mixture was cooled to room temperature overnight. The thick, bright yellow slurry was carefully poured into ice/water, stirred vigorously for 20 min and extracted with dichloromethane (3x). The combined organics were washed with sat'd NaHCC>3, dried over MgS04 and concentrated to provide 263 mg (95%) of 2-chloro-7-(4-phenyl-thiazol-2-yl)-quinoline as a light yellow solid.
Step 4
A 10 ml round-bottomed flask was charged with 2-chloro-7-(4-phenyl-thiazol-2-yl)-quinoline (180 mg, 0.56 mmol), (R)-BINAP (49 mg, 0.08 mmol), sodium tert-butoxide (129 mg, 1.34 mmol) and tris(dibenzylideneacetone)dipalladium (0) (36 mg, 0.04 mmol). Then added toluene (4 ml) followed by benzophenone imine (111 mg, 103 μΐ, 0.61 mmol). The reaction mixture was stirred at 95 °C for 4 h then cooled to room temperature overnight, quenched with water and extracted with EtOAc (3x). The combined organics were dried over MgS04 and concentrated to an orange oil. The residue was dissolved in THF (6 ml) and 1.0 M aqueous HC1 (2 ml) was added. The reaction mixture was stirred at room temperature for 1 h then made basic with 10% aqueous NaOH and extracted with EtOAc (2x). The combined organics were dried over MgS04 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to give an orange-yellow solid. Trituration with EtOAc/hexanes provided 70 mg (41%) of 7-(4-phenyl-thiazol-2-yl)-quinolin-2-ylamine as a light beige solid.
Step 5
A solution of 7-(4-phenyl-thiazol-2-yl)-quinolin-2-ylamine (68 mg, 0.22 mmol) and 3- cyclohexyldihydrofuran-2,5-dione (41 mg, 0.22 mmol) in chloroform (2.5 ml) was heated at 70°C for 1 h then cooled to room temperature. The precipitate was collected via filtration, rinsed with a small amount of dichloromethane/hexanes and dried under high vacuum to afford 53 mg (49%) of 2-cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-quinolin-2-yl]-succinamic acid as an off- white solid. LC/MS: (M-H)" = 484; *H NMR (300 MHz, DMSO-d6) δ: 12.13 (br. s., 1H), 10.87 (s, 1H), 8.36 - 8.43 (m, 1H), 8.26 - 8.35 (m, 3H), 8.01 - 8.17 (m, 4H), 7.46 - 7.55 (m, 2H), 7.34 - 7.44 (m, 1H), 2.77 - 2.90 (m, 1H), 2.55 - 2.74 (m, 2H), 1.51 - 1.79 (m, 6H), 0.96 - 1.32 (m, 5H).
Example 20
N-[3-(4-Cyclobutyl-thiazol-2-yl)-isoquinolin-6-yl]-2-cyclohexyl-succinamic acid
Step 1
To a mixture of 6-chloroisoquinolin-3-ol (3.3 g, 18.4 mmol) and pyridine (7.43 ml, 91.9 mmol) in dichloromethane at 0°C was added triflic anhydride (1.0 M in dichloromethane, 18.4 ml, 18.4 mmol) slowly via syringe. The reaction was allowed to warm to room temperature and stirred for 3 h then most of the solvent was removed by rotary evaporation. The residue was diluted ether and washed water (3x), 1 N HC1, and brine. The organics were dried over MgS04 and concentrated to afford 2.1 g (37%) of trifluoro-methanesulfonic acid 6-chloro-isoquinolin-3-yl ester as a green crystalline solid.
Step 2
In a microwave vial, zinc cyanide (1.19 g, 10.1 mmol) was added to a solution of of trifluoro- methanesulfonic acid 6-chloro-isoquinolin-3-yl ester (2.1 g, 6.74 mmol) in DMF.
Tetrakis(triphenylphosphine)palladium (0) (389 mg, 0.34 mmol) was added and the solution degassed with argon for 2 min. The vial was sealed and the suspension was heated under microwave irradiation at 110°C for 30 min and then again at 110°C for 60 min. After cooling the reaction was diluted with diethyl ether and washed with water (3x). The aqueous layer was back extracted with diethyl ether. The combined organics were washed with brine, dried over MgS04 and concentrated. The residue was triturated 3x with diethyl ether to afford 620 mg (49%) of 6- chloro-isoquinoline-3-carbonitrile as a yellow solid. *H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 8.62 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 8.8, 2.0 Hz, 1H).
Step 3
In a pressure tube under argon were combined tert-butyl carbamate (113 mg, 0.97 mmol), palladium (II) acetate (8 mg, 0.04 mmol), X-Phos (53 mg, 0.11 mmol), and cesium carbonate (339 mg, 1.04 mmol). 6-Chloro-isoquinoline-3-carbonitrile (140 mg, 0.74 mmol) dissolved in 1,4-dioxane (5 ml) was added and argon was bubbled through the mixture for 1.5 min. The tube was flushed with argon and sealed then heated to 100°C with stirring overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite, rinsing
four times with EtOAc. The filtrate was concentrated. The residue was triturated three times with diethyl ether to give 105 mg of a white solid. The ethereal triturates were concentrated and the residue purified by chromatography (15% to 45% EtOAc/hexanes) to give an additional 48 mg of white solid. Overall isolated 153 mg (77%) of (3-cyano-isoquinolin-6-yl)-carbamic acid tert-butyl ester. *H NMR (400 MHz, CDC13) δ: 9.16 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H), 6.90 (s, 1H), 1.60 (s, 9H).
Step 4
To a stirred solution of (3-cyano-isoquinolin-6-yl)-carbamic acid tert-butyl ester (45 mg, 0.167 mmol) in methanol (2 ml) in a microwave vial was added ammonium sulfide (31 μΐ, 0.184 mmol). The vial was sealed and the reaction was heated under microwave irradiation at 80°C for 15 min then stirred at room temperature for 2 h. Additional ammonium sulfide (31 μΐ, 0.184 mmol) was added and the reaction was heated to 50°C in a sealed microwave vial in a sand bath overnight. Heating was continued at 60°C for 1.5 hours then the reaction was cooled to room temperature and concentrated. The residue was triturated with petroleum ether to give 53 mg of (3-thiocarbamoyl-isoquinolin-6-yl)-carbamic acid tert-butyl ester as a yellow solid which was judged to be -90% pure by NMR analysis. *H NMR (400 MHz, CDC13) δ: 9.71 (br. s., 1H), 9.08 (s, 1H), 9.02 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.75 (dd, J = 8.8, 2.0 Hz, 1H), 7.75 (br. s.; 1H), 6.86 (s, 1H), 1.60 (s, 9H).
Step 5
To a solution of (3-thiocarbamoyl-isoquinolin-6-yl)-carbamic acid tert-butyl ester (50 mg, 0.165 mmol) in ethanol (1 ml) was added 2-bromo-l-cyclobutylethanone (35 mg, 0.20 mmol). The reaction mixture was heated at reflux for 4 h. Additional 2-bromo-l-cyclobutylethanone (17 mg, 0.10 mmol) was added and heating was continued at 50°C overnight. The reaction was cooled to room temperature and concentrated. The residue was triturated twice with petroleum
ether/diethyl ether to give 50 mg of 3-(4-cyclobutyl-thiazol-2-yl)-isoquinolin-6-ylamine as a brown solid which was used without further purification.
Step 6
To a solution of 3-(4-cyclobutyl-thiazol-2-yl)-isoquinolin-6-ylamine (50 mg, 0.178 mmol) in chloroform (2.5 ml) was added 3-cyclohexyldihydrofuran-2,5-dione (32 mg, 0.178 mmol). The reaction mixture was heated at 50°C for 6 h during which time a precipitate formed. The reaction was cooled to room temperature and the precipitate was collected via filtration, washed with dichloromethane (3x) and dried to afford 5 mg (6%) of N-[3-(4-cyclobutyl-thiazol-2-yl)- isoquinolin-6-yl]-2-cyclohexyl-succinamic acid as a white solid. LC/MS: (M+H)+ = 464; *H NMR (400 MHz, DMSO-d6) δ: 12.16 (br. s., 1H), 10.48 (s, 1H), 9.21 (s, 1H), 8.42 (s, 2H), 8.11 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 3.73 (quin, J = 8.5 Hz, 1H), 2.70 - 2.85 (m, 2H), 2.55 - 2.64 (m, 1H), 2.25 - 2.43 (m, 4H), 1.99 - 2.12 (m, 1H), 1.89 - 1.99 (m, 1H), 1.55 - 1.81 (m, 6H), 1.00 - 1.33 (m, 5H).
Example 21 Assay Protocols and Results
Cell-Based Proteasome Activity/Selectivity Assay
The Cell-Based Proteasome subunit activity/selectivity assay was a panel of 5 fluorogenic assays that independently measured the activity of β5ι· or β 5i (chymotrypsin-like activity), β 2c/2i (trypsin-like), and β lc or β li (caspase-like) protease activity associated with the proteasome complex in cultured cells. Specifically, the following substrates were used for respective subunit activities: β li: ( PAI .hRh l 10. β lc: ( 1.1.1 · ) Kh l 10. β 2c/2i: (KQL)2Rhl lO, β 5c: (WLA)2Rhl lO, β 5i: (ANW)2Rhl lO. The following procedure was 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 was 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 was similar to previous Ramos cell-based assay as of the substrates, but using human PBMCs in the context of complete RPMI with 10 % FBS as reaction buffer. This assay was designed to assess the level of cellular penetration of test compounds in primary human cells. The following procedure was followed: Fresh isolated PBMC from healthy donor were plated at lxl 05 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 was 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 was 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 lO)/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 was collected in a sterile environment in heparinized tubes. Blood was diluted with an equal volume PBS/2% FCS and 30 ml of this mixture was 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, was removed by Pasteur pipet. These mononuclear cells were washed 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 supernatants were removed. PBMC viability of cells remaining in the well was measured with ATPlite luminescence assay (Perkin-Elmer) per the manufacturer' s instructions. Luminescence was measured on the Perkin-Elmer Envision, using the luminescence filter. IP 10 level was measured with CXCL10/IP10 AlphaLISA kit (Perkin-Elmer) per the manufacturer' s instructions, except halving all volumes. Fluorescence was 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)2- rhll0-(wla)2 rhll0-(kql)2 rhll0-(pal)2 rhll0-(lle)2 rllO
1 5.377 20 20 20 20
2 0.283 20 20 20 20
3 1.97 7.69 13.33 13.66 13.68
4 0.058 2.06 20 20 20
5 0.347 20 20 20 20
6 0.412 8.671 20 13.804 15.193
7 0.459 20 20 20 20
Ic50:ramos:
Ic50:ramos: Ic50:ramos: Ic50:ramos: Ic50:ramos:
Example ac-(anw)2- rhll0-(wla)2 rhll0-(kql)2 rhll0-(pal)2 rhll0-(lle)2 rllO
8 0.278 8.7 20 20 20
9 0.538 12.47 20 20 20
10 0.08 1.308 20 20 20
11 0.115 5.086 20 20 20
12 0.021 1.075 20 20 20
13 0.079 0.341 20 20 20
14 1.538 13.033 20 20 20
15 0.172 20 20 20 20
16 0.03 2.961 7.964 13.068 16.132
17 0.229 7.624 15.862 19.935 20
18 1.86 20 20 20 20
19 0.025 20 20 20 20
20 1.595 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
A compound of formula (I)
R1 is C3-8 cycloalkyl, heterocycloalkyl, dioxo-substituted heterocycloalkyl, aryl or
heteroaryl;
R2 is hydrogen, C1-7 alkyl, C3-8 cycloalkyl, heterocycloalkyl, aryl, aryl substituted with C1-7 alkoxy, benzyl or heteroaryl; or a pharmaceutically acceptable salt or ester thereof.
2. The compound according to claim 1 , wherein both X and Y are CH.
3. The compound according to claim 1, wherein one of X or Y is CH and the other is nitrogen.
4. The compound according to claim 1, wherein R1 is cyclobutyl, tetrahydrofuranyl,
dioxotetrahydrothiophenyl, pyrazinyl or phenyl.
5. The compound according to claim 1, wherein R1 is cyclobutyl or phenyl.
6. The compound according to claim 1 , wherein R2 is hydrogen, cyclohexyl,
tetrahydropyranyl, pyridinyl, butyl, benzyl, phenyl or phenyl substituted with methoxy.
7. The compound according to claim 1, wherein R2 is cyclohexyl, tetrahydropyranyl or
phenyl.
8. The compound according to claim 1, wherein said compound is:
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid;
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid;
(R)-N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid;
(S)-N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid; N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-phenyl-succinamic acid;
2-Benzyl-N-[7-(4-cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid;
2-{ [7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-ylcarbamoyl]-methyl}-hexanoic acid; N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-(4-methoxy-phenyl)-succinamic acid; N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-(tetrahydro-pyran-4-yl)-succinamic acid;
2-Cyclohexyl-N-{7-[4-(tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalen-2-yl}-succinamic acid;
N-{7-[4-(Tetrahydro-furan-3-yl)-thiazol-2-yl]-naphthalen-2-yl}-2-(tetrahydro-pyran-4-yl)- succinamic acid;
2-Cyclohexyl-N- { 7-[4-(l , 1 -dioxo-tetrahydro-1 6-thiophen-3-yl)-thiazol-2-yl]-naphthalen- 2-yl}-succinamic acid;
N-{7-[4-(l,l-Dioxo-tetrahydro- 6-thiophen-3-yl)-thiazol-2-yl]-naphthalen-2-yl}-2- (tetrahydro-pyran-4-yl)-succinamic acid;
N-[7-(4-Pyrazin-2-yl-thiazol-2-yl)-naphthalen-2-yl]-2-(tetrahydro-pyran-4-yl)-succinamic acid;
2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid;
(R)- 2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid;
(S)- 2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-naphthalen-2-yl]-succinamic acid;
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-pyridin-3-yl-succinamic acid;
2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-quinolin-2-yl]-succinamic acid; or
N-[3-(4-Cyclobutyl-thiazol-2-yl)-isoquinolin-6-yl]-2-cyclohexyl-succinamic acid.
9 The compound according to claim 1, wherein said compound is:
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid;
(S)-N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-cyclohexyl-succinamic acid; N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-phenyl-succinamic acid;
N-[7-(4-Cyclobutyl-thiazol-2-yl)-naphthalen-2-yl]-2-(tetrahydro-pyran-4-yl)-succinamic acid; and
2-Cyclohexyl-N-[7-(4-phenyl-thiazol-2-yl)-quinolin-2-yl]-succinamic 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.
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