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HK1169114A - Heterocyclic sulfonamides, uses and pharmaceutical compositions thereof - Google Patents

Heterocyclic sulfonamides, uses and pharmaceutical compositions thereof Download PDF

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Publication number
HK1169114A
HK1169114A HK12109881.9A HK12109881A HK1169114A HK 1169114 A HK1169114 A HK 1169114A HK 12109881 A HK12109881 A HK 12109881A HK 1169114 A HK1169114 A HK 1169114A
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HK
Hong Kong
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
sulfonamide
hydrogen
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HK12109881.9A
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Chinese (zh)
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HK1169114B (en
Inventor
A．F．J．弗利里
R．J．加拉斯丘恩
C．J．奥唐奈
J．B．施瓦茨
B．E．西格尔斯坦
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生物基因Ma公司
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Description

Heterocyclic sulfonamides, their use and pharmaceutical compositions
Technical Field
The present invention relates to a novel class of compounds having the structure of formula I as defined herein and to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof. The invention also includes methods of treating a subject by administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. These compounds are useful in the conditions disclosed herein. The invention further includes processes for the manufacture of compounds of formula I and corresponding intermediates.
Background
The amino acid glutamate, the major excitatory neurotransmitter in the mammalian Central Nervous System (CNS), is signal transduction mediated by ionotropic or metabotropic glutamate receptors (glurs). Ionotropic glutamate receptors (iglurs) comprise 3 subtypes, which 3 subtypes can be distinguished by unique responses to each of the following three selective iGluR agonists: α -amino-3-hydroxy-5-methylisoxazole-4-propanoic acid (AMPA), N-methyl-D-aspartic acid (NMDA) and kainic acid (Parsons, c.g., Danysz, w. and ridge, D. (2002), Ionotropic glutamatereceptates as Therapeutic Targets (Danysz, w., ridge, D. and Parsons, c.g., eds.), pages 1-30, f.p. The AMPA receptor is composed of 4 monomer subunits of about 900 amino acids (each composed of a different gene (Glu)A1-A4) Encoding proteins homotetramers or heterotetramers, in which the subunit proteins are present in any combination of two splice variants, called "flip" and "flop"), which mediate the vast majority of excitatory synaptic transmissions in the mammalian brain and have long been regarded as indispensable components of the neural circuits that mediate cognitive processes (bleekman, D. and Lodge, D. (1998) Neuropharmacology of AMPA and Kainate receptors. Neuropharmacology 37: 1187-1204). The combination of multiple heterotetramer possibilities, the two spliced forms of each of the 4 iGluR monomers, and the Receptor subunit RNA organized with the heterogeneous distribution of AMPA receptors throughout the brain highlights the myriad of Potential AMPA Receptor responses within this organ (Black, M.D. (2005) Therapeutic Potential of Positive AMPA modulators and Therapeutic Relationship to AMPA Receptor subunit. distribution of clinical data. Psychopharmacology 179: 154-. AMPA modulators have now become active targets for drug discovery (see Rogers, B., and Schmidt, C., (2006) Novel Approaches for the Treatment of Schizophrania, Annual Reports in Medicinal Chemistry 3-21).
Summary of The Invention
The present invention relates to compounds having the structure, including pharmaceutically acceptable salts of said compounds:
wherein each R1And each R2And each R7Independently selected from: hydrogen, halogen, hydroxy, -CF3、-CN、-(C＝O)R8、-O-(C＝O)-R8、-(NR8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-O-(C＝O)-OR8、-O-(C＝O)-N(R8)2、-NO2、-N(R8)2、-(NR8)-SO2-R8、-S(O)wR8、-SO2-N(R8)2、(C1-C6) Alkyl, (C)6-C10) Aryl group, (C)1-C9) Heteroaryl, (C)1-C9) Heterocycloalkyl and (C)3-C10) A cycloalkyl group; wherein said (C)1-C6) Alkyl, (C)6-C10) Aryl group, (C)1-C9) Heteroaryl, (C)1-C9) Heterocycloalkyl or (C)3-C10) Cycloalkyl is each independently optionally substituted with 1, 2, 3 or 4R9Substitution;
w is 0, 1 or 2;
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
s is 1 and t is 1; or one of s or t is 1 and the other of s or t is 2;
R3is hydrogen or (C)1-C6) An alkyl group;
each R4Independently selected from hydrogen or (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 OR 4 halogens, -CN OR-OR9Substitution;
or two R on the same carbon atom4The radicals may together form an oxo (═ O) group or (C)3-C6) Spiro cycloalkyl;
R5is hydrogen or (C)1-C6) An alkyl group;
R6is (C)1-C6) Alkyl- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、(C1-C6) alkyl-SO2-、(C3-C10) cycloalkyl-SO2-or [ (C)1-C6) Alkyl radical]2N-SO2-; wherein the [ (C)1-C6) Alkyl radical]2N- (C ═ O) -and [ (C)1-C6) Alkyl radical]2N-SO2Said (C) of (A)1-C6) The alkyl moiety optionally forms a 3-to 6-membered heterocyclic ring together with the nitrogen atom to which it is attached;
each R8Independently selected from: hydrogen, (C)1-C6) Alkyl, (C)6-C10) Aryl group, (C)1-C9) Heteroaryl, (C)1-C9) Heterocycloalkyl and (C)3-C10) A cycloalkyl group; wherein said (C)1-C6) Alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from: hydrogen, halo, -CN, perfluoro (C)1-C6) Alkyl, hydroxy, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) Alkoxy, perfluoro (C)1-C6) Alkoxy, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, formyl, (C) and (d) alkyl1-C6) Alkyl- (C ═ O) -, H2N-(C＝O)-、[(C1-C6) Alkyl radical]-(NH)-(C＝O)-、[(C1-C6) Alkyl radical]2N-(C＝O)-、(C1-C6) Alkyl- (C ═ O) -O-, H (C ═ O) -NH-, (C ═ O-), (C1-C6) Alkyl (C ═ O) -NH-, (C)1-C6) Alkyl (C ═ O) - [ N ((C) — (C)1-C6) Alkyl radical)]-、(C1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、(C1-C6) alkyl-SO2-[N((C1-C6) Alkyl radical)]-、H2N-SO2-、[(C1-C6) Alkyl radical]-NH-SO2-and [ (C)1-C6) Alkyl radical]2N-SO2-; wherein said (C)1-C6) Alkyl may additionally optionally be optionally substituted (C)6-C10) Aryl group, (C)1-C9) Heteroaryl, (C)1-C9) Heterocycloalkyl or (C)3-C10) Cycloalkyl substitution; wherein the optional substituents may be independently substituted with 1, 2, 3 or 4 groups independently selected from: halogen, hydroxy, -CF3、-CN、(C1-C3) Alkyl, (C)1-C3) Alkoxy and amino; wherein R is8To said (C)6-C10) Aryl group, (C)1-C9) Heteroaryl, (C)1-C9) Heterocycloalkyl or (C)3-C10) Each cycloalkyl substituent is optionally further substituted with 1, 2, 3 or 4 groups independently selected from: halogen, hydroxy, -CF3、-CN、(C1-C3) Alkyl, (C)1-C3) Alkoxy and amino;
each R9Independently selected from: halogen, hydroxy, -CF3、-CN、-(C＝O)R10、-O-(C＝O)-R10、-(NR10)-(C＝O)-R10、-(C＝O)-OR10、-(C＝O)-N(R10)2、-OR10、-O-(C＝O)-OR10、-O-(C＝O)-N(R10)2、-NO2、-N(R10)2、-(NR10)-SO2-R10、-S(O)wR10and-SO2-N(R10)2；
Each R10Independently selected from: hydrogen, (C)1-C6) Alkyl, (C)6-C10) Aryl group, (C)1-C9) Heteroaryl, (C)1-C9) Heterocycloalkyl and (C)3-C10) A cycloalkyl group; wherein said (C)1-C6) Alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from: hydrogen, halo, -CN, perfluoro (C)1-C6) Alkyl, hydroxy, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) Alkoxy, perfluoro (C)1-C6) Alkoxy, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, formyl, (C) and (d) alkyl1-C6) Alkyl- (C ═ O) -, H2N-(C＝O)-、(C1-C6) Alkyl radical]-(NH)-(C＝O)-、[(C1-C6) Alkyl radical]2N-(C＝O)-、(C1-C6) Alkyl- (C ═ O) -O-, H (C ═ O) -NH-, (C ═ O-), (C1-C6) Alkyl (C ═ O) -NH-, (C)1-C6) Alkyl (C ═ O) - [ N ((C) — (C)1-C6) Alkyl radical)]-、(C1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、(C1-C6) alkyl-SO2-[N((C1-C6) Alkyl radical)]-、H2N-SO2-、[(C1-C6) Alkyl radical]-NH-SO2-and [ (C)1-C6) Alkyl radical]2N-SO2-; wherein said (C)1-C6) Alkyl may also be optionally substituted (C)6-C10) Aryl group, (C)1-C9) Heteroaryl, (C)1-C9) Heterocycloalkyl or (C)3-C10) Cycloalkyl substitution; wherein the optional substituents may be independently substituted with 1, 2, 3 or 4 groups independently selected fromGroup substitution: halogen, hydroxy, -CF3、-CN、(C1-C3) Alkyl, (C)1-C3) Alkoxy and amino; wherein R is10Said (C) of6-C10) Aryl group, (C)1-C9) Heteroaryl, (C)1-C9) Heterocycloalkyl or (C)3-C10) Each cycloalkyl substituent is optionally further substituted with 1, 2, 3 or 4 groups independently selected from: halogen, hydroxy, -CF3、-CN、(C1-C3) Alkyl, (C)1-C3) Alkoxy and amino;
R11is hydrogen or (C)1-C6) An alkyl group;
ring "A" is (C)6-C10) Aryl group, (C)1-C9) Heteroaryl, (C)4-C10) Cycloalkyl or (C)1-C9) A heterocycloalkyl group; wherein said (C)4-C10) Cycloalkyl and (C)1-C9) Said R on heterocycloalkyl1Two of the substituents are optionally attached to the same carbon atom and optionally together form oxo (oxo);
ring "B" is (C)6-C10) Aryl group, (C)1-C9) Heteroaryl, (C)4-C10) Cycloalkyl or (C)1-C9) A heterocycloalkyl group;
"X" is-O-or > C (R)4)2；
"Y" is > NR11、-(NR11) - (C ═ O) -, > C ═ O, -O-or > C (R)7)2(ii) a And is
"Z" is-O-, -S-, - (S ═ O) -or- (SO)2)-。
The term "alkyl" refers to straight or branched chain saturated, monounsaturated, and polyunsaturated hydrocarbyl substituents (i.e., substituents obtained by removing hydrogen from a hydrocarbon) containing 1 to 6 carbon atoms, and in another embodiment, 1 to 4 carbon atoms. Monounsaturated and polyunsaturated substituents (so-called alkenyl groups) have from 2 to 6 carbon atoms. The alkenyl group may be present in pure E form (E form), pure Z form (Z form), or any mixture thereof. Polyunsaturated includes multiple double bonds and one or more triple bonds. The alkyl group containing a triple bond (so-called alkynyl group) has 2 to 6 carbon atoms. Examples of the saturated substituent include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isopentyl, hexyl and the like. Examples of unsaturated alkyl groups include vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Examples of alkynyl include ethynyl, propynyl, butynyl, 3-dimethylbutynyl, and the like.
In some cases, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, etc.) is preceded by the prefix "Cx-Cy- "indicates where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms therein. Thus, for example, "C1-C6Alkyl "refers to an alkyl substituent containing 1 to 6 carbon atoms. Also for example, C3-C6Cycloalkyl means a saturated cycloalkyl group containing 3 to 6 carbon ring atoms.
As used herein, the term "perfluoro (C)1-C6) Alkyl "means an alkyl group as described above substituted with one or more fluoro groups including, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, and the like.
The term "hydroxy" refers to-OH. When used in combination with other terms, the prefix "hydroxy" indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds having a carbon to which one or more hydroxyl substituents are attached include, for example, alcohols, enols, and phenols.
The term "cyano" (also known as "nitrile") means-CN, which can also be described as-C ≡ N.
The term "carbonyl" means-C (O) -, > C ═ O, - (C ═ O) -, and can also be described as:
the term "amino" refers to the group-NH2。
The term "oxo" refers to ═ O.
The term "alkoxy" means an alkyl group attached to oxygen, which may also be represented as-O-R, where R represents an alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy.
The term "sulfonyl" refers to-S (O)2-, which may also be described asThus, for example, "alkyl-sulfonyl-alkyl" refers to alkyl-S (O)2-an alkyl group. Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
As used herein, the term "cycloalkyl" is defined to include saturated or unsaturated (non-aromatic) bridged, polycyclic, spiro, or fused polycyclic 3 to 10 membered hydrocarbon rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, and bicyclo [5.2.0] nonyl, and the like); optionally substituted with 1 to 5 suitable substituents. Preferably, the cycloalkyl group has 3 to 6 carbon atoms. In one embodiment, the cycloalkyl group optionally contains 1, 2, or more than 2 non-continuous non-aromatic double or triple bonds. Spiro is a particular type of cycloalkyl group that differs from fused rings that form a ring via two shared carbon atoms in that spiro is a ring that forms around one carbon atom.
As used herein, the term "aryl" is defined to include all-carbon monocyclic or fused-ring polycyclic multiple rings having a fully conjugated pi-electron systemCyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. Aryl groups have 6, 8, 9, or 10 carbon atoms in the ring. More preferably, the aryl group has 6 or 10 carbon atoms in the ring. Most preferably, the aryl group has 6 carbon atoms in the ring. For example, as used herein, the term "(C)6-C10) Aryl "means an aromatic group containing 6 to 10 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, anthryl, indanyl, and the like. Aryl is optionally substituted with 1 to 5 suitable substituents.
The term "heteroaryl" as used herein is defined to include monocyclic or fused ring polycyclic aromatic heterocyclic groups having one or more heteroatoms selected from O, S and N in one or more of the rings. Heteroaryl has 5 to 12 ring atoms, including 1 to 5 heteroatoms independently selected from O, S and N. One or more of the rings of the heterocyclyl group may be free of heteroatoms. Preferably, the heteroaryl group has 5 to 10 ring atoms, including 1 to 4 heteroatoms. More preferably, the heteroaryl group has 5 to 8 ring atoms, including 1, 2 or 3 heteroatoms. Most preferably, the heteroaryl group has 6 to 8 ring atoms, including 1 or 2 heteroatoms. For example, as used herein, the term "(C)1-C9) Heteroaryl "means an aromatic group containing at least one ring heteroatom independently selected from O, S and N and 1 to 9 carbon atoms, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1, 3-oxazolyl, 1, 2-oxazolyl), thiazolyl (e.g., 1, 2-thiazolyl, 1, 3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1, 2, 3-triazolyl, 1, 2, 4-triazolyl), oxadiazolyl (e.g., 1, 2, 3-oxadiazolyl), thiadiazolyl (e.g., 1, 3, 4-thiadiazolyl), quinolinyl, isoquinolinyl, benzothiophenyl, benzofuranyl, indolyl, and the like. Heteroaryl is optionally substituted with 1 to 5 suitable substituents.
As used herein, the term "heterocycloalkyl" is defined to include monocyclic, bridged, polycyclic, spiro, or fused polycyclic, saturated or unsaturated non-aromatic 3 to 20 membered rings containing 1 or more heteroatoms independently selected from O, S and N. One or more of the rings of the bridged, polycyclic or fused heterocyclic group may be free of heteroatoms. Examples of such heterocycloalkyl rings include azetidinyl, tetrahydro-furanyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and the like. Further examples of such heterocycloalkyl rings are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1, 3-oxazolidin-3-yl, isothiazolidine, 1, 3-thiazolidin-3-yl, 1, 2-pyrazolidin-2-yl, 1, 3-pyrazolidin-1-yl, 1, 2-tetrahydrothiazin-2-yl, and the like, 1, 3-tetrahydrothiazin-3-yl, 1, 2-tetrahydrodiazin-2-yl, 1, 3-tetrahydrodiazin-1-yl, 1, 4-oxazin-2-yl, 1, 2, 5-oxathiazin-4-yl, and the like. The heterocycloalkyl ring is optionally substituted with 1 to 5 suitable substituents.
If it is stated that the substituents are "independently selected from" a group, the substituents are each independently selected from each other. Thus each substituent may be the same or different from the other substituents.
When an asymmetric center is present in a compound of formula I, hereinafter referred to as "compound of the invention" (hereinafter understood to mean formula I, Ia, Ib, Ic, Id or Ie), the compound may be present in the form of an optical isomer (enantiomer). In one embodiment, the invention encompasses enantiomers and mixtures, including racemic mixtures of compounds of formula I. In another embodiment, for compounds of formula I containing more than one asymmetric center, the invention encompasses diastereomeric forms of the compounds (individual diastereomers and mixtures thereof). When the compounds of formula I contain an alkenyl group or moiety, geometric isomers may result.
The present invention encompasses tautomeric forms of the compounds of formula I. Tautomerism ("tautomerism") can occur when structural isomers can interconvert via a low energy barrier. In compounds of formula I containing, for example, imino, keto or oxime groups, proton tautomeric forms may be employed, or so-called valence tautomeric forms may be employed in compounds containing aromatic moieties. It follows that a single compound may exhibit more than one type of isomerism. The various ratios of tautomers in solid and liquid forms depend on the various substituents on the molecule and the particular crystallization technique used to isolate the compounds.
Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include, where possible, addition salts derived from the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid, sulfonic acid, and sulfuric acid; and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid, and trifluoroacetic acid. Suitable organic acids generally include, for example, organic acids of the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes.
Further, when the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts with suitable organic ligands, for example quaternary ammonium salts. In another embodiment, the base salt is formed from a base that forms a non-toxic salt, including aluminum, arginine, benzathine, choline, diethylamine, diethanolamine, glycine, lysine, meglumine, ethanolamine, tromethamine, and zinc salts.
In one embodiment, half salts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.
The invention also includes isotopically-labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F and36and (4) Cl. The compounds of the invention and pharmaceutically acceptable salts of said compounds or the compounds of the invention and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention. Certain isotopically-labelled compounds of the invention, e.g. incorporated therein3H and14those compounds of the radioisotope of C are suitable for use in drug and/or stromal tissue distribution assays. The tritiated isotope (i.e.,3H) and an isotope of carbon 14 (i.e.,14C) it is particularly preferred for its ease of preparation and detectability. In addition, the metal can be removed from the metal with a solvent such as deuterium (i.e.,2H) may provide certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in certain circumstances. Isotopically labeled compounds of formula I of the present invention can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples and preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
One embodiment of the present invention relates to compounds of the formula:
another embodiment of the invention relates to compounds of the formula:
it will be appreciated by those skilled in the art that the compounds of formula I may exist in alternative stereoisomeric forms including:
another embodiment of the invention, the so-called ethers, relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein "Z" is-O-.
Another embodiment of the present invention, the so-called thioethers, relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein "Z" is-S-.
Another embodiment of the invention, the so-called sulfoxides, relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein "Z" is- (S ═ O) -.
Another embodiment of the invention, the SO-called sulfones, relates to compounds of the formula I (or Ia, Ib, Ic, Id or Ie) where "Z" is- (SO)2)-。
Another embodiment of the invention, the so-called furans or pyrans, relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein X is-O-. The inventors have focused particularly on these compounds, especially because these furans and pyrans can be isolated according to combinations with other embodiments specifically referring to the "Z" embodiment.
Another embodiment of the invention (so-called cyclopentyl or cyclohexyl)) Relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein X is > C (R)4)2More particularly, wherein each R4Is hydrogen. The inventors also have particular interest in such compounds, inter alia because such cyclopentyl or cyclohexyl groups can be isolated in combination with other embodiments specifically referring to the "Z" embodiment.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein ring "A" is phenyl; more particularly, wherein n is 0, 1 or 2; more particularly, wherein R1Selected from: hydrogen, halogen, hydroxy, -CF3、-CN、-(C＝O)R8、-O-(C＝O)-R8、-(NR8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-O-(C＝O)-OR8、-O-(C＝O)-N(R8)2、-NO2、-N(R8)2、-(NR8)-SO2-R8、-S(O)wR8、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9And (4) substitution. The inventors also have particular interest in such "a" phenyl compounds, particularly because they can be isolated according to other embodiments in combination with the specific designation "cyclopentyl" or "cyclohexyl" and/or "Z" embodiments.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein ring "A" is (C)1-C9) A heteroaryl group; more particularly, wherein n is 0, 1 or 2; and more particularly, wherein R1Selected from: hydrogen, halogen, hydroxy, -CF3、-CN、-(C＝O)R8、-O-(C＝O)-R8、-(NR8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-O-(C＝O)-OR8、-O-(C＝O)-N(R8)2、-NO2、-N(R8)2、-(NR8)-SO2-R8、-S(O)wR8、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9And (4) substitution. The inventors are particularly concerned with these "A" (C)1-C9) Heteroaryl compounds may be isolated in combination with other examples specifically designating the "X", "cyclopentyl" or "cyclohexyl" and/or "Z" embodiments and are also of particular interest.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein ring "A" is (C)1-C9) A heterocycloalkyl group; more particularly, wherein n is 0, 1 or 2; and more particularly, wherein R1Selected from: oxo, hydrogen, halogen, hydroxy, -CF3、-CN、-(C＝O)R8、-O-(C＝O)-R8、-(NR8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-O-(C＝O)-OR8、-O-(C＝O)-N(R8)2、-NO2、-N(R8)2、-(NR8)-SO2-R8、-S(O)wR8、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9And (4) substitution. The inventors are particularly concerned with these "A" (C)1-C9) Heterocycloalkyl compounds may be isolated in combination with other examples specifically designating the "X", "cyclopentyl" or "cyclohexyl" and/or "Z" embodiments and are also of particular interest.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein ring "A" is (C)4-C10) A cycloalkyl group; more particularly, wherein n is 0, 1 or 2; and more particularly, wherein R1Selected from: oxo, hydrogen, halogen, hydroxy, -CF3、-CN、-(C＝O)R8、-O-(C＝O)-R8、-(NR8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-O-(C＝O)-OR8、-O-(C＝O)-N(R8)2、-NO2、-N(R8)2、-(NR8)-SO2-R8、-S(O)wR8、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9And (4) substitution. The inventors are particularly concerned with these "A" (C)4-C10) Cycloalkyl compounds may be isolated in combination with other examples specifically designating the "X", "cyclopentyl" or "cyclohexyl" and/or "Z" embodiments and are also of particular interest.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie), wherein R1Is (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, cyano or halogen and is located ortho or para to Y.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein ring "B" is phenyl; more particularly, wherein m is 0 or 1; more particularly, wherein R2Is hydrogen, halogen, hydroxy, -CF3、-CN、-(C＝O)R8、-O-(C＝O)-R8、-(NR8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-O-(C＝O)-OR8、-O-(C＝O)-N(R8)2、-NO2、-N(R8)2、-(NR8)-SO2-R8、-S(O)wR8、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9And (4) substitution. The inventors hereof, inter alia, because such "B" phenyl compounds may be used in accordance with other implementations specifically referring to the "X", "cyclopentyl" or "cyclohexyl" and/or "Z" embodimentsExample combinations to isolate compounds of particular high interest. Each of these embodiments also forms the other embodiments associated with the "a" ring embodiments described above.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein Ring "B" is (C)1-C9) A heteroaryl group; more particularly, wherein m is 0 or 1; and more particularly, wherein R2Is hydrogen, halogen, hydroxy, -CF3、-CN、-(C＝O)R8、-O-(C＝O)-R8、-(NR8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-O-(C＝O)-OR8、-O-(C＝O)-N(R8)2、-NO2、-N(R8)2、-(NR8)-SO2-R8、-S(O)wR8、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9And (4) substitution. The inventors are particularly responsible for these "B" (C)1-C9) Heteroaryl compounds may be isolated in accordance with other embodiments specifically identified as "X", "cyclopentyl" or "cyclohexyl" and/or "Z" embodiments and are of particular high interest. Each of these embodiments also forms the other embodiments associated with the "a" ring embodiments described above.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein Ring "B" is (C)1-C9) A heterocycloalkyl group; more particularly, wherein n is 0 or 1; and more particularly, wherein R2Is hydrogen, halogen, hydroxy, -CF3、-CN、-(C＝O)R8、-O-(C＝O)-R8、-(NR8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-O-(C＝O)-OR8、-O-(C＝O)-N(R8)2、-NO2、-N(R8)2、-(NR8)-SO2-R8、-S(O)wR8、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9And (4) substitution. The inventors are particularly responsible for these "B" (C)1-C9) Heterocycloalkyl compounds may be isolated in combination with other examples specifically designating the "X", "cyclopentyl" or "cyclohexyl" and/or "Z" embodiments and are also of particular interest. Each of these embodiments also forms the other embodiments associated with the "a" ring embodiments described above.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein Ring "B" is (C)4-C10) A cycloalkyl group; more particularly, wherein m is 0 or 1; and more particularly, wherein R2Is hydrogen, halogen, hydroxy, -CF3、-CN、-(C＝O)R8、-O-(C＝O)-R8、-(NR8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-O-(C＝O)-OR8、-O-(C＝O)-N(R8)2、-NO2、-N(R8)2、-(NR8)-SO2-R8、-S(O)wR8、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9And (4) substitution. The inventors are particularly responsible for these "B" (C)4-C10) Cycloalkyl compounds may be isolated in combination with other examples specifically designating the "X", "cyclopentyl" or "cyclohexyl" and/or "Z" embodiments and are also of particular interest. Each of these embodiments also forms the other embodiments associated with the "a" ring embodiments described above.
Another embodiment of the present invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie)In which R is2Is (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, cyano or halogen.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie), wherein R2Is hydrogen.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie), wherein R4Is hydrogen.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein p is 2 and two R are4Together form oxo.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein p is 2 and each R is4Is (C)1-C6) An alkyl group.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein q is 0.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein Y is absent.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein Y is-O-.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie) wherein Y is > C (R7)2。
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie), wherein R6Is (C)1-C5) Alkyl- (C ═ O) -.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie), wherein R6Is [ (C)1-C3) Alkyl radical]2N- (C ═ O) -, wherein said (C) is1-C2) Alkyl radicalThe moieties optionally form together with the nitrogen atom to which they are attached a 4 to 6 membered heterocyclic ring.
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie), wherein R6Is (C)1-C5) alkyl-SO2-。
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie), wherein R6Is (C)3-C5) cycloalkyl-SO2-。
Another embodiment of the invention relates to compounds of formula I (or Ia, Ib, Ic, Id or Ie), wherein R6Is [ (C)1-C3) Alkyl radical]2N-SO2-; wherein said (C)1-C2) The alkyl moiety optionally forms a 4-to 6-membered heterocyclic ring together with the nitrogen atom to which it is attached.
Another embodiment of this invention is also directed to each individual compound described as examples 1-54 in the examples section of this specification and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of the invention include:
propane-2-sulfonic acid [ (3S,4S) -4- (2' -cyano-biphenyl-4-yloxy) -tetrahydro-furan-3-yl ] -amide;
propane-2-sulfonic acid [ (3S,4S) -4- (2 '-cyano-4' -fluoro-biphenyl-4-yloxy) -tetrahydro-furan-3-yl ] -amide;
propane-2-sulfonic acid [ (3S,4S) -4- (2', 4' -difluoro-biphenyl-4-yloxy) -tetrahydro-furan-3-yl ] -amide;
propane-2-sulfonic acid { (3S,4S) -4- [4- (5-cyano-thiophen-2-yl) -phenoxy ] -tetrahydro-furan-3-yl } -amide;
propane-2-sulfonic acid { (1S,2R) -2- [4- (5-cyano-thiophen-2-yl) -3-fluoro-phenoxy ] -cyclopentyl } -amide;
propane-2-sulfonic acid { (1S,2R) -2- [4- (5-cyano-thiophen-2-yl) -phenoxy ] -cyclopentyl } -amide;
propane-2-sulfonic acid { (1S,2R) -2- [ 3-fluoro-4- (2-methylsulfmylamino-ethyl) -phenoxy ] -cyclopentyl } -amide;
propane-2-sulfonic acid { (3S,4S) -4- [5- (2-cyano-phenyl) -pyridin-2-yloxy ] -tetrahydro-furan-3-yl } -amide;
propane-2-sulfonic acid { (1S,2R) -2- [6- (2-cyano-4-fluoro-phenyl) -pyridin-3-yloxy ] -cyclohexyl } -amide; and
propane-2-sulfonic acid { (1S,2R) -2- [6- (5-cyano-thiophen-2-yl) -pyridin-3-yloxy ] -cyclohexyl } -amide;
or a pharmaceutically acceptable salt thereof.
Other specific compounds of the invention and pharmaceutically acceptable salts thereof include the following:
propane-2-sulfonic acid [4- (4-benzyl-phenoxy) -tetrahydro-furan-3-yl ] -amide;
propane-2-sulfonic acid {4- [4- (1-phenyl-ethyl) -phenoxy ] -tetrahydro-furan-3-yl } -amide;
propane-2-sulfonic acid {4- [4- (hydroxy-phenyl-methyl) -phenoxy ] -tetrahydro-furan-3-yl } -amide;
propane-2-sulfonic acid [4- (4-benzoyl-phenoxy) -tetrahydro-furan-3-yl ] -amide;
propane-2-sulfonic acid [4- (4-phenoxymethyl-phenoxy) -tetrahydro-furan-3-yl ] -amide;
propane-2-sulfonic acid {4- [4- (pyrrolidine-1-carbonyl) -phenoxy ] -tetrahydro-furan-3-yl } -amide;
propane-2-sulfonic acid {4- [ 3-fluoro-4- (2-oxo-pyrrolidin-1-ylmethyl) -phenoxy ] -tetrahydro-furan-3-yl } -amide;
propane-2-sulfonic acid {4- [4- (1, 1-dioxo-1. lamda.) -＊6＊-isothiazolidin-2-ylmethyl) -phenoxy]-tetrahydro-furan-3-yl } -amide;
propane-2-sulfonic acid [4- (4-phenoxy) -tetrahydro-furan-3-yl ] -amide;
n- {4- [4- (prop-2-sulfonylamino) -tetrahydro-furan-3-yloxy ] -phenyl } -benzylamide;
propane-2-sulfonic acid {4- [4- (2-oxo-pyrrolidin-1-yl) -phenoxy ] -tetrahydro-furan-3-yl } -amide;
2- [ 2-fluoro-4- (tetrahydro-furan-3-yloxy) -phenyl ] -isothiazolidine 1, 1-dioxide; compounds with propane-2-sulfonic acid amide;
n- [4- (2' -cyano-biphenyl-4-yloxy) -tetrahydro-furan-3-yl ] -methanesulfonamide;
3- [4- (2' -cyano-biphenyl-4-yloxy) -tetrahydro-furan-3-yl ] -1, 1-dimethyl-sulfonylurea;
propane-2-sulfonic acid {4- [5- (2-cyano-phenyl) -pyridin-2-yloxy ] -tetrahydro-furan-3-yl } -amide; and
propane-2-sulfonic acid {4- [5- (2-cyano-phenyl) -pyrimidin-2-yloxy ] -tetrahydro-furan-3-yl } -amide.
The compounds of formula I and pharmaceutically acceptable salts thereof are useful in the treatment of a variety of neurological and psychiatric disorders associated with glutamate dysfunction, including: acute neurological and psychiatric disorders such as brain defects secondary to cardioplegic surgery and transplantation, stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal injury, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscle spasms and conditions associated with muscle spasticity (including tremors, epilepsy, convulsions), migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, ocular injury, diabetic neuropathy, dementia, and substance withdrawal (including substances such as opiates, nicotine, tobacco products, benzodiazepines, cocaine, sedatives, hypnotics), psychosis, and psychoses, Schizophrenia, anxiety disorders (including generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorder), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, cerebral edema, pain (including acute and chronic pain states, severe pain, refractory pain, neuralgia, and post-injury pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, attention deficit disorders, and behavioral disorders. Accordingly, in one embodiment, the present invention provides a method for treating a condition selected from the above conditions in a mammal (such as a human being) comprising administering to the mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The mammal is preferably a mammal in need of such treatment or prevention.
The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition or one or more symptoms of the disorder or condition to which the term applies. The term "treatment", as used herein, unless otherwise indicated, refers to the therapeutic effect of "treating", as defined immediately above.
For example, the present invention provides a method for treating a condition selected from migraine, anxiety, schizophrenia and epilepsy. Exemplary anxiety disorders are generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, and obsessive compulsive disorder. For another example, the invention provides a method for treating a depression selected from major depression, chronic depression (dysthymia), seasonal depression (seasonal affective disorder), psychotic depression, and postpartum depression. For another example, the present invention provides a method for treating a sleep disorder selected from insomnia and sleep deprivation.
In another embodiment, the invention comprises a method of treating a condition in a mammal by administering to the mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the condition is selected from atherosclerotic cardiovascular disease, cerebrovascular disease, and peripheral arterial disease. The mammal is preferably a mammal in need of such treatment or prevention. Other conditions that may be treated according to the invention include hypertension and angiogenesis.
In another embodiment, the present invention provides a method of treating neurological and psychiatric disorders associated with glutamate dysfunction comprising administering to a mammal, preferably a mammal in need thereof, a compound of formula I or a pharmaceutically acceptable salt thereof, in an amount effective to treat said disorders.
A compound of formula I or a pharmaceutically acceptable salt thereof is optionally used in combination with another active agent. The active agent may be, for example, an atypical antipsychotic or an AMPA potentiator. Accordingly, another embodiment of the present invention provides a method of treating neurological and psychiatric disorders associated with glutamate dysfunction comprising administering to a mammal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and additionally comprising administering another active agent.
As used herein, the term "another active agent" refers to any therapeutic agent suitable for treating a condition in a subject other than a compound of formula (I) or a salt thereof. Examples of additional therapeutic agents include antidepressants, antipsychotics, anti-pain agents, anti-alzheimer's agents, and anxiolytics. Examples of specific classes of antidepressants that may be used in combination with the compounds of the present invention include norepinephrine reuptake inhibitors, Selective Serotonin Reuptake Inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMA), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), Corticotropin Releasing Factor (CRF) antagonists, alpha-adrenoceptor antagonists, and atypical antidepressants. Suitable noradrenaline reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Examples of suitable tertiary and secondary amine tricycles include amitriptyline (amitriptyline), clomipramine (clomipramine), doxepin (doxepin), imipramine (imipramine), trimipramine (trimipramine), dothiepin (dothiepin), butriptyline (butriptyline), iprindone (iprindone), lofopramine (lofepramine), nortriptyline (nortriptyline), protriptyline (protriptyline), amoxapine (amoxapine), desipramine (desipramine), and mepriptyline (maprotiline). Examples of suitable selective serotonin reuptake inhibitors include fluoxetine (fluoxetine), fluvoxamine (fluvoxamine), paroxetine (parooxetine), and sertraline (sertraline). Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine and triamcinolone. Examples of suitable reversible inhibitors of monoamine oxidase include moclobemide (moclobemide). Examples of serotonin and norepinephrine reuptake inhibitors suitable for use in the present invention include venlafaxine (venlafaxine). Examples of suitable atypical antidepressants include bupropion (bupropion), lithium, nefazodone (nefazodone), trazodone (trazodone), and viloxazine (viloxazine). Examples of anti-alzheimer's disease agents include dememetin (Dimebon), NMDA receptor antagonists such as memantine (memantine), and cholinesterase inhibitors such as donepezil (donepezil) and galantamine (galantamine). Examples of suitable classes of anxiolytic agents that may be used in combination with the compounds of the present invention include benzodiazepines and serotonin 1A (5-HT1A) agonists or antagonists, particularly 5-HT1A partial agonists, and Corticotropin Releasing Factor (CRF) antagonists. Suitable benzodiazepines include alprazolam (alprazolam), chlordiazepoxide (chloridizazepoxide), clonazepam (clonazepam), chlordiazepoxide (chlorzepam), diazepam (diazepam), halazepam (halazepam), lorazepam (lorazepam), oxazepam (oxazepam) and prazepam (prazepam). Suitable 5-HT1A receptor agonists or antagonists include buspirone (buspirone), fluocinolone (flesinoxan), gepirone (gepirone) and ixabepilone (ipsapirone). Suitable atypical antipsychotics include paliperidone (paliperidone), bifeprunox (bifeprunox), ziprasidone (ziprasidone), risperidone (risperidone), aripiprazole (aripiprazole), olanzapine (olanzapine), and quetiapine (quetiapine). Suitable nicotinic acetylcholine agonists include iprincoline (isproniline), varenicline (varenicline) and MEM 3454. Anti-pain agents include pregabalin (pregabalin), gabapentin (gabapentin), clonidine (clonidine), neostigmine (neostigmine), chloranilide butyric acid (baclofen), midazolam (midazolam), ketamine (ketamine), and ziconotide (ziconotide).
The invention also relates to pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Detailed Description
The compounds of formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or in modified and derivatized forms familiar to those of ordinary skill in the art.
During any of the following synthetic procedures, it is necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting Groups, such as those described in T.W.Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which is incorporated herein by reference.
As the skilled person will appreciate, formula I is used for convenience and it is to be understood that the invention includes each material contained hereinafter as if individually set forth. Thus, the present invention encompasses each of the substances individually and any and all combinations of the substances described. More specifically, in the schemes below, R1To R11M, n, p, q, s, t, w, A, B, X, Y and Z are as defined above.
Scheme 1
Scheme 1 refers to the preparation of compounds of formula I. Referring to scheme 1, aryl halides of formula II (wherein L1Is iodo, bromo or trifluoromethanesulfonate) Can be reacted with the structure (R) under standard palladium catalyzed cross-coupling reaction conditions well known to those of ordinary skill in the art1)n-ArB(OH)2Coupled with an appropriately substituted arylboronic acid wherein Ar represents an appropriately substituted aryl or heteroaryl group and B is boron to give a compound of formula I [ Suzuki, A., Journal of organometallics chemistry, 576, 147-169(1999), Miyaura and Suzuki, Chemical Reviews, 95, 2457-245883 (1995) ].]. The compound of formula II can be prepared from the compound of formula III by reacting(wherein Z is O or S) by L2(wherein L2May be halo, -OSO2CH3(-OMs) or-OSO2CF3(-OTf)) was prepared. Typical conditions comprise reaction in an organic solvent such as acetonitrile in the presence of a base such as cesium carbonate at elevated temperatures such as 150 ℃. Where Z is S, the product II or I may be further oxidised with a reagent such as a peroxide (such as mCPBA) in a solvent such as dichloromethane at room temperature to give > S ═ O or > SO2。
Alternatively, the optical properties may be determined according to a standard analogous to withbroo, g.j.; singer, r.a.; sieser, J.E. "streaming Synthesis of the bipropylos Family of Ligands and Process Res.Dev.2008, 12, 480-Ring 489 by reaction with an appropriately substituted aryl reagent(wherein L2Is halo or-OSO2CF3(-OTf)) is subjected to nucleophilic aromatic substitution reaction (such as with an aryl tin (such as SnAr)) to convert to a compound of formula II (wherein L is2Is ZH and Z is O or S). Typical conditions comprise in an organic solvent such as ethanol, in a base such as potassium hydroxide, such as palladium (such as Pd)2(dba)3) And ligands (such as 1- [2- [ bis (tert-butyl) phosphino)]Phenyl radical]-3, 5-diphenyl-1H-pyrazole (bipyphos)) at elevated temperature, such as 80 ℃.
Alternatively, the compound of formula I may be prepared from L1Compounds of formula II that are silane groups, such as trimethylsilyl, are prepared by first converting the silane group to a halo group, such as by reaction with a halogenating agent such as potassium bromide/N-chlorosuccinimide (NCS) in the presence of an acid, such as acetic acid, followed by an arylation reaction as described above. Suitable solvents for the halogenation reaction include alcohols, such as methanol or ethanol. The reaction may be carried out at a temperature of about 10 ℃ to about 60 ℃ for about 10 to about 120 minutes.
Alternatively, compounds of formula I (wherein q is 0 and Y is O or NR)7) A compound of formula II (wherein L is1Is NH2Or OH) with an aryl halide.
Alternatively, when q is 2 or 3, one skilled in the art will appreciate that multiple coupling reactions of two appropriately functionalized alkyl groups can yield compounds of formula I. Such reactions are within the skill of the art.
The compounds of formula II can be prepared from compounds of formula III by coupling with an appropriately substituted aryl Grignard (Grignard) in ether solvents such as THF at about-30 ℃ to about room temperature. A catalyst such as palladium or copper may promote the reaction.
The compounds OF formula III are commercially available or can be prepared by METHODS well known to those skilled in the art or can be prepared by conventional METHODS known in the art, such as those disclosed in standard references such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol.I-VI (published by Wiley-Interscience).
The compounds of formula I can be separated into enantiomerically pure isomers according to methods well known to those skilled in the art and described in detail in the examples section herein.
The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. The acid addition salts of the basic compounds of the present invention are readily prepared by treating the basic compound with a substantially equivalent amount of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt was obtained.
Basic salts are readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation, followed by evaporation of the resulting solution to dryness, preferably under reduced pressure. Alternatively, it can also be prepared by mixing together a lower alkanol solution of the acidic compound with the desired alkali metal alkoxide, and subsequently evaporating the resulting solution to dryness in the same manner as before. In either case, it is preferred to use stoichiometric amounts of the reagents to ensure reaction completion and maximum product yield.
When the salt is intended for administration to a patient (as compared to, for example, use in an in vitro situation), the salt is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to salts prepared by combining a compound of formula I with an anion or cation, typically considered an acid or base suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the process of the invention because they are more water soluble than the parent compound. For use in medicine, salts of the compounds of the invention are non-toxic "pharmaceutically acceptable salts".
Typically, the compounds of the invention are administered in an amount effective to treat or prevent a condition as described herein. The compounds of the invention may be administered by any suitable route, in the form of pharmaceutical compositions adapted to such route and in dosages effective for the desired treatment or prevention. The therapeutically effective dose of the compound required to treat or prevent the progression of a medical condition can be readily determined by one of ordinary skill in the art using preclinical and clinical methods familiar to those in the medical arts.
The compounds of the invention may be administered orally. Oral administration may comprise swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, whereby the compound enters the blood stream directly from the mouth.
In another embodiment, the compounds of the invention may be administered directly into the bloodstream, muscle or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.
In another embodiment, the compounds of the present invention may be applied topically, i.e., transdermally or transdermally, to the skin or mucosa. In another embodiment, the compounds of the invention may be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention may be administered rectally or vaginally. In another embodiment, the compounds of the present invention may be administered directly to the eye or ear.
The course of administration of the compound and/or composition containing the compound is based on a variety of factors including the type of patient, age, weight, sex, and medical condition; severity of the condition; the route of administration; and the activity of the particular compound used. Thus, the course of administration can vary widely. Dosage levels suitable for treating or preventing the conditions indicated above are from about 0.01mg to about 100mg per kg body weight per day. In one embodiment, the total daily dose of the compounds of the invention (administered in single or divided doses) is typically from about 0.01 to about 100 mg/kg. In another embodiment, the total daily dose of a compound of the invention is from about 0.1 to about 50mg/kg, and in another embodiment, from about 0.5 to about 30mg/kg (i.e., milligrams of a compound of the invention per kilogram of body weight). In one embodiment, the dosage is 0.01 to 10 mg/kg/day. In another embodiment, the dosage is 0.1 to 1.0 mg/kg/day. Unit dosage compositions may contain such amounts or submultiples thereof to make up the daily dose. In many cases, compound administration is repeated multiple times (usually up to 4 times) during a day. Multiple daily administrations are usually used to increase the total daily dose, if necessary.
For oral administration, the compositions are provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, or 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. Medicaments typically contain from about 0.01mg to about 500mg of active ingredient, or in another embodiment, from about 1mg to about 100mg of active ingredient. For intravenous administration, the dosage may range from about 0.1 to about 10 mg/kg/min during a constant rate infusion.
Suitable subjects of the invention include mammalian subjects. Mammals of the present invention include, but are not limited to, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates and the like, and include mammals in utero. In one embodiment, the human is a suitable subject. The human subject may be of any gender and at any stage of development.
In another embodiment, the invention encompasses the use of one or more compounds of the invention in the preparation of a medicament for the treatment or prevention of the conditions listed herein.
For the treatment or prevention of the above-mentioned conditions, the compounds of the invention may be administered as the compound itself. Alternatively, pharmaceutically acceptable salts of the compounds are suitable for pharmaceutical use because they are more water soluble than the parent compound.
In another embodiment, the invention encompasses a pharmaceutical composition. The pharmaceutical composition comprises a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The carrier can be a solid, a liquid, or both, and can be formulated with the compound as a unit dose composition, e.g., a tablet, which can contain from 0.05% to 95% by weight of the active compound. The compounds of the invention may be coupled to suitable polymers as targetable drug carriers. Other pharmacologically active substances may also be present.
The compounds of the present invention and their pharmaceutically acceptable salts may be administered by any suitable route, preferably in the form of pharmaceutical compositions adapted to such route and in dosages effective for the desired treatment or prevention. The active compounds, pharmaceutically acceptable salts and compositions thereof may be administered, for example, orally, rectally, parenterally or topically.
Oral administration of solid dosage forms may be presented, for example, as discrete units such as hard or soft capsules, pills, cachets, buccal tablets, or tablets, each containing a predetermined amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof. In another embodiment, it may be administered orally in powder or granular form. In another embodiment, the oral dosage form is a sublingual dosage form, such as a lozenge. In such solid dosage forms, the compound of formula I, or a pharmaceutically acceptable salt thereof, is typically combined with one or more adjuvants. The capsule or tablet may contain a controlled release formulation. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents or may be prepared with an enteric coating.
In another embodiment, administration may be oral in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art (e.g., water). The compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweetening agents), and/or perfuming agents.
In another embodiment, the invention comprises a parenteral dosage form. "parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting and/or suspending agents.
In another embodiment, the present invention comprises a topical dosage form. "topical administration" includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device; intraocular administration; or intranasally or by inhalation. Compositions for topical application also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient into the skin or other affected area. When the compounds of the present invention and their pharmaceutically acceptable salts are administered by transdermal means, administration is achieved using a reservoir and a patch of porous membrane type or solid matrix type. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, powders, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white soft paraffin, glycerol, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated, see, for example, J Pharm Sci, 88(10), 955-958, Finnin, and Morgan (10 months 1999).
Formulations suitable for topical administration to the eye include, for example, eye drops wherein a compound of the present invention or a pharmaceutically acceptable salt thereof is dissolved or suspended in a suitable carrier. Typical formulations suitable for ocular or otic administration may be in the form of drops of a micronized suspension or solution in isotonic sterile saline with adjusted pH. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, tablets, lenses, and microparticles or vesicular systems, such as non-phospholipid liposomes (niosomes) or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose), or heteropolysaccharide polymers (e.g., gellan gum) may be incorporated with preservatives such as benzalkonium chloride (benzalkonium chloride). The formulations may also be delivered by iontophoresis therapy.
For intranasal or inhalation administration, the active compounds of the invention or pharmaceutically acceptable salts thereof are preferably delivered in the form of a solution or suspension from a pump spray container which is squeezed or aspirated by the patient, or as an aerosol spray from a pressurised container or nebuliser, using a suitable propellant. Formulations suitable for intranasal administration are generally administered from dry powder inhalers either in dry powder form (alone, in admixture, e.g. with lactose, or as particles of a mixing component, e.g. mixed with a phospholipid, such as lecithin), or from pressurised containers, pumps, nebulisers (nebulisers which generate a fine mist using electrohydrodynamic forces are preferred) or nebulisers in the form of aerosol sprays, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive, such as polyglucose or cyclodextrin.
In another embodiment, the invention comprises a rectal dosage form. The rectal dosage form may be in the form of, for example, suppositories. Although cocoa butter is a traditional suppository base, a variety of alternatives may be used as appropriate.
Other carrier materials and modes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above-mentioned items relating to effective formulation and application procedures are well known in the art and are described in standard texts. Pharmaceutical formulations are discussed, for example, in Hoover, John e., Remington's Pharmaceutical Sciences, Mack Publishing co., Easton, Pennsylvania, 1975; coded by Liberman et al, Pharmaceutical document Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al, Handbook of pharmaceutical Excipients (3 rd edition), American pharmaceutical Association, Washington, 1999.
The compounds of the present invention and their pharmaceutically acceptable salts can be used alone or in combination with other therapeutic agents for the treatment or prevention of various conditions or disease states. The compounds of the invention, their pharmaceutically acceptable salts and other therapeutic agents may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially in either order. Exemplary therapeutic agents may be, for example, metabotropic glutamate receptor agonists.
By two or more compounds being administered "in combination" is meant that the two compounds are administered close enough in time that the presence of one compound alters the biological effect of the other compound. The two or more compounds may be administered simultaneously, concurrently or sequentially in either order. In addition, simultaneous administration can be carried out by mixing the compounds prior to administration, or by administering the compounds at the same point in time but at different anatomical sites or using different routes of administration.
The phrases "concurrent administration", "co-administration", and "simultaneous administration" mean that the compounds are administered in combination.
The invention further comprises kits suitable for carrying out the above-described therapeutic or prophylactic methods. In one embodiment, the kit contains a first dosage form comprising one or more compounds of the invention or pharmaceutically acceptable salts thereof, and a container for carrying a dosage form in an amount sufficient to perform the methods of the invention.
In another embodiment, a kit of the invention comprises one or more compounds of the invention or a pharmaceutically acceptable salt thereof.
Single crystal X-ray structural measurements were performed on three compounds of the invention to elucidate their absolute stereochemistry. Crystallographic data are provided below.
Representative crystals were measured (see below for data set characterization of individual compounds and diffractometer used). Friedel pairs (Friedel pairs) were collected to facilitate determination of absolute configuration. Atomic scattering factors were obtained from International Tables for Crystallography, Vol.C, 219, 500, Kluwer Academic Publishers, 1992. All crystallographic calculations were aided by the SHELXTL system, 5.1 th edition, Bruker AXS, 1997. All diffractometer data were collected at room temperature. The relevant crystals, data collection and refinement for each compound are summarized in table I.
The test structures of the respective compounds were obtained by the direct method. The test structures were refined as usual. Whenever possible, the hydrogen position is calculated. Methyl hydrogens were located by differential fourier techniques (difference fourier techniques) and then idealized. Any hydrogen on the nitrogen is located and refined by differential fourier techniques. The hydrogen parameter was added to the structure factor calculation, but it was not refined. The offsets calculated in the last rounds of least squares refinement are all less than 0.1 of the corresponding standard deviation. The final R-index for each structure is given. The final differential fourier reveals the electron density of any of these structures without omission or dislocation.
Absolute configuration was determined by the method of Flack, Acta crystallogr, 1983 a39, 876. The coordinates, anisotropic temperature factors, distances, and angles for each structure are shown below (tables 1-5).
Experimental procedures
The experiments are generally carried out under an inert atmosphere (nitrogen or argon), in particular when oxygen-or moisture-sensitive reagents or intermediates are used. Commercial solvents and reagents were generally used without further purification, including anhydrous solvents as appropriate (typically, Sure-Seal from Aldrich Chemical Company (Milwaukee, Wisconsin)TMProduct). Mass spectral data were reported by Liquid Chromatography Mass Spectrometry (LCMS), Atmospheric Pressure Chemical Ionization (APCI), or Gas Chromatography Mass Spectrometry (GCMS) instruments. Chemical shifts of Nuclear Magnetic Resonance (NMR) data are expressed in parts per million (ppm, δ) with reference to the residual peak of the deuterated solvent used.
For synthetic reference procedures in other examples, preparations, or methods, the reaction conditions (reaction time and temperature) may vary. Generally, after the reaction, thin layer chromatography or mass spectrometry is performed, and if appropriate, processing is performed. If non-product solids are present in the crude reaction mixture, then use is made ofFiltration is carried out. Purification between experiments may vary: in general, the solvent and solvent ratio for the eluent/gradient are selected to provide the appropriate RfOr residence time.
Preparation 1
Synthesis of cis-N- {4- [ (6-bromopyridin-3-yl) oxy ] tetrahydrofuran-3-yl } propane-2-sulfonamide
Step 1 Synthesis of trans-4- [ (6-bromopyridin-3-yl) oxy ] tetrahydrofuran-3-ol
The title compound of step 1 was prepared according to the general procedure for the synthesis of trans-4- (4-bromophenoxy) tetrahydrofuran-3-ol in example 2, substituting 6-bromopyridin-3-ol for 4-bromophenol and purifying the crude product by silica gel chromatography (gradient: 20% to 70% ethyl acetate in heptane). Yield: 5.24g, 20.2mmol, 61%.1H NMR(500MHz，CDCl3)δ3.79(dd，J＝9.9，1.9Hz，1H)，3.87(dd，J＝10.4，1.8Hz，1H)，4.00(dd，J＝9.9，4.3Hz，1H)，4.19(dd，J＝10.4，4.7Hz，1H)，4.38(br m，1H)，4.59(br s，1H)，4.68(br d，J＝4.4Hz，1H)，7.14(dd，J＝8.7，3.2Hz，1H)，7.32(dd，J＝8.7，0.5Hz，1H)，8.01(br d，J＝3.1Hz，1H)。
Step 2 Synthesis of trans-4- [ (6-bromopyridin-3-yl) oxy ] tetrahydrofuran-3-yl methanesulfonate
The title compound of step 2 was prepared according to the general procedure for the synthesis of trans-2- (4-bromophenoxy) cyclopentylmethanesulfonate as in example 5 substituting trans-4- [ (6-bromopyridin-3-yl) oxy]Tetrahydrofuran-3-ol was substituted for trans-2- (4-bromophenoxy) cyclopentanol. The product was obtained as a solid. Yield: 5.95g, 17.6mmol, 87%.1H NMR(400MHz，CDCl3)δ3.07(s，3H)，3.94(br dd，J＝10.5，1.8Hz，1H)，4.00(m，1H)，4.11(dd，J＝11.1，4.1Hz，1H)，4.18(dd，J＝10.6，4.5Hz，1H)，4.97(br d，J＝4.4Hz，1H)，5.13(br d，J＝3.8Hz，1H)，7.19(dd，J＝8.7，3.2Hz，1H)，7.35(dd，J＝8.7，0.5Hz，1H)，8.04(dd，J＝3.2，0.5Hz，1H)。
Step 3 Synthesis of cis-N- {4- [ (6-bromopyridin-3-yl) oxy ] tetrahydrofuran-3-yl } propane-2-sulfonamide
Reacting trans-4- [ (6-bromopyridin-3-yl) oxy]Tetrahydrofuran-3-yl methanesulfonate (591.7mg, 1.75mmol), propane-2-sulfonamide (647mg, 5.25mmol) and cesium carbonate (855mg, 2.62mmol) were combined in acetonitrile (8mL) and subjected to microwave irradiation at 150 ℃ for 55 minutes. The crude reaction mixture was combined with several analogous reactants operating under the same conditions (total starting materials used: 1.527g, 4.515mmol) and saturatedAqueous sodium bicarbonate (100mL) was shaken together. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient: 5% to 40% ethyl acetate in heptane) to give the title compound. Yield: 382mg, 1.046mmol, 23%.1H NMR(400MHz，CDCl3) δ 1.34(d, J ═ 6.8Hz, 3H), 1.36(d, J ═ 6.8Hz, 3H), 3.17 (heptad, J ═ 6.8Hz, 1H), 3.74(dd, J ═ 9, 9Hz, 1H), 3.94(dd, J ═ 10.9, 1.5Hz, 1H), 4.14(dd, J ═ 8, 8Hz, 1H), 4.19(dd, J ═ 10.9, 4.3Hz, 1H), 4.27(m, 1H), 4.84(m, 1H), 5.66(d, J ═ 9.9Hz, 1H), 7.20(dd, J ═ 8.8, 3.2Hz, 1H), 7.40(d, J ═ 8.8, 1H), 8.01(d, J ═ 2H, 1H), 7.40(d, J ═ 8.8, 1H), 3.01 (d, 1H).
Preparation 2
Synthesis of methyl 3-cyano-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate
Step 1 Synthesis of methyl 3-cyano-4- { [ (trifluoromethyl) sulfonyl ] oxy } -benzoate
Treatment of methyl 3-cyano-4-hydroxybenzoate with 4- (dimethylamino) pyridine (432mg, 3.54mmol) [ see P.Madsen et al, J.medicinal Chemistry 2002, 45, 5755-](4.18g, 23.6mmol) in dichloromethane (81mL) and cooled to 0 ℃. After addition of triethylamine (4.93mL, 35.4mmol), the solution was treated dropwise with trifluoromethanesulfonic anhydride (5.96mL, 35.4mmol) and warmed to room temperature. After 2 hours, the reaction was concentrated in vacuo and repeated with dichloromethane and concentrated until 17 grams of material remained. It was subjected to silica gel chromatography (gradient: 0% to 10% ethyl acetate in heptane) to give the product as a colorless oil. Yield: 6.50g, 21.0mmol, 89%.1H NMR(500MHz，CDCl3)δ4.00(s，3H)，7.60(d，J＝8.8Hz，1H)，8.39(dd，J＝8.8，2.1Hz，1H)，8.45(d，J＝2.2Hz，1H)。
Step 2. Synthesis of Compound methyl 3-cyano-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) benzoate
4, 4, 4', 4', 5, 5, 5 ', 5 ' -octamethyl-2, 2' -bis-1, 3, 2-dioxolane (bis (valeryl) diboron (5.81g, 22.9mmol), 3-cyano-4- { [ (trifluoromethyl) sulfonyl]Oxy } benzoic acid methyl ester (5.90g, 19.1mmol), potassium acetate (99%, 9.46g, 95.4mmol) and 1, 1' - [ bis (diphenylphosphino) ferrocene]The dichloropalladium (II) (1.40g, 1.91mmol) was combined in degassed dioxane (83 mL). The reaction was sealed and heated at 100 ℃ for 18 hours, then treated with dichloromethane (100mL), stirred well and passed throughAnd (5) filtering. The filter cake was washed with dichloromethane (2 × 100mL), and the combined filtrates were concentrated in vacuo and subjected to silica gel chromatography (gradient: 0% to 30% ethyl acetate in heptane). The product containing fractions were concentrated and recrystallized from 2-propanol to give the title compound as a white solid. Yield: 3.395g, 11.82mmol, 62%.1H NMR(400MHz，CDCl3)δ1.41(s，12H)，3.97(s，3H)，7.98(d，J＝7.8Hz，1H)，8.20(dd，J＝7.8，1.6Hz，1H)，8.35(br d，J＝1.6Hz，1H)。
Preparation 3
Synthesis of N- [ (1S,2R) -2- (4-bromo-3-fluorophenoxy) cyclopentyl ] propane-2-sulfonamide
Step 1. Synthesis of trans-2- (4-bromo-3-fluorophenoxy) cyclopentanol
4-bromo-3-fluorophenol (8.00g, 41.9mmol) was reacted with 6-oxabicyclo [ 3.1.0%]Hexane (8.25mL, 95.2mmol) was combined in butyronitrile (5.0mL) and treated with sodium carbonate (4.04g, 38.1 mmol). Subjecting the reaction to microwave irradiation at 175 ℃ for 2 hours, followed byAnd (5) filtering. The filter cake was washed with ethyl acetate and then dichloromethane and the combined filtrates were concentrated under reduced pressure to give the product as a dark brown oil. This material was used without additional purification. Yield: 11.59g, > 41.9mmol, quantitative is assumed.1H NMR(400MHz，CDCl3)δ1.61-1.89(m，5H)，2.02-2.24(m，2H)，4.30(m，1H)，4.46(m，1H)，6.63(ddd，J＝8.9，2.8，1.1Hz，1H)，6.73(dd，J＝10.5，2.8Hz，1H)，7.40(dd，J＝8.9，8.0Hz，1H)。
Step 2. Synthesis of (1R, 2R) -2- (4-bromo-3-fluorophenoxy) cyclopentyl acetate
The title compound in step 2 was prepared according to the general procedure for the synthesis of (1R, 2R) -2- (4-bromophenoxy) cyclopentyl acetate in example 7, substituting trans-2- (4-bromo-3-fluorophenoxy) cyclopentanol for trans-2- (4-bromophenoxy) cyclohexanol. The less polar material was purified by silica gel chromatography to give (1R, 2R) -2- (4-bromo-3-fluorophenoxy) cyclopentyl acetate as an oil. Yield: 6.42g, 20.2mmol, 48% (2 steps).1H NMR(400MHz，CDCl3)δ1.67-1.75(m，1H)，1.79-1.92(m，3H)，2.05-2.20(m，2H)，2.08(s，3H)，4.60(m，1H)，5.14(m，1H)，6.66(ddd，J＝8.9，2.8，1.1Hz，1H)，6.78(dd，J＝10.5，2.8Hz，1H)，7.40(dd，J＝8.8，8.1Hz，1H)。
Step 3. Synthesis of (1R, 2R) -2- (4-bromo-3-fluorophenoxy) -cyclopentyl acetate
The title compound in step 3 was prepared according to the general procedure for the synthesis of (1R, 2R) -2- (4-bromophenoxy) cyclohexanol in example 7, substituting acetic acid (1R, 2R) -2- (4-bromo-3-fluorophenoxy) cyclopentyl ester for acetic acid (1R, 2R) -2- (4-bromophenoxy) cyclopentyl ester. The product was obtained as a yellow oil. Yield: 5.29g, 19.2mmol, 95%.1H NMR(500MHz，CDCl3)δ1.62-1.68(m，2H)，1.71-1.90(m，3H)，2.04-2.11(m，1H)，2.15-2.22(m，1H)，4.30(m，1H)，4.47(m，1H)，6.63(ddd，J＝8.9，2.8，1.1Hz，1H)，6.73(dd，J＝10.5，2.8Hz，1H)，7.40(dd，J＝8.9，8.1Hz，1H)。
Step 4, synthesizing (1R, 2R) -2- (4-bromo-3-fluorophenoxy) cyclopentylmethanesulfonate
Synthesis of trans-2- (4-bromophenoxy) cyclopentyl according to example 5General procedure for mesylate the title compound in step 4 was prepared by substituting (1R, 2R) -2- (4-bromo-3-fluorophenoxy) cyclopentanol for trans-2- (4-bromophenoxy) cyclopentanol. The product was obtained as an oil, which was used in the next step without purification. MS (GCMS) M/z 352, 354(M + 1).1H NMR(500MHz，CDCl3)δ1.81-2.00(m，4H)，2.16-2.26(m，2H)，3.04(s，3H)，4.77(m，1H)，5.07(m，1H)，6.65(ddd，J＝8.9，2.8，1.1Hz，1H)，6.74(dd，J＝10.2，2.8Hz，1H)，7.43(dd，J＝8.9，8.0Hz，1H)。
Step 5, (1R,2S) -2-azido cyclopentyl 4-bromo-3-fluorophenyl ether is synthesized
The title compound in step 5 was prepared according to the general procedure for the synthesis of cis-2-azidocyclopentyl 4-bromophenyl ether in example 5, substituting (1R, 2R) -2- (4-bromo-3-fluorophenoxy) cyclopentane mesylate for trans-2- (4-bromophenoxy) cyclopentane mesylate. The product was isolated as a brown oil which was used in the next step without purification.1H NMR(400MHz，CDCl3)δ1.66-1.75(m，1H)，1.88-2.08(m，5H)，3.74(m，1H)，4.65(m，1H)，6.66(ddd，J＝8.9，2.8，1.1Hz，1H)，6.75(dd，J＝10.4，2.8Hz，1H)，7.42(dd，J＝8.8，8.0Hz，1H)。
Step 6, synthesizing (1S,2R) -2- (4-bromo-3-fluorophenoxy) cyclopentylamine
The title compound in step 6 was prepared according to the general procedure for the synthesis of cis-2- (4-bromophenoxy) cyclopentylamine as in example 5, substituting (1R,2S) -2-azidocyclopentyl 4-bromo-3-fluorophenylether for cis-2-azidocyclopentyl 4-bromophenyl ether and cis-2- (4-bromophenoxy) cyclopentylamine for the next step without purification. LCMS M/z 276.2(M + 1).1H NMR(500MHz，CDCl3)δ1.5(v br s，2H)，1.57-1.66(m，2H)，1.80-1.87(m，2H)，1.93-2.01(m，2H)，3.36(m，1H)，4.41(m，1H)，6.63(ddd，J＝8.9，2.8，1.1Hz，1H)，6.71(dd，J＝10.5，2.8Hz，1H)，7.40(dd，J＝8.8，8.0Hz，1H)。
Step 7, synthesizing N- [ (1S,2R) -2- (4-bromo-3-fluorophenoxy) -cyclopentyl ] propane-2-sulfonamide
Synthesis of cis-N- [2- (4-bromophenoxy) cyclopentyl ] according to example 5]General procedure for propane-2-sulfonamide the title compound in step 7 was prepared by substituting (1S,2R) -2- (4-bromo-3-fluorophenoxy) cyclopentylamine for cis-2- (4-bromophenoxy) cyclopentylamine, and purified by chromatography with a gradient of 0% to 10% methanol in dichloromethane to afford the title compound as an off-white solid. Yield: 4.15g, 10.9mmol, 54% starting from acetic acid (1R, 2R) -2- (4-bromo-3-fluorophenoxy) cyclopentyl ester (5 steps).1H NMR(500MHz，CDCl3) δ 1.36(d, J ═ 6.7Hz, 3H), 1.39(d, J ═ 6.8Hz, 3H), 1.62-1.69(m, 1H), 1.77-1.90(m, 3H), 1.92-2.00(m, 1H), 2.10-2.15(m, 1H), 3.14 (heptad, J ═ 6.8Hz, 1H), 3.86(m, 1H), 4.56-4.60(m, 2H), 6.61(ddd, J ═ 8.9, 2.8, 1.1Hz, 1H), 6.70(dd, J ═ 10.3, 2.8Hz, 1H), 7.43(dd, J ═ 8.8, 8.1Hz, 1H). Determination of N- [ (1S,2R) -2- (4-bromo-3-fluorophenoxy) cyclopentyl group in analogy to the stereochemistry of the compounds of example 7 and preparation 6]The absolute configuration of propane-2-sulfonamide.
Preparation 4
Synthesis of (2-cyano-4-fluorophenyl) boronic acid
2-bromo-5-fluorobenzonitrile (6.00g, 30.0mmol) and triisopropyl borate (8.28mL, 36.0mmol) were dissolved in a mixture of toluene (48mL) and tetrahydrofuran (12mL) and the solution was cooled in a dry ice/acetone bath. A solution of n-butyllithium in hexane (2.5M, 14.4mL, 36.0mmol) was added dropwise over 1 hour, and the reaction was then allowed to warm to room temperature over 18 hours with stirring. The mixture was cooled in an ice bath and treated with 2N aqueous hydrochloric acid until the pH reached 1, then warmed to room temperature at which time the layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, once with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-heptane to give (2-cyano-4-fluorophenyl) acid as a white solid. Yield: 2.20g, 13.3mmol, 44%。1H NMR(400MHz，CD3OD)δ7.43(ddd，J＝8.6，8.6，2.5Hz，1H)，7.55(dd，J＝8.8，2.5Hz，1H)，7.69(br s，1H)。
Preparation 5
Synthesis of N- {2- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] ethyl } methanesulfonamide
Step 1 Synthesis of tert-butyl (methanesulfonyl) {2- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] ethyl } carbamate
4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (4.29mL, 29.6mmol) was slowly added to [2- (4-iodophenyl) ethyl](Methanesulfonyl) carbamic acid tert-butyl ester (see J.P.Gardner and W.D.Miller, PCT patent application publication WO 2001090055, 2001) (8.39g, 19.7mmol), triethylamine (9.64mL, 69.1mmol) and 1, 1' - [ bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (217mg, 0.296mmol) in acetonitrile (50mL) and the reaction mixture was heated at 75 ℃ for 4 hours. After removal of the solvent, the residue was mixed with water (240mL) and extracted with methyl-tert-butyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution and water, then dried over magnesium sulfate, filtered and concentrated in vacuo to synthesize (methanesulfonyl) {2- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl } carbamic acid tert-butyl ester, which is used without additional purification. Yield: quantitation is assumed. LCMS M/z 326.1(M + 1).1H NMR(400MHz，CDCl3)δ1.35(s，12H)，2.84(s，3H)，2.90(t，J＝6.8Hz，2H)，3.42(dt，J＝6.6，6.6Hz，2H)，4.18(br t，J＝6Hz，1H)，7.23(d，J＝8.1Hz，2H)，7.78(d，J＝8.1Hz，2H)。
Step 2, synthesizing N- {2- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] ethyl } methanesulfonamide
Trifluoroacetic acid (10mL) was added to (methanesulfonyl) {2- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl } carbamic acid tert-butyl ester (from the previous step, assuming 19.7mmol) in dichloromethane(100mL) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 18 hours. It was then cooled to 0 ℃ and brought to pH 10.5 with 4N aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient: 0% to 5% methanol in dichloromethane) to give the title compound as an off-white solid. Yield: 2.5g, 7.7mmol, 39% (two steps). LCMS M/z 326.1(M + 1).1H NMR(400MHz，CDCl3)δ1.35(s，12H)，2.84(s，3H)，2.90(t，J＝6.8Hz，2H)，3.42(dt，J＝6.6，6.6Hz，2H)，4.18(br t，J＝6Hz，1H)，7.23(d，J＝8.1Hz，2H)，7.78(d，J＝8.1Hz，2H)。
Preparation 6
Synthesis of N- [ (1S,2R) -2- (4-bromo-3-fluorophenoxy) cyclohexyl ] propane-2-sulfonamide
Synthesis of cis-N- [2- (4-bromophenoxy) cyclopentyl ] according to example 5]General procedure for propane-2-sulfonamide the title compound was prepared by substituting (1S,2R) -2- (4-bromo-3-fluorophenoxy) cyclohexylamine for cis-2- (4-bromophenoxy) cyclopentylamine and chromatographic purification using a 0% to 1% methanol in dichloromethane as gradient. (1S,2R) -2- (4-bromo-3-fluorophenoxy) cyclohexylamine was synthesized according to the general procedure described for the synthesis of (1S,2R) -2- (4-bromophenoxy) cyclohexylamine in example 7, substituting 4-bromo-3-fluorophenol for 4-bromophenol. The title compound was obtained as a white solid.1H NMR(400MHz，CDCl3) δ 1.33-1.53(m, 4H), 1.35-1.38(m, 6H), 1.78-1.89(m, 3H), 2.04-2.10(m, 1H), 3.12 (heptad, J ═ 6.8Hz, 1H), 3.54(m, 1H), 4.44(d, J ═ 9.6Hz, 1H), 4.55(m, 1H), 6.67(br dd, J ═ 8.9, 2.8Hz, 1H), 6.75(dd, J ═ 10.2, 2.7Hz, 1H), 7.43(dd, J ═ 8.5, 8.5Hz, 1H). The absolute configuration of the title compound was determined via X-ray crystallography.
Preparation 7
Synthesis of N- { (1S,2R) -2- [ (6-bromopyridin-3-yl) oxy ] cyclohexyl } propane-2-sulfonamide
Step 1 Synthesis of trans-2- [ (6-bromopyridin-3-yl) oxy ] cyclohexanol
The title compound of step 1 was prepared according to the general procedure for the synthesis of trans-2- (4-bromo-3-fluorophenoxy) cyclopentanol of preparation 3, substituting 6-bromopyridin-3-ol for 4-bromo-3-fluorophenol and 7-oxabicyclo [4.1.0]Heptane substituted for 6-oxabicyclo [3.1.0]Hexane. The crude product (4 preparative runs) was recrystallized from heptane to give trans-2- [ (6-bromopyridin-3-yl) oxy) as an off-white solid]Cyclohexanol. Yield: 11.09g, 40.75mmol, 46%.1H NMR(500MHz，CDCl3)δ1.27-1.46(m，4H)，1.76-1.80(m，2H)，2.09-2.13(m，2H)，2.41(d，J＝2.6Hz，1H)，3.74(m，1H)，4.00(m，1H)，7.17(dd，J＝8.7，3.1Hz，1H)，7.37(d，J＝8.5Hz，1H)，8.10(d，J＝3.0Hz，1H)。
Step 2, synthesizing cis-2- [ (6-bromopyridine-3-yl) oxy ] cyclohexylamine
Cis-5- [ (2-azidocyclohexyl) oxy]-2-bromopyridine (from trans-2- [ (6-bromopyridin-3-yl) oxy group by the general procedure described for the conversion of trans-2- (4-bromophenoxy) cyclopentanol to cis-2-azidocyclopentyl 4-bromophenyl ether in example 5]Cyclohexanol preparation) (13.5g, 45.4mmol) was dissolved in tetrahydrofuran (292mL) and water (23mL) and the solution was treated with triphenylphosphine (23.8g, 90.7 mmol). The reaction was stirred at room temperature for 18 h, then partitioned between ethyl acetate (500mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water (2X 200mL) and saturated aqueous sodium chloride (200 mL). The organic layer was then extracted with 1N aqueous hydrochloric acid (4X 150mL) and the combined aqueous layers were washed with ethyl acetate (150 mL). The aqueous layer was then cooled in an ice bath and slowly treated with 2N aqueous sodium hydroxide until the mixture was a white haze; then extracted with ethyl acetate (3 × 150mL) and the combined organic layers were washed with saturated aqueous sodium chloride (150mL), dried over sodium sulfate, filtered and concentrated in vacuo. Cis-2- [ (6-bromopyridin-3-yl) oxy) was obtained as a yellow oil]Cyclohexylamine. Yield: 8.00g, 29.5mmol, 65%.1H NMR(500MHz，CDCl3)δ1.34(d, J ═ 6.8Hz, 3H), 1.35(d, J ═ 6.7Hz, 3H), 1.35-1.52(m, 4H), 1.79-1.85(m, 3H), 2.02(m, 1H), 3.11 (heptad, J ═ 6.8Hz, 1H), 3.53(m, 1H), 4.59(br s, 1H), 4.68(m, 1H), 7.19(dd, J ═ 8.7, 3.1Hz, 1H), 7.38(d, J ═ 8.7Hz, 1H), 8.07(d, J ═ 3.2Hz, 1H).
Step 3. Synthesis of cis-N- {2- [ (6-bromopyridin-3-yl) oxy ] cyclohexyl } -propane-2-sulfonamide
Synthesis of cis-N- [2- (4-bromophenoxy) cyclopentyl ] according to example 5]General procedure for propane-2-sulfonamide the title compound of step 3 was prepared using cis-2- [ (6-bromopyridin-3-yl) oxy]Cyclohexylamine replaces cis-2- (4-bromophenoxy) cyclopentylamine, and 4- (dimethylamino) pyridine is omitted. In this case, silica gel chromatography using 2% methanol in dichloromethane as eluent gave cis-N- {2- [ (6-bromopyridin-3-yl) oxy ] oxy as a beige foam]Cyclohexyl } propane-2-sulfonamide. Yield: 7.96g, 21.1mmol, 72%.1H NMR(500MHz，CDCl3) δ 1.34(d, J ═ 6.8Hz, 3H), 1.35(d, J ═ 6.7Hz, 3H), 1.35-1.52(m, 4H), 1.79-1.85(m, 3H), 2.02(m, 1H), 3.11 (heptad, J ═ 6.8Hz, 1H), 3.53(m, 1H), 4.59(br s, 1H), 4.68(m, 1H), 7.19(dd, J ═ 8.7, 3.1Hz, 1H), 7.38(d, J ═ 8.7Hz, 1H), 8.07(d, J ═ 3.2Hz, 1H).
Step 4 isolation of N- { (1S,2R) -2- [ (6-bromopyridin-3-yl) oxy ] cyclohexyl } propane-2-sulfonamide
Separation of a mixture containing cis-N- {2- [ (6-bromopyridin-3-yl) oxy group by chiral chromatography]Cyclohexyl } propane-2-sulfonamide (7.96g, 21.1mmol) enantiomer. Column:AD-H, 2.1X 25cm, 5 μm; mobile phase: 70: 30 carbon dioxide: methanol; flow rate: 65 g/min. After removal of the solvent in vacuo, the first eluting compound was the enantiomer [ N- { (1R,2S) -2- [ (6-bromopyridin-3-yl) oxy]Cyclohexyl [ propane ] -2-sulfonamides]And the second eluting peak provides the desired product N- { (1S,2R) -2- [ (6-bromopyridin-3-yl) oxy]Cyclohexyl radicalPropane-2-sulfonamide. Yield: 3.13g, 8.30mmol, 39%. The absolute stereochemistry of these enantiomers was determined analogously to example 5.
Preparation 8
Synthesis of cis-N- [4- (4-bromophenoxy) tetrahydrofuran-3-yl ] propane-2-sulfonamide
Synthesis of cis-N- {4- [ (6-bromopyridin-3-yl) oxy ] according to preparation 1]General procedure for tetrahydrofuran-3-yl } propan-2-sulfonamide the title compound was prepared by substituting trans-4- (4-bromophenoxy) tetrahydrofuran-3-ylmethanesulfonate for trans-4- [ (6-bromopyridin-3-yl) oxy)]Tetrahydrofuran-3-yl methanesulfonate and chromatographic purification was carried out with a gradient of 15% to 35% acetone in heptane. Yield: 238mg, 0.65mmol, 31%.1H NMR(400MHz，CDCl3) δ 1.30(d, J ═ 6.8Hz, 3H), 1.33(d, J ═ 6.8Hz, 3H), 3.11 (heptad, J ═ 6.8Hz, 1H), 3.66(dd, J ═ 9.1, 8.4Hz, 1H), 3.89(dd, J ═ 10.7, 1.7Hz, 1H), 4.07-4.13(m, 2H), 4.19(m, 1H), 4.71(m, 1H), 5.12(d, J ═ 9.6Hz, 1H), 6.75(d, J ═ 9.0Hz, 2H), 7.36(d, J ═ 9.0Hz, 2H).
Example 1
Synthesis of N- {1- [ 4-trans- ({4- [ (isopropylsulfonyl) amino ] tetrahydrofuran-3-yl } oxy) phenyl ] pyrrolidin-3-yl } acetamide
Step 1 Synthesis of trans-N- (4-hydroxytetrahydrofuran-3-yl) propane-2-sulfonamide
3, 6-dioxy-bicyclo [3.1.0 ]]Hexane (1.90g, 22.1mmol), propane-2-sulfonamide (prepared according to the procedure of d.c. johnson, II and t.s.widlanski, Tetrahedron Letters 2004, 45, 8483-8487) (3.13g, 25.4mmol), potassium carbonate (584mg, 4.23mmol) and benzyltriethylammonium chloride (963mg, 4.23mmol) were suspended in dioxane (10mL) and heated at reflux for 120 hours. The reactants are cooled to the chamberWeak, filter, concentrate in vacuo and purify by silica gel chromatography (gradient: 40% to 80% ethyl acetate in heptane) to give trans-N- (4-hydroxytetrahydro-furan-3-yl) propan-2-sulfonamide as a solid. Yield: 3.76g, 18.0mmol, 81%.1H NMR(400MHz，CDCl3) δ 1.38(d, J ═ 6.7Hz, 3H), 1.40(d, J ═ 6.7Hz, 3H)2.91(d, J ═ 3.6Hz, 1H), 3.22 (heptad, J ═ 6.8Hz, 1H), 3.67-3.71(m, 2H), 3.82(m, 1H), 4.08-4.12(m, 2H), 4.40(m, 1H), 4.77(d, J ═ 8.4Hz, 1H),13C NMR(100MHz，CDCl3)δ16.44，16.69，54.18，62.06，71.47，73.50，77.64。
step 2 Synthesis of trans-4- [ (isopropylsulfonyl) amino ] tetrahydrofuran-3-yl methanesulfonate
Triethylamine (1.99mL, 14.3mmol) was added to a cooled (0 ℃ C.) solution of trans-N- (4-hydroxytetrahydrofuran-3-yl) propane-2-sulfonamide (1.99g, 9.52mmol) in dichloromethane (20 mL). Methanesulfonyl chloride (0.885mL, 11.4mmol) was then added and the reaction stirred at 0 ℃ for 50 minutes. Saturated aqueous sodium bicarbonate (10mL) was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (gradient: 10% to 50% ethyl acetate in heptane) to give trans-4- [ (isopropylsulfonyl) amino]Tetrahydrofuran-3-yl methanesulfonate. Yield: 2.27g, 7.90mmol, 83%.1H NMR(400MHz，CDCl3) δ 1.40(d, J ═ 6.8Hz, 3H), 1.41(d, J ═ 6.8Hz, 3H), 3.14(s, 3H), 3.25 (heptad, J ═ 6.8Hz, 1H), 3.77(dd, J ═ 9.5, 2.4Hz, 1H), 3.96(dd, J ═ 11.3, 2.2Hz, 1H), 4.08-4.16(m, 2H), 4.21(dd, J ═ 11.3, 5.1Hz, 1H), 4.77(d, J ═ 8.0Hz, 1H), 5.15(m, 1H).13CNMR(100MHz，CDCl3)δ16.48，16.54，38.28，54.28，59.49，71.83，71.87，83.97。
Step 3, synthesizing trans-N- [4- (4-bromophenoxy) tetrahydrofuran-3-yl ] propane-2-sulfonamide
In a microwave vial, trans-4- [ (isopropylsulfonyl) amino]Tetrahydrofuran-3-yl methane sulfonic acidA solution of the ester (546mg, 1.90mmol) in acetonitrile (8mL) was combined with 4-bromophenol (97%, 407mg, 2.28mmol) and cesium carbonate (929mg, 2.85 mmol). The reaction was irradiated in a microwave reactor at 160 ℃ for 2 hours, then cooled to room temperature and treated with saturated aqueous sodium bicarbonate (10 mL). The reaction was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient: 20% to 50% ethyl acetate in heptane) to give trans-N- [4- (4-bromophenoxy) tetrahydrofuran-3-yl]Propane-2-sulfonamide. Yield: 626mg, 1.72mmol, 91%. LCMS M/z 361.9 (M-1).1H NMR(400MHz，CDCl3) δ 1.38(d, J ═ 6.9Hz, 3H), 1.40(d, J ═ 6.8Hz, 3H), 3.19 (heptad, J ═ 6.8Hz, 1H), 3.82(br d, J ═ 8.0, 1H), 3.91(dd, J ═ 10.6, 1.7Hz, 1H), 4.02-4.08(m, 2H), 4.24(dd, J ═ 10.5, 4.7Hz, 1H), 4.85(br d, J ═ 4.7Hz, 1H), 4.95(br d, J ═ 8.3Hz, 1H), 6.88(d, J ═ 9.0Hz, 2H), 7.40(d, J ═ 9.0Hz, 2H).13C NMR(100MHz，CDCl3)δ16.45，16.71，54.14，58.70，71.45，71.81，82.07，113.97，117.20，132.52，155.75。
Step 4 Synthesis of N- {1- [ 4-trans- ({4- [ (isopropylsulfonyl) amino ] -tetrahydrofuran-3-yl } oxy) phenyl ] pyrrolidin-3-yl } acetamide
To 2-methylbutan-2-ol (2.0mL) was added 2' - (dicyclohexylphosphino) -N, N-dimethylbiphenyl-2-amine (3.2mg, 0.008mmol) and tris (dibenzylideneacetone) dipalladium (0) (2.7mg, 0.003 mmol). The purple reaction mixture was then degassed for 20 minutes and trans-N- [4- (4-bromophenoxy) tetrahydrofuran-3-yl was added]Propane-2-sulfonamide (95mg, 0.26mmol) and N-pyrrolidin-3-yl-acetamide (67mg, 0.52 mmol). Potassium hydroxide (32mg, 0.57mmol) was then added and the reaction degassed for an additional 20 minutes. The brown reaction mixture was heated to reflux under nitrogen and turned yellow. The reaction was monitored by GC-MS and when the reaction was complete, saturated aqueous sodium bicarbonate (5mL) was added. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered, concentrated in vacuo, and chromatographed over silica gel (gradient: 50% to 70% ethyl acetate)Heptane solution of (b)) to give a diastereomeric mixture N- {1- [ 4-trans- ({4- [ (isopropylsulfonyl) amino ] amide as a gum]Tetrahydrofuran-3-yl } oxy) phenyl]Pyrrolidin-3-yl } acetamide. Yield: 97.5mg, 0.236mmol, 91%.1H NMR(400MHz，CDCl3) δ 1.31(d, J ═ 6.8Hz, 3H), 1.32(d, J ═ 6.8Hz, 3H), 1.93(s, 3H), 2.22(m, 1H), 2.64(br s, 1H), 3.07-3.13(m, 2H), 3.19(m, 1H), 3.34-3.43(m, 2H), 3.74(dd, J ═ 9.0, 1.8Hz, 1H), 3.85(dd, J ═ 10.3, 1.7Hz, 1H), 4.00-4.13(m, 3H), 4.53(m, 1H), 4.69(br s, 1H), 5.67(d, J ═ 8.0Hz, 1H), 6.46(d, J ═ 8.8, 2H), 6.46(d, J ═ 8, 2H), 6.46 (H), 6.84(d, 8, 2H), and fragrance pattern (d, 8, 2H).13CNMR(100MHz，CDCl3)δ16.37，16.46，22.98，31.44，46.32，49.31，53.61，53.88，58.67，71.45，71.87，82.80，112.72，117.00，143.13，147.98，170.23。
Example 2
N- [ (3S,4S) -4- (biphenyl-4-yloxy) tetrahydrofuran-3-yl ] propane-2-sulfonamide
Step 1. Synthesis of trans-4- (4-bromophenyloxy) tetrahydrofuran-3-ol
3, 6-dioxy-bicyclo [3.1.0 ]]Hexane (100g, 1.16mol), 4-bromophenol (241.1g, 1.39mol), cesium carbonate (492g, 1.51mol), and benzyltriethylammonium chloride (52.9g, 0.23mol) were suspended in dioxane (1L) and heated at reflux for 18 hours. The reaction was cooled to room temperature and diluted with ethyl acetate, followed by washing with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic portions were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which solidified upon standing. It was used in the next step without purification. Yield: 354g, > 100%, assuming quantitation. By means for characterisationSilica gel chromatography (gradient: 10% to 35% ethyl acetate in heptane) purified material from a smaller scale experiment performed in a similar manner to give trans-4- (4-bromophenoxy) tetrahydrofuran-3-ol as a solid.1H NMR(400MHz，CDCl3)δ2.09(br d，J＝4.5Hz，1H)，3.83(m，1H)，3.91(dd，J＝10.3，2.1Hz，1H)，4.05(dd，J＝10.1，4.0Hz，1H)，4.26(dd，J＝10.4，4.9Hz，1H)，4.41(br s，1H)，4.67(m，1H)，6.81(d，J＝9.0Hz，2H)，7.40(d，J＝9.1Hz，2H)。
Step 2. Synthesis of trans-4- (4-bromophenoxy) tetrahydrofuran-3-yl methanesulfonate
Triethylamine (181.9mL, 1.31mol) was added to a solution of trans-4- (4-bromophenoxy) tetrahydrofuran-3-ol (354g, say 300.6g, 1.16mol) from the previous step in dichloromethane (2L) and the reaction was cooled to 0 ℃ in an ice bath. Methanesulfonyl chloride (101.3mL, 1.31mol) was then added dropwise while maintaining the reaction temperature below 5 ℃, and the reaction was stirred at room temperature for 18 hours. Water (1.5L) was added and the aqueous layer was extracted with dichloromethane. The organics were combined and dried over sodium sulfate, filtered and concentrated in vacuo to afford the product as a brown oil. Yield: 399.6g, 1.18mol, quantitative. Materials obtained from smaller scale experiments performed in a similar manner were wet milled with ethanol for characterization.1H NMR(400MHz，CDCl3)δ3.10(s，3H)，4.00(br dd，J＝10.4，1.9Hz，1H)，4.07(m，1H)，4.16(dd，J＝11.1，3.9Hz，1H)，4.23(dd，J＝10.5，4.6Hz，1H)，4.98(br d，J＝4.6Hz，1H)，5.20(m，1H)，6.85(d，J＝9.1Hz，2H)，7.42(d，J＝9.0Hz，2H)。
Step 3, synthesizing cis-3-azido-4- (4-bromophenoxy) tetrahydrofuran
To a solution of trans-4- (4-bromophenoxy) tetrahydrofuran-3-yl methanesulfonate (133.2g, 0.395mol) in dimethylformamide (3L) was added sodium buntanide (192.6g, 2.96mol) and the reaction was heated at 110 ℃ for 66 hours. The reaction was cooled to room temperature and water (12L) was added. The reaction was carried out a total of three times on the same scale and with tert-butylThe combined batches were extracted with methyl ether. The organic layer was then dried over sodium sulfate and concentrated in vacuo to afford the product as a reddish brown oil, contaminated with 18% dimethylformamide. Correcting the yield: 286.7g, 1.01mol, 85%.1H NMR(400MHz，CDCl3)δ3.93-3.97(m，2H)，4.00(m，1H)，4.09(dd，J＝8.7，5.8Hz，1H)，4.17(dd，J＝10.0，5.6Hz，1H)，4.90(ddd，J＝5.4，5.4，4.4Hz，1H)，6.83(d，J＝9.1Hz，2H)，7.41(d，J＝9.0Hz，2H)。
Step 4. Synthesis of cis-4- (4-bromophenyloxy) tetrahydrofuran-3-amine
A solution of cis-3-azido-4- (4-bromophenoxy) tetrahydrofuran (286.7g, 1.01mol) in tetrahydrofuran (1.25L) was cooled to 0 ℃ and treated with triphenylphosphine (278g, 1.06 mol). The reaction was warmed to room temperature and stirred for 18 hours. Water (53mL) was added and the reaction stirred at room temperature for 66 h. The solvent was removed under reduced pressure and the residue was mixed with diethyl ether. The supernatant was decanted and concentrated in vacuo to give a residue which was filtered through a short plug of silica gel (gradient: 0% to 5% methanol in dichloromethane) to give cis-4- (4-bromophenyloxy) tetrahydrofuran-3-amine (155g) and 366 g of impure product. The impurities were subjected to acid/base extraction to give additional product (48.5 g). Total yield: 203.5g, 0.788mol, 68% (4 steps).1H NMR(300MHz，CDCl3)δ3.6(m，1H)，3.7(m，1H)，3.9(m，1H)，4.0(m，1H)，4.1(m，1H)，4.6(m，1H)，6.8(m，2H)，7.3(m，2H)。
Step 5 Synthesis of (3S,4S) -4- (4-bromophenyloxy) tetrahydro-furan-3-amine
A mixture of cis-4- (4-bromophenoxy) tetrahydrofuran-3-amine (191g, 0.74mol) and (1S) - (+) -10-camphorsulfonic acid (154.2g, 0.66mol) was dissolved in 2-propanol (2.4L) and water (100mL) at reflux. The clear solution was cooled to room temperature over 18 hours, and the resulting crystals were separated, washed and dried to give (+) -camphorsulfonate salt of (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-amine (139.2g, 0.284mol) with 85% e.e. (enantiomeric excess). Recrystallization from 2-propanol (1.2L) and water (70mL) gave (3S,4S) -4- (4)-bromophenoxy) tetrahydrofuran-3-amine (+) -camphorsulfonate, e.e. 99%. Yield: 113.2g, 0.23mol, 31%.1H NMR(300MHz，DMSO-d6) δ 0.74(s, 3H), 1.05(s, 3H), 1.23(d, half of AB quartet, J ═ 10Hz, 1H), 1.29(d, half of AB quartet, J ═ 10Hz, 1H), 1.76-1.94(m, 2H), 2.19-2.28(m, estimate 2H), 2.35(d, J ═ 14.7Hz, 1H), 2.66-2.73(m, estimate 1H), 2.85(d, J ═ 14.7, 1H), 3.78-3.84(m, 2H), 3.96-4.10(m, 3H), 5.04(m, 1H), 6.99(d, J ═ 8.8Hz, 2H), 7.52(d, J ═ 9.0Hz, 2H), 8.23(br, 3H). Additional (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-amine (+) -camphorsulfonate (13.6g, 27.7mmol) from another experiment was added and the combined batch was washed with 2N aqueous sodium hydroxide solution (126.8g, 0.258mol) and extracted three times with dichloromethane. The organic layers were combined and concentrated in vacuo to give (3S,4S) -4- (4-bromophenoxy) tetrahydro-furan-3-amine as a white solid, 99% e.e. Yield: 65.6g, 0.254mmol, 98% (neutralization).
The above combined mother liquor enriched in (3R, 4R) -4- (4-bromophenoxy) tetrahydrofuran-3-amine was washed with 2N sodium hydroxide and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a residue (156.3g, 0.606mol product and its enantiomers). This material was combined with (1R) - (-) -10-camphorsulfonic acid (126.2g, 0.54mol) and dissolved in 2-propanol (1.65L) and water (100mL) under reflux. The clear solution was cooled to room temperature over 18 hours and the resulting crystals were isolated, washed and dried. (-) -camphorsulfonate salt of (3R, 4R) -4- (4-bromophenoxy) tetrahydrofuran-3-amine (152.6g, 0.311mol) was obtained at 90% e.e.g.. Recrystallization as described above gave (-) -camphorsulfonic acid salt of (3R, 4R) -4- (4-bromophenoxy) tetrahydrofuran-3-amine as a white solid with an e.e. of 99%. Yield: 132.0g, 0.27mol, 36%.
The mother liquor was concentrated in vacuo, washed with 2N sodium hydroxide and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a mixture of (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-amine and its enantiomer (67.7g, 0.26 mol). This material was dissolved in 2-propanol (425mL) and water (17.5mL) under reflux along with (1S) - (+) -10-camphorsulfonic acid (54.6g, 0.24 mol). The clear solution was brought to room temperature over 18 hours and the resulting crystals were isolated, washed and dried. Additional (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-amine (+) -camphorsulfonate (48.0g, 97.9mmol) was obtained at 89-93% e.e. Recrystallisation gave (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-amine (+) -camphorsulfonate (40.0g, 81.6mmol, another 11%) as an e.e. 99 +%.
Step 6, synthesizing N- [ (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-yl ] propane-2-sulfonamide
To a solution of (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-amine (65.6g, 0.254mol) in dichloromethane (500mL) was added 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (DBU, 53mL, 0.35 mol). The reaction mixture was cooled to 0 ℃ and propane-2-sulfonyl chloride (31.2mL, 0.28mol) was added dropwise. The mixture was then stirred at room temperature for 18 hours. The reaction was monitored by proton NMR: additional propane-2-sulfonyl chloride (2.8mL, 25mmol) was added and the mixture was stirred at room temperature for an additional 18 hours. The reaction was again monitored by NMR and additional propane-2-sulfonyl chloride (2.8mL, 25mmol) was added. After 2.5 hours, the reaction was complete according to NMR analysis. Water (500mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with aqueous hydrochloric acid (1N, 2 × 300mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford N- [ (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-yl) as an orange/brown oil]Propane-2-sulfonamide. Yield: 92.5g, 0.254mol, 100%.1H NMR(300MHz，CDCl3) δ 1.36(d, J ═ 7Hz, 3H), 1.38(d, J ═ 7Hz, 3H), 3.15 (heptad, J ═ 7Hz, 1H), 3.69(dd, J ═ 8.5, 8.5Hz, 1H), 3.93(dd, J ═ 10.6, 1.5Hz, 1H), 4.10-4.28(m, 3H), 4.72-4.81(m, 2H), 6.77(d, J ═ 9.1Hz, 2H), 7.41(d, J ═ 9.1Hz, 2H). Via growth of N- [ (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-yl group from heptane/ethyl acetate solution]Subjecting the crystals of propane-2-sulfonamide to X-ray crystallography to determine the identity of the substanceAbsolute configuration. The results are described below.
Collected on a Bruker APEX diffractometerData set (max sin Θ/λ ═ 0.56). The final R-index was 3.61%.
TABLE 1 Crystal data and Structure refinement
TABLE 2 atomic coordinates (10. times.4) And equivalent isotropic displacement parameterU (eq) is defined as orthogonalized UijOne third of the trace of the tensor.
TABLE 3 bond LengthAnd key angle [ ° ]]
Symmetric transformations to produce equivalent atoms
TABLE 4 Anisotropic Displacement parametersThe anisotropy displacement factor index takes the form: -2 pi2[h2a＊2U11+...+2h k a＊b＊U12]
TABLE 5 Hydrogen coordinates (× 10)4) And isotropic displacement parameter
Step 7, synthesizing N- [ (3S,4S) -4- (biphenyl-4-yloxy) tetrahydrofuran-3-yl ] propane-2-sulfonamide
Adding N- [ (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-yl to a microwave vial]Propane-2-sulfonamide (124mg, 0.340mmol), phenylboronic acid (63.5mg, 0.521mmol), dicyclohexyl (2', 4', 6 ' -triisopropylbiphenyl-2-yl) phosphine (XPhos, 16.2mg, 0.034mmol), palladium (II) acetate (5.2mg, 0.023mmol), and potassium fluoride (99.6mg, 1.71 mmol). The vial was capped and flushed with nitrogen/vacuum three times. A degassed 1: 1 mixture of methanol/toluene (1.5mL) was added and the reaction was microwave irradiated at 130 ℃ for 30 min. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium chloride. The aqueous layer was extracted twice with ethyl acetate and the organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient: 10% to 25% ethyl acetate in heptane) to give the title compound as a solid. Yield: 90mg, 0.25mmol, 73%.1H NMR(400MHz，CDCl3)δ1.37(d，J＝6.8Hz, 3H), 1.40(d, J ═ 6.8Hz, 3H), 3.17 (heptad, J ═ 6.8Hz, 1H), 3.76(dd, J ═ 8.6, 8.6Hz, 1H), 4.01(dd, J ═ 10.6, 1.6Hz, 1H), 4.16-4.30(m, 3H), 4.84(m, 1H), 5.09(d, J ═ 9.4Hz, 1H), 6.97(d, J ═ 8.7Hz, 2H), 7.34(t, J ═ 7.4Hz, 1H), 7.44(d, J ═ 7.6, 7.6Hz, 2H), 7.55(m, 4H).13C NMR(100MHz，CDCl3)δ16.48，16.55，54.27，55.35，70.29，71.96，75.87，115.85，126.65，126.88，128.34，128.68，135.11，140.25，155.93。
Example 3
N- { (3S,4S) -4- [ (2' -Cyanobiphenyl-4-yl) oxy ] tetrahydrofuran-3-yl } propane-2-sulfonamide
The title compound was prepared following the general procedure for the synthesis of example 2 substituting phenyl boronic acid with (2-cyanophenyl) boronic acid to give the product as a solid. Yield: 675.3mg, 1.75mmol, 85%. LCMS M/z 387.0(M + 1).1H NMR(500MHz，CDCl3) δ 1.36(d, J ═ 6.8Hz, 3H), 1.39(d, J ═ 6.8Hz, 3H), 3.19 (heptad, J ═ 6.8Hz, 1H), 3.77(dd, J ═ 8.8, 8.8Hz, 1H), 3.98(dd, J ═ 10.6, 1.6Hz, 1H), 4.16(dd, J ═ 7.9, 7.9Hz, 1H), 4.21(dd, J ═ 10.6, 4.3Hz, 1H)4.30(m, 1H), 4.82(m, 1H), 5.53(d, J ═ 9.6Hz, 1H), 7.03(d, J ═ 8.8, 2H), 7.43(d, J ═ 7.7, 7.7, 7.8, 7, 7.8, 7H), 7.7, 7, 8, 7H, 7, 8, 1H, 7.13C NMR(125MHz，CDCl3)δ16.19，16.24，53.89，55.03，69.86，71.62，75.48，110.47，115.39，118.53，127.00，129.53，129.86，131.26，132.58，133.35，144.32，156.76。
Example 4
N- { (3S,4S) -4- [4- (5-cyano-2-thienyl) phenoxy ] tetrahydrofuran-3-yl } propane-2-sulfonamide
The title compound was prepared following the general procedure for the synthesis of example 2 substituting (5-cyano-2-thienyl) boronic acid for phenylboronic acid to give the product as a solid. Yield: 365mg, 0.93mmol, 58%. LCMS M/z 393.5(M + 1).1H NMR(500MHz，CDCl3) δ 1.39(d, J ═ 6.8Hz, 3H), 1.41(d, J ═ 6.8Hz, 3H), 3.21 (heptad, J ═ 6.8Hz, 1H), 3.77(dd, J ═ 8.8, 8.8Hz, 1H), 3.99(dd, J ═ 10.7, 1.6Hz, 1H), 4.18(dd, J ═ 7.8, 7.8Hz, 1H), 4.23(dd, J ═ 10.7, 4.3Hz, 1H), 4.30(m, 1H), 4.88(m, 1H), 5.31(d, J ═ 9.8Hz, 1H), 6.97(d, J ═ 8.9, 2H), 7.19(d, J ═ 3.9, 1H), 7.53(d, J ═ 8.8, 8Hz, 1H), 7.58H, 7.7.7.7, 8(d, 8H), 7.8H, 1H).13C NMR(125MHz，CDCl3)δ16.35，54.07，55.26，69.84，71.73，75.84，107.00，114.23，116.02，122.36，125.87，127.67，138.35，151.01，157.40。
Example 5
N- { (1S,2R) -2- [ (2' -Cyanobiphenyl-4-yl) oxy ] cyclopentyl } propane-2-sulfonamide
Step 1. Synthesis of trans-2- (4-bromophenoxy) cyclopentanol
Reacting 6-oxabicyclo [3.1.0 ]]Hexane (2.04mL, 23.5mmol), 4-bromophenol (4.49g, 26.0mmol), cesium carbonate (99%, 8.93g, 27.1mmol), and benzyltriethylammonium chloride (99%, 1.09g, 4.74mmol) were suspended in dioxane (65mL) and heated at refluxFor 18 hours. Addition of additional 6-oxabicyclo [3.1.0 ]]Hexane (0.50mL, 5.8mmol) and heating was continued for 66 hours. 6-oxabicyclo [3.1.0 ] is added again]Hexane (0.50mL, 5.8mmol) and the reaction mixture heated under reflux for a further 18 hours. The reaction was then cooled to room temperature, concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over calcium sulfate, filtered and concentrated under reduced pressure to give a gold oil which was purified by silica gel chromatography (gradient: 0% to 20% ethyl acetate in heptane) to give the product as an oil. Yield: 3.21g, 12.5mmol, 48%. GCMS M/z256, 258 (M)+)。1H NMR(400MHz，CDCl3)δ1.64(d，J＝3.7Hz，1H)，1.60-1.68(m，1H)，1.70-1.88(m，3H)，2.07(m，1H)，2.17(m，1H)，4.30(m，1H)，4.48(m，1H)，6.80(d，J＝9.0Hz，2H)，7.37(d，J＝9.0Hz，2H)。
Step 2. Synthesis of trans-2- (4-bromophenyloxy) cyclopentylmethanesulfonate
The title compound of step 2 was prepared according to the general procedure for the synthesis of trans-4- (4-bromophenoxy) tetrahydrofuran-3-yl methanesulfonate in example 2, substituting trans-2- (4-bromophenoxy) cyclopentanol for trans-4- (4-bromophenoxy) tetrahydrofuran-3-ol and quenching the reaction mixture by adding saturated aqueous ammonium chloride solution. The organic layer was then washed with saturated aqueous ammonium chloride, washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo to afford the product as a brown oil. Yield: 3.86g, 11.5mmol, 98%.1H NMR(400MHz，CDCl3)δ1.79-2.00(m，4H)，2.14-2.26(m，2H)，3.03(s，3H)，4.78(m，1H)，5.07(m，1H)，6.82(d，J＝9.0Hz，2H)，7.39(d，J＝9.1Hz，2H)。
Step 3, synthesizing cis-2-azido cyclopentyl 4-bromophenyl ether
To a solution of trans-2- (4-bromophenoxy) cyclopentylmethanesulfonate (3.52g, 10.5mmol) in dimethylformamide (22mL) was added sodium azide (897mg, 13.7mmol) and the reaction was heated at 100 ℃ for 18 h. Reactant coolingTo room temperature and partitioned between ethyl acetate and 1N aqueous lithium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium chloride, dried over calcium sulfate, filtered and concentrated in vacuo to afford the product as a brown oil which was used in the next step without additional purification. Yield: 2.59g, 9.18mmol, 87%.1H NMR(400MHz，CDCl3)δ1.65-1.73(m，1H)，1.89-2.05(m，5H)，3.74(m，1H)，4.66(m，1H)，6.83(d，J＝9.0Hz，2H)，7.39(d，J＝9.0Hz，2H)。
Step 4, synthesizing cis-2- (4-bromophenoxy) cyclopentylamine
A solution of cis-2-azidocyclopentyl 4-bromophenyl ether (2.59g, 9.18mmol) from the previous step in tetrahydro-furan (63mL) and water (5.0mL) was treated with polymer-supported triphenylphosphine (3mmol/g, 7.15g, 21.5 mmol). The reaction was stirred for 18 hours and then passed throughAnd (5) filtering. The filter pad was washed with tetrahydrofuran, then with a mixture of dichloromethane and methanol, and the combined filtrates were concentrated in vacuo and azeotroped with ethanol. The residue was purified by silica gel chromatography (gradient: 0% to 10% methanol in ethyl acetate) to give the product as a light brown oil. Yield: 1.43g, 5.58mmol, 61%. MS (APCI) M/z 257.9(M + 1).1H NMR(400MHz，CDCl3)δ1.47(br s，2H)，1.56-1.68(m，2H)，1.78-1.88(m，2H)，1.91-1.99(m，2H)，3.35(ddd，J＝8.6，7.0，4.7Hz，1H)，4.42(m，1H)，6.80(d，J＝9.0Hz，2H)，7.37(d，J＝9.0Hz，2H)。
Step 5, synthesizing cis-N- [2- (4-bromophenoxy) cyclopentyl ] propane-2-sulfonamide
To a slurry of cis-2- (4-bromophenoxy) cyclopentylamine (1.43g, 5.58mmol) in dichloromethane (38.5mL) was added 1, 8-diazabicyclo [5.4.0] undec-7-ene (1.40mL, 9.36mmol), followed by 4- (dimethylamino) pyridine (915mg, 7.49 mmol). The reaction mixture was cooled to 0 ℃ and propane-2-sulfonyl chloride (0.937mL, 8.38mmol) was added dropwise. The mixture was then warmed to room temperature and stirred for 18 hours. The reaction was treated with 1N aqueous hydrochloric acid and the organic layer was washed with saturated aqueous sodium chloride, dried over calcium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient: 0% to 15% ethyl acetate in heptane) to give the product as a colorless gum. Yield: 1.586g, 4.38mmol, 78%.
Step 6, isolation of N- [ (1S,2R) -2- (4-bromophenoxy) cyclopentyl ] -propane-2-sulfonamide
Separation of a mixture containing cis-N- [2- (4-bromophenoxy) cyclopentyl group by chiral chromatography]Enantiomer of propane-2-sulfonamide (1.586g, 4.38 mmol). Column:AD-H, 2.1X 25cm, 5 μm; mobile phase: 75: 25 carbon dioxide: methanol; flow rate: 65 g/min. After removal of the solvent in vacuo, the first eluting compound was the enantiomer N- [ (1R,2S) -2- (4-bromophenoxy) cyclopentyl]Propane-2-sulfonamide (767mg, 2.12mmol, 48%) and the second eluting peak provided the desired product, N- [ (1S,2R) -2- (4-bromophenoxy) cyclopentyl]Propane-2-sulfonamide. Yield: 758mg, 2.09mmol, 48%. The absolute stereochemistry was determined analogously to the higher homologues of these enantiomers (see example 7). The title compound synthesized in the following step was demonstrated to be more specific than its enantiomer (prepared in the same way from N- [ (1R,2S) -2- (4-bromophenoxy) cyclopentyl]Propane-2-sulfonamide preparation) is significantly more effective. Based on the (1S,2R) configuration, the N- [ (1S,2R) -2- (4-bromophenoxy) cyclopentyl group is determined]Propane-2-sulfonamide. MS (APCI) M/z 364.2(M + 1).1H NMR(500MHz，CDCl3) δ 1.35(d, J ═ 6.8Hz, 3H), 1.38(d, J ═ 6.8Hz, 3H), 1.64(m, 1H), 1.79-1.98(m, 4H), 2.12(m, 1H), 3.13 (heptad, J ═ 6.8Hz, 1H), 3.86(m, 1H), 4.59(m, 1H), 4.63(d, J ═ 9.5Hz, 1H), 6.78(d, J ═ 9.0Hz, 2H), 7.39(d, J ═ 9.1Hz, 2H). N- [ (1R,2S) -2- (4-bromophenoxy) cyclopentyl]Data for propane-2-sulfonamide: MS (APCI) M/z 362.2, 364.2(M + 1).1HNMR(500MHz，CDCl3)δ1.35(d，J＝6.8Hz，3H)，1.38(d, J ═ 6.8Hz, 3H), 1.58-1.68(m, 1H), 1.78-1.97(m, 4H), 2.12(m, 1H), 3.13 (heptad, J ═ 6.8Hz, 1H), 3.86(m, 1H), 4.59(m, 1H), 4.64(d, J ═ 9.5Hz, 1H), 6.78(d, J ═ 9.1Hz, 2H), 7.39(d, J ═ 9.0Hz, 2H).
Step 7 Synthesis of the Compound N- { (1S,2R) -2- [ (2' -Cyanobiphenyl-4-yl) oxy ] cyclopentyl } propane-2-sulfonamide
The title compound of step 7 was prepared according to the general procedure synthesized in example 2 substituting N- [ (1S,2R) -2- (4-bromophenoxy) cyclopentyl]Substitution of propane-2-sulfonamide for N- [ (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-yl]Propane-2-sulfonamide, and (2-cyanophenyl) boronic acid is added instead of phenylboronic acid. In this case, after concentration of the reaction mixture in vacuo, purification directly by silica gel chromatography (eluent: 25% ethyl acetate in heptane) gave the product as a white viscous foam. Wet milling with hexane afforded the product as a white powder. Yield: 53mg, 0.14mmol, 82%. MS (APCI) M/z 382.9 (M-1).1H NMR(400MHz，CDCl3) δ 1.36(d, J ═ 6.7Hz, 3H), 1.40(d, J ═ 6.8Hz, 3H), 1.66(m, 1H), 1.82-2.03(m, 4H), 2.15(m, 1H), 3.15 (heptad, J ═ 6.8Hz, 1H), 3.90(m, 1H), 4.70(m, 2H), 7.01(d, J ═ 8.8Hz, 2H), 7.42(ddd, J ═ 7.6, 7.6, 1.2Hz, 1H), 7.50(m, 1H), 7.52(d, J ═ 8.8Hz, 2H), 7.64(ddd, J ═ 7.7, 7.7, 1.4Hz, 1H), 7.76(m, 1H).
Example 6
N- { (1S,2R) -2- [4- (5-cyano-2-thienyl) phenoxy ] cyclopentyl } propane-2-sulfonamide
Addition of N- [ (1S,2R) -2- (4-bromophenoxy) cyclopentyl to a microwave vial]Propane-2-sulfonamide (150.0mg, 0.414mmol), (5-cyano-2-thienyl) boronic acid (95.0mg, 0.621mmol), dicyclohexyl (2', 4', 6 ' -triiso-hexyl)Propylbiphenyl-2-yl) phosphine (20.2mg, 0.0410mmol), palladium (II) acetate (7.4mg, 0.033mmol) and potassium fluoride (120mg, 2.07 mmol). Dimethoxyethane (1.5mL) was added and the reaction mixture was purged three times with nitrogen/vacuum. The reaction was subjected to microwave irradiation at 120 ℃ for 2 hours, then the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The aqueous layer was extracted with ethyl acetate and the organic layers were combined, dried over calcium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 40% ethyl acetate in heptane) to give the title compound as a yellow oil, which subsequently solidified. Yield: 104mg, 0.266mmol, 64%. LCMS M/z391.0(M + 1).1H NMR(500MHz，CDCl3) δ 1.36(d, J ═ 6.8Hz, 3H), 1.39(d, J ═ 6.8Hz, 3H), 1.66(m, 1H), 1.81-1.94(m, 3H), 1.99(m, 1H), 2.14(m, 1H), 3.15 (heptad, J ═ 6.8Hz, 1H), 3.89(m, 1H), 4.64(d, J ═ 9.5Hz, 1H), 4.69(m, 1H), 6.95(d, J ═ 8.7Hz, 2H), 7.18(d, J ═ 4.0Hz, 1H), 7.54(d, J ═ 8.7Hz, 2H), 7.57(d, J ═ 3.9Hz, 1H).
Example 7
N- { (1S,2R) -2- [ (2' -Cyanobiphenyl-4-yl) oxy ] cyclohexyl } propane-2-sulfonamide
Step 1, synthesizing trans-2- (4-bromophenoxy) cyclohexanol
Sodium metal (2.58g, 112mmol) was combined with absolute ethanol (200mL) and allowed to react completely. 4-bromophenol (19.4g, 112mmol) was added and the reaction stirred for 20 minutes at which time 7-oxabicyclo [4.1.0 ] was added]Hexane (10.0g, 102mmol) and the solution was heated at reflux for 15 hours. After removal of the solvent in vacuo, the residue was partitioned between water (300mL) and ethyl acetate (100 mL). The water was extracted with ethyl acetate (2X 100mL)The layers were combined and the combined organic layers were washed with water (2 × 200mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting pale tan solid was recrystallized from heptane (about 200mL) to give trans-2- (4-bromophenoxy) cyclohexanol as a fluffy white solid. Yield: 12.5g, 46.1mmol, 45%.1HNMR(400MHz，CDCl3)δ1.26-1.46(m，4H)，1.75-1.79(m，2H)，2.08-2.14(m，2H)，2.52(d，J＝2.1 Hz，1H)，3.72(m，1H)，3.96(ddd，J＝10.3，8.6，4.4Hz，1H)，6.84(d，J＝9.0Hz，2H)，7.37(d，J＝9.0Hz，2H)。
Step 2, synthesizing (1R, 2R) -2- (4-bromophenoxy) cyclohexaneacetic ester
Trans-2- (4-bromophenoxy) cyclohexanol (5.305g, 19.56mmol) was dissolved in ethyl acetate (196mL) and treated with vinyl acetate (3.37g, 39.1mmol) followed by lipase from Candida antarctica (Novozyme 435, Sigma L4777, Lipase immobilized on acrylic resin, 5.3 g). The reaction was capped and stirred for 18 hours, then passed throughFiltered and washed with ethyl acetate (500 mL). The filtrate was concentrated in vacuo to give a pale yellow oil which was purified by silica gel chromatography (gradient: 0% to 10% ethyl acetate in heptane) to give the less polar product (1R, 2R) -2- (4-bromophenoxy) cyclohexyl acetate as a colorless oil. Yield: 2.047g, 6.54mmol, 33%. Data for (1R, 2R) -2- (4-bromophenoxy) cyclohexyl acetate:1H NMR(400MHz，CDCl3) δ 1.32-1.59(m, 4H), 1.71-1.80(m, 2H), 1.95(s, 3H), 2.02-2.14(m, 2H), 4.17(ddd, J ═ 9.6, 8.1, 4.4Hz, 1H), 4.96(m, 1H), 6.84(d, J ═ 9.0Hz, 2H), 7.36(d, J ═ 9.1Hz, 2H). The higher polarity product enantiomeric alcohol (1S, 2S) -2- (4-bromophenoxy) cyclohexanol was obtained as a white solid (3.57 g). Data for (1S, 2S) -2- (4-bromophenoxy) cyclohexanol:1H NMR(400MHz，CDCl3)δ1.26-1.46(m，4H)，1.74-1.79(m，2H)，2.08-2.15(m，2H)，2.50(br s，1H)，3.72(ddd，J＝10.68.5, 4.6Hz, 1H), 3.96(m, 1H), 6.84(d, J ═ 9.0Hz, 2H), 7.38(d, J ═ 9.0Hz, 2H). Based on N- [ (1S,2R) -2- (4-bromophenoxy) cyclohexyl]The absolute configuration of these compounds was determined by the X-ray crystal structure of the enantiomer of propane-2-sulfonamide (see step 7 below).
Step 3, synthesizing (1R, 2R) -2- (4-bromophenoxy) cyclohexanol
A solution of (1R, 2R) -2- (4-bromophenoxy) cyclohexaneacetic acid ester (2.047g, 6.54mmol) in methanol (12.2mL) and water (0.32mL) was cooled to 0 deg.C and treated with lithium hydroxide hydrate (95%, 1.73g, 39.2 mmol). The reaction was stirred at 0 ℃ for 15 minutes, then warmed and stirred at room temperature for 18 hours. Methanol was removed under reduced pressure, and the aqueous residue was partitioned between ethyl acetate (200mL) and water (100 mL). After extraction of the aqueous layer with ethyl acetate (100mL), the combined organics were washed with saturated aqueous sodium chloride (100mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give (1R, 2R) -2- (4-bromophenoxy) cyclohexanol as a yellow oil. Yield: 1.76g, 6.49mmol, 99%.1H NMR(400MHz，CDCl3)δ1.26-1.46(m，4H)，1.74-1.79(m，2H)，2.08-2.14(m，2H)，3.72(ddd，J＝10.5，8.4，4.7Hz，1H)，3.96(m，1H)，6.84(d，J＝9.0Hz，2H)，7.37(d，J＝9.0Hz，2H)。
Step 4, synthesizing (1R, 2R) -2- (4-bromophenoxy) cyclohexanesulfonate
The title compound of step 4 was prepared according to the general procedure for the synthesis of trans-2- (4-bromophenoxy) cyclopentanemethanesulfonate in example 5, substituting (1R, 2R) -2- (4-bromophenoxy) cyclohexanol for trans-2- (4-bromophenoxy) cyclopentanol. (1R, 2R) -2- (4-bromophenoxy) cyclohexanesulfonic acid ester was obtained as a pale golden oil. Yield: 3.60g, 10.3mmol, quantitive.1H NMR(400MHz，CDCl3)δ1.26-1.51(m，3H)，1.64-1.84(m，3H)，2.19(m，1H)，2.30(m，1H)，2.97(s，3H)，4.22(ddd，J＝10.2，8.5，4.6Hz，1H)，4.64(ddd，J＝10.6，8.4，4.9Hz，1H)，6.82(d，J＝9.1Hz，2H)，7.39(d，J＝9.1Hz，2H)。
Step 5, (1R,2S) -2-azidocyclohexyl 4-bromophenyl ether is synthesized
To a solution of (1R, 2R) -2- (4-bromophenoxy) cyclohexanesulfonate (3.55g, 10.2mmol) in dimethylformamide (21.8mL) and water (2.43mL) was added sodium buntanide (95%, 2.09mg, 30.5mmol) and the reaction was heated at 120 ℃ for 23 h. The reaction was cooled to room temperature, diluted with water (400mL) and extracted with ethyl acetate (4 × 400 mL). The combined organic layers were washed with aqueous lithium chloride (1N, 400mL), water (400mL), and dried over magnesium sulfate. Filtration and removal of the solvent in vacuo gave (1R,2S) -2-azidocyclohexyl 4-bromophenyl ether as an orange oil, which was used in the next step without additional purification. Yield: 2.85g, 9.62mmol, 94%.1H NMR(400MHz，CDCl3)δ1.36-1.48(m，2H)，1.62-1.76(m，4H)，1.96-2.07(m，2H)，3.63(m，1H)，4.43(m，1H)，6.85(d，J＝9.0Hz，2H)，7.39(d，J＝8.9Hz，2H)。
Step 6, synthesizing (1S,2R) -2- (4-bromophenoxy) cyclohexylamine
A solution of (1R,2S) -2-azidocyclohexyl 4-bromophenyl ether (2.85g, 9.62mmol) from the previous step in tetrahydrofuran (59mL) and water (4.6mL) was treated with polymer-supported triphenylphosphine (3mmol/g, 7.87g, 23.6 mmol). The reaction was stirred for 18 hours, then passed throughAnd (5) filtering. The pad was washed with tetrahydrofuran (250mL) then ethyl acetate (400mL) and the combined filtrates were concentrated in vacuo and azeotroped with ethanol. The residue was purified by silica gel chromatography (gradient: 0% to 10% methanol in dichloromethane) to give (1S,2R) -2- (4-bromophenoxy) cyclohexylamine as a yellow oil. Yield: 1.82g, 6.74mmol, 70%.1H NMR(400MHz，CDCl3)δ1.33-1.55(m，4H)，1.66-1.75(m，3H)，2.00(m，1H)，2.07(br s，2H)，2.97(m，1H)，4.39(m，1H)，6.85(d，J＝9.0Hz，2H)，7.36(d，J＝9.0Hz，2H)。
Step 7, synthesizing N- [ (1S,2R) -2- (4-bromophenoxy) cyclohexyl ] propane-2-sulfonamide
Synthesis of cis-N- [2- (4-bromophenoxy) cyclopentyl ] according to example 5]General procedure for propane-2-sulfonamide the title compound of step 7 was prepared by substituting (1S,2R) -2- (4-bromophenoxy) cyclohexylamine for cis-2- (4-bromophenoxy) cyclopentylamine and purifying the product using a gradient of 0% to 1% methanol in dichloromethane. Obtaining N- [ (1S,2R) -2- (4-bromophenoxy) cyclohexyl as a white foam]Propane-2-sulfonamide. Yield: 1.67g, 4.44mmol, 75%.1H NMR(400MHz，CDCl3) δ 1.36(d, J ═ 6.9Hz, 3H), 1.37-1.48(m, 4H), 1.77-1.88(m, 3H), 2.06(m, 1H), 3.12 (heptad, J ═ 6.8Hz, 1H), 3.54(m, 1H), 4.48(d, J ═ 9.5Hz, 1H), 4.54(m, 1H), 6.84(d, J ═ 9.0Hz, 2H), 7.39(d, J ═ 9.0Hz, 2H). Preparation of N- [ (1S,2R) -2- (4-bromophenoxy) cyclohexyl) using a chemistry similar to that described above in this step 7, substituting (1S, 2S) -2- (4-bromophenoxy) cyclohexanol for (1R, 2R) -2- (4-bromophenoxy) cyclohexanol as starting material]Enantiomers of propane-2-sulfonamide. Determination of N- [ (1S,2R) -2- (4-bromophenoxy) cyclohexyl group by X-ray crystallography]Absolute stereochemistry of enantiomers of propane-2-sulfonamide.
Step 8 Synthesis of N- { (1S,2R) -2- [ (2' -cyanobiphenyl-4-yl) oxy ] cyclohexyl } propane-2-sulfonamide
The title compound was prepared according to the general procedure for the synthesis of example 2 substituting N- [ (1S,2R) -2- (4-bromophenoxy) cyclohexyl]Substitution of propane-2-sulfonamide for N- [ (3S,4S) -4- (4-bromophenoxy) tetrahydrofuran-3-yl]Propane-2-sulfonamide, and microwave irradiation at 140 ℃ for 55 minutes. Then throughThe crude reaction mixture was filtered and washed with methanol. After removal of the solvent in vacuo, a brown solid was obtained, which was dissolved in ethyl acetate (100mL) and washed with water (2 × 75 mL). The aqueous layer was extracted with ethyl acetate (75mL), and saturated aqueous sodium chloride (75mL)The combined organic layers were washed, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting colorless oil was purified by preparative thin layer chromatography on silica gel (eluent: 1% methanol in dichloromethane) to give the title compound as a white foam. Yield: 72mg, 0.18mmol, 34%. LCMS M/z 399(M + 1).1H NMR(400MHz，CDCl3) δ 1.37(d, J ═ 7.2Hz, 3H), 1.39(d, J ═ 7.0Hz, 3H), 1.41-1.55(m, 4H), 1.79-1.94(m, 3H), 2.16(m, 1H), 3.14 (heptad, J ═ 6.8Hz, 1H), 3.59(m, 1H), 4.52(d, J ═ 9.4Hz, 1H), 4.66(m, 1H), 7.06(d, J ═ 8.7Hz, 2H), 7.42(ddd, J ═ 7.6, 7.6, 1.2Hz, 1H), 7.50(m, 1H), 7.52(d, J ═ 8.6Hz, 2H), 7.64(ddd, J ═ 7.7, 7.7, 1.7, 1H), 7.76(m, 1H). The title compound has improved biological activity over 150 times its enantiomer, which is obtained from N- [ (1S,2R) -2- (4-bromophenoxy) cyclohexyl]Enantiomers of propane-2-sulfonamide.
Examples 8 to 54
The method A comprises the following steps: aryl coupling exemplified by the synthesis of trans-N- {4- [ (2' -ethoxybiphenyl-4-yl) oxy ] tetrahydro-furan-3-yl } propane-2-sulfonamide
Reacting trans-N- [4- (4-bromophenoxy) tetrahydrofuran-3-yl]Propane-2-sulfonamide (91.1mg, 0.250mmol), (2-ethoxyphenyl) boronic acid (49.8mg, 0.300mmol), [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (95%, 38.5mg, 0.050mmol) and sodium carbonate (63.6mg, 0.600mmol) in combination in dioxane (3.2mL) and water (0.8mL) and microwave irradiated at 150 ℃ for 20 min. Then throughThe reaction was filtered and partitioned between water (10mL) and ether (10 mL). The aqueous layer was extracted with additional ether (2 × 10mL) and the organic layers were combined, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (gradient: 15% to 35% ethyl acetate in heptane) to give the title compound as a gum. Yield of pure fractions: 16.6mg, 0.041mmol, 16%. See table 1 for characterization data.
Method B
Tetrakis (triphenylphosphine) palladium (0) -mediated coupling of bromine aromatics with boronic acids
Suzuki coupling (Suzuki coupling) was performed via a method similar to that reported by K.Kawaguchi et al, Journal of Organic Chemistry2007, 72, 5119-5128 and corresponding supporting information.
Method C
Amine-to-bromine aromatic coupling mediated by tris (dibenzylideneacetone) dipalladium (0)
The amination reaction is carried out as described in X.Huang et al, Journal of the American Chemical Society2003, 125, 6653-6655.
Method D
Ester hydrolysis
The alkyl esters are hydrolyzed to the corresponding carboxylic acids under standard conditions, for example, with aqueous sodium hydroxide.
Method E
Preparation of cis-N- {4- [ (4-substituted) phenoxy group]Tetrahydrofuran-3-yl } propanesulfonamide boronic acid (0.1mmol) was weighed into a vial and taken as cis-N- [4- (4-bromophenoxy) tetrahydrofuran-3-yl]A solution of propane-2-sulfonamide (18.2mg, 0.05mmol) in degassed ethanol (0.8mL) was treated. A solution of sodium carbonate (26.5mg, 0.25mmol) in water (0.1mL) was then added and the reaction vial was vacuum flushed twice, then refilled with nitrogen. Then degassed toluene (0.1mL) containing tetrakis (triphenylphosphine) palladium (0) (2.9mg, 0.0025mmol) was added and the reaction heated to 80 ℃ for 16 h. The reaction was then treated with aqueous sodium hydroxide (1N, 1.5mL) and ethyl acetate (2.3mL) and the reaction vial was shaken and extracted three times with ethyl acetate. The combined organic layers were passed through a solid phase extraction column loaded with sodium sulfate and the filtrate was concentrated in vacuo. The residue was dissolved in dimethylsulfoxide (1mL) and purified by preparative HPLC (column: XBridgeC)185 μm, 19X 100 mm; solvent A: 0.1% aqueous ammonium hydroxide (v/v); solvent(s)B: 0.1% ammonium hydroxide in acetonitrile (v/v), using an appropriate gradient).
Method F
Preparation of N- [ (1S,2R) -2- (N ', N' -substituted-4-aminophenoxy) cyclohexyl]Propane-2-sulfonamide the amine (0.35mmol) was weighed into a vial. Degassed 2-methyl-2-butanol (0.4mL), a spoon of dicyclohexyl (2', 4', 6 ' -triisopropylbiphenyl-2-yl) phosphine (XPhos, 0.7mg, 0.0015mmol), a spoon of tris (dibenzylideneacetone) dipalladium (0) (0.14mg, 0.00025mmol) and a pellet of potassium hydroxide were added to the dry box. The reaction was then flushed with nitrogen, evacuated with vacuum, and refilled with nitrogen. After shaking the mixture at room temperature for 15 minutes, the mixture was washed with N- [ (1S,2R) -2- (4-bromophenoxy) cyclohexyl]A solution of propane-2-sulfonamide (26.3mg, 0.7mmol) in degassed 2-methyl-2-butanol (0.4mL) was treated and shaken at 100 ℃ for 18 h. The reaction was then treated with water (1.5mL) and extracted with ethyl acetate (3X 2.5 mL). The organic layers were combined, passed through a solid phase extraction column loaded with sodium sulfate and concentrated in vacuo. { Note: to remove any tert-butoxycarbonyl protecting groups present after coupling, a 1: 1 mixture of trifluoroacetic acid/dichloromethane (0.5mL) was added to the appropriate reaction, followed by shaking for 2 hours at room temperature and concentration in vacuo }. The residue was dissolved in dimethylsulfoxide (1mL) and purified by preparative HPLC (column: Xbridge C)185 μm, 19X 50 mm; solvent A: 0.1% aqueous trifluoroacetic acid (v/v); solvent B: 0.1% trifluoroacetic acid in acetonitrile (v/v), using an appropriate gradient).
TABLE 1
TABLE 2
AColumn: waters Sunfire C183.5 μm, 4.6X 50 mm; mobile phase A: 0.05% aqueous TFA; a mobile phase B: CH of 0.05% TFA3CN solution; flow rate: 2.0 mL/min.
Gradient:
0 minute 5％B
4 minutes 95％B
5 minutes 95％B
BColumn: waters Xterra C183.5 μm, 4.6X 50 mm; mobile phase A: 0.1% NH4An aqueous OH solution; a mobile phase B: 0.1% NH4CH of OH3CN solution; flow rate: 2.0 mL/min.
Gradient:
0 minute 5％B
5.83 minutes 95％B
9.0 minutes 95％B
Biological protocols
Growth and maintenance of ES cells
Murine ES cells E14, which have targeted mutations in Sox1 gene and in neuroectodermal markers that provide G418 resistance when expressing Sox1 gene, can be used in all experiments (Stem Cell Sciences, West Mains Road, Edinburgh, Scotland EH93 JQ). ES cell undifferentiated can be maintained as described previously (Methods For The isolation and Maintenance Of The Murine embryo Cells; Roach-M-L, McNeish-J-D., Methods in Molecular Biology, 185, 1-16 (2002)). Briefly, ES cells can be grown to contain KnockoutTMBasal medium of D-MEM (Invitrogen 5791 Van Allen Way, Carlsbad, CA USA 92008) and supplemented with 15% ES-qualified Fetal Bovine Serum (FBS) (Invitrogen), 0.2mM L-glutamine (Invitrogen), 0.1mM MEM non-essential amino acids (Invitrogen), 30. mu.g/ml gentamycin (Gentamicin, G418) (Invitrogen), 1000U/ml ESGROTM(CHEMICON International, Inc., 28820 Single Oak Drive, Temecula, CA 92590) and 0.1mM 2-mercaptoethanol (Sigma, 3050 Sponce St., St. Louis, MO 63103). The ES cells can then be plated on gelatin-coated culture dishes (BD Biosciences, 2350 Qume Drive, San Jose, CA95131) with daily medium changes and every other day cells dissociated with 0.05% trypsin EDTA (Invitrogen).
Neural in vitro differentiation of ES cells
Forming a blank body: prior to formation of Embryoid Bodies (EB), ES cells were disrupted from FBS to knock-out Serum ReplacementTM(KSR) (Invitrogen). To form EBs, ES cells can be dissociated into single cell suspensions, followed by 3X 106Each cell was plated in a bacteriological culture dish (Nunc 4014) and plated with a medium consisting of a medium supplemented with 10% KSR (Invitrogen), 0.2mM L-glutamine (Invitrogen), 0.1mM MEM non-essential amino acids (Invitrogen), 30. mu.g/ml gentamycin (Invitrogen), 1000U/ml ESGROTM(CHEMICONInternational, Inc.), 0.1mM 2-mercaptoethanol (Sigma), and Knockout of 150ng/ml transferrin (Invitrogen)TMSuspension cultures were grown in NeuroEB-I medium consisting of D-MEM (Invitrogen). The plate may then be placed in a Stovall Belly Button in an atmospheric oxygen incubatorTMOn the oscillator. The medium can be replaced with NeuroEB-I on day 2 of EB formation and NeuroEB-II (NeuroEB-I + 1. mu.g/mlmNoggin (R) on day 4&D Systems, 614McKinley Place n.e. minneapolis, MN 55413)).
Selecting and amplifying neuron precursors: on day 5 of EB formation, EBs may be dissociated with 0.05% trypsin EDTA followed by 4X 106Individual cells/100 mM dishes can be plated on laminin-coated tissue culture dishes in NeuroEB-II-G418 media (both from Invitrogen) consisting of a basal medium supplemented with a 1: 1 mixture of D-MEM/F12 supplemented with N2 supplement and a neural basal medium supplemented with B27 supplement and 0.1mM L-glutamine. The basal medium can then be supplemented with 10ng/ml of FGF (Invitrogen), 1. mu.g/ml of mNoggin, 500ng/ml of SHH-N (ProSpecBioRehovot Science Park, P.O.BOX 398, Rehovot 76103, Israel), 100ng/ml of FGF-8b (R.sup.&D Systems), 1. mu.g/ml laminin and 200. mu.g/ml G418(Invitrogen) to select neuronal precursors expressing Sox-1. The plates can then be placed in an incubator containing 2% oxygen and maintained under these conditions. During the 6 day selection period, NeuroEB-II medium should be changed daily. On day 6, surviving neuronal precursor foci can then be dissociated with 0.05% trypsin EDTA and cells plated at 1.5 × 106Each cell/100 mmRice was plated in NeuroII-G418 medium at a density of laminin-coated dishes. Cells may then be dissociated every other day for expansion and prepared for cryopreservation at passage 3 or passage 4. Cryopreservation media typically contained 50% KSR, 10% Dimethylsulfoxide (DMSO) (Sigma), and 40% NeuroII-G418 media. The neuron precursor can be expressed by 4 × 106The individual cells/ml concentrations are cryopreserved and then the overnight 1 ml/cryovials in the controlled rate freezer can be transferred to an ultra-low temperature freezer or liquid nitrogen for long term storage.
Neuronal differentiation: the cryopreserved neuronal precursors obtained from ES cells can be thawed in a 37 ℃ water bath by a rapid thawing method. The cells were then transferred from the frozen vials to 100mm laminin-coated tissue culture dishes containing NeuroII-G418 and equilibrated in a 2% oxygen incubator. The next day the medium was replaced with fresh neuroII-G418. Cells can be dissociated for expansion every other day as described above to produce cells that are sufficiently coated for screening. For screening, by automation(The Automation Partnership York Way, Royston, Hertfordshire SG 85 WY UK) cells were plated at a cell density of 6000 cells/well on 384-well poly-d-lysine coated tissue culture dishes (BD Biosciences) containing neural basal medium/B27 in a ratio of 4: 1: D-MEM/F12/N2 (supplemented with 1. mu.M cAMP (Sigma), 200. mu.M ascorbic acid (Sigma), 1. mu.g/ml laminin (Invitrogen), and 10ng/ml BDNF (R)&D Systems, 614McKinley Place n.e. minneapolis, MN 55413)). The plates were then placed in an incubator containing 2% oxygen and the differentiation process was completed over a period of 7 days. Cells can then be used for high throughput screening over a 5 day period.
In vitro assay
AMPA ES cell FLIPR screening program
On the day of assay, FLIPR assay can be performed using the following method:
determination of buffer:
the pH was adjusted to 7.4 with 1M NaOH. Prepare 2mM (approximate) stock solution of Fluo-4AM (Invitrogen) dye in DMSO-22. mu.l DMSO/50. mu.g vial (440. mu.L/1 mg vial). A working solution of PA at 1mM (approximately) Fluo-4AM per vial was prepared by adding 22. mu.l of DMSO containing 20% Poloxamer Acid (PA) (Invitrogen) to each 50. mu.g vial (440. mu.L/1 mg vial). Stock solutions of 250mM probenecid (Sigma) were prepared. 4 μ M (approximate) dye medium was prepared by adding 2 vials of the contents of 50 μ g per 11ml of DMEM (high glucose and no glutamine) (220ml DMEM/1mg vial). Add 110. mu.L probenecid stock (2.5mM final concentration) per 11ml of medium. Dye concentrations in the range of 2 μ M to 8 μ M dye can be used without altering agonist or potentiator pharmacology. Probenecid was added to the assay buffer for cell washing (but not drug preparation) at 110 μ l probenecid stock per 11ml buffer.
Growth medium was removed from the cell culture plate by flicking. Add 50 μ l/well of dye solution. At 37 ℃ and 5% CO2The cells were incubated for 1 hour. The dye solution was removed and washed 3 times with assay buffer + probenecid (100 μ l probenecid stock/10 ml buffer), leaving 30 μ l/well of assay buffer. Wait at least 10-15 minutes. Compound and agonist challenge additions can be made with FLIPR (molecular devices, 1311 orans Ave, Sunnyvale, CA 94089). Test compound was added first, which was added at a concentration of 15 μ Ι _ 4X. A second addition of 15 μ Ι of 4X concentration of agonist or challenge. All compounds at 1X concentration were achieved only after the second addition. The compounds were pretreated at least 5 minutes prior to agonist addition.
Several baseline images were collected at the FLIPR prior to compound addition and images were collected at least one minute after compound addition. Results were analyzed by subtracting the minimum fluorescence FLIPR value after compound or agonist addition from the peak fluorescence of the FLIPR response after agonist addition to obtain the change in fluorescence. The fluorescence change (RFU, relative fluorescence units) was then analyzed using a standard curve fitting algorithm. Negative controls were defined as AMPA challenge alone and positive controls were defined as AMPA challenge plus maximum concentration of cyclothiazide (10 μ M or 32 μ M).
The compounds were delivered in DMSO stock solutions or powders. The powder was dissolved in DMSO. Compounds were then added to assay drug buffer at 40 μ L max [ concentration ] (4X max screen concentration). The standard agonist challenge for this assay was 32 μ M AMPA.
EC of the Compounds of the invention50The value is preferably 10 micromolar or less than 10 micromolar, more preferably 1 micromolar or less than 1 micromolar, even more preferably 100 nanomolar or less than 100 nanomolar. Data for specific compounds of the invention are provided in table 3 below.
TABLE 3
＊Values represent 2-5 EC50Geometric mean of measured values
When introducing elements of the present invention or the exemplary embodiments thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements. While the present invention has been described with respect to particular embodiments, the details of such embodiments are not to be taken as limiting the invention, which is defined by the appended claims.

Claims (44)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof,
wherein each R1Independently are: hydrogen, halogen, hydroxy, -CN, - (NR)8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-N(R8)2、-SO2-N(R8)2Or (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9Substitution;
each R2Independently hydrogen or halogen;
m is 0 or 1;
n is 0, 1, 2 or 3;
p is 0;
q is 0;
s is 1 and t is 1; or one of s or t is 1 and the other of s or t is 2;
R3is hydrogen;
each R4Is hydrogen;
R5is hydrogen;
R6is (C)1-C6) alkyl-SO2-；
R8Independently are: hydrogen, (C)1-C6) Alkyl, or (C)3-C10) A cycloalkyl group; wherein said (C)1-C6) Alkyl is optionally substituted with 1, 2 or 3 halo;
each R9Independently are: halogen or- (NR)10)-SO2-R10；
R10Independently are: hydrogen or (C)1-C6) An alkyl group;
ring "A" is (C)6-C10) Aryl group, (C)1-C9) Heteroaryl or (C)1-C9) A heterocycloalkyl group; wherein said (C)1-C9) Said R on heterocycloalkyl1Two of the substituents are optionally attached to the same carbon atom and optionally together form oxo; wherein (C)6-C10) Aryl is phenyl or naphthyl; wherein (C)1-C9) Heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuryl or indolyl; and wherein (C)1-C9) The heterocycloalkyl group is azetidinyl, tetrahydro-Furyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl or benzoxazinyl;
ring "B" is phenyl or pyridyl;
"X" is-O-or>C(R4)2；
"Y" is absent; and is
"Z" is-O-.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R1Independently is-CF3。
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula Ia:
4. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula Ib:
5. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is-O-; and the compound has formula I, formula Ia or Ib:
6. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring "a" is phenyl; n is 0, 1 or 2; r1Selected from: hydrogen, halogen, hydroxy, -CN, - (NR)8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-N(R8)2、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9And (4) substitution.
7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein ring "a" is phenyl; n is 0, 1 or 2; r1Selected from: hydrogen, halogen, hydroxy, -CN, - (C ═ O) -OR8、-(C＝O)-N(R8)2、-OR8、-N(R8)2、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or 4R9And (4) substitution.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring "a" is (C)1-C9) A heteroaryl group; n is 0, 1 or 2; and wherein R1Selected from: hydrogen, halogen, hydroxy, -CN, - (NR)8)-(C＝O)-R8、-(C＝O)-OR8、-(C＝O)-N(R8)2、-OR8、-N(R8)2、-SO2-N(R8)2And (C)1-C6) An alkyl group; wherein said (C)1-C6) Alkyl is optionally substituted by 1, 2, 3 or4R9And (4) substitution.
9. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein each R1Independently is-CF3。
10. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein each R1Independently is-CF3。
11. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein each R1Independently is-CF3。
12. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein ring "A" is (C)1-C9) A heteroaryl group; n is 0, 1 or 2; and wherein R1Selected from: hydrogen, halogen, hydroxy, -CF3、-CN、-OR8、-N(R8)2And (C)1-C6) An alkyl group.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring "B" is phenyl; m is 0 or 1; r2Is hydrogen or halogen.
14. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein ring "B" is phenyl; m is 0 or 1; r2Is hydrogen or halogen.
15. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein ring "B" is phenyl; m is 0 or 1; r2Is hydrogen or halogen.
16. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein ring "B" is phenyl; m is 0 or 1; r2Is hydrogen or halogen.
17. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein ring "B" is phenyl; m is 0 or 1; r2Is hydrogen or halogen.
18. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein ring "B" is phenyl; m is 0 or 1; r2Is hydrogen or halogen.
19. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R2Is hydrogen.
20. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R2Is hydrogen.
21. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R2Is hydrogen.
22. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R2Is hydrogen.
23. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R2Is hydrogen.
24. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R2Is hydrogen.
25. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R2Is hydrogen.
26. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R2Is hydrogen.
27. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R6Is (C)1-C5) alkyl-SO2-。
28. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R6Is (C)1-C5) alkyl-SO2-。
29. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R6Is (C)1-C5) alkyl-SO2-。
30. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R6Is (C)1-C5) alkyl-SO2-。
31. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R6Is (C)1-C5) alkyl-SO2-。
32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:
n- {1- [ 4-trans- ({4- [ (isopropylsulfonyl) amino ] tetrahydrofuran-3-yl } oxy) phenyl ] pyrrolidin-3-yl } acetamide;
n- [ (3S,4S) -4- (biphenyl-4-yloxy) tetrahydrofuran-3-yl ] propan-2-sulfonamide;
n- { (3S,4S) -4- [ (2' -cyanobiphenyl-4-yl) oxy ] tetrahydrofuran-3-yl } propane-2-sulfonamide;
n- { (3S,4S) -4- [4- (5-cyano-2-thienyl) phenoxy ] tetrahydrofuran-3-yl } propane-2-sulfonamide;
n- { (1S,2R) -2- [ (2' -cyanobiphenyl-4-yl) oxy ] cyclopentyl } propane-2-sulfonamide;
n- { (1S,2R) -2- [4- (5-cyano-2-thienyl) phenoxy ] cyclopentyl } propane-2-sulfonamide;
n- { (1S,2R) -2- [ (2' -cyanobiphenyl-4-yl) oxy ] cyclohexyl } propane-2-sulfonamide;
cis-N- [4- (4-pyridin-3-ylphenoxy) tetrahydrofuran-3-yl ] propan-2-sulfonamide;
cis-N- {4- [4- (2-thienyl) phenoxy ] tetrahydrofuran-3-yl } propan-2-sulfonamide;
- Λ/- { (3S,4S) -4- [ (2 '-cyano-4' -fluorobiphenyl-4-yl) oxy ] tetrahydrofuran-3-yl } propan-2-sulfonamide;
n- { (3S,4S) -4- [ (4' -fluorobiphenyl-4-yl) oxy ] tetrahydrofuran-3-yl } propane-2-sulfonamide;
- Λ/- { (3S,4S) -4- [ (2 '-ethoxy-4' -fluorobiphenyl-4-yl) oxy ] tetrahydrofuran-3-yl } propan-2-sulfonamide;
cis-N- [4- { [6- (5-cyano-2-thienyl) pyridin-3-yl ] oxy } tetrahydrofuran-3-yl ] propan-2-sulfonamide;
cis-N- {4- [4- (3-thienyl) phenoxy ] tetrahydrofuran-3-yl } propan-2-sulfonamide;
2-cyano-4' - ({ (1R,2S) -2- [ (isopropylsulfonyl) amino ] cyclopentyl } oxy) biphenyl-4-carboxylic acid;
n- { (1S,2R) -2- [ (2 '-cyano-2, 4' -difluorobiphenyl-4-yl) oxy ] cyclopentyl } propane-2-sulfonamide;
n- { (1S,2R) -2- [ (2' -ethoxy-2-fluorobiphenyl-4-yl) oxy ] cyclopentyl } propane-2-sulfonamide;
n- { (1S,2R) -2- [4- (5-cyano-2-thienyl) -3-fluorophenoxy ] cyclopentyl } propane-2-sulfonamide;
n- { (1S,2R) -2- [ (2' -cyano-2-fluorobiphenyl-4-yl) oxy ] cyclohexyl } propane-2-sulfonamide;
n- { (1S,2R) -2- [ (2 '-cyano-2, 4' -difluorobiphenyl-4-yl) oxy ] cyclohexyl } propane-2-sulfonamide;
n- { (1S,2R) -2- [4- (5-cyano-2-thienyl) -3-fluorophenoxy ] cyclohexyl } propane-2-sulfonamide;
n- [ (1S,2R) -2- (4-pyrrolidin-1-ylphenoxy) cyclohexyl ] propane-2-sulfonamide;
n- [ (1S,2R) -2- ({6- [2- (2,2, 2-trifluoroethoxy) phenyl ] pyridin-3-yl } oxy) cyclohexyl ] propan-2-sulfonamide;
n- [ (1S,2R) -2- ({6- [2- (trifluoromethyloxy) phenyl ] pyridin-3-yl } oxy) cyclohexyl ] propan-2-sulfonamide;
n- [ (1S,2R) -2- { [6- (5-cyano-2-thienyl) pyridin-3-yl ] oxy } cyclohexyl ] propane-2-sulfonamide.
33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is N- { (3S,4S) -4- [4- (5-cyano-2-thienyl) phenoxy ] tetrahydrofuran-3-yl } propane-2-sulfonamide.
34. The compound of claim 33 which is N- { (3S,4S) -4- [4- (5-cyano-2-thienyl) phenoxy ] tetrahydrofuran-3-yl } propane-2-sulfonamide.
35. Use of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal injury, dementia, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive disorders, idiopathic and drug-induced parkinson's disease, muscle spasms and disorders associated with muscle spasticity, substance tolerance, substance withdrawal, psychosis, mood disorders, hearing loss, tinnitus, macular degeneration of the eye, emesis, cerebral edema, pain, sleep disorders, attention deficit disorders, and behavioral disorders.
36. Use of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: acute neurological and psychiatric disorders.
37. Use of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: tremor, epilepsy, convulsions, urinary incontinence.
38. Use of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: migraine, schizophrenia, anxiety, trigeminal neuralgia, tardive dyskinesia, and attention deficit/hyperactivity disorder.
39. Use of a compound of claim 34 in the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal injury, dementia, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive disorders, idiopathic and drug-induced parkinson's disease, muscle spasms and disorders associated with muscle spasticity, substance tolerance, substance withdrawal, psychosis, mood disorders, hearing loss, tinnitus, macular degeneration of the eye, emesis, cerebral edema, pain, sleep disorders, attention deficit disorders, and behavioral disorders.
40. Use of a compound of claim 34 in the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: acute neurological and psychiatric disorders.
41. Use of a compound of claim 34 in the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: tremor, epilepsy, convulsions, urinary incontinence.
42. Use of a compound of claim 34 in the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: migraine, schizophrenia, anxiety, trigeminal neuralgia, tardive dyskinesia, and attention deficit/hyperactivity disorder.
43. A pharmaceutical composition comprising a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising a compound of claim 34, and a pharmaceutically acceptable carrier.
HK12109881.9A 2009-06-26 2010-06-22 Heterocyclic sulfonamides, uses and pharmaceutical compositions thereof HK1169114B (en)

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HK1169114B HK1169114B (en) 2015-02-18

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