CN1705481A - Preparation of triazospiro compounds - Google Patents

Preparation of triazospiro compounds Download PDF

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CN1705481A
CN1705481A CN 200380101459 CN200380101459A CN1705481A CN 1705481 A CN1705481 A CN 1705481A CN 200380101459 CN200380101459 CN 200380101459 CN 200380101459 A CN200380101459 A CN 200380101459A CN 1705481 A CN1705481 A CN 1705481A
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alkyl
formula
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cycloalkyl
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P·哈拉格兹罗
G·李
R·R·格希林
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Euro Celtique SA
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Abstract

he present invention relates to processes for producing triazospiro compounds having the formula (IV): wherein A, B. C. R, R1, and W are as defined herein.

Description

Preparation of azido spiro compounds
The invention relates to a preparation method of an azide spiro compound.
Background
A number of therapeutically useful spiro compounds and methods for their preparation have been described in the art.
For example, U.S. Pat. No. 5,852,029(Fisher et al) describes the use and preparation of certain azospiro compounds that act on the cholinergic system. U.S. Pat. No. 5,633,247(Baldwin et al) describes certain nitrogen-containing spiro compounds useful as antiarrhythmic agents.
Us patent 6,277,991(Hohlweg et al) describes the use and preparation of triaza-spiro compounds for the treatment of migraine, non-insulin dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence or vasomotor disorders, especially peripheral vasomotor action known as hot flushes.
U.S. Pat. No. 4,220,773(Wiezer et al) describes some methods for the preparation of aza-spiro-decanes.
U.S. patent application 10/126,506, filed 4/18/2002, discloses spiropyrazole compounds which exhibit affinity for the ORL1 receptor and spiropyrazole compounds which have affinity for the ORL1 receptor and one or more of the μ, δ and κ receptors. The compounds described in this patent application are useful in treating patients with pain or acute pain. This application also describes that some of the disclosed spiropyrazole compounds are useful as analgesics, anti-inflammatory agents, diuretics, anesthetics and neuroprotective agents, antihypertensives, anxiolytics; an appetite regulating agent; a hearing regulator; antitussives, anti-asthmatics, modulators of locomotor activity, modulators of learning and memory, modulators of neurotransmitter and hormone release, modulators of renal function, antidepressants, agents for treating memory loss due to alzheimer's disease or other dementias, anti-epileptics, anticonvulsants, agents for treating withdrawal from alcohol or addictive drugs, agents for controlling water balance (water balance), agents for controlling sodium excretion and agents for controlling arterial blood pressure disorders, and methods of administering these agents.
There is a need in the art for improved methods for preparing azidospiro compounds.
Objects and summary of the invention
It is therefore an object of certain embodiments of the present invention to provide a process for the preparation of an azidospiro compound.
It is an object of certain embodiments of the present invention to provide a process for the preparation of an azidospiro compound having affinity for the ORL1 receptor.
It is an object of certain embodiments of the present invention to provide methods for the preparation of azide spiro compounds having affinity for ORL1 receptor and one or more of the μ, δ or κ receptors.
It is an object of certain embodiments of the present invention to provide a process for the preparation of an azido spiro compound for the treatment of chronic or acute pain in a patient.
It is an object of certain embodiments of the present invention to provide compounds that are useful as analgesics, anti-inflammatory agents, diuretics, anesthetics and neuroprotective agents, antihypertensives, anxiolytics; an appetite control agent; a hearing regulator; antitussives, anti-asthmatics, modulators of locomotor activity, modulators of learning and memory, modulators of neurotransmitter and hormone release, renal function modulators, antidepressants, agents for treating memory loss in alzheimer's disease or other dementias, antiepileptics, anticonvulsants, agents for treating withdrawal from alcohol or addictive drugs, agents for controlling water balance, agents for controlling sodium excretion and agents for controlling arterial blood pressure disorders.
Other objects and advantages of the present invention will become apparent from the following detailed description.
The present invention relates to a process for preparing a compound having the general formula (IV):
in this formula, W is hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C3-12Cycloalkyl radical C1-4Alkyl-, C1-10Alkoxy radical, C3-12Cycloalkoxy-, C substituted by 1-3 halogens1-10Alkyl, C substituted by 1-3 halogens3-12Cycloalkyl, C substituted by 1-3 halogens3-12Cycloalkyl radical C1-4Alkyl-, C substituted by 1-3 halogens1-10Alkoxy, C substituted by 1-3 halogens3-12Cycloalkoxy-, -COOV1，-C1-4COOV1，-CH2OH，-SO2N(V1)2Hydroxy radical C1-10Alkyl-, hydroxy-C3-10Cycloalkyl-, cyano-C1-10Alkyl-, cyano-C3-10Cycloalkyl-, -CON (V)1)2，NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, sulfonamido-C1-10Alkyl-, diaminoalkyl-, -sulfonyl C1-4Alkyl, 6-membered heterocycle, 6-membered heteroaromatic ring, 6-membered heterocycle C1-4Alkyl-, 6-membered heteroaromatic C1-4Alkyl-, 6-membered aromatic ring, 6-membered aromatic C1-4Alkyl-, a 5-membered heterocycle optionally substituted by oxygen or sulphur, a 5-membered heteroaromatic ring, a 5-membered heterocycle optionally substituted by oxygen or sulphur C1-4Alkyl-, 5-membered heteroaromatic C1-4Alkyl-, -C1-5(＝O)W1，-C1-5(＝NH)W1，-C1-5NHC(＝O)W1，-C1-5NHS(＝O)2W1，-C1-5NHS(＝O)W1Wherein W is1Is hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C1-10Alkoxy radical, C3-12Cycloalkoxy, -CH2OH, amino, C1-4Alkylamino-, di-C1-4Alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl groups;
wherein each V1Independently selected from H, C1-6Alkyl radical, C3-6Cycloalkyl, benzyl and phenyl;
A. b and C are each hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C1-10Alkoxy radical, C3-12Cycloalkoxy, -CH2OH，-NH2SO2Hydroxy radical C1-10Alkyl, aminocarbonyl-, C1-4Alkylamino carbonyl-, di-C1-4Alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulphonamido C1-10Alkyl-, or A-B together form C2-6Bridges, or B-C together form C3-7Bridge, or A-C together form C1-5A bridge;
r is-Z-R2Wherein Z is selected from a linkage, straight or branched C1-6Alkylene, -NH-, -CH2O-，-CH2NH-，-CH2N(CH3)-，-NHCH2-，-CH2CONH-，-NHCH2CO-，-CH2CO-，-COCH2-，-CH2COCH2-，-CH(CH3) -, -CH ═ O-and-HC ═ CH-, in which the carbon and/or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;
R2selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C2-10Alkenyl, amino, C1-10Alkylamino-, C3-12Cycloalkylamino-, -COOV1，-C1-4COOV1Cyano, cyano C1-10Alkyl-, cyano-C3-10Cycloalkyl-, NH2SO2-，NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, aminocarbonyl-, C1-4Alkylamino carbonyl-, di-C1-4Alkylaminocarbonyl-, benzyl, C3-12Cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, hetero-monocyclic, hetero-bicyclic system and spiro ring system of general formula (V):
Figure A20038010145900201
wherein, X1And X2Are respectively selected from NH, O, S and CH2(ii) a And wherein said R1Alkyl, cycloalkyl, alkenyl, C1-10Alkylamino-, C3-12Cycloalkylamino-or benzyl optionally substituted by 1-3 substituents selected from halogen, hydroxy, C1-10Alkyl radical, C1-10Alkoxy, nitro, trifluoromethyl, cyano, -COOV1，-C1-4COOV1Cyano group C1-10Alkyl-, -C1-5(＝O)W1，-C1-5NHS(＝O)2W1，-C1-5NHS(＝O)W15-membered heteroaromatic C0-4Alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl and benzyloxy being optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-10Alkyl-, C1-10Alkoxy-and cyano-substituted; wherein said C3-12Cycloalkyl radical, C3-12Cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaromatic rings, hetero-monocyclic, hetero-bicyclic systems or spirocyclic systems of the formula (V) optionally substituted by 1 to 3 substituents selected from halogen, C1-10Alkyl radical, C1-10Alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenoxy and benzyloxy, wherein said phenyl, benzyl, phenoxy or benzyloxy is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-10Alkyl radical, C1-10Alkoxy and cyano;
R1is selected from C1-8Alkyl, 5-8 membered cycloalkyl, 5-8 membered heterocyclyl or 6-membered aryl or heteroaryl; and R is1Quilt (D)nWherein n is an integer of 0 to 3, D is selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl-and halogen, said alkyl or cycloalkyl being optionally substituted by oxo, amino, alkylamino or dialkylamino.
In certain preferred embodiments, R1Is phenyl or 6-membered heteroaryl containing 1 to 3 nitrogen atoms.
In certain preferred embodiments, R2Alkyl is methyl, ethyl, propyl, butyl, pentyl or hexyl.
In certain preferred embodiments, R2Cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl.
In other preferred embodiments, R2The bicyclic ring system is naphthyl. In other preferred embodiments, R2The bicyclic system being tetrahydronaphthyl or decahydronaphthyl, R2The tricyclic ring system is dibenzocycloheptyl. In other preferred embodiments, R2Is phenyl or benzyl.
In other preferred embodiments, R2The bicyclic aromatic ring is a 10-membered ring, preferably quinoline or naphthyl.
In other preferred embodiments, R2The bicyclic aromatic ring is a 9-membered ring, preferably indenyl.
In certain preferred embodiments, Z is a linkage, methyl or ethyl.
In certain preferred embodiments, the Z group is maximally substituted, i.e., without any hydrogen substituents on the Z group. For example, if the Z group is-CH2-, substituted by two methyl radicals from the Z radical CH2-removing hydrogen.
In other preferred embodiments, n is 0.
In certain embodiments, X1And X2Are all O.
In certain embodiments, W is-CH2C＝ONH2，-C(NH)NH2Pyridylmethyl, cyclopentyl, cyclohexyl, furylmethyl, -C ═ OCH3，-CH2CH2NHC＝OCH3，-SO2CH3，CH2CH2NHSO2CH3Furylcarbonyl-, methylpyrrolidylcarbonyl-, oxadiazolyl-carbonyl-, pyrrylmethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolylmethyl-or oxadiazolyl-methyl-.
In certain embodiments, R is cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-, phenethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-or oxooctylpropyl- (oxooctylpropyl) -.
In certain embodiments, at least one of R or W is-CH2COOV1Tetrazolylmethyl-, cyanomethyl-, NH2SO2Methyl-, NH2SO methyl-, aminocarbonylmethyl-, C1-4Alkylaminocarbonylmethyl-or di-C1-4Alkylaminocarbonylmethyl-.
In certain embodiments, R is 3, 3 diphenylpropyl, optionally having the 3-carbon of the propyl group thereof replaced by-COOV1Tetrazolyl radical C0-4Alkyl-, cyano-, aminocarbonyl-, C1-4Alkylamino carbonyl-or di-C1-4Alkylaminocarbonyl-substitution.
In certain embodiments, a is hydrogen. In certain embodiments, B is hydrogen. In certain embodiments, C is hydrogen. In certain embodiments, a and B are hydrogen. In certain embodiments, a and C are hydrogen. In certain embodiments, B and C are hydrogen. In certain embodiments, a, B, and C are hydrogen.
In certain embodiments, A and B are hydrogen and C is selected from C1-4Alkyl and hydroxy C1-4An alkyl group. In certain embodiments, A and C are hydrogen and B is selected from C1-4Alkyl and hydroxy C1-4An alkyl group. In certain embodiments, B and C are hydrogen and A is selected from C1-4Alkyl and hydroxy C1-4An alkyl group.
In other embodiments, R may be
Figure A20038010145900221
Wherein,
Y1is R3-(C1-C12) Alkyl radical, R4-aryl radical, R5-heteroaryl, R6-(C3-C12) Cyclo-alkyl, R7-(C3-C7) Heterocycloalkyl, -CO2(C1-C6) Alkyl, CN or-C (O) NR8R9；Y2Is hydrogen or Y1；Y3Is hydrogen or (C)1-C6) An alkyl group; or Y1, Y2And Y3And together with the carbon atoms to which they are attached form one of the following structures:
Figure A20038010145900231
Figure A20038010145900233
or
Figure A20038010145900235
Wherein r is 0 to 3; w and u are each 0 to 3, provided that the sum of w and u is 1 to 3; c and d are each 1 or 2; s is 1 to 5; and ring E is fused R4-phenyl or R5-a heteroaromatic ring;
R10is independently selected from H, (C)1-C6) Alkyl, -OR8，-(C1-C6) alkyl-OR8，-NR8R9And- (C)1-C6) alkyl-NR8R91 to 3 substituents of (a);
R11is independently selected from R10，-CF3，-OCF3，NO2And 1-3 substituents of halogen, or R on adjacent ring carbon atoms11The substituents may together form methylenedioxyCyclo or ethylenedioxy-cyclo;
R8and R9Are respectively selected from hydrogen, (C)1-C6) Alkyl radical (C)3-C12) Cycloalkyl, aryl and aryl (C)1-C6) An alkyl group;
R3is independently selected from H, R4-aryl radical, R6-(C3-C12) Cycloalkyl radical, R5-heteroaryl, R7-(C3-C7) Heterocycloalkyl, -NR8R9，-OR12and-S (O)0-2R121 to 3 substituents of (a);
R6is independently selected from H, (C)1-C6) Alkyl radical, R4-aryl, -NR8R9，-OR12and-SR121 to 3 substituents of (a);
R4is 1-3 substituents independently selected from hydrogen, halogen, (C)1-C6) Alkyl radical, R13-aryl, (C)3-C12) Cycloalkyl, -CN, -CF3，-OR8，-(C1-C6) alkyl-OR8，-OCF3，-NR8R9，-(C1-C6) alkyl-NR8R9，-NHSO2R8，-SO2N(R14)2，-SO2R8，-SOR8，-SR8，-NO2，-CONR8R9，-NR9COR8，-COR8，-COCF3，-OCOR8，-OCO2R8，-COOR8，-(C1-C6) alkyl-NHCOOC (CH)3)3，-(C1-C6) alkyl-NHCOCF3，-(C1-C6) alkyl-NHSO2-(C1-C6) Alkyl, - (C)1-C6) alkyl-NHCONH- (C)1-C6) -alkyl and
wherein f is 0 to 6; or R on adjacent ring carbon atoms4The substituents may together form a methylenedioxy ring or an ethylenedioxy ring;
R5is independently selected from hydrogen, halogen, (C)1-C6) Alkyl radical, R13-aryl, (C)3-C12) Cycloalkyl, -CN, -CF3，-OR8，-(C1-C6) alkyl-OR8，-OCF3，-NR8R9，-(C1-C6) alkyl-NR8R9，-NHSO2R8，-SO2N(R14)2，-NO2，-CONR8R9，-NR9COR8，-COR8，-OCOR8，-OCO2R8and-COOR81 to 3 substituents of (a);
R7is H, (C)1-C6) Alkyl, -OR8，-(C1-C6) alkyl-OR8，-NR8R9Or- (C)1-C6) alkyl-NR8R9；
R12Is H, (C)1-C6) Alkyl radical, R4-aryl, - (C)1-C6) alkyl-OR8，-(C1-C6) alkyl-NR8R9，-(C1-C6) alkyl-SR8Or aryl (C)1-C6) An alkyl group;
R13is independently selected from H, (C)1-C6) Alkyl radical (C)1-C6) 1-3 substituents of alkoxy and halogen;
R14independently selected from H, (C)1-C6) Alkyl and R13-C6H4-CH2-。
In certain embodiments of the invention, the azide spiro compounds prepared by the methods of the invention exhibit affinity for the ORL1 receptor.
In certain embodiments of the invention, the azide spiro compounds prepared by the methods of the invention exhibit affinity for ORL1 receptor and one or more of the μ, δ or κ receptors.
In certain embodiments of the invention, the azidospiro compounds prepared by the methods of the invention are useful for treating patient or acute pain.
In certain embodiments of the invention, the azidospiro compounds prepared by the process of the invention are useful as analgesics, anti-inflammatory agents, diuretics, anesthetics and neuroprotective agents, antihypertensives, anxiolytics; an appetite control agent; a hearing regulator; antitussives, anti-asthmatics, modulators of locomotor activity, modulators of learning and memory, modulators of neurotransmitter and hormone release, renal function modulators, antidepressants, agents for treating memory loss due to alzheimer's disease or other dementias, anti-seizure agents, anticonvulsants, agents for treating withdrawal from alcohol or addictive drugs, agents for controlling water balance, agents for controlling sodium excretion and agents for controlling arterial blood pressure disorders.
In certain embodiments, the present invention relates to compounds of formula (IV) wherein R1Is hydrogen, A, B, C, R and W are as defined above; a pharmaceutical composition comprising a compound of formula (IV) wherein R is1Is hydrogen, A, B, C, R and W are as defined above; and methods of treatment comprising administering to a subject a compound of formula (IV) having affinity for the ORL1 receptor, wherein R1Is hydrogen, A, B, C, R and W are as defined above.
As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group having one radical and 1 to 10 carbon atoms. Examples of the alkyl group include methyl, propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl. Branched alkyl means one or more alkyl groups, e.g. methyl, ethyl or propyl, substituted in the linear alkyl chain-CH2-one or two hydrogens on the radical. The term "lower alkyl" refers to an alkyl group having 1 to 3 carbon atoms.
The term "alkoxy" refers to an "alkyl" group as defined above attached to an oxygen radical.
The term "cycloalkyl" denotes a non-aromatic monocyclic or polycyclic hydrocarbon ring system having one radical and 3 to 12 carbon atoms. Examples of monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl. Examples of polycyclic cycloalkyl rings include adamantyl and norbornyl.
The term "alkenyl" denotes a straight or branched aliphatic hydrocarbon group containing one radical and a carbon-carbon double bond of 2 to 10 carbon atoms.
"branched" alkenyl means one or more alkyl groups, such as methyl, ethyl or propyl, substituted for-CH in a linear alkenyl chain2-or one or two hydrogens on-CH ═ a. Examples of alkenyl include ethenyl, 1-and 2-propenyl, 1-, 2-and 3-butenyl, 3-methylbut-2-enyl, 2-propenyl, heptenyl, octenyl and decenyl.
The term "cycloalkenyl" denotes a non-aromatic monocyclic or polycyclic hydrocarbon ring system containing one radical and a carbon-carbon double bond of 3 to 12 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. Examples of polycyclic cycloalkenyl rings are norbornenyl.
The term "aryl" denotes a carbocyclic aromatic ring system containing 1, 2 or 3 rings and containing one radical, which rings may be linked together in a pendant or fused manner. Examples of aryl groups include phenyl, naphthyl and acenaphthenyl.
The term "heterocycle" refers to a cyclic compound having one or more heteroatoms (atoms other than carbon) in the ring and containing one radical. The ring may be saturated, partially saturated or unsaturated and the heteroatoms may be selected from nitrogen, sulphur and oxygen. Examples of saturated heterocyclic groups include saturated 3-6 membered hetero-monocyclic groups containing 1-4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; saturated 3-6 membered hetero-monocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as morpholinyl; saturated 3-6 membered hetero-monocyclic groups containing 1-2 sulphur atoms and 1-3 nitrogen atoms, such as thiazolidinyl. Examples of partially saturated heterocyclic groups include dihydrothiophene, dihydropyran, and dihydrofuran. The other heterocyclic group may be a 7-to 10-membered carbocyclic ring substituted with hetero atoms, such as oxetanyl and thiocyano. When the heteroatom is sulfur, the sulfur may be sulfur dioxide, such as thiocyanogen dioxide (thiocyanodide).
The term "heteroaryl" refers to an unsaturated heterocyclic group, wherein "heterocycle" is as described above. Examples of the heteroaryl group include unsaturated 3-6 membered hetero-monocyclic groups having 1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidinyl and pyrazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, quinolyl and isoquinolyl; unsaturated 3-6 membered hetero-monocyclic groups containing one oxygen atom, such as furyl; unsaturated 3-6 membered hetero-monocyclic groups containing one sulfur atom, such as thienyl; unsaturated 3-6 membered hetero-monocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as oxazolyl; unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl; unsaturated 3-6 membered hetero-monocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as thiazolyl; and unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. The term "heteroaryl" also includes unsaturated heterocyclic groups in which "heterocyclic" is as described above, the heterocyclic group is fused to an aryl group, and the aryl group is as described above. Examples of the condensed group include benzofuran, benzodioxole (benzdioxole) and benzothiophene.
As used herein, the term "heterocycle C1-4Alkyl and heteroaromatic C1-4Alkyl "etc. means with C1-4An alkyl-bonded ring structure.
All of the ring structures described herein may be attached at any possible point of attachment, which is known to those skilled in the art.
As used herein, the term "patient" includes humans or animals, such as pets or livestock.
As used herein, the term "halogen" includes fluorine, bromine, chlorine, or a tertiary amine (alabamide).
As used herein, the term "substituted hydrazine" is a substituted hydrazine that, when used in reaction C described herein, can yield a compound of formula IV having a W substituent as described herein.
The W substituent on the spiro ring of the compounds of formula IV may be substituted in reaction c described herein, for example, by a substituted hydrazine or by another reaction after the spiro ring is formed by a reaction known to those skilled in the art. One skilled in the art will recognize that the W substituent may be added by reaction with a substituted hydrazine and may be added by another reaction after the spiro ring is formed.
The resulting compounds disclosed herein may form pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium, potassium, cesium and the like; alkaline earth metal salts such as calcium salts, magnesium salts, etc.; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N' -dibenzylethylenediamine salt and the like; inorganic salts, e.g. salt salts, hydrobromide, sulphite, phosphorus
Salt, and the like; organic salts such as methyl salt, ethyl salt, trifluoroethyl salt, maleic salt, fumaric salt, tartaric salt and the like; sulfonate salts such as methyl sulfonate, benzene sulfonate, p-toluene sulfonate, and the like; amino salt such as arginine salt, aspartyl salt, glutamic salt, etc.
The resulting compounds of the present disclosure may also further form prodrugs. Prodrug refers to any covalently bound carrier that can release the active parent drug in vivo.
The resulting compounds of the present disclosure also include isotopically labeled compounds in which one or more atoms are replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the above compounds include hydrogen, carbon, nitrogen, oxygen,Isotopes of phosphorus, fluorine and chlorine, e.g. each2H，3H，13C，14C，15N，18O，17O，31P，32P，35S，18F and36and (4) Cl. Some of the compounds described herein may contain one or more asymmetric centers and thus may give rise to enantiomeric, diastereomeric and other stereoisomeric forms. The invention also includes all such possible forms as well as their racemic and resolved forms and mixtures thereof. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the E and Z geometric isomers are included. All tautomers are also included in the present invention. As used herein, the term "stereoisomer" generally refers to all isomers of various molecules that differ only in the spatial orientation of the atoms. This term includes enantiomers and isomers of compounds having more than one chiral center that are not mirror images of each other (diastereomers).
The term "chiral center" refers to a carbon atom to which four different groups are attached.
The term "enantiomer" or "enantiomeric" refers to a molecule that is optically active because it does not overlap with its mirror image, wherein the enantiomer rotates in one direction about the plane of polarized light and its mirror image rotates in the opposite direction about the plane of polarized light.
The term "racemic" refers to a mixture of equal amounts of enantiomers which are not optically active.
The term "resolution" refers to the separation or concentration or removal of one of the two enantiomeric forms of a molecule.
The term "modulate" as used herein with respect to the ORL-1 receptor refers to mediating a pharmacodynamic response (e.g., analgesia) in a subject by (1) inhibiting or activating the receptor, or (2) directly or indirectly affecting the normal modulation of the activity of the receptor. Compounds that modulate the activity of the receptor include agonists, antagonists, agonist/antagonist mixtures and compounds that directly or indirectly affect modulation of the activity of the receptor.
Certain preferred compounds of the invention include:
8- (4-propylcyclohexyl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (5-methylhexan-2-yl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8-norbornyl-1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (decahydro-2-naphthyl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (cyclooctylmethyl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (1, 2, 3, 4-tetrahydro-2-naphthyl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- [4- (2-propyl) -cyclohexyl ] -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (1, 3-indan-2-yl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- [ (naphthalen-2-yl-methyl) ] -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (p-phenylbenzyl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- [4, 4-bis (4-fluorophenyl) butyl ] -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (benzyl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (10, 11-dihydro-5H-dibenzo [ a, d ] -cyclohepten-5-yl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (3, 3-di (phenyl) propyl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (p-benzyloxybenzyl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
8- (cyclooctylmethyl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one;
and pharmaceutically acceptable salts and solvates thereof.
Another preferred compound is 8- (acenaphthen-9-yl) -1-phenyl-2, 3, 8-azidospiro [4.5] decan-4-one and pharmaceutically acceptable salts and solvates thereof.
The invention also provides the use of any one of the above compounds in the manufacture of a medicament for the treatment of pain and other disease symptoms mediated through opioid receptors, such as the ORL-1 receptor.
Detailed Description
According to certain embodiments of the invention, the compound of formula (IV) is generally prepared from a compound of formula (III) by the following reaction scheme:
Figure A20038010145900281
wherein R, R1A, B, C and W have the same meanings as described above.
Figure A20038010145900291
Wherein R, R1A, B, C and W have the same meanings as above, G is O or S, R15Selected from straight or branched C1-10Alkyl radical, C3-12Cycloalkyl radical, C3-12Cycloalkyl radical C1-10Alkyl, aryl, heteroaryl, aryl C1-10Alkyl or heteroaryl C1-10An alkyl group;
reaction c is preferably a reduction and cyclization reaction. Preferably, in reaction C, the compound of formula (III) is reacted with hydrazine or a substituted hydrazine, such as hydrazine hydrate, to form the compound of formula (IV).
In certain embodiments, it is desirable to use 1 mole or more than 1 mole of hydrazine or substituted hydrazine to 1 mole of the compound of formula (III).
In certain embodiments, reaction C above is carried out in the absence of a base. In other embodiments, reaction C above is carried out in the presence of a base. Some bases useful for reaction C include, but are not limited to, alcoholic solvents such as methanol, ethanol, isopropanol, ethanol or n-butanol; ketone solvents such as cyclohexanone or methyl isobutyl ketone; hydrocarbon solvents such as benzene, toluene or xylene; halogenated hydrocarbons such as chlorobenzene or dichloromethane or dimethylformamide, etc.
In certain embodiments, a catalyst may be used in reaction C. Suitable catalysts include, for example, platinum catalysts such as platinum chloride, ethylplatinum, platinum hydroxide, platinum oxide, platinum carbon hydroxide, tetrakis (triphenylphosphine) platinum (O), dichlorobis (triphenylphosphine) platinum (II), or benzylchlorobis (triphenylphosphine) platinum (II); or a nickel-phosphine catalyst. The amount of the catalyst is preferably 0.0001 to 0.5 part by weight based on 1 part by weight of the compound of the formula (III).
The reaction temperature is generally from-20 ℃ to 150 ℃, preferably from 0 ℃ to 100 ℃.
In certain embodiments of the present invention, the compounds of formula (IV) above may be prepared by the following reaction scheme:
Figure A20038010145900301
this process of the invention comprises subjecting the compound of formula (II) to an acylation reaction B.
In the acylation, it is preferable to subject the compound of the formula (II) to an acylation reaction with an acid halide of the following formula,
wherein R is1Selected from the group as described above; x is halogen, preferably Br or Cl; preference is given to forming compounds of the formula (III) above in which R, R1A, B and C are selected from the groups mentioned above. Thereafter, the compound of formula (III) undergoes reduction and cyclization (reaction C). Preferably, in reaction C, the compound of formula (III) is reacted with hydrazine or a substituted hydrazine, such as hydrazine hydrate, to form the compound of formula (IV).
In certain embodiments, when G is O and R15When is ethyl, R1Is not phenyl. In certain embodiments, when G is O and R15When ethyl, the acid halide is not benzoyl chloride.
In certain embodiments, the acylation reaction B described above is carried out in the absence of a base.
In certain embodiments, the acylation reaction B described above is carried out in the presence of a suitable non-nucleophilic base, such as potassium tert-butoxide, sodium hydride, lithium diisopropylamide ("LDA"), lithium hexamethyldisilazide ("LHMDS"), potassium hexamethyldisilazide ("KHMDS"), sodium or potassium tetramethylpiperidine, or a related strong base.
Preferably, the acylation reaction B is carried out in the presence of a suitable solvent, for example, a hydrocarbon solvent such as benzene, toluene, xylene or cyclohexane; halogenated hydrocarbons such as chlorobenzene, dichloroethane, dichloromethane, chloroform or carbon tetrachloride; carbon disulfide; dimethylformamide; ether solvents such as tetrahydrofuran and diethyl ether, or dioxane, etc.
In certain embodiments, it is desirable to use from 1 mole to more than 1 mole of the above base to 1 mole of the compound of formula (II).
The reaction temperature is generally from-60 ℃ to 100 ℃, preferably from-40 ℃ to 80 ℃.
In certain embodiments of the invention, compounds of formula (IV) may be prepared using compounds of formula (I) by the following reaction scheme:
Figure A20038010145900311
Figure A20038010145900312
as indicated above, the compound of formula (I) is preferably subjected to reaction A to form the compound of formula (II), followed by reaction B to form the compound of formula (III), and then reaction C to form the compound of formula (IV).
In certain embodiments, reaction a is a reductive amination reaction. In other embodiments, reaction a is an alkylation reaction. In still other embodiments, reaction a is an acylation reaction.
In certain embodiments, reaction A is a reductive amination reaction, reacting a compound of formula (I) with a compound of the formula,
wherein Z is1AAnd Z1BMay be the same or different and are each independently selected from a linkage, straight or branched C1-6Alkylene, -NH-, -CH2O-，-CH2NH-，-CH2N(CH3)-，-NHCH2-，-CH2CONH-，-NHCH2CO-，-CH2CO-，-COCH2-，-CH2COCH2-，-CH(CH3) -, -CH ═ O-and-HC ═ CH-, in which the carbon and/or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;
R1Aand R2AMay be the same or different and are each independently selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C2-10Alkenyl, amino, C1-10Alkylamino radical, C3-12Cycloalkylamino, -COOV1，-C1-4COOV1Cyano, cyano C1-10Alkyl-, cyano-C1-10Cycloalkyl-, NH2SO2，NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, aminocarbonyl-, C1-4Alkylamino carbonyl-, di-C1-4Alkylaminocarbonyl-, benzyl, C3-12Cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, hetero-monocyclic, hetero-bicyclic system and spiro ring system of formula (V):
wherein, X1And X2Are respectively selected from NH, O, S and CH2(ii) a And wherein said R1Alkyl, cycloalkyl, alkenyl, C1-10Alkylamino-, C3-12Cycloalkylamino-or benzyl optionally substituted by 1-3 substituents selected from halogen, hydroxy, C1-10Alkyl radical, C1-10Alkoxy, nitro, trifluoromethyl, cyano, -COOV1，-C1-4COOV1Cyano group C1-10Alkyl-, -C1-5(＝O)W1，-C1-5NHS(＝O)2W1，-C1-5NHS(＝O)W15-membered heteroaromatic C0-4Alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl and benzyloxy being optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-10Alkyl-, C1-10Alkoxy-and cyano-substituted; and wherein said C3-12Cycloalkyl radical, C3-12Cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaromatic rings, hetero-monocyclic, hetero-bicyclic systems or spirocyclic systems of formula (V) optionally substituted by 1 to 3 substituents selected from halogen, C1-10Alkyl radical, C1-10Alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenoxy and benzyloxy, wherein said phenyl, benzyl, phenoxy or benzyloxy is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-10Alkyl radical, C1-10Alkoxy and cyano;
in certain preferred embodiments, R1AAlkyl is methyl, ethyl, propyl, butyl, pentyl or hexyl.
In certain preferred embodiments, R1ACycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norglacialAnd (3) film base.
In other preferred embodiments, R1AThe bicyclic ring system is naphthyl. In other preferred embodiments, R1AThe bicyclic system being tetrahydronaphthyl or decahydronaphthyl, R1AThe tricyclic ring system is dibenzocycloheptyl. In other preferred embodiments, R1AIs phenyl or benzyl.
In other preferred embodiments, R1AThe bicyclic aromatic ring is a 10-membered ring, preferably quinoline or naphthyl.
In other preferred embodiments, R1AThe bicyclic aromatic ring is a 9-membered ring, preferably indenyl.
In certain preferred embodiments, Z1AIs a bond, methyl or ethyl.
In certain preferred embodiments, Z1AThe radicals being maximally substituted, i.e. in Z1AThe group does not have any hydrogen substituents. For example, if Z1AThe radical being-CH2-, substituted by two methyl radicals, which may be derived from-CH2-Z1AThe hydrogen is removed from the radical.
In certain embodiments, X1And X2Are all O.
In certain embodiments, Z1AR1AIs cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-, phenethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-or oxooctylpropyl-.
In certain embodiments, Z1AR1Ais-CH2COOV1Tetrazolylmethyl-, cyanomethyl-, NH2SO2Methyl-, NH2SO methyl-, aminocarbonylmethyl-, C1-4Alkylaminocarbonylmethyl-or di-C1-4Alkylaminocarbonylmethyl-.
In certain embodiments, Z1AR1AIs 3, 3-diphenylpropyl, which is optionally substituted by-COOV on the 3 rd carbon of the propyl group1Tetrazolyl radical C0-4Alkyl-, cyano-, aminocarbonyl-, C1-4Alkylamino carbonyl-or di-C1-4Alkylaminocarbonyl-substitution.
In other embodiments, Z1AR1ACan be
Wherein,
Y1，Y2and Y3As defined above.
In embodiments where reaction A is a reductive amination reaction, the reaction is suitably carried out in the presence of a catalyst.
Suitable are all inorganic and organic protons and Lewis, and also all polymers. These include, for example, hydrogen chloride, hydrogen bromide, sulfur, methyl, ethyl, trifluoroethyl, methyl sulfonic, difluoromethyl sulfonic, toluene sulfonic, boron trifluoride, boron tribromide, aluminum trichloride, zinc chloride, iron (III) chloride, antimony pentachloride, a sexual ion exchanger, sexual alumina and sexual silica gel.
Preferably, the reductive amination reaction A is carried out in a suitable solvent, for example, water, an organic solvent or a mixture thereof. Examples of the organic solvent include, for example, alcohols such as methanol, ethanol, n-or isopropanol, n-, iso-, sec-or tert-butanol, ethylene glycol, propylene-1, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof. Particularly preferred solvents in this case are water or alcohols, such as methanol, ethanol, n-or isopropanol, n-, iso-, sec-or tert-butanol, ethylene glycol, propane-1, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof.
Suitable reducing agents for the reductive amination reaction include, for example, sodium borohydride, potassium borohydride, sodium cyanoborohydride, tetramethylammonium borohydride, and the like.
In certain embodiments, it is desirable to use from 1 mole to more than 1 mole of the above-described oxidizing agent to 1 mole of the compound of formula (I).
The reaction temperature is generally from-20 ℃ to 150 ℃, preferably from 0 ℃ to 100 ℃.
Preferably, the compound of formula (II) is formed in this reaction.
Figure A20038010145900351
Wherein R, A, B, C, G and R15Selected from the groups described above.
Alternatively, where reaction A is an alkylation reaction, the compound of formula (I),
with a compound of formula R-X, wherein R is selected from the group as described above. X is halogen, preferably X is Br or Cl.
In embodiments where reaction A is an alkylation reaction, the reaction is preferably carried out in the presence of a base. Suitable bases are all customary inorganic or organic bases. The preferable ones include: alkaline earth metal or alkali metal hydrides, hydroxides, amides, alkoxides, acetates, carbonates or bicarbonates, such as sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, calcium acetate, ammonium acetate, sodium carbonate, potassium bicarbonate, sodium bicarbonate or ammonium carbonate; tertiary amines, such as trimethylamine, triethylamine, tributylamine, N-dimethylaniline, N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N-dimethylaminopiperidine, Dinitrobicyclooctane (DABCO), Dinitrobicyclononene (DBN) or Dinitrobicyclodecene (DBU). Particularly preferred bases are sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide; and tertiary amines such as trimethylamine, triethylamine, tributylamine, N-dimethylaniline, N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N-dimethylaminopiperidine, Dinitrobicyclooctane (DABCO), Dinitrobicyclononene (DBN) or Dinitrobicyclodecene (DBU).
Preferably, alkylation reaction a is carried out in a suitable solvent, for example, including an alcoholic solvent such as methanol, ethanol, isopropanol or n-butanol; ketone solvents such as methyl isobutyl ketone and methyl ethyl ketone; hydrocarbon solvents such as benzene, toluene, xylene; halogenated hydrocarbons such as chlorobenzene or dichloromethane; or dimethylformamide, and the like.
The reaction temperature is generally from-20 ℃ to 150 ℃, or from 0 ℃ to 100 ℃.
The reaction pressure may be standard atmospheric pressure, or under pressure, such as up to 45 psi.
Preferably, the compound of formula (II) is formed in this reaction.
Alternatively, where reaction A is an acylation reaction, the compound of formula (I),
Figure A20038010145900361
with a compound of the formula,
wherein R and X are selected from the group as described above.
The above reaction may be carried out in the presence or absence of a base. Useful bases for this reaction are any of the bases listed above.
Suitable solvents for the acylation reaction a include, for example, hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane; halogenated hydrocarbons such as chlorobenzene, dichloroethane, dichloromethane, chloroform or carbon tetrachloride; carbon disulfide; dimethylformamide; ether solvents such as tetrahydrofuran and diethyl ether, or dioxane, etc.
The reaction temperature is generally from-60 ℃ to 100 ℃ or from-40 ℃ to 80 ℃.
The reaction pressure may be standard atmospheric pressure, or under pressure, such as up to 45 psi.
Preferably, the compound of formula (II) is formed in this reaction.
After reaction A, the product is preferably quenched by addition of water and a base (e.g., NaOH) to bring the pH to 10. The mixture is then extracted (e.g. with Et)2O, preferably extracted twice) and dried.
The process of the present invention further comprises subjecting the compound of formula (II) to the acylation reaction B described above to form the compound of formula (III).
Preferably, the compound of formula (III) is then subjected to reaction C as described above, and the compound of formula (III) is subjected to reduction and cyclization with hydrazine or a substituted hydrazine, such as hydrazine hydrate, to form the compound of formula (IV).
The following examples illustrate various aspects of the invention, but do not limit the claims in any way.
Example 1
To a solution of compound 1 (1 equivalent) and triethylamine (1 equivalent) in dimethylformamide was added ethyl chloride 1 equivalent at a time. The mixture was stirred and heated to 80 ℃ overnight to give solution 2. TLC indicated the reaction was complete.
Steel at-40 deg.CTo a solution of the prepared LDA in THF (1.1 eq) was added solution 2(1 eq). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. After cooling to-20 ℃ a solution of benzoyl chloride (1.2 eq) in THF was added dropwise. After stirring at-20 ℃ for 1 hour and at room temperature for 16 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed with saturated ammonium chloride, brine and MgSO4Drying, filtration and evaporation of the solvent gave the crude product 3 as an oil which was used in the next step without purification.
To a solution of 3(1 eq) in ethanol was added hydrazine hydrate (3 eq). After 12 hours of reflux, the reaction mixture was cooled to room temperature and the crude product was filtered. The solid was recrystallized from ethanol to give a white solid 4.
Other reactions may be carried out by those skilled in the art, wherein Compound 1 has G and R as described above15A substituent other than the ethoxy group of example 1.
Example 2
Starting materials for preparing embodiments wherein A, B and/or C are other than hydrogen are prepared according to the reaction schemes set forth below.
Obtained from Aldrich

Claims (24)

1. A method for preparing a compound represented by the general formula (IV) or a pharmaceutically acceptable salt or solvate thereof, characterized in that:
in the formula, W is hydrogen or C1-10Alkyl radical, C3-12Cycloalkyl radical, C3-12Cycloalkyl radical C1-4Alkyl-, C1-10Alkoxy radical, C3-12Cycloalkoxy-, C substituted by 1-3 halogen atoms1-10Alkyl, C substituted by 1-3 halogen atoms3-12Cycloalkyl, C substituted by 1 to 3 halogen atoms3-12Cycloalkyl radical C1-4Alkyl-, C substituted by 1-3 halogen atoms1-10Alkoxy, C substituted by 1 to 3 halogen atoms3-12Cycloalkoxy, -COOV1、-C1-4COOV1，-CH2OH，-SO2N(V1)2Hydroxy group C1-10Alkyl-, hydroxy-C3-10Cycloalkyl-, cyano-C1-10Alkyl-, cyano-C3-10Cycloalkyl-, -CON (V)1)2、NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, sulphonamido C1-10Alkyl-, diaminoalkyl-, -sulphonyl C1-4Alkyl, 6-membered heterocycle, 6-membered heteroaromatic ring, 6-membered heterocycle C1-4Alkyl-, 6-membered heteroaromatic C1-4Alkyl-, 6-membered aromatic ring, 6-membered aromatic C1-4Alkyl-, a 5-membered heterocycle optionally substituted by oxygen or sulfur, a 5-membered heteroaromatic ring, a 5-membered heterocycle optionally substituted by oxygen or sulfur C1-4Alkyl-, 5-membered heteroaromatic C1-4Alkyl-, -C1-5(＝O)W1、-C1-5(＝NH)W1、-C1-5NHC(＝O)W1、-C1-5NHS(＝O)2W1、-C1-5NHS(＝O)W1(ii) a Wherein, W1Is hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C1-10Alkoxy radical, C3-12Cycloalkoxy, -CH2OH, amino, C1-4Alkylamino-, di-C1-4Alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl groups;
wherein each V1Independently selected from H, C1-6Alkyl radical, C3-6Cycloalkyl, benzyl or phenyl;
a, B and C are hydrogen and C respectively1-10Alkyl radical, C3-12Cycloalkyl radical, C1-10Alkoxy radical, C3-12Cycloalkoxy, -CH2OH、-NHSO2Hydroxy group C1-10Alkyl-, aminocarbonyl-, C1-4Alkylaminocarbonyl-, di-C1-4Alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, acylAmine, sulphonamido C1-10Alkyl-, or A-B together form C2-6The bridge, or B-C, may together form C3-7The bridge, or A-C, may together form C1-5A bridge;
r is-Z-R2(ii) a Z is selected from a connecting bond, straight chain or branched C1-6Alkylene, -NH-, -CH2O-、-CH2NH-、-CH2N(CH3)-、-NHCH2-、-CH2CONH-、-NHCH2CO-、-CH2CO-、-COCH2-、-CH2COCH2-、-CH(CH3) -CH ═ O-, and-HC ═ CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl groups, hydroxyl groups, halogen atoms, or alkoxy groups;
R2selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C2-10Alkenyl, amino, C1-10Alkylamino-, C3-12Cycloalkyl amino-, -COOV1、-C1-4COOV1Cyano, cyano C1-10Alkyl-, cyano-C3-10Cycloalkyl-, NH2SO2-、NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, aminocarbonyl-, C1-4Alkylaminocarbonyl-, di-C1-4Alkylaminocarbonyl-, benzyl-, C3-12Cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl rings, hetero-monocyclic, hetero-bicyclic systems and spiro ring systems of the general formula (II):
Figure A2003801014590003C1
wherein, X1And X2Are respectively selected from NH, O, S and CH2(ii) a Wherein R is1Said alkyl, cycloalkyl, alkenyl, C1-10Alkylamino-, C3-12Cycloalkylamino-or benzyl optionally substituted with 1-3 substituents selected from halogen atom, hydroxy, C1-10Alkyl radical, C1-10Alkoxy, nitro, trifluoromethyl, cyano, -COOV1、-C1-4COOV1Cyano group C1-10Alkyl, -C1-5(＝O)W1、-C1-5NHS(＝O)2W1、-C1-5NHS(＝O)W15-membered heteroaromatic C0-4Alkyl-, phenyl, benzyl, benzyloxy; said phenyl, benzyl and benzyloxy being optionally substituted by 1 to 3 substituents selected from halogen atom, C1-10Alkyl-, C1-10Alkoxy-and cyano-substituted; wherein said C3-12Cycloalkyl radical, C3-12Cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaromatic ring, hetero-monocyclic, hetero-bicyclic system, or spirocyclic system of formula (V) optionally substituted by 1 to 3 substituents selected from halogen atoms, C1-10Alkyl radical, C1-10Alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenoxy and benzyloxy, wherein said phenyl, benzyl, phenoxy or benzyloxy is optionally substituted by 1 to 3 substituents selected from halogen atoms, C1-10Alkyl-, C1-10Alkoxy-and cyano-substituted;
R1is selected from C1-8Alkyl, 5-8 membered cycloalkyl, 5-8 membered heterocyclyl or 6-membered aryl or heteroaryl; and R is1Quilt (D)nWherein n is an integer of 0 to 3, D is selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl-and halogen, said alkyl or cycloalkyl being optionally substituted by oxo, amino, alkylamino or dialkylamino;
the method comprises the following steps:
compounds of formula (III)
Figure A2003801014590004C1
Wherein, A, B, C, R and R1G is O or S, R, as defined above15Selected from straight or branched C1-10Alkyl radical, C3-12Cycloalkyl radical, C3-12Cycloalkyl radical C1-10Alkyl, aryl, heteroaryl, aryl C1-10Alkyl or heteroaryl C1-10An alkyl group;
reacting the compound of formula (III) with hydrazine, a hydrate thereof, a substituted hydrazine, or a hydrate thereof under conditions effective to form a compound of formula (IV):
wherein, A, B, C, R1And W is as defined above.
2. The method of claim 1, further comprising forming a compound of formula (III) from a compound of formula (II):
wherein, A, B, C, R, G and R15As defined above;
reacting said compound of formula (II) with a compound of the formula (II) under conditions effective to form a compound of formula (III) acylating said compound of formula (II),
Figure A2003801014590005C1
wherein R is1As mentioned above, X is halogen.
3. The method of claim 2, further comprising forming a compound of formula (II) from the compound of formula (I):
Figure A2003801014590005C2
wherein, A, B, C, G and R15As defined above; reacting a compound of formula (I) with a compound of the formula:
wherein Z is1AAnd Z1BMay be the same or different and are each independently selected from a linkage, straight or branched C1-6Alkylene, -NH-, -CH2O-，-CH2NH-，-CH2N(CH3)-，-NHCH2-，-CH2CONH-，-NHCH2CO-，-CH2CO-，-COCH2-，-CH2COCH2-，-CH(CH3) -, -CH ═ O-and-HC ═ CH-, in which the carbon and/or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;
R1Aand R2AMay be the same or different and are each independently selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C2-10Alkenyl, amino, C1-10Alkylamino radical, C3-12Cycloalkylamino, -COOV1，-C1-4COOV1Cyano, cyano C1-10Alkyl-, cyano-C3-10Cycloalkyl-, NH2SO2，NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, aminocarbonyl-, C1-4Alkylamino carbonyl-, di-C1-4Alkylaminocarbonyl-, benzyl, C3-12Cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, hetero-monocyclic, hetero-bicyclic system and spiro ring system of formula (V):
wherein, X1And X2As defined above.
4. The method of claim 2, further comprising forming a compound of formula (II) from the compound of formula (I):
wherein, A, B, C, G and R15As defined above; reacting said formula (I) with a compound of the formula:
R-X
wherein R is as defined above and X is halogen.
5. The method of claim 2, further comprising forming a compound of formula (II) from the compound of formula (I):
Figure A2003801014590006C3
wherein, A, B, C, G and R15As defined above; reacting said formula (I) with a compound of the formula:
wherein R is as defined above and X is halogen.
6. A process for preparing a compound of formula (IV), characterized in that:
Figure A2003801014590007C1
in the formula, W is hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C3-12Cycloalkyl radical C1-4Alkyl-, C1-10Alkoxy radical, C3-12Cycloalkoxy-, C substituted by 1-3 halogens1-10Alkyl, C substituted by 1-3 halogens3-12Cycloalkyl, C substituted by 1-3 halogens3-12Cycloalkyl radical C1-4Alkyl-, C substituted by 1-3 halogens1-10Alkoxy, C substituted by 1-3 halogens3-12Cycloalkoxy-, -COOV1，-C1-4COOV1，-CH2OH，-SO2N(V1)2Hydroxy radical C1-10Alkyl-, hydroxy-C3-10Cycloalkyl-, cyano-C1-10Alkyl-, cyano-C3-10Cycloalkyl-, -CON (V)1)2，NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, sulfonamido-C1-10Alkyl-, diaminoalkyl-, -sulfonyl C1-4Alkyl, 6-membered heterocycle, 6-membered heteroaromatic ring, 6-membered heterocycle C1-4Alkyl-, 6-membered heteroaromatic C1-4Alkyl-, 6-membered aromatic ring, 6-membered aromatic C1-4Alkyl-, a 5-membered heterocycle optionally substituted by oxygen or sulphur, a 5-membered heteroaromatic ring, a 5-membered heterocycle optionally substituted by oxygen or sulphur C1-4Alkyl-, 5-membered heteroaromatic C1-4Alkyl-, -C1-5(＝O)W1，-C1-5(＝NH)W1，-C1-5NHC(＝O)W1，-C1-5NHS(＝O)2W1，-C1-5NHS(＝O)W1Wherein W is1Is hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C1-10Alkoxy radical, C3-12Cycloalkoxy, -CH2OH, amino, C1-4Alkylamino-, di-C1-4Alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl groups;
wherein each V1Independently selected from H, C1-6Alkyl radical, C3-6Cycloalkyl, benzyl and phenyl;
A. b and C are each hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C1-10Alkoxy radical, C3-12Cycloalkoxy, -CH2OH，-NH2SO2Hydroxy radical C1-10Alkyl, aminocarbonyl-, C1-4Alkylamino carbonyl-, di-C1-4Alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulphonamido C1-10Alkyl-, or A-B together form C2-6Bridges, or B-C together form C3-7Bridge, or A-C together form C1-5A bridge;
r is-Z-R2Wherein Z is selected from a linkage, straight or branched C1-6Alkylene, -NH-, -CH2O-，-CH2NH-，-CH2N(CH3)-，-NHCH2-，-CH2CONH-，-NHCH2CO-，-CH2CO-，-COCH2-，-CH2COCH2-，-CH(CH3) -, -CH ═ O-and-HC ═ CH-, in which the carbon and/or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups; when G is O, and R15R is not unsubstituted benzyl when it is ethyl;
R2selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C2-10Alkenyl, amino, C1-10Alkylamino-, C3-12Cycloalkylamino-, -COOV1，-C1-4COOV1Cyano, cyano C1-10Alkyl-, cyano-C3-10Cycloalkyl-, NH2SO2-，NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, aminocarbonyl-, C1-4Alkylamino carbonyl-, di-C1-4Alkylaminocarbonyl-, benzyl, C3-12Cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, hetero-monocyclic, hetero-bicyclic system and spiro ring system of formula (V):
Figure A2003801014590008C1
wherein, X1And X2Are respectively selected from NH, O, S and CH2(ii) a And wherein said R1Alkyl, cycloalkyl, alkenyl, C1-10Alkylamino-, C3-12Cycloalkylamino-or benzyl optionally substituted by 1-3 substituents selected from halogen, hydroxy, C1-10Alkyl radical, C1-10Alkoxy, nitro, trifluoromethyl, cyano, -COOV1，-C1-4COOV1Cyano group C1-10Alkyl-, -C1-5(＝O)W1，-C1-5NHS(＝O)2W1，-C1-5NHS(＝O)W15-membered heteroaromatic C0-4Alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl and benzyloxy being optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-10Alkyl-, C1-10Alkoxy-and cyano-substituted; wherein said C3-12Cycloalkyl radical, C3-12Cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaromatic rings, hetero-monocyclic, hetero-bicyclic systems or spirocyclic systems of the formula (V) optionally substituted by 1 to 3 substituents selected from halogen, C1-10Alkyl radical, C1-10Alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenoxy and benzyloxy, wherein said phenyl, benzyl, phenoxy or benzyloxy is optionally substituted by 1-3 are selected from halogen, C1-10Alkyl radical, C1-10Alkoxy and cyano;
R1is selected from C1-8Alkyl, 5-8 membered cycloalkyl, 5-8 membered heterocyclyl or 6-membered aryl or heteroaryl; and R is1Quilt (D)nWherein n is an integer of 0 to 3, D is selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl-and halogen, said alkyl or cycloalkyl being optionally substituted by oxo, amino, alkylamino or dialkylamino;
the method comprises the following steps:
compounds of formula (III)
Figure A2003801014590008C2
Wherein, A, B, C, R and R1G is O or S, R, as defined above15Selected from straight or branched C1-10Alkyl radical, C3-12Cycloalkyl radical, C3-12Cycloalkyl radical C1-10Alkyl, aryl, heteroaryl, aryl C1-10Alkyl or heteroaryl C1-10An alkyl group;
reacting the compound of formula (III) with hydrazine, a hydrate thereof, a substituted hydrazine, or a hydrate thereof under conditions effective to form a compound of formula (IV):
Figure A2003801014590009C1
wherein, A, B, C, R1And W is as defined above.
7. The method of claim 6, further comprising forming a compound of formula (III) from a compound of formula (II):
wherein, A, B, C, R, G and R15As defined above;
reacting said compound of formula (II) with a compound of the formula (II) under conditions effective to form a compound of formula (III) acylating said compound of formula (II),
Figure A2003801014590009C3
wherein R is1As defined above, X is halogen.
8. The method of claim 7, further comprising forming a compound of formula (II) from the compound of formula (I):
Figure A2003801014590010C1
wherein, A, B, C, G and R15As defined above; reacting a compound of formula (I) with a compound of the formula:
Figure A2003801014590010C2
wherein Z is1AAnd Z1BMay be the same or different and are each independently selected from a linkage, straight or branched C1-6Alkylene, -NH-, -CH2O-，-CH2NH-，-CH2N(CH3)-，-NHCH2-，-CH2CONH-，-NHCH2CO-，-CH2CO-，-COCH2-，-CH2COCH2-，-CH(CH3) -, -CH ═ O-and-HC ═ CH-, in which the carbon and/or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;
R1Aand R2AMay be the same or different and are each independently selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C2-10Alkenyl, amino, C1-10Alkylamino radical, C3-12Cycloalkylamino, -COOV1，-C1-4COOV1Cyano, cyano C1-10Alkyl-, cyano-C3-10Cycloalkyl-, NH2SO2，NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, aminocarbonyl-, C1-4Alkylamino carbonyl-, di-C1-4Alkylaminocarbonyl-, benzyl, C3-12Cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, hetero-monocyclic, hetero-bicyclic system and spiro ring system of formula (V):
Figure A2003801014590010C3
wherein, X1And X2As defined above.
9. The method of claim 7, further comprising forming a compound of formula (II) from the compound of formula (I):
wherein, A, B, C, G and R15As defined above; reacting said formula (I) with a compound of the formula:
R-X
wherein R is as defined above and X is halogen.
10. The method of claim 7, further comprising forming a compound of formula (II) from the compound of formula (I):
wherein, A, B, C, G and R15As defined above; reacting said formula (I) with a compound of the formula:
wherein R is as defined above and X is halogen.
11. A process for preparing a compound of formula (IV), characterized in that:
in the formula, W is hydrogen or C1-10Alkyl radical, C3-12Cycloalkyl radical, C3-12Cycloalkyl radical C1-4Alkyl-, C1-10Alkoxy radical, C3-12Cycloalkoxy-, C substituted by 1-3 halogen atoms1-10Alkyl, C substituted by 1-3 halogen atoms3-12Cycloalkyl, C substituted by 1 to 3 halogen atoms3-12Cycloalkyl radical C1-4Alkyl-, C substituted by 1-3 halogen atoms1-10Alkoxy, C substituted by 1 to 3 halogen atoms3-12Cycloalkoxy, -COOV1、-C1-4COOV1，-CH2OH，-SO2N(V1)2Hydroxy group C1-10Alkyl-, hydroxy-C3-10Cycloalkyl-, cyano-C1-10Alkyl-, cyano-C3-10Cycloalkyl-, -CON (V)1)2、NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, sulphonamido C1-10Alkyl-, diaminoalkyl-, -sulphonyl C1-4Alkyl, 6-membered heterocycle, 6-membered heteroaromatic ring, 6-membered heterocycle C1-4Alkyl-, 6-membered heteroaromatic C1-4Alkyl-, 6-membered aromatic ring, 6-membered aromatic C1-4Alkyl-, a 5-membered heterocycle optionally substituted by oxygen or sulfur, a 5-membered heteroaromatic ring, a 5-membered heterocycle optionally substituted by oxygen or sulfur C1-4Alkyl-, 5-membered heteroaromatic C1-4Alkyl-, -C1-5(＝O)W1、-C1-5(＝NH)W1、-C1-5NHC(＝O)W1、-C1-5NHS(＝O)2W1、-C1-5NHS(＝O)W1(ii) a Wherein, W1Is hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C1-10Alkoxy radical, C3-12Cycloalkoxy, -CH2OH, amino, C1-4Alkylamino-, di-C1-4Alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl groups;
whereinEach V1Independently selected from H, C1-6Alkyl radical, C3-6Cycloalkyl, benzyl or phenyl;
a, B and C are hydrogen and C respectively1-10Alkyl radical, C3-12Cycloalkyl radical, C1-10Alkoxy radical, C3-12Cycloalkoxy, -CH2OH、-NHSO2Hydroxy group C1-10Alkyl-, aminocarbonyl-, C1-4Alkylaminocarbonyl-, di-C1-4Alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulphonamido C1-10Alkyl-, or A-B together form C2-6The bridge, or B-C, may together form C3-7The bridge, or A-C, may together form C1-5A bridge;
r is-Z-R2(ii) a Z is selected from a connecting bond, straight chain or branched C1-6Alkylene, -NH-, -CH2O-、-CH2NH-、-CH2N(CH3)-、-NHCH2-、-CH2CONH-、-NHCH2CO-、-CH2CO-、-COCH2-、-CH2COCH2-、-CH(CH3) -CH ═ O-, and-HC ═ CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl groups, hydroxyl groups, halogen atoms, or alkoxy groups;
R2selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C2-10Alkenyl, amino, C1-10Alkylamino-, C3-12Cycloalkyl amino-, -COOV1、-C1-4COOV1Cyano, cyano C1-10Alkyl-, cyano-C3-10Cycloalkyl-, NH2SO2-、NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, aminocarbonyl-, C1-4Alkylaminocarbonyl-, di-C1-4Alkylaminocarbonyl-, benzyl-, C3-12Cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl rings, hetero-monocyclic, hetero-bicyclic systems and spiro ring systems of the general formula (V):
wherein, X1And X2Are respectively selected from NH, O, S and CH2(ii) a Wherein R is1Said alkyl, cycloalkyl, alkenyl, C1-10Alkylamino-, C3-12Cycloalkylamino-or benzyl optionally substituted with 1-3 substituents selected from halogen atom, hydroxy, C1-10Alkyl radical, C1-10Alkoxy, nitro, trifluoromethyl, cyano, -COOV1、-C1-4COOV1Cyano group C1-10Alkyl, -C1-5(＝O)W1、-C1-5NHS(＝O)2W1、-C1-5NHS(＝O)W15-membered heteroaromatic C0-4Alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl and benzyloxy are optionally substituted by 1 to 3 substituents selected from halogen atoms, C1-10Alkyl-, C1-10Alkoxy-and cyano-substituted; wherein said C3-12Cycloalkyl radical, C3-12Cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaromatic ring, hetero-monocyclic, hetero-bicyclic system, or spirocyclic system of formula (V) optionally substituted by 1 to 3 substituents selected from halogen atoms, C1-10Alkyl radical, C1-10Alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenoxy and benzyloxy, wherein said phenyl, benzyl, phenoxy or benzyloxy is optionally substituted by 1 to 3 substituents selected from halogen atoms, C1-10Alkyl-, C1-10Alkoxy-and cyano-substituted;
R1is selected from C1-8Alkyl, 5-8 membered cycloalkyl, 5-8 membered heterocyclyl or 6-membered aryl or heteroaryl; and R is1Quilt (D)nWherein n is an integer of 0 to 3, D is selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl-and halogen, said alkyl or cycloalkyl being optionally substituted by oxo, amino, alkylamino or dialkylamino;
the method comprises the following steps:
providing a compound of formula (II)
Figure A2003801014590013C2
WhereinA, B, C and R are as defined above, G is O or S, R15Selected from straight or branched C1-10Alkyl radical, C3-12Cycloalkyl radical, C3-12Cycloalkyl radical C1-10Alkyl, aryl, heteroaryl, aryl C1-10Alkyl or heteroaryl C1-10An alkyl group;
when G is O and R15When ethyl, reacting said compound of formula (II) with a compound of formula (II) other than benzyl chloride
Figure A2003801014590014C1
The compounds are reacted under conditions effective to form a compound of formula (III) wherein R1As mentioned above, X is halogen:
wherein, A, B, C, R1G and R15As defined above;
reacting the compound of formula (III) with hydrazine, a hydrate thereof, a substituted hydrazine, or a hydrate thereof under conditions effective to form a compound of formula (IV):
wherein, A, B, C, R1And W is as defined above.
12. The method of claim 11, further comprising forming a compound of formula (II) from the compound of formula (I):
wherein, A, B, C, G and R15As defined above; reacting a compound of formula (I) with a compound of the formula:
wherein Z is1AAnd Z1BMay be the same or different and are each independently selected from a linkage, straight or branched C1-6Alkylene, -NH-, -CH2O-，-CH2NH-，-CH2N(CH3)-，-NHCH2-，-CH2CONH-，-NHCH2CO-，-CH2CO-，-COCH2-，-CH2COCH2-，-CH(CH3) -, -CH ═ O-and-HC ═ CH-, in which the carbon and/or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;
R1Aand R2AMay be the same or different and are each independently selected from hydrogen, C1-10Alkyl radical, C3-12Cycloalkyl radical, C2-10Alkenyl, amino, C1-10Alkylamino radical, C3-12Cycloalkylamino, -COOV1，-C1-4COOV1Cyano, cyano C1-10Alkyl-, cyano-C3-10Cycloalkyl-, NH2SO2，NH2SO2C1-4Alkyl-, NH2SOC1-4Alkyl-, aminocarbonyl-, C1-4Alkylamino carbonyl-, di-C1-4Alkylaminocarbonyl-, benzyl, C3-12Cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, hetero-monocyclic, hetero-bicyclic system and spiro ring system of formula (V):
wherein, X1And X2As defined above.
13. The method of claim 11, further comprising forming a compound of formula (II) from the compound of formula (I):
wherein, A, B, C, G and R15As defined above; make itReacting said compound of formula (I) with a compound of the formula:
R-X
wherein R is as defined above and X is halogen.
14. The method of claim 11, further comprising forming a compound of formula (II) from the compound of formula (I):
Figure A2003801014590016C2
wherein, A, B, C, G and R15As defined above; reacting said formula (I) with a compound of the formula:
wherein R is as defined above and X is halogen.
15. The method of any one of claims 1-14, wherein a is hydrogen.
16. The method of any one of claims 1-14, wherein B is hydrogen.
17. The method of any one of claims 1-14, wherein C is hydrogen.
18. The method of any one of claims 1-14, wherein a and B are hydrogen.
19. The method of any one of claims 1-14, wherein a and C are hydrogen.
20. The method of any one of claims 1-14, wherein B and C are hydrogen.
21. The method of any one of claims 1-14, wherein a, B, and C are hydrogen.
22. The method of any one of claims 1-14, wherein a and B are hydrogen and C is selected from C1-4Alkyl and hydroxy C1-4An alkyl group.
23. The method of any one of claims 1-14, wherein a and C are hydrogen and B is selected from C1-4Alkyl and hydroxy C1-4An alkyl group.
24. The method of any one of claims 1-14, wherein B and C are hydrogen and a is selected from C1-4Alkyl and hydroxy C1-4An alkyl group.
CN 200380101459 2002-10-17 2003-10-16 Preparation of triazospiro compounds Pending CN1705481A (en)

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