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HK1063781B - Pyrazole derivatives for treating hiv - Google Patents

Pyrazole derivatives for treating hiv Download PDF

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Publication number
HK1063781B
HK1063781B HK04106485.5A HK04106485A HK1063781B HK 1063781 B HK1063781 B HK 1063781B HK 04106485 A HK04106485 A HK 04106485A HK 1063781 B HK1063781 B HK 1063781B
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HK
Hong Kong
Prior art keywords
pyrazol
methyl
oxy
diethyl
dichlorophenoxy
Prior art date
Application number
HK04106485.5A
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Chinese (zh)
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HK1063781A1 (en
Inventor
林恩．H．琼斯
查尔斯．E．莫布雷
戴维斯．A．普赖斯
马修．D．塞尔比
保罗．A．斯图普尔
Original Assignee
美国辉瑞有限公司
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Publication date
Priority claimed from GB0108999A external-priority patent/GB0108999D0/en
Priority claimed from GB0127426A external-priority patent/GB0127426D0/en
Application filed by 美国辉瑞有限公司 filed Critical 美国辉瑞有限公司
Priority claimed from PCT/IB2002/001234 external-priority patent/WO2002085860A1/en
Publication of HK1063781A1 publication Critical patent/HK1063781A1/en
Publication of HK1063781B publication Critical patent/HK1063781B/en

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Description

Pyrazole derivatives for the treatment of HIV
The present invention relates to pyrazole derivatives and processes for their preparation, intermediates used in their preparation, compositions containing them and uses of such derivatives.
The compounds of the invention bind to reverse transcriptase and are modulators, especially inhibitors, of this enzyme. Reverse transcriptase is involved in the infectious life cycle of HIV, and compounds that interfere with the function of this enzyme have shown utility in the treatment of conditions including AIDS. It is often desirable to provide new and better modulators, especially inhibitors, of HIV reverse transcriptase because the virus is capable of mutating and becoming resistant to the effects of known modulators.
The compounds of the invention are useful in the treatment of a variety of diseases, including diseases associated with the inhibition of reverse transcriptase. The related diseases include diseases caused by Human Immunodeficiency Virus (HIV) and genetically related retroviruses, such as acquired immunodeficiency syndrome (AIDS).
European patent application EP 0786455 a1 discloses a class of imidazole compounds that inhibit the growth of HIV. Med chem, 2000, 43, 1034 discloses a class of N-phenylpyrazoles which act as reverse transcriptase inhibitors. In us patent 3,303,200, a class of N- (hydroxyethyl) pyrazole derivatives is believed to have antiviral activity.
According to the present invention there is provided a compound of the formula
Or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein:
R1is H, C1-C6Alkyl radical, C3-C7Cycloalkyl, phenyl, benzyl, halogen, -CN, -OR7、-CO2R10、-CONR5R10、R8Or R9Said C is1-C6Alkyl radical, C3-C7Cycloalkyl, phenyl and benzyl optionally substituted by halogen, -CN, -OR10、-S(O)xR10、-CO2R10、-CONR5R10、-OCONR5R10、-NR5CO2R10、-NR10R11、-NR5COR10、-SO2NR5R10、-NR5CONR5R10、-NR5SO2R10Or R10Substitution;
R2is H, C1-C6Alkyl radical, C3-C6Alkenyl radical, C3-C6Alkynyl, C3-C7Cycloalkyl radical, C3-C7Cycloalkenyl, phenyl, benzyl, R8Or R9Said C is1-C6Alkyl radical, C3-C7Cycloalkyl, phenyl and benzyl optionally substituted by halogen, -OR5、-OR12、-CN、-CO2R7、-OCONR5R5、-CONR5R5、-C(＝NR5)NR5OR5、-CONR5NR5R5、-NR6R6、-NR5R12、-NR5COR5、-NR5COR8、-NR5COR12、-NR5CO2R5、-NR5CONR5R5、-SO2NR5R5、-NR5SO2R5、-NR5SO2NR5R5、R8Or R9Substitution;
or R1And R2Together representing unbranched C3-C4Alkylene optionally substituted by oxo, optionally wherein said C3-C4One methylene group in the alkylene group being replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R10Substitution;
R3is H, C1-C6Alkyl radical, C3-C7Cycloalkyl, phenyl, benzyl, halogen, -CN, -OR7、-SO2R5、-CONR5R5、R8Or R9Said C is1-C6Alkyl radical, C3-C7Cycloalkyl, phenyl and benzyl optionally substituted by halogen, -CN, -OR5、-CO2R5、-CONR5R5、-OCONR5R5、-NR5CO2R5、-NR6R6、-NR5COR5、-SO2NR5R5、-NR5CONR5R5、-NR5SO2R5、R8Or R9Substitution;
R4is phenyl, naphthyl or pyridyl, each optionally substituted by R8Halogen, -CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C7A cycloalkyl group, a,C1-C6Alkoxy, -CONR5R5、OR13、SOxR6、O-(C1-C6Alkylene) -CONR5R5、O-(C1-C6Alkylene) -NR5R5Or O- (C)1-C6Alkylene) -OR 6Substitution;
each R5Independently is H, C1-C6Alkyl or C3-C7Cycloalkyl, or when two R are5When the groups are attached to the same nitrogen atom, the two groups together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, optionally substituted by C1-C6Alkyl or C3-C7Cycloalkyl substitution;
each R6Independently is H, C1-C6Alkyl or C3-C7A cycloalkyl group;
R7is C1-C6Alkyl or C3-C7A cycloalkyl group;
R8is a five-or six-membered aromatic heterocyclic group containing (i)1 to 4 nitrogen heteroatoms, or (ii)1 or 2 nitrogen heteroatoms and 1 oxygen or 1 sulfur heteroatom, or (iii)1 or 2 oxygen or sulfur heteroatoms, said heterocyclic group being optionally substituted by halogen, oxo, -CN, -COR5、-CONR5R5、-SO2NR5R5、-NR5SO2R5、-OR5、-NR5R5、-(C1-C6Alkylene) -NR5R5、C1-C6Alkyl, fluoro (C)1-C6) Alkyl or C3-C7Cycloalkyl substitution;
R9is a four-to seven-membered saturated or partially unsaturated heterocyclic radical containing (i)1 or 2 azagensOr (ii)1 nitrogen heteroatom and 1 oxygen or 1 sulfur heteroatom, or (iii)1 oxygen or sulfur heteroatom, said heterocyclic group optionally being oxo, C1-C6Alkyl radical, C3-C7Cycloalkyl, -SO2R5、-CONR5R5、-COOR5、-CO-(C1-C6Alkylene) -OR 5or-COR5Substituted and optionally substituted by halogen, -OR at a carbon atom not adjacent to a heteroatom5、-NR5R5、-NR5COR5、-NR5COOR5、-NR5CONR5R5、-NR5SO2R5or-CN substitution;
R10is H, R8、R9、R13、C1-C6Alkyl radical, C3-C7Cycloalkyl or- (C)1-C6Alkyl group) - (C3-C7Cycloalkyl), said C1-C6Alkyl and C3-C7Cycloalkyl optionally substituted by-OR5、-OR13、R8、R9、R13or-COR13Substitution;
R11is H, C1-C6Alkyl or C3-C7Cycloalkyl radical, said C1-C6Alkyl and C3-C7Cycloalkyl optionally substituted by-OR5、-NR5R5、-NR5COR5、-CONR5R5、R8Or R9Substitution;
R12is C1-C6Alkyl radical, by R8、R9、-OR5、-CONR5R5、-NR5COR5or-NR5R5Substitution;
R13is phenyl, optionally substituted by halogen, -CN, -COR5、-CONR5R5、-SO2NR5R5、-NR5SO2R5、-OR5、-NR5R5、-(C1-C6Alkylene) -NR5R5、C1-C6Alkyl, halogen (C)1-C6) Alkyl or C3-C7Cycloalkyl substitution;
x is 0, 1 or 2;
with the proviso that (a) when R is1And R3When both are phenyl, R2Is not methyl; and (b) when R is1Is ethoxy, R3When it is ethoxycarbonyl, R2Is not phenyl.
In the above definitions, halogen represents fluorine, chlorine, bromine or iodine. Unless otherwise indicated, alkyl, alkenyl, alkynyl, alkylene and alkoxy groups containing the requisite number of carbon atoms may be unbranched or branched. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Examples of alkenyl groups include vinyl, propen-1-yl, propen-2-yl, propen-3-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methylpropen-1-yl or 2-methylpropen-3-yl. Examples of alkynyl groups include ethynyl, propyn-1-yl, propyn-3-yl, 1-butyn-1-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl. Examples of the alkylene group include a methylene group, a 1, 1-ethylene group, a 1, 2-ethylene group, a 1, 1-propylene group, a 1, 2-propylene group, a 2, 2-propylene group and a 1, 3-propylene group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. If R is 1And R2Taken together, they form a 5-or 6-membered ring together with the nitrogen and carbon atoms of the pyrazole ring to which they are attached. If a heterocyclic radical R8Or R9When bound to an oxygen, sulfur or nitrogen heteroatom, heterocyclic radicals R8Or R9Must be attached through a ring carbon atom. Further, if heterocyclic radical R9When bound to an oxygen, sulfur or nitrogen heteroatom, heterocyclic radicals R9Must be attached through a ring carbon atom which is not adjacent to a ring heteroatom.
Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition and base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts, examples being hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts, examples being the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
For a review of suitable salts, see Berge et al, j.pharm.sci., 66, 1-19, 1977.
Pharmaceutically acceptable solvates of the compounds of formula (I) include hydrates thereof.
Also included within the scope of the compounds of formula (I) are polymorphs thereof.
The compounds of formula (I) may be modified at any of their functional groups to provide pharmaceutically acceptable derivatives thereof. Examples of such derivatives are described in: drugs of Today, Volume 19, Number 9, 1983, pp 499-538; topics in Chemistry, Chapter 31, pp 306-316; bundgaard, Elsevier, "Design of produgs", 1985, Chapter 1 (the disclosures of these documents are incorporated herein by reference), including: esters, carbonates, half-esters, phosphates, nitro-esters, sulfates, sulfoxides, amides, sulfonamides, carbamates, azo compounds, phosphoramides, glycosides, ethers, acetals, and ketals.
The compounds of formula (I) may contain one or more asymmetric carbon atoms and thus exist in two or more stereoisomeric forms. The invention includes the individual stereoisomers of the compounds of formula (I), and where appropriate the individual tautomers thereof, and mixtures thereof.
Separation of the diastereomers may be achieved by conventional techniques, for example fractional crystallisation, chromatography or High Performance Liquid Chromatography (HPLC) of a mixture of stereoisomers of the compound of formula (I) or a suitable salt or derivative thereof. The individual enantiomers of the compounds of formula (I) may also be prepared from the corresponding optically pure intermediates, or by resolution of the corresponding racemates, for example by HPLC of the corresponding racemates using a suitable chiral support, or by fractional crystallization of diastereomeric salts formed by reaction of the corresponding racemates with a suitable optically active acid or base, as appropriate.
Preferably, R1When independent is H, C1-C6Alkyl radical, C3-C7Cycloalkyl OR-OR7Said C is1-C6Alkyl and C3-C7Cycloalkyl optionally substituted by halogen, -CN, -OR10、-S(O)xR10、-CO2R10、-CONR5R10、-OCONR5R10、-NR5CO2R10、-NR10R11、-NR5COR10、-SO2NR5R10、-NR5CONR5R10、-NR5SO2R10Or R10And (4) substitution.
Preferably, R1When independent is H, C1-C6Alkyl radical, C3-C7Cycloalkyl OR-OR7Said C is1-C6Alkyl optionally substituted by halogen, -OR10、-NR10R11、-NR5COR10Or R10And (4) substitution.
Preferably, R1When independent is H, C1-C4Alkyl, cyclopropyl or-OCH3Said C is1-C4Alkyl is optionally substituted by bromo, -OH, -O (C)1-C2Alkyl), -NR-10R11、-NHCOR13Or R10And (4) substitution.
Preferably, R1When independent, is H, -CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3Cyclopropyl, -OCH3、-CH2OH、-CH2OCH3、-CH2OCH2CH3、-CH2Br、-CH2NH2、-CH2NHCH3、-CH2N(CH3)2、-CH2NHCH2(cyclopropyl), -CH2NHCH2CH2OCH3、-CH2NHCH2CH2NHCOCH3、-CH2NHCO (4-cyanophenyl), -CH2NHCO (3-cyanophenyl), -CH2NHCH2(4-cyanophenyl), -CH2NHCH2(4-fluorophenyl), -CH2NHCH2(4-methoxyphenyl), -CH2NHCH2(4-aminosulfonylphenyl), -CH2NHCH2(4-aminocarbonylphenyl), -CH2NHCH2(pyridin-3-yl), -CH2N(CH3) (4-cyanophenylmethyl), -CH2N(CH2CH2OH) (4-cyanophenylmethyl), 4-methoxypiperidin-1-ylmethyl, 4-aminocarbonylpiperidin-1-ylmethyl, 4-methylcarbonylaminopiperidin-1-ylmethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylcarbonylpiperazin-1-ylmethyl, 4-methoxymethylcarbonylpiperazin-1-ylmethyl, 4-methoxycarbonylpiperazin-1-ylmethyl, 4-methanesulfonylpiperazin-1-ylmethyl, morpholin-4-ylmethyl, 2-methylimidazol-1-ylmethyl, pyrazol-1-ylmethyl or 1, 2, 4-triazol-1-ylmethyl.
Preferably, R1When independent is-CH3、-CH2CH3Cyclopropyl, -CH2NHCH2(4-cyanophenyl), -CH2NHCH2(4-fluorophenyl), -CH2NHCH2(4-methoxyphenyl), -CH2NHCH2(4-aminosulfonylphenyl) or-CH2NHCH2(4-aminocarbonylphenyl).
Preferably, R2When independent is H, C1-C6Alkyl radical, C3-C6Alkenyl or R9Said C is1-C6Alkyl optionally substituted by halogen, -OR5、-OR12、-CN、-CO2R7、-OCONR5R5、-CONR5R5、-C(＝NR5)NR5OR5、-CONR5NR5R5、-NR6R6、-NR5R12、-NR5COR5、-NR5COR8、-NR5COR12、-NR5CO2R5、-NR5CONR5R5、-SO2NR5R5、-NR5SO2R5、R8Or R9And (4) substitution.
Preferably, R2When independent is H, C1-C6Alkyl radical, C3-C6Alkenyl or R9Said C is1-C6Alkyl optionally substituted by halogen, -OR5、-OR12、-CN、-CO2R7、-CONR5R5、-C(＝NR5)NR5OR5、-CONR5NR5R5、-NR6R6、-NR5R12、-NR5COR8、-NR5COR12、-NR5CO2R5、R8Or R9And (4) substitution.
Preferably, R2When independent is H, C1-C3Alkyl, propenyl or R9Said C is1-C3Alkyl is optionally substituted by-OH, -OCH3、-OCH2CH2NH2、-CN、-CO2CH3、-CO2CH2CH3、-CONH2、-C(＝NH)NHOH、-CONHNH2、-NH2、-NHCH3、-N(CH3)2、-NHCH2CH2NHCOCH3、-NHCH2CH2OCH3、-NHCH2R9、-NHCOR8、-NHCOCH2OCH3、-NHCO2C(CH3)3、R8Or R9And (4) substitution.
Preferably, R2When independent, is H, methyl, -CH2CH＝CH2、-CH2CN、-CH2OCH3、-CH3CONH2、-CH2CONHNH2、-CH2CO2CH3、-CH2CO2CH2CH3、-CH2C(＝NH)NHOH、-CH2CH2OH、-CH2CH2OCH3、-CH2CH2NH2、-CH2CH2NHCOCH2OCH3、-CH2CH2NHCO2C(CH3)32- (pyridin-2-ylcarbonamido) eth-1-yl, 2- (pyrazin-2-ylcarbonamido) eth-1-yl, -CH2CH2OCH2CH2NH2、-CH2CH2NHCH3、-CH2CH2N(CH3)2、-CH2CH2NHCH2CH2NHCOCH3、-CH2CH2NHCH2CH2OCH3、-CH2CH(OH)CH3(3-hydroxypyrazol-5-yl) methyl group, 2-hydroxy-1, 3, 4-oxadiazol-5-ylmethyl group, 2-amino-1, 3, 4-oxadiazol-5-yl group, 5-hydroxy-1, 2, 4-oxadiazol-3-ylmethyl group, 6-hydroxy-2-methylpyrimidin-4-ylmethyl group, 6-hydroxy-2-aminopyrimidin-4-ylmethyl group, 2- (morpholin-4-yl) eth-1-yl group, 2- (4-methylcarbonylpiperazin-1-yl) eth-1-yl group, morpholin-3-ylmethyl group, (2- (tetrahydrofuran-2-ylmethylamino) eth-1-yl group, methyl group, 1-methylazetidin-3-yl or azetidin-3-yl.
Preferably, R2When independent, is H, -CH2CH2OH or-CH2CH2NH2。
Preferably, R1And R2When taken together represent unbranched C3-C4Alkylene optionally substituted by oxo, wherein said C3-C4One methylene group in the alkylene group being replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R10And (4) substitution.
Preferably, R1And R2When taken together, represents an unbranched propylene group in which one methylene group is replaced by an oxygen atom, or represents an unbranched butylene group in which one methylene group is replaced by a nitrogen atom, the propylene and butylene groups being optionally substituted by oxo, the nitrogen atom being optionally substituted by R10And (4) substitution.
Preferably, R1And R2When taken together represent x-OCH2CH2-y、x-CONHCH2CH2-y、x-CH2NHCH2CH2-y、x-CH2N(CH3)CH2CH2-y、x-CH2N (4-cyanophenylmethyl) CH2CH2-y or x-CH2N (4-methoxyphenylmethyl) CH2CH2-y, wherein "x" represents the point of attachment to a carbon atom of the pyrazole ring and "y" represents the point of attachment to a nitrogen atom of the pyrazole ring.
Preferably, R3Is H or C1-C6Alkyl radical, said C1-C6Alkyl optionally substituted by halogen, -CN, -OR5、-CO2R5、-CONR5R5、-OCONR5R5、-NR5CO2R5、-NR6R6、-NR5COR5、-SO2NR5R5、-NR5CONR5R5、-NR5SO2R5、R8Or R9And (4) substitution.
Preferably, R3Is H or C1-C6An alkyl group.
Preferably, R3Is H or C1-C4An alkyl group.
Preferably, R3Is H, -CH3、-CH2CH3、-CH(CH3)2or-C (CH)3)3。
Preferably, R3is-CH3、-CH2CH3、-CH(CH3)2Or a cyclopropyl group.
Preferably, R4Is phenyl, optionally substituted by R 8Halogen, -CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C7Cycloalkyl or C1-C6Alkoxy substitution.
Preferably, R4Is phenyl, by R8Halogen, -CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C7Cycloalkyl or C1-C6Alkoxy substitution.
Preferably, R4Is phenyl, substituted by halogen, -CN or C1-C6Alkyl substitution.
Preferably, R4Is phenyl, substituted by fluorine, chlorine, -CN or methyl.
Preferably, R4Is 3-cyanophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3, 5-dichlorophenyl, 2, 6-dichlorophenyl, 2, 3-dichlorophenyl, 2, 4-dichlorophenyl, 3, 4-dichlorophenyl, 2, 5-dichlorophenyl, 2, 6-difluorophenyl, 2, 3-difluorophenyl, 3, 5-difluorophenyl, 2, 5-difluorophenyl, 3, 5-dicyanophenyl, 3, 5-dimethylphenyl, 4-fluoro-3-methylphenyl, 3-cyano-4-fluorophenyl, 3-cyano-5-fluorophenyl, 2-chloro-4-cyanophenyl, 3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl or 4-cyano-2, 6-dimethylphenyl.
Preferably, R4Is 3, 5-dicyanophenyl, 3-cyano-5-fluorophenyl, 3-chloro-5-cyanophenyl or 3-cyano-5-methylphenyl.
In an alternative set of preferred embodiments:
preferably, R4Is phenyl, optionally substituted by R 8Halogen, -CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C7Cycloalkyl radical, C1-C6Alkoxy, -CONR5R5、OR13、SOxR6、O-(C1-C6Alkylene) -CONR5R5、O-(C1-C6Alkylene) -NR5R5Or O- (C)1-C6Alkylene) -OR6Substitution; or naphthyl.
Preferably, R4Is phenyl, by R8Halogen, -CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C7Cycloalkyl radical, C1-C6Alkoxy, -CONR5R5、OR13、SOxR6、O-(C1-C6Alkylene) -CONR5R5、O-(C1-C6Alkylene) -NR5R5Or O- (C)1-C6Alkylene) -OR6And (4) substitution.
Preferably, R8Is pyrrolyl, imidazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each optionally substituted by halogen, -CN, -COR5、-CONR5R5、-SO2NR5R5、-NR5SO2R5、-OR5、-NR5R5、-(C1-C6Alkylene) -NR5R5、C1-C6Alkyl, fluoro(C1-C6) Alkyl or C3-C7Cycloalkyl is substituted.
Preferably, R8Is imidazolyl, pyrazolyl, 1, 2, 4-triazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyridyl, pyrazinyl or pyrimidinyl, each optionally substituted by halogen, -CN, -COR5、-CONR5R5、-SO2NR5R5、-NR5SO2R5、-OR5、-NR5R5、-(C1-C6Alkylene) -NR5R5、C1-C6Alkyl, fluoro (C)1-C6) Alkyl or C3-C7Cycloalkyl is substituted.
Preferably, R8Is imidazolyl, pyrazolyl, 1, 2, 4-triazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyridyl, pyrazinyl OR pyrimidinyl, each optionally substituted by-OR 5、-NR5R5Or C1-C6Alkyl substitution.
Preferably, R8Is imidazolyl, pyrazolyl, 1, 2, 4-triazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyridyl, pyrazinyl or pyrimidinyl, each optionally substituted by-OH, -NH2Or methyl substitution.
Preferably, R8Is pyrazol-1-yl, 2-methylimidazol-1-yl, 1, 2, 4-triazol-1-yl, 3-hydroxypyrazol-5-yl, 2-hydroxy-1, 3, 4-oxadiazol-5-yl, 2-amino-1, 3, 4-oxadiazol-5-yl, 5-hydroxy-1, 2, 4-oxadiazol-3-yl, 2-methyl-4-hydroxypyrimidin-6-yl, 2-amino-4-hydroxypyrimidin-6-yl, pyridin-3-yl, pyridin-2-yl or pyrazin-2-yl.
Preferably, R9Is azetidinyl, tetrahydropyrrolyl, piperidinyl, azaAn oxetanyl group, a tetrahydrofuryl group, a tetrahydropyranyl group,Oxoheptenyl, morpholinyl, piperazinyl or diazaEach of which is optionally oxo, C1-C6Alkyl radical, C3-C7Cycloalkyl, -SO2R5、-CONR5R5、-COOR5、-CO-(C1-C6Alkylene) -OR5or-COR5Substituted and optionally substituted by halogen, -OR at a carbon atom not adjacent to a heteroatom5、-NR5R5、-NR5COR5、-NR5COOR5、-NR5CONR5R5、-NR5SO2R5or-CN substitution.
Preferably, R9Is azetidinyl, piperidinyl, tetrahydrofuryl, piperazinyl or morpholinyl, each optionally oxo, C 1-C6Alkyl radical, C3-C7Cycloalkyl, -SO2R5、-CONR5R5、-COOR5、-CO-(C1-C6Alkylene) -OR5or-COR5Substituted and optionally substituted by halogen, -OR at a carbon atom not adjacent to a heteroatom5、-NR5R5、-NR5COR5、-NR5COOR5、-NR5CONR5R5、-NR5SO2R5or-CN substitution.
Preferably, R9Is azetidinyl, piperidinyl, tetrahydrofuryl, piperazinyl or morpholinyl, each optionally substituted by C1-C6Alkyl, -SO2R5、-CONR5R5、-COOR5、-CO-(C1-C6Alkylene) -OR5or-COR5Substituted and optionally substituted on a carbon atom not adjacent to the heteroatom by-OR5or-NR5COR5And (4) substitution.
Preferably, R9Is azetidinyl, piperidinyl, tetrahydrofuryl, piperazinyl or morpholinyl, each optionally substituted by-CH3、-SO2CH3、-CONH2、-COOCH3、-COCH2OCH3or-COCH3Substituted and optionally substituted on a carbon atom not adjacent to the heteroatom by-OCH3or-NHCOCH3And (4) substitution.
Preferably, R9Is 4-methoxypiperidin-1-yl, 4-aminocarbonylpiperidin-1-yl, 4-methylcarbonylaminopiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylcarbonylpiperazin-1-yl, 4-methoxymethylcarbonylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, 4-methanesulfonylpiperazin-1-yl, morpholin-4-yl, tetrahydrofuran-2-yl, morpholin-3-yl, azetidin-3-yl or 1-methylazetidi-3-yl.
Preferably, R10Is H, R8、R9、R13、C1-C6Alkyl or- (C)1-C6Alkyl group) - (C3-C7Cycloalkyl), said C 1-C6Alkyl is optionally substituted by-OR5、-OR13、R8、R9、R13or-COR13And (4) substitution.
Preferably, R10Is H, R8、R9、R13、C1-C6Alkyl or- (C)1-C6Alkyl group) - (C3-C7Cycloalkyl), said C1-C6Alkyl is optionally substituted by-OR5Or R13And (4) substitution.
Preferably, R10Is H, R8、R9、R13、-CH3、-CH2CH3or-CH2(cyclopropyl), said-CH3and-CH2CH3Optionally substituted by-OCH3Or R13And (4) substitution.
Preferably, R10Is H, R8、R9、R13、-CH3、-CH2CH3、-CH2CH2OCH3、-CH2(cyclopropyl), 4-cyanophenylmethyl, 4-fluorophenylmethyl, 4-methoxyphenylmethyl, 4-aminosulfonylphenylmethyl or 4-aminocarbonylphenylmethyl.
Preferably, R11Is H or C1-C6Alkyl radical, said C1-C6Alkyl is optionally substituted by-OR5、-NR5R5、-NR5COR5、-CONR5R5、R8Or R9And (4) substitution.
Preferably, R11Is H or C1-C6Alkyl radical, said C1-C6Alkyl is optionally substituted by-OR5or-NR5COR5And (4) substitution.
Preferably, R11Is H, -CH3or-CH2CH3said-CH3and-CH2CH3Optionally substituted by-OH or-NHCOCH3And (4) substitution.
Preferably, R11Is H, -CH3、-CH2CH2NHCOCH3or-CH2CH2OH。
Preferably, R12Is C1-C4Alkyl radical, by R8、R9、-OR5、-CONR5R5、-NR5COR5or-NR5R5And (4) substitution.
Preferably, R12Is C1-C4Alkyl radical, by R9、-OR5、-NR5COR5or-NR5R5And (4) substitution.
Preferably, R12Is C1-C2Alkyl, by tetrahydrofuranyl, -OCH3、-NHCOCH3or-NH2And (4) substitution.
Preferably, R12is-CH2CH2NH2、-CH2CH2OCH3Tetrahydrofuran-2-ylmethyl, -CH2CH2NHCOCH3or-CH2OCH3。
Preferably, R13Is phenyl, substituted by halogen, -CN, -COR5、-CONR5R5、-SO2NR5R5、-NR5SO2R5、-OR5、-NR5R5、-(C1-C6Alkylene) -NR5R5、C1-C6Alkyl, halogen (C)1-C6) Alkyl or C3-C7Cycloalkyl is substituted.
Preferably, R13Is phenyl, substituted by halogen, -CN, -CONR5R5、-SO2NR5R5OR-OR5And (4) substitution.
Preferably, R13Is phenyl, fluorinated, -CN, -CONH2、-SO2NH2or-OCH3And (4) substitution.
Preferably, R13Is 4-cyanophenyl, 3-cyanophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-aminocarbonylphenyl or 4-aminosulfonylphenyl.
Preferred compounds according to the invention include all combinations of the individual substituents preferably defined above.
According to the invention, preference is also given to compounds of the formula (I)
Or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein:
R1is H, C1-C6Alkyl, -OC1-C6Alkyl radical、-OC3-C7Cycloalkyl radical, said C1-C6Alkyl is optionally substituted by R15Substitution;
R2is H, C1-C3Alkyl, propenyl or C-linked R15Said C is1-C3Alkyl is optionally substituted by-OH, -OCH3、-OCH2CH2NH2、-CN、-CO2CH3、-CONH2、-C(＝NH)NH2、-CONHNH2、-NH2、-NHCH3、-N(CH3)2、-NHCH2CH2NHCOCH3、-NHCH2CH2OCH3、-NHCH2R15、-NHCOR15、-NHCOCH2OCH3Or R15Substitution;
R3is C1-C6An alkyl group;
R4is phenyl, optionally substituted by halogen, -CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C7Cycloalkyl or C1-C6Alkoxy substitution;
R15is azetidinyl, tetrahydrofuryl, morpholinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyridinyl or pyrimidinyl, each optionally substituted by-OH, -NH2Oxo, C1-C6Alkyl or-CO (C)1-C6Alkyl) substituted.
Preferred individual compounds according to the invention include the following examples, in particular examples 117, 118, 119, 120, 122, 123, 124, 125, 126, 127 and 128, and pharmaceutically acceptable salts and solvates thereof.
All compounds of formula (I) may be prepared by conventional methods, for example as described in the general methods below, or as specified in the examples, or by methods analogous thereto. The invention also encompasses any one or more methods of preparing the compounds of formula (I), as well as any novel intermediates useful therein.
In the following general procedure, R1、R2、R3And R4Is as defined above for the compound of formula (I), unless otherwise indicated.
Except that R1Or R3Is halogen, -OR7or-CN, the compounds of formula (I) can be prepared by the method shown in the following reaction scheme 1.
In scheme 1, a compound of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula H, optionally in the presence of an acid or base, preferably a tertiary amine base such as triethylamine, and an acid preferably acetic acid2NNHR2(V) condensation of a compound or a salt or hydrate thereof. In a typical process, a solution of a compound of formula (II) in a suitable solvent, for example ethanol, is treated with a compound of formula (V) or a salt or hydrate thereof and, if used, an appropriate acid or base at a temperature from room temperature to the reflux temperature of the solvent. In a preferred method, the reaction mixture is heated under reflux.
Reaction scheme 1
Functional equivalents of the compounds of formula (II) may also be used in this reaction. They include compounds of formula (VI) or (VII) wherein L1And L2Are each a suitable leaving group, preferably-N (C)1-C6Alkyl radical)2Most preferably-N (CH)3)2。
Thus, the compounds of formula (I) may be prepared, optionally in the presence of an acid or baseThe base is preferably a tertiary amine base, such as triethylamine, the acid is preferably acetic acid, and the compound of formula (VI) or (VII) is condensed with the compound of formula (V) or a salt or hydrate thereof. In a typical process, a solution of a compound of formula (VI) or (VII) in a suitable solvent, for example ethanol, is treated with a compound of formula (V) or a salt or hydrate thereof and, if used, an appropriate acid or base at a temperature from room temperature to the reflux temperature of the solvent. In a preferred method, the reaction mixture is heated under reflux. Compounds of the formula (VI) or (VII) are particularly suitable in which R1Or R3Synthesis of compounds of formula (I), each H.
Wherein R is1Is H, L1The compound of formula (VI) which is dimethylamino may be prepared by reacting the compound of formula (VIII) with dimethylformamide dimethyl acetal at elevated temperature, preferably about 100 ℃. Wherein R is1Is H, L1The compound of formula (VII) which is dimethylamino may be prepared by reacting the compound of formula (IX) under the same conditions. Wherein L is 1Or L2Other compounds of formula (VI) or (VII) which are dimethylamino may be prepared in a similar manner.
The compounds of formula (VIII) are commercially available or may be prepared by the reaction of formula R3COCH2Br (X) compounds and the formula R4Reaction preparation of OH (XI) compounds. In a typical process, a solution of a compound of formula (XI) in a suitable solvent, such as acetone, is treated with a suitable base, such as cesium carbonate and a compound of formula (X). In a preferred method, the reaction mixture is heated, for example, under reflux. Optionally, a nucleophilic catalyst, such as sodium iodide or tetrabutylammonium iodide, may be added.
The compounds of formula (IX) are commercially available or may be derived from formula R1COCH2Br (XII) compound and compound of formula (XI) are prepared in the same manner as for the preparation of compound of formula (VIII) from compound of formula (X)。
The compounds of formula (II) may be prepared by reaction of a compound of formula (III) with a compound of formula (XI). In a typical process, a solution of a compound of formula (III) in a suitable solvent, for example acetone, is treated with a compound of formula (XI) and a suitable base, for example potassium carbonate or cesium carbonate, and heated, preferably under reflux. Optionally, a nucleophilic catalyst, such as sodium iodide or tetrabutylammonium iodide, may be added.
The compounds of formula (III) are commercially available or may be prepared by reaction of the compounds of formula (IV) with a chlorinating agent. In a typical process, a cooled solution of the compound of formula (IV) in a suitable solvent, such as acetonitrile, is treated first with tetrabutylammonium bromide and chlorotrimethylsilane and then with anhydrous dimethyl sulfoxide. In another typical process, the compound of formula (IV) is treated with sulfonyl chloride, optionally in the presence of a suitable solvent, such as dichloromethane.
Wherein R is1Or R3is-OR7The compounds of formula (I) can be prepared by the following process as shown in scheme 2, wherein RaIs C1-C6Alkyl radical, L3Is a suitable leaving group, preferably trifluoromethanesulfonic acid (trifluoromethane sulfonate).
In reaction scheme 2, wherein R1is-OR7The compound of formula (I) may be prepared by reacting a compound of formula (XIII) with a compound of formula R in the presence of a suitable palladium catalyst and carbon monoxide7OH (XXI) alcohol reaction. In a typical process, a mixture of a compound of formula (XIII), a suitable palladium catalyst, such as 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride, an alcohol of formula (XXI) and optionally a suitable solvent, such as N, N-dimethylformamide, is heated, preferably to about 50 ℃, under an atmosphere of carbon monoxide, preferably at a pressure of 345 kPa.
Reaction scheme 2
The compounds of formula (XIII) may be prepared by derivatisation of compounds of formula (XV). In which L is3In the case of trifluoromethanesulfonic acid, a suitable derivatizing agent is phenyl triflamide. In a typical process, at L3In the case of trifluoromethanesulfonic acid, a solution of the compound of formula (XV) and a suitable base, preferably a trialkylamine, for example triethylamine, in a suitable solvent, for example dichloromethane, is treated with phenyltriflamide.
The compound of formula (XV) can be prepared by reacting a compound of formula (XVII) with a compound of formula (V) or a salt or hydrate thereof, optionally in the presence of an acid or base, preferably a tertiary amine base, such as triethylamine, and an acid, preferably acetic acid. In a typical process, a solution of a compound of formula (XVII) in a suitable solvent, for example ethanol, is treated with a compound of formula (V) or a salt or hydrate thereof and, if used, an appropriate acid or base at a temperature from room temperature to the reflux temperature of the solvent. In a preferred method, the reaction mixture is heated under reflux.
The compounds of formula (XVII) may be prepared by the reaction of formula (XIX) with a compound of formula (XI). In a typical process, a solution of a compound of formula (XIX) in a suitable solvent, for example acetone, is treated with a compound of formula (XI) and a suitable base, for example potassium carbonate or cesium carbonate, and heated, preferably under reflux. Optionally, a nucleophilic catalyst, such as sodium iodide or tetrabutylammonium iodide, may be added.
In reaction scheme 2, wherein R3is-OR7The compound of formula (I) can be prepared from the compound of formula (XX) by the same method as described below, i.e., from the compound of formula (XIX) wherein R is1is-OR7The process of the compounds of formula (I) as described above, mutatis mutandis.
Chloroketo esters of formulae (XIX) and (XX) are commercially available or can be prepared by chlorination of the corresponding keto esters, for example using sulfonyl chloride.
Another one isIn aspect, wherein R1Or R3is-OR7The compound of formula (I) can be prepared by reacting a compound of formula (XV) or (XVI) with a compound of formula (XXI), respectively, under dehydrating conditions, for example, by the Mitsunobu reaction. In a typical process, a solution of a compound of formula (XV) or (XVI) in a suitable solvent, for example tetrahydrofuran, is treated with diethyl azodicarboxylate, triphenylphosphine and a compound of formula (XXI).
Wherein R is1Or R3The compounds of formula (I) which are halogens may be prepared by reaction of a compound of formula (XV) or a compound of formula (XVI), respectively, with a suitable halogenating agent. In a typical process, a compound of formula (XV) or (XVI) is reacted with POCl, optionally in the presence of a suitable solvent, such as dimethylformamide3Treating to obtain R1Or R 3A compound of formula (I) which is chlorine.
It will be appreciated by those skilled in the art that in many cases, compounds of formula (I) may be converted to other compounds of formula (I) by functional group transformation. For example:
(a) wherein R is2Compounds of formula (I) which are H may be converted to compounds wherein R is2Is optionally substituted C1-C6Alkyl compounds of formula (I). In a typical process, R is2A solution of a compound of formula (I) which is H in a suitable solvent, such as ethanol or N, N-dimethylformamide, is treated with an alkyl bromide and a base, such as sodium ethoxide or sodium hydride, and heated at a temperature ranging from room temperature to the reflux temperature of the solvent. The preferable combination is that N, N-dimethylformamide is used as a solvent, sodium hydride is used as a base, and room temperature is used as a reaction temperature. Examples of specific alkylating agents include bromoacetonitrile, ethyl 4-chloroacetoacetate, methyl bromoacetate, and chloroethylamine hydrochloride. The following examples illustrate the use of other specific alkylating agents;
(b) wherein R is1、R2Or R3Compounds of formula (I) containing ester functionality may be reduced with a suitable reducing agent, such as lithium aluminum hydride, to give compounds wherein R is1、R2Or R3A compound containing a hydroxyl group corresponding to formula (I). In a typical process, R is 1、R2Or R3A solution of the compound of formula (I) containing an ester group in a suitable solvent, for example diethyl ether, is treated with lithium aluminium hydride, preferably cooled to a temperature of-78 ℃ to 0 ℃;
(c) wherein R is1、R2Or R3Is represented by the formula R6Heterocycle-substituted compounds of formula (I) may be prepared by standard heterocycle formation reactions well known to the skilled person (see, for example, Advanced Organic Chemistry, 3rd edition, Gerry March or Comprehensive Heterocyclic Chemistry, A.R.Katritzky, C.W.Rees, E.F.V.Script, Volumes 1-11). For example, wherein R2A compound of formula (I) which is (2-amino-6-hydroxypyrimidin-4-yl) methyl may be represented by wherein R2The compound of formula (I) which is H is prepared by reaction with chloroacetoacetate followed by guanidine hydrochloride. The following examples illustrate this and other similar heterocycle formation reactions;
(d) wherein R is1Or R3is-CO2R5Wherein R is5Compounds of formula (I) other than H may be converted by hydrolysis to compounds of formula (I) wherein R is1Or R3Are each-CO2H, a compound of formula (I). Typically, the reaction will be carried out in a suitable solvent, such as aqueous ethanol or aqueous 1, 4-dioxane, in the presence of a base, such as sodium hydroxide. Such an acid may be converted to a primary amide by reaction with ammonia and a suitable coupling agent, for example a carbodiimide, such as dicyclohexylcarbodiimide. Such a primary amide can then be converted to a nitrile by dehydration with a suitable dehydrating agent, such as phosphorus oxychloride.
(e) Using a suitable halogenating agent, in which R1Or R2Is C1-C6The alkyl compounds of formula (I) can be converted by halogenation into R1Or R3Each being halogen (e.g. bromo) substituted C1-C6Alkyl compounds of formula (I). The reaction is conveniently carried out in the presence of a solvent, such as a haloalkane (e.g. dichloromethane), at ambient temperatureThe process is carried out. Suitable halogenating agents include halogen (e.g., bromine) or N-halogen succinimides (e.g., N-bromosuccinimide).
containing-OH, -NH-or-NH2Can be prepared by reacting a compound of formula (I) with an-OP1、-NP1-or-NHP1By deprotection of the corresponding compound of (a), wherein P1Are suitable protecting groups. Examples of suitable Protecting groups will be apparent to the skilled person (see for example' Protecting groups in organic Synthesis (second edition), Theodora W.Green and Peter G.M.Wuts, 1991, John Wiley and Sons). This type of belt having-OP1、-NP1-or-NHP1The compounds of (3) can be prepared by the methods described above with necessary modifications in detail.
The compounds of formulae (IV), (V) and (XXI) are commercially available or can be readily prepared by methods well known to those skilled in the art.
The compounds of formula (I) may be administered alone, but will generally be administered in admixture with suitable pharmaceutical excipients, diluents or carriers, selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of formula (I) may be administered orally, buccally or sublingually in the form of tablets, capsules, multiparticulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate, delayed, modified, sustained, pulsed or controlled release applications. The compounds of formula (I) may also be administered in a fast dispersing or fast disintegrating dosage form, or in the form of a high energy dispersion or coated particles. Suitable formulations of the compounds of formula (I) may be in coated or uncoated form as desired.
Such solid pharmaceutical compositions, e.g. tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch); disintegrants, for example sodium starch glycolate, croscarmellose sodium and certain complex silicates; and granulation binders such as polyvinylpyrrolidone, Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glycerol behenate and talc may be included.
General examples
Tablets may generally contain from 0.01mg to 500mg of active compound, and tablet fill weights may range from 50mg to 1000 mg. Examples of 10mg tablets are as follows:
composition% w/w
10.000 Compounds or salts of formula (I)*
Lactose 64.125
Starch 21.375
Croscarmellose sodium 3.000
Magnesium stearate 1.500
*The dosage is adjusted according to the activity of the drug.
Tablets are made by standard methods, such as direct compression or wet or dry granulation. The tablet cores may be coated with a suitable coating.
Solid compositions of a similar type may also be employed as fillers in gelatin or HPMC capsules. Preferred excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. With respect to aqueous suspensions and/or elixirs, the compounds of formula (I) may be combined with various sweetening or flavoring agents, coloring matter or dyes, as well as emulsifying and/or suspending agents, and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
The compounds of formula (I) may also be administered parenterally, for example intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by injection or by needleless injection techniques. For such parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably to a pH of 3-9) if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compound of formula (I) will generally be from 0.01 to 30mg/kg, preferably from 0.01 to 5mg/kg (in single or multiple administrations).
Thus, tablets or capsules of a compound of formula (I) may contain 1 to 500mg of the active compound, given one or two or more doses per administration, as the case may be. In any event, the physician will determine the actual dosage which will be most suitable for any individual patient, which will vary with the age, weight and response of the particular patient. The above doses are typical average doses. There may of course be individual cases where higher or lower dosage ranges are also of value, which are also within the scope of the invention. The skilled person will appreciate that in the treatment of certain conditions, the following may be required or calculated: a single dose of the compound of formula (I) is taken.
The compounds of formula (I) may be administered intranasally or by inhalation, suitably in the form of a dry powder inhaler or aerosol delivered from a pressurised container, pump, nebuliser or nebuliser, with or without the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane, for example 1, 1, 1, 2-tetrafluoroethane (HFA 134A [ trade mark ]) or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA227EA [ trade mark ]), carbon dioxide or other suitable gas. In the case of pressurized aerosols, the dosage units can be determined by means of a valve for metered delivery. The pressurised container, pump, spray or atomiser may contain a solution or suspension of the active compound, for example using a mixture of ethanol and propellant as the solvent, which may additionally contain a lubricant, for example sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of formula (I) and a suitable powder base, for example lactose or starch.
Alternatively, the compound of formula (I) may be administered in the form of a suppository or pessary, or it may be administered topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of formula (1) may also be administered transdermally or transdermally, for example using a skin patch. They may also be administered by the pulmonary or rectal route.
They may also be administered by the ocular route. For ophthalmic use, the compounds of the present invention may be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline or solutions preferably in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they may be formulated as an ointment, for example using petrolatum.
For topical application to the skin, the compounds of formula (I) may be formulated in a suitable ointment containing the active compound suspended or dissolved in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, it may be formulated as a suitable lotion or cream, suspended or dissolved in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of formula (I) may also be used in combination with cyclodextrins. Cyclodextrins are known to form entrapped and non-entrapped complexes with drug molecules. The formation of drug-cyclodextrin complexes can improve the solubility, dissolution rate, bioavailability, and/or stability of the drug molecule. Drug-cyclodextrin complexes are generally useful in most dosage forms and routes of administration. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, such as a carrier, diluent or solubiliser. alphA-, betA-and gammA-cyclodextrins are the most commonly used, suitable examples being described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
It will be appreciated that all references to treatment include curative, palliative and prophylactic treatment.
Oral administration is preferred.
Included within the scope of the present invention are embodiments comprising co-administration of a compound of the present invention with one or more other therapeutic agents, and compositions comprising a compound of the present invention with one or more other therapeutic agents. Such a combination therapy is particularly useful for the prevention and/or treatment of HIV and related retroviral infections, which viruses can rapidly evolve into strains that are resistant to any monotherapy. Alternatively, other therapeutic agents may be needed to treat diseases and conditions caused by or accompanied by diseases treated with the compounds of the present invention. For example, in the treatment of HIV or related retroviral infections, additional treatment for opportunistic infections, tumors, and other conditions that exist as a result of a state of lack of immunity in the treated patient may be required.
Preferred combinations of the invention include simultaneous or sequential treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and:
(a) one or more reverse transcriptase inhibitors, such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and adefovir;
(b) One or more non-nucleoside reverse transcriptase inhibitors, such as nevirapine, delavirdine, and efavirenz;
(c) one or more HIV protease inhibitors, such as indinavir, ritonavir, saquinavir, and efavirenz;
(d) one or more CCR5 antagonists, such as TAK-779;
(e) one or more CXCR4 antagonists, such as AMD-3100;
(f) one or more integrase inhibitors;
(g) one or more viral fusion inhibitors, such as T-20;
(h) one or more investigational drugs, such as trizivir, KNI-272, amprenavir, GW-33908, FTC, PMPA, S-1153, MKC-442, MSC-204, MSH-372, DMP450, PNU-140690, ABT-378, KNI-764, DPC-083, TMC-120, or TMC-125; or
(i) One or more antifungal or antibacterial agents, such as fluconazole.
The activity of the compound of the present invention as a reverse transcriptase inhibitor and a therapeutic agent for HIV infection can be measured by the following assay.
A. Inhibition of HIV-1 reverse transcriptase
The reverse transcriptase activity of the compounds of the invention can be determined as follows. Using the purified recombinant HIV-1 reverse transcriptase (RT, EC, 2.7.7.49) obtained by expression in E.coli, a 96-well plate assay system was set up using Poly (rA) -oligo (dT) reverse transcriptase [3H ] ]SPA enzyme assay System (Amersham NK9020) or [3H]The flashplate enzyme assay system (NEN-SMP 103) assayed large numbers of samples and followed the manufacturer's recommendations. Compounds were dissolved in 100% DMSO and diluted with appropriate buffer to a final DMSO concentration of 5%. The inhibitory activity is expressed as percentage inhibition relative to DMSO control. The concentration of a compound that inhibits reverse transcriptase by 50% is expressed as the IC of the compound50. The compounds of examples 7, 20 and 51, when tested according to the methods described above, had IC's of 39000, 3200 and 248 nanomoles, respectively50The value is obtained.
B. Anti-human immunodeficiency virus (HIV-1) cell culture assay
Selected examples of the present invention were tested for anti-HIV activity by the following methods.
1) SupT1 cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, and isolated so that they were in the growth phase on the day of use.
2) Compounds were dissolved in 100% DMSO, diluted to predetermined concentrations with the above medium, and dispensed as 20 μ l aliquots into 96 well microtiter plates (final DMSO concentration of 0.1%).
3) To prepare the infected cells, the cells are treated at 106Mu.l of RF virus (TCID50, 10) was added to each cell7Ml), incubated at 37 ℃ for 1 hour. The cells were then washed twice with PBS and resuspended in culture medium at a density of 2.2X 10 5Cells/ml. 180 μ l of these infected cells were transferred to the wells of a 96-well plate containing the compound.
4) The plates were CO-incubated at 37 deg.C2Culturing in incubator for 4 days. Cell viability was measured following the manufacturer's recommendations (AQueousNon-Radioactive Assay-Promega (cat no: G5430)). The concentration of the compound that inhibits the cytotoxic effect of the virus by 50% is expressed as EC50。
Accordingly, the present invention provides:
(i) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof;
(ii) a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof;
(iii) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof together with a pharmaceutically acceptable excipient, diluent or carrier;
(iv) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a medicament;
(v) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a reverse transcriptase inhibitor or modulator;
(vi) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use in the treatment of infection by HIV or a genetically related retrovirus, or the resulting Acquired Immune Deficiency Syndrome (AIDS);
(vii) Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof in the manufacture of a medicament having reverse transcriptase inhibitory or modulating activity;
(viii) use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof in the manufacture of a medicament for the treatment of infection by HIV or a genetically related retrovirus, or the resulting Acquired Immune Deficiency Syndrome (AIDS);
(ix) a method of treatment of a mammal, including a human being, with a retroviral inhibitor or modulator comprising treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof;
(x) A method of treating infection by HIV or a genetically related retrovirus, or the resulting acquired immunodeficiency syndrome (AIDS), in a mammal, including a human, comprising treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof;
(xi) The invention discloses novel intermediates.
The following examples illustrate the preparation of compounds of formula (I). The synthesis of certain intermediates used therein is described in the preparative examples section which follows the examples.
1The H Nuclear Magnetic Resonance (NMR) spectrum was consistent with the proposed structure in all cases. Characteristic chemical shift (. delta.) ofParts per million of the signal moving from tetramethylsilane to the low magnetic field indicates the main peaks using conventional abbreviations: s, singlet; d, double peak; t, triplet; q, quartet; m, multiplet; br, broad peak. The following abbreviations are used: HRMS, high resolution mass spectrometry; HPLC, high performance liquid chromatography; nOe, nuclear Vouhauser effect; m.p., melting point; CDCl3Deuterated chloroform; d6-DMSO, deuterated dimethyl sulfoxide; CD (compact disc)3OD, deuterated methanol. When Thin Layer Chromatography (TLC) is used, it represents silica gel TLC, using silica gel 60F254Plate, RfIs the distance traveled by the compound on the TLC plate divided by the distance traveled by the previous solvent.
Example 1
2- [4- (3, 5-Dichlorophenoxy) -3, 5-dimethyl-1H-pyrazol-1-yl ] ethanol
To a stirred solution of β -diketone (75mg, 0.287mmol) from preparation 1 in ethanol (2.9ml) was added 2-hydroxyethylhydrazine (21.5 μ l, 0.316mmol) at room temperature under nitrogen and the resulting orange solution was heated at reflux for 18 h. After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (20ml), washed with 2M hydrochloric acid (10ml) and brine (10ml), then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a viscous orange oil. The crude product was purified by flash chromatography on silica gel eluting with pentane: ethyl acetate (10: 1, vol.) then dichloromethane to give the title compound (32mg) as a white powder, m.p.114-115 ℃.
1H NMR(400MHz，CDCl3)：δ＝2.08(s，3H)，2.10(s，3H)，3.30(t，1H)，4.06(m，4H)，6.79(s，2H)，7.01(s，1H)。
LRMS (thermal spray): m/z [ MH+]301。
Micro-analysis: measured value: c, 51.76; h, 4.64; and N, 9.20. C13H14Cl2N2O2Calculated values: c, 51.85; h, 4.69; and N, 9.30 percent.
Example 2
2- [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol
To a stirred solution of chloroketone (500mg, 3.07mmol) of preparation 2 in acetone (15ml) was added 3, 5-dichlorophenol (501mg, 3.07mmol), potassium carbonate (467mg, 3.38mmol) and sodium iodide (461mg, 3.07mmol) successively at room temperature under nitrogen to form an orange/red suspension. The mixture is heated at reflux 221/2In the course of time, a yellow suspension formed. After cooling, the mixture was diluted with water (10ml) and the acetone was removed under reduced pressure in a fume hood (note: possible tear components remained). The residue was diluted with 2M hydrochloric acid and extracted with dichloromethane (1X 20ml, 2X 10 ml). The organic layers were combined, washed with brine (20ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude 4- (3, 5-dichlorophenoxy) -3, 5-heptanedione as an orange oil (777 mg). A portion of the crude 4- (3, 5-dichlorophenoxy) -3, 5-heptanedione (250mg, ca. 0.865mmol) was dissolved in ethanol (8.6ml) and treated with 2-hydroxyethylhydrazine (65. mu.l, 0.951 mmol). The resulting solution was heated at reflux for 16 hours to form a red solution. After cooling, the mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (20 ml). The resulting solution was washed with 2M hydrochloric acid (10ml), 1N sodium hydroxide solution (10ml) and brine (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an orange oil (102 mg). The crude product was purified by flash chromatography on silica eluting with methanol: dichloromethane (5: 95 vol) to give the title compound (23mg) as an orange oil which solidified to a waxy solid on standing.
1H NMR(400MHz，CDCl3)：δ＝108(t，3H)，1.12(t，3H)，2.38(q，2H)，2.48(q，2H)，3.69(br.s，1H)，4.02(m，4H)，6.76(s，2H)，6.97(s，1H)。
LRMS (thermal spray): m/z [ MH+]329。
Example 3
4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazole
A mixture of chloroketone (5g, 30.8mmol) from preparation 2, 3, 5-dichlorophenol (5g, 30.8mmol), cesium carbonate (10g, 30.8mmol) and acetone (40ml) was heated at reflux for 18 hours. After cooling, the solid was removed by filtration and washed with dichloromethane (100 ml). The filtrates were combined and concentrated under reduced pressure. The crude product was dissolved in ethanol (20ml), hydrazine hydrate (1.5ml, 30.8mmol) was added and the mixture was heated at 60 ℃ under nitrogen for 30 min. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with diethyl ether: pentane (1: 1 vol) to give the title compound (5.5g) as a yellow oil which solidified upon standing as a yellow solid m.p.114-115 ℃.
1H NMR(300MHz，CDCl3)：δ＝1.15(6H，t)，2.48(4H，q)，6.78(2H，s)，6.95(1H，s)。
LRMS (thermal spray): m/z [ MH+]285。
Microanalysis: measured value: c, 54.93; h, 5.05; and N, 9.94. C13H14Cl2N2Calculated value of O: c, 54.75; h, 4.95; n, 9.82%.
Example 4
[4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetonitrile
To a stirred solution of 4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazole (3g, 10.5mmol, example 3) in anhydrous N, N-dimethylformamide (20ml) was added sodium hydride (60% oil dispersion, 470mg, 11.8mmol) at 0 ℃ under nitrogen. The mixture was stirred for 5 minutes during which time hydrogen evolved and bromoacetonitrile (0.81ml, 11.6mmol) was added. The yellow solution turned dark brown, and a precipitate formed. Anhydrous N, N-dimethylformamide (5ml) was further added to aid dissolution, and after 45 minutes, the reaction mixture was quenched by addition of water (1 ml). The mixture was partitioned between water (150ml) and diethyl ether (2X 150 ml). The organic layers were combined, washed with water (50ml) and brine (100ml), dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with dichloromethane to give the title compound (3.2g) as a yellow powder, m.p.70-72 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.14(6H，m)，2.38(2H，q)，2.56(2H，q)，4.92(2H，s)，6.75(2H，s)，7.00(1H，s)。
Microanalysis: measured value: c, 55.43; h, 4.69; n, 12.71. C15H15Cl2N3Calculated value of O: c, 55.57; h, 4.60; n, 12.96 percent.
Example 5
5- { [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -1H-pyrazol-3-ol
A mixture of the ester of preparation 3 (120mg, 0.29mmol), hydrazine hydrate (16mg, 0.29mmol) and ethanol (5ml) was stirred and heated at 60 ℃ for 2 hours under nitrogen. After cooling, the mixture was concentrated under reduced pressure and the resulting white solid was stirred in ethyl acetate and then collected by filtration to give the title compound as a white solid, m.p.142-144 ℃.
1H NMR(400MHz，DMSO-d6)：δ＝0.89(3H，t).0.99(3H，t)，2.26(2H，q)，2.45(2H，q)，5.01(2H，s)，5.19(1H，s)，6.88(2H，s)，7.21(1H，s)。
LRMS (electrospray): m/z [ M-H+]379。
Microanalysis: measured value: c, 55.39; h, 4.72; n, 14.69. C17H18Cl2N4O2Calculated values: c, 53.56; h, 4.76; n, 14.69 percent.
Example 6
6- { [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -2-methyl-4 (3H) pyrimidinone
A mixture of the ester of preparation 3 (140mg, 0.34mmol), acetamidine hydrochloride (95mg, 1.0mmol), sodium ethoxide (68mg, 1.0mmol) and ethanol (5ml) was stirred and heated at 70 ℃ for 1h under nitrogen. After cooling, the mixture was concentrated under reduced pressure. The resulting oil was dissolved in dichloromethane (50ml), washed with water (20ml), dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a white foam (100 mg).
1H NMR(300MHz，CDCl3)：δ＝1.10(3H，t)，1.19(3H，t)，2.48(7H，m)，5.08(2H，s)，5.72(1H，s)，6.82(2H，s)，7.03(1H，s)。
LRMS (thermal spray): m/z [ MH+]407。
Example 7
2-amino-6- { [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -4(3H) pyrimidinone
A mixture of the ester of preparation 3 (150mg, 0.365mmol), guanidine hydrochloride (104mg, 1.08mmol) and sodium ethoxide (73mg, 1.08mmol) in ethanol (5ml) was stirred and heated at 70 ℃ for 3 hours under nitrogen. After cooling, the mixture was concentrated under reduced pressure, and the resulting oil was dissolved in dichloromethane (50ml), washed with water (20ml), dried over magnesium sulfate and concentrated under reduced pressure. The crude product was chromatographed on silica gel eluting with dichloromethane, methanol, ammonia (90: 10: 1 vol.) to give the title compound as a white solid (30mg), m.p.238-240 ℃.
1H NMR(400MHz，DMSO-d6)：δ＝0.91(3H，t)，0.99(3H，t)，2.29(2H，q)，2.44(2H，q)，4.75(1H，s)，4.81(2H，s)，6.58(2H，br.s)，6.87(2H，s)，7.22(1H，s)。
LRMS (thermal spray): m/z [ MH+]408。
Example 8
2- [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] -N-hydroxyacetamidine (ethanimide)
To a suspension of the nitrile of example 4 (1g, 3.1mmol) in a mixture of methanol (25ml) and water (10ml) were added hydroxylamine hydrochloride (1.1g, 15.8mmol) and potassium carbonate (2.1g, 15.2mmol), followed by heating at reflux for 3 days. After cooling, the mixture was extracted with dichloromethane (2X 250ml), the organic layers were combined, washed with brine (100ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the product as a white solid (1.1g), m.p.128-130 ℃.
1H NMR(300MHz，CD3OD)：δ＝1.10(6H，m)，2.40(2H，q)，2.60(2H，q)，4.65(2H，s)，6.90(2H，s)，7.10(1H，s)。
LRMS (electrospray): m/z [ MH+]357。
Example 9
[4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetic acid methyl ester
To a stirred solution of pyrazole (2.6g, 9.12mmol) from example 3 in anhydrous N, N' -dimethylformamide (25ml) was added methyl bromoacetate (984. mu.l, 10mmol) at 0 ℃ under nitrogen and sodium hydride (60% oil dispersion, 801mg, 20.1mmol) was added. After stirring at 0 ℃ for 1 hour, ice-water (100ml) was added and the mixture was extracted with ether (3X 50 ml). The ether layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate to pentane (20: 80 vol) to give the title compound (780mg) as a yellow oil which crystallized partially on standing.
1H NMR(400MHz，CDCl3)：δ＝1.10(6H，m)，2.44(4H，m)，3.78(3H，s)，4.80(2H，s)，6.69(2H，s)，6.99(1H，s)。
LRMS (thermal spray): m/z [ MH+]357。
Example 10
2- [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetamide
To a stirred solution of the acid of preparation 4 (125mg, 0.36mmol) in anhydrous N, N-dimethylformamide was added 1, 1' -carbonyldiimidazole (71mg, 0.44mmol) at room temperature and the reaction mixture was stirred for 30 minutes. Adding concentrated ammonia water (d is 0.880 g/cm)3About 0.1ml, about 1.8mmol), stirring was continued for 10 minutes. The solvent was removed under reduced pressure and the residue partitioned between water (10ml) and ethyl acetate (10 ml). The organic layer was concentrated under reduced pressure and the residue was chromatographed on silica gel, eluting with ethyl acetate to give the title compound as a white solid (60mg), m.p.164-166 ℃.
1H NMR(300MHz，CDCl3)：δ＝1.15(6H，m)，2.50(4H，m)，4.70(2H，s)，5.50(1H，br.s)，6.21(1H，br.s)，6.78(2H，s)，7.04(1H，s)。
LRMS (thermal spray): m/z [ MH+]342。
Example 11
2- [4- (3, 5-Dichlorophenoxy-3, 5-diethyl-1H-pyrazol-1-yl ] acethydrazide
To a solution of the ester of example 9 (780mg, 2.18mmol) in ethanol (25ml) was added hydrazine hydrate (520. mu.l, 10.9mmol) and the resulting mixture was heated at reflux for 18 h. After cooling, the precipitate was collected by filtration and washed with diethyl ether (50ml) to give the title compound (550mg) as a white solid, m.p. > 250 ℃.
1H NMR(300MHz，CD3OD)：δ＝1.10(6H，m)，2.39(2H，q)，2.55(2H，q)，4.72(2H，s)，6.93(2H，s)，7.09(1H，s)。
LRMS (electrospray): m/z [ MH+]357。
Example 12
5- { [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -1, 3, 4-oxadiazol-2 (3H) -one
A stirred solution of the hydrazide of example 11 (275mg, 0.77mmol) and 1, 1' -carbonyldiimidazole (187mg, 1.16mmol) in dioxane (50ml) was heated at reflux for 18 h. After cooling, the mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (50ml) and washed with water (25 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (95: 5 vol.) to give the title compound (112mg) as a white solid, m.p.138-142 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.10(6H，m)，2.40(2H，q)，2.55(2H，q)，5.07(2H，s)，6.76(2H，s)，6.98(1H，s)，10.45(1H，br.s)。
LRMS (electrospray): m/z [ MH+]383。
Example 13
2- [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethylamine
A mixture of pyrazole (390mg, 1.37mmol) from example 3 and chloroethylamine hydrochloride (238mg, 2.05mmol) was stirred and heated at 150 ℃ for 24 h. After cooling, the mixture was partitioned between saturated aqueous sodium bicarbonate (100ml) and dichloromethane (2 × 50 ml). The organic layers were combined, washed with brine (30ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash chromatography on silica eluting with methylene chloride: methanol (90: 10 vol.) to give the title compound (244mg) as a brown oil.
1H NMR(400MHz，CDCl3)：δ＝1.09(6H，m)，2.41(2H，q)，2.52(2H，q)，3.18(2H，t)，4.02(2H，t)，6.78(2H，s)，6.99(1H，s)。
LRMS (electrospray): m/z [ MH+]330。
Microanalysis: measured value: c, 52.28; h, 5.70; n, 11.75. C15H19Cl2N3O.H2Calculated value of O: c, 52.03; h, 6.11; n, 12.14 percent.
Example 14
3- { [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -1, 2, 4-oxadiazol-5-ol
To a stirred solution of the amidoxime of example 8 (500mg, 1.39mmol) in pyridine (8ml) was added ethyl chloroformate (0.30ml, 3.08mmol) at 0 ℃ under nitrogen and the resulting solution was stirred for 10 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of water (4ml), tetrahydrofuran (4ml) and 1M aqueous sodium hydroxide (2 ml). The mixture was heated at reflux for 1 hour, cooled to room temperature, and stirred for an additional 2 days. The resulting solution was diluted with 2M aqueous hydrochloric acid (20ml) and extracted with ethyl acetate (2X 50 ml). The organic layers were combined, washed with brine (50ml), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a yellow oil. The oil was purified by flash column chromatography on silica eluting with pentane over ethyl acetate (50: 50 vol/vol) to give a white solid. The solid was dissolved in a mixture of tetrahydrofuran (1ml) and 1M aqueous sodium hydroxide solution (10ml), which was then heated under reflux for 24 hours. The resulting solution was diluted with 2M hydrochloric acid (20ml) and extracted with dichloromethane (2X 50 ml). The organic layers were combined, washed with brine (50ml), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the title compound (113mg) as a white solid, m.p.94-96 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.14(m，6H)，2.56(m，4H)，5.06(s，2H)，6.75(s，2H)，7.03(s，1H)。
LRMS (electrospray): m/z [ M- (H)+)]381。
Example 15
5- { [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -1, 3, 4-oxadiazol-2-amine
Cyanogen bromide (49mg, 0.462mmol) was added to a stirred solution of the hydrazide of example 11 (150mg, 0.420mmol) in ethanol (30ml) at room temperature under nitrogen and the resulting solution was heated under reflux for 2.5 h. After cooling, the mixture was concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (98: 1.75: 0.25 vol.) to give the title compound (71mg) as a white powder, m.p.226-228 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.00(m，6H)，2.29(m，2H)，2.55(m，2H)，5.34(s，2H)，6.90(s，2H)，7.07(s，2H)，7.24(s，1H)。
LRMS (electrospray): m/z [ MH+]382。
Microanalysis: measured value: c, 49.82; h, 4.52; n, 17.81. C16H17Cl2N5O2.0.25H2Calculated value of O: c, 49.69; h, 4.56; n, 18.11 percent.
Example 16
N- {2- [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -2-methoxyacetamide
To a stirred solution of methoxyacetic acid (14.2. mu.l, 0.178mmol) in dichloromethane (1ml) was added a solution of pyrazole (53mg, 0.161mmol), 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (34mg, 0.178mmol) and 4- (dimethylamino) pyridine (22mg, 0.178mmol) in dichloromethane (1ml) at room temperature. The reaction was stirred for 12 hours and then concentrated under a stream of nitrogen to give a yellow solid. The crude product was purified by flash column chromatography on silica eluting with methylene chloride: methanol (98: 2 vol) to give the title compound (54mg) as a brown solid at 75-76 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.08(t，3H)，1.18(t，3H)，2.42(q，2H)，2.52(q，2H)，3.39(s，3H)，3.75(m，2H)，3.90(s，2H)，4.13(t，2H)，6.79(s，2H)，6.99(s，1H)，7.21(br s，1H)。
LRMS (electrospray): m/z [ MH+]400；[M-(H+)]398。
Microanalysis: measured value: c, 54.09; h, 5.79; n, 10.39. C18H23Cl2N3O3Calculated values: c, 54.01; h, 5.79; n, 10.50 percent.
Examples 17 and 18
By a method similar to example 16, using the appropriate acid starting material and the pyrazole of example 13, the compounds of the following general formula examples are prepared, as set forth in the following table:
example 19
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol 4-yl ] oxy } benzonitrile
A mixture of chloroketone (243mg, 1.50mmol), 3-cyanophenol (155mg, 1.50mmol), cesium carbonate (488mg, 1.50mmol) and acetone (10ml) from preparation 2 was heated at reflux for 2 hours. After cooling, the solid was removed by filtration and the filtrate was concentrated under reduced pressure to give a brown oil. The oil was dissolved in ethanol (10ml), hydroxyethylhydrazine (114mg, 1.50mmol) was added and the mixture was heated at 60 ℃ for 18 h. After cooling, the mixture was concentrated under reduced pressure. The residue in dichloromethane (10ml) was washed with 2M aqueous hydrochloric acid (5ml) and water (5ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate to give the title compound (80mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.40(q，2H)，2.50(q，2H)，3.68(br s，1H)，4.07(m，4H)，7.12(s，1H)，7.14(d，1H)，7.28(d，2H)。
LRMS (electrospray): m/z [ MH+]286；[MNa+]308。
Examples 20 to 38
By a method similar to example 19, using the appropriate phenol and preparative example 2 chloroketone, the following compounds of the general formula example are prepared, as set forth in the following table:
example 39
4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1- (2-methoxyethyl) -1H-pyrazole
To a stirred solution of example 34- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazole (200mg, 0.701mmol) and methoxyethyl bromide (117mg, 0.850mmol) in anhydrous N, N-dimethylformamide (2ml) was added sodium hydride (60% oil dispersion, 34mg, 0.850mmol) at 0 ℃ under a nitrogen atmosphere. The mixture was stirred at 0 ℃ for 45 minutes during which time hydrogen evolved and the yellow solution turned dark brown. The reaction mixture was quenched by the addition of water (5ml) and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20ml), washed with water (10ml) and brine (10ml), then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography on silica eluting with pentane: diethyl ether (80: 20 vol) to give the title compound (140mg) as a colourless oil.
1H NMR(300MHz，CDCl3)：δ＝1.09-1.15(m，6H)，2.41-2.49(q，2H)，2.51-2.57(q，2H)，3.34(s，3H)，3.74-3.78(t，2H)，4.15-4.17(t，2H)，6.81(s，2H)，7.01(s，1H)。
LRMS (thermal spray): m/z [ MH+]343。
Microanalysis: measured value: c, 56.25; h, 5.94; and N, 7.95. C 16H20Cl2N2O2Calculated values: c, 55.99; h, 5.87; n, 8.16%.
Examples 40 and 41
By a method similar to example 39, using the appropriate halide and pyrazole of example 3, the following compounds of the general formula example are prepared, as set forth in the following table:
example 42
4- (3, 5-Dichlorophenoxy) -3-ethyl-1H-pyrazole
A solution of the enamine of preparation 6 (2.88g, 10.0mmol) and hydrazine hydrate (0.49ml, 10.0mmol) in ethanol (10ml) was heated at reflux for 12 hours. After cooling, hydrazine hydrate (0.49ml, 10.0mmol) was added and the reaction heated at reflux for 3 hours. After cooling, the mixture was concentrated under reduced pressure, and the residue was subjected to flash silica gel column chromatography, eluting with cyclohexane: ethyl acetate (80: 20 vol.) and then with cyclohexane: ethyl acetate (60: 40 vol.) to give the title compound (620mg) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.23(t，3H)，2.66(q，2H)，6.87(s，2H)，7.02(s，1H)，7.40(s，1H)。
LRMS (electrospray): m/z [ MH+]257；[M-(H+)]255。
Example 43
4- {2- [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } morpholine
To a stirred solution of pyrazole (3.00g, 9.23mmol) from example 64 and sodium periodate (4.93g, 23.1mmol) in acetone (90ml) and water (30ml) was added osmium tetroxide (1.00ml of a 2.5% v/v solution in tert-butanol) dropwise at room temperature. After 5 minutes a white precipitate formed and the suspension was stirred for a further 3 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (300ml) and water (100ml), the organic phase was separated, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the intermediate aldehyde. A sample of the aldehyde (100mg, 0.305mmol) was dissolved in dichloromethane (5ml) and morpholine (30mg, 0.344mmol) and glacial acetic acid (17.1. mu.l, 0.305mmol) were added. After stirring at room temperature for 5 minutes, sodium triacetoxyborohydride (95mg, 0.451mmol) was added in one portion, and the reaction was stirred for 1 hour. The resulting mixture was then diluted with dichloromethane (20ml) and partitioned between water (30ml) and dichloromethane (20 ml). The organic phase was washed with 2M aqueous sodium hydroxide (10ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with dichloromethane, methanol, ammonia (95: 4: 1 vol.) to give the title compound (125mg) as a colourless oil.
1H NMR (400MHz，CDCl3)：δ＝1.06(m，6H)，2.12(m，8H)，2.75(t，2H)，3.64(m，4H)，4.04(t，2H)，6.73(s，2H)，6.95(s，1H)。
LRMS (thermal spray): m/z [ MH+]398。
Microanalysis: measured value: c, 57.18; h, 6.31; n, 10.36. C19H25Cl2N3O2Calculated values: c, 57.29; h, 6.33; n, 10.55 percent.
Examples 44 to 49
By a method similar to example 43, using the appropriate amine starting material and the pyrazole of example 64, the compounds of the following general formula example are prepared, as set forth in the following table:
example 50
3- { [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } morpholine
To a stirred solution of the mesylate of preparation 11 (273mg, 0.925mmol) and pyrazole of example 3 (220mg, 0.772mmol) in anhydrous N, N-dimethylformamide (4ml) was added sodium hydride (60% oil dispersion, 37mg, 0.925mmol) at 0 deg.C under nitrogen. The mixture was heated at 50 ℃ for 3 hours, during which time the yellow solution turned dark brown. The reaction mixture was quenched by the addition of water (5ml) and the mixture was concentrated under reduced pressure. The residue was washed with water (10ml) and brine (10ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a brown oil. The oil was dissolved in dichloromethane (3ml), trifluoroacetic acid (1ml) was added and the reaction stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (10ml) and washed with 1M aqueous hydrochloric acid (2X 5 ml). The aqueous phases were combined, neutralized with solid sodium carbonate and extracted with ethyl acetate (3X 20 ml). The ethyl acetate layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (3mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝1.15(m，6H)，2.41(q，2H)，2.51(q，2H)，2.89(m，2H)，3.30(m，2H)，3 58(m，1H)，3.78(m，2H)，3.87(d，2H)，6.88(s，2H)，7.00(1H，s)。
LRMS (thermal spray): m/z [ MH+]384。
Example 51
1- (3-azetidinyl) -4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazole
To a stirred solution of pyrazole from example 3 (200mg, 0.702mmol) and 1-benzhydryl-3-azetidinesulfonic acid (222mg, 0.702mmol) (see j.org.chem., 1972, 37, 3953) in N, N-dimethylformamide (5ml) was added sodium hydride (60% oil dispersion, 30mg, 0.750mmol) at 0 ℃ under nitrogen. The mixture was heated at 50 ℃ for 4 hours and then cooled to room temperature. Water (30ml) was added to quench the reaction mixture and the aqueous mixture was extracted with diethyl ether (2X 50 ml). The organic phases were combined, washed with water (10ml) and brine (10ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a brown oil. The oil was purified by flash column chromatography on silica eluting with dichloromethane to give intermediate (60mg) as a yellow oil. The oil was dissolved in dichloromethane (5ml) and 1-chloroethyl chloroformate (20. mu.l, 0.182mmol) was added under nitrogen at room temperature. The mixture was heated at reflux for 4 hours, cooled to room temperature and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in methanol (5ml), and the resulting solution was heated at reflux for 1 hour, cooled to room temperature, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (17mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝1.08(t，3H)，1.16(t，3H)，2.48(m，4H)，3.87(t，2H)，4.40(t，2H)，5.07(q，1H)，6.79(s，2H)，7.01(m，1H)。
LRMS (thermal spray): m/z [ MH+]340。
Example 52
7- (3, 5-Dichlorophenoxy) -6-ethyl-2, 3-dihydropyrazolo [5, 1-b ] [1, 3] oxazole
Preparation 15 trifluoromethanesulfonate (282mg, 0.500mmol), tributylvinyltin (175. mu.l, 0.600mmol), palladium dibenzylideneacetone (23mg, 0.025mmol), triphenylarsine (12mg, 0.040mmol) and lithium chloride (64mg, 1.50mmol) were heated in N, N-dimethylformamide (3ml) at 80 ℃ under a nitrogen atmosphere for 12 hours. The reaction was cooled to room temperature and partitioned between water (20ml) and ethyl acetate (20 ml). The organic layer was washed with brine (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (90: 10 vol) to give the title compound (34mg) as a colourless oil.
1H MR(400MHz，CDCl3)：δ＝1.16(t，3H)，2.45(q，2H)，4.29(t，2H)，5.03(t，2H)，6.89(s，2H)，7.02(s，1H)。
LRMS (thermal spray): m/z [ MH+]299。
Example 53
4- (3, 5-Dichlorophenoxy) -3, 5-dimethyl-1H-pyrazole
A mixture of 3-chloro-2, 4-pentanedione (5.00g, 37.0mmol), 3, 5-dichlorophenol (6.03g, 37.0mmol), cesium carbonate (12.0g, 37.0mmol) and acetone (40ml) was heated at reflux for 18 hours. After cooling, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The intermediate was dissolved in ethanol (30ml), hydrazine hydrate (1.85g, 37.0mmol) was added and the mixture was heated at 60 ℃ for 30 min. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica eluting with ethyl acetate pentane (30: 70 vol.) to give the title compound (3.00g) as a yellow oil which solidified on standing to give a yellow solid m.p.85-87 ℃.
1H NMR(300MHz，CDCl3)：δ＝2.14(s，6H)，5.24(br s，1H)，6.81(s，2H)，7.02(s，1H)。
LRMS (thermal spray): m/z [ MH+]257。
Microanalysis: measured value: c, 49.58; h, 4.06; n, 11.05. C11H10Cl2N2O.0.4H2Calculated value of O: c, 49.98; h, 4.12; n, 10.60 percent.
Example 54
1- [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] -2-propanol
To a stirred solution of pyrazole (3.00g, 9.23mmol) from example 64 and sodium periodate (4.93g, 23.1mmol) in acetone (90ml) and water (30ml) was added osmium tetroxide (1.00ml of a 2.5% v/v solution in tert-butanol) dropwise at room temperature. After 5 minutes a white precipitate formed and the suspension was stirred for a further 3 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (300ml) and water (100ml), the organic phase was separated, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the intermediate aldehyde. A sample of this aldehyde (250mg, 0.765mmol) was dissolved in tetrahydrofuran (5ml) and stored under nitrogen. To a stirred solution of methylmagnesium bromide (0.51ml of a 3M solution in diethyl ether, 1.53mmol) in tetrahydrofuran (5ml) was added anhydrous cerium trichloride (377mg, 1.53mmol) in a separate flask at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 1.5 hours, and a tetrahydrofuran solution of aldehyde was added dropwise. The mixture was stirred for 12 hours, then quenched with 1M aqueous acetic acid at room temperature. The mixture was diluted with dichloromethane (20ml), washed with water (5ml) and brine (5ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (70: 30 vol) to give the title compound (30mg) as a colourless oil.
1HNMR(400MHz，CDCl3)：δ＝1.05(t，3H)，1.10(t，3H)，1.21(d，2H)，2.40(q，2H)，2.47(q，2H)，3.79(dd，1H)，3.97(dd，1H)，4.24(s，1H)，6.76(s，2H)，6.98(s，1H)。
LRMS (thermal spray): m/z [ MH+]343。
Example 55
2- {2- [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethoxy } ethanamine
To a stirred solution of pyrazole (100mg, 0.303mmol) from example 2 in anhydrous N, N-dimethylformamide (4ml) was added sodium hydride (60% oil dispersion, 24mg, 0.600mmol) at 0 ℃ under nitrogen. The mixture was stirred at 0 ℃ for 30 minutes and 2-chloroethylamine hydrochloride (53mg, 0.455mmol) was added. The reaction mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 30 minutes. The reaction mixture was cooled to 0 ℃ and sodium hydride (60% oil dispersion, 24mg, 0.600mmol) and 2-chloroethyl amine hydrochloride (53mg, 0.455mmol) were added and the reaction mixture was stirred for 1 hour. Water (5ml) was added to quench the reaction, which was extracted with diethyl ether (10 ml). The organic layer was washed with 2M aqueous hydrochloric acid (30 ml). The acid was neutralized with solid sodium carbonate and extracted with ether (3X 20 ml). The ether layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4.1 vol.) to give the title compound (21mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝1.19(m，6H)，2.42(q，2H)，2.58(q，2H)，2.80(t，2H)，3.38(t，2H)，3.81(t，2H)，4.18(t，2H)，6.78(s，2H)，7.02(s，1H)。
LRMS (thermal spray): m/z [ MH +]372。
Example 56
4- { [4- (3, 5-Dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } morpholine
To a stirred solution of preparation 8 bromide (200mg, 0.531mmol) in isopropanol (4ml) was added morpholine (140. mu.l, 1.59mmol) in one portion at room temperature. The mixture was heated at 50 ℃ for 1 hour, cooled to room temperature and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate to give the title compound (60mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝2.13(s，3H)，2.42(m，4H)，3.38(s，2H)，3.64(m，4H)，6.79(s，2H)，7.02(s，1H)。
LRMS (thermal spray): m/z [ MH+]342。
Example 57
4- (3, 5-Dichlorophenoxy) -3-methyl-5- [ (2-methyl-1H-imidazol-1-yl) methyl ] -1H-pyrazole
To a stirred solution of 2-methylimidazole (65mg, 0.800mmol) in N, N-dimethylformamide (5ml) was added sodium hydride (60% oil dispersion, 32mg, 0.800mmol) at 0 ℃ under nitrogen. The mixture was stirred for 10 min, then preparative example 8 bromide (100mg, 0.261mmol) was added and the reaction stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of 1M aqueous sodium hydroxide (5ml) and the mixture was concentrated under reduced pressure. The residue was washed with water (10ml) and brine (10ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4.5: 0.5 vol.) to give the title compound (10mg) as a colorless oil.
1H NMR(300MHz，CDCl3)：δ＝2.14(s，3H)，2.35(s，3H)，4.89(s，2H)，6.68(s，2H)，6.78(s，1H)，6.82(s，1H)，7.03(s，1H)。
LRMS (thermal spray): m/z [ MH+]337。
Example 58
2- [4- (3, 5-Dichlorophenoxy) -3-ethyl-5-methoxy-1H-pyrazol-1-yl ] ethanol
Preparation 15 trifluoromethanesulfonate (282mg, 0.500mmol) was dissolved in methanol (3ml) and 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride (18mg, 0.025mmol) was added in one portion at room temperature. The mixture was heated at 50 ℃ under carbon monoxide atmosphere (345kPa, 50psi) for 10 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give a brown oil. The oil was dissolved in a mixture of tetrahydrofuran (0.5ml), glacial acetic acid (1.0ml) and water (0.5ml) and stirred at room temperature for 12 h. The solvent was removed under a stream of nitrogen to give a yellow oil, and the crude product was purified by flash column chromatography on silica eluting with dichloromethane: acetonitrile (95: 5 vol) and then dichloromethane: acetonitrile (90: 10 vol) to give the title compound (6mg) as a colourless oil.
1H NMR(300MHz，CDCl3)：δ＝1.13(t，3H)，2.41(q，2H)，3.44(br s，1H)，3.94(s，3H)，4.23(m，4H)，6.87(s，2H)，7.09(s，1H)。
LRMS (thermal spray): m/z [ MH+]331。
Example 59
1- { [4- (3, 5-Dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -1H-1, 2, 4-triazole
A suspension of preparation 8 bromide (100mg, 0.264mmol), 1, 2, 4-triazole (92mg, 1.32mmol) and sodium carbonate (140mg, 1.32mmol) in toluene (5ml) was heated at 100 ℃ for 12 h. The suspension was cooled to room temperature and 1M aqueous sodium hydroxide (5ml) was added. The mixture was extracted with ethyl acetate (3X 20ml) and the organic phases were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a clear oil. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4.5: 0.5 vol.) to give the title compound (62mg) as a colorless oil.
1H NMR(300MHz，CDCl3)：δ＝2.16(s，3H)，5.25(s，2H)，6.70(s，2H)，7.04(s，1H)，7.89(s，1H)，8.04(s，1H)。
LRMS (thermal spray): m/z [ MH+]324。
Example 60
3- [ (3, 5-diethyl-1H-pyrazol-4-yl) oxy ] benzonitrile
To a stirred solution of the diketone of preparation example 9 (771mg, 3.14mmol) in ethanol (16ml) was added hydrazine hydrate (153. mu.l, 3.14mmol), and the resulting solution was heated under reflux for 12 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (75: 25 vol) to give the title compound (712mg) as a yellow solid, m.p.81-84 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.15(t，6H)，2.47(q，4H)，7.11(m，2H)，7.24(d，1H)，7.35(t，1H)。
LRMS (thermal spray): m/z [ MH+]242。
Microanalysis: measured value: c, 69.03; h, 6.43; and N, 17.20. C14H15N3O3.0.13H2Calculated value of O: c, 69.02; h, 6.31; n, 17.25 percent.
Example 61
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } benzonitrile
Pyrazole (200mg, 0.829mmol) from example 60 and 2-chloroethylamine hydrochloride (144mg, 1.24mmol) were heated to a melt at 150 ℃ for 17 hours. After cooling, the solid was dissolved in saturated aqueous sodium bicarbonate (15ml) and extracted with dichloromethane (2X 10 ml). The organic phases were combined, washed with 2M aqueous hydrochloric acid (20ml), the aqueous layer was neutralised with solid sodium carbonate and extracted with dichloromethane (3X 10 ml). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an orange gum. The crude product was purified by flash column chromatography on silica eluting with dichloromethane: methanol (90: 10) and then dichloromethane: methanol: ammonia (90: 9: 1 vol) to give the title compound (124mg) as a pale yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.11(m，6H)，2.41(q，2H)，2.52(q，2H)，3.18(t，2H)，4.04(t，2H)，7.15(m，2H)，7.29(d，1H)，7.38(t，1H)。
LRMS (thermal spray): m/z [ MH+]285。
Example 62
2- [4- (3-cyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetamide
To the example 63 ester (75mg, 0.229mmol) was added a saturated solution of ammonia in methanol (2.3ml) in a vial at room temperature, then the vial was sealed and heated at 75 ℃ for 17 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a cream-like solid. The crude product was purified by flash column chromatography on silica eluting with dichloromethane then dichloromethane to methanol (99: 1 vol) to give the title compound (49mg) as a white solid m.p.159-160 ℃.
1HNMR(400MHz，CDCl3)：δ＝1.10(t，3H)，1.17(t，3H)，2.44(q，2H)，2.53(q，2H)，4.69(s，2H)，5.44(br s，1H)，6.22(br s，1H)，7.14(m，2H)，7.31(d，1H)，7.40(t，1H)。
LRMS (thermal spray): m/z [ MH+]299。
Microanalysis: measured value: c, 64.20; h, 6.12; n, 18.79. C16H18N4O2Calculated values: c, 64.41; h, 6.08; n, 18.78%.
Example 63
[4- (3-Cyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetic acid ethyl ester
To a stirred solution of preparation example 9 β -diketone (140mg, 0.571mmol) and triethylamine (88 μ l, 0.628mmol) in ethanol (1.0ml) was added a solution of ethyl hydrazinoacetate (88mg, 0.571mmol) in ethanol (2.0ml) and the resulting solution was heated at reflux for 18 h. After cooling, the mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (20ml) and water (10 ml). The organic layer was separated, washed with brine (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (75: 25 vol), then ethyl acetate to give the title compound (131mg) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.08(m，6H)，1.25(t，3H)，2.40(m，4H)，4.20(q，2H)，4.77(s，2H)，7.12(m，2H)，7.23(d，1H)，7.34(t，1H)。
LRMS (thermal spray): m/z [ MH+]328。
Example 64
1-allyl-4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazole
To a stirred solution of allyl bromide (1.70ml, 19.2mmol) and pyrazole from example 3 (5.00g, 17.5mmol) in N, N-dimethylformamide (20ml) was added sodium hydride (60% oil dispersion, 770mg, 19.2mmol) at 0 ℃ under nitrogen. The reaction was allowed to warm to room temperature and stirred for 1 hour. Water (100ml) was added to quench the reaction mixture and the aqueous phase was extracted with diethyl ether (2X 50 ml). The organic phases were combined, washed with water (30ml) and brine (30ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (80: 20 vol) to give the title compound (5.00g) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.11(m，6H)，2.46(m，4H)，4.65(d，2H)，5.04(d，1H)，5.22(d，1H)，5.99(m，1H)，6.79(s，2H)，6.99(s，1H)。
LRMS (thermal spray): m/z [ MH+]325。
Example 65
N- { [4- (3, 5-Dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -N- (4-methoxybenzyl) amine
To a stirred solution of preparation 8 bromide (100mg, 0.265mmol) in isopropanol (2ml) was added 4-methoxybenzylamine (0.104ml, 0.800mmol) in one portion at room temperature. The mixture was heated at 50 ℃ for 1 hour, cooled to room temperature and concentrated under reduced pressure to give a yellow oil. The oil was diluted with diethyl ether (20ml), washed with saturated aqueous sodium bicarbonate (5ml) and water (5ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (50mg) as a colorless oil.
1H NMR(300MHz，CDCl3)：δ＝2.13(s，3H)，3.68(s，2H)，3.71(s，2H)，3.80(s，3H)，6.83(m，4H)，7.03(s，1H)，7.17(m，2H)。
LRMS (thermal spray): m/z [ MH+]392。
Examples 66 to 75
By a method similar to example 65, using the appropriate amine starting material and the bromide of preparative example 8, the compounds of the following general formula example are prepared, as set forth in the table below:
example 76
3-chloro-5- [ (3, 5-dimethyl-1H-pyrazol-4-yl) oxy ] benzonitrile
To a stirred solution of the β -diketone of preparation 16 (5.50g, 21.9mmol) in glacial acetic acid (22ml) was added hydrazine hydrate (1.10ml, 21.9mmol), and the resulting solution was stirred at room temperature for 14 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica eluting with dichloromethane and then dichloromethane: ethyl acetate (85: 15 vol.) to give the title compound (4.80g) as a yellow solid m.p.136-140 ℃.
1H NMR(400MHz，CDCl3)：δ＝2.09(s，6H)，7.02(m，1H)，7.10(m，1H)，7.25(m，1H)。
LRMS (electrojet spray)Mist): m/z [ MH+]248。
Microanalysis: found C, 57.91; h, 4.03; n, 16.79. C12H10N3Calculated OCl: c, 58.19; h, 4.07; n, 16.97 percent.
Example 77
3- { [5- (aminomethyl) -3-methyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile
To a saturated solution of ammonia in isopropanol (50ml) was added preparation 18 bromide (300mg, 0.800mmol) at 0 ℃. The reaction was stirred for 2 hours and slowly warmed to room temperature. The mixture was concentrated under reduced pressure and the resulting yellow oil was dissolved in dichloromethane (50 ml). The dichloromethane solution was washed with 1M aqueous sodium carbonate (20ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (220mg) as a white foam.
1H NMR(300MHz，CDCl3)：δ＝2.14(s，3H)，3.79(s，2H)，7.08(1H，s)，7.16(1H，s)，7.31(1H，s)。
LRMS (thermal spray): m/z [ MH+]263。
Example 78
3-chloro-5- { [ 3-methyl-5- (1-piperazinylmethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile
To a stirred solution of preparation 18 bromide (500mg, 1.40mmol) in isopropanol (20ml) was added tert-butyl 1-piperazinecarboxylate (1.17g, 6.30mmol) in one portion at room temperature. The mixture was stirred at 60 ℃ for 1 hour. Cooled to room temperature and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in dichloromethane (100ml) and the resulting solution was washed with 1M aqueous sodium carbonate (20ml) and brine (20ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol and ammonia (95: 4: 1 by volume) to give a yellow foam. The foam was dissolved in methylene chloride (100ml), the resulting solution was cooled to 0 ℃ and trifluoroacetic acid (2ml) was added. The reaction was allowed to warm to room temperature and stirred for 24 hours. The mixture was diluted with dichloromethane (50ml), washed with 1M aqueous sodium carbonate (20ml) and brine (20ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (90: 9: 1 parts by volume) to give the title compound (400mg) as a white foam.
1H NMR(300MHz，CDCl3)：δ＝2.14(s，3H)，2.40(m，4H)，2.83(m，4H)，3.38(s，2H)，7.09(s，1H)，7.16(s，1H)，7.30(s，1H)。
LRMS (thermal spray): m/z [ MH+]332。
Example 79
3-chloro-5- [ (5- { [ (4-cyanobenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile
A mixture of 4-cyanobenzaldehyde (60mg, 0.460mmol), the amine from example 77 (120mg, 0.460mmol), magnesium sulfate (500mg) and dichloromethane (5ml) was stirred at room temperature under nitrogen for 3 days. The mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica eluting with methanol/ethyl acetate (5: 95 vol.) to give a foam. The foam was dissolved in methanol (5ml), sodium borohydride (50mg, 1.31mmol) was added in one portion at room temperature, and the reaction was stirred for 30 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (20 ml). The resulting solution was washed with 1M aqueous sodium carbonate (10ml) and brine (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (35mg) as a white foam.
1H NMR(300MHz，CDCl3)：δ＝2.15(s，3H)，3.69(s，2H)，3.84(s，2H)，7.06(s，1H)，7.15(s，1H)，7.31(s，1H)，7.38(d，2H)，7.60(d，2H)。
LRMS (thermal spray): m/z [ MH+]378。
Example 80
3-chloro-5- [ (3-methyl-5- { [4- (methylsulfonyl) -1-piperazinyl ] methyl } -1H-pyrazol-4-yl) oxy ] benzonitrile
To a stirred solution of the amine from example 78 (80mg, 0.240mmol) and triethylamine (45. mu.l, 0.288mmol) in dichloromethane (3ml) was added dropwise methanesulfonyl chloride (19. mu.l, 0.240mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 30 minutes and then concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash column chromatography on silica eluting with methylene chloride followed by methylene chloride methanol ammonia (95: 4: 1 vol.) to give the title compound (65mg) as a white foam.
1H NMR(400MHz，CDCl3)：δ＝2.14(s，3H)，2.51(m，4H)，2.72(s，3H)，3.12(m，4H)，3.39(s，2H)，7.08(m，1H)，7.13(m，1H)，7.26(s，1H)。
LRMS (thermal spray): m/z [ MH+]410。
Example 81
3-chloro-5- [ (5- { [4- (methoxyacetyl) -1-piperazinyl ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile
To a stirred solution of methoxyacetic acid (37. mu.l, 0.480mmol) and the amine from example 78 (80mg, 0.240mmol) in dichloromethane (5ml) was added N-benzyl-N' -cyclohexylcarbodiimide polymer bound (624mg, 1.3mmol/g, 0.480mmol) in one portion at room temperature under nitrogen. The reaction was stirred for 1 hour and the polymer bound reagent was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by flash column chromatography on silica gel eluting with methylene chloride, methanol, and ammonia (95: 4: 1 by volume) to give the title compound (45mg) as a white foam.
1H NMR(400MHz，CDCl3)：δ＝2.11(s，3H)，2.38(m，4H)，3.37(m，7H)，3.51(m，2H)，4.04(s，2H)，7.04(m，1H)，7.10(m，1H)，7.26(m，1H)。
LRMS (thermal spray): m/z [ MH+]404。
Example 82
4- { [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -1-piperazinecarboxylic acid methyl ester
To a stirred solution of the amine from example 78 (80mg, 0.240mmol) and triethylamine (45. mu.l, 0.288mmol) in dichloromethane (5ml) was added methyl chloroformate (19. mu.l, 0.240mmol) dropwise at room temperature under a nitrogen atmosphere. The reaction was stirred for 90 minutes and then concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash column chromatography on silica eluting with methylene chloride followed by methylene chloride methanol ammonia (95: 4: 1 vol.) to give the title compound (55mg) as a white foam.
1H NMR(400MHz，CDCl3)：δ＝2.09(s，3H)，2.34(m，4H)，3.36(m，6H)，3.64(s，3H)，7.02(m，1H)，7.10(m，1H)，7.25(m，1H)。
LRMS (thermal spray): m/z [ MH+]390。
Example 83
4- [ ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzenesulfonamide
To a stirred suspension of 4-aminomethylbenzenesulfonamide hydrochloride (144mg, 0.590mmol) and preparation 18 bromide (100mg, 0.270mmol) in isopropanol (5ml) was added triethylamine (125. mu.l, 0.860mmol) in one portion at room temperature under a nitrogen atmosphere. The reaction was heated at 70 ℃ for 1 hour and then cooled to room temperature. The mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica eluting with methylene chloride followed by methylene chloride methanol ammonia (90: 9: 1 by volume) to give a foam. Mixing the foam with Phenomenex Luna C 18The column was further purified, eluting with diethylamine: methanol (0.1: 99.1 vol) to give the title compound (8mg) as a white foam.
1H NMR(400MHz，CD3OD)：δ＝2.06(s，3H)，3.27(s，2H)，3.62(s，2H)，3.79(s，2H)，7.17(s，1H)，7.21(s，1H)，7.40(m，3H)，7.77(d，2H)。
LRMS (thermal spray): m/z [ MH+]432。
Example 84
4- (3, 5-Dichlorophenoxy) -5- (methoxymethyl) -3-methyl-1H-pyrazole
To a stirred solution of preparation 8 bromide (590mg, 1.56mmol) in methanol (20ml) and tetrahydrofuran (20ml) was added tetrakis (triphenylphosphine) palladium (60mg) in one portion at room temperature. The mixture was heated at 80 ℃ under carbon monoxide atmosphere (690kPa, 100psi) for 18 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give a brown oil. The oil was dissolved in dichloromethane (100ml) and the resulting solution washed with water (50ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with diethyl ether to give the title compound (110mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝2.15(s，3H)，3.34(s，3H)，4.35(s，2H)，6.83(s，2H)，7.03(s，1H)。
LRMS (thermal spray): m/z [ MH+]287。
Example 85
3-tert-butyl-4- (3, 5-dichlorophenoxy) -5-methyl-1H-pyrazole
A mixture of the diketone of preparation 19 (1.00g, 5.68mmol), 3, 5-dichlorophenol (930mg, 5.68mmol), cesium carbonate (1.85g, 5.68mmol) and acetone (20ml) was heated at reflux for 18 hours. After cooling, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The intermediate was dissolved in ethanol (20ml), hydrazine hydrate (284mg, 5.68mmol) was added and the mixture was heated at 60 ℃ for 1 hour. After cooling, the mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with ethyl acetate: pentane (25: 75 vol.) to give the title compound (200mg) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.30(s，9H)，2.06(s，3H)，6.81(s，2H)，7.02(s，1H)。
LRMS (thermal spray): m/z [ MH+]299。
Example 86
4- (3, 5-Dichlorophenoxy) -3-ethyl-5-methyl-1H-pyrazole
A mixture of the diketone of preparation 50 (4.50g, 30.8mmol), 3, 5-dichlorophenol (5.00g, 30.8mmol), cesium carbonate (10.0g, 30.8mmol) and acetone (40ml) was heated at reflux for 18 hours. After cooling, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The intermediate was dissolved in ethanol (40ml), hydrazine hydrate (1.00ml, 30.8mmol) was added and the mixture was heated at 60 ℃ for 1 hour. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica eluting with ethyl acetate: pentane (20: 80 vol.) to give the title compound (1.50g) as an orange oil.
1H NMR(400MHz，CDCl3)：δ＝1.18(t，3H)，2.11(s，3H)，2.53(q，2H)，6.79(s，2H)，7.01(s，1H)。
LRMS (thermal spray): m/z [ MH+]271。
Example 87
4-cyano-N- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } benzamide
To a stirred solution of the amine from example 109 (120mg, 0.440mmol) and 4-cyanobenzoic acid (71mg, 0.490mmol) in dichloromethane (5ml) was added 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide (93mg, 0.490mmol) in one portion at room temperature under nitrogen. The reaction was stirred for 20 minutes, then washed with 1M aqueous sodium hydroxide (10ml), 1M aqueous hydrochloric acid (10ml) and water (10 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a yellow foam. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (110mg) as a white foam.
1H NMR(400MHz，CDCl3)：δ＝2.09(s，3H)，4.91(d，2H)，6.74(s，2H)，6.95(s，1H)，6.98(d，1H)，7.65(d，2H)，7.77(d，2H)。
LRMS (thermal spray): m/z [ MNH ]4 +]418。
Example 88
3-cyano-N- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } benzamide
To a stirred solution of the amine from example 109 (120mg, 0.440mmol) and 3-cyanobenzoic acid (71mg, 0.490mmol) in dichloromethane (5ml) was added 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide (93mg, 0.490mmol) in one portion at room temperature under nitrogen. The reaction was stirred for 10 minutes, then washed with 1M aqueous sodium hydroxide (10ml), 1M aqueous hydrochloric acid (10ml) and brine (10 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a cream-like foam. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (100mg) as a white foam.
1H NMR(400MHz，CDCl3)：δ＝2.14(s，3H)，4.53(d，2H)，6.78(s，2H)，6.98(m，2H)，7.54(dd，1H)，7.76(d，1H)，7.95(d，1H)，7.99(s，1H)。
LRMS (thermal spray): m/z [ MH+]401。
Example 89
N- { [4- (3, 5-Dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -N- (3-pyridylmethyl) amine
A mixture of 3-pyridinecarboxaldehyde (55mg, 0.514mmol), the amine from example 109 (140mg, 0.514mmol), magnesium sulfate (500mg) and dichloromethane (5ml) was stirred at room temperature under a nitrogen atmosphere for 18 h. Sodium triacetoxyborohydride (163mg, 0.771mmol) was added in one portion followed by acetic acid (3 drops). After 5 minutes, the mixture was filtered. The filtrate was washed with 1M aqueous sodium carbonate (10ml), water (10ml) and brine (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a clear oil. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (60mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝2.09(s，3H)，3.66(s，2H)，3.74(s，2H)，6.75(s，2H)，6.97(s，1H)，7.17(m，1H)，7.55(d，1H)，8.49(m，2H)。
LRMS (electrospray): m/z [ MH+]363。
Example 90
3- ({5- (4-acetyl-1-piperazinyl) methyl ] -3-methyl-1H-pyrazol-4-yl } oxy) -5-chlorobenzonitrile
To a stirred solution of preparation 18 bromide (100mg, 0.271mmol) in isopropanol (5ml) was added N-acetylpiperazine (104mg, 0.810mmol) in one portion at room temperature. The mixture was heated at 50 ℃ for 1 hour, cooled to room temperature and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (90mg) as a colorless oil.
1H NMR (300MHz，CDCl3)：δ＝2.08(s，3H)，2.16(s，3H)，2.43(m，4H)，3.42(m，4H)，3.55(m，2H)，7.08(s，1H)，7.16(s，1H)，7.31(s，1H)。
LRMS (thermal spray): m/z [ MH+]374。
Example 91
3-chloro-5- [ (5- { [ (4-cyanobenzyl) (methyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile
To a stirred solution of preparation 18 bromide (100mg, 0.271mmol) in isopropanol (5ml) was added preparation 20 amine (127mg, 0.870mmol) in one portion at room temperature. The mixture was heated at 50 ℃ for 12 h, cooled to room temperature and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in 1M hydrochloric acid, and the aqueous solution was washed with ethyl acetate (10 ml). Solid sodium carbonate was added until bubbling ceased and the mixture was extracted with ethyl acetate (3X 20 ml). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (45mg) as a colorless oil.
1H NMR(300MHz，CDCl3)：δ＝2.14(s，3H)，2.17(s，3H)，3.45(s，2H)，3.55(s，2H)，7.05(s，1H)，7.14(s，1H)，7.31(m，3H)，7.59(d，2H)。
LRMS (thermal spray): m/z [ MH+]392。
Example 92
3-chloro-5- [ (5- { [ (4-cyanobenzyl) (2-hydroxyethyl) amino ] methyl } -3-methyl-1H-pyrazol 4-yl) oxy ] benzonitrile
To a stirred solution of preparation 18 bromide (100mg, 0.271mmol) in isopropanol (5ml) was added preparation 21 amine (153mg, 0.870mmol) in one portion at room temperature. The mixture was heated at 50 ℃ for 12 h, cooled to room temperature and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in 1M aqueous sodium hydroxide solution and the resulting solution was stirred at room temperature for 1 hour. The aqueous solution was extracted with ethyl acetate (3X 20ml) and the organic phases were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (20mg) as a colorless oil.
1H NMR(300MHz，CDCl3)：δ＝2.14(s，3H)，2.71(m，2H)，3.50(s，1H)，3.58(s，2H)，3.67(m，2H)，3.72(s，2H)，6.99(s，1H)，7.09(s，1H)，7.31(s，1H)，7.41(d，2H)，7.58(d，2H)。
LRMS (thermal spray): m/z [ MH+]422。
Example 93
3-chloro-5- ({ 3-methyl-5- [ (2-methyl-1H-imidazol-1-yl) methyl ] -1H-pyrazol-4-yl } oxy) benzonitrile
A suspension of preparation 18 bromide (100mg, 0.264mmol), 2-methylimidazole (111mg, 1.35mmol) and sodium carbonate (143mg, 1.35mmol) in toluene (5ml) was heated at 100 ℃ for 12 h. The suspension was cooled to room temperature, 1M aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate (3X 20ml) and the organic phases were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a white solid. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4.5: 0.5 vol.) to give the title compound (77mg) as a white solid, m.p.212-214 ℃.
1H NMR(300MHz，CDCl3)：δ＝2.14(s，3H)，2.33(s，3H)，4.92(s，2H)，6.76(s，1H)，6.79(s，1H)，6.86(s，1H)，7.27(s，2H)。
LRMS (thermal spray): m/z [ MH+]328。
Example 94
2- (4- (3, 5-Dichlorophenoxy) -3-methyl-5- { [ (3-pyridylmethyl) amino ] methyl } -1H-pyrazol-1-yl) ethanol
To a stirred solution of the amine of preparation 22 (150mg, 0.290mmol) in dichloromethane (5ml) was added tetrabutylammonium fluoride (0.58ml of a 1.0M solution in tetrahydrofuran, 0.580mmol) in one portion at room temperature. The reaction was stirred for 12 hours and concentrated under reduced pressure to give a colorless oil. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (100mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝2.07(s，3H)，3.65(s，2H)，3.76(s，2H)，3.96(m，2H)，4.24(m，2H)，6.76(s，2H)，7.02(s，1H)，7.26(m，1H)，7.59(d，1H)，8.50(m，2H)。
LRMS (thermal spray): m/z [ MH+]407。
Example 95
5- [ (3-isopropyl-5-methyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile
To a stirred solution of the preparation 24 β -diketone (550mg, 2.04mmol) in glacial acetic acid (5ml) was added hydrazine hydrate (110 μ l, 2.24mmol), and the resulting solution was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (60: 40 vol.) to give the title compound (350mg) as a yellow solid m.p.142-144 ℃.
1H NMR(300MHz，CDCl3)：δ＝1.21(d，6H)，2.09(s，3H)，2.90(sept，1H)，7.40(s，2H)，7.60(s，1H)。
LRMS (thermal spray): m/z [ MH+]267。
Example 96
5- { [1- (2-hydroxyethyl) -3-isopropyl-5-methyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile
To a stirred solution of pyrazole (60mg, 0.140mmol) of preparation example 25 in dichloromethane (5ml) was added tetrabutylammonium fluoride (0.28ml of a 1.0M solution in tetrahydrofuran, 0.280mmol) in one portion at room temperature. The reaction was stirred for 12 hours and concentrated under reduced pressure to give a colorless oil. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (20: 80 vol) to give the title compound (30mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝1.17(d，6H)，2.08(s，3H)，2.76(sept，1H)，3.52(m，2H)，4.10(m，2H)，7.40(s，2H)，7.59(s，1H)。
LRMS (electrospray): m/z [ MH+]311。
Microanalysis: measured value: c, 65.44; h, 5.87; n, 17.91. C17H18N4O2Calculated values: c, 65.79; h, 5.85; n, 18.05 percent.
Example 97
3- (3, 5-Dichlorophenoxy) -2-ethyl-6, 7-dihydropyrazolo [1, 5-a ] pyrazin-4 (5H) -one
To a stirred solution of the pyrazole of preparation 26 (12.3g, 24.6mmol) in tetrahydrofuran (120ml) was added dropwise lithium diisopropylamide (18.0ml of a 1.5M cyclohexane solution, 27.0mmol) at-78 ℃ under a nitrogen atmosphere. The reaction was stirred for 14 h, slowly warmed to room temperature and carefully quenched with saturated aqueous ammonium chloride (20 ml). The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (200 ml). The resulting solution was washed with saturated aqueous ammonium chloride (100ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a white solid. The solid was triturated with a mixture of dichloromethane and pentane (100ml and 100ml) to give the title compound (2.63g) as a white solid, m.p.220-223 ℃.
1H NMR(400MHz，D6-DMSO)：δ＝1.08(t，3H)，2.44(q，2H)，3.60(m，2H)，4.24(t，2H)，7.00(s，2H)，7.26(s，1H)，8.15(s，1H)。
LRMS (thermal spray): m/z [ MNH ]4 +]343。
Microanalysis: measured value: c, 51.52; h, 3.98; n, 12.74.C14H31Cl2N3O2Calculated values: c, 51.55; h, 4.02; n, 12.88 percent.
Example 98
3- (3, 5-Dichlorophenoxy) -2-ethyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a ] pyrazine
To a stirred solution of pyrazole (326mg, 1.00mmol) from example 97 in tetrahydrofuran (10ml) was added borane (2.00ml of a 1.0M solution in tetrahydrofuran, 2.00mmol) at room temperature under a nitrogen atmosphere. The reaction was heated at reflux for 5 hours and further borane (3.00ml of a 1.0M solution in tetrahydrofuran, 3.00mmol) was added. The reaction was heated at reflux for 14 h and further borane (2.00ml of a 1.0M solution in tetrahydrofuran, 2.00mmol) was added. The reaction was heated at reflux for 3 hours and further borane (2.00ml of a 1.0M solution in tetrahydrofuran, 2.00mmol) was added. The mixture was cooled to room temperature, 2M hydrochloric acid (10ml) was added, and the mixture was heated under reflux for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (40ml), washed with 1M aqueous potassium carbonate (30ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol (98: 2 vol), then dichloromethane: methanol (95: 5 vol), then dichloromethane: methanol: ammonia (90: 9: 1 vol) to give the title compound (219mg) as a white solid, m.p.76-77 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.10(t，3H)，2.42(q，2H)，3.24(t，2H)，3.80(s，2H)，4.05(t，2H)，6.76(s，2H)，6.95(s，1H)。
LRMS (thermal spray): m/z [ MH+]312。
Microanalysis: measured value: c, 53.79; h, 4.88; and N, 13.14. C14H15Cl2N3Calculated value of O: c, 53.86; h, 4.84; and N, 13.46 percent.
Example 99
3- (3, 5-Dichlorophenoxy) -2-ethyl-5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a ] pyrazine
To a stirred solution of potassium carbonate (24mg, 0.176mmol) and the amine from example 98 (50mg, 0.160mmol) in N, N-dimethylformamide (2ml) was added methyl iodide (11. mu.l, 0.176mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 3 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20ml), washed with 1M aqueous potassium carbonate (20ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride: methanol (98: 2 vol) to give the title compound (18mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.11(t，3H)，2.42(m，5H)，2.84(t，2H)，3.37(s，2H)，4.11(t，2H)，6.77(s，2H)，6.98(s，1H)。
LRMS (thermal spray): m/z [ MH+]326。
Example 100
4- [ (3- (3, 5-dichlorophenoxy) -2-ethyl-6, 7-dihydropyrazolo [1, 5-a ] pyrazin-5 (4H) -yl) methyl ] benzonitrile
To a stirred solution of potassium carbonate (24mg, 0.176mmol) and the amine from example 98 (50mg, 0.160mmol) in N, N-dimethylformamide (2ml) was added 4-cyanobenzylbromide (35mg, 0.176mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 14 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20ml), and the resulting solution was washed with 1M aqueous potassium carbonate (15ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride: methanol (98: 2 vol) to give the title compound (66mg) as a white solid, m.p.149-150 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.13(t，3H)，2.44(q，2H)，2.92(t，2H)，3.42(s，2H)，3.71(s，2H)，4.13(t，2H)，6.74(s，2H)，6.97(s，1H)，7.42(d，2H)，7.60(d，2H)。
LRMS (thermal spray): m/z [ MH+]427。
Example 101
3- (3, 5-Dichlorophenoxy) -2-ethyl-5- (4-methoxybenzyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a ] pyrazine
To a stirred solution of potassium carbonate (24mg, 0.176mmol) and the amine from example 98 (50mg, 0.160mmol) in N, N-dimethylformamide (6ml) was added 4-methoxybenzyl chloride (24. mu.l, 0.176mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 14 h, then potassium carbonate (12mg, 0.088mmol) and 4-methoxybenzyl chloride (12. mu.l, 0.088mmol) were added. The reaction was stirred for 3 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20ml), and the resulting solution was washed with 1M aqueous potassium carbonate (20ml), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride: methanol (99: 1 vol) to give the title compound (50mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.13(t，3H)，2.45(q，2H)，2.92(t，2H)，3.44(s，2H)，3.60(s，2H)，3.80(s，3H)，4.10(t，2H)，6.77(s，2H)，6.85(d，2H)，7.00(s，1H)，7.23(d，2H)。
LRMS (thermal spray): m/z [ MH+]432。
Example 102
[1- (2-aminoethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-5-yl ] methanol
To a stirred solution of pyrazole (86mg, 0.200mmol) from example 135 in dioxane (0.5ml) was added hydrogen chloride (0.50ml of 4.0M dioxane solution, 2.00mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 24 hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20ml), and the resulting solution was washed with 1M aqueous potassium carbonate (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with dichloromethane: methanol (99: 1 vol.) to give the title compound (40mg) as a white solid, m.p.105-107 ℃.
1H NMR (400MHz，CDCl3)：δ＝1.10(t，3H)，2.42(q，2H)，2.55(s，2H)，3.13(t，2H)，4.13(t，2H)，4.37(s，2H)，6.79(s，2H)，6.98(s，1H)。
LRMS (thermal spray): m/z [ MH+]330。
Microanalysis: measured value: c, 50.61; h, 5.23; n, 12.31. C14H17Cl2N3O2Calculated values: c, 50.92; h, 5.19; n, 12.73%.
Example 103
2- [4- (3, 5-Dichlorophenoxy) -5- (ethoxymethyl) -3-ethyl-1H-pyrazol-1-yl ] ethylamine
To a stirred solution of pyrazole (60mg, 0.130mmol) from example 136 in dioxane (0.5ml) was added hydrogen chloride (0.50ml of 4.0M dioxane solution, 2.00mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 2 days and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20ml), and the resulting solution was washed with 1M aqueous potassium carbonate (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with methylene chloride, methanol, ammonia (99: 9: 1 vol.) to give the title compound (32mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.42(q，2H)，3.15(t，2H)，3.40(q，2H)，4.11(t，2H)，4.29(s，2H)，6.79(s，2H)，6.98(s，1H)。
LRMS (thermal spray): m/z [ MH+]358。
Examples 104 to 106
By a method similar to example 103, using the appropriate starting materials, the compounds of the following general formula example were prepared, as set forth in the following table:
example 107
2- [5- [ (4-acetyl-1-piperazinyl) methyl ] -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylamine
To a stirred solution of the pyrazole of example 139 (150mg, 0.28mmol) in dichloromethane (2ml) was added trifluoroacetic acid (1ml) at room temperature under a nitrogen atmosphere. The reaction was stirred for 3 hours and the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (20ml), and the resulting solution was washed with 1M aqueous potassium carbonate (30ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with dichloromethane: methanol: ammonia (90: 9: 1 vol.) to give the title compound (103mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.11(t，3H)，2.05(s，3H)，2.32(m，4H)，2.42(q，2H)，3.13(m，2H)，3.33(s，2H)，3.34(m，2H)，3.52(m，2H)，4.15(t，2H)，6.73(s，2H)，6.97(s，1H)。
LRMS (thermal spray): m/z [ MH+]440。
Example 108
N- [2- ({ [1- (2-aminoethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-5-yl ] methyl } amino) ethyl ] acetamide
To a stirred solution of pyrazole from example 141 (122mg, 0.24mmol) in dichloromethane (2ml) was added trifluoroacetic acid (1ml) at room temperature under a nitrogen atmosphere. The reaction was stirred for 3 hours and the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50ml), and the resulting solution was washed with 1M aqueous potassium carbonate (30ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with methylene chloride, methanol, ammonia (90: 9: 1 vol.) to give the title compound (64mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝1.15(t，3H)，1.95(s，3H)，2.45(q，2H)，2.69(t，2H)，3.20(t，2H)，3.27(m，2H)，3.65(s，2H)，4.15(t，2H)，6.31(s，1H)，6.81(s，2H)，7.02(s，1H)。
LRMS (thermal spray): m/z [ MH+]414。
Example 109
[4- (3, 5-Dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methylamine hydrobromide
To a saturated solution of ammonia in isopropanol (50ml) was added portionwise preparation 8 bromide (500mg, 1.30mmol) at 0 ℃. The reaction was stirred for 2 hours and slowly warmed to room temperature. The mixture was concentrated under reduced pressure, and the resulting solid was triturated with diethyl ether to give the title compound (340mg) as a white solid.
1H MR(400MHz，CDCl3)：δ＝2.38(s，3H)，4.78(s，2H)，6.88(s，2H)，7.19(s，1H)。
LRMS (thermal spray) )：m/z[MH+]272。
Example 110
N- [4- (3, 5-Dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl-N- (4-fluorobenzyl) amine
To a stirred solution of pyrazole (150mg, 0.400mmol), 4-fluorobenzaldehyde (11mg, 0.080mmol) and acetic acid (3 drops) in dichloromethane (15ml) was added sodium triacetoxyborohydride (36mg, 0.160mmol) in one portion at room temperature under a nitrogen atmosphere. The reaction was stirred for 3 hours and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with dichloromethane: methanol: ammonia (90: 9: 1 vol.) to give the title compound (6mg) as a colourless oil.
1H NMR(300MHz，CDCl3)：δ＝2.17(s，3H)，3.67(s，2H)，3.73(s，2H)，6.81(s，2H)，6.99(s，2H)，7.02(s，1H)，7.22(s，2H)。
LRMS (electrospray): m/z [ M-H+]378。
Example 111
4- [ ({ [4- (3, 5-Dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzonitrile
To a stirred solution of pyrazole (300mg, 0.850mmol), 4-cyanobenzaldehyde (111mg, 0.850mmol) and acetic acid (3 drops) in dichloromethane (25ml) was added sodium triacetoxyborohydride (216mg, 1.09mmol) in one portion at room temperature under a nitrogen atmosphere. The reaction was stirred for 14 h, then washed with 1M aqueous sodium carbonate (2X 10ml) and brine (10ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (10mg) as a colourless oil.
1H NMR(300MHz，CDCl3)：δ＝2.16(s，3H)，3.70(s，2H)，3.85(s，2H)，6.78(s，2H)，7.01(s，2H)，7.35(d，2H)，7.58(d，2H)。
LRMS (electrospray): m/z [ MH+]387。
Example 112
3-chloro-5- [ (1, 3, 5-trimethyl-1H-pyrazol-4-yl) oxy ] benzonitrile
To a stirred solution of the β -diketone of preparation 16 (1.00g, 3.97mmol) in glacial acetic acid (10ml) was added methylhydrazine (250mg, 5.17mmol), and the resulting solution was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure and the resulting orange oil was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (50: 50 vol) to give the title compound (500mg) as a white solid, m.p.114-116 ℃.
1H NMR(300MHz，CDCl3)：δ＝1.85(s，3H)，1.87(s，3H)，3.61(s，3H)，6.88(s，1H)，6.98(s，1H)，7.11(s，1H)。
LRMS (thermal spray): m/z [ MH+]262。
Microanalysis: measured value: c, 59.48; h, 4.60; n, 15.88. C13H12N3Calculated OCl: c, 59.66; h, 4.62; and N, 16.06%.
Example 113
3-chloro-5- [ (5- { [ (4-cyanobenzyl) amino ] methyl } -1, 3-dimethyl-1H-pyrazol-4-yl) oxy ] benzonitrile
To a stirred solution of example 144 bromide (100mg, 0.300mmol) in isopropanol (10ml) was added 4-cyanobenzylamine (155mg, 1.17mmol) in one portion at room temperature. The mixture was heated at 50 ℃ for 1 hour, cooled to room temperature and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (97mg) as a colorless oil.
1H NMR(300MHz，CDCl3)：δ＝2.03(s，3H)，3.66(s，2H)，3.79(s，2H)，3.84(s，3H)，7.02(s，1H)，7.13(s，1H)，7.31(s，1H)，7.37(d，2H)，7.58(d，2H)。
LRMS (thermal spray): m/z [ MH+]392。
Example 114
3-chloro-5- { [1- (2-hydroxyethyl) -3, 5-dimethyl-1H-pyrazol-4-yl ] oxy } benzonitrile
To a stirred solution of the β -diketone of preparation 16 (5.80g, 23.0mmol) in glacial acetic acid (30ml) was added 2-hydroxyethylhydrazine (1.80g, 24.0mmol), and the resulting solution was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure and the resulting brown oil was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (50: 50 vol.) to give the title compound (4.80g) as a yellow solid m.p.114-116 ℃.
1H NMR(300MHz，CDCl3)：δ＝2.04(s，3H)，2.12(s，3H)，3.24(s，1H)，4.08(m，4H)，7.03(s，1H)，7.15(s，1H)，7.28(s，1H)。
LRMS (thermal spray): m/z [ MH+]292。
Microanalysis: measured value: c, 57.40; h, 4.86; n, 14.14. C14H14N3O2Calculated Cl: c, 57.69; h, 4.84; n, 14.40 percent.
Example 115
3-chloro-5- { [5- { [ (4-cyanobenzyl) amino ] methyl } -1- (2-hydroxyethyl) -3-methyl-1H-pyrazol-4-yl ] oxy } benzonitrile
To a stirred solution of pyrazole (120mg, 0.240mmol) of preparation example 30 in N-methylpyrrolidine (10ml) was added 4-cyanobenzylamine (131mg, 0.910mmol), and the resulting solution was heated at 60 ℃ for 3 hours. The mixture was concentrated under reduced pressure, and the resulting brown oil was dissolved in acetic acid (10ml) and heated at 40 ℃ for 6 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography on silica gel eluting with methylene chloride: methanol: ammonia (95: 4: 1 vol.) to give the title compound (5mg) as a white solid.
1H NMR(300MHz，CDCl3)：δ＝2.05(s，3H)，3.04(s，2H)，3.91(s，2H)，3.99(t，2H)，4.32(m，2H)，706(s，1H)，7.11(s，1H)，7.33(s，1H)，7.46(d，2H)，7.62(d，2H)。
LRMS (thermal spray): m/z [ MNa ]+]444。
Example 116
4- [ ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzamide
To a stirred solution of the pyrazole (100mg, 0.270mmol) and triethylamine (81mg, 0.800mmol) of preparation 18 in isopropanol (10ml) and N, N-dimethylformamide (5ml) was added the amine (150mg, 0.800mmol) of preparation 55, and the resulting solution was heated at 60 ℃ for 3 hours. The mixture was concentrated under reduced pressure, and the resulting brown oil was dissolved in ethyl acetate (20 ml). The solution was washed with 1M aqueous sodium carbonate (2X 10ml) and brine (10ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with dichloromethane: methanol: ammonia (90: 9: 1 vol.) to give the title compound (5mg) as a colourless oil.
1H NMR(300MHz，CDCl3)：δ＝2.16(s，3H)，3.68(s，2H)，3.82(s，2H)，7.05(s，1H)，7.13(s，1H)，7.28(s，1H)，7.32(d，2H)，7.76(d，2H)。
LRMS (electrospray): m/z [ MH+]396。
Examples 117 to 120
By a method similar to example 114, using the appropriate diketone starting material and 2-hydroxyethylhydrazine, the following compounds of the general formula example are prepared, as set forth in the following table:
examples 121 to 124
By a method similar to example 76, using the appropriate diketone starting material and hydrazine, the compounds of the following general formula example are prepared, as set forth in the following table:
Examples 125 to 128
By a method similar to example 13, using the appropriate pyrazole starting material and chloroethylamine hydrochloride, the following compounds of the general formula example are prepared, as set forth in the following table:
examples 129 to 131
By a method similar to example 76, using the appropriate diketone starting material and hydrazine, the compounds of the following general formula example are prepared, as set forth in the following table:
example 132
4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1- (1-methyl-3-azetidinyl) -1H-pyrazole
To a stirred solution of pyrazole (120mg, 0.330mmol) from example 51 in formic acid (2ml) was added paraformaldehyde (30mg, 0.330mmol) in one portion at room temperature. The mixture was heated at 100 ℃ for 5 hours, cooled to room temperature and concentrated under reduced pressure to give a colorless oil. The oil was dissolved in ethyl acetate (50ml), the resulting solution was washed with saturated aqueous sodium bicarbonate (20ml), water (20ml) and brine (20ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (85mg) as a colorless oil.
1H NMR(300MHz，CDCl3)：δ＝1.08(t，3H)，1.16(t，3H)，2.49(m，7H)，3.63(m，2H)，3.81(m，2H)，4.79(m，1H)，6.79(s，2H)，7.00(s，1H)。
LRMS (thermal spray): m/z [ MH+]354。
Example 133-
2- [4- (3, 5-Dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylamine (example 133) and 2- [4- (3, 5-Dichlorophenoxy) -5-ethyl-1H-pyrazol-1-yl ] ethylamine (example 134)
A mixture of pyrazole (1.03g, 4.00mmol) from example 42 and chloroethylamine hydrochloride (510mg, 4.40mmol) was stirred and heated at 150 ℃ for 24 hours. After cooling, the mixture was partitioned between 1M aqueous potassium carbonate (30ml) and dichloromethane (30 ml). The organic layer was washed with brine (30ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash chromatography on silica eluting with methylene chloride, methanol, ammonia (93: 6: 1 by volume) to give the title compound (768mg) as a regioisomer in a ratio of 85: 15 as a colourless oil.
1H NMR(400MHz，CDCl3): δ is 1.16 (primary, t, 3H), 1.16 (secondary, t, 3H), 2.48 (primary, q, 2H), 2.60 (secondary, q, 2H), 3.13 (primary, t, 2H), 3.19 (secondary, t, 2H), 4.10 (primary, t, 2H), 4.10 (secondary, t, 2H), 6.85 (primary, s, 2H), 6.85 (secondary, s, 2H), 7.02 (primary, s, 1H), 7.02 (secondary, s, 1H), 7.27 (primary, s, 1H), 7.31 (secondary, s, 1H).
LRMS (thermal spray): m/z [ MH+]300。
Example 135
2- [4- (3, 5-Dichlorophenoxy) -3-ethyl-5- (hydroxymethyl) -1H-pyrazol-1-yl ] ethylcarbamic acid tert-butyl ester
A solution of pyrazole (1.96g, 6.00mmol) from example 97 in concentrated hydrochloric acid (50ml) was heated at reflux for 20 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dioxane (80ml) and water (60ml), di-tert-butyl pyrocarbonate (1.44g, 6.60mmol) and sodium bicarbonate (1.26g, 15.0mmol) were added and the reaction was stirred at room temperature for 3 days. The reaction was concentrated under reduced pressure. The residue in dichloromethane (300ml) was washed with 2M aqueous hydrochloric acid (100ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. A solution of the crude product in tetrahydrofuran (50ml) was cooled to-40 ℃ under nitrogen and triethylamine (0.79ml, 5.68mmol) and isopropyl chloride (5.68ml of a 1.0M solution in toluene, 5.68mmol) were added dropwise. The reaction was stirred at-40 ℃ for 40 minutes and then warmed to 0 ℃. Sodium borohydride (537mg, 14.2mmol) was added in one portion, water (3 drops) was added, and the reaction was stirred at 0 ℃ for 1 hour and at room temperature for 14 hours. The mixture was concentrated under reduced pressure and a solution of the residue in dichloromethane (100ml) was washed with water (100ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with methylene chloride: methanol (97: 3 vol.) to give the title compound (1.37g) as a white foam.
1H NMR(400MHz，CDCl3)：δ＝1.10(t，3H)，1.37(s，9H)，2.40(q，2H)，3.00(s，1H)，3.56(m，2H)，4.20(t，2H)，4.48(d，2H)，5.00(m，1H)，6.80(s，2H)，6.97(s，1H)。
LRMS (thermal spray): m/z [ MH+]430。
Example 136
2- [4- (3, 5-Dichlorophenoxy) -5- (ethoxymethyl) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamic acid tert-butyl ester
To a stirred solution of the alcohol from example 135 (129mg, 0.300mmol) in ethyl iodide (1.75ml) was added silver (I) oxide (210mg, 0.900mmol) in one portion at room temperature under a nitrogen atmosphere. The reaction was heated at 40 ℃ for 1 day and then cooled to room temperature. The mixture was filtered and the residual solid was washed with dichloromethane (10 ml). The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with methylene chloride: methanol (99: 1 vol.) to give the title compound (60mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝1.15(m，6H)，1.44(s，9H)，2.45(q，2H)，3.45(q，2H)，3.58(m，2H)，4.18(m，2H)，4.29(s，2H)，5.26(m，1H)，6.92(s，2H)，7.00(s，1H)。
LRMS (electrospray): m/z [ MNa ]+]480。
Example 137
2- [5- (bromomethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamic acid tert-butyl ester
To a stirred solution of triphenylphosphine (820mg, 3.12mmol) and imidazole (213mg, 3.12mmol) in dichloromethane (15ml) was added dropwise bromine (160. mu.l, 3.12mmol) at room temperature under nitrogen. To the reaction was added a solution of the alcohol from example 135 (1.12g, 2.60mmol) in dichloromethane (5 ml). The reaction was stirred at room temperature for 2 h, diluted with dichloromethane (50ml), washed with brine (20ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with methylene chloride: methanol (98: 2 vol) to give the title compound (969mg) as a white foam.
1H NMR(400MHz，CDCl3)：δ＝1.10(t，3H)，1.40(s，9H)，2.40(q，2H)，3.60(m，2H)，4.18(t，2H)，4.27(s，2H)，4.95(s，1H)，6.82(s，2H)，7.00(s，1H)。
LRMS (electrospray): m/z [ MH+]494。
Microanalysis: measured value: c, 46.22; h, 4.89; n, 8.44. C19H24BrCl2N3O3Calculated values: c, 46.27; h, 4.90; n, 8.52 percent.
Example 138
2- [5- (aminomethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamic acid tert-butyl ester
To a saturated solution (25ml) of ammonia in isopropanol and diisopropylethylamine (173. mu.l, 1.00mmol) at room temperature was added the bromide of example 137 (444mg, 0.900 mmol). The reaction was stirred for 5 hours and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with methylene chloride: methanol (95: 5 vol.) to give the title compound (359mg) as a white solid m.p.112-114 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.11(t，3H)，1.40(s，9H)，2.40(q，2H)，3.55(m，2H)，3.73(s，2H)，4.18(t，2H)，5.60(s，1H)，6.77(s，2H)，6.98(s，1H)。
LRMS (thermal spray): m/z [ MH+]429。
Example 139
2- [5- [ (4-acetyl-1-piperazinyl) methyl ] - (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamic acid tert-butyl ester
To a stirred solution of example 137 bromide (148mg, 0.300mmol) and diisopropylethylamine (57. mu.l, 0.330mmol) in N, N-dimethylformamide (2ml) was added a solution of N-acetylpiperazine (42mg, 0.330mmol) in N, N-dimethylformamide (1ml) at room temperature. The reaction was stirred for 5 hours and the mixture was concentrated under reduced pressure. The residue in dichloromethane (30ml) was washed with 1M aqueous potassium carbonate (10ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with methylene chloride: methanol (98: 2 vol) to give the title compound (150mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.15(t，3H)，1.42(s，9H)，2.06(s，3H)，2.44(m，6H)，3.32(s，2H)，3.47(m，2H)，3.60(m，2H)，3.65(m，2H)，4.23(m，2H)，5.89(s，1H)，6.76(s，2H)，7.02(s，1H)。
LRMS (thermal spray): m/z [ MH+]540。
Example 140
2- [4- (3, 5-Dichlorophenoxy) -3-ethyl-5- (1H-pyrazol-1-ylmethyl) -1H-pyrazol-1-yl ] ethylcarbamic acid tert-butyl ester
To a stirred solution of example 137 bromide (148mg, 0.300mmol) and sodium hydride (60% oil dispersion, 13.2mg, 0.330mmol) in N, N-dimethylformamide (2ml) was added pyrazole (23mg, 0.330mmol) in one portion at room temperature under nitrogen. The reaction was stirred for 5 h, quenched with water (1.00ml) and concentrated under reduced pressure. The residue was dissolved in dichloromethane (30ml), and the resulting solution was washed with 1M aqueous potassium carbonate (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with methylene chloride: methanol (98: 2 vol) to give the title compound (125mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.13(t，3H)，1.44(s，9H)，2.42(q，2H)，3.52(m，2H)，4.26(t，2H)，5.18(s，2H)，5.48(s，1H)，6.16(s，1H)，6.73(s，2H)，7.00(s，1H)，7.18(s，1H)，7.45(s，1H)。
LRMS (thermal spray): m/z [ MH+]480。
Example 141
Tert-butyl 2- [5- ({ [2- (acetylamino) ethyl ] amino } methyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamate
To a stirred solution of example 137 bromide (148mg, 0.300mmol) and diisopropylethylamine (57. mu.l, 0.330mmol) in isopropanol (2ml) was added a solution of N-acetylethylenediamine (153mg, 1.50mmol) in isopropanol (1ml) at room temperature. The reaction was stirred for 5 hours and the mixture was concentrated under reduced pressure. The residue in dichloromethane (50ml) was washed with 1M aqueous potassium carbonate (20ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane: methanol (90: 10 vol), then dichloromethane: methanol: ammonia (90: 9: 1 vol) to give the title compound (122mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.13(t，3H)，1.42(s，9H)，1.94(d，3H)，2.44(q，2H)，2.74(m，2H)，3.35(m，2H)，3.58(m，4H)，4.19(m，2H)，5.68(s，1H)，6.77(s，2H)，7.00(s，1H)，7.65(s，1H)。
LRMS (thermal spray): m/z [ MH+]514。
Example 142
Tert-butyl 2- (4- (3, 5-dichlorophenoxy) -3-ethyl-5- { [ (4-methoxybenzyl) amino ] methyl } -1H-pyrazol-1-yl) ethylcarbamate
A mixture of 4-methoxybenzaldehyde (46. mu.l, 0.380mmol), the amine from example 138 (172mg, 0.400mmol) and magnesium sulphate (200mg) in dichloromethane (4ml) was stirred at room temperature for 4 days. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a yellow oil. The oil was dissolved in methanol (4ml) and sodium borohydride (18mg, 0.480mmol) was added with vigorous stirring. Once the addition was complete, the reaction was stirred for 4 hours, then water (2ml) was added. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (50 ml). The resulting solution was washed with 1M aqueous potassium carbonate (20ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane: methanol (99: 1 vol) and then dichloromethane: methanol (95: 5 vol) to give the title compound (142mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.10(t，3H)，1.40(s，9H)，2.42(m，2H)，3.55(m，5H)，3.66(s，2H)，3.77(s，2H)，4.15(m，2H)，6.11(s，1H)，6.74(s，2H)，6.80(d，2H)，7.00(s，1H)，7.11(d，2H)。
LRMS (thermal spray): m/z [ MH+]549。
Example 143
2- [5- { [ (4-cyanobenzyl) amino ] methyl } -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamic acid tert-butyl ester
A mixture of 4-cyanobenzaldehyde (50mg, 0.380mmol), the amine from example 138 (172mg, 0.400mmol), magnesium sulfate (200mg) and dichloromethane (4ml) was stirred at room temperature for 4 days. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a yellow oil. The oil was dissolved in methanol (4ml) and sodium borohydride (18mg, 0.480mmol) was added with vigorous stirring. Once the addition was complete, the reaction was stirred for 4 hours, then water (2ml) was added. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (50 ml). The resulting solution was washed with 1M aqueous potassium carbonate (20ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane: methanol (99: 1 vol) and then dichloromethane: methanol (95: 5 vol) to give the title compound (120mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.10(t，3H)，1.35(s，9H)，2.40(q，2H)，3.55(m，2H)，3.58(s，2H)，3.76(s，2H)，4.16(m，2H)，5.45(s，1H)，6.73(s，2H)，6.98(s，1H)，7.32(d，2H)，7.55(d，2H)。
LRMS (thermal spray): m/z [ MH+]544。
Example 144
3- { [5- (bromomethyl) -1, 3-dimethyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile
To a stirred solution of pyrazole (500mg, 1.90mmol) from example 112 in carbon tetrachloride (10ml) and azobisisobutyronitrile (20mg) was added N-bromosuccinimide (340mg, 1.90mmol) at room temperature under a nitrogen atmosphere. The reaction was heated at reflux for 1 hour, cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (80: 20 vol) to give the title compound (340mg) as a white solid, m.p.76-78 ℃.
1H NMR(300MHz，CDCl3)：δ＝2.03(s，3H)，3.45(s，3H)，4.32(s，2H)，7.12(s，1H)，7.19(s，1H)，7.34(s，1H)。
LRMS (thermal spray): m/z [ MH+]342。
Example 145
3- [ (3, 5-diethyl-1-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile
To a solution of example 60 pyrazole (100mg, 0.41mmol) and methyl iodide (34. mu.l, 0.53mmol) in dimethylformamide (1.5ml) was added sodium hydride (60% oil dispersion, 22mg, 0.53mmol) at 0 ℃ under nitrogen. The reaction was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched with water and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate (20ml) and water (10ml), the organic phase washed with water (2X 10ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with a solvent gradient of 100% pentane to 100% ethyl acetate and finally ethyl acetate: methanol (10: 1 vol) to give the title compound (65mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.09(t，3H)，1.12(t，3H)，2.41(q，2H)，2.50(q，2H)，3.77(s，3H)，7.12-7.38(m，4H)。
LRMS (electrospray): m/z [ MH+]256，[MNa+]278。
Microanalysis: measured value: c, 70.15; h, 6.78; n, 16.42. C15H15N3O.0.08H2Calculated value of O: c, 70.17; h, 6.74; n, 16.37 percent.
Example 146
3- { [3, 5-diethyl-1- (2-methoxyethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile
To a solution of pyrazole (100mg, 0.41mmol) from example 60 and 1-bromo-2-methoxyethane (51. mu.l, 0.54mmol) in dimethylformamide (1.5ml) was added sodium hydride (60% oil dispersion, 22mg, 0.53mmol) at 0 ℃ under nitrogen. The reaction was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched with water and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate (20ml) and water (10ml), the organic phase washed with water (2X 10ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with a solvent gradient of 100% pentane to 100% ethyl acetate and finally ethyl acetate: methanol (90: 10 vol) to give the title compound (66mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.09(t，3H)，1.12(t，3H)，2.42(q，2H)，2.54(q，2H)，3.34(s，3H)，3.75(t，2H)，4.16(t，2H)，7.11-7.38(m，4H)。
LRMS (electrospray): m/z [ MH+]300，[MNa+]322。
Microanalysis: measured value: c, 68.21; h, 7.07; n, 14.04. C17H21N3O2Calculated values: c, 67.85; h, 7.12; n, 14.09%.
Example 147
3- ({5- [2- (benzyloxy) ethyl ] -3-ethyl-1H-pyrazol-4-yl } oxy) -5-fluorobenzonitrile
To a solution of preparation 60 enol (2.47g, 6.69mmol) in acetic acid (5ml) was added hydrazine hydrate (390. mu.l, 8.00mmol) at room temperature under nitrogen. After stirring for 18 h, the mixture was concentrated under reduced pressure and purified by flash chromatography on silica eluting with pentane: ethyl acetate (70: 30 to 50: 50 vol.) to give the title compound (5.8g) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.13(t，3H)，2.41(q，2H)，2.67(t，2H)，3.62(t，2H)，4.48(s，2H)，6.79(m，1H)，6.98(m，2H)，7.24(m，5H)。
LRMS (electrospray): m/z [ M-H+]364。
Microanalysis: measured value: c, 66.96; h, 5.62; n, 11.25. C21H20N3O2F.0.60H2Calculated value of O: c, 67.04; h, 5.68; n, 11.17 percent.
Example 148
3- { [ 3-Ethyl-5- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5-fluorobenzonitrile
To a solution of pyrazole (2.10g, 5.75mmol) from example 147 in dichloromethane (90ml) was added iron (III) chloride (9.30g, 57.5mmol) at room temperature under a nitrogen atmosphere. After stirring for 20 minutes, the mixture was diluted with dichloromethane (50ml), washed with water (100ml) and then with saturated aqueous sodium ethylenediaminetetraacetate solution (70ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with methylene chloride: methanol (98: 2 to 95: 5 vol.) to give the title compound (1.2g) as a brown oil which solidified on standing.
1H NMR(400MHz，CDCl3)：δ＝1.16(t，3H)，2.44(q，2H)，2.63(t，2H)，3.82(t，2H)，6.82(m，1H)，6.98(m，2H)。
LRMS (electrospray): m/z [ MH+]276。
Microanalysis: measured value: c, 60.69; h, 5.12; and N, 15.08. C14H14N3O2Calculating the value of F: c, 61.08; h, 5.13; and N, 15.26%.
Example 149
3- ({5- [2- (4-cyanophenoxy) ethyl ] -3-ethyl-1H-pyrazol-4-yl } oxy) -5-fluorobenzonitrile
To a solution of the alcohol from example 148 (74mg, 0.27mmol) in tetrahydrofuran (2ml) was added 4-hydroxy-benzonitrile (49mg, 0.41mmol), triphenylphosphine (106mg, 0.41mmol) and diethyl azodicarboxylate (65. mu.l, 0.41mmol) successively at 0 ℃ under nitrogen. The reaction was allowed to warm to room temperature and stirred for 18 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with toluene: ethyl acetate (75: 25 vol) to give the title compound (50mg) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.18(t，3H)，2.49(q，2H)，2.98(t，2H)，4.21(t，2H)，6.82(m，3H)，6.99(m，2H)，7.56(m，2H)。
LRMS (electrospray): m/z [ MH+]377。
Example 150-
By a method similar to example 149, using the appropriate aryl alcohol as the starting material, the compounds of the following general formula example were prepared, as set forth in the following table:
P123
1these compounds were purified by chromatography on silica gel using cyclohexane/ethyl acetate (75: 25; again)66: 34 to 50: 50 by volume) to ethyl acetate and finally a solvent gradient of ethyl acetate to methanol (90: 10 by volume).
Example 153
5- ({5- [2- (benzyloxy) ethyl ] -3-ethyl-1H-pyrazol-4-yl } oxy) isophthalonitrile
To a solution of the crude enol from preparation 61 (917mg, 2.40mmol) in acetic acid (10ml) at room temperature under nitrogen atmosphere was added hydrazine hydrate (177. mu.l, 3.66 mmol). After stirring for 18 h, the mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with pentane: cyclohexane (75: 25 vol.%) to toluene: ethyl acetate (50: 50 vol.%) to give the product which was further purified by preparative HPLC using a Develosil combi-rp C3050X 4.6mm 3 μm column with 5: 95 aqueous solution containing 0.1% trifluoroacetic acid: acetonitrile was eluted with a solvent gradient to give the title compound (5mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.18(t，3H)，2.44(q，2H)，2.77(t，2H)，3.63(t，2H)，4.52(s，2H)，7.30(m，7H)，7.55(s，1H)。
LRMS (electrospray): m/z [ MH+]231，[MNa+]253。
Example 154
5- { [ 3-Ethyl-5- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile
To a solution of pyrazole (50mg, 0.13mmol) from example 153 in dichloromethane (5ml) was added iron (III) chloride (217mg, 1.30mmol) at room temperature under a nitrogen atmosphere. After stirring for 30 minutes, the mixture was diluted with dichloromethane (20ml), washed with water (100ml) and then with saturated aqueous sodium ethylenediaminetetraacetate solution (20ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with methylene chloride: methanol (98: 2 to 95: 5 vol.) to give the title compound (20mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝1.19(t，3H)，2.51(q，2H)，2.69(t，2H)，3.88(t，2H)，7.40(s，2H)，7.59(s，1H)。
LRMS (electrospray): m/z [ MH+]283。
Example 155
3- { [5- (aminomethyl) -1- (2-hydroxyethyl) -3-methyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile
The protected alcohol of preparation 31 (100mg, 0.23mmol) and tert-butylammonium fluoride (360. mu.l of a 1M solution in tetrahydrofuran, 0.36mmol) were stirred in dichloromethane (5ml) at room temperature under nitrogen for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol (2ml) inPurification on a column of SCX polymer supported sulfonic acid, washing with methanol (2 × 3ml) removed impurities and washing with 2N ammonia removed product. This procedure was repeated twice to give the title compound (40mg) as a colourless oil.
1H NMR(400MHz，CD3OD)：δ＝1.99(s，3H)，3.85(t，2H)，4.02(s，2H)，4.32(t，2H)，7.22(s，1H)，7.28(s，1H)，7.47(s，1H)。
LRMS (thermal spray): m is/z[MH+]309。
Microanalysis: measured value: c, 53.32; h, 5.17; n, 16.38. C14H15ClN4O2.0.85CH3Calculated OH: c, 53.40; h, 5.55; n, 16.77%.
Example 156
5- [ (1-allyl-3-tert-butyl-5-methyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile
To a solution of pyrazole (800mg, 2.80mmol) and allyl bromide (345mg, 2.80mmol) in dimethylformamide (30ml) as described in example 130 was added sodium hydride (60% oil dispersion, 120mg, 3.15mmol) at room temperature under nitrogen and the reaction was stirred for 3 h. The reaction was diluted with ethyl acetate (50ml), washed with water (2X 50ml) and then brine (50ml) and the organic phase concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with a solvent gradient of pentane to ethyl acetate to pentane (20: 80 vol.) to give the title compound (600mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.21(s，9H)，1.96(s，3H)，4.66(s，2H)，5.04(d，1H)，5.24(d，1H)，5.98(m，1H)，7.37(s，2H)，7.57(s，1H)。
LRMS (thermal spray): m/z [ MH+]322。
Microanalysis: measured value: c, 70.79; h, 6.29; n, 17.11. C19H20N4O.0.05CH2Cl2Calculated values: c, 70.48; h, 6.24; and N, 17.26%.
Example 157
5- { [ 3-tert-butyl-1- (2-hydroxyethyl) -5-methyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile
Sodium periodate (1.00g, 4.60mmol), osmium tetroxide (1.5% in tert-butanol, 190mg, 0.02mmol) and example 156 pyrazole (600mg, 1.86mmol) were dissolved in acetone (9ml) and water (3ml) at room temperature under a nitrogen atmosphere and the reaction was stirred for 5 h. The acetone was removed under reduced pressure and the residue was extracted with ethyl acetate (30 ml). The organic phase was washed with water (2X 30ml) and then brine (30ml), dried over magnesium sulphate and concentrated under reduced pressure. The crude aldehyde was then dissolved in methanol (15ml) and sodium borohydride (84mg, 2.22mmol) was added portionwise at room temperature under nitrogen. The reaction was stirred for 3 hours, then the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (10ml) and water (10ml), the organic phase washed with water (2X 10ml) then brine (10ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with a solvent gradient of pentane to ethyl acetate to pentane (50: 50 vol.) to give the title compound (250mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.17(s，9H)，1.98(s，3H)，3.67(s，1H)，4.04(m，4H)，7.35(s，2H)，7.54(s，1H)。
LRMS (thermal spray): m/z [ MH+]325。
Microanalysis: measured value: c, 64.30; h, 6.10; n, 16.35. C18H20N4O2.0.20CH2Cl2Calculated values: c, 64.04; h, 6.02; n, 16.41 percent.
Example 158
5- { [1- (2-aminoethyl) -3-tert-butyl-5-methyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile
Diphenylphosphorylazide (305mg, 1.10mmol) was dissolved in tetrahydrofuran (5ml) at room temperature under a nitrogen atmosphere, and added to a solution of pyrazole (180mg, 0.55mmol), triphenylphosphine (291mg, 1.10mmol) and diethyl azodicarboxylate (193mg, 1.10mmol) in tetrahydrofuran (20 ml). The reaction was stirred for 18 h, then triphenylphosphine (291mg, 1.10mmol) was added and the reaction stirred for another 18 h. Water (180. mu.l, 10.0mmol) was then added and the reaction stirred for 64 hours. The solvent was removed under reduced pressure and the remaining white paste was purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (95: 4.5: 0.5 vol) to give the title compound (55mg) as a colourless oil.
1H NMR(300MHz，CDCl3)：δ＝1.22(s，9H)，1.78(s，2H)，2.03(s，3H)，3.18(t，2H)，4.05(m，2H)，7.38(s，2H)，7.58(s，1H)。
LRMS (thermal spray): m/z [ MH+]324。
Microanalysis: measured value: c, 64.46; h, 6.48; and N, 20.47. C18H21N5O.0.20CH2Cl2Calculated values: c, 64.22; h, 6.34; n, 20.57%.
Example 159
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5- (1H-1, 2, 4-triazol-1-yl) benzonitrile
To a solution of 1H- [1, 2, 4] triazole (38mg, 0.55mmol) in dimethyl sulfoxide (1ml) was added cesium carbonate (179mg, 0.55mmol) at room temperature under a nitrogen atmosphere and the reaction was stirred for 10 min. A solution of preparation 62 aryl fluoride (210mg, 0.5mmol) in dimethyl sulfoxide (1ml) was then added and the reaction heated to 100 ℃ for 18 h. After cooling to room temperature, the reaction was diluted with water (15ml) and extracted with ethyl acetate (25 ml). The organic phase was washed with brine (15ml), dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with a solvent gradient dichloromethane: methanol (98: 2 to 90: 10 vol.) to give the title compound (67.5mg) as a white solid, m.p.122-124 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.39(q，2H)，2.51(q，2H)，3.61(brs，1H)，4.04(m，2H)，4.07(m，2H)，7.10(s，1H)，7.52(s，1H)，7.60(s，1H)，8.07(s，1H)，8.54(s，1H)。
LRMS (thermal spray): m/z [ MH+]353。
Microanalysis: measured value: c, 60.69, H, 5.83; n, 22.98. C18H20N6O2.0.08CH2Cl2Calculated values: c, 60.46; h, 5.66; and N, 23.40%.
Example 160-162
By a method similar to example 159, using the appropriate heterocycle as starting material, the compounds of the following general formula example are prepared, as set forth in the following table:
1both compounds were isolated from a single reaction mixture starting with 1, 2, 3-triazole, with example 161 being the most polar.
Example 163
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5-fluorobenzamide
The protected alcohol of preparation 64 (432mg, 1.07mmol) and p-toluenesulfonic acid (30.3mg, 0.11mmol) were dissolved in methanol (4ml) and stirred at room temperature under nitrogen for 18 h. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate (20ml) and dichloromethane (20 ml). The aqueous phase was extracted with dichloromethane (10ml), the organic extracts combined, dried over magnesium sulfate, concentrated under reduced pressure and the residue purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane: methanol (100: 0 to 93: 7 vol) to give the title compound (241mg) as a white foam.
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.39(q，2H)，2.49(q，2H)，3.68(brs，1H)，4.04(m，4H)，5.59(brs，1H)，5.88(brs，1H)，6.71(d，1H)，7.11(m，2H)。
LRMS (thermal spray): m/z [ MH+]322。
Microanalysis: measured value: c, 57.91; h, 6.32; n, 12.56. C16H20FN3O3.0.13CH2Cl2.0.12H2Calculated value of O: c, 57.91, H, 6.18, N, 12.56%.
Example 164-
By a method similar to example 163, using the appropriate protected alcohol as the starting material, the compounds of the following general formula example were prepared, as set forth in the following table:
1the eluent used for the flash column chromatographic purification of these compounds was dichloromethane: methanol (99: 1 to 80: 20 volume ratio).
2The eluent used for the flash column chromatographic purification of this compound was dichloromethane: methanol (99: 1 to 98: 2 volume ratio).
Example 168
5- { [ 3-cyclopropyl-5-ethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile
And
example 169
5- { [ 5-cyclopropyl-3-ethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile
To a solution of pyrazole (152mg, 0.55mmol) from example 129 in dimethylformamide (4ml) were added potassium carbonate (91mg, 0.66mmol) followed by 2- (2-bromoethoxy) -tetrahydropyran (91. mu.l, 0.61mmol) and the reaction was heated to 35 ℃ under nitrogen for 5 h. The starting material remained, so the temperature was raised to 80 ℃ and the reaction was stirred for a further 18 hours. The reaction was cooled to room temperature, sodium hydride (60% oil dispersion, 24mg, 0.60mmol) was added, and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with water (50ml) and extracted with ethyl acetate (2X 50 ml). The combined organic extracts were washed with brine (30ml), dried over magnesium sulphate, concentrated under reduced pressure and the residue purified by flash chromatography on silica eluting with pentane: cyclohexane (75: 25 vol) to give a mixture of regioisomers (239 mg). The regioisomer (239mg, 0.55mmol) and p-toluenesulfonic acid (10mg, 0.05mmol) were dissolved in methanol (5ml) and stirred at room temperature under nitrogen for 18 h. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate (20ml) and dichloromethane (30 ml). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and the residual oil was purified by flash chromatography on silica gel eluting with toluene/ethyl acetate (50: 50 vol.) to give the two products as colorless oils.
Lowest polarity fraction (example 168) -34mg
1H NMR (400MHz，CDCl3)：δ＝0.76(m，4H)，1.05(t，3H)，1.45(m，1H)，2.48(q，2H)，3.39(brs，1H)，4.02(m，4H)，7.39(s，2H)，7.56(s，1H)。
LRMS (electrospray): m/z [ M-H+]321。
Highest polarity fraction (example 169) -9mg
1H NMR (400MHz，CDCl3)：δ＝0.62(m，2H)，0.78(m，2H)，1.18(t，3H)，1.46(m，1H)，2.38(q，2H)，3.42(brs，1H)，4.02(m，2H)，4.21(t，2H)，7.38(s，2H)，7.57(s，1H)。
LRMS (electrospray): m/z [ MH+]323，[MH-]321。
Example 170
5- { [ 5-Ethyl-1- (2-hydroxyethyl) -3-isopropyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile
To a solution of pyrazole (153mg, 0.55mmol) from example 131 in dimethylformamide (4ml) was added 2- (2-bromoethoxy) -tetrahydropyran (91 μ l, 0.60mmol) at room temperature under nitrogen, followed by sodium hydride (60% oil dispersion, 24mg, 0.60mmol) and the reaction was stirred at room temperature for 3 h. The mixture was diluted with water (50ml) and extracted with ethyl acetate (2X 50 ml). The combined organic extracts were washed with brine (30ml), dried over magnesium sulphate, concentrated under reduced pressure and the residue purified by flash chromatography on silica eluting with toluene: ethyl acetate (85: 15 vol) to give the isolated isomer as a colourless oil (83mg of isomer 1,55mg of isomer 2).
The least polar isomer (isomer 1) (83mg, 0.20mmol) and p-toluenesulfonic acid (4mg, 0.02mmol) were dissolved in methanol (5ml) and stirred at room temperature under nitrogen for 18 h. The solvent was removed under reduced pressure and the residue partitioned between water (30ml) and dichloromethane (30 ml). The aqueous phase was extracted with dichloromethane (20ml), the combined organic extracts were dried over magnesium sulfate, concentrated under reduced pressure and the residual oil was purified by flash chromatography on silica gel eluting with toluene/ethyl acetate (66: 34 vol) to give the title compound (39mg) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.05(t，3H)，1.14(d，6H)，2.44(q，2H)，2.68(sept，1H)，3.77(brs，1H)，4.06(m，4H)，7.38(s，2H)，7.58(s，1H)。
LRMS (electrospray): m/z [ MH+]325。
Example 171
5- { [ 3-Ethyl-1- (2-hydroxyethyl) -5-isopropyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile
The most polar isomer from example 170 (isomer 2) (55mg, 0.13mmol) and p-toluenesulfonic acid (3mg, 0.01mmol) were dissolved in methanol (5ml) and stirred at room temperature under nitrogen for 18 h. The solvent was removed under reduced pressure and the residue partitioned between water (30ml) and dichloromethane (30 ml). The aqueous phase was extracted with dichloromethane (20ml), the combined organic extracts were dried over magnesium sulphate, concentrated under reduced pressure and the residual oil was purified by flash chromatography on silica gel eluting with toluene/ethyl acetate (66: 33 vol) to give the title compound (39mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝1.08(t，3H)，1.13(d，6H)，2.49(q，2H)，2.97(sept，1H)，3.59(t，1H)，4.06(m，4H)，7.37(s，2H)，7.57(s，1H)。
LRMS (electrospray): m/z [ MH+]325。
Example 172
Carbamic acid 2- [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl ester
To a solution of the alcohol from example 119 (100mg, 0.32mmol) in dichloromethane (3.2ml) was added trichloroacetyl-isocyanate (46. mu.l, 0.38mmol) at 0 ℃ under nitrogen. After stirring for 2 h, the dichloromethane was removed under reduced pressure, methanol (1.6ml), water (1.6ml) and potassium carbonate (134mg, 0.96mmol) were added and the reaction stirred for a further 2 h. Methanol was removed under reduced pressure and the residue was extracted with dichloromethane (3X 10 ml). The combined organic extracts were dried over magnesium sulfate, concentrated under reduced pressure and the residual solid was purified by flash chromatography on silica gel eluting with methylene chloride: methanol (98: 2 vol.) to give the title compound (60mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.39(q，2H)，2.48(q，2H)，4.26(m，2H)，4.44(m，2H)，4.62(brs，2H)，7.41(s，2H)，7.58(s，1H)。
LRMS (thermal spray): m/z [ MH+]354。
Microanalysis: measured value: c, 60.00; h, 5.55; n, 19.82. C18H19N5O30.23EtOAc calculated: c, 60.30; h, 5.67; n, 18.58 percent.
Example 173
N- {2- [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } sulfamide
To a solution of example 127 amine (100mg, 0.32mmol) in dioxane (0.5ml) was added sulfamide (31mg, 0.32mmol) at room temperature under a nitrogen atmosphere. The reaction was heated to 100 ℃ for 18 h, cooled to room temperature and partitioned between ethyl acetate (15ml) and water (15 ml). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and the residual brown oil was purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (95: 5: 0.5 vol.) to give the title compound (25mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝1.12(m，6H)，2.39(q，2H)，2.51(q，2H)，3.61(m，2H)，4.20(m，2H)，4.78(s，2H)，5.42(s，1H)，7.40(s，2H)，7.59(s，1H)。
Microanalysis: measured value: c, 50.33; h, 5.07; n, 20.60. C17H20N6O3S.0.95H2Calculated value of O: c, 50.35; h, 5.44; and N, 20.72 percent.
Example 174
N- {2- [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -2-methoxyacetamide
To a solution of 1-methoxyacetic acid (27. mu.l, 0.35mmol) in dichloromethane (10ml) was added the amine of example 127 (100mg, 0.32mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (68mg, 0.35mmol) and N, N-dimethylaminopyridine (43mg, 0.35mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 18 h, concentrated under reduced pressure and the residual yellow oil was purified by flash chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 vol) to give the title compound (32mg) as a colourless oil.
1HNMR(400MHz，CDCl3)：δ＝1.11(t，3H)，1.16(t，3H)，2.38(q，2H)，2.47(q，2H)，3.41(s，3H)，3.77(dd，2H)，3.89(s，2H)，4.15(m，2H)，7.19(brs，1H)，7.40(s，2H)，7.59(s，1H)。
LRMS (thermal spray): m/z [ MH+]382。
Microanalysis: measured value: c, 61.26; h, 6.18; n, 17.59. C20H23N5O3.0.60H2Calculated value of O: c, 61.24; h, 6.22; and N, 17.85%.
Example 175
5- { [1- (3-azetidinyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile
The amine of preparation 69 (178mg, 0.42mmol) was dissolved in 4M hydrochloric acid in dioxane (1ml) and the reaction was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue partitioned between dichloromethane (20ml) and saturated aqueous sodium bicarbonate (20 ml). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane: methanol: 0.88 ammonia (100: 0, 98: 2: 0, 95: 5: 0.5, 90: 10: 1, 80: 20: 1 by volume) to give the title compound (33mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝1.05(t，3H)，1.11(t，3H)，2.44(m，4H)，3.85(m，2H)，4.38(m，2H)，5.05(m，1H)，7.37(s，2H)，7.56(s，1H)。
LRMS (electrospray): m/z [ MH+]322。
Microanalysis: measured value: c, 65.87; h, 5.94; n, 20.98. C18H19NO.0.38H2Calculated value of O: c, 65.87; h, 6.07; n, 21.04 percent.
Example 176
5- { [3, 5-diethyl-1- (3-hydroxypropyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile
The protected alcohol of preparation 70 (215mg, 0.53mmol) and p-toluenesulfonic acid (10mg, 0.05mmol) were dissolved in methanol (2ml) at room temperature under nitrogen and stirred for 18 h. The solvent was removed under reduced pressure and the residue partitioned between water (10ml) and dichloromethane (10 ml). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (148mg) as a pale yellow solid, m.p.93-95 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.11(m，6H)，2.04(tt，2H)，2.37(q，2H)，2.53(q，2H)，3.06(t，1H)，3.69(dt，2H)，4.18(t，2H)，7.38(s，2H)，7.58(s，1H)。
LRMS (electrospray): m/z [ MH+]325，[MNa+]347。
Microanalysis: measured value: c, 66.27; h, 6.27; n, 17.00. C18H20N4O2Calculated values: c, 66.28; h, 6.24; n, 17.18 percent.
Example 177
5- [ (3, 5-diethyl-1-methyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile
To a solution of pyrazole (200mg, 0.75mmol) from example 122 in dimethylformamide (3ml) was added sodium hydride (60% oil dispersion, 33mg, 0.82mmol) at 0 ℃ under nitrogen and the reaction was stirred for 10 min. Methyl iodide (117mg, 0.82mmol) was added and the reaction stirred at room temperature for 18 h. The reaction was quenched with water (0.2ml) and concentrated under reduced pressure. The residue was partitioned between dichloromethane (5ml) and water (5ml), the organic phase separated using a 5 μ M Whatman PTFE frit glass cartridge and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of ethyl acetate to pentane (20: 80 vol.) to ethyl acetate to methanol (90: 10 vol.) and then dichloromethane to methanol to 0.88 ammonia (90: 10: 1 to 80: 20: 1 vol.) to give the title compound (170mg) as a yellow solid.
1H NMR (400MHz，CDCl3)：δ＝1.10(m，6H)，2.39(q，2H)，2.49(q，2H)，3.80(s，3H)，7.40(s，2H)，7.56(s，1H)。
LRMS (electrospray): m/z [ MH+]281。
Microanalysis: measured value: c, 68.41; h, 5.71; n, 19.93. C 16H16N4Calculated value of O: c, 68.55; h, 5.75; and N, 19.99 percent.
Example 178-
By a method similar to example 177, using the appropriate alkyl halide as the starting material, the compounds of the following general formula example are prepared, as set forth in the following table:
1the two reagents were heated together to a melt at 160 ℃ for 24 hours, the reaction was partitioned between dichloromethane and saturated sodium bicarbonate solution, the organic phase was extracted with 2M aqueous hydrochloric acid and the aqueous phase was basified with sodium carbonate. After extraction with dichloromethane, the organic phase is dried and concentrated to give the crude product.
2The eluent used for the flash column chromatography purification of this compound was dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 to 80: 20: 1 by volume).
3The eluent used for the flash column chromatographic purification of this compound was pentane: ethyl acetate (75: 25 to 66: 34 to 50: 50 by volume).
4The starting alkyl halide hydrochloride is used.
Example 181
2- [4- (3, 5-dicyano-phenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetamide
The ester from example 180 (200mg, 0.59mmol) was dissolved in 2M ammonia in methanol (5ml) and the reaction stirred at 75 ℃ under nitrogen for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 vol) to give the title compound (6 mg).
1H NMR(400MHz，CDCl3)：δ＝1.10(t，3H)，1.15(t，3H)，2.44(q，2H)，2.54(q，2H)，4.69(s，2H)，5.55(brs，1H)，6.22(brs，1H)，7.38(s，2H)，7.59(s，1H)。
LRMS (electrospray): m/z [ M-H+]322。
Microanalysis: measured value: c, 68.41; h, 5.71; n, 19.93. C16H16N4Calculated value of O: c, 68.55; h, 5.75; and N, 19.99 percent.
Example 182
5- { [3, 5-diethyl-1- (hydroxymethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile
To a solution of pyrazole (440mg, 1.65mmol) from example 122 in ethanol (5ml) was added formaldehyde (37% in water, 253. mu.l, 3.14mmol) and the reaction was stirred at 80 ℃ for 18 h. After cooling to room temperature, the solvent was removed under reduced pressure and the remaining yellow solid was partitioned between ethyl acetate (15ml) and water (10ml) and the organic phase was removed. The aqueous phase was washed with ethyl acetate (2X 15ml) and the organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (490mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝1.13(t，3H)，1.14(t，3H)，2.39(q，2H)，2.61(q，2H)，5.49(s，2H)，5.68(brs，1H)，7.40(s，2H)，7.56(s，1H)。
LRMS (thermal spray): m/z [ MH ] 267.
Microanalysis: measured value: c, 64.28; h, 5.52; n, 18.47. C16H16N4O2.0.15H2Calculated value of O: c, 64.27; h, 5.49; n, 18.24 percent.
Example 183
3- [ ({ [4- (3-cyano-5-fluorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzamide
Preparation 75 pyrazole (320mg, 0.91mmol) and preparation 80 amine (680mg, 4.61mmol) were refluxed in isopropanol (5ml) for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (95: 5: 0.5 vol.) to give the product which was further purified by preparative HPLC using a Develosil combi-rp C3050X 4.6mm 3 μm column with 5: 95 acetonitrile containing 0.1% aqueous trifluoroacetic acid: acetonitrile (0-6min 95: 5 to 50: 50; 6-7min 50: 50; 7-7.1min 50: 50 to 5: 95; 7.1-8min 5: 95) to give the title compound (38 mg).
1H NMR(400MHz，CD3OD)：δ＝2.14(s，3H)，4.10(s，2H)，4.34(s，2H)，7.03(m，1H)，7.10(s，1H)，7.25(m，1H)，7.54(t，1H)，7.64(d，1H)，7.92(d，1H)，7.97(s，1H)。
LRMS (electrospray): m/z [ MH+]380。
Microanalysis: measured value: c, 51.32; h, 3.91; n, 13.69. C20H18N5O2F.1.00CF3CO2H1.10H2Calculated value of O: c, 51.49; h, 4.16; and N, 13.65%.
Example 184-
By a method similar to example 177, using the appropriate pyrazole (P) and amine (a) as starting materials, the following compounds of the general formula examples are prepared, as listed in the following table:
1purification of this compound does not require preparative HPLC.
2The eluent used for the flash column chromatography purification of this compound was dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 to 90: 10: 1 by volume).
3The product was triturated with dichloromethane containing traces of methanol and a solid crystallized out, which was an impurity. The residue is filtered off, the filtrate is concentrated under reduced pressure and the residue is purified by flash chromatography eluting with dichloromethane: methanol: 0.88 ammonia (90: 10: 1 vol.) to give the title compound.
4The column used for preparative HPLC was LUNA C1810 μm 150X 21.2 mm.
Example 189
5- [ (3, 5-Bicyclopropyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile
To a solution of the diketone of preparation 82 (735mg, 2.50mmol) in acetic acid (25ml) was added hydrazine hydrate (133. mu.l, 2.75mmol) at room temperature under nitrogen. After stirring for 64 h, the mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (25ml) and saturated aqueous sodium bicarbonate solution (25 ml). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with methylene chloride: methanol (98: 2 to 96: 4 vol.) to give the title compound (473mg) as a white solid m.p.168-170 ℃.
1H NMR(400MHz，CDCl3)：δ＝0.77(m，4H)，0.85(m，4H)，1.59(m，2H)，7.44(s，2H)，7.59(s，1H)。
LRMS (thermal spray): m/z [ MH+]291。
Microanalysis: measured value: c, 69.90; h, 4.85; n, 19.18. C17H14N4O.0.10H2Calculated value of O: c, 69.90; h, 4.90; n, 19.18 percent.
Example 190
5- { [3, 5-Bicyclopropyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile
To a solution of the diketone of preparation 82 (294mg, 1.00mmol) in acetic acid (10ml) was added 2-hydroxyethylhydrazine (84mg, 1.10mmol) at room temperature under nitrogen. After stirring for 64 h, the mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (25ml) and saturated aqueous sodium bicarbonate solution (25 ml). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with methylene chloride: methanol (99: 1 to 95: 5 vol.) to give the title compound (137mg) as a white solid, m.p.115-117 ℃.
1H NMR(400MHz，CDCl3)：δ＝0.67(m，2H)，0.80(m，4H)，0.85(m，2H)，1.52(m，2H)，3.39(brs，1H)，4.05(m，2H)，4.22(t，2H)，7.42(s，2H)，7.58(s，1H)。
LRMS (thermal spray): m/z [ MH ] 355.
Microanalysis: measured value: c, 67.63; h, 5.55; n, 16.35. C19H18N4O2.0.17H2Calculated value of O: c, 67.63; h, 5.48; n, 16.60 percent.
Example 191
5- { [1- (2-aminoethyl) -3, 5-bicyclopropyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile
2-chloroethylamine hydrochloride (192mg, 1.65mmol) and the pyrazole of example 189 (440mg, 1.50mmol) were heated to the melt at 160 ℃ for 18 h and the residue was partitioned between dichloromethane (25ml) and 10% aqueous potassium carbonate (25 ml). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (95: 5: 0 to 95: 5: 0.5 vol.) to give the title compound (9.2mg) as a white solid, m.p.175-177 ℃.
1H NMR(400MHz，CDCl3)：δ＝0.70(m，2H)，0.79(m，4H)，0.88(m，2H)，1.57(m，1H)，1.66(m，1H)，3.46(t，2H)，4.41(t，2H)，7.62(s，2H)，7.58(s，1H)。
Example 192
3- { [ 3-cyclopropyl-1- (2-hydroxyethyl) -5-methyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile
And
example 193
3- { [ 5-cyclopropyl-1- (2-hydroxyethyl) -3-methyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile
To a solution of the diketone of preparation 86 (1.00g, 4.37mmol) in acetic acid (10ml) was added 2-hydroxyethylhydrazine (326. mu.l, 4.80mmol) at room temperature under nitrogen. After stirring for 18 h, the mixture was concentrated under reduced pressure and the residual orange oil was purified by flash chromatography on silica eluting with ethyl acetate: pentane (50: 50 to 100: 0 vol.) to give two pale yellow oils.
Lowest polarity fraction (example 192) -419mg
1H NMR(400MHz，CDCl3)：δ＝0.69(m，2H)，0.82(m，2H)，1.54(m，1H)，2.00(s，3H)，2.35(s，3H)，3.46(brs，1H)，4.05(t，2H)，4.22(t，2H)，6.88(s，1H)，6.94(s，1H)，7.08(s，1H)。
LRMS (thermal spray): m/z [ MH+]298。
Microanalysis: measured value: c, 68.29; h, 6.51; n, 13.92. C17H19N3O2Calculated values: c, 68.67; h, 6.44; n, 14.13 percent.
Highest polarity fraction (example 193) -201mg
1H NMR(400MHz，CDCl3)：δ＝0.75(m，4H)，1.58(m，1H)，2.07(s，3H)，2.35(s，3H)，3.45(brs，1H)，4.00(m，4H)，6.92(s，1H)，7.00(s，1H)，7.10(s，1H)。
LRMS (thermal spray): m/z [ MH+]298。
Microanalysis: measured value: c, 68.44; h, 6.49; and N, 13.95. C17H19N3O2Calculated values: c, 68.67; h, 6.44; n, 14.13 percent.
Example 194
3- [ 3-cyclopropyl-1- (2-amino-ethyl) -5-methyl-1H-pyrazol-4-yloxy ] -5-methyl-benzonitrile
Example 192 alcohol (140mg, 0.47mmol), triphenylphosphine (309mg, 1.18mmol) and phthalimide (174mg, 1.18mmol) were dissolved in tetrahydrofuran (9ml) at 0 ℃ under nitrogen and a solution of diisopropyl azodicarboxylate (232. mu.l, 1.18mmol) in tetrahydrofuran (2ml) was added over 10 minutes. The reaction was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethanol (11ml), and hydrazine hydrate (114. mu.l, 2.35mmol) was added. The thick white slurry was stirred at room temperature under nitrogen for 18 hours, methanol (10ml) was added and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 ml). The organic phase was extracted with 2M aqueous hydrochloric acid (20ml), the aqueous phase was washed with dichloromethane (5X 10ml), basified with 1M aqueous sodium hydroxide and extracted with dichloromethane (50 ml). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (135mg) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝0.70(m，4H)，1.56(m，1H)，2.06(s，3H)，2.30(s，3H)，3.10(t，2H)，3.97(t，2H)，6.87(s，1H)，6.92(s，1H)，7.05(s，1H)。
LRMS (electrospray): m/z [ MH+]297。
Microanalysis: measured value: c, 63.81; h, 6.51; and N, 17.30. C17H20N4O.0.36CH2Cl2Calculated values: c, 63.78; h, 6.39; n, 17.14 percent.
Example 195
3- [ (3-cyclopropyl-5-methyl-1H-pyrazol-4-yl) oxy ] -5-methylbenzonitrile
To a solution of the diketone of preparation 86 (150mg, 0.58mmol) in acetic acid (1.3ml) was added hydrazine hydrate (31. mu.l, 0.64mmol) at room temperature under nitrogen. After stirring for 24 h, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with pentane: ethyl acetate (60: 40 to 40: 60 vol) to give the title compound (140 mg).
1H NMR(400MHz，CDCl3)：δ＝0.60(m，4H)，1.69(m，1H)，2.09(s，3H)，2.34(s，3H)，6.95(s，1H)，6.99(s，1H)，7.10(s，1H)。
LRMS (thermal spray): m/z [ MH+]254。
Microanalysis: measured value: c, 68.35; h, 6.13; and N, 15.10. C15H15N3O.0.29etoac calculated: c, 68.72; h, 6.32; n, 14.88 percent.
Example 196
3- { [1- (3-aminopropyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile
3-Chloropropylamine hydrochloride (62mg, 0.48mmol) and the pyrazole from example 123 (113mg, 0.44mmol) were heated to the melt at 150 ℃ for 18 hours. After cooling, the residue was purified by flash chromatography on silica eluting with methylene chloride: methanol: 0.88 ammonia (98: 2: 0 to 95: 5: 0.5 vol.). After impurities remained, the oil was dissolved in acetone (3ml), and (L) -tartaric acid (54mg, 0.44mmol) was added to dissolve the mixture by heating, and then cooled. The resulting precipitate was separated by filtration and washed with acetone (10ml) to give the title compound (127mg) as a white solid as the tartrate salt.
1H NMR(400MHz，CD3OD)：δ＝1.05(m，6H)，2.07(m，2H)，2.37(q，2H)，2.53(s，3H)，2.57(q，2H)，2.99(t，2H)，4.15(t，2H)，4.38(s，2H)，6.89(s，1H)，7.01(s，1H)，7.19(s，1H)。
LRMS (thermal spray): m/z [ MH+]313。
Microanalysis: measured value: c, 56.81; h, 6.57; n, 12.06.C22H30N4O7Calculated values: c, 57.13; h, 6.54; n, 12.11 percent.
Example 197
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -4-methoxybenzonitrile
To a stirred solution of 2-methoxy-5-cyanophenol (285mg, 2.15mmol) and the diketone of preparation example 2 (348mg, 2.15mmol) in acetone (20ml) was added cesium carbonate (700mg, 2.14mmol) at room temperature. The reaction was heated at 50 ℃ for 3 hours and then cooled to room temperature. The mixture was concentrated under reduced pressure, dissolved in dichloromethane (5ml) and washed with water (5 ml). The organic phase was separated using a 5 μ M Whatman PTFE frit cartridge and then concentrated under reduced pressure. The residue was dissolved in acetic acid (5.4ml) and 2-hydroxy-ethyl-hydrazine (160. mu.l, 2.15mmol) was added at room temperature under nitrogen. After stirring for 18 h, the mixture was concentrated under reduced pressure and the residual orange oil was purified by flash chromatography on silica gel eluting with a solvent gradient of ethyl acetate to pentane (25: 75 to 50: 50 vol) to give the title compound (182 mg).
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.39(q，2H)，2.51(q，2H)，3.71(brs，1H)，4.00(s，3H)，4.08(m，2H)，4.09(m，2H)，6.89(s，1H)，6.99(d，1H)，7.32(d，1H)。
LRMS (thermal spray): m/z [ MH+]316。
Microanalysis: measured value: c, 64.57; h, 6.73; and N, 13.15. C 17H21N3O3Calculated values: c, 64.74; h, 6.71; and N, 13.32%.
Example 198-
By a method similar to example 197, using the preparation 2 β -diketone and the appropriate aryl alcohol as starting materials, the compounds of the following general formula example were prepared, as listed in the following table:
example 200
2- {4- [3, 5-bis (1H-pyrazol-1-yl) phenoxy ] -3, 5-diethyl-1H-pyrazol-1-yl } ethanol
The protected alcohol of preparation 88 (254mg, 0.53mmol) and p-toluenesulfonic acid (10mg, 0.05m mol) were dissolved in methanol (4ml) at room temperature under nitrogen and stirred for 18 h. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate (20ml) and dichloromethane (20 ml). The aqueous phase was extracted with dichloromethane (10ml) and the combined organic extracts were dried over magnesium sulphate, concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with a solvent gradient dichloromethane: methanol (100: 0 to 93: 7 vol.) to give the title compound (56mg) as a white solid, m.p.108-110 ℃.
1HNMR(400MHz，CDCl3)：δ＝1.11(m，6H)，2.46(q，2H)，2.53(q，2H)，4.01(t，2H)，4.07(t，2H)，6.44(s，2H)，7.16(s，2H)，7.68(s，3H)，7.92(s，2H)。
LRMS (electrospray): m/z [ MH+]393，[MNa+]415。
Microanalysis: measured value: c, 63.62; h, 6.11; n, 21.11. C21H24N6O2.0.06CH2Cl2Calculated values: c, 63.63; h, 6.12; and N, 21.14%.
Example 201
2- {3, 5-diethyl-4- [ 3-fluoro-5- (1H-pyrazol-1-yl) phenoxy ] -1H-pyrazol-1-yl } ethanol
The protected alcohol of preparation 89 (38.6mg, 0.09mmol) and p-toluenesulfonic acid (3.5mg, 0.01mmol) were dissolved in methanol (1ml) at room temperature under nitrogen and stirred for 18 h. The solvent was removed under reduced pressure and the residue partitioned between 10% aqueous potassium carbonate (4ml) and dichloromethane (4 ml). The aqueous phase was extracted with dichloromethane (10ml) and the combined organic extracts were dried over magnesium sulphate, concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with a solvent gradient dichloromethane: methanol (99: 1 to 98: 2 vol.) to give the title compound (23mg) as a white solid, m.p.120-122 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.14(m，6H)，2.46(q，2H)，2.55(q，2H)，4.06(m，2H)，4.09(m，2H)，6.47(s，1H)，6.49(s，1H)，7.09(s，1H)，7.12(s，1H)，7.71(s，1H)，7.86(s，1H)。
LRMS (electrospray): m/z [ MNa ]+]367。
HRMS：[MH+]Found 345.1717.C18H22FN4O2Calculated values: 345.1722.
example 202
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5-methoxybenzonitrile
The protected alcohol of preparation 90 (400mg, 1.00mmol) and p-toluenesulfonic acid (19mg, 0.10mmol) were dissolved in methanol (10ml) at room temperature under nitrogen and stirred for 18 h. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate (20ml) and dichloromethane (20 ml). The aqueous phase was extracted with dichloromethane (40ml) and the combined organic extracts were dried over magnesium sulphate, concentrated under reduced pressure and purified by flash chromatography on silica eluting with dichloromethane: methanol (97: 3 vol) to give the title compound (174mg) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.09(m，6H)，2.40(q，2H)，2.49(q，2H)，3.78(s，3H)，4.04(m，2H)，4.08(m，2H)，6.66(s，1H)，6.71(s，1H)，6.79(s，1H)。
LRMS (electrospray): m/z [ MH+]316。
Microanalysis: measured value: c, 63.63; h, 6.76; and N, 13.06. C17H21N3O3.0.08CH2Cl2Calculated values: c, 63.68; h, 6.68; and N, 13.04%.
Example 203
2- [4- (3, 5-Difluorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethylamine
Example 38 alcohol (371mg, 1.25mmol), triphenylphosphine (984mg, 3.75mmol) and phthalimide (552mg, 3.75mmol) were dissolved in tetrahydrofuran (20ml) at 0 ℃ under nitrogen and a solution of diisopropyl azodicarboxylate (738 μ l, 3.75mmol) in tetrahydrofuran (2ml) was added over 10 minutes. The reaction was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethanol (25ml), and hydrazine hydrate (303. mu.l, 6.25mmol) was added. The slurry was stirred at 45 ℃ under nitrogen for 4 hours, concentrated under reduced pressure and the residue was dissolved in methanol. The solution was then passed through an SCX column eluting with methanol to remove impurities and then the product was eluted with 2M ammonia in methanol. The product was then purified by flash alumina chromatography eluting with methylene chloride: methanol: 0.88 ammonia (90: 10: 1 vol.) to give the title compound (212mg) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.12(m，6H)，2.43(q，2H)，2.54(q，2H)，3.21(t，2H)，4.07(t，2H)，6.43(m，3H)。
Microanalysis: measured value: c, 59.78; h, 6.50; n, 14.35. C 15H19F2N3O.0.26H2Calculated value of O: c, 60.05; h, 6.56; n, 14.01 percent.
Example 204
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-fluorobenzamide
Example 163 alcohol (142mg, 0.44mmol), triphenylphosphine (346mg, 1.32mmol) and phthalimide (194mg, 1.32mmol) were dissolved in tetrahydrofuran (8ml) at 0 ℃ under nitrogen and a solution of diisopropyl azodicarboxylate (260. mu.l, 1.32mmol) in tetrahydrofuran (1ml) was added over 10 minutes. The reaction was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethanol (9ml), and hydrazine hydrate (107. mu.l, 2.2mmol) was added. The slurry was stirred at 45 ℃ under nitrogen for 4 hours, concentrated under reduced pressure and the residue was dissolved in methanol. The solution was then passed through a column of polymer-supported sulfonic acid, eluting with methanol to remove impurities, and then eluting the product with 2M ammonia in methanol. The product was then purified by flash alumina chromatography eluting with methylene chloride/methanol/0.88 ammonia (90: 10: 1 vol.) to give the title compound (60mg) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.11(m，6H)，2.43(q，2H)，2.53(q，2H)，3.17(t，2H)，4.05(t，2H)，6.01(brs，1H)，6.25(brs，1H)，6.75(d，1H)，7.16(m，2H)。
HRMS：[MH+]Found value of 321.1718.C16H21FN4O2Calculated values: 321.1722.
example 205
3- [ (3-isopropyl-5-methyl-1H-pyrazol-4-yl) oxy ] -5-methylbenzonitrile
To a solution of the diketone of preparation 91 (544mg, 2.10mmol) in acetic acid (10ml) was added hydrazine hydrate (100. mu.l, 2.10mmol) at room temperature under nitrogen. After stirring for 64 h, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with pentane: ethyl acetate (66: 34 vol) to give the title compound (308mg) as a pale yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.22(d，6H)，2.09(s，3H)，2.56(s，3H)，2.84(m，1H)，6.91(s，1H)，6.94(s，1H)，7.11(s，1H)。
LRMS (thermal spray): m/z [ MH+]256。
Example 206
3- { [1- (2-aminoethyl) -3-isopropyl-5-methyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile
Pyrazole (70mg, 0.27mmol) from example 205 and 2-chloroethylamine hydrochloride (38mg, 0.33mmol) were heated to the melt at 150 ℃ for 18 hours. The residue was cooled and purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (95: 5: 0.5 vol) to give the title compound (25 mg).
1H NMR(400MHz，CDCl3)：δ＝1.18(m，6H)，2.06(s，3H)，2.35(s，3H)，2.79(m，1H)，3.19(m，2H)，4.04(m，2H)，6.89(s，1H)，6.97(s，1H)，7.12(s，1H)。
LRMS (electrospray): m/z [ MH+]300。
Example 207
2- [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] -N- (2-pyridylmethyl) acetamide
Standard solution: the acid of preparation 4 (800mg, 2.33mmol), 1H-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate (822mg, 3.50mmol) and diisopropylethylamine (603mg, 4.66mmol) were dissolved in N, N-dimethylformamide (3X 13ml), respectively. In a 96-well plate, 2- (methylamino) pyridine (3mg, 0.029mmol) was treated with a standard solution of acid and coupling agent (3X 170. mu.l), and the mixture was shaken at room temperature for 14 hours. The solvent was removed under reduced pressure, the mixture was dissolved in dimethyl sulfoxide (500. mu.l) and purified by HPLC (Magellen C) 8(2) 150X 10mm column; a gradient mobile phase from 5: 95 (vol) to 95: 5 (vol) acetonitrile was used: water containing 0.1% trifluoroacetic acid).
Retention time: 5.69 minutes
LRMS (electrospray): m/z [ MH+]434。
Example 208
[4- (3, 5-chlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] acetonitrile
To a solution of sodium cyanide (284mg, 5.20mmol) in water (10ml) was added in one portion a solution of the pyrazole (1.00g, 2.60mmol) of preparation 8 in tetrahydrofuran (10ml) at room temperature. The reaction was heated at 80 ℃ for 14 h and cooled to room temperature. The solvent was removed under reduced pressure and the resulting brown solid was dissolved in dichloromethane (50ml) and water (50 ml). The organic layer was separated, washed with water (50ml), brine (30ml), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a brown solid. The product was purified by flash chromatography on silica gel eluting with pentane: ethyl acetate (50: 50 vol) to give the title compound as a yellow solid (500mg), m.p.150-152 ℃.
1H NMR(400MHz，CDCl3)：δ＝2.17(s，3H)，3.56(s，2H)，6.77(s，2H)，7.02(s，1H)。
LRMS (thermal spray): m/z [ MH+]282。
Example 209
1- { [4- (3, 5-Dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] acetyl } piperidine
Standard solution: the acid of preparation 92 (680mg, 2.16mmol) and 1H-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate (761mg, 3.23mmol) were dissolved in N, N-dimethylformamide, respectively; triethylamine (96: 4) (2X 17 ml). In a 96-well plate, piperidine (3mg, 0.031mmol) was treated with a standard solution of acid and coupling agent (250. mu.l each), and the mixture was shaken at 80 ℃ for 14 hours. The solvent was removed under reduced pressure, the mixture was dissolved in dimethyl sulfoxide (500. mu.l) and purified by HPLC (Magellen C) 18(2) 150X 10mm column; a gradient mobile phase from 5: 95 (vol) to 95: 5 (vol) acetonitrile was used: water containing 0.1% trifluoroacetic acid).
Retention time: 4.7 minutes
LRMS (electrospray): m/z [ MH+]368。
Example 210-
By a method similar to example 209, using the appropriate amine, the following compounds of the general formula example are prepared, as set forth in the following table:
example 218
3-chloro-5- [ (5- { [ (2-chlorobenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile
Standard solution: preparation 18 bromide (850mg, 2.30mmol) was dissolved in N-methylpyrrolidone (43 ml). In a 96-well plate, 2-chlorobenzylamine (19mg, 0.13mmol) was treated with a solution of preparation 18 bromide (500. mu.l) and the mixture was shaken at 80 ℃ for 14 h. The solvent was removed under reduced pressure, the mixture was dissolved in dimethyl sulfoxide (500. mu.l) and purified by HPLC (Magellen C)8(2) 150X 10mm column; a gradient mobile phase from 5: 95 (vol) to 95: 5 (vol) acetonitrile was used: water containing 0.1% trifluoroacetic acid).
Retention time: 5.3 minutes
LRMS (electrospray): m/z [ MH+]386.
Example 219-
By a method similar to example 218, using the appropriate amine, the following compounds of the general formula example are prepared, as set forth in the table below:
Example 250
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5- (methylthio) benzonitrile
The protected alcohol of preparation 93 (687mg, 1.65mmol) and p-toluenesulfonic acid (32mg, 0.17mmol) were dissolved in methanol (16ml) and stirred at room temperature under nitrogen. After 4 hours, a second portion of p-toluenesulfonic acid (32mg, 0.17mmol) was added. After 18 h, the solvent was removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate (20ml) and dichloromethane (20 ml). The aqueous phase was extracted with dichloromethane (40ml) and the combined organic extracts were dried over magnesium sulphate, concentrated under reduced pressure and purified by flash chromatography on silica eluting with dichloromethane: methanol (97: 3 vol) to give the title compound (487mg) as a white solid. m.p.72 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.14(m，6H)，2.44(q，2H)，2.49(s，3H)，2.53(q，3H)，4.08(m，2H)，4.14(m，2H)，6.84(s，1H)，7.00(s，1H)，7.10(s，1H)。
LRMS(electrospray): m/z [ MH+]332。
Microanalysis: measured value: c, 61.36; h, 6.43; n, 12.55. C17H21N3O2S calculated value: c, 61.61; h, 6.39; n, 12.68 percent.
Example 251
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5- (methylsulfinyl) benzonitrile
Wet alumina was prepared by adding water (1ml) to Brockman grade I alumina (5 g). To a stirred solution of sulfide (134mg, 0.40mmol) from example 250 in dichloromethane (2ml) was added wet alumina (400mg) followed by oxone (123mg, 0.4mmol) and the mixture was heated at reflux. After 1 hour, a second portion of Oxone (123mg, 0.4mmol) was added and the mixture was heated for another 2 hours. After cooling to room temperature, the reaction mixture was filtered, and the resulting solid was washed with dichloromethane (20 ml). The filtrate was concentrated and purified by flash chromatography on silica gel eluting with methylene chloride: methanol (gradient 99: 1 to 90: 10 vol.) to give the title compound (92mg) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.12(m，6H)，2.44(q，2H)，2.53(q，2H)，2.73(s，3H)，4.06(m，2H)，4.18(m，2H)，7.24(s，1H)，7.45(s，1H)，7.49(s，1H)。
LRMS (electrospray): m/z [ M + Na ]+]370。
Example 252
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5- (methylsulfonyl) benzonitrile
To a stirred solution of sulfide from example 250 (133mg, 0.4mmol) in dichloromethane (2ml) was added a solution of m-chloroperbenzoic acid (138mg of 50 wt% mixture, 0.4mmol) in dichloromethane (2ml) at-78 ℃. The cooling bath was removed and the solution was stirred at room temperature for 4 hours. The mixture was quenched by the addition of saturated aqueous sodium bicarbonate (6ml) and extracted with dichloromethane (3X 5 ml). The combined organic fractions were dried over magnesium sulfate and concentrated.1H NMR(400MHz，CDCl3) Analysis indicated a mixture of the desired product with the sulfoxide of example 251. The crude product mixture was dissolved in dichloromethane (2ml), cooled to-78 ℃ and a solution of m-chloroperbenzoic acid (138mg of 50% by weight mixture, 0.4mmol) in dichloromethane (2ml) was added. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour. The mixture was quenched by the addition of saturated aqueous sodium bicarbonate (6ml) and extracted with dichloromethane (3X 5 ml). The combined organic fractions were dried over magnesium sulfate and concentrated. The crude product mixture was purified by flash chromatography on silica eluting with methylene chloride: methanol (98: 2 vol.) to give the title compound contaminated with meta-chloroperbenzoic acid. To a solution of the crude product in dichloromethane was added dimethyl sulfoxide (30. mu.l, 0.4mmol) at-78 ℃. The cooling bath was removed and the mixture was stirred at room temperature for 15 minutes. The mixture was quenched by the addition of 10% aqueous potassium carbonate (10ml) and the dichloromethane was evaporated. The remaining aqueous mixture was then extracted with diethyl ether (2X 10ml) and ethyl acetate (10 ml). The organic fractions were combined, dried over magnesium sulfate, and concentrated to give a crude product mixture which was purified by flash chromatography on silica gel eluting with methylene chloride: methanol (98: 2 vol.) to give the title compound (26mg) as a white solid. m.p.133 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.39(q，2H)，2.51(q，2H)，3.06(s，3H)，4.05(m，2H)，4.10(m，2H)，7.39(s，1H)，7.67(s，1H)，7.84(s，1H)。
LRMS (electrospray): m/z [ M + Na ]+]385。
HRMS：[MH+]364.1329.C18H20N6O2Calculated values: 364.1326.
example 253
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5- [2- (dimethylamino) ethoxy ] benzonitrile
To a stirred solution of the protected alcohol of preparation 94 (180mg, 0.39mmol) in methanol (4ml) was added p-toluenesulfonic acid (89mg, 0.47 mmol). After 18 hours at room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane (5ml) and 10% aqueous potassium carbonate (5 ml). The aqueous phase was separated and extracted with dichloromethane (3 ml). The organic fractions were combined, dried over magnesium sulfate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with dichloromethane: methanol (95: 5 vol) followed by dichloromethane: methanol: ammonia (80: 20: 1 vol) to give the title compound (63mg) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.13(m，6H)，2.43(m，8H)，2.52(q，2H)，2.85(m，2H)，3.81(broad s，1H)，4.08(m，6H)，6.70(s，1H)，6.78(s，1H)，6.81(s，1H)。
LRMS(APO)：m/z[MH+]373。
HRMS：[MH+]373.2234.C20H29N4O3Calculated values: 373.2234.
example 254-
By a method similar to example 253, starting with the appropriate Protected Alcohol (PA) of preparations 95-97, the following compounds of the general formula example are prepared, as set forth in the following table:
example No. 2 PA preparation example No. 2 R Analyzing data
254 95 CHCHNHMe 1H NMR(400MHz，CDCl)：δ＝1.13(m，6H)，2.42(q，2H)，2.53(q，2H)，2.59(s，3H)，3.12(t，2H)，4.05(m，2H)，4.09(m，2H)，4.16(t，2H)，6.75(s，1H)，6.81(s，1H)，6.82(s，1H).LRMS(APCl)：m/z [MH]359HRMS：[MH]359.2083.CHNOCalculated 359.2078.
255 96 CHCONH 1H NMR(400MHz，CDCl)：δ＝1.11(m，6H)，2.41(q，2H)，2.52(q，2H)，4.05(t，2H)，4.09(t，2H)，4.46(s，2H)，5.74(broads，1H)，6.42(broad s，1H)，6.69(s，1H)，6.85(s，2H).LRMS(APCl)：m/z 359(MH)
256 97 CHCHOCH 1H NMR(400MHz，CDCl): δ is 1.12(m, 6H), 2.42(q, 2H), 2.51(q, 2H), 3.44(s, 3H), 3.73(t, 2H), 4.09(m, 6H), 6.71(s, 1H), 6.77(s, 1H), 6.83(s, 1H). LRMS (electrospray): m/z 360 (MH) )HRMS：[MH]360.1920.CHNOCalculated 360.1918.
Example 257
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methoxybenzonitrile
Example 202 alcohol (87mg, 0.28mmol), triphenylphosphine (220mg, 0.84mmol) and phthalimide (124mg, 0.84mmol) were dissolved in tetrahydrofuran (5ml) at 0 ℃ under a nitrogen atmosphere, and a solution of diisopropyl azodicarboxylate (165. mu.l, 0.84mmol) in tetrahydrofuran (1ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethanol (6ml), and hydrazine hydrate (68. mu.l, 1.40mmol) was added. The slurry was stirred at room temperature under nitrogen for 48 hours, concentrated under reduced pressure and the residue was dissolved in methanol. The solution was then passed through an SCX column eluting with methanol to remove impurities and then the product was eluted with 2M ammonia in methanol. The product was then purified by flash chromatography on silica gel eluting with dichloromethane: methanol (95: 5) and then with dichloromethane: methanol: 0.88 ammonia (90: 10: 1 vol) to give the title compound (67mg) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.13(m，6H)，2.19(broad s，2H)，2.43(q，2H)，2.54(q，2H)，3.19(t，2H)，3.60(s，3H)，4.06(t，2H)，6.68(s，1H)，6.73(s，1H)，6.80(s，1H)。
LRMS (electrospray): m/z 315 (MH)+)。
HRMS：[MH+]315.1819.C17H23N4O2Calculated values: 315.1816.
example 258
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5- (1H-pyrazol-1-yl) benzonitrile
Example 164 alcohol (162mg, 0.46mmol), triphenylphosphine (362mg, 1.38mmol) and phthalimide (203mg, 1.38mmol) were dissolved in tetrahydrofuran (8ml) at 0 ℃ under a nitrogen atmosphere, and a solution of diisopropyl azodicarboxylate (272. mu.l, 1.38mmol) in tetrahydrofuran (1ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethanol (9ml), and hydrazine hydrate (112. mu.l, 2.3mmol) was added. The slurry was stirred at room temperature under nitrogen for 48 hours, concentrated under reduced pressure and the residue was dissolved in methanol. The solution was then passed through an SCX column eluting with methanol to remove impurities and then the product was eluted with 2M ammonia in methanol. The product was then purified by flash chromatography on silica gel eluting with dichloromethane: methanol (95: 5) and then with dichloromethane: methanol: 0.880 ammonia (90: 10: 1 vol) to give the title compound (62mg) as an oil.
1H NMR(400MHz，CD3OD)：δ＝1.15(m，6H)，2.46(q，2H)，2.63(q，2H)，3.13(t，2H)，4.13(t，2H)，6.54(s，1H)，7.17(s，1H)，7.69(s，1H)，7.72(s，1H)，7.82(s，1H)，8.32(s，1H)。
LRMS(APCl)：m/z 351(MH+)。
HRMS：MH+]351.1929.C19H22N4O2Calculated values: 351.1928.
example 259
3, 5-dichlorophenyl-3-methyl-5- [ (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl ] -1H-pyrazol-4-yl ether
To a stirred solution of the acid of preparation 92 (100mg, 0.33mmol) in dimethylformamide (2ml) was added carbonyldiimidazole (59mg, 0.36mmol) in one portion. After 30 min at room temperature, (1Z) -N' -hydroxyacetamidine (27mg, 0.36mmol) was added and the reaction mixture was stirred at room temperature for 3 h. A second portion of carbonyldiimidazole (59mg, 0.36mmol) was added and the mixture was heated at 100 ℃ for 12 hours. After cooling to room temperature, water (30ml) was added and the mixture was extracted with ethyl acetate (3X 20 ml). The organic fractions were combined, dried over magnesium sulfate and concentrated under reduced pressure to give a brown oil. The crude product mixture was purified by flash chromatography on silica eluting with ethyl acetate to pentane (30: 70 vol) to give the title compound (40mg) as a pale yellow oil.
1H NMR(400MHz，CDCl3)：δ＝2.12(s，3H)，2.29(s，3H)，4.08(s，2H)，6.74(s，2H)，6.98(s，1H)。
LRMS (electrospray): m/z 339 (MH)+)。
Example 260
3-fluoro-5- { [1- (2-hydroxyethyl) -5-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile
To a stirred solution of the protected alcohol of preparation 99 (85mg, 0.21mmol) in methanol (0.5ml) was added p-toluenesulfonic acid (4mg, 0.02 mmol). After 5 h, the reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (20ml), washed with saturated sodium bicarbonate solution (20ml), dried over magnesium sulfate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with pentane: ethyl acetate (60: 40 then 40: 60 vol) to give the title compound (54mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝2.19(s，3H)，2.45(t，1H)，4.10(m，2H)，4.20(m，2H)，6.87(d，1H)，6.96(s，1H)，7.05(d，1H)。
LRMS(APCl)：m/z 330(MH+)。
Microanalysis: measured value: c, 51.38; h, 3.52; n, 12.37. C14H11F4N3O2Calculated values: c, 51.07; h, 3.37; n, 12.76 percent.
Example 261
5- [ (3, 5-diethyl-1- {2- [ (2-methoxyethoxy) methoxy ] ethyl } -1H-pyrazol-4-yl) oxy ] isophthalonitrile
To a stirred solution of the alcohol of example 119 (5.0g, 16.11mmol) in tetrahydrofuran (65ml) was added 2-methoxyethoxymethyl chloride (2.39ml, 20.94mmol) followed by sodium hydride (838mg of a 60% by weight oil dispersion, 20.94mmol) at 0 ℃. After 10 minutes, the reaction mixture was heated at 50 ℃ for 18 hours. After cooling to room temperature, the mixture was diluted dropwise with saturated aqueous ammonium chloride solution (3 ml). The mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (250ml) and water (200 ml). The aqueous phase was separated and extracted with dichloromethane (150 ml). The organic fractions were combined, dried over magnesium sulfate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with dichloromethane and then dichloromethane: methanol (99: 1 vol.) to give the title compound (5.38g) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.39(q，2H)，2.55(q，2H)，3.38(s，3H)，3.51(m，2H)，3.56(m，2H)，3.93(t，2H)，4.20(t，2H)，4.66(s，2H)，7.38(s，2H)，7.56(s，1H)。
LRMS(APCl)：m/z 399(MH+)。
Microanalysis: measured value: c, 62.11; h, 6.67; n, 13.51. C21H26N4O4+0.43H2Calculated value of O: c, 62.09; h, 6.67; n, 13.79 percent.
Example 262
3-cyano-5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } benzamide
To a stirred solution of pyrazole (60mg) of preparation 100 in dichloromethane (4ml) was added aluminum trichloride (134mg, 1 mmol). After 18 h ice was added and the mixture was neutralised with saturated aqueous sodium bicarbonate, diluted with water (30ml) and extracted with dichloromethane (2X 40 ml). The organic fractions were combined, dried over magnesium sulfate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with methylene chloride: methanol (95: 5 vol.) to give the title compound (27mg) as a colorless glass.
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.40(q，2H)，2.52(q，2H)，4.07(m，4H)，7.25(s，1H)，7.60(s，1H)，7.65(s，1H)。
LRMS(APCl)：m/z 329(MH+)。
Example 263
5- { [ 5-Ethyl-3- (1-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile
To a stirred solution of pyrazole (219mg, 0.57mmol) of preparation 102 in tetrahydrofuran (2.5ml) was added saturated aqueous sodium carbonate (0.5 ml). The reaction mixture was stirred at room temperature for 4 hours and then heated at reflux for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (20ml) and water (20 ml). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with methylene chloride: methanol (gradient from 100: 0 to 90: 10 vol.) to give the title compound (68mg) as a white solid.
1HNMR(400MHz，CDCl3)：δ＝1.21(t，3H)，1.51(d，3H)，2.54(q，2H)，4.89(q，1H)，7.25(s，2H)，7.43(s，1H)。
LRMS(APCI)：m/z 283(MH+)。
Example 264
5- { [ 5-Ethyl-3- (1-hydroxyethyl) -1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile
To a stirred solution of pyrazole (80mg, 0.19mmol) of preparation 103 in methanol (1ml) was added p-toluenesulfonic acid (4mg, 0.02 mmol). After 5 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (20ml) and water (20 ml). The organic fraction was dried over magnesium sulfate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with methylene chloride: methanol (gradient from 100: 0 to 95: 5 vol.) to give the title compound (44mg) as a white solid.
1HNMR(400MHz，CDCl3)：δ＝1.11(t，3H)，1.46(d，3H)，2.54(q，2H)，4.10(q，2H)，4.17(q，2H)，4.79(q，1H)，7.44(s，2H)，7.57(s，1H)。
LRMS(APCI)：m/z 327(MH+)。
Example 265
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5- (5-trifluoromethyl-1, 2, 4-oxadiazol-3-yl) benzonitrile
To a stirred solution of pyrazole (235mg, 0.46mmol) of preparation 105 in dichloromethane (2ml) was added aluminum trichloride (373mg, 2.8 mmol). The reaction mixture was stirred at room temperature for 48 hours, diluted with water (6ml) and extracted with dichloromethane (6 ml). Concentrating the organic fraction under reduced pressure, and subjecting to flash evaporationPurification by chromatography on silica gel eluting with dichloromethane: methanol (gradient from 99: 1 to 80: 20 vol) followed by dichloromethane: methanol: 0.88 ammonia (80: 20: 1 vol) gave an impure sample of the title compound (44mg) as a white solid. The product was further purified by HPLC using Phenomonex Luna C 18150X 21.2mm column, purified with 5: 95 acetonitrile containing 0.1% aqueous trifluoroacetic acid: acetonitrile in a solvent gradient (0-1min 80: 20; 1-7min 80: 20 to 0: 100; 7-12min 0: 100; 12-12.1min 0: 100 to 80: 20; 12.1-15min 80: 20) to give the title compound (38mg) as a white solid.
Retention time 5.7 minutes
LRMS (electrospray): m/z 422 (MH)+)
Example 266-
By a method similar to example 265, starting with the appropriate preparation 106-108 Protected Alcohol (PA), the following compounds of the general formula examples are prepared, as listed in the table below:
example No. 2 PA preparation example No. 2 R Analyzing data
266 106 Me Retention time 4.8 min LRMS (electrospray): m/z [ MH]368
267 107 Et Retention time 5.3 min LRMS (electrospray): m/z [ MH]382
268 108 1Pr Retention time 5.7 min LRMS (electrospray): m/z 396 (MH))
Example 269
5- [ ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] nicotinamide
To a stirred solution of the amine of preparation 111 (650mg, 1.70mmol) in isopropanol (6ml) was added pyrazole of preparation 18 (210mg, 0.57mmol) followed by potassium carbonate (240mg, 1.70mm0 l). The reaction mixture was heated at reflux for 1.5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the crude product mixture was purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (95: 5: 0.5, 90: 10: 1 and 80: 20: 1 by volume) to give an impure sample of the desired product. Purification by flash chromatography was repeated, eluting with dichloromethane: methanol: 0.88 ammonia (100: 0: 95: 5.0.5 then 90.10.1 vol) to give the title compound (10mg) as a pale yellow solid.
1H NMR(400MHz，CD3OD)：δ＝2.05(s，3H)，3.62(s，2H)，3.79(s，2H)，7.16(m，1H)，7.18(m，1H)，7.38(s，1H)，8.15(s，1H)，8.54(s，1H)，8.84(s，1H)。
LRMS(APCI)：m/z 419(M+Na+)。
HRMS：[MH+]397.1173.C19H18N6O2Calculated Cl: 397.1175.
example 270
2- [ ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] isonicotinamide
To a stirred solution of the amine of preparation 115 (250mg, 1.66mmol) and the pyrazole of preparation 18 (155mg, 0.42mmol) in isopropanol (6ml) was added tetrahydrofuran (2 ml). The mixture was heated at reflux for 2 hours, then the reaction mixture was concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (85: 15: 1 by volume) to give an impure sample of the title compound. The product was further purified by HPLC using Phenomonex Luna C8(II) 10. mu.M 150X 21.2mm column, purified with 5: 95 acetonitrile containing 0.1% aqueous trifluoroacetic acid: a solvent gradient of acetonitrile (0-6min 95: 5 to 0: 100; 6-10min 0: 100) gave the title compound (65mg) as an off-white solid.
Retention time: 3.40 minutes
1H NMR(400MHz，CD3OD)：δ＝2.14(s，3H)，4.21(s，2H)，4.50(s，2H)，7.19(s，1H)，7.27(m，1H)，7.43(m，1H)，7.48(m，1H)，7.78(m，1H)，8.68(d，1H)。
LRMS (electrospray): m/z 397 (MH)+)。
Microanalysis: measured value: c, 44.56; h, 3.41; n, 14.07. C19H17N6O2Cl+1.9CF3CO2H calculated value: c, 44.64; h, 3.11; and N, 13.70 percent.
Example 271
2- [4- (3, 5-Dicyanophenyloxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl phosphate di (tert-butyl) ester
To a stirred solution of the alcohol of example 119 (500mg, 1.60mmol) in dichloromethane (5ml) was added tetrazole (226mg, 3.20mmol) followed by di-tert-butyl N, N-diisopropylphosphoramidate (1.02ml, 3.20 mmol). After stirring at room temperature for 4 hours, the reaction mixture was cooled to 0 ℃ and m-chloroperbenzoic acid (1.0g of 50% by weight mixture, 3mmol) was added portionwise (cautiously, exothermically). After 10 min, the mixture was allowed to warm to room temperature and diluted with dichloromethane (50 ml). The solution was washed with saturated aqueous sodium carbonate (20ml), the aqueous component was separated and extracted with dichloromethane (20 ml). The organic fractions were combined, washed with brine (20ml), dried over magnesium sulfate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (100: 0, then 99: 1: 0.1, then 98: 2: 0.2 by volume) to give a sample of the title compound (660 mg).
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，1.43(s，18H)，2.38(q，2H)，2.55(q，2H)，4.26(m，4H)，7.38(s，2H)，7.54(s，1H)。
LRMS (electrospray): m/z525(MH+)。
Microanalysis: measured value: c, 57.77; h, 7.38; n, 10.33. C25H35N4O5P+H2Calculated value of O: c, 57.68; h, 7.16; n, 10.76 percent.
Example 272
2- [4- (3, 5-Dicyanophenyloxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl dihydrogen phosphate
To a stirred solution of the phosphate ester of example 271 (250mg, 0.48mmol) in dichloromethane (10ml) was added trifluoroacetic acid (0.5ml) at 0 ℃. The reaction mixture was allowed to warm to room temperature and concentrated under reduced pressure after 4 hours. The residue was purified by HPLC using Phenomonex Luna C 8(II) 10. mu.M 150X 21.2mm column, purified with 5: 95 acetonitrile containing 0.1% aqueous trifluoroacetic acid: acetonitrile (0-1.9min 95: 5; 2-10min 90.10 to 30: 70; 10.0-13.8min 30.70; 13.8-13.9min 30: 70 to 95: 5; 13.9-15min 95: 5) to obtain a sample of the desired product. This sample was further purified by recrystallization from acetonitrile/water to give the title compound as a white solid, m.p.198-199 ℃.
Retention time: 2.31 minutes
1H NMR(400MHz，CD3OD)：δ＝1.09(m，6H)，2.35(q，2H)，2.61(q，2H)，4.28(m，4H)，7.55(s，2H)，7.79(s，1H)。
LRMS(APCI)：m/z 391(MH+)。
Microanalysis: measured value: c, 50.99; h, 4.92; n, 14.06. C17H19N4O5P+0.5H2Calculated value of O: c, 51.13; h, 5.05; n, 14.03 percent.
Example 273
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile sulfate
To a stirred solution of pyrazole (200mg, 0.65mmol) from example 119 in acetone (5ml) was added sulfuric acid (0.32ml of a 2M aqueous solution, 0.64mmol), the mixture was stirred at room temperature, and the solvent was evaporated. The residue was recrystallized (toluene/acetone) to give the title compound (160mg) as a white powder, m.p.105-110 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.22(m，6H)，2.70(m，4H)，4.12(bs，1H)，4.59(m，2H)，4.75(bs，1H)，7.66(s，1H)，7.69(m，1H)，7.72(s，1H)。
Microanalysis: measured value: c, 50.29; h, 4.90; and N, 13.48. C17H18N4O2.H2SO4Calculated values: c, 49.99; h, 4.93; and N, 13.72 percent.
Example 274
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile benzenesulfonate
To a stirred solution of pyrazole (20g, 65mmol) from example 119 in acetone (200ml) was added benzenesulfonic acid (10.7g, 68mmol) and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure and the residue was recrystallized twice (acetone) to give the title compound (16.2g) as a white powder, m.p.142-144 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.05-1.08(m，6H)，2.59(q，2H)，2.68(q，2H)，4.04(t，2H)，4.54(t，2H)，7.35-7.42(m，3H)，7.55(s，1H)，7.64(s，1H)，7.86(d，2H)。
Microanalysis: measured value: c, 58.86; h, 5.13; n, 11.88. C23H24N4O5S calculated value: c, 58.96; h, 5.16; n, 11.96 percent.
Example 275
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile tosylate
To a stirred suspension of pyrazole (300mg, 1.00mmol) from example 119 in ethanol (2ml) was added p-toluenesulfonic acid (202mg, 1.10mmol) and the mixture was heated on an oil bath until the solid dissolved. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was crystallized (diethyl ether), filtered, and recrystallized (isopropanol) to give the title compound (200mg) as a white solid, m.p.120 ℃.
1H NMR(400MHz，DMSO-d6)：δ＝1.00(m，6H)，2.24(m，5H)，2.49(m，2H)，4.00(m，2H)，7.11(d，2H)，7.45(d，2H)，7.73(s，2H)，8.09(s，1H)。
Microanalysis: measured value: c, 59.64; h, 5.46; n, 11.60. C24H26N4O5S calculated value: c, 59.74; h, 5.43; n, 11.61%.
Example 276
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile mesylate
To a stirred suspension of the pyrazole of example 119 (250mg, 0.83mmol) in isopropanol (3ml) was added methanesulfonic acid (52. mu.l, 0.91mmol) and the mixture was heated on an oil bath until the solid dissolved. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to a volume of 1 ml. A white solid precipitated out and was washed with cold isopropanol to give the title compound (239mg) as a white solid, m.p.144-146 ℃.
1H NMR(400MHz，DMSO-d6)：δ＝1.02(m，6H)，2.32(q，2H)，2.43(s，3H)，2.52(m，2H)，3.73(m，2H)，4.02(m，2H)，7.75(s，2H)，8.11(s，1H)。
Microanalysis: measured value: c, 53.20; h, 5.52; n, 13.68.C18H22N4O5S calculated value: c, 53.19; h, 5.46; n, 13.78%.
Example 277
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile bismesylate salt
To a stirred solution of the amine from example 125 (119mg, 0.40mmol) in ethanol (2ml) was added methanesulfonic acid (1.00ml of a 0.84M solution in ethanol, 0.84 mmol). The reaction mixture was concentrated under reduced pressure to remove some ethanol. A mixture of diethyl ether and acetone was added and a white solid precipitated out, filtered and washed (diethyl ether/acetone) to give the title compound (153mg) as a white solid, m.p.146-148 ℃.
1H NMR(400MHz，CD3OD)：δ＝1.09(m，6H)，2.33(s，3H)，2.39(q，2H)，2.55(q，2H)，2.68(s，6H)，3.42(t，2H)，4.29(t，2H)，6.93(s，1H)，7.06(s，1H)，7.19(s，1H)。
LRMS (thermal spray): m/z [ free base + H+]299。
Microanalysis: measured value: c, 45.83; h, 6.12; n, 11.27. C 19H30N4O7S2.0.50H2Calculated value of O: c, 45.68; h, 6.25; n, 11.21%.
Example 278
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile phosphate
To a stirred solution of the amine from example 125 (251mg, 0.84mmol) in ethanol (5ml) was added phosphoric acid (63. mu.l, 0.93 mmol). The resulting precipitate was filtered, washed (ethanol with diethyl ether) and dried to give the title compound (265mg) as a white solid, m.p.210-211 ℃.
1H NMR(400MHz，CD3OD)：δ＝1.08(m，6H)，2.32(s，3H)，2.39(q，2H)，2.56(q，2H)，3.39(m，2H)，4.29(m，2H)，6.93(s，1H)，7.05(s，1H)，7.18(s，1H)。
LRMS (thermal spray): m/z [ free base + H+]299。
Microanalysis: measured value: c, 51.26; h, 6.36; n, 14.08.C17H25N4O5P calculated value: c, 51.51; h, 6.36; n, 14.14 percent.
Example 279
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile (L) -tartrate
To a stirred solution of the amine from example 125 (500mg, 1.68mmol) in acetone (15ml) was added (L) -tartaric acid (252mg, 1.68mmol) and the mixture was heated on an oil bath until complete dissolution had occurred. The mixture was cooled to room temperature, a white precipitate formed, filtered and washed (acetone) to give the title compound (515mg) as a white powder, m.p.159-161 ℃.
1H NMR(400MHz，CD3OD)：δ＝1.05-1.10(m，6H)，2.32(s，3H)，2.34-2.41(m，2H)，2.53-2.57(m，2H)，3.40(m，2H)，4.27(m，2H)，4.35(s，2H)，6.93(s，1H)，7.05(s，1H)，7.17(s，1H)。
LRMS (electrospray): m/z [ free base + H+]299。
Microanalysis: measured value: c, 54.80; h, 6.38; n, 12.11. C 21H28N4O7.0.65H2Calculated value of O: c, 54.81; h, 6.42; and N, 12.10%.
Example 280
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile succinate
To a stirred solution of the amine from example 125 (235mg, 0.79mmol) in acetone (7ml) was added succinic acid (93mg, 0.79 mmol). After 2 minutes, the mixture was concentrated to-3 ml with a stream of nitrogen, resulting in the formation of white crystals. The precipitate was filtered and washed (acetone) to give the title compound (172mg) as white crystals, m.p.155 ℃.
1H NMR(400MHz，CD3OD)：δ＝1.03-1.07(m，6H)，2.34(s，3H)，2.40(q，2H)，2.50(s，4H)，2.59(q，2H)，3.34(t，2H)，4.23(t，2H)，6.95(s，1H)，7.06(s，1H)，7.22(s，1H)。
LRMS (electrospray): m/z [ free base + H+]299。
Microanalysis: measured value: c, 60.47; h, 6.77; n, 13.39. C21H28N4O5Calculated values: c, 60.56; h, 6.78; and N, 13.45%.
Example 281
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile (L) -citrate
To a stirred solution of the amine from example 125 (140mg, 0.47mmol) in acetone (3ml) was added citric acid (90mg, 0.47 mmol). The mixture was stirred until complete dissolution had occurred. The mixture was concentrated to-1 ml with a nitrogen stream and cooled in a refrigerator for 1.5 hours. The precipitate was collected by filtration to give the title compound (149mg) as a white powder, m.p.180-182 ℃.
1H NMR(400MHz，CD3OD)：δ＝1.04-1.07(m，6H)，2.35(s，3H)，2.40(q，2H)，2.58(q，2H)，2.73(d，2H)，2.80(d，2H)，3.42(t，2H)，4.30(t，2H)，6.95(s，1H)，7.08(s，1H)，7.21(s，1H)。
LRMS (electrospray): m/z [ free base + H +]299。
Microanalysis: measured value: c, 56.19; h, 6.20; n, 11.31. C23H30N4O8Calculated values: c, 56.32; h, 6.16; n, 11.42 percent.
Example 282
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile
To a solution of the diketone of preparation 45 (30.5g, 113mmol) in acetic acid (300ml) was added dropwise 2-hydroxyethylhydrazine (8.43ml, 124mmol) at room temperature under nitrogen. The reaction was stirred at room temperature for 90 minutes and the solvent was removed under reduced pressure to give an orange solid. Another reaction was carried out in the same manner and the resulting orange solids were combined. The combined crude product was purified by flash column chromatography on silica eluting with ethyl acetate to pentane (75: 25 vol.) to give the title compound as a white solid. Proton NMR analysis showed a small amount of impurity present, so the product was purified by flash column chromatography on silica eluting with ethyl acetate pentane (50: 50 vol.) to give the title compound (50g) as a white solid, m.p.125 ℃.
1H NMR(400MHz，CDCl3)：δ＝1.13(6H，m)，2.40(2H，q)，2.53(2H，q)，3.53(1H，m)，4.11(4H，m)，7.40(2H，s)，7.58(1H，s)。
LRMS (electrospray): m/z [ MH+]311。
Microanalysis: measured value: c, 65.62; h, 5.85; n, 18.04.C17H18N4O2Calculated values: c, 65.64; h, 5.84; n, 18.05 percent.
Example 283
2- [4- (3, 5-Dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylamine and 2- [4- (3, 5-Dichlorophenoxy) -5-ethyl-1H-pyrazol-1-yl ] ethylamine
Pyrazole (1.03g, 4.00mmol) from example 42 and 2-chloroethylamine hydrochloride (510mg, 4.40mmol) were heated to the melt at 150 ℃ for 24 h. The reaction was cooled and the residue in dichloromethane (100ml) was washed with 1M aqueous potassium carbonate (50ml), brine (50ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with dichloromethane, methanol, ammonia (93: 7: 1 vol.) to give the title compound (768mg) as a 85: 15 regioisomer as a colorless oil.
1H NMR(400MHz，CDCl3): δ is 1.16 (primary, t, 3H), 1.16 (secondary, t, 3H), 2.47 (primary, q, 2H), 2.60 (secondary, q, 2H), 3.13 (primary, m, 2H), 3.13 (secondary, m, 2H), 4.10 (primary, m, 2H), 4.10 (secondary, m, 2H), 4.24 (primary, t, 2H), 4.24 (secondary, t, 2H), 6.85 (primary, s, 2H), 6.85 (secondary, s, 2H), 7.02 (primary, s, 1H), 7.02 (secondary, s, 1H), 7.27 (primary, s, 1H), 7.31 (secondary, s, 1H).
LRMS (thermal spray): m/z [ MH+]300。
The following preparations describe the preparation of certain intermediates used in the preceding examples.
Preparation example 1
3- (3, 5-Dichlorophenoxy) -2, 4-pentanedione
To a stirred suspension of 3, 5-dichlorophenol (250mg, 1.53mmol) and potassium carbonate (233mg, 1.69mmol) in acetone (7.7ml) was added 3-chloro-2, 4-pentanedione (183. mu.l, 1.53mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred for 30 minutes and then heated at reflux for 3.5 hours. After cooling, sodium iodide (230mg, 1.53mmol) was added and reflux continued for another 3.5 hours. After cooling again, the mixture was diluted with water (5ml) and concentrated under reduced pressure in a fume hood (note: tear components may remain) to remove acetone. The resulting red aqueous solution was diluted with 2M hydrochloric acid (5ml) and extracted with dichloromethane (3X 10 ml). The organic layers were combined, washed with saturated aqueous sodium sulfite (10ml) and brine (10ml), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a red oil (344 mg). The crude product was purified by flash chromatography on silica gel eluting with pentane-ethyl acetate (20: 1 vol.) to give the title compound (118mg) as a cream solid m.p.91-92 ℃.
1H NMR(400MHz，CDCl3)：δ＝2.04(s，6H)，6.84(s，2H)，7.06(s，1H)，14.38(br.s，1H)。
LRMS (thermal spray): m/z [ MNH ]4 +]278。
Microanalysis: measured value: c, 50.43; h, 3.84. C11H10Cl2O3Calculated values: c, 50.60; h, 3.86 percent.
Preparation example 2
4-chloro-3, 5-heptanedione
Chlorotrimethylsilane (29.7ml, 0.234mol) was added dropwise to a stirred, pale yellow solution of tetrabutylammonium bromide (1.26g, 3.9mmol) in anhydrous acetonitrile (116ml) at room temperature under a nitrogen atmosphere. The resulting solution was cooled in ice and 3, 5-heptanedione (10.6ml, 78.0mmol) and anhydrous dimethyl sulfoxide (16.6ml, 0.234mol) were added dropwise over 5 minutes to form a yellow solution, which was allowed to warm slowly to room temperature over 4 hours while stirring. The mixture was diluted with water (1 l), stirred for 10 min and then extracted with ether (1X 500ml, 2X 250 ml). The ether layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. The crude product was purified by distillation under reduced pressure to give the title compound (5.5g) as a pale yellow oil, b.p.102-105 ℃ C./54 mmHg, containing about 10% 4, 4-dichloro-3, 5-heptanedione according to the estimation of microanalysis.
1H NMR (400MHz，CDCl3): δ ═ 1.12(t, 6H), 2.59(q, 4H), 4.77(s, 0.2H, diketone), 15.50(s, 0.8H, enol).
LRMS (thermal spray): m/z [ MNH ]4 +]180 is the title compound and 214 is the dichloride impurity.
Preparation example 3
4- [4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] -3-oxobutanoic acid ethyl ester
To a stirred solution of 4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazole (800mg, 2.81mmol, example 3) in anhydrous N, N-dimethylformamide (5ml) was added sodium hydride (60% oil dispersion, 250mg, 6.17mmol) at 0 ℃ under nitrogen. The mixture was stirred for 5 minutes during which time hydrogen evolved and ethyl 4-chloroacetoacetate (0.42ml, 3.09mmol) was added. After 30 minutes, the reaction mixture was quenched by addition of water (0.5ml) and concentrated under reduced pressure. The ethyl acetate (50ml) solution of the residue was washed with saturated aqueous ammonium chloride (20ml) and water (20ml), dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate to pentane (30: 70 vol.) to give the title compound (1.1g) as a white solid m.p.82-84 ℃.
1H NMR(300MHz，CDCl3)：δ＝1.40(6H，m)，1.26(3H，t)，2.44(4H，q)，3.47(2H，s)，4.22(2H，q)，4.96(2H，s)，6.82(2H，s)，7.02(1H，s)。
LRMS (thermal spray): m-z[MH+]413。
Microanalysis: measured value: c, 55.13; h, 5.34; and N, 6.98. C15H15Cl2N3Calculated value of O: c, 55.22; h, 5.37; n, 6.78%.
Preparation example 4
[4- (3, 5-Dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetic acid
To a stirred solution of the ester of example 9 (2g, 5.6mmol) in tetrahydrofuran (20ml) was added aqueous sodium hydroxide (1N, 6.2ml, 6.2mmol) dropwise at 0 ℃. After 1 hour, the solvent was removed under reduced pressure, and aqueous hydrochloric acid (20ml) was added while stirring vigorously. The resulting white precipitate was collected by filtration, washed with diethyl ether (3X 30ml) and dried in a vacuum gun at 60 deg.C/10 mmHg to give the title compound as a white solid (1.5g), m.p.157-158 deg.C.
1H NMR(300MHz，CDCl3)：δ＝1.13(6H，m)，2.52(2H，q)，2.60(2H，q)，5.03(2H，s)，6.95(2H，s)，7.14(1H，s)。
LRMS (electrospray): m/z [ M-H+]341。
Preparation example 5
1- (3, 5-Dichlorophenoxy) -2-butanone
To a stirred solution of 3, 5-dichlorophenol (49g, 0.30mol) in acetone (900ml) was added cesium carbonate (108g, 0.33mol) in one portion at room temperature under a nitrogen atmosphere. To the suspension was added dropwise a solution of 1-bromo-2-butanone (30.6ml, 0.30mol) in acetone (300ml), and the resulting suspension was heated under reflux for 2 hours. The suspension was cooled to room temperature, water (200ml) was added and the acetone was removed under reduced pressure. The mixture was extracted with dichloromethane (2X 300ml) and the organic phases were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a clear oil. The crude product was purified by flash column chromatography on silica eluting with dichloromethane: cyclohexane (50: 50 vol) to give the title compound (65g) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.13(t，3H)，2.60(q，2H)，4.58(s，2H)，6.78(s，2H)，7.01(s，1H)。
LRMS (thermal spray): m/z [ MNH ]4 +]250。
Preparation example 6
2- (3, 5-Dichlorophenoxy) -1- (dimethylamino) -1-penten-3-one
A solution of the ketone from preparation 5 (65g, 0.28mol) in N, N-dimethylformamide dimethyl acetal (75ml, 0.56mol) was heated at 100 ℃ for 10 hours using a dean-Stark apparatus. The reaction was cooled and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (90: 10 vol) and then pentane: ethyl acetate (60: 40 vol) to give the title compound (55g) as a yellow oil which solidified on standing. The resulting yellow solid was washed with pentane (100ml) and dried to give the title compound (28g) as a yellow solid, m.p.96-97 ℃.
1H NMR(400MHz，CDCl3)：δ＝0.98(t，3H)，2.30(br s，2H)，2.94(s，6H)，6.77(s，2H)，6.95(s，1H)，7.24(s，1H)。
LRMS (thermal spray): m is/z[MNH4 +]288。
Preparation example 7
1-acetyl-4- (3, 5-dichlorophenoxy) -3, 5-dimethyl-1H-pyrazole
To a stirred solution of acetyl chloride (1.21ml, 17.1mmol) and pyrazole from example 53 (4.00g, 15.6mmol) in N, N-dimethylformamide (20ml) was added sodium hydride (60% oil dispersion, 684mg, 17.1mmol) at 0 ℃ under nitrogen. The reaction was stirred at 0 ℃ for 1 hour and then quenched by addition of water (100 ml). The aqueous phase was extracted with diethyl ether (2X 50 ml). The organic phases were combined, washed with water (30ml) and brine (30ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flash column chromatography on silica eluting with pentane: diethyl ether (90: 10 vol) to give the title compound (3.0g) as a white solid, m.p. < 60 ℃.
1H NMR(300MHz，CDCl3)：δ＝2.11(s，3H)，2.43(s，3H)，2.70(s，3H)，6.78(s，2H)，7.03(s，1H)。
LRMS (thermal spray): m/z [ MH+]299。
Preparation example 8
1-acetyl-3- (bromomethyl) -4- (3, 5-dichlorophenoxy) -5-methyl-1H-pyrazole
To a stirred solution of the pyrazole (3.00g, 10.0mmol) of preparation 7 in 1, 1, 1-trichloroethane (40ml) was added N-bromosuccinimide (2.70g, 15.0mmol) at room temperature under a nitrogen atmosphere. The reaction was heated at 80 ℃ for 1 hour, then azobisisobutyronitrile (2mg) was added and the reaction mixture was heated for another 3 hours. The reaction was cooled to room temperature and filtered to remove solids. The filtrate was concentrated under reduced pressure, and the resulting yellow oil was dissolved in ethyl acetate (100 ml). The ethyl acetate solution was washed with 1M aqueous sodium carbonate (30ml), water (30ml) and brine (30ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flash column chromatography on silica gel eluting with pentane: ethyl acetate (90: 10 vol.) to give a yellow solid which was washed with ice cold diethyl ether (20ml) to give the title compound (2.3g) as a white solid, m.p.111-113 ℃.
1H NMR(300MHz，CDCl3)：δ＝2.10(s，3H)，2.73(s，3H)，4.73(s，2H)，6.86(s，2H)，7.11(s，1H)。
LRMS (thermal spray): m/z [ MH+]379。
Preparation example 9
4- (3-cyanophenoxy) -3, 5-heptanedione
A mixture of preparation 2. beta. -diketone (1.79g, 11.0mmol), 3-cyanophenol (1.31g, 11.0mmol), cesium carbonate (3.58g, 11.0mmol) and acetone (44ml) was heated at reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (50ml) and water (25 ml). The organic layer was separated, washed with brine (25ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash column chromatography on silica eluting with ethyl acetate to pentane (10: 90 vol) to give the title compound (1.10g) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.04(t，6H)，2.49(q，4H)，7.16(m，2H)，7.30(d，1H)，7.39(t，2H)，14.51(s，1H)。
LRMS (thermal spray) m/z MNH4 +]263。
Preparation example 10
3- (hydroxymethyl) -4-morpholinecarboxylic acid tert-butyl ester
To a stirred suspension of 3-morpholinecarboxylic acid (1.00g, 7.63mmol) in tetrahydrofuran (50ml) was added borane (38.1ml of 1.0M tetrahydrofuran solution, 38.1mmol) dropwise at room temperature under a nitrogen atmosphere. The reaction was heated under reflux to homogenize and heating was continued for 12 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give a brown oil. The residue was dissolved in 1M aqueous sodium hydroxide solution and stirred at room temperature for 5 days. After this time di-tert-butyl dicarbonate (1.66g, 7.63mmol) was added and the reaction stirred for 12 h. The reaction was diluted with diethyl ether (100 ml). The organic layer was separated, washed with brine (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (50: 50 vol.) followed by ethyl acetate to give the title compound (1.30g) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.48(s，9H)，2.05(s，1H)，3.19(br t，1H)，3.47(td，1H)，3.60(dd，1H)，3.87(m，6H)。
LRMS (thermal spray): m/z [ MH+]218。
Preparation example 11
3- { [ (Methylsulfonyl) oxy ] methyl } -4-morpholinecarboxylic acid tert-butyl ester
To a stirred solution of the alcohol of preparation 10 (1.20g, 5.52mmol) and methanesulfonic anhydride (1.44g, 5.52mmol) in dichloromethane (50ml) was added triethylamine (1.15ml, 8.29mmol) dropwise at room temperature under nitrogen. The reaction was stirred for 1 hour and then poured into water (50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (50: 50 vol) to give the title compound (1.20g) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.49(s，9H)，3.06(s，3H)，3.50(td，1H)，3.60(dd，1H)，3.80(m，4H)，4.26(br s，1H)，4.39(m，2H)。
LRMS (thermal spray): m/z [ MNH ]4 +]313。
Preparation example 12
2- (3, 5-Dichlorophenoxy) -3-oxopentanoic acid methyl ester
A mixture of methyl 2-chloro-3-pentanoate (25.0g, 152mmol), 3, 5-dichlorophenol (24.6g, 152mmol), cesium carbonate (54.4g, 167mmol) and acetone (500ml) was heated at reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (100ml) and water (50 ml). The organic layer was separated, washed with brine (25ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an orange oil. The crude product was purified by flash column chromatography on silica eluting with pentane: toluene (90: 10 vol.) to give the title compound (40.0g) as a pink oil.
1H NMR(300MHz，CDCl3)：δ＝1.16(t，3H)，2.60(m，2H)，3.77(s，3H)，5.13(s，1H)，6.84(s，2H)，7.10(s，1H)。
LRMS (thermal spray): m/z [ MNH ]4 +]308。
Preparation example 13
4- (3, 5-Dichlorophenoxy) -5-ethyl-2- (2-hydroxyethyl) -2, 4-dihydro-3H-pyrazol-3-one
To a stirred solution of the keto ester of preparation 12 (15.0g, 51.5mmol) in glacial acetic acid (100ml) was added a solution of 2-hydroxyethylhydrazine (4.30g, 56.7mmol) in glacial acetic acid (2.0ml), and the resulting solution was stirred at room temperature for 48 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography on silica gel eluting with methylene chloride: methanol (95: 5 vol.) to give the title compound (10.1g) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝1.02(t，3H)，2.29(m，2H)，3.63(m，2H)，3.80(m，2H)，6.92(s，2H)，7.21(s，1H)。
LRMS (thermal spray): m/z [ MH+]317。
Microanalysis: measured value: c, 48.86; h, 4.44; n, 9.01.C13H14N2O3Cl2Calculated values: c, 49.23; h, 4.45; n, 8.83 percent.
Preparation example 14
2- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -4- (3, 5-dichlorophenoxy) -5-ethyl-2, 4-dihydro-3H-pyrazol-3-one
To a stirred solution of pyrazole (14.3g, 45.0mmol) of preparation example 13 and imidazole (3.98g, 58.5mmol) in N, N-dimethylformamide (90ml) was added tert-butyldimethylsilyl chloride (8.14g, 54.0mmol), and the resulting solution was stirred at room temperature for 48 hours. The mixture was partitioned between ethyl acetate (100ml) and water (300 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with methylene chloride: methanol (95: 5 vol.) to give the title compound (9.56g) as a colorless oil.
1HNMR(400MHz，CDCl3)：δ＝0.15(s，6H)，0.94(s，9H)，1.16(t，3H)，2.45(m，2H)，3.94(m，4H)，6.85(s，2H)，6.97(s，1H)。
LRMS (thermal spray): m/z [ MH+]431。
Microanalysis: measured value: c, 52.87; h, 6.52; n, 6.46.C19H28N2O3Cl2Calculated Si: c, 52.90; h, 6.54; and 6.49 percent of N.
Preparation example 15
1- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazole 5-yl trifluoromethanesulfonate
To a stirred solution of the pyrazole of preparation 14 (4.10g, 9.50mmol) and triethylamine (1.60ml, 11.4mmol) in dichloromethane (20ml) at room temperature under nitrogen was added phenyl trifluoromethanesulfonamide (3.70g, 10.5mmol) in one portion. The reaction was stirred for 2 hours and then poured into water (50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with dichloromethane to give the title compound (5.10g) as a magenta oil.
1H NMR(300MHz，CDCl3)：δ＝0.01(s，6H)，0.86(s，9H)，1.17(t，3H)，2.45(q，2H)，4.01(m，2H)，4.14(m，2H)，6.84(s，2H)，7.08(s，1H)。
LRMS (thermal spray): m/z [ MH+]563。
Preparation example 16
3- (1-acetyl-2-oxopropoxy) -5-chlorobenzonitrile
A mixture of 3-chloro-2, 4-pentanedione (6.73g, 50.0mmol), preparation 36 phenol (7.67g, 50.0mmol), cesium carbonate (18.0g, 55.4mmol) and acetone (40ml) was heated at reflux for 2 hours. The reaction was cooled to room temperature, N-dimethylformamide (6ml) and acetone (30ml) were added and the reaction was heated at 70 ℃ for another 12 hours. After cooling, the solid was removed by filtration and dissolved in 1M aqueous hydrochloric acid (150 ml). The resulting solution was extracted with dichloromethane (3X 100ml) and the organic phases were combined, washed with brine (30ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (5.50g) as a brown solid, m.p.105-108 ℃.
1H NMR (300MHz，CDCl3)：δ＝2.04(s，6H)，7.13(s，1H)，7.19(s，1H)，7.35(s，1H)，14.40(s，1H)。
Preparation example 17
3- [ (1-acetyl-3, 5-dimethyl-1H-pyrazol-4-yl) oxy ] -5-chlorobenzonitrile
To a stirred solution of acetyl chloride (1.50ml, 21.0mmol) and pyrazole (4.80g, 19.4mmol) from example 76 in N, N-dimethylformamide (20ml) was added sodium hydride (60% oil dispersion, 840mg, 21.0mmol) at 0 ℃ under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes and then quenched by the addition of water (200 ml). The reaction mixture was extracted with ethyl acetate (3X 120 ml). The organic phases were combined, washed with water (50ml) and brine (50ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane to give the title compound (5.00g) as a white solid, m.p. < 60 ℃.
1H NMR(400MHz，CDCl3)：δ＝2.06(s，3H)，2.38(s，3H)，2.65(s，3H)，6.99(m，1H)，7.08(m，1H)，7.29(m，1H)。
LRMS (thermal spray): m/z [ MH+]290。
Preparation example 18
3- { [ 1-acetyl-3- (bromomethyl) -5-methyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile
To a stirred solution of pyrazole (5.00g, 17.3mmol) of preparation 17 in 1, 1, 1-trichloroethane (70ml) and azobisisobutyronitrile (20mg) was added N-bromosuccinimide (4.60g, 25.6mmol) at room temperature under a nitrogen atmosphere. The reaction was heated at 80 ℃ for 3 hours and then cooled to room temperature. A second portion of N-bromosuccinimide (2.00g, 11.2mmol) was added and the reaction mixture was heated at 80 ℃ for an additional 4 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, and the resulting yellow oil was purified by flash column chromatography on silica eluting with pentane: dichloromethane (25: 75 vol.) to give the title compound (2.30g) as a white solid, m.p.122-123 ℃.
1H NMR(300MHz，CDCl3)：δ＝2.10(s，3H)，2.74(s，3H)，473(s，2H)，7.12(s，1H)，7.22(s，1H)，7.39(s，1H)。
Preparation example 19
3-chloro-5, 5-dimethyl-2, 4-hexanedione
Chlorotrimethylsilane (26.8ml, 0.21mol) was added dropwise to a stirred, pale yellow solution of tetrabutylammonium bromide (1.13g, 3.50mmol) in anhydrous acetonitrile (100ml) at room temperature under a nitrogen atmosphere. The resulting solution was cooled in ice, 5-dimethylhexane-2, 4-dione (10.0g, 70.4mmol) and anhydrous dimethyl sulfoxide (14.7ml, 0.21mol) were added dropwise over 5 minutes to form a yellow solution, which was allowed to warm slowly to room temperature over 3 hours while stirring. The mixture was diluted with water (1000ml), stirred for 10 minutes and then extracted with ether (1X 500ml, 2X 250 ml). The ether layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. The crude product was purified by distillation under reduced pressure to give the title compound (10.0g) as a pale yellow oil, b.p.220-225 ℃ C./60 mmHg.
1H NMR(400MHz，CDCl3)：δ＝1.25(s，9H)，2.39(s，3H)，5.10(s，1H)。
LRMS (thermal spray): m/z [ MNH ]4 +]194。
Preparation example 20
4- [ (methylamino) methyl ] benzonitrile
4-Cyanobenzaldehyde (12.0g, 92.0mmol), methylamine (69ml of a 2.0M tetrahydrofuran solution, 137mmol) and magnesium sulfate (45g) were stirred in dichloromethane (300ml) at room temperature for 5 days. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a yellow oil. The oil was dissolved in methanol (200ml) and sodium borohydride (4.10g, 109mmol) was added carefully with vigorous stirring. Once the addition was complete, the reaction was stirred for 1 hour and the mixture was concentrated under reduced pressure. The residue was dissolved in 1M aqueous sodium hydroxide solution (200ml), and the mixture was stirred at room temperature for 1 hour. The resulting solution was extracted with dichloromethane (2X 200ml), the organic phases combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (13.4g) as a pale yellow oil.
1H NMR(300MHz，CDCl3)：δ＝1.46(s，1H)，2.46(s，3H)，3.82(s，2H)，7.47(d，2H)，7.64(d，2H)。
LRMS (electrospray): m/z [ MH+]147。
Preparation example 21
4- { [ (2-hydroxyethyl) amino ] methyl } benzonitrile
Using a dean Stark apparatus, a mixture of 4-cyanobenzaldehyde (14.1g, 107mmol0, ethanolamine (6.56g, 107mmol) and toluene (100ml) was heated at reflux for 14 hours to remove water, the reaction was cooled to room temperature and concentrated under reduced pressure to give a yellow oil, the oil was dissolved in dichloromethane (200ml), cooled to 0 ℃, triethylamine (16.3ml, 117mmol) and chlorotrimethylsilane (14.9ml, 117mmol) were added dropwise with white precipitate, after stirring for 1 hour, the mixture was filtered, the filtrate was concentrated under reduced pressure to give an orange solid (25.0g), sodium borohydride (4.50g, 122mmol) was added carefully, while stirring vigorously, the reaction was stirred for 1 hour once added, then the mixture was concentrated under reduced pressure, the residue was concentrated in 1M aqueous hydroxide solution (200ml), the mixture was stirred at room temperature for 1 hour. The resulting solution was extracted with dichloromethane (3X 200ml) and the organic phases were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with dichloromethane: methanol: ammonia (95: 4: 1 vol.) to give the title compound (12.0g) as a pale yellow oil which solidified upon standing to give a yellow solid m.p. < 60 ℃.
1H NMR(300MHz，CDCl3)：δ＝1.84(s，2H)，2.84(t，2H)，3.68(t，2H)，3.89(s，2H)，7.45(d，2H)，7.65(d，2H)。
LRMS (thermal spray): m/z [ MH+]177。
Preparation example 22
N- { [1- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -N- (3-pyridylmethyl) amine
To a stirred solution of preparation 28 bromide (300mg, 0.610mmol) in isopropanol (5ml) was added 3- (methylamino) pyridine (327mg, 3.04mmol) in one portion at room temperature. The mixture was heated at 50 ℃ for 1 hour, cooled to room temperature and concentrated under reduced pressure to give an orange oil. The crude product was purified by flash column chromatography on silica eluting with methylene chloride, methanol, ammonia (95: 4: 1 vol.) to give the title compound (50mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝0.15(s，6H)，0.77(s，9H)，2.02(s，3H)，3.64(s，2H)，3.70(s，2H)，3.95(t，2H)，4.17(t，2H)，6.75(s，2H)，6.97(s，1H)，7.15(dd，1H)，7.53(d，1H)，8.47(m，2H)。
LRMS (thermal spray): m/z [ MH+]521。
Preparation example 23
3-chloro-5-methyl-2, 4-hexanedione
Chlorotrimethylsilane (13.4ml, 105mmol) was added dropwise to a stirred, pale yellow solution of tetrabutylammonium iodide (566mg, 1.53mmol) in anhydrous acetonitrile (100ml) at room temperature under nitrogen. The resulting solution was cooled in ice and 5-methylhexane-2, 4-dione (4.50g, 35.1mmol) and anhydrous dimethyl sulfoxide (7.47ml, 105mmol) were added dropwise over 5 minutes to form a yellow solution which was allowed to warm slowly to room temperature over 1 hour while stirring. Tetrabutylammonium bromide (566mg, 1.75mmol) was then added in one portion and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with water (200ml), stirred for 10 min and then extracted with ether (3X 100 ml). The ether layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (98: 2 vol) to give the title compound (2.00g) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.15(d，6H)，2.29(s，3H)，3.25(sept，1H)，15.60(s，1H)。
LRMS (thermal spray): m/z [ MNH ]4+]180。
Preparation example 24
5- (1-acetyl-3-methyl-2-oxobutoxy) isophthalonitrile
A mixture of the diketone of preparation 23 (1.12g, 6.94mmol), the phenol of preparation 39 (1.00g, 6.94mmol), cesium carbonate (2.25g, 6.94mmol) and acetone (30ml) was heated at reflux for 4 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give a brown solid. The solid was dissolved in 1M aqueous hydrochloric acid (50ml) and the solution was extracted with dichloromethane (3X 30 ml). The organic phases were combined, washed with brine (30ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (90: 10 vol) to give the title compound (580mg) as a yellow solid.
1H NMR(300MHz，CDCl3)：δ＝1.08(d，6H)，2.02(s，3H)，2.24(sept，1H)，7.47(s，2H)，7.63(s，1H)，14.71(s，1H)。
LRMS (electrospray): m/z [ M-H+]269。
Preparation example 25
5- { [1- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -3-isopropyl-5-methyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile
To a stirred solution of 2-bromoethoxy-tert-butyldimethylsilane (270mg, 1.12mmol) and the pyrazole (250mg, 0.930mmol) from example 95 in N, N-dimethylformamide (5ml) was added sodium hydride (60% oil dispersion, 45mg, 1.12mmol) at 0 ℃ under nitrogen. The reaction was allowed to warm to room temperature and stirred for 12 hours. Water (50ml) was added to quench the reaction mixture and the aqueous phase was extracted with ethyl acetate (3X 30 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography on silica eluting with pentane: ethyl acetate (80: 20 vol) to give the title compound (60mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝0.02(s，6H)，0.85(s，9H)，1.19(d，6H)，2.09(s，3H)，2.79(sept，1H)，3.99(m，2H)，4.10(m，2H)，7.39(s，2H)，7.57(s，1H)。
LRMS (electrospray): m/z [ MH+]425。
Preparation example 26
Di (tert-butyl) 2- [4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylimino dicarbonate and di (tert-butyl) 2- [4- (3, 5-dichlorophenoxy) -5-ethyl-1H-pyrazol-1-yl ] ethylimino dicarbonate
To a stirred solution of the amine of example 283 (7.72g, 25.7mmol) in acetonitrile (128ml) was added di-tert-butyl dicarbonate (14.0g, 64.2mmol) and 4, 4-dimethylaminopyridine (630mg, 5.14mmol) portionwise at room temperature under a nitrogen atmosphere. The reaction was stirred for 14 hours and concentrated under reduced pressure. The residue was washed with water (100ml) and a solution of dichloromethane (300ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with methylene chloride: methanol (99: 1 vol.) to give the title compound (12.3g) as a colorless oil in the 85: 15 regioisomer.
1H NMR(400MHz，CDCl3): δ is 1.15 (primary, t, 3H), 1.15 (secondary, t, 3H), 1.52 (primary, s, 18H), 1.52 (secondary, s, 18H), 2.47 (primary, q, 2H), 2.56 (secondary, q, 2H), 4.00 (primary, t, 2H), 4.00 (secondary, t, 2H), 4.24 (primary, t, 2H), 4.24 (secondary, t, 2H), 6.85 (primary, s, 2H), 6.85 (secondary, s, 2H), 7.00 (primary, s, 1H), 7.00 (secondary, s, 1H), 7.21 (primary, s, 1H), 7.25 (secondary, s, 1H).
LRMS (thermal spray): m/z [ MH+]500。
Microanalysis: measured value: c, 54.94; h, 6.26; n, 8.27.C23H31Cl2N3O5Calculated values: c, 55.20; h, 6.24; and N, 8.40%.
Preparation example 27
1- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -4- (3, 5-dichlorophenoxy) -3, 5-dimethyl-1H-pyrazole
To a stirred solution of pyrazole (3.50g, 11.6mmol) from example 1 and imidazole (1.03g, 15.1mmol) in N, N-dimethylformamide (23ml) was added chloro-tert-butyldimethylsilane (1.93g, 12.8mmol) in one portion at room temperature under nitrogen. The reaction was stirred for 2 days and water (200ml) was added. The aqueous phase was extracted with diethyl ether (3X 200ml) and the organic phases were combined, washed with water (2X 50ml) and brine (2X 50ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with pentane: ethyl acetate (80: 20 vol.) to give the title compound (4.82g) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝0.09(s，6H)，0.78(s，9H)，2.01(s，3H)，2.05(s，3H)，3.88(q，2H)，4.02(q，2H)，6.76(s，2H)，6.88(s，1H)。
LRMS (thermal spray): m/z [ MH+]415。
Preparation example 28
5- (bromomethyl) -1- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazole
To a stirred solution of pyrazole (1.00g, 2.40mmol) of preparation 27 in carbon tetrachloride (15ml) and azobisisobutyronitrile (20mg) was added N-bromosuccinimide (640mg, 3.60mmol) at room temperature under a nitrogen atmosphere. The reaction was heated at reflux for 5 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by flash column chromatography on silica gel eluting with methylene chloride: methanol: ammonia (97: 2.5: 0.5 vol.) to give the title compound (300mg) as a colorless oil.
1H NMR(300MHz，CDCl3)：δ＝0.04(s，6H)，0.82(s，9H)，2.02(s，3H)，3.96(m，2H)，4.22(m，2H)，4.41(s，2H)，6.81(s，2H)，7.01(s，1H)。
LRMS (thermal spray): m/z [ MH+]495。
Preparation example 29
3- { [1- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -3, 5-dimethyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile
To a stirred solution of pyrazole (4.89g, 16.8mmol) from example 114 and imidazole (1.48g, 21.8mmol) in N, N-dimethylformamide (30ml) was added chloro-tert-butyldimethylsilane (2.78g, 18.5mmol) in one portion at room temperature under a nitrogen atmosphere. The reaction was stirred for 3 days and water (200ml) was added. The aqueous phase was extracted with diethyl ether (3X 200ml) and the organic phases were combined, washed with water (2X 50ml) and brine (2X 50ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with dichloromethane to give the title compound (5.60g) as a yellow oil.
1H NMR(400MHz，CDCl3).δ＝-0.02(s，6H)，0.82(s，9H)，2.02(s，3H)，2.12(s，3H)，3.97(q，2H)，4.06(m，2H)，7.02(s，1H)，7.11(s，1H)，7.24(s，1H)。
LRMS (thermal spray): m/z [ MH+]408。
Microanalysis: measured value: c, 58.95; h, 6.96; n, 10.22.C20H28N3O2Calculated ClSi: c, 59.13; h, 6.95; n, 10.35 percent.
Preparation example 30
3- { [5- (bromomethyl) -1- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -3-methyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile
To a stirred solution of pyrazole (5.56g, 13.7mmol) of preparation 29 in carbon tetrachloride (50ml) and azobisisobutyronitrile (20mg) was added N-bromosuccinimide (2.44g, 13.7mmol) at room temperature under a nitrogen atmosphere. The reaction was heated at reflux for 1 hour, cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with pentane: dichloromethane (75: 25 vol) to give the title compound (3.00g) as a colourless oil.
1H NMR(300MHz，CDCl3)：δ＝-0.02(s，6H)，0.83(s，9H)，2.04(s，3H)，3.97(q，2H)，4.25(m，2H)，4.43(s，2H)，7.09(s，1H)，7.18(s，1H)，7.33(s，1H)。
LRMS (thermal spray): m/z [ MH+]486。
Preparation example 31
3- { [5- (aminomethyl) -1- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -3-methyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile
To a saturated solution of ammonia in isopropanol (50ml) at 0 deg.C was added preparation 30 bromide (1.58g, 3.26 mmol). The reaction was stirred for 6 hours and slowly warmed to room temperature. The mixture was concentrated under reduced pressure and the resulting yellow oil was dissolved in dichloromethane (50 ml). The solution was washed with 1M aqueous sodium carbonate (2X 20ml) and brine (20ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (1.00g) as a yellow oil.
1H NMR(300MHz，CDCl3)：δ＝-0.23(s，6H)，0.62(s，9H)，1.22(s，2H)，1.82(s，3H)，2.56(s，2H)，3.78(m，2H)，4.02(m，2H)，6.85(s，1H)，6.96(s，1H)，7.06(s，1H)。
LRMS (thermal spray): m/z [ MH+]421。
Preparation example 32
1-bromo-3-chloro-5-methoxybenzene
To a stirred solution of 1-fluoro-3-chloro-5-bromobenzene (1.00g, 4.77mmol) in methanol (28ml) was added dropwise sodium methoxide (2.20ml of 4.5M methanol solution, 10.0mmol) at room temperature under nitrogen. The reaction was heated at reflux for 3 days and cooled to room temperature. The mixture was concentrated under reduced pressure and the resulting yellow oil was dissolved in dichloromethane (30 ml). The resulting solution was washed with water (2 × 20ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with cyclohexane to give the title compound (302mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝3.77(s，3H)，6.82(s，1H)，6.94(s，1H)，7.09(s，1H)。
Microanalysis: measured value: c, 37.94; h, 2.75. C7H6BrClO calculated: c, 37.96; h, 2.73 percent.
Preparation example 33
3-fluoro-5-methoxybenzonitrile
To a stirred solution of 3, 5-difluorobenzonitrile (1.00g, 7.10mmol) in N, N-dimethylformamide (36ml) was added dropwise sodium methoxide (1.50ml of 4.5M methanol solution, 7.100mmol) at 0 ℃ under nitrogen. The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was diluted with ether (40ml), washed with water (3X 100ml) and brine (100ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane: ethyl acetate (95: 5 vol.) to give the title compound (418mg) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝3.84(s，3H)，6.82(dd，1H)，6.95(dd，1H)，6.96(s，1H)。
LRMS (thermal spray): m/z [ MNH ]4 +]169。
Microanalysis: measured value: c, 63.46; h, 3.95; and N, 9.14. C8H6Calculated NOF: c, 63.58; h, 4.00; and N, 9.27%.
Preparation example 34
3-fluoro-5-hydroxybenzonitrile
Boron trichloride (1.65ml of a 1.0M solution in dichloromethane, 1.65mmol) was added dropwise to a stirred solution of the nitrile of preparation 33 (100mg, 0.660mmol) and tetrabutylammonium iodide (268mg, 0.728mmol) in dichloromethane (3ml) at-78 ℃. The reaction was allowed to warm to 0 ℃ and stirred for 2 hours, then to room temperature and stirred for 14 hours. The reaction was cooled to 0 ℃, carefully quenched with ice, and then concentrated under reduced pressure. The residue was dissolved in ether (40ml) and the resulting solution was washed with water (3X 40ml) and brine (40ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane: ethyl acetate (90: 10 vol.) to give the title compound (50mg) as a white solid, m.p.138-139 ℃.
1H NMR(300MHz，CDCl3)：δ＝5.81(s，1H)，6.80(dd，1H)，6.94(dd，1H)，6.95(s，1H)。
Microanalysis: measured value: c, 60.99; h, 3.01; n, 10.16. C7H4Calculated NOF: c, 61.32; h, 2.94; n, 10.22 percent.
Preparation example 35
3-chloro-5-methoxybenzonitrile
To a stirred solution of preparation 32 bromide (500mg, 2.26mmol) and zinc cyanide (146mg, 1.24mmol) in N, N-dimethylformamide (3ml) at room temperature under nitrogen was added tetrakis (triphenylphosphine) palladium (174mg, 0.150mmol) in one portion. The reaction was heated at 100 ℃ for 14 h and cooled to room temperature. The mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica gel eluting with cyclohexane: ethyl acetate (95: 5 vol.) to give the title compound (380mg) as a yellow oil.
1H NMR(300MHz，CDCl3)：δ＝3.82(3H，s)，7.04(s，1H)，7.12(s，1H)，7.23(s，1H)。
Microanalysis: measured value: c, 57.50; h, 3.63; n is added to the reaction solution to form a reaction solution,8.16。C8H6calculated NOCl: c, 57.33; h, 3.61; and N, 8.36 percent.
Preparation example 36
3-chloro-5-hydroxybenzonitrile
To a stirred solution of the nitrile of preparation 35 (1.80g, 10.0mmol) and tetrabutylammonium iodide (4.36g, 11.0mmol) in dichloromethane (50ml) was added boron trichloride (26.0ml of a 1.0M solution in dichloromethane, 26.0mmol) dropwise at-78 ℃. The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was cooled to 0 ℃, quenched carefully with ice and diluted with dichloromethane (100 ml). The organic phase was washed with water (3X 40ml) and brine (40ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane: ethyl acetate (80: 20 vol) to give the title compound (900mg) as a white solid.
1H NMR(400MHz，d6-DMSO)：δ＝7.12(m，2H)，7.38(s，1H)，10.65(s，1H)。
Microanalysis: measured value: c, 54.76; h, 2.81; and N, 8.94. C7H4Calculated NOCl: c, 54.75; h, 2.63; and N, 9.12%.
Preparation example 37
1, 3-dibromo-5-methoxybenzene
To a stirred solution of 3, 5-dibromofluorobenzene (5.00g, 19.0mmol) in N, N-dimethylformamide (95ml) was added dropwise sodium methoxide (8.80ml of 4.5M methanol solution, 41.0mmol) at 0 ℃ under a nitrogen atmosphere. The reaction was allowed to warm to room temperature, stirred for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in ether, and the resulting solution was washed with water (3X 300ml) and brine (300ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (5.13g) as a white solid.
1H NMR(300MHz，CDCl3)：δ＝3.79(s，3H)，7.00(s，2H)，7.26(s，1H)。
LRMS (thermal spray): m/z [ MH+]266。
Microanalysis: measured value: c, 31.56; h, 2.29.C7H6OBr2Calculated values: c, 31.62; h, 2.27 percent.
Preparation example 38
3, 5-dicyanomethoxybenzene
To a stirred solution of bromide from preparation 37 (38.0g, 143mmol) and zinc cyanide (20.0g, 172mmol) in N, N-dimethylformamide (300ml) was added tris (dibenzylideneacetone) dipalladium (6.53g, 7.15mmol) in one portion at room temperature under nitrogen. The reaction was heated at 100 ℃ for 14 h and cooled to room temperature. Water (1500ml) was added to the solution, and the mixture was extracted with ethyl acetate (3X 500 ml). The organic layers were combined, filtered and the filtrate was washed with water (500ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting solid was triturated with toluene (1000ml) to give the title compound (18.0g) as a tan solid.
1H NMR(300MHz，CDCl3)：δ＝3.83(3H，s)，7.31(2H，s)，7.48(1H，s)。
Preparation example 39
3, 5-dicyano hydroxy benzene
To a stirred suspension of aluminum trichloride (32.4g, 243mmol) in dichloromethane (250ml) was added in portions, at 0 ℃ under nitrogen, preparation 38 nitrile (9.60g, 60.7 mmol). The suspension was heated to 45 ℃ and stirred for 6 days. The reaction was cooled to room temperature and carefully poured onto ice (450 ml). Concentrated hydrochloric acid (450ml) was added dropwise and the resulting suspension was stirred at room temperature for 10 minutes. The resulting solid was collected by filtration, washed with water, and dried over phosphorus pentoxide to give the title compound (7.83g) as a tan solid,1h NMR and microanalysis contained about 11% starting material.
1H NMR(400MHz，CDCl3)：δ＝7.36(m，2H)，7.56(m，1H)。
Preparation example 40
3-methoxy-5-methylphenyl trifluoromethanesulfonate
To a stirred solution of 3-methoxy-5-methylphenol (1.50g, 10.9mmol) in pyridine (20ml) was added dropwise triflic anhydride (2.02ml, 12.0mmol) at-20 ℃ under nitrogen. The reaction was warmed to 0 ℃, stirred for 90 minutes, and cooled again to-20 ℃. More trifluoromethanesulfonic anhydride (1.01ml, 6.00mmol) was added dropwise. The reaction was allowed to warm to room temperature, stirred for 14 h and poured carefully into water (100 ml). The aqueous phase was extracted with ether (150ml), and the organic phase was washed with water (3X 75ml), 0.2M hydrochloric acid (3X 75ml), 1.0M aqueous sodium carbonate (2X 75ml), water (75ml) and brine (75ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (2.86g) as a pale brown oil.
1H NMR(400MHz，CDCl3)：δ＝2.35(s，3H)，3.80(s，3H)，6.60(s，1H)，6.68(s，1H)，6.73(s，1H)。
Preparation example 41
3-methoxy-5-methylbenzonitrile
At room temperature, while stirringSuspension of zinc (supplied by Aldrich chemical company, 100ml tetrahydrofuran containing 5g zinc) (74mg, 1.14mmol) in acetonitrile (4ml) was added successively to preparative example 40 trifluoromethanesulfonate (1.94g, 7.10mmol), dibromobis (triphenylphosphine) nickel (369mg, 0.490mmol), 1' -bis (diphenylphosphino) ferrocene (331mg, 0.590mmol) and potassium cyanide (1.38g, 21.3 mmol). The reaction was heated to 75 ℃ for 8 hours and then cooled to room temperature. The mixture was partitioned between ether (200ml) and water (150ml), the organic phase was separated, washed with water (2X 100ml) and brine (75ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a light brown oil. The crude product was purified by flash chromatography on silica eluting with pentane: ethyl acetate (85: 15 vol) to give the title compound (815mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝2.34(s，3H)，3.80(s，3H)，6.93(s，1H)，6.94(s，1H)，7.04(s，1H)。
Preparation example 42
3-hydroxy-5-methylbenzonitrile
To a stirred solution of preparation 41 nitrile (866mg, 5.88mmol) and tetrabutylammonium iodide (2.61g, 7.05mmol) in dichloromethane (50ml) was added boron trichloride (17.6ml of a 1.0M solution in dichloromethane, 17.6mmol) dropwise at-78 ℃. The reaction was allowed to warm to room temperature and stirred for 20 minutes. The reaction was cooled to 0 ℃, quenched carefully with ice and diluted with dichloromethane (100 ml). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with pentane: ethyl acetate (50: 50 vol) to give the title compound (677mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝2.32(s，3H)，5.05(s，1H)，6.88(s，1H)，6.90(s，1H)，7.04(s，1H)。
Preparation examples 43 to 46
By a method similar to preparation 9, using the appropriate phenolic starting material and preparation 2 chloride, the following compounds of the general formula preparations were prepared, as shown in the following table:
preparation example 47
1-cyclopropyl-1, 3-pentanedione
A stirred suspension of magnesium turnings (1.83g, 75.0mmol) in methanol (85ml) was heated at reflux for 90 minutes. The suspension was cooled to room temperature and a solution of 3-ketopentanoic acid (17.4g, 150.0mmol) in methanol (15ml) was added. The white suspension was dissolved to give a pale yellow solution. The reaction was stirred at room temperature for 1 hour, then concentrated under reduced pressure to give a pale yellow solid, which was dissolved in N, N-dimethylformamide (50 ml). To a stirred solution of cyclopropanecarboxylic acid (6.46g, 75.0mmol) in N, N-dimethylformamide (150ml) was added carbonyldiimidazole (13.4g, 83.0mmol) portionwise at room temperature under nitrogen in a separate flask. The reaction was stirred for 90 minutes and then the magnesium salt prepared previously was added dropwise. The reaction was stirred for 3 days and then poured into 1.0M hydrochloric acid (150 ml). The aqueous phase is extracted with diethyl ether (3X 200ml) and the organic phases are combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with pentane: ethyl acetate (90: 10 vol.) to give the title compound (9.33g) as a yellow oil.
1H NMR(400MHz，CDCl3): in the form of ketones and enols, predominantly enols; enol signal δ is 1.00(m, 7H), 1.60(m, 1H), 2.25(m, 2H), 5.59(s, 1H), 15.62(s, 1H); ketone signal δ is 1.00(m, 7H), 2.01(m, 1H), 2.52(m, 2H), 3.68(s, 2H).
LRMS (electrospray): m/z [ M-H+]139。
Microanalysis: measured value: c, 68.35; h, 8.72. C8H12O2Calculated values: c, 68.55; h, 8.63 percent.
Preparation example 48
By a method similar to preparation 47, using the appropriate keto acid and carboxylic acid starting materials, the following compounds of the general formula preparations are prepared, as set forth in the following table:
preparation examples 49 to 51
By a method similar to preparation 2, using the appropriate diketone starting material, the following compounds of the general formula preparations are prepared, as set forth in the following table:
preparation examples 52 to 54
By a method similar to preparation 9, using the appropriate diketone starting material and preparation 39 phenol, the following compounds of the general formula preparations are prepared, as shown in the following table:
preparation example 55
4- (aminomethyl) benzamide
To a stirred solution of 4- (aminomethyl) benzonitrile (200mg, 1.5mmol) in 2-methyl-2-propanol (20ml) was added in one portion, under reflux and under nitrogen, comminuted sodium hydroxide (340mg, 6 mmol). The reaction was heated at reflux for 30 minutes and cooled to room temperature. The mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica gel eluting with dichloromethane: methanol: ammonia (95: 5: 0.5 vol.) to give the title compound (150mg) as a white solid.
1H NMR(300MHz，CD3OD)：δ＝3.85(s，2H)，7.43(d，2H)，7.82(d，2H)。
LRMS (thermal spray): m/z [ MH+]151。
Preparation example 56
3-oxopentanoic acid
To a solution of methyl 3-oxopentanoate (80g, 0.62mol) in tetrahydrofuran (300ml) and water (300ml) was added sodium hydroxide (54g, 1.35mol) portionwise at 0 ℃. The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was washed with diethyl ether (500ml) and the aqueous phase was acidified to pH1 with concentrated hydrochloric acid (140ml) at 0 ℃. The aqueous phase was extracted with dichloromethane (2X 300ml) and the organic extracts combined, dried over magnesium sulphate and concentrated under reduced pressure to give the title compound (44g) as a white solid.
1H NMR (400MHz，CDCl3)：δ＝1.12(t，3H)，2.59(q，2H)，3.49(s，2H)。
Preparation example 57
3- (benzylchloro) propionic acid
To benzyl alcohol (30g, 278mmol) was added sodium metal (249mg, 10.8mmol) at room temperature under nitrogen and the reaction was stirred for 30 min. Methyl acrylate (25.9ml, 259mmol) was then added dropwise and the reaction stirred at room temperature for 18 h. After quenching with saturated aqueous ammonium chloride (200ml), the mixture was extracted with ethyl acetate (2X 300ml), and the organic extracts were combined, washed with brine (100ml), dried over magnesium sulfate and concentrated under reduced pressure. The remaining oil was dissolved in ethanol (300ml), and a 1M aqueous solution of sodium hydroxide (300ml) was added dropwise. After 3 hours, the ethanol was removed under reduced pressure and the aqueous residue was washed with dichloromethane (200 ml). The aqueous phase was then acidified with 2N aqueous hydrochloric acid (150ml), extracted with dichloromethane (2X 250ml), the organic extracts combined, dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was dissolved in 10% aqueous potassium carbonate (300ml), washed with diethyl ether (300ml) and the aqueous phase acidified to pH1 with concentrated hydrochloric acid. The mixture was then extracted with dichloromethane (2X 300ml) and the organic extracts combined, dried over magnesium sulphate and concentrated under reduced pressure to give the title compound (44.4g) as a colourless oil.
1H NMR(300MHz，CDCl3)：δ＝2.67(t，2H)，3.89(t，2H)，4.58(s，2H)，7.18(m，5H)。
Preparation example 58
(4Z) -1- (benzyloxy) -5-hydroxy-4-hepten-3-one
A suspension of magnesium turnings (1.74g, 71.6mmol) in methanol (85ml) was heated at reflux under nitrogen for 1.5 h, cooled to room temperature and the preparation 56 beta-keto acid (16.6g, 143mmol) was added. The reaction was stirred for 1.5 hours and the solvent was removed under reduced pressure to give the magnesium salt of the acid as a white solid. Meanwhile, preparation 57 acid (12.9g, 71.6mmol) was dissolved in dimethylformamide (150ml0, carbonyldiimidazole (12.8g, 78.8mmol) was added portionwise at room temperature under nitrogen atmosphere, stirred for 1 hour, dimethylformamide (50ml) solution of the above magnesium salt was added, note that there was gas evolution, the reaction was stirred at room temperature for 18 hours, the mixture was concentrated under reduced pressure, the remaining orange oil was dissolved in dichloromethane (300ml), washed with 0.5M aqueous hydrochloric acid (250ml) containing methanol (10ml), the aqueous phase was separated, extracted with dichloromethane (2X 300ml), the organic extracts were combined, washed with brine (300ml) containing methanol (20ml), dried over magnesium sulfate, concentrated under reduced pressure, the remaining orange oil was purified by flash silica gel chromatography, eluted with cyclohexane: ethyl acetate (80: 20 volume ratio) to give the title compound (12.0g), an orange oil.
1H NMR(400MHz，CDCl3)：δ＝1.17(t，3H)，2.33(q，2H)，2.58(t，2H)，3.76(t，2H)，4.53(s，2H)，5.57(s，1H)，7.13(m，5H)。
LRMS (electrospray): m/z [ MNa ]+]257。
Microanalysis: measured value: c, 71.77; h, 7.74. C14H18O3Calculated values: c, 71.76; h, 7.69 percent.
Preparation example 59
(4E) -1- (benzyloxy) -4-chloro-5-hydroxy-4-hepten-3-one
To a solution of preparation 58 enol (4.0g, 17.1mmol) in acetonitrile (25ml) was added trimethylsilyl chloride (10ml, 51.3mmol) at 0 ℃ under nitrogen. Then dimethyl sulfoxide (3.6ml, 51.3mmol) was added followed by tert-butylammonium bromide (275mg, 0.85mmol) and the reaction stirred at 0 ℃ for 2 h. The mixture was diluted with water (100ml), extracted with diethyl ether (100ml) and the organic phase washed with brine (50ml), dried over magnesium sulphate and concentrated under reduced pressure. The remaining pink oil was purified by flash chromatography on silica gel eluting with cyclohexane: ethyl acetate (80: 20 vol) to give the title compound (3.76g) as a pink oil.
1H NMR(400MHz，CDCl3)：δ＝1.17(t，3H)，2.62(q，2H)，2.96(t，2H)，3.79(t，2H)，4.57(s，2H)，7.12(m，5H)，15.49(s，1H)。
LRMS (electrospray): m/z [ MNa ]+]291。
Preparation example 60
3- ({ (E) -1- [3- (benzyloxy) propionyl ] -2-hydroxy-1-butenyl } oxy) -5-fluorobenzonitrile
To a stirred solution of phenol of preparation 34 (8.80g, 48.0mmol) in tetrahydrofuran (450ml) was added sodium hydride (60% oil dispersion, 1.92g, 48.0mmol) at room temperature under nitrogen. After stirring for 1 hour, the enol of preparation 59 (12.9g, 48.0mmol) was added and the reaction stirred for 64 hours. The mixture was diluted with water (200ml) and 2N aqueous hydrochloric acid (40ml), extracted with ethyl acetate (2X 150ml), the organic extracts combined, washed with brine (100ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual orange oil was purified by flash chromatography on silica eluting with cyclohexane to pentane (10: 90 vol) to give the title compound (5.80g) as an orange oil.
1H NMR(400MHz，CDCl3)：δ＝1.08(t，3H)，2.31(q，2H)，2.59(t，2H)，3.75(t，2H)，4.45(s，2H)，6.92(m，1H)，7.02(m，2H)，7.29(m，5H)，14.50(s，1H)。
LRMS (electrospray): m/z [ MNa ]+]392。
Preparation example 61
5- ({ (1E) -1- [3- (benzyloxy) propionyl ] -2-hydroxy-1-butenyl } oxy) isophthalonitrile
To a stirred solution of phenol of preparation 39 (1.48g, 10.3mmol) in tetrahydrofuran (70ml) was added sodium hydride (60% oil dispersion, 412mg, 12.3mmol) at room temperature under nitrogen. After stirring for 30 minutes, the enol of preparation 59 (2.76g, 10.3mmol) was added and the reaction stirred for 18 hours. Water (100ml) and 2N aqueous hydrochloric acid (10ml) were added carefully, the mixture was extracted with ethyl acetate (2X 150ml), the organic extracts combined, washed with brine (100ml), dried over magnesium sulphate and concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with pentane: ethyl acetate (90: 10 vol) to give the title compound (1.00g) as a yellow oil.
LRMS (thermal spray): m/z [ MH+]375。
Preparation example 62
3- { [1- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-fluorobenzonitrile
To a solution of example 117 alcohol (1.65g, 5.40mmol) in dimethylformamide (11ml) was added imidazole (477mg, 7.02mmol) followed by tert-butyl-dimethyl-silyl chloride (977mg, 6.48mmol) at room temperature under nitrogen. The reaction was stirred for 18 h, the mixture diluted with water (100ml) and extracted with diethyl ether (4X 50 ml). The combined organic extracts were dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with dichloromethane: methanol (99: 1 vol.) to give the title compound (2.12g) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝0.03(s，6H)，0.84(s，9H)，1.10(m，6H)，2.42(q，2H)，2.56(q，2H)，4.00(t，2H)，4.09(t，2H)，6.86(d，1H)，6.99(m，2H)。
LRMS (thermal spray): m/z [ MH+]419。
Microanalysis: measured value: c, 62.73; h, 7.83; and N, 9.75. C22H32FN3O2Si.0.06CH2Cl2Calculated values: c, 62.68; h, 7.66; and N, 9.94 percent.
Preparation example 63
3- ({3, 5-diethyl-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -1H-pyrazol-4-yl } oxy) -5-fluorobenzonitrile
To a solution of the alcohol from example 117 (5.04g, 16.6mmol) and dihydropyran (7.57ml, 83mmol) in dichloromethane (65ml) was added p-toluenesulfonic acid (32mg, 0.17mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 2 hours, but starting material remained, so another portion of p-toluenesulfonic acid (284mg, 1.49mmol) was added and the reaction stirred for 1 hour. The mixture was diluted with diethyl ether (90ml) and washed with a mixed aqueous solution (water 50ml, brine 25ml and saturated aqueous sodium bicarbonate solution 25 ml). The aqueous phase was extracted with diethyl ether (2X 60ml), the combined organic extracts were dried over magnesium sulphate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (98: 2 vol) to give the title compound (6.31g) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.08(m，6H)，1.52(m，6H)，2.39(q，2H)，2.54(q，2H)，3.45(m，1H)，3.64(m，1H)，3.75(m，1H)，4.06(m，1H)，4.17(t，2H)，4.51(s，1H)，6.82(d，1H)，7.22(m，2H)。
LRMS (thermal spray): m/z [ MH+]388。
Preparation 64
3- ({3, 5-diethyl-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -1H-pyrazol-4-yl } oxy) -5-fluorobenzamide
To a solution of 3-methyl-3-pyrazolin-5-one (74mg, 0.75mmol) in dimethyl sulfoxide (1ml) was added cesium carbonate (269mg, 0.82mmol) at room temperature under a nitrogen atmosphere, and the reaction was stirred for 15 minutes. A solution of the aryl fluoride of preparation 63 (291mg, 0.75mmol) in dimethyl sulfoxide (1ml) was then added and the reaction heated to 100 ℃ for 18 h. After cooling to room temperature, the reaction was diluted with water (7ml) and extracted with diethyl ether (12 ml). The organic phase was washed with brine (3.5ml), dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with a solvent gradient of dichloromethane: methanol (99: 1 to 95: 5 vol.) to give the unexpected title compound (108mg) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.12(m，6H)，1.56(m，6H)，2.44(q，2H)，2.59(q，2H)，3.48(m，1H)，3.69(m，1H)，3.79(m，1H)，4.08(m，1H)，4.20(t，2H)，4.54(s，1H)，6.72(d，1H)，7.15(m，2H)。
LRMS (thermal spray): m/z [ MH+]406。
Microanalysis: measured value: c, 60.57; h, 6.97; and N, 9.97. C21H28FN3O4.0.08CH2Cl2.0.32H2Calculated value of O: c, 60.57; h, 6.94; n, 10.05 percent.
Preparation example 65
3- ({3, 5-diethyl-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -1H-pyrazol-4-yl } oxy) -5- (1H-pyrazol-1-yl) benzonitrile
To a solution of pyrazole (51mg, 0.75mmol) in anhydrous dimethyl sulfoxide (1ml) was added cesium carbonate (269mg, 0.82mmol) at room temperature under a nitrogen atmosphere and the reaction was stirred for 15 min. A solution of the aryl fluoride of preparation 63 (291mg, 0.75mmol) in anhydrous dimethyl sulfoxide (1ml) was then added and the reaction heated to 100 ℃ for 18 h. After cooling to room temperature, the reaction was diluted with water (7ml) and extracted with diethyl ether (10 ml). The organic phase was washed with brine (3ml), dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with a solvent gradient of dichloromethane: methanol (100: 0 to 90: 10 vol.) to give the title compound (55 mg).
1H NMR(400MHz，CDCl3)：δ＝1.13(m，6H)，1.58(m，6H)，2.44(q，2H)，2.60(q，2H)，3.49(m，1H)，3.69(m，1H)，3.80(m，1H)，4.10(m，1H)，4.21(t，2H)，4.55(s，1H)，6.50(s，1H)，6.98(s，1H)，7.57(s，1H)，7.63(s，1H)，7.72(s，1H)，7.89(s，1H)。
LRMS (thermal spray): m/z [ MH+]436，[MNa+]458。
HRMS：[MH+]Found 436.2352. C24H30N5O3Calculated values: 436.2343 MNa+]Found 458.2168.C24H29N5O3Calculated Na: 458.2162.
preparation examples 66 to 68
By a method similar to preparation 65, using the appropriate heterocycle as starting material, the compounds of the following general formula preparations are prepared, as set forth in the following table:
1the eluent used for the flash column chromatographic purification of this compound was dichloromethane: methanol (99: 1 to 95: 5 volume ratio).
Preparation example 69
3- [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] -1-azetidinecarboxylic acid tert-butyl ester
To a solution of pyrazole (200mg, 0.75mmol) from example 122 in dimethylformamide (3ml) was added sodium hydride (60% oil dispersion, 33mg, 0.82mmol) at 0 ℃ under nitrogen and the reaction was stirred for 10 min. Tert-butyl 3-iodo-azetidine-1-carboxylate (234mg, 0.82mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was quenched with water (0.2ml) and concentrated under reduced pressure. The residue was partitioned between dichloromethane (5ml) and water (5ml), the organic phase separated using a 5 μ M Whatman PTFE frit cartridge and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: pentane (20: 80; 25: 75; 34: 66; 50: 50; 75: 25; 100: 0 vol) to ethyl acetate: methanol (10: 1 vol) and then a solvent gradient of dichloromethane: methanol: 0.88 ammonia (90: 10: 1; 80: 20: 1 vol) to give the title compound (189mg) as a pale yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.03-1.17(m，6H)，1.49(s，9H)，2.39-2.52(m，4H)，4.32(m，2H)，4.50(m，2H)，4.94(m，1H)，7.38(s，2H)，7.56(s，1H)。
LRMS (thermal spray): m/z [ MH+]422，[MNa+]444。
Microanalysis: measured value: c, 65.08; h, 6.49; n, 16.48. C23H27N5O3.0.18H2Calculated value of O: c, 65.04; h, 6.49; n, 16.49 percent.
Preparation example 70
5- ({3, 5-diethyl-1- [3- (tetrahydro-2H-pyran-2-yloxy) propyl ] -1H-pyrazol-4-yl } oxy) isophthalonitrile
To a solution of pyrazole (200mg, 0.75mmol) from example 122 in dimethylformamide (3ml) was added sodium hydride (60% oil dispersion, 33mg, 0.82mmol) at 0 ℃ under nitrogen and the reaction was stirred for 10 min. 2- (3-bromo-propoxy) -tetrahydropyran (184mg, 0.82mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was quenched with water (0.2ml) and concentrated under reduced pressure. The residue was partitioned between dichloromethane (5ml) and water (5ml), the organic phase separated using a 5 μ M Whatman PTFE frit cartridge and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: pentane (20: 80; 25: 75; 34: 66; 50: 50; 75: 25; 100: 0 vol) to ethyl acetate: methanol (10: 1 vol) and then a solvent gradient of dichloromethane: methanol: 0.88 ammonia (90: 10: 1; 80: 20: 1 vol) to give the title compound (238mg) as a pale yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.09(m，6H)，1.47-1.63(m，2H)，1.66-1.88(m，2H)，2.15(dd，2H)，2.38(q，2H)，2.53(q，2H)，3.37-3.55(m，2H)，3.75-3.90(m，2H)，4.11(m，2H)，4.56(m，1H)，7.37(s，2H)，7.55(s，1H)。
LRMS (electrospray): m/z [ MH+]409，[MNa+]421。
Microanalysis: measured value: c, 66.59; h, 6.91; and N, 13.40. C23H28N4O3.0.36H2Calculated value of O: c, 66.57; h, 6.98; and N, 13.50%.
Preparation 71
3- [ (1-acetyl-3, 5-dimethyl-1H-pyrazol-4-yl) oxy ] -5-fluorobenzonitrile
Preparation 34 phenol (10.0g, 72.7mmol), 3-chloro-2, 4-pentanedione (7.10g, 72.7mmol) and cesium carbonate (23.6g, 72.9mmol) were heated under nitrogen at reflux in acetone (100ml) for 2 hours. The reaction was cooled to room temperature, 1N aqueous hydrochloric acid (50ml) was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate (3X 100 ml). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The remaining yellow oil was dissolved in methanol (100ml), hydrazine (5.3ml, 109mmol) was added and the reaction stirred at room temperature under nitrogen for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in dimethylformamide (50ml) at 0 ℃. Acetyl chloride (5.1ml, 72.0mmol) was added slowly followed by sodium hydride (60% oil dispersion, 2.8g, 72.0mmol) in portions. The reaction was stirred for 15 minutes, saturated ammonium chloride solution (50ml) was added and the reaction was allowed to warm to room temperature. The mixture was extracted with ethyl acetate (3X 100ml) and the organic extracts combined, dried over magnesium sulphate and concentrated under reduced pressure to give an oil. After 18 hours standing there was a solid formed in the oil which was isolated by filtration and washed with diethyl ether (50ml) to give the title compound (3.50g) as a white solid, m.p.109-111 ℃.
1H NMR(400MHz，CDCl3)：δ＝2.06(s，3H)，2.37(s，3H)，2.65(s，3H)，6.81(d，1H)，6.91(s，1H)，7.04(d，1H)。
LRMS (thermal spray): m/z [ MH+]273。
Microanalysis: measured value: c, 61.62; h, 4.44; and N, 15.09. C14H12N3O2Calculating the value of F: c, 61.53; h, 4.43; and N, 15.38 percent.
Preparation examples 72 to 74
By a method similar to preparation 71, using the appropriate phenol as the starting material, the following compounds of the general formula preparations are prepared, as shown in the following table:
preparation example No. (raw Material preparation example No.) R’ Analyzing data
72(39) CN m.p.204-206℃1H NMR(400MHz，CDCl): δ — 2.06(s, 3H), 2.38(s, 3H), 2.66(s, 3H), 7.33(s, 2H), 7.58(s, 1H). m/z [ MH]281. Microanalysis: measured value: c, 63.30; h, 4.25; n, 19.59.CHNO.0.30HO calculated C, 63.06; h, 4.45; n is added to the reaction solution to form a reaction solution,19.61％.
731(42) Me m.p.152-154℃1H NMR(400MHz，CDCl)：δ＝2.05(s，3H)，2.33(s，3H)，2.38(s，3H)，2.66(s，3H)，6.88(s，1H)，6.91(s，1H).7.12(s，1H).
LRMS (thermal spray): m/z [ MH]270. Microanalysis: measured value: c, 66.67; h, 5.71; n, 15.25.CHNOCalcd for C, 66.9; h, 5.61; and N, 15.60 percent.
74(commercially available) H m.p.131-133℃1H NMR(400MHz，CDCl): δ — 2.13(s, 3H), 2.40(s, 3H), 2.70(s, 3H), 7.15(m, 2H), 7.35(m, 1H), 7.40(m, 1H), LRMS (thermal spray): m/z [ MH]278. Microanalysis: measured value: c, 65.87; h, 5.11; n, 16.33.CHNOCalculated C, 65.87; h, 5.13; n, 14.46 percent.
1The product was purified by flash column chromatography on silica eluting with ethyl acetate to pentane (10: 90 vol/vol).
2Purifying the product by flash silica gel column chromatography, and purifying with ethyl acetateEster pentane (10: 90 to 20: 80 vol).
Preparation example 75
3- { [ 1-acetyl-3- (bromomethyl) -5-methyl-1H-pyrazol-4-yl ] oxy } -5-fluorobenzonitrile
Pyrazole (1.00g, 3.66mmol) of preparation 71 was dissolved in carbon tetrachloride (20ml), and the solution was degassed by introducing nitrogen at room temperature for 20 minutes. N-bromosuccinimide (973mg, 5.49mmol) was added followed by 2, 2' -azobisisobutyronitrile (30mg) and the reaction was heated to 95 ℃ for 1 hour. The reaction was cooled to room temperature, concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with pentane: ethyl acetate (80: 20 vol) to give the title compound (1.30g) as a pale yellow oil.
1H NMR(400MHz，CDCl3)：δ＝2.05(s，3H)，2.69(s，3H)，4.68(s，2H)，6.89(d，1H)，6.99(s，1H)，7.08(d，1H)。
LRMS (thermal spray): m/z [ M-BrH+]272。
Microanalysis: measured value: c, 45.08; h, 3.14; n, 11.44. C14H11BrN3O2F.1.05H2Calculated value of O: c, 45.31; h, 3.56; n, 11.32%.
Preparation examples 76 to 78
By a method similar to preparation 75, using the appropriate pyrazole as starting material, the compounds of the following general formula preparations are prepared, as set forth in the following table:
preparation example No. (raw Material preparation example No.) R Analyzing data
76(72) CN m.p.132-134℃1H NMR(400MHz，CDCl): δ 2.06(s, 3H), 2.66(s, 3H), 4.67(s, 2H), 7.40(s, 2H), 7.63(s, 1H). Measured value: c, 47.65; h, 3.03; n, 14.79.C HBrNO.0.93HO calcd for C, 47.92; h, 3.45; n, 14.90 percent.
77(73) Me m.p.107-109℃1H NMR(400MHz，CDCl): δ 2.05(s, 3H), 2.35(s, 3H), 2.70(s, 3H), 4.70(s, 2H), 6.95(s, 1H), 6.99(s, 1H), 7.18(s, 1H). Measured value: c, 50.34; h, 3.89; n, 11.58.CHBrNO.0.40HO calculated C, 50.69; h, 4.20; n, 11.82%.
78(74) H m.p.120-124℃1H NMR(400MHz，CDCl)：δ＝2.05(s，3H)，2.70(s，3H)，4.75(s，2H)，7.20(m，2H)，7.45(m，1H).
Microanalysis: measured value: c, 49.01; h, 3.47; n, 12.14.CHBrNO.0.50HCalculated value of O: c, 49.00; h, 3.82; and N, 12.24%.
1To this reaction was added another portion of 2, 2' -azobisisobutyronitrile (30mg), and refluxing was continued for another 2 hours.
2The product was purified by flash column chromatography on silica eluting with a solvent gradient of ethyl acetate to pentane (0: 100, then 2: 98, then 5: 95, then 10: 90, then 15: 85, then 30: 70 vol).
3The product was purified by flash column chromatography on silica eluting with ethyl acetate pentane (10: 90 to 20: 80 vol.).
Preparation example 79
3-cyanobenzamides
To a solution of 3-cyanobenzoyl chloride (10g, 60.3mmol) in dichloromethane (100ml) was added a 0.88 ammonia solution (30ml) at 0 ℃ under nitrogen and the reaction was stirred for 20 min. The mixture was filtered and the solid was washed with water (50ml) then diethyl ether (50ml), azeotroped with toluene and dried in vacuo to give the title compound (9g) as a white solid.
1H NMR(400MHz，CD3OD)：δ＝7.62(m，1H)，7.86(m，1H)，8.12(m，1H)，8.18(s，1H)。
Preparation example 80
3- (aminomethyl) benzamide
Preparation 79 nitrile (6.4g, 43.8mmol) was suspended in acetic acid (60ml) and 10% palladium on carbon (100mg) was added. The reaction was pressurized to 60psi with hydrogen at room temperature and stirred for 18 hours. The process was repeated with the starting material remaining, so another 10% palladium on carbon (500mg) was added. The reaction mixture was filtered through Arbocel, washed with acetic acid and the filtrate was concentrated under reduced pressure. The residue was azeotroped with toluene and purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (100: 0 to 90: 10: 1 and then 85: 15: 1.5 vol.) to give the title compound (5.3g) as a colorless oil.
1H NMR(400MHz，CD3OD)：δ＝3.83(s，2H)，7.39(dd，1H)，7.49(d，1H)，7.73(d，1H)，7.81(s，1H)。
Preparation example 81
2-chloro-1, 3-dicyclopropyl-1, 3-propanedione
To a solution of tetrabutylammonium bromide (0.70g, 2.17mmol) in acetonitrile (50ml) was added trimethylsilyl chloride (16.6ml, 130mmol) at 0 ℃ under nitrogen. Then a solution of 1, 3-dicyclopropyl-propane-1, 3-dione (see WO 98/55438) (6.62g, 43.5mmol) in acetonitrile (15ml) was added and dimethyl sulfoxide (9.25ml, 130mmol) was added dropwise and the reaction was allowed to warm to room temperature over 4 hours. The mixture was diluted with water (75ml), extracted with diethyl ether (3X 35ml), the organic extracts combined, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with pentane: diethyl ether (95: 5 vol) to give the title compound (3.76g) as an oil which is an enol: an 80: 20 mixture of the ketone forms.
1H NMR(400MHz，CDCl3)：δ＝1.02(m，4H)，117(m，4H)，2.24(m，0.2H)，2.39(m，0.8H)，5.05(s，0.2H)，16.34(s，0.8H)。
Microanalysis: measured value: c, 57.59; h, 5.89. C9H11ClO2.0.02CH2Cl2Calculated values: c, 57.92; h, 5.94.
Preparation example 82
5- [ 2-cyclopropyl-1- (cyclopropylcarbonyl) -2-oxoethoxy ] isophthalonitrile
To a stirred solution of the phenol of preparation 39 (0.865g, 6.00mmol) in acetone (24ml) was added cesium carbonate (1.97g, 6.06mmol) under nitrogen and reflux. After stirring for 5 minutes, a solution of the diketone of preparation 81 (1.12g, 6.00mmol) in acetone (6ml) was added and the reaction stirred for 4 hours. After cooling, the mixture was diluted with water (25ml) and the acetone was removed under reduced pressure. The aqueous phase was acidified with 2N aqueous hydrochloric acid, extracted with dichloromethane (50ml) and the organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient of pentane: ethyl acetate (95: 5 to 90: 10 and then 80: 20 vol.) to give the title compound (1.03g) as a white solid which exists as the enol tautomer m.p.135-137 ℃.
1H NMR(400MHz，CDCl3)：δ＝0.93(m，4H)，1.19(m，4H)，1.74(m，2H)，7.53(s，2H)，15.25(s，1H)。
LRMS (electrospray): m/z [ M-H+]293。
Microanalysis: measured value: c, 69.18; h, 4.82; and N, 9.35. C17H14N2O3Calculated values: c, 69.38; h, 4.79; n, 9.52 percent.
Preparation example 83
3-oxobutanoic acid
Sodium hydroxide (37.9g, 0.947mol) was dissolved in water (770ml) and added to a solution of methyl 3-oxobutyrate (100g, 0.861mol) over 20 minutes at room temperature. The reaction was stirred for 18 h, quenched with ammonium sulfate (700g), and acidified slowly with a solution of concentrated hydrochloric acid (21.5ml) in water (250ml) while cooling with ice. The reaction mixture was extracted with diethyl ether (6 × 200ml) and the organic extracts combined, dried over magnesium sulphate and concentrated under reduced pressure to give the title compound (58.2g) as a pale yellow oil which is the ketone: a mixture of enol tautomers.
1H NMR(400MHz，CDCl3): δ ═ 2.00(s, 3H-enol), 2.30(s, 3H-ketone), 3.51(s, 2H-ketone), 5.02(s, 1H-enol).
Preparation example 84
1-cyclopropyl-1, 3-butanedione
Magnesium turnings (3.04g, 125mmol) were suspended in methanol (145ml) under nitrogen, heated to reflux for 1 hour, cooled to room temperature, and a solution of the preparation 83 β -keto acid (25.5g, 250mmol) in methanol (25ml) was added dropwise while cooling with ice. The reaction was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure to give the magnesium salt of the acid. At the same time, cyclopropanecarboxylic acid (9.91ml, 125mmol) was dissolved in dimethylformamide (200ml) and carbonyldiimidazole (22.4g, 138mmol) was added portionwise at 0 ℃ under nitrogen. This was stirred for 1.5 hours and a solution of the above magnesium salt in dimethylformamide (100ml) was added at 0 ℃. The reaction was stirred at room temperature for 92 hours, and the mixture was taken up in 2M aqueous hydrochloric acid (85ml) and then diluted with water (170 ml). The mixture was extracted with diethyl ether (6X 200ml) and the organic extracts were combined, washed with brine (3X 200ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual orange oil was purified by flash chromatography on silica eluting with pentane: diethyl ether (100: 0 to 90: 10 to 80: 20 vol) to give the title compound (7.39g) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝0.83-0.95(m，2H)，1.06-1.10(m，2H)，1.54-1.63(m，1H)，2.00(s，3H)。
LRMS (electrospray): m/z [ MNa ]+]149。
Preparation example 85
2-chloro-1-cyclopropyl-1, 3-butanedione
To a solution of tetrabutylammonium bromide (932mg, 2.89mmol) in anhydrous acetonitrile (50ml) was added trimethylsilyl chloride (18.9ml, 174mmol) at room temperature under a nitrogen atmosphere and the mixture was cooled to 0 ℃. A solution of the diketone of preparation 84 (7.3g, 57.9mmol) in acetonitrile (36ml) was added, followed by dropwise addition of anhydrous dimethyl sulfoxide (12.3ml, 174 mmol). The reaction was stirred at 0 ℃ for 1.5 h, the mixture was diluted with water (500ml), extracted with diethyl ether (2X 200ml, 1X 100ml), the organic extracts combined, dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with pentane: diethyl ether (100: 0 to 95: 5 and then 90: 10 vol.) to give the title compound (5.76g) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝0.99-1.08(m，2H)，1.15-1.20(m，2H)，2.27(s，3H)，2.38-2.46(m，1H)。
LRMS (electrospray): m/z [ M-H+]159。
Preparation example 86
3- [1- (cyclopropylcarbonyl) -2-oxopropoxy ] -5-methylbenzonitrile
To a stirred solution of the diketone of preparation 85 (1.3g, 8.30mmol) in acetone (44ml) was added cesium carbonate (2.45g, 8.30mmol) and the phenol of preparation 42 (1g, 7.50mmol) at 60 ℃ under nitrogen and the reaction was stirred for 5 hours. After cooling, the mixture was quenched with water and the acetone was removed under reduced pressure. The aqueous phase was acidified with 1N aqueous hydrochloric acid, extracted with ethyl acetate and the organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with pentane: ethyl acetate (85: 15 vol) to give the title compound (1.03g) as a pale red solid.
1H NMR(400MHz，CDCl3)：δ＝0.85(m，2H)，1.12(m，2H)，1.86(m，1H)，1.94(s，3H)，2.35(s，3H)，6.99(m，2H)，7.10(s，1H)。
LRMS (electrospray): m/z [ M-H+]256。
Preparation example 87
4- (3, 5-Difluorophenoxy) -3, 5-diethyl-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -1H-pyrazole
To a solution of the alcohol of example 38 (5.6g, 18.9mmol) and dihydropyran (8.62ml, 94.5mmol) in dichloromethane (75ml) was added p-toluenesulfonic acid (360mg, 1.89mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 2 hours, diluted with diethyl ether (100ml) and washed with a mixed aqueous solution (water 60ml, brine 30ml and saturated aqueous sodium bicarbonate solution 30 ml). The aqueous phase was extracted with diethyl ether (2X 60ml), the combined organic extracts were dried over magnesium sulphate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (98: 2 vol) to give the title compound (6.31g) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.09(m，6H)，1.57(m，6H)，2.40(q，2H)，2.55(q，2H)，3.44(m，1H)，3.62(m，1H)，3.73(m，1H)，4.05(m，1H)，4.16(t，2H)，4.50(s，1H)，6.39(m，3H)。
LRMS (thermal spray): m/z [ MH+]381。
Microanalysis: measured value: c, 62.16; h, 6.92; and N, 7.16. C20H26N2O3.0.09CH2Cl2Calculated values: c, 62.18; h, 6.80; and N, 7.22 percent.
Preparation example 88
4- [3, 5-bis (1H-pyrazol-1-yl) phenoxy ] -3, 5-diethyl-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -1H-pyrazole
And
preparation example 89
3, 5-diethyl-4- [ 3-fluoro-5- (1H-pyrazol-1-yl) phenoxy ] -1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl 1-1H-pyrazole
To a solution of pyrazole (102mg, 1.50mmol) in anhydrous dimethyl sulfoxide (2ml) was added cesium carbonate (538mg, 1.65mmol) at room temperature under a nitrogen atmosphere and the reaction was stirred for 15 min. A solution of the aryl difluoride of preparation 87 (570mg, 1.50mmol) in anhydrous dimethyl sulfoxide (2ml) was added and the reaction heated to 100 ℃ for 18 h. After cooling to room temperature, the reaction was diluted with water (20ml) and extracted with diethyl ether (2X 20 ml). The organic phase was washed with brine (10ml), dried over magnesium sulfate and concentrated under reduced pressure. Some starting material remained, so the residue was dissolved in dimethyl sulfoxide (12ml), pyrazole (510mg, 7.50mmol) was added followed by cesium carbonate (2.5g, 7.66mmol), and the reaction was heated to 100 ℃ for 18 hours. After cooling to room temperature, the reaction was diluted with water (6ml), extracted with diethyl ether (20ml), the organic phase washed with brine (10ml), dried over magnesium sulphate, concentrated under reduced pressure and the residue purified by flash chromatography on silica eluting with a solvent gradient of dichloromethane: methanol (100: 0 to 96: 4 vol). This results in two fractions, the first being a single product (least polar) and the other being a mixture of the two products. The second fraction was purified again eluting with dichloromethane to acetonitrile (93: 7 to 90: 10 by volume) to give the most polar product.
Least polar product-preparation 88(254mg)1H NMR(400MHz，CDCl3)：δ＝1.11(m，6H)，1.50(m，6H)，2.46(q，2H)，2.58(q，2H)，3.43(m，1H)，3.64(m，1H)，3.75(m，1H)，4.04(m，1H)，4.18(t，2H)，4.50(s，1H)，6.42(s，2H)，7.15(s，2H)，7.67(s，3H)，7.90(s，2H)。
LRMS (electrospray): m/z [ MH+]477，[MNa+]499。
HRMS：[MH+]Found 477.2612.C26H33N6O3Calculated values: 477.2609.
highest polarity product-preparation 89(37.7mg)1H NMR(400MHz，CDCl3)：δ＝1.11(m，6H)，1.46(m，6H)，2.43(q，2H)，2.57(q，2H)，3.43(m，1H)，3.64(m，1H)，3.75(m，1H)，4.05(m，1H)，4.17(t，2H)，4.51(s，1H)，6.42(m，2H)，7.07(m，2H)，7.66(s，1H)，7.82(s，1H)。
LRMS (thermal spray): m/z [ MH+]429。
Preparation example 90
3- ({3, 5-diethyl-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -1H-pyrazol-4-yl } oxy) -5-methoxybenzonitrile
To a solution of aryl fluoride (387mg, 1.00mmol) in dimethylformamide (5ml) of preparation 63 was added dropwise sodium methoxide (25% w/v methanol solution, 230. mu.l, 1.00mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred for 5 h, diluted with water (10ml) and extracted with diethyl ether (50 ml). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with methylene chloride: methanol (97: 3 vol.) to give the title compound (400mg) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.09(m，6H)，1.49(m，6H)，2.41(q，2H)，2.55(q，2H)，3.46(m，1H)，3.66(m，1H)，3.77(m+s，4H)，4.07(m，1H)，4.19(t，2H)，452(m，1H)，6.66(s，1H)，6.69(s，1H)，6.77(s，1H)。
LRMS(thermal spraying): m/z [ MH+]400。
Microanalysis: measured value: c, 65.59; h, 7.32; n, 10.42. C22H29N3O4.0.04CH2Cl2Calculated values: c, 65.71; h, 7.28; n, 10.43 percent.
Preparation example 91
3- (1-acetyl-3-methyl-2-oxobutoxy) -5-methylbenzonitrile
To a stirred solution of the diketone of preparation 23 (750mg, 4.61mmol) in acetone (23ml) was added cesium carbonate (1.50g, 4.61mmol) and the phenol of preparation 42 (609mg, 4.61mmol) at 50 ℃ under a nitrogen atmosphere and the reaction was stirred for 3 hours. After cooling, the mixture was quenched with water (10ml) and the acetone was removed under reduced pressure. The aqueous phase was extracted with dichloromethane (4X 25ml) and the organic extracts were combined, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with pentane: ethyl acetate (90: 10 vol) to give the title compound (544 mg).
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.09(s，3H)，2.42(s，3H)，2.69(m，1H)，7.00(s，2H)，7.19(s，1H)。
LRMS (thermal spray): m/z [ MNH ]4 +]277。
Preparation example 92
[4- (3, 5-Dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] acetic acid
Pyrazole (400mg, 1.41mmol) from example 208 was stirred in concentrated hydrochloric acid (20ml) at 100 ℃ for 14 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure to give a yellow solid. The solid was dissolved in methylene chloride (50ml) and 1N aqueous hydrochloric acid (50ml), and the organic layer was separated. The organic layer was washed with 1N aqueous hydrochloric acid (50ml), dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to give the title compound (400mg) as a pale yellow solid, m.p.156-158 ℃.
1H NMR(400MHz，CD3OD)：δ＝2.02(s，3H)，4.89(s，2H)，6.82(s，2H)，7.02(s，1H)。
LRMS (thermal spray): m/z [ MH+]303。
Microanalysis: measured value: c, 47.50; h, 3.50; and N, 9.46. C12H10Cl2N2O3Calculated values: c, 47.86; h, 3.35; and N, 9.30 percent.
Preparation example 93
3- ({3, 5-diethyl-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -1H-pyrazol-4-yl } oxy) -5- (methylthio) benzonitrile
To a stirred solution of aryl fluoride of preparation 63 (774mg, 2.00mmol) in dimethylformamide (10ml) at room temperature under nitrogen was added sodium thiomethoxide (180mg, 2 mmol). The reaction mixture was stirred for 5 hours and then heated at 100 ℃ for 18 hours. A second portion of sodium thiomethoxide (90mg, 1mmol) was added and the reaction mixture was heated at 100 ℃ for a further 5 hours. After cooling to room temperature, the mixture was diluted with water (10ml) and extracted with diethyl ether (2X 50 ml). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with methylene chloride: methanol (97: 3 vol.) to give the title compound (700mg) as an oil.
1H NMR(400MHz，CDCl3)：δ＝1.14(m，6H)，1.52(m，6H)，2.44(q，2H)，2.49(s，3H)，2.59(q，3H)，3.50(m，1H)，3.70(m，1H)，3.80(m，1H)，4.10(m，1H)，4.23(m，2H)，4.55(m，1H)，6.82(s，1H)，7.01(s，1H)，7.09(s，1H)。
LRMS(APCI+)：m/z[MH+]416。
Preparation 94
3- ({3, 5-diethyl-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -1H-pyrazol-4-yl } oxy) -5- [2- (dimethylamino) ethoxy ] benzonitrile
To a stirred solution of N, N-dimethylethanolamine (83. mu.l, 0.83mmol) in dimethylformamide (2ml) was added sodium hydride (36mg of a 60% by weight oil dispersion, 0.90 mmol). After 10 min, a solution of the aryl fluoride of preparation 63 (291mg, 0.75mmol) in dimethylformamide (2ml) was added and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with 10% aqueous potassium carbonate (12ml) and extracted with diethyl ether (2X 7 ml). The organic fractions were combined, dried over magnesium sulfate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with methylene chloride: methanol (gradient 99: 1 to 90: 10 vol.) to give the title compound (180mg) as an oil.
1H NMR (400MHz，CDCl3)：δ＝1.09(m，6H)，1.50(m，6H)，2.39(q，2H)，2.47(s，6H)，2.55(q，2H)，2.87(m，2H)，3.47(m，1H)，3.67(m，1H)，3.78(m，1H)，4.05(m，1H)，4.17(m，4H)，4.52(m，1H)，6.70(s，2H)，6.79(s，1H)。
LRMS (electrospray): m/z [ MH+]457。
HRMS：[MH+]457.2810.C25H37N4O4Calculated values: 457.2810.
preparation examples 95 to 97
By a method similar to preparation 94, using the appropriate alcohol as the starting material, the compounds of the following general formula preparations are prepared, as set forth in the following table:
preparation example No. (raw Material preparation example No.) R Analyzing data
95(63) CHCHNHMe 1H NMR(400MHz，CDCl): δ is 1.09(m, 6H), 1.50(m, 6H), 2.39(q, 2H), 2.54(m, 5H), 3.04(t, 2H), 3.46(m, 1H), 3.66(m, 1H), 3.78(m, 1H), 4.05(m, 1H), 4.11(t, 2H), 4.17(t, 2H), 4.52(s, 1H), 6.70(s, 2H), 6.81(s, 1H), LRMS (electrospray): m/z [ MH ]443HRMS：[MH]+443.2654.CHNOCalculated 443.2653.
96(63) CHCONH 1H NMR(400MHz，CDCl): δ is 1.11(m, 6H), 1.48(m, 6H), 2.43(q, 2H), 2.58(q, 2H), 3.46(m, 1H), 3.67(m, 1H), 3.80(m, 1H), 4.08(m, 1H), 4.25(m, 2H), 4.45(s, 2H), 4.52(m, 1H), 5.54(broad s, 1H), 6.37(broad s, 1H), 6.72(s, 1H), 6.85(s, 2H), LRMS (electrospray): m/z 465 (MH))HRMS：[MH]443.2282.CHNOCalculated 443.2289.
97(63) CHCHOCH 1H NMR(400MHz，CDCl): δ is 1.10(m, 6H), 1.50(m, 6H), 2.41(q, 2H), 2.55(q, 2H), 3.41(s, 3H), 3.47(m, 1H), 3.70(m, 3H), 3.79(m, 1H), 4.06(m, 3H), 4.20(m, 2H), 4.52(s, 1H), 6.70(s, 2H), 6.79(s, 1H). ms (electrospray): m/z 466 (MH))HRMS：[MH]443.2282.CHNOCalculated 443.2289.
Preparation example 98
5-methyl-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -3- (trifluoromethyl) -1H-pyrazol-4-ol
To a stirred solution of 1- (2-hydroxyethyl) -5-methyl-3- (trifluoromethyl) -1H-pyrazol-4-ol (600mg, 2.86 mmol; Kenkyu Hokoku-Asahi Garasu Kogyo Gijutsu Shoreikai, 1988, 51, 139-49) in dichloromethane (10ml) and ethyl acetate (4ml) was added p-toluenesulfonic acid (27mg, 0.14mmol) followed by 3, 4-dihydro-2H-pyran (340. mu.l, 3.7 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with pentane: ethyl acetate (60: 40 vol) to give the title compound (560mg) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝1.60(m，6H)，2.23(s，3H)，3.44(m，1H)，3.60(m，1H)，3.72(m，1H)，4.04(m，1H)，4.18(m，2H)，4.50(broad s，1H)。
LRMS (electrospray): m/z [ M-H+]293。
Preparation example 99
3-fluoro-5- { [ 5-methyl-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -3- (trifluoromethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile
To a stirred solution of pyrazole (214mg, 0.73mmol) of preparation 98 in dimethylformamide (0.7ml) were added 3, 5-difluorobenzonitrile (304mg, 2.2mmol) and potassium carbonate (304mg, 2.2 mmol). The reaction mixture was heated at 90 ℃ for 7 hours. After cooling to room temperature, brine (20ml) was added, and the mixture was extracted with ethyl acetate (20 ml). The organic fraction was separated, washed with brine (20ml), dried over magnesium sulfate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with pentane: ethyl acetate (80: 20 vol) to give the title compound (267mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.61(m，6H)，2.18(s，3H)，3.48(m，1H)，3.64(m，1H)，3.75(m，1H)，4.30(t，2H)，4.50(broad s，1H)，6.85(d，1H)，6.94(s，1H)，7.05(d，1H)。
LRMS (electrospray): m/z [ M-H+]412。
Preparation example 100
3-cyano-5- [ (3, 5-diethyl-1- {2- [ (2-methoxyethoxy) methoxy ] ethyl } -1H-pyrazol-4-yl) oxy ] benzamide
To a stirred solution of pyrazole (193mg, 0.49mmol) from example 261 in tetrahydrofuran (2ml) was added 2M aqueous sodium hydroxide (8.7. mu.l, 0.49mmol) and the reaction mixture was heated at 65 ℃ for 24 h. After cooling to room temperature, a second portion of 2M sodium hydroxide solution (8.7. mu.l, 0.49mmol) was added and the mixture was heated at 65 ℃ for 24 h. 6M aqueous sodium hydroxide (100. mu.l) was added and the mixture was heated at 65 ℃ for 24 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (75ml), neutralised to pH 7 with 2M aqueous hydrochloric acid and extracted with dichloromethane (2X 25 ml). The combined organic fractions were dried over magnesium sulfate and concentrated under reduced pressure to give a crude product mixture which was purified by flash chromatography on silica gel eluting with methylene chloride: methanol (100: 0, 98: 2, 96.5: 3.5 and 95: 5 vol.) to give the title compound (60mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.10(m，6H)，2.40(q，2H)，2.55(q，2H)，3.36(s，3H)，3.50(q，2H)，3.59(q，2H)，3.94(q，2H)，4.20(q，2H)，4.64(s，2H)，7.30(s，1H)，7.59(s，1H)，7.70(s，1H)。
Preparation example 101
5- [ (1-acetyl-3, 5-diethyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile
To a stirred solution of pyrazole (3.0g, 11.3mmol) from example 122 in dimethylformamide (45ml) was added acetyl chloride (1.2ml, 17.0mmol) at 0 ℃ followed by sodium hydride (678mg of a 60% by weight oil dispersion, 17.0mmol) in portions. The cooling bath was removed and the reaction mixture was stirred at room temperature for 40 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride (4ml) and concentrated under reduced pressure to give an orange residue. It was partitioned between ethyl acetate (200ml) and water (200 ml). The organic fraction was washed with water (100ml), brine (75ml), then dried over magnesium sulphate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with methylene chloride: methanol (100: 0, 99: 1, and then 98: 2 volumes) to give the title compound (2.67g) as a white solid.
1H NMR(400MHz，CDCl3)：δ＝1.15(t，3H)，1.19(t，3H)，2.43(q，2H)，2.72(s，3H)，3.85(q，2H)，7.38(s，2H)，7.61(s，1H)。
LRMS (electrospray): m/z 331[ M + Na ]+]。
Preparation example 102
5- { [ 1-acetyl-3- (1-bromoethyl) -5-ethyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile
A solution of pyrazole (881mg, 2.86mmol) in carbon tetrachloride (12ml) from preparation 101 was degassed by passing a nitrogen stream for 20 minutes. N-bromosuccinimide (763mg, 4.28mmol) was added followed by AIBN (30mg) and the reaction mixture was heated at 85 ℃ for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with pentane: ethyl acetate (gradient 100: 0 to 67: 33 vol.) to give the title compound (348mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.10(t，3h)，2.00(d，3H)，2.70(s，3H)，2.80(m，2H)，4.95(q，1H)，7.42(s，2H)，7.60(s，1H)。
LRMS (electrospray): m/z 283[ MH+]。
Preparation example 103
5- ({ 5-Ethyl-3- (1-hydroxyethyl) -1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -1H-pyrazol-4-yl } oxy) isophthalonitrile
To a stirred solution of pyrazole (197mg, 0.70mmol) from example 263 in dimethylformamide (3ml) was added 2- (2-bromoethoxy) tetrahydro-2H-pyran (105. mu.l, 0.70mmol) followed by sodium hydride (31mg, 0.77mmol) at 0 ℃. After 15 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 60 hours. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (0.5ml) and then concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with methylene chloride: methanol (gradient from 100: 0 to 95: 5 vol.) to give the title compound (84mg) as a white foam which turned into an oil on standing.
1H NMR(400MHz，CDCl3)：δ＝1.11(t，3H)，1.45(d，3H)，1.65(m，6H)，2.59(q，2H)，3.50(m，1H)，3.70(m，1H)，3.81(m，1H)，4.11(m，1H)，4.25(t，2H)，4.56(m，1H)，4.76(m，1H)，7.40(s，2H)，7.55(s，1H)。
LRMS (electrospray): m/z 411[ MH+]。
Preparation example 104
3-cyano-5- [ (3, 5-diethyl-1- {2- [ (2-methoxyethoxy) methoxy ] ethyl } -1H-pyrazol-4-yl) oxy ] -N-hydroxybenzamidine (carboximidamide)
To a stirred solution of pyrazole (1.5g, 3.76mmol) from example 261 in ethanol (7.5ml) was added a solution of sodium carbonate (200mg, 1.88mmol) and hydroxylamine hydrochloride (262mg, 3.76mmol) in water (7.5 ml). After stirring at room temperature for 5 hours, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (50ml) and water (40 ml). The aqueous phase was separated and extracted with dichloromethane (30 ml). The organic fractions were combined, dried over magnesium sulfate and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica eluting with methylene chloride: methanol (gradient from 100: 0 to 96: 4 vol.) to give the title compound (1.13mg) as a colorless oil.
1H NMR(400MHz，CDCl3)：δ＝1.11(m，6H)，2.42(q，2H)，2.58(q，2H)，3.41(s，3H)，3.59(m，4H)，3.95(t，2H)，4.17(t，2H)，4.61(s，2H)，4.77(broad s，2H)，7.38(m，1H)，7.49(m，2H)。
LRMS (electrospray): m/z 432[ MH+]。
Microanalysis: measured value: c, 57.50; h, 6.71; and N, 16.01. C21H26N4O4+0.4H2Calculated value of O: c, 57.50; h, 6.85; and N, 15.96 percent.
Preparation example 105
3- [ (3, 5-diethyl-1- {2- [ (2-methoxyethoxy) methoxy ] ethyl } -1H-pyrazol-4-yl) oxy ] -5- [5- (trifluoromethyl) -1, 2, 4-oxadiazol-3-yl ] benzonitrile
To a stirred solution of amidoxime of preparation 104 (300mg, 0.70mmol) in pyridine (3ml) was added trifluoroacetic anhydride (118. mu.l, 0.83 mmol). After stirring at room temperature for 2 hours, the reaction mixture was heated at 110 ℃ for 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue partitioned between 2M aqueous HCl (6ml) and dichloromethane (6 ml). The organic phase was separated and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (gradient from 100: 0 to 90: 10 vol.) to give the title compound (259mg) as a colourless oil.
1H NMR(400MHz，CDCl3)：δ＝1.14(m，6H)，2.46(q，2H)，2.59(q，2H)，3.39(s，3H)，3.53(q，2H)，3.59(q，2H)，3.95(q，2H)，4.29(q，2H)，4.68(s，2H)，7.34(s，1H)，7.87(s，1H)，8.04(s，1H)。
LRMS(APCI)：m/z 532(MH+)。
Preparation examples 106-108
By a method similar to preparation 105, using the appropriate acid chloride as the acylating agent instead of trifluoroacetic anhydride, the following preparation compounds of the general formula are prepared, as set forth in the following table:
preparation example No. 2 R Analyzing data
106 Me 1H NMR(400MHz，CDCl): δ is 1.14(m, 6H), 2.46(q, 2H), 2.59(q, 2H), 2.67(s, 3H), 3.39(s, 3H), 3.55(q, 2H), 3.59(q, 2H), 3.95(q, 2H), 4.22(q, 2H), 4.68(s, 2H), 7.27(s, 1H), 7.82(s, 1H), 8.00(s, 1H). ms (electrospray): m/z 478[ M + Na ]]Microanalysis: measured value: c, 59.91; h, 6.27; n, 15.38.CHNO+0.3HO calcd for C, 59.94; h, 6.475; and N, 15.19 percent.
107 Et 1H NMR(400MHz，CDCl): δ is 1.14(m, 6H), 1.44(t, 3H), 2.42(q, 2H), 2.48(q, 2H), 2.98(q, 2H), 3.39(s, 3H), 3.53(q, 2H), 3.59(q, 2H), 3.95(q, 2H), 4.20(q, 2H), 4.48(s, 2H), 7.30(s, 1H), 7.84(s, 1H), 8.01(s, 1H). LRMS (electrospray): m/z 492(M + Na))
108 iPr 1H NMR(400MHz，CDCl): δ is 1.11(m, 6H), 1.49(d, 6H), 2.44(q, 2H), 2.49(q, 2H), 3.30(sept, 1H), 3.39(s, 3H), 3.54(m, 2H), 3.59(m, 2H), 3.95(t, 2H), 4.23(t, 2H), 4.91(s, 2H), 7.22(m, 1H), 7.83(m, 1H), 8.02(m, 1H). LRMS (electrospray): m/z 506(M + Na)) Microanalysis: measured value: c, 61.87; h, 6.76; n, 14.62.CHNOCalcd for I, C, 62.10; h, 6.88; n, 14.48 percent.
Preparation example 109
Ethyl 5- { [ (tert-butoxycarbonyl) amino ] methyl } nicotinate
To a stirred solution of ethyl 5-cyanonicotinate (3.0g, 17.0 mmol; Annalen Der Chemie, 1959, 621, 106-. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (50psi) for 18 hours. By passingThe reaction mixture was filtered and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia (gradient 95: 5: 0.5 to 85: 5: 1.5 vol.) to give the intermediate amine (2.1g) as a yellow oily solid. This (2.1g, 11.7mmol) was suspended in dichloromethane (22ml), to which was added triethylamine (1.8ml, 13.0mmol) followed by di-tert-butyl dicarbonate (2.84g, 13 mmol). After 48 hours, the reaction mixture was diluted with dichloromethane (50ml) and washed with water (50 ml). The organic fraction was dried over magnesium sulfate, concentrated under reduced pressure and then purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (gradient from 100: 0 to 95: 5: 0.5 vol.) to give the title compound (2.0g) as a yellow oil.
1H NMR(400MHz，CDCl3)：δ＝1.40(m，12H)，4.42(m，4H)，8.22(s，1H)，8.71(s，1H)，9.12(s，1H)。
LRMS(APCI)：m/z 279(M-H+)。
Preparation example 110
5- { [ (tert-Butoxycarbonyl) amino ] methyl } nicotinic acid
To a stirred solution of the ester of preparation 109 (2.00g, 7.10mmol) in 1M aqueous sodium hydroxide (15ml, 15mmol) was added methanol (15 ml). The reaction mixture was stirred at room temperature for 18 hours, after which methanol was removed under reduced pressure. The aqueous solution was washed with diethyl ether (2X 25ml), cooled to 0 ℃ and neutralized to pH 7 by the addition of 2M aqueous hydrochloric acid (7.5 ml). The mixture was concentrated under reduced pressure to give a yellow oil (1.5 g).
1H NMR(400MHz，(CD3)2SO)：δ＝1.37(s，9H)，4.16(d，2H)，7.51(m，1H)，8.07(s，1H)，8.50(s，1H)，8.88(s，1H)。
LRMS(APCI)：m/z 251(M-H+)。
Preparation example 111
5- (aminomethyl) nicotinamide
To a stirred solution of preparative example 110 acid (770mg, 3.10mmol) in dimethylformamide (15ml) was added carbonyldiimidazole (600mg, 3.70 mmol). After 10 minutes, 0.880 ammonia (1ml) was added. After a further 1h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (gradient 95: 5: 0.5 to 80: 20: 1 by volume) to give the boc-protected intermediate. To a stirred solution of this material in dichloromethane (20ml) was added trifluoroacetic acid (6 ml). After 18 hours, a second portion of trifluoroacetic acid (6ml) was added and the reaction mixture was stirred at room temperature for 24 hours. The solution was concentrated under reduced pressure to give an oily residue which was purified by flash chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (100: 0, 90: 10: 1 and 80: 20: 1 by volume) to give the title compound (650mg) as a yellow oil.
1H NMR(400MHz，(CD3)2SO): δ is 4.11(s, 2H), 7.5 (width s), 7.59 (width s), 8.14 (width s), 8.31(m, 1H), 8.72(m, 1H), 8.90(m, 1H).
LRMS (electrospray): m/z 152 (MH)+)。
HRMS：[MH+]152.0819.C7H10N3Calculated value of O: 152.0818.
preparation example 112
2- { [ (tert-Butoxycarbonyl) amino ] methyl } isonicotinic acid ethyl ester
To a stirred solution of ethyl 2-cyanoisonicotinate (2.00g, 11.0mmol, J.Med.chem., 1976, 19, 483) in ethanol (20ml) was added 2M aqueous hydrochloric acid (7.5ml) followed by 5% palladium on carbon (200 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (60psi) for 48 hours. The mixture was filtered through Arbocel and the filtrate was concentrated under reduced pressure. The residue was azeotropically distilled with toluene under reduced pressure and dried. To a stirred solution of the residue (3.00g) in dichloromethane (22ml) was added triethylamine (4.6ml, 33mmol) followed by di-tert-butyl dicarbonate (2.62g, 12.0 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with dichloromethane (100ml) and washed with water (50 ml). The organic fraction was washed with brine (50ml), dried over magnesium sulfate and concentrated under reduced pressure to give a brown oily solid. The crude product mixture was purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (98: 2: 0.2 and 97: 3: 0.3 vol.) to give the title compound (2.20g) as a yellow oil.
1H NMR(400MHz，CDCl3): δ is 1.38(t, 3H), 1.45(s, 9H), 4.38(q, 2H), 4.50(m, 2H), 5.50 (width s, 1H), 7.73(d, 1H), 7.81(s, 1H), 8.65(d, 1H).
LRMS (electrospray): m/z 281 (MH)+)。
Preparation example 113
2- { [ (tert-Butoxycarbonyl) amino ] methyl } isonicotinic acid
To a stirred solution of the ester of preparation 112 (1.50g, 5.35mmol) in methanol (10ml) was added 1M aqueous sodium hydroxide (10 ml). After 1 hour, the reaction mixture was cooled to 0 ℃ and neutralized by the addition of 2M aqueous hydrochloric acid (5 ml). The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia (80: 20: 1 vol.) to give the title compound (1.30g) as a yellow foam.
1H NMR(400MHz，(CD3OD)：δ＝1.43(s，9H)，4.36，(s，2H)，7.68(m，1H)，7.81(s，1H)，8.47(m，1H)。
LRMS (electrospray): m/z 251 (M-H)+)。
HRMS：[MH+]253.1179。C12H17N2O4Calculated values: 253.1183.
preparation example 114
[4- (aminocarbonyl) -2-pyridinyl ] methylcarbamic acid tert-butyl ester
To a stirred solution of the acid of preparation 113 (1.3g, 5.20mmol) in dimethylformamide (10ml) was added 1-hydroxybenzotriazole (950mg, 6.20mmol) followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.20g, 6.20 mmol). After 1 hour, 0.880 ammonia (5ml) was added and the reaction mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure and dried by azeotropic distillation with toluene under reduced pressure to give a yellow semi-solid. The crude product mixture was purified by flash chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (95: 5: 0.5 vol.) to give the title compound (1.1g) as a clear oil which crystallized upon standing. This was further purified by trituration with diethyl ether (10ml) to give a sample of the desired product (1.0g) as a white powder.
1H NMR(400MHz，d6-DMSO): δ is 1.39(s, 9H), 4.25(m, 2H), 7.44(m, 1H), 7.61(m, 1H), 7.66 (width s, 2H), 8.21 (width s, 1H), 8.59(d, 1H).
LRMS (electrospray): m/z 250 (M-H)+)。
Microanalysis: measured value: c, 57.26; h, 6.86; n, 16.65. C12H17N3O3Calculated values: c, 57.36; h, 6.82; n, 16.72 percent.
Preparation example 115
2- (aminomethyl) isonicotinamide
To a stirred solution of pyridine (1.00g, 3.98mmol) from preparation 114 in dichloromethane (50ml) was added trifluoroacetic acid (15 ml). After stirring at room temperature for 18 h, the reaction mixture was concentrated under reduced pressure and purified by ion exchange chromatography on Dowex 50-X8-200 eluting with water and then 0.880 ammonia: methanol: water (5: 90 vol) to give the title compound (265mg) as a white solid.
1H NMR(400MHz，d6-DMSO): δ is 2.1 (width s, 1H), 3.4 (width s, 1H), 3.85(2H, s), 7.57(m, 1H), 7.60 (width s, 1H), 7.80(m, 1H), 8.16 (width s, 1H), 8.59(m, 1H).
LRMS(APCI)：m/z 152(MH+)。

Claims (21)

1. A compound of formula (I)
Or a pharmaceutically acceptable salt or solvate thereof, wherein:
R1when independent is H, C1-C6Alkyl radical, C3-C7Cycloalkyl OR-OR7Said C is1-C6Alkyl and C3-C7Cycloalkyl optionally substituted by halogen, -CN, -OR10、-S(O)xR10、-CO2R10、-CONR5R10、-OCONR5R10、-NR5CO2R10、-NR10R11、-NR5COR10、-SO2NR5R10、-NR5CONR5R10、-NR5SO2R10Or R10Substitution;
R2when independent is H, C1-C6Alkyl radical, C3-C6Alkenyl or R9Said C is1-C6Alkyl optionally substituted by halogen, -OR5、-OR12、-CN、-CO2R7、-OCONR5R5、-CONR5R5、-C(＝NR5)NR5OR5、-CONR5NR5R5、-NR6R6、-NR5R12、-NR5COR5、-NR5COR8、-NR5COR12、-NR5CO2R5、-NR5CONR5R5、-SO2NR5R5、-NR5SO2R5、R8Or R9Substitution;
or R1And R2Together representing unbranched C3-C4Alkylene optionally substituted by oxo, optionally wherein said C3-C4One methylene group in the alkylene group being replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R10Substitution;
R3is H or C1-C6Alkyl radical, said C1-C6Alkyl optionally substituted by halogen, -CN, -OR5、-CO2R5、-CONR5R5、-OCONR5R5、-NR5CO2R5、-NR6R6、-NR5COR5、-SO2NR5R5、-NR5CONR5R5、-NR5SO2R5、R8Or R9Substitution;
R4is phenyl, substituted by halogen, -CN or C1-C6Alkyl substitution;
each R5Independently is H, C1-C6Alkyl or C3-C7Cycloalkyl, or when two R are5When the groups are attached to the same nitrogen atom, the two groups together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, optionally substituted by C1-C6Alkyl or C 3-C7Cycloalkyl substitution;
each R6Independently is H, C1-C6Alkyl or C3-C7A cycloalkyl group;
R7is C1-C6Alkyl or C3-C7A cycloalkyl group;
R8is imidazolyl, pyrazolyl, 1, 2, 4-triazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyridyl, pyrazinyl OR pyrimidinyl, each optionally substituted by-OR5、-NR5R5Or C1-C6Alkyl substitution;
R9is azetidinyl, piperidinyl, tetrahydrofuryl, piperazinyl or morpholinyl, each optionally substituted by C1-C6Alkyl, -SO2R5、-CONR5R5、-COOR5、-CO-(C1-C6Alkylene) -OR5or-COR5Substituted and optionally substituted on a carbon atom not adjacent to the heteroatom by-OR5or-NR5COR5Substitution;
R10is H, R8、R9、R13、C1-C6Alkyl radical, C3-C7Cycloalkyl or- (C)1-C6Alkyl radical)-(C3-C7Cycloalkyl), said C1-C6Alkyl and C3-C7Cycloalkyl optionally substituted by-OR5、-OR13、R8、R9、R13or-COR13Substitution;
R11is H, C1-C6Alkyl or C3-C7Cycloalkyl radical, said C1-C6Alkyl and C3-C7Cycloalkyl optionally substituted by-OR5、-NR5R5、-NR5COR5、-CONR5R5、R8Or R9Substitution;
R12is C1-C6Alkyl radical, by R8、R9、-OR5、-CONR5R5、-NR5COR5or-NR5R5Substitution;
R13is phenyl, optionally substituted by halogen, -CN, -COR5、-CONR5R5、-SO2NR5R5、-NR5SO2R5、-OR5、-NR5R5、-(C1-C6Alkylene) -NR5R5、C1-C6Alkyl, halogen (C)1-C6) Alkyl or C3-C7Cycloalkyl substitution;
x is 0, 1 or 2.
2. A compound according to claim 1, wherein R1When independent is H, C1-C6Alkyl radical, C3-C7Cycloalkyl OR-OR7Said C is1-C6Alkyl optionally substituted by halogen, -OR10、-NR10R11、-NR5COR10Or R10And (4) substitution.
3. A compound according to claim 1, wherein R 2When independent is H, C1-C6Alkyl radical, C3-C6Alkenyl or R9Said C is1-C6Alkyl is optionally substituted by-OR5、-OR12、-CN、-CO2R7、-CONR5R5、-C(＝NR5)NR5OR5、-CONR5NR5R5、-NR6R6、-NR5R12、-NR5COR8、-NR5COR12、-NR5CO2R5、R8Or R9And (4) substitution.
4. A compound according to claim 1, wherein R1And R2When taken together represent unbranched C3-C4Alkylene optionally substituted by oxo, wherein said C3-C4One methylene group in the alkylene group being replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R10And (4) substitution.
5. A compound according to claim 4, wherein R1And R2When taken together, represents an unbranched propylene group in which one methylene group is replaced by an oxygen atom, or represents an unbranched butylene group in which one methylene group is replaced by a nitrogen atom, the propylene and butylene groups being optionally substituted by oxo, the nitrogen atom being optionally substituted by R10And (4) substitution.
6. A compound according to claim 1, wherein R3Is H or C1-C6An alkyl group.
7. A compound according to claim 1, wherein R10Is H, R8、R9、R13、C1-C6Alkyl or- (C)1-C6Alkyl group) - (C3-C7Cycloalkyl), said C1-C6Alkyl is optionally substituted by-OR5、-OR13、R8、R9、R13or-COR13And (4) substitution.
8. A compound according to claim 7, wherein R10Is H, R8、R9、R13、C1-C6Alkyl or- (C)1-C6Alkyl group) - (C3-C7Cycloalkyl), said C1-C6Alkyl is optionally substituted by-OR5Or R13And (4) substitution.
9. A compound according to claim 1, wherein R 11Is H or C1-C6Alkyl radical, said C1-C6Alkyl is optionally substituted by-OR5、-NR5R5、-NR5COR5、-CONR5R5、R8Or R9And (4) substitution.
10. A compound according to claim 9, wherein R11Is H or C1-C6Alkyl radical, said C1-C6Alkyl is optionally substituted by-OR5or-NR5COR5And (4) substitution.
11. A compound according to claim 1, wherein R12Is C1-C4Alkyl radical, by R8、R9、-OR5、-CONR5R5、-NR5COR5or-NR5R5And (4) substitution.
12. A compound according to claim 11, wherein R12Is C1-C4Alkyl radical, by R9、-OR5、-NR5COR5or-NR5R5And (4) substitution.
13. A compound according to claim 1, wherein R13Is phenyl, substituted by halogen, -CN, -COR5、-CONR5R5、-SO2NR5R5、-NR5SO2R5、-OR5、-NR5R5、-(C1-C6Alkylene) -NR5R5、C1-C6Alkyl, halogen (C)1-C6) Alkyl or C3-C7Cycloalkyl is substituted.
14. A compound according to claim 13, wherein R13Is phenyl, substituted by halogen, -CN, -CONR5R5、-SO2NR5R5OR-OR5And (4) substitution.
15. A compound according to claim 1 selected from:
2- [4- (3, 5-dichlorophenoxy) -3, 5-dimethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazole;
[4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetonitrile;
5- { [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -1H-pyrazol-3-ol;
6- { [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -2-methyl-4 (3H) -pyrimidinone;
2-amino-6- { [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -4(3H) -pyrimidinone;
2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] -N-hydroxyacetamidine;
methyl [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetate;
2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetamide;
2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetohydrazide;
5- { [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -1, 3, 4-oxadiazol-2 (3H) -one;
2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethylamine;
3- { [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -1, 2, 4-oxadiazol-5-ol;
5- { [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } -1, 3, 4-oxadiazol-2-amine;
n- {2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -2-methoxyacetamide;
n- {2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -2-pyridinecarboxamide;
n- {2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -2-pyrazinecarboxamide;
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
4- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -3, 5-dimethylbenzonitrile;
3-chloro-4- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -2-fluorobenzonitrile;
2- [4- (4-chlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (3-chlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (2-chlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (2, 6-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (2, 3-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (2, 4-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [3, 5-diethyl-4- (2-fluorophenoxy) -1H-pyrazol-1-yl ] ethanol;
2- [3, 5-diethyl-4- (3-fluorophenoxy) -1H-pyrazol-1-yl ] ethanol;
2- [4- (3, 5-dimethylphenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [3, 5-diethyl-4- (4-fluoro-3-methylphenoxy) -1H-pyrazol-1-yl ] ethanol;
2- [4- (2, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (2, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (3, 4-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (2, 6-difluorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (2, 5-difluorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
2- [4- (3, 5-difluorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethanol;
4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1- (2-methoxyethyl) -1H-pyrazole;
4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1- (methoxymethyl) -1H-pyrazole;
4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1-methyl-1H-pyrazole;
4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazole;
4- {2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } morpholine;
n- {2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -N- (2-methoxyethyl) amine;
1- (1- {2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -4-piperidinyl) ethanone;
n- {2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -N, N-dimethylamine;
n- [2- { (2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } amino) ethyl ] acetamide;
N- {2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -N-methylamine;
n- {2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -N- (tetrahydro-2-furylmethyl) amine;
3- { [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] methyl } morpholine;
1- (3-azetidinyl) -4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazole;
7- (3, 5-dichlorophenoxy) -6-ethyl-2, 3-dihydropyrazolo [5, 1-b ] [1, 3] oxazole;
4- (3, 5-dichlorophenoxy) -3, 5-dimethyl-1H-pyrazole;
1- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] -2-propanol;
2- {2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl) ethoxy } ethanamine;
4- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } morpholine;
4- (3, 5-dichlorophenoxy) -3-methyl-5- [ (2-methyl-1H-imidazol-1-yl) methyl ] -1H-pyrazole;
2- [4- (3, 5-dichlorophenoxy) -3-ethyl-5-methoxy-1H-pyrazol-1-yl ] ethanol;
1- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -1H-1, 2, 4-triazole;
3- [ (3, 5-diethyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } benzonitrile;
2- [4- (3-cyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetamide;
ethyl [4- (3-cyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetate;
1-allyl-4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazole;
n- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -N- (4-methoxybenzyl) amine;
n- (cyclopropylmethyl) [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methylamine;
[4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] -N, N-dimethylmethylamine;
[4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] -N-methylmethanamine;
1- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -4-methylpiperazine;
1- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -4-piperidinecarboxamide;
n- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -2-methoxyethylamine;
1-acetyl-4- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } piperazine;
n- [2- ({ [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) ethyl ] acetamide;
n- (1- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -4-piperidinyl) acetamide;
1- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -4-methoxypiperidine;
3-chloro-5- [ (3, 5-dimethyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3- { [5- (aminomethyl) -3-methyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile;
3-chloro-5- { [ 3-methyl-5- (1-piperazinylmethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
3-chloro-5- [ (5- { [ (4-cyanobenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (3-methyl-5- { [4- (methylsulfonyl) -1-piperazinyl ] methyl } -1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (5- { [4- (methoxyacetyl) -1-piperazinyl ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
4- { [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -1-piperazinecarboxylic acid methyl ester;
4- [ ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzenesulfonamide;
4- (3, 5-dichlorophenoxy) -5- (methoxymethyl) -3-methyl-1H-pyrazole;
3-tert-butyl-4- (3, 5-dichlorophenoxy) -5-methyl-1H-pyrazole;
4- (3, 5-dichlorophenoxy) -3-ethyl-5-methyl-1H-pyrazole;
4-cyano-N- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } benzamide;
3-cyano-N- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } benzamide;
n- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -N- (3-pyridylmethyl) amine;
3- { [5- (4-acetyl-1-piperazinyl) methyl ] -3-methyl-1H-pyrazol-4-yl ] oxy) -5-chlorobenzonitrile;
3-chloro-5- [ (5- { [ (4-cyanobenzyl) (methyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (5- { [ (4-cyanobenzyl) (2-hydroxyethyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- ({ 3-methyl-5- [ (2-methyl-1H-imidazol-1-yl) methyl ] -1H-pyrazol-4-yl } oxy) benzonitrile;
2- (4- (3, 5-dichlorophenoxy) -3-methyl-5- { [ (3-pyridylmethyl) amino ] methyl } -1H-pyrazol-1-yl) ethanol;
5- [ (3-isopropyl-5-methyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile;
5- { [1- (2-hydroxyethyl) -3-isopropyl-5-methyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile;
3- (3, 5-dichlorophenoxy) -2-ethyl-6, 7-dihydropyrazolo [1, 5-a ] pyrazin-4 (5H) -one;
3- (3, 5-dichlorophenoxy) -2-ethyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a ] pyrazine;
3- (3, 5-dichlorophenoxy) -2-ethyl-5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a ] pyrazine;
4- [ (3- (3, 5-dichlorophenoxy) -2-ethyl-6, 7-dihydropyrazolo [1, 5-a ] pyrazin-5 (4H) -yl) methyl ] benzonitrile;
3- (3, 5-dichlorophenoxy) -2-ethyl-5- (4-methoxybenzyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a ] pyrazine;
[1- (2-aminoethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-5-yl ] methanol;
2- [4- (3, 5-dichlorophenoxy) -5- (ethoxymethyl) -3-ethyl-1H-pyrazol-1-yl ] ethylamine;
2- [4- (3, 5-dichlorophenoxy) -3-ethyl-5- (1H-pyrazol-1-ylmethyl) -1H-pyrazol-1-yl ] ethylamine;
n- { [1- (2-aminoethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-5-yl ] methyl } -N- (4-methoxybenzyl) amine;
4- [ ({ [1- (2-aminoethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzonitrile;
2- [5- [ (4-acetyl-1-piperazinyl) methyl ] -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylamine;
n- [2- ({ [1- (2-aminoethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-5-yl ] methyl } amino) ethyl ] acetamide;
[4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methylamine hydrobromide;
n- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } -N- (4-fluorobenzyl) amine;
4- [ ({ [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzonitrile;
3-chloro-5- [ (1, 3, 5-trimethyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (5- { [ (4-cyanobenzyl) amino ] methyl } -1, 3-dimethyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- { [1- (2-hydroxyethyl) -3, 5-dimethyl-1H-pyrazol-4-yl ] oxy } benzonitrile;
3-chloro-5- { [5- { [ (4-cyanobenzyl) amino ] methyl } -1- (2-hydroxyethyl) -3-methyl-1H-pyrazol-4-yl ] oxy } benzonitrile;
4- [ ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzamide;
3- { [3, 5-diethyl-1- (2-hydroxyethyl) 1-H-pyrazol-4-yl ] oxy } -5-fluorobenzonitrile;
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile;
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
3-chloro-5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
3- [ (3, 5-diethyl-1H-pyrazol-4-yl) oxy ] -5-fluorobenzonitrile;
5- [ (3, 5-diethyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile;
3- [ (3, 5-diethyl-1H-pyrazol-4-yl) oxy ] -5-methylbenzonitrile;
3-chloro-5- [ (3, 5-diethyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile;
5- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-fluorobenzonitrile;
5- [ (3-cyclopropyl-5-ethyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile;
5- [ (3-tert-butyl-5-methyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile;
5- [ (5-ethyl-3-isopropyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile;
4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1- (1-methyl-3-azetidinyl) -1H-pyrazole;
2- [4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylamine;
2- [4- (3, 5-dichlorophenoxy) -5-ethyl-1H-pyrazol-1-yl ] ethylamine;
tert-butyl 2- [4- (3, 5-dichlorophenoxy) -3-ethyl-5- (hydroxymethyl) -1H-pyrazol-1-yl ] ethylcarbamate;
tert-butyl 2- [4- (3, 5-dichlorophenoxy) -5- (ethoxymethyl) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamate;
tert-butyl 2- [5- (bromomethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamate;
Tert-butyl 2- [5- (aminomethyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamate;
tert-butyl 2- [5- [ (4-acetyl-1-piperazinyl) methyl ] -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamate;
2- [4- (3, 5-dichlorophenoxy) -3-ethyl-5- (1H-pyrazol-1-ylmethyl) -1H-pyrazol-1-yl ] ethylcarbamic acid tert-butyl ester;
tert-butyl 2- [5- ({ [2- (acetylamino) ethyl ] amino } methyl) -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamate;
tert-butyl 2- (4- (3, 5-dichlorophenoxy) -3-ethyl-5- { [ (4-methoxybenzyl) amino ] methyl } -1H-pyrazol-1-yl) ethylcarbamate;
tert-butyl 2- [5{ [ (4-cyanobenzyl) amino ] methyl } -4- (3, 5-dichlorophenoxy) -3-ethyl-1H-pyrazol-1-yl ] ethylcarbamate;
3- { [5- (bromomethyl) -1, 3-dimethyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile;
3- [ (3, 5-diethyl-1-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3- { [3, 5-diethyl-1- (2-methoxyethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
3- ({5- [2- (benzyloxy) ethyl ] -3-ethyl-1H-pyrazol-4-yl } oxy) -5-fluorobenzonitrile;
3- { [ 3-ethyl-5- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5-fluorobenzonitrile;
3- ({5- [2- (4-cyanophenoxy) ethyl ] -3-ethyl-1H-pyrazol-4-yl } oxy) -5-fluorobenzonitrile;
3- [ (3-ethyl-5- {2- [ (2-methyl-3-pyridinyl) oxy ] ethyl } -1H-pyrazol-4-yl) oxy ] -5-fluorobenzonitrile;
3- ({ 3-ethyl-5- [2- (3-pyridinyloxy) ethyl ] -1H-pyrazol-4-yl } oxy) -5-fluorobenzonitrile;
3- [ (5- [2- [ (2-amino-3-pyridinyl) oxy ] ethyl } -3-ethyl-1H-pyrazol-4-yl) oxy ] -5-fluorobenzonitrile;
5- ({5- [2- (benzyloxy) ethyl ] -3-ethyl-1H-pyrazol-4-yl } oxy) isophthalonitrile;
5- { [ 3-ethyl-5- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
3- { [5- (aminomethyl) -1- (2-hydroxyethyl) -3-methyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile;
5- [ (1-allyl-3-tert-butyl-5-methyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile;
5- { [ 3-tert-butyl-1- (2-hydroxyethyl) -5-methyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- { [1- (2-aminoethyl) -3-tert-butyl-5-methyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- { [ 3-cyclopropyl-5-ethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- { [ 5-cyclopropyl-3-ethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- { [ 5-ethyl-1- (2-hydroxyethyl) -3-isopropyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- { [ 3-ethyl-1- (2-hydroxyethyl) -5-isopropyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile;
2- [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethylcarbamate;
n- {2- [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } aminosulfonamide;
n- {2- [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl } -2-methoxyacetamide;
5- { [1- (3-azetidinyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- { [3, 5-diethyl-1- (3-hydroxypropyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- [ (3, 5-diethyl-1-methyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile;
5- { [3, 5-diethyl-1- (2-methoxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- { [1- (3-aminopropyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile;
methyl [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetate;
2- [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] acetamide;
5- { [3, 5-diethyl-1- (hydroxymethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
3- [ ({ [4- (3-cyano-5-fluorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzamide;
4- [ ({ [4- (3-cyano-5-fluorophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzamide;
4- [ ({ [4- (3, 5-dicyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzamide;
3- [ ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzamide;
4- [ ({ [4- (3-cyano-5-methylphenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzamide;
4- [ ({ [4- (3-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] benzamide;
5- [ (3, 5-bicyclopropyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile;
5- { [3, 5-bicyclopropyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- { [1- (2-aminoethyl) -3, 5-bicyclopropyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile;
3- { [ 3-cyclopropyl-1- (2-hydroxyethyl) -5-methyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile;
3- { [ 5-cyclopropyl-1- (2-hydroxyethyl) -3-methyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile;
3- [ 3-cyclopropyl-1- (2-amino-ethyl) -5-methyl-1H-pyrazol-4-yloxy ] -5-methyl-benzonitrile;
3- [ (3-cyclopropyl-5-methyl-1H-pyrazol-4-yl) oxy ] -5-methylbenzonitrile;
3- { [1- (3-aminopropyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile;
2- [4- (3, 5-difluorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethylamine;
3- [ (3-isopropyl-5-methyl-1H-pyrazol-4-yl) oxy ] -5-methylbenzonitrile;
3- { [1- (2-aminoethyl) -3-isopropyl-5-methyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile;
2- [4- (3, 5-dichlorophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] -N- (2-pyridylmethyl) acetamide;
[4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] acetonitrile;
1- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] acetyl } piperidine;
(3R) -1- { [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] acetyl } -3-piperidinol;
2- [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] acetamide;
2- [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] -N- (6-methyl-2-pyridinyl) acetamide;
2- [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] -N- [4- (trifluoromethyl) benzyl ] acetamide;
2- [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] acetamide;
2- [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] -N- [2- (trifluoromethyl) benzyl ] acetamide;
2- [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] -N- (4-fluorobenzyl) acetamide;
n-benzyl-2- [4- (3, 5-dichlorophenoxy) -3-methyl-1H-pyrazol-5-yl ] -N-methylacetamide;
3-chloro-5- [ (5- { [ (2-chlorobenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3- ({5- [ (benzylamino) methyl ] -3-methyl-1H-pyrazol-4-yl } oxy) -5-chlorobenzonitrile;
3- [ (5- { [ benzyl (methyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] -5-chlorobenzonitrile;
3-chloro-5- { [5- ({ [ (5-chloro-2-pyridinyl) methyl ] amino } methyl) -3-methyl-1H-pyrazol-4-yl ] oxy } benzonitrile;
3-chloro-5- [ (3-methyl-5- { [ (4-pyridylmethyl) amino ] methyl } -1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (3-methyl-5- { [ (4-methylbenzyl) amino ] methyl } -1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (5- { [ (3-methoxypropyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
4- [2- ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) ethyl ] benzenesulfonamide;
3-chloro-5- { [ 3-methyl-5- ({ [ (1S) -1-phenylethyl ] amino } methyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
3-chloro-5- [ (5- { [ (4-chlorobenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (3-methyl-5- { [ methyl (2-phenylethyl) amino ] methyl } -1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- ({ 3-methyl-5- [ (1H-pyrazol-3-ylamino) methyl ] -1H-pyrazol-4-yl } oxy) benzonitrile;
n- [2- ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) ethyl ] acetamide;
3-chloro-5- [ (5- { [ (3-chlorobenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- { [5- ({ [ 3-fluoro-5- (trifluoromethyl) benzyl ] amino } methyl) -3-methyl-1H-pyrazol-4-yl ] oxy } benzonitrile;
3-chloro-5- [ (3-methyl-5- { [ (6-methyl-2-pyridyl) amino ] methyl } -1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (5- { [ (4-hydroxy-6-methyl-2-pyrimidinyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (5- { [ (4-fluorobenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- { [5- ({ [ (1R) -2-hydroxy-1-phenylethyl ] amino } methyl) -3-methyl-1H-pyrazol-4-yl ] oxy } benzonitrile;
3- (5- [ (benzylamino) methyl ] -3-methyl-1H-pyrazol-4-yl } oxy) -5-chlorobenzonitrile;
3-chloro-5- [ (5- { [ (3-methoxybenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- { [ 3-methyl-5- ({ [4- (trifluoromethyl) benzyl ] amino } methyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
3-chloro-5- { [5- ({ [ (1R) -1- (hydroxymethyl) -2-methylpropyl ] amino } methyl) -3-methyl-1H-pyrazol-4-yl ] oxy } benzonitrile;
3-chloro-5- [ (5- { [ (2-methoxybenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- { [ 3-methyl-5- ({ [2- (2-thienyl) ethyl ] amino } methyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
3-chloro-5- [ (3-methyl-5- { [ (3-pyridylmethyl) amino ] methyl } -1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- { [ 3-methyl-5- ({ [2- (trifluoromethyl) benzyl ] amino } methyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
3-chloro-5- [ (5- { [ (2, 4-dichlorobenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (3-methyl-5- { [ (2-pyridylmethyl) amino ] methyl } -1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (5- { [ (3, 4-dichlorobenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (3-methyl-5- { [ (3-phenylpropyl) amino ] methyl } -1H-pyrazol-4-yl) oxy ] benzonitrile;
3-chloro-5- [ (5- { [ (4-methoxybenzyl) amino ] methyl } -3-methyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3, 5-dichlorophenyl-3-methyl-5- [ (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl ] -1H-pyrazol-4-yl ether;
3-fluoro-5- { [1- (2-hydroxyethyl) -5-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
5- [ (3, 5-diethyl-1- {2- [ (2-methoxyethoxy) methoxy ] ethyl } -1H-pyrazol-4-yl) oxy ] isophthalonitrile;
5- { [ 5-ethyl-3- (1-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- { [ 5-ethyl-3- (1-hydroxyethyl) -1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
5- [ ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] nicotinamide;
2- [ ({ [4- (3-chloro-5-cyanophenoxy) -3-methyl-1H-pyrazol-5-yl ] methyl } amino) methyl ] isonicotinamide;
di (tert-butyl) 2- [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl phosphate;
2- [4- (3, 5-dicyanophenoxy) -3, 5-diethyl-1H-pyrazol-1-yl ] ethyl dihydrogen phosphate;
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile sulfate;
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile benzenesulfonate;
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile tosylate;
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile mesylate;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy ] -5-methylbenzonitrile bismesylate;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile phosphate;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile (L) -tartrate;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy ] } -5-methylbenzonitrile succinate;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy) } -5-methylbenzonitrile (L) -citrate salt;
or a pharmaceutically acceptable salt or solvate thereof.
16. A compound according to claim 15 selected from:
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5-fluorobenzonitrile;
3- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile;
5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile;
3-chloro-5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } benzonitrile;
5- [ (3, 5-diethyl-1H-pyrazol-4-yl) oxy ] isophthalonitrile;
3- [ (3, 5-diethyl-1H-pyrazol-4-yl) oxy ] -5-methylbenzonitrile;
3-chloro-5- [ (3, 5-diethyl-1H-pyrazol-4-yl) oxy ] benzonitrile;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-methylbenzonitrile;
3- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } -5-chlorobenzonitrile;
5- { [1- (2-aminoethyl) -3, 5-diethyl-1H-pyrazol-4-yl ] oxy } isophthalonitrile;
or a pharmaceutically acceptable salt or solvate thereof.
17. A compound according to claim 1 which is 5- { [3, 5-diethyl-1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] oxy } isophthalonitrile; or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 17, together with one or more pharmaceutically acceptable excipients, diluents or carriers.
19. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18 in the manufacture of a medicament having reverse transcriptase inhibitory or modulating activity.
20. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18 in the manufacture of a medicament for the treatment of infection by HIV or a genetically related retrovirus or the resulting acquired immunodeficiency syndrome.
21. A process for the preparation of a compound of formula (I) according to claim 1, comprising:
(A) reacting a compound of formula (II), (VI) or (VII)
And formula H2NNHR2(V) condensation of a compound or a salt or hydrate thereof; wherein R is1、R3And R4As defined in claim 1, except that R1Or R3Is halogen, -OR7Or other than-CN, and L1And L3Is a leaving group, wherein R2As defined in claim 1; or
(B) Reacting a compound of formula (XIII) or (XIV), respectively, in the presence of a suitable palladium catalyst and carbon monoxide
And formula R7OH (XXI) alcohol reaction; wherein R is2And R4As defined in claim 1, wherein R is1And R3One of them is-OR7And the other is as defined in claim 1, and L3Is a leaving group, wherein R7As defined in claim 1;
(C) under dehydrating conditions, reacting a compound of formula (XV) or (XVI), respectively
And formula R7Reaction of OH (XXI) compounds; wherein R is2And R4As defined in claim 1, wherein R is1And R3One of them is-OR7And the other is as defined in claim 1, wherein R is7As defined in claim 1;
(D) reacting a compound of formula (XV) or (XVI), respectively
Reacting with a halogenating agent; wherein R is2And R4As defined in claim 1, wherein R is1And R3One is halogen and the other is as defined in claim 1; or
(E) Interconversion of one compound of formula (I) with another compound of formula (I);
(F) Deprotection of a protected compound of formula (I);
optionally converting a compound of formula (I) prepared by any one of the methods (a) to (F) into a pharmaceutically acceptable salt or solvate thereof.
HK04106485.5A 2001-04-10 2002-04-04 Pyrazole derivatives for treating hiv HK1063781B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB0108999.4 2001-01-10
GB0108999A GB0108999D0 (en) 2001-04-10 2001-04-10 Pyrazole derivatives
GB0127426.5 2001-11-15
GB0127426A GB0127426D0 (en) 2001-11-15 2001-11-15 Pyrazole derivatives
PCT/IB2002/001234 WO2002085860A1 (en) 2001-04-10 2002-04-04 Pyrazole derivatives for treating hiv

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Publication Number Publication Date
HK1063781A1 HK1063781A1 (en) 2005-01-14
HK1063781B true HK1063781B (en) 2008-11-07

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