CN102459158B - New acid amides and amidine derivative and its purposes - Google Patents

New acid amides and amidine derivative and its purposes Download PDF

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Publication number
CN102459158B
CN102459158B CN201080026472.4A CN201080026472A CN102459158B CN 102459158 B CN102459158 B CN 102459158B CN 201080026472 A CN201080026472 A CN 201080026472A CN 102459158 B CN102459158 B CN 102459158B
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cyano
methyl
adamantyl
alkyl
amino
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CN102459158A (en
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S.佩迪
M.V.帕特尔
J.J.罗德
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AbbVie Inc
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AbbVie Inc
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Abstract

The inhibitor that the present invention relates to 11-beta-hydroxysteroid dehydrogenase 1 type enzyme is treating the purposes in following disease and illness with them: non-insulin-dependent type ii diabetes, insulin resistant, obesity, lipid metabolism disorders, metabolic syndrome, central nervous system disorders and the disease relevant to excess glucocorticoid and illness.

Description

Novel amide and amidine derivatives and use thereof
Technical Field
The present invention relates to novel amides, cyanoamidines, thioamides, amidines, hydroxyimine amides, alkoxyimine amides, aryloxyiimine amides, and related compounds which are inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD 1) enzyme. The invention further relates to the use of an inhibitor of the 11 β -HSD1 enzyme for therapy in a human in need thereof.
Background
Glucocorticoids circulate in the blood in both active (i.e., cortisol in humans) and inactive (i.e., corticosterone in humans) forms. Many studies have shown that 11 β -HSD1 acts primarily as a reductase in vivo and in intact cells. It converts inactive 11-ketoglucocorticoids (i.e. corticosterone or corticosterone) into active 11-hydroxyglucocorticoids (i.e. cortisol or corticosterone) and thereby enhances the glucocorticoid action in a tissue-specific manner, resulting in higher local concentrations of cortisol. Inhibition of 11 β -HSD1 may prevent or reduce tissue-specific enhancement of glucocorticoid action and thereby provide beneficial effects.
11 β -HSD1 is a low affinity enzyme with a K in the micromolar range for corticosterone mThe range is preferably NADPH/NADP+(nicotinamide adenine dinucleotide phosphate) as a cofactor. 11 β -HSD1 is widely expressed in various tissues, such as liver, bone, brain, lung, fat and vascular smooth muscle cells.
In the liver and adipose tissue, excessive glucocorticoid action can lead to insulin resistance, type II diabetes, dyslipidemia, increased abdominal obesity and hypertension (Su et al,Progress in Medicinal Chemistry46, 29-130(2008), Webster et al,Expert Opin. Ther. Patents, 17(12), 1407-1422(2007); Wang, Drug Discovery Today: Ther. Strategies, 4(2), 117-122(2007); Link, Current Opin. In Invest. Drugs4(4), 421-429(2003); Seckl et al,Endocrinology142, 1371-1376(2001) and references cited therein). Accordingly, the 11 β -HSD1 inhibitor class has been recognized as one of the most promising therapeutic classes (Norman p.,Insight Pharma Reports, 103-110(April 2007))。
the published data indicate that elevated glucocorticoid levels in the mammalian brain can lead to neuronal degeneration and dysfunction, particularly in the elderly (de Quervain)And the like, Hum Mol Genet., 13, 47-52(2004); Belanoff et al. J. Psychiatr Res., 35, 127-35,(2001)). Evidence in rodents and humans suggests that prolonged elevation of plasma glucocorticoid levels can impair cognitive function, which impairment is accompanied by agingAnd become more severe (Issa)And the like, J. Neurosci., 10, 3247-3254(1990); Lupien et al., Nat. Neurosci., 1, 69-73(1998); Yau et al., Neuroscience, 66, 571-581(1995)). Long-term excessive cortisol levels in the brain can lead to neuronal loss and neuronal dysfunction. (Kerr) And the like, Psychobiology, 22, 123-133(1994); Woolley, Brain Res., 531, 225-231,(1990); Landfield, Science, 272, 1249-1251(1996))。
in addition, glucocorticoid-induced acute psychosis accounts for the more pharmacologically induced effects of this response, and is a major consideration by physicians when treating patients with these steroidal agents (Wolkowitz et al,Ann NY Acad Sci., 1032, 191-194(2004)). It has recently been shown that 11 β -HSD1 mRNA is expressed in the human hippocampus, frontal cortex and cerebellum, and that treatment of elderly diabetic patients with the non-selective 11 β -HSD1 and 11 β -HSD2 inhibitors carbenoxolone can improve speech fluency and memory (Thekkapat et al,Proc Natl Acad Sci USA, 101, 6743-6749(2004)). Excessive glucocorticoid levels also affect psychopathology, as shown in animal models, which leads to increased anxiety and aggressive behavior. Chronic elevation of cortisol is also associated with depression in Cushing's disease (McEwen,Metab. Clin. & Exp., 54, 20-23(2005)). Numerous animal and clinical studies have provided evidence of a link between elevated glucocorticoid levels and neuropsychiatric disorders (e.g., major depressive disorder, psychotic depression, anxiety disorders, panic disorder, post-traumatic stress disorder and depression in Cushing's syndrome) (budziszews ka,Polish J. of Pharmacol54, 343-349, (2002); Strohle et al, Pharmacopsychiatry, 36, S207-S214(2003), DeBattista et al,TRENDS in Endocr. Metab.,17, 117-120(2006); Norman et al,Expert Rev. Neurotherapeutics, 7, 203-213(2007))。
thus, inhibition of 11 β -HSD1 may benefit patients suffering from: non-insulin dependent type II diabetes mellitus, insulin resistance, obesity, disorders of lipid metabolism, metabolic syndrome, central nervous system disorders, age-related or glucocorticoid-related decline in cognitive function, such as those seen in alzheimer's disease and related dementias, major depressive disorder, psychotic depression, anxiety, panic disorder, post-traumatic stress disorder, depression in Cushing's syndrome, refractory depression, and other diseases and disorders mediated by excessive glucocorticoid action.
Summary of the invention
One embodiment relates to compounds of formula (I)
(I),
Wherein
L is- (CH)2)n-，-(CR38R39)m-X-(CR38R39)n-or- (CR)38R39)m-X-(CR38R39)n-Y-；
m is independently at each occurrence 0, 1 or 2;
n is independently at each occurrence 0, 1 or 2;
R1is cycloalkyl or heterocycle;
R2is hydrogen, alkyl or aryl; or R1And R2Together with the atoms to which they are attached form a heterocyclic ring; or R2And R3Together with the atoms to which they are attached form a heterocyclic ring;
R3and R4Independently hydrogen, alkyl or cycloalkyl; or R 3And R4Together with the atom to which they are attached form cycloalkyl, heteroA ring, heteroaryl or aryl;
R5is hydrogen, alkyl, amino, aryl, cycloalkyl, heteroaryl or heterocycle, with the proviso that: when L is- (CR)38R39)m-X-(CR38R39)n-Y-is, R5Is not an amino group; or R4And R5Together with the atoms to which they are attached form a cycloalkyl or heterocyclic ring;
x is-O-, -S-, -S (O)2-，-NR36-or-CR36R37-；
Y is O or NR40；
R36And R37Independently at each occurrence is hydrogen or alkyl; or R36And R2Together with the atoms to which they are attached form a heterocyclic ring;
R38、R39and R40Independently at each occurrence is hydrogen or alkyl;
w is O, N-CN, N-OR6，N-R6Or S; and
R6is hydrogen, alkyl or aryl; or
A pharmaceutically acceptable salt, ester, amide, N-oxide or prodrug thereof.
Another embodiment includes the use of a compound of formula (I) for the treatment of 11 β -HSD1 enzyme mediated disorders, such as non-insulin dependent type II diabetes, insulin resistance, obesity, disorders of lipid metabolism, metabolic syndrome, age-related or glucocorticoid-related decline in cognitive function, such as those seen in alzheimer's disease and related dementias, major depressive disorder, psychotic depression, anxiety, panic disorder, post-traumatic stress disorder, depression in Cushing's syndrome, refractory depression, and other diseases and disorders mediated by excessive glucocorticoid action.
Another embodiment relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically suitable carrier.
Detailed description of the invention
Definition of terms
For any substituent herein or variable that occurs more than one time in a compound of the invention or any other formula, its definition on each occurrence is independent of its definition at other occurrences. Substituents may be combined as long as such combination can yield a stable compound. Stabilizing compounds are compounds that can be isolated from the reaction mixture in useful purity.
As used in this specification and the appended claims, the following terms have the following meanings
The term "acetyl" refers to-C (O) CH3A group.
The term "acyl" refers to an alkyl group attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of acyl groups include, but are not limited to: acetyl, 1-oxopropyl, 2, 2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.
The term "acyloxy" refers to an acyl group attached to the parent molecular moiety through an oxygen atom. Representative examples of acyloxy groups include, but are not limited to: acetoxy, propionyloxy and isobutyryloxy.
The term "alkenyl" refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons, preferably 2, 3, 4, 5 or 6 carbons, and containing at least one carbon-carbon double bond. Representative examples of alkenyl groups include, but are not limited to: vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3-decenyl.
The term "alkoxy" means an alkyl group attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy and the like.
The term "alkoxyalkoxy" means an alkoxy group attached to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy groups include, but are not limited to: t-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy and methoxymethoxy.
The term "alkoxyalkyl" means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group. Representative examples of alkoxyalkyl groups include, but are not limited to: t-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl and methoxymethyl.
The term "alkoxycarbonyl" refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl groups include, but are not limited to: methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
The term "alk (alkyl) oxyiminamides" meansA group.
The term "alkoxyimino" refers to an alkoxy group attached to the parent molecular moiety through a-C (= NH) -group (which is also defined as an imino group). Representative examples of alkoxyimino groups include, but are not limited to: imino (methoxy) methyl, ethoxy (imino) methyl and tert-butoxy (imino) methyl.
The term "alkoxysulfonyl" refers to an alkoxy group attached to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkoxysulfonyl groups include, but are not limited to: methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.
The term "alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms. Representative examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl.
In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is preceded by the prefix "Cx-Cy- "wherein x is the minimum number of carbon atoms in the substituent and y is the maximum number. Thus, for example, "C1-C6-alkyl "means an alkyl substituent containing from 1 to 6 carbon atoms. To further illustrate, C3-C6-cycloalkyl means a saturated hydrocarbon-based ring containing from 3 to 6 carbon ring atoms.
The term "alkyl-NH-alkyl" refers to an alkyl group attached through an-NH-group to a second alkyl group as defined herein. The second alkyl group is attached to the parent molecular moiety.
The term "alkylcarbonyl" refers to an alkyl group attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl groups include, but are not limited to: acetyl, 1-oxopropyl, 2, 2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.
The term "cycloalkylalkyl" refers to an alkyl group attached to the parent molecular moiety through a cycloalkyl group, as defined herein. Representative examples of alkylcycloalkyl groups include, but are not limited to: 4-ethylcyclohexyl, 3-methylcyclopentyl and 2-isopropylcyclopropyl.
The term "alkylsulfonyl" refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group, as defined herein. Examples of alkylsulfonyl groups include, but are not limited to: methylsulfonyl and ethylsulfonyl.
The term "alkylthio" refers to an alkyl group attached to the parent molecular moiety through a sulfur atom. Representative examples of alkylthio groups include, but are not limited to: methylthio, ethylthio, tert-butylthio and hexylthio.
The term "amino" is-NR90R91Wherein R is90And R91Each independently is hydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, aralkyl, aryloxy, aryloxyalkyl, arylsulfonyl, alkyl-NH-alkyl, aryl-NH-alkyl, aralkyl, haloalkyl, aryl-heterocycle, carboxyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroaralkyl, heteroaryloxyalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle-NH-alkyl, heterocycle-heterocycle, heterocyclooxyalkyl, heterocyclooxy, heterocyclosulfonyl or hydroxyl.
The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 10 carbon atoms, preferably 2, 3, 4 or 5 carbon atoms, and containing at least one carbon-carbon triple bond. Representative examples of alkynyl groups include, but are not limited to: ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.
The term "amidine" or "iminamide" refers to A group.
The term "amido" refers to an amino, alkylamino, or dialkylamino group attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of amide groups include, but are not limited to: aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl and ethylmethylaminocarbonyl.
The term "aryl" refers to phenyl, bicyclic aryl, or tricyclic aryl. Bicyclic aryl is naphthyl, phenyl fused to a cycloalkyl, cycloalkenyl, heteroaryl or heterocycle as defined herein. The bicyclic aryl must be attached to the parent molecular moiety through any available carbon atom contained within the phenyl ring. Representative examples of bicyclic aryl groups include, but are not limited to: indanyl, indenyl, naphthyl, dihydronaphthyl and tetrahydronaphthyl. Tricyclic fused ring systems may be illustrated by bicyclic aryl radicals fused to cycloalkyl, phenyl, heteroaryl or heterocycle as defined herein. The tricyclic aryl group is attached to the parent molecular moiety through any carbon atom contained within the phenyl ring. Representative examples of aryl groups include, but are not limited to: an anthracene group, a phenanthrene group,phenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
The aryl groups of the present invention may be substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, aryl, aralkoxy, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkoxy, heteroarylalkyl, heteroarylcarbonyl, heterocycle-alkoxy, heterocycle-carbonyl, heterocycle-oxy, heterocycle-sulfonyl, hydroxy, hydroxyalkyl, methylenedioxy, nitro, -C (O) N (H) S (O)2Alkyl, -RfRgN-，RfRgN alkyl radical, RfRgN carbonyl, -N (H) C (O) N (H) (alkyl), and RfRgN-sulfonyl, wherein RfAnd RgIndependently selected from: hydrogen, alkyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, haloalkyl, haloalkylcarbonyl and cycloalkylalkyl, wherein R isfAnd RgThe cycloalkyl groups represented by cycloalkyl, cycloalkylalkyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, alkyl and haloalkyl. The substituent aryl, aralkoxy aryl, arylcarbonyl aryl, aryloxy aryl, arylsulfonyl aryl, substituent heteroaryl, heteroaralkyl heteroaryl, heteroarylcarbonyl heteroaryl, substituent heterocycle, heterocyclic carbonyl heterocycle, heterocyclic oxy heterocycle, heterocyclic sulfonyl heterocycle may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkoxy, alkoxyalkyl, alkoxycarbonyl, alkane Alkyl carbonyl, alkynyl, carboxyl, carboxyalkyl, cyano, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, RfRgN-，RfRgN alkyl radical, RfRgN-carbonyl and RfRgN-sulfonyl, wherein RfAnd RgAs described herein.
The term "aralkoxy" refers to an aryl group attached to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of aralkoxy groups include, but are not limited to: 2-phenylethoxy, 3-naphthalen-2-ylpropoxy and 5-phenylpentyloxy.
The term "aralkoxycarbonyl" refers to an aralkoxy group attached to the parent molecular moiety through a carbonyl group as defined herein. Representative examples of aralkoxycarbonyl groups include, but are not limited to: benzyloxycarbonyl and naphthalen-2-ylmethoxycarbonyl.
The term "aralkyl" refers to an aryl group attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aralkyl groups include, but are not limited to: benzyl, 2-phenylethyl and 3-phenylpropyl.
The term "arylcarbonyl" refers to an aryl group attached to the parent molecular moiety through a carbonyl group, as defined herein. Examples of arylcarbonyl groups include, but are not limited to: benzoyl and naphthoyl.
The term "aryloxy" refers to an aryl group attached to the parent molecular moiety through an oxygen atom. Examples of aryloxy groups include, but are not limited to: phenoxy and tolyloxy.
The term "aryloxyalkyl" refers to an aryloxy group attached to the parent molecular moiety through an alkyl group, as defined herein.
The term "aryl (aryl) oxyiminamides" meansA group.
The term "arylsulphonyl" refers to an aryl group attached to the parent molecular moiety through a sulphonyl group, as defined herein. Representative examples of arylsulfonyl groups include, but are not limited to: benzenesulfonyl, 4-bromobenzenesulfonyl and naphthylsulfonyl.
The term "carbonyl" refers to a-C (O) -group.
The term "carboxy" refers to-CO2And (4) an H group.
The term "carboxyalkyl" refers to a carboxy group attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl groups include, but are not limited to: carboxymethyl, 2-carboxyethyl and 3-carboxypropyl.
The term "carboxyalkyl" means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "combination therapy" is defined as: administering a single pharmaceutical dose of the formulation comprising two or more therapeutic agents.
The term "cyano" refers to a-CN group attached to the parent molecular moiety through a carbon.
The term "cyanoalkyl" refers to a — CN group attached to the parent molecular moiety through an alkyl group. Representative examples of "cyanoalkyl" groups include, but are not limited to: 3-cyanopropyl and 4-cyanobutyl.
The term "cyanoamidine" refers toA group.
The term "cycloalkyloxy" refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom. Examples of cycloalkoxy groups include, but are not limited to: cyclohexyloxy and cyclopropoxy.
The term "cycloalkylalkoxy" refers to a cycloalkyl group attached to the parent molecular moiety through an alkyl group, where alkyl is as defined herein. Representative examples of cycloalkoxyalkyl radicals include, but are not limited to: cyclobutoxymethyl, cyclopentyloxymethyl, 2- (cyclopentyloxy) ethyl and cyclohexyloxymethyl.
The term "cycloalkyl" refers to a monocyclic, bicyclic or tricyclic ring system. The monocyclic ring system may comprise 3 to 4 carbon atoms ((C)3-C4) Cycloalkyl), 5 to 6 carbon atoms ((C)5-C6) Cycloalkyl group), 3 to 6 carbon atoms ((C)3-C6) Cycloalkyl), 7 to 8 carbon atoms ((C)7-C8) Cycloalkyl) or 3 to 8 carbon atoms ((C)3-C8) Cycloalkyl) are exemplified. Examples of monocyclic systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A bicyclic ring system can be exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are connected by one and three alkylene bridges of an additional carbon atom between them. Representative examples of bicyclic ring systems include, but are not limited to: bicyclo [3.1.1 ]Heptyl, bicyclo [2.2.1]Heptyl, bicyclo [2.2.2]Octyl, bicyclo [5.1.0]Octyl, bicyclo [3.2.2]Nonyl, bicyclo [3.3.1]Nonyl and bicyclo [4.2.1]Nonyl radical. Bicyclic ring systems can also be exemplified by a monocyclic ring system fused to a phenyl or heteroaryl ring. Representative examples of bicyclic ring systems include, but are not limited to: 1,2,3, 4-tetrahydronaphthyl, indanyl and 6, 7-dihydro-5H-cyclopenta [ c ]]A pyridyl group. The bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the unsaturated cycloalkyl ring. A tricyclic ring system can be illustrated by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are connected by a bond or an alkylene bridge between one and three carbon atoms. Representative examples of tricyclic ring systems include, but are not limited to: octahydro-2, 5-methylenepentalene, tricyclo [3.3.1.03,7]Nonyl and tricyclo [3.3.1.13,7]Decyl (adamantyl).
The cycloalkyl groups of the present invention may be substituted with 0, 1,2,3 or 4 substituents independently selected from the group consisting of: alkyl, alkenyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, alkylthio, aryl, aralkyl, aryloxyalkyl, arylcarbonyl, Arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, halogen, haloalkyl, heterocyclylcarbonyl, heterocyclosulfonyl, heteroaryl, heteroaralkyl, heterocycle-alkyl, heterocyclyloxyalkyl, -NO2,-NR8-[C(R9R10)]p-C(O)-R11,-[C(R12R13)]q-CR12(OH)-R14,-[C(R12R13)]q-C(O)-R14,-CR12=R13-C(O)-R14,-[C(R12R13)]q-S(O)2-R14,-[C(R12R13)]q-S(O)-R14,-[C(R12R13)]q-S-R14,-O-[C(R12R13)]q-C(O)-R14,-OR15,-N(R16R17), NR8C(O)N(R19R20),-CO2R18,-C(O)-N(R19R20),-[C(R12R13)]p-C(O)-N(R19R20),-C(NH)NH2,-C(R21R22)-OR23, and-C(R24R25)-N(R26R27),-C(=NOH)-N(H)2,-C(R28R29)-C(O)N(R30R31),-S(O)2-N(R32R33),-S(O)2-[C(R9R10)]p-C(O)N(R32R33), and-C(R28R29)-S(O)2-N(R32R33) Wherein
p is 1, 2, 3, 4, 5 or 6;
q is 0, 1, 2, 3, 4, 5 or 6;
R8is hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aralkyl, aryloxyalkyl, aryloxy, hydroxy, alkoxy, cycloalkyloxy, heterocycloxy, heterocycle, heterocyclylalkyl or heterocycloxyalkyl;
R9and R10Each independently is hydrogen, alkyl, carboxyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aralkyl, aryloxyalkyl, heterocycle, heterocyclylalkyl, or heterocycloxyalkyl, or R9And R10Together with the atoms to which they are attached form a cycloalkyl or heterocyclic ring;
R11is hydrogen, alkyl, carboxyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aryloxy, aralkyl, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclyloxy, heterocycle, heterocyclylalkyl, heterocyclyloxyalkyl, or-N (R)28R29)；
R12And R13Each independently is hydrogen, alkyl, carboxyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aralkyl, aryloxyalkyl, heterocycle, heterocyclylalkyl, heterocycloxyalkyl or-N (R) 28R29) Or R is12And R13Together with the atoms to which they are attached form a cycloalkyl or heterocyclic ring;
R14is hydrogen, alkyl, carboxyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aralkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heterocycloxy, heterocycle, heterocyclylalkyl, heterocycloxyalkyl, or-N (R)30R31)；
R15Is hydrogen, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aralkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclylalkyl or heterocycloxyalkyl;
R16and R17Each independently is hydrogen, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aralkyl, aryloxyalkyl, haloalkyl, heterocycle, heterocyclylalkyl, heterocycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, formyl or heterocyclosulfonyl, or R16And R17Together with the atoms to which they are attached form a heterocyclic ring;
R18is hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, aralkyl, aryloxyalkyl, heterocycle, heterocyclylalkyl or heterocycloxyalkyl;
R19and R20Each independently is hydrogen, alkyl, carboxyl, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, aralkyl, aryloxy, aryloxyalkyl, heteroaralkyl, heterocycle, heterocyclylalkyl, heterocycloalkylalkyl, heterocyclooxyalkyl, heterocyclooxygroup, hydroxyl, alkoxy, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclosulfonyl, or- [ C (R) is 12R13)]qC(O)R14Or R is19And R20Together with the atoms to which they are attached form a heterocyclic ring;
R21、R22and R23Each independently is hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, heterocycle or heterocyclylalkyl;
R24and R25Each independently is hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclocarbonyl, heterocyclosulfonyl, cycloalkyl, aryl or heterocycle;
R26and R27Each independently is hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclocarbonyl, heterocyclosulfonyl, hydroxy, alkoxy, cycloalkyloxy, aryloxy, heterocycloxy, cycloalkyl, aryl or heterocycle, or R26And R27Together with the atoms to which they are attached form a heterocyclic ring;
R28and R29Each occurrence is independently hydrogen or alkyl;
R30and R31Each occurrence is independent of the otherImmediately hydrogen, alkyl, alkylcarbonyl, alkoxy, alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclocarbonyl, heterocyclooxy, heterocyclosulfonyl or hydroxy, or R 30And R31Together with the atoms to which they are attached form a heteroaryl or heterocyclic ring; and
R32and R33Each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, aralkyl, aryloxy, aryloxyalkyl, arylsulfonyl, alkyl-NH-alkyl, aryl-NH-alkyl, aralkyl, haloalkyl, aryl-heterocycle, carboxyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroaralkyl, heteroaryloxyalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle-NH-alkyl, heterocyclylalkyl, heterocycle-heterocycle, heterocycloalkylalkyl, heterocyclooxy, heterocyclosulfonyl, and hydroxyl, or R32And R33Together with the atoms to which they are attached form a heterocyclic ring.
The term "cycloalkylalkyl" refers to a cycloalkyl group attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl groups include, but are not limited to: cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
The term "cycloalkylcarbonyl" refers to a cycloalkyl group attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl groups include, but are not limited to: cyclopropylcarbonyl, 2-cyclobutylcarbonyl and cyclohexylcarbonyl.
The term "cycloalkylsulfonyl" refers to a cycloalkyl group attached to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of cycloalkylsulfonyl groups include, but are not limited to: cyclohexylsulfonyl and cyclobutylsulfonyl.
The term "formyl" refers to the-C (O) H group.
The term "halogen" or "halo" refers to-Cl, -Br, -I or-F.
The term "haloalkoxy" means at least one halogen attached to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy groups include, but are not limited to: fluoroalkoxy, chloroalkoxy, bromoalkoxy and iodoalkoxy radicals, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, trifluoromethoxy, 2,2, 2-trifluoroethoxy and pentafluoroethoxy.
The term "haloalkyl" means at least one halogen attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl groups include, but are not limited to: difluoromethyl, chloromethyl, 2-fluoroethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.
The term "halocycloalkyl" means at least one halogen attached to the parent molecular moiety through a cycloalkyl group, as defined herein. Representative examples of halocycloalkyls include, but are not limited to: fluorocyclohexyl, bromocyclopropyl and trans-2, 3-dichlorocyclopentyl.
The term "halocycloalkylalkyl" refers to a halocycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group. Representative examples of halocycloalkylalkyl groups include, but are not limited to: (4-fluorocyclohexyl) methyl, (2, 2-difluorocyclobutyl) methyl and the like.
The term "haloalkoxyalkyloxy" means at least one halogen attached to the parent molecular moiety through a thioalkoxy group as defined herein. Representative examples of haloalkylthioalkoxy groups include, but are not limited to: 2-chloroethylsulfane and trifluoromethylsulfane.
The term "heteroaryl" refers to a monocyclic heteroaryl or a bicyclic heteroaryl. Monocyclic heteroaryl is a 5 or 6 membered ring comprising at least one heteroatom selected from nitrogen, oxygen and sulfur. The 5-membered ring comprises twoThe double bond, 6-membered ring contains three double bonds. The 5-or 6-membered heteroaryl is attached to the parent molecular moiety through any carbon atom or any substitutable nitrogen atom contained within the heteroaryl, provided that: maintaining the correct valency. Representative examples of monocyclic heteroaryls include, but are not limited to: furyl, imidazolyl, isoAn azole group, an isothiazolyl group,(ii) a diazolyl group,oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. Bicyclic heteroaryls include: a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a cycloalkyl, or a monocyclic heteroaryl fused to a cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl. The bicyclic heteroaryl is attached to the parent molecular moiety through any carbon atom or any substitutable nitrogen atom contained within the bicyclic heteroaryl, provided that: maintaining the correct valency. Representative examples of bicyclic heteroaryls include, but are not limited to: azaindolyl, benzimidazolyl, benzofuranyl Oxadiazolyl, benzisoxazolylAzole, benzisothiazole, benzoOxazole, 1, 3-benzothiazolyl, benzothienyl, cinnolinyl, furopyridine, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, naphthyridinyl,azolopyridine, 1H-pyrrolo [2,3-b ] compounds]Pyridyl, quinolyl, quinoxalinyl and thienopyridyl.
Heteroaryl may be optionally substituted with 1, 2,3 or 4 substituents independently selected from the group consisting of: acyloxy, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkylthio, alkynyl, amide, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkoxy, formyl, haloalkoxy, haloalkyl, halogen, haloalkthioalkoxy, heteroaryl, thioalkoxy, thioaryloxy, nitro and-NR96R97Wherein R is96And R97Independently is hydrogen, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, cycloalkyl, haloalkyl, heteroaryl, or heterocycle, or R96And R97Together with the nitrogen to which they are attached form a heterocyclic ring. In addition, the nitrogen heteroatom may optionally be quaternized or oxidized to the corresponding N-oxide.
The term "heteroarylalkoxy" as used herein, means a heteroaryl group attached to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of heteroarylalkoxy groups include, but are not limited to: furan-3-ylmethoxy, 1H-imidazol-2-ylmethoxy, 1H-imidazol-4-ylmethoxy, 1- (pyridin-4-yl) ethoxy, pyridin-3-ylmethoxy, 6-chloropyridin-3-ylmethoxy, pyridin-4-ylmethoxy, (6- (trifluoromethyl) pyridin-3-yl) methoxy, (6- (cyano) pyridin-3-yl) methoxy, (2- (cyano) pyridin-4-yl) methoxy, (5- (cyano) pyridin-2-yl) methoxy, (2- (chloro) pyridin-4-yl) methoxy, pyrimidin-5-ylmethoxy, 2- (pyrimidin-2-yl) propoxy, 1, 3-thiazol-4-ylmethoxy, thiophen-2-ylmethoxy and thiophen-3-ylmethoxy.
The term "heteroarylalkyl" refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group, as defined herein.
The term "heteroarylcarbonyl" refers to a heteroaryl group attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heteroarylcarbonyl groups include, but are not limited to: furan-3-ylcarbonyl, 1H-imidazol-2-ylcarbonyl, 1H-imidazol-4-ylcarbonyl, pyridin-3-ylcarbonyl, 6-chloropyridin-3-ylcarbonyl, pyridin-4-ylcarbonyl, (6- (trifluoromethyl) pyridin-3-yl) carbonyl, (6- (cyano) pyridin-3-yl) carbonyl, (2- (cyano) pyridin-4-yl) carbonyl, (5- (cyano) pyridin-2-yl) carbonyl, (2- (chloro) pyridin-4-yl) carbonyl, pyrimidin-5-ylcarbonyl, pyrimidin-2-ylcarbonyl, thiophen-2-ylcarbonyl and thiophen-3-ylcarbonyl.
The term "heterocycle" or "heterocyclic" refers to a monocyclic, bicyclic, or tricyclic heterocycle. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring comprising at least one heteroatom, wherein the heteroatom is independently selected from O, N and S. The 3-or 4-membered ring contains 1 heteroatom selected from O, N and S. The 5-membered ring contains zero or one double bond and one, two or three heteroatoms selected from O, N and S. The 6-or 7-membered ring comprises zero, one or two double bonds and one, two, three or four heteroatoms selected from O, N and S, with the proviso that: when the ring is combined with a substituent, it does not interconvert with the substituent to form an aromatic ring. The monocyclic heterocycle is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle.
Representative examples of monocyclic heterocycles include, but are not limited to: azetidinyl, azepanyl, aziridinyl, diazepanyl, 1, 3-diAlkyl, 1, 3-dioxolanyl, 1, 3-dithiocyclopentyl, 1, 3-dithiocyclohexyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinylAzolinyl, isoAn oxazolidinyl group, a morpholinyl group,an diazolinyl group, wherein the diazolinyl group,an diazole alkyl group, An oxazoline group, a carboxyl group,oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1, 1-dioxothiomorpholinyl (thiomorpholinyl), thiopyranyl and trithianyl (trithianyl). Bicyclic heterocycles are: a monocyclic heterocycle fused to a phenyl group, a monocyclic heterocycle fused to a cycloalkyl group, a monocyclic heterocycle fused to a cycloalkenyl group, or a monocyclic heterocycle fused to a monocyclic heterocycle. The bicyclic heterocycle is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of bicyclic heterocycles include, but are not limited to: azabicyclo [3.2.0]Hept-3-yl, 1-azabicyclo [2.2.2]Octyl (quinuclidinyl), 1, 3-benzodioxolyl, 2, 3-dihydro-1, 4-benzodioxinyl, 3, 7-diazabicyclo [3.3.1 ]]Nonyl, 3, 9-diazabicyclo [4.2.1]Nonyl, 2, 3-dihydro-1-benzofuranyl, 2, 3-dihydro-1-benzothienyl, 2, 3-dihydro-1H-indolyl, hexahydropyrrolo [3,4-b ] ]Pyrrol-1 (2H) -yl, indolinyl, isoindolinyl, 2,3,4, 5-tetrahydro-1H-3-benzazepineRadical, octahydropyrrolo [3,4-c]Pyrrolyl, tetrahydro-1H-pyrrolo [3,4-b ]]Pyridin-6 (2H,7H,7aH) -yl, 3-azabicyclo [3.2.0]Heptane, quinuclidine and 1,2,3, 4-tetrahydroquinolinyl. Representative examples of tricyclic heterocyclic systems include, but are not limited to: aza-adamantyl, oxa-adamantyl and 7,8,9, 10-tetrahydro-6H-[1,3]Dioxacyclopenteno [4,5-g][3]Benzazepine compoundsAnd (4) a base.
The heterocycle may be substituted with 0, 1,2,3,4, 5, 6, 7,8, or 9 substituents independently selected from the group consisting of: acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkylthio, alkynyl, amide, aryl, arylalkoxycarbonyl, aralkyl, aryloxy, aryloxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heteroaryloxyalkyl, hydroxyl, hydroxyalkyl, mercapto, nitro, oxo, -alkyl NR98R99，-NR98R99，(NR98R99) Carbonyl group, -SO 2N(R98)(R99)，-SO2R98，-NR98(C=O)NR98R99，-NR98(C = O) Oalkyl and-N (R)98)SO2(R99) Wherein R is98And R99Each independently selected from acyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcycloalkyl, alkylsulfonyl, amido, aryl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, haloalkyl, halocycloalkyl, halocycloalkylalkyl, heteroaryl, heterocycle, hydrogen, formyl, hydroxy and hydroxyalkyl. In addition, the nitrogen heteroatom may optionally be quaternized or oxidized to the corresponding N-oxide.
The term "heterocyclylalkoxy" as used herein, means a heterocyclyl group attached to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of heterocyclylalkoxy groups include, but are not limited to: 2-morpholin-4-ylethoxy, 2-morpholin-4-ylethoxy and (tetrahydrofuran-2-yl) methoxy.
The term "heterocyclylalkyl" refers to a heterocycle attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclylalkyl groups include, but are not limited to: (pyrrolidin-2-yl) methyl, 2- (morpholin-4-yl) ethyl and (tetrahydrofuran-3-yl) methyl.
The term "heterocyclocarbonyl" refers to a heterocycle attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclic carbonyl groups include, but are not limited to: 1-piperidinylcarbonyl, 4-morpholinylcarbonyl, pyridin-3-ylcarbonyl and quinolin-3-ylcarbonyl.
The term "heterocycle-heterocycle" refers to a heterocycle that is linked to the parent molecular moiety through a second heterocycle as defined herein.
The term "heterocycloalkoxyalkyl" means a heterocycloxy group attached to the parent molecular moiety through an alkyl group, as defined herein.
The term "heterocyclosulfonyl" refers to a heterocycle attached to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of heterocyclic sulfonyl groups include, but are not limited to: 1-piperidinylsulfonyl, 4-morpholinylsulfonyl, pyridin-3-ylsulfonyl and quinolin-3-ylsulfonyl.
The term "hydroxy" refers to an-OH group.
The term "hydroxyalkyl" refers to at least one hydroxyl group attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl groups include, but are not limited to: hydroxymethyl, 2-hydroxyethyl, 2-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypentyl and 2-ethyl-4-hydroxyheptyl.
The term "hydroxyiminoamides" meansA group.
The term "imino" refers to a-C (= NH) -group.
The term "mercapto" refers to the-SH group.
The term "nitro" refers to-NO2A group.
The term "oxo" means (= O).
The term "parenteral" refers to modes of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.
The term "pharmaceutically acceptable salt" or "salt" refers to: those salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like are within the scope of sound medical judgment and are commensurate with a reasonable benefit/risk ratio and effectiveness for their intended use. Pharmaceutically acceptable salts are well known in the art. Salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or isolated by reaction of the free base functionality with a suitable organic acid. Representative acid addition salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. In addition, lower halogenated hydrocarbon reagents (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides); dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates); long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides); aralkyl halides (e.g., benzyl and phenethyl bromides) and other agents quaternize groups containing basic nitrogen. Thereby obtaining a water or oil soluble or dispersible product.
Can be used for the shapeExamples of acids which form pharmaceutically acceptable acid addition salts include: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids, such as oxalic acid, maleic acid, succinic acid and citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention by reacting a carboxylic acid-containing moiety with a suitable base (e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation) or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to: cations based on alkali or alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and non-toxic quaternary ammonia and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium, and the like. Other representative organic amines useful for forming base addition salts include: ethylenediammonium, ethanolammonium, diethanolammonium, piperidineAnd piperazine。
The term "pharmaceutically acceptable ester" or "ester" refers to esters of the compounds of the present invention that are hydrolyzable in vivo and includes those esters that readily decompose in the human body to yield the parent compound or a salt thereof. Examples of pharmaceutically acceptable non-toxic esters of the invention include, but are not limited to: c 1-C6Alkyl esters and C5-C7A cycloalkyl ester. Esters of the compounds of formula (I) may be prepared according to conventional methods. The pharmaceutically acceptable ester can be attached to the hydroxyl group by reacting the hydroxyl containing compound with an acid and an alkyl carboxylic acid (e.g., acetic acid) or with an acid and an aryl carboxylic acid (e.g., benzoic acid). In the case where the compound contains a carboxyl group, a pharmaceutically acceptable ester may be prepared from the compound containing a carboxyl group by reaction of the compound with a base (e.g., triethylamine) and an alkyl halide (e.g., methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl trifluoromethanesulfonate). They can also be prepared by reaction of the compounds with acids (e.g. hydrochloric acid) and alcohols (e.g. ethanol or methanol).
The term "pharmaceutically acceptable amide" or "amide" refers to non-toxic amides of the present invention derived from: ammonia, primary C1-C3Alkylamines, primary C4-C6Alkylamine, secondary C1-C2Dialkyl amine and secondary C3-C6A dialkyl amine. In the case of secondary amines, the amines may also be in the form of 5-or 6-membered heterocyclic rings containing one nitrogen atom. The amides of the compounds of formula (I) can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reacting a compound containing an amino group with an alkyl anhydride, aryl anhydride, acid halide, or aroyl halide. In the case where the compound contains a carboxyl group, a pharmaceutically acceptable amide may be prepared from the compound containing a carboxyl group by reaction of the compound with a base (e.g., triethylamine), a dehydrating agent (e.g., dicyclohexylcarbodiimide or carbonyldiimidazole), and an alkylamine, dialkylamine (e.g., methylamine, diethylamine and piperidine). They may also be prepared by reaction of the compounds with acids (e.g., sulfuric acid) and alkyl carboxylic acids (e.g., acetic acid) or with acids and aryl carboxylic acids (e.g., benzoic acid) under dehydration conditions (e.g., addition of molecular sieves). The compositions may comprise a compound of the invention in the form of a pharmaceutically acceptable prodrug.
The term "pharmaceutically acceptable prodrug" or "prodrug" refers to a prodrug of a compound of the present invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio and effectiveness for its intended use. The prodrugs of the invention may be rapidly converted in vivo to the parent compound of formula (I), for example, by hydrolysis. A thorough review is provided in the following: higuchi et al, Pro-drugs as Novel Delivery Systems, V.14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).
The term "pharmaceutically acceptable carrier" or "carrier" refers to a non-toxic inert solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation aid of any type. Some examples of substances that can act as pharmaceutically acceptable carriers are: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelling; talc powder; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; a ringer's solution; ethanol; and a phosphate buffer solution; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, detackifying agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the person skilled in the art of formulation.
The term "sulfonyl" refers to-SO2-a group.
The phrase "therapeutically effective amount" refers to a sufficient amount of a compound to treat a condition at a reasonable benefit/risk ratio applicable to any treatment.
The term "therapeutically suitable excipient" broadly refers to pharmaceutically suitable solid, semi-solid, or liquid fillers, diluents, encapsulating substances, formulation aids, and the like.
The term "therapeutically suitable metabolite" broadly refers to a pharmaceutically active compound formed by the in vivo biotransformation of a compound of formula I.
The term "thioalkoxy" refers to an alkyl group attached to the parent molecular moiety through a sulfur atom. Representative examples of thioalkoxy groups include, but are not limited to: methylthio, ethylthio, tert-butylthio and hexylthio.
The term "thioamides" refers toA group.
The term "thiocycloalkoxy" refers to a cycloalkyl group attached to the parent molecular moiety through a sulfur atom. Examples of thiocycloalkoxy groups include, but are not limited to: cyclopentylsulfane and cyclohexylsulfane.
The term "thioaryloxy" refers to an aryl group attached to the parent molecular moiety through a sulfur atom. Examples of thioaryloxy groups include, but are not limited to: thiophenoxy and tolylsulfane.
Compounds of the invention
One embodiment relates to compounds of formula (I)
(I),
Wherein
L is- (CH)2)n-，-(CR38R39)m-X-(CR38R39)n-or- (CR)38R39)m-X-(CR38R39)n-Y-；
m is independently at each occurrence 0, 1 or 2;
n is independently at each occurrence 0, 1 or 2;
R1is cycloalkyl or heterocycle;
R2is hydrogen, alkyl or aryl; or R1And R2Together with the atoms to which they are attached form a heterocyclic ring; or R2And R3Together with the atoms to which they are attached form a heterocyclic ring;
R3and R4Independently hydrogen, alkyl or cycloalkyl; or R3And R4Together with the atoms to which they are attached form a cycloalkyl, heterocycle, heteroaryl, or aryl group;
R5is hydrogen, alkyl, amino, aryl, cycloalkyl, heteroaryl or heterocycle, with the proviso that: when L is- (CR)38R39)m-X-(CR38R39)n-Y-is, R5Is not an amino group; or R4And R5Together with the atoms to which they are attached form a cycloalkyl or heterocyclic ring;
x is-O-, -S-, -S (O)2-,-NR36-or-CR36R37-；
Y is O or NR40；
R36And R37Independently at each occurrence is hydrogen or alkyl; or R36And R2Together with the atoms to which they are attached form a heterocyclic ring;
R38、R39and R40Independently at each occurrence is hydrogen or alkyl;
w is N-CN, N-OR6，N-R6Or S; and
R6is hydrogen, alkyl or aryl; or
A pharmaceutically acceptable salt, ester, amide, N-oxide or prodrug thereof.
Another embodiment are compounds of formula (I), wherein R 1Is a cycloalkyl group.
Another embodiment are compounds of formula (I), wherein R1Is a heterocyclic ring.
Another embodiment are compounds of formula (I), wherein R1Is a cycloalkyl or heterocycle selected from:
。
another embodiment are compounds of formula (I), wherein R1Is a cycloalkyl or heterocycle selected from:
another embodiment are compounds of formula (I), wherein R1Is a cycloalkyl or heterocycle selected from:
。
another embodiment are compounds of formula (I), wherein R1Is a cycloalkyl group selected from:
another embodiment are compounds of formula (I), wherein R1Is a cycloalkyl group selected from:
。
another embodiment are compounds of formula (I), wherein R1Is a cycloalkyl group selected from:
wherein A is a substituent as defined in "cycloalkyl" in the definitions section of the terms.
Another embodiment are compounds of formula (I), wherein R1Is a cycloalkyl group as follows:
。
another embodiment are compounds of formula (I), wherein R1Is a cycloalkyl group of formula (iia):
,
wherein A is a substituent as defined in "cycloalkyl" in the definitions section of the terms.
Another embodiment are compounds of formula (I), wherein R1Is a heterocycle selected from:
。
another embodiment are compounds of formula (I), wherein R 1Is a heterocycle selected from:
。
another embodiment are compounds of formula (I), wherein R1Is a heterocycle selected from:
or
Corresponding N-oxides (xvi) and (xvii)
。
Another embodiment are compounds of formula (I), wherein R1Is a heterocycle which is azaadamantane.
Another embodiment are compounds of formula (I), wherein R1Is cycloalkyl substituted with 0, 1, 2, 3 or 4 substituents selected from: alkyl, alkenyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, alkylthio, aryl, aralkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, halogen, haloalkyl, heterocyclocarbonyl, heterocyclosulfonyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclylalkyl, heterocycloxyalkyl, -NO2,-NR8-[C(R9R10)]p-C(O)-R11,-[C(R12R13)]q-CR12(OH)-R14,-[C(R12R13)]q-C(O)-R14,-CR12=R13-C(O)-R14,-[C(R12R13)]q-S(O)2-R14,-[C(R12R13)]q-S(O)-R14,-[C(R12R13)]q-S-R14,-O-[C(R12R13)]q-C(O)-R14,-OR15,-N(R16R17), NR8C(O)N(R19R20),-CO2R18,-C(O)-N(R19R20),-[C(R12R13)]p-C(O)-N(R19R20),-C(NH)NH2,-C(R21R22)-OR23and-C (R)24R25)-N(R26R27),-C(=NOH)-N(H)2,-C(R28R29)-C(O)N(R30R31),-S(O)2-N(R32R33),-S(O)2-[C(R9R10)]p-C(O)N(R32R33) and-C (R)28R29)-S(O)2-N(R32R33) (ii) a Wherein p, q, R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32And R33As described in the definition of "cycloalkyl" in the definition of terms.
Another embodiment are compounds of formula (I), wherein R1Substituted with 0, 1, 2, 3 or 4 substituents selected from: alkylsulfonyl, cyano, halogen, -C (R)12R13)-C(O)-R14,-OR15,-CO2R18,-C(O)-N(R19R20) and-S (O)2-N(R32R33)。
Another embodiment are compounds of formula (I), wherein R 1Substituted with 0, 1 or 2 substituents selected from: fluoro, methylsulfonyl, cyano, -OH, -OCH3,-OCF3,-OCHF2, -CO2H,-CH2-CO2H,-CH(CH3)-CO2H,-C(CH3)2-CO2H,-CHF2,-CH(CH3)(OH),-C(CH3)2(OH),-CH2OH,-C(O)-NH2and-S (O)2-NH2。
Another embodiment are compounds of formula (I), wherein R1Substituted with at least one substituent selected from the group consisting of: fluoro, methylsulfonyl, cyano, -OH, -CO2H,-CH2-CO2H,-CH(CH3)-CO2H,-C(CH3)2-CO2H,-CH(CH3)(OH),-C(O)-NH2And-S(O)2-NH2。
Another embodiment are compounds of formula (I), wherein R1Substituted with 0, 1, 2, 3 or 4 substituents selected from: alkylsulfonyl, cyano, -OR15,-CO2R18,-C(O)-N(R19R20) and-S (O)2-N(R32R33)。
Another embodiment are compounds of formula (I), wherein R2Is hydrogen, alkyl or aryl.
Another embodiment are compounds of formula (I), wherein R2Is hydrogen.
Another embodiment are compounds of formula (I), wherein R2Is an alkyl group.
Another embodiment are compounds of formula (I), wherein R2Is an aryl group.
Another embodiment are compounds of formula (I), wherein R1And R2Together with the atoms to which they are attached form a heterocyclic ring.
Another embodiment are compounds of formula (I), wherein R3And R4Each is hydrogen.
Another embodiment are compounds of formula (I), wherein R3And R4Each is an alkyl group.
Another embodiment are compounds of formula (I), wherein R3Is hydrogen, R4Is an alkyl group.
Another embodiment are compounds of formula (I), wherein R 2And R3Together with the atoms to which they are attached form a heterocyclic ring.
Another embodiment are compounds of formula (I), wherein R2And R3Together with the atoms to which they are attached form a 5-membered heterocyclic ring, R4Is hydrogen; and is represented by the formula (II)
(II),
Wherein
R34And R35Independently hydrogen or alkyl; or R34And R35Together with the atoms to which they are attached form a cycloalkyl group, and
r is 1 or 2.
Another embodiment are compounds of formula (I), wherein R3And R4Together with the atoms to which they are attached form a cycloalkyl, heterocycle, heteroaryl, or aryl group.
Another embodiment are compounds of formula (I), wherein R3And R4Together with the atoms to which they are attached form a cycloalkyl, heterocycle, heteroaryl, or aryl group; l is a bond (i.e., when L is- (CH)2)n-n is 0).
Another embodiment are compounds of formula (I), wherein R3And R4Together with the atoms to which they are attached form a cycloalkyl or heterocyclic ring.
Another embodiment are compounds of formula (I), wherein R3And R4Together with the atom to which they are attached form a cycloalkyl group, wherein cycloalkyl is (C)3-C6) A cycloalkyl group.
Another embodiment are compounds of formula (I), wherein R3And R4Together with the atoms to which they are attached form a heteroaryl or aryl group.
Another embodiment are compounds of formula (I), wherein R 4And R5Together with the atoms to which they are attached form a cycloalkyl or heterocyclic ring.
Another embodiment are compounds of formula (I), wherein R3Is hydrogen, R4And R5Together with the atoms to which they are attached form a cycloalkyl or heterocyclic ring.
Another embodiment are compounds of formula (I), wherein R3Is hydrogen, R4And R5Together with the atoms to which they are attached form a heterocyclic ring.
Another embodiment are compounds of formula (I) wherein L is- (CR)38R39)m-X-(CR38R39)n-or- (CR)38R39)m-X-(CR38R39)n-Y-; wherein m is 0 and X is-CR36R37-，R36And R2Together with the atoms to which they are attached form a heterocycle and are represented by the formulae (III) and (IV)
Wherein s is independently 1 or 2.
Another embodiment are compounds of formula (III) wherein n is 0 and R5Is aryl or heteroaryl.
Another embodiment are compounds of formula (IV) wherein R5Is aryl or heteroaryl.
Another embodiment are compounds of formula (I) wherein L is- (CR)38R39)m-X-(CR38R39)n-or- (CR)38R39)m-X-(CR38R39)n-Y-; wherein m is 0 and X is-NR36-，R36And R2Form a heterocyclic ring together with the atoms to which they are attached, and are represented by the formulae (Va) and (Vb
Wherein t is 1 or 2.
Another embodiment are compounds of formula (I), wherein R5Is amino, aryl, cycloalkyl, heteroaryl or heterocycle.
Another embodiment are compounds of formula (I), wherein R 5Is cycloalkyl, wherein the cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkoxy, alkyl, aryloxy, aryl, carboxyl, carboxyalkyl, cycloalkyl, cycloalkoxy, halogen, haloalkoxy, haloalkyl, halothioalkoxy, heteroaryl, hydroxyl, mercapto, thioalkoxy, thiocycloalkoxy and thioaryloxy.
Another embodiment are compounds of formula (I), wherein R5Is an amino group.
Another embodiment are compounds of formula (I), wherein R5Is aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkoxy, alkyl, aryloxy, carboxyl, carboxyalkyl, cycloalkyl, cycloalkoxy, cyano, halogen, haloalkoxy, haloalkyl, halothioalkoxy, heteroaryl, hydroxyl, mercapto, thioalkoxy, thiocycloalkoxy and thioaryloxy.
Another embodiment are compounds of formula (I), wherein R5Is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, cyano, halogen, haloalkyl and heteroaryl.
Another embodiment are compounds of formula (I), wherein R5Is a heteroaryl selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, wherein the heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkoxy, alkyl, aryl, aryloxy, carboxy, carboxyalkyl, cycloalkyl, cycloalkoxy, cyano, halogen, haloalkoxy, haloalkyl, halothioalkoxy, hydroxy, mercapto, thioalkoxy, thiocycloalkoxy and thioaryloxy.
Another one isAn embodiment are compounds of formula (I) wherein R5Is a pyridyl group, wherein the pyridyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, cyano, halogen and haloalkyl.
Another embodiment are compounds of formula (I), wherein R5Is a heterocycle selected from: azabicyclo [3.2.0]Hept-3-yl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, wherein the heterocycle is optionally substituted with 1, 2 or 3 substituents independently selected from: alkoxy, alkyl, aryl, cyano, halogen, haloalkyl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with halogen or haloalkyl.
Another embodiment are compounds of formula (I), wherein R5Is a heterocycle selected from piperazinyl or piperidinyl, wherein the heterocycle is optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, aryl, cyano, halogen, haloalkyl and heteroaryl, wherein the aryl is phenyl and the heteroaryl is pyridyl, each optionally substituted with halogen or haloalkyl.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)n-, where n is 0, 1 or 2.
Another embodiment are compounds of formula (I) wherein L is- (CH) 2)n-, where n is 0.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)n-, where n is 1.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where m is 0 and n is 0.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where m is 0 and n is 1.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where m is 0 and n is 2.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where m is 1 and n is 0.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where m is 1 and n is 1.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where m is 1 and n is 2.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where m is 2 and n is 0.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where m is 2 and n is 1.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where m is 2 and n is 2.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, wherein X is-O-.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where X is-S-.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where X is-S (O) -.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where X is-S (O)2-。
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where X is-NR36-。
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, wherein X is-CR36R37-。
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, where X is-NR36-; wherein R is36Is hydrogen or alkyl.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-, wherein X is-CR36R37-; wherein R is36And R37Independently hydrogen or alkyl.
Another embodiment are compounds of formula (I) wherein L is a bond (i.e., when L is- (CH)2)nWhen n is 0), R5Is an amino group. In further embodiments, R5Is aryl or heteroaryl. In further embodiments, R5Is a heterocyclic ring.
Another embodiment are compounds of formula (I) wherein L is- (CH)2)m-X-(CH2)n-Y-wherein X is-CR36R37-, Y is O or NCH3N is 1, R5Is aryl or heteroaryl.
Another embodiment are compounds of formula (I) wherein W is N-CN.
Another embodiment are compounds of formula (I) wherein W is S.
Another embodiment are compounds of formula (I) wherein W is N-R 6Wherein R is6Is hydrogen, alkyl or aryl.
Another embodiment are compounds of formula (I) wherein W is N-R6Wherein R is6Is hydrogen or alkyl.
Another embodiment are compounds of formula (I) wherein W is N-OR6Wherein R is6Is hydrogen, alkyl or aryl.
Another embodiment are compounds of formula (I) wherein W is N-OR6Wherein R is6Is hydrogen or alkyl.
Another embodiment are compounds of formula (I), wherein R1Is adamantyl (ii), R2Is hydrogen, R3And R4Each is methyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are both 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R2Is hydrogen, R3And R4Each is methyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are both 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R 2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, haloalkyl, cyano, methoxy or haloalkyl, W is N-R6，R6Is hydrogen, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 or 1 and X is O.
Another embodiment is of formula(I) Wherein R is1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R2Is hydrogen, R3And R4Both are hydrogen, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from alkyl, halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)n-, where n is 1.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)n-, where n is 1.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, R 6Is hydrogen, W is NR6L is- (CH)2)n-, where n is 1.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R2Is hydrogen, R3And R4Each is methyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are each 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R2Is hydrogen, R3And R4Each is hydrogen, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are each 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R2Is hydrogen, R3And R4Each is hydrogen, R5Is pyridyl optionally substituted by halogen, W is N-CN, L is- (CH)2)n-, where n is 1.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R2Is hydrogen, R 3And R4Taken together with the atom to which they are attached is (C)3-C6) Cycloalkyl radical, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)n-, where n is 0.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R2Is hydrogen, R3And R4Taken together with the atom to which they are attached is (C)3-C6) Cycloalkyl radical, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are each 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted adamantyl (ii) wherein R15Is hydrogen, R2Is hydrogen, R3And R4Each of which is an alkyl group,R5is heteroaryl optionally substituted by halogen or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is adamantyl (ii), R optionally substituted with alkylsulfonyl2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is S, L is- (CH) 2)m-X-(CH2)n-, where m and n are each 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is adamantyl (ii), R optionally substituted with alkylsulfonyl2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, R6Is alkyl, W is N-OR6L is- (CH)2)m-X-(CH2)n-, where m and n are each 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is adamantyl (ii), R optionally substituted with alkylsulfonyl2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are each 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is adamantyl (ii), R optionally substituted with alkylsulfonyl2Is hydrogen, R3And R4Each is alkyl, R5Is heteroaryl optionally substituted by halogen or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0 and n is 0And X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-S (O)2-N(R32R33) Substituted adamantyl (ii), R 2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are each 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-S (O)2-N(R32R33) Substituted adamantyl (ii), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, haloalkoxy, methoxy or haloalkyl, W is N-CN or S, L is- (CH)2)m-X-(CH2)n-, where m and n are each 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-S (O)2-N(R32R33) Substituted adamantyl (ii), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-R6，R6Is hydrogen, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 or 1 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-S (O)2-N(R32R33) Substituted adamantyl (ii), R2Is hydrogen, R3And R4Each is alkyl, R5Is heteroaryl optionally substituted by halogen or haloalkyl, W is N-CN, L is- (CH) 2)m-X-(CH2)n-, where m is 0, n is 0 and X isO。
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-CO2R18Substituted adamantyl (ii) wherein R18Is alkyl, R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, haloalkoxy, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are each 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-CO2R18Substituted adamantyl (ii) wherein R18Is alkyl, R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are each 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-CO2R18Substituted adamantyl (ii) wherein R18Is alkyl, R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 1 and X is O.
Another embodiment are compounds of formula (I), wherein R 1Is optionally substituted by-CO2R18Substituted adamantyl (ii) wherein R18Is alkyl, R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is S, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 1 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-CO2R18Substituted adamantyl (ii) wherein R18Is alkyl, R2Is hydrogen, R3And R4Each is alkyl, R5Is a heterocycle optionally substituted with heteroaryl, which is optionally substituted with haloalkyl, W is S, L is- (CH)2)n-, where n is 0.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-CO2R18Substituted adamantyl (ii) wherein R18Is hydrogen, R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 1 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-CO2R18Substituted adamantyl (ii) wherein R18Is alkyl, R2Is hydrogen, R3And R4Each is alkyl, R5Is a heterocycle, W is N-CN, L is- (CH)2)n-, where n is 0.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-C (O) -N (R)19R20) Substituted adamantyl (ii), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 or 1 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-C (O) -N (R)19R20) Substituted adamantyl (ii), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-R6，R6Is hydrogen, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 or 1 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-C (O) -N (R)19R20) Substituted adamantyl (ii), R2Is hydrogen, R3And R4Each is alkyl, R5Is heteroaryl optionally substituted by halogen or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 or 1 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is adamantyl (ii), R optionally substituted with cyano2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH) 2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is adamantyl (ii), R optionally substituted with cyano2Is hydrogen, R3And R4Each is alkyl, R5Is heteroaryl optionally substituted by halogen or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is adamantyl (i), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-CO2R18Substituted bicyclo [2.2.2]Octyl (vi) wherein R18Is hydrogen or alkyl, R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-C (O) -N (R)19R20) Substituted bicyclo [2.2.2]Octyl (vi), R2Is hydrogen, R3And R4Each is alkyl, R 5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is bicyclo [2.2.2 ] optionally substituted by cyano]Octyl (vi), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-OR15Substituted bicyclo [2.2.2]Octyl (vi) wherein R15Is hydrogen, alkyl or haloalkyl, R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-CHF2Substituted bicyclo [2.2.2]Octyl (vi), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH) 2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is cyclooctyl (v), R2Is hydrogen, R3And R4Each is methyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are both 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is outer (exo) -bicyclo [2.2.1]Heptyl (xvi), R2Is hydrogen, R3And R4Each is methyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are both 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is octahydro-2, 5-methylenepentalenyl (xvii), R2Is hydrogen, R3And R4Each is methyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are both 0 and X is O.
Another embodiment are compounds of formula (I)Wherein R is1Is 1-azabicyclo [2.2.2]Octyl (xvii), R2Is hydrogen, R 3And R4Each is methyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m and n are both 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-C (O) -N (R)19R20) Substituted bicyclo [2.2.1]Heptane- (viii), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is bicyclo [2.2.1 ] optionally substituted by cyano]Heptane- (viii), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is optionally substituted by-CHF2Substituted bicyclo [2.2.1]Heptane- (viii), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH) 2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Another embodiment are compounds of formula (I), wherein R1Is bicyclo [2.2.1 ] optionally substituted by-OH]Heptane- (viii), R2Is hydrogen, R3And R4Each is alkyl, R5Is phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methoxy or haloalkyl, W is N-CN, L is- (CH)2)m-X-(CH2)n-, where m is 0, n is 0 and X is O.
Exemplary compounds of the various embodiments include, but are not limited to
(1E) -2- (2-chloro-4-fluorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylpropionamidine (propanimidamide);
(1E) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2- (2-methylphenyl) acetamidine (ethanimide);
1- (4-chlorophenyl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] cyclobutanecarboxamidine (carboximidamide);
(1E) -N' -cyano-2- (2, 4-difluorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine;
(1E) -N' -cyano-2- (2-fluorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine;
(1E) -2- (2-chloropyridin-3-yl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine;
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine;
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylpropionamidine;
2- (4-chlorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] thiopropionamide;
(1E) -N- [ (E) -5- (aminosulfonyl) -2-adamantyl ] -2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
(E) -methyl 4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylate;
2- (2-chloro-4-fluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] thiopropionamide;
(1E) -2- (4-chlorophenoxy) -N' -methoxy-2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] propionamidine;
(E) -4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
1- (3-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] cyclobutanecarboxamidine;
(E) -methyl 4- [ (2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } thiopropionyl (propanothyl)) amino ] adamantane-1-carboxylate;
(E) -methyl 4- [ ((1E) -N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxylate;
(1E) -2- (2-chloro-4-fluorophenoxy) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] propionamidine;
(1E) -2- (4-chlorophenoxy) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] propionamidine;
N- [ (E) -5- (aminosulfonyl) -2-adamantyl ] -2-methyl-2- [2- (trifluoromethoxy) phenoxy ] thiopropionamide;
(E) -methyl 4- [ (2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } thiopropionyl) amino ] adamantane-1-carboxylate;
3- (4-chlorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] -2, 2-dimethylpropanamidine;
(1E) -3- (4-chlorophenyl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2, 2-dimethylpropanamidine;
(E) -4- [ ((1E) -N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxylic acid;
(E) -4- [ ((1E) -N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
(E) -4- [ (2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } thiopropionyl) amino ] adamantane-1-carboxylic acid;
(1E) -N' -cyano-N- [ (E) -5-cyano-2-adamantyl ] -2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } propionamidine;
(E) -methyl 4- ({ (1E) -N-cyano-2- [ (4-methoxybenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylate;
(E) -methyl 4- [ ((1E) -N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylate;
(E) -4- [ ((1E) -N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid;
(E) -4- [ ((1E) -N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxamide;
6- ({4, 4-dimethyl-1- [ (E) -5- (methylsulfonyl) -2-adamantyl ] -5-thiopyrrolidin-3-yl } methoxy) nicotinonitrile (nicotinonitril);
(2Z) -4- { [ (5-cyanopyridin-2-yl) oxy ] methyl } -3, 3-dimethyl-1- [ (E) -5- (methylsulfonyl) -2-adamantyl ] pyrrolidin-2-ylidene cyanamide (cyanamide);
(3S) -1- [ (3-chloro-2-methylphenyl) sulfonyl ] -N-cyclohexylpiperidine-3-thioamide;
(3S) -1- [ (3-chloro-2-methylphenyl) sulfonyl ] -N' -cyano-N-cyclohexylpiperidine-3-carboxamidine;
(E) -4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-cyano-2-adamantyl ] -2-methylpropionamidine;
(1E) -2- (4-chlorophenoxy) -N' -cyano-N-hexahydro-2, 5-methano-pentalene (pentalen) -3a (1H) -yl-2-methylpropionamidine;
(1E) -N- [ (4s) -1-azatricyclo [3.3.1.13,7]Decan-4-yl]-2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
N-1-azabicyclo [2.2.2] oct-3-yl-2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
2- (4-chlorophenoxy) -N' -cyano-N-cyclooctyl-2-methylpropionamidine;
n- [ exo-bicyclo [2.2.1] hept-2-yl ] -2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
(1E) -N-1-adamantyl-2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
(1E) -N' -cyano-2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine;
2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] thiopropionamide;
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine;
2- (2, 4-difluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] thiopropionamide;
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } bicyclo [2.2.2] octane-1-carboxylic acid;
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } bicyclo [2.2.2] octane-1-carboxamide;
(E) -methyl 4- ({ (1E) -2- [ (1R, 5S, 6R) -6- (4-chlorophenyl) -3-azabicyclo [3.2.0] hept-3-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylate;
(E) -methyl 4- ({2- [ (1R, 5S, 6R) -6- (4-chlorophenyl) -3-azabicyclo [3.2.0] hept-3-yl ] -2-methylthiopropionyl } amino) adamantane-1-carboxylate;
(1E) -N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methyl-2-phenoxypropionamidine;
(E) -4- { [ (1E) -N-cyano-2-methyl-2-phenoxymalonimidoyl ] amino } adamantane-1-carboxamide;
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine;
(1E) -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2- (2, 4-difluorophenoxy) -2-methylpropionamidine;
(1E) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2-methylpropionamidine;
(1E) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine;
(1E) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine;
n- [ (exo) -bicyclo [2.2.1] hept-2-yl ] -N' -cyano-2- (2, 4-difluorophenoxy) -2-methylpropionamidine;
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine;
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine;
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2-methylpropionamidine;
(1E) -N- (adamantan-1-yl) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine;
2- (4-chloro-2-fluorophenoxy) -N' -cyano-N-cyclooctyl-2-methylpropionamidine;
(1E) -N- [ (E) -adamantan-2-yl ] -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine;
(E) -methyl 4- { [ (1E) -2- (4-chloro-2-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylate;
(1E) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] -2-phenoxypropionamidine;
n' -cyano-N-cyclooctyl-2- (2, 4-difluorophenoxy) -2-methylpropionamidine;
n- (exo-bicyclo [2.2.1] hept-2-yl) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine;
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine;
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine;
n' -cyano-2- (2, 4-difluorophenoxy) -N- (hexahydro-2, 5-methanocyclopenta-len-3 a (1H) -yl) -2-methylpropionamidine;
(E) -4- { [ (1E) -N-cyano-2- (2, 4-difluorophenoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
(1E) -N- [ (3R,5R) -adamantan-1-yl ] -N' -cyano-2- (2, 4-difluorophenoxy) -2-methylpropionamidine;
(1E) -N- (1-azabicyclo [2.2.2] oct-3-yl) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine;
2- (4-chloro-2-fluorophenoxy) -N' -cyano-N- (hexahydro-2, 5-methanocyclopenta-len-3 a (1H) -yl) -2-methylpropionamidine;
(E) -4- { [ (1E) -2- (4-chloro-2-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
(E) -4- ({ (1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
(E) -4- [ (2-methyl-2-phenoxyiminoacyl) amino ] adamantane-1-carboxamide;
(1E) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] -2- (pyridin-2-yloxy) propionamidine;
(1E) -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2- (2-fluorophenoxy) -2-methylpropionamidine;
(1E) -N' -cyano-2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine;
(1E) -N' -cyano-2- (2-fluorophenoxy) -N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine;
4- { [ N-cyano-2-methyl-2-phenoxyiminoacyl ] amino } bicyclo [2.2.1] heptane-1-carboxamide;
4- { [ N-cyano-2-methyl-2-phenoxypropiriminoyl ] amino } bicyclo [2.2.2] octane-1-carboxamide;
n' -cyano-N- (4-cyanobicyclo [2.2.1] hept-1-yl) -2-methyl-2-phenoxypropionamidine;
n' -cyano-N- (4-cyanobicyclo [2.2.2] oct-1-yl) -2-methyl-2-phenoxypropionamidine;
2- (4-chlorophenoxy) -N' -cyano-N- [4- (difluoromethyl) bicyclo [2.2.2] oct-1-yl ] -2-methylpropionamidine;
n' -cyano-N- [4- (difluoromethyl) bicyclo [2.2.2] oct-1-yl ] -2-methyl-2-phenoxypropionamidine;
4- { [ N-cyano-2-methyl-2-phenoxyiminoacyl ] amino } bicyclo [2.2.2] octane-1-carboxylic acid;
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } bicyclo [2.2.1] heptane-1-carboxamide;
n' -cyano-N- [4- (difluoromethyl) bicyclo [2.2.1] hept-1-yl ] -2-methyl-2-phenoxypropionamidine;
2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine;
2- (2-fluorophenoxy) -N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine;
n- [ (E) -5-hydroxyadamantan-2-yl ] -2-methyl-2-phenoxypropionamidine;
5-chloro-N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methoxybenzamidine;
2- (4-chlorophenoxy) -N' -cyano-N- (4-hydroxybicyclo [2.2.2] oct-1-yl) -2-methylpropionamidine;
n' -cyano-N- (4-hydroxybicyclo [2.2.2] oct-1-yl) -2-methyl-2-phenoxypropionamidine;
2- (4-chlorophenoxy) -N' -cyano-N- (4-cyanobicyclo [2.2.2] oct-1-yl) -2-methylpropionamidine; and
n' -cyano-N- (4-hydroxybicyclo [2.2.1] hept-1-yl) -2-methyl-2-phenoxypropionamidine.
Isomers
The compounds of the present invention may exist in stereoisomeric forms in which an asymmetric or chiral center is present. Depending on the configuration of the substituents around the chiral element, these stereoisomers are in either the "R" or "S" configuration. The terms "R" and "S" as used herein are the configurations defined in the following: IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present invention includes various stereoisomers and mixtures thereof, and is specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers. Single stereoisomers of the compounds of the invention may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution as is well known to those of ordinary skill in the art. These resolution methods can be illustrated by the following: (1) the mixture of enantiomers is linked to a chiral auxiliary, the resulting mixture of diastereomers is separated by recrystallization or chromatography, and the optically pure product is optionally liberated from the auxiliary, as follows: furniss, Hannaford, Smith, and taschell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM 202 JE, England, or (2) direct separation of mixtures of enantiomers on chiral chromatography columns, or (3) fractional recrystallization methods.
However, sometimes the relative stereochemistry of the enantiomeric pairs is known and the absolute configuration is not. In this case, the terms "R" and "S" are described using relative stereochemistry. The terms "R" and "S" as used herein are defined in the following: eliel, E.L., Wilen, S.H. Stereochemistry of Organic Compounds, John Wiley & Sons, Inc. New York, 1994, pp 119-120 and 1206.
Compounds that include carbon-carbon double bonds and geometric isomers of carbon-nitrogen double bonds are included in the present invention. Substituents around carbon-carbon or carbon-nitrogen double bonds are referred to as Z or E configuration, and substituents around cycloalkyl or heterocycle are referred to as cis or trans configuration. All geometric isomeric forms of the compounds described herein and mixtures thereof are included within the scope of the present invention.
The aza-adamantane moiety of example 39 is not chiral, however the C-4 carbon attached to the oxygen is considered pseudo-asymmetric. The structural assignment of the amino aza-adamantane moiety of example 39 was assigned as 4s as described in the following: synthesis, 1992, 1080, Becker, D.P., Flynn, D.L., and Stereochemistry of Organic Compounds, E.L. Eliel, S.H Wilen, John Wiley and Sons, Inc. 1994.
Isotopically enriched or labelled compounds
The compounds of the invention may exist in isotopically-labelled or enriched forms comprising one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atom most commonly found in nature. The isotope canAs radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to:2H，3H，13C，14C，15N，18O，32P，35S，18F，36cl and125I. compounds containing other isotopes of these and/or other atoms are within the scope of the present invention.
In another embodiment, the isotopically labeled compound comprises deuterium (I), (II), (III), (IV), (V), (2H) Tritium (a)3H) Or14Isotope of C. Isotopically labeled compounds of the present invention can be prepared by conventional methods well known to those of ordinary skill in the art. Such isotopically labelled compounds can be conveniently prepared as follows: the methods disclosed in the examples and schemes disclosed herein are performed with readily available isotopically labeled reagents in place of non-labeled reagents. In some cases, compounds may be treated with isotopic tagging reagents to replace normal atoms with their isotopes, for example, in deuterium-containing acids (e.g., D) 2SO4/D2O), hydrogen may be replaced by deuterium. In addition to the above, related processes and intermediates are also disclosed, for example, in the following: the results of Lizondo, J et al,Drugs Fut21(11), 1116(1996); Brickner, S J et al,J Med Chem39(3), 673(1996), Mallesham, B et al,Org Lett5(7), 963(2003), PCT publications WO1997010223, WO2005099353, WO1995007271, WO2006008754, U.S. Pat. Nos. US7538189, 7534814, 7531685, 7528131, 7521421, 7514068, 7511013, and U.S. patent application publications 20090137457, 20090131485, 20090131363, 20090118238, 20090111840, 20090105338, 20090105307, 20090105147, 20090093422, 20090088416, and 20090082471, which are incorporated herein by reference.
Isotopically labeled compounds of the present invention can be used as standards for determining the effectiveness of 11- β -HSD1 inhibitors in binding assays. In pharmaceutical research, isotopically-containing compounds have been used, and studies have been conducted to evaluate the mechanism of action and metabolic pathways of the parent non-isotopically labeled compoundsExactly the in vivo metabolism of the compound (Blake et al)J. Pharm. Sci. 64, 3, 367-391(1975)). This metabolic study is important in the design of safe and effective therapeutic drugs to demonstrate whether the active compound or metabolite produced by the parent compound administered to a patient in vivo is toxic or carcinogenic (Foster et al, Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al, J. Labelled Comp. Radiopharmaceut.927-932(1995); Kushner et al,Can. J. Physiol. Pharmacol., 77, 79-88(1999)。
in addition, drugs containing non-radioactive isotopes, such as deuterated drugs known as "heavy drugs," can be used to treat diseases and conditions associated with 11- β -HSD1 activity. The amount of isotope present in a compound above its natural abundance is called enrichment. Examples of amounts of enrichment include about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%. Up to about 15% of normal atoms have been replaced with heavy isotopes and minimal side effects have been observed in mammals, including rodents and dogs, for periods of days to weeks (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 196084: 770; Thomson J F, Ann. New York Acad. Sci. 196084: 736; Czakja D M et al, Am. J. Physiol. 1961201: 357). In human body fluids, up to 15% -23% acute substitution with deuterium was found not to cause toxicity (Blagojevic N et al in "diagnosis & Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes metals. 23: 251 (1997)).
Stable isotopically labeled drugs can alter their physicochemical properties, such as pKa and lipid solubility. If isotopic substitution affects the regions involved in ligand-receptor interactions, then these effects and changes can affect the pharmacodynamic response of the drug molecule. Although some of the physical properties of the stable isotopically labelled molecules differ from those of the unlabelled molecules, the chemical and biological properties are the same, an important difference being that any bond involving the heavy isotope and another atom is stronger than the same bond between the light isotope and that atom because of the increased mass of the heavy isotope. Accordingly, the introduction of isotopes at the site of metabolic or enzymatic conversion will slow the reaction, possibly altering the pharmacokinetic properties or effects, relative to non-isotopic compounds.
Amides, esters and prodrugs
Prodrugs are derivatives of the active drug that are intended to improve some defined, undesirable physical or biological property. Physical properties are usually solubility (too high or insufficient lipid or water solubility) or related stability, whereas problematic biological properties include too rapid metabolism or poor bioavailability, which may itself be related to physicochemical properties.
Prodrugs are typically prepared by a) forming esters, half-esters, carbonates, nitrates, amides, hydroxamic acids, carbamates, imines, mannich bases and enamines of the active drug, b) functionalizing the drug with azo, glycoside, peptide and ether functionalities, c) using polymer, salt, complex, phosphoramide, acetal, hemiacetal and ketal forms of the drug. See, for example, Andrejus Korolkovass's, "essences of medical Chemistry", John Wiley-Interscience Publications, John Wiley and Sons, New York (1988), pp. 97-118, the entire contents of which are incorporated herein by reference.
Esters can be prepared from substrates of formula (I) containing hydroxyl or carboxyl groups using general methods known to those skilled in the art. Typical reactions of these compounds are substitution of one heteroatom by another atom, e.g.
Reaction scheme 1
Amides may be prepared in analogous form from substrates of formula (I) containing amino or carboxyl groups. Esters may also react with amines or ammonia to form amides.
Reaction scheme 2
Another method for preparing amides from compounds of formula (I) is to heat the carboxylic acid and amine together.
Reaction scheme 3
In schemes 2 and 3, R and R' are independently a substrate of formula (I), an alkyl group or hydrogen. Various embodiments of formula (I) for substrates of prodrugs and esters include, but are not limited to: examples 1, 2, 3, 4, 5, 6, 7, 8, 15, 22, 23, 24, 26, 30, 46, 49, 51, 55, 58, 80, 87 and 91. Examples 11, 16, 17, 21, 28, 29, 48 and 63 represent esters of the invention. Examples 14, 25, 31, 47, 50, 70, 74, 75, 76, 81, 82 and 88 represent amides of the invention.
Compositions of the invention
The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
The pharmaceutical compositions of the present invention may be administered to humans and other mammals in the following manner: oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (e.g., powders, ointments or drops), buccal or buccal, or nasal spray.
Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like, and suitable mixtures thereof), vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate) or suitable mixtures thereof. Proper fluidity of the composition can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size of the dispersion and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents (e.g., sugars, sodium chloride, and the like). Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents which delay absorption, for example, aluminum monostearate and gelatin.
In some cases, it is often desirable to slow the absorption of a subcutaneously or intramuscularly injected drug in order to prolong the effect of the drug. This can be achieved by using liquid suspensions of crystalline or amorphous materials that are poorly soluble in water. The rate of absorption of a drug may depend on its rate of dissolution and thus it may depend on crystal size and crystalline form. Alternatively, a parenterally administered drug form may be administered by dissolving or suspending the drug in an oil vehicle.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
If desired, the compounds of the invention may be incorporated into sustained release or targeted delivery systems, such as polymer matrices, liposomes and microspheres, for more effective distribution.
Injectable depot formulations (depots) are prepared by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Long acting injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions (which are compatible with body tissues).
Injectable formulations can be sterilized, for example, by filtration through a bacteria-containing filter, or by the addition of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Injectable preparations (e.g., sterile aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion (in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol). Among the acceptable excipients and solvents that may be used, water, ringer's solution, u.s.p. and isotonic sodium chloride solution may be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.
Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, one or more compounds of the invention are mixed with at least one inert pharmaceutically acceptable carrier (e.g., sodium citrate or calcium hydrogen phosphate) and/or: a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retarders, such as paraffin hydrocarbons; f) absorption promoters, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules (using lactose or milk sugar as well as high molecular weight polyethylene glycols).
Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or in a certain part of the intestinal tract, in a delayed manner. Examples of materials that may be used to delay release of the active agent may include polymers and waxes.
Oral liquid dosage forms include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
In addition to inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Topical or transdermal administration forms of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The desired compound of the present invention is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers. Eye preparations, ear drops, eye ointments, powders and solutions are also included within the scope of the present invention.
In addition to the active compounds according to the invention, the ointments, pastes, creams and gels may contain animal and vegetable fats, oils, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of the invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can also contain customary propellants, such as chlorofluorocarbons.
The compounds and compositions of the present invention may also be administered in the form of liposomes. Liposomes are generally derived from phospholipids or other lipid substances, as is known in the art. Liposomes are formed from single or multilamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form may also contain stabilizers, preservatives, and the like in addition to the compounds of the present invention. In one embodiment of the invention, the lipids are natural and synthetic phospholipids and choline phospholipids (lecithins) used separately or together. Methods of forming liposomes are known in the art. See, e.g., Prescott, ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, n. y. (1976), p 33 et seq., the contents of which are incorporated herein by reference.
Topical administration forms of the compounds of the present invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers, or propellants. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of the present invention. The aqueous liquid composition of the present invention is particularly effective.
In another embodiment of the invention, the composition for rectal or vaginal administration is a suppository, which may be prepared by: the compounds of the invention are mixed with a suitable non-irritating carrier such as cocoa butter, polyethylene glycol or suppository waxes, which are solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.
The compositions comprise an effective amount of a compound of the invention formulated with one or more therapeutically suitable excipients. Examples of therapeutically suitable excipients include, but are not limited to: sugars, cellulose and its derivatives, oils, glycols, solutions, buffers, colorants, detackifiers, coating agents, sweeteners, flavors, fragrances, and the like.
The effective dosage of the active ingredient employed may vary depending upon the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages can be readily determined by one skilled in the art.
When treating or preventing the diseases against which the compounds of formula (I) are directed, satisfactory results are generally obtained when the compounds of the invention are administered in daily doses of from about 0.1 mg to about 100 mg per kg of animal body weight, preferably in a single daily dose or in divided doses two to six times a day, or in sustained release form. For most mammals, the total daily dosage is from about 1.0 mg to about 1000 mg, preferably, from about 1 mg to about 50 mg. In the case of a 70 kg adult, the total daily dose will generally be from about 7 mg to about 350 mg. Such dosing regimens may be adjusted to provide the optimal therapeutic response.
Method of the invention
Glucocorticoids are steroidal hormones that play an important role in regulating a variety of physiological processes across a wide range of tissues and organs. Glucocorticoids, for example, are potent regulators of glucose and lipid metabolism. Excessive glucocorticoid action can lead to insulin resistance, type II diabetes, dyslipidemia, visceral obesity and hypertension. In humans, cortisol and corticosterone are the major active and inactive forms of glucocorticoids, respectively, while corticosterone and dehydrocorticosterone are the major active and inactive forms in rodents.
Glucocorticoid action is triggered by the binding of glucocorticoids to receptors such as the glucocorticoid receptor and mineralocorticoid receptor. By binding to its receptors, the major mineralocorticoid hormone aldosterone controls water and electrolyte balance within the body. However, mineralocorticoid receptors have a high affinity for both cortisol and aldosterone.
Although cortisol is an important and well-recognized anti-inflammatory agent (j. mixer,Pharmac. Ther2,605-. For example, cortisol has an anti-insulin effect in the liver, resulting in decreased insulin sensitivity and increased gluconeogenesis. Thus, patients who have suffered from impaired glucose tolerance have a greater probability of developing type II diabetes in the presence of abnormally high levels of cortisol.
Since glucocorticoids are potent regulators of glucose and lipid metabolism, excessive glucocorticoid action can lead to insulin resistance, type II diabetes, dyslipidemia, visceral obesity, and hypertension. The present invention relates to the administration of therapeutically effective doses of inhibitors of 11 β -HSD1 for the treatment, control, amelioration, and/or delay of onset of diseases and conditions mediated by excessive or uncontrolled amounts or activity of cortisol and/or other corticosteroids. Inhibition of the 11 β -HSD1 enzyme may limit the conversion of inactive corticosterone to active cortisol. Cortisol, if present in excess amounts, can cause or contribute to the symptoms of these diseases and disorders.
Dysregulation of glucocorticoid activity is associated with metabolic disturbances, including type II diabetes, metabolic syndrome, Cushing's syndrome, Addison's disease and other diseases. Glucocorticoids up-regulate key gluconeogenic enzymes in the liver, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), and thus, it is expected that lowering local glucocorticoid levels in this tissue may improve glucose metabolism in type II diabetes. The 11 β -HSD1 receptor knockout mice systemically and mice overexpressing 11 β -HSD2 in oil (resulting in reduced levels of active glucocorticoid in oil) have better glucose control capacity than their wild-type counterparts (Masuzaki et al, Science294, 2166-2170(2001); Harris et al,Endocrinology,142,114-120 (2001), Kershaw et al,Diabetes,54, 1023-1031(2005)). Thus, specific 11 β -HSD1 inhibitors may be useful for the treatment or prevention of type II diabetes and/or insulin resistance.
By lowering insulin resistance and maintaining serum glucose at normal concentrations, the compounds of the present invention may also have utility in the treatment and prevention of a number of conditions often associated with type II diabetes and insulin resistance, including metabolic syndrome, obesity, reactive hypoglycemia, and diabetic dyslipidemia. The following diseases, disorders and conditions are related to type II diabetes and may be treated, controlled, prevented and/or delayed in their onset by treatment with the compounds of the present invention hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid metabolism disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative diseases, retinopathy, nephropathy, neuropathy, metabolic syndrome and other conditions for which insulin resistance is a component.
Abdominal obesity is closely related to glucose intolerance (Montaque et al, Diabetes, 49, 883-888(2000)), hyperinsulinemia, hypertriglyceridemia, and other factors of metabolic syndrome (also known as syndrome X) (e.g., hypertension, increased LDL and decreased HDL). A large body of animal data supports the role of HSD1 in the pathogenesis of metabolic syndrome. (Masuzaki et al,Science,294, 2166-2170(2001); Paterson et al,Proc Natl. Acad. Sci. USA101, 7088-93, (2004); Montague et al,Diabetes,49, 883-888(2000)). Thus, administration of an effective amount of an inhibitor of 11 β -HSD1 may be useful in the treatment or control of metabolic syndrome. Furthermore, administration of 11 β -HSD1 inhibitors may be useful for treating or controlling obesity by controlling excess cortisol, independently of the effect of 11 β -HSD1 inhibitors in the therapeutic or prophylactic treatment of NIDDM (non-insulin dependent diabetes mellitus). Long-term treatment with 11 β -HSD1 inhibitors may also be effective in delaying the onset of obesity, or may completely prevent obesity, if the patient is treated with 11 β -HSD1 inhibitors in combination with diet control and exercise. A potent and selective 11 β -HSD1 inhibitor should also have therapeutic value in the treatment of glucocorticoid related effects characterized by metabolic syndrome or any of the following related conditions: hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, vascular restenosis, pancreatitis, obesity, neurodegenerative diseases, retinopathy, nephropathy, hepatic lipidosis or related liver diseases and syndrome X, and other disorders where insulin resistance is a component.
11 β -HSD1 was expressed in islet cells (pancreatic islet cells), where active glucocorticoids had a negative effect on glucose-stimulated insulin secretion (Davani et al,Biol. Chem10, 34841-34844(2000); Tadayyon et al,Expert Opin. Investig. Drugs, 12, 307, 324(2003), Billaudel et al,J. Endocrinol.,95, 315-20(1982)). Conversion of dehydrocorticosterone to corticosterone (via 11 β -HSD1) was reported to inhibit insulin secretion from isolated murine pancreatic β -cells. Culturing isolated islets with 11 β -HSD1 inhibitor increases glucose-stimulated insulin secretion. Previous studies have shown that glucocorticoids can reduce insulin secretion in vivo (b. billaude et al,Horm. Metab. Res11, 555-560(1979)), therefore, inhibition of 11 β -HSD1 enzyme in the pancreas increased glucose stimulationInsulin release.
Glucocorticoids can bind to and activate glucocorticoid receptors (and possibly mineralocorticoid receptors), thereby potentiating the vasoconstrictive effects of both catecholamines and angiotensin II (pirpirpiris et al,Hypertension19, 567-574(1992); Kornel et al,Steroids58, 580- & 587(1993): Walker et al,Clin. Sci., 82, 597-605(1992)). The 11 β -HSD1 enzyme is present in vascular smooth muscle and is thought to control the contractile response in conjunction with 11 β -HSD 2. The presence of high levels of cortisol in tissues where mineralocorticoid receptors are present can lead to hypertension. Thus, administration of a therapeutic dose of an inhibitor of 11 β -HSD1 should be effective in treating or prophylactically treating, managing and ameliorating the symptoms of hypertension.
Cushing's syndrome is a life-threatening metabolic disorder characterized by long-term elevated glucocorticoid levels, either due to endogenous production of excess cortisol from the adrenal gland, or due to administration of high doses of exogenous glucocorticoids (e.g., dehydrocortisone or dexamethasone) as part of an anti-inflammatory treatment regimen. Typical Cushinoid characteristics include central obesity, diabetes and/or insulin resistance, dyslipidemia, hypertension, cognitive decline, dementia, osteoporosis, atherosclerosis, lunar surface appearance, Buffalo shoulders, thinning of the skin and insomnia, as well as other characteristics (Principles and Practice of Endocrinology and metabolism, Edied by Kenneth Becker, Lippincott Williams and Wilkins Publishers, Philadelphia, 723-8 (2001)). Thus, potent and selective inhibitors of 11 β -HSD1 would be expected to be effective in the treatment of Cushing's disease.
The effect of elevated cortisol levels was also observed in patients with Cushing's syndrome (Orth et al,J. Med332, 791-,Lancet357, 783- nded. Blackwell, 592-612(2002), which is characterized by high levels of cortisol in the blood. Patient suffering fromPatients with Cushing's syndrome often develop many symptoms of type II diabetes, obesity, metabolic syndrome, and dyslipidemia, including insulin resistance, central obesity, hypertension, glucose intolerance, and the like.
As noted above, 11 β -HSD1 inhibitors may be effective in treating many of the features of metabolic syndrome, including hypertension and dyslipidemia. The combination of hypertension and dyslipidemia aids in the development of atherosclerosis and it is therefore desirable that administration of a therapeutically effective amount of an inhibitor of 11 β -HSD1 treat, control, delay the onset of and/or prevent atherosclerosis and other metabolic syndromes of cardiovascular origin.
One significant side effect associated with topical and systemic glucocorticoid therapy is glaucoma caused by corticosteroids. This condition results in a severe increase in intraocular pressure, potentially leading to blindness (Armaly et al,Arch Ophthalmol,78, 193-7(1967), Stokes et al,Invest Ophthalmol Vis Sci., 44, 5163-7(2003)). The cells that produce most aqueous humor in the eye are non-pigmented epithelial cells (NPE). These cells have been shown to express 11 β -HSD1, consistent with the expression of 11 β -HSD1, and found to have an elevated cortisol to corticosterone ratio in the aqueous humor (Rauz et al, Invest Ophthalmol Vis Sci., 42, 2037-2042(2001)). Furthermore, it has been shown that there is an elevated cortisol level relative to corticosterone in the aqueous humor of patients suffering from glaucoma, but who have not ingested exogenous steroids (Rauz et al,QJM,96, 481-490(2003)). Treatment of patients with the non-selective 11 β -HSD1 and 11 β -HSD2 inhibitors carbenoxolone for 4 and 7 days, respectively, significantly reduced intraocular pressure by 10% and 17%, respectively, and reduced topical cortisol production in the eye (Rauz et al,QJM,96, 481-490(2003)). Thus, administration of a particular inhibitor of 11 β -HSD1 may be useful in the treatment of glaucoma.
In certain disease states, such as tuberculosis, psoriasis and stress responses, high glucocorticoid activity alters humoral responses, often when in fact cell-based responses may be more beneficial to the patientAn immune response. Inhibition of 11 β -HSD1 activity may decrease glucocorticoid levels, thereby altering the immune response to cell-based responses (Mason,Immunology Today, 12, 57-60(1991); Rook, Baillier ’ s Clin. Endocrinol. Metab., 13, 576-581(1999)). Thus, administration of 11 β -HSD1 specific inhibitors may be useful in the treatment of tuberculosis, psoriasis, stress, and diseases or conditions where high glucocorticoid activity alters the immune response to humoral responses in general.
Glucocorticoids are known to cause various skin-related side effects, including skin thinning and defects in wound healing (Anstead, Adv Wound Care,11, 277-85(1998); Beer et al,Vitam Horm., 59, 217-39(2000)). 11 β -HSD1 was expressed in human dermal fibroblasts and it has been shown in a cutaneous vasoconstrictor assay that topical treatment with the non-selective 11 β -HSD1 and the 11 β -HSD2 inhibitor glycyrrhizic acid could increase the efficacy of locally applied hydrocortisone (Hammami et al,J. Clin. Endocrinol. Metab., 73, 326-34(1991)). The beneficial effects of selective 11 β -HSD1 inhibitors on wound healing have also been disclosed (International publication WO 2004/11310). Thus, it would be desirable to have a potent selective 11 β -HSD1 inhibitor that could treat wound healing or skin thinning due to excessive glucocorticoid activity.
Excess glucocorticoids can reduce skeletal mineral density and increase the risk of bone fracture. This effect is mediated primarily by the inhibition of osteoblastic bone formation, resulting in net bone loss (Kim et al,J. Endocrinol162,371-,Bone23, 119-,Bone, 27, 375-381(2000)). Glucocorticoids are also known to increase bone resorption and decrease bone formation in mammals (Turner et al,Calcif. Tissue Int54, 311-5(1995), Lane et al,Med. Pediatr. Oncol., 41, 212-6(2003)). 11 β -HSD1 mRNA expression and reductase activity has been demonstrated in primary cultures of human osteoblasts in human bone homogenate (Bland et al, J. Endocrinol161, 455-464(1999); Cooper et al,Bone, 23, 119-125(2000) the methods of Cooper et al, in general,J. Bone Miner. Res.,17, 979-986(2002)). In the surgically obtained explants from plastic surgery, 11 β -HSD1 was found to be expressed approximately 3-fold higher in primary cultures of osteoblasts between young and elderly donors (Cooper et al,J. Bone Miner. Res.,17, 979-986(2002)). Glucocorticoids (e.g., dehydrocortisone and dexamethasone) are also commonly used to treat various inflammatory disorders, including arthritis, inflammatory bowel disease, and asthma. These steroidal agents have been shown to increase the expression and activity of 11 β -HSD1 mRNA in human osteoblasts (Cooper et al,J. Bone Miner. Res.,17, 979-986(2002)). Similar results have been shown in primary osteoblasts and MG-63 osteosarcoma cells, where inflammatory cytokines TNF α and IL-1 β increase 11 β -HSD1 mRNA expression and activity (Cooper et al,J. Bone Miner. Res., 16, 1037-1044(2001)). These studies suggest that 11 β -HSD1 plays a potentially important role in the development of bone-related adverse conditions as a result of excessive glucocorticoid levels or activity. Bone samples taken from healthy human volunteers (oral non-selective 11 β -HSD1 and the 11 β -HSD2 inhibitor carbenoxolone) showed significant reduction in bone resorption markers (Cooper et al, Bone,27, 375-81(2000)). Thus, administration of a 11 β -HSD1 specific inhibitor may be useful in preventing bone loss due to glucocorticoid-induced or age-dependent osteoporosis.
Studies have shown that in homogenates of the hippocampus, dehydrogenation and reduction occur (Lakshmi et al,Endocrinol128, 1741-,Hum Mol Genet13, 47-52 (2004); belanoff et al, having a high frequency,J. Psychiatr. Res., 35, 127-35(2001)). Several studies have shown 11 β -HSD activity, immunoreactivity and mRNA expression in hippocampal neurons (Moisan et al,Endocrinol,127, 1450-1455(1990), Lakshmi et al,Endocrinol128, 1741-,J. Neuroendocrinol., 4, 101-106(1992)). Administration of 11 beta-HSD inhibitorsTo alter functional activity in vivo in the hippocampus (Seckl et al,J. Endocrinol.,136, 471-477(1993)). Evidence in rodents and humans suggests that prolonged elevation of plasma glucocorticoid levels can lead to impairment of cognitive function, which becomes more severe with aging(The Issa et al person to which the present invention relates,J. Neurosci10, 3247-3254(1990), Lupien et al,Nat. Neurosci1, 69-73(1998) Yau et al, Neuroscience, 66, 571-581(1995)). Long-term excessive cortisol levels in the brain can lead to neuronal loss and neuronal dysfunction (Kerr et al,Psychobiology, 22, 123-133(1994); Woolley, Brain Res., 531, 225-231(1990); Landfield, Science, 272, 1249-1251(1996)). In addition, glucocorticoid-induced acute psychosis accounts for the more pharmacologically induced effects of this response, and is a major consideration by physicians when treating patients with these steroidal agents (Wolkowitz et al,Ann NY Acad Sci., 1032, 191-4(2004)). Thekkapat et al have demonstrated that 11 β -HSD1 mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum, and that treatment of elderly diabetic patients with the non-selective 11 β -HSD1 and 11 β -HSD2 inhibitors carbenoxolone can improve speech fluency and memory (Thekkapat et al,Proc Natl Acad Sci USA. 101, 6743-9(2004)). In addition, Walker et al have tested 11 β -HSD activity and its function in primary cultures of fetal hippocampal cells (US 7,122,531; US7,087,400; Rajan et al,J. Neurosci.,16, 65-70(1996))。
accordingly, CNS diseases, disorders and conditions can be treated, controlled, prevented or delayed by treatment with the compounds of the present invention. Administration of a therapeutic dose of an 11 β -HSD1 inhibitor may reduce, ameliorate, control and/or prevent a disorder, such as general stress, neurodegeneration, age-related cognitive deficits, neuronal dysfunction, dementia, steroid-induced acute psychosis, cognitive dysfunction in Alzheimer's disease and related dementias, cognitive deficits related to aging and neurodegeneration, dementia, senile dementia, AIDS dementia, melancholia, major depressive disorder, psychotic depression, treatment-refractory melancholia, anxiety disorders, panic disorders, post-traumatic stress disorder, cognitive dysfunction in Cushing's syndrome, depression in Cushing's syndrome, steroid-induced acute psychosis, cognitive deficits related to diabetes, general attention-deficit disorder, attention-deficit hyperactivity disorder (ADHD), mild cognitive deficits, steroid-induced acute psychosis and schizophrenia.
Accordingly, one embodiment is a method of inhibiting 11 β -HSD1, the method comprising: administering to the mammal a therapeutically effective amount of a compound of formula (I). Another embodiment is the therapeutic or prophylactic treatment of the above-mentioned conditions in a mammal. In mammals, this condition may be mediated by excessive glucocorticoid action.
Another embodiment is a method of treating a disorder, including but not limited to: cushing's syndrome, non-insulin dependent type II diabetes mellitus, insulin resistance, obesity, disorders of lipid metabolism (dyslipidemia), metabolic syndrome, hyperglycemia, low glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, retinopathy, nephropathy (nephropathies), neuropathy, hypertension, other conditions of which insulin resistance is a component, glaucoma, arthritis, osteoporosis, neuronal dysfunction, neurodegeneration, cognitive deficits associated with aging, dementia, alzheimer's disease, cognitive dysfunction and associated dementia in alzheimer's disease, cognitive deficits associated with aging and neurodegeneration, dementia, senile dementia, AIDS dementia, anxiety disorders, panic disorders, post-traumatic stress disorder, steroid-induced acute psychosis, cognitive deficits associated with diabetes, attention deficit disorders in general, Attention Deficit Hyperactivity Disorder (ADHD), mild cognitive deficits, cognitive decline in Cushing's syndrome, schizophrenia, melancholia, major depressive disorder, psychotic depression, melancholia in Cushing's syndrome, treatment-refractory melancholia, steroid-induced acute psychosis, and other disorders associated with cortisol or glucocorticoid.
Another embodiment provides a method of treating alzheimer's disease in a patient, and thereby reducing signs and symptoms.
For treating a neurodegenerative or neuropsychiatric disorder, the method comprises: administering to a patient (e.g., a mammal, such as a human) in need of such treatment a therapeutically effective amount of any of the compounds described herein, or a pharmaceutically acceptable salt thereof. Alternatively, the method comprises: administering to the patient a therapeutically effective amount of any of the compounds described herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of at least one cognition enhancing agent. A "cognition enhancing agent" as defined herein is an agent that improves impaired cognitive ability (i.e., thinking, learning and memory) of the human brain. Cognition enhancing drugs act by altering the availability of neurochemicals (e.g., neurotransmitters, enzymes and hormones), increasing oxygen supply, stimulating nerve growth or inhibiting nerve damage. Examples of cognition enhancing drugs include: compounds that increase the activity of acetylcholine such as, but not limited to: acetylcholine receptor agonists (e.g., nicotinic a-7 receptor agonists or allosteric modulators, a 4 ss 2 nicotinic receptor agonists or allosteric modulators), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine and galantamine (galantamine)), butyrylcholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., Memantine), activity-dependent neuroprotective protein (ADNP) agonists, serotonin 5-HT1A receptor agonists (e.g., zaliloden (xaprolide)), 5-HT 4Receptor agonists, 5-HT6Receptor antagonists, serotonin 1A receptor antagonists, histamine H3Receptor antagonists, calpain inhibitors, Vascular Endothelial Growth Factor (VEGF) proteins or agonists, trophic growth factors, anti-apoptotic compounds, AMPA-type glutamate receptor activators, L-type or N-type calcium channel blockers or modulators, potassium channel blockers, Hypoxia Inducible Factor (HIF) activators, HIF prolyl 4-hydroxylase inhibitors, anti-inflammatory agents, inhibitors of amyloid A beta peptide or amyloid plaques, tau hyperphosphorylatedInhibitors, phosphodiesterase 5 inhibitors (e.g., tadalafil, sildenafil), phosphodiesterase 4 inhibitors, monoamine oxidase inhibitors, or pharmaceutically acceptable salts thereof. Specific examples of such cognition enhancing agents include, but are not limited to: cholinesterase inhibitors, e.g. donepezil (Aricept)®), rivastigmine(Exelon®) Galantamine (remininyl)®) N-methyl-D-aspartic acid antagonists, e.g. Memantine (Namenda)®). The at least one cognition enhancing agent may be administered concurrently with a compound of the invention, or sequentially (in any order) with a compound of the invention. In addition, when used in the above treatments, it is contemplated that the combinations described herein may have additive or synergistic effects.
In yet another embodiment, the invention relates to a method of preventing (developing) a disease condition, e.g., a neurodegenerative condition or a neuropsychiatric condition. The term "preventing" a disease condition (by administration of any of the compounds described herein), e.g., a neurodegenerative or neuropsychiatric condition, as used herein, means that no detectable physiological characteristic or symptom of the disease or condition is formed following administration of the compounds described herein. Specifically, the method of the present invention comprises: administering to a patient (e.g., a mammal, such as a human) in need of treatment a therapeutically effective amount of any of the compounds described herein or a pharmaceutically acceptable salt thereof. Alternatively, the method comprises: administering to the patient a therapeutically effective amount of any of the compounds described herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of at least one cognition enhancing agent.
In yet another embodiment, the invention relates to a method of preventing the development (e.g., worsening) of a disease condition, e.g., a neurodegenerative disorder or a neuropsychiatric disorder. The method comprises the following steps: administering to a patient (e.g., a mammal, such as a human) in need of treatment a therapeutically effective amount of any of the compounds described herein or a pharmaceutically acceptable salt thereof. Alternatively, the method comprises: administering to the patient a therapeutically effective amount of any of the compounds described herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of at least one cognition enhancing agent.
In the above-described methods of preventing the development or progression of a neurodegenerative or neuropsychiatric disorder, one or more biomarkers, diagnostic tests, or a combination of biomarkers and diagnostic tests known to those of skill in the art can be used to determine: (1) whether the patient is at risk of developing one or more neurodegenerative or neuropsychiatric disorders; or (2) whether a neurodegenerative or neuropsychiatric disorder is developing (e.g., worsening) in a patient previously diagnosed with one or more of the above-mentioned disorders.
Another embodiment provides a method of determining whether an 11 β -HSD1 inhibitor is effective in treating a patient in need thereof. This method can be used to determine the effect of 11 β -HSD1 inhibitors, including those inhibitors that are not known or demonstrated to have such an effect.
Formula (II) (I) Preparation of the Compounds
AbbreviationAc: acetyl; AcSH: thioacetic acid; bu: a butyl group; cbz: a benzyloxycarbonyl group; CbzCl: benzyloxycarbonyl chloride; DAST: (diethylamino) sulfur trifluoride DMSO: dimethyl sulfoxide; DPPA: diphenyl phosphorazidate; et: an ethyl group; et (Et)3N: triethylamine; EtOH: ethanol; HPLC: high performance liquid chromatography; LCMS: liquid chromatography/mass spectrometry; mCPBA: m-chloroperbenzoic acid; me: a methyl group; MeOH: methanol; ms: a methanesulfonyl group; MsCl: methanesulfonyl chloride; NaOMe: sodium methoxide; NaSMe: sodium methyl mercaptide; t-Bu: a tertiary butyl group; t-BuOH: tert-butanol.
The methods described below can be used with a variety of enantiomers. The compounds of the invention can be prepared according to the synthetic methods described in this section, the methods of the invention, and the examples section. Certain groups depicted in the schemes are intended to be illustrative of certain substituents included in the present invention and are not intended to limit the scope of the present invention. Representative methods are shown in, but not limited to, schemes 4-13.
Reaction scheme 4
As depicted in scheme 4, compounds of formula (4-4) and (4-5), wherein R is defined in the summary of the invention1、R2、R3、R4、R5And L, which can be prepared from the compound of formula (4-1). Accordingly, the nitrile of formula (4-1) can be converted to the corresponding imidate of formula (4-2) by treatment with HCl in a solvent such as ethanol. Further examples of the preparation of compounds of formula (4-2) can be found in U.S. patent application US 2006/0025614. The compound of formula (4-2) may then be treated with cyanamide in ethanol or phosphate buffer to provide the compound of formula (4-3). The amine (R) may then be used in an optionally heated solvent, such as ethanol1)(R2) NH-treating the compound of formula (4-3) to obtain a compound of formula (4-4). Amine (R)1)(R2) NH is commercially available, prepared as described in the following reaction scheme or prepared as described J. Med. Chem., 50, 149-164(2007); Bioorg. Med. Chem. Lett., 17, 527-532(2007); Bioorg. Med. Chem. Lett., 16, 5555-5560(2006); Bioorg. Med. Chem. Lett., 16, 5414-5419(2006); Bioorg. Med. Chem. Lett., 16, 5408-5413(2006); J. Am. Chem. Soc., 75, 637-640(1953); J. Med. Chem., 13, 926-935(1970); Australian J. Chem., 47, 1833-1841(1994); J. Org. Chem., 33, 877-880(1968). In a similar transformation, the compound of formula (4-2) may be converted to the compound of formula (4-5). The compounds of formulae (4-4) and (4-5) are representative of compounds of formula (I).
Reaction scheme 5
Compounds of formulae (4-4), (5-3) and (5-4) as depicted in scheme 5, whereinR1、R2、R3、R4、R5、R6And L is as defined in the summary of the invention, can be prepared from compounds of formula (5-1). The compound of formula (5-1) can be prepared as follows: in Sorensen et al,Bioorg. Med. Chem. Lett. 17, 527-532(2007). In addition, the preparation of the compound of formula (5-1) is described in the following: US patent US7,528,282; 7,511,175, respectively; 7,435,833 and 7,217,838; U.S. application publications 2009/0054426, 2008/0312214, 2008/0076819, 2006/0281773, 2005/0277747, 2006/0149070, 2007/0208001, 2007/0129345, 2007/0167622, 2007/0066584, 2007/0088088; international publications WO 2007118185, WO 2007111921, WO 2007145834, WO 2007145835, WO 2008088540, WO 2008011453, WO 2008099145, WO 2008012532, WO 2008053194, WO 2008024892, WO 2008074384, WO 2008052638, WO 2007124337, WO 2007127765, WO 2007127726, WO 2007127693, WO 2007127704, WO 2007127688, WO 2007127901, WO 2007127763, WO 2007124329, WO 2007124254, WO 2007107470, WO 2007101270, WO 2008069313, WO 2007084314, WO 2008157752, WO 2008142859, WO 2008006703, WO 2008006702, WO 2007107550, WO 2007115935, WO 2007051810, WO 2007051811, WO 2008110196, WO 2007144394, WO 2008134221, WO 2008127924, WO 2006048750, WO 2007058346, WO 2007114124, WO 2008142986, WO 2007114125, WO 2008101886, WO 2008101907, WO 2008101885, WO 2008101914, WO 2008119017 and US patent application US 11/697044, the entire contents of which are incorporated herein by reference. The compound of formula (5-1) may be converted to the thioamide of formula (5-2) when contacted with Lawesson's reagent in a heated solvent (e.g., toluene). Then, in the presence of mercury (II) acetate, optionally in the presence of a base (e.g. triethylamine), in an optionally heated solvent (e.g. acetonitrile), with a compound of formula H 2N-R6、H2N-CN or H2N-OR6The amine-treated compound of formula (5-2) of (a) provides compounds of formulae (5-3), (4-4) and (5-4), respectively. The compounds of the formulae (5-3), (4-4) and (5-4) are representative of the compounds of the formula (I).
Reaction scheme 6
As shown in scheme 6, compounds of formula (6-5), wherein R is defined in the summary of the invention1、R2、R3、R4、R5L and W can be prepared from the compound of the formula (6-1). A compound of formula (6-1) wherein LG is a leaving group such as chloro, bromo, iodo, trifluoromethanesulfonic or p-toluenesulfonate, may be prepared with H-L-R in the presence of a base such as cesium carbonate in an optionally heated solvent such as N, N-dimethylformamide5Treatment, wherein L is O or S, affords a compound of formula (6-2). Subsequent hydrolysis under conditions known in the art provides compounds of formula (6-3). Reacting a compound of formula (6-3) with an amine (R) using amide bond formation conditions known in the art1)(R2) NH coupling to give the compound of formula (6-4). Using the method described in scheme 5, the compound of formula (6-4) is converted into the compound of formula (6-5). The compounds of the formula (6-5) are representative of the compounds of the formula (I).
Reaction scheme 7
As shown in reaction scheme 7, compound (7-7) can be produced from compound (7-1). Compound (7-1) can be converted into compound (7-2) in two steps. The amine is first protected, in this case, revealing the benzyloxycarbonyl group. The ester is then hydrolyzed using methods known in the art. Compound (7-2) is treated as described in Tetrahedron Lett.,43,8687-8691(2002) to give compound (7-3). Compound (7-3) can then be hydrolyzed to give compound (7-4). Then, compound (7-4) can be converted into compound (7-5) in three steps Bioorg. Med. Chem. Lett., 17, 527-532(2002)). In the first step, the tertiary alcohol is sulfonylated. And then replaced with thioacetic acid. Then, a protecting group is attached to the residue to obtain compound (7-5). Then, nail can be usedSodium mercaptide removed the acetate group of compound (7-5). Reaction with chloramine followed by oxidation with m-chloroperbenzoic acid gives compound (7-6). The amine protecting group is removed using methods known in the art to provide compound (7-7). The compound (7-7) is typically (R)1)(R2) NH, and can be used in schemes 4 and 6.
Reaction scheme 8
Compound (8-4) can be prepared from compound (8-1) as described in scheme 8. Compound (8-1) is prepared when the acetic acid moiety is removed from compound (7-5) as depicted in scheme 7. Compound (8-1) can be methylated with methyl iodide in the presence of a base to give compound (8-2). Compound (8-1) can be oxidized with sodium perborate to give sulfone (8-3). The amine protecting group is removed using methods known in the art to provide compound (8-4). The compound (8-4) is typically (R)1)(R2) NH, and can be used in schemes 4 and 6.
Reaction scheme 9
Such as Wilcox et al (J. Org. Chem29, 2209-2211(1964)), the compound (9-1) can be prepared. Then using Wilcox et al ( J. Org. Chem33, 877-880(1968)), the compound (9-1) can be converted into the compound (9-2). Then, by treatment with ammonia, the compound (9-2) can be converted into the compound (9-3). Alternatively, compound (9-2) can be converted to compounds of formulae (9-4) and (9-6) using the procedures described in scheme 7. Compound (9-2) can also be converted into compound (9-5) using the procedures shown in scheme 8. Compounds (9-3), (9-4), (9-5) and (9-6) are representative of (R)1)(R2) NH, and can be used in schemes 4 and 6.
As described in scheme 10, compounds of formulae (5-3), (4-4) and (5-4) can be prepared from compounds of formula (5-2). In a solvent (e.g., hot methylene chloride), triethyloxy can be usedTreating the compound of formula (5-2) with a tetrafluoroborate salt to obtain a compound of formula (10-1). The compound of formula (10-1) can then be treated as described in scheme 5 to give compounds of formulae (5-3), (4-4) and (5-4). The compounds of the formulae (5-3), (4-4) and (5-4) are representative of the compounds of the formula (I).
Reaction scheme 10
Reaction scheme 11
As shown in scheme 11, compounds of formulae (11-2) and (11-4) can be prepared from compounds of formula (11-1). The compound of (11-1), wherein v is 1 or 2, R "is an alkyl group, and P is a nitrogen protecting group, can be converted into the compound of formula (11-2) by removing the protecting group. The person skilled in the art can adapt the protecting group used to the deprotection reaction conditions. For example, when P is benzyloxycarbonyl, P can be removed by hydrogenation in the presence of a palladium catalyst.
The compound of (11-1) may also be reduced to the corresponding alcohol of formula (11-3). The ester moiety of the compound of formula (11-1) may be reduced using, for example, borane-tetrahydrofuran complex to give the hydroxymethyl group in the compound of formula (11-3). Compounds of formula (11-3) may be oxidized with a reagent such as Dess-Martin periodinane to produce an intermediate aldehyde. Subsequent treatment with (diethylamino) sulfur trifluoride (DAST) converts the aldehyde to a difluoromethyl moiety. Removal of the protecting group P under suitable reaction conditions provides a compound of formula (11-4).
The compounds of formulae (11-2) and (11-4) are representative of (R)1)(R2) NH, and can be used in schemes 4 and 6.
Reaction scheme 12
As shown in reaction scheme 12, the compound of formula (11-1) can also be converted into compounds of formulae (12-3) and (12-4). The compound of formula (11-2) wherein v is 1 or 2, R '' is alkyl, and P is a nitrogen protecting group can be converted into the compound of formula (12-1) by partial hydrolysis of the ester. The compound of formula (12-1) can be converted to the corresponding acid chloride by treatment with a reagent such as oxalyl chloride. The intermediate acid chloride may then be reacted with ammonia to give the carboxamide of formula (12-2). Removal of the protecting group under conditions known to those skilled in the art provides compounds of formula (12-3). The compound of formula (12-2) may also be dehydrated with a reagent such as trifluoroacetic anhydride to convert the carboxamide moiety to a cyano group. Removal of the protecting group affords compounds of formula (12-4). The compounds of formulae (12-2) and (12-4) are representative of (R) 1)(R2) NH, and can be used in schemes 4 and 6.
Reaction scheme 13
As depicted in scheme 13, compounds of formula (13-1), wherein R '' is alkyl and v is 1 or 2, can be converted to compounds of formula (13-3). Accordingly, compounds of formula (13-1) can be treated under Hunsdiecker reaction conditions to convert the carboxylic acid moiety toThe corresponding bromide. Followed by contacting the hydroxide to convert the bromide to the corresponding alcohol and also to hydrolyze the ester to the carboxylic acid of formula (13-2). The Curtius rearrangement of the compound of formula (13-2) is carried out by treatment with diphenylphosphorylazide in the presence of an alcohol (e.g., t-butanol) to provide the intermediate t-butyl carbamate. The tert-butoxycarbonyl group is removed by treatment with an acid (e.g., hydrochloric acid or trifluoroacetic acid) to give a compound of the formula (13-3). The compound of formula (13-3) is representative of (R)1)(R2) NH, and can be used in schemes 4 and 6.
In addition, nitrogen protecting groups may be used to protect the amino group during synthesis of the compounds of formula (I). This method and some suitable nitrogen protecting Groups are described In Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1999). For example, suitable nitrogen protecting groups include, but are not limited to: t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), acetyl and trifluoroacetyl. More specifically, the Boc protecting group can be removed by treatment with an acid (e.g., trifluoroacetic acid or hydrochloric acid). The Cbz and Bn protecting groups can be removed by catalytic hydrogenation and the acetyl and trifluoroacetyl protecting groups can be removed by a variety of conditions including the use of sodium hydroxide, potassium hydroxide or lithium hydroxide in aqueous organic or alcoholic solvents.
The compounds and intermediates of the invention can be isolated and purified using methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds may include, but are not limited to: chromatography on a solid support (e.g., silica gel, alumina or silica derivatized with alkylsilanes), recrystallization at high or low temperatures (optionally pretreated with activated carbon), thin layer chromatography, distillation at various pressures, vacuum sublimation, trituration, e.g., as described below: "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Furniss et al, pub. Longman Scientific & Technical, Essex CM 202 JE, England.
Some of the compounds of the present invention have at least one basic site whereby the compound can be treated with an acid to form the desired salt. For example, the compound can be reacted with an acid at or above room temperature to provide the desired salt, allowed to settle, cooled, and collected by filtration. Examples of acids suitable for this reaction include, but are not limited to: tartaric, lactic, succinic, and mandelic, o-phthalic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, carbonic, fumaric, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric or hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, glutamic, and the like.
The invention includes pharmaceutically active compounds which may be chemically synthesized or formed by in vivo biotransformation as compounds of formula (I).
The compounds, compositions and methods of the present invention may be better understood by reference to the following examples and reference examples, which are intended to be illustrative only and are not intended to limit the scope of the invention.
Examples
Preparation of bicyclic amines
Bicyclic amine intermediate 1(BAI-1)
1- (2-chloroethyl) cyclohexane-1, 4-dicarboxylic acid dimethyl ester
Freshly prepared lithium diisopropylamide (110.0 mL of n-butyllithium (2.5M solution in hexanes) and 41.0 mL of diisopropylamine mixed at-30 ℃ in 300 mL of tetrahydrofuran) was cooled to-78 ℃ under a nitrogen atmosphere and stirred for 30 minutes. Anhydrous hexamethylphosphoramide (180 mL, 1.0 mol) was added dropwise over 30 minutes. To the resulting mixture was added cyclohexane-1, 4-dicarboxylic acid dimethyl ester (50 g, 0.25 mol) over 30 minutes. After stirring for 1 hour, 1-bromo-2-chloroethane (21 mL, 0.25 mol) was added over 1 hour. The mixture was then stirred at-78 ℃ for 3 hours, then stirred overnight and allowed to warm to room temperature. To the reaction mixture was added HCl (3N, 100 mL), and the mixture was stirred for 10 minutes. By reducing the pressure The solvent was removed by evaporation. The aqueous layer was extracted with ethyl acetate (3X 150 mL). The combined extracts were washed with HCl (3N, 2X 100 mL), water (200 mL), saturated NaHCO3Aqueous solution (100 mL), brine (2X 100 mL), Na2SO4And (5) drying. Concentration gave the title compound which was used in the next step without further purification.
Preparation of bicyclic amine intermediate 2(BAI-2)
Bicyclo [2.2.2] octane-1, 4-dicarboxylic acid dimethyl ester
Freshly prepared lithium diisopropylamide (110.0 mL of n-butyllithium (2.5M solution in hexanes) and 41.0 mL of diisopropylamine mixed at-30 ℃ in 150 mL of tetrahydrofuran) was cooled to-78 ℃ under a nitrogen atmosphere and stirred for 30 minutes. A mixture of dimethyl 1- (2-chloroethyl) cyclohexane-1, 4-dicarboxylate (BAI-1, 70 g, 0.25 mol) and anhydrous hexamethylphosphoramide (180 mL, 1.0 mol) in tetrahydrofuran (500 mL) was stirred at-78 ℃ for 30 minutes under a nitrogen atmosphere. To this solution was added the above lithium diisopropylamide solution over 1 hour through a transfer line. The resulting mixture was stirred at-78 ℃ for 2 hours and then warmed to room temperature. After stirring overnight at room temperature, saturated NH was added4Aqueous Cl solution. The mixture was concentrated to 1/2 volumes, then diluted with 500 mL of water and extracted with hexane (3X 300 mL). The combined extracts were washed with brine, dried over sodium sulfate and concentrated. The crude product was crystallized from hexane to give the title compound. 1H NMR(400 MHz, CDCl3), ppm 3.65(s, 6H), 1.81(s, 12H); LCMS(ESI+) m/z 227(M+H)+。
Preparation of bicyclic amine intermediate 3(BAI-3)
Bicyclo [2.2.1] heptane-1, 4-dicarboxylic acid dimethyl ester
Freshly prepared lithium diisopropylamide (15 mL of n-butyllithium (2.5M solution in hexanes) and 5 mL of diisopropylamine mixed at-30 ℃ in 50 mL of tetrahydrofuran) was cooled to-78 ℃ under a nitrogen atmosphere and stirred for 30 minutes. By 10 minutesTo a solution of dimethyl cyclopentane-1, 3-dicarboxylate (2.67 g, 14.37 mmol) in tetrahydrofuran (12 mL) was added dropwise the above new lithium diisopropylamide solution (-75 ℃ C. to-70 ℃ C.). The cooling bath was then removed and the mixture was warmed to 0 ℃ and held at that temperature for 20 minutes and then cooled to-80 ℃. A solution of bromochloroethane (2 mL, 24 mmol) in tetrahydrofuran (25 mL) was slowly added to the reaction mixture (-75 ℃ C. to-70 ℃ C.) over 35 minutes. The reaction solution was then stirred overnight while gradually warming to room temperature. By adding saturated NH4Cl solution (20 mL) to quench the reaction. After removal of the solvent, 200 mL of ethyl acetate was added. The organic phase was washed with 2N HCl (120 mL. times.2), brine and then Na2SO4And (5) drying. After filtration and concentration, the residue was purified by silica gel column chromatography (eluting with ethyl acetate/petroleum ether = 1/10) to give the title compound. 1H NMR(400 MHz, CDCl3), (ppm): 3.68(s, 6H), 2.02~2.03(m, 4H), 1.91(s, 2H), 1.68(s, 4H); LCMS(ESI+) m/z 213.1(M+H)+。
Preparation of bicyclic amine intermediate 4(BAI-4)
4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid
Bicyclo [2.2.2]A solution of dimethyl octane-1, 4-dicarboxylate (BAI-2, 22 g, 0.1 mol) in methanol (500 mL) was heated to slight reflux. To this solution was added KOH (5.6 g, 0.1 mol) in methanol (100 mL) and water (10 mL) over 30 minutes. The reaction mixture was then refluxed for 24 hours. After cooling to room temperature, the solvent was removed and diluted with water. The aqueous solution was extracted with ethyl acetate (100 mL. times.2), the starting material BAI-2 was removed, and then the aqueous layer was acidified to pH-3 by the addition of concentrated HCl. A precipitate formed and was extracted with ethyl acetate (250 mL. times.3). The combined extracts were washed with brine, Na2SO4Drying and evaporation gave the title compound.1H NMR(400 MHz, DMSO-d 6) ppm 12.09(s 1H), 3.57(s, 3H), 1.70(s, 12H); LCMS(ESI+) m/z 213(M+H)+。
Preparation of bicyclic amine intermediate 5(BAI-5)
4- (methoxycarbonyl) bicyclo [2.2.1] heptane-1-carboxylic acid
Bicyclo [2.2.1] by the method described in the preparation of BAI-4]Heptane-dimethyl 1, 4-dicarboxylate (BAI-3) the title compound was prepared.1H NMR(400 MHz, DMSO-d 6), ppm 11.99(br, 1H), 3.60(s, 3H), 1.90~1.92(m, 4H), 1.76(s 2H), 1.57~1.60(m, 4H); LCMS(ESI+) m/z 199.1(M+H)+。
Preparation of bicyclic amine intermediate 6(BAI-6)
4- { [ (benzyloxy) carbonyl ] amino } bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To a solution of 4- (methoxycarbonyl) bicyclo [2.2.2] in toluene (200 mL)]To a mixture of octane-1-carboxylic acid (BAI-4, 11.0 g, 0.05 mol) and triethylamine (7.5 g, 0.075 mol) was added diphenylphosphoryl azide (16.5 g, 0.06 mol). After stirring at reflux for 2 hours, benzyl alcohol (8.1 g, 0.075 mol) was added and the mixture was refluxed overnight. After removal of the solvent, the residue was dissolved in ethyl acetate and taken up with saturated NaHCO 3And (4) washing with an aqueous solution. After concentration, the residue was purified by reverse phase flash chromatography (30-60% methanol in water) to give the title compound.1H NMR(400 MHz, CDCl3), ppm 7.27~7.37(m, 5H), 5.02(s, 2H), 4.68(s, 1H), 3.63(s, 3H), 1.87(s, 12H); LCMS(ESI+) m/z 318(M+H)+。
Preparation of bicyclic amine intermediate 7(BAI-7)
4- { [ (benzyloxy) carbonyl ] amino } bicyclo [2.2.1] heptane-1-carboxylic acid methyl ester
Using the procedure used for the preparation of BAI-6, starting from 4- (methoxycarbonyl) bicyclo [2.2.1]Heptane-1-carboxylic acid (BAI-5) the title compound was prepared. LCMS (ESI +) m-z 304.1(M+H)+。
Preparation of bicyclic amine intermediate 8(BAI-8)
4- { [ (benzyloxy) carbonyl ] amino } bicyclo [2.2.2] octane-1-carboxylic acid
To 4- { [ (benzyloxy) carbonyl]Amino } bicyclo [2.2.2]To a solution of octane-1-carboxylic acid methyl ester (BAI-6, 10.3 g, 32.5 mmol) in methanol (200 mL) was added aqueous NaOH (50 mL, 0.1 mol). The reaction mixture was refluxed for 2 hours. After removal of the solvent, the residue was extracted with ethyl acetate (50 mL. times.2). The aqueous layer was adjusted to pH =2 with concentrated HCl and extracted with ethyl acetate (200 mL × 4). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated to give the title compound.1H NMR(400 MHz, CDCl3), ppm 7.33~7.36(m, 5H), 5.03(s, 2H), 4.61(s, 1H), 1.89(s, 12H); LCMS(ESI+) m/z 304(M+H)+。
Preparation of bicyclic amine intermediate 9(BAI-9)
4- { [ (benzyloxy) carbonyl ] amino } bicyclo [2.2.1] heptane-1-carboxylic acid
Using the procedure used for the preparation of BAI-8, starting from 4- { [ (benzyloxy) carbonyl ]Amino } bicyclo [2.2.1]Heptane-1-carboxylic acid methyl ester (BAI-7) the title compound was prepared.1H NMR(400 MHz, DMSO-d 6), ppm 12.14(br, 1H), 7.57(br, 1H), 7.31~7.37(m, 5H), 4.99(s, 2H), 1.83~1.93(m, 4H), 1.79(s, 2H), 1.55~1.64(m, 4H); LCMS(ESI+) m/z 290.1(M+H)+。
Preparation of bicyclic amine intermediate 10(BAI-10)
Benzyl (4-carbamoylbicyclo [2.2.2] oct-1-yl) carbamate
To 4- { [ (benzyloxy) carbonyl cooled in an ice water bath under nitrogen atmosphere]Amino } bicyclo [2.2.2]Anhydrous CH for octane-1-carboxylic acid (BAI-8, 3.03 g, 0.01mol)2Cl2To the solution (80 mL) was added oxalyl chloride (1.9 g, 0.015 mol). The mixture was stirred at room temperature for 1 hour. The solvent and excess oxalyl chloride were removed under reduced pressure. The obtained residue was dissolved in anhydrous CH2Cl2(50 mL), and adding NH3Gas was bubbled through this solution cooled with an ice bath. The resulting mixture was stirred at room temperature for 5 minutes and CH was used2Cl2And (6) diluting.The solution was washed with water, brine and dried over sodium sulfate. Concentration gave the title compound.1H NMR(400 MHz, CDCl3) ppm 7.31~7.36(m, 5H), 5.51(br, 2H), 5.03(s, 2H), 4.63(s, 1H), 1.89(s, 12H); LCMS(ESI+) m/z 303(M+H)+。
Preparation of bicyclic amine intermediate 11(BAI-11)
Benzyl (4-carbamoylbicyclo [2.2.1] hept-1-yl) carbamate
Using the method used in the preparation of BAI-10, starting from 4- { [ (benzyloxy) carbonyl]Amino } bicyclo [2.2.1]Heptane-1-carboxylic acid (BAI-9) the title compound was prepared.1H NMR(400 MHz, CDCl3), ppm 7.30~7.36(m, 5H), 5.74(br, 1H), 5.59(br, 1H), 5.07(s, 2H), 1.99~2.02(m, 6H), 1.75~1.77(m, 4H); LCMS(ESI+) m/z 289.1(M+H)+。
Preparation of bicyclic amine intermediate 12(BAI-12)
Benzyl (4-cyanobicyclo [2.2.2] oct-1-yl) carbamate
At 0 deg.C to (4-carbamoylbicyclo [ 2.2.2)]Oct-1-yl) carbamic acid benzyl ester (BAI-10, 3.0g, 0.01mol) in anhydrous CH2Cl2To a solution (50 mL) and triethylamine (3.03g, 0.03mol) was added trifluoroacetic anhydride (3.15 g, 0.015 mol). After the addition was complete, the solution was allowed to warm to room temperature and stirring was continued overnight. By CH2Cl2After dilution (100 mL), with saturated NaHCO3The solution was washed with aqueous solution (50 mL. times.3), water, brine, and dried over sodium sulfate. Evaporation gave the title compound.1H NMR(400 MHz, CDCl3) ppm 7.33~7.36(m, 5H), 5.02(s, 2H), 4.60(s, 1H), 2.01~2.05(m, 6H), 1.88~1.92(m, 6H); LCMS(ESI+) m/z 285(M+H)+。
Preparation of Bicycloamine 1(BA-1)
4-Aminobicyclo [2.2.2] octane-1-carbonitrile
To (4-cyanobicyclo [2.2.2]]Oct-1-yl) aminoBenzyl chloroformate (BAI-12, 2.1 g, 7.4 mmol) in methanol (100 mL) was added Pd (OH)2C (100 mg). To the stirred reaction mixture was bubbled hydrogen gas for 1 hour at room temperature. After filtration, the filtrate was concentrated to give the title compound.1H NMR(400 MHz, DMSO-d 6) ppm 8.08(s, 2H), 1.98~2.02(m, 6H), 1.70~1.74(m, 6H); LCMS(ESI+) m/z 151(M+H)+。
Preparation of bicyclic amine 2(BA-2)
4-Aminobicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To 4- { [ (benzyloxy) carbonyl]Amino } bicyclo [2.2.2]To a solution of methyl octane-1-carboxylate (BAI-6, 951 mg, 3 mmol) in methanol (50 mL) was added Pd (OH)2/C (100 mg). To the stirred reaction mixture was bubbled hydrogen gas for 1 hour at room temperature. After filtration, the filtrate was concentrated to give the title compound. 1H NMR(400 MHz, CDCl3) ppm 3.64(s, 3H), 1.84~1.88(m, 6H), 1.73(s, 2H), 1.53~1.57(m, 6H); LCMS(ESI+) m/z 184(M+H)+。
Preparation of bicyclic amine 3(BA-3)
4-Aminobicyclo [2.2.1] heptane-1-carboxylic acid methyl ester
Using the procedure described for the preparation of BA-2, starting from 4- { [ (benzyloxy) carbonyl]Amino } bicyclo [2.2.1]Heptane-1-carboxylic acid methyl ester (BAI-7) the title compound was prepared. LCMS (ESI +) m-z 170.1(M+H)+。
Preparation of bicyclic amine intermediate 13(BAI-13)
Benzyl [4- (hydroxymethyl) bicyclo [2.2.2] oct-1-yl ] carbamate
To the ice-cooled 4- { [ (benzyloxy) carbonyl]Amino } bicyclo [2.2.2]To a solution of octane-1-carboxylic acid (BAI-8, 1.0 g, 3.3mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise a borane/tetrahydrofuran solution (1M, 1 mL). Hydrogen was evolved and the resulting clear solution was stirred at room temperature for 1 hour. Quench the reaction with water and use K2CO3Aqueous solution treatmentThe aqueous phase was extracted with ethyl acetate (50 mL. times.3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give the title compound. LCMS (ESI +) m-z 290(M+H)+。
Preparation of bicyclic amine intermediate 14(BAI-14)
Benzyl [4- (hydroxymethyl) bicyclo [2.2.1] hept-1-yl ] carbamate
Using the procedure described in the preparation of BAI-13, starting from 4- { [ (benzyloxy) carbonyl]Amino } bicyclo [2.2.1]Heptane-1-carboxylic acid methyl ester (BAI-7) the title compound was prepared.1H NMR(400 MHz, CDCl3) ppm 7.31~7.36(m, 5H), 5.06(s, 2H), 3.64(s, 2H), 1.92~1.93(m, 2H), 1.67~1.78(m, 4H), 1.43(s, 2H), 1.38~1.41(m, 2H); LCMS(ESI+) m/z 275.1(M+H)+。
Preparation of bicyclic amine intermediate 15(BAI-15)
Benzyl (4-formylbicyclo [2.2.2] oct-1-yl) carbamate
To [4- (hydroxymethyl) bicyclo [2.2.2]]Oct-1-yl]Benzyl carbamate (BAI-13, 1.00 g, 3.5 mmol) in anhydrous CH2Cl2(25 mL) to the solution was added Dess-Martin periodinane (1.7 g, 4.0 mmol) in portions. The clear solution became cloudy and stirred for 2 hours. By CH2Cl2The reaction mixture was diluted (100 mL) and aqueous NaOH (1N, 10 equiv.) was added. The resulting suspension was stirred for 30 minutes. By CH2Cl2The aqueous layer was extracted and the combined organic phases were washed with 1N aqueous NaOH, water, brine and dried over sodium sulfate. Concentration gave the title compound.1H NMR(400 MHz, CDCl3) ppm 9.44(s, 1H)7.31~7.37(m, 5H), 5.03(s, 2H), 4.66(s, 1H), 1.88~1.92(m, 6H), 1.71~1.75(m, 6H); LCMS(ESI+) m/z 288(M+H)+。
Preparation of bicyclic amine intermediate 16(BAI-16)
Benzyl (4-formylbicyclo [2.2.1] hept-1-yl) carbamate
Using the method used for the preparation of BAI-15, starting from [4- (hydroxymethyl) bicyclo [2.2.1]Hept-1-yl]Benzyl carbamate (BAI-14) the title compound was prepared. LCMS (ESI +) m-z 274.1(M+H)+。
Preparation of bicyclic amine intermediate 17(BAI-17)
Benzyl [4- (difluoromethyl) bicyclo [2.2.2] oct-1-yl ] carbamate
To (4-formylbicyclo [2.2.2]]Octyl-1-yl) carbamic acid benzyl ester (BAI-15, 920 mg, 3.2 mmol) in anhydrous CH2Cl2(diethylamino) sulfur trifluoride (516 mg, 3.2 mmol) was added to the solution (10 mL). The reaction mixture was stirred at room temperature for 2 hours and poured into water (10 mL). The resulting mixture was stirred for 30 minutes. The organic layer was separated and saturated NaHCO was used 3The aqueous solution, water and brine were washed and dried over sodium sulfate. Concentration gave the title compound.1H NMR(400 MHz, CDCl3) ppm 7.32~7.35(m, 5H), 5.36(t, J=56.8Hz, 1H)5.03(s, 2H), 4.60(s, 1H), 1.85~1.89(m, 6H), 1.62~1.66(m, 6H); LCMS(ESI+) m/z 310(M+H)+。
Preparation of bicyclic amine intermediate 18(BAI-18)
Benzyl [4- (difluoromethyl) bicyclo [2.2.1] hept-1-yl ] carbamate
Using the method described in the preparation of BAI-17, starting from (4-formylbicyclo [ 2.2.1)]Hept-1-yl) carbamic acid benzyl ester (BAI-16) the title compound is prepared.1H NMR(400 MHz, CDCl3) ppm 7.33~7.36(m, 5H), 5.78(t, J=56.7Hz, 1H), 5.07(s, 2H), 1.83~1.96(m, 5H), 1.73~1.77(m, 5H); LCMS(ESI+) m/z 296.1(M+H)+。
Preparation of bicyclic amine 4(BA-4)
4- (difluoromethyl) bicyclo [2.2.2] octan-1-amine
To [4- (difluoromethyl) bicyclo [2.2.2]]Oct-1-yl]Benzyl carbamate (BAI-17, 600 mg, 2 mmol) in methanol (100 mL)Adding Pd (OH)2C (100 mg). To the stirred reaction mixture was bubbled hydrogen gas at room temperature for 0.5 hour. After filtration, the filtrate was concentrated to give the title compound.1H NMR(400 MHz, CDCl3) ppm 5.37(t, J=56.8Hz, 1H), 1.60~1.64(m, 6H), 1.52-1.56(m, 6H), 1.45(s, 2H)。
Preparation of bicyclic amine 5(BA-5)
4- (difluoromethyl) bicyclo [2.2.1] hept-1-amine
Using the procedure described for the preparation of BA-4, starting from [4- (difluoromethyl) bicyclo [2.2.1]Hept-1-yl]Benzyl carbamate (BAI-18) the title compound was prepared.1H NMR(400 MHz, CDCl3) ppm 5.76(t, J=56.7Hz, 1H), 2.01(s, 2H, 1.81~1.88(m, 2H), 1.61~1.65(m, 4H), 1.48~1.55(m, 2H), 1.44(s, 2H); LCMS(ESI+) m/z 162.1(M+H)+。
Preparation of bicyclic amine 6(BA-6)
4-Aminobicyclo [2.2.2] octane-1-carboxamides
To (4-carbamoylbicyclo [ 2.2.2)]Octyl-1-yl) carbamic acid benzyl ester (BAI-10, 780 mg, 2.58 mmol) in methanol (100 mL) Pd (OH) 2C (100 mg). To the stirred reaction mixture was bubbled hydrogen gas for 2 hours at room temperature. After filtration, the filtrate was concentrated to give the title compound.1H NMR(400 MHz, CDCl3) ppm 5.57(br, 2H), 1.84~1.88(m, 6H), 1.53~1.59(m, 6H)。
Preparation of bicyclic amine 7(BA-7)
4-aminobicyclo [2.2.1] heptane-1-carboxamide
Using the procedure described for the preparation of BA-6, starting from (4-carbamoylbicyclo [ 2.2.1)]Hept-1-yl) carbamic acid benzyl ester (BAI-11) the title compound is prepared.1H NMR(400 MHz, DMSO-d 6) ppm 6.96(s, 1H), 6.74(s, 1H), 1.76~1.83(m, 2H), 1.50~1.55(m, 4H), 1.44(s, 2H), 1.40~1.42(m, 2H); LCMS(ESI+) m/z 155.1(M+H)+。
Preparation of bicyclic amine intermediate 19(BAI-19)
4-Bromobicyclo [2.2.2] octane-1-carboxylic acid methyl ester
To 4- (methoxycarbonyl) bicyclo [2.2.2]To a suspension of octane-1-carboxylic acid (BAI-4, 0.424 mg, 2 mmol) in acetone (3 mL) was added phenolphthalein. To this mixture was added 1M aqueous NaOH (approximately 2 mL, 1 eq) until the color of the solution turned red. Then, AgNO was added3(340 mg, 2 mmol) of an aqueous solution (0.5 mL). The precipitate formed was collected by filtration, washed with water, acetone and diethyl ether and dried under vacuum at 100 ℃ for 6 hours. The obtained solid was suspended in hexane (5 mL), and then bromine (260 mg, 1.62 mmol) was added dropwise to the reaction mixture at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered to remove solids, and the filter cake was washed with hexane (100 mL). With saturated NaHCO 3The combined organic filtrates were washed with MgSO4Drying, filtering and concentrating to obtain the title compound.1H NMR(400 MHz, CDCl3) ppm 3.64(s, 3H), 2.18~2.27(m, 6H), 1.94~1.98(m, 6H); GCMS m/z 248(M+H)+。
Preparation of bicyclic amine intermediate 20(BAI-20)
4-Hydroxybicyclo [2.2.2] octane-1-carboxylic acid
Reacting 4-bromobicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (BAI-19, 0.246 g, 0.001 mol) was refluxed in 25 mL of 1% sodium hydroxide solution for 24 hours. After cooling, the reaction solution was acidified with 6N hydrochloric acid and extracted with ether (50 mL. times.6). The combined ether layers were dried over magnesium sulfate and concentrated to at least volume. Recrystallization from n-hexane and diethyl ether (40:10 mL) gave the title compound.1H NMR(400 MHz, DMSO-d 6) ppm 1.1.68-1.78(m, 6H), 1.48-1.52(m, 6H), 4.00(s, 1H), 12.00(s, 1H)。
Preparation of bicyclic amine intermediate 21(BAI-21)
(4-Hydroxybicyclo [2.2.2] oct-1-yl) carbamic acid tert-butyl ester
To 4-hydroxybicyclo [2.2.2]Di (2 mol) of octane-1-carboxylic acid (BAI-20, 340 mg)To a solution of triethylamine (202 mg, 2 mmol), diphenylphosphorylazide (550 mg, 2 mmol) and tert-butanol (3 g, 40 mmol) were added a solution of 5 mL. The reaction mixture was stirred for 45 minutes and at 80 ℃ overnight. The mixture was then concentrated under reduced pressure. The residue was dissolved in 30 mL ethyl acetate and then saturated NaHCO3And a brine wash. With anhydrous Na2SO4The organic layer was dried and concentrated to give the crude title compound, which was used in the next step without further purification.
Preparation of bicyclic amine 8(BA-8)
4-Aminobicyclo [2.2.2] octan-1-ol
To (4-hydroxybicyclo [2.2.2]]Oct-1-yl) carbamic acid tert-butyl ester (BAI-21, 241 mg, 1 mmol) in CH2Cl2To the solution (5 mL) was added 1.14 g of trifluoroacetic acid (10 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give the trifluoroacetate salt of the title compound. LCMS (ESI +) m-z 142(M+H)+。
Preparation of N-cyano-2-methyl-2-phenoxyalanine ethyl ester (CI-1)
Step A
2-methyl-2-phenoxypropionic acid ethyl ester
To a mixture of phenol (0.01 mol) and ethyl 2-bromo-2-methylpropionate (0.01 mol) in acetonitrile was added Cs2CO3(0.015mol) and the reaction mixture is refluxed overnight. After removal of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 1N aqueous NaOH, water and brine, and then dried over sodium sulfate. Concentration gave the title compound.1H NMR(400 MHz, CDCl3) ppm 7.21~7.25(m, 2H), 6.98(t, J=7.2Hz 1H), 6.83~6.86(m, 2H), 4.23(q, J=7.2Hz 4H), 1.60(s, 6H), 1.24(t, J=7.2Hz 3H); LCMS(ESI+) m/z 209(M+H)+。
Step B
2-methyl-2-phenoxypropionic acid
To a solution of 2-methyl-2-phenoxypropionic acid (0.05 mmol) in methanol (200 mL) from step A was added an aqueous solution of LiOH (150 mL, 1 mol). The reaction mixture was refluxed for 3 hours. After removal of the solvent, the residue was extracted with ethyl acetate (50 mL. times.2). The aqueous layer was adjusted to pH =2 with concentrated HCl and extracted with ethyl acetate (200 mL × 4). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated to give the title compound. 1H NMR(400 MHz, CDCl3) ppm 7.26~7.30(m, 2H), 7.06(t, J=7.2Hz 1H), 6.93~6.95(m, 2H), 1.61(s, 6H); LCMS(ESI+) m/z 181(M+H)+。
Step C
2-methyl-2-phenoxypropionamide
To the anhydrous CH of 2-methyl-2-phenoxypropionic acid (0.01 mol) of step B cooled with an ice-water bath under nitrogen atmosphere2Cl2To the solution (150 mL) was added oxalyl chloride (1.9 g, 0.015 mol). The mixture was stirred at room temperature for 1 hour. The solvent and excess oxalyl chloride were removed under reduced pressure. The obtained residue was dissolved in anhydrous CH2Cl2(50 mL), and adding NH3Gas was bubbled through this solution cooled with an ice bath. The resulting mixture was stirred at room temperature for 5 minutes and CH was used2Cl2And (6) diluting. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated to give the title compound.1H NMR(400 MHz, CDCl3) ppm 7.27~7.31(m, 2H), 7.08(t, J=7.6Hz 1H), 6.95~6.97(m, 2H), 5.98(s, 1H), 1.61(s, 6H); LCMS(ESI+) m/z 180(M+H)+。
Step D
2-methyl-2-phenoxypropionitrile
To the anhydrous CH of 2-methyl-2-phenoxypropionamide (0.01 mol) of step C at 0 deg.C2Cl2Trifluoroacetic anhydride (3.15 g, 0.015 mol) was added to a solution of (50 mL) and triethylamine (3.03 g, 0.03 mol). After the addition was complete, the solution was allowed to warm to room temperature and stirring was continued overnight at ambient temperature. The reaction mixture was then refluxed for 3 hours. After cooling to room temperature, use CH2Cl2(100 mL) diluted and the solution was saturated NaHCO3Aqueous solution (50 ml. times.3), water and brine, and dried over sodium sulfate. Evaporation gave the title compound. 1H NMR(400 MHz, CDCl3) ppm 7.32~7.36(m, 2H), 7.14~7.20(m, 3H), 1.71(s, 6H)。
Step E
N-cyano-2-methyl-2-phenoxyalanine ethyl ester
To a freshly prepared ethanolic solution of sodium ethoxide with sodium (0.02 mol) and ethanol (50 mL) was added 2-methyl-2-phenoxypropionitrile (0.05 mol) from step D. The mixture was stirred at room temperature overnight, then acetic acid (0.07 mol) was added followed by NH2CN (0.05 mol). The mixture was stirred for 3 hours and the solvent was removed. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate =4:1 to 1:1) to give the title compound.1H NMR(400 MHz, CDCl3) ppm 7.27(t, J=8.0Hz 2H), 7.05(t, J=7.2Hz 1H), 6.88~6.90(m, 2H), 4.38(q, J=7.2Hz, 2H), 1.61(s, 6H), 1.39(t, J=7.2Hz, 3H); LCMS(ESI+) m/z 233(M+H)+。
Example 1
(1E) -2- (2-chloro-4-fluorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylpropionamidine
A-958549 example 1A
(1E) -2- (2-chloro-4-fluorophenoxy) -N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylpropanamide
According to Sorensen et al (Bioorg. Med. Chem. Lett.2007, 17, 527-532), the title compound was synthesized.
Example 1B
(1E) -2- (2-chloro-4-fluorophenoxy) -N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylthiopropanamide
To a solution of example 1A (0.76 g, 2 mmol) in toluene (25 mL) was added Lawesson's reagent (0.81 g, 2 mmol), and the reaction mixture was heated at 80 ℃ for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was taken up in saturated NaHCO 3Partitioned between aqueous and ethyl acetate. The organic layers were combined and dried (MgSO)4) Filtering, and concentrating. Purify the residue by flash chromatography (SiO)20-40% ethyl acetate/hexanes) to provide the title compound. MS (DCI)+) m/z 398(M+H)+。
Example 1C
(1E) -2- (2-chloro-4-fluorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylpropionamidine
A solution of example 1B (0.46 g, 2.0 mmol) in acetonitrile (20 mL) was treated with cyanamide (0.12 g, 2.9 mmol), mercury (II) acetate (0.56 g, 1.7 mmol) and triethylamine (0.33 mL, 2.3 mmol) and the reaction mixture was heated at 80 ℃ for 18 h. The mixture was then concentrated under reduced pressure and the residue was taken up in saturated NaHCO3And ethyl acetate. The combined organic layers were dried (MgSO)4) Filtered, concentrated, and the residue purified by flash chromatography (hexane-ethyl acetate, 1:2) to give the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.36-1.81(m, 16 H), 1.97-2.09(m, 1 H), 2.15-2.28(m, 2 H), 4.01(s, 1 H), 4.51(s, 1 H), 7.16-7.35(m, 2 H), 7.57(dd, J=8.5, 3.1 Hz, 1 H), 7.88(d, J=7.1 Hz, 1 H); MS(DCI+) m/z 406(M+H)+。
Example 2
(1E) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2- (2-methylphenyl) acetamidine
A mixture of E-2-amino-5-hydroxyadamantane (Jaroskova et al, Tetrahedron Letters 2006, 47(46), 8063-8067) (0.35 g, 2.0 mmol) and ethyl (E) -N-cyano-2-o-tolylimidodiacetate (acetimidate, U.S. patent application publication US2006/0025614) (0.42 g, 2.0 mmol) was stirred in ethanol (1 mL) at 80 ℃ for 16 hours. The reaction mixture was concentrated on a rotary evaporator and purified by flash chromatography using 0-100% ethyl acetate/hexane as eluent to provide the title compound. 1H NMR(300 MHz, DMSO-d 6) ppm 1.38(d, J=12.9 Hz, 2 H), 1.55-1.90(m, 7 H), 1.93-2.20(m, 4 H), 2.30(s, 3 H), 3.89(s, 2 H), 3.95(dd, J=6.3, 3.2 Hz, 1 H), 4.43-4.52(m, 1 H), 7.00(dd, J=5.1, 3.7 Hz, 1 H), 7.12-7.32(m, 3 H), 8.57(d, J=6.8 Hz, 1 H); MS(DCI+) m/z 324(M+H)+. C21H27ClN2O3S2 •0.5H2The analytically calculated values of O are C, 72.26, H, 7.88, N, 12.64, the actually measured values are C, 72.82, H, 7.65 and N, 13.08.
Example 3
1- (4-chlorophenyl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] cyclobutanecarboxamidine
Example 3A
1- (4-chlorophenyl) cyclobutanemethanimidate (carbemidate) ethyl ester hydrochloride
Cooled 1- (4-chlorophenyl) cyclobutyronitrile (5.0 g, 26.1 mmol, Aldrich) and ethanol (2.3 mL, 39.1 mmol) were dissolved at 0 deg.CHCl gas was bubbled through the solution for 30 minutes. After standing at 4 ℃ for 24 hours, the reaction mixture was concentrated and triturated with diethyl ether. The precipitate was collected and dried to obtain the title compound. MS (ESI)+) m/z 238(M+H)+。
Example 3B
1- (4-chlorophenyl) -N-cyanocyclobutanemethyleneimidate ethyl ester
To a solution of example 3A (2.5 g, 9.1 mmol) in acetonitrile (7 mL) was added an aqueous solution (70.0 mL) of monosodium phosphate monohydrate (5.0 g, 36.5 mmol), disodium phosphate heptahydrate (4.9 g, 18.2 mmol) and cyanamide (0.8 g, 18.2 mmol). The reaction mixture was stirred at room temperature for 72 hours, after which the mixture was extracted with dichloromethane (3X 30 mL). With anhydrous Na2SO4The combined organic extracts were dried, filtered, and concentrated under reduced pressure to give the title compound. MS (ESI)+) m/z 263(M+H)+。
Example 3C
1- (4-chlorophenyl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] cyclobutanecarboxamidine
A mixture of E-2-amino-5-hydroxyadamantane (Jaroskova et al, Tetrahedron Letters 2006, 47(46), 8063-8067) (0.2 g, 1.2 mmol) and example 3B (0.3 g, 1.2 mmol) was stirred at 80 ℃ for 16 h. The reaction mixture was then cooled, dissolved in dichloromethane (2 mL), purified by column chromatography using Analogix Intelliwash 280TM(SiO20-100% ethyl acetate/dichloromethane) to yield the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.29-1.46(m, 2 H), 1.52-1.69(m, 6 H), 1.71-1.82(m, 2 H), 1.82-1.95(m, 2 H), 1.99-2.08(m, 1 H), 2.11-2.24(m, 2 H), 2.60-2.73(m, 2 H), 2.72-2.87(m, 2 H), 3.62-3.89(m, 1 H), 4.44(s, 1 H), 7.48(d, J=8.3 Hz, 2 H), 7.66(d, J=5.6 Hz, 1 H), 7.70(d, J=8.7 Hz, 2 H)); MS(ESI+) m/z 384(M+H)+. C22H26ClN3The analytically calculated values of O are C, 68.83, H, 6.83, N, 10.95, the measured values are C, 69.05, H, 7.28 and N, 10.46.
Example 4
(1E) -N' -cyano-2- (2, 4-difluorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine
Example 4A
2- (2, 4-difluorophenyl) imido ethyl acetoacetate hydrochloride
The title compound was obtained by treating commercially available 2- (2, 4-difluorophenyl) acetonitrile (Aldrich), HCl gas and ethanol using the method described in example 3A, except that the reaction time was 72 hours. MS (ESI)+) m/z 200(M+H)+。
Example 4B
N-cyano-2- (2, 4-difluorophenyl) imidoacetic acid ethyl ester
To a solution of example 4A (7.0 g, 29.7 mmol) in ethanol (100 mL) was added a solution of cyanamide (1.25 g, 29.7 mmol) in diethyl ether (25 mL). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then filtered and the filtrate was concentrated to obtain the title compound. MS (ESI) +) m/z 225(M+H)+。
Example 4C
(1E) -N' -cyano-2- (2, 4-difluorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 4B for example 3B.1H NMR(300 MHz, DMSO-d 6) ppm 1.30-1.45(m, 2 H), 1.55-1.73(m, 6 H), 1.74-1.94(m, 2 H), 1.96-2.19(m, 3 H), 3.83-3.91(m, 1 H), 3.94(s, 2 H), 4.47(s, 1 H), 7.10(td, J=8.5, 3.4 Hz, 1 H), 7.19-7.44(m, 2 H), 8.69(d, J=6.8 Hz, 1 H); MS(ESI+) m/z 346(M+H)+。
Example 5
(1E) -N' -cyano-2- (2-fluorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine
The title compound was synthesized according to the procedure described for example 3C substituting ethyl N-cyano-2- (2-fluorophenyl) imidoacetate (U.S. patent application publication No. US2006/0025614) for example 3B.1H NMR(300 MHz, DMSO-d 6) ppm 1.29-1.45(m, 2 H), 1.56-1.76(m, 6 H), 1.76-1.93(m, 2 H), 1.95-2.19(m, 3 H), 3.85-3.92(m, 1 H), 3.97(s, 2 H), 4.47(s, 1 H), 7.19(d, 3 H), 7.37(d, 1 H), 8.69(d, J=6.8 Hz, 1 H); MS(ESI+) m/z 328(M+H)+. C19H22FN3The analytically calculated values of O are C, 69.70, H, 6.77, the measured values of N, 12.83, C, 69.31, H, 6.87 and N, 12.54.
Example 6
(1E) -2- (2-chloropyridin-3-yl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine
Example 6A
2- (2-Chloropyridin-3-yl) imidoacetic acid ethyl ester
To a cooled solution of 2- (2-chloropyridin-3-yl) acetonitrile (Synthesis (6), 528-30, 1992) (1.7 g, 11.1 mmol), ethanol (1.0 mL, 16.7 mmol) and dichloromethane (25 mL) was bubbled with HCl gas for 30 min at 0 deg.C. After standing at 4 ℃ for 24 hours, the reaction mixture was concentrated,and the residue was triturated with diethyl ether. The precipitate was collected and dried to obtain the title compound. MS (ESI) +) m/z 199(M+H)+。
Example 6B
2- (2-Chloropyridin-3-yl) -N-cyanoiminoacetic acid ethyl ester
Example 6A and cyanamide (Aldrich) were processed using the method described for example 4B to obtain the title compound. MS (ESI)+) m/z 224(M+H)+。
Example 6C
(1E) -2- (2-chloropyridin-3-yl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 6B for example 3B.1H NMR(300 MHz, DMSO-d 6) ppm 1.30-1.47(m, 2 H), 1.56-1.73(m, 6 H), 1.76-1.92(m, 2 H), 1.97-2.19(m, 3 H), 3.90-3.98(m, 1 H), 4.05(s, 2 H), 4.48(s, 1 H), 7.46(dd, J=7.5, 4.7 Hz, 1 H), 7.62(dd, J=7.6, 1.9 Hz, 1 H), 8.36(dd, J=4.6, 1.9 Hz, 1 H), 8.74(d, J=6.4 Hz, 1 H); MS(ESI+) m/z 345(M+H)+. C18H21ClN4O∙0.05H2The analytically calculated values of O are C, 62.53, H, 6.15, N, 16.20, C, 62.13, H, 6.02 and N, 16.58.
Example 7
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine
Example 7A
2- (4-chlorophenoxy) iminoethanoic acid ethyl ester hydrochloride
The title compound was obtained by treating commercially available 2- (4-chlorophenoxy) acetonitrile (Aldrich), HCl gas and ethanol using the procedure described in example 4A. MS (ESI)+) m/z 214(M+H)+。
Example 7B
2- (4-chlorophenoxy) -N-cyanoiminoacetic acid ethyl ester
Example 7A and cyanamide (Aldrich) were processed using the method described for example 4B to obtain the title compound. MS (ESI)+) m/z 239(M+H)+。
Example 7C
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 7B for example 3B. 1H NMR(300 MHz, DMSO-d 6) ppm 1.30-1.42(m, 2 H), 1.55-1.70(m, 6 H), 1.73-1.84(m, 2 H), 1.95-2.15(m, 3 H), 3.78-3.90(m, 1 H), 4.47(s, 1 H), 4.93(s, 2 H), 6.90-7.10(m, 2 H), 7.31-7.49(m, 2 H), 8.60(d, J=5.1 Hz, 1 H); MS(ESI+) m/z 360(M+H)+。 C19H22ClN3O2∙0.1H2The analytically calculated values of O are C, 63.10, H, 6.19 and N, 11.62. Found C, 62.82, H, 6.32, N, 11.43.
Example 8
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylpropionamidine
Example 8A
2- (4-chlorophenoxy) -2-methylalanine ethyl ester hydrochloride
The title compound was obtained by treating commercially available 2- (4-chlorophenoxy) -2-methylpropanenitrile (Maybridge), HCl gas and ethanol using the method described in example 4A. MS (ESI)+) m/z 242(M+H)+。
Example 8B
2- (4-chlorophenoxy) -N-cyano-2-methylalanineimine ethyl ester
Example 8A and cyanamide (Aldrich) were processed using the method described for example 3B to obtain the title compound. MS (ESI)+) m/z 267(M+H)+。
Another preparation method of example 8B
Example 8B was also prepared according to the procedure described for the preparation of ethyl N-cyano-2-methyl-2-phenoxyalanine (CI-1) using 4-chlorophenol instead of phenol.
Example 8C
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 8B for example 3B.1H NMR(300 MHz, DMSO-d 6) ppm 1.31-1.48(m, 2 H), 1.57-1.77(m, 8 H), 1.64(s, 6 H), 1.94-2.04(m, 1 H), 2.14-2.25(m, 2 H), 3.90-4.02(m, 1 H), 4.50(s, 1 H), 6.96-7.06(m, 2 H), 7.32-7.43(m, 2 H), 7.57(d, J=6.8 Hz, 1 H); MS(ESI+) m/z 388(M+H)+。 C21H26ClN3O2∙0.25H2The analytically calculated values of O are C, 64.28, H, 6.81 and N, 10.71. Found C, 64.53, H, 6.70, N, 10.31.
Example 9
2- (4-chlorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] thiopropionamide
Example 9A
2- (4-chlorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] propanamide
According to Sorensen et al (Bioorg. Med. Chem. Lett.2007, 17, 527-532), the title compound was synthesized.
Example 9B
2- (4-chlorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] thiopropionamide
The title compound was synthesized according to the procedure described for example 1B substituting example 9A for example 1A.1H NMR(300 MHz, DMSO-d 6) ppm 1.50-1.83(m, 10 H), 1.87-2.15(m, 7 H), 2.41(s, 2 H), 2.87(s, 3 H), 4.28-4.53(m, 1 H), 7.13-7.31(m, 2 H), 7.55(dd, J=10.0, 1.9 Hz, 1 H), 9.43(d, J=7.1 Hz, 1 H); MS(DCI+) m/z 460(M+H)+。 C21H27ClN2O3S2The analytical calculation values of (1) are C, 57.06, H, 6.38 and N, 3.17. Found C, 57.16, H, 6.50, N, 3.05.
Example 10
(1E) -N- [ (E) -5- (aminosulfonyl) -2-adamantyl ] -2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine
The samples were processed using the method described in example 2Examples 8B and (E) -4-aminoadamantane-1-sulfonamide (Sorensen et al,Bioorg. Med. Chem. Lett.,2007, 17, 527-532), the title compound was obtained.1H NMR(300 MHz, DMSO-d 6) ppm 1.42-1.54(m, 2 H), 1.65(s, 6 H), 1.70-1.82(m, 2 H), 1.84-2.08(m, 7 H), 2.22-2.33(m, 2 H), 3.90-4.08(m, 1 H), 6.63(s, 2 H), 7.01(d, J=9.1 Hz, 2 H), 7.38(d, J=9.1 Hz, 2 H), 7.67(d, J=6.3 Hz, 1 H); MS(ESI+) m/z 451(M+H)+。 C21H27ClN4O3The analytical calculation values of S are C-55.93, H-6.03 and N-12.42. Found C-56.19, H-6.05 and N-12.25.
Example 11
(E) -4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid methyl ester
Example 11A
E-2-amino-5-carboxyadamantane methyl ester
E-2-amino-5-carboxy adamantane methyl ester hydrochloride (Becker et al,Org. Process R & D2008, 12, 1114-1118) (5 g, 20.4 mmol) in saturated NaHCO3The aqueous solution (60 mL) and dichloromethane (100 mL) were partitioned. The aqueous layer was further extracted with dichloromethane (3X 50 mL). With anhydrous Na2SO4The combined organic extracts were dried, filtered, and concentrated under reduced pressure to give the title compound. MS (ESI)+) m/z 210(M+H)+。
Example 11B
(E) -4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid methyl ester
Example 8B and example 2 were processed using the method described in example 2Example 11A the title compound was obtained.1H NMR(300 MHz, DMSO-d 6) ppm 1.46-1.58(m, 2 H), 1.62-1.68(m, 6 H), 1.68-1.84(m, 4 H), 1.85-1.96(m, 5 H), 2.10-2.23(m, 2 H), 3.59(s, 3 H), 3.98-4.11(m, 1 H), 6.96-7.07(m, 2 H), 7.32-7.44(m, 2 H), 7.65(d, J=6.3 Hz, 1 H); MS(ESI+) m/z 430(M+H)+。 C23H28ClN3O3The analytical calculation values of (1) are C-64.25, H-6.56 and N-9.77. Found C-64.31, H-6.58 and N-9.79.
Example 12
2- (2-chloro-4-fluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] thiopropionamide
Example 12A
2- (2-chloro-4-fluorophenoxy) -2-methyl-N- [ (1E) -5- (methylsulfonyl) -2-adamantyl ] thiopropionamide
According to Sorensen et al (Bioorg. Med. Chem. Lett.2007, 17, 527-532), the title compound was synthesized.
Example 12B
2- (2-chloro-4-fluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] thiopropionamide
The title compound was synthesized according to the procedure described for example 1B substituting example 12A for example 1A.1H NMR(300 MHz, DMSO-d 6) ppm 1.50-1.84(m, 10 H), 1.86-2.18(m, 8 H), 2.41(s, 2 H), 2.87(s, 3 H), 4.30-4.55(m, 1 H), 7.11-7.29(m, 1 H), 7.55(dd, J=10.0, 1.9 Hz, 1 H), 9.43(d, J=7.1 Hz, 1 H); MS(DCI+) m/z 460(M+H)+。 C21H27ClNFO3S2C, 54.94, H, 5.92 and N, 3.04. Found C, 54.94, H, 6.11, N, 2.98.
Example 13
(1E) -2- (4-chlorophenoxy) -N' -methoxy-2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] propionamidine
A solution of example 9(200 mg, 0.45 mmol) in acetonitrile (20 mL) was treated with O-methylhydroxylamine hydrochloride (94 mg, 1.1 mmol), mercury (II) acetate (216 mg, 0.67 mmol) and triethylamine (0.12 mL, 0.90 mmol). The reaction mixture was heated at 80 ℃ for 18 hours. The mixture was then concentrated under reduced pressure and the residue was taken up in saturated NaHCO3Partitioned between aqueous and ethyl acetate. The combined organic layers were dried (MgSO)4) Filtering, and concentrating. The residue was purified by chromatography (hexane-ethyl acetate, 1:2) to give the title compound.1H NMR(500 MHz, DMSO-d 6) ppm 1.36-1.70(m, 10 H), 1.72-2.07(m, 9 H), 2.73-2.92(m, 3 H), 3.70(s, 3 H), 4.14(d, J=10.1 Hz, 1 H), 5.32(d, J=10.1 Hz, 1 H), 6.95-7.04(m, 2 H), 7.25-7.39(m, 2 H); MS(DCI+) m/z 455(M+H)+。
Example 14
(E) -4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide
Example 14A
(E) -4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid
To a solution of example 11(0.48 g, 1.1 mmol) in tetrahydrofuran (2 mL), methanol (4 mL) and water (4 mL) was added aqueous 5N NaOH (1.1 mL, 5.6 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated to half volume, the pH was adjusted to-5, And the mixture was extracted with ethyl acetate (3 × 15 mL). With anhydrous Na2SO4The combined organic extracts were dried, filtered and concentrated under reduced pressure to give the title compound in crude form, which was used without additional purification. MS (ESI)+) m/z 416(M+H)+。
Example 14B
(E) -4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide
To a solution of example 14A (0.37 g, 0.9 mmol) in dichloromethane (10mL) was added 1-hydroxy-benzotriazole hydrate (0.16 g, 1.1 mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.25 g, 1.3 mmol) and 30% aqueous ammonium hydroxide (1.0 mg, 8.9 mmol). The reaction mixture was stirred at room temperature for 16 hours and then quenched with water (10 mL). The aqueous layer was extracted with dichloromethane (3X 20 mL). Mixing the organic extracts with anhydrous Na2SO4Dried, filtered, and concentrated. The residue was purified by column chromatography using Analogix Intelliflash 280 @TM(SiO20-50% methanol/ethyl acetate (1/10) in hexanes) to give the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.45-1.55(m, 2 H), 1.62-1.68(m, 6 H), 1.67-1.78(m, 4 H), 1.82-1.94(m, 5 H), 2.08-2.20(m, 2 H), 3.98-4.06(m, 1 H), 6.74(s, 1 H), 6.96-7.06(m, 3 H), 7.33-7.45(m, 2 H), 7.62(d, J=6.7 Hz, 1 H); MS(ESI+) m/z 415(M+H)+。 C27H27ClN4O2The analysis calculated value of (1) is C-63.68, H-6.56 and N-13.50. Found values are C-63.35, H-6.53 and N-13.06.
Example 15
1- (3-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] cyclobutanecarboxamidine
Example 15A
1- (3-chlorophenoxy) cyclobutanecarboxylic acid ethyl ester
To a solution of 3-chlorophenol (7.5 g, 58.0 mmol) in N, N-dimethylformamide (125 mL) was added cesium carbonate (28.3 g, 87 mmol) followed by ethyl 1-bromocyclobutanecarboxylate (9.8 mL, 58.0 mmol). The reaction mixture was stirred at 55 ℃ overnight. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. Purification by column chromatography (silica, heptane/ethyl acetate, 7:1) gave ethyl 1- (3-chlorophenoxy) cyclobutanecarboxylate. MS (ESI)+) m/z 255(M+H)+。
Example 15B
1- (3-chlorophenoxy) cyclobutanecarboxylic acid
Lithium hydroxide monohydrate (1.7 g, 40.3 mmol) was added to a suspension of example 15A (4.7 g, 13.4 mmol) in tetrahydrofuran (320 mL) and water (160 mL) at room temperature. The reaction mixture was stirred at 55 ℃ overnight. The reaction was concentrated under reduced pressure to remove tetrahydrofuran and acidified to pH-3 by addition of 1M aqueous HCl while cooling. The precipitate was collected by filtration and dried overnight in a desiccator comprising KOH. Recrystallization from heptane yielded the title compound. MS (ESI)+) m/z 227(M+H)+。
Example 15C
(1E) -2- (3-chlorophenoxy) -N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylpropanamide
To E-2-amino-5-hydroxyadamantane (Jaroskova et al, Tetrahedron Letters2006, 47(46), 8063-8067) (0.25 g, 1.5 mmol) in N, N-dimethylformamide (10 mL) was added example 15B (0.34 g, 1.5 mmol), 2- (1H-benzo [ d ] B][1,2,3]Triazol-1-yl) -1,1,3, 3-Tetramethylisourea tetrafluoroborate (0.72 g, 2.2 mmol) and diisopropylEthylamine (0.78 mL, 4.5 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then quenched with water (10 mL). The resulting layers were separated and the aqueous layer was extracted with ethyl acetate (3X 20 mL). Mixing the organic extracts with anhydrous Na2SO4Dried, filtered, and concentrated. The residue was purified by column chromatography using Analogix Intelliflash 280 @TM(SiO20-80% methanol/dichloromethane (1/10) in dichloromethane) to obtain the title compound. MS (ESI)+) m/z 376(M+H)+。
Example 15D
1- (3-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] cyclobutanecarboxamidine
The title compound was synthesized according to the procedures described for example 1B and example 1C, substituting example 15B for example 1A.1H NMR(300 MHz, DMSO-d 6) ppm 1.17-1.38(m, 2 H), 1.48-1.70(m, 7 H), 1.80-2.04(m, 6 H), 2.05-2.17(m, 2 H), 2.82-2.95(m, 2 H), 3.89-4.01(m, 1 H), 4.44(s, 1 H), 6.74-6.91(m, 2 H), 7.07(d, J=7.6 Hz, 1 H), 7.32(t, J=8.2 Hz, 1 H), 7.73-7.86(m, 1 H); MS(ESI+) m/z 400(M+H)+。
Example 16
(E) -4- [ (2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } thiopropionyl) amino ] adamantane-1-carboxylic acid methyl ester
Example 16A
(E) -4- [ (2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } propanecarbonyl) amino ] adamantane-1-carboxylic acid methyl ester
According to Patel et al (Bioorg. Med. Chem. Lett.2007, 17, 750-755) of the title compound。
Example 16B
(E) -4- [ (2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } thiopropionyl) amino ] adamantane-1-carboxylic acid methyl ester
The title compound was synthesized according to the procedure described for example 1B substituting example 16A for example 1A.1H NMR(300 MHz, DMSO-d 6) ppm 1.35-1.66(m, 10 H), 1.74-1.96(m, 7 H), 2.15(d, J=2.4 Hz, 2 H), 3.58(s, 3 H), 4.16-4.37(m, 1 H), 4.63(s, 2 H), 7.57-7.69(m, 2 H), 7.70-7.82(m, 2 H), 9.01(d, J=7.1 Hz, 1 H); MS(DCI+) m/z 460(M+H)+。
Example 17
(E) -4- [ ((1E) -N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } propiriminoyl) amino ] adamantane-1-carboxylic acid methyl ester
The title compound was synthesized according to the procedure described for example 1C substituting example 16 for example 1B.1H NMR(300 MHz, DMSO-d 6) ppm 1.42-1.59(m, 4 H), 1.65(s, 6 H), 1.72-1.96(m, 7 H), 2.08(d, J=2.0 Hz, 2 H), 3.58(s, 3 H), 3.98(d, J=6.8 Hz, 1 H), 4.70(s, 2 H), 7.51(d, J=7.1 Hz, 1 H), 7.57-7.69(m, 2 H), 7.71-7.82(m, 2 H); MS(DCI+) m/z 478(M+H)+。 C25H30N3F3O3•0.75H2The analytically calculated values of O are C, 61.15, H, 6.47 and N, 8.56. Found C, 61.24, H, 6.22, N, 8.20.
Example 18
(1E) -2- (2-chloro-4-fluorophenoxy) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] propionamidine
The title compound was synthesized according to the procedure described for example 1C substituting example 12 for example 1B.1H NMR(300 MHz, DMSO-d 6) ppm 1.52-1.64(m, 1 H), 1.69(s, 6 H), 1.75-2.19(m, 10 H), 2.33(s, 2 H), 2.86(s, 3 H), 4.08(s, 1 H), 7.17-7.36(m, 2 H), 7.58(dd, J=8.5, 3.0 Hz, 1 H), 7.96(d, J=6.7 Hz, 1 H); MS(DCI+) m/z 478(M+H)+。
Example 19
(1E) -2- (4-chlorophenoxy) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] propionamidine
The title compound was synthesized according to the procedure described for example 1C substituting example 9 for example 1B.1H NMR(300 MHz, DMSO-d 6) ppm 1.44-1.59(m, 1 H), 1.66(s, 6 H), 1.84-2.14(m, 10 H), 2.31(s, 2 H), 2.78-2.94(m, 3 H), 4.03(d, J=7.1 Hz, 1 H), 6.96-7.07(m, 2 H), 7.33-7.46(m, 2 H), 7.68(d, J=6.4 Hz, 1 H); MS(DCI+) m/z 450(M+H)+。 C22H28N3O3The analytical calculation values of S are C, 58.72, H, 6.27 and N, 8.59. Found C, 58.43, H, 6.43, N, 8.59.
Example 20
N- [ (E) -5- (aminosulfonyl) -2-adamantyl ] -2-methyl-2- [2- (trifluoromethoxy) phenoxy ] thiopropionamide
Example 20A
N- [ (E) -5- (aminosulfonyl) -2-adamantyl ] -2-methyl-2- [2- (trifluoromethoxy) phenoxy ] propanamide
The title compound was synthesized according to the method described by Sorensen et al (bioorg. med. chem. lett. 2007, 17, 527-532).
Example 20B
N- [ (E) -5- (aminosulfonyl) -2-adamantyl ] -2-methyl-2- [2- (trifluoromethoxy) phenoxy ] thiopropionamide
The title compound was synthesized according to the procedure described for example 1B substituting example 20A for example 1A.1H NMR(300 MHz, DMSO-d 6) ppm 1.42-1.62(m, 3 H), 1.66(s, 6 H), 1.80-2.10(m, 8 H), 2.31(s, 2 H), 4.24-4.48(m, 1 H), 6.63(s, 2 H), 7.07(d, J=8.3 Hz, 1 H), 7.13-7.22(m, 1 H), 7.30-7.39(m, 1 H), 7.44(d, J=8.3 Hz, 1 H), 9.11(d, J=7.1 Hz, 1 H); MS(DCI+) m/z 493(M+H)+。
Example 21
(E) -4- [ (2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } thiopropionyl) amino ] adamantane-1-carboxylic acid methyl ester
Example 21A
(E) -4- [ (2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propanoyl) amino ] adamantane-1-carboxylic acid methyl ester
According to Becker et al (Org. Process R & D2008, 12, 1114-1118) to synthesize the title compound.
Example 21B
(E) -4- [ (2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } thiopropionyl) amino ] adamantane-1-carboxylic acid methyl ester
The title compound was synthesized according to the procedure described for example 1B substituting example 21A for example 1A. 1H NMR(300 MHz, DMSO-d 6) ppm 1.22-1.38(m, 6 H), 1.68(q, J=13.0 Hz, 4 H), 1.81-2.06(m, 7 H), 2.19(s, 2 H), 3.32(s, 6 H), 3.52-3.76(m, 5 H), 4.24-4.42(m, 1 H), 6.98(d, J=9.2 Hz, 1 H), 7.81(dd, J=9.2, 2.4 Hz, 1 H), 8.42(d, J=1.7 Hz, 1 H), 10.23(d, J=7.8 Hz, 1 H); MS(DCI+) m/z 525(M+H)+。
Example 22
3- (4-chlorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] -2, 2-dimethylpropanamidine
Example 22A
3- (4-chlorophenyl) -2, 2-dimethylpropionitrile
To a solution of lithium diisopropylamide (11.0 mL, 21.9 mmol, 2M in tetrahydrofuran, Aldrich) in tetrahydrofuran (100 mL) at 0-5 deg.C was added isobutyronitrile (2.0 mL, 21.9 mmol). After stirring for 30 minutes, a solution of 1- (bromomethyl) -4-chlorobenzene (3.0 g, 14.6 mmol) in tetrahydrofuran (10 mL) was added at the same temperature. After stirring at room temperature for 2 hours, the reaction mixture was treated with 10% hydrochloric acid (50 mL), concentrated under reduced pressure, and tetrahydrofuran was removed. The concentrate was extracted with ethyl acetate (3X 50 mL). The combined organic extracts were sequentially treated with NaHCO3The aqueous solution (50 mL) and brine (50 mL) were washed with anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure. The residue was then purified by column chromatography using Analogix Intelliwash 280-TM(SiO20-30% ethyl acetate/hexanes) to afford the title compound. MS (DCI)+) m/z 211(M+NH4)+。
Example 22B
3- (4-chlorophenyl) -2, 2-dimethylacrylonitrile ethyl ester hydrochloride
Using the method described in example 4A, treatmentExample 22A, HCl gas and ethanol to give the title compound. MS (ESI)+) m/z 240(M+H)+。
Example 22C
3- (4-chlorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] -2, 2-dimethylpropanamidine
E-2-amino-5-hydroxyadamantane (Jaroskova et al,Tetrahedron Lettersa mixture of 2006, 47(46), 8063-8067) (59 mg, 0.36 mmol) and ethyl 3- (4-chlorophenyl) -2, 2-dimethylacrylonitrile (obtained after bicarbonate washing example 22B) (85 mg, 0.36 mmol) was stirred at 120 ℃ for 16 h. The reaction mixture was cooled, dissolved in dichloromethane (2 mL), purified by preparative HPLC (on Phenomenex Luna C8(2)5 um 100 a AXIA column (30mM x 75mM) using a gradient of 20% to 95% acetonitrile/10 mM ammonium acetate over 10 minutes at a flow rate of 50 mL/min) to provide the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.09-1.19(m, 2 H), 1.37(s, 6 H), 1.40-1.51(m, 2 H), 1.66-1.82(m, 4 H), 1.99-2.12(m, 7 H), 3.00(s, 2 H), 3.42-3.56(m, 1 H), 4.11(s, 1 H), 7.11(d, J=8.3 Hz, 2 H), 7.17-7.28(m, 2 H); MS(ESI+) m/z 361(M+H)+。
Example 23
(1E) -3- (4-chlorophenyl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2, 2-dimethylpropanamidine
Example 23A
3- (4-chlorophenyl) -N-cyano-2, 2-dimethylacrylonitrile ethyl ester
Example 22A and cyanamide (Aldrich) were processed using the method described for example 3B to obtain the title compound. MS (ESI)+) m/z 265(M+H)+。
Example 23B
(1E) -3- (4-chlorophenyl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2, 2-dimethylpropanamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 23A for example 3B. 1H NMR(300 MHz, DMSO-d 6) ppm 1.18-1.32(m, 4 H), 1.35(s, 6 H), 1.50-1.70(m, 6 H), 1.80-1.91(m, 1 H), 1.94-2.04(m, 2 H), 3.11(s, 2 H), 3.77-3.87(m, 1 H), 4.44(s, 1 H), 6.36(s, 1 H), 7.13(d, J=8.3 Hz, 2 H), 7.35(d, J=8.3 Hz, 2 H); MS(ESI+) m/z 386(M+H)+. C21H28ClN3O ∙ 0.2.2 analysis and calculation of ethyl acetate C-67.86, H-7.39, N-10.41, found C-67.48, H-7.51, N-10.17.
Example 24
(E) -4- [ ((1E) -N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } propiriminoyl) amino ] adamantane-1-carboxylic acid
A solution of example 17(0.35 g, 0.7 mmol) in methanol: tetrahydrofuran (1:1, 10 mL) was treated with 2N NaOH (0.5 mL, 3.5 mmol) and stirred for 30 h. The reaction mixture was concentrated in vacuo, diluted with water, acidified to pH-5 and extracted with ethyl acetate. The organic layer was washed with brine and dried (MgSO)4) And concentrated to give the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.32-1.61(m, 3 H), 1.65(s, 6 H), 1.71-1.96(m, 8 H), 2.06(s, 2 H), 3.89-4.04(m, 1 H), 4.70(s, 2 H), 7.51(d, J=7.1 Hz, 1 H), 7.63(d, J=8.3 Hz, 2 H), 7.69-7.87(m, 2 H), 12.12(s, 1 H); MS(DCI+) m/z 464(M+H)+。
Example 25
(E) -4- [ ((1E) -N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } propiriminoyl) amino ] adamantane-1-carboxamide
CH from example 24(0.34 g, 0.72 mmol)2Cl2(20 mL) solution with 1H-benzo [ d ]][1,2,3]Triazol-1-ol hydrate (0.12 g, 0.8 mmol) was treated and then treated with N1- ((ethylimino) methylene) -N3,N3-dimethylpropane-1, 3-diamine hydrochloride (0.17 g, 0.91 mmol) and the reaction mixture was stirred for 1 hour. Then 30% NH was added4Aqueous OH (0.5 mL, 3.6 mmol) and the reaction mixture stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The combined organic layers were then washed with brine and dried (MgSO) 4) And (4) concentrating. Purification by flash chromatography using 0-18% ethanol/ethyl acetate as eluent provided the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.39-1.58(m, 4 H), 1.61-1.90(m, 14 H), 2.04(s, 2 H), 3.94(s, 1 H), 4.71(s, 1 H), 6.73(s, 1 H), 6.99(s, 1 H), 7.50(d, J=7.1 Hz, 1 H), 7.59-7.69(m, 2 H), 7.70-7.81(m, 2 H); MS(DCI+) m/z 463(M+H)+。 C25H30N3F3O3 •0.2 H2The analytically calculated values of O are C, 61.84, H, 6.36 and N, 12.02. Found C, 61.64, H, 6.34, N, 11.97.
Example 26
(E) -4- [ (2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } thiopropionyl) amino ] adamantane-1-carboxylic acid
Reacting (E) -4- { 2-methyl-2- [4- (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl]A stirred solution of-propionylamino } -adamantane-1-carboxylic acid (0.085 mmol, U.S. patent application 2005/0277647), Lawesson's reagent (0.085 mmol) and toluene was heated to 120 ℃ for 2 hours. The reaction mixture was cooled to 23 ℃ and concentrated in vacuo. The residue obtained is filtered through a short quick plug of silica gel, first of allDichloromethane, then ethyl acetate. The collected fractions were confirmed by LCMS for the desired product, concentrated in vacuo, and further purified by reverse phase HPLC (YMC ODS Guardpak column, acetonitrile/10 mM ammonium acetate-water gradient) to provide the title compound.1H NMR(400 MHz, DMSO-d 6)8.41(s, 1H), 7.80(m, 1H), 7.72(m, 1H), 6.97(d, J=8 Hz, 1H), 3.81(m, 1H), 3.66(m, 4H), 2.54(m, 4H), 2.07-1.69(m, 11H), 1.65-1.50(m, 2H), 1.13(s, 6H); MS(APCI) m/z 511(M+H)+。
Example 27
(1E) -N' -cyano-N- [ (E) -5-cyano-2-adamantyl ] -2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } propionamidine
The product of example 25 (73 mg, 0.158 mmol) was purified over bisThe alkane/pyridine (1.5 mL/0.15 mL) solution was cooled to 0 deg.C and treated with trifluoroacetic anhydride (0.022 mL, 0.158 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated in vacuo, and partitioned between ethyl acetate and brine. The organic layer was washed with water (2 × 30 mL) and dried (MgSO)4) And (4) concentrating. Purification by the reverse phase HPLC method using Phenomenex Luna C8(2)5 um 100A AXIA column (30 mM. times.75 mM) and a gradient of 10-100% acetonitrile and 10 mM ammonium acetate/water provided the title compound.1H NMR(300 MHz, CDCl3) ppm 1.43-1.63(m, 9 H), 1.84-2.28(m, 10 H), 3.90-4.09(m, 1 H), 4.58(s, 2 H), 6.98(d, J=7.8 Hz, 1 H), 7.45(d, J=8.1 Hz, 2 H), 7.63(d, J=8.1 Hz, 2 H); MS(DCI+) m/z 445(M+H)+。
Example 28
(E) -4- ({ (1E) -N-cyano-2- [ (4-methoxybenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid methyl ester
(E) -4- ({2- [ (4-methoxybenzyl) oxy group]-2-methylpropionyl } amino) adamantane-1-carboxylic acid methyl ester according to Patel et al (Bioorg. Med. Chem. Lett.2007, 17, 750-755), the title compound was synthesized.
Example 28B
(E) -4- ({2- [ (4-methoxybenzyl) oxy ] -2-methylthiopropionyl } amino) adamantane-1-carboxylic acid methyl ester
To a solution of example 28A (2.1g, 5 mmol) in tetrahydrofuran (25 mL) was added Lawesson's reagent (2.04 mg, 5 mmol) and the reaction mixture was heated at 50 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in saturated NaHCO 3And ethyl acetate. The combined organic layers were dried (MgSO)4) Filtering, and concentrating. Purify the residue by flash chromatography (SiO)20-40% ethyl acetate/hexanes) to provide the title compound. MS (DCI +) M/z 432(M + H)+。
Example 28C
(E) -4- ({ (1E) -N-cyano-2- [ (4-methoxybenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid methyl ester
The title compound was synthesized according to the procedure described for example 1C substituting example 28B for example 1B.1H NMR(300 MHz, DMSO-d 6) ppm 1.33-1.56(m, 4 H), 1.63(s, 6 H), 1.70-2.13(m, 9 H), 3.58(s, 3 H), 3.67-3.79(m, 3 H), 3.97(d, J=4.4 Hz, 1 H), 4.50(s, 2 H), 6.90-7.01(m, 2 H), 7.28-7.39(m, 2 H), 7.55(d, J=7.5 Hz, 1 H); MS(DCI+) m/z 440(M+H)+。
Example 29
(E) -4- [ ((1E) -N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid methyl ester
Example 21(366 mg, 0.7 mmol) in dichloromethane (8 mL) was treated with 1 mol of triethyloxyTetrafluoroborate in dichloromethane (1 mL, 1 mmol). The reaction mixture was stirred at 45 ℃ for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol and treated with cyanamide (120 mg, 2.8 mmol) and triethylamine (0.3 mL, 2.2 mmol). The reaction mixture was heated at 80 ℃ for 18 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. Drying (MgSO)4) The organic layer was concentrated in vacuo. Purification by flash chromatography (SiO) 20-10% ethanol/ethyl acetate) to provide the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.28-1.43(m, 6 H), 1.51-2.20(m, 13 H), 2.54-2.64(m, 4 H), 3.60(s, 3 H), 3.66(s, 4 H), 4.14(s, 1 H), 6.99(d, J=9.1 Hz, 1 H), 7.81(dd, J=8.9, 2.6 Hz, 1 H), 8.42(s, 1 H), 8.67(d, J=5.6 Hz, 1 H); MS(DCI+) m/z 533(M+H)+。
Example 30
(E) -4- [ ((1E) -N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid
The title compound was synthesized according to the procedure described for example 14A substituting example 29 for example 11.1H NMR(300 MHz, DMSO-d 6) ppm 1.12-1.33(m, 6 H), 1.53(d, J=12.5 Hz, 2 H), 1.64-2.10(m, 12 H), 2.50-2.63(m, 4 H), 3.64(s, 4 H), 3.81(s, 1 H), 6.98(d, J=8.8 Hz, 1 H), 7.26(d, J=8.5 Hz, 1 H), 7.80(dd, J=9.2, 2.7 Hz, 1 H), 8.41(s, 1 H); MS(DCI+) m/z 519(M+H)+。
Example 31
(E) -4- [ ((1E) -N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxamide
The title compound was synthesized according to the procedure described for example 14B substituting example 30 for example 14A.1H NMR(300 MHz, DMSO-d 6) ppm 1.35(s, 6 H), 1.50-2.18(m, 13 H), 2.52-2.66(m, 4 H), 3.67(s, 4 H), 4.11(s, 1 H), 6.74(s, 1 H), 6.99(d, J=9.2 Hz, 2 H), 7.81(dd, J=9.2, 2.4 Hz, 1 H), 8.42(s, 1 H), 8.66(d, J=7.5 Hz, 1 H); MS(DCI+) m/z 518(M+H)+。 C26H34F3N7The analytically calculated values of O are C, 60.34, H, 6.65 and N, 18.94. Found C, 60.34, H, 6.65 and N, 18.55.
Example 32
6- ({4, 4-dimethyl-1- [ (E) -5- (methylsulfonyl) -2-adamantyl ] -5-thiopyrrolidin-3-yl } methoxy) nicotinonitrile
Example 32A
6- ({4, 4-dimethyl-1- [ (E) -5- (methylsulfonyl) -2-adamantyl ] -5-oxopyrrolidin-3-yl } methoxy) nicotinonitrile
The title compound was synthesized according to the methods described in the following references: the result of Yeh et al,Bioorg. Med. Chem. Lett. 2006，16，5555-5560。
example 32B
6- ({4, 4-dimethyl-1- [ (E) -5- (methylsulfonyl) -2-adamantyl ] -5-thiopyrrolidin-3-yl } methoxy) nicotinonitrile
The title compound was synthesized by the method described for example 28 substituting example 32A for example 28A.1H NMR(300 MHz, DMSO-d 6) ppm 0.97-1.13(m, 3 H), 1.18-1.39(m, 3 H), 1.61(t, J=14.7 Hz, 2 H), 1.75-2.23(m, 10 H), 2.76-2.97(m, 3 H), 3.87(dd, J=10.9, 8.5 Hz, 1 H), 4.13(dd, J=11.1, 7.9 Hz, 1 H), 4.28-4.64(m, 3 H), 6.85(d, J=8.7 Hz, 1 H), 8.24(dd, J=8.7, 2.8 Hz, 1 H), 8.72(d, J=2.4 Hz, 1 H), 9.51(s, 1 H), 9.84(s, 1 H); MS(DCI+) m/z 474(M+H)+。
Example 33
(2Z) -4- { [ (5-cyanopyridin-2-yl) oxy ] methyl } -3, 3-dimethyl-1- [ (E) -5- (methylsulfonyl) -2-adamantyl ] pyrrolidin-2-ylidenecyanamide
The title compound was synthesized by the method described for example 29, substituting example 32 for example 21.1H NMR(400 MHz, DMSO-d 6) ppm 1.23-1.36(m, 3 H), 1.52(s, 3 H), 1.56(s, 1 H), 1.68-2.25(m, 12 H), 2.43(s, 2 H), 2.57-2.74(m, 1 H), 3.64-4.06(m, 4 H), 4.35-4.64(m, 2 H), 7.04(d, J=8.5 Hz, 1 H), 8.18(dd, J=8.7, 2.3 Hz, 1 H), 8.72(d, J=2.1 Hz, 1 H); MS(DCI+) m/z 482(M+H)+。
Example 34
(3S) -1- [ (3-chloro-2-methylphenyl) sulfonyl ] -N-cyclohexylpiperidine-3-carbothioic acid amide
The title compound was synthesized according to the procedure described for example 1B, substituting (S) -1- (3-chloro-2-methylbenzenesulfonyl) -N-cyclohexylpiperidine-3-carboxamide for example 1A.1H NMR(300 MHz, DMSO-d 6) ppm 1.05-1.36(m, 5 H), 1.45-1.95(m, 9 H), 2.57-2.68(m, 1 H), 2.59(s, 3 H), 2.78(t, 1 H), 2.99(t, J=11.5 Hz, 1 H), 3.48-3.70(m, 2 H), 4.01-4.33(m, 1 H), 7.46(t, J=7.9 Hz, 1 H), 7.80(t, J=8.3 Hz, 2 H), 9.88(d, J=7.5 Hz, 1 H); MS(ESI+) m/z 415(M+H)+。
Example 35
(3S) -1- [ (3-chloro-2-methylphenyl) sulfonyl ] -N' -cyano-N-cyclohexylpiperidine-3-carboxamidine
To a solution of example 34(200 mg, 0.48 mmol) in dichloromethane (15 mL) was added triethyloxyTetrafluoroborate (0.96 mL, 0.96 mmol, 1M in dichloromethane), and the mixture was stirred at room temperature overnight. The reaction mixture was then heated to 50 ℃ and held for an additional 3 days while stirring was continued. The reaction mixture was cooled, concentrated and triturated in ether. The obtained product was dissolved in ethanol (2 mL) and cyanamide (61 mg, 1.4mmol), and triethylamine (0.2 mL, 1.4mmol) was added. After stirring at 80 ℃ for 16 h, the reaction mixture was cooled, diluted with water (10mL) and extracted with ethyl acetate (3 × 10 mL). Mixing the organic extracts with anhydrous Na 2SO4Dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using Analogix Intelliflash 280 @TM(SiO20-100% ethyl acetate/hexane).1H NMR(300 MHz, DMSO-d 6) ppm 1.04-1.34(m, 5 H), 1.44-1.91(m, 9 H), 2.60(s, 3 H), 2.60-2.70(m, 1 H), 2.83-2.98(m, 1 H), 3.08(t, J=11.4 Hz, 1 H), 3.64(t, 3 H), 7.47(t, J=8.3 Hz, 1 H), 7.80(dd, J=8.1, 1.0 Hz, 1 H), 7.83-7.89(m, 1 H), 8.31(d, J=7.5 Hz, 1 H); MS(ESI+) m/z 423(M+H)+。 C20H27ClN4O2The analytical calculation values of S are C, 56.79, H, 6.43 and N, 13.29. Found C, 56.42, H, 6.41, N, 12.98.
Example 36
(E) -4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid
Another preparation of example 14A is described herein. To example 14B (50 mg, 0.12 mmol) of 1, 4-bisTo a solution of alkane (0.5 mL) was added 5M hydrochloric acid/water (0.5 mL, 2.5 mmol). After stirring at 60 ℃ for 6 h, the reaction mixture was cooled, diluted with water (5mL) and extracted with ethyl acetate (2 × 10 mL). Mixing the organic extracts with anhydrous Na2SO4Dried, filtered, and concentrated under reduced pressure. The title compound was obtained by preparative HPLC purification of the residue on Phenomenex Luna C8(2)5 um 100A AXIA column (30 mm. times.75 mm) using a gradient of 10-95% (acetonitrile/0.1% trifluoroacetic acid-water) at a flow rate of 50 mL/min over 10 minutes.1H NMR(500 MHz, DMSO-d 6) ppm 1.46-1.57(m, 2 H), 1.65(s, 6 H), 1.69-1.77(m, 2 H), 1.77-1.82(m, 2 H), 1.84-1.93(m, 5 H), 2.11-2.22(m, 2 H), 3.95-4.08(m, 1 H), 7.01(d, J=8.8 Hz, 2 H), 7.38(d, J=8.8 Hz, 2 H), 7.64(d, J=6.1 Hz, 1 H), 12.13(s, 1 H); MS(ESI+) m/z 416(M+H)+。
Example 37
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-cyano-2-adamantyl ] -2-methylpropionamidine
The title compound was synthesized according to the procedure described in example 3C substituting E-2-amino-5-hydroxyadamantane and example 3B with E-4-amino-adamantane-1-carbonitrile (international publication WO 2007/118185, filed 10/18/2007) and example 8B, respectively. 1H NMR(300 MHz, DMSO-d 6) ppm 1.50-1.61(m, 2 H), 1.65(s, 6 H), 1.68-1.79(m, 2 H), 1.85-1.92(m, 1 H), 1.96-2.00(m, 2 H), 2.07-2.13(m, 4 H), 2.15-2.22(m, 2 H), 4.04(d, 1 H), 6.99(dt, 2 H), 7.34-7.43(m, 2 H), 7.63(d, J=6.1 Hz, 1 H); MS(ESI+) m/z 397(M+H)+。 C22H26ClN4Analytical calculation of OThe values C, 66.57, H, 6.35, N, 14.12. Found C, 66.39, H, 6.26, N, 14.22.
Example 38
(1E) -2- (4-chlorophenoxy) -N' -cyano-N-hexahydro-2, 5-methanobridged cyclopenta-3 a (1H) -yl-2-methylpropionamidine
A mixture of 3-noramantadine hydrochloride (100 mg, 0.58 mmol), triethylamine (0.24 mL, 1.73 mmol) and example 8B (184 mg, 0.69 mmol) in ethanol (2 mL) was stirred at 80 ℃ for 16 h. The reaction mixture was then cooled, concentrated, and diluted with saturated NaHCO3Aqueous solution (10 mL). The aqueous mixture was extracted with ethyl acetate (3 × 20 mL). Mixing the organic extracts with anhydrous Na2SO4Dried, filtered, and concentrated under reduced pressure. The title compound was obtained by purification of the residue by preparative HPLC (gradient of 50-95% (acetonitrile/10 mM trifluoroacetic acid-water) on Phenomenex Luna C8(2)5 um 100A AXIA column (30 mM. times.75 mM) at a flow rate of 50 mL/min over 10 minutes).1H NMR(300 MHz, DMSO-d 6) ppm 1.48-1.58(m, 4 H), 1.64(s, 6 H), 1.85-2.16(m, 6 H), 2.19-2.30(m, 2 H), 2.58(t, J=6.8 Hz, 1 H), 6.96(dt, 2 H), 7.37(dt, 2 H), 8.06(s, 1 H); MS(ESI+) m/z 358(M+H)+。
Example 39
(1E) -N- [ (4s) -1-azatricyclo [3.3.1.13,7]Decan-4-yl]-2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine
The l-azatricyclo [3.3.1.13,7) A mixture of dec-4 s-amine dihydrochloride (Synthesis, 11, 1080-2, 1992) (80 mg, 0.36 mmol), triethylamine (0.15 mL, 1.1 mmol) and example 8B (142 mg, 0.53 mmol) in ethanol (2 mL) was stirred at 80 ℃ for 16 h. The reaction mixture was then cooled, concentrated, and diluted with saturated NaHCO 3Aqueous solution (10 mL). The aqueous mixture was taken up in ethyl acetate (3X 20 mL)) And (4) extracting. Mixing the organic extracts with anhydrous Na2SO4Dried, filtered, and concentrated under reduced pressure. The title compound was obtained by preparative HPLC purification of the residue on Phenomenex Luna C8(2)5 um 100A AXIA column (30 mm. times.75 mm) using a gradient of 10-95% (acetonitrile/0.1% trifluoroacetic acid-water) at a flow rate of 50 mL/min over 10 minutes.1H NMR(300 MHz, DMSO-d 6) ppm 1.20-1.31(m, 3 H), 1.69(s, 6 H), 1.73-2.01(m, 4 H), 3.18-3.63(m, 6 H), 4.19-4.31(m, 1 H), 6.96-7.03(m, 2 H), 7.32-7.43(m, 2 H), 7.87(d, J=5.4 Hz, 1 H); MS(ESI+) m/z 373(M+H)+。
Example 40
N-1-azabicyclo [2.2.2] oct-3-yl-2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine
The procedure described in example 39 was followed, substituting quinuclidin-3-amine dihydrochloride (Aldrich) for the l-azatricyclo [3.3.1.13,7) Deca-4 s-amine dihydrochloride, the title compound was synthesized.1H NMR(300 MHz, DMSO-d 6) ppm 1.18-1.31(m, 1 H), 1.59-1.73(m, 6 H), 1.72-1.99(m, 3 H), 2.23-2.37(m, 1 H), 3.09-3.79(m, 6 H), 4.28-4.53(m, 1 H), 6.96-7.06(m, 2 H), 7.34-7.45(m, 2 H), 8.66-8.84(m, 1 H); MS(ESI+) m/z 347(M+H)+。
EXAMPLE 41
2- (4-chlorophenoxy) -N' -cyano-N-cyclooctyl-2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting cyclooctylamine (Aldrich) and example 8B for E-2-amino-5-hydroxyadamantane and example 3B, respectively.1H NMR(300 MHz, DMSO-d 6) ppm 1.37-1.57(m, 7 H), 1.59(s, 6 H), 1.61-1.79(m, 7 H), 4.02-4.18(m, 1 H), 6.94(d, J=9.2 Hz, 2 H), 7.37(d, J=9.2 Hz, 2 H), 8.43(d, J=8.1 Hz, 1 H); MS(ESI+) m/z 348(M+H)+。 C19H26ClN3The analytically calculated values of O are C, 65.60, H, 7.53 and N, 12.08. Found C, 65.70, H, 7.35, N, 11.97.
Example 42
N- [ exo-bicyclo [2.2.1] hept-2-yl ] -2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting exo-2-aminonorbornane (Aldrich) and example 8B for E-2-amino-5-hydroxyadamantane and example 3B, respectively. 1H NMR(300 MHz, DMSO-d 6) ppm 1.03-1.23(m, 3 H), 1.35-1.50(m, 3 H), 1.56-1.62(m, 6 H), 1.61-1.66(m, 2 H), 2.18-2.23(m, 1 H), 2.24-2.33(m, 1 H), 3.68-3.83(m, 1 H), 6.88-7.00(m, 2 H), 7.32-7.44(m, J=9.2 Hz, 2 H), 8.13(d, J=5.8 Hz, 1 H); MS(ESI+) m/z 332(M+H)+。C18H22ClN3The analytically calculated values of O are C, 65.15, H, 6.68 and N, 12.66. Found C, 65.18, H, 6.91, N, 12.43.
Example 43
(1E) -N-1-adamantyl-2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting 1-amantadine (Aldrich) and example 8B for E-2-amino-5-hydroxyadamantane and example 3B, respectively.1H NMR(300 MHz, DMSO-d 6) ppm 1.60-1.68(m, 6 H), 1.63(s, 6 H), 2.01-2.13(m, 9 H), 6.94-7.04(m, 2 H), 7.14(s, 1 H), 7.33-7.44(m, 2 H); MS(ESI+) m/z 372(M+H)+。 C21H26ClN3The analytically calculated values of O are C, 67.82, H, 7.05 and N, 11.30. Found C, 67.83, H, 6.87, N, 11.09.
Example 44
(1E) -N' -cyano-2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine
Example 44A
2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propanamide
The title compound was synthesized according to the methods described in the following references: sorensen, b., et al, bioorg. med. chem. lett. 2007, 17, 527-532. MS (DCI +) m-z 410(M+H)+。
Example 44B
2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] thiopropionamide
The title compound was synthesized according to the procedure described for example 1B substituting example 44A for example 1A.1H NMR(300 MHz, DMSO-d 6) ppm 1.43-1.79(m, 10 H), 1.83-2.20(m, 7 H), 2.39(s, 2 H), 2.87(s, 3 H), 4.32-4.49(m, 1 H), 7.02-7.24(m, 3 H), 7.22-7.45(m, 1 H), 9.42(d, J=7.1 Hz, 1 H); MS(DCI+) m/z 426(M+H)+。
Example 44C
(1E) -N' -cyano-2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine
A solution of example 44B (60 mg, 0.14 mmol) in dichloromethane (3 mL) was treated with commercially available triethyloxy oxygen at room temperatureTetrafluoroborate salt(1M solution in tetrahydrofuran, 0.21 mL, 0.21 mmol) was treated dropwise. The reaction mixture was stirred at 45 ℃ for 16 hours and then concentrated in vacuo. Ethanol (3 mL) was added to thioimine acid salt, and the mixture was treated with cyanamide (24 mg, 0.57 mmol) and triethylamine (43 mg, 0.42 mmol). The reaction mixture was heated at 80 ℃ overnight. Purification by the reverse phase HPLC method using Phenomenex Luna C8, 5. mu.M 100A AXIA ™ column (30 mM. times.75 mM) and a gradient of 10-100% acetonitrile and 10 mM ammonium acetate/water provided the title compound.1H NMR(500 MHz, CDCl3) ppm 1.57-1.81(m, 6 H), 1.87(d, J=13.4 Hz, 2 H), 2.00-2.32(m, 9 H), 2.40(s, 2 H), 2.68-2.86(m, 3 H), 4.19(s, 1 H), 7.01-7.23(m, 4 H), 7.92(d, J=6.7 Hz, 1 H); MS(DCI+) m/z 434(M+H)+。
Example 45
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine
Example 45A
2- (2, 4-Difluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propanamide
The title compound was synthesized according to the methods described in the following references: sorensen, b., et al, bioorg. med. chem. lett. 2007, 17, 527-532.
Example 45B
2- (2, 4-Difluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] thiopropionamide
The title compound was synthesized according to the procedure described for example 1B substituting example 45A for example 1A.1H NMR(300 MHz, DMSO-d 6) ppm 1.48-1.85(m, 9 H), 1.87-2.20(m, 8 H), 2.40(s, 2 H), 2.87(s, 3 H), 4.32-4.46(m, 1 H), 6.94-7.13(m, 1 H), 7.14-7.32(m, 1 H), 7.32-7.51(m, 1 H), 9.40(d, J=7.1 Hz, 1 H); MS(DCI+) m/z 444(M+H)+。C21H27NF2O3S2The analysis of (1) calculated values of C, 56.86, H, 6.14 and N, 3.16. Found C, 57.61, H, 5.82, N, 3.11.
Example 45C
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine
The title compound was synthesized according to the procedure described for example 1C substituting example 45B for example 1B.1H NMR(500 MHz, CDCl3) ppm 1.39-1.77(m, 9 H), 1.86(t, J=14.0 Hz, 2 H), 2.03-2.33(m, 8 H), 2.69-2.86(m, 3 H), 3.95-4.15(m, 1 H), 6.69-6.99(m, 2 H), 7.01-7.16(m, 1 H), 7.42(d, J=7.6 Hz, 1 H); MS(DCI+) m/z 452(M+H)+。
Example 46
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } bicyclo [2.2.2] octane-1-carboxylic acid
Example 46A
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } bicyclo [2.2.2] octane-1-carboxylic acid methyl ester
Example 8B and 4-Aminobicyclo [2.2.2] were treated using the method described in example 2]Octane-1-carboxylic acid methyl ester (4-methoxycarbonyl-bicyclo [2.2.2] washed with aqueous bicarbonate solution]Octyl-1-ammonium chloride salt, Prime Organics) to obtain the title compound. LCMS (ESI)+) m/z 404(M+H)+。
Example 46B
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } bicyclo [2.2.2] octane-1-carboxylic acid
The title compound was synthesized according to the procedure described for example 14A substituting example 46A for example 11. 1H NMR(300 MHz, DMSO-d 6) ppm 1.62(s, 6 H), 1.72-1.88(m, 6 H), 1.90-2.06(m, 6 H), 6.92-7.01(m, 2 H), 7.25(s, 1 H), 7.34-7.42(m, 2 H), 12.09(s, 1 H); MS(ESI+) m/z 391(M+H)+。
Example 46 Another preparation method
The title compound was also prepared using the method described for example 87, substituting example 8B for N-cyano-2-methyl-2-phenoxyalanine ethyl ester (CI-1). Purification by preparative reverse phase HPLC [ Waters 2767; benetnach 10-C1820 × 250 mm, 10 μm; 45-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/min; detection at 214 and 254 nm ].
Example 47
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } bicyclo [2.2.2] octane-1-carboxamide
The title compound was synthesized according to the procedure described for example 14B substituting example 46B for example 14A.1H NMR(300 MHz, DMSO-d 6) ppm 1.62(s, 6 H), 1.69-1.83(m, 6 H), 1.89-2.05(m, 6 H), 6.73(s, 1 H), 6.92-7.01(m, 2 H), 6.95(s, 1 H), 7.24(s, 1 H), 7.33-7.44(m, 2 H); MS(ESI+) m/z 390(M+H)+。
Example 47 first alternative preparation method
Example 47 was also prepared using the procedure described for example 85 substituting 4- (difluoromethyl) bicyclo [2.2.2] octan-1-amine (BA-4) with 4-aminobicyclo [2.2.2] octane-1-carboxamide (BA-6).
Example 47A second alternative preparation method
Example 8B (524 mg, 2 mmol) and 4-aminobicyclo [2.2.2]Octane-1-carbonitrile (BA-1) (300 mg, 2 mmol) was mixed and the neat mixture was heated to 130 ℃ under nitrogen and stirred for 3 hours. After cooling, the mixture was dissolved in a small amount of ethanol and purified by preparative reverse phase HPLC [ Waters 2767; benetnach 10-C1820 × 250 mm, 10 μm; 40-60% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/min; detection at 214 and 254 nm ]To yield the title compound.1H NMR(400 MHz, CDCl3) ppm 11.23(br, 1H), 9.72(s, 1H), 7.22(d, J=8.5Hz, 2H), 6.88(d, J=8.6Hz, 2H), 4.03(s, 2H), 2.00~2.10(m, 12H), 1.50(s, 6H); LCMS(ESI+) m/z 389.7(M+H)+。
Example 48 methyl (E) -4- ({ (1E) -2- [ (1R, 5S, 6R) -6- (4-chlorophenyl) -3-azabicyclo [3.2.0] hept-3-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylate
Example 48A
2- [ (1R, 5S, 6R) -6- (4-chlorophenyl) -3-azabicyclo [3.2.0] hept-3-yl ] -2-methylpropanoic acid methyl ester
To (1R, 5S, 6R) -6- (4-chlorophenyl) -3-azabicyclo [3.2.0]To a solution of heptane (Steiner, G., et al, Heterocycles, 1995, 40, 319-330) (1.0 g, 1.3 mmol) in N, N-dimethylformamide (40 mL) were added potassium carbonate (1.0 g, 7.5 mmol) and methyl 2-bromo-2-methylpropionate (0.4 mL, 3.0 mmol, Aldrich). After stirring at 80 ℃ for 16 h, the reaction mixture was cooled and quenched with water (30 mL). With ethyl acetate (3X 50)mL) the aqueous layer was extracted. Mixing the organic extracts with anhydrous Na2SO4Dried, filtered, and concentrated under reduced pressure. The residue was then purified by column chromatography using Analogix Intelliwash 280-TM(SiO20-50% ethyl acetate/hexanes) to afford the title compound. MS (ESI)+) m/z 308(M+H)+。
Example 48B
(E) -methyl 4- ({2- [ (1R, 5S, 6R) -6- (4-chlorophenyl) -3-azabicyclo [3.2.0] hept-3-yl ] -2-methylpropanoyl } amino) adamantane-1-carboxylate
To a solution of example 48A (0.44 g, 1.4 mmol) in methanol (4 mL) and water (4 mL) was added aqueous 5N NaOH (1.4 mL, 7.1 mmol). After stirring at 60 ℃ for 16 h, the reaction mixture was cooled, neutralized to pH 7 with 3N HCl, and concentrated to give crude 2- [ (1S,5R,6S) -6- (4-chlorophenyl) -3-azabicyclo [3.2.0] hept-3-yl ] -2-methylpropanoic acid.
To a solution of the above acid (1.0 g, 3.4 mmol) in N, N-dimethylformamide (25 mL) and tetrahydrofuran (25 mL) was added 1-hydroxybenzotriazole hydrate (0.6 g, 3.9 mmol, Aldrich), N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (0.8 g, 4.1 mmol, Aldrich), (E) -4-aminoadamantane-1-carboxylic acid methyl ester hydrochloride (Becker, C.L., et al, org. Process R&D, 2008, 12, 1114-1118) (0.8 g, 3.4 mmol) and triethylamine (0.7 mL, 5.1 mmol). The reaction mixture was stirred at room temperature for 16 hours and then quenched with water (30 mL). The aqueous layer was extracted with dichloromethane (3X 50 mL). Mixing the organic extracts with anhydrous Na2SO4Dried, filtered, and concentrated under reduced pressure. The residue was then purified by column chromatography using Analogix Intelliwash 280-TM(SiO20-50% ethyl acetate/hexanes) to afford the title compound. MS (ESI) +) m/z 485(M+H)+。
Example 48C
(E) -methyl 4- ({2- [ (1R, 5S, 6R) -6- (4-chlorophenyl) -3-azabicyclo [3.2.0] hept-3-yl ] -2-methylthiopropionyl } amino) adamantane-1-carboxylate
The title compound was synthesized according to the procedure described for example 1B substituting example 48B for example 1A. MS (ESI)+) m/z 501(M+H)+。
Example 48D
(E) -methyl 4- ({ (1E) -2- [ (1R, 5S, 6R) -6- (4-chlorophenyl) -3-azabicyclo [3.2.0] hept-3-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylate
To a solution of example 48C (240 mg, 0.48 mmol) in dichloromethane (15 mL) was added triethyloxyTetrafluoroborate (1.5 mL, 1.5 mmol, 1M in dichloromethane, Aldrich) and the mixture was stirred at 50 ℃ for 3 days. The reaction mixture was then concentrated under reduced pressure and triturated in ether. The obtained precipitate was dissolved in ethanol (2 mL) and cyanamide (60 mg, 1.5 mmol), and triethylamine (0.2 mL, 1.5 mmol) was added. After stirring at 80 ℃ for 16 h, the reaction mixture was cooled, concentrated under reduced pressure, and diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (3X 10 mL). Mixing the organic extracts with anhydrous Na2SO4Dried, filtered, and concentrated under reduced pressure. The residue was then purified by column chromatography using Analogix Intelliwash 280- TM(SiO20-100% ethyl acetate/hexanes) to afford the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.40(s, 3 H), 1.41(s, 3 H), 1.57-1.69(m, 2 H), 1.77-1.99(m, 10 H), 2.07-2.31(m, 4 H), 2.40-2.49(m, 2 H), 2.68-2.94(m, 4 H), 3.60(s, 3 H), 4.11-4.20(m, 1 H), 7.24-7.30(m, 2 H), 7.33-7.40(m, 2 H), 8.84(d, J=8.1 Hz, 1 H); MS(ESI+) m/z 510(M+H)+。
Example 49
(1E) -N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methyl-2-phenoxypropionamidine
To a solution of example 8(50 mg, 0.13 mmol) in methanol (2 mL) was added ammonium formate (81 mg, 1.3 mmol) and 10% Pd/C (2 mg) under an inert atmosphere. The reaction mixture was stirred at room temperature for 2 hours, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (on Phenomenex ^ Luna C8(2)5 μm 100A AXIA column (30 mM. times.75 mM) using a gradient of 20% to 95% acetonitrile/10 mM ammonium acetate over 10 minutes at a flow rate of 50 mL/minute) to provide the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.34-1.47(m, 2 H), 1.55-1.78(m, 9 H), 1.64(s, 6 H), 1.94-2.02(m, 1 H), 2.13-2.25(m, 2 H), 3.89-4.05(m, 1 H), 6.98(d, J=8.7 Hz, 2 H), 7.12(t, J=7.3 Hz, 1 H), 7.27-7.41(m, 2 H), 7.59(d, J=6.7 Hz, 1 H); MS(ESI+) m/z 354(M+H)+。
Example 50
(E) -4- { [ (1E) -N-cyano-2-methyl-2-phenoxyiminoacyl ] amino } adamantane-1-carboxamide
The title compound was synthesized by the method described for example 49 substituting example 14B for example 8.1H NMR(300 MHz, DMSO-d 6) ppm 1.45-1.56(m, 2 H), 1.65(s, 6 H), 1.67-1.78(m, 4 H), 1.79-1.94(m, 5 H), 2.10-2.19(m, 2 H), 3.97-4.09(m, 1 H), 6.73(s, 1 H), 6.95-7.04(m, 3 H), 7.08-7.17(m, 1 H), 7.29-7.40(m, 2 H), 7.65(d, J=6.8 Hz, 1 H); MS(ESI+) m/z 381(M+H)+。
Example 51
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine
Example 51A
2- (2, 4-Difluorophenoxy) -2-methylpropanamide
To a solution of 2- (2, 4-difluorophenoxy) -2-methylpropionic acid (10.0 g, 46.3 mmol, Chembridge) in dichloromethane (200 mL) was added 1-hydroxybenzotriazole hydrate (8.5 g, 55.5 mmol, Aldrich), N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (10.6 g, 55.5 mmol, Aldrich) and ammonium hydroxide (54.0 g, 463 mmol). The reaction mixture was stirred at room temperature for 16 hours and then quenched with water (100 mL). The aqueous layer was extracted with dichloromethane (3X 100 mL). The combined organic extracts were washed with brine, 5% citric acid and brine (100 mL each), anhydrous Na 2SO4Drying, filtering and concentrating under reduced pressure to obtain the title compound. MS (ESI)+) m/z 233(M+NH4)+。
Example 51B
2- (2, 4-Difluorophenoxy) -2-methylpropanenitrile
To a solution of example 51A (0.9 g, 4.0 mmol) in dichloromethane (10 mL) and triethylamine (2.2 mL, 15.8 mmol) was added 2,2, 2-trifluoroacetic anhydride (1.6 mL, 11.9 mmol) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for three hours, after which methanol was added and the reaction was quenched. With saturated NaHCO3The reaction mixture was washed with an aqueous solution and dried over anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure. The residue was purified by column chromatography using Analogix Intelliflash 280 @TM(SiO20-100% methanol/ethyl acetate (1/10) in hexanes) to give the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.71(s, 6 H), 7.08-7.18(m, 1 H), 7.36-7.49(m, 2 H)。
Example 51C
2- (2, 4-Difluorophenoxy) -2-methylalanine ethyl ester hydrochloride
A cooled solution of example 51B (6.5 g, 33 mmol) and ethanol (9.6 mL, 165 mmol) in dichloromethane (10 mL) was bubbled with HCl gas for 30 min at 0 ℃. The reaction was kept in a refrigerator at 4 ℃ for 60 hours. The reaction mixture was then concentrated and triturated with diethyl ether to obtain a precipitate of the title compound. MS (ESI)+) m/z 244(M+H)+。
Example 51D
N-cyano-2- (2, 4-difluorophenoxy) -2-methylalanineimine ethyl ester
Example 51C and cyanamide (Aldrich) were processed using the method described for example 3B to obtain the title compound. MS (ESI)+) m/z 286(M+NH4)+。
Example 51E
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 51D for example 3B.1H NMR(300 MHz, DMSO-d 6) ppm .39-1.50(m, 2 H), 1.62(s, 6 H), 1.62-1.80(m, 8 H), 1.99-2.10(m, 1 H), 2.14-2.25(m, 2 H), 3.93-4.04(m, 1 H), 4.50(s, 1 H), 7.01-7.18(m, 1 H), 7.25-7.49(m, 2 H), 7.82(d, J=6.4 Hz, 1 H); MS(ESI+) m/z 390(M+H)+。
Example 52
(1E) -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2- (2, 4-difluorophenoxy) -2-methylpropionamidine
The title compound was synthesized according to the procedure described in example 3C substituting E-2-amino-5-hydroxyadamantane and example 3B with E-4-amino-adamantane-1-carbonitrile (international publication WO 2007/118185, filed 10/18/2007) and example 51D, respectively.1H NMR(300 MHz, DMSO-d 6) ppm 1.52-1.69(m, 2 H), 1.63(s, 6 H), 1.72-1.83(m, 2 H), 1.87-2.25(m, 8 H), 2.42-2.61(m, 1 H), 3.99-4.15(m, 1 H), 7.02-7.15(m, 1 H), 7.23-7.35(m, 1 H), 7.35-7.46(m, 1 H), 7.88(d, J=6.7 Hz, 1 H); MS(ESI+) m/z 390(M+H)+。
Example 53
(1E) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2-methylpropionamidine
Example 53A
2- (4-chloro-2-fluorophenoxy) -2-methylpropionic acid ethyl ester
A mixture of 4-chloro-2-fluorophenol (11.280g, 77 mmol), ethyl 2-bromoisobutyrate (12.61 mL, 85 mmol), and cesium carbonate (37.6 g, 115 mmol) in N, N-dimethylformamide (100 mL) was stirred at 55 ℃ for 18 hours. The reaction mixture was poured into brine and extracted with ethyl acetate (2 × 250 mL). The combined organic phases were washed with brine and dried (MgSO) 4) And (4) concentrating. The crude product was used in the next step without additional purification. MS (DCI +) m-z 278(M+NH4)+。
Example 53B
2- (4-chloro-2-fluorophenoxy) -2-methylpropanoic acid
Example 53A (18 g, 70 mmol) was treated with LiOH (4.96 g, 207 mmol) in a mixture of tetrahydrofuran (100 mL) and water (50 mL). In thatThe reaction mixture was stirred overnight at 55 ℃ and then concentrated under reduced pressure to remove tetrahydrofuran. The basic aqueous layer was extracted with ethyl acetate (2X 100 mL) to extract the unreacted starting phenol. The aqueous layer was acidified to pH-3 and extracted with ethyl acetate (2X 200 mL). The combined organic layers were washed with brine and dried (MgSO)4) And (4) concentrating. The crude product was used in the next step without additional purification. MS (DCI +) m-z 233(M+H)+。
Example 53C
2- (4-chloro-2-fluorophenoxy) -2-methylpropanamide
To a solution of example 53B (14.6 g, 62.8 mmol) in dichloromethane (200 mL) was added N1- ((ethylimino) methylene) -N3,N3Dimethylpropane-1, 3-diamine hydrochloride (8.50 g, 55.5 mmol) and the reaction mixture was stirred for 1 hour. Ammonium hydroxide (87 mL, 628 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then quenched with water (100 mL). The aqueous layer was extracted with dichloromethane (3X 100 mL). With saturated NaHCO 3The combined organic layers were washed with brine (100 mL) and dried (MgSO)4) Filtering, and concentrating. The residue was triturated with hexanes/ethyl acetate (95/5) to provide the title compound. MS (DCI +) m-z 232(M+H)+。
Example 53D
2- (4-chloro-2-fluorophenoxy) -2-methylpropanenitrile
To a solution of example 53C (8 g, 34.5 mmol) in dichloromethane (100 mL) and triethylamine (19.25 mL, 138 mmol) was added trifluoroacetic anhydride (added slowly, 14.63 mL, 104 mmol) at 0 ℃. After the addition, the solution was warmed to room temperature and stirred for 2 hours, after which methanol (20 mL) was added and the reaction was quenched. With saturated NaHCO3The solution was washed and dried (Na)2SO4) And (4) concentrating. The residue was purified by column chromatography using Analogix Intelliflash 280 @TM(SiO20-60% ethyl acetate/hexanes) to provide the title product. MS (DCI +) m-z 214(M+H)+。
Example 53E
2- (4-chloro-2-fluorophenoxy) -2-methylalanine ethyl ester hydrochloride
A cooled solution of example 53D (7.2 g, 33.7 mmol) in ethanol (75 mL) and dichloromethane (30 mL) was bubbled with HCl gas for 30 min at 0 ℃. The reaction was kept in the refrigerator for 24-72 hours (checked by LCMS). The reaction mixture was then concentrated and the residue triturated with diethyl ether. The title compound was collected by filtration.
Example 53F
2- (4-chloro-2-fluorophenoxy) -N-cyano-2-methylalanineimine ethyl ester
A solution of example 53E (9.9 g, 33.4 mmol) in acetonitrile (15 mL) was added to a solution of sodium hydrogenmonophosphate monohydrate (18.32 g, 134 mmol) and sodium hydrogenphosphate heptahydrate (17.92 g, 66.9 mmol) in water (70 mL) followed by cyanamide (2.81 g, 66.9 mmol). The reaction mixture was stirred at room temperature for 55 hours, then extracted with dichloromethane (3X 50 mL). Drying (Na)2SO4) The combined organic extracts were filtered and concentrated to give the title compound. MS (DCI +) m-z 302(M+NH4)+。
Example 53G
(1E) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2-methylpropionamidine
Following the procedure described in example 3C, example 53F was used instead of example 3B, E-4-aminoadamantane-1-carbonitrile (International publication WO 2007/118185, filed on 10/18 2007) was used instead of E-5-hydroxy-2-aminoadamantane,the title compound was synthesized.1H NMR(300 MHz, DMSO-d 6) ppm 1.47-1.84(m, 9 H), 1.85-2.29(m, 10 H), 4.02-4.17(m, 1 H), 7.12-7.35(m, 2 H), 7.47-7.66(m, 1 H), 7.85(d, J=6.8 Hz, 1 H); MS(DCI+) m/z 415(M+H)+。 C22H24N4The analytical scores of ClFO are C, 63.69, H, 5.83 and N, 13.50. Found C, 63.50, H, 5.89, N, 13.32.
Example 54
(1E) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 53F for example 3B, (E) -4-aminoadamantane-1-sulfonamide (Sorensen, B., et al, bioorg, med. chem. lett., 2007, 17, 527-532) for E-5-hydroxy-2-aminoadamantane. 1H NMR(300 MHz, DMSO-d 6) ppm 1.45-1.72(m, 8 H), 1.73-2.14(m, 10 H), 2.27(s, 2 H), 6.63(s, 2 H), 7.17-7.37(m, 2 H), 7.49-7.68(m, 1 H), 7.89(d, J=6.7 Hz, 1 H); MS(DCI+) m/z 469(M+H)+。C21H26N4ClFO3The analytical calculation values of S are C, 63.69, H, 5.83 and N, 13.50. Found C, 53.18, H, 5.95, N, 10.28.
Example 55
(1E) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 53F for example 3B.1H NMR(300 MHz, DMSO-d 6) ppm 1.43(d, J=13.2 Hz, 2 H), 1.56-1.81(m, 14 H), 1.93-2.07(m, 1 H), 2.19(s, 2 H), 4.01(d, J=7.1 Hz, 1 H), 4.50(s, 1 H), 7.19-7.37(m, 2 H), 7.48-7.67(m, 1 H), 7.79(d, J=6.8 Hz, 1 H); MS(DCI+) m/z 406(M+H)+。 C21H25N3ClFO2·0.25H2The analytically calculated values of O are C, 61.46, H, 6.26 and N, 10.24. Found to be 61.76 for C, 6.26 for H, 10.17 for N.
Example 56
N- [ (exo) -bicyclo [2.2.1] hept-2-yl ] -N' -cyano-2- (2, 4-difluorophenoxy) -2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting exo-2-aminonorbornane (Aldrich) and example 51D for E-2-amino-5-hydroxyadamantane and example 3B, respectively.1H NMR(300 MHz, DMSO-d 6) ppm 1.00-1.25(m, 4 H), 1.37, 1.38(s, 3 H), 1.40-1.55(m, 4 H), 1.56, 1.58(s, 3 H), 1.61-1.67(m, 1 H), 2.08-2.31(m, 2 H), 3.51-3.60, 3.70-3.80(m, 1 H), 6.98-7.21(m, 2 H), 7.25-7.41(m, 2 H), 7.66, 8.27(d, J=6.4 Hz, d, J=6.8 Hz, 1 H); MS(ESI+) m/z 334(M+H)+。
Example 57
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine
Example 51D and (E) -4-aminoadamantane-1-sulfonamide (Sorensen, b. et al, bioorg. med. chem. lett., 2007, 17, 527-532) were treated using the method described in example 3C to obtain the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.48-1.57(m, 2 H), 1.63(s, 6 H), 1.74-2.11(m, 9 H), 2.22-2.32(m, 2 H), 3.96-4.06(m, 1 H), 6.64(s, 2 H), 7.08(t, J=7.8 Hz, 1 H), 7.27-7.35(m, 1 H), 7.38-7.45(m, 1 H), 7.92(d, J=6.1 Hz, 1 H); MS(ESI+) m/z 456(M+H)+。
Example 58
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine
Example 58A
2- (5-chloropyridin-2-yloxy) -2-methylpropanamide
The title compound was synthesized according to the procedure described for example 51A substituting 2- (5-chloropyridin-2-yloxy) -2-methylpropionic acid for 2- (2, 4-difluorophenoxy) -2-methylpropionic acid. (Liu, P., et al, Journal of Medicinal Chemistry, 2007, 50,15, 3427-3430). MS (ESI)+) m/z 215(M+H)+。
Example 58B
2- (5-chloropyridin-2-yloxy) -2-methylpropanenitrile
The title compound was synthesized by the method described for example 51B substituting example 58A for example 51A. MS (ESI)+) m/z 197(M+H)+。
Example 58C
2- (5-Chloropyridin-2-yloxy) -2-methylalanine ethyl ester hydrochloride
The title compound was synthesized by the method described for example 51C substituting example 58B for example 51B. MS (ESI)+) m/z 244(M+H)+。
Example 58D
2- (5-Chloropyridin-2-yloxy) -N-cyano-2-methylalanineimine ethyl ester
Using the method described in example 3BExample 58C and cyanamide (Aldrich) were processed to obtain the title compound. MS (ESI)+) m/z 268(M+NH4)+。
Example 58E
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 58D for example 3B. 1H NMR(300 MHz, DMSO-d 6) ppm 1.34-1.47(m, 2 H), 1.56-1.74(m, 7 H), 1.77(s, 6 H), 1.95-2.04(m, 2 H), 2.13-2.21(m, 2 H), 3.79-3.87(m, 1 H), 4.44(s, 1 H), 6.94(d, J=8.8 Hz, 1 H), 7.16(d, J=6.4 Hz, 1 H), 7.85(dd, J=8.8, 2.7 Hz, 1 H), 8.00(d, J=2.4 Hz, 1 H); MS(ESI+) m/z 390(M+H)+。
Example 59
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2-methylpropionamidine
The title compound was synthesized according to the procedure described in example 3C substituting E-2-amino-5-hydroxyadamantane and example 3B with E-4-aminoadamantane-1-carbonitrile (international publication WO 2007/118185, filed on 2007, 10/18), and example 58D, respectively.1H NMR(300 MHz, DMSO-d 6) ppm 1.51-1.64(m, 2 H), 1.78(s, 6 H), 1.80-1.94(m, 3 H), 1.98(d, 2 H), 2.06(d, 4 H), 2.17(d, 2 H), 3.92(d, 1 H), 6.94(d, J=8.7 Hz, 1 H), 7.26(d, J=5.6 Hz, 1 H), 7.86(dd, J=8.7, 2.8 Hz, 1 H), 7.99(d, J=2.8 Hz, 1 H); MS(ESI+) m/z 399(M+H)+。
Example 60
(1E) -N- (adamantan-1-yl) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 53F for example 3B, 1-amantadine for E-5-hydroxy-2-aminoadamantane.1H NMR(300 MHz, DMSO-d 6) ppm 1.50-1.92(m, 12 H)2.01-2.17(m, 9 H)7.13-7.33(m, 2 H)7.37(s, 1 H)7.56(dd, J=10.71, 2.38 Hz, 1 H); MS(DCI+) m/z 390(M+H)+。
Example 61
2- (4-chloro-2-fluorophenoxy) -N' -cyano-N-cyclooctyl-2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 53F for example 3B, 1-cyclooctylamine for E-5-hydroxy-2-aminoadamantane.1H NMR(300 MHz, DMSO-d 6) ppm 1.30-1.84(m, 20 H), 4.11(d, J=5.6 Hz, 1 H), 7.10(t, J=8.9 Hz, 1 H), 7.19-7.31(m, 1 H), 7.54(dd, J=10.5, 2.6 Hz, 1 H), 8.58(d, J=7.9 Hz, 1 H); MS(DCI+) m/z 366(M+H)+。
Example 62
(1E) -N- [ (E) -adamantan-2-yl ] -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 53F for example 3B, 2-amantadine for E-5-hydroxy-2-aminoadamantane.1H NMR(300 MHz, DMSO-d 6) ppm 1.51-1.94(m, 18 H)2.06(s, 2 H)4.00-4.15(m, 1 H)7.23-7.31(m, 2 H)7.59(dd, J=10.17, 1.70 Hz, 1 H)7.86(d, J=7.12 Hz, 1 H); MS(DCI+) m/z 390(M+H)+。 C21H25ClN3The analysis of FO calculated C, 64.69, H, 6.46 and N, 10.78. Measured value: C, 64.33; H, 6.34; N, 9.79。
Example 63
(E) -4- { [ (1E) -2- (4-chloro-2-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid methyl ester
Following the procedure described in example 3C, example 53F was used instead of example 3B, (E) -4-aminoadamantane-1-carboxylic acid methyl ester (Becker, c.l., et al, org. Process R)&D, 2008, 12, 1114-1118) instead of E-5-hydroxy-2-aminoadamantane, the title compound was synthesized.1H NMR(300 MHz, DMSO-d 6) ppm 1.56(d, J=13.22 Hz, 2 H)1.65(s, 6 H)1.71-2.00(m, 10 H)2.17(s, 2 H)3.60(s, 3 H)4.05(dd, J=3.73, 1.36 Hz, 1 H)7.14-7.33(m, 1 H)7.58(dd, J=10.17, 1.70 Hz, 1 H)7.87(d, J=7.12 Hz, 1 H); MS(DCI+) m/z 390(M+H)+。 C23H27N3FO3The analysis calculated value of (1) is C, 61.67, H, 6.08 and N, 9.38. Found 61.46 for C, 5.89 for H, 9.29 for N.
Example 64
(1E) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] -2-phenoxypropionamidine
The title compound was synthesized according to the procedure described for example 78 substituting example 19 for example 53.1H NMR(300 MHz, DMSO-d 6) ppm 1.43-1.84(m, 10 H)1.86-2.15(m, 7 H)2.32(s, 2 H)2.85(s, 3 H)4.04(d, J=1.36 Hz, 1 H)6.99(d, J=7.80 Hz, 2 H)7.12(t, J=7.29 Hz, 1 H)7.23-7.43(m, 2 H)7.70(d, J=6.44 Hz, 1 H); MS(DCI+) m/z 415(M+H)+。 C22H24N4The analytical scores of ClFO are C, 63.59, H, 7.03 and N, 10.11. Found C, 63.06, H, 7.03, N, 9.97.
Example 65
N' -cyano-N-cyclooctyl-2- (2, 4-difluorophenoxy) -2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting cyclooctylamine (Aldrich) and example 51D for E-2-amino-5-hydroxyadamantane and example 3B, respectively.1H NMR(300 MHz, DMSO-d 6) ppm 1.38-1.56(m, 8 H), 1.55-1.61(m, 6 H), 1.62-1.82(m, 6 H), 4.02-4.20(m, J=7.9 Hz, 1 H), 7.01-7.10(m, 1 H), 7.11-7.21(m, 1 H), 7.31-7.42(m, J=23.0 Hz, 1 H), 8.58(d, J=8.3 Hz, 1 H); MS(ESI+) m/z 350(M+H)+。
Example 66
N- (exo-bicyclo [2.2.1] hept-2-yl) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine
Exo-bicyclo [2.2.1 ] example 53F instead of example 3B was performed as described in example 3C]The title compound was synthesized with heptylamine in place of E-5-hydroxy-2-aminoadamantane.1H NMR(300 MHz, DMSO-d 6) ppm 0.99-1.29(m, 3 H)1.35-1.77(m, 11 H)2.09-2.36(m, 2 H)3.61-3.92(m, 1 H)7.10(t, J=8.82 Hz, 1 H)7.18-7.36(m, 1 H)7.53(dd, J=10.68, 2.54 Hz, 1 H)8.27(d, J=6.44 Hz, 1 H); MS(DCI+) m/z 349(M+H)+。
Example 67
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine
Example 58D and (E) -4-aminoadamantane-1-sulfone (Sorensen, b. et al, bioorg. med. chem. lett., 2007, 17, 527-532) were treated using the method described in example 3C to obtain the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.47-1.62(m, 2 H), 1.79(s, 6 H), 1.82-2.11(m, 9 H), 2.23-2.38(m, 2 H), 2.84(s, 3 H), 3.84-3.96(m, 1 H), 6.94(d, J=9.5 Hz, 1 H), 7.29(d, J=5.8 Hz, 1 H), 7.86(dd, J=8.8, 2.7 Hz, 1 H), 8.01(d, J=2.4 Hz, 1 H); MS(ESI+) m/z 452(M+H)+。
Example 68
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine
Example 58D and (E) -4-aminoadamantane-1-sulfonamide (Sorensen, b. et al, bioorg. med. chem. lett., 2007, 17, 527-532) were treated using the method described in example 3C to obtain the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.41-1.55(m, 2 H), 1.78(s, 6 H), 1.80-2.09(m, 9 H), 2.21-2.29(m, 2 H), 3.80-3.89(m, 1 H), 6.59(s, 2 H), 6.94(d, J=8.8 Hz, 1 H), 7.29(d, J=6.4 Hz, 1 H), 7.86(dd, J=8.8, 2.7 Hz, 1 H), 8.02(d, J=2.7 Hz, 1 H); MS(ESI+) m/z 453(M+H)+。
Example 69
N' -cyano-2- (2, 4-difluorophenoxy) -N- (hexahydro-2, 5-methanocyclopenta-len-3 a (1H) -yl) -2-methylpropionamidine
The title compound was synthesized by the method described for example 38, substituting example 51D for example 8B.1H NMR(300 MHz, DMSO-d 6) ppm 1.48-1.59(m, J=11.9 Hz, 4 H), 1.62(s, 6 H), 1.87-2.16(m, 6 H), 2.21-2.30(m, 2 H), 2.60(t, J=6.5 Hz, 1 H), 7.02-7.13(m, 1 H), 7.14-7.26(m, 1 H), 7.32-7.46(m, 1 H), 8.23(s, 1 H); MS(ESI+) m/z 360(M+H)+。
Example 70
(E) -4- { [ (1E) -N-cyano-2- (2, 4-difluorophenoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide
Example 70A
(E) -4- { [ (benzyloxy) carbonyl ] amino } adamantane-1-carboxylic acid methyl ester
Benzyl chloroformate (6.9 mL, 48.8 mmol) was added dropwise to (E) -4-aminoadamantane-1-carboxylic acid methyl ester hydrochloride (Becker, C.L., et al, org. Process R)&D, 2008, 12, 1114-1118) (10.0 g, 40.7 mmol) and diisopropylethylamine (21.3 mL, 122 mmol) in dry dichloromethane (100 mL) was stirred and cooled (0 ℃ C.). After stirring at room temperature for 2 hours, the reaction mixture was taken up with saturated NaHCO3Aqueous solution (50 mL) was quenched. With 50% NaHSO4Aqueous solution (50 mL) and saturated NaHCO3The organic phase was washed with aqueous solution (50 mL) and dried (Na)2SO4) And concentrated under reduced pressure. The residue was triturated in hexanes and filtered to give the title compound. MS (ESI)+) m/z 344(M+H)+。
Example 70B
(E) -4- { [ (benzyloxy) carbonyl ] amino } adamantane-1-carboxylic acid
The title compound was synthesized according to the procedure described for example 14A substituting example 70A for example 11. LCMS (ESI)+) m/z 330(M+H)+。
Example 70C
[ (E) -5-carbamoyl adamantan-2-yl ] carbamic acid benzyl ester
The title compound was synthesized by the method described in example 14B, substituting example 70B for example 11A compound (I) is provided. MS (ESI)+) m/z 329(M+H)+。
Example 70D
(E) -4-aminoadamantane-1-carboxamide
To a solution of example 70C (1.0 g, 3.0 mmol) in methanol (20 mL) was added Pd (OH)2C (0.2 g, 0.3 mmol). At H2The reaction mixture was stirred at room temperature for 4 hours under an atmosphere (balloon). The reaction mixture was then filtered through a pad of celite and concentrated under reduced pressure to provide the title compound. MS (ESI)+) m/z 195(M+H)+。
Example 70E
(E) -4- { [ (1E) -N-cyano-2- (2, 4-difluorophenoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide
Example 51D and example 70D were processed using the methods described for example 3C to obtain the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.46-1.58(m, 2 H), 1.64(s, 6 H), 1.70-2.00(m, 9 H), 2.10-2.20(m, 2 H), 3.98-4.10(m, 1 H), 6.75(s, 1 H), 7.02(s, 1 H), 7.04-7.14(m, 1 H), 7.25-7.36(m, 1 H), 7.36-7.49(m, 1 H), 7.89(d, J=7.1 Hz, 1 H); MS(ESI+) m/z 417(M+H)+。
Example 71
(1E) -N- (adamantan-1-yl) -N' -cyano-2- (2, 4-difluorophenoxy) -2-methylpropionamidine
Example 51D and 1-aminoadamantane were processed using the method described for example 38 to give the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.62(s, 6 H), 1.63-1.69(m, 6 H), 2.08(s, 9 H), 7.03-7.12(m, 1 H), 7.26(d, J=24.2 Hz, 1 H), 7.35-7.45(m, J=22.6 Hz, 1 H), 7.39-7.42(m, 1 H); MS(ESI+) m/z 375(M+H)+。
Example 72
(1E) -N- (1-azabicyclo [2.2.2] oct-3-yl) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine
Example 3B, 1-azabicyclo [2.2.2] as described in example 3C substituting example 53F for example 3B]The title compound was synthesized by substituting octyl-3-ylamine for E-5-hydroxy-2-aminoadamantane.1H NMR(300 MHz, DMSO-d 6) ppm 1.14(t, J=7.29 Hz, 2 H)1.35-1.57(m, 2 H)1.55-1.82(m, 9 H)2.11(d, J=2.71 Hz, 1 H)2.76-3.06(m, 3 H)4.04-4.30(m, 1 H)7.15(t, J=8.82 Hz, 1 H)7.22-7.31(m, 1 H)7.56(dd, J=10.68, 2.54 Hz, 1 H)8.67(d, J=6.10 Hz, 1 H); MS(DCI+) m/z 364(M+H)+。
Example 73
2- (4-chloro-2-fluorophenoxy) -N' -cyano-N- (hexahydro-2, 5-methanocyclopenta-len-3 a (1H) -yl) -2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 53F for example 3B and hexahydro-2, 5-methanocyclopenta-3 a (1H) -ylamine for E-5-hydroxy-2-aminoadamantane.1H NMR(300 MHz, DMSO-d 6) ppm 1.43-1.71(m, 10 H)1.83-2.16(m, 6 H)2.25(s, 2 H)2.60(t, J=6.61 Hz, 1 H)7.14(t, J=8.82 Hz, 1 H)7.21-7.36(m, 1 H)7.54(dd, J=10.68, 2.54 Hz, 1 H)8.21(s, 1 H); MS(DCI+) m/z 375(M+H)+。 C20H23N3The analytical scores of ClFO are C, 64.08, H, 5.92 and N, 11.21. Found C, 63.17, H, 6.26, N, 10.76.
Example 74
(E) -4- { [ (1E) -2- (4-chloro-2-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide
The title compound was synthesized according to the procedure described for example 14, substituting example 63 for example 11.1H NMR(300 MHz, DMSO-d 6) ppm 1.45-1.70(m, 8 H)1.70-1.99(m, 9 H)2.14(s, 2 H)3.88-4.19(m, 1 H)6.74(s, 1 H)7.01(s, 1 H)7.18-7.37(m, 2 H)7.58(dd, J=9.66, 1.86 Hz, 1 H)7.85(d, J=7.12 Hz, 1 H); MS(DCI+) m/z 430(M+H)+。
Example 75
(E) -4- ({ (1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide
Example 58D and example 70D were processed using the methods described for example 3C to obtain the title compound.1H NMR(300 MHz, CDCl3) ppm 1.62-1.66(m, 4 H), 1.85(s, 6 H), 1.88-1.94(m, 2 H), 1.98-2.05(m, 5 H), 2.15-2.24(m, 2 H), 4.13-4.23(m, 1 H), 5.20(s, 1 H), 5.57(s, 1 H), 6.85(d, J=9.5 Hz, 1 H), 6.84-6.91(m, 1 H), 7.62(dd, J=8.7, 2.4 Hz, 1 H), 8.03(d, J=2.8 Hz, 1 H); MS(ESI+) m/z 417(M+H)+。
Example 76
(E) -4- [ (2-methyl-2-phenoxyiminoacyl) amino ] adamantane-1-carboxamide
The title compound was obtained as a by-product by the method described in example 50.1H NMR(300 MHz, DMSO-d 6) ppm 1.30-1.42(m, 2 H), 1.50(s, 6 H), 1.69-1.88(m, 9 H), 1.93-2.13(m, 2 H), 3.44-3.54(m, 1 H), 6.66(s, 1 H), 6.87-6.99(m, 4 H), 7.17-7.27(m, 2 H)); MS(ESI+) m/z 356(M+H)+。
Example 77
(1E) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] -2- (pyridin-2-yloxy) propionamidine
The title compound was synthesized by the method described for example 49 substituting example 67 for example 8. 1H NMR(300 MHz, DMSO-d 6) ppm 1.45-1.56(m, 2 H), 1.65(s, 6 H), 1.67-1.78(m, 4 H), 1.79-1.94(m, 5 H), 2.10-2.19(m, 2 H), 3.97-4.09(m, 1 H), 6.73(s, 1 H), 6.95-7.04(m, 3 H), 7.08-7.17(m, 1 H), 7.29-7.40(m, 2 H), 7.65(d, J=6.8 Hz, 1 H); MS(ESI+) m/z 381(M+H)+。
Example 78
(1E) -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2- (2-fluorophenoxy) -2-methylpropionamidine
A solution of example 53(50 mg, 0.111 mmol) in methanol (3ml) was treated with ammonium formate (70.1 mg, 1.111 mmol) and palladium-10% palladium on carbon (1.182 mg, 0.011 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and concentrated. Purification by the reverse phase HPLC method using Phenomenex Luna C8, 5. mu.M 100A AXIA ™ column (30 mM. times.75 mM) and a gradient of 10-100% acetonitrile and 10 mM ammonium acetate/water provided the title compound.1H NMR(300 MHz, DMSO-d 6) ppm 1.52-1.83(m, 10 H)1.89-2.26(m, 9 H)4.07(s, 1 H)7.08-7.42(m, 4 H)7.91(d, J=6.35 Hz, 1 H); MS(DCI+) m/z 380(M+H)+。
Example 79
(1E) -N' -cyano-2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine
Pressing to realThe title compound was synthesized by the method described for example 78 substituting example 54 for example 53.1H NMR(300 MHz, DMSO-d 6) ppm 1.45-1.71(m, 8 H)1.72-2.13(m, 9 H)2.27(s, 2 H)4.02(dd, J=4.92, 1.53 Hz, 1 H)6.63(s, 2 H)7.14-7.42(m, 4 H)7.95(d, J=6.44 Hz, 1 H); MS(DCI+) m/z 435(M+H)+。
Example 80
(1E) -N' -cyano-2- (2-fluorophenoxy) -N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine
The title compound was synthesized according to the procedure described for example 78 substituting example 55 for example 53.1H NMR(300 MHz, DMSO-d 6) ppm 1.45(d, J=13.09 Hz, 2 H)1.54-1.78(m, 14 H)1.91-2.29(m, 3 H)3.99(d, J=2.38 Hz, 1 H)4.51(s, 1 H)7.06-7.44(m, 4 H)7.86(d, J=7.14 Hz, 1 H); MS(DCI+) m/z 372(M+H)+。
Example 81
4- { [ N-cyano-2-methyl-2-phenoxypropirimimido ] amino } bicyclo [2.2.1] heptane-1-carboxamide
To ethyl N-cyano-2-methyl-2-phenoxyalanine (CI-1) (300 mg, 1.29 mmol) and 4-aminobicyclo [ 2.2.1% ]To a mixture of heptane-1-carboxamide (BA-7) (217 mg, 1.29mmol) in ethanol (3 mL) was added 4- (dimethylamino) pyridine (47 mg, 0.387 mmol). The mixture was stirred at room temperature for 5 hours, then heated to 75 ℃ and stirred overnight. After concentration, the residue was purified by preparative reverse phase HPLC [ Waters 2767; benetnach 10-C1820 × 250 mm, 10 μm; 35-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/min; detection at 214 and 254 nm]To yield the title compound.1H NMR(400 MHz, CD3OD) ppm 7.34(t, J=7.8Hz, 2H), 7.14(t, J=7.4Hz, 1H), 7.0(d, J=8.4Hz, 2H), 2.10~2.15(m, 4H), 2.01~2.03(m,4H), 1.79~1.83(m,2H), 1.72(s, 6H); LCMS(ESI+) m/z 341.7(M+H)+。
Example 82
4- { [ N-cyano-2-methyl-2-phenoxypropirimimido ] amino } bicyclo [2.2.2] octane-1-carboxamide
Using the procedure described in example 81, with 4-aminobicyclo [2.2.2]Octane-1-carboxamide (BA-6) instead of 4-aminobicyclo [2.2.1]Heptane-1-carboxamide (BA-7), the title compound was prepared.1H NMR(400 MHz, CDCl3) ppm 7.32(t, J=8.0Hz, 2H),7.17(t, J=7.2Hz, 1H), 7.06(s, 1H), 6.91(d, J=8.0Hz, 2H), 6.20(s, 1H), 5.85(s, 1H), 4.81(br, 1H), 2.05~2.06(m, 6H), 1.92~1.94(m。6H), 1.68(s, 6H); LCMS(ESI+) m/z 355.7(M+H)+。
Example 83
N' -cyano-N- (4-cyanobicyclo [2.2.1] hept-1-yl) -2-methyl-2-phenoxypropionamidine
The title compound was prepared using the procedure described for example 84 substituting example 81 for example 82.1H NMR(400 MHz, CDCl3) ppm 7.47(s, 1H), 7.34(t, J=7.95Hz, 2H), 7.20(t, J=7.4Hz, 1H), 6.93(d, J=8.9Hz, 2H), 2.26(s, 2H), 2.07~2.16(m, 4H), 1.90~1.99(m, 4H), 1.71(s, 6H); LCMS(ESI+) m/z 323.7(M+H)+。
Example 84
N' -cyano-N- (4-cyanobicyclo [2.2.2] oct-1-yl) -2-methyl-2-phenoxypropionamidine
To a solution of example 82(70 mg, 0.2 mmol) and triethylamine (120 mg, 1.2 mmol) in dichloromethane cooled in an ice bath was added trifluoroacetic anhydride (125 mg, 0.6 mmol) dropwise. After the addition is completed, the The mixture was stirred at room temperature overnight. After removal of the solvent, the residue was purified by preparative reverse phase HPLC [ Waters 2767; benetnach 10-C1820 × 250 mm, 10 μm; 35-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/min; detection at 214 and 254 nm]To yield the title compound.1H NMR(400 MHz, CDCl3) ppm 7.33(t, J=7.85Hz, 2H), 7.19(t, J=7.4Hz, 1H), 7.01(s, 1H), 6.91(d, J=7.6Hz, 2H), 2.01~2.08(m, 12H), 1.69(s, 6H); LCMS(ESI+) m/z 337.7(M+H)+。
Example 85
2- (4-chlorophenoxy) -N' -cyano-N- [4- (difluoromethyl) bicyclo [2.2.2] oct-1-yl ] -2-methylpropionamidine
Reacting 4- (difluoromethyl) bicyclo [2.2.2]Octanol-1-amine (BA-4) and example 8B were mixed and the neat mixture was heated to 100 ℃ under nitrogen and stirred for 3 hours. After cooling, the mixture was dissolved in a small amount of ethanol and purified by preparative HPLC [ Waters 2767; benetnach 10-C1820 × 250 mm, 10 μm; 35-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/min; detection at 214 and 254 nm]To yield the title compound.1H NMR(400 MHz, DMSO-d 6) ppm 7.38(dd, J=8.8Hz 2H), 7.29(s, 1H), 6.96(d, J=8.8Hz 2H), 5.71(t, J=56.4Hz 1H), 1.98(m, 6H), 1.62(s, 6H), 1.58(m, 6H); LCMS(ESI+) m/z 396.7(M+H)+。
Example 86
N' -cyano-N- [4- (difluoromethyl) bicyclo [2.2.2] oct-1-yl ] -2-methyl-2-phenoxypropionamidine
The title compound was prepared using the method described for example 85 substituting N-cyano-2-methyl-2-phenoxyalanine ethyl ester (CI-1) for example 8B. Purification was accomplished by preparative reverse phase HPLC [ Waters 2767; benetnach 10-C1820 × 250 mm, 10 μm; 58-78% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/min A clock; detection at 214 and 254 nm]。1H NMR(400 MHz, DMSO-d 6) ppm 7.33(t, J=7.8Hz, 3H), 7.10(t, J=7.2Hz, 1H), 6.94(d, J=7.7Hz, 2H), 5.70(t, J=56.7Hz, 1H), 1.97~2.01(m, 6H), 1.62(s, 6H), 1.56~1.60(m, 6H); LCMS(ESI+) m/z 362(M+H)+。
Example 87
4- { [ N-cyano-2-methyl-2-phenoxypropirimimido ] amino } bicyclo [2.2.2] octane-1-carboxylic acid
N-cyano-2-methyl-2-phenoxyalanine ethyl ester (CI-1) (1 mmol) and 4-aminobicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (BA-2) (1 mmol) was mixed and the neat mixture was heated to 100 ℃ under nitrogen and stirred for 5 hours. After cooling, the mixture is purified by column chromatography on silica gel (mobile phase: CH)2Cl2/CH3OH =50/1) to give an impure ester product, which was dissolved in methanol (10 mL). To this solution was added a solution of LiOH (10 mg) in methanol (40 mL) and water (1 mL). The mixture was refluxed overnight. After removal of the solvent, the residue was dissolved in water, adjusted pH = 5-6 with HCl (1mol/L), and extracted with ethyl acetate (50 mL × 3). The combined extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by preparative reverse phase HPLC [ Waters 2767; benetnach 10-C1820 × 250 mm, 10 μm; 35-60% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/min; detection at 214 and 254 nm]To yield the title compound.
Example 88
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } bicyclo [2.2.1] heptane-1-carboxamide
Using the procedure described in example 85, with 4-aminobicyclo [2.2.1]]Heptane-1-carboxamide (BA-7) instead of 4- (difluoromethyl) bicyclo [2.2.2]Oct-1-amine (BA-4), the title compound was prepared. Purification by preparative reverse phase HPLC [ Waters 2 ]767; benetnach 10-C1820 × 250 mm, 10 μm; 36-60% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/min; detection at 214 and 254 nm]。1H NMR(400 MHz, CDCl3) ppm 7.36(s, 1H), 7.30(d, J=8.6Hz, 2H), 6.88(d, J=8.7Hz, 2H), 5.58(s, 1H), 5.41(s, 1H), 1.97~2.13(m, 8H), 1.78~1.82(m, 2H), 1.71(s, 6H); LCMS(ESI+) m/z 375.1(M+H)+。
Example 89
N' -cyano-N- [4- (difluoromethyl) bicyclo [2.2.1] hept-1-yl ] -2-methyl-2-phenoxypropionamidine
Using the procedure described in example 85, 4- (difluoromethyl) bicyclo [2.2.1]Hept-1-amine (BA-5) instead of 4- (difluoromethyl) bicyclo [2.2.2]The title compound was prepared from oct-1-amine (BA-4), N-cyano-2-methyl-2-phenoxyalanine ethyl ester (CI-1) instead of example 8B.1H NMR(400 MHz, CDCl3) ppm 7.50(s, 1H), 7.9(t, J=7.9Hz, 2H), 7.19(t, J=7.6Hz, 1H), 6.94(d, J=7.6Hz, 2H), 5.82(t, J=56.4Hz, 1H), 2.0(m, 8H), 1.72(s, 6H), 1.6~2.0(m, 2H); LCMS(ESI+) m/z 348.2(M+H)+。
Example 90
2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propanamidine
The title compound was isolated as a by-product from the synthesis of example 79.1H NMR(300 MHz, DMSO-d 6) ppm 1.24-1.40(m, 2 H)1.42-1.56(m, 6 H)1.79-2.18(m, 12 H)3.20-3.64(m, 2 H)6.52(s, 2 H)6.88-7.26(m, 4 H); MS(DCI+) m/z 410(M+H)+。
Example 91
2- (2-fluorophenoxy) -N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine
The title compound was isolated as a by-product from the synthesis of example 80.1H NMR(300 MHz, DMSO-d 6) ppm 1.39-1.63(m, 10 H), 1.72(s, 2 H), 1.88(s, 11 H), 6.89-7.15(m, 3 H), 7.14-7.29(m, 1 H)。MS(DCI+) m/z 347(M+H)+。
Example 92
N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methyl-2-phenoxypropionamidine
The title compound was obtained as a by-product by the method described in example 49.1H NMR(300 MHz, DMSO-d 6) ppm 1.17-1.33(m, 2 H), 1.48(s, 6 H), 1.50-1.80(m, 6 H), 1.81-2.06(m, 6 H), 4.17-4.39(m, 1 H), 6.84-7.00(m, 3 H), 7.14-7.30(m, 2 H); MS(ESI+) m/z 329(M+H)+。
Example 93
5-chloro-N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methoxybenzamidine
Example 93A
5-chloro-2-methoxybenzeneimidate ethyl ester hydrochloride
The title compound was synthesized according to the procedure described for example 51C, substituting 5-chloro-2-methoxybenzonitrile (Maybridge) for example 51B. MS (ESI)+) m/z 214(M+H)+。
Example 93B
5-chloro-N-cyano-2-methoxybenzylidene imino acid ethyl ester
The samples were processed using the method described in example 3BExample 93A and cyanamide (Aldrich) to obtain the title compound. MS (ESI)+) m/z 239(M+NH4)+。
Example 93C
5-chloro-N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methoxybenzamidine
The title compound was synthesized according to the procedure described for example 3C substituting example 93B for example 3B.1H NMR(300 MHz, DMSO-d 6) ppm 1.29-1.40(m, 2 H), 1.58-1.76(m, 6 H), 1.85-2.03(m, 3 H), 2.13-2.21(m, 2 H), 3.81(s, 3 H), 3.90-3.98(m, 1 H), 4.46(s, 1 H), 7.21(d, J=9.1 Hz, 1 H), 7.35(d, J=2.8 Hz, 1 H), 7.55(dd, J=8.9, 2.6 Hz, 1 H), 8.87(d, J=6.7 Hz, 1 H); MS(ESI+) m/z 361(M+H)+。
The following compounds may be prepared using knowledge known to those skilled in the art, or using the methods described in the examples above.
Example 93
2- (4-chlorophenoxy) -N' -cyano-N- (4-hydroxybicyclo [2.2.2] oct-1-yl) -2-methylpropionamidine.
Example 94
N' -cyano-N- (4-hydroxybicyclo [2.2.2] oct-1-yl) -2-methyl-2-phenoxypropionamidine.
Example 95
2- (4-chlorophenoxy) -N' -cyano-N- (4-cyanobicyclo [2.2.2] oct-1-yl) -2-methylpropionamidine.
Example 96
N' -cyano-N- (4-hydroxybicyclo [2.2.1] hept-1-yl) -2-methyl-2-phenoxypropionamidine.
The following examples were prepared using the procedures described in the schemes and examples above, or using procedures well known to those skilled in the art
4- ({2- [ (4-chlorobenzyl) oxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [4- (methylsulfonyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (pyridin-2-ylmethoxy) propyleneiminoyl ] amino } adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [4- (trifluoromethoxy) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- { [4- (trifluoromethoxy) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (4-cyanobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (4-methoxybenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- [ (N-cyano-2- { [ 2-fluoro-4- (trifluoromethyl) benzyl ] oxy } -2-methylpropanimidoyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2- { [4- (difluoromethoxy) benzyl ] oxy } -2-methylpropanimidoyl) amino ] adamantane-1-carboxylic acid;
4- [ (N-cyano-2- { [4- (difluoromethoxy) benzyl ] oxy } -2-methylpropanimidoyl) amino ] adamantane-1-carboxamide;
4- ({2- [ (4-chloro-2-fluorobenzyl) oxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [ (4-chloro-2-fluorobenzyl) oxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (4-methoxybenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- [ (N-cyano-2- { [ 2-fluoro-4- (trifluoromethyl) benzyl ] oxy } -2-methylpropanimidoyl) amino ] adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (pyridin-2-ylmethoxy) propyleneiminoyl ] amino } adamantane-1-carboxylic acid;
4- [ (2- { [ 2-bromo-4- (trifluoromethyl) benzyl ] oxy } -N-cyano-2-methylpropanimidoyl) amino ] adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (2, 6-difluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [ (2, 3-difluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [ (3, 4-difluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- { [2- (benzyloxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (2, 5-difluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [ (3, 5-difluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [ (3-methoxybenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [ (2-fluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [ (2, 6-difluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (2-cyanobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (2, 3-difluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (2-methoxybenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [ (4-fluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [ (3-chlorobenzyl) oxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (4-isopropylbenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- { [3- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- ({ N-cyano-2-methyl-2- [ (4-methylbenzyl) oxy ] malonimidoyl } amino) adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxylic acid methyl ester;
4- { [2- (1, 3-benzodioxol-5-ylmethoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [ (2, 4-dichlorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [ (2-methoxybenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (3-cyanobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (2-fluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({2- [ (4-tert-butylbenzyl) oxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (3-fluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [3- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [ (4-methylbenzyl) oxy ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (3, 5-difluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (3-methoxybenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [ (6-methylpyridin-2-yl) methoxy ] malonimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2-methyl-2- [ (6-methylpyridin-2-yl) methoxy ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (4-fluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [3- (trifluoromethoxy) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- { [3- (trifluoromethoxy) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (quinolin-2-ylmethoxy) propylimidoyl ] amino } adamantane-1-carboxamide;
methyl 4- { [ (cyanoimino) (1- { [4- (trifluoromethyl) benzyl ] oxy } cyclobutyl) methyl ] amino } adamantane-1-carboxylate;
4- ({ N-cyano-2- [ (2, 4-dichlorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (quinolin-2-ylmethoxy) propylimidoyl ] amino } adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [ (4-isopropylbenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [ (3-methylbenzyl) oxy ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (2, 5-difluorobenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- { [ (cyanoimino) (1- { [4- (difluoromethoxy) benzyl ] oxy } cyclopropyl) methyl ] amino } adamantane-1-carboxylic acid;
4- ({ (cyanoimino) [1- (quinolin-8-ylmethoxy) cyclopropyl ] methyl } amino) adamantane-1-carboxylic acid;
4- { [ (cyanoimino) (1- { [4- (difluoromethoxy) benzyl ] oxy } cyclopropyl) methyl ] amino } adamantane-1-carboxamide;
4- ({ (cyanoimino) [1- (quinolin-8-ylmethoxy) cyclopropyl ] methyl } amino) adamantane-1-carboxamide;
4- { [ (cyanoimino) (1- { [4- (trifluoromethyl) benzyl ] oxy } cyclobutyl) methyl ] amino } adamantane-1-carboxylic acid;
4- { [ (cyanoimino) (1- { [4- (trifluoromethyl) benzyl ] oxy } cyclobutyl) methyl ] amino } adamantane-1-carboxamide;
N' -cyano-N- (5-hydroxy-2-adamantyl) -2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } ethanamidine;
n' -cyano-2- (2, 6-dimethylmorpholin-4-yl) -N- (5-hydroxy-2-adamantyl) propionamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -2- (4-hydroxypiperidin-1-yl) propionamidine;
2-azepan-1-yl-N' -cyano-N- (5-hydroxy-2-adamantyl) propionamidine;
carbamic acid 4- [ (N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } ethanimidoyl) amino ] -1-adamantyl ester;
4- [ (N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } ethanimidoyl) amino ] -1-adamantyl acetate;
n- {4- [ (N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } ethanimidoyl) amino ] -1-adamantyl } acetamide;
n' -cyano-N- (5-hydroxy-2-adamantyl) -2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
n' -cyano-N- (5-fluoro-2-adamantyl) -2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } ethanamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -2- [4- (5-methylpyridin-2-yl) piperazin-1-yl ] propionamidine;
2- { [2- (4-chlorophenyl) ethyl ] amino } -N' -cyano-N- (5-hydroxy-2-adamantyl) propionamidine;
2- (4-benzylpiperidin-1-yl) -N' -cyano-N- (5-hydroxy-2-adamantyl) propionamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -2- (6,7,9, 10-tetrahydro-8H- [1,3]Dioxacyclopenteno [4,5-g][3]Benzazepine compounds-8-yl) propionamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -2- (4-pyridin-2-ylpiperazin-1-yl) propionamidine;
n' -cyano-2- [4- (4-fluorophenyl) piperazin-1-yl ] -N- (5-hydroxy-2-adamantyl) propionamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -2- [4- (4-methoxyphenyl) piperazin-1-yl ] propionamidine;
n' -cyano-2- [4- (5-cyanopyridin-2-yl) piperazin-1-yl ] -N- (5-hydroxy-2-adamantyl) propionamidine;
n' -cyano-2- [4- (2-furoyl) piperazin-1-yl ] -N- (5-hydroxy-2-adamantyl) propionamidine;
n' -cyano-2- (1, 3-dihydro-2H-isoindol-2-yl) -N- (5-hydroxy-2-adamantyl) propionamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -2- {4- [4- (trifluoromethyl) phenyl ] piperazin-1-yl } propionamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
2- [3- (4-chlorophenoxy) azetidin-1-yl ] -N' -cyano-N- (5-hydroxy-2-adamantyl) propionamidine;
N' -cyano-2- [4- (2-fluorophenoxy) piperidin-1-yl ] -N- (5-hydroxy-2-adamantyl) propionamidine;
n' -cyano-2- [3- (2-fluorophenoxy) piperidin-1-yl ] -N- (5-hydroxy-2-adamantyl) propionamidine;
n' -cyano-2- [3- (3-fluorophenoxy) pyrrolidin-1-yl ] -N- (5-hydroxy-2-adamantyl) propionamidine;
n' -cyano-2- [ [2- (3, 4-dichlorophenyl) ethyl ] (methyl) amino ] -N- (5-hydroxy-2-adamantyl) propanamidine;
2- [ [2- (4-chlorophenyl) -1-methylethyl ] (methyl) amino ] -N' -cyano-N- (5-hydroxy-2-adamantyl) propionamidine;
2- (5-chloro-2, 3-dihydro-1H-indol-1-yl) -N' -cyano-N- (5-hydroxy-2-adamantyl) propionamidine;
2- [4- (6-chloropyridin-3-yl) piperazin-1-yl ] -N' -cyano-N- (5-hydroxy-2-adamantyl) propionamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -2- (3-phenylazetidin-1-yl) propionamidine;
n' -cyano-N- [5- (hydroxymethyl) -2-adamantyl ] -2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -N-methyladamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -N-methoxyadamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -N-hydroxyadamantane-1-carboxamide;
n- [5- (aminomethyl) -2-adamantyl ] -N' -cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -1- { [4- (trifluoromethyl) benzyl ] amino } cyclopropanecarboxamidine;
4- ({ N-cyano-2-methyl-2- [2- (trifluoromethyl) pyrrolidin-1-yl ] malonimidoyl } amino) adamantane-1-carboxamide;
4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
n' -cyano-N- (5-hydroxy-2-adamantyl) -1-piperidin-1-cyclopropanecarboxamidine;
n' -cyano-2-methyl-N- [5- (5-methyl-1, 2, 4-)Oxadiazol-3-yl) -2-adamantyl]-2- {4- [5- (trifluoromethyl) pyridin-2-yl]Piperazin-1-yl } propionamidine;
n' -cyano-2-methyl-N- [5- (2H-tetrazol-5-yl) -2-adamantyl ] -2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
4- [ (2- {4- [ [ (4-chlorophenyl) sulfonyl ] (cyclopropyl) amino ] piperidin-1-yl } -N-cyanomalonimidoyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxamide;
N' -cyano-N- (5-hydroxy-2-adamantyl) -2-methyl-2- [2- (trifluoromethyl) pyrrolidin-1-yl ] propionamidine;
4- { [ N-cyano-2- (3-fluoropyrrolidin-1-yl) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2- (3-fluoropyrrolidin-1-yl) malonimidoyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) propyleneiminoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2- [2- (trifluoromethyl) pyrrolidin-1-yl ] malonimidoyl } amino) adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (4-pyridin-2-ylpiperazin-1-yl) propyleneiminoyl ] amino } adamantane-1-carboxylic acid methyl ester;
4- { [ N-cyano-2-methyl-2- (4-pyridin-2-ylpiperazin-1-yl) propyleneiminoyl ] amino } adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (2-methyl-4-pyridin-2-ylpiperazin-1-yl) propyleneiminoyl ] amino } adamantane-1-carboxylic acid;
4- ({2- [4- (5-chloropyridin-2-yl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) ethylimidoyl ] amino } adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [2- (trifluoromethyl) pyrrolidin-1-yl ] ethylimidoyl } amino) adamantane-1-carboxylic acid;
4- { [ (cyanoimino) (1- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } cyclopropyl) methyl ] amino } adamantane-1-carboxylic acid;
4- [ (N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } ethanimidoyl) amino ] adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (4-pyridin-2-ylpiperazin-1-yl) propyleneiminoyl ] amino } adamantane-1-carboxamide;
4- [ (N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } ethanimidoyl) amino ] adamantane-1-carboxamide;
n' -cyano-2-methyl-N- [5- (4H-1,2, 4-triazol-3-yl) -2-adamantyl ] -2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) -2-methylpropanimidoyl ] amino } -N- (2-furylmethyl) adamantane-1-carboxamide;
4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) -2-methylpropanimidoyl ] amino } -N- (pyridin-4-ylmethyl) adamantane-1-carboxamide;
4- { [ (cyanoimino) (1- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } cyclopropyl) methyl ] amino } adamantane-1-carboxamide;
4- ({2- [4- (4-chlorophenyl) piperidin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (4-phenylpiperidin-1-yl) propylimidoyl ] amino } adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (1,2,4, 5-tetrahydro-3H-3-benzazepine-3-yl) malonimidoyl]Amino } adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- {4- [4- (trifluoromethyl) phenyl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [2- (trifluoromethyl) pyrrolidin-1-yl ] ethylimidoyl } amino) adamantane-1-carboxamide;
4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) ethylimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [ 2-methyl-4- (5-methylpyridin-2-yl) piperazin-1-yl ] propyleneiminoyl } amino) adamantane-1-carboxylic acid;
4- { [ N-cyano-2- (3-fluoropiperidin-1-yl) propyleneimido ] amino } adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- [ (N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- [ (N-cyano-2- {2- (trifluoromethyl) -4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } ethanimidoyl) amino ] adamantane-1-carboxamide;
4- ({ N-cyano-2- [4- (5-fluoropyridin-3-yl) -1, 4-diazepan-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- [ (N-cyano-2-cyclopropyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } ethanimidoyl) amino ] adamantane-1-carboxylic acid;
4- { [ (cyanoimino) (1- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } cyclobutyl) methyl ] amino } adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- {5- [3- (trifluoromethyl) phenyl ] -1, 5-diazacyclooctan-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- ({ N-cyano-2-methyl-2- [4- (3-methylphenyl) -1, 4-diazepan-1-yl ] imidylyl } amino) adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2-phenoxyiminoacyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
4- ({2- [7- (5-bromopyridin-2-yl) -3, 7-diazabicyclo [3.3.1] non-3-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({2- [5- (6-chloropyridin-3-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (3-pyridin-3-yl-3, 9-diazabicyclo [4.2.1] non-9-yl) propyleneiminoyl ] amino } adamantane-1-carboxamide;
4- ({ [ (4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) -2-methylpropanimidoyl ] amino } -1-adamantyl) carbonyl ] amino } methyl) benzoic acid;
4- [ (N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } butylimidoyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2-cyclopropyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } ethanimidoyl) amino ] adamantane-1-carboxamide;
4- { [ (cyanoimino) (1- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } cyclobutyl) methyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [ (2-methylcyclohexyl) oxy ] malonimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2-methyl-2- [ (3-methylcyclohexyl) oxy ] malonimidoyl } amino) adamantane-1-carboxylic acid;
4- { [ N-cyano-2- (cycloheptyloxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
4- { [ N-cyano-2- (cyclohexylmethoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
4- { [2- (benzyloxy) -N-cyanoethylimidoyl ] amino } adamantane-1-carboxylic acid;
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) -2-methylpropanimidoyl ] amino } -N- (1, 3-thiazol-5-ylmethyl) adamantane-1-carboxamide;
4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) -2-methylpropanimidoyl ] amino } -N- (2-methoxybenzyl) adamantane-1-carboxamide;
4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) -2-methylpropanimidoyl ] amino } -N- (3, 4-dimethoxybenzyl) adamantane-1-carboxamide;
4- ({2- [9- (6-chloropyridin-3-yl) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- [ (2-anilino-N-cyano-2-methylpropanimidoyl) amino ] adamantane-1-carboxamide;
4- ({ N-cyano-2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (4-phenylpiperazin-1-yl) propyleneiminoyl ] amino } adamantane-1-carboxylic acid;
4- ({ N-cyano-2-methyl-2- [4- (4-methylphenyl) piperazin-1-yl ] malonimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (1, 3-benzothiazol-2-yl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [4- (3, 4-dichlorophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2-methyl-2- [4- (3-methylphenyl) piperazin-1-yl ] malonimidoyl } amino) adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- {4- [2- (trifluoromethyl) phenyl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [4- (2, 4-difluorophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2-methyl-2- [4- (6-methylpyridin-2-yl) piperazin-1-yl ] malonimidoyl } amino) adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (4-pyrimidin-2-ylpiperazin-1-yl) propyleneiminoyl ] amino } adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [4- (4-fluorophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- {4- [3- (trifluoromethyl) phenyl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- {4- [3- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- ({2- [4- (3-chlorophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (4-acetylphenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -N, N-dimethyladamantane-1-carboxamide;
4- { [ [1- (4-chlorophenyl) cyclobutyl ] (cyanoimino) methyl ] amino } adamantane-1-carboxylic acid;
4- { [ (cyanoimino) (1-phenylcyclopropyl) methyl ] amino } adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2-phenylpropanimidoyl) amino ] adamantane-1-carboxylic acid;
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [ (4-methylcyclohexyl) oxy ] malonimidoyl } amino) adamantane-1-carboxamide;
n- {4- [ (N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -1-adamantyl } acetamide;
4- { [ N-cyano-2-methyl-2- (4-pyrimidin-2-ylpiperazin-1-yl) propyleneiminoyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (4-pyrazin-2-ylpiperazin-1-yl) propyleneiminoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2- [4- (4-fluorophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [4- (3-cyanopyridin-2-yl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [4- (6-methylpyridin-3-yl) -1, 4-diazacyclohept-1-yl ] malonimidoyl } amino) adamantane-1-carboxamide;
4- [ (2- {4- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } -N-cyano-2-methylpropanimidoyl) amino ] adamantane-1-carboxylic acid;
4- [ (N-cyano-2-phenoxyiminoacyl) amino ] adamantane-1-carboxamide;
4- { [2- (benzyloxy) -N-cyanoethylimidoyl ] amino } adamantane-1-carboxamide;
4- (2- { [ (4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) -2-methylpropanimidoyl ] amino } -1-adamantyl) carbonyl ] amino } ethyl) benzoic acid;
4- { [ N-cyano-2-methyl-2- (2-methylphenoxy) propylimidoyl ] amino } adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (4-methylphenoxy) propylimidoyl ] amino } adamantane-1-carboxylic acid;
4- { [2- (2-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2-phenylpropanimidoyl) amino ] adamantane-1-carboxamide;
4- { [ (cyanoimino) (1-phenylcyclopropyl) methyl ] amino } adamantane-1-carboxamide;
4- { [ [1- (4-chlorophenyl) cyclobutyl ] (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
n' -cyano-N- {5- [ (methylsulfonyl) amino ] -2-adamantyl } -2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
4- { [ N-cyano-2- (2-methoxyphenoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2- (4-methoxyphenoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [3- (trifluoromethyl) phenoxy ] malonimidoyl } amino) adamantane-1-carboxamide;
n' -cyano-N- [5- (1-hydroxy-1-methylethyl) -2-adamantyl ] -2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
4- { [ N-cyano-2-methyl-2- (4-methylphenoxy) propylimidoyl ] amino } adamantane-1-carboxamide;
4- { [2- (3-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (tetrahydro-2H-pyran-2-ylmethoxy) propylimidoyl ] amino } adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (4-phenylpiperazin-1-yl) propyleneiminoyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2- (3-methoxyphenoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [4- (trifluoromethoxy) phenoxy ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [4- (2-methoxyphenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [ methyl (phenyl) amino ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [4- (2, 4-dimethoxyphenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- { [ N-cyano-2- (cyclohexylmethoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2- [4- (2, 3-dicyanophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
n' -cyano-N- [5- (cyanomethyl) -2-adamantyl ] -2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
4- ({ N-cyano-2-methyl-2- [4- (4-nitrophenyl) piperazin-1-yl ] malonimidoyl } amino) adamantane-1-carboxylic acid;
2- (4-chlorophenoxy) -N' -cyano-N- (5-hydroxy-2-adamantyl) -2-methylpropionamidine;
4- ({ N-cyano-2- [4- (2, 4-dichlorophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
n-2-adamantyl-2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
N-2-adamantyl-N' -cyano-2-methyl-2-phenylpropionamidine;
N-2-adamantyl-N' -cyano-1-phenylcyclopropanecarboxamidine;
{4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -1-adamantyl } acetic acid;
4- ({2- [4- (4-chloro-2-fluorophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- [ (N-cyano-2-methyl-2- {4- [4- (trifluoromethyl) pyrimidin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- ({2- [4- (3-chloro-4-fluorophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [4- (4-cyanophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (4-bromophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (5-chloro-2-methoxyphenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (2-chlorophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [4- (2-cyanophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [4- (2-fluorophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2-methyl-2- [4- (2-methylphenyl) piperazin-1-yl ] malonimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (4-chlorophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
6- [ (1-cycloheptyl-4, 4-dimethyl-5-oxopyrrolidin-3-yl) methoxy ] nicotinonitrile;
4- ({2- [4- (3-chloropyridin-2-yl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- [ (2- {4- [ 2-chloro-4- (trifluoromethyl) phenyl ] piperazin-1-yl } -N-cyano-2-methylpropanimidoyl) amino ] adamantane-1-carboxylic acid;
4- { [ N-cyano-2- (3-fluoropyrrolidin-1-yl) -2-methylpropanimidoyl ] amino } -N- (pyridin-3-ylmethyl) adamantane-1-carboxamide;
4- ({2- [ (4-chlorophenyl) thio ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (3-phenylpiperidin-1-yl) propylimidoyl ] amino } adamantane-1-carboxamide;
4- ({2- [4- (2-chloro-4-methylphenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- { [2- (3-bromophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
1-cycloheptyl-4- { [ (2-fluorophenyl) (methyl) amino ] methyl } -3, 3-dimethylpyrrolidin-2-one;
4- ({ N-cyano-2- [4- (2-fluorophenyl) piperidin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2-methyl-2- [4- (2-methylphenyl) piperidin-1-yl ] imidylyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (2-chloro-4-fluorophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ [ (4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) carbonyl ] amino } methyl) benzoic acid;
4- { [2- ({1- [ (benzyloxy) carbonyl ] piperidin-4-yl } methoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [4- (2-furoyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (2-chloro-4-cyanophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (2-chloro-4-fluorophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
1-cycloheptyl-3, 3-dimethyl-4- (phenoxymethyl) pyrrolidin-2-one;
4- { [ [1- (4-chlorophenyl) cyclohexyl ] (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
4- { [ [1- (4-chlorophenyl) cyclopropyl ] (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
4- { [ [1- (4-chlorophenyl) cyclopentyl ] (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
4- { [2- (4-chlorophenyl) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- { [ (cyanoimino) (1-phenylcyclopentyl) methyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2- (2, 3-dimethylphenoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
carbamic acid 4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -1-adamantyl ester;
4- [ (2- {4- [ (4-chlorophenyl) sulfonyl ] piperazin-1-yl } -N-cyano-2-methylpropanimidoyl) amino ] adamantane-1-carboxylic acid;
4- { [2- (benzyloxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
4- (4- { [ (5-cyanopyridin-2-yl) oxy ] methyl } -3, 3-dimethyl-2-oxopyrrolidin-1-yl) azepane-1-carboxamide;
4- ({ N-cyano-2- [4- (2, 4-difluorophenyl) piperidin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
6- { [1- (5-hydroxycyclooctyl) -4, 4-dimethyl-5-oxopyrrolidin-3-yl ] methoxy } nicotinonitrile;
4- ({ N-cyano-2- [4- (4-cyano-2-fluorophenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- (2- (cyanoimino) -4- { [ (5-cyanopyridin-2-yl) oxy ] methyl } -3, 3-dimethylpyrrolidin-1-yl) adamantane-1-carboxamide;
9- (4- { [ (5-cyanopyridin-2-yl) oxy ] methyl } -3, 3-dimethyl-2-oxopyrrolidin-1-yl) bicyclo [3.3.1] nonane-3-carboxamide;
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- [2- { [5- (aminocarbonyl) -2-adamantyl ] amino } -2- (cyanoimino) -1, 1-dimethylethoxy ] phenylcarbamic acid tert-butyl ester;
ethyl 4- (4- { [ (5-cyanopyridin-2-yl) oxy ] methyl } -3, 3-dimethyl-2-oxopyrrolidin-1-yl) bicyclo [5.1.0] octane-8-carboxylate;
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
[ (4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) carbonyl ] glycine;
3- ({ [ (4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) carbonyl ] amino } methyl) benzoic acid;
4- ({ (cyanoimino) [1- (3-fluorophenyl) cyclopentyl ] methyl } amino) adamantane-1-carboxamide;
4- { [ [1- (2-chloro-4-fluorophenyl) cyclopentyl ] (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
4- ({ (cyanoimino) [1- (4-fluorophenyl) cyclopentyl ] methyl } amino) adamantane-1-carboxamide;
4- ({ (cyanoimino) [1- (2-fluorophenyl) cyclopentyl ] methyl } amino) adamantane-1-carboxamide;
4- { [ (cyanoimino) (1-methylcyclohexyl) methyl ] amino } adamantane-1-carboxamide;
4- ({ (cyanoimino) [1- (2, 4-dichlorophenyl) cyclopropyl ] methyl } amino) adamantane-1-carboxamide;
4- ({ (cyanoimino) [1- (4-methoxyphenyl) cyclopropyl ] methyl } amino) adamantane-1-carboxamide;
4- ({ (cyanoimino) [1- (4-methylphenyl) cyclopropyl ] methyl } amino) adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { 3-methyl-4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [4- (4-cyanophenyl) -3, 5-dimethyl-1H-pyrazol-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2- [4- (4-cyanophenyl) -3, 5-dimethyl-1H-pyrazol-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
6- { [4, 4-dimethyl-1- (4-methylbicyclo [2.2.2] oct-1-yl) -5-oxopyrrolidin-3-yl ] methoxy } nicotinonitrile;
4- { [ N-cyano-2-methyl-2- (4-pyridin-4-ylphenyl) propyleneiminoyl ] amino } adamantane-1-carboxamide;
6- { [1- (5-cyanocyclooctyl) -4, 4-dimethyl-5-oxopyrrolidin-3-yl ] methoxy } nicotinonitrile;
4- [ (N-cyano-2-methyl-2-thiophen-2-ylpropanimidoyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2-thiophen-3-ylpropanimidoyl) amino ] adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [5- (trifluoromethyl) pyridin-2-yl ] malonimidoyl } amino) adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] phenyl } malonimidoyl) amino ] adamantane-1-carboxamide;
4- ({2- [ 4-chloro-2- (pyrrolidin-1-ylsulfonyl) phenoxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [4- (methylsulfonyl) phenoxy ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({ (cyanoimino) [1- (4-methoxyphenyl) cyclopentyl ] methyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [ (3-methylphenyl) amino ] malonimidoyl } amino) adamantane-1-carboxamide;
4- [2- { [5- (aminocarbonyl) -2-adamantyl ] amino } -2- (cyanoimino) -1, 1-dimethylethyl ] piperazine-1-carboxylic acid tert-butyl ester;
n' -cyano-2- (3-fluoropyrrolidin-1-yl) -N- (5-hydroxy-2-adamantyl) propionamidine;
4- ({ N-cyano-2-methyl-2- [2- (methylsulfonyl) phenoxy ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({2- [4- (2-bromophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- { [2- (4-bromophenyl) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({2- [ (3-chlorophenyl) amino ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (3-methoxyphenyl) amino ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [4- (4-cyanophenyl) -3, 5-dimethyl-1H-pyrazol-1-yl ] -2-methylpropanimidoyl } amino) -N- (1, 3-thiazol-5-ylmethyl) adamantane-1-carboxamide;
4- ({2- [4- (6-chloropyrimidin-4-yl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (6-chloropyridazin-3-yl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (2-chloropyrimidin-4-yl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- [ (2- { 4-chloro-2- [ (diethylamino) sulfonyl ] phenoxy } -N-cyano-2-methylpropanimidoyl) amino ] adamantane-1-carboxamide;
n- [ ({4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -1-adamantyl } amino) carbonyl ] glycine;
4- ({ N-cyano-2- [4- (5-cyanopyridin-2-yl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [4- (3-chloro-5-cyanopyridin-2-yl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
4- ({ N-cyano-2-methyl-2- [4- (1, 3-thiazol-2-yl) piperazin-1-yl ] malonimidoyl } amino) adamantane-1-carboxylic acid;
4- ({2- [ (5-bromopylidin-2-yl) oxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
1- (5-cyano-2-adamantyl) -4- { [ (5-cyanopyridin-2-yl) oxy ] methyl } -3, 3-dimethylpyrrolidin-2-ylidene cyanamide;
4- ({ N-cyano-2-methyl-2- [4- (pyrrolidin-1-ylsulfonyl) phenoxy ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (4-methoxyphenyl) amino ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- [ (N-cyano-2- { [4- (dimethylamino) phenyl ] amino } -2-methylpropanimidoyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [4- (trifluoromethyl) phenyl ] amino } propionimidyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [3- (trifluoromethyl) phenyl ] amino } propionimidyl) amino ] adamantane-1-carboxamide;
4- ({ (cyanoimino) [ 3-methyl-1- (2-methylbenzyl) -2-oxopiperidin-3-yl ] methyl } amino) adamantane-1-carboxamide;
4- { [ N-cyano-2- (2-cyanophenoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- (2- (cyanoimino) -3, 3-dimethyl-4- { [4- (1H-1,2, 4-triazol-1-yl) phenoxy ] methyl } pyrrolidin-1-yl) adamantane-1-carboxamide;
4- (2- (cyanoimino) -4- { [4- (1H-imidazol-1-yl) phenoxy ] methyl } -3, 3-dimethylpyrrolidin-1-yl) adamantane-1-carboxamide;
4- ({ N-cyano-2- [4- (2-hydroxyphenyl) piperazin-1-yl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylic acid;
2- (2-chloro-4-fluorophenoxy) -N' -cyano-N- (5-hydroxy-2-adamantyl) -2-methylpropionamidine;
4- [2- { [5- (aminocarbonyl) -2-adamantyl ] amino } -2- (cyanoimino) -1, 1-dimethylethyl ] -N- (tert-butyl) piperazine-1-carboxamide;
4- { [ N-cyano-2- (4-hydroxyphenoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (4-methoxyphenyl) thio ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
n' -cyano-N- [5- (carboxamido) -2-adamantyl ] -2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
4- { [ (1-benzyl-3-methyl-2-oxopyrrolidin-3-yl) (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
4- ({ (cyanoimino) [ 3-methyl-1- (2-methylbenzyl) -2-oxopyrrolidin-3-yl ] methyl } amino) adamantane-1-carboxamide;
4- { [ [1- (2-chlorobenzyl) -3-methyl-2-oxopyrrolidin-3-yl ] (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
4- { [ [1- (3-chlorobenzyl) -3-methyl-2-oxopyrrolidin-3-yl ] (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
2- (2-chloro-4-fluorophenoxy) -N' -cyano-2-methyl-N- [5- (2H-tetrazol-5-yl) -2-adamantyl ] propionamidine;
4- ({ N-cyano-2-methyl-2- [4- (1-methyl-1H-pyrazol-4-yl) phenyl ] imidyl } amino) adamantane-1-carboxamide;
2- (2-chloro-4-fluorophenoxy) -N' -cyano-2-methyl-N- [5- (methylthio) -2-adamantyl ] propionamidine;
2- (2-chloro-4-fluorophenoxy) -N' -cyano-2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
2- (2-chloro-4-fluorophenoxy) -N' -cyano-2-methyl-N- [5- (methylsulfinyl) -2-adamantyl ] propionamidine;
4- { [2- (3-bromophenyl) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2- [4- (3, 5-dimethyliso-3)Oxazol-4-yl) phenyl]-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (4-pyridin-3-ylphenyl) propyleneiminoyl ] amino } adamantane-1-carboxamide;
n- [5- (aminosulfonyl) -2-adamantyl ] -2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
4- { [ ({4- [ (N-cyano-2-methyl-2-thiophen-2-ylpropanimidoyl) amino ] -1-adamantyl } carbonyl) amino ] methyl } benzoic acid;
4- ({ N-cyano-2-methyl-2- [4- (1H-pyrazol-4-yl) phenyl ] malonimidoyl } amino) adamantane-1-carboxamide;
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -N- (4- { [ (methylsulfonyl) amino ] carbonyl } benzyl) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (4-methoxyphenyl) sulfinyl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2- [ (4-methoxyphenyl) sulfonyl ] -2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ (cyanoimino) [ 3-methyl-1- (1-methyl-1-phenylethyl) -2-oxopyrrolidin-3-yl ] methyl } amino) adamantane-1-carboxamide;
4- ({ (cyanoimino) [ 3-methyl-2-oxo-1- (1-phenylethyl) pyrrolidin-3-yl ] methyl } amino) adamantane-1-carboxamide;
2- (4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) acetamide;
4- { [ N-cyano-2-methyl-2- (1, 3-thiazol-2-yl) propyleneiminoyl ] amino } adamantane-1-carboxamide;
4- { [ [1- (4-chlorobenzyl) -3-methylpiperidin-3-yl ] (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2- (4-hydroxyphenyl) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- [2- (cyanoimino) -3, 3-dimethyl-4- ({ [5- (trifluoromethyl) pyridin-2-yl ] oxy } methyl) pyrrolidin-1-yl ] -N' -hydroxyadamantane-1-carboxamidine;
4- [2- (cyanoimino) -3, 3-dimethyl-4- ({ [5- (trifluoromethyl) pyridin-2-yl ] oxy } methyl) pyrrolidin-1-yl ] adamantane-1-carboxamide;
4- { [ (1-benzyl-3-methyl-2-oxopiperidin-3-yl) (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (4-phenoxyphenyl) propionimidoyl ] amino } adamantane-1-carboxamide;
(4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) acetic acid;
4- [2- (cyanoimino) -3, 3-dimethyl-4- ({ [5- (trifluoromethyl) pyridin-2-yl ] oxy } methyl) pyrrolidin-1-yl ] adamantan-1-carboxamidine;
2- (4-chlorophenoxy) -N' -cyano-2-methyl-N- [5- (2H-tetrazol-5-ylmethyl) -2-adamantyl ] propionamidine;
4- { [2- (1-benzothien-3-yl) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
n- {5- [ (aminosulfonyl) methyl ] -2-adamantyl } -2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
4- { [ [1- (4-chlorophenoxy) cyclobutyl ] (cyanoimino) methyl ] amino } adamantane-1-carboxamide;
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -N' -hydroxyadamantane-1-carboxamidine;
4- [ ({ [ (4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) methyl ] sulfonyl } amino) methyl ] benzoic acid;
2- (4-chlorophenoxy) -N' -cyano-N- [5- (1H-imidazol-2-yl) -2-adamantyl ] -2-methylpropionamidine;
4- { [ N-cyano-2- (5-fluoropyridin-2-yl) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
3- (4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) acrylic acid;
4- [ (N-cyano-2-methyl-2- { [5- (1H-pyrazol-1-yl) pyridin-2-yl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
2- (4-chlorophenoxy) -N' -cyano-N- (5-iso-phenoxy)Oxazol-5-yl-2-adamantyl) -2-methylpropionamidine;
4- [ (N-cyano-2-methyl-2-quinoxalin-2-ylpropanimidoyl) amino ] adamantane-1-carboxamide;
2- (4-chlorophenoxy) -N' -cyano-2-methyl-N- {5- [ (2-morpholin-4-ylethoxy) methyl ] -2-adamantyl } propionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -2- (2-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2-methyl-2- (2-methylphenoxy) propionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2-methyl-2- (4-methylphenoxy) propionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2-methyl-2- [2- (trifluoromethyl) phenoxy ] propionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2-methyl-2- [2- (trifluoromethoxy) phenoxy ] propionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -2- (2-chloro-4-fluorophenoxy) -N' -cyano-2-methylpropionamidine;
n' -cyano-N- [5- (1-hydroxyethyl) -2-adamantyl ] -2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
2- {4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -1-adamantyl } propanoic acid;
4- [ (N-cyano-3-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } butylimidoyl) amino ] adamantane-1-carboxamide;
(2R) -N' -cyano-N- [ 5-hydroxy-2-adamantyl ] -2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } butanamidine;
4- [ ((2R) -N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid;
4- [ ((2R) -N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } butylimidoyl) amino ] adamantane-1-carboxylic acid;
4- [ ((2R) -N-cyano-3-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } butylimidoyl) amino ] adamantane-1-carboxylic acid;
4- [ ((2R) -N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -N, N-dimethyladamantane-1-carboxamide;
4- [ ((2R) -N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } butylimidoyl) amino ] -N, N-dimethyladamantane-1-carboxamide;
n- {4- [ ((2R) -N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } butylimidoyl) amino ] -1-adamantyl } acetamide;
N- {4- [ ((2R) -N-cyano-3-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } butylimidoyl) amino ] -1-adamantyl } acetamide;
n' -cyano-2- (3, 3-difluoropiperidin-1-yl) -N- [ 5-hydroxy-2-adamantyl ] propionamidine;
n' -cyano-N- [ 5-hydroxy-2-adamantyl ] -2- [ (3S) -3- (trifluoromethyl) pyrrolidin-1-yl ] acetamidine;
4- ({ N-cyano-2- [ (3R) -3-fluoropiperidin-1-yl ] malonimidoyl } amino) adamantane-1-carboxamide;
n' -cyano-N- [ 5-methoxy-2-adamantyl ] -2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
4- [ (N-cyano-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } pentanimidoyl) amino ] adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (phenylsulfanyl) propylimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [ methyl (phenyl) amino ] malonimidoyl } amino) adamantane-1-carboxylic acid;
4- { [ N-cyano-2-methyl-2- (2-methylphenoxy) propylimidoyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2-methyl-2- (3-methylphenoxy) propylimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [ methyl (phenyl) amino ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({2- [ (4-chlorophenyl) amino ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- { [2- (2-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2- (3, 3-difluoropiperidin-1-yl) butanoimidyl ] amino } adamantane-1-carboxamide;
4- [ 3-benzyl-2- (cyanoimino) pyrrolidin-1-yl ] adamantane-1-carboxamide;
4- ({2- [4- (2-chloro-4-cyanophenyl) piperazin-1-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
n' -cyano-N- [ 5-hydroxy-2-adamantyl ] -2-methyl-2-phenylpropionamidine;
2- (4-chlorophenyl) -N' -cyano-N- [ 5-hydroxy-2-adamantyl ] -2-methylpropionamidine;
n' -cyano-N- [ 5-hydroxy-2-adamantyl ] -1-phenylcyclopropanecarboxamidine;
4- { [2- (4-bromo-3, 5-dimethyl-1H-pyrazol-1-yl) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- (2- (cyanoimino) -4- { [ (5-cyanopyridin-2-yl) oxy ] methyl } -3, 3-dimethylpyrrolidin-1-yl) adamantane-1-carboxamide;
4- { [2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -N-methyladamantane-1-carboxamide;
4- { [2- (2-chloro-4-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [4'- (methylsulfonyl) -1,1' -biphenyl-4-yl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
4- { [ N-cyano-2- (3-cyanopyridin-2-yl) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [2- (trifluoromethoxy) phenoxy ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [4- (trifluoromethyl) pyridin-2-yl ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({2- [ (5-bromopylidin-2-yl) oxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [2- (trifluoromethyl) phenoxy ] malonimidoyl } amino) adamantane-1-carboxamide;
4- (2- (cyanoimino) -3, 3-dimethyl-4- { [4- (1H-1,2, 4-triazol-1-yl) phenoxy ] methyl } pyrrolidin-1-yl) adamantane-1-carboxamide;
4- { [ (cyanoimino) (2-methylphenyl) methyl ] amino } adamantane-1-carboxamide;
4- { [2- (3-bromo-4-methoxyphenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- { [2- (2-bromo-4-methoxyphenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({ (cyanoimino) [ 3-methyl-2-oxo-1- (pyridin-2-ylmethyl) pyrrolidin-3-yl ] methyl } amino) adamantane-1-carboxamide;
4- ({ (cyanoimino) [ 3-methyl-2-oxo-1- (pyridin-3-ylmethyl) pyrrolidin-3-yl ] methyl } amino) adamantane-1-carboxamide;
4- ({ (cyanoimino) [ 3-methyl-2-oxo-1- (pyridin-4-ylmethyl) pyrrolidin-3-yl ] methyl } amino) adamantane-1-carboxamide;
4- ({ (cyanoimino) [ 3-methyl-2-oxo-1- (2-pyridin-2-ylethyl) pyrrolidin-3-yl ] methyl } amino) adamantane-1-carboxamide;
4- { [ N-cyano-3- (4-methoxyphenyl) -2, 2-dimethyl-3-oxopropanimidoyl ] amino } adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [4- (trifluoromethoxy) phenyl ] amino } propaneiminoacyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [4- (trifluoromethoxy) phenyl ] thio } propylimidoyl) amino ] adamantane-1-carboxamide;
4- [2- (cyanoimino) -3, 3-dimethyl-4- ({ [5- (trifluoromethyl) pyridin-2-yl ] oxy } methyl) pyrrolidin-1-yl ] adamantane-1-carboxamide;
4- { [2- (2-chloro-4-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -N, N-dimethyladamantane-1-carboxamide;
4- ({ (cyanoimino) [ 3-methyl-2-oxo-1- (1-pyridin-2-ylethyl) pyrrolidin-3-yl ] methyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [3- (1, 3-thiazol-4-ylmethoxy) phenyl ] malonimidoyl } amino) adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [3- (2-morpholin-4-ylethoxy) phenyl ] imidyl } amino) adamantane-1-carboxamide;
n- [5- (5-amino-4H-1, 2, 4-triazol-3-yl) -2-adamantyl ] -2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
4- { [ N-cyano-2- (6-fluoropyridin-3-yl) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
2- (4-chlorophenoxy) -N' -cyano-N- [5- (hydroxymethyl) -2-adamantyl ] -2-methylpropionamidine;
4- { [ N-cyano-2-methyl-2- (6-morpholin-4-ylpyridin-3-yl) propyleneiminoyl ] amino } adamantane-1-carboxamide;
4- { [ N-cyano-2- (5-fluoropyridin-2-yl) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
4- ({ N-cyano-2-methyl-2- [6- (methylamino) pyridin-3-yl ] malonimidoyl } amino) adamantane-1-carboxamide;
4- [ (N-cyano-2- { [5- (1H-imidazol-1-yl) pyridin-2-yl ] oxy } -2-methylpropanimidoyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [5- (1H-pyrazol-1-yl) pyridin-2-yl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2-quinoxalin-2-ylpropanimidoyl) amino ] adamantane-1-carboxamide;
N- [5- (aminosulfonyl) -2-adamantyl ] -2- (3-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2-methyl-2- (3-methylphenoxy) propionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2- (2-methoxyphenoxy) -2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2- (3-methoxyphenoxy) -2-methylpropionamidine;
(2S) -amino (4- { [2- (2-chloro-4-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) acetic acid;
2- [ (4- { [2- (2-chloro-4-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) sulfonyl ] acetamide;
n' -cyano-N- [ 5-hydroxy-2-adamantyl ] -2-methyl-2- (4-nitrophenyl) propionamidine;
n' -cyano-N- [5- (methylsulfonyl) -2-adamantyl ] -1-phenylcyclopropanecarboxamidine;
2- [ (4-bromopyridin-2-yl) oxy ] -N' -cyano-2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
(2S) -2- (4- { [2- (2-chloro-4-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) propionic acid;
n- [5- (aminosulfonyl) -2-adamantyl ] -2- (1,1 '-biphenyl-2-yloxy) -N' -cyano-2-methylpropionamidine;
4- { [2- (1,1' -biphenyl-2-yloxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine, N' -cyano-2- (2, 4-dichlorophenoxy);
2- (2-bromo-4-fluorophenoxy) -N' -cyano-2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
n' -cyano-2-methyl-2- (2-methylphenoxy) -N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
n' -cyano-2-methyl-2- (4-methylphenoxy) -N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
2- (2-chlorophenoxy) -N' -cyano-2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
2- (4-chlorophenoxy) -N' -cyano-2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine, N' -cyano-2- (4-methoxyphenoxy) -2- (methylsulfonyl);
n' -cyano-2- (2-cyanophenoxy) -2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine, N' -cyano-2- (2-methoxyphenoxy) -2-methyl;
2- [ (3-bromopyridin-2-yl) oxy ] -N' -cyano-2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -2- (2-bromo-4-fluorophenoxy) -N' -cyano-2-methylpropionamidine;
N' -cyano-N- [ 5-hydroxy-2-adamantyl ] -3-methyl-2-oxo-1-pyridin-2-ylpyrrolidin-3-carboxamidine;
2- (4-chlorophenoxy) -N' -cyano-2-methyl-N- {5- [ (methylthio) methyl ] -2-adamantyl } propionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2- (2, 4-dichlorophenoxy) -2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2- (2, 4-dimethylphenoxy) -2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2- (4-fluoro-2-methylphenoxy) -2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2- (2, 6-dichloro-4-methylphenoxy) -2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2- (2, 6-dichloro-4-fluorophenoxy) -2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -2- (2-chloro-4-methylphenoxy) -N' -cyano-2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2- (2,4, 6-trimethylphenoxy) -2-methylpropionamidine;
2- (4-chlorophenoxy) -N' -cyano-2-methyl-N- {5- [ (methylsulfonyl) methyl ] -2-adamantyl } propionamidine;
N- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2- (2, 4-difluorophenoxy) -2-methylpropionamidine;
n- [5- (aminosulfonyl) -2-adamantyl ] -N' -cyano-2- (4-fluorophenoxy) -2-methylpropionamidine;
2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine, N' -cyano-2- (2, 4-difluorophenoxy) -2-methyl;
n' -cyano-2- (2-isopropylphenoxy) -2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
2-methyl-N- [5- (methylsulfonyl) -2-methyl-N' -cyano-2- (4-fluoro-2-methylphenoxy) -propionamidine;
n' -cyano-2- (2-fluorophenoxy) -2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
n' -cyano-2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] -2- [2- (trifluoromethyl) phenoxy ] propionamidine;
4- { [ (cyanoimino) (3-methyl-2-oxo-1-pyridin-2-ylpyrrolidin-3-yl) methyl ] amino } adamantane-1-carboxamide;
(2S) -2-amino-2- (4- { [2- (2-chloro-4-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } -1-adamantyl) acetamide;
n' -cyano-2- [ 4-fluoro-2- (1H-pyrazol-1-yl) phenoxy ] -2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine, N' -cyano-2- (2, 6-dichloro-4-fluorophenoxy) -2-methyl;
N' -cyano-2- [ 4-fluoro-2- (1H-pyrazol-4-yl) phenoxy ] -2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] propionamidine;
n' -cyano-2-methyl-N- [5- (methylsulfonyl) -2-adamantyl ] -2- [3- (trifluoromethoxy) phenoxy ] propionamidine;
3-deuterated 4- [ (N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] -7-deuterated-adamantane-1-carboxamide;
n- [ 1-deuterated-4-adamantyl ] -N' -cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } propionamidine;
3-deuterated 4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxamide;
4- [ (N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] -7-deuterated-adamantane-1-carboxamide;
n- [ 1-deuterated-4-adamantyl ] -N' -cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
3- [ (N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
n-1-azabicyclo [2.2.2] oct-3-yl-N' -cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } propionamidine;
N- [ 1-azatricyclo [3.3.1.13,7] decan-4-yl ] -N' -cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
n' -cyano-N-cyclohexyl-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } propionamidine;
{4- [ (4-methylphenyl) sulfonyl ] piperazin-1-yl } (4-nitrophenyl) methylene cyanamide;
n' -cyano-N- {1- [ (1-cyanocyclopropyl) methyl ] piperidin-4-yl } -N-cyclopropyl-4- (2,2, 2-trifluoro-1-hydroxy-1-methylethyl) benzamidine;
carbamic acid [4- [ { (cyanoimino) [4- (2,2, 2-trifluoro-1-hydroxy-1-methylethyl) phenyl ] methyl } (cyclopropyl) amino ] -1- (4-fluorophenyl) cyclohexyl ] methyl ester;
n' -cyano-N-cyclopropyl-N- [4- (2-hydroxyethyl) cyclohexyl]-4-isopropylbenzamidine; [5- (4-methylphenyl) isoAzol-4-yl](3-pyridin-3-ylpyrrolidin-1-yl) methylene cyanamide;
4- [4- [ (1-adamantylamino) (cyanoimino) methyl ] -5- (1-methylcyclopropyl) -1H-pyrazol-1-yl ] benzoic acid;
n' -cyano-N-cyclohexyl-2- [ (2-phenylethyl) thio ] pyridine-3-carboxamidine;
4- [5- [ (2-adamantylamino) (cyanoimino) methyl ] -6- (propylsulfanyl) pyridin-2-yl ] morpholine-2-carboxylic acid;
n' -cyano-N-cyclopropyl-N- (4-cyclopropyl-4-hydroxycyclohexyl) -4- (2,2, 2-trifluoro-1-hydroxy-1-methylethyl) benzamidine;
2- [2- (4-fluorophenyl) -6-hydroxy-2-adamantyl ] -1- (3-hydroxyazetidin-1-yl) ethylene cyanamide;
2- {1- [2- (2-adamantylamino) -2- (cyanoimino) ethyl ] cyclopentyl } -N-isobutylacetamide;
2- {4- [ (2-fluorophenyl) sulfonyl ] -1, 4-diazepan-1-yl } -1-octahydroquinolin-1 (2H) -yl ethylene cyanamide;
1-cyclohexyl-3- [ (3, 5-dichloro-4 '- { [4- (2-fluoroethyl) piperazin-1-yl ] carbonyl } -1,1' -biphenyl-4-yl) methyl ] pyrrolidin-2-ylidenecyanamide;
3- [ (3, 5-dichloro-4 '- { [4- (trifluoromethyl) piperidin-1-yl ] carbonyl } -1,1' -biphenyl-4-yl) methyl ] -1-piperidin-1-ylpyrrolidin-2-ylidenecyanamide;
3-cyclohexyl-1- [ (3, 5-dichloro-4 '- { [4- (2-fluoroethyl) piperazin-1-yl ] carbonyl } -1,1' -biphenyl-4-yl) methyl ] pyrrolidin-2-ylidenecyanamide;
3- [ (3, 5-dichloro-4 '- { [4- (trifluoromethyl) piperidin-1-yl ] carbonyl } -1,1' -biphenyl-4-yl) methyl ] -1- (4, 4-difluorocyclohexyl) pyrrolidin-2-ylidenecyanamide;
3- [ (3, 5-dichloro-4 '-fluoro-1, 1' -biphenyl-4-yl) methyl ] -1- (4, 4-difluorocyclohexyl) pyrrolidin-2-ylidenecyanamide;
3- [ (3, 5-dichloro-4 '- { [4- (trifluoromethyl) piperidin-1-yl ] carbonyl } -1,1' -biphenyl-4-yl) methyl ] -1- (4-hydroxypiperidin-1-yl) pyrrolidin-2-ylidenecyanamide;
4- {2- (cyanoimino) -3- [ (3, 5-dichloro-4 '- { [4- (trifluoromethyl) piperidin-1-yl ] carbonyl } -1,1' -biphenyl-4-yl) methyl ] pyrrolidin-1-yl } piperidine-1-carboxylic acid methyl ester;
2- [ (3, 5-dichloro-4 '- { [4- (trifluoromethyl) piperidin-1-yl ] carbonyl } -1,1' -biphenyl-4-yl) methyl ] -2-azaspiro [4.5] decan-1-ylidenecyanamide;
3- [ (3, 5-dichloro-4 '- { [4- (trifluoromethyl) piperidin-1-yl ] carbonyl } -1,1' -biphenyl-4-yl) methyl ] -1- (4,5,6, 7-tetrahydro-1H-benzimidazol-6-yl) pyrrolidin-2-ylidenecyanamide;
3- [ (3, 5-dichloro-4 '-fluoro-1, 1' -biphenyl-4-yl) methyl ] -1- (4,5,6, 7-tetrahydro-2H-indazol-5-yl) pyrrolidin-2-ylidenecyanamide;
n-2-adamantyl-2 ' -tert-butyl-N ' -cyano-2 ' H-1,3' -dipyrazole-4 ' -carboxamidine;
2- (4-bromo-2-fluorophenyl) -2-hydroxy-1- (3-oxo-1 ' H, 3H-spiro [ 2-benzofuran-1, 3' -pyrrolidin ] -1' -yl) ethylene cyanamide;
n' -cyano-N- (1- { [4- (2, 5-dimethylphenyl) piperazin-1-yl ] carbonyl } piperidin-3-yl) -4-hydroxyadamantane-1-carboxamidine;
1- {3- [1- (4-chlorophenyl) cyclopropyl ] -1-oxa-2, 7-diazaspiro [4.4] non-2-en-7-yl } ethylene cyanamide;
7- (2-chlorophenyl) -1-isobutyl-1, 7-diazaspiro [4.4] non-6-ylidenecyanamide;
8- (3-chloropyridin-2-yl) -2-cyclohexyl-2, 8-diazaspiro [4.5] decan-1-ylidenecyanamide;
5- {4- [1- (cyanoimino) -2- (4-hydroxycyclohexyl) -2, 7-diazaspiro [4.5] decan-7-yl ] -3-fluorophenyl } -N, N-dimethylpyridine-2-carboxamide;
2- (2-acetylphenyl) -N' -cyano-N-cyclooctyl-1, 3-thiazole-4-carboxamidine;
(5-cyclopropyl-1-piperidin-4-yl-1H-pyrazol-4-yl) {3- [2- (trifluoromethyl) phenyl ] pyrrolidin-1-yl } methylenecyanamide;
2- [4- (2- { [ (4-chlorophenyl) (cyanoimino) methyl ] amino } ethyl) phenoxy ] -2-methylpropanoic acid;
1'- { [2- (trifluoromethyl) phenoxy ] acetyl } spiro [ indole-3, 4' -piperidin ] -2(1H) -ylidenecyanamide;
1- {4- [ (2-adamantylamino) (cyanoimino) methyl ] phenyl } piperidine-4-carboxylic acid;
n- (1- {4- [ 3-azabicyclo [3.2.2] non-3-yl (cyanoimino) methyl ] phenyl } pyrrolidin-3-yl) -N-methyl-1-phenylmethanesulfonamide;
1-adamantyl {4- [2- (1H-imidazol-2-ylsulfanyl) ethyl ] piperidin-1-yl } methylene cyanamide;
N-2-adamantyl-N' -cyano-4- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) benzamidine;
n- {4- [ (cyanoimino) (1,3, 3-trimethyl-6-azabicyclo [3.2.1] oct-6-yl) methyl ] benzyl } -1,1, 1-trifluoro-N-isopropylmethanesulfonamide;
1-acetyl-N- (2- {5- [ (cyanoimino) (1,3, 3-trimethyl-6-azabicyclo [3.2.1] oct-6-yl) methyl ] -1H-benzimidazol-1-yl } ethyl) piperidine-4-carboxamide;
Ethyl 3- {4- [ (cyanoimino) (1,3, 3-trimethyl-6-azabicyclo [3.2.1] oct-6-yl) methyl ] -1H-indol-1-yl } propanoate;
N-1-adamantyl-N' -cyano-1- (thiophen-2-ylsulfonyl) piperidine-4-carboxamidine;
n' -cyano-4- (2, 4-dichlorophenoxy) -N- [4- (hydroxymethyl) -2-adamantyl ] butamidine;
4- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-N- [4- (hydroxymethyl) cyclohexyl ] -N-methylbenzamidine;
N-2-adamantyl-N' -cyano-2- [ cyclohexyl (methyl) amino ] acetamidine;
N-2-adamantyl-N' -cyano-1-methyl-5- (2-phenylethoxy) -1H-pyrazole-4-carboxamidine;
2, 4-dichloro-N- [1- ({ [5- { (cyanoimino) [ (5-hydroxy-2-adamantyl) amino)]Methyl } -4- (cyclopentylthio) iso-methylAzol-3-yl]Oxy } methyl) cyclopropyl]A benzamide;
carbamic acid 4- [ ((cyanoimino) {1- [ 3-cyano-3-methylbut-1-enyl ] -5-isobutoxy-1H-pyrazol-4-yl } methyl) amino ] -1-adamantyl ester;
2- (5-hydroxy-2-adamantyl) -3-oxo-2, 3-dihydro-1H-isoindol-1-ylidene cyanamide and 2- (6-hydroxy-2-adamantyl) -3-oxo-2, 3-dihydro-1H-isoindol-1-ylidene cyanamide;
n' -cyano-N- (5-hydroxy-2-adamantyl) -4- [ (pyridin-2-ylsulfonyl) methoxy ] benzamidine;
N' -cyano-3- (cyclohexylmethoxy) -N- [5- (hydroxymethyl) -2-adamantyl ] benzamidine;
n' -cyano-N- (3-hydroxy-1-adamantyl) -4- [ (methylsulfonyl) methoxy ] benzamidine;
n' -cyano-N- (5-hydroxy-2-adamantyl) -N-methyl-3- (2-phenylethoxy) benzamidine;
(3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) (9-methyl-9H-carbazol-3-yl) methylene cyanamide; and
1- (4- { [2- (4-chlorophenoxy) phenyl ] amino } piperidin-1-yl) ethylene cyanamide.
Determination of biological Activity
AbbreviationEDTA: ethylene diamineTetraacetic acid; tris (Tris): tris (hydroxymethyl) aminomethane; NADPH: nicotinamide adenine dinucleotide phosphate.
Determination of inhibition constant
The ability of test compounds to inhibit the enzymatic activity of human 11 β -HSD1 in vitro was evaluated in a Scintillation Proximity Assay (SPA). Tritiated corticosterone substrate, NADPH cofactor and titrated compound were incubated with truncated (24-287aa) human 11 β -HSD1 enzyme at room temperature for conversion to cortisol. The reaction was stopped by addition of glycyrrhetinic acid, a non-specific 11 β -HSD inhibitor. Tritiated cortisol was collected using anti-cortisol monoclonal antibodies and SPA beads coated with anti-mouse antibodies. The reaction plate was shaken at room temperature and then the radiolabel binding to the SPA beads was determined on a scintillation counter. 11 β -HSD1 assays (total volume 220 μ L) were performed in 96-well microtiter plates. For the initiation of the experiment, 188 μ L contained 75 nM 3A master mix (master mix) of H-corticosterone, 100 nM corticosterone and 181 μ M NADPH was added to the wells. To drive the reaction indicated with 11. beta. -reductase, 1 mM glucose-6-phosphate (G-6-P) and 1U/mL G-6-P dehydrogenase were also added as NADPH-producing system. The solid compound was dissolved in dimethyl sulfoxide to prepare a 10 mM stock, which was then serially diluted 10-fold with dimethyl sulfoxide. Each compound solution (in dimethylsulfoxide) was diluted 10-fold in Tris/EDTA buffer (pH 7.4). 22 μ L of titrated compound (in duplicate) was then added to the substrate. The reaction was initiated by adding 10 μ L of 0.1 mg/mL E.coli lysate (overexpressing 11 β -HSD1 enzyme). After shaking and incubation of the plates for 30 minutes at room temperature, the reaction was terminated by adding 10 μ L of 1 mM glycyrrhetinic acid. The product (tritiated cortisol) was collected by adding 10 μ L of 1 μ M monoclonal mouse anti-cortisol antibody and 50 μ L of SPA beads coated with anti-mouse antibody. After shaking for 30 minutes, plates were read in a Microbeta scintillation counter. Percent inhibition was calculated based on background and maximum signal. Wells containing substrate but no compound or enzyme were used as background, whereas wells containing substrate and enzyme but no compound were considered the maximum signal. Calculate the percent inhibition for each compound relative to the maximum signal And then forming an IC50Curve line. Assuming competitive inhibition, the Cheng-Prusoff equation was used from IC50Values apparent Ki values were calculated. This assay can also be used for 11 β -HSD2, in which 6 nM tritiated cortisol and 250 uM NAD are present+Used as substrate and cofactor, respectively.
The compounds of the present invention were active in the 11 β -HSD1 assay described above, as shown in Table 1. The symbols in the following table are defined as follows: A- -Ki. ltoreq.0.01. mu.M; b-0.1 mu M is more than or equal to Ki and more than 0.01 mu M; c-1 mu M is more than or equal to Ki and more than 0.1 mu M; and D-Ki > 1 μ M; ND-was not determined.
TABLE 1 SPA assay for human 11 β -HSD1 enzyme
Example # Ki 11β-HSD1[μM] Example # Ki 11β-HSD1[μM]
1 B 47 B
2 D 48 C
3 D 49 B
4 D 50 A
5 D 51 A
6 D 52 B
7 D 56 A
8 A 57 B
9 B 58 C
10 C 59 C
11 C 60 B
12 B 61 C
13 C 62 B
14 A 63 B
15 C 64 A
16 C 65 C
17 C 66 C
18 B 67 C
19 B 68 D
20 ND 69 B
21 B 70 A
22 D 71 B
23 C 72 D
24 B 73 C
25 B 74 A
27 A 75 B
28 C 76 D
29 C 77 C
30 D 78 B
31 C 79 B
33 C 80 A
35 D 81 D
36 C 82 B
37 B 83 C
38 B 84 C
39 D 85 C
40 D 86 B
41 B 87 D
42 C 88 C
43 B 89 B
45 A 93 D
46 D
The data in table 1 show that the compounds of the invention are active compounds in the SPA assay described above for the human 11 β -HSD1 enzyme. The 11 β -HSD1 inhibitors of the invention typically have an inhibition constant Ki of less than 600 nM, preferably less than 50 nM.
It should be understood that the detailed description and examples, while indicating the scope of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art (see, e.g., Moreira et al, Current Med. chem. 12, 23-49(2005); EP 1889842). Such changes and modifications, including but not limited to those relating to chemical structures, substituents, derivatives, intermediates, syntheses, formulations, and/or methods of use of the invention, may be made without departing from the spirit and scope of the invention. Such modifications are intended to fall within the scope of the appended claims.
All patents, patent applications, and references cited herein are incorporated by reference in their entirety.

Claims (19)

1. A compound of the formula (I)
Wherein
L is- (CH)2)n-or- (CR)38R39)m-X-(CR38R39)n-or- (CR)38R39)m-X-(CR38R39)n-Y-；
m is independently at each occurrence 0, 1 or 2;
n is independently at each occurrence 0, 1 or 2;
R1is adamantyl, substituted with 0 or 1 substituent selected from the group consisting of: alkylsulfonyl, cyano, -OR15,-CO2R18,-C(O)-N(R19R20) and-S (O)2-N(R32R33)；
R15Is hydrogen, alkyl, or haloalkyl;
R18is hydrogen, or alkyl;
R19and R20Each independently is hydrogen, or alkyl, or R19And R20Together with the atoms to which they are attached form a heterocyclic ring;
R32and R33Each occurrence independently selected from hydrogen and alkyl, or R32And R33Together with the atoms to which they are attached form a heterocyclic ring;
R2is hydrogen or alkyl;
R3and R4Are all hydrogen or are all alkyl; or R3And R4Together with the atoms to which they are attached form a cycloalkyl group;
R5is phenyl, pyridyl or heterocycle; or R4And R5Together with the atoms to which they are attached form a heterocyclic ring;
x is-O-, -NR-36-or-CR36R37-；
Y is O or NR40；
R36And R37Independently at each occurrence is hydrogen or alkyl; or R36And R2Together with the atoms to which they are attached form a heterocyclic ring;
R38、R39and R40Independently at each occurrence is hydrogen;
w is N-CN, N-OR6Or N-R6(ii) a And
R6is hydrogen, or alkyl; or
A pharmaceutically acceptable salt thereof,
wherein,
alkyl means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms,
The phenyl group may be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of: alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxyalkyl, cyano, haloalkoxy, haloalkyl and halogen,
cycloalkyl means a saturated cyclic hydrocarbon group containing 3 to 8 carbon atoms, i.e. (C)3-C8) A cycloalkyl group,
halogen or halo means-Cl, -Br, -I or-F;
the pyridyl group may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, amido, carboxyl, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl and halogen;
heterocycle refers to monocyclic heterocycle or bicyclic heterocycle;
a monocyclic heterocycle is a 5 or 6 membered ring comprising at least one heteroatom, wherein the heteroatoms are independently selected from O, N and S;
bicyclic heterocycles are monocyclic heterocycles fused to cycloalkyl groups,
the heterocycle may be substituted with 0, 1 or 2 substituents independently selected from the group consisting of: alkyl, phenyl and pyridyl.
2. The compound of claim 1, wherein R5Is phenyl, pyridyl or heterocycle.
3. The compound of claim 1, wherein R3And R4Both are hydrogen or both are alkyl.
4. The compound of claim 1, wherein R3And R4Together with the atoms to which they are attached form a cycloalkyl group.
5. The compound of claim 4, wherein cycloalkyl is (C)3-C6) A cycloalkyl group.
6. The compound of claim 1, wherein L is- (CH)2)n-, where n is 0, or- (CR)38R39)m-X-(CR38R39)n-, where m and n are both 0, and X is O.
7. The compound of claim 1, wherein R4And R5Together with the atoms to which they are attached form a heterocyclic ring.
8. The compound of claim 1, wherein R36And R2Together with the atoms to which they are attached form a heterocyclic ring.
9. The compound of claim 1, wherein R6Is an alkyl group.
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from
(1E) -2- (2-chloro-4-fluorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylpropionamidine;
(1E) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2- (2-methylphenyl) acetamidine;
1- (4-chlorophenyl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] cyclobutanecarboxamidine;
(1E) -N' -cyano-2- (2, 4-difluorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine;
(1E) -N' -cyano-2- (2-fluorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine;
(1E) -2- (2-chloropyridin-3-yl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine;
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] acetamidine;
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2-methylpropionamidine;
(E) -methyl 4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylate;
(1E) -2- (4-chlorophenoxy) -N' -methoxy-2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] propionamidine;
(E) -4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
1- (3-chlorophenoxy) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] cyclobutanecarboxamidine;
(E) -methyl 4- [ ((1E) -N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxylate;
(1E) -2- (2-chloro-4-fluorophenoxy) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] propionamidine;
(1E) -2- (4-chlorophenoxy) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) -2-adamantyl ] propionamidine;
3- (4-chlorophenyl) -N- [ (E) -5-hydroxy-2-adamantyl ] -2, 2-dimethylpropanamidine;
(1E) -3- (4-chlorophenyl) -N' -cyano-N- [ (E) -5-hydroxy-2-adamantyl ] -2, 2-dimethylpropanamidine;
(E) -4- [ ((1E) -N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxylic acid;
(E) -4- [ ((1E) -N-cyano-2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } malonimidoyl) amino ] adamantane-1-carboxamide;
(1E) -N' -cyano-N- [ (E) -5-cyano-2-adamantyl ] -2-methyl-2- { [4- (trifluoromethyl) benzyl ] oxy } propionamidine;
(E) -methyl 4- ({ (1E) -N-cyano-2- [ (4-methoxybenzyl) oxy ] -2-methylpropanimidoyl } amino) adamantane-1-carboxylate;
(E) -methyl 4- [ ((1E) -N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylate;
(E) -4- [ ((1E) -N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxylic acid;
(E) -4- [ ((1E) -N-cyano-2-methyl-2- {4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } malonimidoyl) amino ] adamantane-1-carboxamide;
(2Z) -4- { [ (5-cyanopyridin-2-yl) oxy ] methyl } -3, 3-dimethyl-1- [ (E) -5- (methylsulfonyl) -2-adamantyl ] pyrrolidin-2-ylidenecyanamide;
(E) -4- { [ (1E) -2- (4-chlorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylic acid;
(1E) -2- (4-chlorophenoxy) -N' -cyano-N- [ (E) -5-cyano-2-adamantyl ] -2-methylpropionamidine;
(1E) -N-1-adamantyl-2- (4-chlorophenoxy) -N' -cyano-2-methylpropionamidine;
(1E) -N' -cyano-2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine;
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine;
(E) -methyl 4- ({ (1E) -2- [ (1R, 5S, 6R) -6- (4-chlorophenyl) -3-azabicyclo [3.2.0] hept-3-yl ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxylate;
(1E) -N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methyl-2-phenoxypropionamidine;
(E) -4- { [ (1E) -N-cyano-2-methyl-2-phenoxymalonimidoyl ] amino } adamantane-1-carboxamide;
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine;
(1E) -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2- (2, 4-difluorophenoxy) -2-methylpropionamidine;
(1E) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2-methylpropionamidine;
(1E) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine;
(1E) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine;
(1E) -N' -cyano-2- (2, 4-difluorophenoxy) -2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine;
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine;
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2-methylpropionamidine;
(1E) -N- (adamantan-1-yl) -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine;
(1E) -N- [ (E) -adamantan-2-yl ] -2- (4-chloro-2-fluorophenoxy) -N' -cyano-2-methylpropionamidine;
(E) -methyl 4- { [ (1E) -2- (4-chloro-2-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxylate;
(1E) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] -2-phenoxypropionamidine;
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] propionamidine;
(1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N' -cyano-2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine;
(E) -4- { [ (1E) -N-cyano-2- (2, 4-difluorophenoxy) -2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
(1E) -N- [ (3R,5R) -adamantan-1-yl ] -N' -cyano-2- (2, 4-difluorophenoxy) -2-methylpropionamidine;
(E) -4- { [ (1E) -2- (4-chloro-2-fluorophenoxy) -N-cyano-2-methylpropanimidoyl ] amino } adamantane-1-carboxamide;
(E) -4- ({ (1E) -2- [ (5-chloropyridin-2-yl) oxy ] -N-cyano-2-methylpropanimidoyl } amino) adamantane-1-carboxamide;
(E) -4- [ (2-methyl-2-phenoxyiminoacyl) amino ] adamantane-1-carboxamide;
(1E) -N' -cyano-2-methyl-N- [ (E) -5- (methylsulfonyl) adamantan-2-yl ] -2- (pyridin-2-yloxy) propionamidine;
(1E) -N' -cyano-N- [ (E) -5-cyanoadamantan-2-yl ] -2- (2-fluorophenoxy) -2-methylpropionamidine;
(1E) -N' -cyano-2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine;
(1E) -N' -cyano-2- (2-fluorophenoxy) -N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine;
2- (2-fluorophenoxy) -2-methyl-N- [ (E) -5-sulfamoyladamantan-2-yl ] propionamidine;
2- (2-fluorophenoxy) -N- [ (E) -5-hydroxyadamantan-2-yl ] -2-methylpropionamidine; and
n- [ (E) -5-hydroxyadamantan-2-yl ] -2-methyl-2-phenoxypropionamidine.
11. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the therapeutic or prophylactic treatment of a condition in a mammal in need thereof, wherein the condition is selected from the group consisting of: cushing's syndrome, non-insulin dependent type II diabetes mellitus, insulin resistance, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, retinopathy, nephropathy, neuropathy, hypertension, osteoporosis, glaucoma, arthritis, neuronal dysfunction, neurodegeneration, alzheimer's disease, anxiety, panic, post-traumatic stress disorder, steroid-induced acute psychosis, general attention deficit disorder, attention deficit hyperactivity disorder, mild cognitive deficit, schizophrenia, depression, and other diseases associated with cortisol or glucocorticoids.
12. The use of claim 11, wherein the disorder is non-insulin dependent type II diabetes.
13. The use of claim 11, wherein the condition is alzheimer's disease.
14. The use of claim 11, wherein the disorder is depression.
15. The use of claim 11, wherein the disorder is schizophrenia.
16. The use of claim 11, wherein the disorder is dyslipidemia.
17. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the therapeutic or prophylactic treatment of a condition in a mammal in need thereof, wherein the condition is selected from the group consisting of: obesity, disorders of lipid metabolism, hyperglycemia, low glucose tolerance, cognitive deficits associated with aging, cognitive function decline in alzheimer's disease and related dementias, cognitive deficits associated with aging and neurodegeneration, senile dementia, AIDS dementia, cognitive deficits associated with diabetes, cognitive function decline in Cushing's syndrome, major depressive disorder, psychotic depression, depression and depressive disorders and refractory melancholia in Cushing's syndrome.
18. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the therapeutic or prophylactic treatment of dementia in a mammal in need thereof.
19. The use of claim 17, wherein the obesity is abdominal obesity.
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