HK1116173A - Halogen substituted benzodiazepine derivatives - Google Patents
Halogen substituted benzodiazepine derivatives Download PDFInfo
- Publication number
- HK1116173A HK1116173A HK08105689.7A HK08105689A HK1116173A HK 1116173 A HK1116173 A HK 1116173A HK 08105689 A HK08105689 A HK 08105689A HK 1116173 A HK1116173 A HK 1116173A
- Authority
- HK
- Hong Kong
- Prior art keywords
- triazolo
- imidazo
- benzodiazepine
- chloro
- formula
- Prior art date
Links
Description
The present invention relates to halogen substituted imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine * derivatives of formula I:
wherein
R1Is hydrogen, halogen, lower alkyl, Si (CH)3)3Or lower alkyl substituted by halogen, or lower alkoxy substituted by halogen, or lower alkenyl, lower alkenyloxy, CN, bicyclo [2.2.1]Hept-5-en-2-yl, aryl optionally substituted by lower alkyl, amino or lower alkoxy, or aryloxy, heteroaryl, benzo [1, 3]]Dioxolyl, cycloalkyl, heterocycloalkyl, -O (CH)2)mOH, -CO (O) -lower alkyl, -NR'2or-C.ident.C-R ";
r' is hydrogen, lower alkyl, cycloalkyl, -C (O) -lower alkyl, -C (O) -cycloalkyl, -S (O)2-lower alkyl or aryl unsubstituted or substituted by one or two substituents selected from: halogen or lower alkyl substituted by halogen;
r' is hydrogen, -Si (CH)3)3Lower alkyl, cycloalkyl or- (CH)2)m-O-lower alkyl;
R2is hydrogen, methyl or aryl;
R3is halogen;
R4is hydrogen or halogen;
n is 1 or 2;
m is 1, 2 or 3.
It has now been found that such compounds of formula I show high affinity and selectivity for GABA a α 5 receptor binding sites and are useful as cognitive enhancers or for the treatment of cognitive disorders, anxiety, schizophrenia or alzheimer's disease.
The receptors for the important inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two broad classes: (1) GABA a receptors, which are members of the ligand-gated ion channel superfamily; and (2) the GABAB receptor, which is a member of the G protein-linked receptor family. The GABA a receptor complex is a membrane-bound heteropentameric protein polymer composed primarily of α, β and γ subunits.
A total of 21 subunits of GABA a receptor have been cloned and sequenced. Three types of subunits (α, β and γ) are required to construct recombinant GABA a receptors that most closely function biochemically, electrophysiologically and pharmacologically with native GABA a receptors derived from mammalian brain cells. There has been strong evidence that the benzodiazepine * binding site is located between the alpha and gamma subunits. In recombinant GABA a receptors, α 1 β 2 γ 2 mimics many of the effects of the typical type I BzR subtype, whereas α 2 β 2 γ 2, α 3 β 2 γ 2 and α 5 β 2 γ 2 ion channels are referred to as type II BzR.
McNamara and Skelton in Psychobiology, 21: 101-108, the benzodiazepine * receptor inverse agonist β -CCM may enhance spatial learning in the Morris water maze. However, β -CCM and other conventional benzodiazepine * receptor inverse agonists are proconvulsant or convulsant agents, thereby preventing their use as cognitive enhancers in humans. Furthermore, these compounds are not selective between GABA a receptor subunits, whereas partial or full inverse agonists of GABA a α 5 receptors which are relatively inactive against GABA a α 1 and/or α 2 and/or α 3 receptor binding sites may be useful as medicaments for enhancing cognition without or with diminished convulsive activity. GABA a α 5 inverse agonists that are active at the GABA a α 1 and/or α 2 and/or α 3 receptor binding site but selectively act on α 5-containing subunits may also be used. However, GABA a α 5 inverse agonists that are selective for the GABAA α 5 subunit and relatively inactive at the GABA a α 1, α 2 and α 3 receptor binding sites are preferred.
Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of the above-mentioned types of illnesses and disorders or in the manufacture of corresponding medicaments.
The most preferred indication of the present invention is Alzheimer's disease.
The following definitions apply, both individually and in combination, to the general terms used in this specification.
The term "lower alkyl" as used herein refers to a straight or branched chain alkyl group containing 1 to 7, preferably 1 to 4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and the like.
The term "lower alkyl substituted by halogen" refers to the above-mentioned straight-chain or branched alkyl group in which at least one hydrogen atom is substituted by a halogen atom. An example of a preferred group is CF3、CHF2、CH2F、CH2CH2F、CH2CF2H or CH2CF3Or CF2CH3。
The term "lower alkenyl" refers to a straight or branched chain carbon-containing group containing 2 to 7, preferably 2 to 4 carbon atoms and at least one double bond.
The term "aryl" refers to phenyl, benzyl or naphthyl. Preferred groups are phenyl or benzyl.
The term "heteroaryl" refers to a five or six membered aromatic ring containing 1 to 3 heteroatoms such as O, N or S. Examples of said heteroaryl group are imidazole or pyridine.
The term "halogen" refers to chlorine, iodine, fluorine and bromine.
The term "cycloalkyl" refers to a cyclic alkyl ring having 3 to 7 carbon ring atoms, such as cyclopropyl, cyclopentyl or cyclohexyl.
The term "heterocycloalkyl" denotes a cyclic alkyl ring containing from 3 to 7 carbon ring atoms and from 1 to 3 heteroatoms such as N, O or S, for example the following groups: morpholine, thiomorpholine, piperazine, piperidine and the like.
The term "pharmaceutically acceptable acid addition salts" includes salts with inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Exemplary preferred compounds are the following: the compounds have a binding activity (Ki) of less than 15nM, are selective for the GABA A α 5 subunit and are relatively inactive at the GABA A α 1, α 2 and α 3 receptor binding sites.
Preferred compounds of the formula I are those in which R3A compound that is chlorine.
Of this group of compounds, the most preferred compound is that in which R is2Compounds which are hydrogen, for example the following compounds:
10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-fluoro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-methoxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-ethoxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (2-fluoro-ethoxy) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (2, 2-difluoro-ethoxy) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (2, 2, 2-trifluoro-ethoxy) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-vinyloxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-methylamino-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *, 10-chloro-3-dimethylamino-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-benzylamino-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *, 10-chloro-3-thiomorpholin-4-yl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-imidazol-1-yl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-acetylamino-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3, 10-dichloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-bromo-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-ethynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-prop-1-ynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-cyclopropylethynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-ethyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-cyclopropyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-difluoromethyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-benzyl-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-phenyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-cyano-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (pyridin-3-yl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-propyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-butyl-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-vinyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (methoxy-carbonyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (prop-1, 2-dienyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3- (cyclopropanecarbonyl-amino) -10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine * or
10-chloro-3-cyclopropylamino-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *.
In this group of compounds, R is also preferred2Compounds which are methyl, for example the following compounds:
3, 10-dichloro-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-bromo-10-chloro-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-ethynyl-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-cyclopropyl-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine * or
10-chloro-3-cyano-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *.
Preferred compounds of formula I also include those wherein R is3Compounds which are bromine, for example the following compounds:
10-bromo-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine * or
10-bromo-3-fluoro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *.
Preferred compounds of the formula I are also those in which R3Compounds which are iodine, such as the following:
3-chloro-10-iodo-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *.
Another embodiment of the present invention is a compound of formula IA:
wherein
R1Is hydrogen, halogen, lower alkyl or lower alkyl substituted by halogen, or is lower alkoxy or lower alkoxy substituted by halogen, or is lower alkenyl, lower alkenyloxy, CN, aryl, or is aryloxy, heteroaryl, cycloalkyl, heterocycloalkyl, -O (CH)2)mOH、-NR’2or-C.ident.C-R ";
r' is hydrogen, lower alkyl, -C (O) -cycloalkyl, -S (O)2-lower alkyl or aryl unsubstituted or substituted by one or two substituents selected from: halogen or lower alkyl substituted by halogen;
r' is hydrogen, -Si (CH)3)3Lower alkyl, cycloalkyl or- (CH)2)m-O-lower alkyl;
R2is hydrogen, methyl or aryl;
R3is halogen;
R4is hydrogen or halogen;
n is 1 or 2;
m is 1, 2 or 3.
The compounds of formula I and pharmaceutically acceptable salts thereof of the present invention can be prepared by methods known in the art, for example, by the methods described below, which methods comprise
Reacting a compound of formula II
With halogenating agents such as N-chlorosuccinimide, 1, 3-dichloro-5, 5-dimethylhydantoin, bromine or iodine to give compounds of the formula I
Wherein R is1、R2、R3、R4And n is as described above with respect to,
and, if desired, converting the compound of formula I into a pharmaceutically acceptable salt.
According to the invention, the compounds of the general formula I can be prepared by the following method: the compound of formula II is halogenated with an appropriate reagent such as N-chlorosuccinimide, N-bromosuccinimide, iodine, and the like in an appropriate solvent to give the compound of formula I.
The following schemes (schemes 1-4) describe in more detail the methods of preparing the compounds of formula I. The starting materials are known compounds or can be prepared according to methods known in the art.
Scheme 1
The corresponding intermediate compounds of formula VIII according to scheme 1 are known (EP 519307) and can be prepared by methods known in the art, for example according to the following method.
Reacting the corresponding compound of formula III mono-R1The substituted 2-aminobenzoic acid derivative and chloroacetonitrile are dissolved in dioxane and a weak stream of dry HCl is introduced over a period of several hours at 5 ℃ to 15 ℃. After addition of chloroacetonitrile, the mixture was stirred at room temperature for several hours. The resulting compound of formula IV was purified in a conventional manner and dissolved in chloroform in the presence of N, N-dimethyl-p-toluidine. Phosphorus oxychloride was added and the solution was heated. The resulting compound of formula V is purified by known methods and then heated in toluene with a compound of formula VI-hydrazide to give a compound of formula VII, e.g. the compound 5-chloromethyl-9-fluoro-1, 2, 4-triazolo [ 4]，3-c]A quinazoline. Finally, the compound of formula VIII is obtained by: the compound of formula VII is dissolved in dioxane and then treated with aqueous sodium hydroxide to bring the reaction temperature between 10 ℃ and 15 ℃. Conventional work-up and purification gives the corresponding intermediate of the formula VIII, for example 10-fluoro-5H- [1, 2, 4]Triazolo [1, 5-d][1，4]Benzodiazepine * -6(7H) -one.
Scheme 2
According to scheme 2, the corresponding intermediate compounds of formula VIII can also be prepared according to the following method: reacting a corresponding compound of formula IX- -R1-heating the substituted 2-aminobenzonitrile with ethyl chloroformate to obtain the carbamate of formula X, which is treated with the compound of formula VI-hydrazide in 1-methyl-2-pyrrolidone at 160 ℃ while removing ethanol. Conventional work-up gives a urea of the formula XI which is heated with aqueous sodium hydroxide in ethylene glycol to give the compound of the formula XII. Treatment of the compound of formula XII with chloroacetyl chloride in acetic acid affords the amide of formula XIII, which is treated with aqueous sodium hydroxide in dioxane at room temperature to afford the intermediate of formula VIII. Alternatively, the compounds of formula XII may be converted directly to compounds of formula VIII by dissolving the compounds of formula XII in dioxane and pyridine, followed by the dropwise addition of chloroacetyl chloride at 10 ℃ to 15 ℃. After a short stirring time, aqueous sodium hydroxide solution is added and the reaction mixture is stirred at room temperature for several hours to give the compound of formula VIII.
Scheme 3
According to scheme 3, the compound of formula VIII is treated with an activating agent in the presence of a base at elevated temperature, for example with a solution of phosphoryl chloride in toluene or chloroform in the presence of N, N-dimethyl-p-toluidine to give the compound of formula IX, which is isolated in a conventional manner or used directly in the next reaction step. Finally, the compound of the formula X is obtained by reacting IX with a cooled mixture of lithium diisopropylamide or lithium hexamethyldisilazane in THF and (E) - (dimethylamino-methyleneamino) -acetic acid ethyl ester or with a cooled mixture of ethyl isocyanoacetate in THF and potassium tert-butoxide or sodium hydride.
Scheme 4
According to scheme 4, the compound of formula X is hydrolyzed to the corresponding carboxylic acid XI, for example by treatment with an ethanolic solution of sodium hydroxide at elevated temperature. The decarboxylation of the compound of formula XI to produce the compound of formula II can be accomplished by stirring for a period of time in a suitable solvent such as diethylene glycol dibutyl ether at elevated temperatures, e.g., 200 ℃. Finally, the compounds of formula II are halogenated to compounds of formula I by reaction with a suitable halogenating agent such as N-chlorosuccinimide or 1, 3-dichloro-5, 5-dimethylhydantoin, bromine, iodine and the like in a suitable solvent such as N, N-dimethylformamide, dichloromethane and the like, at room temperature or at an elevated temperature.
As mentioned previously, the compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. It has now been found that the compounds of the present invention are ligands for GABA a receptors containing the α 5 subunit and are therefore useful in therapies requiring enhanced cognition.
This compound was investigated according to the tests given below.
Preparation of membranes and binding assays
The affinity of the compound for the GABA A receptor subtype and [2 ]3H]Flumazenil (85 Ci/mmol; Roche) has a competition and expression composition of alpha 1 beta 3 gamma 2α 2 β 3 γ 2, α 3 β 3 γ 2 and α 5 β 3 γ 2, or human (transiently transfected) receptors.
Cell pellets were suspended in Krebs-tris buffer (4.8mM KCl, 1.2mM CaCl)2，1.2mM MgCl2120mM NaCl, 15mM Tris; pH 7.5; binding assay buffer), homogenized by polytron on ice for about 20 seconds, then centrifuged at 4 ℃ for 60 minutes (50000 g; sorvall, rotor: SM24 ═ 20000 rpm). The cell particles were resuspended in Krebs-tris buffer and homogenized by polytron on ice for about 15 seconds. Proteins were assayed (Bradford method, Bio-Rad) and 1mL aliquots were prepared and stored at-80 ℃.
The radioligand binding assay is performed on a cell membrane containing 100. mu.L of cell membrane3H]Flumazenil at a concentration of 1nM (for the. alpha.1,. alpha.2,. alpha.3 subunits) and 0.5nM (for the. alpha.5 subunit) and a concentration of 10 of the test compound-10-3×10-6M in 200. mu.L volumes (96-well plates). Non-specific binding through 10-5M diazepam, which is usually less than 5% of the total binding. The assay was incubated at 4 ℃ for 1 hour until equilibrium was reached, then collected by filtration onto a GF/C uni-filter (Packard) by a Packard harvester and washed with ice cold wash buffer (50mM Tris; pH 7.5). After drying, the radioactivity retained on the filter was detected by liquid scintillation counting. Ki values were calculated using Excel-Fit (Microsoft) and are the average of two determinations.
The compounds of the following examples were tested in the above assay and as a result, all of the compounds were found to displace from the α 5 subunit of the GABAA receptor in rats3H]The Ki values of flumazenil are all equal to or less than 100 nM. In a preferred embodiment, the compounds of the invention bind selectively to the α 5 subunit relative to the α 1, α 2 and α 3 subunits.
The following table shows activity data for certain preferred compounds:
| example No. 2 | Ki[nM]hα1 | Ki[nM]hα2 | Ki[nM]hα3 | Ki[nM]hα5 |
| 1 | 3.8 | 1.5 | 0.7 | 0.3 |
| 2 | 0.7 | 1.2 | 0.78 | 0.3 |
| 3 | 12.2 | 17.2 | 11.7 | 0.8 |
| 7 | 18.5 | 25.0 | 20.7 | 1.3 |
| 8 | 22.1 | 29.4 | 24.4 | 2.0 |
| 10 | 22.4 | 25.6 | 11.4 | 1.2 |
| 12 | 5.9 | 15.7 | 8.0 | 1.8 |
| 21 | 33.0 | 24.1 | 8.8 | 1.4 |
| 22 | 19.6 | 40.5 | 21.4 | 1.8 |
| 30 | 28.7 | 18.7 | 20.4 | 1.2 |
| 32 | 20.5 | 40.1 | 16.0 | 1.1 |
| 46 | 2.4 | 0.8 | 0.6 | 0.2 |
| 47 | 2.1 | 3.7 | 3.9 | 0.5 |
| 48 | 9.2 | 14.7 | 11.3 | 1.4 |
| 50 | 15.8 | |||
| 57 | 9.4 | 33.9 | 21.7 | 6.7 |
| 64 | 58.8 | 135.6 | 186.6 | 7.0 |
| 65 | 39.2 | 105.8 | 115.0 | 9.6 |
| 66 | 20.6 | 17.5 | 16.8 | 1.4 |
| 69 | 7.5 | 11.6 | 7.5 | 1.0 |
| 70 | 26.9 | 30.3 | 30.7 | 3.2 |
| 72 | 21.0 | 93.7 | 78.8 | 2.2 |
The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. But may also be administered rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their pharmaceutically acceptable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as excipients for the preparation of tablets, dragees and hard gelatine capsules. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.
Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.
Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.
Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically beneficial substances.
The dosage can vary within wide limits but in each particular case, of course, should be adjusted to the individual requirements. In the case of oral administration, a daily dose of about 10 to 1000mg of a compound of formula I per person is generally appropriate, although the upper limit may be exceeded when desired.
The following examples are intended to illustrate the invention without limiting it. All temperatures are given in degrees celsius.
Example A
Tablets having the following composition were produced in a conventional manner:
mg/tablet
Active substance 5
Lactose 45
Corn starch 15
Microcrystalline cellulose 34
Magnesium stearate 1
Tablet weight 100
Example B
Capsules having the following composition were produced:
mg/capsule
Active substance 10
Lactose 155
Corn starch 30
Talc 5
Capsule fill weight 200
The active substance, lactose and corn starch are first mixed in a mixer and then in a mill. The mixture was returned to the mixer, talc was added thereto and mixed well. The mixture was filled by machine into hard gelatin capsules.
Example C
Producing suppositories having the following composition:
mg/suppository
Active substance 15
Suppository base 1285
Total 1300
The suppository base is melted in a glass or stainless steel vessel, mixed well and cooled to 45 ℃. The active substance in the form of a fine powder is added thereto and stirred until completely dispersed. The mixture is poured into suppository molds of appropriate size, cooled, and the suppositories are then removed from the molds and individually packaged in wax paper or metal foil.
The following examples serve to illustrate the invention. They should not be considered as limiting the scope of the invention, but merely as being representative examples thereof.
Example 1
10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
Reacting 9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10-carboxylic acid1(1.5g, 5.61mmol) was heated at 290 deg.C-310 deg.C under argon for 10 minutes (evolution of CO)2). The residue was purified by chromatography (SiO)2Chloroform: ethanol 100: 0-98: 2) and recrystallised from ethyl acetate gave the title compound as an off-white crystalline solid (1.05g, 84%). MS: 224.2[ M + H ] M/e]+。
b) 10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
To 9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzodiazepine * (100mg, 0.45mmol) in DMF (2.3mL) was added N-chlorosuccinimide at room temperature. The resulting mixture was stirred at this temperature for 90 hours and then extracted with dichloromethane (2X 20 mL). The combined organic layers were washed with water (20mL) and sulfuric acidAnd (4) drying sodium. Purification by chromatography (SiO)2Heptane ethyl acetate dichloromethane 75: 15: 10) and trituration with water (20mL) gave the title compound as a white solid (37mg, 32%). MS: 258.0[ M + H ] M/e]+。
Example 2
10-chloro-3-fluoro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 3-fluoro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
Reacting 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10-carboxylic acid1A suspension of diethylene glycol dibutyl ether (100mL) (25.3g, 88.5mmol) was stirred at 200 deg.C under nitrogen for 48 hours. The resulting suspension was treated with 500mL heptane and stirred at 0 ℃ for 0.5 h. Filtration and washing with heptane (2X 100mL) gave the title compound as an off-white solid (20.5g, 96%). MS: 242.3[ M + H ] M/e]+。
b) 10-chloro-3-fluoro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
To 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]To a suspension of benzodiazepine * (5.66g, 2.35mmol) in DMF (56mL) was added 1, 3-dichloro-5, 5-dimethylhydantoin (2.54g, 1.29mmol) in portions over 5 hours at room temperature. The mixture was stirred at this temperature for an additional 18 hours and diluted with ethyl acetate (150mL), washed with aqueous sodium carbonate (100mL) and extracted with ethyl acetate (150 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Dichloromethane: ethyl acetate 7: 3-5: 5) gave the title compound as a white solid (4.24g, 66%). MS: 276.0[ M + H ] M/e]+。
Example 3
10-chloro-3-methoxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 3-methylhydro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
To 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]To a suspension of benzodiazepine * (1.00g, 4.15mmol) in DMSO (10mL) was added sodium methoxide (291mg, 5.39 mmol). The mixture was stirred at 150 ℃ for 3 hours. Sodium methoxide (291mg, 5.39mmol) was added and stirring was continued at 150 ℃ for 3 hours. The mixture was concentrated in vacuo and the residue was purified by chromatography (SiO)2Ethyl acetate: methanol 100: 0-90: 10) to give the title compound (650mg, 62%). MS: 254.1[ M + H ] M/e]+。
b) 10-chloro-3-methoxy-9H-imidazo [1, 5-a ]] [1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
To 3-methoxy-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzodiazepine * (200mg, 0.79mmol) in DMF (3mL) was added N-chlorosuccinimide (116mg, 0.87mmol) and the resulting suspension was stirred at room temperature for 14 days. The mixture was diluted with ethyl acetate (20mL) and washed with aqueous sodium carbonate (2N). After extraction with ethyl acetate (20mL), the combined organic layers were washed with water (20mL) and dried over sodium sulfate. Purification by chromatography (SiO)2Heptane ethyl acetate dichloromethane 7: 2: 1-4: 5: 1) gave the title compound as a white solid (47mg, 21%). MS: 288.0[ M + H ] M/e]+。
Example 4
10-chloro-3-ethoxy-9H-imidazo [1, 5-a ]1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 3-ethoxy-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
To 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (600mg, 2.49 mmol)) To a solution of sodium ethoxide in ethanol (21%, 1.20mL, 3.23mmol) was added and stirred at 130 ℃ for 4 hours. The mixture was concentrated in vacuo and the residue was purified by chromatography (SiO)2Ethyl acetate: dichloromethane: methanol 8: 2: 0-6: 2) to give the title compound (613mg, 92%). MS: 268.2[ M + H ] M/e]+。
b) 10-chloro-3-ethoxy-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
To 3-ethoxy-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzodiazepine * (200mg, 0.75mmol) in DMF (2mL) at room temperature was added 1, 3-dichloro-5, 5-dimethylhydantoin (81mg, 0.41mmol) and stirred for 24 h. 1, 3-dichloro-5, 5-dimethylhydantoin (40mg, 0.15mmol) was added and stirring continued at room temperature for 18 h. The mixture was diluted with ethyl acetate (20mL), washed with aqueous sodium carbonate solution and dried over sodium sulfate. Purification by chromatography (SiO)2Heptane ethyl acetate dichloromethane 6: 2-3: 5: 2) gave the title compound as a white solid (126mg, 56%). MS: m/e is 302.0[ M + H ]]+。
Example 5
3-benzyloxy-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 3-benzyloxy-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
To a solution of benzyl alcohol (1.1mL, 10mmol) in DMSO (5mL) was added sodium hydride (55% dispersion in mineral oil, 136mg, 3.11mmol) at room temperature and stirred for 2 h. Adding 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (500mg, 2.07mmol) and stirred at 130 ℃ for 3 h. Water (15mL) was added slowly and the resulting suspension was stirred at room temperature for 15 minutes. Filtration, washing with water (3mL) and purification by chromatography (SiO)2Ethyl acetate, dichloromethane and methanol8: 2: 0) to give the title compound as a white solid (490mg, 72%). MS: 330.1[ M + H ] M/e]+。
b) 3-benzyloxy-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 4b) using 3-benzyloxy-9H-imidazo [1, 5-a)][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (410mg, 1.25mmol) in place of 3-ethoxy-9H-imidazo [1, 5-a ]][1，2，4]-triazolo [1, 5-d][1，4]Conversion of benzodiazepine * gave the title compound (SiO) as a white foam2Heptane, ethyl acetate: dichloromethane 6: 2-3: 5: 2, 276mg, 61%). MS: 364.1[ M + H ] M/e]+。
Example 6
10-chloro-3-phenoxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 3-phenoxy-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
3-fluoro-9H-imidazo [1, 5-a ] by the method described in example 5a) using phenol instead of benzyl alcohol][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (500mg, 2.07mmol) was converted to the title compound (SiO) as a white solid2Ethyl acetate: dichloromethane: methanol 8: 2: 0-6: 2, 330mg, 51%). MS: 316.0[ M + H ] M/e]+。
b) 10-chloro-3-phenoxy-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 4b) using 3-phenoxy-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (410mg, 1.25mmol) in place of 3-ethoxy-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * gave the title compound (SiO) as a white solid2'Heng' for treating hepatitisAlkyl, ethyl acetate, dichloromethane 7: 2: 1-4: 5: 1, 183mg, 72%). MS: 350.2[ M + H ] M/e]+。
Example 7
10-chloro-3- (2-fluoro-ethoxy) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Sodium hydride (55% dispersion in mineral oil, 158mg, 3.6mmol) was added to DMSO (5mL) and stirred at room temperature for 15 min. 2-Fluoroethanol (524. mu.l, 9.1mmol) was added dropwise and stirring was continued for 1.5 h. Adding 10-chloro-3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]After benzodiazepine * (200mg, 0.73mmol), the resulting mixture was heated at 130 ℃ for 3 hours, then diluted with ethyl acetate (20mL) and Na2CO3The aqueous solution was washed and extracted with ethyl acetate (20 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 6: 2-3: 5: 2) gave the title compound as a white solid (107mg, 46%). MS: 320.2[ M + H ] M/e]+。
Example 8
10-chloro-3- (2, 2-difluoro-ethoxy) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
10-chloro-3-fluoro-9H-imidazo [1, 5-a ] by the method of example 7, substituting 2, 2-difluoroethanol for 2-fluoroethanol][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (400mg, 1.45mmol) to give the title compound (SiO) as a white solid2Heptane, ethyl acetate, dichloromethane 6: 2-3: 5: 2, 243mg, 50%). MS: 338.1[ M + H ] M/e]+。
Example 9
10-chloro-3- (2, 2, 2-trifluoro-ethoxy) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
The procedure is as described in example 7, using 2, 2, 2-trifluoroEthanol instead of 2-fluoroethanol is prepared by reacting 10-chloro-3-fluoro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (200mg, 0.73mmol) gave the title compound (SiO) as a white solid2Heptane, ethyl acetate, dichloromethane 6: 2-3: 5: 2, 62mg, 24%). MS: 356.1[ M + H ] M/e]+。
Example 10
10-chloro-3-vinyloxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Sodium hydride (55% dispersion in mineral oil, 158mg, 3.6mmol) was added to DMSO (5mL) and stirred at room temperature for 15 min. 2-Fluoroethanol (524. mu.l, 9.1mmol) was added dropwise and stirring was continued for 1.5 h. Adding 10-chloro-3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]After benzodiazepine * (200mg, 0.73mmol), the resulting mixture was heated at 130 ℃ for 3 hours, then diluted with ethyl acetate (20mL) and Na2CO3The aqueous solution was washed and extracted with ethyl acetate (20 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 6: 2-3: 5: 2) gave the title compound as a white solid (32mg, 15%). MS: 300.2[ M + H ] M/e]+。
Example 11
10-chloro-3- (2-hydroxy-ethoxy) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 10-chloro-3-fluoro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]To a suspension of benzo-diaza * (200mg, 0.73mmol) in ethylene glycol (2mL) was added potassium hydroxide (81mg, 1.5mmol) and the resulting mixture was stirred at 170 ℃ for 2 h. The resulting solution was diluted with ethyl acetate (20mL) and Na2CO3The aqueous solution was washed and extracted with ethyl acetate (20 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Ethyl acetate: methanol-1: 0-9: 1) gave the title compound as a white solid (79mg, 34%). MS: m/e is 318.1[M+H]+。
Example 12
10-chloro-3-methylamino-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 3-acetylamino-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzodiazepine * (840mg, 2.67mmol) in DMF (16mL) was added potassium bis (trimethylsilyl) amide (0.9M in THF, 3.81mL, 3.47mmol) and the mixture was stirred at room temperature for 45 min. Methyl iodide (217mL, 3.47mmol) was added and stirring was continued for 2 hours. The resulting mixture was diluted with ethyl acetate and Na2CO3The aqueous solution was washed and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Purification by chromatography (SiO)2Heptane ethyl acetate dichloromethane 6: 2-3: 5: 2) gave the title compound as a white crystalline solid (65mg, 9%). MS: 287.1[ M + H ]]+。
Example 13
10-chloro-3-dimethylamino-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To a solution of dimethylamine hydrochloride (621mg, 7.62mmol) in DMSO (3mL) was added sodium hydride (55% dispersion in mineral oil, 261mg, 10.9mmol) and the mixture was stirred at room temperature for 1.5 h. Adding 10-chloro-3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (300mg, 1.09mmol) and stirred at 130 ℃ for 2 days. The resulting mixture was diluted with water (30mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water (30mL) and brine (20 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 6: 2-3: 5: 2) gave the title compound as a white solid (94mg, 29%). MS: 301.2[ M + H ] M/e]+。
Example 14
3-benzylamino-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Reacting 10-chloro-3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]A mixture of benzodiazepine * (400mg, 1.45mmol) and benzylamine (793. mu.L, 7.26mmol) was stirred at 130 ℃ for 4 days, then water (10mL) was added. Extracted with ethyl acetate (20mL) followed by Na2CO3Aqueous solution (20mL) and water (20 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 7: 2: 1-4: 5: 1) gave the title compound as a yellow solid (120mg, 23%). MS: 363.1[ M + H ] M/e]+。
Example 15
3- (benzyl-methyl-amino) -10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 3-benzylamino-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzo-diaza * (104mg, 0.29mmol) in DMF (1mL) was added potassium bis (trimethylsilyl) amide (0.9M in THF, 410. mu.L, 0.37mmol) and the mixture was stirred at room temperature for 45 min. Methyl iodide (23 μ L, 0.37mmol) was added followed by stirring for 20 h. The resulting mixture was washed with ethyl acetate (30mL) and Na2CO3And (5) diluting the aqueous solution. The aqueous layer was extracted with ethyl acetate (30mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO)2Heptane ethyl acetate dichloromethane 7: 2: 1-4: 5: 1) gave the title compound as a light brown solid (26mg, 24%). MS: m/e 377.0[ M + H ]]+。
Example 16
10-chloro-3-morpholin-4-yl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
10-chloro-3-fluoro-9H-imidazo [1, 5-a ] in a sealed tube]-[1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (206mg, 0.75mmol) in DMMorpholine (98. mu.l, 1.1mmol) was added to the SO (2mL) solution and the mixture was stirred at 130 ℃ for 18 h. Morpholine (325. mu.l, 3.74mmol) was added and stirring was continued at 130 ℃ for 48 h. The resulting mixture was diluted with ethyl acetate (20mL) and Na2CO3The aqueous solution was washed and extracted with ethyl acetate (20 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Heptane, ethyl acetate, dichloromethane, methanol 5: 3: 2: 0-0: 75: 20: 5) gave the title compound (182mg, 71%) as a white solid. MS: 343.1[ M + H ] M/e]+。
Example 17
10-chloro-3-thiomorpholin-4-yl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 10-chloro-3-fluoro-9H-imidazo [1, 5-a]-[1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzodiazepine * (500mg, 1.81mmol) in DMSO (5mL) was added thiomorpholine (935mg, 9.1mmol) and the mixture was stirred at 130 ℃ for 18 h and then at 150 ℃ for 3 days. The resulting mixture was diluted with ethyl acetate (20mL) and Na2CO3The aqueous solution was washed and extracted with ethyl acetate (20 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 6: 2-3: 5: 2) gave the title compound as a light brown solid (490mg, 75%). MS: 359.2[ M + H ] M/e]+。
Example 18
10-chloro-3-imidazol-1-yl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Sodium hydride (55% dispersion in mineral oil, 126mg, 2.90mmol) was added to DMSO (4mL) and stirred at room temperature for 15 min. Imidazole (493mg, 7.26mmol) was added at room temperature and stirring was continued for 18 h. Adding 10-chloro-3-fluoro-9H-imidazo [1, 5-a ]]-[1，2，4]Triazolo [1, 5-d][1，4]After benzodiazepine * (400mg, 1.45mmol), the mixture was heated at 80 ℃ for 3 hours. The resulting mixture was extracted with ethyl acetate (20mL)Diluting with Na2CO3The aqueous solution was washed and extracted with ethyl acetate (20 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Ethyl acetate: methanol 9: 1) gave the title compound as a white solid (82mg, 17%). MS: 324.1[ M + H ] M/e]+。
Example 19
3-acetyl-amino-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 3-amino-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
Reacting 3-fluoro-9H-imidazo [1, 5-a ]]-[1，2，4]Triazolo [1, 5-d][1，4]A mixture of benzodiazepine * (5.00g, 20.7mmol) and benzylamine (50.0mL, 458mmol) was heated at 190 ℃ for 22 hours. After evaporation the residue was dissolved in ethyl acetate and washed with water and brine. The aqueous layer was extracted with ethyl acetate. Drying with sodium sulfate to obtain crude product 3-benzylamino-9H-imidazo [1, 5-a ] as brown solid]-[1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *, dissolved in methanol (100 mL). After addition of palladium (10%, on activated carbon, 680mg, 0.64mmol), the mixture is stirred under a hydrogen atmosphere at 70 ℃ for 2 hours. Aqueous HCl (1N, 32mL) was added and the resulting mixture was stirred under hydrogen atmosphere at 90 ℃ for 19 hours. Filtered through Hyflo ® and dichloromethane and Na were added2CO3The aqueous layer was extracted with dichloromethane. Dried over sodium sulfate and purified by chromatography (SiO)2Ethyl acetate: dichloromethane: methanol 9: 2: 0-6: 2) gave the title compound as a light brown solid (2.36g, 48%). MS: 239.1[ M + H ] M/e]+。
b) 3-acetylamino-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
To 3-amino-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (2.63g, 9.91mmol) in dichloromethane (100mL) pyridine (1.78mL, 22.1mmol) and acetic anhydride (1.25mL, 13.2mmol) were added to the solution. The resulting suspension was stirred at room temperature for 18 hours. Adding Na2CO3After the aqueous solution, the crystalline solid formed was filtered and Na was added2CO3Aqueous solution and water wash. Drying in vacuo afforded the title compound as an off-white solid (1.22g, 44%). MS: 281.1[ M + H ] M/e]+。
c) 3-acetylamino-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepines Hetero *
The procedure is as described in example 4b) using 3-acetylamino-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (1.20mg, 4.28mmol) instead of 3-ethoxy-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * gave the title compound (SiO) as a white solid2Dichloromethane: methanol 97: 3-95: 5, 840mg, 62%). MS: 315.1[ M + H ] M/e]+。
Example 20
3, 10-dichloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 3-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 2a) using 3-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * -10-carboxylic acid (EP 519307) (17.5g, 57.8mmol) in place of 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]-triazolo [1, 5-d][1，4]Conversion of benzodiazepine * -10-carboxylic acid gave the title compound as an off-white solid (14.1g, 94%). MS: 258.0[ M + H ] M/e]+。
b) 3, 10-dichloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
As described in example 1b)Method using 3-chloro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (302mg, 1.17mmol) in place of 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * gave the title compound as a white solid (ethyl acetate: heptane: dichloromethane: 4: 5: 1-8: 1, 236mg, 69%). MS: 292.0[ M ] M/e]+。
Example 21
3-bromo-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) (4-bromo-2-cyano-phenyl) -carbamic acid ethyl ester
A suspension of 2-amino-5-bromobenzonitrile (58.5g, 297mmol) in ethyl chloroformate (141mL, 1.48mol) was heated at reflux for 5 h. The excess ethyl chloroformate (99mL) was distilled off and toluene (96mL) was added. Cyclohexane (228mL) was added slowly to induce crystallization. The solid formed was collected by filtration and washed with cyclohexane. Drying in vacuo afforded the title compound (54.3g, 68%) as an orange solid. MS: m/e-267.1/269.2 [ M-H ]-]。
b) 9-bromo-6H- [1, 2, 4]Triazolo [1, 5-c]Quinazolin-5-ones
To a solution of (4-bromo-2-cyano-phenyl) -carbamic acid ethyl ester (40.4g, 150mmol) in NMP (170mL) was added formylhydrazine (10.0g, 150 mmol). The resulting mixture was stirred at 160 ℃ under a gentle stream of nitrogen for 1.5 hours. It was cooled to below 100 ℃ and water (340mL) was added slowly. The resulting slurry was cooled to 25 ℃ and stirred for 15 minutes. The solid was collected by filtration and washed with water and 2-propanol. Drying in vacuo afforded the title compound (32.4g, 81%) as a pale yellow solid. MS: 264.9/267.0[ M + H ═ M/e+]。
c) 4-bromo-2- (2H- [1, 2, 4)]Triazol-3-yl) -phenylamines
To well stirred 9-bromo-6H- [1, 2, 4] heated at 100 deg.C]Triazolo [1, 5-c]Quinazoline-To a slurry of 5-ketone (32.0g, 171mmol) in ethylene glycol (146mL) was added aqueous NaOH (32%, 22.4mL, 241 mmol). The slurry was heated at 140 ℃ for 17.5 hours. The resulting solution was cooled to 27 ℃ and the product started to crystallize. Water (146mL) and 1-octanol (1.73mL) were added and the pH of the suspension was adjusted to 6.5 by slow addition of glacial acetic acid (14 mL). The resulting slurry was stirred for 30 minutes and the solids were collected by filtration and washed with water and 2-propanol. Drying in vacuo afforded the title compound (25.2g, 87%) as a pale yellow solid. MS: m/e is 239.0/241.1[ M + H%+]。
d) 9-bromo-6H-1, 3, 3a, 6-tetraaza-benzo [ e ]]Azulen-5-ones
Reacting 4-bromo-2- (2H- [1, 2, 4)]A solution of triazol-3-yl) -phenylamine (25.0g, 105mmol) in dioxane (870mL) and pyridine (10.0mL) was cooled to 12 ℃. A solution of chloroacetyl chloride (9.56mL, 121mmol) in diethyl ether (34.7mL) was added dropwise over 8 minutes. The mixture was stirred at 10-12 ℃ for 75 minutes and treated with aqueous NaOH (2N, 126mL, 251mmol) over 5 minutes. The mixture was stirred at room temperature for 17.5 hours. The pH was thus lowered to about pH 9, which was then adjusted to pH 8 with HCl (3N, 6 mL). After evaporation, the residue was stirred in water (650mL) and ethyl acetate (22mL) at 15 ℃ for 30 min. The crystals were filtered off, washed with cold water and dried in vacuo. Trituration with ethyl acetate (100mL) gave the title compound (13.4g, 46%) as a light yellow solid. MS: m/e is 279.0/281.0[ M + H ]+]。
e) 3-bromo-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10-carboxylic acid ethyl ester Esters
To 9-bromo-6H-1, 3, 3a, 6-tetraaza-benzo [ e ]]To a suspension of azulen-5-one (10.7g, 38.5mmol) in chloroform (270mL, filtered with Alox basic) was added 4, N, N-trimethylaniline (13.9mL, 96.1mmol) and phosphonochloride (5.28mL, 57.7 mmol). The mixture was stirred under reflux for 22 hours, then cooled to 30 ℃ and poured into NaHCO3Aqueous solution (10%, 575 mL). After extraction with chloroform (50mL), the organic layer was dried over sodium sulfate and concentrated.
While potassium tert-butoxide (4.31g, 38.5mmol) was added portionwise to a solution of ethyl isocyanoacetate (4.42mL, 38.5mmol) in THF (115mL) at-25 deg.C to-10 deg.C. The resulting suspension was stirred at-10 ℃ for 45 minutes and then cooled to-65 ℃. The above solution was added dropwise over 10 minutes and the mixture was stirred at room temperature for 16 hours. Acetic acid (1.6mL) was added, stirred for 15 minutes, and then poured into NaHCO3Aqueous (5%, 460mL) and ethyl acetate (96 mL). The crystals formed were filtered off and washed with ethyl acetate (25mL), water (50mL) and ethyl acetate (25 mL). Drying in vacuo afforded the title compound as a light brown solid (4.81g, 33%). MS: 373.7/375.7[ M/e ═ M]+。
f) 3-bromo-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10-carboxylic acid
Reacting 3-bromo-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]A mixture of benzodiazepine * -10-carboxylic acid ethyl ester (7.08g, 18.9mmol), NaOH 1N (76mL, 76mmol) in ethanol (70mL) was stirred at room temperature for 18 h. The solvent was distilled off (55mbar, 45 ℃) and the resulting light brown suspension was adjusted to pH 1.5 at 0 ℃ with aqueous HCl (1N, 85 mL). The suspension was stirred at 0 ℃ for 1 hour, filtered and washed 2 times with water (total 50 mL). The solid was dried in vacuo at 60 ℃ to give the title compound as a pale brown solid (6.65g, 99%). MS: 346.0/348.2 [ M + H ] M/e+]。
g) 3-bromo-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 2a) using 3-bromo-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * -10-carboxylic acid (6.25g, 18.1mmol) in place of 3-fluoro-9H-imidazo [1, 5-a ]]-[1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * -10-carboxylic acid gave the title compound (SiO) as an off-white solid2Ethyl acetate: dichloromethane: methanol 75: 20: 5, 4.20g, 77%). MS: m/e is 301.9/304.0[ M + H ]]+。
h) 3-bromo-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 2b) using 3-bromo-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (4.00g, 13.2mmol) in place of 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * to give the title compound (SiO) as a white solid2Heptane ethyl acetate dichloromethane 6: 2-2: 4, 2.69g, 60%). MS: m/e 335.9/337.9[ M + H ]]+。
Example 22
10-chloro-3-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 3-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 2a) using 3-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * -10-carboxylic acid (EP 519307) (400mg, 1.42mmol) instead of 3-fluoro-9H-imidazo [1, 5-a ]]-[1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * -10-carboxylic acid gave the title compound (SiO) as a white solid2Ethyl acetate: dichloromethane: methanol 8: 2: 0-7: 2: 1, 240mg, 71%). MS: 238.1[ M + H ] M/e]+。
b) 10-chloro-3-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 2b) using 3-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (210mg, 0.89mmol) in place of 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * to give the title compound (SiO) as a white solid2Heptane ethyl acetateDichloromethane 7: 2: 1-4: 5: 1, 120mg, 50%). MS: 272.0[ M + H ] M/e]+。
Example 23
10-chloro-3-trimethylsilylethynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Reacting 3-bromo-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]A suspension of benzodiazepine * (800mg, 2.38mmol), trimethylsilylacetylene (0.51mL, 3.68mmol), bis (triphenylphosphine) -palladium (II) chloride (83mg, 0.12mmol), triphenylphosphine (19mg, 0.07mmol) and triethylamine (1.2mL, 8.6mmol) in THF (12mL) was stirred at room temperature for 15 min. Copper (I) bromide (3mg, 0.02mmol) was added and the resulting mixture was stirred at 70 ℃ under argon for 18 h. The mixture was diluted with ethyl acetate (50mL) and washed with aqueous citric acid (10%, 100 mL). The aqueous phase was extracted with ethyl acetate (100mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO)2Heptane, ethyl acetate, dichloromethane, methanol 7: 2: 1: 0-0: 7: 1: 2) gave the title compound (820mg, 97%) as a white solid. MS: 354.2[ M + H ] M/e]+。
Example 24
10-chloro-3-ethynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 10-chloro-3-trimethylsilylethynyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d]-[1，4]A solution of benzodiazepine * (750mg, 2.12mmol) in a mixture of THF (7.5mL) and MeOH (0.4mL) under argon at-70 deg.C was added tetrabutylammonium fluoride trihydrate (702mg, 2.23 mmol). The dry ice bath was replaced by an ice bath and the resulting mixture was stirred at 0 ℃ for 1 hour. Dilute with ethyl acetate (20mL) and Na2CO3The aqueous solution was washed and extracted with ethyl acetate (20 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 5: 2) gave the title as a white solidTitle compound (443mg, 74%). MS: 282.0[ M + H ] M/e]+。
Example 25
10-chloro-3-prop-1-ynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Reacting 10-chloro-3-ethynyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]A solution of benzodiazepine * (200mg, 0.710mmol) in THF (10mL) was cooled to-78 deg.C and butyllithium (1.6M in hexane, 0.47mL, 0.75mmol) was added dropwise. The resulting brown solution was stirred at-78 ℃ for 45 minutes, then methyl iodide (48. mu.l, 0.78mmol) was added at this temperature. The dry ice bath was removed and the resulting mixture was stirred at room temperature for 18 hours. The resulting mixture was diluted with ethyl acetate (10mL) and tert-butyl methyl ether (10mL) and washed with aqueous sodium hydroxide (1N) and brine. The aqueous layer was washed with THF/TBME 1: 1(10mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO)2Heptane ethyl acetate triethylamine 63: 32: 5) gave the title compound as a white solid (86mg, 41%). MS: 296.3[ M + H ] M/e]+。
Example 26
10-chloro-3-cyclopropylethynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
3-bromo-10-chloro-9H-imidazo [1, 5-a ] by the method described in example 23) using cyclopropylacetylene instead of trimethylsilylacetylene][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (200mg, 0.59mmol) gave the title compound (SiO) as a light brown solid2Heptane, ethyl acetate: dichloromethane 6: 2-3: 5: 2, 95mg, 50%). MS: 322.2[ M + H ] M/e]+。
Example 27
10-chloro-3- (3-methyl-but-1-ynyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
3-bromo-10-chloro-9H-imidazo [1, 5-a ] by the method described in example 23) using 3-methyl-1-butyne instead of trimethylsilylacetylene][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (200mg, 0.59mmol) gave the title compound (SiO) as a white solid2Heptane, ethyl acetate, dichloromethane 6: 2-3: 5: 2, 39mg, 20%). MS: 324.2[ M + H ] M/e]+。
Example 28
10-chloro-3- (3-methoxy-prop-1-ynyl)) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] -benzodiazepine *
3-bromo-10-chloro-9H-imidazo [1, 5-a ] by the method described in example 23) using 3-methoxy-propyne instead of trimethylsilylacetylene][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (200mg, 0.59mmol) gave the title compound (SiO) as a white solid2Heptane, ethyl acetate, dichloromethane 6: 2-3: 5: 2, 44mg, 23%). MS: 325.9[ M/e ═ M]+。
Example 29
10-chloro-3-ethyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 3-bromo-10-chloro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzodiazepine * (200mg, 0.59mmol) in THF (4mL) were added a solution of diethylzinc (1.0M in hexane, 2.3mL, 2.3mmol) and bis (triphenylphosphine) palladium (II) chloride (20mg, 29mmol) and the resulting dark brown suspension was stirred at room temperature under argon for 20 h. The mixture formed is treated with NH4Aqueous Cl (saturated, 20mL) was diluted and stirred for 30 min, then extracted with ethyl acetate (30 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 6: 2-3: 5: 2) gave the title compound as an off-white solid (39mg, 23%). MS: 286.1[ M + H ] M/e]+。
Example 30
10-chloro-3-cyclopropyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
3-bromo-10-chloro-9H-imidazo [1, 5-a ] was prepared as described in example 29) using the freshly prepared cyclopropylzinc chloride solution (0.38M in THF) instead of the diethylzinc solution][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (200mg, 0.59mmol) gave the title compound (SiO) as a white solid2Heptane to ethyl acetate 50: 50-40: 60, 118mg, 67%). MS: 298.0[ M + H ] M/e]+。
Example 31
10-chloro-3-cyclopentyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
3-bromo-10-chloro-9H-imidazo [1, 5-a ] was synthesized as described in example 29) using a solution of cyclopentyl zinc bromide (0.5M in THF) instead of the solution of diethyl zinc][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (166mg, 0.49mmol) gave the title compound (SiO) as a white solid2Heptane, ethyl acetate, dichloromethane 6: 2-3: 5: 2, 19mg, 12%). MS: 326.2[ M + H ] M/e]+。
Example 32
10-chloro-3-difluoromethyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 10-chloro-3-formyl-9H-imidazo [1, 5-a ]] [1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
Reacting 3-bromo-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]A suspension of benzodiazepine * (448mg, 1.33mmol), bis (triphenylphosphine) palladium (II) chloride (19mg, 0.03mmol) and sodium formate (136mg, 2.00mmol) in DMF (8mL) was stirred at 110 ℃ under a carbon monoxide atmosphere for 4 h. Additional bis (triphenylphosphine) palladium (II) chloride (19mg, 0.03mmol) and sodium formate (136 mg)2.00mmol) and stirring is continued for 2 hours under an atmosphere of carbon monoxide. The resulting mixture was diluted with ethyl acetate (30mL) and Na2CO3Aqueous solution (saturated), water and Na2CO3Aqueous (saturated) wash. The aqueous layer was extracted with ethyl acetate (30mL) and dried over sodium sulfate. Purification by chromatography (SiO)2Dichloromethane: methanol 99: 1-95: 5) to give the title compound as a white solid (194mg, 51%). MS: 318.1[ M + MeOH + H ]]+。
b) 10-chloro-3-difluoromethyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
Reacting 10-chloro-3-formyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]A mixture of benzodiazepine * (192mg, 0.67mmol) and bis (2-methoxyethyl) aminosulfur trifluoride (163. mu.L, 1.61mmol) in dichloromethane (4mL) was stirred at room temperature for 2 hours. Di (2-methoxyethyl) aminosulfur trifluoride (163. mu.L, 1.61mmol) was added and stirring was continued for 16 hours. The resulting mixture was diluted with ethyl acetate (20mL) and Na2CO3The aqueous solution (saturated) was washed and extracted with ethyl acetate (20 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 6: 2-3: 5: 2) gave the title compound as a white solid (136mg, 66%). MS: 308.2[ M + H ] M/e]+。
Example 33
3-benzyl-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
3-bromo-10-chloro-9H-imidazo [1, 5-a ] is reacted as described in example 29) using benzylzinc bromide solution (0.5M in THF) instead of diethylzinc solution][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (238mg, 0.71mmol) was converted to the title compound (SiO) as an off-white solid2Heptane ethyl acetate dichloromethane 6: 2-3: 5: 2, 117mg, 48%). MS: 348.0[ M + H ] M/e]+。
Example 34
10-chloro-3-phenyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
3-bromo-10-chloro-9H-imidazo [1, 5-a ] is treated as described in example 29) using a phenylzinc iodide solution (0.5M in THF) instead of the diethylzinc solution][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (257mg, 0.76mmol) was converted to the title compound (SiO) as an off-white solid2Heptane, ethyl acetate, dichloromethane 6: 2-3: 5: 2, 43mg, 17%). MS: 334.0[ M + H ] M/e]+。
Example 35
10-chloro-3-cyano-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Reacting 3-bromo-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]A mixture of benzo-diaza * (200mg, 0.59mmol) and copper (I) cyanide (106mg, 1.19mmol) in 1-methyl-2-pyrrolidone (2mL) was stirred at 160 ℃ for 3 hours and then at 210 ℃ for 3 hours. The resulting mixture was diluted with ethyl acetate (20mL) and Na2CO3Aqueous solution (saturated), water washed, then Na again2CO3Aqueous (saturated) wash. The aqueous layer was extracted with ethyl acetate (30 mL). Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 7: 2: 1-4: 5: 1) gave the title compound as an off-white solid (50mg, 30%). MS: 283.0[ M + H ] M/e]+。
Example 36
3, 10-dichloro-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) (4-chloro-2-cyano-phenyl) -carbamic acid ethyl ester
As described in example 21a)The conversion of 2-amino-5-chlorobenzonitrile (33.4g, 219mmol) instead of 2-amino-5-bromobenzonitrile gave the title compound (46.9g, 95%) as a pale yellow solid. MS: 242.3[ M + NH ═ M/e4]+。
b) 9-chloro-2-methyl-6H- [1, 2, 4]Triazolo [1, 5-c]Quinazolin-5-ones
Conversion as described for example 21b) using (4-chloro-2-cyano-phenyl) -carbamic acid ethyl ester (10.0g, 44.5mmol) instead of (4-bromo-2-cyano-phenyl) -carbamic acid ethyl ester and acetohydrazide instead of formylhydrazine gave the title compound as a light yellow solid (9.81g, 94%). MS: 234.9[ M/e ═ M]+。
c) 4-chloro-2- (5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -phenylamines
The process is carried out as described in example 21c) using 9-chloro-2-methyl-6H- [1, 2, 4]Triazolo [1, 5-c]Quinazolin-5-one (9.67g, 41.2mmol) instead of 9-bromo-6H- [1, 2, 4]Triazolo [1, 5-c]Conversion of quinazolin-5-one gave the title compound as an off-white solid (6.57g, 76%). MS: 209.0[ M + H ] M/e]+。
d) 9-chloro-2-methyl-6H-1, 3, 3a, 6-tetraaza-benzo [ e]Azulen-5-ones
The process is carried out as described in example 21d) using 4-chloro-2- (5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -phenylamine (9.44g, 30.9mmol) instead of 4-bromo-2- (2H- [1, 2, 4)]Triazol-3-yl) -phenylamine conversion afforded the title compound as a white solid (4.83g, 63%). MS: 248.9[ M ] M/e]+。
e) 3-chloro-6-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10- Formic acid ethyl ester
The procedure is as described in example 21e) using 9-chloro-2-methyl-6H-1, 3, 3a, 6-tetraaza-benzo [ e ]]Azulen-5-one (2.49g, 10.0mmol) instead of 9-bromo-6H-1, 3, 3a, 6-tetraaza-benzo [ e ]]Azulene-5-one conversion to light brownThe title compound (1.19g, 35%) was solid. MS: 344.0[ M + H ] M/e]+。
f) 3-chloro-6-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
Reacting 3-chloro-6-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]A mixture of ethyl benzo-diaza * -10-carboxylate (800mg, 2.33mmol), ethanol (10mL), and aqueous sodium hydroxide (1N, 9.31mL, 9.31mmol) was stirred at 80 ℃ for 30 minutes. The mixture was evaporated, the residue dissolved in water (10mL) and adjusted to pH 1.5 with aqueous HCl (1N, 9 mL). The resulting suspension was stirred at 0 ℃ for 30 minutes, filtered, washed with water (20mL) and dried in vacuo. The pale yellow solid was suspended in diethylene glycol dibutyl ether (3.0mL) and stirred under nitrogen at 200 ℃ for 88 hours. The suspension was treated with heptane (15mL) and stirred at 0 ℃ for 30 minutes, filtered and washed with heptane (5 mL). Drying in vacuo afforded the title compound (409mg, 65%) as a light brown solid. MS: 272.0[ M + H ] M/e]+。
g) 3, 10-dichloro-6-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 2b) using 3-chloro-6-methyl-9H-imidazo [1, 5-a)][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (300mg, 1.10mmol) in place of 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]-triazolo [1, 5-d][1，4]Conversion of benzodiazepine * to give the title compound (SiO) as an off-white solid2Heptane, ethyl acetate: dichloromethane 75: 15: 10-0: 90: 10, 106mg, 31%). MS: 306.1[ M ] M/e]+。
Example 37
3, 10-dichloro-6-phenyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 9-chloro-2-phenyl-6H- [1, 2, 4]Triazolo [1, 5-c]Quinazolin-5-ones
Conversion as described for example 21b) using (4-chloro-2-cyano-phenyl) -carbamic acid ethyl ester (5.00g, 22.3mmol) instead of (4-bromo-2-cyano-phenyl) -carbamic acid ethyl ester using benzoyl hydrazine instead of formyl hydrazine afforded the title compound as an off-white solid (6.50g, 98%). MS: m/e 297.1[ M + H ]]+。
b) 4-chloro-2- (5-phenyl-2H- [1, 2, 4)]Triazol-3-yl) -phenylamines
The process is carried out as described in example 21c) using 9-chloro-2-phenyl-6H- [1, 2, 4]Triazolo [1, 5-c]Quinazolin-5-one (6.34g, 21.4mmol) in place of 9-bromo-6H- [1, 2, 4]Triazolo [1, 5-c]Conversion of quinazolin-5-one gave the title compound as a light brown solid (5.35g, 92%). MS: 271.0[ M + H ]]+。
c) 9-chloro-2-phenyl-6H-1, 3, 3a, 6-tetraaza-benzo [ e]Azulen-5-ones
The process is carried out as described in example 21d) using 4-chloro-2- (5-phenyl-2H- [1, 2, 4)]Triazol-3-yl) -phenylamine (5.24g, 19.3mmol) instead of 4-bromo-2- (2H- [1, 2, 4)]Triazol-3-yl) -phenylamine conversion afforded the title compound as an off-white solid (4.40g, 73%). MS: 311.0[ M + H ] M/e]+。
d) 3-chloro-6-phenyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10- Formic acid ethyl ester
The procedure is as described in example 21e) using 9-chloro-2-phenyl-6H-1, 3, 3a, 6-tetraaza-benzo [ e ]]Azulen-5-one (3.11g, 10.0mmol) instead of 9-bromo-6H-1, 3, 3a, 6-tetraaza-benzo [ e ]]Azulen-5-one was converted to give the title compound as a pale yellow solid (1.26g, 31%). MS: 406.2[ M + H ] M/e]+。
e) 3-chloro-6-phenyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
According to implementationExample 36f) Using 3-chloro-6-phenyl-9H-imidazo [1, 5-a)][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10-carboxylic acid ethyl ester (1.00g, 2.46mmol) in place of 3-chloro-6-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * -10-carboxylic acid ethyl ester yielded the title compound as an off-white solid (727mg, 88%). MS: m/e is 334.2[ M + H ]]+。
f) 3, 10-dichloro-6-phenyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 2b) using 3-chloro-6-phenyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (500mg, 1.50mmol) in place of 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]-triazolo [1, 5-d][1，4]Conversion of benzodiazepine * to give the title compound (SiO) as a pale yellow solid2Heptane, ethyl acetate: dichloromethane 85: 5: 10-25: 65: 10, 124mg, 22%). MS: 368.1[ M/e ═ M]+。
Example 38
3-bromo-10-chloro-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 3-bromo-2-methyl-6H- [1, 2, 4]Triazolo [1, 5-c]Quinazolin-5-ones
According to the method described in example 21b) (4-bromo-2-cyano-phenyl) -carbamic acid ethyl ester (30.0g, 111mmol) was converted using acethydrazide instead of formylhydrazine to give the title compound as an off-white solid (28.5g, 91%). MS: m/e 277.0/279.1[ M-H ]]-。
b) 4-bromo-2- (5-methyl-2H- [1, 2, 4)]Tri-3-Yl-PhenylAmines
The process is as described in example 21c) using 9-bromo-2-methyl-6H- [1, 2, 4]Triazolo [1, 5-c]Quinazolin-5-one (28.5g, 102mmol) instead of 9-bromo-6H- [1, 2, 4]Triazolo [1, 5-c]Conversion of quinazolin-5-one to yieldThe title compound (25.5g, 99%) was obtained as an off-white solid. MS: 251.0/253.1[ M-H ]]-。
c) 9-bromo-2-methyl-6H-1, 3, 3a, 6-tetraaza-benzo [ e]Azulen-5-ones
The process is carried out as described in example 21d) using 4-bromo-2- (5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -phenylamine (24.9g, 98.3mmol) instead of 4-bromo-2- (2H- [1, 2, 4)]Triazol-3-yl) -phenylamine conversion afforded the title compound as an off-white solid (17.0g, 59%). MS: m/e 291.0/293.2[ M-H ]]-。
d) 3-bromo-6-methyl-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10- Formic acid ethyl ester
The procedure is as described in example 21e) using 9-bromo-2-methyl-6H-1, 3, 3a, 6-tetraaza-benzo [ e ]]Azulen-5-one (16.8g, 57.3mmol) instead of 9-bromo-6H-1, 3, 3a, 6-tetraaza-benzo [ e ]]Azulen-5-one conversion gave the title compound as an off-white solid (14.7g, 66%). MS: 388.2/390.1[ M + H ═ M/e]+。
e) 3-bromo-6-methyl-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10- Formic acid
The procedure is as described in example 21f) using 3-bromo-6-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10-carboxylic acid ethyl ester (11.5g, 29.5mmol) in place of 3-bromo-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * -10-carboxylic acid ethyl ester gave the title compound as a light brown solid (3.46g, 33%). MS: 358.1/360.2[ M-H ] M/e]-。
f) 3-bromo-6-methyl-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 2a) using 3-bromo-6-methyl-9H-imidazo [1, 5-a)][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * -10-carboxylic acid (3.39g, 9.41mmol) in place of 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * -10-carboxylic acid gave the title compound as a light brown solid (2.12mg, 71%). MS: m/e 316.0/319.9[ M + H ]]+。
g) 3-bromo-10-chloro-6-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine *
The procedure is as described in example 2b) using 3-chloro-6-methyl-9H-imidazo [1, 5-a)][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (200mg, 0.63mmol) in place of 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]-triazolo [1, 5-d][1，4]Conversion of benzodiazepine * to give the title compound (SiO) as a white solid2Heptane, ethyl acetate, dichloromethane 7: 2: 1-4: 5: 1, 88mg, 40%). MS: 349.9/351.9[ M/e ═ M]+。
Example 39
10-chloro-6-methyl-3-trimethylsilylethynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described in example 23, 3-bromo-10-chloro-6-methyl-9H-imidazo [1, 5-a ] was used][1，2，4]Triazolo- [1, 5-d][1，4]Benzodiazepine * (400mg, 1.14mmol) in place of 3-bromo-10-chloro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * gave the title compound (SiO) as an off-white solid2Heptane, ethyl acetate, dichloromethane 9: 1: 0-4: 5: 1, 374mg, 89%). MS: 368.2[ M + H ] M/e]+。
Example 40
10-chloro-3-ethynyl-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described in example 24, using 10-chloro-6-methyl-3-trimethylsilylethynyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo compounds[1，5-d]-[1，4]Benzodiazepine * (450mg, 1.22mmol) in place of 10-chloro-3-trimethylsilylethynyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d]-[1，4]Conversion of benzodiazepine * gave the title compound (SiO) as a white solid2Heptane, ethyl acetate, dichloromethane 7: 2: 1-4: 5: 1, 153mg, 42%). MS: 296.1[ M + H ] M/e]+。
EXAMPLE 41
10-chloro-3-cyclopropyl-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
The diethyl zinc solution was replaced by a freshly prepared solution of cyclopropylzinc chloride (0.38M in THF) and 3-bromo-10-chloro-6-methyl-9H-imidazo [1, 5-a ] was used as described in example 29][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (500mg, 1.43mmol) in place of 3-bromo-10-chloro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * gave the title compound (SiO) as a white solid2Heptane, ethyl acetate, dichloromethane 25: 45: 20, 168mg, 38%). MS: 312.2[ M + H ] M/e]+。
Example 42
10-chloro-3-cyano-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
The procedure was followed as described in example 35 using 3-bromo-10-chloro-6-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (200mg, 0.57mmol) in place of 3-bromo-10-chloro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * gave the title compound (SiO) as a white solid2Heptane, ethyl acetate, dichloromethane 7: 2: 1-4: 5: 1, 66mg, 39%). MS: m/e 297.1[ M + H ]]+。
Example 43
10, 12-dichloro-3-methoxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 3-methoxy-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzodiazepine * (200mg, 0.79mmol) in DMF (3mL) was added N-chlorosuccinimide (116mg, 0.87mmol) and the resulting suspension was stirred at room temperature for 14 days. The mixture was diluted with ethyl acetate (20mL) and washed with aqueous sodium carbonate (2N). After re-extraction with ethyl acetate (20mL), the combined layers were washed with water (20mL) and dried over sodium sulfate. Purification by chromatography (SiO)2Heptane ethyl acetate dichloromethane 7: 2: 1-4: 5: 1) gave the title compound as a white solid (64mg, 25%). MS: m/e 322.2[ M%]+。
Example 44
10, 12-dichloro-3-ethoxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 3-ethoxy-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzodiazepine * (200mg, 0.75mmol) in DMF (2mL) at room temperature was added 1, 3-dichloro-5, 5-dimethylhydantoin (81mg, 0.41mmol) and stirred for 24 h. Another portion of 1, 3-dichloro-5, 5-dimethylhydantoin (40mg, 0.15mmol) was added and stirring continued at room temperature for 18 hours. The mixture was diluted with ethyl acetate (20mL), washed with aqueous sodium carbonate solution and dried over sodium sulfate. Purification by chromatography (SiO)2Heptane ethyl acetate dichloromethane 6: 2-3: 5: 2) gave the title compound as a light brown solid (50mg, 20%). MS: 336.0[ M/e ═ M]+。
Example 45
10, 12-dichloro-3-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
The procedure is as described in example 2b) using 3-methyl-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (210mg, 0.89mmol) in place of 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]-benzo (b)Diaza * conversion to give the title compound (SiO) as a white solid2Heptane, ethyl acetate, dichloromethane 7: 2: 1-4: 5: 1, 45mg, 17%). MS: 306.1[ M ] M/e]+。
Example 46
10-bromo-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzodiazepine * (690mg, 3.09mmol) in dimethylformamide (15mL) was added bromine (0.48mL, 9.3 mmol). The resulting solution was stirred at 50 ℃ for 48 hours, then NaHCO was added3Aqueous solution (saturated) and the mixture was extracted with dichloromethane. Dried over sodium sulfate and purified by chromatography (SiO)2Dichloromethane: ethanol 100: 0-97: 3) to give the title compound as a white crystalline solid (265mg, 28%). MS: m/e 302.0/304.0[ M + H ]]+。
Example 47
10-bromo-3-fluoro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described in example 46, using 3-fluoro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzo-diaza * (482mg, 2.00mmol) in place of 9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * to give the title compound (SiO) as a white solid2Dichloromethane: ethanol 100: 1-97: 3, 170mg, 27%). MS: 319.9/321.9[ M/e ═ M]+。
Example 48
3-chloro-10-iodo-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 3-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Iodine (14.6g, 57.5mmol) was added to a solution of benzodiazepine * (7.40g, 28.7mmol) in dimethylformamide (240 mL). Mixing the obtained mixtureThe mixture was stirred at 55 ℃ for 6 days, then water (3L) and Na were added2S2O3Aqueous (10%, 500mL) and the mixture extracted with dichloromethane. Dried over sodium sulfate and purified by chromatography (SiO)2Dichloromethane: ethanol 100: 0-97: 3) gave the title compound as a white crystalline solid (3.10g, 35%). MS: 383.9[ M/e ═ M]+。
Example 49
3-Methanesulfonylamino-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To a solution of methanesulfonamide (690mg, 7.26mmol) in DMSO (6mL) was added sodium hydride (55% dispersion in mineral oil, 253mg, 5.80mmol) at 0 ℃. Stirring at room temperature for 2 hours, adding 3-fluoro-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (400mg, 1.45mmol) and the resulting mixture was stirred sequentially at 80 ℃ for 2 hours, 130 ℃ for 2 hours and 170 ℃ for 17 hours. After cooling to room temperature, the resulting mixture was treated with acetic acid (0.5mL), water (20mL) and dichloromethane (30mL) and stirred for 10 minutes. The organic layer was washed with water and dried over sodium sulfate. Purification by chromatography (SiO)2Dichloromethane: methanol-10: 0-9: 1) gave the title compound as a white solid (126mg, 25%). MS: 351.2[ M/e ═ M]+。
Example 50
3- (cyclopropanecarbonyl-amino) -10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
10-chloro-3-fluoro-9H-imidazo [1, 5-a ] is prepared as described in example 49, substituting cyclopropanecarboxamide for methanesulfonamide][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (400mg, 1.45mmol) to give the title compound (SiO) as a white solid2Heptane, ethyl acetate: dichloromethane 40: 20-0: 80: 20, 36mg, 7%). MS: 341.1[ M + H ] M/e]+。
Example 51
10-chloro-3- (3, 4-difluoro-phenyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Reacting 3-bromo-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]A solution of benzodiazepine * (200mg, 0.59mmol), tetrakis (triphenylphosphine) palladium (0) (7mg, 0.006mmol), 3, 4-difluorophenylboronic acid (103mg, 0.65mmol) and aqueous sodium bicarbonate (1N, 1.4mL, 1.4mmol) in 1, 2-dimethoxyethane (2mL) was stirred at 100 ℃ under argon for 2 hours. The reaction mixture was diluted with dichloromethane (10mL) and washed with water (10mL) and aqueous sodium carbonate (10 mL). Drying over sodium sulfate, concentration and washing with water (10mL) and 1, 2-dimethoxyethane (10mL) afforded the title compound as an off-white solid (139mg, 63%). MS: 370.0[ M + H ] M/e]+。
Example 52
10-chloro-3- (3, 5-bis-trifluoromethyl-phenyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described in example 52, 3-bromo-10-chloro-9H-imidazo [1, 5-a ] was substituted for difluorophenylboronic acid with 3, 5-bis-trifluoromethyl-phenylboronic acid][1，2，4]Triazolo [1, 5-d][1，4]-benzodiazepine * (200mg, 0.59mmol) was converted to give the title compound as a white solid (160mg, 57%). MS: 470.3[ M + H ] M/e]+。
Example 53
10-chloro-3- (2-fluoro-phenyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described in example 51, 3-bromo-10-chloro-9H-imidazo [1, 5-a ] was substituted for difluorophenylboronic acid with 2-fluoro-phenylboronic acid][1，2，4]Triazolo [1, 5-d][1，4]Conversion of-benzodiazepine * (200mg, 0.59mmol) gave the title compound as an off-white solid (128mg, 61%). MS: 352.2[ M + H ] M/e]+。
Example 54
10-chloro-3- (2, 4-difluorobenzyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
3-bromo-10-chloro-9H-imidazo [1, 5-a ] was synthesized as described in example 29, substituting 2, 4-difluorobenzylzinc bromide solution (0.5M in THF) for the diethylzinc solution][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (200mg, 0.59mmol) gave the title compound as a light brown solid (142mg, 62%). MS: 384.1[ M + H ] M/e]+。
Example 55
10-chloro-3- (3, 4-difluorobenzyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
3-bromo-10-chloro-9H-imidazo [1, 5-a ] was synthesized as described in example 29, substituting 3, 4-difluorobenzylzinc bromide solution (0.5M in THF) for diethylzinc solution][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (200mg, 0.59mmol) gave the title compound as a light brown solid (86mg, 38%). MS: 384.1[ M + H ] M/e]+。
Example 56
10-chloro-3- (pyridin-4-yl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described in example 51, 3-bromo-10-chloro-9H-imidazo [1, 5-a ] was substituted for difluorophenylboronic acid with pyridin-4-ylboronic acid][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (400mg, 1.19mmol) gave the title compound as a white solid (295mg, 74%). MS: 335.0[ M + H ] M/e]+。
Example 57
10-chloro-3- (pyridin-3-yl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
As described in example 51Process for preparing 3-bromo-10-chloro-9H-imidazo [1, 5-a ] boronic acid using pyridin-3-ylboronic acid instead of difluorophenylboronic acid][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (400mg, 1.19mmol) gave the title compound as a grey solid (205mg, 52%). MS: 335.0[ M + H ] M/e]+。
Example 58
10-chloro-3- (2-tolyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described in example 51, 3-bromo-10-chloro-9H-imidazo [1, 5-a ] was substituted with 2-tolylboronic acid instead of difluorophenylboronic acid][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (300mg, 0.89mmol) gave the title compound as a grey solid (300mg, 97%). MS: 347.1[ M ═ M/e ═ M]+。
Example 59
3- (3-amino-phenyl) -10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described in example 51, 3-bromo-10-chloro-9H-imidazo [1, 5-a ] was substituted for difluorophenylboronic acid with 3-amino-phenylboronic acid][1，2，4]Triazolo [1, 5-d][1，4]-benzodiazepine * (400mg, 1.19mmol) was converted to give the title compound as a white solid (300mg, 72%). MS: 349.1[ M + H ] M/e]+。
Example 60
10-chloro-3- (2-methoxy-phenyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described for example 51, 3-bromo-10-chloro-9H-imidazo [1, 5-a ] was substituted with 2-methoxy-phenylboronic acid instead of difluorophenylboronic acid][1，2，4]Triazolo [1, 5-d][1，4]Conversion of-benzodiazepine * (400mg, 1.19mmol) gave the title compound as a pale yellow solid (396mg, 92%). MS: 363.1[ M/e ═ M]+。
Example 61
10-chloro-3- (3-methoxy-phenyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described for example 51, 3-bromo-10-chloro-9H-imidazo [1, 5-a ] was substituted for difluorophenylboronic acid with 3-methoxy-phenylboronic acid][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (300mg, 0.89mmol) gave the title compound as an off-white solid (292mg, 90%). MS: 363.1[ M/e ═ M]+。
Example 62
10-chloro-3- (4-tolyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described for example 51, 3-bromo-10-chloro-9H-imidazo [1, 5-a ] was substituted with 4-tolylboronic acid instead of difluorophenylboronic acid][1，2，4]Triazolo [1, 5-d][1，4]Conversion of-benzodiazepine * (300mg, 0.89mmol) gave the title compound as a grey solid (261mg, 84%). MS: 347.1[ M ═ M/e ═ M]+。
Example 63
3- (benzo [1, 3] dioxol-5-yl) -10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Following the procedure described for example 51, 3-bromo-10-chloro-9H-imidazo [1, 5-a ] was substituted with 4-tolylboronic acid instead of difluorophenylboronic acid][1，2，4]Triazolo [1, 5-d][1，4]-benzodiazepine * (300mg, 0.89mmol) was converted to give the title compound as a white solid (266mg, 79%). MS: m/e 377.1[ M [ ]]+。
Example 64
10-chloro-3-propyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
3-bromine was added as described in example 29, using a solution of diisopropylzinc (1M in toluene) instead of the solution of diethylzinc-10-chloro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Conversion of-benzodiazepine * (200mg, 0.59mmol) gave the title compound as a white solid (112mg, 63%). MS: 300.4[ M + H ] M/e]+。
Example 65
3-butyl-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
3-bromo-10-chloro-9H-imidazo [1, 5-a ] was synthesized according to the procedure described in example 29, substituting cyclopropylzinc bromide solution (0.29M in THF) for diethylzinc solution][1，2，4]Triazolo [1, 5-d][1，4]Conversion of benzodiazepine * (200mg, 0.59mmol) gave the title compound as a white solid (34mg, 18%). MS: 314.1[ M + H ] M/e]+。
Example 66
10-chloro-3-vinyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 3-bromo-10-chloro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]-benzodiazepine * (200mg, 0.59mmol) in toluene (2mL) was added vinyltributyltin (0.21mL, 0.71mmol), tetrakis (triphenylphosphine) palladium (0) (34mg, 0.03mmol) and 2, 6-di-tert-butyl-4-methylphenol (some crystals) under argon atmosphere. The resulting mixture was stirred at 100 ℃ for 18 hours. Diluted with dichloromethane and washed with aqueous sodium carbonate (half saturated) and water, then extracted with dichloromethane. Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 60: 20-30: 50: 20) gave the title compound as a white solid (145mg, 86%). MS: 284.1[ M ] M/e]+。
Example 67
3- (bicyclo [2.2.1] hept-5-en-2-yl) -10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Reacting 10-chloro-3-vinyl-9H-imidazo [ 1]，5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (200mg, 0.71mmol) was dissolved in hot THF (10 mL). After cooling to room temperature, dicyclopentadiene (95. mu.l; 0.71mmol) was added and the reaction mixture was stirred at this temperature for 18 h. Dicyclopentadiene (0.48mL, 0.36mmol) was added and THF was distilled off. The resulting suspension was stirred at 160 ℃ under nitrogen for 18 hours and concentrated. Purification by chromatography (SiO)2Heptane ethyl acetate dichloromethane 60: 20-30: 50: 20) gave the title compound as a white foam (93mg, 38%). MS: 350.1[ M + H ] M/e]+。
Example 68
10-chloro-3-trimethylsilyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Reacting 3-bromo-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]-benzodiazepine * (200mg, 0.59mmol) in 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2- (1H) -pyrimidinone (2ml) was evacuated and filled with argon and repeated 5 times. A mixture of 2- (tert-butylphosphine) biphenyl (16mg, 0.05mmol), tetrakis (dibenzylideneacetone) dipalladium (0) chloroform complex (9mg, 0.01mmol) and potassium fluoride (172mg, 2.97mmol) was added to the solution. After stirring for 5 minutes under argon, water (0.19mL, 10.7mmol) and hexamethyldisilane (0.14mL, 0.71mmol) were added and the resulting mixture was stirred at 100 ℃ for 23 hours. Hexamethyldisilane (0.14mL, 0.71mmol) was added and stirring was continued at 100 ℃ for 24 h. The mixture was diluted with dichloromethane (10ml) and washed with aqueous sodium carbonate (half saturated) and water. Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 60: 20-30: 50: 20) gave the title compound as a white solid (25mg, 13%). MS: 330.1[ M ] M/e]+。
Example 69
10-chloro-3- (methoxy-carbonyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
To 3-bromo-10-chloro-9H-imidazo [1, 5-a ]][1，2，4]Triazolo [1, 5-d][1，4]Suspension of benzodiazepine * (200mg, 0.59mmol) in methanol (2mL) and THF (2mL) under argon was added palladium (II) acetate (13mg, 0.06mmol), triphenylphosphine (62mg, 0.24mmol) and sodium acetate (5mg, 0.06 mmol). The white suspension was evacuated and filled with carbon monoxide, repeated 5 times, and then stirred under an atmosphere of carbon monoxide at 65 ℃ for 18 hours. The suspension becomes a solution. Stirring was continued at 65 ℃ for 3 days. Sodium formate (61mg, 0.89mmol) and bis (triphenylphosphine) palladium (II) chloride (21mg, 0.03mmol) were added and the mixture was stirred at 60 ℃ under carbon monoxide atmosphere for 18 h. Filtered through hyflo ® and concentrated in vacuo. Purification by chromatography (SiO)2Heptane ethyl acetate dichloromethane 60: 20-30: 50: 20) gave the title compound as a white solid (89mg, 47%). MS: 316.1[ M + H ] M/e]+。
Example 70
10-chloro-3- (prop-1, 2-dienyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
a) 10-chloro-3- (3-diethylamino-prop-1-ynyl) -9H-imidazo [1, 5-a][1，2，4]Triazolo compounds [1，5-d][1，4]Benzodiazepine *
To 3-bromo-10-chloro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]-benzodiazepine * (600mg, 1.78mmol) in THF (40mL) was added 3-diethylamino-1-propyne (317mg, 2.86mmol), bis (triphenylphosphine) -palladium (II) dichloride (63mg, 0.09mmol), triphenylphosphine (14mg, 0.05mmol) and triethylamine (890. mu.L, 6.41 mmol). The resulting mixture was stirred at room temperature for 15 minutes, then copper (I) bromide (3mg, 0.02mmol) was added. After heating at reflux for 15 hours, the mixture was poured onto water (20mL) and extracted with ethyl acetate. Dried over sodium sulfate, concentrated and purified by chromatography (SiO)2Ethyl acetate: methanol 80: 20) to give the title compound as an off-white solid (440mg, 67%). MS: 367.0[ M + H ] M/e]+。
b) 10-chloro-3- (prop-1, 2-dienyl) -9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzo (b) is Diaza *
Reacting 10-chloro-3- (3-diethylamino-prop-1-ynyl) -9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (200mg, 0.54mmol) was dissolved in dioxane (2mL) and tris (dibenzylideneacetone) dipalladium chloroform complex (14mg, 0.01mmol) and tris (pentafluorophenyl) phosphine (58mg, 0.11mmol) were added. The resulting brown solution was heated to reflux for 26 hours. The resulting mixture was poured onto water (30mL) and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO)2Ethyl acetate: dichloromethane: methanol 90: 9: 1) gave the title compound as a yellow solid (14mg, 9%). MS: 295.0[ M/e ═ M]+。
Example 71
3- (acetyl-methyl-amino) -10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
Reacting 3- (acetyl-amino) -10-chloro-9H-imidazo [1, 5-a][1，2，4]Triazolo [1, 5-d][1，4]Benzodiazepine * (840mg, 2.67mmol) was dissolved in DMF (16mL) and potassium hexamethyldisilazide (0.91M in THF, 3.80mL, 3.47mmol) was added. After stirring at room temperature for 45 min, methyl iodide (217 μ L, 3.47mmol) was added and the resulting mixture was stirred for an additional 2 h. The resulting mixture was separated between aqueous sodium carbonate (saturated) and ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. Purification by chromatography (SiO)2Heptane ethyl acetate dichloromethane 60: 20-30: 50: 20) gave the title compound as a white solid (234mg, 27%). MS: m/e is 329.1[ M [ ]]+。
Example 72
10-chloro-3-cyclopropylamino-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *
10-chloro-in sealed tubes3-fluoro-9H-imidazo [1, 5-a]-[1，2，4]Triazolo [1, 5-d][1，4]To a solution of benzodiazepine * (200mg, 0.73mmol) in DMSO (2mL) was added cyclopropylamine (254. mu.L, 3.63mmol) and the mixture was stirred at 180 deg.C (microwave) for 90 minutes. Potassium carbonate (300mg, 2.17mmol) was added and stirring continued at 180 deg.C (microwave) for 60 minutes. The reaction mixture was diluted with ethyl acetate (20mL), washed with aqueous sodium carbonate (saturated) and extracted with ethyl acetate. Dried over sodium sulfate and purified by chromatography (SiO)2Heptane ethyl acetate dichloromethane 40: 20-10: 70: 20) gave the title compound as a brown solid (15mg, 7%). MS: 313.1[ M + H ] M/e]+。
Claims (19)
1. A halogen substituted imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine * derivative of formula I:
wherein
R1Is hydrogen, halogen, lower alkyl, Si (CH)3)3Or lower alkyl substituted by halogen, or is lower alkoxy or is substituted by halogenLower alkoxy of lower substituent, or lower alkenyl, lower alkenyloxy, CN, bicyclo [2.2.1]Hept-5-en-2-yl, aryl optionally substituted by lower alkyl, amino or lower alkoxy, or aryloxy, heteroaryl, benzo [1, 3]]Dioxolyl, cycloalkyl, heterocycloalkyl, -O (CH)2)mOH, -CO (O) -lower alkyl, -NR'2or-C.ident.C-R ";
r' is hydrogen, lower alkyl, cycloalkyl, -C (O) -lower alkyl, -C (O) -cycloalkyl, -S (O)2-lower alkyl or aryl unsubstituted or substituted by one or two substituents selected from: halogen or lower alkyl substituted by halogen;
r' is hydrogen, -Si (CH)3)3Lower alkyl, cycloalkyl or- (CH)2)m-O-lower alkyl;
R2is hydrogen, methyl or aryl;
R3is halogen;
R4is hydrogen or halogen;
n is 1 or 2;
m is 1, 2 or 3.
2. Halogen substituted imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine * derivatives of formula I-a and pharmaceutically acceptable acid addition salts thereof:
wherein
R1Is hydrogen, halogen, lower alkyl or lower alkyl substituted by halogen, or is lower alkoxy or lower alkoxy substituted by halogen, or is lower alkenyl, lower alkenyloxy, CN, aryl, or is aryloxy, heteroaryl, cycloalkyl, heterocycloalkyl, -O (CH)2)mOH、-NR’2or-C.ident.C-R ";
r' is hydrogen, lower alkyl, -C (O) -cycloalkyl, -S (O)2Lower alkyl or unsubstituted or substituted by one or twoAryl substituted with a substituent selected from the group consisting of: halogen or lower alkyl substituted by halogen;
r' is hydrogen, -Si (CH)3)3Lower alkyl, cycloalkyl or- (CH)2)m-O-lower alkyl;
R2is hydrogen, methyl or aryl;
R3is halogen;
R4is hydrogen or halogen;
n is 1 or 2;
m is 1, 2 or 3.
3. A compound of formula I according to claim 1, wherein R3Is chlorine.
4. A compound of formula I according to claim 3, wherein R2Is hydrogen.
5. A compound of formula I according to claim 4, which is:
10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-fluoro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-methoxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-ethoxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (2-fluoro-ethoxy) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (2, 2-difluoro-ethoxy) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (2, 2, 2-trifluoro-ethoxy) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-vinyloxy-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-methylamino-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-dimethylamino-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-benzylamino-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-thiomorpholin-4-yl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-imidazol-1-yl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-acetylamino-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3, 10-dichloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-bromo-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-ethynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-prop-1-ynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-cyclopropylethynyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-ethyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-cyclopropyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-difluoromethyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-benzyl-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-phenyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-cyano-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (pyridin-3-yl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-propyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-butyl-10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-vinyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (methoxy-carbonyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3- (prop-1, 2-dienyl) -9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3- (cyclopropanecarbonyl-amino) -10-chloro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine * or
10-chloro-3-cyclopropylamino-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *.
6. A compound of formula I according to claim 3, wherein R2Is methyl.
7. A compound of formula I according to claim 6, which is
3, 10-dichloro-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
3-bromo-10-chloro-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-ethynyl-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *,
10-chloro-3-cyclopropyl-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine * or
10-chloro-3-cyano-6-methyl-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *.
8. A compound of formula I according to claim 1, wherein R3Is bromine.
9. A compound of formula I according to claim 8, which is
10-bromo-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine * or
10-bromo-3-fluoro-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *.
10. A compound of formula I according to claim 1, wherein R3Is iodine.
11. A compound of formula I according to claim 10, which is
3-chloro-10-iodo-9H-imidazo [1, 5-a ] [1, 2, 4] triazolo [1, 5-d ] [1, 4] benzodiazepine *.
12. A process for the preparation of a compound of formula I as defined in claim 1, which process comprises
Reacting a compound of formula II
With halogenating agents to give compounds of the formula I
Wherein R is1、R2、R3、R4And n is as defined in claim 1,
and, if desired, converting the compound of formula I into a pharmaceutically acceptable salt.
13. A compound of formula I according to claim 1, whenever prepared by a process as claimed in claim 12 or by an equivalent method.
14. A medicament containing one or more compounds of formula I as claimed in claim 1 and pharmaceutically acceptable excipients.
15. A medicament according to claim 14 for the treatment of diseases related to the GABA a α 5 subunit selected from cognitive enhancer or cognitive disorders.
16. A medicament according to claim 15 for the treatment of alzheimer's disease.
17. The use of a compound of formula I as claimed in claim 1 for the preparation of a medicament for the treatment of cognitive enhancement, cognitive disorders, anxiety or schizophrenia.
18. The use of a compound of formula I according to claim 1 for the preparation of a medicament for the treatment of alzheimer's disease.
19. The invention as hereinbefore described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04105167.3 | 2004-10-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1116173A true HK1116173A (en) | 2008-12-19 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4088151B2 (en) | Benzodiazepine derivatives as GABAA receptor modulators | |
| EP2627178B1 (en) | Quinazolinone-type compounds as crth2 antagonists | |
| IL182697A (en) | Halogen substituted imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine derivatives, process for their preparation and use thereof in the manufacture of medicaments for the treatment of cognitive disorders | |
| JP4864982B2 (en) | Aryl-isoxazol-4-yl-imidazo [1,5-a] pyridine derivatives | |
| KR100923399B1 (en) | Imidazo-benzodiazepine derivatives | |
| JP2008515941A (en) | Substituted benzodiazepine derivatives | |
| EP1828194B1 (en) | Tetracyclic imidazo-benzodiazepines as gaba receptors modulators | |
| HK1116173A (en) | Halogen substituted benzodiazepine derivatives | |
| JPWO1999003857A1 (en) | 5-Substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivatives | |
| CN116600803A (en) | macrocyclic urea orexin receptor agonist | |
| MX2008008318A (en) | Aryl-isoxazol-4-yl-imidazo[1, 5-a]pyridine derivatives |