JP2002536449A - Triazolo-pyridazine derivatives as ligands for GABA receptors - Google Patents

Abstract

(57) Abstract: Substituted 1,2,4-triazolo [4,3-b] pyridazine derivatives having an optionally substituted phenyl ring at the 3-position and a C-substituted triazolyl-methoxy moiety at the 6-position are GABA _A receptors And especially ligands with high affinity for its α2 and / or α3 subunits, and thus are useful for the treatment and / or prevention of diseases of the central nervous system, including anxiety and convulsions.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substituted triazolo-pyridazine derivatives and their use in therapy. More particularly, the present invention relates to substituted 1,2,4-triazolo [4,3-b] pyridazine derivatives which are ligands for the GABA _A receptor and are therefore useful in the treatment of poor mental states.

Γ-Aminobutyric acid (GAB) is a receptor for major inhibitory neurotransmitters
A) falls into two main classes: (1) GABA _A receptor, a member of the ligand-gated ion channel superfamily, and (2) GABA _B receptor, a member of the G protein-coupled receptor superfamily. Individual G
After the initial cDNA encoding the ABA _A receptor subunit was cloned, the number of known mammalian members increased to at least six α subunits, four β subunits, and three γ subunits. Unit, one δ subunit, 1
Ε subunits and two ρ subunits.

[0003] Knowledge of the diversity of the GABA _A receptor gene family represents a significant advance in our understanding of this ligand-gated ion channel, but insights into the extent of subtype diversity remain at an early stage. is there. α subunit, β
It has been pointed out that the subunit and the γ subunit are at a minimum necessary to form a fully functional GABA _A receptor that is expressed by transiently transfecting the cDNA into cells. As indicated above, the δ, ε and ρ subunits are also present, but only to a lesser extent in the GABA _A receptor population.

[0004] Studies of receptor size and visualization by electron microscopy have shown that natural GA
It has been concluded that the BA _A receptor, like other members of the ligand-gated ion channels, exists in a pentameric form. By selecting at least one α, one β, one γ subunit type from 17 repertoires,
The presence of combinations of pentamer subunits of more than 0000 is possible. In addition, this calculation is based on the additional permutation that would be possible if the sequence of the subunits around the ion channel were unconstrained (ie, a receptor consisting of five different subunits could have 120 variants). I'm overlooking).

[0005] Existing receptor subtype assemblies include, among others, α1β2γ2, α
2β2 / 3γ2, α3βγ2 / 3, α2βγ1, α5β3γ2 / 3, α6βγ2
, Α6βγδ and α4βδ. Subtype assemblies containing the α1 subunit are present in most regions of the brain and are thought to exceed 40% of GABA _A receptors in rats. Subtype assemblies containing the α2 and α3 subunits, respectively, are thought to be approximately 25% and 17% of the GABA _A receptor in rats. The subtype assembly containing the α5 subunit is predominantly expressed in the hippocampus and cortex, and is thought to represent about 4% of the GABA _A receptor in rats.

[0006] _A characteristic property of all known GABA _A receptors is the presence of a number of regulatory sites, one of which is the benzodiazepine (BZ) binding site.
The BZ binding site is the most sought site among the GABA _A receptor regulatory sites, through which mild stabilizing drugs such as diazepam and temazepam exert their effects. Prior to the cloning of the GABA _A receptor gene line, the benzodiazepine binding site has historically been further divided into two subtypes, BZ1 and BZ2, based on radioligand binding studies. The BZ1 subtype has been determined to be pharmacologically equivalent to a GABA _A receptor comprising the β subunit and γ2 in combination with the α1 subunit. It is the most abundant GABA _A receptor subtype and is thought to represent nearly half of all GABA _A receptors in the brain.

[0007] Two other major populations are the α2βγ2 and α3βγ2 / 3 subtypes.
Together, they make up about an additional 35% of the total GABA _A receptor repertoire. Pharmacologically, this combination appears to be equivalent to the BZ2 subtype previously defined by radioligand binding, but the BZ2 subtype can also include certain α5-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonist or antagonist was known.

[0008] It is now believed that agents that act as BZ agonists in the α1βγ2, α2βγ2 or α3βγ2 subunits have desirable anxiolytic properties. Compounds that are modulators of the benzodiazepine binding site of the GABA _A receptor by acting as BZ agonists are hereinafter referred to as "GABA _A receptor agonists". The α1-selective GABA _A receptor agonists alpidem and zolpidem are clinically prescribed as hypnotics and at least some sedative effects associated with known mild stabilizers acting at the BZ1 binding site are
Suggests that it is mediated by a GABA _A receptor containing one subunit. It is therefore believed that GABA _A receptor agonists that interact better with α2 and / or α3 than with α1 would be more effective in treating anxiety with anxiety and reduced propensity. Also, agents that are antagonists or inverse agonists at α1 can be used to reverse the sedation and hypnosis provided by α1 agonists.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention, which are selective ligands for the GABA _A receptor, are therefore for use in the treatment and / or prevention of various disorders of the central nervous system.
Such disorders include panic disorder with or without phobia, animal phobia including social phobia without a history of panic disorder, social phobia, and other phobias,
Anxiety disorders, such as obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorders; and systemic or substance-induced anxiety disorders; neuroses; convulsions; migraine; depression or bipolar disorders, such as solitary or Recurrent major depressive disorder, dysthymia, bipolar I and II manic and cardiovascular disease; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit disorder with hyperactivity; Rhythmic disorders, for example, when a subject becomes ill due to jet lag or the effects of shift work.

[0010] Additional disorders for which selective ligands to the GABA _A receptor can be helpful include pain and nociception; acute, delayed and expected vomiting, especially vomiting induced by chemotherapy or radiation, and postoperative nausea and Vomiting, including vomiting; eating disorders including anorexia nervosa and anorexia nervosa; premenstrual syndrome; muscle spasm or spasticity, for example in paraplegic patients; and hearing loss.
Selective ligands for the GABA _A receptor are also useful as premedication prior to anesthesia or small procedures such as endoscopy, including endoscopy of the stomach.

[0011] WO 98/04559 describes substituted and 7,8-ring fused 1,2,4-triazolo [4,3-b] pyridazine derivatives, which are useful in neuronal disorders including anxiety and convulsions It is stated to be a selective ligand for the GABA _A receptor, which is useful for treating and / or preventing disease.

[0012] The present invention provides triazolo-pyridazine derivatives having desirable binding properties at various GABA _A receptor subtypes. The compounds according to the present invention have good binding properties as ligands for the α2 and / or α3 subunit of the human GABA _A receptor. The compounds of the present invention may interact better with the α2 and / or α3 subunits than with the α1 subunit. Desirably, the compounds of the present invention will exhibit functional selectivity in terms of the selective effect on the α2 and / or α3 subunit compared to the α1 subunit.

[0013] The compounds of the present invention have less than 100 nM, typically less than 50 nM, ideally less than 10 nM relative to the α2 and / or α3 subunit as determined in an assay described later herein. GABA _A receptor subtype ligand with binding affinity (K _i ). The compounds according to the invention may have a selective affinity for the α2 and / or α3 subunit of at least 2 times, suitably at least 5 times, advantageously at least 10 times compared to the α1 subunit. However, compounds that are not selective for α2 and / or α3 compared to the α1 subunit in terms of their binding are also included within the scope of the invention. Such compounds will desirably exhibit functional selectivity in terms of the selective effect on the α2 and / or α3 subunits compared to the α1 subunit. In addition, the compounds according to the invention can have interesting pharmacokinetics, in particular in terms of improved oral physiological availability.

The present invention provides a compound of formula I:

[0015]

Embedded image Wherein Z represents t-butyl, cyclobutyl, phenyl or pyrrolidin-1-yl; R ¹ represents hydrogen, methyl, methoxy or fluoro; R ² represents hydrogen or fluoro; R ³ Represents hydrogen, methyl or ethyl; R ⁴ represents trifluoromethyl, chloromethyl or a group of the formula —CH ₂ OR ^a or —CH ₂ NR ^b R ^c ; R ^a represents hydrogen, methyl or t-. And R ^b and R ^c both represent methyl, or R ^b and R ^c together represent azetidine, 3,3-difluoroazetidine, pyrrolidine, morpholine or N-methyl Which represents the residue of the piperazine moiety) or a pharmaceutically acceptable salt thereof.

Certain compounds of the present invention fall within the generic scope of WO 98/04559. However, there is no specific disclosure there for compounds corresponding to the compounds of formula I as defined above.

For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. However, other salts may be useful in the preparation of the compounds of formula I or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of formula I include, for example, solutions of the compounds of formula I in hydrochloric, sulfuric, methanesulfonic, fumaric, maleic, succinic, acetic, benzoic, oxalic, Acid addition salts formed by mixing with solutions of pharmaceutically acceptable acids, such as citric, tartaric, carboxylic or phosphoric acids.

In the compounds of formula I above, the Z moiety suitably represents t-butyl, phenyl or pyrrolidin-1-yl.

Suitably, R ¹ represents hydrogen or fluoro.

Suitably, R ² represents hydrogen.

Suitably, R ³ represents methyl or ethyl.

[0022] Suitably, ^{R a} represents hydrogen or methyl.

Particular subclasses of compounds according to the present invention are compounds of formulas IIA and IIB,
And their pharmaceutically acceptable salts:

[0024]

Embedded image (Wherein, Z, R ¹ , R ² , R ³ and R ⁴ are as defined above).

Specific compounds within the scope of the present invention include: N- [5- (3,7-diphenyl-1,2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl)- 2-methyl-2H-1,2,4-triazol-3-ylmethyl] -N, N-dimethylamine; [5- (3,7-diphenyl-1,2,4-triazolo [4,3-b] Pyridazin-6-yloxymethyl) -1-methyl-1H-1,2,4-triazol-3-yl] methanol; N- [5- (3,7-diphenyl-1,2,4-triazolo [4 , 3-b] pyridazin-6-yloxymethyl) -1-methyl-1H-1,2,4-triazol-3-ylmethyl] -N, N-dimethylamine; [1-methyl-5- (3- Phenyl-7- (pyrrolidin-1-yl) -1,2
, 4-Triazolo [4,3-b] pyridazin-6-yloxymethyl) -1H-
1,2,4-triazol-3-yl] methanol; 6- (5-chloromethyl-2-methyl-2H-1,2,4-triazole-3
-Ylmethoxy) -3-phenyl-7- (pyrrolidin-1-yl) -1,2,4
-Triazolo [4,3-b] pyridazine; N- [5- (3-phenyl-7- (pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazin-6-yl Oxymethyl) -1-methyl-1
H-1,2,4-triazol-3-ylmethyl] -N, N-dimethylamine; 6- [2-methyl-5- (morpholin-4-ylmethyl) -2H-1,2,4
-Triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-
Yl) -1,2,4-triazolo [4,3-b] pyridazine; 6- [5- (azetidin-1-ylmethyl) -2-methyl-2H-1,2,4
-Triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-
Yl) -1,2,4-triazolo [4,3-b] pyridazine; 6- [2-methyl-5- (4-methylpiperazin-1-ylmethyl) -2H-
1,2,4-triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine; 6- [5- (3 , 3-Difluoroazetidin-1-ylmethyl) -2-methyl-2H-1,2,4-triazol-3-ylmethoxy] -3-phenyl-7-
(Pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine; 6- [2-methyl-5- (pyrrolidin-1-ylmethyl) -2H-1,2,4
-Triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-
Yl) -1,2,4-triazolo [4,3-b] pyridazine; 7-t-butyl-6- [5- (t-butyldimethylsilanyloxymethyl)-
2-methyl-2H-1,2,4-triazol-3-ylmethoxy] -3- (2
-Fluorophenyl) -1,2,4-triazolo [4,3-b] pyridazine; [5- (7-t-butyl-3- (2-fluorophenyl) -1,2,4-triazolo [4 3-b] pyridazin-6-yloxymethyl) -1-methyl-1H
-1,2,4-triazol-3-yl] methanol; 7-t-butyl-3- (2-fluorophenyl) -6- (5-methoxymethyl-2-methyl-2H-1,2,4- Triazol-3-ylmethoxy) -1,2
, 4-Triazolo [4,3-b] pyridazine; 7-t-butyl-3- (2-fluorophenyl) -6- (5-trifluoromethyl-1H-1,2,4-triazol-3-ylmethoxy ) -1,2,4-triazolo [4,3-b] pyridazine; 7-tert-butyl-3- (2-fluorophenyl) -6- (2-methyl-5-trifluoromethyl-2H-1, 2,4-triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine; 7-t-butyl-3- (2-fluorophenyl) -6- (1-methyl-5-trifluoromethyl-1H-1,2,4 -Triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine; 7-t-butyl-3- (2-fluorophenyl) -6- (2-ethyl-5-trifluoromethyl-2H-1,2,4 -Triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine; 7-t-butyl-3- (2-fluorophenyl) -6- (1-ethyl-5-trifluoromethyl-1H-1,2,4 -Triazol-3-ylmethoxy) -1
, 2,4-triazolo [4,3-b] pyridazine; and pharmaceutically acceptable salts thereof.

The present invention also provides a method for the treatment and / or prevention of anxiety, comprising providing a patient in need of such treatment with an effective amount of a compound of formula I or a medicament as defined above. And administering a salt thereof which is acceptable as

Further, the present invention provides a method for the treatment and / or prevention of convulsions (eg, in a patient suffering from epilepsy or a related disorder), the method comprising: It comprises administering an effective amount of a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof.

The binding affinity (K _i ) of the compounds according to the invention for the α3 subunit of the human GABA _A receptor is conveniently determined in an assay described hereinafter. The α3 subunit binding affinity (K _i ) of the compounds of the invention is ideally 1
0 nM or less, preferably 2 nM or less, more preferably 1 nM or less.

The compounds according to the invention increase the potential of the GABA EC ₂₀ receptor response in stably transfected recombinant cell lines expressing the α3 subunit of the human GABA _A receptor, ideally by at least 40%. Preferably at least 50%
, More preferably at least 60%. In addition, the compounds of the invention increase the potential of the GABA EC ₂₀ receptor response in stably transfected recombinant cell lines expressing the α1 subunit of the human GABA _A receptor, ideally by at most 30%. , Preferably at most 20%, more preferably at most 10%
Only% will be induced.

The potential of the GABA EC ₂₀ receptor response in a stably transfected recombinant cell line expressing the α3 and α1 subunits of the human GABA _A receptor is described by Wafford et al. , Mol. Pharmacol. , 1996
, 50, 670-678, as appropriate. This procedure may be suitably performed using stably transfected eukaryotic cells, typically stably transfected mouse Ltk fibroblasts.

The compounds according to the invention show an anxiolytic effect, as can be demonstrated by a positive response in the suppression of habituation of elevated plus maze tests and drinking tests (Daw
son et al. , Psychopharmacology, 1995, 1
21, 109-117). In addition, the compounds of the invention can be used in response sensitivity (chain tension) tests (Bayley et al., J Psychopharmacol).
. , 1996, 10, 206-213), as can be confirmed by the appropriate results obtained.

The compounds of the present invention can also exhibit anticonvulsant effects. This is described in J.A. Phar
macol. Exp. Ther. , 1996, 279, 492-501, and can be demonstrated by the ability to inhibit pentylenetetrazole-induced seizures in rats and mice according to a protocol similar to that described by Bristow et al.

In order to elicit behavioral effects, the compounds of the invention are ideally brain permeable, in other words the compounds will be able to cross the so-called “blood-brain barrier” . Preferably, the compounds of the present invention will be able to exert beneficial therapeutic effects when administered by the oral route.

The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier together with one or more compounds of the present invention. Preferably, these compositions are in unit dosage form, such as tablets, pills, capsules, powders, granules, sterile injectable solutions or suspensions, metered aerosol or liquid sprays, drops, ampules, self-injectors or suppositories, For oral, parenteral, nasal, sublingual or enteral application or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the main active ingredient is a pharmaceutical carrier such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum such as rubber. Mixing with conventional tableting ingredients, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a pharmaceutically acceptable salt thereof.
When these pre-formulated compositions are referred to as homogeneous compositions, the active ingredients are dispersed evenly throughout the composition and the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. Means that you can. This solid preformulation composition is later subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. A typical unit dosage form contains from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg of active ingredient.
The tablets or pills of the novel compositions can be coated or otherwise formulated to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill can comprise an internal dispensing component and an external dispensing component, with the external dispensing component wrapping the internal dispensing component. The two components are separated by an enteric layer to withstand disintegration in the stomach and to pass the inner composition intact to the duodenum or delay release. A variety of materials can be used for such enteric layers or coatings, including materials containing a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl, alcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the present invention can be formulated for oral administration or for administration by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and cottonseed oil, sesame oil, Included are flavored emulsions with edible oils such as coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,
Examples include methylcellulose, polyvinylpyrrolidone or gelatin.

In the treatment of anxiety, suitable dosage levels are about 0.01 to 250 m / day
g / kg, preferably about 0.05-100 mg / kg per day, especially about 0.05-5 mg / kg per day. The compounds can be administered on a one to four times daily basis.

Compounds of formula I as defined above include compounds of formula III and compounds of formula IV:

[0038]

Embedded image Wherein Z, R ¹ , R ² , R ³ and R ⁴ are as defined above, and L ¹ represents a suitable leaving group. can do.

The leaving group L ¹ is typically a halogen atom, especially chloro. The reaction between compounds III and IV is carried out in a suitable solvent, typically N, N-dimethylformamide, Suitably, it is carried out by stirring the reaction in the presence of a strong base such as sodium chloride.

The intermediate of formula III above is obtained by reacting a compound of formula V with a substantially equimolar amount of a hydrazine derivative of formula VI,

[0041]

Embedded image Wherein Z, R ¹ , R ² and L ¹ are as defined above, and L ² is
If necessary, they can be prepared by separating the resulting mixture of isomers by conventional means.

The leaving group L ² is typically a halogen atom, especially chloro. In the intermediate of formula V, the leaving groups L ¹ and L ² may be the same or different, but are suitably the same, preferably both are chloro.

The reaction between compounds V and VI is carried out in the presence of a source of protons such as triethylamine hydrochloride, typically in an inert solvent such as xylene or 1,4-dioxane.
Suitably, this is done by heating the reaction under reflux.

Alternatively, the intermediate of formula III above may be a hydrazine derivative of formula VII and a compound of formula VII
Reacting with an aldehyde derivative of I,

[0045]

Embedded image Wherein Z, R ¹ , R ² , and L ¹ are as defined above. Subsequently, it can be prepared by crystallizing the resulting intermediate Schiff base.

The reaction between compounds VII and VIII is suitably carried out under acidic conditions, for example in the presence of a mineral acid such as hydrochloric acid. The crystallization of the resulting Schiff base intermediate is then carried out at elevated temperature using lead (IV) acetate in acetic acid or using iron (III) chloride in a suitable solvent, for example an alcoholic solvent such as ethanol. And typically 60-
It is appropriate to carry out the treatment at a temperature in the range of 70 ° C.

The intermediate of formula VII above is reacted with a suitable compound of formula V as defined above with hydrazine hydrate, typically in 1,4-dioxane, at the reflux temperature of the solvent,
If desired, it can be prepared subsequently by separating the resulting mixture of isomers by conventional means.

In another approach, the intermediate of formula III above is of formula VII as defined above
And a compound of formula IX:

[0049]

Embedded image Wherein R ¹ and R ² are as defined above and Q represents a reactive carboxylate moiety, followed by the reaction of a hydrazine derivative of formula X:

[0050]

Embedded image Wherein Z, R ¹ , R ² , and L ¹ are as defined above.

Suitable values for the reactive carboxylate moiety Q include esters, eg, C _1-4 alkyl esters; acid anhydrides, eg, acid anhydrides mixed with C _1-4 alkanoic acids; acid halides, eg, , Acid chlorides; and acylimidazoles. Suitably, Q represents an acid chloride moiety.

The reaction between compounds VII and IX is carried out under basic conditions, for example in the presence of triethylamine, suitably in an inert solvent such as diethyl ether, typically at a temperature near 0 ° C. It is appropriate. Next, crystallization of the resulting compound of formula X is 1,2
Using dibromo-1,1,2,2-tetrachloroethane and triphenylphosphine in the presence of a base such as triethylamine, suitably in an inert solvent such as acetonitrile, typically around 0 ° C. It is appropriate to carry out the treatment at a temperature of.

The reaction between compound V and hydrazine hydrate, ie compound VI as shown above, usually depends on whether the hydrazine nitrogen atom replaces the leaving group L ¹ or L ² . This gives a mixture of isomer products. Thus, in addition to the required product of Formula III, isomers are generally obtained to some extent with the moiety Z attached at the 8-position, and similarly for Formula VII. For this reason, it will generally be necessary to separate the resulting mixture of isomers by conventional methods such as chromatography.

In another procedure, the compound of formula I as defined above is of formula XI (or its 1,2,4-triazolo [4,3-b] pyridazin-6-one tautomer) And a compound of formula XII:

[0055]

Embedded image Wherein Z, R ¹ , R ² , R ³ and R ⁴ are as defined above, and L ³ represents a suitable leaving group. can do.

The leaving group L ³ is suitably a halogen atom, typically chloro or bromo.

The reaction between compounds XI and XII is carried out by stirring the reaction in a suitable solvent, typically N, N-dimethylformamide, in the presence of a strong base such as sodium hydride. It is appropriate.

The intermediate of formula XI above can be suitably prepared by reacting a compound of formula III as defined above with a hydroxide of an alkali metal, for example sodium hydroxide. The reaction is suitably performed in an inert solvent such as an aqueous 1,4-dioxane solution, ideally at the reflux temperature of the solvent.

In a further procedure, the compound of formula I as defined above is of the formula Z—CO ₂ H
And a compound of formula XIII:

[0060]

Embedded image Wherein Z, R ¹ , R ² , R ³ and R ⁴ are as defined above, in the presence of silver nitrate and ammonium persulfate. .

The reaction is conveniently carried out in a suitable solvent, for example water or aqueous acetonitrile, optionally under acidic conditions, for example with sulfuric acid, typically at elevated temperature.

The intermediate of formula XIII corresponds to a compound of formula I as defined above, wherein Z is hydrogen, and thus the process described above for preparing a compound corresponding to formula I Can be prepared by a method similar to

In a further procedure, a compound of formula I, as defined above, comprises a compound of formula XIV and a compound of formula XV:

[0064]

Embedded image Wherein Z, R ¹ , R ² , R ³ and R ⁴ are as defined above, and M is —B (OH) ₂ or —Sn (Alk) ₃ (where Alk is A C _1-6 alkyl group, typically representing n-butyl) and L ⁴ represents a suitable leaving group) in the presence of a transition metal catalyst. Can be.

The leaving group L ⁴ is suitably a halogen atom, for example bromo.

Suitable transition metal catalysts for use in the reaction between compounds XIV and XV include dichlorobis (triphenylphosphine) palladium (II) or tetrakis (triphenylphosphine) palladium (0).

The reaction between compounds XIV and XV is conveniently carried out in an inert solvent such as N, N-dimethylformamide, typically at elevated temperatures.

An intermediate of formula XIV comprises a compound of formula IV as defined above and a compound of formula XVI:

[0069]

Embedded image Wherein Z, L ¹ and L ⁴ are as defined above, under the conditions similar to those described above for the reaction between compounds III and IV Can be prepared.

In a further procedure, the compound of formula I wherein R ⁴ represents trifluoromethyl and R ³ represents hydrogen comprises a compound of formula XVII and a hydrazide of formula XVIII:

[0071]

Embedded image (Wherein Z, R ¹ and R ² are as defined above).

The reaction is carried out by treating compound XVII with sodium methoxide in methanol, neutralizing with acetic acid, adding hydrazide XVIII, and in a solvent such as methanol, typically around 60 ° C. Conveniently achieved by heating at a temperature.

The intermediate of formula XVII above can be used with a suitable compound of formula XI as defined above (or its 1,2,4-triazolo [4,3-b] pyridazin-6-one tautomer). , the compound of formula L ³ -CH 2 _CN (wherein, L ³ is as defined above) and a similar conditions to the conditions described above for the reaction between compound XI and XII It can be prepared by reacting in the first place.

The hydrazide of formula XVIII is described in Magn. Reson. Chem. , 19
90, 28, 331-336.

If not commercially available, formulas IV, V, VI, VIII, IX, XII, X
The starting materials for V and XVI can be prepared by methods analogous to those described in the accompanying examples or by standard methods well known in the art.

Any compound of formula I initially obtained from any of the above methods, if appropriate,
Thereafter, a further compound of formula I is prepared by techniques known in the art.
Can be synthesized into For example, R in the formula³Is the first formula that is hydrogen
Compounds of formula I can be prepared by standard alkylation procedures, typically iodomethane.
Or iodoethane using sodium hydride and N, N-dimethylforma
By treating in the presence of a mid, R³Is methyl or ethyl
Can be converted to the corresponding compound represented. R in the formula⁴Is the formula -CH₂OR ^a Represents a group of^aRepresents t-butyldimethylsilanyl of the formula I initially obtained
The compound is prepared using the usual protodecylation procedure, typically in ethanolic hydrogen chloride.
By heating at^aTo the corresponding compound in which is hydrogen
be able to. R in the formula⁴Is the formula -CH₂The resulting compound of formula I representing OH is
Using iodomethane, sodium hydride and N, N-dimethylformamide
By methylating in the presence, R⁴Is the formula -CH₂OR^aRepresents
Then R^aCan be converted to the corresponding compound in which is methyl. Or,
R in the formula⁴Is the formula -CH₂The compound of formula I representing OH is stirred in phosphorus oxychloride.
By doing, R in the formula⁴Converts to the corresponding compound representing chloromethyl
Can be Furthermore, R in the formula⁴Is the formula -CH₂Compounds of formula I representing OH are
Triethylamine and oxalyl chloride and dimethyl sulfoxide.
-CH 2 by treatment in the presence of₂OH part is -C
Oxidizing to HO; followed by converting the resulting aldehyde derivative to a compound of formula H-NR^bR ^c The presence of a reducing agent such as sodium cyanoborohydride using the appropriate amine
In a two-stage process comprising the step of processing under R⁴Is the formula -CH₂NR^bR ^c Can be converted to the corresponding compound: R in the formula⁴Is chloromethyl
A compound of formula I which represents a compound of formula H-NR^bR^cTreatment with a suitable amine
And typically, sodium hydride and N, N-dimethylacetamide
By heating in the presence of C⁴Is the formula -CH₂NR^bR^cTo
Can be converted to the corresponding compound represented.

During any of the above synthetic procedures, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is Pro
active Groups in Organic Chemistry,
ed. J. F. W. McOmie, Plenum Press, 1973; W. Greene & P.S. G. FIG. M. Wuts, Protective
Groups in Organic Synthesis, John Wil
eye & Sons, 1991, by means of conventional protecting groups. Protecting groups may be removed at a convenient subsequent stage using methods known in the art.

The following examples illustrate the preparation of compounds according to the present invention.

Compounds according to the present invention may comprise α2 or α2 stably expressed in Ltk cells
Strongly inhibits [ ³ H] -flumazenil binding to the benzodiazapine binding site of the human GABA _A receptor containing three subunits.

Reagents Phosphate buffered saline (PBS).

Assay buffer: 10 mM KH ₂ PO ₄ , 100 mM KCl, pH 7.0 at room temperature.
4.

[ ³ H] -flumazenil (18 nM for α1β3γ2 cells in assay buffer)
18 nM for α2β3γ2 cells; 10 nM for α3β3γ2 cells) 100 μM flunitrazepam in assay buffer.

Cells resuspended in assay buffer (1 tray to 10 mL).

Cell recovery The supernatant is removed from the cells. Add PBS (about 20 mL). Scrape off the cells and place in a 50 mL centrifuge tube. Repeat this procedure with an additional 10 mL of PBS to ensure that most cells are removed. At 3000 rpm for 20 minutes,
Pellet cells by centrifugation in a benchtop centrifuge tube,
Thereafter, freeze if desired. Resuspend the pellet in a tray of cells (25 cm x 25 cm), 10 mL per buffer.

Analysis can be performed in deep 96-well plates or tubes. Each tube contains 300 μL of assay buffer.

50 μL of [ ³ H] -flumazenil (final concentration against α1β3γ2 cells: 1
. (8 nM; final concentration for α2β3γ2 cells: 1.8 nM; final concentration for α3β3γ2 cells: 1.0 nM).

If compounds are dissolved in 10% DMSO, 50 μL of buffer or solvent carrier (eg, 10% DMSO) (total); test compound or flunitrazepam (no specific binding determined), 100 μL final concentration 10 μM House cells.

The analytes are incubated for 1 hour at 40 ° C., then filtered using a Tomtec or Brandel cell harvester on GF / B filters, followed by three washes with 3 mL of ice-cold analysis buffer. Filters are dried and counted by liquid scintillation counter. The expected value for total binding is 3000-40 for all counts when using a liquid scintillation counter.
00 dmp, less than 200 dpm for non-specific binding, or a meltirex solid scintillant
When counting using t), 1500 to 2000 d for all counts
pm, less than 200 dpm for non-specific binding. The binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constants K _i for each test compound can be calculated.

[0089] The compounds of the accompanying examples were tested in the above analysis, the human GABA _A ^[3 H] from α2 and / or α3 subunit of the receptor - for substitution of flumazenil, all, _{K i} values of less than 100nM It was found to have

Example 1 N- [5- (3,7-diphenyl-1,2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl) -2-methyl-2H-1,2 , 4-Triazol-3-ylmethyl] -N, N-dimethylamine a) 4-phenyl-1,2-dihydropyridazine-3,6-dione phenylmaleic anhydride (30 g, 0.17 mmol), thorium acetate 3 Hydrate (28 g, 0.21 mmol) and hydrazine monohydrate (10 mL, 0.1 mL).
21 mol) were heated together under reflux in 40% acetic acid (600 mL) for 18 hours. The mixture was cooled at 7 ° C. for 2 hours and then filtered. The solid was washed with diethyl ether and dried in vacuo to give 11 g (34%) of the title compound: ¹ H
_{NMR (250MHz, DMSO-d 6} ) δ7.16 (1H, br s), 7
. 44 (5H, m), 7.80 (2H, br s); MS (ES ⁺ ) m / e18.
9 [MH ⁺ ].

B) 3,6-Dichloro-4-phenylpyridazine 4-phenyl-1,2-dihydropyridazine-3,6-dione (3.4 g, 1
(8 mmol) was heated under reflux in phosphorous oxychloride (70 mL) for 6 hours. The solution was concentrated under vacuum, after which the residue was dissolved in dichloromethane (100 mL) and neutralized by the addition of cold 10% aqueous sodium bicarbonate (150 mL). The aqueous phase is washed with dichloromethane (2 × 50 mL), then the combined organic phases are washed with saturated aqueous sodium chloride solution (50 mL), dried (Na ₂ SO ₄ ), concentrated in vacuo and 3.9 g (97%) %) Of the title compound: ¹ H NMR (2
_{50MHz, DMSO-d 6) δ7.54~7.66} (5H, m), 8.14 (
1H, s); MS (ES ⁺ ) m / e 225/227/229 [MH ⁺ ].

C) 6-chloro-3,7-diphenyl-1,2,4-triazolo [4,3-b
Pyridazine 3,6-dichloro-4-phenylpyridazine (2.9 g, 13 mmol),
Benzoic acid hydrazide (1.9 g, 21 mmol) and triethylammonium chloride
(2.0 g, 14 mmol) in xylene (150 mL) under reflux for 3 days
And heated together. Additional hydrazine benzoate (0.88 g, 6.5 mmol)
Was added and the mixture was heated as before another day. The solvent is removed in vacuo and the residual
The product was flash chromatographed (silica gel, 0-50% EtOAc / CH) ₂ Cl₂) To give 1.4 g (36%) of the title compound as a solid.
Tied:¹1 H NMR (250 MHz, CDCl₃) Δ 7.55 (8H, m), 8
. 12 (1H, s) 8.50 (2H, m); MS (ES⁺) M / e 307/30
9 [MH⁺].

D) 5- (t-butyldimethylsilanyloxymethyl) -2-methyl-2H-
1,2,4-Triazole-3-carbaldehyde At −40 ° C., with stirring, 3- (t-butyldimethylsilanyloxymethyl) -1-methyl-1H-1,2,2 in THF (10 mL). 4-triazole (E
To (PA-0421210) (0.50 g, 2.2 mmol), butyllithium (1.5 mL of a 1.6 M solution in hexane, 2.3 mmol) was added dropwise. The solution was stirred at −40 ° C. under nitrogen for 15 minutes before DMF (0.18 mL
, 0.17 g, 2.3 mmol) was added and the mixture was allowed to warm to room temperature over 90 minutes. A saturated aqueous solution of ammonium chloride (5 mL) was added, after which the organic phase was separated, diluted with ethyl acetate (10 mL), dried (MgSO ₄ ) and concentrated in vacuo. Flash chromatography of the residue (silica gel, 50%
Purification by EtOAc / hexane) provided 0.29 g (56%) of the title compound as a colorless solid: ¹ H NMR (360 MHz, CDCl ₃ ) δ 0.14.
(6H, s), 0.93 (9H, s), 4.18 (3H, s) 4.80 (2H,
m), 9.98 (1 H, s); MS (ES ^<+> ) m / e 288 [M + MeOH] ^< +>.

E) N- [5- (t-butyldimethylsilanyloxymethyl) -2-methyl-
2H-1,2,4-triazol-3-ylmethyl] -N, N-dimethylamine 5- (t-butyldimethylsilanyloxymethyl) -2-methyl in methanol (15 mL) at room temperature with stirring -2H-1,2,4-triazole-3
-Carbaldehyde (0.23 g, 0.88 mmol) in 3% molecular sieve (180 mg) and dimethylamine (0.49 m of a 2M solution in methanol)
L, 0.98 mmol). The mixture was stirred at room temperature under nitrogen for 1 hour. Add the resulting mixture to room temperature, adding sodium cyanoborohydride (63 mg, 1.0 mmol) and, if necessary, maintaining the pH of the solution at 5 by adding methanolic hydrogen chloride (methyl orange indicator). Stirred under nitrogen for 3 hours. The solution was diluted with water (70 mL) and saturated aqueous sodium bicarbonate was added until the pH was about 8. Thereafter, the solution was washed with dichloromethane (3 × 50 mL).
Combine the organic phases, wash with saturated aqueous sodium chloride solution (50 mL) and dry (
MgSO ₄ ) and concentrated in vacuo. Flash chromatography of the residue
Silica gel and purified by _{0~5% MeOH / CH 2 Cl 2} ), 0.20g
(81%) of the title compound was obtained as a solid: ¹ H NMR (400 MHz, CD
Cl ₃ ) δ 0.12 (6H, s), 0.92 (9H, s), 2.26 (6H, s)
), 3.57 (2H, s), 3.90 (3H, s), 4.75 (2H, s); M
S (ES ⁺ ) m / e 285 [MH ⁺ ].

F) N- [5- (5-hydroxymethyl-2-methyl-2H-1,2,4-triazol-3-ylmethyl) -N, N-dimethylamine N- [5- ( t-butyldimethylsilanyloxymethyl) -2-methyl-2H-1,2,4-triazol-3-ylmethyl] -N
, N-Dimethylamine (0.19 g, 0.69 mmol) was added 4N sodium hydroxide solution (0.34 mL) and the solution was stirred at 45 ° C. for 18 hours. The solvent is removed in vacuo and the residue is flash chromatographed (silica gel, 10% M
Purification by MeOH / CH ₂ Cl ₂ ) afforded 71 g (61%) of the title compound as a colorless solid: ¹ H NMR (360 MHz, CDCl ₃ ) δ 2.26 (6
H, s), 3.57 (2H, s), 3.90 (3H, s), 4.68 (2H, s)
); MS (ES ^<+> ) m / e 171 [MH ^<+ >].

G) Hydrochloric acid N- [5- (3,7-diphenyl-1,2,4-triazolo [4,3
-B] pyridazin-6-yloxymethyl) -2-methyl-2H-1,2,4-
Triazol-3-ylmethyl] -N, N-dimethylamine N- (5-hydroxymethyl-2-methyl-2H-1,
2,4-triazol-3-ylmethyl) -N, N-dimethylamine (71 mg
, 0.42 mmol) with sodium hydride (33 mg of a 60% dispersion in mineral oil)
0.83 mmol) was added and the resulting slurry was stirred at room temperature under nitrogen for 5 minutes. 6-chloro-3,7-diphenyl-1,2,4-triazolo [4,3-b
] Pyridazine (from step c) (0.11 g, 0.35 mmol) was added and the mixture was stirred as before 5 minutes. Water (50 mL) was added and the resulting precipitate was filtered off before flash chromatography (silica gel, 0-5%
It was purified by MeOH / _CH 2 Cl _2). The product is treated with methanolic hydrogen chloride (
2 mL), concentrated in vacuo and recrystallized from ethanol / diethyl ether to give 9.0 mg (5%) of the title compound as a white solid: ¹ H N
MR (400 MHz, DMSO-d ₆ ) δ 2.81 (6H, s), 3.92 (3
H, s), 4.53 (2H, s), 5.59 (2H, s), 7.50 (2H, m
), 7.58 (1H, m), 7.64 (3H, m), 7.75 (2H), 8.4
4 (1H, s), 8.49 (2H, m), 10.52 (1H, br s); MS
(ES ^<+> ) m / e 441 [MH ^<+ >].

Example 2 [5- (3,7-diphenyl-1,2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl) -1-methyl-1H-1,2,4 -Triazol-3-yl] methanol a) [5- (t-butyldimethylsilanyloxymethyl) -2-methyl-2H
-1,2,4-triazol-3-yl] methanol With stirring at -40 ° C, 3- (t-butyldimethylsilanyloxymethyl) -1-methyl-1H-1,2 in THF (70 mL). , 4-triazole (EP
-A-0421210) (3.5 g, 0.015 mol) was added dropwise n-butyllithium (10.2 mL of a 1.6 M solution in hexane, 0.016 mol). The solution was stirred at −40 ° C. under nitrogen for 15 minutes, after which DMF (1.3
mL, 1.2 g, 0.016 mol) was added and the mixture was allowed to warm to room temperature over 90 minutes. Methanol (20 mL) was added and the solution was cooled to 0 ° C.
Sodium borohydride (0.64 g, 0.017 mol) was added and the slurry was stirred for 5 minutes, during which time the slurry cleared and became a solution. A saturated aqueous solution of sodium chloride (50 mL) was added, after which the mixture was filtered to remove insoluble material. The organic phase of the filtrate was dried (MgSO ₄ ) and concentrated in vacuo. The residue was taken up in dichloromethane (50 mL), filtered to remove insoluble material, and the filtrate was concentrated in vacuo to yield 3.3 g (83%) of the title compound as a colorless solid: ¹ H NMR. (250 MHz, CDCl ₃ ) δ 0.11 (6H, s), 0,
91 (9H, s), 3.89 (3H, s), 4.68 (2H, s), 4.72 (
1H, br s); MS (ES ⁺ ) m / e 258 [MH ⁺ ].

B) 6- [5- (t-butyldimethylsilanyloxymethyl) -2-methyl-
2H-1,2,4-triazol-3-ylmethoxy] -3,7-diphenyl-
1,2,4-Triazolo [4,3-b] pyridazine This uses the procedure described in Example 1, step g, but with N- (5-hydroxymethyl-2-methyl-2H-1,2,2, 4-triazol-3-ylmethyl)-
Using [5- (t-butyldimethylsilanyloxymethyl) -2-methyl-2H-1,2,4-triazol-3-yl] methanol instead of N, N-dimethylamine, yield 72%. Was prepared. Data on the title compound: ¹ H NMR
(250 MHz, CDCl ₃ ) δ 0.11 (6H, s), 0, 91 (9H, s)
3.70 (3H, s), 4.73 (2H, s), 5.64 (2H, s), 7.
46-7.59 (8H, m), 8.06 (1H, s), 8.44 (2H, m);
MS (ES ^<+> ) m / e 528 [MH ^<+ >].

C) [5- (3,7-Diphenyl-1,2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl) -1-methyl-1H-1,2,4- Triazol-3-yl] methanol 6- [5- (t-butyldimethylsilanyloxymethyl) -2-methyl-2H
-1,2,4-triazol-3-ylmethoxy] -3,7-diphenyl-1,
2,4-triazolo [4,3-b] pyridazine (0.58 g, 1.1 mmol)
Was stirred in a mixture of ethanol (10 mL) and 2N hydrochloric acid (20 mL) at 60 ° C. for 1 hour. The solution was allowed to cool to room temperature and the pH was adjusted to above 7 with a saturated solution of sodium bicarbonate to precipitate the title compound as a colorless solid (0.
41 g, 90%). This material was recrystallized from ethanol to analytical purity.
Data for the title compound: ¹ H NMR (360 MHz, CDCl ₃ ) δ2.
49 (1H, t, J 5.8 Hz), 3.71 (3H, s), 4.73 (2H, d
, J5.8 Hz), 5.64 (2H, s), 7.47 to 7.60 (8H, m),
8.06 (1H, s), 8.43 (2H, m); MS (ES ⁺ ) m / e 414 [
MH ⁺ ].

Example 3 N- [5- (3,7-diphenyl-1,2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl) -1-methyl-1H-1,2 , 4-Triazol-3-ylmethyl] -N, N-dimethylamine Oxalyl chloride (15 mL) in dichloromethane (15 mL) with stirring at -78 ° C.
63 μL, 92 mg, 0.73 mmol) in DMSO (110 μL, 1.5 mm
ol) was added and the resulting solution was stirred at −78 ° C. under nitrogen for 30 minutes. [5
-(3,7-diphenyl-1,2,4-triazolo [4,3-b] pyridazine-
6-yloxymethyl) -1-methyl-1H-1,2,4-triazole-3-
Yl] methanol (from step c of Example 2) (0.25 g, 0.61 mmol)
Was added and the mixture was stirred as before 90 minutes. Triethylamine (0.42m
L, 0.31 g, 3.0 mmol) was added and the solution was cooled to −78 ° C. under nitrogen for 15 minutes.
Stirred for minutes, then allowed to warm to room temperature over 90 minutes. Water was added with vigorous stirring, after which the aqueous phase was washed with dichloromethane (2 × 15 mL).
The organic phases were combined, dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in methanol (10 mL), and then 3M molecular sieve (0.20 g)
And dimethylamine (0.33 mL of a 2M solution in methanol, 0.67 mmol
l) was added. The slurry was stirred at room temperature for 30 minutes under nitrogen, after which sodium cyanoborohydride (58 mg, 0.93 mmol) was added. If necessary, the slurry was stirred as before 24 hours, maintaining the pH of the solution at 5 by adding methanolic hydrogen chloride (methyl orange indicator). Water (50m
L) was added and a solid precipitated. Wash the slurry with dichloromethane (3 × 3
0 mL), then the organic phases were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-7% MeO
And purified by H / _{CH 2} Cl 2). The product was triturated under diethyl ether to give 18 mg (6%) of the title compound as a colorless solid: ¹ H NMR (
400 MHz, CDCl ₃ ) δ 2.33 (6H, s), 3.54 (2H, s),
3.69 (3H, s), 5.64 (2H, s), 7.48 to 7.61 (8H, m
), 8.08 (1H, s), 8.46 (2H, m); MS (ES ^<+> ) m / e44.
1 [MH ⁺ ].

Example 4 [1-Methyl-5- (3-phenyl-7- (pyrrolidin-1-yl) -1,2]
, 4-Triazolo [4,3-b] pyridazin-6-yloxymethyl) -1H-
1,2,4-Triazol-3-yl] methanol a) 4-Bromo-1,2-dihydropyridazine-3,6-dione Bromomaleic anhydride (50 g, 280) in 40% acetic acid / water (750 mL)
mmol) and sodium acetate (76.5 g, 560 mmol) was treated with hydrazine monohydrate (16.5 mL, 340 mmol) at room temperature under nitrogen. The brown solution was stirred and heated at 100 ° C. for 18 hours. After cooling, the mixture was poured into water (1 L) and extracted with ethyl acetate (6 × 500 mL). The combined extracts were dried (MgSO ₄ ), filtered and evaporated to give 20 g (37%) of the title compound as an orange solid: ¹ H NMR (250 MHz, DMSO-d ₆ ).
δ 7.68 (1H, br s); MS (ES ⁺ ) m / e 191/193 [MH ⁺ ]. This material was used without further purification.

B) 4-bromo-3,6-dichloropyridazine 4-bromo-1,2-dihydropyridazine in phosphorus oxychloride (100 mL)
Stir -3,6-dione (10 g, 52 mmol) at 100 ° C. under nitrogen for 1 hour.
Heat for 6 hours. After cooling, excess phosphorus oxychloride was removed under vacuum. Residue
It was azeotroped with toluene (twice) and then taken up in dichloromethane / water. mixture
The material was carefully basified with solid sodium bicarbonate. To get two transparent phases
For this, the mixture needed to be further diluted. The two phases are separated and the aqueous phase
Was extracted with dichloromethane (3 times). The combined extracts are dried (Na₂SO₄),
Filtered and evaporated. The residue was chromatographed (silica gel, CH₂Cl ₂ To give 5.0 g (42%) of the title compound as a colorless solid
Was:¹1 H NMR (250 MHz, CDCl₃) Δ 7.68 (1H, br s)
MS (ES⁺) M / e 228/230 [MH⁺].

C) 3,6-Dichloro-4- (pyrrolidin-1-yl) pyridazine 4-bromo-3,6-dichloropyridazine (115 g, 0.51 mol) in DMF (1 L) with stirring at 0 ° C. ) And potassium carbonate (209 g, 1.5 m
ol) was added pyrrolidine (46 mL, 0.56 mol). The mixture was allowed to warm to room temperature and then stirred overnight under nitrogen. Water (1.5 L) was added and the resulting slurry was filtered. The residue was washed thoroughly with water and diethyl ether to give the title compound (110 g, 100%) as a fine white powder: ¹ H NMR (250 MHz, CDCl ₃ ) δ 2.03 (4H, m), 3 .6
4 (4H, m), 6.46 (1 H, s); MS (ES ⁺ ) m / e 218/220.
[MH ⁺ ].

D) [6-Chloro-5- (pyrrolidin-1-yl) pyridazin-3-yl] h
3,6-Dichloro-4- (pyrrolidine in drazine 1,4-dioxane (820 mL)
-1-yl) pyridazine (53 g, 0.24 mol) and hydrazine monohydrate
(105 mL, 2.2 mol) was heated under reflux overnight. Leave the solution
Upon cooling, dichloromethane was added to precipitate a solid. Filter this out
This gave the title compound as a pale yellow solid (14 g, 27%). Furnace liquid under vacuum
Concentrate and concentrate the residue by flash chromatography (silica gel, 2-5% MeO
H / CH containing 0.1% concentrated aqueous ammonia₂Cl₂) And further purified
This gave 5 g (4%) of the title compound:¹1 H NMR (250 MHz, CDCl ₃ ) Δ 1.98 (4H, m), 3.26 (2H, brs), 3.57 (4H, m).
m), 6.11 (1H, s), 6.41 (1H, br s); MS (ES⁺) M
/ E214 / 216 [MH⁺].

E) N-benzylidene-N ′-[6-chloro-5- (pyrrolidin-1-yl)
Pyridazin-3-yl] hydrazine To a solution of [6-chloro-5- (pyrrolidin-1-yl) pyridazin-3-yl] hydrazine (14 g, 0.063 mol) in 0.1 N hydrochloric acid (600 mL)
At room temperature, benzaldehyde (6.4 mL, 0.063 mol) was added dropwise. The mixture was stirred at 60 ° C. for 15 minutes, producing a thick slurry. The pH of the solution was adjusted to １１11 using 4N aqueous sodium hydroxide solution and the precipitate was filtered off. The residue was washed with water, ethanol and diethyl ether to give 14 g (7
3%) of the title compound as a white solid: ¹ H NMR (360 MHz, D
_{MSO-d 6) δ1.93 (4H} , m), 3.58 (4H, m), 6.57 (1
H, s), 7.35 (1H, m), 7.39 (2H, m), 7.66 (2H, d
, J 7.1 Hz), 8.06 (1H, s), 11.16 (1H, s); MS (E
S ⁺ ) m / e 302/304 [MH ⁺ ].

F) 6-chloro-3-phenyl-7- (pyrrolidin-1-yl) -1,2,4
-Triazolo [4,3-b] pyridazine N-benzylidene-N '-[6-chloro-5- (pyrrolidin-1-yl) pyridazin-3-yl] hydrazine in acetic acid (300 mL) (14 g, 0.046 m)
ol) and a slurry of lead (IV) acetate (24 g, 0.055 mol) at 60 ° C.
And stirred under nitrogen overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography (silica gel, 0-10% MeOH / EtOAc) to yield 4.1 g (30%) of the title compound as a yellow solid: ¹ H NMR. (
250 MHz, CDCl ₃ ) δ 2.05 (4H, m), 3.56 (4H, m),
7.05 (1H, s), 7.51 (3H, m), 8.42 (2H, m); MS (
ES ^<+> ) m / e 300/302 [MH] ^<+> .

G) 6- [5- (t-Butyldimethylsilanyloxymethyl) -2-methyl-
2H-1,2,4-triazol-3-ylmethoxy] -3-phenyl-7- (
Pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine This uses the procedure described in step g of Example 1, but uses N- (5-hydroxymethyl-2-methyl -2H-1,2,4-triazol-3-ylmethyl)-
Using [5- (t-butyldimethylsilanyloxymethyl) -2-methyl-2H-1,2,4-triazol-3-yl] methanol instead of N, N-dimethylamine, and 6-chloro -3,7-diphenyl-1,2,4-triazolo [
Using 6-chloro-3-phenyl-7- (pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine instead of 4,3-b] pyridazine,
Prepared in 75% yield. Data for the title compound: ¹ H NMR (250 MH
z, CDCl ₃ ) δ 0.11 (6H, s), 0.91 (9H, s), 1.92 (
4H, m), 3.39 (4H, m), 3.99 (3H, s), 4.76 (2H,
s), 5.54 (2H, s), 6.60 (1H, s), 7.41 to 7.53 (3
H, m), 8.30 (2H, m); MS (ES ⁺ ) m / e 521 [MH ⁺ ].

H) [1-Methyl-5- (3-phenyl-7- (pyrrolidin-1-yl) -1
, 2,4-Triazolo [4,3-b] pyridazin-6-yloxymethyl) -1
H-1,2,4-triazol-3-yl] methanol This was followed according to the procedure described in step c of example 2, but with 6- [5- (t-butyldimethylsilanyloxymethyl) -2-methyl -2H-1,2,4-triazol-3-ylmethoxy] -3,7-diphenyl-1,2,4-triazolo [
6- [5- (t-Butyldimethylsilanyloxymethyl) -2-methyl-2H-1,2,4-triazol-3-ylmethoxy] -3-phenyl-7 instead of 4,3-b] pyridazine Prepared using-(pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine in 92% yield. Data for the title compound: ¹ H NMR (360 MHz, DMSO-d ₆ ) δ 1.90 (4H,
m), 3.47 (4H, m), 4.40 (2H, s), 5.23 (1H, br)
s), 5.64 (2H, s), 6.83 (1H, s), 7.47 to 7.59 (3
H, m), 8.31 (2H, m); MS (ES ^<+> ) m / e 407 [MH ^<+ >].

Example 5 6- (5-Chloromethyl-2-methyl-2H-1,2,4-triazole-3
-Ylmethoxy) -3-ylmethoxy) -3-phenyl-7- (pyrrolidine-1
-Yl) -1,2,4-triazolo [4,3-b] pyridazine [1-methyl-5- (3-phenyl-7- (pyrrolidin-1-yl) -1,2]
, 4-Triazolo [4,3-b] pyridazin-6-yloxymethyl) -1H-
1,2,4-Triazol-3-yl] methanol (from step h of Example 4) (
1.0 g, 2.5 mmol) was stirred in phosphorus oxychloride (50 mL) at room temperature for 18 hours. The solvent was removed under vacuum and the residue was partitioned between dichloromethane (50mL) and water (50mL). Wash the aqueous phase with additional dichloromethane (2 × 5
0 mL), then the organic phases were combined, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was eluted through a plug of silica with 7.5% methanol in dichloromethane to yield 1.2 g (100%) of the title compound as a colorless solid. After recrystallization from ethanol / ethyl acetate / hexane, an analytically pure sample was obtained. Data for the title compound: ¹ H NMR (360 MHz, DM
_{SO-d 6) δ1.96 (4H} , m), 3.68 (4H, m), 3.92 (3H
, S), 4.72 (2H, s), 5.73 (2H, s), 6.81 (1H, s)
, 7.68 (3H, m), 8.29 (2H, m); MS (ES ^<+> ) m / e 425.
/ 427 [MH ^<+ >].

Example 6 N- [5- (3-phenyl-7- (pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl) -1 -Methyl-1
H-1,2,4-Triazol-3-ylmethyl] -N, N-dimethylamine Dimethylamine hydrochloride (73 mg) in N, N-dimethylacetamide (2 mL)
, 0.90 mmol) in sodium hydride (60% dispersion in mineral oil; 88 mg)
, 2.2 mmol) was added and the resulting slurry was stirred at room temperature under nitrogen for 90 minutes. 6- (5-chloromethyl-2-methyl-2H-1,2,4-triazol-3-ylmethoxy) -3-phenyl-7- (pyrrolidin-1-yl) -1,
2,4-triazolo [4,3-b] pyridazine (from Example 5) (99 mg, 0
. 23 mmol) was added and the mixture was stirred at 50 ° C. under nitrogen for 18 hours. Water (15 mL) was added and the solution was washed with dichloromethane (3 × 10 mL).
The combined organic phases were washed with water (1 × 10 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residual oil was triturated under diethyl ether / hexane to give a solid. This was recrystallized from ethyl acetate / ethanol / hexane to give 13 mg (1
3%) of the title compound were obtained as colorless crystals: ¹ H NMR (400 MHz, C
DCl ₃ ) δ 1.97 (4H, m), 2.34 (6H, s), 3.46 (4H,
m), 3.57 (2H, s), 3.93 (3H, s), 5.56 (2H, s),
6.72 (1H, s), 7.44 to 7.54 (3H, m), 8.33 (2H, m
); MS (ES ^<+> ) m / e 434 [MH ^<+ >], 218 [MH ^< 2 ⁺ >] / 2.

Example 7 6- [2-Methyl-5- (morpholin-4-ylmethyl) -2H-1,2 hydrochloride
, 4-Triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-
1-yl) -1,2,4-triazolo [4,3-b] pyridazine except that morpholine was used in place of dimethylamine hydrochloride and the free base was dissolved in methanolic hydrogen chloride before recrystallization. Prepared according to the procedure described in Example 6 in 31% yield. Data for the title compound: ¹ H NMR (360 MH
_{z, DMSO-d 6) δ1.94} (4H, m), 3.63 (4H, m), 3.8
3 (8H, brm), 3.97 (3H, s), 4.40 (2H, s), 5.7
6 (2H, s), 6.83 (1H, s), 7.64 (3H, m), 8.27 (2
H, m); MS (ES ^<+> ) m / e 476 [MH ^<+ >], 239 [MH ^< 2 ⁺ >] / 2.

Example 8 6- [5- (azetidin-1-ylmethyl) -2-methyl-2H-1,2,4
-Triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-
Yl) -1,2,4-triazolo [4,3-b] pyridazine This was prepared in 23% yield according to the procedure described in Example 6, but using azetidine instead of dimethylamine hydrochloride. Data for title compound: ¹ H N
MR (360 MHz, DMSO-d ₆ ) δ 1.95 (4H, m), 2.10 (2
H, quintet, J 7.0 Hz), 3.33 (4H, t, J 7.0 Hz), 3.44
(4H, m), 3.65 (2H, s), 3.93 (3H, s), 5.54 (2H
, S), 6.68 (1H, s), 7.45 to 7.53 (3H, m), 8.30 (
2H, m); MS (ES ⁺ ) m / e 446 [MH ⁺ ], 224 [MH ²⁺ ] / 2
.

Example 9 6- [2-Methyl-5- (4-methylpiperazin-1-ylmethyl) -2H-
1,2,4-Triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine This is described in Example 6. Prepared according to the procedure described, but using 1-methylpiperazine instead of dimethylamine hydrochloride in 38% yield. Data for the title compound: ¹ H NMR (360 MHz, CDCl ₃ ) δ 1.95 (4H, m), 2.2
8 (3H, s), 2.48 (4H, br s), 2.63 (4H, br s),
3.43 (4H, m), 3.66 (2H, s), 3.95 (3H, s), 5.5
6 (2H, s), 6.68 (1H, s), 7.43 to 7.53 (3H, m), 8
. ^{33 (2H, m); MS} (ES +) m / e489 [MH +], 245 [MH 2 +] / 2.

Example 10 6- [5- (3,3-Difluoroazetidin-1-ylmethyl) -2-methyl-2H-1,2,4-triazol-3-ylmethoxy] -3-phenyl-7-
(Pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine a) 1-benzhydryl azetidin-3-one 1-benzhydryl in DMSO (100 mL) at 15 ° C. Azetidine-
3-ol (10 g, 0.042 mol) and triethylamine (58 mL,
To 42 g (0.42 mol) was added sulfur trioxide-pyridine complex (40 g, 0.25 mol) in DMSO (50 mL) over 5 minutes. The reaction was stirred at room temperature under nitrogen for 3.5 hours, then poured into a mixture of crushed ice (200 g) and saturated ammonium chloride solution (100 mL). The slurry was extracted with ethyl acetate (3 × 200 mL) and the combined organic phases were saturated aqueous ammonium chloride (200 mL)
And washed with water (200 mL), dried (MgSO ₄ ) and concentrated in vacuo, leaving 6.4 (64%) of the title compound as a pale yellow solid: ¹ H NMR (2
50 MHz, CDCl ₃ ) δ 4.00 (4H, s), 4.59 (1H, s), 7
. 18-7.34 (6H, m), 7.47 (4H, m).

B) 1-Benzhydrylazepin-3-one (5.0 g) in 1-benzhydryl-3,3-difluoroazetidine benzene (50 mL).
, 0.021 mol) in diethylaminosulfur trifluoride (7.8 mL, 0.063
mol) was added and the mixture was stirred overnight at room temperature under nitrogen. Add the solution to water (1
00 mL) and ethyl acetate (100 mL), then the organic phase was separated with water (1 mL).
00 mL) and saturated sodium chloride solution (1 × 100 mL), dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10% EtOAc / hexane) and then recrystallized from hexane to yield 3.0 g (54%) of the title compound as a colorless solid: ¹ H NMR (250 MHz) , CDCl ₃ ) δ 3.51 (4H, t, J12
Hz), 4.44 (1H, s), 7.16 to 7.32 (6H, m), 7.42 (
4H, m).

C) 3,3-Difluoroazetidine hydrochloride 1-benzhydryl-3,3-difluoroazetidine (3.0 g, 0.011)
mol) was hydrogenated at 50 psi for 18 hours using a palladium hydroxide catalyst (20% on activated carbon, 600 mg) in a mixture of methanol (70 mL) and 2N hydrochloric acid (7 mL). The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was triturated under diethyl ether to give 1.3 g (88%) of the title compound as a pale yellow solid: ¹ H NMR (250 MHz, DMSO-d ₆ ) δ 4.50 (
2H, t, J12 Hz), 10.05 (2H, brs).

D) 6- [5- (3,3-Difluoroazetidin-1-ylmethyl) -2-methyl-2H-1,2,4-triazol-3-ylmethoxy] -3-phenyl-
7- (Pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine This is according to the procedure described in Example 6, but instead of dimethylamine hydrochloride 3,3-difluorohydrochloride Prepared with azetidine in 20% yield. Data for the title compound: ¹ H NMR (360 MHz, CDCl ₃ ) δ 1.96 (
4H, m), 3.44 (4H, m), 3.75 (4H, t, J12Hz), 3.
84 (2H, s), 3.95 (3H, s), 5.55 (2H, s), 6.69 (
1H, s), 7.49 (3H, m), 8.30 (2H, m); MS (ES ⁺ ) m
/ E463 [M-F] ^<+> .

Example 11 6- [2-Methyl-5- (pyridazin-1-ylmethyl) -2H-1,2,4
-Triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-
Yl) -1,2,4-Triazolo [4,3-b] pyridazine This was prepared in 3% yield according to the procedure described in Example 6, but using pyrrolidine instead of dimethylamine hydrochloride. Data for title compound: ¹ H NM
R (400 MHz, DMSO-d ₆ ) δ 1.81 (2H, m), 1.92 (6H
, M), 3.09 (2H, m), 3.40 (2H, m), 3.56 (4H, m)
5.96 (3H, s), 4.46 (2H, s), 5.74 (2H, s), 6.
86 (1H, s), 7.59 (3H, m), 8.25 (2H, m); MS (ES
) M / e 460 [MH] ⁺ , 230 [MH ²⁺ ] / 2.

Example 12 7-t-butyl-6- [5- (t-butyldimethylsilanyloxymethyl)-
2-methyl-2H-1,2,4-triazol-3-ylmethoxy] -3- (2
-Fluorophenyl) -1,2,4-triazolo [4,3-b] pyridazine a) 4-t-butyl-3,6-dichloropyridazine concentrated sulfuric acid (53.6 mL, 1.0 mol) was added to water (1 .25 L) was carefully added to a stirred suspension of 3,6-dichloropyridazine (50.0 g, 0.34 mol). Next, the mixture was heated to 70 ° C. (internal temperature), after which trimethylacetic acid (47.5 mL, 0.41 mol) was added. Thereafter, a solution of silver nitrate (11.4 g, 0.07 mol) in water (20 mL) was added over about 1 minute. This gave the reaction mixture a milky appearance. Then, water (0.63 mL)
A solution of ammonium persulfate (230 g, 1.0 mol) in was added over 20-30 minutes. The internal temperature rose to about 85 ° C. During the addition, the product was formed as a sticky precipitate. Upon completion of the addition, the reaction was stirred for an additional 10 minutes, then allowed to cool to room temperature. The mixture was then poured onto ice and basified with concentrated aqueous ammonia, keeping the temperature below 10 ° C. by adding more ice if necessary. The aqueous solution was extracted with dichloromethane (3 × 300 mL). The combined extracts were dried (MgSO ₄ ), filtered and evaporated to yield 55.8 g of crude product as an oil. This was subjected to flash chromatography (silica gel, 0-15% EtO
Ac / hexane) to give, 37.31g (of the title compound ^{53%): 1 H NMR (} 360MHz, DMSO-d 6) δ1.50 (9H, s)
, 7.48 (1H, s); MS (ES ⁺ ) m / e 205/207 [MH] ⁺ .

B) 7-tert-butyl-6-chloro-3- (2-fluorophenyl) -1,2,2
4-triazolo [4,3-b] pyridazine 4-t-butyl-3,6-dichloropyridazine in dioxane (1.2 L) (
20 g, 0.097 mol), 2-fluorobenzhydrazine (22.6 g, 0
. 145 mol) and triethylamine hydrochloride (20 g, 0.014
(5 mol) was stirred and heated under reflux for 4 days with flowing nitrogen. Upon cooling, volatiles were removed under vacuum and the residue was anesthetized with dichloromethane (200 mL), filtered and concentrated in vacuo. The residue was purified by chromatography (silica _{gel, 0~25% EtOAc / CH 2 Cl} 2), 12.95g (
44%) yielded the title compound as a white solid: ¹ H NMR (360 MHz,
_{CDCl 3) δ1.57 (9H, s} ), 7.26~7.35 (2H, m), 7.
53 to 7.60 (1H, m), 7.89 to 7.93 (1H, m), 8.17 (1
H, s); MS (ES ^<+> ) m / e 305/307 [MH] ^<+> .

C) 7-t-butyl-6- [5- (t-butyldimethylsilanyloxymethyl) -2-methyl-2H-1,2,4-triazol-3-ylmethoxy] -3-
(2-Fluorophenyl) -1,2,4-triazolo [4,3-b] pyridazine 7-tert-butyl-6-chloro-3- (2) in anhydrous DMF (22 mL) under nitrogen
-Fluorophenyl) -1,2,4-triazolo [4,3-b] pyridazine (1
. 0087 g, 3.31 mmol) to a stirred solution of [5- (t-butyldimethylsilanyloxymethyl) -2-methyl-2H-1,2,4-triazole-3-.
Il] methanol (from step a of Example 2) (1.0224 g, 3.97 mmol)
l), followed by sodium hydride (60% dispersion in oil; 0.1589 g)
, 3.97 mmol) was added in portions over 2 minutes. The mixture was stirred for 30 minutes at room temperature. Water (78 mL) was added and the resulting solid was collected by filtration,
Washed with water and hexane, dried at 60 ° C. under vacuum and dried at 1.6129 g (9
3%) of the title compound were left as a white solid: mp 121-123 ° C. (CH ₂ C
1 ₂ -EtOAc-hexane); ¹ H NMR (360 MHz, CDCl ₃ ) δ
0.09 (6H, s), 0.90 (9H, s), 1.40 (9H, s), 3.7
9 (3H, s), 4.73 (2H, s), 5.49 (2H, s), 7.27 (1
H, m), 7.33 (1H, t, J7.6Hz), 7.56 (1H, m), 7.
87 (1H, td, J7.4, J'1.7 Hz), 7.98 (1H, s); MS
(ES ^<+> ) m / e 526 [MH] ^<+> . Analytical found: C, 59.31; H, 6.9
1; N, 18.53. The _{C 26 H 36 FN 7 O 2} Si, C, 59.40; H,
6.90; N, 18.65% required.

Example 13 [5- (7-tert-butyl-3- (2-fluorophenyl) -1,2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl) -1- Methyl-1H
-1,2,4-triazol-3-yl] methanol This procedure uses a procedure similar to that described in step c of Example 2, but
[5- (t-butyldimethylsilanyloxymethyl) -2-methyl-2H-1,
2,4-Triazol-3-ylmethoxy] -3,7-diphenyl-1,2,4
-Instead of triazolo [4,3-b] pyridazine, 7-t-butyl-6- [5
-(T-butyldimethylsilanyloxymethyl) -2-methyl-2H-1,2,2
4-triazol-3-ylmethoxy] -3- (2-fluorophenyl) -1,
Prepared using 2,4-triazolo [4,3-b] pyridazine in 93% yield. Data relating to the title compound: mp 225-230 ℃ _{(CH 2} Cl ₂ -EtOA
c) ¹ H NMR (360 MHz, CDCl ₃ ) δ 1.41 (9H, s);
34 (1H, brt), 3.80 (3H, s) 4.72 (2H, d, J5.6)
Hz), 5.50 (2H, s), 7.28 (1H, m), 7.35 (1H, t,
J7.6, J'1.0 Hz), 7.57 (1H, m), 7.87 (1H, td,
J7.4, J'1.8 Hz), 7.99 (1H, s); MS (ES ⁺ ) m / e4
12 [MH] ⁺ . Found: C, 58.14; H, 5.24; N, 23.70.
. The _{C 20 H 22 FN 7 O 2} , C, 58.39; H, 5.39; N, 23.8
3% is required.

Example 14 7-tert-butyl-3- (2-fluorophenyl) -6 (5-methoxymethyl-
2-methyl-2H-1,2,4-triazol-3-ylmethoxy) -1,2,2
4-Triazolo [4,3-b] pyridazine [5- (7-tert-butyl-3- (2-fur) in anhydrous DMF (5 mL) under nitrogen.
Orophenyl) -1,2,4-triazolo [4,3-b] pyridazin-6-yl
Oxymethyl) -1-methyl-1H-1,2,4-triazol-3-yl] me
Stanol (from Example 13) (0.1017 g, 0.247 mmol) with stirring
Add sodium hydride (60% dispersion in oil; 10.9 mg, 0.273 mm)
ol) was added. The mixture was stirred at room temperature for 5 minutes before the iodomethane (1
8.5 μL, 0.297 mmol) was added dropwise. Allow the mixture to stand for another 3 hours
Stir and add additional sodium hydride after 45 minutes (60% dispersion in oil; 1.1 mg
, 0.028 mmol) was added. Water (20 mL) was added and the mixture was filtered
The solid was washed with additional water. A saturated aqueous solution of NaCl is added to the filtrate, which is
Extracted with ethyl acetate (3 × 40 mL). The combined organic extracts are dried (Na₂SO ₄ ), Evaporated under vacuum. Flash chromatography of the residue (silica gel
3% MeOH / CH₂Cl₂80.0 mg (76%)
The title compound was obtained as a white solid: mp 138-140 ° C (CH₂Cl₂-E
tOAc-isohexane);¹1 H NMR (360 MHz, CDCl₃) Δ1.
40 (9H, s), 3.47 (3H, s), 3.82 (3H, s) 4.51 (2
H, s), 5.50 (2H, s), 7.27 (1H, m), 7.35 (1H, t
, J7.5, J'0.9 Hz), 7.56 (1H, m), 7.88 (1H, td)
, J7.4, J'1.8 Hz), 7.99 (1H, s); MS (ES⁺) M / e
426 [MH]⁺. Found: C, 59.02; H, 5.48; N, 22.7.
4. C₂₁H₂₄FN₇O₂C, 59.28; H, 5.69; N, 23.
05% is required.

Example 15 7-t-Butyl-3- (2-fluorophenyl) -6- (5-trifluoromethyl
Tyl-1H-1,2,4-triazol-3-ylmethoxy) -1,2,4-to
Liazolo [4,3-b] pyridazine a) 7-t-butyl-3- (2-fluorophenyl) -1,2,4-triazo
B [4,3-b] pyridazin-6-one 7-tert-butyl- in 1,4-dioxane (60 mL) and water (12 mL)
6-chloro-3- (2-fluorophenyl) -1,2,4-triazolo [4,3
-B] pyridazine (from step b of Example 12) (1.0468 g, 3.43 mm
ol) in a stirred solution of 4M aqueous NaOH (4.29 mL, 17.2 mmol)
) Was added and the solution was heated under reflux for 23 hours. The solvent is removed under vacuum and the residue
Was partitioned between water (200 mL) and diethyl ether (100 mL). afterwards
The aqueous phase was acidified to pH 3 or less using 5M aqueous HCl. The obtained sunk
The solids are collected by filtration, washed with water and hexane, at 60 ° C., vacuum
Drying under yielded 0.8990 g (91%) of the title compound as a white solid: ¹ 1 H NMR (360 MHz, DMSO-d₆6.) δ 1.40 (9H, s);
40-7.48 (2H, m), 7.65 (1H, m) 7.84 (1H, td, J
7.3, J'1.8 Hz), 8.00 (1H, s), 12.64 (1H, br)
s); MS (ES⁺) M / e 287 [MH]⁺.

B) 7-tert-butyl-6-cyanomethoxy-3- (2-fluorophenyl)-
1,2,4-Triazolo [4,3-b] pyridazine 7-t-butyl-3- (2-fluorophenyl) -1,2,4-triazolo [4,4 in anhydrous DMF (47 mL) under nitrogen. 3-b] pyridazin-6-one (0.
Sodium hydride (60% dispersion in oil; 0.1878 g, 4.70 mmol) is added to a stirred solution of 8953 g, 3.13 mmol) and the mixture is stirred at room temperature for 25 minutes, then at 80 ° C. for 25 minutes Stirred. After allowing to cool, bromoacetonitrile (0.327 mL, 4.69 mmol) was added dropwise and the mixture was stirred at room temperature for 18 hours. Thereafter, water (160 mL) was added and the resulting precipitated solid was collected by filtration, washed with water and hexane, dried at 60 ° C. under vacuum, and 0.8506 g (84%). The title compound was obtained as a white solid: ¹ H NMR (360 MHz, CDCl ₃ ) δ 1.45 (9H, s), 5.07 (
2H, s), 7.30 (1H, m) 7.36 (1H, td, J7.6, J'0.
9Hz), 7.57 (1H, m), 7.93 (1H, td, J7.3, J'1.
8 Hz), 8.04 (1 H, s); MS (ES ^<+> ) m / e 326 [MH] ^<+> .

C) 7-tert-butyl-3- (2-fluorophenyl) -6- (5-trifluoromethyl-1H-1,2,4-triazol-3-ylmethoxy) -1,2,4
-Triazolo [4,3-b] pyridazine 7-t-butyl-6-cyanomethoxy-3- (2-fluorophenyl) -1,2,4-triazolo [4,4 in anhydrous methanol (7 mL) under nitrogen. To a stirred solution of [3-b] pyridazine (0.5455 g, 1.68 mmol) in methanol was added 0.1 ml of methanol.
A 4 M sodium methoxide solution (0.126 mL, 0.0504 mmol) was added and the mixture was stirred at room temperature for 5 hours. Acetic acid (2.9 μL, 0.051 mm
ol) was added to neutralize the mixture, followed by anhydrous methanol (2m
L) in trifluoroacetic acid hydrazide (Fritz, H. et al., Mag.
n. Reson. Chem. , 1990, 28, 331-336) (0.224).
(6 g, 1.75 mmol) was added and the mixture was heated at 60 ° C. for 18 hours. The solvent is removed under vacuum and the residue is flash chromatographed (silica gel, 5
% MeOH / _CH 2 Cl ₂₎ to afford leaving the title compound 0.6893g (94%) as a white solid: mp 206~217 ℃ _(CHCl 3 -EtO
Ac-isohexane); ¹ H NMR (360 MHz, CDCl ₃ ) δ 1.34.
(9H, s), 5.70 (2H, s), 7.13 (1H, m), 7.22 (1H
, T, J7.5 Hz), 7.45 (1H, m), 7.72 (1H, m), 8.8
3 (1H, s); MS (ES ⁺ ) m / e 436 [MH] ⁺ . Analysis actual measurement value: C, 5
2.70; H, 3.78; N, 22.31. C ₁₉ H ₁₇ F ₄ N ₇ O includes C,
52.42; H, 3.94; N, 22.52% are determined.

Example 16 7-t-butyl-3- (2-fluorophenyl) -6- (2-methyl-5-trifluoromethyl-2H-1,2,4-triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine and 7-t-butyl-3- (
2-fluorophenyl) -6- (1-methyl-5-trifluoromethyl-1H-
1,2,4-triazol-3-ylmethoxy) -1,2,4-triazolo [4
, 3-b] pyridazine Sodium hydride (60% dispersion in oil; 32.7 mg, 0.818 mmol) and iodomethane (50 mL) in anhydrous DMF (4 mL) cooled to -3 ° C under nitrogen.
. 7 μL, 0.814 mmol) into a stirred mixture of 7 mL of anhydrous DMF (6 mL).
-T-butyl-3- (2-fluorophenyl) -6- (5-trifluoromethyl-1H-1,2,4-triazol-3-ylmethoxy) -1,2,4-triazolo [4,3- b] Pyridazine solution (from Example 15) (0.2953 g, 0.1.
(678 mmol) was added dropwise over 11 minutes. The mixture was stirred at -2 ° C for 15 minutes, then allowed to warm to 18 ° C over 2 hours and stirred at this temperature for an additional 45 minutes. The mixture was partitioned between ethyl acetate (40mL) and brine (40mL). The aqueous phase was further extracted with ethyl acetate (40 mL), the combined extracts were dried _(Na 2 _SO 4), and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 2% MeOH / CH ₂ Cl ₂ ) to yield 0.2405 g (79%) of a 4: 1 mixture of the two title compounds as a white solid.
These were subjected to flash chromatography (silica gel, 70-100% EtOA).
c / isohexane).

7-t-butyl-3- (2-fluorophenyl) -6- (2-methyl-5-to
Trifluoromethyl-2H-1,2,4-triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine: mp 139-141 ° C (CH ₂ Cl₂-EtOAc-isohexane);¹1 H NMR (400 MHz, CDC
l₃) Δ 1.45 (9H, s), 4.04 (3H, s), 5.46 (2H, s)
, 7.25 (1H, m), 7.32 (1H, td, J7.6, J'0.9 Hz)
, 7.53 (1H, m), 7.92 (1H, td, J7.5, J'1.7Hz)
, 7.96 (1H, s); MS (ES⁺) M / e450 [MH]⁺. Analysis measured value
: C, 52.94; H, 4.11; N, 21.19. C₂₀H₁₉F₄N₇O ・
0.3H₂For O, C, 52.82; H, 4.34; N, 21.56% are determined.
It is.

7-t-butyl-3- (2-fluorophenyl) -6- (1-methyl-5-to
Trifluoromethyl-1H-1,2,4-triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine: melting point 160-162 ° C (CH ₂ Cl₂-EtOAc-isohexane);¹1 H NMR (400 MHz, CDC
l₃) Δ 1.44 (9H, s), 3.85 (3H, s), 5.54 (2H, s)
, 7.25 (1H, m), 7.33 (1H, td, J7.6, J'1.0 Hz)
, 7.54 (1H, m), 7.84 (1H, td, J7.4, J'1.7 Hz)
, 7.99 (1H, s); MS (ES⁺) M / e450 [MH]⁺. Analysis measured value
: C, 53.43; H, 4.19; N, 21.89. C₂₀H₁₉F₄N₇To O
Is found to be C, 53.45; H, 4.26; N, 21.82%.

Example 17 7-t-butyl-3- (2-fluorophenyl) -6- (2-ethyl-5-trifluoromethyl-2H-1,2,4-triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine and 7-t-butyl-3- (
2-fluorophenyl) -6- (1-ethyl-5-trifluoromethyl-1H-
1,2,4-triazol-3-ylmethoxy) -1,2,4-triazolo [4
, 3-b] pyridazines These were prepared in a 92% overall yield following a procedure similar to that described in Example 16, but using iodoethane instead of iodomethane.

7-t-butyl-3- (2-fluorophenyl) -6- (2-ethyl-5-to
Trifluoromethyl-2H-1,2,4-triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine: 132-140 ° C (CH ₂ Cl₂-EtOAc-isohexane);¹1 H NMR (360 MHz, CDC
l₃) Δ 1.45 (9H, s), 1.49 (3H, t, J 7.3 Hz), 4.3
3 (2H, d, J7.3 Hz), 5.48 (2H, s), 7.25 (1H, m)
, 7.32 (1H, td, J7.6, J'1.0 Hz), 7.53 (1H, m)
, 7.93 (1H, td, J7.4, J'1.7 Hz), 7.96 (1H, s)
MS (ES⁺) M / e 464 [MH]⁺.

7-t-butyl-3- (2-fluorophenyl) -6- (1-ethyl-5-to
Trifluoromethyl-1H-1,2,4-triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine: mp 175-178 ° C (CH ₂ Cl₂-EtOAc-isohexane);¹1 H NMR (360 MHz, CDC
l₃) Δ 1.42 (9H, s), 1.45 (3H, t, J 7.3 Hz), 3.8
5 (2H, d, J 7.3 Hz), 5.56 (2H, s), 7.28 (1H, m)
, 7.36 (1H, td, J7.5, J'1.0 Hz), 7.57 (1H, m)
, 7.88 (1H, td, J7.5, J'1.8 Hz), 8.01 (1H, s)
MS (ES⁺) M / e 464 [MH]⁺. Analysis found: C, 54.44; H,
4.52; N, 21.03. C₂₁H₂₁F₄N₇O has C, 54.43; H
, 4.57; N, 21.16%.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72 ) Inventor Mitschinson, Andrieu United Kingdom, Esetsx C.M. 20.2 K. Earl, Harlow, Eastwick Road, Tarlings Park (72) Inventor Ratsell, Michael Jeffrey Neil United Kingdom , Esetsx C.M. 20.2 K. Earl, Harlow, Eastwick Road, Tarlings Park (72) Inventor Street, Leslie Jyozhif United Kingdom, Esetsus C.M.20.2 K R, Harlow, East Wick Road, Tarlings Park F Term (reference) 4C050 AA01 BB06 CC08 EE04 FF02 GG01 HH04 4C086 AA01 AA03 BA02 BC07 BC50 BC60 BC73 CB05 GA06 GA07 GA09 MA01 MA04 NA14 ZA06 ZA15 4H039 CA99 CD20

Claims (10)

[Claims] 1. Formula I: ## STR1 ## Wherein Z represents t-butyl, cyclobutyl, phenyl or pyrrolidin-1-yl; R ¹ represents hydrogen, methyl, methoxy or fluoro; R ² represents hydrogen or fluoro; R ³ Represents hydrogen, methyl or ethyl; R ⁴ represents trifluoromethyl, chloromethyl or a group of the formula —CH ₂ OR ^a or —CH ₂ NR ^b R ^c ; R ^a represents hydrogen, methyl or t-. And R ^b and R ^c both represent methyl, or R ^b and R ^c together represent azetidine, 3,3-difluoroazetidine, pyrrolidine, morpholine or N-methyl Or a pharmaceutically acceptable salt thereof. 2. A compound of formula IIA: A compound according to claim ¹ , wherein Z, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1, and a pharmaceutically acceptable salt thereof. 3. A compound of formula IIB: A compound according to claim ¹ , wherein Z, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1, and a pharmaceutically acceptable salt thereof. 4. A compound as claimed in any one of the preceding claims, wherein R ¹ represents hydrogen or fluoro. 5. A compound according to any one of the preceding claims, wherein R ³ represents methyl or ethyl. 6. N- [5- (3,7-diphenyl-1,2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl) -2-methyl-2H-1,
2,4-triazol-3-ylmethyl] -N, N-dimethylamine; [5- (3,7-diphenyl-1,2,4-triazolo [4,3-b] pyridazin-6-yloxymethyl) -1-methyl-1H-1,2,4-triazol-3-yl] methanol; N- [5- (3,7-diphenyl-1,2,4-triazolo [4,3-b] pyridazine-6) -Yloxymethyl) -1-methyl-1H-1,2,4-triazol-3-ylmethyl] -N, N-dimethylamine; [1-methyl-5- (3-phenyl-7- (pyrrolidine-1) -Il) -1,2
, 4-Triazolo [4,3-b] pyridazin-6-yloxymethyl) -1H-
1,2,4-triazol-3-yl] methanol; 6- (5-chloromethyl-2-methyl-2H-1,2,4-triazole-3
-Ylmethoxy) -3-phenyl-7- (pyrrolidin-1-yl) -1,2,4
-Triazolo [4,3-b] pyridazine; N- [5- (3-phenyl-7- (pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazin-6-yl Oxymethyl) -1-methyl-1
H-1,2,4-triazol-3-ylmethyl] -N, N-dimethylamine; 6- [2-methyl-5- (morpholin-4-ylmethyl) -2H-1,2,4
-Triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-
Yl) -1,2,4-triazolo [4,3-b] pyridazine; 6- [5- (azetidin-1-ylmethyl) -2-methyl-2H-1,2,4
-Triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-
Yl) -1,2,4-triazolo [4,3-b] pyridazine; 6- [2-methyl-5- (4-methylpiperazin-1-ylmethyl) -2H-
1,2,4-triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine; 6- [5- (3 , 3-Difluoroazetidin-1-ylmethyl) -2-methyl-2H-1,2,4-triazol-3-ylmethoxy] -3-phenyl-7-
(Pyrrolidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine; 6- [2-methyl-5- (pyrrolidin-1-ylmethyl) -2H-1,2,4
-Triazol-3-ylmethoxy] -3-phenyl-7- (pyrrolidin-1-
Yl) -1,2,4-triazolo [4,3-b] pyridazine; 7-t-butyl-6- [5- (t-butyldimethylsilanyloxymethyl)-
2-methyl-2H-1,2,4-triazol-3-ylmethoxy] -3- (2
-Fluorophenyl) -1,2,4-triazolo [4,3-b] pyridazine; [5- (7-t-butyl-3- (2-fluorophenyl) -1,2,4-triazolo [4 3-b] pyridazin-6-yloxymethyl) -1-methyl-1H
-1,2,4-triazol-3-yl] methanol; 7-t-butyl-3- (2-fluorophenyl) -6- (5-methoxymethyl-2-methyl-2H-1,2,4- Triazol-3-ylmethoxy) -1,2
, 4-Triazolo [4,3-b] pyridazine; 7-t-butyl-3- (2-fluorophenyl) -6- (5-trifluoromethyl-1H-1,2,4-triazol-3-ylmethoxy ) -1,2,4-triazolo [4,3-b] pyridazine; 7-tert-butyl-3- (2-fluorophenyl) -6- (2-methyl-5-trifluoromethyl-2H-1, 2,4-triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine; 7-t-butyl-3- (2-fluorophenyl) -6- (1-methyl-5-trifluoromethyl-1H-1,2,4 -Triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine; 7-t-butyl-3- (2-fluorophenyl) -6- (2-ethyl-5-trifluoromethyl-2H-1,2,4 -Triazol-3-ylmethoxy) -1
, 2,4-Triazolo [4,3-b] pyridazine; 7-t-butyl-3- (2-fluorophenyl) -6- (1-ethyl-5-trifluoromethyl-1H-1,2,4 -Triazol-3-ylmethoxy) -1
, 2,4-triazolo [4,3-b] pyridazine; and pharmaceutically acceptable salts thereof. 7. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 8. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prevention of anxiety. 9. A compound of formula III and a compound of formula IV: Wherein Z, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 and L ¹ represents a suitable leaving group; or ) A compound of formula XI (or its 1,2,4-triazolo [4,3-b]
Pyridazin-6-one tautomer) and a compound of formula XII: Wherein Z, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 and L ³ represents a suitable leaving group; or (C) Compounds of formula Z-CO ₂ H and compounds of formula XIII: Wherein Z, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1) in the presence of silver nitrate and ammonium persulfate; or (D) A compound of formula XIV and a compound of formula XV: (Wherein, Z, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1, and M is —B (OH) ₂ or —Sn (Alk) ₃ (where Alk Is
C _{1 to 6} alkyl group represents a), and ^{L 4} is suitable represents a leaving group) and the reacting under transition metal catalyst; or (E) a compound of formula XVII and formula XVIII hydrazide : Wherein Z, R ¹ and R ² are as defined in claim 1; and (F) then, if necessary, first obtaining Converting the compound of formula I to a further compound of formula I. 10. A method for the treatment and / or prevention of anxiety, comprising administering to a patient in need of such treatment an effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof. A method comprising administering a salt.