Difluoromethyl-phenyltriazoles as GABA receptor modulators

Abstract

The present invention relates to difluoromethyl-phenyl triazoles of general formula (I), which are GABA containing α5 subunits A The present invention relates to a method for preparing a pharmaceutical composition and a method for producing a compound of the present invention.

Description

Technical Field

[0001] The present invention relates to difluoromethyl-phenyltriazoles of general formula (I), which are GABA containing α5 subunits. A The present invention relates to a method for preparing a pharmaceutical composition and a method for producing a compound of the present invention. Background Art

[0002] GABA has been proposed in the literature A The α5 subunit represents a therapeutic target for the treatment of various diseases and disorders of the central nervous system and has been used as a therapeutic target in GABA A The α5 subunit has been linked to various neurological disorders, circadian rhythm disorders, and pain disorders, and is particularly expected to modulate GABA A Compounds that bind to α-receptors are useful candidates for treating, for example, cognitive disorders, Alzheimer's disease, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, and cognitive deficits associated with Down syndrome, autism, neurofibromatosis type I, or post-stroke (see, e.g., Neuroscience Letts. (2005) 81: 108-13, Neuropsychobiology (2001) 43 (3): 141-44, Amer. J. Med. Genetics (2004) 131B: 51-9, Autism (2007) 11 (2): 135-47, Investigacion Clinica (2007) 48: 529-41, Nature Neuroscience (2007) 10: 411-13, Neuroscience Letts(2008)433:22-7, Cell(2008)135:549-60).

[0003] Able to regulate GABA AIsoxazole derivatives of receptor complexes are known from, for example, WO 2007 / 039389, WO 2007 / 042420, WO 2007 / 054444, WO 2007 / 071598, WO 2007 / 074078, WO 2007 / 074089, WO 2007 / 137954, WO 2009 / 000662、WO 2009 / 071464、WO 2009 / 071476、WO 2009 / 071477、WO 2010 / 097368、WO 2010 / 112475、WO 2010 / 125042、WO 2010 / 127968、WO 2010 / 127974、WO 2010 / 127975, WO 2010 / 127976, WO 2010 / 127978, WO 2012 / 059482 and WO 2018 / 104419. Capable of regulating GABA A Phenyl-triazole derivatives of receptor complexes are known, for example, from WO 2012 / 062687, WO 2014 / 001281 and WO2014 / 001282. In addition, WO 2007 / 140174, WO 2008 / 025539, WO 2008 / 025540, WO 2009 / 149795 and WO 2011 / 020615 describe heterocyclic compounds useful as NR1 H4 (FXR) receptor agonists, including certain phenyltriazole derivatives. Other structurally related compounds as PDE10a inhibitors are disclosed in WO2012 / 133607. Summary of the invention

[0004] Surprisingly, phenyl-triazoles of the general formula (I) have been found

[0005]

[0006] Where R 1 It is a heteroaryl group, and the phenyl group has a difluoromethyl group, which is GABA A GABA with improved properties in terms of 5R binding properties A Excellent negative regulator of 5R (i.e., GABA A The compounds of the present invention are negative regulators of the α5 subunit, which can be understood as a low effective dose of the compound for disease treatment, thus having advantages such as minimization of side effects. In addition, the compounds of the present invention have excellent CNS permeability and low outflow rate from the ventricles, which is necessary for drugs intended to act in the CNS and have high metabolic stability. In addition, the compounds have very high IC for cytochrome P450 3A4, 2C8, 2C9, 2D6 and 2C19. 50 value.

[0007] Therefore, one aspect of the present invention relates to GABA A A compound of formula (I) or a salt thereof which is a negative regulator of 5R.

[0008] Another aspect of the present invention relates to GABA A A compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a negative regulator of 5R, has a high GABA A 5R binding properties.

[0009] Another aspect of the present invention relates to GABA A A compound of formula (I) or a pharmaceutically acceptable salt thereof which is a negative regulator of 5R and has high GABA A 5R binding properties and excellent CNS penetration, low efflux from the ventricles, and high metabolic stability and / or very high IC for cytochrome P450 3A4, 2C8, 2C9, 2D6, and 2C19 50 value.

[0010] In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and optionally one or more inert carriers and / or diluents.

[0011] Another aspect of the invention relates to methods of making the compounds of the invention.

[0012] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in preventing and / or treating GABA-sensitive ADiseases or conditions affected by the negative regulation of 5R, such as acute neurological disorders, chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory disorders, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, bipolar disorder, autism, Down syndrome, neurofibromatosis type I, postoperative cognitive decline, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis, AIDS-induced dementia, psychotic disorders, substance-induced psychotic disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug addiction, movement disorders, Parkinson's disease, restless legs syndrome, cognitive deficit disorder, multi-infarct dementia, mood disorders, depression, major dementia Depressive disorder, neuropsychiatric disorder, psychosis, attention deficit hyperactivity disorder, neuropathic pain, stroke, attention disorder, eating disorder, anorexia, anorexia nervosa, cachexia, weight loss, muscle atrophy, pain disorder, chronic pain, nociceptive pain, postoperative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, eye pain, pain caused by inflammation, pain caused by fracture, hyperalgesia, neuropathic pain, herpes-related pain, HIV-related neuropathic pain, traumatic nerve injury, recovery after traumatic brain injury, post-stroke pain, post-ischemic pain, fibromyalgia, chronic headache, migraine, tension headache, diabetic neuropathic pain, phantom limb pain, visceral pain, and cutaneous pain.

[0013] Other objects of the present invention will become clear to the skilled person directly from the foregoing and following descriptions. DETAILED DESCRIPTION

[0014] In a first aspect, the present invention relates to a compound of formula (I) or a salt thereof

[0015]

[0016] in

[0017] R 1 is selected from the group consisting of heteroaryl 1a ,

[0018] wherein the heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from the following: 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, H(O)C-, HOOC-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R3 )3N + -C 1-5 -alkyl-, (R 3 )2N-C(O)-, NC-, HO-, oxo, C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2-, halogen and imidazolyl, and

[0019] The above C 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )3N + -C 1-5 -alkyl-, (R 3 )2N-C(O)-、C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2- and imidazolyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, halogen, NC- and HO-, and

[0020] The heteroaryl group is a monocyclic or bicyclic ring system consisting of 5 to 10 ring atoms, containing 1 to 3 atoms selected from N, O or S(O) r wherein r = 0, 1 or 2, wherein at least one of the heteroatoms is part of an aromatic ring;

[0021] R 2 Selected from H-, halogen and C 1-3 -alkyl-group R 2a ,

[0022] The above C 1-3 -alkyl- may be optionally substituted by 1 to 7 substituents independently selected from the group consisting of halogen, NC- and HO-;

[0023] R 3 Select from H- and C 1-3 -alkyl-group R 3a ,

[0024] The above C 1-3 -Alkyl- may be optionally substituted by 1 to 7 substituents independently selected from the group consisting of halogen, NC- and HO-.

[0025] Unless otherwise stated, radicals, residues and substituents, especially R 1 , R 2 and R 3 As defined above and below. If a residue, substituent or group occurs several times in a compound, it may have the same or different meanings. Some preferred meanings of the groups and substituents of the compounds of the invention are given below.

[0026] In another embodiment of the present invention,

[0027] R 1 Selected from the group consisting of aromatic monocyclic rings R 1b , the aromatic monocyclic ring consists of 5 or 6 ring atoms, which contains 1 to 3 heteroatoms selected from N and O,

[0028] The above aromatic monocyclic ring is optionally substituted by 1 to 3 substituents independently selected from the following: 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, H(O)C-, HOOC-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )2N-C(O)-, NC-, HO-, oxo, C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2-, halogen and imidazolyl, and

[0029] The above C 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )2N-C(O)-、C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2- and imidazolyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, halogen, NC- and HO-.

[0030] In another embodiment of the present invention,

[0031] R 1Selected from the group consisting of aromatic monocyclic ring systems R 1c , the aromatic monocyclic ring system consists of 5 to 6 ring atoms, which contains 1 to 3 heteroatoms selected from N, O,

[0032] wherein the aromatic monocyclic ring system is optionally substituted with 1 to 3 substituents independently selected from the following: 1-5 -alkyl-, C 1-5 -alkyl-O-, C 3-6 -cycloalkyl-, (R 3 )2N-C(O)-, NC- and halogen, and

[0033] The above C 1-5 -alkyl-, C 1-5 -alkyl-O-, C 3-6 -cycloalkyl- and (R 3 The )2N-C(O)- group is optionally substituted with 1 to 5 substituents independently selected from halogen and NC-.

[0034] In another embodiment of the present invention,

[0035] R 1 Select from the group consisting of 1d :

[0036] wherein the above aromatic monocyclic ring system is optionally substituted by 1 to 3 substituents independently selected from the following: 1-5 -alkyl-, C 1-5 -alkyl-O-, C 3-6 -cycloalkyl-, (R 3 )2N-C(O)-, NC- and halogen, and

[0037] The above C 1-5 -alkyl-, C 1-5 -alkyl-O-, C 3-6 -cycloalkyl- and (R 3 The )2N-C(O)- group is optionally substituted with 1 to 5 substituents independently selected from halogen and NC-.

[0038] In another embodiment of the present invention,

[0039] R 2 Choose from C 1-3 -alkyl-group R 2b ,

[0040] The above C 1-3 -Alkyl- may be optionally substituted by 1 to 7 substituents independently selected from the group consisting of halogen, NC- and HO-.

[0041] In another embodiment of the present invention,

[0042] R 2 Selected from the group consisting of H3C-, FH2C-, F2HC- and F3C- 2c .

[0043] In another embodiment of the present invention,

[0044] R 2 Selected from the group consisting of H3C- 2d .

[0045] In another embodiment of the present invention,

[0046] R 3 Selected from the group consisting of H- and H3C- 3b .

[0047] Each R 1x , R 2x and R 3x = ... 1x , R 2x and R 3x ), wherein for each index x an independent number is given, ranging from "a" to the highest letter given above. With reference to the above definition, all individual embodiments described by the terms in brackets in the case of a complete arrangement of the index x are included in the present invention.

[0048] Table 1 below shows such embodiments E-1 to E-31 of the present invention which are considered to be preferred. Embodiment E-31 represented by the entry in the last row of Table 1 is the most preferred embodiment.

[0049] Table 1: Embodiments E-1 to E-31 of the present invention

[0050]

[0051]

[0052] Thus, for example, E-5 encompasses compounds of formula (I) or salts thereof,

[0053] in

[0054] R 1 is selected from the group consisting of heteroaryl 1a ,

[0055] wherein the heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from the following:1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, H(O)C-, HOOC-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )2N-C(O)-, NC-, HO-, oxo, C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2-, halogen and imidazolyl, and

[0056] The above C 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )2N-C(O)-、C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2- and imidazolyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, halogen, NC- and HO-, and

[0057] The heteroaryl group is a monocyclic or bicyclic ring system consisting of 5 to 10 ring atoms, containing 1 to 3 atoms selected from N, O or S(O) r wherein r = 0, 1 or 2, wherein at least one of the heteroatoms is part of an aromatic ring;

[0058] R 2 Selected from the group consisting of H3C-, FH2C-, F2HC- and F3C- 2c ;

[0059] R 3 Selected from the group consisting of H- and H3C- 3b .

[0060] Thus, for example, E-15 encompasses compounds of formula (I) or salts thereof,

[0061] Where R 1 Selected from the group consisting of aromatic monocyclic rings R 1b, the aromatic monocyclic ring consists of 5 or 6 ring atoms, which contains 1 to 3 heteroatoms selected from N and O,

[0062] The above aromatic monocyclic ring is optionally substituted by 1 to 3 substituents independently selected from the following: 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, H(O)C-, HOOC-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )2N-C(O)-, NC-, HO-, oxo, C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2-, halogen and imidazolyl, and

[0063] The above C 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )2N-C(O)-、C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2- and imidazolyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, halogen, NC- and HO-;

[0064] R 2 Selected from the group consisting of H3C- 2d ;

[0065] R 3 Selected from the group consisting of H- and H3C- 3b .

[0066] Further preferred are the following compounds or salts thereof listed in Table 2:

[0067]

[0068]

[0069]

[0070]

[0071]

[0072] Certain terms used above and below to describe the compounds of the present invention will now be more closely defined.

[0073] The meaning of terms not specifically defined herein should be that which one skilled in the art would give them based on the disclosure and context. However, as used in this specification, unless specifically stated otherwise, the following terms have the indicated meanings and comply with the following conventions.

[0074] In the groups, radicals or moieties defined below, the number of carbon atoms is usually specified before the group, e.g. 1-6 -alkyl refers to an alkyl group having 1 to 6 carbon atoms. In general, in groups such as HO-, H2N-, (O)S-, (O)2S-, NC- (cyano), HOOC-, F3C-, etc., the skilled person can understand the free radical attachment point to the molecule from the free valence of the group itself. For a combined group containing two or more subgroups, the last named subgroup is the free radical attachment point, for example, the substituent "aryl-C 1-3 -alkyl-" refers to a compound attached to a C 1-3 -alkyl aryl, the C 1-3 -Alkyl- is attached to the core or group to which the substituent is attached.

[0075] In general, unless otherwise indicated, the site of attachment of a given residue to another group will be variable, ie, any atom within the residue carrying a hydrogen to be replaced can be the point of attachment to the group being attached.

[0076] Where compounds of the present invention are described in terms of a chemical name and a chemical formula, in the event of any discrepancy, the chemical formula shall prevail.

[0077] Unless otherwise specified, throughout the specification and the appended claims, a given chemical formula or chemical name shall encompass tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or mixtures in any of the foregoing forms (in which isomers and enantiomers exist), and salts thereof (including pharmaceutically acceptable salts thereof) and solvates thereof (such as hydrates, including solvates of free compounds or solvates of salts of said compounds).

[0078] The phrases "pharmaceutically acceptable" or "physiologically acceptable" are used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0079] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0080] Other pharmaceutically acceptable salts can be formed with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)aminomethane.

[0081] Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing alkaline or acidic moieties by conventional chemical methods. Usually, such salts can be prepared by reacting these compounds in free acid or alkaline form with a sufficient amount of appropriate alkali or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile or a mixture thereof. Salts of other acids other than the above-mentioned salts (which can be used, for example, for purifying or separating compounds of the present invention) (e.g., trifluoroacetate) also form a part of the present invention.

[0082] As used herein, the term "substituted" means that any one or more hydrogens on the designated atom are replaced with a selection from a designated group, provided that the effective valency of the designated atom is not exceeded and that the substitution results in a stable compound.

[0083] As used herein, the term "partially unsaturated" means that in the specified group or moiety, there are 1, 2 or more double bonds, preferably 1 or 2 double bonds. Preferably, as used herein, the term "partially unsaturated" does not encompass fully unsaturated groups or moieties.

[0084] The term "halogen" generally refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0085] The term "C 1-n-alkyl" (wherein n is an integer from 2 to n) refers to an acyclic, saturated, branched or straight-chain hydrocarbon group having 1 to n C atoms. For example, the term C 1-5 -Alkyl groups include free radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0086] The term "C 3-n -cycloalkyl" (wherein n is an integer from 4 to n) refers to a cyclic, saturated, unbranched hydrocarbon group having 3 to n C atoms. For example, the term C 3-7 -Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0087] As used herein, the term "aryl", alone or in combination with another radical, refers to a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which may be further fused to another 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

[0088] The term "heteroaryl" refers to a monocyclic or bicyclic ring system consisting of 5 to 10 ring atoms containing 1 to 3 atoms selected from N, O or S(O) r (where r = 0, 1 or 2), wherein at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is meant to include all possible isomeric forms.

[0089] Thus, the term "heteroaryl" includes the following exemplary structures, which are not depicted as free radicals because each form may be covalently attached to any atom as long as the proper valence is maintained:

[0090]

[0091] Many of the terms given above may be used repeatedly in the definitions of the formulae or radicals and have in each case, independently of one another, one of the meanings given above.

[0092] The compounds of the invention can in principle be obtained using known synthesis methods. Preferably, the compounds are obtained by the following process according to the invention, which is described in more detail below.

[0093] The intermediate {1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol has been synthesized according to the following two routes:

[0094] Route 1

[0095] After the formation of p-toluenesulfonylhydrazone under standard conditions, aniline was added and nucleophilic attack on p-toluenesulfonylhydrazone was carried out, followed by intramolecular cyclization and aromatization to form the desired triazole. Deprotonation of the triazole using a strong base and trapping of the corresponding anion by paraformaldehyde gave the alcohol I.

[0096]

[0097] Route 2

[0098] After the formation of p-toluenesulfonylhydrazone under standard conditions, aniline is added and nucleophilic attack on p-toluenesulfonylhydrazone is carried out, followed by intramolecular cyclization and aromatization to form the ester-triazole. The ester-triazole is then reduced to give the corresponding alcohol I.

[0099]

[0100] The final molecule has been synthesized via either Scheme 3 or Scheme 4 starting from {1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol.

[0101] Route 3

[0102] Treatment of {1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol with 3,6-dichloropyridazine formed the corresponding chloride, which was further functionalized by Suzuki coupling, Buchwald coupling or aromatic nucleophilic substitution to provide the desired product.

[0103]

[0104] Route 4

[0105] The synthesis begins with the formation of a chlorinated intermediate via Suzuki coupling, Buchwald coupling or aromatic nucleophilic substitution using 3,6-dichloropyridazine.

[0106] Subsequent coupling with {1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol under standard conditions afforded the desired product.

[0107]

[0108] The following examples are intended to illustrate the present invention, not to limit it.The terms "ambient temperature" and "room temperature" are used interchangeably and refer to temperatures above about 20°C.

[0109] abbreviation:

[0110]

[0111]

[0112] Analytical HPLC method

[0113] Method A

[0114]

[0115] Analytical column: Sunfire (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0116] Method B

[0117]

[0118] Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0119] Method C

[0120]

[0121] Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0122] Method D

[0123]

[0124] Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0125] Method E

[0126]

[0127] Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0128] Method F

[0129]

[0130] Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0131] Method G

[0132]

[0133] Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0134] Method H

[0135]

[0136] Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C Method I

[0137]

[0138] Analytical column: Sunfire C18 2.5μm 2.1x 30mm; column temperature: 60℃

[0139] Method J

[0140]

[0141] Analytical column: Sunfire C18 2.5μm; 3.0x 30mm; column temperature: 60℃

[0142] Method K

[0143]

[0144] Analytical column: XBridge C18_3.0x 30mm, 2.5μm; column temperature: 60℃

[0145] Method L

[0146]

[0147] Analytical column: Xbridge BEH C18, 2.1x 30mm, 1.7μm; column temperature: 60℃

[0148] Preparation of starting compounds

[0149] Example I - Route 1 in the general scheme

[0150] {1-[4-(Difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol

[0151]

[0152] Example I.1

[0153] N'-[1,1-dichloropropane-2-ylidene]-4-methylbenzene-1-sulfonylhydrazide

[0154]

[0155] E / Z configuration unknown

[0156] To a suspension of p-toluenesulfonyl hydrazide (150.0 g, 781.3 mmol) in iPrOH (3.00 L) and acetic acid (22.4 mL, 391 mmol) was added dropwise 1,1-dichloroacetone (79.6 mL, 820 mmol) at room temperature over 25 min. The dropping funnel was rinsed with cyclohexane (20 mL) and the suspension was diluted with iPrOH (500 mL). After stirring for 18 h, the suspension was filtered and washed with cyclohexane (250 mL). The isolated solid was dried at 40 ° C to give 187 g of product. The compound was not characterized by MS and was used in subsequent steps without further purification.

[0157] Example I.2

[0158] 4-(Difluoromethyl)aniline hydrochloride

[0159]

[0160] Palladium on carbon (10%, 0.5 g) was added to ethyl acetate (250 mL) containing 1-difluoromethyl-4-nitrobenzene (50.0 g, 288.8 mmol). The reaction mixture was stirred at 0°C under a hydrogen atmosphere (1 bar) for 22 h. The mixture was filtered and washed with ethyl acetate (50 mL). HCl in dioxane (80 mL, 4 mol / L, 320 mmol) was added dropwise to the filtrate over 20 min. The resulting suspension was stirred at 0°C for 30 min, then filtered and washed with ethyl acetate (50 mL). The isolated solid was dried at 30°C to give 44.0 g of product.

[0161] ESI-MS: 144.070 [M+H] + very small signal.

[0162] 1 H NMR (400 MHz, DMSO-d6) δ = 7.79-7.64 (m, 2H), 7.62-7.51 (m, 2H), 7.26-6.89 (t, J = 55.6 Hz, 1H) – NH2 is not visible in the spectrum.

[0163] Example I.3

[0164] 1-[4-(Difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazole

[0165]

[0166] To a suspension of 4-(difluoromethyl)aniline hydrochloride (Example 1.2, 5.0 g, 27.8 mmol) and N'-[1,1-dichloropropane-2-ylidene]-4-methylbenzene-1-sulfonylhydrazide (8.2 g, 27.8 mmol) in acetonitrile (23.75 mL) and water (1.25 mL) was added pyridine (7.0 mL, 86.7 mmol) dropwise at 5°C over 12 min. The mixture was stirred at 0°C for 2 h, then warmed to 20°C over 1 h. After 4 h, water (30 mL) was added, and the mixture was cooled to 5°C.

[0167] After stirring for 35 min, the suspension was filtered and washed with a cold mixture of acetonitrile (5 mL) and water (10 mL). The isolated solid was dried at 40°C to give 4.1 g of product.

[0168] ESI-MS: 210.110[M+H] +

[0169] 1 H NMR (400MHz, DMSO-d6) δ = 8.61 (s, 1H), 8.11-7.94 (m, 2H), 7.79 (d, J = 8.6Hz, 2H), 7.38-6.82 (m, 1H), 2.34 (s, 3H)

[0170] Embodiment 1

[0171] {1-[4-(Difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol

[0172]

[0173] To a suspension of 1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazole (Example I.3, 15.8 g, 75.5 mmol) in anhydrous THF (300 mL) was added dropwise n-BuLi in hexane (51.4 mL, 128.4 mmol, 2.5 M) at -70°C over 30 min in a flask with a stirring bar. After 40 min, paraformaldehyde (13.6 g, 151.1 mmol) was added and the cooling bath was removed. After 19 h at room temperature, the reaction mixture was added to a mixture of water (100 mL) and ethyl acetate (200 mL). The organic layer was concentrated in vacuo. The crude product was purified by flash silica gel column chromatography to give 12.8 g of product.

[0174] ESI-MS:240.050[M+H]+

[0175] 1 H NMR (400MHz, DMSO-d6) δ = 8.00-7.68 (m, 5H), 7.35-6.92 (t, J = 55.5Hz, 1H),, 5.53(t,J=5.4Hz,1H),4.52(d,J=5.3Hz,1H),4.59-4.41(m,1H),2.35(s,4H)

[0176] Example 1 - Route 2 in the general scheme

[0177] Example I.4

[0178] Ethyl 2,2-dichloro-3-[(4-methylbenzenesulfonylamino)imino]butyrate

[0179]

[0180] E / Z configuration unknown

[0181] To a suspension of p-toluenesulfonyl hydrazide (25.0 g, 134.2 mmol) in iPrOH (100 mL) was added dropwise ethyl 2,2-dichloro-3-oxobutanoate (21.3 mL, 141.0 mmol). After the product was seeded and stirred at 20 ° C for 2.5 h, the suspension was cooled to 0 ° C (1 h) and then filtered. The separated solid was dried to obtain 39.5 g of product. The compound was used in the next step without further purification.

[0182] Example I.5

[0183] 1-[4-(Difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazole-5-carboxylic acid ethyl ester

[0184]

[0185] Under ice cooling, triethylamine (32.0 mL, 230.0 mmol) was added to a suspension of 4-(difluoromethyl)aniline hydrochloride (Example 1.2, 10.0 g, 55.5 mmol) and ethyl 2,2-dichloro-3-[(4-methylbenzenesulfonylamino)imino]butyrate (Example 1.4, 21.0 g, 57.0 mmol) in iPrOH (400 mL). The mixture was stirred at room temperature for 22 h. The orange suspension was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL). The solution was washed three times with 1M HCl aqueous solution (100 mL each time). The organic layer was dried over Na2SO4 and concentrated after filtration. The residue was mixed with silica gel (20 g) and methylcyclohexane (480 mL). After refluxing for 1 h, the hot suspension was filtered and the filtrate was concentrated to a yellow suspension. The suspension was cooled to 0 ° C. The suspension was filtered and the isolated solid was dried at 40°C to give 12.2 g of product.

[0186] ESI-MS:282.090[M+H]+

[0187] 1 H NMR (400MHz, DMSO-d6) δ=7.86-7.60(m,4H),7.33-6.98(t,J=56.0Hz,1H),4.20(q,J=7.1Hz,2H),2.54(s,3H),1.13(t,J=7.2Hz,3H)

[0188] Embodiment 1

[0189] {1-[4-(Difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol

[0190]

[0191] In 1h, to a cooled (ice bath) solution of 1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazole-5-carboxylic acid ethyl ester (15.5g, 55.1mmol) in anhydrous THF (300mL) was added dropwise CH2Cl2 (121mL, 121.0mmol) containing 1M DIBAL. The reaction mixture was stirred at room temperature for 21.5h. Water (1mL) was added and the suspension was concentrated in vacuo. The residue was treated with ethyl acetate (300mL) and the resulting mixture was washed three times with 1M HCl aqueous solution (100mL each time). The organic layer was dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo to dryness to give 12g of product.

[0192] ESI-MS: 240.050[M+H]+

[0193] 1 H NMR (400MHz, DMSO-d6) δ = 8.00-7.68 (m, 5H), 7.35-6.92 (t, J = 55.5Hz, 1H),, 5.53(t,J=5.4Hz,1H),4.52(d,J=5.3Hz,1H),4.59-4.41(m,1H),2.35(s,4H)

[0194] Example II

[0195] 3-Chloro-6-[4-(difluoromethyl)-1H-imidazol-1-yl]pyridazine

[0196]

[0197] Under ice-bath cooling, diethylaminosulfur trifluoride (4.2 ml, 0.03 mol) was added dropwise to 200 ml of DCM containing 1-(6-chloropyridazine-3-yl)-1H-imidazole-4-carboxaldehyde (Example VII.1, 2.1 g, 0.01 mol). The mixture was stirred at room temperature (RT) for 4 days, quenched with ice water under ice-water bath cooling, and neutralized with aqueous NaHCO3 solution (aq.). The aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4 and the solvent was removed. The residue was purified by silica gel column to give 1.2 g of product.

[0198] C6H4BrF2N (M=231.00g / mol)

[0199] ESI-MS: 232[M+H] +

[0200] R t (HPLC): 0.69min (Method K)

[0201] Example III.1

[0202] 3-Chloro-6-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazine

[0203]

[0204] Under ice cooling, sodium hydride (273 mg, 6.27 mmol) was added to 2 mL THF containing Example I (1.00 g, 4.18 mmol). The reaction mixture was stirred at 0 ° C for 30 min, then a solution of 3,6-dichloropyridazine (934 mg, 6.27 mmol) in 2 mL THF was added and stirred at room temperature overnight (o / n). The mixture was quenched with water and the product was extracted with EE. The organic phase was washed with water and brine, dried and concentrated. The crude product was purified by preparative HPLC to obtain 1.25 g of product.

[0205] C 15 H 12 ClF2N5O (M=351.74g / mol)

[0206] ESI-MS: 352[M+H] +

[0207] R t (HPLC): 0.54min (Method L)

[0208] The following compounds were prepared according to the general procedure above (Example III.1):

[0209]

[0210] Example IV

[0211] 1-(6-Chloropyridazin-3-yl)-1H-imidazole-4-carboxylic acid methyl ester

[0212]

[0213] At 0°C, 1H-imidazole-4-carboxylic acid methyl ester (5.0 g, 39.6 mmol) was added to 50 mL DMF containing sodium hydride (1.74 g, 43.6 mmol). The reaction mixture was stirred for 30 min. At 0°C, a solution of 3,6-dichloropyridazine (5.9 g, 39.6 mmol) in 30 mL DMF was added to the reaction mixture, and the mixture was stirred for 20 h to reach room temperature. The reaction mixture was quenched with water under ice cooling, and the precipitate was filtered, washed and dried to obtain 3.9 g of product.

[0214] C9H7ClN4O2 (M=238.63g / mol)

[0215] ESI-MS: 239[M+H] +

[0216] 1H NMR (400MHz, DMSO-d6) δ = 8.74 (d, J = 1.3Hz, 1H), 8.72 (d, J = 1.0Hz, 1H), 8.43 (d, J = 9.3Hz, 1H), 8.25 (d, J = 9.3Hz, 1H), 3.82 (s, 3H)

[0217] Example V

[0218] 1-(6-Chloropyridazin-3-yl)-1H-imidazole-4-carboxylic acid

[0219]

[0220] To 100 mL of 1,4-dioxane containing Example IV (3.79 g, 15.8 mmol) was added 1 M NaOH (16 mL, 16.0 mmol) and stirred at room temperature for 18 h. The reaction mixture was quenched with ice and 1 M HCl (16 mL, 16.0 mmol). The precipitate was filtered, washed and dried to give 3.3 g of product.

[0221] C8H5ClN4O2 (M=224.60g / mol)

[0222] ESI-MS: 225[M+H] +

[0223] R t (HPLC): 0.58min (Method A)

[0224] Example VI.1

[0225] 1-(6-Chloropyridazin-3-yl)-N-methyl-1H-imidazole-4-carboxamide

[0226]

[0227] To 5 mL of DMF containing Example V (1.0 g, 4.45 mmol) was added DIPEA (2.30 mL, 13.4 mmol) and TBTU (1.43 g, 4.45 mmol) and stirred at room temperature for 10 min. Methylamine (2.23 mL, 4.45 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with ice and the precipitate was filtered, washed and dried to give 0.8 g of product.

[0228] C9H8ClN5O (M=237.65g / mol)

[0229] ESI-MS: 238[M+H] +

[0230] Rt (HPLC): 0.65min (Method A)

[0231] The following compounds were prepared according to the general procedure described above (Example VI.1):

[0232]

[0233] Example VII.1

[0234] 1-(6-Chloropyridazin-3-yl)-1H-imidazole-4-carbaldehyde

[0235]

[0236] 3,6-Dichloropyridazine (7.55 g, 50.68 mmol) and sodium carbonate (14.0 g, 101.4 mmol) were added to 1H-imidazole-4-carboxaldehyde (4.87 g, 50.7 mmol) in 25 mL of DMF, and the reaction mixture was stirred for 18 h at 80° C. The mixture was quenched with water, and the precipitate was filtered, washed and dried to give 5.1 g of the product.

[0237] C8H5ClN4O (M=208.60g / mol)

[0238] ESI-MS: 209[M+H] +

[0239] R t (HPLC): 0.61min (Method A)

[0240] The following compounds were prepared according to the general procedure described above (Example VII.1):

[0241]

[0242]

[0243] Example VIII.1

[0244] 1-(6-Chloropyridazin-3-yl)-1H-imidazole-4-carbonitrile

[0245]

[0246] 3,6-dichloropyridazine (5.60 g, 37.6 mmol) and sodium carbonate (7.79 g, 56.4 mmol) were added to 40 mL DMSO containing 1H-imidazole-4-carbonitrile (5.00 g, 37.6 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was quenched with water and the precipitate was filtered. The residue was diluted in EE and extracted with water. The organic phase was dried over MgSO4, filtered and the solvent was removed. Purification was performed by silica gel column to obtain 2.1 g of product.

[0247] C8H4ClN5 (M=205.60g / mol)

[0248] ESI-MS: 206[M+H] +

[0249] R t (HPLC): 0.66min (Method L)

[0250] The following compounds were prepared according to the general procedure described above (Example VIII.1):

[0251]

[0252] Example IX.1

[0253] 3,6-Bis(1H-1,2,4-triazol-1-yl)pyridazine

[0254]

[0255] 1H-1,2,4-triazole (460 mg, 6.71 mmol) and cesium carbonate (2.41 g, 7.38 mmol) were added to 3,6-dichloropyridazine (500 mg, 3.36 mmol) in 5 mL of DMF, and the reaction mixture was stirred for 18 h at 60° C. The mixture was quenched with water, and the precipitate was filtered, washed and dried to give 0.7 g of the product.

[0256] C8H6N8 (M=214.19g / mol)

[0257] ESI-MS: 215[M+H] +

[0258] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 8.47 (s, 1H), 8.44 (s, 1H)

[0259] The following compounds were prepared according to the general procedure described above (Example IX.1):

[0260]

[0261]

[0262] Example X.1

[0263] 1-[6-(4-cyano-1H-imidazol-1-yl)pyridazin-3-yl]-1H-imidazole-4-carbonitrile

[0264]

[0265] To 1H-imidazole-4-carbonitrile (9.29 g, 99.9 mmol) in 100 mL of DMF were added Example VIII.1 (20.5 g, 99.9 mmol) and sodium carbonate (41.4 g, 299 mmol), and the reaction mixture was stirred at 50° C. for 18 h. 1H-imidazole-4-carbonitrile (5.00 g, 53.7 mmol) was added, and the mixture was stirred at 50° C. for 3 days. The mixture was quenched with water, and the precipitate was filtered to give 25.8 g of the product after drying.

[0266] C 12 H6N8 (M=262.23g / mol)

[0267] ESI-MS: 263[M+H] +

[0268] R t (HPLC): 0.74min (Method A)

[0269] The following compounds were prepared according to the general procedure described above (Example X.1):

[0270]

[0271] Example XII

[0272] 3-Chloro-6-[4-methylsulfonyl-1H-imidazol-1-yl]pyridazine

[0273]

[0274] To 2 mL of acetic acid containing Example VIII.2 (100 mg, 0.44 mmol) was added H2O2 (35%) aqueous solution (379 μL, 4.41 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with DCM. The organic phase was washed with brine, dried and concentrated to give 87 mg of product.

[0275] C8H7ClN4O2S (M=258.69g / mol)

[0276] ESI-MS: 259[M+H]+

[0277] R t (HPLC): 0.39min (Method J)

[0278] Example XIII

[0279] 3-Chloro-6-(pyrimidin-5-yl)pyridazine

[0280]

[0281] Under argon, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (3.29 g, 16.0 mmol), Pd(PPh3)4 (346 mg, 0.30 mmol) and 2M Na2CO3 aqueous solution (7.5 mL, 15.0 mmol) were added to 25 mL 1,4-dioxane containing 3,6-dichloropyridazine (2.23 g, 15.0 mmol), and the mixture was stirred at 80°C for 2 h. The reaction mixture was quenched with water and extracted with EE. The organic phase was washed with brine, dried and concentrated. Purification was performed by silica gel column to obtain 442 mg of product.

[0282] C8H5ClN4 (M=192.60g / mol)

[0283] ESI-MS: 193[M+H] +

[0284] 1 H NMR (400 MHz, DMSO-d6) shift = 9.51 (s, 2H), 9.36 (s, 1H), 8.52 (d, J = 9.0 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H)

[0285] Example XIV

[0286] 3-Chloro-6-(4-methanesulfinyl-1H-imidazol-1-yl)pyridazine

[0287]

[0288] To Example VIII.2 (150 mg, 0.66 mmol) in 1 mL of DCM was added 3-chlorobenzene-1-peroxycarboxylic acid (163 mg, 0.66 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and used without further purification.

[0289] C8H7ClN4OS (M=242.69g / mol)

[0290] R t(HPLC): 0.34min (Method J)

[0291] Example XV

[0292] 2H,4H,5H,6H,7H-Pyrazolo[4,3-c]pyridin-4-one

[0293]

[0294] To (3Z)-3-[(dimethylamino)methylene]piperidine-2,4-dione (1.49 g, 8.84 mmol) in 5 mL of ethanol was added hydrazine hydrate (0.64 mL, 13.3 mmol), and the mixture was stirred under reflux overnight. The reaction mixture was concentrated and purified by silica gel column to give 250 mg of product.

[0295] C6H7N3O (M=137.14g / mol)

[0296] ESI-MS: 138[M+H] +

[0297] 1 H NMR (400MHz, DMSO-d6) δ = 8.25 (br s, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 3.41 (t, J = 6.8Hz, 2H), 2.83 (t, J = 6.8Hz, 2H)

[0298] Example XVI

[0299] 2-(6-Chloropyridazin-3-yl)-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-4-one

[0300]

[0301] To 3,6-dichloropyridazine (50 mg, 0.33 mmol) in 1 mL of THF were added Example XV (103 mg, 0.75 mmol), sodium tert-butoxide (80 mg, 0.84 mmol) and Pd-PEPPSI (28 mg, 0.03 mmol), and the reaction mixture was stirred overnight at 120° C. The reaction mixture was quenched with water and purified by preparative HPLC to give 125 mg of the product.

[0302] C 10 H8ClN5O (M=249.66g / mol)

[0303] ESI-MS: 250[M+H] +

[0304] Rt (HPLC): 0.32min (Method L)

[0305] Example XVII

[0306] 6-(Pyrazin-2-yl)pyridazin-3-ol

[0307]

[0308] To a mixture of acetylpyrazine (2.0 g, 15.9 mmol) and glyoxylic acid monohydrate (1.54 g, 16.7 mmol) in water (30 mL) was added triethylamine (2.64 mL, 19.1 mmol) at 35 ° C within 2 minutes. After 40 min at 40 ° C, the reaction mixture was cooled to -6 ° C and hydrazine hydrate (1.8 mL, 23.8 mmol) was added at 5 ° C within 2 min. After 1 min, acetic acid (2.7 mL, 47.6 mmol) was added and the reaction mixture was heated to 95 ° C within 40 min. After 2 h, the mixture was slowly cooled to 2 ° C. The suspension was filtered and washed twice with water. The isolated solid was dried at 50 ° C to obtain 2.2 g of product.

[0309] MS:175.110[M+H]+

[0310] 1 H NMR (400MHz, DMSO-d6) δ = 13.46 (br s, 1H), 9.25 (d, J = 1.4Hz, 1H), 8.74-8.63 (m, 2H), 8.21 (d, J = 9.9Hz, 1H), 7.07 (d, J = 9.9Hz, 1H)

[0311] Example XVIII

[0312] 3-Chloro-6-(pyrazin-2-yl)pyridazine

[0313]

[0314] POCl3 (2.3 mL, 25.3 mmol) was added to a heated mixture (70°C) of 6-(pyrazine-2-yl)pyridazine-3-ol (Example XVII, 4.0 g, 23.0 mmol) in dioxane (36.0 mL) and acetonitrile (4.0 mL). The mixture was stirred at 75°C for 2.5 h. While stirring, the hot reaction mixture was added to cooled water (80 mL). The reaction flask was rinsed with a mixture of dioxane (5.0 mL) and acetonitrile (5.0 mL), and the suspension was stirred at 20°C for 2.5 h. The suspension was filtered and washed with water. The isolated solid was dried at 50°C to give 4.0 g of product.

[0315] MS:193.080 / 195.040[M+H]+

[0316] 1 H NMR (400MHz, DMSO-d6) δ = 9.67 (s, 1H), 8.86 (s, 2H), 8.54 (d, J = 9.0Hz, 1H), 8.13 (d, J = 9.0Hz, 1H)

[0317] Preparation of final compounds

[0318] Example 1

[0319] 1-[6-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazin-3-yl]-1H-imidazole-4-carbonitrile

[0320]

[0321] To 400 mL of ACN containing Example I (20.03 g, 83.74 mmol) was added cesium carbonate (30.01 g, 92.12 mmol) and Example X.1 (21.96 g, 83.74 mmol) and the mixture was stirred at 50 °C for 6 h. The mixture was quenched with EE and extracted twice with water. Extracted with 20% KHSO4 aqueous solution. The organic phase was washed with brine, dried and concentrated. The precipitate was filtered, washed with EE and dried to give 26.7 g of product.

[0322] C 19 H 14 F2N8O (M=408.36g / mol)

[0323] ESI-MS: 409[M+H] +

[0324] R t (HPLC): 0.90min (Method A)

[0325] 1 H NMR (400MHz, DMSO-d6) δ = 8.91 (d, J = 1.3Hz, 1H), 8.72 (d, J = 1.3Hz, 1H), 8.19 (d, J = 9.5Hz, 1H) ,7.80(s,4H),7.57(d,J=9.4Hz,1H),7.30-6.97(t,J=55,6Hz,1H),5.67(s,2H),2.44(s,3H)

[0326] Example 2

[0327] 4-[6-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazin-3-yl]pyridin-2-ol

[0328]

[0329] Under argon, to (2-hydroxypyridin-4-yl)boronic acid (35 mg, 0.150 mmol) was added a solution of Example III.1 (37 mg, 0.100 mmol) in 0.5 mL of methanol, 1 mL of 1,4-dioxane, 2M aqueous sodium carbonate solution (0.10 ml, 0.200 mmol) and Pd-PEPPSI (1.68 mg, 0.002 mmol), and the reaction mixture was stirred for 2 h at 120° C. The mixture was purified by preparative HPLC to give 4 mg of product.

[0330] ESI-MS: 411[M+H] +

[0331] R t (HPLC): 0.60min (Method B)

[0332] The following compounds were prepared according to the general procedure described above (Example 2):

[0333]

[0334]

[0335]

[0336] Example 12

[0337] 3-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridazine

[0338]

[0339] Under argon, to tert-butyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (48 mg, 0.150 mmol) was added a solution of Example III.1 (35 mg, 0.10 mmol) in 0.5 mL of methanol, 1 mL of 1,4-dioxane, 2M aqueous sodium carbonate solution (0.10 ml, 0.20 mmol) and Pd-PEPPSI (0.84 mg, 0.001 mmol), and the reaction mixture was stirred at 120 ° C for 30 min. The reaction mixture was evaporated. The residue was diluted with 2 mL of TFA and stirred at room temperature for 1 h. The mixture was purified by preparative HPLC to give 29.8 mg of product.

[0340] ESI-MS: 412[M+H] +

[0341] R t (HPLC): 0.61min (Method E)

[0342] Embodiment 13

[0343]

[0344] At 0°C, sodium tert-amyl alcohol 30% solution in Me-THF (928 μL, 2.3 mmol) was added dropwise to 7.5 mL NMP containing Example I (500 mg, 2.1 mmol) and Example XVIII (402.6 mg, 2.1 mmol) and stirred at room temperature for 20 min. 7.5 mL of water was added and stirred at room temperature for 30 min. The suspension was filtered and washed twice with 5 mL of water and the residue was dried at 60°C to give 717 mg of product.

[0345] ESI-MS: 397[M+H] +

[0346] R t (HPLC): 0.92min (Method C)

[0347] 1 H NMR (400MHz, DMSO-d6) δ = 9.58 (d, J = 1.3Hz, 1H), 8.78 (m, 2H), 8.40 (d, J = 9.3Hz, 1H), 7.84- 7.78(m,4H),7.39(d,J=9.3Hz,1H),7.32-6.95(t,J=55.6Hz,1H),5.73(s,2H),2.46(s,3H)

[0348] The following compounds were prepared according to the general procedure above (Example 13):

[0349]

[0350]

[0351]

[0352]

[0353] Embodiment 27

[0354] 1-[6-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazin-3-yl]-1H-imidazole-4-carboxamide

[0355]

[0356] Concentrated H2SO4 (2 mL) was added to 1 mL of water containing Example 1 (20 mg, 0.049 mmol) and stirred at room temperature for 18 h. The mixture was quenched with ice water and NaHCO3. The product was extracted with EE. The organic phase was washed with water and brine, dried and concentrated. The crude product was purified by preparative HPLC to give 5 mg of product.

[0357] ESI-MS: 427[M+H] +

[0358] R t (HPLC): 0.82min (Method A)

[0359] Embodiment 28

[0360] 3-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-6-(1H-1,2,4-triazol-1-yl)pyridazine

[0361]

[0362] To Example I (50 mg, 0.21 mmol) in 2 mL ACN was added cesium carbonate (204 mg, 0.63 mmol) and Example IX.1 (45 mg, 0.21 mmol), and the mixture was stirred for 18 h at 80° C. The reaction mixture was concentrated and purified by silica gel column to give 45 mg of product.

[0363] ESI-MS: 385[M+H] +

[0364] R t (HPLC): 0.90min (Method A)

[0365] The following compounds were prepared according to the general procedure above (Example 27):

[0366]

[0367]

[0368] Embodiment 35

[0369] {1-[6-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazin-3-yl]-1H-imidazol-4-yl}methanamine

[0370]

[0371] To 10 mL of methanolic ammonia solution containing Example 1 (200 mg, 0.49 mmol) was added Ra-Ni (50 mg) and stirred at room temperature and 50 psi for 16 h under a hydrogen atmosphere. The reaction mixture was filtered and concentrated by evaporation. The crude product was purified by preparative HPLC to give 120 mg of product.

[0372] ESI-MS: 413[M+H] +

[0373] R t (HPLC): 0.54min (Method D)

[0374] Embodiment 36

[0375] ({1-[6-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazin-3-yl]-1H-imidazol-4-yl}methyl)trimethylammonium trifluoroacetate

[0376]

[0377] To Example 35 (50 mg, 0.12 mmol) in 1 mL THF was added DIPEA (62 μL, 0.36 mmol) and iodomethane (15 μl, 0.24 mmol) and stirred at room temperature for 20 h. The reaction mixture was purified by preparative HPLC to give 35 mg of product.

[0378] ESI-MS: 455[M] +

[0379] R t (HPLC): 0.74min (Method A)

[0380] Embodiment 37

[0381] 1-[6-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazin-3-yl]-1H-imidazole-4-carboxylic acid

[0382]

[0383] To 6 mL of 1,4-dioxane containing Example 29 (120 mg, 0.27 mmol) was added 1 M NaOH (272 μl, 0.54 mmol) and 1 mL of methanol and stirred at room temperature for 4 h. 1 M NaOH (272 μL, 0.54 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was neutralized with 1 M HCl and concentrated. The residue was diluted in DCM / MeOH 9:1, filtered, concentrated and dried to give 118 mg of product.

[0384] ESI-MS: 428[M+H] +

[0385] R t (HPLC): 0.82min (Method A)

[0386] Embodiment 38

[0387] {1-[6-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazin-3-yl]-1H-imidazol-4-yl}methanol

[0388]

[0389] 1,1'-Carbonyldiimidazole (100 mg, 0.62 mmol) was added to 4 mL of THF containing Example 37 (110 mg, 0.26 mmol), and the mixture was stirred at room temperature for 1 h. The solution was added dropwise to a solution of sodium borohydride (100 mg, 2.64 mmol) in 2 mL of water and stirred at room temperature for 1 h. The reaction mixture was acidified to pH 2 with KHSO4 aqueous solution (20%) and extracted with EE. The organic phase was dried, filtered and the solvent removed. Purification was performed by preparative HPLC to obtain 30 mg of product.

[0390] ESI-MS: 414[M+H] +

[0391] R t (HPLC): 0.73min (Method A)

[0392] Example 39 (General Route)

[0393] 2-{1-[6-({1-[4-(difluoromethyl)phenyl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazin-3-yl]-1H-imidazol-4-yl}propan-2-ol

[0394]

[0395] Under ice cooling, methylmagnesium bromide (433 μl, 0.61 mmol) was added to 3 mL THF containing Example 32 (86 mg, 0.20 mmol), and the mixture was stirred at 0 ° C for 1 h. Under ice cooling, methylmagnesium bromide (150 μl, 0.21 mmol) was added, and the mixture was stirred at room temperature for 18 h. Under ice cooling, methylmagnesium bromide (200 μL, 0.28 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with cold NH4Cl solution (20%) and extracted with EE. The organic phase was dried, filtered and the solvent was removed. Purification was carried out by preparative HPLC to obtain 45 mg of product.

[0396] ESI-MS: 442[M+H] +

[0397] R t (HPLC): 0.75min (Method A)

[0398] The following compounds were prepared according to the general procedure above (Example 39):

[0399]

[0400] Biological Examples

[0401] Assay A: Binding of expressed human GABA A α5β3γ2S receptor in HEK cells 3 H-Flumazenil ( 3 H-Ro 15-1788) In vitro inhibition of

[0402] Benzodiazepines The modulator unit can optionally be used as an antagonist 3 H-Flumazenil labeling.

[0403] 3 The affinity of H-flumazenil for different subunit combinations has been reported as follows: α1β2γ2, α2β2γ2, α3β2γ2, and α5β2γ 2s The concentrations for the α4β2γ2 and α6β2γ2 receptors were 1.0 nM, 1.1 nM, 1.5 nM and 0.4 nM, respectively, and for the α4β2γ2 and α6β2γ2 receptors were 107 nM and 90 nM (see Sieghart; Pharmacol. Rev. 1995 47 181-234).

[0404] about 3H-flumazenil binding, mutant α5β3γ 2s GABA A The pharmacology of the receptor is similar to that of the wild-type receptor.

[0405] Cell culture and membrane preparation

[0406] Stably express recombinant human GABA A α5β3γ 2s HEK-293 cells expressing the receptor (plasmid H46 / E9 / B10) were seeded in T175 polystyrene flasks or roller bottles (1700 cm 2 , Fisher Scientific CCI-431191) and in Dulbecco's Modified Eagle Medium (DMEM) supplemented with GlutaMAX supplemented with 10% fetal bovine serum and one or two of the following antibiotics TM Culture (37°C, 5% CO~): Hygromycin B (50 pg / ml; γ2 subunit) or G418 (0.5 mg / ml; o5 subunit).

[0407] When the culture reaches confluence, DMEM is removed and the cells are washed once in Dulbecco's Phosphate Buffered Saline (DPBS) (10 ml for T175 flasks and 50 ml for roller bottles). After DPBS is added to the culture (10 ml for T175 flasks; 100 ml for roller bottles) for about 5 min, cells are easily peeled off from the surface by gently shaking or tapping the flask. The cell suspension is transferred to a Falcon tube and centrifuged at 23,500 x g for 10 min at 2 ° C. The precipitate is washed once in 15 ml Tris citrate buffer (50 mM, pH 7.1) using an Ultra-Turrax homogenizer and centrifuged at 27,000 x g for 10 min at 2 ° C. The washed precipitate is resuspended in 15 ml Tris citrate buffer and frozen at -80 ° C until the day of the binding test.

[0408] Determination

[0409] On the day of the experiment, cell membrane preparations were thawed and centrifuged at 27,000 xg for 10 min at 2° C. The pellets were resuspended in Tris-citrate buffer using an Ultra-Turrax homogenizer to 15-50 pg protein per assay and then used in binding assays.

[0410] A 500 μl aliquot of the cell suspension was added to 25 μl of the test compound solution and 25 μl 3 H-flumazenil (1 nM, final concentration) was added, mixed and incubated for 40 min at 2° C. Nonspecific binding was determined using clonazepam (1 μM, final concentration).

[0411] All dilutions of test compounds and incubations of the assays were performed in glass vials / 96-well plates. 3 Solutions of H-flumazenil were made at 22 times the desired final concentration. Compounds were dissolved in 100% DMSO (10 mM stock solution), diluted in 48% ethanol-water, and tested in triplicate in serial 1:3 or 1:10 dilutions. When screening a large number of compounds, only one concentration of each compound was tested in a single well. Reference compounds were routinely not included, but for each experiment performed, total binding and nonspecific binding were compared to data obtained during assay validation.

[0412] The binding is terminated by performing a quick filter on either:

[0413] 1) Whatman GF / C glass fiber filters, using a Brandel cell harvester, followed by washing 5 times with 1 ml of ice-cold buffer, or 2) UniFilter GF / C glass fiber filter plates, using a Tomtec cell harvester, followed by washing with approximately 5 ml of ice-cold buffer.

[0414] The amount of radioactivity on the filter was determined by conventional liquid scintillation counting using the following apparatus:

[0415] 1) Tri-Garb for single large filter TM Counter (PerkinElmer Life and Analytical Sciences), or

[0416] 2) Topcount for 96-well filter plates TM Counter (PerkinElmer Life and AnalyticalSciences). Specific binding is total binding minus nonspecific binding.

[0417] calculate

[0418] In computing IC 50 (make 3 Before the concentration of test compound (μM) that inhibits the specific binding of H-flumazenil by 50%, a 25-75% inhibition of specific binding must be obtained.

[0419] The IC of the test compound was determined according to the following formula: 50 value:

[0420] B=100—(100*C n / (IC50 n +C n ))

[0421] Where B is the binding as a percentage of total specific binding; C is the concentration of the test compound; and n is the Hill coefficient. For screening purposes, n was set to 1. IC was calculated from the concentration-response curves by nonlinear regression using the curve fitting program GraphPadPrism. 50 value.

[0422] The Ki value of the test compound can be calculated using the following formula of Cheng and Prusoff, from IC 50 Value calculation:

[0423] K=IC 50 / (1+L / K d )

[0424] in 3 H-Flumazenil K d is 0.36nM, L is the inhibition assay 3 Measured concentration of H-flumazenil.

[0425] Assay B: α5β2γ2 GABA A In vitro assessment of receptor modulation

[0426] The modulatory efficacy of the compounds of formula (I) was determined by electrophysiological recordings in oocytes using the two-electrode voltage clamp (TEVC) technique. Oocytes were injected with human GABA at a ratio of 3:1:3. A cRNAs for receptor subunits α5, β2, and γ2 and compared with a submaximal EC control called GABA 5-20 GABA concentration (0.5 μM) is used together to assess the efficacy of regulation. As a standard, each oocyte is tested for five concentrations (3.16 μM, 0.316 μM, 0.0316 μM, 0.00316 μM and 0.000316 μM) of the compound, starting from the lowest concentration. The peak current amplitude minus the background is standardized to the corresponding GABA control current, converted to % change, and + / -SEM is depicted as a function of increasing compound concentration. The data points drawn are fitted to the empirical Hill equation using nonlinear regression. From this fitting program, the maximum efficacy (bottom) and effectiveness (Log EC 50 ) with a 95% confidence interval.

[0427]

[0428] These data indicate that the compounds of the present invention exhibit target engagement and strong negative regulation of GABA receptor function. The data also indicate that, with respect to GABA A In terms of 5R binding, these compounds have improved properties, which can be understood as a lower effective dose of the compound for disease treatment (see Ballard, TM et al., (2009). RO4938581, a novel cognitive enhancer acting at GABA A α5 subunit-containing receptors, Psychopharmacology (2009) 202:207-223; J. Pharmacol. Exp. Ther. (2006) 316:1335-1345).

[0429] In Madin-Darby canine kidney (MDCK) cells transfected with 30 human MDR1 gene Assessment of outflow to assess brain permeability (Drug Metabolism and Disposition, February 2008, 36(2)268-275; DOI: https: / / doi.org / 10.1124 / dmd.107.017434).

[0430] The apparent permeability coefficient (PE) of the compound across the MDCK-MDR1 cell monolayer was measured (pH 7.4, 37°C) in the top to base (AB) and base to top (BA) transport directions. The AB permeability (PEAB) represents the absorption of drugs from the blood to the brain, and the BA permeability (PEBA) represents the efflux of drugs from the brain back to the blood by passive osmosis and active transport mechanisms, which are mediated by efflux and absorption transporters expressed on MDCK-MDR1 cells, mainly by overexpressed human MDR1 P-gp. By comparing the AB permeability with the AB permeability of reference compounds (with known in vitro permeability and oral absorption in humans), the compounds are divided into permeation / absorption categories. The same or similar permeability in the two transport directions represents passive permeation, and the vector permeability points to other active transport mechanisms. PEBA is higher than PEAB, indicating that it is involved in the active efflux mediated by MDR1 P-gp. Active transport is concentration-dependent and saturated.

[0431] MDCK-MDR1 cells (1-2x 10e5 cells / 1cm2 area) were seeded on filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 7 days. Subsequently, MDR1 expression was enhanced by culturing cells for 2 days in complete medium with 5mM sodium butyrate. The compounds were dissolved in an appropriate solvent (e.g., DMSO, 1-20mM stock solution). The stock solution was diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4 x 7H2O, 0.41 mM NaH2PO4xH2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.4) to prepare the transport solution (0.1-300 μM compound, final DMSO <= 0.5%). The transport solution (TL) was applied to the top or basolateral donor side to measure AB or BA permeability, respectively (repeated 3 filters). The receiver side contained the same buffer as the donor side. At the beginning and end of the experiment, samples were collected from the donor, and samples were also collected from the receiver side at different time intervals (up to 2 hours) to measure concentration by HPLC-MS / MS or scintillation counting. The sampled receiver volume was replaced by fresh receiving solution.

[0432]

[0433] These data indicate that the compounds of the present invention have excellent brain penetration properties with low efflux rates from the cerebral ventricles.

[0434] Evaluation of metabolic stability in human liver microsomes (human MST)

[0435] The metabolic stability of the compounds of the present invention can be studied as follows:

[0436] Metabolic degradation of the test compounds was determined at 37°C using pooled human liver microsomes. The final incubation volume of 100 μL at each time point contained TRIS buffer pH 7.6 (0.1 M), MgCl2 (5 mM), microsomal protein (1 mg / mL) and the test compound at a final concentration of 1 μM at room temperature. After a short pre-incubation period at 37°C, the reaction was initiated by adding the reduced form of β-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM) and terminated by transferring aliquots to solvent after different time points. After centrifugation (10000 g, 5 min), aliquots of the supernatant were determined for the amount of parent compound by LCMS / MS. The half-life (t1 / 2) was determined by the slope of the semi-logarithmic plot of the concentration-time curve.

[0437] Example Human MST t1 / 2[min] Example Human MST t1 / 2>[min] 1 >130 22 >130 2 >130 24 31 4 >130 25 >130 5 >130 26 >130 6 >130 27 >130 8 73 28 >130 9 >130 29 26 10 >130 30 >130 11 >130 31 >130 12 25 32 >130 13 >130 33 >130 14 >130 35 >130 15 >130 36 >130 16 >130 37 >130 17 10 38 >130 18 >130 39 >130 19 >130 40 >130 21 37

[0438] Given that they regulate GABA containing α5 subunits A The compounds of the general formula (I) of the present invention or their physiologically acceptable salts are suitable for the treatment and / or prophylactic treatment of GABA receptors containing α5 subunits. A Therefore, the compounds of the present invention, including their physiologically acceptable salts, are particularly suitable for preventing or treating diseases, especially acute neurological disorders, chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory disorders, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, bipolar disorder, autism, Down syndrome, neurofibromatosis type I, postoperative cognitive decline, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis, AIDS-induced dementia, psychotic disorders, substance-induced psychotic disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug addiction, movement disorders, Parkinson's disease, restless legs syndrome, cognitive deficit disorder, multi-infarct dementia Depression, major depressive disorder, neuropsychiatric disease, psychosis, attention deficit hyperactivity disorder, neuropathic pain, stroke, attention disorder, eating disorder, anorexia, anorexia nervosa, cachexia, weight loss, muscle atrophy, pain disorder, chronic pain, nociceptive pain, postoperative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, eye pain, pain caused by inflammation, pain caused by fracture, hyperalgesia, neuropathic pain, herpes-related pain, HIV-related neuropathic pain, traumatic nerve injury, recovery after traumatic brain injury, post-stroke pain, post-ischemic pain, fibromyalgia, chronic headache, migraine, tension headache, diabetic neuropathic pain, phantom limb pain, visceral pain and cutaneous pain.

[0439] The compounds of the present invention, including their physiologically acceptable salts, are even more suitable for the treatment of the following: cognitive disorders, postoperative cognitive decline, Alzheimer's disease, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, cognitive deficits associated with Down syndrome, cognitive deficits associated with autism, cognitive deficits associated with neurofibromatosis type I or cognitive deficits after stroke.

[0440] In another aspect of the present invention, the present invention relates to a method for treating or preventing the above-mentioned diseases and disorders, which comprises administering to a human an effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0441] The dosage range of the compound of the general formula (I) which can be administered daily is usually 0.1 mg to 1000 mg, preferably 1 mg to 500 mg by oral route, in each case administered 1 to 4 times a day.

[0442] Each dosage unit may conveniently contain from 0.1 mg to 500 mg, preferably from 1 mg to 100 mg.

[0443] The actual pharmaceutically effective amount or therapeutic dose will of course depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the combined dosage and mode of administration will be such that a pharmaceutically effective amount is delivered according to the patient's unique condition.

[0444] Suitable formulations for administering a compound of Formula I (including pharmaceutically acceptable salts thereof) will be clear to those of ordinary skill in the art, and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injections, inhalants, powders, etc. The content of the pharmaceutically active compound should be 0.1% to 95% by weight, preferably 5.0% to 90% by weight, of the overall composition.

[0445] Suitable tablets can be obtained, for example, by mixing one or more compounds of formula I with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. Tablets can also consist of several layers.

[0446] For this purpose, the compounds of formula I prepared according to the invention can be formulated, optionally together with other active substances, with one or more inert conventional carriers and / or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, citric acid, tartaric acid, water, polyvinylpyrrolidone, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof.

[0447] The compounds according to the invention can also be employed in combination with other active substances, in particular for the treatment and / or prevention of the abovementioned diseases and disorders. A list of examples is: donepezil, memantine, acetazolamide, carbamazepine, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, brivaracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, zonisamide, levodopa, carbidopa, haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, perphenazine, chlorpromazine, aripiprazole, asenapine maleate, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone and zolpidem.

[0448] The dosage of the above combination partner is usefully from 1 / 5 of the usually recommended minimum dosage to 1 / 1 of the usually recommended dosage.

[0449] Therefore, in another aspect, the present invention relates to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with at least one of the above active substances as a combination partner for the preparation of a pharmaceutical composition suitable for the treatment or prevention of the above diseases or disorders.

[0450] The use of a compound of the invention in combination with another active substance can occur simultaneously or at staggered times, but in particular within a short period of time. If they are administered simultaneously, the two active substances are given to the patient at the same time; and if they are used at staggered times, the two active substances are given to the patient within a period of less than or equal to 12 hours, but in particular less than or equal to 6 hours.

[0451] Therefore, in another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one of the above-mentioned active substances as a combination partner, and optionally one or more inert carriers and / or diluents.

[0452] The compounds of the invention can be present together in one preparation, for example a tablet or a capsule, or separately in two identical or different preparations, for example as a so-called kit-of-parts.

Claims

1. A compound of formula (I) or a salt thereof in R 1 is selected from the group consisting of heteroaryl 1a , wherein the heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from the following: 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, H(O)C-, HOOC-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )3N + -C 1-5 -alkyl-, (R 3 )2N-C(O)-, NC-, HO-, oxo, C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2-, halogen and imidazolyl, and The above C 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )3N + -C 1-5 -alkyl-, (R 3 )2N-C(O)-、C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2- and imidazolyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, halogen, NC- and HO-, and The heteroaryl group is a monocyclic or bicyclic ring system consisting of 5 to 10 ring atoms, containing 1 to 3 atoms selected from N, O or S(O) r wherein r = 0, 1 or 2, wherein at least one of the heteroatoms is part of an aromatic ring; R 2 Selected from H-, halogen and C 1-3 -alkyl-group R 2a , The above C 1-3 -alkyl- may be optionally substituted by 1 to 7 substituents independently selected from the group consisting of halogen, NC- and HO-; R 3 Select from H- and C 1-3 -alkyl-group R 3a , The above C 1-3 -Alkyl- may be optionally substituted by 1 to 7 substituents independently selected from the group consisting of halogen, NC- and HO-.

2. The compound or salt thereof according to claim 1, wherein R 1 Selected from the group consisting of aromatic monocyclic rings R 1b , the aromatic monocyclic ring consists of 5 or 6 ring atoms, which contains 1 to 3 heteroatoms selected from N and O, The above aromatic monocyclic ring is optionally substituted by 1 to 3 substituents independently selected from the following: 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, H(O)C-, HOOC-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )2N-C(O)-, NC-, HO-, oxo, C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2-, halogen and imidazolyl, and The above C 1-5 -alkyl-, C 1-5 -alkyl-O-, C 1-5 -alkyl-C(O)-, C 1-5 -alkyl-OC(O)-, C 3-6 -cycloalkyl-, (R 3 )2N-、(R 3 )2N-C 1-5 -alkyl-, (R 3 )2N-C(O)-、C 1-5 -alkyl-S(O)-, C 1-5 -alkyl-S(O)2- and imidazolyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, halogen, NC- and HO-.

3. The compound or salt thereof according to claim 1, wherein R 1 Selected from the group consisting of aromatic monocyclic ring systems R 1c , the aromatic monocyclic ring system consists of 5 to 6 ring atoms, which contains 1 to 3 heteroatoms selected from N, O, wherein the aromatic monocyclic ring system is optionally substituted with 1 to 3 substituents independently selected from the following: 1-5 -alkyl-, C 1-5 -alkyl-O-, C 3-6 -cycloalkyl-, (R 3 )2N-C(O)-, NC- and halogen, and The above C 1-5 -alkyl-, C 1-5 -alkyl-O-, C 3-6 -cycloalkyl- and (R 3 The )2N-C(O)- group is optionally substituted with 1 to 5 substituents independently selected from halogen and NC-.

4. The compound or salt thereof according to claim 1, wherein R 1 Select from the group consisting of 1d : wherein the above aromatic monocyclic ring system is optionally substituted by 1 to 3 substituents independently selected from the following: 1-5 -alkyl-, C 1-5 -alkyl-O-, C 3-6 -cycloalkyl-, (R 3 )2N-C(O)-, NC- and halogen, and The above C 1-5 -alkyl-, C 1-5 -alkyl-O-, C 3-6 -cycloalkyl- and (R 3 The )2N-C(O)- group is optionally substituted with 1 to 5 substituents independently selected from halogen and NC-.

5. The compound or salt thereof according to any one of claims 1 to 4, wherein R 2 Choose from C 1-3 -alkyl-group R 2b , The above C 1-3 -Alkyl- may be optionally substituted by 1 to 7 substituents independently selected from the group consisting of halogen, NC- and HO-.

6. The compound or salt thereof according to any one of claims 1 to 4, wherein R 3 Selected from the group consisting of H- and H3C- 3b .

7. A compound selected from the group consisting of:

8. A pharmaceutically acceptable salt of any one of the compounds according to claim 7.

9. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of GABA containing α5 subunit A Use as a receptor modulator.

10. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

11. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, in the preparation of a medicament for preventing or treating Down syndrome, neurofibromatosis type I, amyotrophic lateral sclerosis, neuropsychiatric diseases, cachexia, weight loss, muscle atrophy or pain.

12. The method of claim 11, wherein the pain disorder is neuropathic pain, musculoskeletal pain, eye pain, pain caused by inflammation, pain caused by fracture, hyperalgesia, herpes-related pain, post-stroke pain, post-ischemic pain, chronic headache, migraine, tension headache, phantom limb pain, visceral pain or cutaneous pain.

13. The use according to claim 12, wherein the musculoskeletal pain is fibromyalgia.

14. The use according to claim 12, wherein the pain caused by inflammation is osteoarthritis pain or rheumatoid arthritis pain.

15. The use according to claim 12, wherein the neuropathic pain is HIV-related neuropathic pain or diabetic neuropathic pain.

16. The use according to claim 11, wherein the pain disorder is chronic pain.

17. The use according to claim 11, wherein the pain disorder is nociceptive pain.

18. The use according to claim 17, wherein the nociceptive pain is postoperative pain or burn pain.

19. The method of claim 11, wherein the neuropsychiatric disease is an acute neurological disorder, a chronic neurological disorder, a cognitive disorder, Alzheimer's disease, memory impairment, postoperative cognitive decline, a sleep disorder, a circadian rhythm disorder, dementia caused by AIDS, a psychotic disorder, an anxiety disorder, a generalized anxiety disorder, a panic disorder, a delusional disorder, an obsessive-compulsive disorder, an acute stress disorder, a drug addiction, a movement disorder, Parkinson's disease, restless legs syndrome, a cognitive deficit disorder, multi-infarct dementia, a mood disorder, attention deficit hyperactivity disorder, a stroke, an attention disorder, an eating disorder, anorexia, or a traumatic nerve injury.

20. The use according to claim 19, wherein the neuropsychiatric disease is a substance-induced psychotic disorder.

21. The use according to claim 19, wherein the neuropsychiatric disease is a psychosis.

22. The use according to claim 19, wherein the neuropsychiatric disease is schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism or depression.

23. The use according to claim 19, wherein the neuropsychiatric disease is major depressive disorder.

24. The use according to claim 19, wherein the neuropsychiatric disease is cognitive impairment associated with schizophrenia.

25. The use according to claim 19, wherein the neuropsychiatric disorder is recovery after traumatic brain injury.

26. The use according to claim 19, wherein the neuropsychiatric disease is anorexia nervosa.

27. Use of a compound or salt thereof according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing or treating cognitive impairment, postoperative cognitive impairment, Alzheimer's disease, schizophrenia, or positive, negative and / or cognitive symptoms associated with schizophrenia.

28. The use according to claim 27, wherein the cognitive disorder is cognitive impairment associated with schizophrenia, cognitive deficits associated with Down syndrome, cognitive deficits associated with autism, cognitive deficits associated with neurofibromatosis type I, or cognitive deficits after stroke.

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