ES2357970T3 - COMPOUNDS THAT HAVE ACTIVITY IN THE RECEIVER M1 AND ITS USES IN MEDICINE. - Google Patents

Abstract

A compound of formula (I) or a salt or solvate thereof: ** Formula ** in which: R 4 is fluorine; R 6 R 5 R 4 R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkyl substituted with one or more fluorine atoms, C 1-6 alkoxy and C 1-6 alkoxy substituted with one or more atoms of fluorine; R 6 is selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkyl substituted with one or more fluorine atoms, C 3-6 cycloalkyl, C 3-6 cycloalkyl substituted with one or more fluorine atoms, C 1-6 alkoxy and C1-6 alkoxy substituted with one or more fluorine atoms, and Q is hydrogen or C1-6 alkyl.

Description

This invention relates to new compounds, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents.

The muscarinic acetylcholine receptors are members of the superfamily of 5G protein-coupled receptors that mediate the actions of the neurotransmitter acetylcholine both in the central nervous system and in the peripheral nervous system. Five subtypes of muscarinic receptors, from M1 to M5, have been cloned. The M1 muscarinic receptor is predominantly expressed in the cerebral cortex and in the hippocampus, although it is also expressed in the periphery, for example, in exocrine glands.

Muscarinic receptors in the central nervous system, especially M1, play a critical role in the mediation of higher cognitive processes. Some diseases associated with cognitive impairments, such as Alzheimer's disease, are accompanied by loss of cholinergic neurons in the basal forebrain. In addition, in animal models, blockage or injury of central cholinergic pathways results in profound cognitive deficits.

Cholinergic replacement therapy has relied heavily on the use of acetylcholinesterase 15 inhibitors to prevent the degradation of endogenous acetylcholine. These compounds have shown efficacy against symptomatic cognitive decline in medicine, but they produce side effects resulting from the stimulation of peripheral muscarinic receptors including impaired gastrointestinal motility and nausea.

The dopamine hypothesis of schizophrenia suggests that an excess of dopamine stimulation is responsible for the positive symptoms of the disease, hence the usefulness of dopamine receptor antagonists to reduce psychotic symptoms. However, conventional dopamine receptor antagonists can produce extrapyramidal side effects (EPS) in patients, including tremor and tardive dyskinesias.

M1 receptor agonists have been sought for the symptomatic treatment of cognitive reduction. More recently, several groups have shown that muscarinic receptor agonists have an atypical antipsychotic type profile in a series of preclinical paradigms. The xanomelin muscarinic agonist reverses 25 various dopamine-directed behaviors, including amphetamine-induced locomotion in rats, apomorphine-induced climbing in mice, dopamine-agonist-driven spin in rats with unilateral lesions in 6-OH-DA and amphetamine-induced displacement impulse in monkeys (no propensity to EPS). It has also been shown to inhibit A10, but not A9, cell stimulation by dopamine and conditioned avoidance and induce c-fos expression in the prefrontal cortex and nucleus accumbens, but not in the striatum 30 in rats. All these data suggest an atypical antipsychotic type profile.

It has also been shown that xanomeline reduces psychotic symptoms such as suspicion, hallucinations and delusions in Alzheimer's patients. However, the relatively non-selective nature of the compound produces dose-limiting peripheral cholinergic side effects.

Selective M1 receptor agonists have the potential utility of improving the positive and cognitive symptoms of 35 psychotic disorders such as schizophrenia, schizoaffective disorders, schizophreniform diseases, psychotic depression, mania, acute mania, paranoid disorders and delusional disorders, and cognitive disorders including disorders of memory such as Alzheimer's disease without peripheral cholinergic side effects predominantly mediated through M2 and M3 receptors.

M1 receptor agonists may also be suitable for combination with other typical or atypical antipsychotics and other active agents such as mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and cognitive enhancers, to provide an improved treatment of psychotic disorders

A new group of compounds that are useful for the treatment of psychotic disorders has now been discovered.

Therefore, in a first aspect, the invention provides a compound of formula (I) or a salt or solvate thereof:

in which:

R4 is fluorine;

R5 is selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 alkyl substituted with one or more fluorine atoms, C1-6 alkoxy and C1-6 alkoxy substituted with one or more fluorine atoms; 5

R6 is selected from halogen, cyano, C1-6 alkyl, C1-6 alkyl substituted with one or more fluorine atoms, cycloalkyl, C3-6 cycloalkyl substituted with one or more fluorine atoms, C1-6 alkoxy and C1-6 alkoxy substituted with one or more fluorine atoms, and

Q is hydrogen or C1-6 alkyl.

As used herein, the term "alkyl" refers to linear or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C1-6 alkyl means a linear or branched alkyl containing at least 1, and at most 6, carbon atoms. The term "C1-3 alkyl" means a straight or branched chain alkyl containing at least 1, and at most 3, carbon atoms. Examples of "alkyl", as used herein, include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1, 1-dimethylpropyl. fifteen

As used herein, the term "alkoxy" refers to a linear or branched alkoxy group containing the specified number of carbon atoms. For example, C1-6 alkoxy means a linear or branched alkoxy group containing at least 1, and at most 6, carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2- methylprop-2-oxy, pentoxy or hexyloxy. twenty

As used herein, the term "cycloalkyl" refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms. For example, C3-6 cycloalkyl means a non-aromatic ring containing at least three, and at most six, carbon atoms in the ring. Examples of "cycloalkyl," as used herein, include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "halogen" (or the abbreviated form "halo") refers to the elements fluorine 25 (which may be abbreviated as "fluoro"), chlorine (which may be abbreviated as "chlorine"), bromine (which can be abbreviated as "bromine") and iodine (which can be abbreviated as "iodine"). Examples of fluorine, chlorine and bromine halogens are.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or its salt) and a solvent. These solvents, for the purposes of the invention, must not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. If the solvent used is water, the solvate may be called hydrate.

As used herein, the term "substituted" refers to a substitution with the substituent or substituents mentioned, allowing multiple degrees of substitution unless otherwise indicated. For example, there may be 1, 2, 3 or 4 substituents in a given substituted group. For example, if R6 is a C1-6 alkyl group, this may be substituted with 1, 2, 3 or 4 fluoro groups; and if R6 is a C1-6 alkoxy group, this may be substituted with 1, 2, 3 or 4 fluorine groups. For example, R6 may be a C1-6 alkyl group substituted with 3 fluoro groups; and R6 may be a C1-6 alkoxy group substituted with 3 fluorine groups.

In one embodiment, R5 is selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 alkyl substituted with one, two or three fluorine atoms, C1-6 alkoxy and C1-6 alkoxy substituted with one, two or three fluorine atoms 40

In one embodiment, R 5 is selected from hydrogen, chlorine, bromine, fluorine, C 1-4 alkyl, C 1-4 alkyl substituted with one or more fluorine atoms, and C 1-4 alkoxy.

In one embodiment, R 5 is selected from hydrogen, chlorine, bromine, fluorine, C 1-4 alkyl, C 1-4 alkyl substituted with one, two or three fluorine atoms, and C 1-4 alkoxy.

In one embodiment, R5 is selected from hydrogen, chlorine, bromine, fluorine, methyl, ethyl, methoxy and trifluoromethyl.

In one embodiment, R5 is hydrogen or fluorine.

In one embodiment, R6 is selected from halogen, cyano, C1-6 alkyl, C1-6 alkyl substituted with one, two or three fluorine atoms, C3-6 cycloalkyl, C3-6 cycloalkyl substituted with one, two or three atoms of fluorine, C1-6 alkoxy and C1-6 alkoxy substituted with one, two or three fluorine atoms. 5

In one embodiment of the invention, R6 is selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with one or more fluorine atoms, C3-6 cycloalkyl, C3-6 cycloalkyl substituted with one or more fluorine atoms, alkoxy C1-6 and C1-6 alkoxy substituted with one or more fluorine atoms.

In another embodiment of the invention, R6 is selected from chlorine, bromine, fluorine, methyl, ethyl, isopropyl, methoxy, trifluoromethoxy and trifluoromethyl, for example chlorine, fluorine, methyl, methoxy, trifluoromethoxy and trifluoromethyl. 10

In a further embodiment of the invention, R6 is selected from chlorine, methyl and methoxy.

In one embodiment, R 6 is selected from chlorine, bromine, fluorine, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethoxy and trifluoromethyl.

In another embodiment, R 6 is chlorine, fluorine, methyl, cyclopropyl, methoxy, trifluoromethoxy or trifluoromethyl.

In one embodiment, R 6 is selected from methyl, fluorine, chlorine, methoxy and cyclopropyl. fifteen

In one embodiment of the invention, Q is selected from hydrogen and C1-3 alkyl. In a further embodiment, Q is selected from hydrogen, methyl, ethyl and propyl. In one embodiment, Q is hydrogen or methyl. In one embodiment, Q is hydrogen.

In another embodiment of the invention, a compound of formula (Ia) is provided:

 twenty

in which:

R4 is fluorine;

R5 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkyl substituted with one or more fluorine atoms, C1-6 alkoxy and C1-6 alkoxy substituted with one or more fluorine atoms; Y

- R6 is selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with one or more fluorine atoms, C3-25 cycloalkyl 6, C3-6 cycloalkyl substituted with one or more fluorine atoms, C1-6 alkoxy and alkoxy C1-6 substituted with one or more fluorine atoms

or its pharmaceutically acceptable salt or solvate.

In another embodiment, the invention provides a compound of formula (Ib):

 30

in which:

R4 is fluorine; Y

R6 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkyl substituted with one or more fluorine atoms, C3-6 cycloalkyl, C3-6 cycloalkyl substituted with one or more fluorine atoms, C1-6 alkoxy and alkoxy C1-6 substituted with one or more fluorine atoms, 5

or its pharmaceutically acceptable salt or solvate.

All features and embodiments for formula (I) apply to the compounds of formulas (Ia) and (Ib) mutatis mutandis. Hereinafter, all references to compounds of formula (I) include compounds of formula (Ia) and compounds of formula (Ib).

It will be noted that for use in medicine, the salts of formula (I) must be pharmaceutically acceptable. Suitable salts will be apparent to those skilled in the art and include, for example, acid salts, for example sodium, potassium, calcium, magnesium, tetraalkylammonium and the like, or mono- or di-basic salts formed with inorganic acids, for example acid. hydrochloric, hydrobromic, sulfuric, nitric, sulfamic or phosphoric; and organic acids, for example succinic, maleic, malic, mandelic, acetic, isethionic, fumaric, glutamic, lactic, citric, tartaric, benzoic, lactobionic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, ethanesulfonic or naphthalenesulfonic acids. Examples of salts additionally include trifluoroacetate salts and formate salts. Other salts that are not pharmaceutically acceptable can be used, e.g. eg, oxalates, for example to isolate the compounds of formula (I), and are included within the scope of this invention.

Some of the compounds of this invention can be crystallized or recrystallized from solvents, such as aqueous and organic solvents. In such cases solvates can be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing varying amounts of water that can be produced by processes such as lyophilization.

Certain compounds of formula (I) can form acid addition salts with less than one equivalent (for example, 0.5 equivalents of a dibasic acid) or one or more equivalents of an acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. 25

Certain compounds of formula (I) may exist in stereoisomeric forms (for example, they may contain one or more asymmetric carbon atoms). Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the present invention. The present invention also includes the individual isomers of the compounds represented by formula (I) as mixtures with their isomers, in which one or more chiral centers are inverted. Similarly, it is understood that the compounds of formula (I) 30 may exist in tautomeric forms other than those shown in the formula, and these are also included within the scope of the present invention.

The present invention includes within the scope all pharmaceutically acceptable derivatives of the compounds of formula (I). As used herein, the term "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, solvate or prodrug, for example ester, of a compound of formula (I), which after administration to the recipient is able to provide ( directly or indirectly) a compound of formula (I), or an active metabolite or remainder thereof. Such derivatives can be recognized by those skilled in the art, without excessive experimentation. However, reference is made to the teaching of Burger’s Medicinal Chemistry and Drug Discovery, 5th Edition, Vol 1: Principles and Practice, which is incorporated herein as a reference to increase the teaching of such derivatives. 40

Those skilled in the art will appreciate that certain protected derivatives of the compounds of formula (I), which may be prepared before a final deprotection step, may not possess pharmacological activity as such, but may, in certain cases, be administered via orally or parenterally and then metabolized in the body to form the compounds of the invention that are pharmacologically active. Such derivatives can therefore be described as "prodrugs." In addition, certain compounds of the invention may act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of the compounds of the invention are within the scope of the invention. Examples of suitable protecting groups of the compounds of the present invention are described in Drugs of Today, volume 19, number 9, 1983, p. 499-538 and in Topics in Chemistry, chapter 31, p. 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, chapter 1 (discoveries whose documents are incorporated herein by reference). Those skilled in the art will also appreciate that certain groups, known to those skilled in the art as "pro-remains", for example as described by H. Bundgaard in "Design of Prodrugs" (the description of which is incorporated herein by reference ) can be placed in appropriate functional groups when said functional groups are present in the compounds of the invention. Suitable prodrugs of the compounds of the invention comprise: esters, carbonate esters, 55 hemiesters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals.

Particular compounds according to the invention include those specifically exemplified in the Examples section and presented hereinafter, including, but not limited to:

4-Fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one

6-Chloro-4-fluoro-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one

4-Fluoro-6-methoxy-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 5

4,5-Difluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one

6-Cyclopropyl-4-fluoro-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one

4,5-Difluoro-6-methyl-1- [1- (4-methyltetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one

and salts and solvates thereof, for example the hydrochloride salt, the trifluoroacetate salt or the formate salt of any of the foregoing compounds. 10

Specific examples of salts of the present invention include:

4-Fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride

4-Fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole-2-one monocytrate

4-Fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one methanesulfonate

6-Chloro-4-fluoro-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride 15

4-Fluoro-6-methoxy-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride

4,5-Difluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride

6-Cyclopropyl-4-fluoro-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one e hydrochloride

4,5-Difluoro-6-methyl-1- [1- (4-methyltetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride. twenty

In a further embodiment, the invention provides a general process (A1) for preparing compounds of formula (I), wherein Q = H, said process comprising:

coupling a compound of formula (II)

with a compound of formula (III):

in which

R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible into R5, and R6 'is a group R6 as defined above , or a convertible group in R6. 30

The reaction is carried out under conditions suitable for reductive alkylation. The reductive alkylation reaction is typically performed using sodium triacetoxyborohydride in dichloroethane, optionally in the presence of triethylamine, and optionally in the presence of titanium tetraisopropoxide. Alternatively, sodium cyanoborohydride can be used as a reduction reagent in solvents such as methanol or ethanol, or reductive alkylation can be performed under catalytic hydrogenation conditions using a palladium catalyst. In a further variation, the compounds (II) and (III) can be condensed under dehydrating conditions, for example molecular sieves or

magnesium sulfate, and the resulting imine or enamine can be reduced using for example sodium borohydride or by catalytic hydrogenation.

A modification of the general process (A1) is required when Q = C1-6 alkyl. Thus, in the general process (A2), a compound of formula (II) can be reacted with a compound of formula (III) in the presence of a cyanide source, for example potassium cyanide or acetone cyanohydrin, to form the intermediate cyano 5 (XXXX) which can be reacted with a QMgX alkyl Grignard reagent to form compounds of formula (I).

in which

R5 'is a group R5 as defined above, or a group convertible into R5, R6' is a group R6 as defined above, or a group convertible into R6, R4 'is a group R4 as defined above , or a group convertible into R4, Q is hydrogen or C1-6 alkyl, and X is chlorine, bromine or iodine.

The reaction is performed using conditions similar to those described in the literature (Arch Pharm (Weinheim), 1987, 320 (4), 348-361). The piperidine and ketone components are treated with potassium cyanide in water at pH 3 or reacted with acetone cyanohydrin in dimethylacetamide at an elevated temperature to form the adduct (XXXX). The reaction of the adduct (XXXX) with the Grignard reagent of alkyl QMgX in ether or tetrahydrofuran provides compounds of formula (I).

In a further embodiment, the invention provides a general process (B) for preparing compounds of formula (I) comprising said process:

coupling a compound of formula (IV) 20

with a compound of formula (V)

where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible into R5, and R6 'is a group R6 as defined above, 25 or a group convertible into R6, Q is hydrogen or C1-6 alkyl, both X and Y represent leaving groups. X and Y may be the same or different and examples are Cl, PhO, EtO and imidazole. When X and Y are both Cl, that is, phosgene, this reagent can be generated in situ, for example, from diphosgene or triphosgene.

The above reaction is performed using conventional methodology, for example by reacting diamine (IV) with reagent (V) in an inert solvent, for example dichloromethane, toluene or dimethylformamide, optionally in the presence of a base such as triethylamine or potassium carbonate , and optionally with heating.

In a further embodiment, the invention provides a general process (C) for preparing compounds of formula (I) comprising said process:

treatment of a compound of formula (VI)

with a palladium or copper (VII) catalyst to perform an intramolecular cyclization

where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible into R5, and R6 'is a group R6 as defined above, 5 or a group convertible into R6, Q is hydrogen or C1-6 alkyl, and Z is a leaving group such as bromine, iodine, chlorine or triflate.

The cyclization reaction can be performed using a variety of palladium or copper reagents as described in the literature (JACS, 2003, 125, 6653, Tet. Lett., 2004, 45, 8535, or JACS, 2002, 124, 7421) .

In a further embodiment, the invention provides a general process (D) for preparing compounds of formula 10 (I) comprising said process:

coupling a compound of formula (VIII)

with a compound of formula (IX)

 fifteen

where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible into R5, and R6 'is a group R6 as defined above, or a group convertible into R6, Q is hydrogen or C1-6 alkyl and R is a C1-5 alkyl group.

This condensation and cyclization reaction can be carried out under reaction conditions similar to those described in the literature for an analogous process (US 3161645) (for example heating in an inert solvent 20 such as xylene) followed by reduction of the piperidine double bond using example catalytic hydrogenation on palladium or Raney nickel.

In a further embodiment, the invention provides a general process (E) for preparing compounds of formula (I) comprising said process:

reaction of a compound of formula (X) 25

with diphenylphosphorylazide or other reagent / combination of reagents to perform Curtius redisposition of compound (X), followed by intramolecular cyclization.

where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible into R5, and R6 'is a group R6 as defined above, or a group convertible into R6, and Q is hydrogen or C1-6 alkyl.

Curtius redisposition is typically performed by mixing the two reagents in an inert solvent such as toluene, optionally with heating. 5

In a further aspect, the invention provides a general process (F) for preparing compounds of formula (I), said process comprising:

coupling a compound of formula (XI)

with a compound of formula (XII) 10

where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible into R5, and R6 'is a group R6 as defined above, or a group convertible into R6, Q is hydrogen or C1-6 alkyl, and Z is hydroxy or a leaving group such as chlorine, bromine or iodine, or alkyl / aryl sulfonate. fifteen

The alkylation reaction (Z = a leaving group) can be carried out under classical alkylation or Mitsunobu reaction conditions (Z = OH). Using classical alkylation conditions, the benzimidazolone intermediate (XI) can be protected using a base such as sodium hydride in an inert solvent such as dimethylformamide, and then treated with the alkylation reagent (XII), optionally with heating. The reaction of Mitsunobu with (XII) Z = OH can be carried out using conventional conditions, for example triphenylphosphine and diethylazodicarboxylate in an inert solvent such as dichloromethane or tetrahydrofuran at room temperature.

The conversion of R6 ’into R6 or the interconversions of R6 can be carried out as indicated below.

For example, when R6 'is a halogen, it can be converted into an alkoxy or trifluoromethyl group by reaction catalyzed with copper, using a methyl alcohol or fluorosulfonyl (difluoro) acetate, respectively. It can also be converted into an alkyl group with an organometallic reagent, for example an alkyltannan. 25

As another example, when R6 'is hydroxy, it can be converted into alkoxy by reaction with an alkyl halide or sulphonate, or trifluoromethoxy by conversion to the xanthate followed by oxidation in the presence of fluoride ion.

As a further example, when R6 'is methyl, it can be converted to trifluoromethyl by chlorination or bromination followed by displacement of the halogens introduced with fluoride.

The conversion of R5 'into R5 or interconversions of R5 can be performed in a manner similar to that indicated for the conversion of R6' into R6 or interconversions of R6.

The conversion of R4 'into R4 can be carried out in various ways; for example, by displacement of a halide group with fluoride, or by fluorination of an organometallic derivative with an electrophilic fluorine source such as N-fluorobenzenesulfonimide, or by decomposition of a diazonium tetrafluoroborate.

The compounds of formula (II) are generally known in the literature or can be prepared by several different processes, for example:

(a) displacement of an ortho-fluoro or ortho-chloro nitrobenzene intermediate (XIII) with the amine (XIV), where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible in R5, and R6 'is a group R6 as defined above, or a group convertible in R6, and P represents a nitrogen protecting group, for example Boc, acetyl, trifluoroacetyl , Ethoxycarbonyl, benzyloxycarbonyl, to give (XXIII), followed by reduction of the nitro group, cyclization using phosgene or a phosgene equivalent, and deprotection of piperidine nitrogen using bibliographic conditions

conventional (Scheme 1).

Scheme 1:

  NHNNHOR6'R4'R5'R6'F or ClNO2R4'R5'NNH2PNNHPR6'NO2R4'R5'NNHPR6'NH2R4'R5'NNNHOR6'PR4'R5 '(ll) + (Xlll) (XlV) (XXlll)

The compounds of formula (XIII) are commercially available or can be prepared by conventional methodology. The compound (XIV) in which P = Boc is commercially available. 5

(b) catalyzed cyclisation with a metal of an intermediate (XV) followed by deprotection of the piperidine nitrogen, where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible in R5, and R6 'is a group R6 as defined above, or a group convertible in R6, P represents a nitrogen protecting group for example Boc, acetyl, trifluoroacetyl or benzyloxycarbonyl, and Z represents a leaving group such as bromine, iodine, chlorine or triflate. The reaction conditions for Buchwald cyclization are summarized in Process C. Urea (XV) can be prepared using any of the classic methods for urea formation as illustrated in Scheme 2. The starting materials for this process are commercially available or can be prepared using conventional methodology.

Scheme 2:

(c) Curtius redisposition of an intermediate (XVI), where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible into R5, and R6 'is a group R6 as defined above, or a group convertible into R6, P represents a nitrogen protecting group 5 for example Boc, acetyl, trifluoroacetyl or benzyloxycarbonyl, and R represents H or a C1- alkyl group 5 for example methyl or ethyl, followed by intramolecular cyclization and deprotection of the piperidine nitrogen (Scheme 3). The starting materials acid or anthranilic ester (XVII) are commercially available or can be prepared by conventional methodology. The starting material piperidone (R = Boc or benzyl) is commercially available. Curtius redisposition can be performed using the conditions described in process E. 10

Scheme 3:

   NHNNHOR6'R4'R5'NNHPR6'CO2HR4'R5'NNNHOR6'PR4'R5'NH2R6'CO2RR4'R5'NPONNHPR6'CO2RR4'R5 '(ll) (XVl) + (XVll) (XVlll)

(d) Condensation of an orthophenylenediamine (VIII) with a 3-alkoxycarbonyl-4-piperidone (XX), where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible in R5, and R6 'is a group R6 as defined above, or a group 5 convertible in R6, P represents a nitrogen protecting group for example Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl and R is a C1-5 alkyl group (Scheme 4), by heating in an inert solvent at an elevated temperature, to produce the tetrahydropyridine intermediate (XXI). The hydrogenation of the double bond and the deprotection of the piperidine nitrogen can be carried out separately or concomitantly depending on the precise nature of the protecting group P, to produce the desired product (II). The compounds of formula 10 (VIII) are commercially available or can be prepared by conventional methodology. The compounds of formula (XX) are commercially available or can be prepared by conventional methodology.

Scheme 4

  NHNNHOR6'R4'R5'NNNHOR6'PR4'R5'NH2R6'NH2R4'R5'NPOCO2RNNNHOR6'PR4'R5 '(ll) + (Vlll) (XX) (XXl)

(e) Reductive alkylation of an ortonitroaniline (XXII) with an N-protected 4-piperidone (XVIII), where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible into R5, and R6 'is a group R6 as defined above, or a group

convertible into R6, and P represents a nitrogen protecting group for example Boc, acetyl, trifluoroacetyl or benzyloxycarbonyl, using for example sodium triacetoxyborohydride to give the intermediate (XXIII). Reduction of the nitro group, followed by cyclization and deprotection as described hereinbefore, provides the desired product (II) (Scheme 5). The compounds of formula (XXII) and (XVIII) are commercially available or can be prepared by conventional methodology. 5

Scheme 5

  NHNNHOR6'R4'R5'NH2R6'NO2R4'R5'NOPNHR6'NO2NPR4'R5'NHR6'NH2NPR4'R5'NNNHOR6'PR4'R5 '(ll) + (XXll) (XVlll) (XXlll)

(f) catalyzed reaction with a metal between the amine (XlV) and a suitably substituted nitrobenzene compound (XXIV) where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible in R5, and R6 'is a group R6 as defined above, or a group convertible in R6, P represents a nitrogen protecting group for example Boc, acetyl, trifluoroacetyl or benzyloxycarbonyl , and Z represents a leaving group such as bromine, iodine, chlorine or triflate (Scheme 6). This process generates intermediates of formula (XXIII) and subsequent reactions are similar to those of Scheme 5. Compounds of formula (XXIV) are commercially available or can be prepared by known methodology. The compound (XIV) in which P = Boc is commercially available. fifteen

Scheme 6

  NHNNHOR6'R4'R5'ZR6'NO2R4'R5'NNH2PNHR6'NO2NPR4'R5'NHR6'NH2NPR4'R5'NNNHOR6'PR4'R5 '(ll) + (XXlV) (XlV) (XXlll) Z = Br, I, OTf

(g) catalyzed reaction with a metal between the amine (XIV) and the protected aniline (XXV), where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible in R5, and R6 'is a group R6 as defined above, or a group convertible in R6, P represents a nitrogen protecting group for example Boc, acetyl, trifluoroacetyl or benzyloxycarbonyl, and Z represents a leaving group such as bromine, iodine, chlorine or triflate, to give intermediate 5 (XXVI) (Scheme 7). Deprotection of the aniline followed by the same sequence of reactions as in Scheme 6 produces the desired intermediate (II). The compounds of formula (XXV) are commercially available or can be prepared by known methodology, for example halogenation ortho to the aniline group. The compound (XIV) in which P = Boc is commercially available.

Scheme 7 10

  NHNNHOR6'R4'R5'ZR6'NHP'R4'R5'NNH2PNHR6'NHNPP'R4'R5'NHR6'NH2NPR4'R5'NNNHOR6'PR4'R5 '(ll) + (XXV) (XlV) (XXVl) Z = Br , I, OTf

The compound of formula (III) is commercially available.

The compounds of formula (IV) can be prepared by several different processes, for example

(h) displacement of an ortho-fluoro or ortho-chloro nitrobenzene intermediate (XIII) with the amine (XXVII) to produce the compound (XXVIII) where R4 'is a group R4 as defined above, or a group convertible into R4 , R5 '15 is a group R5 as defined above, or a group convertible into R5, and R6' is a group R6 as defined above, or a group convertible into R6, and Q is hydrogen or C1-6 alkyl , followed by reduction of the nitro group using conventional conditions, for example hydrogenation on palladium or Raney nickel (Scheme 8). The compounds of formula (XIII) are commercially available or can be prepared by conventional methodology. twenty

Scheme 8

  R6'F or ClNO2R4'R5'NNH2OQNNHR6'NO2OR4'R5'QNNHR6'NH2OR4'R5'Q + (Xlll) (XXVll) (XXVlll) (lV)

(i) catalyzed reaction with an amine metal (XXVII) with ortho substituted nitrobenzene (XXIX) to produce compound (XXVIII) where R4 'is a group R4 as defined above, or a group convertible into R4, R5 'is a group R5 as defined above, or a group convertible into R5, and R6' is a group R6 as defined above, or a group convertible into R6 (Scheme 9) and Q is hydrogen or C1- alkyl 6, followed by the same reaction conditions set forth in Scheme 8. Compounds of formula (XXIX) are commercially available or can be prepared by conventional methodology.

Scheme 9

 10 R6'ZNO2R4'R5'NNH2OQNNHR6'NO2OR4'R5'QNNHR6'NH2OR4'R5'Q + (XXlX) (XXVll) (XXVlll) (lV) Z = Br, I, Cl, OTf

(j) catalyzed reaction with an amine metal (XXVII) with the protected aniline derivative (XXV), where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible in R5, and R6 'is a group R6 as defined above, or a group convertible in R6, Q is hydrogen or C1-6 alkyl, and P represents a nitrogen protecting group such as acetyl, trifluoroacetyl, Boc or phthalimide, to produce compound (XXXI) (Scheme 10) followed by deprotection of the aniline group. The compounds of formula (XXV) are commercially available or can be prepared by conventional methodology.

Scheme 10

  R6'ZNHPR4'R5'NNH2OQNNHR6'NHOPR4'R5'QNNHR6'NH2OR4'R5'Q + (XXV) (XXVll) (XXXl) (lV) Z = Br, I, Cl, OTf

(k) Reductive alkylation of an ortho nitroaniline (XXII) with piperidone (XXXII) using for example sodium triacetoxyborohydride in dichloroethane to give intermediate (XXVIII) where R4 'is an R4 group as defined above, or a convertible group in R4, R5 'is a group R5 as defined above, or a group convertible into R5, and R6' is a group R6 as defined above, or a group convertible into R6, and Q is hydrogen or C1- alkyl 6, using for example sodium triacetoxyborohydride in dichloroethane to give the intermediate (XXVIII) (Scheme 11). Reduction of the nitro group using, for example, palladium on carbon or Raney nickel produces the desired intermediate (IV).

10

Scheme 11

  NH2R6'NO2R4'R5'NOOQNHR6'NO2NOR4'R5'QNHR6'NH2NOR4'R5'Q + (XXll) (XXXll) (XXVlll) (lV)

The compounds of formula (V) are commercially available, for example carbonyldiimidazole, phosgene, phosgene solution in toluene, diphosgene, triphosgene, phenyl chloroformate and diethyl carbonate.

The compounds of formula (VI) can be prepared by a variety of processes, for example, urea formation 5 can be performed as shown in Scheme 12

combining the two amines (XXXIV) and (XXVII) with phosgene or a phosgene equivalent using conventional conditions. Phosgene equivalents include carbonyldiimidazole, diphosgene, triphosgene and phenyl chloroformate

by reacting the amine (XXVII) with the isocyanate (XXXV) 10

by reacting the amine (XXXIV) with the isocyanate (XXXVI)

The two isocyanates (XXXV) and (XXXVI) can be prepared from the corresponding amines using conventional methodology for isocyanate formation where R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible into R5, and R6 'is a group R6 as defined above, or a group convertible into R6, and Q is hydrogen or C1-6 alkyl.

Scheme 12

Palladium and copper (VII) catalysts are commercially available or can be prepared as described in the literature (see references in Process C).

The compounds of formula (VIII) are commercially available or can be prepared by known literature routes, for example reduction of a mono or dinitrobenzene precursor.

The compounds of formula (IX) can be prepared by reductive alkylation of 3-alkoxycarbonyl-4-piperidone with tetrohydropyran-4-one.

The compounds of formula (X) in which R4 'is a group R4 as defined above, or a group convertible into R4, R5' is a group R5 as defined above, or a group convertible into R5, and R6 'is a group R6 as defined above, or a group convertible into R6, and Q is hydrogen or C1-6 alkyl, can be prepared as shown in Scheme 13. Reductive alkylation of an anthranilic acid or ester (XVII) with ketone (XXXII), followed if appropriate, of hydrolysis of the ester group.

Scheme 13

 fifteen NNHR6'CO2HOR4'R5'QNH2R6'CO2RR4'R5'NOOQCO2RNNHR6'OR4'R5'Q + (XVll) (X) (XXXll)

The compounds of formula (XI) are commercially available or can be prepared by bibliographic processes.

The compounds of formula (XII) can be prepared as shown in Scheme 14, by reductive alkylation of (XXXVII) where Z 'represents Z or a group convertible into Z with the ketone (III), and Q = H. The conversion of a

hydroxy group Z 'in Z = chlorine or bromine can be carried out using conventional methodology, for example treatment with thionyl chloride or triphenylphosphine / carbon tetrabromide.

Scheme 14

  NOZ'QNHZ'OO (Xll) + (lll) (XXXVll)

The compound (XXVII) in which Q = H can be prepared as shown in Scheme 15. The reductive alkylation of the commercially available amine (XXXVIII) with tetrahydropyran-4-one (III) using for example sodium triacetoxyborohydride in dichloroethane it provides the intermediate (XXXIX) that is deprotected using HCl in ethanol or trifluoroacetic acid to produce the primary amine (XXVII).

Scheme 15

 10 NH2NOQNHNHBocOONHNOBocQ + (XXVll) (XXXVlll) (lll) (XXXlX)

The compounds of formula (I) are expected to be useful in the treatment of psychotic disorders or cognitive disorders.

The terms that describe the indications used in this document are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and / or the International Classification of Diseases, 10th Edition (ICD- 10). The various subtypes of disorders mentioned herein are contemplated as part of the present invention. The numbers in brackets after the diseases listed below refer to the classification code in DSM-IV.

Within the context of the present invention, the term psychotic disorder includes schizophrenia, including subtypes of the paranoid type (295.30), of the disorganized type (295.10), of the catatonic type (295.20), of the undifferentiated type (295.90) and of the residual type ( 295.60); schizophreniform disorder (295.40); schizoaffective disorder 20 (295.70) that includes bipolar and depressive type subtypes; delusional disorder (297.1) which includes the subtypes of the erotomanic type, delusional type of grandeur, celotypy, persecutory type, somatic type, mixed type and unspecified type; brief psychotic disorder (298.8); shared psychotic disorder (297.3); psychotic disorder due to a generalized condition that includes subtypes with delusions and hallucinations; drug-induced psychotic disorder that includes subtypes with delusions (293.81) and hallucinations (293.82); and 25 psychotic disorder not otherwise specified (298.9);

Depression and mood disorders that include the main depressive episode, manic episode, mixed episode and the hypomanic episode; depressive disorders that include the main depressive disorder, dysthymic disorder (300.4), depressive disorder not otherwise specified (311); bipolar disorders that include bipolar I disorder, bipolar II disorder (major recurrent depressive episodes with hypomanic episodes) 30 (296.89), cyclothymic disorder (301.13) and bipolar disorder not otherwise specified (296.80); other mood disorders including mood disorders due to a generalized condition (293.83) comprising subtypes with depressive manifestations, with major depressive episodes, with manic manifestations and with mixed manifestations), mood disorder drug-induced (including subtypes with depressive manifestations, with manic manifestations and with mixed manifestations) and mood disorder not otherwise specified (296.90);

Anxiety disorders including social anxiety disorder, panic attack, agoraphobia, panic disorder, agoraphobia without a history of panic disorder (300.22), specific phobia (300.29) including subtypes of animal type, of natural medium type, of type blood-injection-injury, exogenous and other types), social phobia (300.23), obsessive-compulsive disorder (300.3), post-traumatic stress disorder (309.81), acute stress disorder (308.3), generalized anxiety disorder (300.02), anxiety disorder due to a generalized disease (293.84), drug-induced anxiety disorder, other unspecified anxiety disorder

way (300.00);

Drug-related disorders including drug use disorders such as drug dependence, drug craving and drug addiction; drug-induced disorders such as drug intoxication, drug withdrawal, drug-induced delirium, drug-induced persistent dementia, drug-induced persistent amnestic disorder, drug-induced psychotic disorder, drug-induced mood disorder, disorder of drug-induced anxiety, drug-induced sexual dysfunction, drug-induced sleep disorder and disorder with persistent hallucinogenic perception (retrospective scenes); alcohol-related disorders such as alcohol dependence (303.90), alcoholism (305.00), alcohol intoxication (303.00), alcohol withdrawal (291.81), alcohol intoxication delirium, alcohol withdrawal delirium, persistent dementia induced by alcohol, alcohol-induced persistent amnesic disorder, alcohol-induced psychotic disorder, alcohol-induced mood disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder and other unspecified disorder alcohol-related manner (291.9); disorders related to amphetamines (or similar to amphetamines) such as amphetamine dependence (304.40), amphetamine abuse (305.70), amphetamine poisoning (292.89), amphetamine withdrawal (292.0), delirium from 15 amphetamine poisoning, psychotic disorder Amphetamine-induced mood disorder, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder, and an otherwise-specified amphetamine-related disorder (292.9); caffeine-related disorders such as caffeine intoxication (305.90), caffeine-induced anxiety disorder, caffeine-induced sleep disorder and otherwise not specified caffeine-related disorder (292.9); cannabis-related disorders such as cannabis dependence (304.30), cannabis abuse (305.20), cannabis poisoning (292.89), delirium from cannabis poisoning, cannabis-induced psychotic disorder, cannabis-induced anxiety disorder and related disorder with cannabis not otherwise specified (292.9); Cocaine-related disorders such as cocaine dependence (304.20), cocaine abuse (305.60), cocaine poisoning (292.89), cocaine withdrawal (292.0), 25 delirium from cocaine intoxication, cocaine-induced psychotic disorder, cocaine-induced mood disorder, cocaine-induced anxiety disorder, cocaine-induced sexual dysfunction, cocaine-induced sleep disorder and cocaine-related disorder not otherwise specified (292.9); hallucinogen-related disorders such as hallucinogen dependence (304.50), hallucinogen addiction (305.30), hallucinogen poisoning (292.89), hallucinogenic disorder with persistent perception (flashbacks) 30 (292.89), hallucinogen poisoning, psychotic disorder hallucinogen-induced, hallucinogen-induced mood disorder, hallucinogen-induced anxiety disorder and hallucinogen-related disorder not otherwise specified (292.9); inhaler-related disorders such as inhaler dependence (304.60), inhaler addiction (305.90), inhaler poisoning (292.89), delirium from inhaler poisoning, persistent inhaler-induced dementia, inhaler-induced psychotic disorder, state disorder Inhaler-induced mood, inhaler-induced anxiety disorder and inhaler-related disorder not otherwise specified (292.9); nicotine-related disorders such as nicotine dependence (305.1), nicotine withdrawal (292.0) and nicotine-related disorder not otherwise specified (292.9); Opioid-related disorders such as opioid dependence (304.00), opioid addiction (305.50), opioid poisoning (292.89), opioid withdrawal (292.0), 40 opioid intoxication delirium, opioid-induced psychotic disorder, opioid disorder opioid-induced mood, opioid-induced sexual dysfunction, opioid-induced sleep disorder and opioid-related disorder not otherwise specified (292.9); disorders related to phencyclidine (or similar to phencyclidine) such as dependence on phencyclidine (or similar to phencyclidine) (304.60), addiction to phencyclidine (305.90), intoxication with phencyclidine (292.89), delirium from poisoning with phencyclidine 45 psychotic disorder induced by phencyclidine, mood disorder induced by phencyclidine, anxiety disorder induced by phencyclidine and disorder related to phencyclidine not otherwise specified (292.9); sedative, hypnotic or anxiolytic related disorders such as sedative, hypnotic or anxiolytic dependence (304.10), sedative, hypnotic or anxiolytic addiction (305.40), sedative, hypnotic or anxiolytic poisoning (292.89), sedative, hypnotic or withdrawal Anxiolytics (292.0), delirium from sedative poisoning, 50 hypnotics or anxiolytics, delirium from sedative withdrawal, hypnotics or anxiolytics, persistent dementia from sedatives, hypnotics or anxiolytics, persistent amnesic disorder from sedatives, hypnotics or anxiolytics, sedative-induced psychotic disorder , hypnotic or anxiolytic, sedative, hypnotic or anxiolytic-induced mood disorder, sedative, hypnotic or anxiolytic-induced anxiety disorder, sedative, hypnotic or anxiolytic-induced sexual dysfunction, sedative, hypnotic or anxiolytic-induced sleep disorder and disorder 55 relationship onado with sedatives, hypnotics or anxiolytics not otherwise specified (292.9); polypharmaceutical related disorder such as polypharmaceutical dependence (304.80); and other disorders related to drugs (or unknown) such as anabolic steroids, nitrate inhalers and nitrous oxide;

Sleep disorders including primary sleep disorders such as dysomnias such as primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), sleep disorders related to breathing (780.59), circadian rhythm disorder of sleep (307.45) and dysomnia not otherwise specified (307.47); primary sleep disorders such as parasomnios such as nightmare disorder (307.47), sleep terror disorder (307.46), sleepwalking disorder (307.46) and unspecified parasomnios

otherwise (307.47); sleep disorders related to another mental disorder such as insomnia related to another mental disorder (307.42) and hypersomnia related to another mental disorder (307.44); sleep disorder due to a generalized condition; and drug-induced sleep disorder including insomnia, hypersomnia, parasomnia and mixed type subtypes;

Eating disorders such as anorexia nervosa (307.1) including subtypes of the restrictive type and the type of overeating / vomiting; bulimia nervosa (307.51) including subtypes of type with vomit and type without vomit; obesity; binge eating disorder; and eating disorder not otherwise specified (307.50);

Autistic disorder (299.00); Inattention / hyperactivity disorder including subtypes of the combined type of inattention / hyperactivity disorder (314.01), inattention / hyperactivity disorder 10 predominantly in inattention type (314.00), inattention disorder attention / hyperactivity of hyperactive impulse type (314.01) and inattention disorder / hyperactivity not otherwise specified (314.9); hyperkinetic disorder; destructive behavior disorders such as behavior disorder that includes the subtypes of the type of onset in childhood (321.81), the type of onset in adolescence (312.82) and of unspecified onset (312.89), provocative disorder with resistance ( 313.81) and destructive behavior disorder 15 not otherwise specified; and tic disorders such as Tourette's disorder (307.23);

Personality disorders including subtypes of paranoid personality disorder (301.0), schizoid personality disorder (301.20), schizoid personality disorder (301.22), antisocial personality disorder (301.7), ambiguous personality disorder (301.83), disorder of histrionic personality (301.50), narcissistic personality disorder (301.81), elusive personality disorder (301.82), dependent personality disorder (301.6), obsessive-compulsive personality disorder (301.4) and personality disorder not otherwise specified (301.9); Y

sexual dysfunctions including sexual desire disorders such as hypoactive sexual desire disorder (302.71) and sexual aversion disorder (302.79); sexual arousal disorder such as female sexual arousal disorder (302.72) and male erectile disorder (302.72); orgasm disorders such as female orgasm disorder (302.73), male orgasm disorder (302.74) and premature ejaculation (302.75); sexual pain disorder such as dyspareunia (302.76) and vaginismus (306.51); sexual dysfunction not otherwise specified (302.70); paraphilias such as exhibitionism (302.4), fetishism (302.81), rubbing (302.89), pedophilia (302.2), sexual masochism (302.83), sexual sadism (302.84), tragic fetishism (302.3), voyeurism (302.82) and non-paraphilias otherwise specified (302.9); 30 sexual identity disorders such as sexual identity disorder in children (302.6) and sexual identity disorder in adolescents or adults (302.85); and sexual disorder not otherwise specified (302.9).

It is also expected that the compounds of Formula (I) are useful for enhancing cognition, including both the treatment of cognitive impairment itself and the treatment of cognitive impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychotic disorders and conditions Psychotic associated with 35 cognitive impairment.

In the context of the present invention, the term "cognitive impairment" includes for example the treatment of the alteration of cognitive functions including attention disorders, orientation, learning, memory (i.e., memory disorders, amnesia, amnesic disorders, syndrome of transient global amnesia and the alteration of age-related memory) and of language function; cognitive impairment as a result 40 of stroke, Alzheimer's disease, Huntington's disease, Pick's disease, AIDS-related dementia or other dementia states such as multi-infarct dementia, alcoholic dementia, hypothyroidism-related dementia and dementia related to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or subacute conditions that can cause cognitive decline such as delirium or depression (pseudodemential states) trauma, head trauma, age-related cognitive decline, stroke, neurodegeneration, drug induced states, neurotoxic agents, mild cognitive impairment, age-related cognitive impairment, cognitive impairment related to autism, Down syndrome, cognitive impairment related to psychosis and cognitive disorders related to post-electroconvulsive treatment; and dyskinetic disorders such as Parkinson's disease, induced neuroleptic parkinsonism and tardive dyskinesias. fifty

The therapy of the present invention can also be used as a memory and / or cognition enhancer in healthy humans without memory and / or cognitive deficits.

Therefore, in a further aspect, the invention provides a compound of formula (I) as described hereinbefore or a salt or solvate thereof for use in therapy.

In another aspect, the invention provides a compound of formula (I) or a salt or solvate thereof for use in treating a condition that requires agonism of an M1 muscarinic receptor.

In another aspect, the invention provides a compound of formula (I) as described above in this

document or a salt or solvate thereof for use in the treatment of a psychotic disorder. The invention also provides a compound of formula (I) as described hereinbefore or a salt or solvate thereof for use in the treatment of cognitive impairment.

In another aspect, the invention provides the use of a compound of formula (I) as described hereinbefore or a salt or solvate thereof in the preparation of a medicament for the treatment of a condition that requires agonism of a M1 muscarinic receptor.

In another aspect, the invention provides the use of a compound of formula (I) as described hereinbefore or a salt or solvate thereof in the preparation of a medicament for the treatment of a psychotic disorder. The invention also provides the use of a compound of formula (I) as described hereinbefore or a salt or solvate thereof in the preparation of a medicament for the treatment of cognitive impairment.

The compounds of formula (I) and their salts and solvates may also be suitable to be combined with other active agents, such as typical and atypical antipsychotics, mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and cognitive enhancers to provide an improved treatment of psychotic disorders. fifteen

The combination therapies of the invention, for example, are co-administered. By adjuvant administration is meant the overlapping or coincidental administration of each of the components as pharmaceutical compositions or separate devices. This regimen of therapeutic administration of two or more therapeutic agents is generally referred to by those skilled in the art and herein adjuvant therapeutic administration; It is also known as additive therapeutic administration. Within the scope of the present invention are each and every treatment regimen where a patient receives a separate but overlapping or matching therapeutic administration of the compounds of formula (I) or a salt or solvate thereof and at least one antipsychotic agent, a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects or a cognitive enhancer. In one embodiment of adjuvant therapeutic administration as described herein, a patient typically stabilizes with the therapeutic administration of one or more of the components over a period of time and then receives administration of another component. The compounds of formula (I) or a salt or solvate thereof can be administered as adjunctive therapeutic treatment to patients who are receiving the administration of at least one antipsychotic agent, a mood stabilizer, an antidepressant, an anxiolytic agent, a drug. for extrapyramidal side effects or a cognitive enhancer, but the scope of the invention also includes the adjuvant therapeutic administration of at least one antipsychotic agent, a mood stabilizer, an antidepressant, an anxiolytic agent, a drug for extrapyramidal side effects or a cognitive enhancer to patients who are receiving the administration of compounds of formula (I) or a salt or solvate thereof.

The combination therapies of the invention can also be administered simultaneously. Simultaneous administration means a treatment regimen in which the individual components are administered together, in the form of a single pharmaceutical composition or device comprising or containing the two components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. These combinations of the separate individual components for simultaneous combination can be provided in the form of a kit of parts. 40

Therefore, in a further aspect, the invention provides a method for the treatment of a psychotic disorder by means of the adjuvant therapeutic administration of compounds of formula (I) or a salt or solvate thereof to a patient receiving administration. therapeutic of at least one antipsychotic agent. In a further aspect, the invention provides the use of compounds of formula (I) or a salt or solvate thereof in the preparation of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of at least one antipsychotic agent. The invention additionally provides compounds of formula (I) or a salt or solvate thereof for use for adjuvant therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of at least one antipsychotic agent.

In a further aspect, the invention provides a method for the treatment of a psychotic disorder by means of the adjuvant therapeutic administration of at least one antipsychotic agent to a patient receiving the therapeutic administration of compounds of formula (I) or a salt or solvate of them. In a further aspect, the invention provides the use of at least one antipsychotic agent in the preparation of a medicament for the adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of compounds of formula (I) or a salt or solvate thereof. The invention 55 additionally provides at least one antipsychotic agent for use for adjuvant therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of compounds of formula (I) or a salt or solvate thereof.

In a further aspect, the invention provides a method for the treatment of a psychotic disorder by means of the simultaneous therapeutic administration of compounds of formula (I) or a salt or solvate thereof in combination with at least one antipsychotic agent. The invention further provides the use of a combination of compounds of formula (I) or a salt or solvate thereof and at least one antipsychotic agent in the preparation of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides the use of compounds of formula (I) or a salt thereof in the preparation of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides compounds of formula (I) or a salt thereof for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides the use of at least one antipsychotic agent in the preparation of a medicament for simultaneous therapeutic administration with compounds of formula (I) or a salt thereof in the treatment of a psychotic disorder.

In a further aspect, the invention provides a kit of parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising compounds of formula (I) or a salt or solvate thereof and one or more forms of additional dosages each comprising an antipsychotic agent for simultaneous therapeutic administration.

In another aspect, the invention provides a method of treating a psychotic disorder by the adjunctive therapeutic administration of a compound of the present invention to a patient receiving the therapeutic administration of an active ingredient selected from the group consisting of: a stabilizer of mood, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer.

In a further aspect, the invention provides the use of a compound of the present invention in the preparation of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of an active ingredient selected from the group. consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer.

The invention also provides the use of a compound of the present invention in adjuvant therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer. 30

The invention further provides the use of a compound of the present invention for use in adjuvant therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of an active ingredient selected from the group consisting of: a stabilizer of the state of Mood, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer. 35

In a further aspect, the invention provides a method for the treatment of a psychotic disorder by the adjunctive therapeutic administration of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer to a patient receiving therapeutic administration of a compound of the present invention. 40

In a further aspect, the invention provides the use of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer in the preparation of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of a compound of the present invention. Four. Five

The invention also provides the use of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer for adjunctive therapeutic administration for the treatment of a disorder psychotic in a patient receiving therapeutic administration of a compound of the present invention

In a further aspect, the invention provides a method of treating a psychotic disorder by the simultaneous therapeutic administration of a compound of the present invention in combination with an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer.

The invention further provides the use of a combination of a compound of the present invention and an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and an enhancer cognitive, in the

Preparation of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.

The invention further provides the use of a combination of a compound of the present invention and an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer , for 5 simultaneous therapeutic administration in the treatment of a psychotic disorder.

The invention further provides the use of a compound of the present invention in the preparation of a medicament for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for Extrapyramidal side effects and a cognitive enhancer in the treatment of a psychotic disorder. 10

The invention further provides the use of a compound of the present invention for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and an enhancer Cognitive in the treatment of a psychotic disorder.

The invention further provides a compound of the present invention for use for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and an enhancer Cognitive in the treatment of a psychotic disorder.

The invention also provides the use of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer, in the manufacture of a medicament for administration simultaneous therapy with a compound of the present invention in the treatment of a psychotic disorder.

The invention also provides the use of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer, for simultaneous therapeutic administration with a compound of the The present invention in the treatment of a psychotic disorder.

In a further aspect, the invention provides a kit of parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising a compound of the present invention and one or more additional dosage forms, each comprising an ingredient. active selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer for simultaneous therapeutic administration.

Examples of antipsychotic drugs that may be useful in the present invention include, but are not limited to: sodium channel blockers; mixed antagonists of the 5HT receptor / dopamine receptor; mGluR5 positive modulators; D3 antagonists; 5HT6 antagonists; alpha-7 nicotinic receptor modulators; GlyT1 glycine transporter inhibitors; partial D2 agonist / D3 antagonist / H3 antagonist; 35 AMPA modulators; NK3 antagonists such as osanetant and talnetant; an atypical antipsychotic, for example clozapine, olanzapine, risperidone, quetiapine, aripyrazole, ziprasidone and amisulpride; butyrophenones, such as haloperidol, pimozide and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, tiflupromazine, prochlorperazine and acetophenazine; thioxanthenes, such as thiothixen and chlorprothixen; thienobenzodiazepines; dibenzodiazepines; benzoisoxazoles; dibenzothiazepines; imidazolidinones; 40 benzoisothiazolyl piperazines; triazine such as lamotrigine; dibenzoxacepins, such as loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that have antipsychotic activity.

Examples of trade names and suppliers of selected antipsychotic drugs that may be suitable for use in the present invention are: clozapine (available under the trade name CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the trade name 45 ZYPREXA®, from Lilly; ziprasidone (available under the trade name GEODON®, from Pfizer); risperidone (available under the trade name RISPERDAL®, from Janssen); quetiapine fumarate (available under the name trade name SEROQUEL®, from AstraZeneca); sertindole (available under the trade name SERLECT®); amisulpride (available under the trade name SOLION®, from Sanofi-Synthelabo); haloperidol (available under the trade name HALDOL®, from Ortho-McNeilo) ; haloperidol decanoate (available under the trade name HALDOL 50 decanoate®); haloperidol lactate (available under the trade names HALDOL® and INTENSOL®); chlorpromazine (available under the trade name THORAZINE®, from SmithKline Beecham (GSK); fluphenazine (available under the trade name PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); fluphenazine decanoate (available under the trade name PROLIXIN from canoate®); fluphenazine enanthate (available under the trade name PROLIXIN®); fluphenazine hydrochloride 55 (available under the trade name PROLIXIN®); thiothixen (available under the trade name NAVANE®; from Pfizer); thiothixen hydrochloride (available under the trade name PAVANE®); trifluoperazine (10- [3- (4-methyl-1-piperazinyl) propyl] -2- (trifluoromethyl) phenothiazine dihydrochloride, available under the trade name STELAZINE®, from

SmithKline Beckman; Perphenazine (available under the trade name TRILAFON®; from Schering); Perfenazine hydrochloride and amitriptyline (available under the trade name ETRAFON TRILAFON®); thioridazine (available under the trade name MELLARIL®; from Novartis, Roxane, HiTech, Teva, and Alpharma); molindone (available under the trade name MOBAN®, from Endo); molindone hydrochloride (available under the trade name MOBAN®); loxapine (available under the trade name LOXITANE®; from Watson); loxapine hydrochloride (available under the trade name LOXITANE®); and loxapine succinate (available under the trade name LOXITANE®). In addition, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®)) can be used.

Other suitable antipsychotic drugs include promazine (available under the trade name SPARINE®), triflurpromazine (available under the trade name VESPRIN®), chlorprotixen (available under the trade name TARACTAN®), droperidol (available under the trade name INAPSINE®), acetofenazine (available under the trade name TINDAL®;), prochlorperazine (available under the trade name COMPAZINE®), metotrimeprazine (available under the trade name NOZINAN®), pipothiazine (available under the trade name PIPOTRIL®), iloperidone, pimozide and flupentixol .

Antipsychotic drugs indicated above by the trade name may also be available from other providers with a different trade name. fifteen

In a further aspect of the invention, suitable antipsychotic agents include olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone, talnetant and osanetant.

Mood stabilizers that can be used in the therapy of the present invention include lithium, sodium valproate / valproic acid / divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine and thiagabine. twenty

Antidepressant drugs that can be used in the therapy of the present invention include serotonin antagonists, CRF-1 antagonists, dual Cox-2 / SSRI inhibitors; triple dopamine / noradrenaline / serotonin reuptake inhibitors; NK1 antagonists; dual antagonists of NK1 and NK2; dual NK1 / SSRI antagonists; NK2 antagonists; serotonin agonists (such as rauwolscin, yohimbine and metoclopramide); serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, fluvoxamine, femoxetine, indalpine, zimeldine, paroxetine and sertraline); dual serotonin / noradrenaline reuptake inhibitors (such as venlafaxine, reboxetine, duloxetine and milnacipran); norepinephrine reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); 5HT3 antagonists (such as, for example, ondansetron and granisetron); and others (such as bupropion, aminaptin, radafaxine, mianserin, mirtazapine, nefazodone and trazodone).

Anxiolytics that can be used in the therapy of the present invention include V1b antagonists, 5HT7 antagonists and benzodiazepines such as alprazolam and lorazepam.

The drugs for extrapyramidal side effects that can be used in the therapy of the present invention include anticholinergics (such as benztropine, biperidene, procyclidine and trihexyphenyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine).

Cognitive enhancers that can be used in the therapy of the present invention include, for example, cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine), H3 antagonists and M1 muscarinic receptor agonists (such as cevimeline). 40

In one embodiment, the active ingredient for use in combination with a compound of the present invention is an atypical antipsychotic, for example clozapine, olanzapine, risperidone, quetiapine, aripyrazole, ziprasidone or amisulpride.

In one embodiment, the active ingredient for use in combination with a compound of the present invention is a typical antipsychotic, for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perfenazine, prochlorperazine, trifluoperazine, thiothixin, haloperidol, tiflurpromazine, pimozid, droperzid, chloropridix , molindone or loxapine. Four. Five

In another embodiment, the active ingredient for use in combination with a compound of the present invention is a mood stabilizer, for example lithium, sodium valpropate / valproic acid / divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine or thiagabine.

In another embodiment, the active ingredient for use in combination with a compound of the present invention is an antidepressant, for example a serotonin optician (such as rauwolscin, yohimbine or metoclopramide); a serotonin reuptake inhibitor (such as citalopram, escitalopram, fluoxetine, fluvoxamine, femoxetine, indalpine, zimeldine, paroxetine or sertraline); a double serotonin / noradrenaline inhibitor (such as venlafaxine, reboxetine, duloxetine or milnacipran); a norepinephrine reuptake inhibitor (such as reboxetine); a tricyclic antidepressant (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline or trimipramine); a monoamine oxidase inhibitor (such as isocarboxazide, moclobemide, phenelzine or tranylcypromine); or others (such 55

such as bupropion, aminaptin, radafaxine, mianserin, mirtazapine, nefazodone or trazodone). In another embodiment, the active ingredient for use in combination with a compound of the present invention is an anxiolytic, for example a benzodiazepine such as alprazolam or lorazepam.

For use in medicine, the compounds of the present invention are usually administered in the form of a normal pharmaceutical composition. Therefore, the present invention, in a further aspect, provides a pharmaceutical composition comprising a compound of formula (I) as described hereinbefore or a salt or solvate thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be used in the treatment of any of the conditions described herein.

The compounds of formula (I) may be administered by any convenient method, for example, by oral, parenteral (e.g., intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions must be adapted from I agree with that.

The compounds of formula (I) as described hereinbefore and their salts or solvates that are active when administered orally can be formulated as liquids or solids, for example, syrups, suspensions or emulsions, tablets, capsules and dragees. .

A liquid formulation in general will consist of a suspension or solution of the compound or salt or solvate in a suitable liquid vehicle or vehicles, for example, an aqueous solvent such as water, ethanol or glycerin, or a non-aqueous solvent, such as polyethylene glycol or an oil The formulation may also contain a suspending agent, preservative, flavoring agent or coloring agent.

A composition in the form of a tablet can be prepared using any pharmaceutically acceptable carrier or vehicles commonly used to prepare solid formulations. Examples of such vehicles include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using standard encapsulation procedures. For example, granules containing the active ingredient can be prepared using standard carriers and then loaded into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any pharmaceutically acceptable carrier or vehicles, for example, aqueous gums, celluloses, silicates, or oils, and then loading the dispersion or suspension into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or salt or solvate in a sterile aqueous vehicle or parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just before administration. 30

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent, and are usually presented in amounts of a single dose or multiple doses in sterile form in a closed container, which can be shaped. of a cartridge or recharged for use with an atomization device. Alternatively, the closed container may be a unit dispensing device such as a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve that is intended to be discarded once the contents of the package have been finished. When the dosage form comprises an aerosol dispenser, it will contain a propellant that can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also be in the form of a pump atomizer. 40

Compositions suitable for oral and sublingual administration include tablets, grajeas and tablets, in which the active ingredient is formulated with a vehicle such as sugar and gum arabic, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter. Four. Five

Compositions suitable for transdermal administration include ointments, gels and patches. The composition may be in a unit dose form such as a tablet, capsule or blister.

Each dosage unit for oral administration preferably contains from 1 to 250 mg (and for parenteral administration preferably contains from 0.1 to 25 mg) of a compound of the formula (I) or a salt thereof calculated as the free base. . fifty

The compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, such as between 10 mg and 400 mg, e.g. ex. between 10 and 250 mg or an intravenous, subcutaneous or intramuscular dose of between 0.1 mg and 100 mg, such as between 0.1 mg and 50 mg, e.g. ex. between 1 and 25 mg of the compound of the formula (I) or a salt thereof calculated as the free base,

administering the compound 1 to 4 times a day. Suitably, the compounds will be administered during a period of continuous therapy, for example for a week or more.

The antipsychotic agent component or components used in the adjuvant therapy of the present invention can also be administered in their acidic or basic forms as appropriate or, when appropriate, as a salt or other derivative. All solvates and all alternative physical forms of the agent or antipsychotic agents or their salts or derivatives as described herein, including but not limited to alternative crystalline forms, amorphous and polymorphic forms, are also within the scope of this invention. In the case of the antipsychotic agent or agents, the forms and derivatives are, for example, those that are approved for therapeutic administration as monotherapies, including those mentioned above, but all references to antipsychotic agents herein include all salts or other derivatives. , and all 10 solvates and alternative physical forms thereof.

For adjuvant therapeutic administration according to the invention, the compounds of formula (I) or salts or solvates and the antipsychotic agent or agents or their salts, derivatives or solvates can be administered, each, in pure form, but each of the Components will be formulated, for example, in any pharmaceutically acceptable and effective composition that provides effective levels of the respective component in the body. The choice of the most appropriate pharmaceutical compositions for each component is within the skill in the art, and may be the same or different forms for each of the components. Suitable formulations include, but are not limited to, tablets, powders, granules, dragees, suppositories, reconstitutable powders or liquid preparations such as oral or sterile parenteral solutions or suspensions.

For simultaneous administration as a combined composition of compounds of formula (I) and the antipsychotic agent or agents according to the invention, the compounds of formula (I) or their salts and solvates and the antipsychotic agent or agents and their salts, derivatives or solvates can be co-administered in pure form, but the combined components will be formulated, for example, in any pharmaceutically acceptable and effective composition that provides effective levels of each of the components in the body. The choice of the most appropriate pharmaceutical compositions for the combined components is within the skill in the art. Suitable formulations include, but are not limited to, tablets, sublingual tablets, buccal compositions, capsules, powders, granules, dragees, suppositories, reconstitutable powders or liquid preparations such as sterile oral or parenteral solutions or suspensions.

In order to achieve consistency of adjuvant administration, the compositions of each of the components or of the combination of the components are, for example, in the form of a unit dose. 30

The term "treatment" includes prophylaxis, when it is appropriate for the relevant condition or conditions.

Biological test methods

FLIPR experiments on M1 receptors to determine agonist / antagonist potency

The compounds of the invention were characterized in a functional assay to determine their ability to activate the intracellular calcium pathway in CHO cells with stable expression of human muscarinic receptors using FLIPR (Fluorometric Imaging Plate Reader) technology. In summary, CHO-M1 cells (20,000 / well) were grown and allowed to grow overnight at 37 degrees. The medium was removed and 30 µl of loading buffer containing FLIPR Calcium 3 dye (Molecular Devices Co., Sunnyvale, CA) was added according to the manufacturer's instructions. After incubation at 37 degrees for 45-60 minutes, 10 µl of the test buffer containing the test compounds was added to each well in a FLIPR instrument. The calcium response was monitored to determine agonism. The plates were then incubated for another 10-15 minutes before adding 10 µl of assay buffer containing acetylcholine as exposure to the agonist. The calcium response was then checked again to determine the antagonism of the compound to acetylcholine. Concentration-response curves of both agonism and antagonism were performed on M1 receptors for each compound. The results were taken to a series of ActivityBase data analysis (ID Business Solution Inc., Parsippany, NJ) 45 where the curves were analyzed by a non-linear curve fit and the resulting pCE50 / pCI50 values were calculated.

FLIPR experiments on M1 receptors to determine intrinsic agonist activity

To determine the intrinsic activities of M1 agonist compounds, compounds of the invention were characterized in FLIPR experiments with U2OS cells with transient expression of human M1 50 muscarinic receptors. In summary, U20S cells were transduced with M1 BacMam virus (#) in 2 x 10e5 / ml cell suspension with a virus / cell ratio of 0.1% (v / v). The relationship between viruses and cells was determined in separate experiments through the most appropriate functional assessment to measure the intrinsic activities of partial agonists. After mixing with virus in suspension, the cells were then cultured (10,000 / well) and allowed to grow overnight at 37 degrees. A FLIPR experiment was then performed the next day using the same protocol as described above for CHO-M1 cells. The results were taken to a series of ActivityBase data analysis where the curves were analyzed by means of a non-linear curve fit and

calculated the resulting pCE50 values. The intrinsic activities of the agonist compounds were calculated as a percentage of the maximum FLIPR response induced by acetylcholine added as a control on the same compound plates, and became a fraction between 0 and 1.

#: Ames, R S; Fornwald, J A; Nuthulaganti, P; Trill, J J; Foley, J J; Buckley, P T; Kost, T A; Wu, Z and Romanos, M A. (2004) Use of BacMam recombinant baculoviruses to support G protein-coupled receptor drug discovery. Receptors 5 and Channels 10 (3-4): 99-109

The exemplified compounds have a pCE50 value of> 6.0 in the M1 muscarinic receptor, and an intrinsic activity> 0.5.

FLIPR experiments on M2-5 receptors to determine selectivity by receptor subtypes

To determine the selectivity of the compounds of the invention against other subtypes of muscarinic receptors, the compounds were characterized in FLIPR experiments in CHO cells with stable expression of human muscarinic receptors M2, M3, M4 or M5. In the case of M2 and M4 receptors, the Gqi5 chimeric G protein was also coexpressed to couple receptors to the calcium signaling pathway. In summary, the cells were cultured (20,000 / well) and allowed to grow overnight at 37 degrees. A FLIPR experiment was then performed the next day using the same protocol as described above for CHO-M1 cells. The 15 results were taken to a series of ActivityBase data analysis where the curves were analyzed by means of a non-linear curve fit and the resulting pCE50 / pCI50 values were calculated.

The exemplified compounds are selective for the M1 receptor with respect to the M2, M3, M4 and M5 receptors, with a typical selectivity (ratio of pCE50 values) of ≥ 10 times, and in certain cases ≥ 100 times.

The invention is further illustrated by the following non-limiting examples. twenty

MDAP refers to mass-directed automated purification using reverse phase chromatography on a stationary C18 phase eluted with 0.1% acetonitrile / water / formic acid.

SCX refers to a sulfonic acid ion exchange resin supplied by Varian.

All reactions were performed under an argon atmosphere or can be performed under an argon atmosphere, unless otherwise indicated (for example, hydrogenation reactions). 25

Description 1. 2-Fluoro-6-iodo-4-methylaniline (D1)

A solution of 2-fluoro-4-methylaniline (1.0 g, 8 mmol) (purchased from Avocado, Lancaster or Aldrich) in glacial acetic acid (10 ml) was treated with sodium acetate trihydrate (2.2 g, 16 mmol ) and then with iodine monochloride (1.3 g). After 30 min at room temperature, aqueous sodium bicarbonate / sodium sulphite and diethyl ether were added and the organic phase was dried (MgSO4), evaporated and chromatographed on silica eluting with 0 to 30% ethyl acetate in hexane to give the title compound, 370 mg.

Description 2. 1-Fluoro-3-iodo-2-isocyanate-5-methylbenzene (D2)

A mixture of 2-fluoro-6-iodo-4-methylaniline (D1) (370 mg, 1.5 mmol), triphosgene (150 mg, 0.05 mmol) and dioxane (3 35 mL) was heated at reflux for 1 h and 15 min and then cooled and evaporated to give the crude title compound.

Description 3. 4 - ({[(2-Fluoro-6-iodo-4-methylphenyl) amino] -carbonyl} amino) -1-piperidinecarboxylate of 1,1-dimethylethyl (D3)

A mixture of the crude 1-fluoro-3-iodo-2-isocyanate-5-methylbenzene of the description D2, 4-amino-1-N-Boc-piperidine (200 mg, 1 mmol) and dichloromethane (3 ml) was stirred at room temperature for 1 h and then purified directly by chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. Another purification by MDAP (mass directed self-purification) gave the title compound 300 mg.

Description 4. 4- (4-Fluoro-6-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-1-yl) -1-1,1-dimethylethyl piperidinecarboxylate (D4)

 10

Under an argon atmosphere, a mixture of 1,4-dioxane (3 ml), 1,1'-bis (diphenylphosphino) ferrocene dichloride (10 mol%, 0.0623 mmol, ~ 50 mg) was sonicated, NatBuO (2 equiv., 1.26 mmol, 121 mg) for 10 minutes at room temperature, 4 - ({[(2-fluoro-6-iodo-4-methylphenyl) amino] carbonyl} amino) -1- 1,1-dimethylethyl (D3) piperidine carboxylate (1 equiv., 0.623 mmol, 300 mg) at room temperature and the mixture was heated at reflux at 80 ° C overnight. The reaction mixture was cooled to room temperature, poured into NH4Cl15 (saturated solution) and the aqueous solution obtained was repeatedly extracted with ethyl acetate; The organic extracts were combined, dried over Na2SO4, filtered and the solvent evaporated to yield the crude compound (250 mg) which was purified by MDAP to yield the title compound, 30 mg, 11%.

1 H NMR δ (DMSO, 400 MHz) 1.44 (9H, s), 1.68 (2H, broad d), 2.20 (2H, dddd), 2.32 (3H, s), 2.85 ( 2H, wide s), 4.05 (2H, wide m), 4.30 (1H, wide m), 6.72 (1H, d), 6.90 (1H, s), 11.3 (1H, s width). twenty

Description 4a. Scaling procedure of 1,1-dimethylethyl 4- (4-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1-piperidinecarboxylate (D4a)

Under an argon atmosphere, bis (3 ', 5'-dimethoxy-dibenzylideneacetone) palladium (0) (6 mol%, 1.1 mmol, 0.9 g), 1,1'-bis (diphenylphosphino) were dissolved ferrocene (6 mol%, 0.61 g), NatBuO (2 equiv., 36 mmol, ~ 3.5 g) in 1.4-25 dioxane (40 ml) and the system was purged with argon. The mixture was stirred at room temperature for 15 minutes and 4 - ({[(2-Bromo-6-fluoro-4-methylphenyl) amino] -carbonyl} amino) -1-piperidinecarboxylate of 1,1-dimethylethyl (D32) was added ) (7.7 g, 17.9 mmol) at room temperature and the mixture was heated at 80 ° C for 1.5 hours and then at 100 ° C for a further 2 hours; then, the mixture was cooled to room temperature, diluted with ethyl acetate and the phase

The organic obtained was washed with water and brine. The organic extracts were dried over Na2SO4, filtered and the solvent evaporated to yield the crude product that was purified by chromatography (ethyl acetate-n-hexane) to yield the title compound, 4.3 g, 70%, solid. pale gray, M + - H = 348.

Description 5. 4-Fluoro-6-methyl-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D5).

 5

1,1-Dimethyl ethyl D4 (0.072 mmol, 25 mg) 4- (4-fluoro-6-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-1-yl) -1-piperidinecarboxylate (0.072 mmol, 25 mg) was dissolved in dichloromethane (5 ml) and treated with HCl (3 ml of a 4M solution in 1,4-dioxane) at room temperature; The mixture was stirred at room temperature for two hours. The solvent was evaporated to produce the title compound, monohydrochloride salt, M + + H = 250.

Description 5a. Scaling procedure. 4-Fluoro-6-methyl-1- (4-piperidinyl) -1,3-10 dihydro-2H-benzimidazol-2-one hydrochloride (D5a)

1,1-Dimethyl ethyl 4- (4-fluoro-6-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-1-yl) -1-piperidinecarboxylate (~ 12.3 mmol, 4, 3 g) (D4a) in dichloromethane / methanol (50 ml / 20 ml) and treated with HCl (10 equiv., 0.123 mol, ~ 30 ml of a 4M solution in 1,4-dioxane) at room temperature; and the mixture was stirred at room temperature overnight. The solvent was evaporated and the solid obtained was triturated with diethyl ether to yield the title compound (3.5 g, approximately 12.3 mmol, brown solid) as the monohydrochloride salt, M + + H = 250.

Description 6. 1-Bromo-5-chloro-3-fluoro-2-isocyanatobenzene (D6).

2-Bromo-4-chloro-6-fluoroaniline (5 mmol, 1,125 g), bis (trichloromethyl) carbonate (1.7 mmol, 0.50 g) and 1.4-20 dioxane (10 ml) were mixed and the mixture was heated at 100 ° C for 15 minutes; then, the mixture was cooled to room temperature and filtered. The filtrate was concentrated to produce a mixture of products (2.2 g) containing the title compound, M + + MeO = 283 (LC-MS was performed in methanol).

Description 7. 4 - ({[(2-Bromo-4-chloro-6-fluorophenyl) amino] -carbonyl} amino) -1-piperidinecarboxylate 1,1-dimethylethyl (D7). 25

1,1-dimethylethyl (1 equiv.) 1-bromo-5-chloro-3-fluoro-2-isocyanatobenzene (D6) (4.4 mmol, 1.1 g) and 4-amino-1-piperidinecarboxylate (1 equiv. 4.4 mmol, 0.88 g). To the mixture was added dichloromethane (5 ml) at room temperature for 1 hour. THF (5 µl) was added at room temperature for one hour. Then, the solvent was evaporated and the crude material obtained was purified by chromatography to yield the title compound, 0.6 g, 30%. 30

1 H NMR δ DMSO, 400 MHz) 1.26 (2H, m), 1.39 (9H, s), 1.77 (2H, dd), 2.86 (2H, wide s), 3.60 (1H , m), 4.03 (2H, d),

6.48 (1H, d), 7.59 (1H, dd), 7.65 (1H, t), 7.78 (1H, s).

Description 8. 4- 1,1-Dimethylethyl (D8) 4- (6-Chloro-4-fluoro-2-oxo-2,3-dihydro-1 H -benzimidazol-1-yl) -1-piperidinecarboxylate (D8).

Under an argon atmosphere, 4 - ({[(2-bromo-4-chloro-6 fluorophenyl) amino] carbonyl} amino) -1-5 piperidinecarboxylate of 1,1-dimethylethyl (D7) (1.09 mmol) was mixed , 0.493 g), 1,4-dioxane (4.4 ml), Pd2dba3 (0.05 equiv., 0.054 mmol, 50 mg), BINAP (0.055 equiv., 0.059 mmol, 37 mg) and NatBuO (1.5 equiv., 1.63 mmol, 157 mg) and the mixture was heated at 80 ° C under an argon atmosphere for 4 days. The reaction mixture was cooled to room temperature, quenched with water and the aqueous solution obtained was extracted with ethyl acetate. The solvent was evaporated and the crude material was purified by MDAP. The fractions were collected and the solvent was evaporated to yield the title compound, 15 mg, 3%, M + - H = 368.

Description 9. 6-Chloro-4-fluoro-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D9).

1,1-Dimethylethyl (D8) 1,1-dimethyl ethyl 4- (6-chloro-4-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1-piperidinecarboxylate (D8) (0.203 mmol, 75 mg) ) and HCl (233 microliters of a 4M solution in 1,4-dioxane) and the mixture was stirred at room temperature for two hours. The solvent was evaporated to yield the title compound, monohydrochloride salt, complete conversion, M + + H = 270.

Description 10. 4-Nitro-3,5-difluorophenol (D10).

A solution of 3,5-difluorophenol (1.3 g, 10 mmol) in dichloromethane (50 ml) at 0 ° C was treated with nitric acid (70%, 0.7 ml, 10 mmol). The cooling bath was removed and after 30 min at room temperature the solution was washed with water, then dried over MgSO4, filtered and evaporated. The product was purified by silica gel chromatography eluting with 20 to 50% ethyl acetate in hexane to yield the title compound, 440 mg.

1H NMR δ (DMSO, 400 MHz): 6.7 (2H, d) and 11.8 (1H, s a).

Description 11. 4-Nitro-3,5-difluoroanisole (D11).

A mixture of 4-nitro-3,5-difluorophenol (D10) (440 mg, 2.5 mmol), potassium carbonate (600 mg, 4.6 mmol), iodomethane (1 ml) and dimethylformamide (5 ml) was stirred overnight at room temperature, then ethyl acetate and water were added and the solution was washed with water, then dried over MgSO4, filtered and evaporated to yield the title compound, pale brown oil, 370 mg.

1H NMR δ (DMSO, 400 MHz): 3.9 (3H, s) and 7.1 (2H, d).

Description 12. 4 - [(2-Nitro-3-fluoro-5-methoxyphenyl) amino] -piperidinecarboxylate of 1,1-dimethylethyl (D12).

4-Nitro-3,5-difluoroanisole (D11) (370 mg, 2 mmol) was dissolved in dry dimethylformamide (3 ml) and 10 diisopropylethylamine (0.4 ml) and 4-amino-1-piperidinecarboxylate of 1, 1-dimethyl ethyl (400 mg, 2 mmol) at room temperature. The mixture was stirred at room temperature for 18 h, then cooled to room temperature and water and ethyl acetate were added. The organic layer was dried over MgSO4, filtered, evaporated and the residue was crystallized from diethyl ether to yield the title compound, 380 mg. M- - H = 368.

Description 13a. 1,1-dimethylethyl 4-[(2-Amino-3-fluoro-5-methoxyphenyl) amino] -1-piperidinecarboxylate (D13a). fifteen

1,1-dimethylethyl (D12) 4-[(2-nitro-3-fluoro-5-methoxyphenyl) amino] -piperidinecarboxylate (D12) (380 mg, 1 mmol) was dissolved in ethanol (10 ml) and nickel was added Raney (50% aqueous suspension, 1 ml) at room temperature; The mixture was heated to 40 ° C and hydrazine monohydrate (0.5 ml) was added dropwise. After an additional 30 min, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent evaporated. The product was purified by silica gel chromatography eluting with 20 to 50% ethyl acetate in hexane to yield the title compound, 250 mg. M + - H = 340.

Description 13b. 1,1-dimethylethyl 4- (4-Fluoro-6-methoxy-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1-piperidinecarboxylate (D13b)

A mixture of 1,1-dimethylethyl 4 - [(2-amino-3-fluoro-5-methoxyphenyl) amino] -1-piperidinecarboxylate (D13a) (230 mg, 0.7 mmol), carbonyldiimidazole (150 mg, 1 , 0 mmol) and tetrahydrofuran (6 ml) was heated for 1 h at 50 ° C and then partitioned between dichloromethane and water. The organic layer was purified by chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane containing 0.2 M ammonia to give the title compound as white crystals, 47%, 120 mg, M- - H = 364.

Description 14. 4-Fluoro-6-methoxy-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D14).

 10

1,1-Dimethylethyl (D13b) 4- (4-fluoro-6-methoxy) -2-oxo-2,3-dihydro-1 H -benzimidazol-1-yl) -1-piperidinecarboxylate (D13b) (120 mg, 0 , 33 mmol) in methanol (2 ml) and dichloromethane (1 ml) and the mixture was treated with HCl (4 M in 1,4-dioxane, 1 ml) at room temperature. The mixture was stirred at room temperature for 4 h and then evaporated to give the title compound, 100 mg. M + - H = 266.

Description 15, 2- (2,3-Difluoro-4-nitrophenyl) diethyl malonate (D15). fifteen

To diethyl malonate (5.1 g, 32 mmol) in N-methylpyrrolidone (50 ml) at 0 ° C were added sodium hydride (1.6 gx 60% in oil) and then 2,3,4-trifluoronitrobenzene (5, 4 g, 31 mmol) in more N-methylpyrrolidone (10 ml) at 20 ° C. After 2 h at room temperature, the reaction was poured into aqueous ammonium chloride and extracted with ethyl acetate. Drying, (MgSO4), evaporation and chromatography of a 10% sample of the product (20 g of silica with 20 0-25% ethyl acetate in hexane) gave 0.5 g of a 1: 1 mixture of title compound and diethyl 2- (2,3-difluoro-6-nitrophenyl) malonate that was used directly in D16.

1H NMR δ (DMSO, 400 MHz): 1.2 (6H, m), 4.2 (4H, m), 5.45 and 5.6 (1H, 2 s), 7.5 and 7.8 ( 1H, 2 m), 8.1 (1H, m).

Description 16. 2,3-Difluoro-4-nitrophenylacetic acid (D16).

The mixture of diethyl 2- (2,3-difluoro-4-nitrophenyl) malonate and diethyl 2- (2,3-difluoro-6-nitrophenyl) malonate of D15 (0.5 g) was refluxed with acid 11 M hydrochloric acid (5 ml) overnight and then evaporated to give 320 mg of the title compound (pale yellow solid) as a 1: 1 mixture with 2,3-difluoro-6-nitrophenylacetic acid. M- - CO2H = 172.

Description 17. 2,3-Difluoro-4-nitrotoluene (D17) 5

The mixture of 2,3-difluoro-4-nitrophenylacetic acid and 2,3-difluoro-6-nitrophenylacetic acid of D16 (13.5 g) was dissolved in dimethylformamide (100 ml) and potassium carbonate (8.5 g ). After stirring at 50 ° C for 30 min, the cooled solution was partitioned between aqueous hydrochloric acid and hexane. Drying (MgSO4), evaporation and chromatography (0-5% ethyl acetate in hexane, 70 g silica column) gave 3.2 g of a 3: 1 mixture of the title compound and 2.3 -difluoro-6-nitrotoluene.

1H NMR δ (DMSO, 400 MHz): 2.4 and 2.5 (3H, m), 7.3 and 7.6 (1H, 2 m), 7.9 (1H, m).

Description 18. 2,3-Difluoro-4-methylaniline (D18).

The mixture of 2,3-difluoro-4-aminotoluene and 2,3-difluoro-6-nitrotoluene from D17 (3.2 g, 18 mmol) was dissolved in ethanol 15 (50 ml) and Raney nickel (5 ml) was added x 50% aqueous suspension). The mixture was heated to 40 ° C and hydrazine hydrate (3.7 ml, 74 mmol) was added portionwise for 30 min. After an additional 1 h at 40 ° C, the mixture was cooled, filtered, evaporated and the residue was partitioned between dichloromethane and water at pH 9. Drying (MgSO4), evaporation and chromatography (0-25 ethyl acetate % in hexane) gave 240 mg of the title compound.

1H NMR δ (DMSO, 400 MHz): 2.5 (3H, m); 5.2 (2H, broad s), 6.4 (1H, m), 6.7 (1H, m). twenty

Description 19. 2,3-Difluoro-6-iodo-4-methylaniline (D19).

A solution of 2,3-difluoro-4-methylaniline (D19) (240 mg, 1.7 mmol) in glacial acetic acid (2 ml) was treated with sodium acetate trihydrate (440 mg, 3.2 mmol) and then with iodine monochloride (300 mg, 1.8 mmol). After 30 min at room temperature, aqueous sodium bicarbonate / sodium sulphite and diethyl ether were added and the organic phase was dried (MgSO4) and evaporated to give the title compound, dark red gum (72%), 330 mg.

1H NMR δ (DMSO, 400 MHz): 2.1 (3H, s), 5.2 (2H, s a), 7.3 (1H, d).

Description 20- 2,3-Difluoro-6-iodo-4-methylphenyl isocyanate (D20).

A mixture of 2,3-difluoro-6-iodo-4-methylaniline D19 (330 mg, 1.2 mmol), triphosgene (150 mg, 0.5 mmol) and dioxane 30

(5 ml) was heated at 100 ° C for 15 min and then cooled and evaporated to give the crude title compound that was used directly in the next step.

Description 21. 4 - ({[(2,3-Difluoro-6-iodo-4-methylphenyl) amino] -carbonyl} amino) -1-piperidinecarboxylate of 1,1-dimethylethyl (D21).

 5

A mixture of the crude 2,3-difluoro-6-iodo-4-methylphenyl isocyanate of D20, 4-amino-1-N-Boc-piperidine (480 mg) and dichloromethane (5 ml) was stirred at room temperature for 18 h, then evaporated and purified directly by chromatography on 20 g of silica gel eluting with 10-50% ethyl acetate in hexane to give the title compound, 300 mg. M- - H = 494.

Description 22. 4- (4,5-Difluoro-6-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-1-yl) -1-1,1-dimethyl ethyl piperidinecarboxylate (D22).

1,1-Dimethylethyl D21 4-({[(2,3-difluoro-6-iodo-4-methylphenyl) amino] carbonyl} amino) -1-piperidinecarboxylate was dissolved in 1 ml of dioxane. Under an argon atmosphere, a mixture of 1,4-dioxane (3 ml), Pd2dba3 (35 mg, 0.4 mmol), NatBuO (120 mg, 1.20 mmol) and 1,1'-bis ( diphenylphosphino) ferrocene (21 mg, 0.4 mmol) for 10 minutes at room temperature, then 4 - ({[(2,3-difluoro-6-iodo-4-methylphenyl) amino] carbonyl} amino) - 1,1-dimethylethyl D21 1-piperidine carboxylate (300 mg) and the mixture was heated at 80 ° C for 2 h. The reaction mixture was cooled to room temperature, quenched with NH4Cl (saturated solution) and extracted with ethyl acetate. Drying (MgSO4), evaporation and crystallization from diethyl ether gave 150 mg of the title compound. M- - H = 366.

Description 23. 4,5-Difluoro-6-methyl-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D23). twenty

1,1-Dimethylethyl D22 4- (4,5-difluoro-6-methyl-2-oxo-2,3-dihydro-1 H -benzimidazol-1-yl) -1-piperidinecarboxylate (150 mg, 0, 4 mmol) in dichloromethane (5 ml) and the mixture was treated with HCl in 1,4-dioxane (1 ml x 4 M) at room temperature for 4 h. Then, the solvent was evaporated to yield the title compound, 120 mg. M + + H = 268. 25

Description 24. 5-Bromo-1,3-difluoro-2-nitrobenzene (D24)

To a suspension of sodium perborate tetrahydrate (1.78 mmol, 0.27 g) in 10 ml of stirred acetic acid at 65 ° C was added dropwise a solution of (4-bromo-2,6-difluorophenyl) amine (1 , 78 mmol, 0.42 g, 1 equiv.) In 5 ml of acetic acid for one hour. The reaction was heated at 65 ° C for 3 days. Sodium perborate 5 tetrahydrate (2 equiv., 3.56 mmol, 0.54 g) was added again. After 3 hours, sodium perborate tetrahydrate (1 equiv., 1.78 mmol, 0.27 g) was added again. Again, more sodium perborate tetrahydrate (3 equiv., 5.34 mmol, 0.81 g) was added. Then, the reaction was allowed to reflux overnight at 70 ° C and under an argon atmosphere. Then, the solution was cooled to room temperature, poured onto ice and extracted with ethyl acetate (2 x). The combined organic extracts were washed with water and brine. The organic extracts were dried over MgSO4, filtered and the organic solvent was removed under reduced pressure to yield the crude product which was purified by chromatography on silica (4% ethyl acetate-96% n-hexane) to yield the title compound, 0.29 g, 68%.

1 H NMR δ (d6DMSO, 400 MHz): 7,964 (2H, d).

Description 25. 5-Cyclopropyl-1,3-difluoro-2-nitrobenzene (D25)

 fifteen

5-Bromo-1,3-difluoro-2-nitrobenzene (D24, 560 mg, 2.35 mmol), cyclopropylboronic acid (1 equiv., 2.35 mmol, 0.2 g), K3PO4 (3 equiv. , 7.1 mmol, 1.50 g), NaBr (1 equiv., 2.35 mmol, 0.24 g) and Pd (PPh3) 4 (280 mg) to 3 ml of dry toluene and the mixture was heated with microwave at 160 ° C for 40 minutes. Then, the mixture was poured into water (10 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were dried over MgSO4, filtered and the solvent evaporated to yield 660 mg of the crude brown product which was purified by chromatography on silica gel (5-20% diethyl ether-40-60 ° petroleum ether) to produce the title compound as a yellow oil, 300 mg, 64%.

1 H NMR δ (d6DMSO, 400 MHz): 1.37 (2H, m), 1.60 (2H, m), 2.55 (1H, m), 7.71 (2H, d).

Description 26, 4 - [(5-Cyclopropyl-3-fluoro-2-nitrophenyl) amino] -1-piperidinecarboxylate 1,1-dimethylethyl (D26)

 25

To a solution of 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 equiv., 1.51 mmol, 302 mg) in dry dimethylformamide (10 ml) was added diisopropylethylamine (1 equiv., 1.51 mmol , 0.26 ml) and 5-cyclopropyl-1,3-difluoro-2-nitrobenzene (D25, 1 equiv., 1.51 mmol, 300 mg) at room temperature and the mixture was stirred under an argon atmosphere at 120 ° C during one night Then, the crude mixture was cooled to room temperature and poured into water (10 ml). The aqueous solution was extracted with ethyl acetate (3 x 100 ml) and the organic extracts were combined, washed alternately with water and brine (5 x 100 ml), dried over Na2SO4, filtered and the solvent evaporated to producing the crude compound that was purified by chromatography (30% ethyl acetate-60% n-hexane) to produce the title compound; 300 g, 0.79 mmol, 52%, M- - H = 378.

Description 27. 4 - [(2-Amino-5-cyclopropyl-3-fluorophenyl) amino] -1-piperidinecarboxylate of 1,1-dimethylethyl (D27)

1,1-dimethylethyl 4 - [(5-cyclopropyl-3-fluoro-2-nitrophenyl) amino] -1-piperidinecarboxylate (D26, 0.8 mmol, 300 mg) was dissolved in MeOH (15 ml) and reduced with a THALIS H-CUBE device (purchased from Asynt) using a 5 palladium cartridge. The process produced 280 mg of the title compound, complete conversion, M + - COOC (CH3) 3 = 250.

Description 28. 4- (6-Cyclopropyl-4-fluoro-2-oxo-2,3-dihydro-1 H -benzimidazol-1-yl) -1-piperidinecarboxylate 1,1-dimethylethyl (D28)

1,1-dimethylethyl 4 - [(2-amino-5-cyclopropyl-3-fluorophenyl) amino] -1-piperidinecarboxylate (D27, 0.80 mmol, 10 280 mg) was dissolved in 4 ml of tetrahydrofuran and CDI (1,1 '- (oxomethanediyl) bis-1H-imidazole) (2.5 equiv., 2.0 mmol, 0.33 g) at room temperature and the mixture was stirred at 50 ° C overnight in an atmosphere of argon. More CDI (1 equiv., 0.13 g, 0.80 mmol) was added and the mixture was heated at reflux for two more hours. The mixture was cooled to room temperature and the solvent was evaporated to yield the crude compound that was purified by chromatography (ethyl acetate (50) -n-hexane (50)) to yield the title compound, 102 mg, 36%, M- - H = 374. 15

Description 29. 6-Cyclopropyl-4-fluoro-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D29)

1,1-Dimethyl ethyl 4- (6-cyclopropyl-4-fluoro-2-oxo-2,3-dihydro-1 H -benzimidazol-1-yl) -1-piperidinecarboxylate (D28, 0.28 mmol, 107 mg) in 1 ml of dichloromethane, the mixture was treated with HCl (1 ml of a 4M solution in 1.4-20 dioxane) at room temperature and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated to yield the title compound, 100 mg, 0.32 mmol, complete conversion, M + + H = 276.

Description 30. 4,5-Difluoro-6-methyl-1- [1- (4-cyanotetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one (D30)

4,5-Difluoro-6-methyl-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D23, 90 mg, 0.3 mmol) was converted into its free base using SCX, and then it was mixed with tetrahydro-4H-pyran-4-one (100 mg, 1.2 mmol), 5 acetone cyanohydrin (100 mg, 1.2 mmol), magnesium sulfate (0.33 g) and dimethylacetamide (1 ml). The mixture was stirred in a slow stream of argon at 60 ° C overnight and then partitioned between water and dichloromethane. Drying and evaporation gave the crystalline title compound in diethyl ether, 70 mg.

1H NMR δ (DMSO, 400 MHz): 1.6-1.8 (4H, m), 2.1 - 2.4 (8H, m), 2.3 (3H, d), 3.2-3 , 5 (4H, m), 3.9 (1H, d), 4.2 (1H, m), 7.0 (1H, m). 10

Description 31. 2-Bromo-6-fluoro-4-methylaniline (D31)

A stirred solution of 4-methyl-2-fluoroaniline (15 g, 0.12 mol) in acetic acid (120 ml) at 15 ° C under an argon atmosphere was treated portionwise for 20 minutes with solid N-bromosuccinimide (24 g, 0.135 mol), then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was treated with water (500 ml) and extracted with ethyl acetate (2 x 300 ml). The combined extract was washed with water (2 x 500 ml) and then with an excess of 10% Na2CO3 solution (400 ml). The ethyl acetate solution was dried (Na2SO4) and concentrated in vacuo to give the title compound as a dark red oil (24.0 g, 98%).

1H NMR δ (CDCl3, 400MHz): 2.22 (3H, s), 3.95 (2H, s a), 6.78 (1H, d), 7.02 (1H, s).

Description 32. 4 - ({[(2-Bromo-6-fluoro-4-methylphenyl) -amino] carbonyl} amino) -1-20 piperidinecarboxylate of 1,1-20 dimethylethyl (D32)

2-Bromo-6-fluoro-4-methylaniline (5.2 g, 25.5 mmol) (D31) was dissolved in 1,4-dioxane (40 ml), bis (trichloromethyl) carbonate (9.3 mmol , ~ -2.7 g) at room temperature and the mixture was heated at 60 ° C for 15 minutes and then brought to 100 ° C for another 15 minutes. Then, the mixture was cooled to room temperature, filtered and the solvent evaporated thoroughly; The crude material was redissolved in dichloromethane (40 ml) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (2 equiv., 51 mmol, ~ 10.2 g) was added very slowly at room temperature. The mixture was stirred at room temperature for 1.5 hours, then the solvent was completely evaporated and then the crude material was left under vacuum for 10 minutes; dichloromethane was added again and the obtained mixture was filtered to produce a solid that was the first extraction (5.2 g) of the desired product; the solvent was evaporated from the organic filtrate and the obtained mixture was re-dissolved in dichloromethane and filtered again to produce the second extraction (1 g) of the desired product; The solvent was evaporated from the organic filtrate and the obtained mixture was re-dissolved in diethyl ether, filtered again and washed with methanol and then with diethyl ether to produce the third extraction (1.5 g) of the desired product. The three extractions were combined

to produce 7.7 g of the title compound, 70%, M + + H = 432.

Example 1a. 4-Fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one (E1a) hydrochloride.

4-Fluoro-6-methyl-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D5) (0.072 mmol, 21 5 mg) was dissolved in dichloromethane (2 ml) , triethylamine (3 equiv., 0.216 mmol, 30 microliters) and tetrahydro-4H-pyran-4-one (7 equiv., 0.5 mmol, 47 microliters) were added and the mixture was stirred at room temperature for 10 minutes; sodium triacetoxyborohydride (7 equiv., 0.5 mmol, 106 mg) was added at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent evaporated to produce the crude product. The crude material obtained was dissolved in 1,2-dichloroethane (3 ml), again triethylamine (3 equiv., 0.216 mmol, 30 microliters) and tetrahydro-4H-pyran-4-one (7 equiv., 0 , 5 mmol, 47 microliters) and the mixture was stirred at room temperature for 10 minutes; then sodium triacetoxyborohydride (7 equiv., 0.5 mmol, 106 mg) was added at room temperature and the mixture was stirred at room temperature for a further 3 hours. The reaction mixture was quenched with NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to yield the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to yield 4-fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran -4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one, 10 mg, 42%, M + + H = 334, which was converted to the HCl salt using 1M HCl in ether diethyl

1 H NMR δ (DMSO, 400 MHz, HCl salt) 1.74 (2H, m), 1.91 (2H, d), 2.03 (2H, d), 2.34 (3H, s), 2, 80 (2H, c), 3.17 (3H, m), 3.34 (2H, m), 4.00 (2H, dd), 4.56 (1H, m), 6.75 (1H, d ), 7.31 (1H, s), 10.5 (1H, wide s), 11.35 (1H, wide s); 20 remaining 1H signals not discernible by the spectrum

Example 1 b. Scaling procedure using an alternative process. 4-Fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one (E1b) free base

4-Fluoro-6-methyl-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one (12.5 mmol, 3.6 g) (D5a) was dissolved in dichloromethane (50 ml) and diisopropylethylamine (3 equiv., 37.6 mmol, ~ 6.4 ml) and tetrahydro-4H-pyran-4-one (4 equiv., 50 mmol, ~ 5 g) were added in that order at room temperature ; sodium triacetoxyborohydride (3 equiv., 37.6 mmol, ~ 8 g) was added at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (100 ml) and quenched with NaHCO3 (saturated aqueous solution); methanol was added to dissolve the solid that developed in the organic layer; the two phases were separated and the aqueous phase was extracted with dichloromethane (2 x); The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the solvent evaporated to yield 3.8 g, 92%. The material was triturated with diethyl ether and filtered to yield 3.6 g of the title compound. This was dissolved in MeOH / DCM and 2 equiv. of HCl (1 M in Et2O). The mixture was stirred at room temperature for 10 minutes, the solvent was evaporated and the solid was triturated with Et2O to yield another extraction, 3.8 g, pale gray solid. 35

1H NMR δ (DMSO, 600 MHz, free base) 1.45 (2H; m), 1.70 (4H, m), 2.25 (4H, m), 2.33 (3H, s), 2, 48 (1H, m), 3.01 (2H,

m), 3.33 (2H, t), 3.88 (2H, m), 4.12 (1H, m), 6.65 (1H, d), 6.88 (1H, s), and 11 , 3 (1H, wide s).

Example 1c Scaling procedure. 4-Fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one (E1c) hydrochloride

The free base of 4-fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-5 benzimidazol-2-one was suspended (102.73 mmol, 34.25 g, 1 by weight) in methanol (10 vol. 342 ml). 1M HCl in diethyl ether (154 ml, 1.5 equiv.) Was added dropwise over 20 min. The suspension was magnetically stirred at temp. atmosphere for 3 hours. The solvents were evaporated and the solid was triturated in diethyl ether (14.5 vol., 500 ml) for 20 min. The diethyl ether was decanted and the white solid dried under high vacuum at 40 ° C overnight. Residual MeOH (7% w / w by NMR) was discovered. The solid was dried under high vacuum overnight at 40 ° C. The solid was triturated in 10 diethyl ether (14.5 vol, 500 ml), filtered and dried again in the oven at 40 ° C / high vacuum for 4 hours, then at 60 ° C overnight and then at 80 ° C for two hours . 36.1 g, 95%.

1 H NMR δ (DMSO, 600 MHz, hydrochloride) 1.69 (2H, m), 1.89 (4H, m), 1.95 (2H, m), 2.31 (3H, s), 2.67 (2H, m), 3.17 (2H, m), 3.34 (2H, m), 3.42 (1H, m), 3.57 (2H, m), 3.98 (2H, m) , 4.52 (1H, m), 6.75 (1H, d), 7.15 (1H, sa), 9.95 (1H, m) and 11.36 (1H, s). fifteen

Example 1d. 4-Fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one (E1d) monocytrate.

The free base of 4-fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one ( 1,499 mmol, 500 mg, 1 by weight) in a 250 ml round bottom flask and citric acid (1 equiv., 1,499 mmol, 288 mg) was added. Acetonitrile (95 vol. 47.5 ml) was added, a white suspension was obtained and dissolution was not achieved with heating using a hot air gun. The suspension was magnetically stirred at 35 ° C for four days under nitrogen. The solid was cooled, isolated by vacuum filtration and washed with acetonitrile (10 vol. 5 ml). The solid (1.0 g not dried) was recombined with the mother liquor plus acetonitrile (29 vol., 14.5 ml) and n-propanol (22 vol. 11 ml) was added. The suspension was stirred at room temperature overnight. The solid was isolated by vacuum filtration and washed with acetonitrile (10 vol, 5 ml). The white solid was dried under vacuum at 60 ° C for 25 hours. 506 mg, 64%.

1 H NMR δ (DMSO, 400 MHz, citrate) 1.60 (2H, m), 1.86 (4H, m), 2.36 (3H, s), 2.50 (2H, m), 2.56 (2H, d), 2.64 (2H, d), 2.79 (2H, m), 3.04 (1H, m), 3.32 (4H, m), 3.98 (2H, dd) , 4.33 (1H, t), 6.75 (1H, d), 6.93 (1H, m), 11.27 (3H, m) and 11.29 (1H, s) 30

Example 1e 4-Fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one (E1e) methanesulfonate.

The free base of 4-fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one ( 1,499 mmol, 500 mg, 1 by weight) in a 250 ml round bottom flask and acetonitrile (95 vol., 5 47.5 ml) and n-propanol (80 vol., 40 ml) were added, giving a suspension white Methanesulfonic acid (1 equiv., 1,499 mmol, 97 µl) was pipetted into the flask. The contents of the flask were heated using a hot air gun - the suspension dissolved and a white precipitate formed. The precipitate was magnetically stirred at 35 ° C for four days under nitrogen. After cooling to room temperature, the solid was isolated by vacuum filtration and washed with acetonitrile (10 vol. 5 ml). The white solid was dried under high vacuum at 60 ° C for 25 hours. 561 mg, 87%, 10 white solid.

1 H NMR δ (DMSO, 500 MHz, methanesulfonate salt) 1.69 (2H, m), 1.96 (4H, m), 2.31 (3H, s), 2.34 (3H, s), 2, 64 (2H, m), 3.17 (2H, m), 3.34 (2H, m), 3.48 (1H, m), 3.62 (2H, d), 3.98 (2H, d ), 4.52 (1H, m), 6.75 (1H, d), 6.96 (1H, sa), 9.25 (1H, m) and 11.36 (1H, s).

Example 1f. Alternative method for 4-fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-15 2H-benzimidazol-2-one

Step 1 Preparation of 1,1-dimethylethyl (3,5-difluoro-4-nitrophenyl) acetate

A mixture of potassium tert-butoxide (248 g) in NMP (2000 ml) was cooled under a nitrogen atmosphere at -20 ° C. A mixture of 2,6-difluoronitrobenzene (100 g) and tert-butyl chloroacetate (160 g) in NMP 20 (2000 ml) at -10 ° C to -20 ° C for 1.5 hours was added slowly. After 30 minutes, one more portion of potassium tert-butoxide (88 g) was added. The reaction mass was interrupted in 1600 ml of 2M HCl and 1 kg of crushed ice, then 2000 ml of hexane was added and the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (2 x 1500 ml). The combined hexane layers were washed with saturated brine (2 x 1000 ml), then dried over anhydrous sodium sulfate and then filtered and washed with 200 ml of hexane. Then, the solution was evaporated to give the title compound as a brown liquid (152 g).

Stage 2 Preparation of (3,5-difluoro-4-nitrophenyl) acetic acid

1,1-dimethylethyl acetate (3,5-difluoro-4-nitrophenyl) acetate (150 g) and 4M HCl in 1,4-dioxane (1150 ml) were stirred for 18 h at approximately 25 ° C. Nitrogen was bubbled through the mixture to remove excess HCl for 7-30 hours and then the mixture was concentrated. The toluene (300 ml) was distilled off and then the residue was stirred with hexane (300 ml) for 10 minutes. The hexane was removed by decantation, the residue was stirred with hexane (150 ml) for 10 minutes and then the hexane was removed by decantation. The residue was stirred with toluene (450 ml) for 2 hours at approximately 25 ° C. The solid was filtered, washed with 1: 1 toluene / hexane (300 ml) and then

dried under vacuum to give the title compound as a fine brown powder (41.5 g).

300 MHz NMR in DMSO-d6. DMSO-d5 as a reference at 2.5 ppm.

δ (ppm): 3.78 (2H) s; 7.44 (2H) d;

Step 3 Preparation of 1,3-Difluoro-5-methyl-2-nitrobenzene

 5

A mixture of (3,5-difluoro-4-nitrophenyl) acetic acid (41 g), potassium carbonate (24.6 g) and DMF (205 ml) was slowly heated at about 50 ° C for 30 minutes. Then, the reaction was cooled to about 25 ° C, quenched in 2M HCl (1025 ml) and hexane (400 ml) and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (400 ml). The combined hexane layers were washed with saturated brine (2 x 200 ml), then dried with anhydrous sodium sulfate and the solution was concentrated to give the title compound as a solid with a low melting point (26 g ).

300 MHz NMR in CDCl3. TMS as a reference at 0.0 ppm.

δ (ppm): 2.44 (3H) s; 6.91 (2H) d

Step 4 Preparation of 1- (tetrahydro-2H-pyran-4-yl) -4-piperidinamine, dihydrochloride

 fifteen

To a solution of 1,1-dimethylethyl 4-piperidinylcarbamate (50 g) was added tetrahydro-4H-pyran-4-one (35.75 g) in dry DCM (1000 ml) and then sodium triacetoxyborohydride was added portionwise (141 g) for 10 minutes at approximately 25 ° C. The mixture was stirred under a nitrogen atmosphere for approximately 30 hours and then cooled to 0 ° C. Water (107 ml) was added portionwise for 20 minutes followed by saturated aqueous potassium carbonate (178 ml) and saturated brine (178 g in 178 ml). The mixture was stirred for 10 minutes at about 25 ° C, then the layers were separated and the organic layer was washed with saturated brine (3 x 214 ml). After drying over anhydrous sodium sulfate, the organic layer was concentrated and the residue was treated with 100 ml of isopropanol and reconcentrated. The residue was slowly heated to reflux with 11% HCl in isopropanol (200 ml) for 2 hours and then cooled to about 25 ° C. The solid was filtered and the suspension was washed with diethyl ether (100 ml) and then dried under high vacuum to give the title product (43 g). 25

300 MHz NMR in D2O. HDO signal as a reference at 4.70 ppm.

δ (ppm): 1.72 (2H) m; 1.88 (2H) m; 1.99 (2H) m; 2.29 (2H) m; 3.08 (2H) m; 3.40 (4H) m; 3.65 (2H) m; 4.02 (2H) m

Step 5 Preparation of N- (3-fluoro-5-methyl-2-nitrophenyl) -1- (tetrahydro-2H-pyran-4-yl) -4-piperidinamine

A mixture of 1,3-difluoro-5-methyl-2-nitrobenzene (1 g), 1- (tetrahydro-2H-pyran-4-yl) -4-piperidinamine, dihydrochloride (1.63 g), sodium bicarbonate ( 1.94 g) and tetrabutylammonium iodide (100 mg) in NMP (15 ml) was slowly heated to approximately 50 ° C for 3 hours. After cooling to approximately 25 ° C, the reaction mixture was added to ethyl acetate (15 ml) and saturated brine (15 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (15 ml). Then, the combined ethyl acetate layers were washed with saturated brine (4 x 4 ml), dried with 2 g of anhydrous sodium sulfate and then concentrated in vacuo. The residue was heated with acetonitrile (4 ml) at approximately 60 ° C to give a solution, then cooled from 0 to 5 ° C and stirred for 1 hour. The solid was filtered, washed with cooled acetonitrile (2 ml) and then dried at 40-45 ° C under high vacuum to give the title compound as an orange solid (0.83 g). 10

300 MHz NMR in CDCl3. TMS as a reference at 0.0 ppm.

δ (ppm): 1.62 (4H) m; 1.76 (2H) m; 2.05 (2H) m; 2.30 (3H) s; 2.42 (2H) m; 2.51 (1 H) m; 2.88 (2H) m; 3,390 (2H) m; 3.49 (1 H) m; 4.05 (2H) m; 6.23 (1H) d; 6.36 (1H) s; 7.51 (1 H) m;

Step 6 Preparation of (2-amino-3-fluoro-5-methylphenyl) [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] amine

 fifteen

A mixture of N- (3-fluoro-5-methyl-2-nitrophenyl) -1- (tetrahydro-2H-pyran-4-yl) -4-piperidinamine (10 g), ethyl acetate (200 ml) and Pd 10% / C (1 g), stirred at approximately 30 ° C under hydrogen pressure for 9 hours. The catalyst was filtered and the filtrate was concentrated. The residue was stirred with ethyl acetate (20 ml) and hexane (40 ml) for 1 hour at room temperature, then filtered and the solid dried at 50 ° C to give the title compound as a solid (6.3 g). twenty

300 MHz NMR in CDCl3. TMS as a reference at 0.0 ppm.

δ (ppm): 1.50 (2H) m; 1.64 (2 H) m; 1.76 (2H) m; 2.08 (2H) m; 2.23 (3H) s; 2.34 (2 H) m; 2.50 (1 H) m; 2.94 (2H) m; 3.07 (2H) s a; 3.27 (1 H) m; 3.38 (2H) m; 4.02 (2H) m; 6.23 (1H) s; 6.32 (1H) d;

Step 7 Preparation of 4-fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one

A mixture of (2-amino-3-fluoro-5-methylphenyl) [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] amine (0.5 g), N, N'-carbonyldiimidazole ( 0.66 g) and tetrahydrofuran (7 ml) was heated to reflux. After 30 minutes, tetrahydrofuran (3 ml) was added and the mixture was heated at reflux for an additional 1.5 hours. The reaction mixture was filtered, washed with tetrahydrofuran (10 ml) and then the solid was dried at 40-45 ° C under high vacuum to give the title compound (0.323 g).

300 MHz NMR in CDCl3 + TFA + 1 drop of DMSO-d6. TMS as a reference at 0.0 ppm. δ (ppm): 2.00 (2H) m; 2.12 (2H) m; 2.22 (2H) m; 2.37 (3H) s; 2.92 (2H) m; 3.24 (2H) m; 3.60 (3H) m; 3.87 (2H) m; 4.29 (2H) m; 4.63 (1 H) m; 6.81 (1H) 10 d; 6.84 (1H) s;

Example 2. 6-Chloro-4-fluoro-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one (E2) hydrochloride ).

6-Chloro-4-fluoro-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one D9 hydrochloride (0.36 mmol, 0.1 g) was dissolved in dichloromethane (10 ml), triethylamine (3 equiv., 1.08 mmol, 80 microliters), tetrahydro-4H-pyran-4-one (4.5 equiv., 1.62 mmol, 162 mg) and sodium triacetoxyborohydride (4, 5 equiv., 1.62 mmol, 345 mg) at room temperature and the mixture was stirred at room temperature for 2 hours. More tetrahydro-4H-pyran-4-one (2 equiv., 0.72 mmol, 72 microliters) and sodium triacetoxyborohydride (2 equiv., 0.72 mmol, 0.015 g) were added at room temperature and the mixture was stirred at room temperature for two more hours. The mixture was quenched with water and brought to pH = 10 with sodium hydroxide (aqueous solution). The organic phase was separated from the aqueous phase (with hydrophobic filters) and the organic solvent was evaporated to yield the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to yield 6-chloro-4-fluoro-1- [ 1- (tetrahydro-2H-piran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one, 15 mg, 11%, M + + H = 354 and 356, which became in the hydrochloride salt using 1M HCl in diethyl ether. 25

1 H NMR (free base) δ (DMSO, 400 MHz) 1.45 (2H, m), 1.68 (4H, t), 2.29 (4H, m), 3.00 (2H, d), 3 , 27 (2H, t), 3.89 (2H, dd), 4.10 (1H, broad m), 7.08 (1H, d), 7.20 (1H, s), 11.6 (1H , s width); the remaining 1H signals were not discernible by the spectrum.

Example 3. 4-Fluoro-6-methoxy-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E3) ).

4-Fluoro-6-methoxy-5-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one D14 hydrochloride (100 mg, 0.33 mmol), Ti (iPrO) was stirred 4 (0.3 ml, 1.0 mmol) and tetrahydro-4H-pyran-4-one (100 mg, 1.0 mmol, 0.3 ml) at room temperature for 1 h; Dry methanol (2 ml) was added followed by NaBH3CN (60 mg, 1 mmol) and the mixture was stirred at room temperature for 4 h. Then, the crude mixture was quenched with methanol and first purified by SCX column chromatography followed by silica gel chromatography (methanol-NH3-dichloromethane). Conversion into the hydrochloride gave the title compound, 30 mg, MH + = 350.

1 H NMR (HCl salt) (DMSO-d6) δ: 1.75 (2H, m), 1.92 (2H, m), 2.08 (2H, m), 2.81 (2H, m), 3 , 20 (2H, m), 3.36 (2H, m), 10 3.44 (1H, m), 3.82 (3H, s) 4.01 (2H, m), 4.62 (1H, m), 6.59 (1H, d, J = 12 Hz), 7.61 (1H, s), 10.82 (1H, sa) and 11.40 (1H, s); 1H remaining signals not discernible by the spectrum

Example 4. 4,5-Difluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E4).

 fifteen

4,5-Difluoro-6-methyl-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one D23 hydrochloride (120 mg) in dichloromethane (5 ml) was dissolved, diisopropylethylamine was added (0.2 ml, 1.2 mmol), tetrahydro-4H-pyran-4-one (0.2 ml, 2.0 mmol) and sodium triacetoxyborohydride (250 mg, 1.2 mmol) and the mixture was stirred at room temperature for 4 h. The mixture was partitioned between water and MDC at pH 9. Drying (MgSO4), evaporation and crystallization of the residue in diethyl ether, washing with dichloromethane, gave the free base of the title compound, which was converted into hydrochloride. Trituration with diethyl ether gave 35 mg of the hydrochloride salt. MH + = 352.

1 H NMR (HCl salt) (DMSO) δ: 1.7 (2H, m), 2.0 (4H, m), 2.3 (3H, d, J = 2Hz), 2.8 (2H, m) , 3.1 (3H, m), 4.0 (2H, broad d), 4.5 (1H, m), 7.3 (1H, d, J = 5Hz), 10.3 (1H, s anchors ), and 11.1 (1H, wide s); 1H remaining signals not discernible by the spectrum

Example 5. 6-Cyclopropyl-4-fluoro-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one (E5) hydrochloride )

6-Cyclopropyl-4-fluoro-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D29, 0.28 mmol, 86 mg) was dissolved in 1,2-dichloroethane (3 ml), triethylamine (3 equiv., 0.83 mmol, 0.086 g), tetrahydro-4H-pyran-4-one 5 (7 equiv., 1.99 mmol, 0.2 g) and sodium triacetoxyborohydride were added (3 equiv., 0.83 mmol, 0.052 g) at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with NaHCO3 (saturated solution), diluted with dichloromethane, then the two phases were separated with a hydrophobic filter and the aqueous phase was washed again with dichloromethane. The organic phases were combined and the solvent was evaporated to yield the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to yield the free base 10 of the title compound, 100 mg, 98%, M + + H = 360. This material was dissolved in methanol (2 ml), HCl (3 equiv., 0.046 ml of a 1 M solution in diethyl ether) was added at room temperature and the mixture was stirred at room temperature for 5 minutes. Then, the solvent was evaporated to yield the title compound, 90 mg, 82%.

1 H NMR δ (d6DMSO, 400 MHz, monohydrochloride): 0.75 (2H, m), 0.91 (2H, m), 1.76 (2H, m), 1.93 (2H, m), 2, 04 (2H, d), 2.84 (2H, c), 3.18 (4H, c), 3.44 (1H, m), 3.59 (2H, d), 3.99 (2H, m ), 4.11 (1H, broad m), 4.57 (1H, m), 6.63 (1H, d), 7.19 (1H, s), 10.85 (1H, wide s), 11.30 (1H, s).

Example 6. 4,5-Difluoro-6-methyl-1- [1- (4-methyltetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole-2 hydrochloride -ona (E6)

A stirred solution of 3M methylmagnesium bromide in diethyl ether (0.7 ml, 2.0 mmol) was treated with a solution in tetrahydrofuran (5 ml) of 4,5-difluoro-6-methyl-1- [1 - (4-cyanotetrahydro-2H-piran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one (D30, 70 mg, 6.2 mmol) for 2 h at room temperature, It was then poured into a saturated aqueous solution of Rochelle salt and extracted with dichloromethane. The organic layer was dried (MgSO4), evaporated and purified by chromatography (10 g of silica, 0-10% methanol in dichloromethane with 0.2 M ammonia) to give the title compound (35 mg), which was isolated in the form of the hydrochloride salt in diethyl ether. MH + = 366. 25

1 H NMR (HCl salt) δ (d6DMSO): 1.4 (3H, s), 1.9 (4H, m), 2.1 (2H, m), 2.3 (3H, d, J = 2 Hz ), 2.8 (2H, m) 3.2 (2H, m), 3.9 (2H, m), 4.6 (1H, m), 7.5 (1H, d, J = 5 Hz) , 10.3 (1H, sa) and 11.6 (1H, s); the remaining protons were not discernible by the spectrum.

All 1 H NMR agreed with the structures shown.

Claims (17)

1. A compound of formula (I) or a salt or solvate thereof:   NNNHOOR6R4R5Q in which: R4 is fluorine; 5 R5 is selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 alkyl substituted with one or more fluorine atoms, C1-6 alkoxy and C1-6 alkoxy substituted with one or more fluorine atoms; R6 is selected from halogen, cyano, C1-6 alkyl, C1-6 alkyl substituted with one or more fluorine atoms, C3-6 cycloalkyl, C3-6 cycloalkyl substituted with one or more fluorine atoms, C1-6 alkoxy and alkoxy C1-6 substituted with one or more fluorine atoms, and 10 Q is hydrogen or C1-6 alkyl. 2. A compound according to claim 1 wherein R5 is selected from hydrogen, chlorine, bromine, fluorine, C1-4 alkyl, C1-4 alkyl substituted with one or more fluorine atoms, and C1-4 alkoxy. 3. A compound according to claim 1 or claim 2, wherein R6 is selected from chlorine, bromine, fluorine, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethoxy and trifluoromethyl. fifteen 4. A compound according to any of claims 1-3, wherein Q is selected from hydrogen and methyl. 5. A compound according to claim 1, which is selected from the group consisting of: 4-Fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 6-Chloro-4-fluoro-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 20 4-Fluoro-6-methoxy-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 4,5-Difluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 6-Cyclopropyl-4-fluoro-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 4,5-Difluoro-6-methyl-1- [1- (4-methyltetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one and 25 salts and solvates thereof. 6. A compound according to claim 1 which is 4-fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole- 2-one 7. A compound according to claim 1 which is 4-fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H- hydrochloride benzimidazol-2-one. 30 8. A compound according to claim 1 which is 4-fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H- monoitrate benzimidazol-2-one. 9. A compound according to claim 1 which is 4-fluoro-6-methyl-1- [1- (tetrahydro-2H-pyran-4-yl) -4-piperidinyl] -1,3-dihydro-2H- methanesulfonate benzimidazol-2-one. 10. A pharmaceutical composition comprising a compound according to any one of the 35 claims 1 to 9, and a pharmaceutically acceptable carrier thereof. 11. A compound according to any one of claims 1 to 9 for use in therapy. 12. A compound according to any one of claims 1 to 9 for use in the treatment of a condition that requires agonism of an M1 muscarinic receptor. 13. A compound according to any one of claims 1 to 9 for use in the treatment of a psychotic disorder or cognitive impairment. 14. Use of a compound according to any one of claims 1 to 9 in the preparation of a medicament for the treatment of a condition that requires agonism of an M1 muscarinic receptor. 15. Use of a compound according to any one of claims 1 to 9 in the preparation of a medicament for the treatment of a psychotic disorder or cognitive impairment. 10 16. A process for preparing a compound of formula (I) or a salt or solvate thereof as defined in claim 1, wherein said process is selected from: - process (A1) comprising coupling a compound of formula (II)   NHNNHOR6'R4'R5 '(ll) with a compound of formula (III):   OO (lll) wherein R4 'is a group R4 as defined in claim 1, or a group convertible into R4, R5' is a group R5 as defined in claim 1, or a group convertible into R5, and R6 'is a group R6 as defined in claim 1, or a group convertible into R6; under conditions suitable for reductive alkylation; and 20 - process (A2) comprising reacting a compound of formula (II) with a compound of formula (III) in the presence of a cyanide source to form the cyano intermediate (XXXX) that can be reacted with an alkyl Grignard reagent QMgX to form compounds of formula (I).   NNNHOR6'OCNR4'R5 '(XXXX) + QMgX wherein R4 'is a group R4 as defined in claim 1, or a group convertible in R4, R5' is a group 25 R5 as defined in claim 1, or a group convertible in R5, R6 'is a R6 group as defined in claim 1, or a group convertible into R6, and Q is hydrogen or C1-6 alkyl; under conditions suitable for Grignard reactions; Y - process (B) comprising coupling a compound of formula (IV)   NOR6'NHNH2R4'R5'Q (lV) with a compound of formula (V)   XYO (V) wherein R4 'is a group R4 as defined in claim 1, or a group convertible into R4, R5' is a group 5 R5 as defined in claim 1, or a group convertible into R5, and R6 'is an R6 group as defined in claim 1, or a group convertible into R6, Q is hydrogen or C1-6 alkyl, both X and Y represent leaving groups optionally in an inert solvent, optionally in the presence of a base and optionally with heating; and 10 - process (C) comprising treatment of a compound of formula (VI)   R6'NHZNHONOR4'R5'Q (Vl) with a palladium or copper (VII) catalyst for intramolecular cyclization, wherein R4 'is a group R4 as defined in claim 1, or a group convertible into R4, R5' is a group R5 as defined in claim 1, or a group convertible in R5, and R6 'is a group R6 as defined in claim 1, or a group convertible in R6, Q is hydrogen or C1-6 alkyl, and Z is a leaving group such as bromine, iodine, chlorine or triflate; Y - process (D) comprising coupling a compound of formula (VIII)   R6'NH2NH2R4'R5 '(Vlll) with a compound of formula (IX) 20   NOOCO2RQ (lX) wherein R4 'is a group R4 as defined in claim 1, or a group convertible into R4, R5' is a group R5 as defined in claim 1, or a group convertible into R5, and R6 'is a R6 group as defined in claim 1, or a group convertible into R6, Q is hydrogen or C1-6 alkyl, and R is an alkyl group C1-5 by heating in an inert solvent, for example xylene, followed by reduction of the piperidine double bond; Y - process (E) comprising reacting a compound of formula (X)   NOR6'NHCO2HR4'R5'Q (X) with a reagent / combination of reagents to perform Curtius redisposition of compound (X), followed by intramolecular cyclization; wherein R4 'is a group R4 as defined in claim 1, or a group convertible into R4, R5' is a group R5 as defined in claim 1, or a group convertible into R5, and R6 'is a R6 group as defined in claim 1, or a group convertible into R6, and Q is hydrogen or C1-6 alkyl; Y - process (F) comprising coupling a compound of formula (XI) 10   R4'NHNHOR6'R5 '(Xl) with a compound of formula (XII)   NOZQ (Xll) wherein R4 'is a group R4 as defined in claim 1, or a group convertible into R4, R5' is a group R5 as defined in claim 1, or a group convertible into R5, and R6 'is a R6 group as defined in claim 1, or a group convertible into R6, Q is hydrogen or C1-6 alkyl, and Z is hydroxy or a leaving group under alkylation reaction or Mitsunobu reaction conditions; and optionally, after that, for any of the above processes: - remove any protective group; I - converting a compound of formula (I) or a salt or solvate thereof into another compound of formula (I) or a salt or solvate thereof. 17. A compound of formula (XXXX) or a salt or solvate thereof:   NNNHOR6'OCNR5'R4 '(XXXX) wherein R4 'is a group R4 as defined in claim 1, or a group convertible into R4, R5' is a group R5 as defined in claim 1, or a group convertible into R5, and R6 'is a group R6 as defined in claim 1, or a group convertible into R6.