EA040024B1 - POLYCYCLIC AMIDES AS POSITIVE ALLOSTERIC MODULATORS OF MUSCARINIC RECEPTORS M1 - Google Patents

Description

The field of technology to which the invention belongs

The invention relates to compounds of formula (I) or their isotopic forms, stereoisomers or pharmaceutically acceptable salts as positive allosteric modulators of M1 muscarinic receptors (M1 PAM). The present invention also describes a method for preparing such compounds, pharmaceutical compositions containing such compounds, and their use.

State of the art invention

Muscarinic acetylcholine receptors (mAChRs), which belong to class A of the G-protein coupled receptor (GPCR) family, are widely expressed throughout the body. So far, five subtypes, designated M1-M5, have been identified that respond to the endogenous neurotransmitter acetylcholine (ACh). They play a key role in regulating the activity of many important functions of the central and peripheral nervous system, including cognitive functions. M1, M3 and M5 bind to Gq, while M2 and M4 bind via Gi/o to downstream signaling pathways and their respective effector systems (Critical Reviews in Neurobiology, 1996, 10, 69-99; Pharmacology & Therapeutics, 2008, 117, 232 -243). M2 and M3 are highly expressed in the periphery and are known to be involved in gastrointestinal (GI) motility and parasympathetic responses such as salivation (Life Sciences, 1993, 52, 441-448). The M1 muscarinic receptor is predominantly expressed in areas of the brain such as the cerebral cortex, hippocampus, and amygdala that are involved in cognition, and therefore selective activation of the M1 receptor would be expected to enhance cognitive performance (Annals of Neurology, 2003, 54, 144 -146).

Xanomeline, a muscarinic acetylcholine receptor agonist with acceptable selectivity for the M1 and M4 subtypes, has a significant effect on cognition in the Alzheimer's Disease (AD) clinical trial (Alzheimer Disease and Associated Disorders, 1998, 12(4), 304312), although gastrointestinal intestinal side effects have led to a high dropout rate in clinical trials. There is a high degree of conservatism between muscarinic receptor subtypes at their orthosteric acetylcholine ligand-binding sites, making it difficult to identify a selective M1 agonist.

To address this selectivity and safety issue, an alternative approach has been taken to develop M1 PAMs that act at a less conserved allosteric binding site. Merck reported the development of M1 PAM, PQCA (1-{[4-cyano-4-(pyridin-2-yl)piperidin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylic acid). This compound is highly selective for M1 over other muscarinic receptor subtypes and has been found to be effective in several preclinical models of cognition (Psychopharmacology, 2013, 225(1), 21-30) without gastrointestinal side effects. tract at doses equal to or less than five times the limit of the minimum effective dose required to improve cognitive performance. In preclinical studies, M1 activation has been shown to increase the concentration of the neurotransmitter acetylcholine in the brain. In addition, M1 activation has potential as a disease-modifying therapy for AD by shifting APP processing towards the non-amyloidogenic α-secretase pathway and by reducing τ-protein hyperphosphorylation. Positive allosteric modulators at the M1 receptor have been shown to increase sAPPa synthesis in vitro (The Journal of Neuroscience, 2009, 29, 14271-14286). Thus, M1 PAMs provide an approach aimed at both symptomatic and disease-modifying treatment of cognitive impairment in AD and schizophrenia.

PCT patent application publications WO 2017155050, WO 2017143041, WO 2017123482 and WO 2011149801 describe some M1 PAM compounds. Although several M1 PAMs have been described in the literature to date, no drug acting as an M1 PAM has been marketed.

Although the prior art describes M1 PAM compounds that are suitable for the treatment of diseases associated with the CNS, there is a problem of poor brain penetration and cholinergic side effects such as hypersalivation, diarrhea and vomiting. Thus, there is an unmet need and opportunity to discover and develop novel M1 PAMs with good brain penetration and no cholinergic side effects for the treatment of CNS related disorders.

The essence of the invention

In a first aspect, the invention relates to an M1 PAM compound of formula (I)

- 1 040024 where R ¹ represents phenyl or pyridinyl; each of which is optionally substituted with one or more substituents selected from halogen, -OH, -O-(C _1-6 )alkyl, -S-(C _1-6 )alkyl, -N(CH ₃ )2,

-(C _1-6 )alkyl, -(C _3-6 )cycloalkyl, halo(C _1-6 )alkyl, -NH2, -CN and R ^1a ;

R ^1a is phenyl, pyrazolyl or thiazolyl; each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, -CN, -O-(C _1-6 )alkyl, -S-(C _1-6 )alkyl, - (C _1-6 )alkyl and -(C _3-6 )cycloalkyl;

A ¹ is CH2;

ring A is selected from the group consisting of

R ³ R ³

I I or । '7''..'- denotes the attachment point;

R ² is hydrogen, -(C _1-6 )alkyl or -(C _3-6 )cycloalkyl;

R ³ is hydrogen, halogen, -OH, -(C _1-6 )alkyl, -O-(C _1-6 )alkyl or halo(C _1-6 )alkyl;

R ⁴ is hydrogen, -(C _1-6 )alkyl or halo(C _1-6 )alkyl;

R ⁵ is hydrogen, -(C _1-6 )alkyl or halo(C _1-6 )alkyl;

X ¹ is independently selected from O, S, NH or NCH ₃ ;

Y ¹ is independently selected from N or CH;

X is CH2 or O; And

Y is CH2;

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients or carriers.

In yet another aspect, the present invention relates to a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents selected from acetylcholinesterase inhibitors and an NMDA receptor antagonist.

In yet another aspect, the present invention provides a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, for use as positive allosteric modulators of the M1 muscarinic receptor.

In yet another aspect, the present invention relates to a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorders selected from cognitive disorders, pain disorders or sleep disorders.

In yet another aspect, the present invention relates to a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorders selected from Alzheimer's disease, schizophrenia, Parkinson's disease dementia, Lewy body dementia, pain disorders, or sleep disorders. .

In another aspect, the present invention relates to a method of treating a disease or disorders associated with the M1 muscarinic receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention relates to the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorders associated with M1 muscarinic receptors.

Brief description of the drawings

The figure shows the effect of the test compound (Example 11) in combination with donepezil on hippocampal θ oscillations.

Detailed description of the invention

Unless otherwise stated, the following terms used in the description and claims have the meanings given below.

The term (C _1-6 )alkyl as used herein refers to a branched or straight chain aliphatic hydrocarbon containing from 1 to 6 carbon atoms. Examples of (C _1-6 )alkyl

- 2 040024 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Preferably (C _1-6 )alkyl is methyl, ethyl or isopropyl.

The term halogen or halo as used herein refers to fluorine, chlorine, bromine or iodine. Preferably, the halogen is fluorine, chlorine or bromine. More preferably, the halogen is fluorine or chlorine.

The term halo(C _{1 .6} )alkyl as used herein refers to (C _{1 .6} )alkyl as defined above in which one or more hydrogen atoms of the same or different carbon atom are replaced by the same or different halogens. Examples of halo(C ₁ . ₆ )alkyl include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, trifluoromethyl, difluoroethyl and the like.

The term, (C ₃ . ₆ )cycloalkyl, as used herein, refers to a saturated monocyclic hydrocarbon ring containing three to six carbon atoms. Examples of the (C ₃ . ₆ )cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term, (C ₆ . ₁₀ )aryl, as used herein, refers to aromatic hydrocarbon rings containing six to ten carbon atoms. Examples of the (C ₆ . ₁₀ )aryl group include phenyl or naphthyl.

The term (C ₅ . ₁₀ )heteroaryl as used herein refers to aromatic monocyclic or aromatic bicyclic heterocyclic ring systems containing five to ten atoms. Examples of the ( _C5.10 )heteroaryl group include 1,2,4- _oxadiazolyl , 1,3,4oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, furyl, imidazolyl, изоксазолил, изотиазолил, оксазолил, пирролил, пиразолил, тиазолил, тиенил, пиридил, пиразинил, пиримидинил, пиридазинил, бензодиоксолил, бензофуранил, бензофуразанил, бензимидазолил, бензопиразолил, бензотиазолил, бензотриазолил, бензотиофенил, бензоксазепинил, бензоксазолил, имидазопиридинил, тиенопиридинил, фуропиридинил, пирролопиридинил, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyrazolinyl, and their N-oxylinyl, quinoxalinyl.

The phrase therapeutically effective amount is defined as the amount of a compound of the present invention that (i) treats a particular disease, condition, or disorder; (ii) relieves one or more of the symptoms of a particular disease, condition, or disorder; (iii) delays the onset of one or more of the symptoms of a particular disease, condition, or disorder described herein.

The term isotopic form as used herein refers to a compound of formula (I) in which one or more atoms of the compound of formula (I) have been replaced by their respective isotopes. For example, isotopes of hydrogen include 2H (deuterium) and ^3H (tritium).

The term stereoisomers as used herein refers to isomers of a compound of formula (I) that differ in the arrangement of their atoms in space. The compounds described herein may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such individual stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.

The term pharmaceutically acceptable salt as used herein refers to salts of the active compound, i.e. compounds of formula (I), and which are obtained by reaction with the appropriate acid or acid derivative, depending on the specific substituents present in the compounds described in this description. The term cognitive disorder as used herein refers to a group of mental health disorders that primarily affect learning, memory, perception, and problem solving and include amnesia, dementia, and delirium. Cognitive impairment may result from a disease, disorder, disease state, or toxic effect. Preferably the cognitive disorder is dementia. An example of dementia includes, without limitation, Alzheimer's disease dementia, Parkinson's disease dementia, Huntington's disease dementia, Down's syndrome-associated dementia, Tourette's syndrome-associated dementia, postmenopausal dementia, frontotemporal dementia, Lewy body dementia, vascular dementia, HIV dementia, Creutzfeldt-Jakob disease dementia, substance-induced persistent dementia, Pick's disease dementia, schizophrenia dementia, senile dementia, and dementia associated with general medical conditions.

The term patient as used herein refers to an animal. Preferably, the term patient refers to a mammal. The term mammal includes animals such as mice, rats, dogs, rabbits, pigs, monkeys, horses, pigeons, Xenopus laevis, zebrafish, guinea pigs and humans. More preferably, the patient is a human.

Embodiments.

The present invention covers all compounds described by the compound of formula (I), without any limitation, however, the preferred aspects and elements of the invention are discussed in this description in the form of the following embodiments.

In one aspect, the present invention provides a compound of formula (I) wherein ring A is selected from the group consisting of

R ¹ is phenyl or pyridinyl; each of which is optionally substituted with one or more substituents selected from halo and R ^1a ;

R ^1a is pyrazolyl or thiazolyl; which is optionally substituted with -(C _{1 .6} )alkyl;

A ¹ is CH2;

Mlll denotes the place of attachment;

R ² is hydrogen or -(C1.6)alkyl; R ⁵ is hydrogen; X is CH2 or O; and Y is CH ₂ or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of formula (I) wherein ring A is selected from the group consisting of

R ¹ is phenyl or pyridinyl; each of which is optionally substituted with one or more substituents selected from halo and R ^1a ;

R ^1a is pyrazolyl or thiazolyl; which is optionally substituted with -(C _{1 .6} )alkyl;

A ¹ is CH ₂ ;

.j4jt_aj-. indicates the point of attachment;

R ² R ³

^x1

Y ¹ is hydrogen or -(C1.6)alkyl;

is hydrogen or -(C1.6)alkyl;

independently selected from O or NH;

independently selected from N or CH;

X is CH ₂ ; And

Y represents CH ₂ or its stereoisomer, tautomer or pharmaceutically acceptable salt.

In another embodiment, the present invention provides a compound of formula (I) wherein ring A is

R ¹ is phenyl; which is optionally substituted with one or more substituents selected from halo and R ^1a ;

R ^1a is phenyl, pyrazolyl or thiazolyl; each of which is optionally substituted with -(C ₁ . ₆ )alkyl;

A ¹ is CH2;

and-<; · - denotes the place of attachment;

R ² is hydrogen or -(C ₁ . ₆ )alkyl;

X is CH ₂ ;

Y is from CH ₂ , or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

In another embodiment, a preferred compound of the invention is selected from the group consisting of the following:

- 4 040024 Na(cis-18,28-2-hydroxycyclohexyl)-6-(2-chloropyridin-4-ylmethyl)-5methylquinolin-8-carboxamide;

Na(cis-18,28-2-hydroxycyclohexyl)-6-(2,3-difluorobenzyl)-5-methylquinoline-8carboxamide;

N-(cis-38,48-3-hydroxytetrahydropyran-4-yl)-6-(2-chloropyridin-5-ylmethyl)-5-methylquinolin-8-carboxamide;

N-(cis-18,28-2-hydroxycyclohexyl)-6-(2-fluoropyridin-4-ylmethyl)-5-methylquinolin-8-carboxamide;

N-(cis-18,28-2-hydroxycyclohexyl)-6-(2-fluorobenzyl)-5-methylquinoline-8carboxamide;

N-(cis-18,28-2-hydroxycyclohexyl)-6-(2-chloropyridin-5-ylmethyl)-5-methylquinolin-8-carboxamide;

H-(cis-18,28-2-hydroxycyclohexyl)-6-[2-(1-methyl-1H-pyrazol-4-yl)-pyridine in-5ylmethyl]-5-methylquinolin-8-carboxamide;

X-(cis-18,28-2-hydroxycyclohexyl)-6-[2,3-difluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]-5-methylquinoline-8-carboxamide;

N-(uhc-I 8,28-2-hydroxycyclohexyl)-6-[3-fluoro-4-(1-methyl-1 H-pyrazol-4-yl)benzyl]-5-methylquinoline-8-carboxamide;

N-(uhc-I 8,28-2-hydroxycyclohexyl)-6-(4-pyrazol-1-yl-benzyl)-5-methylquinoline 8-carboxamide;

N-(uhc-I 8,28-2-hydroxycyclohexyl)-6-[2-fluoro-4-(1-methyl-1 H-pyrazol-4-yl)benzyl]-5-methylquinoline-8-carboxamide;

N-(uhc-I 8,28-2-hydroxycyclohexyl)-6-(4-thiazol-4-yl-benzyl)-5-methylquinoline-8 carboxamide;

M-(cis-38,48-3-hydroxytetrahydropyran-4-yl)-6-(4-thiazol-4-yl-benzyl)-5methylquinoline-8-carboxamide;

N-(cis-18,28-2-hydroxycyclohexyl)-6-benzyl-5-methylquinoline-8-carboxamide;

Na(cis-18,28-2-hydroxycyclohexyl)-6-[4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-5methylquinoline-8-carboxamide;

N-(cis-18,28-2-hydroxycyclohexyl)-6-[4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-5methyl-3,4-dihydro-2H-benzo[1 ,4]oxazine-8-carboxamide;

^(cis-18,28-2-hydroxycyclohexyl)-6-(4-pyrazol-1-yl-benzyl)-5-methyl-3,4dihydro-2H-benzo[1,4]oxazine-8-carboxamide;

- 5 040024

N-(hhc-I 8,28-2-hydroxycyclohexyl)-5-methyl-6-[4-(1-methyl-1 H-pyrazol-4-yl)benzyl]imidazo[1,2-а]pyridine -8-carboxamide;

N-(uhc-I 8,28-2-hydroxycyclohexyl)-5-methyl-6-(4-pyrazol-1-yl-benzyl)imidazo[1,2-a]pyridine-8-carboxamide;

N-(uhc-I 8,28-2-hydroxycyclohexyl)-5-methyl-6-[2-fluoro-4-(1-methyl-1 H-pyrazol-4 yl)-benzyl]-imidazo[1, 2-a]pyridine-8-carboxamide;

A-(cis-18,28-2-hydroxycyclohexyl)-6-[2,3-difluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2-a]pyridine -8-carboxamide;

N-(ijhc-18,28-2-hydroxycyclohexyl)-6-(2,3-difluorobenzyl)imidazo[1,2a]pyridine-8-carboxamide;

A-(cis-18,28-2-hydroxycyclohexyl)-6-(4-thiazol-4-yl-benzyl)imidazo[1,2a]pyridine-8-carboxamide;

A-(cis-18,28-2-hydroxycyclohexyl)-6-(4-phenyl-benzyl)-imidazo[1,2-a]pyridine 8-carboxamide;

18-(cis-18,28-2-hydroxycyclohexyl)-6-[4-(1-methyl-1H-pyrazol-4-yl)-benzyl]imidazo[1,2-a]pyridine-8-carboxamide;

18G-(cis-18,28-2-hydroxycyclohexyl)-6-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2-a]pyridine-8 -carboxamide;

A-(cis-18,28-2-hydroxycyclohexyl)-7-methyl-6-(4-pyrazol-1-yl-benzyl)-1H-benzimidazole-4-carboxamide;

A-(cis-18,28-2-hydroxycyclohexyl)-7-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-1 H-benzimid azole-4-carboxamide;

N-(ijhc-18,28-2-hydroxycyclohexyl)-6-[4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-1H-benzimidazole-4-carboxamide;

A-(cis-18,28-2-hydroxycyclohexyl)-7-methyl-6-[2-fluoro-4-(1-methyl-1H-pyrazol-4 yl)-benzyl]-1H-benzimidazole-4- carboxamide;

T4-(cis-1 S,2 8-2-hydroxycyclohexyl)-7-methyl-6-[2-chloropyride in-3-ylmethyl]-1H-benzimidazole-4-carboxamide;

N-(ijhc- 1 S,2 8-2-hydroxycyclohexyl)-7-methyl-6-[4-(thiazol-4-yl)-benzyl]-1H-benzimidazole-4-carboxamide;

A-(cis-18,28-2-hydroxycyclohexyl)-7-methyl-6-[2,3-difluorobenzyl]-1H-benzimidazole-4-carboxamide;

A-(cis-18,28-2-hydroxycyclohexyl)-7-methyl-6-[3,4-difluorobenzyl]-1H-benzimidazole-4-carboxamide;

A-(cis-18,28-2-hydroxycyclohexyl)-7-methyl-6-[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ylmethyl]-1 H-benzimid azol- 4-carboxamide;

M-(cis-1 S,2 8-2-hydroxycyclohexyl)-7-methyl-6- [2,3-d iftoro-4-(1-methyl-1Hpyrazol-4-yl)-benzyl] -1 H- benzimide azole-4-carboxamide;

A-(cis-18,28-2-hydroxycyclohexyl)-6-[2,3-difluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]-1 H-benzimid azole-4-carboxamide ;

- 6 040024

N-(cis-18,28-2-hydroxycyclohexyl)-2,7-dimethyl-6-(4-pyrazol-1-yl-benzyl)-1H-benzimidazole-4-carboxamide;

N-(ijhc-IS, 28-2-hydroxycyclohexyl)-2,7-dimethyl-6-[4-(1-methyl-1H-pyrazol-4yl)-benzyl]-1H-benzimidazole-4-carboxamide;

N-(cis-18,28-2-hydroxycyclohexyl)-2,7-dimethyl-6-(4-thiazol-4-yl-benzyl)-1H-benzimidazole-4-carboxamide;

N-(hhc-1 8,28-2-hydroxycyclohexyl)-3,7-dimethyl-b-[2-fluoro-4-(4-methyl-1 Hpyrazol-4-yl)-benzyl]-3H-benzimidazol- 4-carboxamide;

N-(cis-18,28-2-hydroxycyclohexyl)-3,7-dimethyl-6-[4-(1-methyl-1H-pyrazol-4yl)-benzyl]-3H-benzimidazole-4-carboxamide;

N-(cis-18,28-2-hydroxycyclohexyl)-3,7-dimethyl-6-[2,3-difluoro-4-(1-methyl-1Hpyrazol-4-yl)-benzyl]-3H-benzimidazol- 4-carboxamide;

Na(cis-18,28-2-hydroxycyclohexyl)-3,7-dimethyl-6-[6-(1-methyl-1H-pyrazol-4yl)-pyridin-3-ylmethyl]-3H-benzimidazole-4-carboxamide ;

b1-(cis-18,28-2-hydroxycyclohexyl)-3,7-dimethyl-6-[4-(thiazol-4-yl)-benzyl]-3H-benzimidazole-4-carboxamide; and N(cis-18,28-2-hydroxycyclohexyl)-2,4-dimethyl-5-[4-(1-methyl-1H-pyrazol-4yl)-benzyl]-benzofuran-7-carboxamide;

or a pharmaceutically acceptable salt thereof.

Experimental methods.

Scheme 1 shows the general methods for obtaining compounds of formula (I), where T represents -(C _1-6 )alkyl; A ¹ is CH2; ring A, R ¹ , X and Y are as defined above.

Scheme 1

Step 1. Obtaining the compound of formula 2.

A compound of formula 1 reacts with a compound of formula A,

R ¹ -A ¹ -Cl (A) in the presence of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and a base selected from potassium carbonate, cesium carbonate and sodium carbonate in a mixture of solvents such as water , THF and 1,4-dioxane, at reflux for 3-7 hours to obtain a compound of formula 2.

Step 2. Obtaining the compound of formula 3.

The compound of formula 2 is hydrolyzed to the compound of formula 3 in a mixture of solvents such as

- 7 040024 water, THF and methanol using sodium hydroxide at reflux for 2-17 hours.

Stage 1a. Preparation of a compound of formula 2a.

The compound of formula 1a reacts with the compound of formula A

R1-A1-Cl (A) in the presence of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and a base selected from potassium carbonate and sodium carbonate in a mixture of solvents such as water and 1,4- dioxane, at reflux for 3-5 hours to give a compound of formula 2a.

Stage 1b. Preparation of a compound of formula 2b.

The compound of formula 2a is hydrolyzed to the compound of formula 2b in a mixture of solvents such as water and ethanol using potassium hydroxide under reflux for 2-4 hours.

Stage 2a. Obtaining a compound of formula 3.

The compound of formula 2b is hydrolyzed to the compound of formula 3 using aq. HCl at a temperature in the range of 95-105°C for 5-7 hours.

Step 3: Preparation of a compound of formula (I).

The compound of formula 3 is combined with an amine

in the presence of a coupling agent, HATU, DCC or EDC, and a base, DIPEA, in a solvent selected from DMF, THF, dichloromethane or 1,4-dioxane at RT overnight to give a compound of formula (I).

Preparation of a Pharmaceutically Acceptable Salt of a Compound of Formula (I)

The compound of formula (I) may optionally be converted to its pharmaceutically acceptable salt by reaction with an appropriate acid or acid derivative. Suitable pharmaceutically acceptable salts will be known to those skilled in the art. Salts are formed with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, or with organic acids, such as oxalic, succinic, maleic, acetic, fumaric, citric, malic, tartaric, benzoic, p-toluic, p-toluenesulfonic, benzenesulfonic acid, methanesulfonic or naphthalenesulfonic acid.

Preparation of stereoisomers of the compound of formula (I).

Stereoisomers of the compounds of formula (I) can be obtained by one or more of the traditional methods below:

a. One or more of the reactants may be used in their optically active form.

b. The reduction process can use an optically pure catalyst or chiral ligands along with a metal catalyst. The metal catalyst may be rhodium, ruthenium, indium and the like. Chiral ligands may preferably be chiral phosphines.

c. A mixture of stereoisomers can be separated by conventional means such as the formation of diastereomeric salts with chiral acids or chiral amines or chiral amino alcohols or chiral amino acids. The resulting mixture of diastereomers can then be separated by methods such as fractional crystallization, chromatography, and the like, followed by an additional step of isolating the optically active product from the separated substance/salt.

d. A mixture of stereoisomers can be separated by conventional methods such as microbial separation and separation of diastereomeric salts formed from chiral acids or chiral bases. Chiral acids that can be used may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids and the like. Chiral bases that can be used may be cinchona alkaloids, brucine, or a basic amino acid such as lysine, arginine, and the like.

In another embodiment, a suitable pharmaceutically acceptable salt includes hydrochloride, hydrobromide, oxalate, fumarate, tartrate, maleate, and succinate.

In another aspect of the present invention, the compounds of formula (I) are positive allosteric modulators of M1 muscarinic receptors.

In another aspect, the present invention relates to a method of treating a disease or disorder selected from a cognitive disorder, schizophrenia, pain disorder or sleep disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a method of treating Alzheimer's disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a method for treating Alzheimer's disease,

- 8 040024 including mild Alzheimer's disease, moderate Alzheimer's disease, severe Alzheimer's disease, mild to moderate Alzheimer's disease or moderate to severe Alzheimer's disease, comprising administering to a patient in need thereof a therapeutically effective amount of the compound formula (I) or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention relates to a compound of formula (I) for use in the treatment of a disease or disorder selected from a cognitive disorder, schizophrenia, pain disorder, or sleep disorder.

In another aspect, the present invention relates to the use of a compound of formula (I) in the manufacture of a medicament for the treatment of diseases or disorders selected from a cognitive disorder, schizophrenia, pain disorder or sleep disorder.

In yet another aspect, the present invention relates to the use of a compound of formula (I) in the manufacture of a medicament for the treatment of diseases or disorders selected from cognitive impairment.

In yet another aspect, the present invention relates to the use of a compound of formula (I) in the manufacture of a medicament for the treatment of Alzheimer's disease.

In yet another embodiment, the present invention relates to the combination of a compound of formula (I) with one or more other therapeutic agents such as acetylcholinesterase inhibitors and an NMDA receptor antagonist.

In another embodiment, the compound of formula (I) of the present invention can be used in combination with one or more other therapeutic agents in the treatment of diseases or disorders for which the compound of formula (I) of the present invention is beneficial. Examples of combinations of compounds of the present invention include combination with therapeutic agents for the treatment of Alzheimer's disease, for example, acetylcholinesterase inhibitors such as galantamine, rivastigmine, donepezil and tacrine; and an NMDA receptor antagonist such as memantine.

In yet another embodiment, the present invention relates to the combination of a compound of formula (I) with at least one therapeutic agent selected from galantamine, rivastigmine, donepezil, tacrine and memantine.

In yet another embodiment, the present invention provides a combination of a compound of formula (I) with one or more other therapeutic agents such as acetylcholinesterase inhibitors and an NMDA receptor antagonist for use in the treatment of cognitive impairment, schizophrenia, pain disorders and sleep disorders.

In yet another embodiment, the present invention provides a combination of a compound of formula (I) with one or more other therapeutic agents such as acetylcholinesterase inhibitors and an NMDA receptor antagonist for use in the treatment of Alzheimer's disease.

In yet another aspect, the present invention relates to a pharmaceutical composition of a compound of formula (I). For the use of a compound of formula (I) or its stereoisomers and its pharmaceutically acceptable salts in therapy, they are usually formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.

Pharmaceutical compositions of the present invention can be obtained in the usual way using one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are diluents, disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, co-solvents, preservatives, wetting agents, thickeners, defoamers, sweeteners, flavors, antioxidants, colorants, solubilizers, plasticizers, dispersants, etc. similar. The excipients are selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sodium starch glycolate, corn starch or derivatives thereof, povidone, crospovidone, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, stearate zinc, stearic acid or hydrogenated vegetable oil, gum arabic, magnesium oxide, glucose, fats, waxes, natural or hardened oils, water, saline sodium chloride or alcohols such as ethanol, propanol or glycerin, sugar solutions such as glucose solutions or mannitol solutions and the like, or mixtures of various excipients.

In another aspect, the active compounds of the invention may be in the form of pills, tablets, coated tablets, capsules, powder, granules, pellets, patches, implants, films, liquids, semi-solids, gels, aerosols, emulsions, elixirs, and the like. Such pharmaceutical compositions and methods for their preparation are well known in the art.

In another aspect, the pharmaceutical composition of the present invention contains 1-90%, 575% and 10-60% by weight of the compounds of the present invention or their pharmaceutically acceptable salt. The amount of active compounds, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition(s) may range from about 1 mg to about 500 mg, or from about 5 mg to about 400 mg, or from about 5 mg to about 250 mg, or from about 7 mg to about 150 mg, or any range falling within the wider range of 1 to 500 mg.

The dosage of the active compounds may vary depending on such factors as the age and weight of the patient, the nature and severity of the disease being treated, and other such factors. Accordingly, any reference regarding a pharmacologically effective amount of compounds of general formula (I), their stereoisomers and pharmaceutically acceptable salts refers to the above factors.

In the present description, the following abbreviations are used.

AMP: adenosine monophosphate;

AUC: area under the curve;

C _max : maximum concentration;

CDCl ₃ : deuterated chloroform;

Cs ₂ CO ₃ : cesium carbonate;

DCM: dichloromethane;

DCC: K,K'-dicyclohexylcarbodiimide;

DIPEA: N-diisopropylethylamine;

DMF: N,N-dimethylformamide;

DMSO: dimethyl sulfoxide;

EC ₅₀ : half maximum effective concentration;

EDC: ethylene dichloride;

EtOAc: ethyl acetate;

EtOH: ethanol;

h: hour(s);

HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate;

HCl: hydrochloric acid;

H2O: water;

H ₂ SO ₄ : sulfuric acid;

K ₂ CO ₃ : potassium carbonate;

KNO ₃ : potassium nitrate;

LCMS/MS: liquid chromatography with tandem mass spectrometry;

mmol: millimole (millimoles);

NaHCO ₃ : sodium bicarbonate;

NaOH: sodium hydroxide;

Na2SO4: sodium sulfate;

NH4Cl: ammonium chloride;

RT: room temperature (25 to 30°C);

ROA: route of administration;

p.o: orally;

THF: tetrahydrofuran;

T _1/2 : half-life;

X-Phos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

Examples

Compounds of the present invention were obtained in accordance with the following experimental procedures, using appropriate substances and conditions. The following examples are given only to illustrate and not to limit the scope of the present invention.

Preparation of intermediate compounds.

Intermediate 1: 6-bromo-5-methylquinoline-8-carboxylic acid (I-1).

To a stirred solution of 2-amino-5-bromo-4-methylbenzoic acid (15.9 g, 69.1 mmol) in nitrobenzene (22.8 ml) at RT was added glycerol (24.8 g, 269.6 mmol), after which conc. H ₂ SO ₄ (22.28 g, 222.8 mmol). The reaction mixture was gradually heated to 125° C. and stirred at this temperature for 16 h. After cooling to RT, the reaction mixture was quenched with ice and diluted with water and EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc. The aqueous layer was further extracted with a solvent system including a 10% methanolic ammonia solution in DCM. The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the title compound.

Yield: 9.65 g (52%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 16.49 (br s, 1H), 8.94 (s, 1H), 8.93 (d, J=6.2 Hz, 1H), 7 .69 (dd, J=4.3, 8.6 Hz, 1H), 2.87 (s, 3H); MS (m/z): 265.8, 267.8 (M+H)+.

Intermediate 2: methyl 6-bromo-5-methylquinoline-8-carboxylate (I-2).

To a stirred solution of 6-bromo-5-methyl-quinoline-8-carboxylic acid (I-1) (9.65 g, 36.2 mmol) in methanol (145.1 ml) cooled at 0°C was slowly added thionyl chloride (15.7 ml, 145.1 mmol). The reaction mixture was gradually heated to reflux and stirred at this temperature for 16 hours. After cooling to RT, the volatiles were removed under reduced pressure and the crude product was dissolved in 10% aqueous NalKO and EtOAc.

The two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give the title compound.

Yield: 9.7 g; ¹ H-NMR (400 MHz, CDCI3): δ 9.05 (d, J=3.8 Hz, 1H), 8.42 (d, J=8.5 Hz, 1H), 8.18 (s, 1H), 7.52 (dd, J=4.0 Hz, 8.5 Hz 1H), 4.04 (s, 3H), 2.81 (s, 3H); MS (m/z): 280.1, 282.1 (M+H)+.

Intermediate 3: tert-butyl-(3-cyano-6-methylpyridin-2-yl)carbamate (I-3).

To a stirred solution of 2-chloro-6-methylnicotinonitrile (0.4 g, 2.62 mmol) in dry THF (10.4 ml) cooled at 0°C was added tert-butyl carbamate (1.5 g, 13. 1 mmol), Cs ₂ CO ₃ (3.25 g, 9.99 mmol), X-Phos (0.025 g, 0.052 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.12 g, 0.13 mmol) . The reaction mixture was gradually heated to 65° C. and stirred at this temperature for 7 h. After cooling to RT, additional Cs ₂ CO ₃ (3.25 g, 9.99 mmol) was added. The reaction mixture was gradually heated to 65° C. and stirred at this temperature for an additional 7 hours. The reaction mixture was cooled to RT and filtered through a pad of celite. The Celite layer was washed with EtOAc. The filtrate was washed with 10% aqueous NaHCO ₃ solution. The organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the title compound.

Yield: 0.55 g (87%); ¹ H-NMR (400 MHz, CDCI3): δ 7.82 (d, J=5.6 Hz, 1H), 7.29 (broad s, 1H), 7.00 (d, J=7.80 Hz, 1H), 2.56 (s, 1H), 1.47 (s, 9H); MS (m/z): 234.1 (M+H) ⁺ .

Intermediate 4: 2-amino-6-methylnicotinonitrile (I-4).

To a stirred solution of tert-butyl-(3-cyano-6-methylpyridin-2-yl)-carbamate (I-3) (0.55 g, 2.36 mmol) in DCM (9.4 ml) cooled at 0 °C, TFA (0.22 ml, 10.7 mmol) was added. The reaction mixture was gradually warmed to RT and stirred at this temperature for 16 h. Volatiles were removed under reduced pressure and the crude mass was diluted with 10% aqueous NaHCO3 and EtOAc. The two layers were separated. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the title compound.

Yield: 0.31 g (100%); ¹ H-NMR (400 MHz, DMSO): δ 7.73 (d, J=7.60 Hz, 1H), 6.78 (bc, 2H), 6.53 (d, J=8 Hz, 1H) , 2.34 (s, 3H); MS (m/z): 134.0 (M+H) ⁺ .

Intermediate 5: 2-amino-5-bromo-6-methylnicotinonitrile (I-5).

Freshly recrystallized NBS (0.46 g, 2.6 mmol). The reaction mixture was gradually heated to 85°C and stirred at this temperature for 3 hours, the Reaction mixture was cooled to RT and diluted with water and CHCl ₃ . The two layers were separated. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the title compound.

Yield: 0.38 g (87%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.74 (s, 1H), 5.12 (bc, 2H), 2.52 (s, 3H); MS (m/z): 212.0, 214.0 (M+H) ⁺ .

Intermediate 6: 6-bromo-5-methylimidazo[1,2-a]pyridine-8-carbonitrile (I-6).

To a stirred solution of 2-amino-5-bromo-6-methylnicotinonitrile (I-5) (0.38 g, 1.8 mmol) in ethanol (7.1 ml) was added chloroacetaldehyde (49% aqueous solution, 0. 23 ml, 3.56 mmol). The reaction mixture was gradually heated to 85°C and stirred at this temperature for 6 hours. The reaction mixture was cooled to RT, the volatiles were removed under reduced pressure, and the crude product was purified by silica gel column chromatography to give the title compound.

Yield: 0.1 g (23%); ¹ H-NMR (400 MHz, CDCI3): δ 7.87 (s, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 2.86 (s, 3H); MS (m/z): 235.9, 238.0 (M+H) ⁺ .

Intermediate 7: methyl 2-acetylamino-5-bromo-4-methylbenzoate (I-7).

Triethylamine (1.7 ml, 8.2 mmol) and acetyl chloride (0.65 g, 8.19 mmol). The reaction mixture was gradually brought to RT and stirred for 2 h, after which it was diluted with DCM and water. The two layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to give the title compound.

Yield: 2.3 g (95%); ¹ H-NMR (400 MHz, DMSO): δ 10.46 (br s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 3.85 (s, 3H), 2.37 (s, 3H), 2.12 (s, 3H); MS (m/z): 286.0, 288.2 (M+H) ⁺ .

Intermediate 8: methyl 2-acetylamino-5-bromo-4-methyl-3-nitrobenzoate (I-8).

Methyl 2-acetylamino-5-bromo-4-methylbenzoate (I-7) (1.0 g, 3.49 mmol) was added to fuming nitric acid (98%, 3.5 ml) cooled at 0°C, within 15 min. After stirring for an additional 15 min, the reaction mixture was quenched by adding ice water and EtOAc. The two layers were separated and the aqueous layer was further extracted with EtOAc.

The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the title compound as a brown solid (1.0 g) in 95% yield. ¹ H-NMR (400 MHz,

DMSO): δ 10.49 (s, 1H), 8.17 (s, 1H), 3.79 (s, 3H), 2.34 (s, 3H), 1.97 (s, 3H); MS (m/z): 330.9, 332.9 (M+H)+.

Intermediate 9: ethyl 6-bromo-2,7-dimethyl-1H-benzimidazole-4-carboxylate (I-9).

To a stirred solution of methyl 2-acetylamino-5-bromo-4-methyl-3-nitrobenzoate (I-8) (1.0 g, 3.02 mmol) in 1:2:4 H2O:THF:EtOH (12 0 ml) iron powder (0.85 g, 15.1 mmol) and NH ₄ Cl (0.82 g, 15.1 mmol) were added at RT. The reaction mixture was gradually heated to reflux and stirred for 2 h. After cooling the reaction mixture to RT, it was filtered through a pad of celite. The Celite layer was washed with ethanol. The filtrate was evaporated under reduced pressure and the crude mass thus obtained was diluted with EtOAc and water. The two layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give the above title compound.

Yield: 0.47 g (50%); ¹ H-NMR (400 MHz, DMSO): δ 12.40 (s, 1H), 7.84 (s, 1H), 4.44 (q, 2H), 2.61 (s, 3H), 2, 56 (s, 3H), 1.37 (t, J=7.0 Hz, 3H); MS (m/z): 297.0, 299.0 (M+H) ⁺ .

Intermediate 10: methyl 2-formylamino-5-bromo-4-methylbenzoate (I-10).

A stirred solution of methyl 2-amino-5-bromo-4-methylbenzoate (2.0 g, 8.19 mmol) in formic acid (32.7 ml) was heated to 100° C. and stirred at this temperature for 16 h. The reaction mixture was gradually cooled to RT, diluted with EtOAc and water. The two layers were separated and the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the title compound.

Yield: 2.0 g (90%); ¹ H-NMR (400 MHz, CDC13): δ 10.91 (br s, 1H), 8.65 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 3.91 (s, 3H), 2.45 (s, 3H); MS (m/z): 272.2, 274.0 (M+H) ⁺ .

Intermediate 11: methyl 2-formylamino-5-bromo-4-methyl-3-nitrobenzoate (I-11).

Methyl 2-formylamino-5-bromo-4-methylbenzoate (I-10) (2.5 g, 9.19 mmol) was added to fuming nitric acid (98%, 9.2 ml) cooled at 0°C, within 15 min. After stirring for an additional 15 min, the reaction mixture was quenched by adding ice water and EtOAc. The two layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the title compound.

Yield: 2.0 g (70%); ¹ H-NMR (400 MHz, CDCI3): δ 9.47 (br s, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 3.98 (s, 3H), 2.50 (s, 3H); MS (m/z): 315.2, 317.0 (M+H) ⁺ .

Intermediate 12: ethyl 6-bromo-7-methyl-1H-benzimidazole-4-carboxylate (I-12).

To a stirred solution of methyl 2-formylamino-5-bromo-4-methyl-3-nitrobenzoate (I-11) (2.0 g, 6.31 mmol) in 1:2:4 H ₂ O:THF:EtOH (25.0 ml) iron powder (1.76 g, 31.55 mmol) and NH4Cl (1.7 g, 31.55 mmol) were added at RT. The reaction mixture was gradually heated to reflux and stirred for 6 h. After cooling the reaction mass to RT, it was filtered through a pad of celite. The Celite layer was washed with ethanol. The filtrate was evaporated under reduced pressure and the crude mass thus obtained was diluted with EtOAc and water. The two layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give the above title compound.

Yield: 0.72 g (40%); ¹ H-NMR (400 MHz, CDCI3): δ 10.51 (br s, 1H), 8.10 (s, 2H), 4.47 (q, 2H), 2.79 (s, 3H), 1.44 (t, J=6.8 Hz, 3H); MS (m/z): 282.9, 285.0 (M+H) ⁺ .

Intermediate 13: methyl 2-hydroxy-4-methylbenzoate (I-13).

To a solution of 2-hydroxy-4-methyl-benzoic acid (10 g, 0.065 mol) in methanol (50 ml) was added thionyl chloride (15 ml, mol) at 0°C. The reaction mixture was heated at 80°C for 12 h, cooled to RT, concentrated under vacuum to obtain the crude product. To the crude product was added 200 ml of water and basified with aqueous ammonia and extracted with dichloromethane (200 ml x 3). The organic layer was washed with brine (50 ml) and dried over Na2SO4. The organic layer was concentrated in vacuo to give the title compound.

Yield: 10.7 g (98.1%); 1H NMR (CDCl ₃ , 400 MHz) δ ppm: 2.34 (s, 3H), 3.92 (s, 3H), 6.68-6.70 (d, J=8 Hz, 1H) , 6.79 (s, 1H), 7.69-7.71 (d, J=8.12 Hz, 1H), 10.71 (s, 1H); MS (m/z): 167.1 (M+H) ⁺ .

Intermediate 14: methyl 5-bromo-2-hydroxy-4-methylbenzoate (I-14).

To a solution of methyl 2-hydroxy-4-methylbenzoate (10.6 g, 0.06 mol) in chloroform (20 ml) was added dropwise bromine (3.27 ml, 0.06 mol) at 0°C and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with sodium sulfite solution under ice cooling, pH 8, and the mixture was extracted with dichloromethane (100 ml x

- 12 040024

3). The organic layer was washed with brine (50 ml) and dried over Na ₂ SO ₄ and the solvent was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using n-hexane:ethyl acetate (97:3) to give the title in the connection header. Yield: 15 g (98.1%); 1H NMR (CDCl ₃ , 400 MHz) δ ppm: 2.38 (s, 3H), 3.94 (s, 3H), 6.88 (s, 1H),

7.96 (s, 1H), 10.58 (s, 1H); MS (m/z): 244.8 (M+H)+.

Intermediate 15: methyl 5-bromo-2-hydroxy-4-methyl-3-nitrobenzoate (I-15).

To a mixture of methyl 5-bromo-2-hydroxy-4-methylbenzoate (13.3 g, 0.05 mol) in H ₂ SO ₄ (60 ml) was added KNO3 (8.2 g, 0.08 mol) at 0 °C and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1000 ml of chilled water, during which solids precipitated. These solids were filtered and dissolved in CH ₂ Cl ₂ (500 ml). The organic layer was washed with brine (250 ml), dried over anhydrous Na2SO4, filtered and concentrated on a rotary vacuum evaporator to give a crude mass of the title compound.

Yield: 13.9 g; 1H NMR (CDCl ₃ , 400 MHz) δ ppm: 2.39 (s, 3H), 3.98 (s, 3H), 8.12 (s, 1H), 11.14 (s, 1H) ; MS (m/z): 290.0 (M+H) ⁺ .

Intermediate 16: Methyl 2-hydroxy-4-methyl-3-nitro-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzoate (I-16) .

To a solution of methyl 5-bromo-2-hydroxy-4-methyl-3-nitrobenzoate (0.1 g, 0.0003 mol) in 1,4-dioxane (10 ml) in a hermetically sealed tube under N2 atmosphere at 25° C was added potassium acetate (0.101 g, 0.001 mol), bis(pinacolato)diboron (0.131 g, 0.0005 mol) and 1,1-bis(diphenylphosphino)ferrocenepalladium(11)dichloride dichloromethane complex (0.028 g, 0.00003 mol ). The reaction mixture was heated at 100°C for 16 h, cooled to RT, filtered through a pad of celite and washed with ethyl acetate (20 ml x 2). The filtrate was concentrated in vacuo to give the crude product of the title compound.

Yield: 1.4 g; MS (m/z): 336.2 (M+H) ^- .

Intermediate 17: Methyl 2-hydroxy-4-methyl-5-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]3-nitrobenzoate (I-17).

To a solution of methyl 2-hydroxy-4-methyl-3-nitro-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoate (1.5 g, 0.004 mol ) methyl ester 2-hydroxy-4-methyl-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane) was added to a mixture of 100 ml of THF and 10 ml of water under N2 -2-yl)benzoic acid (1.11 g, 0.004 mol), cesium carbonate (2.90 g, 0.008 mol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), 1:1 complex with dichloromethane (0.369 g, 0.0004 mol). The mixture was refluxed for 7 h, cooled to RT, filtered through celite and washed with ethyl acetate (100 ml x 2). The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate:n-hexane (60:40) to give the title compound.

Yield: 0.196 g; 1H NMR (CDC13, 400 MHz) δ ppm: 2.19 (s, 3H), 2.37 (s, 3H), 3.91-3.97 (m, 5H), 7.147.25 (d , J=8.1 Hz, 1H), 7.44 (s, 1H), 7.46-7.50 (m, 2H), 7.59 (s, 1H), 7.73-7.77 ( m, 2H), 11.14 (s, 1H); MS (m/z): 382.1 (M+H) ⁺ .

Intermediate 18: methyl 3-amino-2-hydroxy-4-methyl-5-[4-(1-methyl-1H-pyrazol-4yl)-benzyl]-benzoate (I-18).

To a solution of methyl 2-hydroxy-4-methyl-5-[4-(1-methyl-1 H-pyrazol-4-yl)benzyl]-3-nitrobenzoate (0.196 g, 0.0005 mol) in methanol (20 ml) was added 10% palladium on carbon (0.109 g, 0.001 mol) and stirred in an atmosphere of hydrogen for 5 h and the mass was filtered through celite and washed with methanol (50 ml). The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate:hexane (60:40) to give the title compound.

Yield: 0.93 g; 1H NMR (CDCl·,, 400 MHz) δ ppm: 2.04 (s, 3H), 3.84 (bc, 2H), 3.92 (s, 3H), 3.93 (s, 3H ), 3.94 (s, 2H), 7.06-7.08 (d, J=7.9 Hz, 2H), 7.15 (s, 1H), 7.34-7.36 (d, J=8.04 Hz, 2H), 7.56 (s, 1H), 7.72 (s, 1H), 10.83 (s, 1H); MS (m/z): 352.2 (M+H) ⁺ .

Intermediate 19: methyl 5-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-3,4-dihydro2H-benzo[1,4]oxazine-8-carboxylate (I -19).

Cs ₂ CO ₃ (0.430 g, 0.001 mol) was added to a stirred solution of methyl 3-amino-2-hydroxy-4methyl-5-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]benzoate (0 .93 g, 0.0026 mol), 1-bromo-2-chloroethane (0.06 ml, 0.007 mol) in DMF (2 ml). The reaction mixture was stirred at room temperature for 30 h, cooled, poured into water (50 ml) and extracted with ethyl acetate (50 ml x 3). The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated on a rotary vacuum evaporator to give a crude mass which was purified by column chromatography using methanol:dichloromethane (2:98) to give the title compound.

Yield: 0.99 g; MS (m/z): 378.1 (M+H) ⁺ .

Intermediate 20: methyl 5-bromo-4-methyl-2-prop-2-ynyloxybenzoate (I-20).

K ₂ CO3 (0.633 g, 4 .60 mmol) and propargyl bromide (0.2 ml, 3.36 mmol). The reaction mixture was stirred at reflux for 16 h, cooled to RT, diluted with EtOAc and water. The two layers were separated and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound.

Yield: 0.85 g (98%); ¹ H-NMR (400 MHz, DMSO): δ 7.82 (s, 1H), 7.26 (s, 1H), 4.89 (s, 2H), 3.78 (s, 3H), 3, 62 (s, 1H), 2.38 (s, 3H); MS (m/z): 283.0, 285.0 (M+H)+.

Intermediate 21: methyl 5-bromo-2,4-dimethylbenzofuran-7-carboxylate (I-21).

Methyl 5-bromo-4-methyl-2-prop-2-ynyloxybenzoate (0.85 g, 3.0 mmol) in N-methylpyrrolidinone (1.49 ml) was heated at 202 to 205°C for 18 h. The reaction mixture was cooled to 0°C and extinguished by adding a mixture of ice water. The reaction mixture was diluted with EtOAc and the two layers were separated and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound as an off-white solid.

Yield: 0.3 g (35%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.02 (s, 1H), 6.43 (s, 1H), 3.98 (s, 3H), 2.53 (s, 6H); MS (m/z): 282.6, 284.9 (M+H) ⁺ .

Example 1 N-(cis-1S,2S-2-Hydroxycyclohexyl)-6-(2-chloropyridin-4-ylmethyl)-5-methylquinolin-8carboxamide

Step 1. Synthesis of methyl 6-(2-chloropyridin-4-ylmethyl)-5-methylquinoline-8-carboxylate.

To a stirred solution of methyl 6-bromo-5-methylquinoline-8-carboxylate (I-2) (0.25 g, 0.89 mmol) in 1,4-dioxane (5.9 ml) cooled at RT was added potassium acetate (0.27 g, 3.1 mmol); and bis(pinacolato)diboron (0.34 g, 1.33 mmol). The reaction mixture was degassed with nitrogen for 15 min and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (72.8 mg, 0.08 mmol) was added. The reaction mixture was gradually heated to 100° C. and stirred at this temperature for 10 h. After cooling to RT, the volatiles were removed under reduced pressure. The resulting crude product was dissolved in a 4:1 mixture of 1,4-dioxane and water (5.9 ml). Solid K2CO3 (0.16 g, 1.14 mmol) and 2-chloro-4-chloromethylpyridine (0.19 g, 1.15 mmol) were added. The reaction mixture was degassed with nitrogen for 15 min and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (62.3 mg, 0.07 mmol) was added. The reaction mixture was gradually heated to 100° C. and stirred at this temperature for 8 hours. After cooling to RT, the volatiles were removed under reduced pressure and the crude boronate ester was dissolved in water and EtOAc. The reaction mass was filtered through a Celite pad and the two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed once with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give the title compound.

Yield: 111 mg (40%); ¹ H-NMR (400 MHz, CDC^): δ 9.07 (d, J=4.0 Hz, 1H), 8.44 (d, J=8.6 Hz, 1H), 8.28 (d , J=5.0 Hz, 1H), 7.86 (s, 1H), 7.53 (dd, J=4.0, 8.6 Hz, 1H), 7.06 (s, 1H), 6 .97 (d, J=4.9 Hz, 1H), 4.23 (s, 2H), 4.04 (s, 3H), 2.58 (s, 3H); MS (m/z): 327.2, 328.9 (M+H) ⁺ .

Stage 2. Synthesis of 6-(2-chloropyridin-4-ylmethyl)-5-methylquinoline-8-carboxylic acid.

To a stirred solution of methyl 6-(2-chloropyridin-4-ylmethyl)-5-methylquinolin-8-carboxylate from Step 1 (0.11 g, 0.34 mmol) in 1:1 H2O and methanol (2 0 ml) cooled at 0° C., solid NaOH (0.04 g, 1.01 mmol) was added. After stirring for 2 hours at reflux temperature, the reaction mixture was cooled to RT, acidified with 2N HCl. HCl and extracted with DCM. The combined organic layer was washed once with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give the title compound.

Yield: 0.11 g (100%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 16.65 (br s, 1H), 8.94 (d, J=3.2 Hz, 1H), 8.68 (s, 1H), 8 .65 (d, J=8.7 Hz, 1H), 8.29 (d, J=5.1 Hz, 1H), 7.68 (dd, J=4.3, 8.6 Hz, 1H) , 7.04 (s, 1H), 6.99 (d, J=4.9 Hz, 1H) 4.29 (s, 2H), 2.65 (S, 3H); MS (m/z): 312.9, 314.9 (M+H) ⁺ .

Stage 3. Synthesis of N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(2-chloropyridin-4-ylmethyl)-5-methylquinolin-8-carboxamide.

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To a stirred solution of 6-(2-chloropyridin-4-ylmethyl)-5-methylquinolin-8-carboxylic acid (114 mg, 0.34 mmol) in DCM (3.4 ml) cooled at 0°C was added DIPEA successively (0.18 ml, 1.1 mmol), cis-2-aminocyclohexanol hydrochloride (50.6 mg, 0.43 mmol) and TBTU (151.6 mg, 0.40 mmol). After stirring for 16 h at RT, the reaction mixture was diluted with water and DCM. The two layers were separated and the aqueous layer was extracted with DCM. The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give the title compound.

Yield: 90.0 mg (64%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 11.52 (br s, 1H), 8.92 (d, J=4.1 Hz, 1H), 8.7 (s, 1H), 8 .53 (d, J=8.6 Hz, 1H), 8.26 (d, J=5.12 Hz, 1H), 7.56 (dd, J=4.1 Hz, 8.6 Hz, 1H ), 7.03 (s, 1H), 6.98 (s J=5.08 Hz, 1H), 4.39 (broad s, 1H), 4.28 (s, 2H), 4.00- 3.94 (m, 1H), 3.64-3.50 (m, 1H), 2.58 (s, 3H), 2.17-2.13 (m, 2H), 1.81-1, 78 (m, 2H), 1.48-1.45 (m, 4H); MS (m/z): 410.1, 412.1 (M+H)+.

Compounds of the following examples were synthesized using the following experimental procedure described in the preparation of the compound of example 1, using the appropriate intermediate compound I-2 with some . non-critical changes .__________________________________

Example No. Structure and name according to SHRAS Characteristic data Example 2 °fl Yj i -- γ f LJ,. γkA N-(hhc-1S,2S-2hydroxycyclohexyl)-6-(2,3 difluorobenzyl)-5-methylquinoline8-carboxamide Ή-NMR (400 MHz, CDC1 ₃ ): δ 11.51 (br s, 1H), 8.89 (d, J=3.92 Hz, 1H), 8.70 (s, 1H), 8, 53 (d, >7.4 Hz, 1H), 7.53 (dd, >4.2 Hz, 8.6 Hz, 1H), 7.02 (dd, >8.5 Hz, 17.2 Hz, 1H), 6.93 (dd, >7.9 Hz, 13.1 Hz, 1H), 6.68 (t, >6.8 Hz, 1H), 4.45 (broad s, 1H), 4 .30 (be, 2H), 3.99-3.96 (m, 1H), 3.623.59 (m, 1H), 2.63 (s, 3H), 2.16-2.12 (m, 2H ), 1.76-1.80 (m, 2H), 1.50-1.45 (m, 4H); MS(m/z): 411.1 (M+H) ⁺ . Example 3 ij O X) IJ ⁿ lX '''Ύ A: N-(uhc-3S,4S-3-hydroxytetrahydropyran-4-yl)6-(2-chloropyridin-5-ylmethyl)-5methylquinolin-8-carboxamide Ή-NMR (400 MHz, CDC1 ₃ ): δ 11.78 (br s, 1H), 8.91 (d, >7.4 Hz, 1H), 8.72 (s, 1H), 8.54 (d, >8.3 Hz, 1H), 8.25 (s, 1H), 7.57 (dd, >3.8 Hz, 8.2 Hz, 1H), 7.36 (d, >7, 4 Hz, 1H), 7.22 (d, >8.2 Hz, 1H), 5.07 (broad s, 1H), 4.27 (s, 2H), 4.13-4.11 (m , ZN), 3.73-3.72 (m, 1N), 3.65-3.52 (m, 1N), 3.3-3.25 (m, 1N), 2.62 (s, ZN ), 2.15-2.12 (m, 1H), 1.99-1.90 (m, 1H); MS (m/z): 412.1, 414.2 (M+H) ⁺ . Example 4 ij ''A o 'A // 1 J ' i ^OH Xj N-(phc-1S,2S-2hydroxycyclohexyl)-6-(2fluoropyridin-4-ylmethyl)-5methylquinolin-8-carboxamide Ή-NMR (400 MHz, CDCI3): δ 11.50 (br s, 1H), 8.92 (d, >3.6 Hz, 1H), 8.71 (s, 1H), 8.54 ( d, >8.5 Hz, 1H), 8.10 (d, >4.8 Hz, 1H), 7.57 (dd, >4.0 Hz, 8.4 Hz, 1H), 7.00 ( d, >16.14 Hz, 1H), 6.62 (s, 1H), 4.37 (broad s, 1H), 4.32 (s, 2H), 4.00-3.97 (m, 1H), 3.64-3.59 (m, 1H), 2.59 (s, 3H), 2.20-2.16 (m, 2H), 1.85-1.75 (m, 2H) , 1.401.26 (m, 4H); MS (m/z): 394.0 (M+H) ⁺ .

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N-(mic-lS,2S-2hydroxycyclohexyl)-6-(2fluorobenzyl)-5-methylquinoline-8carboxamide

N-(mic-lS,2S-2hydroxycyclohexyl)-6-(2chloropyridin-5-ylmethyl)-5methylquinoline-8-carboxamide

N-(mic-lS,2S-2hydroxycyclohexyl)-6-[2-(1methyl-1 H-pyrazol-4-yl)pyridin-5-ylmethyl]-5methylquinolin-8-carboxamide

Ή-NMR (400 MHz, CDC1 ₃ ): δ 11.51 (br s, 1H), 8.88 (d, J=3.9 Hz, 1H), 8.72 (s, 1H), 8. 53 (d, J=8.64 Hz, 1H), 7.52 (dd, J=4.l Hz, 8.6 Hz, 1H), 7.25-7.15 (m, 1H), 7. 07 (t, J=9.3 Hz, 1H), 6.99 (t, J=7.3 Hz, 1H), 6.92 (t, J=7.l Hz, 1H), 4.50 ( brs, 1H), 4.28 (be, 2H), 4.03-3.93 (m, 1H), 3.612-3.52 (m, 1H), 2.63 (s, 3H), 2 .2-2.10 (m, 2H), 1.85-1.75 (m, 2H), 1.50-1.30 (m, 4H); MS (m/z): 392.9 (M+H) ⁺ .

Ή-NMR (400 MHz, CDCI3): δ 11.51 (br s, 1H), 8.90 (d, J=3.0 Hz, 1H), 8.70 (s, 1H), 8.52 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 7.55 (dd, J=4.0 Hz, 8.5 Hz, 1H), 7.35 (d, J =6.0 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 4.40 (broad s, 1H), 4.26 (s, 2H), 4.0-3 .91 (m, 1H), 3.62-3.55 (m, 1H), 2.63 (s, ZN), 2.22.10 (m, 2H), 1.82-1.73 (m , 2H), 1.38-1.23 (m, 4H); MS (m/z): 410.0, 412.1 (M+H) ⁺ .

Ή-NMR (400 MHz, CDCI3): δ 11.51 (d, J=6.3 Hz, 1H), 8.89 (s, 1H), 8.75 (s, 1H), 8.51 (d , J=8.7 Hz, 1H), 8.39 (s, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 7.53 (dd, J=4,l, 8.6 Hz, 1H), 7.40-7.30 (m, 2H), 4.47 (brs, 1H), 4.27 (s, 2H), 4.04-3.90 (m , 1H), 3.93 (s, 3H), 3.64-3.50 (m, 1H), 2.63 (s, 3H), 2.17-2.13 (m, 2H), 1, 81-1.78 (m, 2H), 1.48-1.45 (m, 4H); MS (m/z): 456.1 (M+H) ⁺ .

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Example 8

N-( ₄ hc-1S,2S-2hydroxycyclohexyl)-6-[2,3 difluoro-4-(1-methyl-1 H-pyrazol4-yl)-benzyl]-5-methylquinoline8-carboxamide

Ή-NMR (400 MHz, CDC1 ₃ ): δ 11.52 (br s, 1H), 8.89 (d, J=3.6 Hz, 1H), 8.72 (s, 1H), 8, 53 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.53 (dd, J=4,l, 8.4 Hz, 1H ), 7.13 (d, J=7.6 Hz, 1H), 6.68 (d, J=7.4 Hz, 1H), 4.46 (broad s, 1H), 4.29 (s , 2H), 3.993.97 (m, 1H), 3.95 (s, 3H), 3.62-3.58 (m, 1H), 2.65 (s, 3H), 2.29-2, 18 (m, 2H), 1.821.78 (m, 2H), 1.45-1.35 (m, 4H); MS (m/z): 491.0 (M+H) ⁺ .

Example 9

N-(phc-1S,2S-2hydroxycyclohexyl)-6-[3-fluoro-4-(1-methyl-1H-pyrazol-4yl)-benzyl]-5-methylquinoline-8carboxamide

Ή-NMR (400 MHz, CDCh): δ 11.79 (br s, 1H), 8.74 (d, J=7.6 Hz, 1H), 8.66 (s, 1H), 8.33 (d, J=8.5 Hz, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.60-7.49 (m, 1H), 7.43 (dd, J=4.l, 8.6 Hz, 1H), 7.19-7.08 (m, 2H), 5.61 (brs, 1H), 4.83 (s, 2H), 4.03 -3.98 (m, 1H), 3.96 (s, ZN), 3.70-3.58 (m, 1H), 2.80 (s, ZN), 2.25-2.18 (m , 2H), 1.81-1.70 (m, 2H), 1.43-1.32 (m, 4H); MS (m/z): 473.1 (M+H) ⁺ .

Example

N-(uhc-1S,2S-2hydroxycyclohexyl)-6-(4pyrazol-1-yl-benzyl)-5methylquinoline-8-carboxamide

Ή-NMR (400 MHz, CDCI3): δ 11.52 (br s, 1H), 8.89 (d, J=3.6 Hz, 1H), 8.75 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.61-7.52 (m, 4H), 7.21 (s, 1H), 7.18 (s, 1H), 6.43 (s, 1H), 4.46 (broad s, 1H), 4.32 (s, 2H), 3.99-3.96 (m , 1H), 2.62 (s, 3H), 2.18-2.12 (m, 2H), 1.93-1.79 (m, 2H), 1.42-1.30 (m, 4H ); MS (m/z): 441.1 (M+H) ⁺ .

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Example

AND

N-(uhc-1S,2S-2hydroxycyclohexyl)-6-[2fluoro-4-(1-methyl-1H-pyrazol-4yl)-benzyl]-5-methylquinoline-8carboxamide

Ή-NMR (400 MHz, CDC1 ₃ ): δ 11.50 (br s, 1H), 8.88 (d, J=4.4 Hz, 1H), 8.73 (s, 1H), 8, 54 (d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.50 (s, 1H), 7.54 (dd, J=4,l, 8.6 Hz, 1H ), 7.16-7.08 (m, 2H), 6.91 (d, J=2.4 Hz, 1H), 4.50 (brs, 1H), 4.27 (s, 2H) , 4.04-3.95 (m, 1H), 3.92 (s, ZN), 3.65-3.55 (m, 1H), 2.65 (s, ZN), 2.25-2 .18 (m, 2H), 1.85-1.70 (m, 2H), 1.56-1.42 (m, 4H); MS (m/z): 473.1 (M+H) ⁺ .

Example

N-(uhc-1S,2S-2hydroxycyclohexyl)-6-(4thiazol-4-yl-benzyl)-5methylquinoline-8-carboxamide

Ή-NMR (400 MHz, CDCI3): δ 11.54 (br s, 1H), 8.88 (d, J=3.0 Hz, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 8.52 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.52 (dd, J=3.7, 8.4 Hz, 1H), 7.47 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 4.54 (broad s, 1H), 4.32 (s, 2H), 4.123.91 (m, 1H), 3.65-3.52 (m, 1H), 2.65 (s, 3H), 2.20-2.11 (m, 2H), 1.84 -1.73 (m, 2H), 1.48-1.36 (m, 4H); MS (m/z): 458.2 (M+H) ⁺ .

Example

N-(uhc-3S,4S-3hydroxytetrahydropyran-4-yl)6-(4-thiazol-4-yl-benzyl)-5methylquinoline-8-carboxamide

Ή-NMR (400 MHz, CDCI3): δ 11.83 (br s, 1H), 8.89 (d, J=3.1 Hz, 1H), 8.85 (s, 1H), 8.75 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.0 Hz, 2H), 7.54 (dd, J=4,l, 8.6 Hz, 1H), 7.47 (s, 1H), 7.22 (d, J=8.0 Hz, 2H), 5.21 (broad s, 1H), 4.33 (s, 2H), 4.294.13 (m, 2H), 4.11-4.0 (m, 1H), 3.78-3.69 (m, 1H), 3.55-3.48 (m, 2H) , 2.64 (s, 3H), 2.19 (m, 1H), 2.0-1.93 (m, 1H); MS (m/z): 460.1 (M+H) ⁺ .

- 18 040024

Example

N-(hhc-1S,2S-2hydroxycyclohexyl)-6-benzyl5-methylquinoline-8-carboxamide

Example

N-(hhc-1S,2S-2hydroxycyclohexyl)-6-[4-(1methyl-1 H-pyrazol-4-yl)benzyl]-5-methylquinoline-8carboxamide

Ή-NMR (300 MHz, CDC1 ₃ ): δ 11.55 (d, J=6.0 Hz, 1H), 8.87 (d, J=3.2 Hz, 1H), 8.75 (s, 1H), 8.52 (d, J=8.4 Hz, 1H), 7.52 (dd, J=3.7, 8.4 Hz, 1H), 7.24 (d, J=6.9 Hz, 2H), 7.19 (d, J=6.9 Hz, 1H), 7.13 (d, J=6.9 Hz, 2H), 4.57 (brs, 1H), 4, 29 (s, 2H), 4.123.91 (m, 1H), 3.65-3.52 (m, 1H), 2.62 (s, 3H), 2.20-2.11 (m, 2H) , 1.84-1.73 (m, 2H), 1.48-1.36 (m, 4H); MS (m/z): 375.2 (M+H) ⁺ .

Ή-NMR (400 MHz, CDCh): δ 11.51 (br s, 1H), 8.87 (d, J=4.4 Hz, 1H), 8.76 (s, 1H), 8.51 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.54 (s, 1H), 7.54 (s, 1H), 7.51 (0d, J=4, 4, 8.8 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 4.50 (brs, 1H), 4.28 (s, 2H), 4.03-3.92 (m, 1H), 3.91 (s, 3H), 3.653.57 (m, 1H), 2.64 (s, 3H ), 2.20-2.10 (m, 2H), 1.83-1.75 (m, 2H), 1.60-1.25 (m, 4H); MS (m/z): 455.1 (M+H) ⁺ .

Compounds of examples 16 and 17 were prepared using the following experimental procedure described in the preparation of the compound of example 1 using the corresponding intermediate compound I-19 with some non-critical changes.

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Characteristic data

N-(uhc-1S,2S-2 Example 18 N-(cis-1S,2 S-2-Hidroxycyclohexyl)-5-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl )ben1.24 (m 4H), 1.55-1.62 (m, 2H), 1.82-1.83 m, 2H), 1.92 (s, 3H), 2.82-2.84 (m, 2H),

3.34 (s, 3H), 3.54-3.55 (m, 2H), 3.90 (s, 2H),

4.19 (s, 2H), 6.50 (s, 1H), 7.00 (s, 1H), 7.177.19 (dJ=8.3 Hz, 2H), 7.65-7.69 ( m, ZN),

8.34 (s, 1H); MS (m/z): 447.2 (M+NG

1.18 (m 4H), 1.56-1.64 (m, 2H), 1.83-1.85 m, 1H), 1.93 (s, ZN), 1.99-2.02 ( m, 1H),

3.19-3.21 (m, 2H), 3.56-3.60 (m, 2H), 3.84 s, 3H), 3.86 (s, 2H), 4.21 (m, 2H ), 4.69-4.71 d, 1=5.2Hz, 1H), 5.31 (s, 1H), 7.00 (s, 1H),

7.04-7.06 (d J=7.8 Hz, 2H), 7.41-7.43 (d,

J=7.90 Hz, 2H), 7.77 (s, 1H), 7.96-7.97 (d,

J=7.04 Hz, 1H), 8.04 (s, 1H); MS (m/z):

460.9 (M+NG

N-(mic-lS,2S-2hydroxycyclohexyl)-6-(4carboxamide hydroxycyclohexyl)-6-[4-(1methyl-1H-pyrazol-4-yl)-benzyl]-5methyl-3,4-dihydro-2H ¹ NMR(DMSO-c1 ₆ , 400 MHz) δ ppm: ,4]oxazine-8zyl]imidazo[1,2-a]pyridine-8-carboxamide ¹ NMR (DMSO-a ₆ , 400 MHz) δ ppm: 1,22-

Stage 1. Synthesis of 5-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-imidazo[1,2-a]pyridine-8carbonitrile.

To a stirred solution of 6-bromo-5-methylimidazo[1,2-a]pyridine-8-carbonitrile (I-6) (0.1 g, 0.42 mmol) in toluene (5.9 ml) was added acetate potassium (0.14 g, 1.43 mmol) and bis(pinacolato)diboron (0.16 g, 0.63 mmol). The reaction mixture was degassed with nitrogen for 15 min and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (17.0 mg, 0.02 mmol) was added. The reaction mixture was gradually heated to 100° C. and stirred at this temperature for 20 hours. After cooling to RT, the crude product in toluene was diluted with a 9:1 mixture of 1,4-dioxane and water (3.7 ml). Solid K ₂ CO ₃ (0.07 g, 0.5 mmol) and 4-(4-chloromethylphenyl)-1-methyl-1H-pyrazole (0.07 g, 0.35 mmol) were added. The reaction mixture was degassed with nitrogen for 15 min and [1,1'-bis(diphenylphosphino)ferrocene]palladium(H) dichloride (28.0 mg, 0.04 mmol) was added. The reaction mixture was gradually heated to 100°C and stirred at this temperature for 6 h. After cooling to RT, the volatiles

- 20 040024 was removed under reduced pressure and the crude product was dissolved in water and EtOAc. The reaction mass was filtered through a Celite pad and the two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give the title compound.

Yield: 40 mg (35%); 1H-NMR (400 MHz, CDCI3): δ 7.82 (s, 1H), 7.73 (s, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.42 (d, J=8.04 Hz, 2H), 7.10 (d, J=8.00 Hz, 2H), 4.07 (s, 2H), 3.94 (s, 3H), 2.66 (s, 3H); MS (m/z): 328.1 (M+H)+.

Stage 2. Synthesis of 5-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-imidazo[1,2-a]pyridine-8-carboxamide.

To a stirred solution of 5-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2a]pyridine-8-carbonitrile prepared in Step 1 (0.02 g, 0 .06 mmol) in a 1:1 mixture of H2O and ethanol (1.0 mL), solid KOH (0.009 g, 0.15 mmol) was added at RT. After stirring for 3 hours at 85° C., the reaction mixture was cooled to RT, the volatiles were removed under reduced pressure to give the title compound.

Yield: 0.02 g (95%); 1H-NMR (400 MHz, DMSO): δ 8.05 (s, 1H), 7.77 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.51 (d , J=5.9 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 6.88 (s, 1H ), 4.96 (s, 2H), 3.98 (s, 3H), 2.86 (s, 3H); MS (m/z): 346.1 (M+H)+.

Stage 3. Synthesis of 5-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2-a]pyridine-8-carboxylic acid.

To a stirred solution of 5-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2-a]pyridine-8-carboxamide obtained in step 2 (0.02 g , 0.06 mmol), aq. HCl (5N, 1.0 ml). After stirring for 6 h at 100° C., the reaction mixture was cooled to RT, the reaction mixture was made basic with aq. ammonia solution. The crude product was extracted with a 9:1 mixture of DCM and methanol to give the title compound.

Yield: 0.02 g (100%); 1H-NMR (400 MHz, DMSO): δ 8.49 (s, 1H), 8.40 (s, 1H), 8.24 (s, 1H) 8.09 (d, J=4.5 Hz, 1H), 7.82 (d, J=4.5 Hz, 1H), 7.50 (d, J=7.6 Hz, 2H), 7.24 (d, J=7.6 Hz, 2H) , 6.86 (s, 1H), 4.19 (s, 2H), 3.99 (s, 3H), 2.84 (s, 3H); MS (m/z): 347.1 (M+H) ⁺ .

Stage 4. Synthesis of N-(cis-1S,2S-2-hydroxycyclohexyl)-5-methyl-6-[4-(1-methyl-1H-pyrazol-4yl)benzyl]imidazo[1,2-a]pyridine- 8-carboxamide.

To a stirred solution of 5-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2a]pyridine-8-carboxylic acid prepared in step 3 (20.0 mg, 0.06 mmol), in DCM (1.0 ml) cooled at 0°C, DIPEA (0.02 ml, 0.15 mmol), cis-2-aminocyclohexanol hydrochloride (8.7 mg, 0.06 mmol) and HATU (24.1 mg, 0.063 mmol). After stirring for 1 h at RT, the reaction mixture was diluted with water and DCM. The two layers were separated and the aqueous layer was extracted with DCM. The combined organic layer was washed once with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give the title compound.

Yield: 18.0 mg (72%); 1H-NMR (400 MHz, CDC13): δ 10.44 (d, J=6.2 Hz, 1H), 8.05 (s, 1H), 7.44 (s, 1H), 7.70 (d , J=8.2 Hz, 1H), 7.51 (d, J=5.96 Hz, 2H), 7.45 (d, J=8.16 Hz, 2H), 7.21 (d, J =6.6 Hz, 2H), 4.96 (s, 2H), 3.98 (s, 3H); 3.97-3.90 (m, 1H), 3.62-3.56 (m, 1H), 2.86 (s, 3H); 2.18-2.08 (m, 2H), 1.77-1.75 (m, 2H), 1.41-1.43 (m, 4H); MS (m/z): 444.1 (M+H) ⁺ .

Compounds of the following examples 19 to 26 were synthesized using the following experimental procedure described in the preparation of the compound of example 18 using the corresponding intermediate compound I-6 with some non-critical changes

- 21 040024

Example No. Structure and name according to SHRAS Characteristic data Example 19 π ί L x ''Ή 'bg L J "· \X'··. N N-(uhc-1S,2S-2- hydroxycyclohexyl)-5-methyl-6(4-pyrazol-1-yl-benzyl)- imidazo[1,2-а]pyridine-8carboxamide Ή-NMR (400 MHz, CDC1 ₃ ): δ 10.34 (d, J=5.5 Hz, 1H), 8.18 (d, J=7.5 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.67 (s, 2H), 7.59 (d, J=8.8, ZH), 7.2 (d, J=3.2 Hz, 2H), 6.81 (d, J=7.2 Hz, 1H), 4.05 (s, 2H), 3.90 (m, 1H), 3.57 (m, 1H), 2.65 (s, ZN ), 2.12 (d, 1H), 1.77-1.75 (m, 4H), 1.41-1.43 (m, 4H); MS (m/z): 430.2 (M+H) ⁺ . Example 20 ft--N O < 1 Г “ 1 I he WF Г Ν--- _N . (cis-18,28-2-hydroxycyclohexyl)-5-methyl-6[2-fluoro-4-(1-methyl-1H-pyrazol4-yl)-benzyl]imidazo[1,2а]pyridine-8-carboxamide Ή-NMR (400 MHz, CDC1 ₃ ): δ 10.43 (d, J=6.l Hz, 1H), 8.16 (s, 1H), 7.75-7.65 (m, 2H), 7.60-7.50 (m, 2H), 7.18-7.0 (m, 2H), 7.04-6.98 (m, 1H), 4.10 (s, 2H), 4. 08-3.98 (m, 1H), 3.94 (s, ZN), 3.62-3.53 (m, 1H), 2.80 (s, ZN), 2.16-2.12 ( m, 2H); 1.77-1.75 (m, 2H), 1.41-1.43 (m, 4H); MS (m/z): 462.1 (M+H) ⁺ . Example 21 L y kJ ⁿ 0H st ^F Cn N N-(hhc-1S,2S-2hydroxycyclohexyl)-6-[2,3 - Ή-NMR (400 MHz, CDCh): δ 10.3 (broad s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7 .75 (d, >2.0Hz, 1H), 7.61 (d, J=4.4Hz, 2H), 7.27 (s, 1H), 7.0-6.96 (m, 1H) , 4.05 (s, 2H), 3.96 (s, 3H), 3.95-3.89 (m, 1H), 3.6-3.5 (m, 1H), 2.13 (d , J=12.8 Hz, 2H), 1.78 (d, J=9.2 Hz, 2H), 1.48-1.25 (m, 4H); MS (m/z): 466.2 (M+H) ⁺ .

- 22 040024

difluoro-4-(1-methyl-1H-pyrazol-4yl)-benzyl]imidazo[1,2а]pyridine-8-carboxamide Example 22 e-N 0 f ύ P 1 1 XJ ^H 0H F N-(uhc-1S,2S-2hydroxycyclohexyl)-6-(2,3 difluorobenzyl)-imidazo[1,2а]pyridine-8-carboxamide Ή-NMR (400 MHz, CDC1 ₃ ): δ 10.4 (br s, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 7.60 (s, 1H), 7.59 (s, 1H), 7.15-6.95 (m, 3H), 4.05 (s, 2H), 3.95-3.8 (m, 2H), 3.613.48 (m, 1H), 2.20-2.10 (m, 2H), 1.85-1.75 (m, 2H), 1.40-1.22 (m, 4H); MS (m/z): 386.1 (M+H) ⁺ . Example 23 Λ-Ν 0 < 1 R 1 J Xx H ^OH V N-(uhc-1S,2S-2hydroxycyclohexyl)-6-(4thiazol-4-yl-benzyl)-imidazo[1,2а]pyridine-8-carboxamide Ή-NMR (400 MHz, CDCI3): δα 10.41 (d, J=6.0 Hz, 1H), 8.87 (s, 1H), 8.12 (s, 1H), 7.96 (s , 1H), 7.90 (d, J=8.0 Hz, 2H), 7.58 (s, 1H), 7.55 (s, 1H), 7.52 (s, 1H), 7.24 (d, J=8.0 Hz, 2H), 4.06 (s, 2H), 3.93-3.90 (m, 1H), 3.6-3.58 (m, 1H), 2, 14 (d, J=10.8 Hz, 2H), 1.78 (d, J=9.6 Hz, 2H), 1.42-1.23 (m, 4H); MS (m/z): 433.1 (M+H) ⁺ . Example 24 nj? Π Lj ^Η 0Н N-(uhc-1S,2S-2hydroxycyclohexyl)-6-(4phenyl-benzyl)-imidazo[1,2а]pyridine-8-carboxamide Ή-NMR (400 MHz, CDCI3): δ 10.42 (d, J=6.4 Hz, 1H), 8.26 (d, J=6.4 Hz, 1H), 8.21 (d, J =7.2 Hz, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.65 (d, J=6.4 Hz, 2H), 7.60-7.52 (m, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.35 (t, J=7.2 Hz, 1H), 7.24 (d, J=6.4 Hz , 2H), 4.05 (s, 2H), 3.93-3.85 (m, 2H), 3.62-3.57 (m, 1H), 2.172.11 (m, 2H), 1, 79-1.77 (m, 2H), 1.58-1.33 (m, 4H); MS (m/z): 426.2 (M+H) ⁺ .

- 23 040024

Example

MS (m/z): 430.2 (M+H) ⁺ .

N-( _4hc -1S,2S-2hydroxycyclohexyl)-6-[4-(1methyl-1H-pyrazol-4-yl)-benzyl]imidazo[1,2-а]pyridine-8carboxamide

N-( _4hc -1S,2S-2hydroxycyclohexyl)-6-[2-fluoro4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2-a]pyridine8-carboxamide

Example 27 N-(cis-1S,2S-2-Hydroxycyclohexyl)-7-methyl-6-(4-pyrazol-1-yl-benzyl)-1H-benzy midazol-4-carboxamide

Step 1. Synthesis of ethyl 7-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole4-carboxylate.

Potassium acetate ( 0.35 g, 3.6 mmol) and bis(pinacolato)diboron (0.4 g, 1.6 mmol). The reaction mixture was degassed with nitrogen for 15 min and [1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloride (86.6 mg, 0.11 mmol) was added. The reaction mixture was gradually heated to 110°C and stirred at this temperature for 12 h. After cooling to RT, the reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain the title compound.

Yield: 0.24 g (70%); ¹ H-NMR (400 MHz, CDQ3): δ 10.50 (br s, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 4.49 (q, 2H), 2.98 (s, 3H), 1.44 (t, J=3.2 Hz, 3H), 1.39 (s, 12H); MS (m/z): 331.1 (M+H) ⁺ .

Step 2. Synthesis of ethyl 7-methyl-6-(4-pyrazol-1-yl-benzyl)-1H-benzimidazole-4-carboxylate.

Ethyl 7-methyl-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole-4-carboxylate obtained in step 1 (0.1 g, 0.3 mmol) was dissolved in a 5:1 mixture of 1,4-dioxane and water (3.6 ml). Solid K2CO3 (0.06 g, 0.42 mmol) and 1-(4-chloromethylphenyl)-1H-pyrazole (0.06 g, 0.31 mmol) were added. The reaction mixture was degassed with nitrogen for 15 min and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (24.7mg, 0.03mmol) was added. The reaction mixture was gradually heated to a temperature

- 24 040024 and stirred at this temperature for 12 hours. After cooling to RT, the reaction mass was filtered through a pad of celite and the filtrate was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain the title compound.

Yield: 87.0 mg (80%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 10.45 (br s, 1H), 8.12 (s, 1H), 7.89-7.88 (d, J=2.2 Hz, 2H), 7.87 (s, 1H), 7.61-7.59 (d, J=6.9 Hz, 2H), 7.24 (d, J=6.5 Hz, 2H), 6, 44 (s, 1H), 4.47 (q, 2H), 4.21 (s, 2H), 2.65 (s, 3H), 1.44 (t, J=7.1 Hz, 3H); MS (m/z): 361.1 (M+H)+.

Stage 3. Synthesis of 7-methyl-6-(4-pyrazol-1-yl-benzyl)-1H-benzimidαzol-4-carboxylic acid.

To a stirred solution of ethyl 7-methyl-6-(4-pyrazol-1-yl-benzyl)-1H-benzimidazole-4-carboxylate from step 2 (0.1 g, 0.28 mmol) in mixture 1: 1 H2O and methanol (3.0 ml) cooled at 0°C was added solid NaOH (0.022 g, 0.55 mmol). After stirring for 2 h at reflux temperature, the reaction mixture was evaporated under reduced pressure to half its volume, cooled to RT, acidified with 1N. HCl and extracted with a 9:1 mixture of DCM and methanol. The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the title compound.

Yield: 0.083 g (90%); ¹ H-NMR (400 MHz, DMSO): δ 15.59 (br s, 1H), 9.45 (br s, 1H), 8.45 (s, 1H), 7.91 (s, 1H ), 7.91 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.70 (s, 1H), 7.29-7.27 (d, J=8, 4 Hz, 2H), 6.51 (s, 1H), 4.24 (s, 2H), 2.66 (s, 3H); MS (m/z): 333.1 (M+H) ⁺ .

Step 4 Synthesis of N-(cis-1S,2S-2-hydroxycyclohexyl)-7-methyl-6-(4-pyrazol-1-yl-benzyl)-1Hbenzimidazole-4-carboxamide.

To a stirred solution of 7-methyl-6-(4-pyrazol-1-yl-benzyl)-1H-benzimidazole-4-carboxylic acid from Step 3 (100.0 mg, 0.3 mmol) in DCM (3 0 ml) cooled at 0°C, DIPEA (0.075 ml, 0.45 mmol), cis-2-aminocyclohexanol hydrochloride (45.5 mg, 0.17 mmol) and HATU (114.0 mg, 0 .3 mmol). After stirring for 2 h at RT, the reaction mixture was diluted with water and DCM. The two layers were separated and the aqueous layer was extracted with DCM. The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give the title compound.

Yield: 83.9 mg (65%); 1H-NMR (400 MHz, CDCl ₃ ): δ 10.3 (br s, 1H), 9.89 (br s, 1H), 8.01 (s, 1H), 7.88 (s, 1H ), 7.70 (s, 1H), 7.50-7.52 (d, J=5.36 Hz, 2H), 7.13-7.11 (d, J=6.48 Hz, 2H) , 6.44 (s, 1H), 4.24 (s,

2H), 4.15 (brs, 1H), 4.03.90 (m, 1H), 3.65-3.55 (m, 1H), 3.49 (s, 3H), 2.60 (s, 3H), 2.20-2.10 (m, 2H), 1.861.77 (m, 2H), 1.43-1.39 (m, 4H); MS (m/z): 430.5 (M+H) ⁺ .

Compounds of the following examples 28 to 45 were synthesized using the following experimental procedure described in the preparation of the compound of example 27 using the appropriate intermediates I-9 and I-12 with some non-critical changes

hydroxycyclohexyl)-7-methyl-6Characteristic data

Ή-NMR (400 MHz, CDC1 ₃ ): δ 10.15 (br s, 1H), 9.89 (br s, 1H), 8.04 (s, 1H), 8.03 (s, 1H ), 7.69 (s, 1H), 7.52 (s, 1H), 7.3-7.29 (d, J=7.2 Hz, 2H), 7.09-7.07 (d, J=8.0 Hz, 2H), 4.24 (s, 2H), 3.49 (s, ZN), 3.56 (m, 2H), 2.60 (s, ZN), 2.12 ( e, 1H), 1.86-1.77 (m, 4H), 1.43-1.39 (m, 4H); MS (m/z): 444.1 (M+H) ⁺ .

[4-(1-methyl- 1H-pyrazol-4-yl) benzyl] -1 H-benzimidazol-4- 25 040024

carboxamide Example 29 l..o [J t Y OH ^-N N-(uhc-1S,2S-2hydroxycyclohexyl)-6-[4-( 1 methyl-1 H-pyrazol-4-yl)-benzyl] 1 H-benzimidazole-4-carboxamide Ή-NMR (400 MHz, CDC1 ₃ ): δ 9.91 (br s, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.42 (d, J=7 .6 Hz, 2H), 7.26 (d, J=7.6 Hz, 2H), 7.16 (s, 1H), 7.14 (s, 1H), 6.99 (s, 1H), 4.14 (s, 2H), 3.97 (s, 3H), 3.70-3.60 (m, 1H), 3.60-3.50 (m, 2H), 2.19-2, 01 (m, 2H), 1.82-1.70 (m, 2H), 1.42-1.31 (m, 4H); MS (m/z): 430.2 (M+H) ⁺ . Example 30 <X1.0 Yjl ι J he ΎΊ \ N-(uhc-1S,2S-2- hydroxycyclohexyl)-7-methyl-6[2-fluoro-4-(1-methyl-1H-pyrazol-4yl)-benzyl]-1H-benzimidazole-4carboxamide Ή-NMR (300 MHz, CDCI3): δ 8.08 (s, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.18-7.03 (m, 4H) , 6.92-6.80 (m, 2H), 4.16 (s, 2H), 3.92 (s, 3H), 3.62-3.43 (m, 2H), 2.48 (breadth .s, 1H), 2.20-2.08 (m, 2H), 1.831.73 (m, 2H), 1.50-1.20 (m, 4H); MS (m/z): 462.2 (M+H) ⁺ .

- 26 040024

Example 31 1 „O Pr I Jkx fl OH yal cr Ή N-(uhc-1S,2S-2hydroxycyclohexyl)-7-methyl-6[2-chloropyridin-3-ylmethyl]-1Hbenzimidazole-4-carboxamide Ή-NMR (400 MHz, CDC1 ₃ ): δ 9.84 (br s, 1H), 8.22 (s, 1H), 8.15-7.90 (m, 2H), 7.51 (s , 1H), 7.68-7.55 (m, 1H), 7.05 (s, 1H), 4.23 (s, 2H), 4.19 (br. s, 1H), 4.02- 3.90 (m, 1H), 3.75-3.65 (m, 1H), 2.80 (s, 3H), 2.20-2.01 (m, 2H), 1.82-1, 64 (m, 2H), 1.48-1.58 (m, 4H); MS (m/z): 399.1, 401.0 (M+H) ⁺ . Example 32 yul o L γ fl he '8 N-(uhc-1S,2S-2- hydroxycyclohexyl)-7-methyl-6[4-(thiazol-4-yl)-benzyl]-1Hbenzimidazole-4-carboxamide Ή-NMR (400 MHz, CDCI3): δ 8.85 (s, 1H), 8.60 (d, J=3.2 Hz, 1H), 8.09 (s, 1H), 7.80 (d , J=8.0 Hz, 2H), 7.51 (s, 2H), 7.26 (d, J=8.0 Hz, 2H), 4.20 (s, 2H), 4.18 (broad .s, 1H), 3.98-3.90 (m, 1H), 3.363.50 (m, 1H), 2.49 (s, 3H), 2.20-2.10 (m, 2H), 1.89-1.67 (m, 2H), 1.48-1.44 (m, 2H), 1.37-1.28 (m, 2H); MS (m/z): 447.2 (M+H) ⁺ . Example 33 ii ΓΊ L L.-k to Yf I D/ fl he jQ F N-(uhc-1S,2S-2hydroxycyclohexyl)-7-methyl-6[2,3-d ifluorobenzyl]-1Hbenzimidazole-4-carboxamide Ή-NMR (400 MHz, CDCI3): δ 10.02 (br s, 1H), 8.04 (s, 1H), 7.80 (dd, J=8.0 Hz, 1H), 7.43 (dd, J=7.2 Hz, 1H), 6.98 (dd, J=8.0 Hz, 1H), 6.62 (s, 1H), 4.15 (s, 2H), 3.99 -3.90 (m, 2H), 3.66 (brs, 1H), 2.80 (s, 3H), 2.20-2.05 (m, 2H), 1.771.69 (m, 2H ), 1.55-1.29 (m, 4H); MS (m/z): 400.4 (M+H) ⁺ .

- 27 040024

Example 34 * D on χχ Χ^ 'Ί ' F N-(uhc-1S,2S-2hydroxycyclohexyl)-7-methyl-6[3,4-difluorobenzyl]-1Hbenzimidazole-4-carboxamide Ή-NMR (400 MHz, CDC1 ₃ ): δ 8.08 (s, 1H), 7.85-7.75 (m, 1H), 7.10-7.0 (m, 2H), 6.90 -6.78(m, 2H), 4.12(s, 2H), 4.0-3.92(m, 2H), 3.75-3.60(m, 1H), 2.80(s , 3H), 2.20-2.10 (m, 2H), 1.80-1.70 (m, 2H), 1.49-1.25 (m, 4H); MS (m/z): 400.4 (M+H) ⁺ . Example 35 1 "O IJ ^and ι J ΟΕΙ L> \ N-(uhc-1S,2S-2-hydroxycyclohexyl)-7-methyl-6[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3 -ylmethyl]-1Hbenzimidazole-4-carboxamide Ή-NMR (400 MHz, CDC1 ₃ ): δ 9.83 (broad s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.31 (s, 1H), 7.30-7.25 (m, 2H), 4.15 (s, 2H), 4.0-3.90 (m, 1H), 3.93 (s, 3H), 3.65-3.49 (m, 2H), 2.41 (s, 3H), 2.15-2.05 (m, 2H), 1.85 -1.75 (m, 2H), 1.44-1.40 (m, 4H); MS (m/z): 445.2 (M+H) ⁺ . fj~ ΝΗ o XX n 11 1 J γ % II 2 Ji X on f _F Example 36 N \ N-(uhc-1S,2S-2- hydroxycyclohexyl)-7-methyl-6[2,3-d iftoro-4-(1-methyl-1H- pyrazol-4-yl)-benzyl] -1H- MS (m/z): 480.2 (M+H) ⁺ .

- 28 040024

benzimidazole-4-carboxamide p~yn o m\11 ΥΥΤ· _E ° ⁿ u g t t Example 37 G MS (m/z): 466.1 (M+H) ⁺ . M-(cis-18,28-2- hydroxycyclohexyl)-6-[2,3 difluoro-4-(1-methyl-1H-pyrazol-4yl)-benzyl]-1H-benzimidazole-4carboxamide \__ o Wu Ή-NMR (400 MHz, CDC1 ₃ ): δ 9.94 (s, 1 G 1 1 A J 1H), 7.93 (s, 2H), 7.67 (s, 1H), 7.54 (d, GL L f ⁿ 1 J=8.0Hz, 2H), 7.09(d, J=6.5Hz, 2H), 6.44(s, 1H), 4.11(s, 2H), 4.05-3, 95 (m, 1H), 3.65-3.56 (m, 1H), 3.81 (s, 3H), 2.61 Example 38 ABOUT (s, 3H), 2.35 (s, 1H), 2.21-2.15 (m, 2H), 1.80-1.78 (m, 2H), 1.47-1.41 (m , 4H); MS N-(ijhc-1S,2S-2hydroxycyclohexyl)-2,7 dimethyl-6-(4-pyrazol-1-ylbenzyl)-1H-benzimidazole-4carboxamide (m/z): 444.5 (M+H) ⁺ . hn, 1L 1 J Ή-NMR (400 MHz, CDC1 ₃ ): δα 9.93 (br s, 1H), 9.81 (br s, 1H), 7.89 (s, ''N^X I 1H), 7.76 (s, 1H), 7.49 (s, 1H), 7.24 (d, J.A. 1J oil J=4.68 Hz, 2H), 7.04 (d, J=7.9 Hz, 2H), Example 39 XX, — 3.90 (s, 2H), 3.89 (s, 3H), 3.56 (m, 2H), 2.760 (s, 6H), 2.12 (d, 1H), 1.86-1.77 (m, 4H), 1.43-1.39 (m, 4H); MS (m/z): 458.1 (M+H) ⁺ . N-(pnc-lS,2S-2-

- 29 040024

hydroxycyclohexyl)-2,7 dimethyl-6-[4-(1-methyl-1Hpyrazol-4-yl)-benzyl]-1Hbenzimidazole-4-carboxamide O nor Jl 11 J Ή-NMR (400 MHz, CDC1 ₃ ): δ 9.95 (br s, 1H), 9.81 (br s, 1H), 8.86 (s, χX XC ^u^ 1 ^,[ ^ 1H), 7.92 (d, J=6.l Hz, 2H), 7.45 (s, 1H), θ ^,[ ιΓΊ 7.00 (d, J=6.l Hz, 2H), 6.96 (s, 1H), 4.11 (s, 2H), 4.05-3.95 (m, 1H), 3.65 -3.55 (m, 1H), 2.81 (s, ZN), 2.63 (s, ZN), 2.2 (s, 1H), Example 40 2.18-2.10 (m, 2H), 1.80-1.77 (m, 2H), 1.47-1.44 (m, 4H); MS (m/z): 461.2 N-(uhc-1S,2S-2hydroxycyclohexyl)-2,7 dimethyl-6-(4-thiazol-4-yl-benzyl)1 N-benzimidazole-4-carboxamide (M+H) ⁺ . i Ή-NMR (400 MHz, DMSO): δ 8.25 (d, Chl.O J=8.0 Hz, 1H), 8.12 (s, 2H), 7.85 (s, 1H), Yj X 7.41 (d, J=10.8 Hz, 1H), 7.26 (d, J=7.6 Hz, XXX ^0.1 11 1H), 7.19 (s, 1H), 6.94 (t, J=8.4 Hz, 1H), 4.63 (d, J=5.2 Hz, 1H), 4.06 (s, 2H), 3.83 (s, 6H), 3.64 (broad s, 1H), 2.47 (s, 3H), Example 41 V- 1.97-1.89 (m, 2H), 1.87-1.62 (m, 2H), λ N-(phc-1S,2S-2- hydroxycyclohexyl)-3,7 dimethyl-6-[2-fluoro-4-(1-methyl-1Ηpyrazol-4-yl)-benzyl]-3Hbenzimidazole-4-carboxamide 1.32-1.23 (m, 4H); MS (m/z): 476.2 (M+H) ⁺

- 30 040024

Example 42 XX Y-y ^{H he} \ N-(hhc-1S,2S-2hydroxycyclohexyl)-3,7 dimethyl-6-[4-(1-methyl-1Hpyrazol-4-yl)-benzyl]-3Hbenzimidazole-4-carboxamide Ή-NMR (400 MHz, CDC1 ₃ ): δ 7.83 (s, 1H), 7.7 (s, 1H), 7.56 (s, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.19 (s, 1H), 7.08 (d, J=7.6 Hz, 2H), 6.03 (d, J=7.2 Hz, 1H), 4.14 ( s, 2H), 3.92 (s, 6H), 3.3 (broad s, 1H), 2.61 (s, 3H), 2.17 (s, 1H), 2.23-2.09 (m, 2H), 1.92-1.95 (m, 2H), 1.41-1.32 (m, 4H); MS (m/z): 458.4 (M+H) ⁺ . Example 43 Hu ^H he ^F Xn \ N-( ₄ hc-1S,2S-2hydroxycyclohexyl)-3,7 dimethyl-6-[2,3-d iftoro-4-( 1 methyl-1 H-pyrazol-4-yl)- benzyl] - 3H-benzimidazole-4-carboxamide Ή-NMR (400 MHz, CDCI3): δ 7.84 (s, 1H), 7.78 (s, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.0 (s , 1H), 7.12-7.08 (m, 1H), 6.63-6.61 (m, 1H), 6.05 (d, J=7.2 Hz, 1H), 4.14 ( s, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.90-3.85 (m, 1H), 3.73-3.63 (m, 1H), 3 .29 (d, J=4.4 Hz, 1H), 2.61 (s, ZN), 2.16-2.08 (m, 2H), 1.82-1.75 (m, 2H), 1.45-1.20 (m, 4H); MS (m/z): 494.3 (M+H) ⁺ . Example 44 / n 1 U 1 J V Ί Ν ⁴ H i XXX he Ln \ N- (hhc-1S,2S-2hydroxycyclohexyl) -3,7 - Ή-NMR (400 MHz, CDCI3): δ 9.96 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 8.06 (s, 1H), 7.99 (s , 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.43-7.32 (m, 2H), 4.17 (s, 2H), 4.08 (s, ZN), 4.0-3.90 (m, 1H), 3.94 (s, ZN), 3.753.58 (m, 1H), 2.61 (s, ZN), 2.20-2.10 (m, 2H), 2.04 (brs, 1H), 1.78-1.70 (m, 2H), 1.32-1.25 (m, 4H); MS (m/z): 459.2 (M+H) ⁺ .

- 31 040024

dimethyl-6-[6-(1-methyl-1Hpyrazol-4-yl)-pyridin-3 ylmethyl]-3H-benzimidazole-4carboxamide ld o n 1 xLg ^he 11 η Ή-NMR (400 MHz, CDC1 ₃ ): δ 8.86 (s, 1H), 8.75 (Od, >4.0 Hz, 1H), 8.29 (s, 1H), 7.9-7 .8 (m, 2H), 7.49-7.44 (m, 2H), 7.23 Example 45 ΐιΝ (s, 2H), 4.28 (s, 2H), 4.20 (brs, 1H), L / 4.06 (s, 3H), 3.73 (broad s, 1H), 2.80 (s, N-(hhc-1S,2S-2- 3H), 2.67-2.55 (m, 4H), 1.3-1.24 (m, 2H), hydroxycyclohexyl) -3,7 - 0.97-0.86 (m, 2H); MS (m/z): 461.2 dimethyl-6-[4-(thiazol-4-yl)benzyl]-3H-benzimidazole-4carboxamide (M+H) ⁺ .

Example 46 N-(ijhc-IS,28-2-Hydroxycyclohexyl)-2,4-dimethyl-5-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]benzofuran-7-carboxamide

Step 1: Methyl 2,4-dimethyl-5-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]benzofuran-7-carboxylate.

Potassium acetate (0.106 g, 1.43 mmol) and bis(pinacolato)diboron (0.13 g, 0.53 mmol). The reaction mixture was degassed with nitrogen for 15 min and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (43.0 mg, 0.053 mmol) was added. The reaction mixture was gradually heated to 100° C. and stirred at this temperature for 20 h. After cooling to RT, the crude product in toluene was diluted with a 9:1 mixture of 1,4-dioxane and water (3.7 ml). Solid K ₂ CO ₃ (0.06 g, 0.42 mmol) and 4-(4-chloromethylphenyl)-1-methyl-1H-pyrazole (0.06 g, 0.30 mmol) were added. The reaction mixture was degassed with nitrogen for 15 min and [1,H-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (25.0 mg, 0.03 mmol) was added. The reaction mixture was gradually heated to 100°C and stirred at this temperature for 6 hours After cooling to RT, the volatiles were removed under reduced pressure and the crude product was dissolved in water and EtOAc. The reaction mass was filtered through a Celite pad and the two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give the title compound.

Yield: 0.59 mg (52%); ^-NMR (400 MHz, CDC1 ₃ ): δ 7.72 (d, 1=7.6 Hz, 2H), 7.55 (s, 1H), 7.36 (d, >8.1 Hz, 2H ), 7.10 (d, >8.0 Hz, 2H), 6.41 (s, 1H), 4.11 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3N), 2.52 (s, 3N), 2.37 (s, 3N); MS (m/z): 375.0 (M+H) ⁺ .

Step 2: 2,4-dimethyl-5-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]benzofuran-7-carboxylic acid.

To a stirred solution of methyl 2,4-dimethyl-5-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]benzofuran-7-carboxyplat (0.06 g, 0.16 mmol) in mixture 1 :1 H ₂ O and methanol (0.6 ml) cooled at 0° C., solid NaOH (0.013 g, 0.31 mmol) was added. After stirring for 2 h at reflux temperature, the reaction mixture was cooled to RT, acidified with 2N. HC1 and extracted 32040024 with DCM. The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure to give the title compound as an off-white solid.

Yield: 0.045 g (80%); 1H-NMR (400 MHz, DMSO): δ 13.8 (br s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.56 (s, 1H), 7 .46 (d, J=8.04 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 6.71 (s, 1H), 4.05 (s, 2H), 3 .85 (s, 3H), 2.46 (s, 3H), 2.39 (s, 3H); MS (m/z): 360.9 (M+H)+.

Step 3: N-(cis-1S,2S-2-hydroxycyclohexyl)-2,4-dimethyl-5-[4-(1-methyl-1H-pyrαzol-4-yl)benzyl]benzofuran-7-carboxamide.

To a stirred solution of 2,4-dimethyl-5-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]benzofuran-7carboxylic acid (45.0 mg, 0.12 mmol) in DCM (0.5 ml) cooled at 0°C, DIPEA (0.05 ml, 0.31 mmol), cis-2-aminocyclohexanol hydrochloride (19.0 mg, 0.12 mmol) and HATU (52.3 mg, 0 .14 mmol). After stirring for 2 h at RT, the reaction mixture was diluted with water and DCM. The two layers were separated and the aqueous layer was extracted with DCM. The combined organic layer was washed once with brine, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give the title compound.

Yield: 21.1 mg (36%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.8 (s, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 7.39 (d, J=8, 16 Hz, 2H), 7.10 (d, J=7.96 Hz, 2H), 6.46 (s, 1H), 4.15 (s, 2H), 3.97 (m, 3H), 3 .92 (s, 3H), 3.56-3.49 (m, 1H), 2.51 (s, 3H), 2.35 (s, 3H), 2.16-2.12 (m, 2H ), 1.80-1.77 (m, 2H), 1.49-1.38 (m, 4H); MS (m/z): 458.0 (M+H) ⁺ .

Example 47.

Determination of EC ₅₀ values of allosteric activity for the muscarinic receptor M1:

For cell analysis, a stable CHO cell line expressing the recombinant human M1 muscarinic receptor and the pCRE-Luc reporter system was used. The assay provides a non-radioactive method for determining the binding of a compound to a GPCR. This specific assay measures intracellular cyclic AMP, which is modulated by receptor activation or inhibition. Recombinant cells contain a luciferase reporter gene under the control of a cAMP response element.

The above cells were grown in white 96-well clear bottom plates in Hams F12 medium containing 10% fetal bovine serum (FBS). Prior to addition of compounds or standard agonist, cells were cultured in serum-free medium overnight. Increasing concentrations of test compounds were added to cells along with EC ₅₀ of acetylcholine in OptiMEM medium. Incubation was continued at 37° C. in a CO ₂ incubator for 4 hours. The medium was removed and the cells were washed with phosphate buffered saline. Cells were lysed and luciferase activity was measured with a luminometer. The luminescence pulses at each test element concentration were normalized to the maximum acetylcholine-induced response and the data was analyzed using the Graphpad software. The EC ₅₀ values of the compounds were determined as the concentration,

- 33 040024

15 197 38 694 16 798 39 895 17 1116 40 1498 18 248 41 1063 19 178 42 10000 20 28 43 1460 21 1046 44 208 22 3822 45 10000 23 308 46 299

Example 48.

Pharmacokinetic study in rodents.

Male Wistar rats (260±50 g) were used as experimental animals. Animals were kept individually in a polypropylene cage. Two days prior to the start of the study, male Wistar rats were anesthetized with isoflurane for surgical insertion of a catheter into the jugular vein. Rats were randomly divided for oral (3 mg/kg) and intravenous (i.v) (1 mg/kg) dosing (n=3 per group) and fasted overnight before oral administration (p.o). However, rats isolated for intravenous (i.v.) dosing were given food and water ad libitum.

At a predetermined point, blood was collected through the jugular vein and replenished with an equivalent volume of saline. The collected blood was transferred into a labeled Eppendorf tube containing 10 µl of heparin as an anticoagulant. Typically, blood samples were taken at the following time points: 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose. Blood was centrifuged at 4000 rpm for 10 min. Plasma was separated and stored frozen at -80°C until analysis. Test compound concentrations were quantified in plasma by an established LCMS/MS method using an appropriate extraction technique. Test compounds were quantified over a calibration range of about 1-1000 ng/mL in plasma. The test samples were analyzed using calibration samples in the lot and control samples distributed throughout the lot.

Pharmacokinetic parameters C _max , T _max (h), AUC _t , T _1/2 , clearance and bioavailability (F) were calculated from a non-compartmental model using a standard non-compartmental model using Phoenix WinNonlin software version 6.0.2 or 6.0.3__________________________

Example no. ROA Stax (ng/ml) T _W x (h) AUCo-t (ng-h/ml) Т1/2 (h) Clearance (ml/min/kg) F(%) 1 oral 150±39 0.501.0 360±117 1.1±0.1 - 24±8 i.v. - - 492±22 1.3±0.5 34±1.5 2 orally 48±23 0.50- 158±58 2.0±0, - 14±5

- 34 040024

th 2.0 2 i.v. - - 367±39 1.6±0.3 45±5 6 oral 582±72 0.5 1001±38 1.3±0.2 - 50±2 i.v. - - 664±81 1.5±0.6 25±3.3 8 oral 2327±441 2 18400 3.6±0.2 - 100±1 6 i.v. - - 6147±485 3.3±0.7 2.7±0.2 AND oral 9693±141 5 1.0-2.0 40300±941 8 4.8±1.6 - 105±2 5 i.v. - - 12767±214 6 3.9±0.2 1.3±0.2 14 oral 70±23 0.5 137±28 1.9±0.1 - 13±2.7 i.v. - 346±25 0.8±0.1 48±3.4 15 oral 1540±397 2.0 8187±2176 3.7±0.3 40±11 i.v. 6857±1806 3.1±0.3 2.5±0.6 17 oral 288±26.5 1 705±118 1.3±0.1 - 37±6 i.v. - - 635±70 1.3±0.2 26±3

Example 49.

Study of penetration into the brain of rodents.

Male Wistar rats (260±40 g) were used as experimental animals. Three animals were kept in each cage. Animals were given water and food ad libitum throughout the experiment and maintained a 12 h light/dark cycle.

Penetration into the brain in rats was determined by a discrete method. One day prior to dosing, male Wistar rats were acclimatized and randomly assigned to groups according to their weight. At each time point (0.5, 1 and 2 h) n=3 animals were used.

The test compounds were suitably pre-formulated and administered orally in an amount (free base equivalent) of 3 mg/kg. Blood samples were collected by cardiac puncture using isoflurane anesthesia. Animals were sacrificed for brain tissue sampling. Plasma was separated and brain samples were homogenized and stored frozen at -20° C. until analysis. Plasma and brain concentrations of test compounds were determined by LCMS/MS.

Test compounds were quantified in plasma and brain homogenate by an established LCMS/MS method using an appropriate extraction technique. Test compounds were quantified over a calibration range of 1-500 ng/mL in plasma and brain homogenate. The test samples were analyzed using calibration samples in the lot and control samples distributed throughout the lot. The degree of brain/plasma ratio (C _b /C _p ) was calculated and the results were tabulated_______________________________________________

Example No. Penetration of a single dose into the rat brain ( _Cb / _Cp ) 3 mg/kg, r.o. @ 1.0 h 1 0.54±0.04 2 1.74±0.03 6 0.26±0.04 AND 0.14±0.01 14 1.27±0.07 15 0.78±0.22 17 0.32±0.06

Example 50.

Model of the problem of object recognition.

The cognitive enhancing properties of the compounds of the present invention were evaluated using this model.

Male Wistar rats (aged 8-10 weeks) were used as experimental animals. Animals were placed four in each cage. The day before the experiment, the animals were given 20% less food. Water was given ad libitum throughout the experiment. Animals

- 35 040024 were kept under 12 hour light/dark conditions in a temperature and humidity controlled room.

The experiment was carried out on a circular acrylic arena. Rats were habituated to individual arenas for up to 45 minutes in the absence of any objects on day 1.

One group of 12 rats received vehicle and another group of animals received a compound of formula (I) prior to familiarization (T1) and choice (T ₂ ) tests. During the familiarization phase (T1), the rats were placed in the arena separately for 3 minutes, with two identical objects (a ₁ and a ₂ ) placed at a distance of 10 cm from the wall. 24 hours after T ₁ a long-term memory test was performed. The same rats were placed in the same arena as in the T1 trial. During the selection phase (T ₂ ), rats were allowed to explore the arena for 3 min in the presence of a copy of the familiar object (a ₃ ) and one new object (b). During the T1 and T ₂ trials, the exploration of each object (defined as sniffing, licking, chewing, or vibrissa movement while pointing the nose toward an object at a distance of less than 1 cm) was recorded using a stopwatch.

Ti - total time spent studying familiar objects (a1+a ₂ ).

T ₂ is the total time spent studying a familiar object and a new object (a ₃ +b).

The object recognition test was performed as described in Ennaceur A., Delacour J., 1988, A new onetrial test for neurobiological studies of memory in rats - Behavioral data, Behav. Brain Res., 31.47-59.

Example number Dose Average study time±8.U.M (s) Conclusion familiar object New object AND 0.3 mg/kg, s.o. 12.20±1.89 17.33±1.39 active 14 3 mg/kg, s.o. 8.35±1.98 15.54±3.58 active 15 1 mg/kg, s.o. 12.93±1.83 20.42±3.42 active

Example 51.

Evaluation of θ-modulation in the dorsal hippocampus of anesthetized male Wistar rats in combination with the acetylcholinesterase inhibitor donepezil.

The effect of Example 11 in combination with donepezil on brain activity was evaluated as a pharmacodynamic endpoint.

Male Wistar rats (240-320 g) were anesthetized with intraperitoneal injection of urethane (1.2-1.5 g/kg) to implant a catheter in the left femoral vein. The animal was placed in a stereotaxic frame for electrode implantation (stainless steel wire, Plastics One) in the dorsal hippocampus (AP: -3.8 mm; ML: +2.2 mm; DV: -2.5 mm; Paxinos and Watson, 2004 ). A bipolar stimulating electrode (non-twisted stainless steel wires separated by 0.75-1.0 mm at their ends, Plastics One) was implanted into a Nucleus Pontis Oralis (NPO; AP: -7.8 mm; ML: 1.8 mm; DV: -6.0 mm; Paxinos and Watson, 2004). In addition, one electrode was implanted in the cerebellum, which served as a reference. The hippocampal θ rhythm was induced with a 6 s series of electrical stimulation (20-160 μA, pulse duration 0.3 ms, 250 Hz) applied to the NPO at a rate of 0.01 series/s using a Grass S88 stimulator and a PSIU6 stimulus isolation device ( Grass Medical Instruments, Quincy, MA). EEG was recorded at 1000 Hz using Ponemah software (version 5.2) and saved for offline analysis using NeuroScore (version 3.0). The baseline amplitude was achieved using the current required to produce the θ-rhythm up to 50% of the maximum amplitude under control conditions. After a stabilization period of 1 hour, baseline recording was performed for 30 minutes, followed by treatment with vehicle or compound of example 11 (1 mg/kg, i.v.). Donepezil (0.3 mg/kg, i.v.) was administered 30 minutes after treatment with the compound of example 11, and recording was continued for another 1 hour.

Statistical analysis.

The power of the θ-rhythm frequency was calculated during the stimulation period for 30 min of recording the initial level and the % change in these indicators after treatment was calculated. The % change in relative power of the θ-oscillations after the combination of the compound of Example 11 and donepezil was compared to donepezil using a two-way analysis of variance (time and treatment) followed by a Bonferroni post-test. Statistical significance was considered at a p value of less than 0.05.

Link.

Paxinos G. and Watson C. (2004) Rat brain in stereotaxic coordinates. Academic Press, New York.

Results.

Treatment with donepezil resulted in a moderate increase in the power of the hippocampal θ rhythm. The compound of example 11 in combination with donepezil resulted in a significant increase in the power levels of the θ-rhythm. The combined treatment effect was found to be significantly greater than donepezil alone (see figure).

The mean area under the curve (AUC) calculated after treatment with the compound of example 11 and donepezil was significantly greater compared to treatment with donepezil alone (see figure).

Claims (12)

CLAIM 1. Compound of formula (I) where R ¹ represents phenyl or pyridinyl; each of which is optionally substituted with one or more substituents selected from halogen, -OH, -O-(C ₁ _ ₆ )alkyl, -S-(C ₁ _ ₆ )αalkyl, -N(CH3)2, -(C ₁ _ ₆ )αlkula, -(C ₃ _ ₆ )cycloalkylα, halo(C ₁ _ ₆ )alkyl, -NH ₂ , -CN and R ^1a ; R ^1a is phenyl, pyrazolyl or thiazolyl; each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, -CN, -O-(C ₁ _ ₆ )αkyl, -S-(C ₁ _ ₆ )alkyl, - (C ₁ _ ₆ )alkyl and -(C ₃ - ₆ )cycloalkyl; A ¹ is CH2; ring A is selected from the group consisting of alal denotes the place of attachment; R ² is hydrogen, -(C ₁ _ ₆ )alkyl or -(C ₃ _ ₆ )cycloalkyl; R ³ is hydrogen, halogen, -OH, -(C ₁ _ ₆ )alkyl, -O-(C ₁ _ ₆ )alkyl, or halo(C ₁ _ ₆ )αkyl; R ⁴ is hydrogen, -(C ₁ _ ₆ )alkyl or halo(C ₁ _ ₆ )alkyl; R ⁵ is hydrogen, -(C ₁ _ ₆ )alkyl or halo(C ₁ _ ₆ )alkyl; X ¹ is independently selected from O, S, NH or NCH ₃ ; Y ¹ is independently selected from N or CH; X is CH ₂ or O; And Y is CH2; or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 2. The compound of formula (I) according to claim 1, where ring A is selected from the group consisting of R ¹ is phenyl or pyridinyl; each of which is optionally substituted with one or more substituents selected from halo and R ^1a ; R ^1a is pyrazolyl or thiazolyl; which is optionally substituted with -(C ₁ _ ₆ )alkyl; A ₁ is CH ₂ ; Mlll denotes the place of attachment; R ² is hydrogen or -(C ₁ _ ₆ )alkyl; R ⁵ is hydrogen; X is CH2 or O; And Y is CH2; or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 3. The compound of formula (I) according to claim 1, where the ring A is selected from the group consisting of - 37 040024 R ¹ is phenyl or pyridinyl; each of which is optionally substituted with one or more substituents selected from halo and R ^1a ; R ^1a is pyrazolyl or thiazolyl; which is optionally substituted with -(^^alkyl; A ¹ is CH2; schall denotes the place of attachment; R ² is hydrogen or -(C ₁ .6)alkyl; R ³ is hydrogen or -(C ₁ .6)alkyl; X ¹ is independently selected from O or NH; Y ¹ is independently selected from N or CH; X is CH2; And Y is CH2; or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 4. The compound of formula (I) according to claim 1, where ring A is ^R2 LA R ¹ is phenyl; which is optionally substituted with one or more substituents selected from halo and R ^1a ; R ^1a is phenyl, pyrazolyl or thiazolyl; each of which is optionally substituted with -(C ₁ . ₆ )alkyl; A ¹ is CH ₂ ; Mull denotes the point of attachment; R ² is hydrogen or -(C ₁ . ₆ )alkyl; X is CH2; Y is from CH ₂ ; or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, where the compound is selected from the group consisting of the following: N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(2-chloropyridin-4-ylmethyl)-5-methylquinolin-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(2,3-difluorobenzyl)-5-methylquinoline-8-carboxamide; N-(cis-3S,4S-3-hydroxytetrahydropyran-4-yl)-6-(2-chloropyridin-5-ylmethyl)-5-methylquinolin-8carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(2-fluoropyridin-4-ylmethyl)-5-methylquinolin-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(2-fluorobenzyl)-5-methylquinoline-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(2-chloropyridin-5-ylmethyl)-5-methylquinolin-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[2-(1-methyl-1H-pyrazol-4-yl)pyridin-5-ylmethyl]-5-methylquinolin-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[2,3-difluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]-5-methylquinoline-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]-5-methylquinoline-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(4-pyrazol-1-yl-benzyl)-5-methylquinoline-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]-5-methylquinoline-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(4-thiazol-4-yl-benzyl)-5-methylquinoline-8-carboxamide; N-(cis-3S,4S-3-hydroxytetrahydropyran-4-yl)-6-(4-thiazol-4-yl-benzyl)-5-methylquinoline-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-benzyl-5-methylquinoline-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-5-methylquinoline-8carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-5-methyl-3,4-dihydro- 38 040024 2H-benzo[1,4]oxazine-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(4-pyrazol-1-yl-benzyl)-5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin- 8 - carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-5-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2a]pyridine-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-5-methyl-6-(4-pyrazol-1-yl-benzyl)imidazo[1,2-a]pyridine-8carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-5-methyl-6-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2-a] pyridine-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[2,3-difluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2-а]pyridin- 8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(2,3-difluorobenzyl)imidazo[1,2-a]niridine-8-kαrboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(4-thiazol-4-yl-benzyl)imidazo[1,2-a]pyridine-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-(4-phenylbenzyl)imidazo[1,2-a]pyridine-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2-a]pyridine-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]imidazo[1,2a]pyridine-8-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-7-methyl-6-(4-pyrazol-1-yl-benzyl)-1H-benzimidazole-4-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-7-methyl-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-1H-benzimidazole-4-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-1H-benzimidazole-4carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-7-methyl-6-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]-1Hbenzimidazole-4-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-7-methyl-6-[2-chloropyridin-3-ylmethyl]-1H-benzimidazole-4carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-7-methyl-6-[4-(thiazol-4-yl)benzyl]-1H-benzimidazole-4-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-7-methyl-6-[2,3-difluorobenzyl]-1H-benzimidazole-4-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-7-methyl-6-[3,4-difluorobenzyl]-1H-benzimidazole-4-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-7-methyl-6-[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ylmethyl]1 H-benzimidazole-4-carboxamide ; N-(cis-1S,2S-2-hydroxycyclohexyl)-7-methyl-6-[2,3-difluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]1 H-benzimidazole-4 -carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-6-[2,3-difluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]-1H-benzimidazole-4-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-2,7-dimethyl-6-(4-pyrazol-1-yl-benzyl)-1H-benzimidazole-4carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-2,7-dimethyl-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-1H-benzimidazole-4-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-2,7-dimethyl-6-(4-thiazol-4-yl-benzyl)-1H-benzimidazole-4carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-3,7-dimethyl-6-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]3H-benzimidazole-4- carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-3,7-dimethyl-6-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-3H-benzimidazole-4-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-3,7-dimethyl-6-[2,3-difluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]-3H-benzimidazole -4-carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-3,7-dimethyl-6-[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ylmethyl]-3H-benzimidazol-4 -carboxamide; N-(cis-1S,2S-2-hydroxycyclohexyl)-3,7-dimethyl-6-[4-(thiazol-4-yl)benzyl]-3H-benzimidazole-4carboxamide; And N-(cis-1S,2S-2-hydroxycyclohexyl)-2,4-dimethyl-5-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]benzofuran-7-carboxamide; or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and pharmaceutically acceptable excipients. - 39 040024 7. The use of a pharmaceutical composition according to claim 6 for the treatment of a disease or disorder mediated by the Ml muscarinic receptor, wherein said disease or disorder is selected from the group consisting of cognitive disorders, Alzheimer's disease, schizophrenia, pain disorders, or sleep disorders. 8. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of pi. 1-5 for the treatment of a disease or disorder mediated by the Ml muscarinic receptor, wherein the disease or disorder is selected from the group consisting of cognitive disorders, Alzheimer's disease, schizophrenia, pain disorders, or sleep disorders. 9. The use of claim 8, wherein the cognitive impairment is selected from the group consisting of Alzheimer's disease dementia, Parkinson's disease dementia, Huntington's disease dementia, Down's syndrome-associated dementia, Tourette's syndrome-associated dementia, postmenopausal, frontotemporal dementia, Lewy body dementia, vascular dementia, HIV dementia, Creutzfeldt-Jakob disease dementia, substance-induced persistent dementia, Pick's disease dementia, schizophrenia dementia, senile dementia, and dementia associated with general medical conditions. 10. The use of a pharmaceutical composition according to claim 6 in the manufacture of a medicament for the treatment of a disease or disorder selected from cognitive disorders, Alzheimer's disease, schizophrenia, pain disorders or sleep disorders. 11. The use of a compound of formula (I) according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of a disease or disorder selected from cognitive disorders, Alzheimer's disease, schizophrenia, pain disorders or sleep disorders. 12. Combination for the treatment of a disease or disorder selected from cognitive disorders, Alzheimer's disease, schizophrenia, pain disorders or sleep disorders, containing a compound of formula (I) according to any one of claims 1 to 5, and an acetylcholinesterase inhibitor, which is donepezil or its pharmaceutically acceptable salt.