EA035599B1 - Muscarinic m1 receptor positive allosteric modulators - Google Patents

Abstract

The present invention relates to compounds of formula (I), wherein the meanings of radicals Rand Rare defined in the claims, or pharmaceutically acceptable salts thereof as muscarinic M1 receptor positive allosteric modulators (M1 PAMs). The present invention describes a preparation, a pharmaceutical composition and the use of a compound of formula (I).

Description

Scope of invention

The present invention relates to compounds of formula (I) or their pharmaceutically acceptable salts as positive allosteric modulators of mucarinic M1 receptors (M1 PAM). The present invention describes the preparation, pharmaceutical composition and use of such compounds.

State of the art

Muscarinic acetylcholine receptors (mAChRs), belonging to the class A family of G-protein coupled receptors (GPCRs), are widely expressed in the body. So far, five subtypes have been identified, designated M1-M5, 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 corresponding 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 muscarinic M1 receptor is predominantly expressed in areas of the brain such as the cortex, hippocampus and amygdala, which are involved in the process of cognition, and, accordingly, selective activation of the muscarinic M1 receptor is expected to increase cognitive function. (Proc. Natl. Acad. Sci. USA, 1996, 93, 13541-13546).

There is a high degree of conservatism between muscarinic receptor subtypes at their orthosteric acetylcholine ligand binding sites, which makes it difficult to identify a selective muscarinic M1 receptor agonist. To overcome this problem, an alternative approach has been adopted, which is to develop M1 PAMs acting at a less conserved allosteric binding site that exhibits less sequence homology. It is reported that M1 PAM, PQCA, (1 - {[4-cyano-4- (pyridin-2-yl) piperidin-1-yl] methyl} -4-oxo-4Hquinolysine-3-carboxylic acid) is highly selective for muscarinic M1 receptor in comparison with other muscarinic receptor subtypes and is effective in several preclinical models of the cognitive process (Psychopharmacology, 2013, 225 (1), 21-30) without the occurrence of gastrointestinal side effects at doses equal to or less than fivefold the range of the minimum effective dose required to improve the cognitive process. 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 Alzheimer's disease (AD), both by altering the processing of the β-amyloid precursor protein (eAPP) relative to the non-amyloidogenic α-secretase pathway and by reducing hyperphosphorylation of the tau protein. M1 PAMs have demonstrated an increase in sAPPa synthesis in an in vitro system (The Journal of Neuroscience, 2009, 29, 14271-14286). Thus, M1 PAMs provide a symptomatic and disease-modifying approach for the treatment of cognitive disorders.

PCT patent applications publication WO 2015/110370, WO 2011/084368, WO 2011/159554 and WO 2011/149801 disclose M1 PAM compounds. Although several M1 PAMs have been described in the literature to date, no formulation has been presented on the market that acts as M1 PAM. Accordingly, there remains an unmet need to develop new and more effective M1 PAMs that modulate muscarinic M1 receptors for the treatment of M1 mediated diseases such as Alzheimer's disease and others described herein.

The essence of the invention

In a first aspect, the present invention relates to an M1 PAM compound of formula (I) wherein ring A is selected from

- 1 035599

And ¹ represents CH2, CHF or CF2; R ^{1 is} selected from

R ^a R ^a

R ^a is OH;

X ^{1 is} independently selected from CH2 and O; a is 0 or 1;

R2 is selected from the group consisting of

And ³ represents N or CH;

And ⁴ represents CH or CF;

R ^b in each occurrence is independently selected from halogen, -O- (C _1-4 ) alkyl, ^ - (O ^ alkyl, -N (CH ₃ ) ₂ , - (C _1-4 ) alkyl, - (C _{3- 6} ) cycloalkyl, halogen (C _1-4 ) alkyl, -OH, -NH2, -CN, phenyl, pyridyl, pyrazolyl, thiazolyl and oxazolyl, where phenyl, pyridyl, pyrazolyl, thiazolyl and oxazolyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH ₂ , -CN, -O- (C _1-2 ) alkyl, ^ - (C _1-2 ) alkyl, - (C _1-2 ) alkyl, or - (C _3-6 ) cycloalkyl;

R ^c represents hydrogen or - (C _1-4 ) alkyl;

X ^{2 is} independently selected from NH, —No (C _1-2 ) alkyl, O and S;

X ^{3 is} independently selected from CH and N;

b is 0, 1 or 2;

^ лг represents the place of attachment;

R ³ is - (C _1-4 ) alkyl, halo (C _1-4 ) alkyl, or hydrogen;

R ⁴ is hydrogen, - (C _1-4 ) alkyl, or halo (C _1-4 ) alkyl, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by the muscarinic M1 receptor, comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients, wherein the disease or disorder is selected from cognitive disorders , pain or sleep disorder.

In another aspect, the present invention relates to the combination of a compound of formula (I) with other therapeutic agents selected from acetylcholinesterase inhibitors, wherein the acetylcholinesterase inhibitor is donepezil, or a pharmaceutically acceptable salt thereof, for the treatment of a muscarinic M1 receptor mediated disease or disorder.

In another aspect, the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of a muscarinic M1 receptor mediated disease or disorder, wherein the disease or disorder is selected from cognitive disorders, pain and sleep disorder.

In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or disorders associated with muscarinic M1 receptors, wherein the disease is selected from cognitive disorders, pain and sleep disorders

Brief Description of Drawings

The figure shows the effect of co-processing the compound of Example 1 with donepezil on cognition enhancing properties using an object recognition task performance model.

Detailed description of the invention

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

As used herein, the term (C _1-4 ) alkyl refers to a branched or straight chain aliphatic hydrocarbon containing from 1 to 4 carbon atoms. Examples of (C _1-4 ) alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Preferably (C _1-4 ) alkyl is methyl, ethyl or isopropyl.

As used herein, the term (C _1-2 ) alkyl refers to a straight chain aliphatic hydrocarbon containing 1 to 2 carbon atoms. Examples of (C _1-2 ) alkyl include methyl or ethyl.

- 2 035599

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

As used herein, the term halogen ^ - ^ alkyl refers to ^ - ^ alkyl as defined above, wherein one or more hydrogen atoms of the same or different carbon atom are replaced by the same or different halogens. Examples of halogen-d-d-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 from three to six carbon atoms. Examples of the (C _3-6 ) cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term (C ₅ - ₇₎ cycloalkyl, as used herein, refers to a saturated monocyclic hydrocarbon ring containing five to seven carbon atoms. Examples of (C ₅ - ₇₎ cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl, etc.

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

As used herein, the term (C ₅ - ₇₎ heterocycloalkyl refers to a saturated hydrocarbon ring containing one or two heteroatoms selected from oxygen, nitrogen and sulfur. Examples of the (C _5-7 ) heterocycloalkyl group include tetrahydropyran, tetrahydrothiopyran, piperidine, azepane, morpholine, thiomorpholine, tetrahydrofuran, pyrrolidine, or ortetrahydrothiophene.

The phrase a 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) eliminates one or more symptoms of a particular disease, condition or disorder, (iii) inhibits one or more symptoms of a particular disease , condition, or disorder described herein.

The term pharmaceutically acceptable salt, as used herein, refers to salts of the active compound, i. E. compounds of formula (I), which are prepared by reaction with a suitable acid or acid derivative, depending on the specific substituents present in the compounds described herein.

The term cognitive disorder, as used in this document, refers to a group of mental disorders that primarily affect learning, memory, perception, and problem solving and include amnesia, dementia, and delirium. Cognitive impairments can result from illness, disorder, illness, or toxicity. Preferably, the cognitive disorder is dementia. An example of dementia includes, but is not limited to, Alzheimer's dementia, Parkinson's dementia, Huntington's dementia, Down's syndrome dementia, Tourette's dementia, postmenopausal dementia, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, dementia in HIV, dementia in Creutzfeldt-Jakob disease, persistent dementia due to substance use, dementia in Pick's disease, dementia in schizophrenia, senial dementia and dementia in general disorders of the body.

Embodiments of the invention

The present invention encompasses all compounds represented by the compound of formula (I) without any limitation, however, preferred aspects and elements of the invention are considered herein in the form of the following embodiments.

In a second aspect, the present invention relates to an M1 PAM compound of formula (I) o. N. JL .R ¹

A ¹

R ² (I) where ring A is selected from

And ¹ represents CH2, CHF or CF2;

- 3 035599

R ^{1 is} selected from

R R

R ^a is OH;

X ^{1 is} independently selected from CH2 and O; a is 0 or 1;

R2 is selected from the group consisting of

And ³ represents N or CH;

And ⁴ represents CH or CF;

R ^b in each occurrence is independently selected from halogen, —O- (C _1-4 ) alkyl, —3- (C _1-4 ) alkyl, —N (CH ₃ ) 2, - (C _1-4 ) alkyl, - (C _3-6 ) cycloalkyl, halo (C _1-4 ) alkyl, —OH, —NH2, —CN, phenyl, pyridyl, pyrazolyl, thiazolyl, and oxazolyl, where phenyl, pyridyl, pyrazolyl, thiazolyl and oxazolyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH ₂ , -CN, -O- (C _1-2 ) alkyl, -8- (C1 _-2 ) alkyl, - (C _1-2 ) alkyl or - (C _3-6 ) cycloalkyl;

R ^c represents hydrogen or - (C _1-4 ) alkyl;

X2 is independently selected from NH, -No- (C _1-2 ) alkyl, O and S;

X ^{3 is} independently selected from CH and N;

b is 0, 1 or 2;

^^ iho represents the place of attachment;

R ³ is - (C _1-4 ) alkyl, halo (C _1-4 ) alkyl, or hydrogen;

R ⁴ is hydrogen, - (C _1-4 ) alkyl, or halo (C _1-4 ) alkyl, or a pharmaceutically acceptable salt thereof.

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

- 4 035599

Ν- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-4ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-methoxypyridine-5ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-5ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -1-methyl1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-thiazol-4-ylbenzyl) 1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-pyrazol-1-ylbenzyl) 1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- [4- (1-methyl-1H-pyrazol4-yl) benzyl] -1-methyl-1H-pyrrolo [2,3-b] pyridine-6 -carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- [2-fluoro-4- (1-methyl-1Hpyrazol-4-yl) benzyl] -1-methyl-1H-pyrrolo [2,3-b ] pyridine-6carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-methylpyridine-5ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-chloropyridine-4ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2,5-difluoropyridine-4ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (benzothiazole-6ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2'-fluoro [2,5 '] bipyridinyl-5-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine- 6 carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -4- (pyridin-4-ylmethyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -4- [2- (1-methyl-1H-pyrazol4-yl) pyridin-5-ylmethyl] -1-methyl-1H-pyrrolo [2,3-b ] pyridine-6carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2,3-difluorobenzyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-methylpyridin-4-5,035599 ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-chloropyridine-5ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-methoxybenzyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2methylsulfanylpyridin-5-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- [4- (2-methylpyridine-Zyl) benzyl] -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (1-methyl-1Hbenzimidazol-4-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-chloropyridine-5ylmethyl) -1- (2-fluoroethyl) -1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- (2-hydroxy-2-methylpropyl) -4- [4- (thiazol-4-yl) benzyl] -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (3-fluorobenzyl) -1-methyl1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- (1-hydroxycyclopentylmethyl) -4- [4- (thiazol-4-yl) benzyl] -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -4- (pyridin-3-ylmethyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-cyclopropylpyridin5-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-4ylmethyl) -1-ethyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-4ylmethyl) -1-isopropyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2,3-difluorophenylmethyl) 1,3-dimethyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) 1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-II);

6,035599 racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-II);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (2-fluoropyridin-4-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (2-fluoropyridin4-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer- eleven);

racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4 (3,4-difluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (3,4-difluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer- eleven);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (2,3-difluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (2,3-difluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer- eleven);

racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4 (2,3-difluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (2,3-difluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer- eleven);

racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (2fluoropyridin-4-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (2-fluoropyridin-4ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer- eleven);

racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (2-7 035599 chloropyridin-5-ylmethyl) -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (2-chloropyridine-5ylmethyl) -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6-carboxamide (isomer-1 and isomer- eleven);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (2-chloropyridin-5-ylmethyl) -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (2-chloropyridin5-ylmethyl) -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6-carboxamide (isomer-1 and isomer- eleven);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (3,4-difluorobenzyl) -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (3,4-difluorobenzyl) -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6-carboxamide (isomer-1 and isomer- eleven);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 [4- (thiazol-4-yl) benzyl] -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4yl) benzyl] -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6-carboxamide (isomer-1 and isomer-11);

racemic cis-N- <3-hydroxytetrahydropyran-4-yl) -4- [4 (thiazol-4-yl) benzyl] -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6-carboxamide (isomer I and isomer-II);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 [4- (1-methyl-1H-pyrazol-4-yl) benzyl] -1-methyl-1H-pyrrolo [2,3b] pyridine-6 -carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (1-methyl-1Hpyrazol-4-yl) benzyl] -1-methyl-1H-pyrrolo [2, 3-b] pyridine-6carboxamide (isomer-1 and isomer-11);

racemic cis-N- / 3-hydroxytetrahydropyran-4-yl) -4- [4- 8 035599 (1-methyl-1H-pyrazol-4-yl) benzyl] -1-methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (1-methyl-1Hpyrazol-4-yl) benzyl] -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide (isomer-1 and isomer-11);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (4-methoxybenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4methoxybenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-11);

racemic cis-N- / 3-hydroxytetrahydropyran-4-yl) -4- (4methoxybenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-methoxybenzyl) 1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-II);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (3-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (3-fluorobenzyl) 1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-II);

racemic cis-N- / 3-hydroxytetrahydropyran-4-yl) -4- (3fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (3-fluorobenzyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-II);

racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-II);

racemic trans-N- (4-hydroxytetrahydropyran-3-yl) -4 (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

trans-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) 1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-II);

9 035599 racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4methoxybenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-methoxybenzyl) 1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-II);

racemic trans-N- (4-hydroxytetrahydropyran-3-yl) -4 (4-methoxybenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

trans-N- (4-hydroxytetrahydropyran-3-yl) -4- (4methoxybenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-11);

racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (2methylpyridin-5-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (2-methylpyridin-5ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer- eleven);

racemic trans-N- (4-hydroxytetrahydropyran-Z-yl) -4 (2-methylpyridin-5-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide trans-N- (4- hydroxytetrahydropyran-3-yl) -4- (2-methylpyridin5-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-11);

(3S _r 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4- (4fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

(3S _r 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4- (4methoxybenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

(3S _r 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4- (2methylpyridin-5-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-chloropyridine-5ylmethyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-4ylmethyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

- 10 035599

Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-5ylmethyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -1-methyl- (6-methylpyridin3-ylmethyl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -1-methyl2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-methoxybenzyl) -1methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -4- (2'-fluoro [2,5 '] bipyridinyl-5-ylmethyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2, 3 - b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2,3-difluorobenzyl) -1methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-methyl-4pyridinylmethyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-11);

racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4 methoxybenzyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

(3S _r 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4- (4fluorobenzyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

(3S _r 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4- (4methoxybenzyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-6carboxamide;

(3S _r 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4- (2methylpyridin-5-ylmethyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3b] pyridine-6- carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide;

- 11 035599

Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-chlorobenzide) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-chlorobenzide) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (3-fluorobenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (3-fluorobenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- [4- (1-methyl-1H-pyrazol4-yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2 β-carboxamide hydrochloride;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- [4- (1-methyl-1H-pyrazol4-yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2 -carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-5ylmethyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-5ylmethyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-methoxybenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-methoxybenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-4ylmethyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-4ylmethyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-pyrazol-1-ylbenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-pyrazol-1-ylbenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -7-methyl5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -7-ethyl5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4- 12 035599 yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-11);

racemic cis-N - ('3-hydroxytetrahydropyran-4-yl) -4- [4 (thiazol-4-yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer- 1 and isomer-11) racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 [4- (thiazol-4-yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine -2carboxamide hydrochloride;

racemic cis-N- <3-hydroxytetrahydropyran-4-yl) -4- [4 (thiazol-4-yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-1 and isomer-11);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 [4- (thiazol-4-yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-1 and isomer-11);

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-1 and isomer-11) ;

racemic cis-N- ('3-hydroxytetrahydropyran-4-yl) -4- (4fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-1 and isomer-11) ;

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

racemic cis-N- <3-hydroxytetrahydropyran-4-yl) -4- (4-13 035599 fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-1 and isomer-II);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-1 and isomer-II);

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazole-1ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-1 and isomer -eleven);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride;

racemic cis-N- / 3-hydroxytetrahydropyran-4-yl) -4- (4pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazol-1ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-1 and isomer -eleven);

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4 (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazole-1ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-1 and isomer- eleven);

racemic cis-N- <3-hydroxytetrahydropyran-4-yl) -4- (4pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazole-1ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-1 and isomer- eleven);

cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-1 and isomer-11) ;

- 14,035599 racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

racemic trans-N- (4-hydroxytetrahydropyran-3-yl) -4 (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride;

trans-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-1 and isomer-11) ;

racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide;

cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-1 and isomer-II);

racemic trans-N- (4-hydroxytetrahydropyran-3-yl) -4 (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide;

trans-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) 5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-1 and isomer-II);

racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride;

cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazole-1ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-1 and isomer -eleven);

racemic trans-N- (4-hydroxytetrahydropyran-3-yl) -4 (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride;

trans-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazole-1ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-1 and isomer -eleven);

racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide;

cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazole-1ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide

- 15 035599 (isomer-I and isomer-II);

racemic trans-N- (4-hydroxytetrahydropyran-3-yl) -4 (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide;

trans-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazole-1ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-I and isomer- eleven);

N - [(IS, 2S) -2-hydroxycyclohexyl] -8- (4-fluorobenzyl) -2,3 dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -8- (4-methoxybenzyl) -2,3 dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -8- (2-chloropyridine-5ylmethyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -8- [4- (1-methyl-1H-pyrazol4-yl) benzyl] -2,3-dihydro- [1,4] dioxino [2,3- B] pyridine-6carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -8- (2,3-difluorobenzyl) -2,3 dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -8- (1-methyl-1H-pyrazole-4ylmethyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6 -carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -8- [4- (pyrazol-1yl) benzyl] -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -8- (2-methylpyridine-5ylmethyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -8- (2-fluoropyridine-5ylmethyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -8- (2-fluoropyridine-4ylmethyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) 2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide (isomer-1 and isomer-II);

cis-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) 2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide (isomer-I and isomer-II);

racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-16 035599 fluorobenzyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6carboxamide;

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -8 (4-fluorobenzyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6carboxamide;

(3S _r 4S) -N- (4-hydroxytetrahydropyran-3-yl) -8- (4methoxybenzyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6carboxamide;

(3S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -8- (4fluorobenzyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6carboxamide;

(3S _r 4S) -N- (4-hydroxytetrahydropyran-3-yl) -8- (2chloropyridin-5-ylmethyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine6-carboxamide ;

(3S _r 4S) -N- (4-hydroxytetrahydropyran-3-yl) -8- (2methylpyridin-5-ylmethyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine6-carboxamide ;

racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -8- (4 fluorobenzyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6carboxamide;

racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -8- (4 methoxybenzyl) -2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -8- (4-fluorobenzyl) -4-methyl2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -8- (3-fluorobenzyl) -4-methyl2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide;

N - [(IS, 2S) -2-hydroxycyclohexyl] -8- [4- (1-methyl-1H-pyrazol4-yl) benzyl] -4-methyl-2H-pyrido [3,2-b] [1, 4] oxazine-6carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -8- (2-fluoropyridine-4ylmethyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide;

racemic cis-N- <3-hydroxytetrahydropyran-4-yl) -8- (4 fluorobenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) -4methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide (isomer-1);

17 035599 racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -8 (4-fluorobenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6carboxamide;

trans-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) 4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide (isomer-1 and isomer-II);

trans-N- (3-hydroxytetrahydropyran-4-yl) -8- (4methoxybenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6carboxamide (isomer-1 and isomer-11 );

racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -8 (4-methoxybenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6carboxamide;

racemic cis-N- ('3-hydroxytetrahydropyran-4-yl) -8- (4methoxybenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6carboxamide;

cis-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-methoxybenzyl) 4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide (isomer-1 and isomer-II);

N- [(IS, 2S) -2-hydroxycyclohexyl] -8- (2-chloropyridine-5ylmethyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-b-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -8- (4-methoxybenzyl) -4methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -8- (2-methylpyridine-5ylmethyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -8- [4-pyrazol-1-ylbenzyl] 4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide;

N- [(IS, 2S) -2-hydroxycyclohexyl] -4-methyl-8- (1-methyl-1Hpyrazol-4-ylmethyl) -2H-pyrido [3,2-b] [1,4] oxazine-6 -carboxamide;

racemic cis-N- / 4-hydroxytetrahydropyran-3-yl) -8- (4fluorobenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide;

racemic cis-N- / 4-hydroxytetrahydropyran-3-yl) -8- (4methoxybenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine bcarboxamide;

(3S _r 45) -N- (4-hydroxytetrahydropyran-3-yl) -8- (4fluorobenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-b-carboxamide;

(3S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -8- (4methoxybenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine bcarboxamide;

(35,45) -N- (4-hydroxytetrahydropyran-3-yl) -8- (4-pyrazol-1ylbenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-b -carboxamide and (35,45) -N- (4-hydroxytetrahydropyran-3-yl) -4-methyl-8- (1methyl-1H-pyrazol-4-ylmethyl) -2H-pyrido [3,2-b] [ 1,4] oxazine-bcarboxamide;

or a pharmaceutically acceptable salt thereof.

- 18 035599

Experimental procedure

Scheme 1 depicts methods for preparing a compound of formula (I) wherein A ¹ is

CH2; R ¹ , R2, R ³ and R ⁴ are as defined above.

Scheme 1

Stage 1. Obtaining a compound of formula B.

The compound of formula A is reacted with potassium hydroxide in water at reflux temperature for 5-8 hours to provide the compound of formula B.

Step 2. Obtaining a compound of formula C.

The compound of formula B obtained in step 1 is reacted with an alkyl iodide selected from methyl iodide or ethyl iodide in the presence of a base such as sodium hydride, sodium t-butoxide, potassium t-butoxide or cesium carbonate in a solvent selected from DMF, THF or acetonitrile , at a temperature in the range of 60-70 ° C for 8-10 hours to obtain a compound of formula C.

Step 3. Obtaining a compound of formula D.

The compound of formula C obtained in step 2 is reacted with bis- (pinacolato) diborone and 1,1'-bis- (diphenylphosphino) ferrocenepalladium (II) dichloromethane complex in the presence of potassium acetate in a solvent selected from toluene or 1,4 β-dioxane, in a temperature range of 90-110 ° C for 7-9 hours to obtain a compound of formula D.

Stage 3 a. Preparation of a compound of formula E.

The compound of formula C obtained in step 2 is reacted with 4-fluorobenzyl cine chloride in the presence of bis- (tri-tert-butylphosphine) palladium in a solvent selected from THF, DMF or acetonitrile at reflux temperature for 2-5 hours to give a compound of formula E.

Step 4. Obtaining a compound of formula E.

The compound of formula D, prepared in step 3, is reacted with a compound of formula 1c, R2-A1-X (where X is halogen, A ¹ is CH2) in the presence of a base such as cesium carbonate, potassium carbonate or sodium carbonate; potassium iodide, sodium iodide or lithium iodide and [1,1'-bis- (diphenylphosphino) ferrocene] dichloropalladium (P) complex with dichloromethane 1: 1 in a mixture of solvents selected from THF, 1,4-dioxane and water, in a microwave ovens at 70-80 ° C for 1-2 hours to obtain a compound of formula E.

Step 5. Obtaining a compound of formula F.

The compound of formula E obtained in step 3a or step 4 is hydrolyzed using a base selected from sodium hydroxide or potassium hydroxide in a solvent selected from H ₂ O, THF, ethanol and methanol at a temperature range of 50-100 ° C for 2-4 hours to give a compound of Formula F.

Step 6. Obtaining a compound of formula (I).

The compound of formula F obtained in step 5 is condensed with an amine R1-NH2-HCl in the presence of a condensing reagent, HATU, DCC or EDC and a base such as triethylamine, DIPEA or DABCO, in a solvent selected from DMF, THF, dichloromethane or 1 , 4-dioxane, at room temperature for 6-16 hours to give a compound of formula (I) (wherein A ¹ is CH ₂ ). Amines R1-NH2 such as (^^) - trans-2-aminocyclohexanol hydrochloride (CAS No. 13374-30-6), (1R, 2R) -2-aminocyclohexanol (CAS No. 931-16-8), 1 α-amino-2-methyl-2-propanol, 2-amino-3-methyl-1-butanol, 2-aminobenzyl alcohol and (1R, 2R) -trans-2-aminocyclopentanol (CAS No. 68327-11-7) were obtained from commercial sources.

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Preparation of a compound of formula (I) (wherein A ¹ is CHF or CF2).

A compound of formula (I) (wherein A ¹ is CH2) is reacted with a brominating agent such as N-bromosuccinimide (NBS) in the presence of a radical initiator such as azo-bis-isobutyronitrile (AIBN), followed by hydrolysis under aqueous conditions to obtain a biarylmethanol / biaryl ketone derivative intermediate.

An intermediate containing a hydroxyl group / oxo group is reacted with a fluorinating agent selected from an HF-amine complex such as HF-pyridine, DAST or triethylamine trihydrofluoride, and an activating agent such as 1,1,2,2,3,3, 4,4,4-nonaftorbutan1-sulfonyl fluoride in the presence of triethylamine trihydrofluoride to give a compound of formula (I) (wherein a ¹ represents CHF or CF2).

Preparation of a pharmaceutically acceptable salt of a compound of formula (I).

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

Alternatively, a compound of formula (I) can also be prepared according to Scheme 1a, as indicated below.

Scheme 1a

Stage 1. Obtaining a compound of formula A-1.

The compound of formula A is reacted with 4-fluorobenzylzinc chloride in the presence of bis- (tri-tert-butylphosphine) palladium in a solvent selected from THF, DMF, or acetonitrile at reflux temperature for 2-5 hours to give a compound of formula A- 1.

Step 2. Obtaining a compound of formula F.

The compound of formula A-1 obtained in step 1 is hydrolyzed using a base selected from sodium hydroxide or potassium hydroxide in a solvent selected from H2O, THF, ethanol or methanol at a temperature range of 50-100 ° C for 2-4 h to obtain a compound of formula F.

Step 3. Obtaining a compound of formula (I).

The compound of formula F obtained in step 2 is condensed with an amine R1-NH ₂ -HCl in the presence of a condensing reagent, HATU, DCC or EDC and a DIPEA base in a solvent selected from DMF, THF, dichloromethane or 1,4-dioxane at room temperature. temperature overnight to give a compound of formula (I) (wherein A ¹ is CH 2). Amines R1-NH2 such as (^^) - trans-2aminocyclohexanol (CAS No. 13374-30-6), (1R, 2R) -2-aminocyclohexanol (CAS No. 931-16-8), 1-amino2- methyl 2-propanol, 2-amino-3-methyl-1-butanol, 2-aminobenzyl alcohol and (1R, 2R) -trans-2aminocyclopentanol (CAS No. 68327-11-7) were obtained from commercial sources.

Scheme 1b shows an alternative method for preparing a compound of formula (I) wherein Ring A is a 5-8 membered saturated ring containing nitrogen atom (s).

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Scheme 1b

where A is a 5-membered ring containing nitrogen

Stage 1. Obtaining a compound of formula 2.

The compound of formula 1 is reacted with 4-fluorobenzylzinc chloride in the presence of bis- (tri-tert-butylphosphine) palladium in a solvent selected from THF, DMF or acetonitrile at reflux temperature for 2-5 hours to give a compound of formula 2.

Stage 2. Obtaining a compound of formula 3.

The compound of formula 2 obtained in step 2 is hydrolyzed using a base selected from lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent selected from H2O, THF, methanol or ethanol at a temperature range of 50-100 ° C for 2- 4 hours to give a compound of Formula 3.

Stage 3. Obtaining a compound of formula 4.

The compound of formula 3 obtained in step 2 is condensed with an amine R1-NH2-HQ in the presence of a condensing reagent, HATU, DCC or EDC and a base such as triethylamine, DIPEA and DABCO, in a solvent selected from DMF, THF, dichloromethane or 1 , 4-dioxane, at room temperature overnight to give a compound of Formula 4 (wherein A ¹ is CH 2). Amines R1-NH2 such as (^^) - trans-2-aminocyclohexanol (CAS No. 13374-30-6), (1R, 2R) -2aminocyclohexanol (CAS No. 931-16-8), 1-amino 2-methyl-2-propanol, 2-amino-3-methyl-1-butanol, 2-aminobenzyl alcohol and (1R, 2R) -trans-2-aminocyclopentanol (CAS No. 68327-11-7) were obtained from commercial sources.

Step 4. Obtaining a compound of formula 5.

The compound of formula 4 obtained in step 3 is reacted with IPA-HCl at a temperature in the range of 25-30 ° C for 4-6 hours to obtain a compound of formula 5.

Step 5. Obtaining a compound of formula (I).

The compound of Formula 5 is basified using bases such as aqueous ammonia, sodium bicarbonate, sodium hydroxide to give compounds of Formula (I) (wherein Ring A is a 5-8 membered saturated ring containing nitrogen atom (s)).

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

Stereoisomers of compounds of formula (I) can be prepared by one or more of the conventional methods outlined below:

a) One or more reagents can be used in their optically active form.

b) An optically pure catalyst or chiral ligands can be used in the reduction process together with a metal catalyst. The metal catalyst can be rhodium, ruthenium, indium, etc. Chiral ligands may preferably be chiral phosphines.

c) The mixture of stereoisomers can be separated by conventional methods such as the formation of diastereomeric salts with chiral acids or chiral amines or chiral amino alcohols or chiral amino acids. Then the resulting mixture of diastereomers can be separated by methods such as fractional crystallization, chromatography, etc., followed by additional

21 035599 a step of separating an optically active product from the separated substance / salt.

d) A mixture of stereoisomers can be separated by conventional methods such as microbial separation, separation of diastereomeric salts formed by 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. The chiral bases that can be used can be cinchona alkaloids, brucine, or a basic amino acid such as lysine, arginine, and the like.

Scheme 2 depicts methods for preparing intermediates of a compound of Formula 1.

Scheme 2 ^1Yu L%>

Υ <f __ | GM__ A

YvYv la lb1c

Reduction of a compound of formula 1a (wherein Y is COOCH3 or CHO; A ¹ is CH ₂ , A ³ , R ^b and b are as defined in the first aspect) using LAH, NaBH4 in a solvent selected from THF, an alcohol selected from methanol, ethanol and IPA, at a temperature range of 25-30 ° C for 2-5 hours, gives the compound of formula 1b.

The compound of formula 1b is reacted with halogenating agents selected from SOCl ₂ , SOBr ₂ , PCl ₃ , PBr ₃ , CBr4 / PPh ₃ and CCl4 / PPh ₃ , in the presence of solvents such as DCM, and at a temperature range of 25-30 ° C. within 2-5 hours to obtain a compound of formula 1c (where X is

C1 is halogen; A ¹ is CH2 and R ² is b).

Scheme 3 depicts methods for preparing intermediates of a compound of Formula 1a.

Scheme 3

The compound of formula 1-1 is reacted with a compound of formula 1-2 (where R ^b is pyridinyl) in the presence of tetrakis- (triphenylphosphine) palladium (0) in a mixture of solvents selected from DME and water at reflux temperature for 11 to 14 hours to give a compound of Formula 1a.

The compound of formula 1-3 is reacted with a compound of formula 1-4 (where R ^b is pyridinyl, thiazolyl and isoxazolyl) in the presence of Pd (dppf) Cl ₂ -CH ₂ Cl ₂ and a base selected from sodium carbonate and potassium carbonate, in a mixture of solvents selected from water and 1,4-dioxane at a temperature of 70-100 ° C for 5-7 hours to obtain a compound of formula 1a.

The compound of formula 1-5 is reacted with a compound of formula 1-6 (where R ^b is pyrazolyl) in the presence of Pd (dppf) Cl ₂ -CH ₂ Cl ₂ and a base selected from sodium carbonate and potassium carbonate in a mixture of solvents selected from water and 1,4-dioxane, at a temperature in the range of 70-100 ° C for 5-7 hours to obtain a compound of formula 1a.

A compound of formula 1-7 (where Y is COOH, R ^b is S-CH3) is reacted with (trimethylsilyl) diazomethane in a mixture of solvents selected from DCM and methanol at a temperature range of 25-30 ° C for 24-27 h to obtain a compound of formula 1a.

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 compound of formula (I) are muscarinic M1-positive allosteric modulators.

In another aspect, the present invention relates to a compound of formula (I) for use in the treatment of a disease or disorder selected from cognitive disorder, pain 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 a disease or disorder mediated by the muscarinic M1 receptor selected from cognitive disorder, pain or sleep disorder.

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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 a disease or disorder mediated by a muscarinic M1 receptor selected from a cognitive 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 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 acetylcholinesterase inhibitors.

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 useful. Examples of combinations of compounds of the present invention include combination with therapeutic agents for Alzheimer's disease, for example, acetylcholinesterase inhibitors such as donepezil.

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 donepezil.

In another embodiment, the present invention relates to the combination of a compound of formula (I) with one or more other therapeutic agents, acetylcholinesterase inhibitors, for use in the treatment of cognitive impairment, schizophrenia, pain and sleep disorders.

In 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 their pharmaceutically acceptable salts in therapy, they are usually formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.

The pharmaceutical compositions of the present invention can be prepared in a conventional manner 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, antifoam agents, sweeteners, flavors, antioxidants, colorants, solubilizers, plasticizers dispersing agents and the like. The excipients are selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sodium starch glycolate, corn starch or its derivatives, povidone, crospovidone, calcium stearate, glyceryl monostearate, glyceryl palmitoxy stearate sodium magnetide, thallic sodium starch zinc stearate, stearic acid or hydrogenated vegetable oil, gum arabic, magnesium oxide, glucose, fats, waxes, natural or hardened oils, water, saline sodium chloride solution 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 formulated as pills, tablets, coated tablets, capsules, powder, granules, pellets, patches, implants, films, liquids, semi-solids, gels, aerosols, emulsions, tinctures, etc. P. Such pharmaceutical compositions and methods for their preparation are well known in the art.

In yet another aspect, the pharmaceutical composition of the present invention contains 1 to 90%, 5 to 75% and 10 to 60% by weight of the compounds of the present invention or a pharmaceutically acceptable salt thereof. The amount of active compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition (s) can range from about 1 to about 500 mg, or from about 5 to about 400 mg, or from about 5 to about 250 mg, or from about 7 to about 150 mg. , or any range that falls within the wider range of 1 mg to 500 mg.

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

The following abbreviations are used in this document:

AMP: adenosine monophosphate,

AUC: area under the curve,

CBr ₄ : carbon tetrabromide,

CCl ₄ : carbon tetrachloride,

C _max : maximum concentration,

CDCl ₃ : deuterated chloroform,

DAST: diethylaminosulfur trifluoride,

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DAB CO: 1,4-diazabicyclo [2.2.2] octane, DCM: dichloromethane, DCC: N.N'-dicyclohexylcarbodiimide.

DEA: diethylamine,

DIPEA: Ν, Ν-diisopropylethylamine, DME: dimethoxyethane, DMF: Ν, Ν-dimethylformamide, DMSO: dimethyl sulfoxide, EC50: half maximum effective concentration, EDC: ethylene dichloride,

HATU: 2- (7-aza-III-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, HCl: hydrochloric acid, H2O: water, IPA: isopropyl alcohol, K ₂ CO ₃ : potassium carbonate , LC-MS / MS: tandem mass spectrometry combined with liquid chromatography, MeOH: methanol, MeOD: deuterated methanol, NaBH ₄ : sodium borohydride, NaOH: sodium hydroxide, Na ₂ SO ₄ : sodium sulfate, PBr ₃ : phosphorus tribromide , PCl3: phosphorus trichloride,

Pd (dppf) Cl ₂ -CH ₂ Cl ₂ : [1,1 '-bis- (diphenylphosphino) ferrocene] dichloropalladium (II),

PPh ₃ : triphenylphosphine,

rt: room temperature (25-30 ° C), ROA: route of administration, SEM: standard error of the mean, SoBr ₂ : thionyl bromide, SOC12: thionyl chloride, Т: temperature, THF: tetrahydrofuran, T _1/2 : half-life ...

Examples of

Compounds of the present invention were prepared according to the following experimental procedures using appropriate materials and conditions. The following examples are presented for illustration only and not to limit the scope of the present invention.

Preparation 1.4-Bromomethyl-2-fluoropyridine (I-1)

To a solution of 2-fluoro-4-methylpyridine (2.5 g, 0.022 mol) in CCl ₄ (75 ml) under N2 at 25 ° C were added N-bromosuccinimide (4.4 g, 0.024 mol) and benzoyl peroxide (0, 81 g, 0.003 mol). The reaction mixture was heated to 85 ° C for 5 h, cooled to room temperature, filtered in vacuo, and washed with CCl4 (40 ml). The filtrate was concentrated in vacuo to give the crude compound, which was further purified by flash chromatography using ethyl acetate: n-hexane (02:98) to give the title compound.

Yield: 1.1 g;

1H-NMR (CDCl3, 400 MHz) δ ppm: 4.71 (s, 2H), 7.27 (s, 1H), 7.42-7.43 (d, J = 4.9 Hz, 1H), 8.24-8.25 (d, J = 5.1 Hz, 1H);

Mass (m / z): 190.0, 192.1 (M + H) +.

Getting 2.5-Bromomethyl-2-fluoropyridine (I-2)

Bg

The title compound, 5-bromomethyl-2-fluoropyridine, was synthesized from 2-fluoro-5methylpyridine following the procedure outlined in Preparation 1.

1H-NMR (CDCl ₃ , 400 MHz) δ ppm: 4.75 (s, 2H), 7.18-7.21 (dd, J = 2.7, 8.4 Hz, 1H), 8 04-8.09 (m, 1H); 8.32-8.33 (d, J = 1.5 Hz, 1H);

Mass (m / z): 190.0, 192.2 (M + H) +.

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Preparation 3.5-Bromomethyl-2-chloropyridine (I-3) Br

N CI

Stage 1. A solution of 6-chloronicotinic acid (2.0 g, 0.012 mol) in DMF (5 ml) was added to a suspension of sodium hydride (0.76 g, 0.015 mol) in DMF (3 ml) under N ₂ at 25 ° C and stirred for 1 h. Methyl iodide (1.5 ml, 0.025 mol) was added at room temperature and heated to 50 ° C for 2 h. The reaction mixture was cooled to room temperature, quenched with ice water (50 ml) and extracted with using ethyl acetate (3x50 ml). The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give methyl 6-chloronicotinate.

Yield: 1.6 g;

Mass (m / z): 172.0, 174.0 (M + H) +.

Stage 2. To a solution of methyl 6-chloronicotinate (1.08 g, 0.009 mol) in THF (30 ml) at 0 ° C in an N2 atmosphere was added dropwise lithium aluminum hydride (1 M in THF, 7.5 ml, 0.0075 mol). The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was cooled to 0 ° C, diluted with ethyl acetate and treated with water (2 ml). The mixture was filtered through a pad of celite and concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using a mixture (40:60) to give 2-chloro-5-hydroxymethylpyridine.

Yield: 0.55 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 2.09 (brs, 1H), 4.72 (s, 2H), 7.31-7.34 (d, J = 8 , 1 Hz, 1H), 7.687.71 (dd, J = 2.2, 8.4 Hz, 1H), 8.36 (s, 1H);

Mass (m / z): 144.1, 146.0 (M + H) +.

Stage 3. To a solution of 2-chloro-5-hydroxymethylpyridine (0.45 g, 0.003 mol) in DCM (10 ml) at 0 ° C under N _{2 was} added dropwise phosphorus tribromide (0.44 ml, 0.0037 mol ). The reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was diluted with DCM (75 ml), treated with saturated aqueous sodium bicarbonate solution (20 ml). The organic layer was washed with water (20 ml), brine (20 ml) and dried over Na2SO4 and concentrated in vacuo to give the title compound.

Yield: 0.49 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 4.35 (s, 2H), 7.32-7.34 (d, J = 8.2 Hz, 1H), 7.69- 7.71 (dd, J = 2.2, 7.9 Hz, 1H); 8.40-8.41 (d, J = 1.7 Hz, 1H);

Mass (m / z): 205.9, 208.0 (M + H) +.

Preparation 4.5- (Chloromethyl) -2-methoxypyridine (I-4)

N O '

Step 1. 2-Methoxypyridine-5-carboxylic acid was converted to 2-methoxy-5hydroxymethylpyridine following the procedure described in Step 2 of Preparation 3.

Yield: 0.72 g;

Mass (m / z): 140.1 (M + H) +.

Step 2. To a solution of 2-methoxy-5-hydroxymethylpyridine (0.71 g, 0.005 mol) in DCM (5 ml) at 0 ° C under N _{2 was} added thionyl chloride (0.7 ml, 0.009 mol) dropwise. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with DCM (50 ml) and treated with saturated aqueous sodium bicarbonate solution (10 ml). The organic layer was washed with water (20 ml), brine (20 ml), dried over Na2SO4 and concentrated in vacuo to give the title compound.

Yield: 0.58 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 3.94 (s, 3H), 4.55 (s, 2H), 6.75-6.77 (d, J = 8.5 Hz, 1H), 7.61-7.64 (dd, J = 2.2, 8.5 Hz, 1H), 8.14 (s, 1H);

Mass (m / z): 158.0-160.0 (M + H) +.

Preparation 5.5-Chloromethyl-2-methylpyridine (I-5)

The title compound, 5-chloromethyl-2-methylpyridine, was synthesized from 6-methylnicotinic acid following the procedure outlined in Preparation 4.

Yield: 1.7 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 2.58 (s, 3H), 4.56 (s, 2H), 7.16-7.18 (d, J = 7.9 Hz, 1H), 7.61-7.64 (dd, J = 1.6, 7.8 Hz, 1H), 8.49 (s, 1H);

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Mass (m / z): 142.0, 144.1 (M + H) +.

Preparation 6.4-Chloromethyl-2-methylpyridine (I-6)

The title compound, 4-chloromethyl-2-methylpyridine, was synthesized from 2-methylisonicotinic acid following the procedure outlined in Preparation 4.

Yield: 0.47 g;

¹ H-NMR (CDCl3, 400 MHz) δ ppm: 2.58 (s, 3H), 4.51 (s, 2H), 7.12-7.13 (d, J = 4.8 Hz , 1H), 7.19 (s, 1H), 8.48-8.50 (d, J = 5.1 Hz, 1H);

Mass (m / z): 142.0, 144.0 (M + H) ⁺ .

Preparation 7.4-Bromomethyl-2,5-difluoropyridine (I-7)

The title compound, 4-bromomethyl-2,5-difluoropyridine, was synthesized from 2,5-difluoropyridine-4-carboxylic acid following the procedure outlined in Preparation 3.

Yield: 0.23 g;

¹ H-NMR (DMSO-6, 400 MHz) δ ppm: 4.68 (s, 2H), 7.20 (s, 1H), 8.16 (s, 1H);

Mass (m / z): 208.1, 210.1 (M + H) ⁺ .

Getting 8. 4-Bromomethyl-2-chloropyridine (I-8)

The title compound, 4-bromomethyl-2-chloropyridine, was synthesized from 2-chloroisonicotinic acid following the procedure outlined in Preparation 3.

Yield: 0.49 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 4.35 (s, 2H), 7.36 (s, 1H), 8.37-8.38 (d, J = 4.9 Hz, 1H);

Mass (m / z): 205.9, 208.0 (M + H) ⁺ .

Preparation 9.4-Chloromethylpyridine (I-9)

Step 1. Thionyl chloride (0.7 ml, 0.009 mol) was added dropwise to a stirred suspension of isonicotinic acid (5 g, 0.04 mol) in methanol (50 ml) under N2 at 0-5 ° C. Then the reaction mixture was boiled under reflux for 3 hours to obtain a clear solution. The reaction mass was cooled to room temperature and concentrated to give a residue, which was diluted with water (20 ml) and extracted with ethyl acetate (3x100 ml). The organic extracts were combined, washed with aqueous sodium bicarbonate (10 ml), brine (20 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was further purified by flash chromatography using ethyl acetate: hexane (40:60) to obtain methyl isonicotinate.

Yield: 2.82 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 3.96 (s, 3H), 7.83-7.85 (d, J = 5.3 Hz, 2H), 8.77- 8.78 (d, J = 5.2 Hz, 2H);

Mass (m / z): 138.0 (M + H) ⁺ .

Step 2. Methyl isonicotinate was reacted with lithium aluminum hydride in the manner described in Step 2 of Preparation 3 to provide crude 4-hydroxymethylpyridine, which was further purified by chromatography using ethyl acetate: hexane (80:20) to give the pure compound.

Yield: 3.05 g;

¹ H-NMR (CDCl3, 400 MHz) δ ppm: 4.74 (s, 2H), 7.29-7.30 (d, J = 5.3 Hz, 2H), 8.51-8 , 52 (d, J = 5.5 Hz, 2H);

Mass (m / z): 110.0 (M + H) ⁺ .

Step 3. 4-Hydroxymethylpyridine was reacted with thionyl chloride in the manner described in Step 2 of Preparation 4 to provide the title compound, 4-chloromethylpyridine.

Yield: 0.35 g;

¹ H-NMR (MeOH, 400 MHz) δ ppm: 4.71 (s, 2H), 7.51-7.53 (d, J = 5.7 Hz, 2H), 8.56-8 , 58 (d, J = 5.9 Hz, 2H);

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Mass (m / z): 128.0, 130.0 (M + H) +.

Preparation 10.4- (4-Bromomethylphenyl) -1-methyl-1H-pyrazole (I-10) ^VG + / - / + \ = Ν

Stage 1. To a solution of 4-bromobenzaldehyde (0.50 g, 0.0027 mol) in a mixture of 1,4-dioxane (18 ml) and water (5 ml) in an atmosphere of N2 was added 1-methyl-4- (4.4 , 5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -III-pyrazole (1.12 g, 0.0054 mol), sodium carbonate (0.85 g, 0.0081 mol) and complex of [1,1'-bis- (diphenylphosphino) ferrocene] dichloro-palladium (II) with dichloromethane 1: 1 (0.043 g, 0.00013 mol). The reaction mixture was heated at 80 ° C for 4 h, cooled to room temperature, filtered through celite and washed with ethyl acetate (30 ml). The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (40:60) to give 4- (1-methyl-1 H-pyrazol-4-yl) benzaldehyde.

Yield: 0.49 g;

¹ H-NMR (CDCl3, 400 MHz) δ ppm: 3.96 (s, 3H), 7.60-7.62 (d, J = 8.0 Hz, 2H), 7.72 (s , 1H), 7.84-7.87 (m, 3H), 9.97 (s, 1H);

Mass (m / z): 187.2 (M + H) +.

Stage 2. To a cooled solution of 4- (1-methyl-1H-pyrazol-4-yl) benzaldehyde (0.49 g, 0.0026 mol) in methanol (10 ml) under N2 was added sodium borohydride (0.12 d, 0.0032 mol). The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, dissolved in ice water (50 ml) and extracted with ethyl acetate (3x50 ml). The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give 4- (4-hydroxymethylphenyl) -1methyl-1H-pyrazole.

Yield: 0.45 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 3.85 (s, 3H), 4.46-4.47 (d, J = 5.7 Hz, 2H), 5.11- 5.14 (t, J = 5.7 Hz, 1H), 7.27-7.29 (d, J = 7.9 Hz, 2H), 7.49-7.51 (d, J = 8, 0 Hz, 2H), 7.82 (s, 1H), 8.09 (s, 1H);

Mass (m / z): 189.1 (M + H) +.

Step 3. 4- (4-Hydroxymethylphenyl) -1-methyl-N-pyrazole was converted to the title compound using a procedure similar to that described in Step 3 of Preparation 3.

Yield: 0.17 g;

'h-NMR (DMSO-de, 400 MHz) δ ppm: 3.85 (s, 3H), 5.27 (s, 2H), 7.41-7.43 (d, J = 8, 0 Hz, 2H), 7.53-7.55 (d, J = 8.0 Hz, 2H), 7.87 (s, 1H), 8.15 (s, 1H);

Mass (m / z): 251.0, 253.0 (M + H) ⁺ .

Preparation 11.4- (4-Chloromethyl-3-fluorophenyl) -1-methyl-1H-pyrazole (I-11)

Step 1. 4- (4-Hydroxymethyl-3-fluorophenyl) -1-methyl-1H-pyrazole was synthesized from 2-fluoro-4-bromobenzaldehyde according to the procedure described in Step 1 and Step 2 of Preparation 10. The resulting crude compound purified further by flash chromatography using ethyl acetate: n-hexane (70:30) to give pure compound.

Yield: 0.95 g;

'H-NMR (CDCI3, 400 MHz) δ ppm: 3.94 (s, 3H), 4.75 (s, 2H), 7.13-7.16 (m, 1H), 7.23 -7.24 (d, J = 1.2 Hz, 1H), 7.37-7.41 (t, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.74 ( s, 1H);

Mass (m / z): 207.2 (M + H) ⁺ .

Step 2. 4- (4-Hydroxymethyl-3-fluorophenyl) -1-methyl-1H-pyrazole was converted to the title compound using a procedure similar to that described in Step 2 of Preparation 4.

Yield: 0.13 g;

'H-NMR (CDCI3, 400 MHz) δ ppm: 3.95 (s, 3H), 4.64 (s, 2H), 7.15-7.17 (m, 1H), 7.23 -7.24 (m, 1H), 7.367.40 (m, 1H), 7.61 (s, 1H), 7.74 (s, 1H);

Mass (m / z): 225.2 (M + H) ⁺ .

Preparation 12.5-Bromomethyl-2'-fluoro [2,5 '] bipyridinyl (I-12)

Stage 1. Methyl iodide (1.06 g, 0.007 mol) was added at 0-5 ° C to a stirred suspension of 6-bromonicotinic acid (1.0 g, 0.004 mol) and K ₂ CO ₃ (2.06 g, 0.014 mol) in DMF (15 ml) at 25-30 ° C and then the reaction mass was heated to 55 ° C for 4 h. The reaction mixture was poured into cold water (50 ml) and was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to give methyl 6-bromonicotinate.

Yield: 0.909 g;

1H-NMR (DMSO, 400 MHz) δ ppm: 3.89 (s, 3H), 7.83-7.85 (d, J = 8.3 Hz, 1H), 8.18-8, 21 (dd, J = 2.3, 8.2 Hz, 1H), 8.87-8.88 (d, J = 2.3 Hz, 1H);

Mass (m / z): 216.1 (M + H) +.

Stage 2. Pd (PPh ₃ ) _{4 was} added to a stirred mixture of methyl 6-bromonicotinate (0.70 g, 0.003 mol), 6-fluoropyridine-3-boronic acid (0.505 g, 0.003 mol) and K ₂ CO ₃ (0, 9 g, 0.006 mol) in a mixture of DME and water (12 ml, 5: 1) and the reaction mixture was refluxed for 12 hours. Then the reaction mixture was cooled to room temperature, filtered through celite and the residue was washed with ethyl acetate. The filtrate was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give methyl 2'-fluoro [2.5 '] bipyridinyl 5-carboxylate.

Yield: 0.38 g;

1H-NMR (DMSO-de, 400 MHz) δ ppm: 3.9 (s, 3H), 7.36-7.39 (m, 1H), 8.23-8.25 (d, J = 8.3 Hz, 1H), 8.398.42 (m, 1H), 8.72-8.73 (d, J = 2.2 Hz, 1H), 9.02-9.02 (d, J = 1.8 Hz, 1H), 9.18-9.19 (d, J = 1.5 Hz, 1H);

Mass (m / z): 233.2 (m + H) ⁺ .

Step 3. Methyl 2'-fluoro [2.5 '] bipyridinyl-5-carboxylate was reacted with lithium aluminum hydride according to the procedure described in Step 2 of Preparation 3 to give 5-hydroxymethyl-2'-fluoro [2.5 '] bipyridine.

Yield: 0.294 g;

1H-NMR (DMSO-06, 400 MHz) δ ppm: 4.59 (s, 2H), 5.38-5.41 (t, 1H), 7.29-7.32 (d, J = 8.0 Hz, 1H), 7.847.86 (d, J = 1.8 Hz, 1H), 8.02-8.04 (d, J = 8.2 Hz, 1H), 8.61-8 , 65 (m, 2H), 8.92-8.92 (d, J = 1.8, 1H);

Mass (m / z): 205.1 (M + H) +.

Step 4. 5-Hydroxymethyl-2'-fluoro [2,5 '] bipyridine was reacted with phosphorus tribromide following the procedure outlined in Step 3 of Preparation 3 to provide the title compound, 5-bromomethyl-2'-fluoro [2,5 '] bipyridinyl.

Yield: 0.150 g;

1H-NMR (CDCl ₃ , 400 MHz) δ ppm: 4.53 (s, 2H), 7.04-7.07 (m, 1H), 7.72-7.74 (d, J = 8.0 Hz, 1H), 7.86-7.88 (d, J = 7.2 Hz, 1H), 8.47-8.50 (m, 1H), 8.773 (s, 1H), 8, 80-8.80 (d, J = 1.84 Hz, 1H);

Mass (m / z): 267.0, 269.0 (M + H) +.

Preparation 13. 5-Bromomethyl-2- (1-methyl-1H-pyrazol-4-yl) pyridine (I-13)

Stage 1. Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (0.13 g, 0.0001 mol) was added to a stirred mixture of 6-bromopyridine-3-carboxaldehyde (0.6 g, 0.003 mol), sodium carbonate (1 , 02 g, 0.0096 mol) and 1-methyl4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (1.34 g, 0.006 mol ) in a mixture of 1,4-dioxane and water (25 ml, 4: 1). The reaction mixture was heated to 70-80 ° C and the temperature was maintained for 6 hours, cooled to room temperature, diluted with H2O (10 ml), extracted with ethyl acetate (3x25 ml). The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was further purified by flash chromatography using ethyl acetate: hexane (60:40) to give 6- (1-methyl-1H-pyrazol4-yl) pyridine-3-carboxaldehyde.

Yield: 0.54 g;

1H-NMR (CDCI3, 400 MHz) δ ppm: 3.98 (s, 3H), 7.57-7.59 (d, J = 8.2 Hz, 1H), 8.03-8, 04 (d, J = 3.44 Hz, 2H), 8.11-8.14 (m, 1H), 8.96-8.96 (d, J = 1.0 Hz, 1H), 10.04 (s, 1H);

Mass (m / z): 188.0 (M + H) +.

Step 2. 6- (1-Methyl-1H-pyrazol-4-yl) pyridine-3-carboxaldehyde was reacted with NaBH4 according to the procedure described in Step 2 of Preparation 3 to give 5-hydroxymethyl-2- (1- methyl-1H-pyrazol-4-yl) pyridine.

Yield: 0.50 g;

1H-NMR (DMSO, 400 MHz) δ ppm: 3.87 (s, 3H), 4.48-4.50 (d, J = 5.52 Hz, 2H), 5.24-5, 27 (m, 1H), 7.587.60 (d, J = 8.04 Hz, 1H), 7.68-7.69 (d, J = 1.56 Hz, 1H), 7.96 (s, 1H ), 8.24 (s, 1H), 8.43 (s, 1H);

Mass (m / z): 190.1 (m + H) ⁺ .

Step 3. A solution of 5-hydroxymethyl-2- (1-methyl-1H-pyrazol-4-yl) pyridine (0.4 g, 0.002 mol) in DCM (20 ml) was added to a stirred solution of carbon tetrabromide (0.84 g , 0.0025 mol) and triphenylphosphine (1.6 g, 0.006 mol) in DCM (25 ml) at 0-5 ° C and then stirred at room temperature for 2 hours. The reaction mixture was poured into water (50 ml) and the organic layer was separated. The organic layer was washed with aqueous sodium bicarbonate solution (25 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which additionally

- 28 035599 was purified by flash chromatography using ethyl acetate: hexane (60:40) to give

5-bromomethyl-2- (1-methyl-1H-pyrazol-4-yl) pyridine, which was directly used for further reaction.

Preparation 14. 4- (4-Bromomethylphenyl) thiazole (I-14)

Stage 1. Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (0.65 g, 0.0008 mol) was added to a sealed vessel containing a mixture of 4-bromobenzaldehyde (1.51 g, 0.008 mol), potassium acetate (1, 96 g, 0.02 mol) and bis (pinacolato) diboron (2.6 g, 0.01 mol) in toluene (20 ml) and the contents were heated to 90-100 ° C for 6 hours and then cooled to room temperature. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (2x20 ml). The filtrate was concentrated in vacuo to give the crude compound, which was further purified by flash chromatography using ethyl acetate: hexanes (10:90) to give 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) benzaldehyde.

Yield: 1.77 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 1.36 (s, 12H), 7.85-7.89 (d, J = 7.8 Hz, 2H), 7.95- 7.97 (d, J = 7.8 Hz, 2H), 10.04 (s, 1H).

Stage 2. To a stirred mixture of 4-bromothiazole (0.7 g, 0.004 mol), sodium carbonate (1.3 g, 0.012 mol) and 4- (4,4,5,5-tetramethyl- [1,3,2 ] dioxaborolan-2-yl) benzaldehyde (1.89 g, 0.008 mol) in a mixture of 1,4-dioxane and water (25 ml, 4: 1), Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (0.17 d, 0.0002 mol). The reaction mixture was heated to 80 ° C and the temperature was maintained for 6 h, cooled to room temperature, diluted with H ₂ O (10 ml), extracted with ethyl acetate (3x25 ml). The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give crude 4- (thiazol-4-yl) benzaldehyde, which was used without further purification for further reaction.

Step 3. 4- (Thiazol-4-yl) benzaldehyde was reacted with NaBH ₄ to give 4- (4-hydroxymethylphenyl) thiazole according to the procedure described in Step 2 of Preparation 10.

Yield: 0.58 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 1.76-1.79 (m, 1H), 4.73-4.74 (d, J = 5.0 Hz, 2H), 7.43-4.74 (d, J = 8.0 Hz, 2H), 7.54-7.54 (d, J = 1.8 Hz, 1H), 7.92-7.94 (d, J = 8.2 Hz, 2H), 8.87-8.88 (d, J = 1.5 Hz, 1H);

Mass (m / z): 192.1 (M + H) +.

Step 4. 4- (4-Hydroxymethylphenyl) thiazole was reacted with phosphorus tribromide following the procedure outlined in Step 3 of Preparation 3 to provide the title compound, 4- (4-bromomethylphenyl) thiazole.

Yield: 0.42 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 4.54 (s, 2H), 7.46-7.48 (d, J = 8.02 Hz, 2H), 7.56- 7.56 (d, J = 1.44 Hz, 1H), 7.90-7.92 (d, J = 8.24 Hz, 2H), 8.89-8.89 (d, J = 1, 36 Hz, 1H);

Mass (m / z): 253.8, 255.9 (M + H) ⁺ .

Preparation 15.1- (4-Bromomethylphenyl) -III-pyrazole (I-15)

Stage 1. To a solution of 4-bromobenzaldehyde (2.0 g, 0.010 mol) in DMF 20 ml in an N2 atmosphere at 25 ° C was added III-pyrazole (0.668 g, 0.0098 mol), copper iodide (0.185 g, 0, 0009 mol), L-proline (0.224 g, 0.0019 mol) and cesium carbonate (6.4 g, 0.0196 mol). The reaction mixture was heated at 120 ° C for 20 h, cooled to room temperature, filtered through celite and washed with ethyl acetate (50 ml). The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (40:60) to give 4- (pyrazol-1-yl) benzaldehyde.

Yield: 1.0 g;

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 6.62 (s, 1H), 7.84 (s, 1H), 8, 01-8.03 (d, J = 8, 4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 8.67 (s, 1H), 10.00 (s, 1H);

Mass (m / z): 173.1 (M + H) ⁺ .

Step 2. 1- (4-Hydroxymethylphenyl) -1H-pyrazole was synthesized from 4- (pyrazol-1-yl) benzaldehyde following the procedure described in step 2 of Preparation 10.

Yield: 0.5 g;

1H-NMR (DMSO-dg, 400 MHz) δ ppm: 4.52-4.53 (d, J = 5.6 Hz, 2H), 5.23-5.26 (t, J = 5 , 7 Hz, 1H), 6.52 (s, 1H), 7.41-7.43 (d, J = 8.3 Hz, 2H), 7.72 (s, 1H), 7.77-7 , 79 (d, J = 8.3 Hz, 2H); 8.09 (d, J = 2.3 Hz, 1H);

Mass (m / z): 175.1 (M + H) ⁺ .

Step 3. The title compound was synthesized from 1- (4-hydroxymethylphenyl) -1Hpyrazole following the procedure outlined in Step 3 of Preparation 3.

- 29 035599

Yield: 0.33 g;

Ή-NMR (DMSO-dg, 400 MHz) δ ppm: 4.76 (s, 2H), 6.55 (s, 1H), 7.56-7.58 (d, J = 8.5 Hz, 2H), 7.75 (s,

1H), 7.82-7.84 (d, J = 8.4 Hz, 2H), 8.51-8.52 (d, J = 2.4 Hz, 1H);

Mass (m / z): 237.0 (M + H) +, 238.9 (M + H) ⁺ .

Preparation 16. 5-Chloromethyl-2-methylsulfanylpyridine (I-16)

Step 1. To a solution of 6-chloronicotinic acid (0.5 g, 0.0031 mol) in DMSO (10 ml) under N2 at 25 ° C was added sodium methanethiolate (0.55 g, 0.0079 mol). The reaction mixture was heated to 80 ° C for 2 h, cooled to room temperature, treated with 2.2 ml of HCl and stirred for 15 min. The reaction mixture was then diluted with ethyl acetate (30 ml) and concentrated in vacuo to give 6-methylsulfanylnicotinic acid.

Yield: 0.46 g;

Mass (m / z): 168.3 (M-H) ^- .

Stage 2. To a solution of 6-methylsulfanylnicotinic acid (0.53 g, 0.0031 mol) in a mixture of DCM (10 ml) and methanol (5 ml) in an N2 atmosphere at 25 ° C was added (trimethylsilyl) diazomethane (2.0 M in nhexane, 16 ml, 0.0314 mol). The reaction mixture was stirred for 26 h at room temperature, quenched with ice water (20 ml) and extracted with ethyl acetate (3x50 ml). The organic layer was washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give methyl 6-methylsulfanyl nicotinate.

Yield: 0.56 g;

Ή-NMR (DMSOD ₆ , 400 MHz) δ ppm: 2.58-2.60 (s, 3H), 3.73-3.77 (s, 3H), 7.42-7.44 ( d, J = 8.0 Hz, 1H), 8.06-8.08 (d, J = 8.4 Hz, 1H), 8.90 (s, 1H);

Mass (m / z): 184.3 (M + H) +.

Stage 3. To a solution of methyl 6-methylsulfanylnicotinate (0.76 g, 0.00415 mol) in a mixture of diethyl ether (8 ml) and DCM (8 ml) at 0 ° C in an N2 atmosphere was added dropwise lithium borohydride (2.0 M in n-hexane, 4.1 ml, 0.008 mol), then methanol (0.25 ml, 0.008 mol). The mass was stirred for 5 min and then warmed to room temperature, stirred for 3 h, an additional amount of lithium borohydride (2.0 M in n-hexane, 4.1 ml, 0.008 mol) and methanol (0.25 ml, 0.008 mol) and stirred for an additional 15 h at room temperature. Then the reaction mixture was treated with saturated sodium bicarbonate solution and was extracted with DCM (3x50 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give (2-methylsulfanylpyridin-5-yl) methanol.

Yield: 0.47 g;

Ή-NMR (DMSOD6, 400 MHz) δ ppm: 2.44-2.48 (s, 3H), 4.50-4.55 (s, 2H), 4.88-4.91 (t , 1H), 7.26-7.28 (d, J = 8.2 Hz, 1H), 7.53-7.56 (d, J = 8.1 Hz, 1H), 8.35 (s, 1H);

Mass (m / z): 156.0 (M + H) +.

Step 4 (2-Methylsulfanylpyridin-5-yl) methanol was converted to 5-chloromethyl-2methylsulfanylpyridine following the procedure described in Step 2 of Preparation 4.

Yield: 0.17 g;

Ή-NMR (DMSO ^ 6, 400 MHz) δ ppm: 3.25-3.27 (s, 3H), 4.76 (s, 2H), 7.30-7.32 (d, J = 8.2 Hz, 1H), 7.697.71 (d, J = 8.1 Hz, 1H), 8.47 (s, 1H);

Mass (m / z): 173.9, 176.2 (M + H) +.

Preparation 17.6-Bromomethylbenzothiazole (I-17)

The title compound was synthesized from benzothiazole-6-carboxylic acid following the procedure outlined in Preparation 3.

Yield: 0.19 g;

Ή-NMR (CDCl ₃ , 400 MHz) δ ppm: 4.65 (s, 2H), 7.54-7.55 (d, J = 8.0 Hz, 1H), 8.0 (s , 1H), 8.10-8.12 (d, J = 8.4 Hz, 1H), 9.02 (s, 1H);

Mass (m / z): 228.0, 229.8 (M + H) +.

- 30 035599

Preparation 18. 4-bromomethyl-1-methyl-1H-benzimidazole hydrobromide (I-18)

Stage 1. To a solution of 2-amino-3-nitrobenzoic acid (2.0 g, 0.01092 mol) in methanol (30 ml) at 25 ° C, was added Pd / C (2.0 g) and stirred for 15 h in an atmosphere of gaseous H ₂ . The reaction mixture was filtered through celite, washed with methanol (50 ml) and the filtrate was concentrated in vacuo to give 2,3-diaminobenzoic acid.

Yield: 1.5g;

¹ H-NMR (DMSO-d ^ 400 MHz) δ ppm: 4.92-5.22 (m, 4H), 6.34-6.35 (t, J = 7.6 Hz, 1H) , 6.66-6.68 (d, J = 7.3 Hz, 1H), 7.08-7.10 (d, J = 7.9 Hz, 1H), 8.12 (m, 1H);

Mass (m / z): 153.2 (M + H) +.

Stage 2. To a solution of 2,3-diaminobenzoic acid (1.4 g, 0.0092 mol) in 6N. HCl (18.2 ml) was added formic acid (1.2 ml, 0.028 mol), the temperature was raised to 105 ° C and maintained for 18 h. The reaction mixture was treated with aqueous ammonia until pH ~ 4.5, filtered through celite, washed with water (50 ml), n-hexane (50 ml), dissolved in methanol and concentrated in vacuo to give 1H-benzimidazole-4-carboxylic acid.

Yield: 1.37 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 4.00-4.10 (m, 1H), 7.27-7.46 (m, 1H), 7.90-7, 91 (d, J = 2.2 Hz, 2H), 8.38 (m, 1H), 13.5 (br s, 1H);

Mass (m / z): 163.1 (M + H) ⁺ .

Step 3. 1-Methyl-III-benzimidazole-4-carboxylate was synthesized according to the procedure described in Step 1 of Preparation 3.

Yield: 0.38 g;

¹ H-NMR (DMSO ^ ₆ , 400 MHz) δ ppm: 3.88 (s, 6H), 7.35-7.39 (t, 1H), 7.78-7.80 (d, J = 7.9 Hz, 1H), 7.857.87 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H);

Mass (m / z): 191.1 (M + H) ⁺ .

Step 4. 4-Hydroxymethyl-1-methyl-III-benzimidazole was synthesized according to the procedure described in Step 2 of Preparation 3.

Yield: 0.40 g;

¹ H-NMR (DMSO-dfo 400 MHz) δ ppm: 3.84 (s, 3H), 4.90-4.91 (d, 2H), 5.13-5.15 (t, 1H ), 7.24-7.25 (d, J = 6.9 Hz, 2H), 7.41-7.43 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H) ;

Mass (m / z): 163.0 (M + H) ⁺ .

Stage 5. To a solution of 4-hydroxymethyl-1-methyl-III-benzimidazole (0.45 g, 0.003 mol) in DCM (10 ml) at 0 ° C in an N2 atmosphere was added dropwise thionyl bromide (0.44 ml, 0, 0037 mol). Warm the reaction mixture to room temperature and stir for 3 hours. Concentrate the reaction mixture in vacuo to give the title compound.

Yield: 0.18 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 3.99 (s, 3H), 5.05 (s, 2H), 7.56-7.58 (d, J = 7, 8 Hz, 1H), 7.65-7.67 (d, J = 7.3 Hz, 1H), 7.89-7.91 (d, J = 8.2 Hz, 1H), 9.43 ( s, 1H);

Mass (m / z): 225.0, 226.9 (M + H) ⁺ .

Preparation 19. 3- (4-Chloromethylphenyl) -2-methylpyridine (I-19)

CI

J

H ₃ C N

Stage 1. In a hermetically sealed vessel containing a mixture of 4-bromobenzaldehyde (1 g, 0.005 mol), potassium acetate (1.31 g, 0.013 mol) and bis- (pinacolato) diboron (1.6 g, 0.006 mol) in toluene (20 ml), Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (0.48 g, 0.0005 mol) was added and the contents were heated at 90-100 ° C for 6 hours and then cooled to room temperature. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (2x20 ml). The filtrate was concentrated in vacuo to give the crude compound, which was further purified by flash chromatography using ethyl acetate: hexanes (10:90) to give 4- (4,4,5,5-tetramethyl- [1,3, 2] dioxaborolane-2yl) benzaldehyde.

Yield: 1.12 g;

'11 -51MP (CDCls, 400 MHz) δ ppm: 1.36 (s, 12H), 7.85-7.87 (d, J = 7.72 Hz, 2H), 7.95-7 , 97 (d, J = 7.8 Hz, 2H), 10.05 (s, 1H);

Mass (m / z): 233.0 (M + H) +.

Step 2. 4- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) benzaldehyde was reacted with 3-bromo-2-methylpyridine in accordance with the procedure described in step 2 of preparation 14 to provide the title compound, 4- (2-methylpyridin-3-yl) benzaldehyde.

Yield: 0.19 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 2.52 (s, 3H), 7.06 (s, 1H), 7.50-7.53 (m, 3H), 7, 96-7.98 (d, J = 8.04 Hz, 2H), 8.56-8.57 (d, J = 1.24 Hz, 1H), 10.09 (s, 1H);

Mass (m / z): 198.0 (M + H) +.

Step 3. 4- (2-Methylpyridin-3-yl) benzaldehyde was reacted with NaBH ₄ to give 3- (4-hydroxymethylphenyl) -2-methylpyridine according to the procedure described in Step 2 of Preparation 10.

Yield: 0.17 g;

'11 -51MP (CDCl ₃ , 400 MHz) δ ppm: 1.97 (m, 1H), 2.50 (s, 3H), 4.77 (s, 2H), 7.17-7, 20 (m, 1H), 7.31-7.33 (d, J = 7.96 Hz, 2H), 7.46-7.46 (d, J = 7.86 Hz, 2H), 7.50 -7.52 (m, 1H), 8.48-8.50 (m, 1H);

Mass (m / z): 200.0 (M + H) +.

Step 4. 3- (4-Hydroxymethylphenyl) -2-methylpyridine was reacted with thionyl chloride following the procedure outlined in Step 2 of Preparation 4 to provide the title compound, 3- (4-chloromethylphenyl) -2-methylpyridine.

Yield: 0.14 g;

'11 -51MP (CDCl ₃ , 400 MHz) δ ppm: 2.51 (s, 3H), 4.65 (s, 2H), 7.18-7.21 (m, 1H), 7, 31-7.33 (d, J = 8.04 Hz, 2H), 7.46-7.52 (m, 3H), 8.50-8.52 (m, 1H);

Mass (m / z): 217.9, 220.0 (M + H) +.

Preparation 20.cis-4-Aminotetrahydropyran-3-ol (I-20)

NH _a

Stage 1. To a solution of KOH (23.5 g, 0.419 mol) in methanol (230 ml) at 5 ° C was added tetrahydropyran-4-one over 20 min, a solution of iodine in methanol (300 ml) over 1 h. The reaction mixture was warmed to room temperature for 30 min, stirred for 1 h, diluted with toluene and concentrated to 1/3 of its volume. Toluene was added again and concentrated to 1/3 of its volume, filtered and the filtrate was diluted with ethyl acetate. The organic layer was washed with water (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give 4,4-dimethoxytetrahydropyran-3-ol.

Yield: 17.5 g;

'11 -51MR (DMSOL, 400 MHz) δ ppm: 1.57-1.60 (m, 1H), 1.75-1.82 (m, 1H), 3.09-3.10 ( s, 6H), 3.21-3.31 (m, 1H), 3.43-3.45 (m, 1H), 3.48-3.51 (s, 1H), 3.56-3, 59 (m, 2H), 4.47-4.75 (m, 1H).

Step 2. To a solution of the above compound (17.5 g, 0.108 mol) in THF (170 ml) at 5 ° C under N2 was added sodium butoxide (11.8 g, 0.123 mol) in one portion. The reaction mass was heated to 35 ° C for 1 h and cooled to room temperature for 1 h. Tert-butyl ammonium iodide (1.99 g, 0.005 mol) and benzyl bromide were added at room temperature and heated to 50 ° C for 2 h, cooled to room temperature, quenched with water and extracted with ethyl acetate (3x100 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude residue, which was then purified by flash chromatography using ethyl acetate: hexane (5:95) to give 3-benzyloxy-4,4-dimethoxytetrahydropyran.

Yield: 15.5 g;

'11 -51MR (DMSO-de, 400 MHz) δ ppm: 1.65-1.76 (m, 2H), 3.08-3.11 (d, 6H), 3.40-3, 44 (m, 3H), 3.63-3.66 (m, 1H), 3.92-3.95 (m, 1H), 4.47-4.49 (m, 1H), 4.61- 4.64 (m, 1H), 7.27-7.35 (m, 5H).

Step 3. To a solution of the above compound (14.1 g, 0.056 mol) in THF (75 ml) at 25 ° C under N2 was added dropwise 2N. HCl (75 ml) and stirred at room temperature for 1.5 hours. The reaction mixture was neutralized with saturated aqueous K2CO3 solution and extracted with ethyl acetate (3x100 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: hexane (15:85) to give 3-benzyloxytetrahydropyran-4-one.

Yield: 9.9 g;

'11 -51MR (DMSO-dfe 400 MHz) δ ppm: 2.32-2.37 (m, 1H), 2.61-2.67 (m, 1H), 3.39-3.43 (m, 1H), 3.57-3.63 (m, 1H), 4.02-4.06 (m, 1H), 4.09-4.16 (m, 2H), 4.75-4 , 50 (m, 1H), 4.69-4.72 (m, 1H), 7.21-7.36 (m, 5H).

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Step 4. To a solution of the above compound (2.5 g, 0.012 mol) in DCM (50 ml) at 25 ° C under N _2, benzylamine (1.4 g, 0.013 mol) was added in one portion and stirred for 1 h Sodium triacetoxyborohydride (4.7 g, 0.022 mol) was then added at 10 ° C. and stirred for 12 hours. The reaction mixture was quenched with water and extracted with DCM (3x50 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using methanol: chloroform (2:98) to give n-benzyl (3benzyloxytetrahydropyran-4-yl) amine.

Yield: 2.6 g;

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 1.49-1.53 (m, 1H), 1.59-1.62 (m, 1H), 1.84-1, 87 (m, 1H), 2.73-2.75 (m, 1H), 3.24-3.32 (m, 2H), 3.55-3.63 (m, 3H), 3.73- 3.76 (m, 1H), 3.88-3.92 (m, 1H), 4.41-4.44 (m, 1H), 4.554.58 (m, 1H), 7.20-7, 33 (m, 10P);

Mass (m / z): 298.2 (M + H) +.

Step 5. To a solution of the above compound (1.8 g, 0.0 6 mol) in methanol (50 ml) was added 10% Pd / C (1.8 g) in one portion and stirred for 6 hours while bubbling with H ₂ gas ... The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound.

Yield: 0.65 g;

¹ H-NMR (DMSO-dfe 400 MHz) δ ppm: 1.45-1.48 (m, 1H), 1.56-1.60 (m, 1H), 1.87 (m, 3H ), 2.89-2.90 (m, 1H), 3.16 (m, 1H), 3.27-3.34 (m, 1H), 3.47 (m, 1H), 3.60- 3.63 (m, 1H); 3.69-3.72 (m, 1H);

Mass (m / z): 118.1 (M + H) +.

Preparation 21. Trans-4-aminotetrahydropyran-3-ol hydrochloride (I-21) | c (^ NH ₂ _ ^OH HCI relative

Trans-4aminotetrahydropyran-3-ol was prepared according to the procedure specified in WO 2013/055577. This compound was converted to the hydrochloride salt using the following procedure.

To a solution of the above compound (1.2 g, 0.01 mol) in DCM (10 ml) at 0-10 ° C under N _{2 was} slowly added IPA-HCl (17% w / w, 2.9 g, 0.08 mol). After the addition, the reaction mass was left to warm to 25 ° C and stirred for 5 h. The reaction mass was concentrated in vacuo. Triturate the reaction with diethyl ether (2x10), decant the solvent and dry the solids in vacuo to give the title compound.

Yield: 1.5g;

¹ H-NMR (DMSO-dfo 400 MHz) δ ppm: 1.53-1.64 (m, 1H), 1.89-1.93 (m, 1H), 2.94-2.99 (m, 2H), 3.23-3.29 (m, 1H), 3.43-3.48 (m, 1H), 3.76-3.80 (m, 2H), 5.62-5 , 64 (d, J = 4.6 Hz, 1H), 8.17 (brs, 3H);

Mass (m / z): 118.1 (M + H) +.

Preparation 22. Trans-4-aminotetrahydropyran-3-ol hydrochloride (isomer-II) (I-22) | О \\ νη ₂

ON _NG | relative I 1 </ 1

Stage 1. 4-Benzyloxycarbonylamino-3-hydroxytetrahydropyran

To a solution of trans-4-aminotetrahydropyran-3-ol hydrochloride (preparation 21, 2.0 g, 0.013 mol) in water (50 ml) at 0 ° C was added sodium carbonate (6.9 g, 0.06 mol) and stirred within 10 minutes. Benzyl chloroformate (6.7 g, 0.03 mol) was added at 0 ° C, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (50 ml) and was extracted with ethyl acetate (3x100 ml). The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (50:50) to give the title connections.

Yield: 1.4 g;

1H-NMR (DMSO-de, 400 MHz) δ ppm: 1.34-1.44 (m, 1H), 1.74-1.78 (m, 1H), 2.91-2.99 (m, 1H), 3.23-3.30 (m, 3H), 3.34-3.37 (m, 1H), 3.72-3.76 (m, 2H), 4.86-4 , 89 (d, J = 4.6 Hz, 1H), 5.01 (s, 2H), 7.20-7.22 (d, J = 7.5 Hz, 1H), 7.29-7, 33 (m, 1H), 7.35-7.38 (m, 3H);

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Mass (m / z): 252.1 (M + H) +.

The enantiomers were separated by chiral chromatography.

Isomer-I: Chiral HPLC: 99.70%; Conditions: CHIRALPAK AD-H, 250x4.6 mm, 5 microns; Solvent = 0.1% DEA in MEOH; Constant composition mobile phase flow rate = 0.8 ml / min;

T = 25 ° C, retention time = 7.64 min, wavelength = 210 nm.

Isomer-II: Chiral HPLC: 99.06%; Conditions: CHIRALPAK AD-H, 250x4.6 mm, 5 microns; Solvent = 0.1% DEA in MEOH; Constant composition mobile phase flow rate = 0.8 ml / min; T = 25 ° C, retention time = 7.99 min, wavelength = 210 nm.

Stage 2. Trans-4-aminotetrahydropyran-3-ol hydrochloride (isomer-II).

To a solution of 4-benzyloxycarbonylamino-3-hydroxytetrahydropyran (isomer-II, 0.52 g, 0.0009 mol) in methanol (25 ml) was added 10% palladium on carbon (0.03 g, 0.00002 mol) and stirred in atmosphere of hydrogen for 3 hours and the mass was filtered through celite. The filtrate was acidified with IPA-HCl (5 volumes) and concentrated in vacuo to give trans-4-aminotetrahydropyran-3-ol hydrochloride.

Yield: 0.15 g;

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 1.54-1.58 (m, 1H), 1.88-1.92 (m, 1H), 2.92-3, 01 (m, 2H), 3.23-3.29 (m, 1H), 3.36-3.42 (m, 1H), 3.78-3.83 (m, 2H), 5.60 ( brs, 1H), 8.03 (brs, 3H).

Preparation 23. Cis-3-aminotetrahydropyran-4-ol hydrochloride (I-23)

OH HCI

Step 1. 4,4-Dimethoxy-dihydropyran-3-one was synthesized according to PCT / US2010 / 060007 using 4,4-dimethoxytetrahydropyran-3-ol (Preparation 20, step 1).

Yield: 4.1 g;

1 H-NMR (DMSO-de, 400 MHz) δ ppm: 2.11-2.14 (m, 2H), 3.14 (s, 6H), 3.82-3.84 (m, 2H ), 3.99 (s, 2H).

Step 2. N-Benzyl- (4,4-dimethoxytetrahydropyran-3-yl) amine was synthesized according to the procedure described in Step 4 of Preparation 20, using 4,4-dimethoxydihydropyran-3-one (Step 1) and EDC as solvent ... The crude residue was further purified by flash chromatography using methanol: DCM (1:99).

Yield: 3.4 g;

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 1.61-1.65 (m, 1H), 1.75-1.82 (m, 1H), 3.12 (s, 6H), 3.35-3.39 (m, 1H), 3.62-3.67 (m, 2H), 3.76-3.85 (m, 2H), 4.23-4.24 ( d, 2H), 7.21-7.25 (m, 2H), 7.29-7.35 (m, 3H), 8.33 (brs, 1H);

Mass (m / z): 252.2 (M + H) +.

Step 3. To a solution of the above compound (3.4 g, 0.014 mol) in THF (50 ml) at 10-15 ° C under N2 was added HCl (102 ml) dropwise and stirred at room temperature overnight. The reaction mixture was neutralized with saturated aqueous K ₂ CO ₃ solution and extracted with ethyl acetate (4x100 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the compound, 3-benzylaminotetrahydropyran-4-one.

Output: 2.4G;

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 1.49-1.55 (m, 1H), 1.71-1.78 (m, 1H), 3.39-3, 45 (m, 2H), 3.62-3.66 (m, 2H), 3.76-3.78 (m, 2H), 4.47-4.49 (m, 1H), 7.23- 7.25 (m, 2H), 7.30-7.33 (m, 3H), 8.34 (br s, 1H);

Mass (m / z): 206.2 (M + H) +.

Stage 4. To a solution of 3-benzylaminotetrahydropyran-4-one (3.5 g, 0.165 mol) in THF (30 ml) at 0 ° C under N2 was added lithium aluminum hydride (1 M in THF, 20 ml, 0.02 mol ), stirred for 30 min at this temperature and warmed to room temperature for 1 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using methanol: chloroform (2: 98) to give 3-benzylaminotetrahydropyran-4-ol.

Yield: 0.85 g;

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 1.36-1.39 (m, 1H), 1.73-1.78 (m, 1H), 2.86-2, 92 (m, 1H), 3.23-3.29 (m, 2H), 3.35-3.37 (m, 2H), 3.71-3.74 (m, 2H), 3.82- 3.85 (m, 1H), 4.88-4.90 (m, 1H), 7.21-7.22 (m, 2H), 7.277.32 (m, 3H), 8.33 (br. s, 1H);

Mass (m / z): 208.2 (M + H) +.

Stage 5. To a solution of 3-benzylaminotetrahydropyran-4-ol (0.42 g, 0.002 mol) in methanol (50 ml) was added 10% palladium-carbon (0.42 g, 0.002 mol) in one portion and stirred for 6 h when bubbling with H2 gas. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo to 1/3 of its volume, IPA-HCl (17% w / w, 0.58 g, 0.16 mol) was slowly added at 0 ° C and concentrated in vacuo. Triturate the reaction with diethyl ether (2x10), decant the solvent and dry the solids in vacuo to give the title compound.

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Yield: 0.16 g;

1H-NMR (DMSOD ₆ , 400 MHz) δ ppm: 1.43-1.53 (m, 1H), 1.89-1.91 (m, 1H), 2.82-2.85 ( m, 1H), 3.18-3.32 (m, 2H), 3.56-3.60 (m, 1H), 3.80-3.83 (m, 1H), 3.89-3, 93 (m, 1H), 5.52-5.54 (brs, 1H), 7.99 (brs, 3H).

Example 1. N - [(1S, 2S) -2-F hydroxycyclohexyl] -4- (2-fluoropyridin-4-ylmethyl) -1 -methyl-1Hpyrrolo [2,3-b] pyridine-6-carboxamide

Stage 1. 4-Bromo-1H-pyrrolo [2,3-b] pyridine-7-oxide

To a solution of 4-bromo-1H-pyrrolo [2,3-b] pyridine (10.1 g, 0.52 mol) in DCM (120 ml) at 0-5 ° C under N2 was added meta-chloroperoxybenzoic acid (13 , 5 g, 0.59 mol), warmed to room temperature and stirred for 20 h. The reaction mixture was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using DCM: methanol (98: 2) to give 4-bromo-1H-pyrrolo [2,3-b] pyridine-7-oxide.

Yield: 8.3 g;

1H-NMR (DMSOD ₆ , 400 MHz) δ ppm: 6.50-6.51 (d, J = 3.1 Hz, 1H), 7.32-7.33 (d, J = 6, 5 Hz, 1H), 7.56-7.57 (d, J = 3.1 Hz, 1H), 8.07-8.08 (d, J = 6.5 Hz, 1H), 12.88 ( broad s, 1H);

Mass (m / z): 213.1 (M + H) +, 215.1 (M + H) +.

Stage 2. 4-Bromo-1H-pyrrolo [2,3-b] pyridine-6-carbonitrile

CN

CO

To a solution of 4-bromo-1H-pyrrolo [2,3-b] pyridine-7-oxide (8.1 g, 0.038 mol) in acetonitrile (80 ml) at 20-25 ° C in an N2 atmosphere was added trimethylsilyl cyanide (56, 4 g, 0.57 mol), heated to 85 ° C and stirred for 20 h. The reaction mixture was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (30:70) to give 4-bromo-6-cyano-1H-pyrrolo [2,3-b] pyridine.

Yield: 4.96 g;

1H-NMR (DMSOD _& 400 MHz) δ ppm: 6.60-6.61 (m, 1H), 7.97-7.98 (m, 1H), 8.02-8.3 (m , 1H), 12.67 (s,

1H);

Mass (m / z): 222.0 (M + H) +, 223.1 (M + H) +.

Step 3. 4-Bromo-1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid

To a solution of potassium hydroxide (10.1 g, 0.18 mol) in water (130 ml) at 25 ° C was added 4-bromo-6-cyano1H-pyrrolo [2,3-b] pyridine (2 g, 0.009 mol) and heated to 100 ° C for 7 hours. The reaction mass was cooled to 2-5 ° C, acidified with dilute HCl, filtered the solids, dissolved in 200 ml of DCM: methanol (80:20) and dried over Na ₂ SO ₄ . The organic phase was concentrated in vacuo to give 4-bromo-1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid.

Yield: 2.0 g;

1H-NMR (DMSO-de, 400 MHz) δ ppm: 6.53 (s, 1H), 7.86-7.88 (m, 1H), 7.96 (s, 1H), 12, 45 (s, 1H), 13.14 (brs, 1H);

Mass (m / z): 241.1 (M + H) +, 243.0 (M + H) +.

Stage 4. Methyl 4-bromo-1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylate

To a suspension of sodium hydride (0.99 g, 0.024 mol) in DMF (10 ml) was added a solution of 4-bromo-1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid (2.0 g, 0.0083 mol) in DMF (10 ml) under N2 at 25 ° C and stirred for 1 h. Methyl iodide (1.6 ml, 0.025 mol) was added at room temperature and heated to 65 ° C for 6 h. The reaction mixture was quenched with ice water (75 ml) and extracted with 35 035599 with ethyl acetate (3x50 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (30:70 ) to obtain methyl 4-bromo-1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylate.

Yield: 1.51 g;

Ή-NMR (DMSO-de, 400 MHz) δ ppm: 3.89 (s, 3H), 3.91 (s, 3H), 6.56-6.57 (d, J = 3.45 Hz, 1H), 7.93-7.94 (d, J = 3.4 Hz, 1H), 8.00 (s, 1H);

Mass (m / z): 269.0, 271.1 (M + H) +.

Stage 5. Methyl 1-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -III-pyrrolo [2,3 ^ pyridine N-carboxylate

To a solution of methyl 4-bromo-1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylate (0.49 g, 0.0018 mol) in toluene (15 ml) in a sealed vessel under N2 at 25 ° C potassium acetate (0.57 g, 0.0058 mol), bis- (pinacolato) dibor (0.57 g, 0.0023 mol) and 1,1-bis- (diphenylphosphino) ferrocene-palladium dichloride complex ( II) with dichloromethane (0.10 g, 0.00012 mol). The reaction mixture was heated at 95 ° C for 8 h, cooled to room temperature, filtered through a pad of celite and washed with toluene (2x10). The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: nhexane (30:70) to give methyl 1-methyl-4- (4,4,5,5-tetramethyl- [1,3 , 2] dioxaborolan-2-yl) -Spyrrolo [2,3-b] pyridine-6-carboxylate.

Yield: 0.4 g;

Ή-NMR (DMSO-de, 400 MHz) δ ppm: 1.36 (s, 12H), 3.88 (s, 3H), 3.90 (s, 3H), 6.74-6, 75 (d, J = 3.2 Hz, 1H), 7.85-7.86 (d, J = 3.1 Hz, 1H), 8.09 (s, 1H);

Mass (m / z): 317.2 (M + H) +.

Stage 6. Methyl 1-methyl-4- (2-fluoropyridin-4-ylmethyl) -1H-pyrrolo [2,3-b] pyridine-6-carboxylate

To a solution of methyl 1-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -III-pyrrolo [2,3 ^ pyridine ^ -carboxylate (0.45 g, 0.0014 mol) in a mixture of 8 ml of THF and 0.8 ml of water in an atmosphere of N2, 4-bromomethyl-2-fluoropyridine (I-1, 0.3 g, 0.0017 mol), cesium carbonate (1, 85 g, 0.0056 mol) and the complex [1, G-bis- (diphenylphosphino) ferrocene] dichloro-palladium (II) with dichloromethane 1: 1 (0.116 g, 0.00014 mol). The mixture was irradiated in a microwave reactor at 75 ° C for 60 min, cooled to room temperature, filtered through celite and washed with ethyl acetate (2x30 ml). The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (30:70) to give the title compound.

Yield: 0.32 g;

-NMR (DMSO-de, 400 MHz) δ ppm: 3.85 (s, 3H), 3.88 (s, 3H), 4.40 (s, 2H), 6.70-6, 71 (d, J = 3.3 Hz, 1H), 7.15 (s, 1H), 7.25-7.26 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H ), 7.77-7.78 (d, J = 1.8 Hz, 1H), 8.11-8.12 (d, J = 5.1 Hz, 1H);

Mass (m / z): 300.0 (M + H) +.

Stage 7. 1-Methyl-4- (2-fluoropyridin-4-ylmethyl) -1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid / ^ν Ή ' ^Ν ''Τ^'' ^οη

To a solution of methyl 1-methyl-4- (2-fluoropyridin-4-ylmethyl) -1H-pyrrolo [2,3-b] pyridine-6carboxylate (0.25 g, 0.856 mol) in THF (6 ml) at 25 ° C was added 2N. aqueous sodium hydroxide solution (2.6 ml, 0.005 mol). The reaction mixture was heated to 60 ° C for 3 h, then cooled to room temperature and acidified with 1N HCl. HCl and extracted with ethyl acetate (3x30 ml). The organic layer was washed with saturated brine (30 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

- 36 035599

Yield: 0.05 g;

'H-NMR (DMSO-di, 400 MHz) δ ppm: 3.86 (s, 3H), 4.39 (s, 2H), 6.69-6.70 (d, J = 3, 2 Hz, 1H), 7.06 (s, 1H), 7.25-7.26 (d, J = 4.8 Hz, 1H), 7.74-7.75 (d, J = 2.2 Hz, 2H), 8.11-8.13 (d, J = 5.1 Hz, 1H), 12.83 (brs, 1H);

Mass (m / z): 286.0 (M + H) +.

Step 8. No. [(^^) - 2-Hydroxycyclohexyl] -4- (2-fluoropyridin-4-ylmethyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide.

To a solution of 1-methyl-4- (2-fluoropyridin-4-ylmethyl) -1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid (0.23 g, 0.00081 mol) in DMF (10 ml ) at 25 ° C under N _2, HATU (0.372 g, 0.00009 mol) was added, stirred for 10 min, then (1S, 2S) -2 aminocyclohexanol hydrochloride (0.136 g, 0.00089 mol) and DIPEA (0 , 6 ml, 0.0032 mol) for 10 min and stirred for 15 h. The reaction mixture was quenched with ice water (50 ml) and extracted with ethyl acetate (3x30 ml). The organic layer was washed with saturated brine (50 ml) and dried over Na ₂ SO ₄ . The organic layer was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (65:35) to give the title compound.

Yield: 0.25 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 1.25-1.27 (m, 4H), 1.64-1.67 (m, 2H), 1.89-1, 95 (m, 2H), 3.47-3.48 (m, 1H), 3.60-3.62 (m, 1H), 3.91 (s, 3H), 4.39 (s, 2H) , 4.71-4.72 (d, J = 5.3 Hz, 1H), 6.67-6.68 (d, J = 3.1 Hz, 1H), 7.14 (s, 1H), 7.23-7.24 (d, J = 4.4 Hz, 1H), 7.68-7.69 (d, J = 3.2 Hz, 1H), 7.72 (s, 1H), 8 , 11-8.12 (d, J = 5.0 Hz, 1H); 8.28-8.30 (d, J = 7.9 Hz, 1H);

Mass (m / z): 383.4 (M + H) ⁺ .

Examples 2-26. The compounds of examples 2-26 were prepared according to the experimental procedure described in example 1, with some non-critical changes.

Example No. Structure and IUPAC nomenclature Characteristic data 2 VLJ ^H & H 1 N - [(IS, 2S) -2-hydroxycyclohexyl] -4 (2-methoxypyridin-5-ylmethyl) -1-methyl-1H-pyrrolo [2,3-L] pyridine-6carboxamide Yu-NMR (CDC1 _3, 4, 00 MHz) δ ppm .: 1,15-1,39 (m, 4H), 1,77-1, 80 (m, 2H), 2.01-2.11 (m, 2H), 3.41-3.53 (m, 1H), 3.77-3.86 (m, 2H), 3.89 (s, 6H), 4.18 (s, 2H), 6.43-6.45 (m, 1H), 6, 62-6, 64 (m, 1H), 7.27-7.28 (m, 1H), 7.36-7.38 (d, J = 7.9 Hz, 1H), 7.86 (s, 1H), 8.02-8.04 (d, J = 6.5 Hz, 1H), 8.10 (s, 1H); Mass (m / z): 395.3 (M + H) ⁺ . 3 VAJ ⁿ bn NF Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridine-5ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6carboxamide S-NMR (CDCI3, 4 00 MHz) δ ppm: 1.15-1.39 (m, 4H), 1.78-1, 80 (m, 2H), 2.09-2.13 ( m, 2H), 3.51-3.56 (m, 1H), 3.65-3.70 (m, 1H), 3.82-3.88 (m, 1H), 3.92 (s, 3H), 4.26 (s, 2H), 6.41-6.42 (d, J = 3.3 Hz, 1H), 6, 80-6, 83 (m, 1H), 7.29-7 , 30 (d, J = 3.30 Hz, 1H), 7.55-7.59 (m, 1H), 7.88 (s, 1H), 8, 02-8.04 (d, J = 6 , 5 Hz, 1H), 8.15 (m, 1H); Mass (m / z): 383.4 (M + H) ⁺ .

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4 ADU ^Η 0H Ν- [(IS, 2S) -2-hydroxycyclohexyl] -4 (4-fluorobenzyl) -1-methyl1H-pyrrolo [2,3-b] pyridine-6-carboxamide ^ -NMR (CDC1 _3, 4, 00 MHz) δ ppm: : 1.15-1.48 (m, 4H), 1.77-1, 80 (m, 2H), 2.08-2.15 (m, 2H), 3.51-3.53 (m, 1H), 3.78-3, 80 (m, 1H), 3.82-3.85 (m, 1H), 3.89 (s, 3H), 4.24 (s, 2H), 6.41 -6.42 (d, J = 2.8 Hz, 1H), 6, 92-6.99 (m, 2H), 7.16-7.19 (m, 2H), 7.27-7.28 (m, 1H), 7.87 (s, 1H), 8.048.05 (d, J = 6.7 Hz, 1H); Mass (m / z): 382.3 (M + H) ⁺ . five 0J1J ⁿ bn Ν- [(IS, 2S) -2-hydroxycyclohexyl] -4 (4-thiazol-4-ylbenzyl) -1methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide ^ -NMR (DMSO-de, 4 00 MHz) δ ppm: 1.23-1.27 (m, 2H), 1.29-1.36 (m, 2H), 1.62 -1, 66 (m, 2H), 1.89-1.95 (m, 2H), 3.46-3.48 (m, 1H), 3.58-3.67 (m, 1H), 3.89- 3.98 (s, 3H), 4.32 (s, 2H), 4.70-4.71 (d, 1H), 6.66-6.67 (d, J = 3.4 Hz, 1H) , 7.35-7.37 (d, J = 8.08 Hz, 1H), 7.65-7.76 (d, J = 3.32 Hz, 2H), 7.68 (s, 1H), 7.89-7.91 (d, J = 8.04 Hz, 2H), 8.09-8.09 (d, J = l, 36 Hz, 1H), 8.26-8.28 (d, J = 7.92 Hz, 1H), 9.16-9.16 (d, J = 1, 32 Hz, 1H); Mass (m / z): 447.0 (M + H) ⁺ . 6 0Д0 ⁿ he N- [(IS, 2S) -2-hydroxycyclohexyl] -4- ^ -NMR (CDCI3, 4 00 MHz) δ ppm: 1.15-1.45 (m, 4H), 1.77-1, 80 (m, 2H), 2.09-2.15 (m, 2H), 3.51-3.56 (m, 1H), 3.64-3.68 (m, 1H), 3.80-3.83 (m, 1H), 3.90 (s, 3H), 4.31 (s, 2H), 6, 43-6, 44 (d, J = 2, l

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(4-pyrazol-1-ylbenzyl) 1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide Hz, 2H), 7.25-7.28 (m, 1H), 7.29-7.31 (d, J = 7.98 Hz, 2H), 7.57-7.59 (d, J = 8, l Hz, 2H), 7.69 (s, 1H), 7.87 (s, 1H), 7.92 (s, 1H), 8.05-8.06 (m, 1H); Mass (m / z): 430.5 (M + H) ⁺ . 7 ⁿ he xx. Ν \ Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4 [4- (1-methyl-1H-pyrazol4-yl) benzyl] -1-methyl1H-pyrrolo [2,3 - b] pyridine-6- carboxamide T-NMR (DMSO-L ₆ 4 00 MHz) δ ppm .: 1,25-1,29 (m, 4H), 1, 63-1, 66 (m, 2H), 1,89-1 , 93 (m, 2H), 3.37-3.41 (m, 1H), 3.46-3.47 (m, 1H), 3.58 (s, 3H), 3.92 (s, 3H ), 4.26 (s, 2H), 4.70-4.72 (m, 1H), 6.666.67 (d, J = 3.25 Hz, 1H), 7.25-7.27 (d, J = 7.9 Hz, 2H), 7.44-7.46 (d, J = 7.9 Hz, 2H), 7, 63-7, 65 (s, 2H), 7.87 (s, 1H ), 8.05 (s, 1H), 8.26-8.28 (d, J = 8.0 Hz, 1H); Mass (m / z): 444.2 (M + H) ⁺ . 8 \ ϊ ΓΊ ¹⁴ he tu \ N- [(IS, 2S) -2-hydroxycyclohexyl] -4 [2-fluoro-4- (1-methyl-1Hpyrazol-4-yl) benzyl] -1methyl-1H-pyrrolo [2 , 3- b] pyridine-6-carboxamide T-NMR (DMSO-cT 4 00 MHz) δ ppm: 1.24-1.28 (m, 4H), 1.68-1.70 (m, 2H), 1.90-1.95 (m, 2H), 3.50-3.55 (m, 1H), 3.82-3.84 (m, 1H), 3.89 (s, 3H), 3.92 (s, 3H), 4.28 (s, 2H), 4.75-4.78 (m, 1H), 6.516.52 (d, J = 3.4 Hz, 1H), 7.117.18 (m, 3H), 7.27 -7.28 (d, J = 3.9 Hz, 1H), 7.55-7.57 (m, 1H), 7.78-7.79 (m, 1H), 7.89 (s, 1H ), 8.04-8.05 (d, J = 6.9 Hz, 1H); Mass (m / z): 462.4 (M + H) ⁺ .

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nine ⁿ he ιχ Ν ^ · Ν- [(IS, 2S) -2-hydroxycyclohexyl] -4 (2-methylpyridin-5-ylmethyl) -1-methyl-1Hpyrrolo [2, 3-b] pyridine6-carboxamide ^ -NMR (CDC1 _3, 4, 00 MHz) δ ppm .: 1,18-1,37 (m, 4H), 1,75-1, 80 (m, 2H), 2.01-2.11 (m, 2H), 2.50 (s, 3H), 3.523.53 (m, 1H), 3.83-3.87 (m, 2H), 3.91 (s, 3H), 4.23 ( s, 2H), 6.42-6.43 (d, J = 3.40 Hz, 1H), 7.03-7.05 (d, J = 7.9 Hz, 1H), 7.27-7 , 28 (d, J = 3.50 Hz, 1H), 7.38-7.40 (dd, J = l, 7, 7.7 Hz, 1H), 7.86 (s, 1H), 8, 03-8.05 (d, J = 7.0 Hz, 1H), 8.46 (s, 1H); Mass (m / z): 379, 2 (M + H) ⁺ . ten K / uchKh ⁿ on N- [(IS, 2S) -2-hydroxycyclohexyl] -4 (2-chloropyridin-4-ylmethyl) -1-methyl-1Hpyrrolo [2, 3-b] pyridine6-carboxamide ^ -NMR (DMSO-de, 4 00 MHz) δ ppm: 1.25-1.27 (m, 4H), 1.64-1, 67 (m, 2H), 1.90-1, 92 (m, 2H), 3.46-3.48 (m, 1H), 3.51-3.62 (m, 1H), 3.91 (s, 3H), 4.36 (s, 2H) , 4.70-4.72 (d, J = 5.3 Hz, 1H), 6.67-6.68 (d, J = 3, l Hz, 1H), 7.30-7.32 (d , J = 4.8 Hz, 1H), 7.48 (s, 1H), 7, 68-7, 69 (d, J = 3.2 Hz, 1H), 7.71 (s, 1H), 8 , 28-8.30 (m, 2H); Mass (m / z): 399.2 (M + H) ⁺ . eleven N ^ N ^ _n zO IDJ ⁿ 0n g N- [(IS, 2S) -2- hydroxycyclohexyl] -4- ^ -NMR (DMSO-c ^, 4 00 MHz) δ ppm: 1.25-1.27 (m, 4H), 1.63 -1.67 (m, 2H), 1.91-1 , 94 (m, 2H), 3.47-3.49 (m, 1H), 3.593.61 (m, 1H), 3.91 (s, 3H), 4.42 (s, 2H), 4.70-4.71 (d, J = 5.4 Hz, 1H), 6, 66-6, 66 (d, J = 3.3 Hz, 1H), 7.26 (s, 1H),

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(2,5-difluoropyridine-4ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine6-carboxamide 7.65 (s, 1H), 7.70 -7.71 (d, J = 3.3 Hz, 1H), 8.21 (s, 1H), 8.28-8.30 (d, J = 7.9 Hz, 1H); Mass (m / z): 401.2 (M + H) ⁺ . 12 VXj ^H OH XX / N - [(IS, 2S) -2-hydroxycyclohexyl] -4 (benzothiazol-6-ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine6-carboxamide A-NMR (DMSO-s / _b , 4 00 MHz) δ ppm: 1.24-1.26 (m, 4H), 1.62 -1.66 (m, 2H), 1.89- 1.94 (m, 2H), 3.48-3.49 (m, 1H), 3.583.60 (m, 1H), 3.89 (s, 3H), 4.44 (s, 2H), 4 , 71-4.72 (d, J = 5.2 Hz, 1H), 6, 69-6, 70 (d, J = 3, l Hz, 1H), 7.45-7.47 (d, J = 8.3 Hz, 1H), 7, 65-7, 66 (d, J = 3, l Hz, 1H), 7.68 (s, 1H), 7.97-7.99 (d, J = 8.3 Hz, 1H), 8.10 (s, 1H), 8.27-8.29 (d, J = 7.8 Hz, 1H), 9.31 (s, 1H); Mass (m / z): 421.0 (M + H) ⁺ . 13 'nude X) V-XJ ⁿ on N - [(IS, 2S) -2-hydroxycyclohexyl] -4 (2'-fluoro- [2,5'] bipyridinyl-5-ylmethyl) -1-methyl-1Hpyrrolo [2 , 3-b] pyridine6-carboxamide A-NMR (DMSO-d ^, 4 00 MHz) δ ppm: 1.25-1.27 (m, 4H), 1.63 -1.66 (m, 2H), 1.89-1 , 95 (m, 2H), 3.43-3.47 (m, 1H), 3.593.61 (m, 1H), 3.91 (s, 3H), 4.38 (s, 2H), 4, 70-4.71 (d, J = 5.3 Hz, 1H), 6, 73-6, 74 (d, J = 3.2 Hz, 1H), 7.27-7.30 (dd, J = 2, l, 8.4 Hz, 1H), 7.68-7.69 (d, J = 3, l Hz, 1H), 7.71 (s, 1H), 7.80-7.82 (d , J = 7.8 Hz, 1H), 7.95-7.97 (d, J = 8, l Hz, 1H), 8.27-8.29 (d, J = 7.9 Hz, 1H) , 8.56-8, 60 (m, 1H), 8.71 (s, 1H), 8.87 (s, 1H); Mass (m / z): 460, 0 (M + H) ⁺ .

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^ -NMR (DMSO-d _ς , 400 MHz) δ FROM Μ ”ib ppm; 1.23-1, 1.63-1.67 (m, (m, 2H), 3.46- 29 2H), -3.50 (m, 4H), 1.90-1.95 (m, 1H), 3.59-3.61 (m, 1H), 3.90 (s, fourteen N- [(IS, 2S) -2- hydroxycyclohexyl] -4- (pyridin-4-ylmethyl) -1- methyl-1H-pyrrolo [2,3- B] pyridine-6-carboxamide 3H), 4.32 (s, 2H), 4.70-4.71 (d, J = 5.49 Hz, 1H), 6.64-6.65 (d, J = 3.44 Hz, 1H ), 7.28-7.29 (d, J = 5.36 Hz, 2H), 7.67-7.68 (m, 2H), 8.26 -8.28 (d, J = 7.96 Hz, 1H), 8.44-8.45 (d, J = 5.56 Hz, 2H); Mass (m / z): 365, 1 (M + H) ⁺ . ^ -NMR (DMSO-d o, 400 MHz) δ c / h ppm; 1.17-1, 1.63-1.66 (m, (m, 2H), 3.33- 27 2H), -3.48 (m, 4H), 1.90-1.98 (m, 1H), 3.59-3 .60 (m, 1H), 3.85 (s, L-N \ ZN), 3.90 (s, ZN), 4.29 (s, 2H), 4.70-4.71 (d, J = 5.32 Hz, 15 N- [(IS, 2S) -2- hydroxycyclohexyl] -4 [2- (1-methyl-1H-pyrazol4-yl) pyridin-5ylmethyl] -1-methyl-1Hpyrrolo [2,3-b] pyridine6-carboxamide 1H), 6, 68-6, 69 (d, 1H), 7.52-7.54 (d, 1H), 7.61-7.63 (d, 1H), 7.67 (s, 2H) , 1H), 8.20 (s, 1H), (d, J = 7.92 Hz, (s, 1H); Mass 445, 0 (M + H) ⁺ . J = 3.08 Hz, J = 8.04 Hz, J = 8 Hz, 7.92 (s, 8.26-8.28 1H), 8.50 (m / z): ⁿ ^ -NMR (DMSO-d ppm: 1.25-1, 1.62-1.66 (m, ₅ , 400 MHz) δ 26 (m, 4H), 2H), 1.91 (m, sixteen 2H), 3.46-3.50 (m, 1H), 3.58- F 3, 60 (m, 1H), 4.37 (s, 2H), 3, 91 4.70 (s, ZN), -4.71 (d, Ν- [(IS, 2S) -2- J = 5.4 Hz, 1H), 6, 63-6, 63 (d,

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hydroxycyclohexyl] -4 (2,3-difluorobenzyl) -1methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide J = 3, 2H), (s, Hz, Hz, (M + H 12 Hz, 1H), 7.15-7.18 (m, 7.30-7.32 (m, 1H), 7.60 1H), 1H), 1H); ) ⁺ . 7, 68-7, 69 (d, J = 3.32 8.27-8.29 (d, J = 7.88 Mass (m / z): 400.4 \ _N ? η ^ -NMR (DMSO-cA, 4 00 MHz) δ ppm ; 1, 23-1.27 (m, 4H), LL ⁿ bn 1, 60 2H), -1.67 2.38 (m, 2H), 1.91 (m, (s, 3H), 3.46-3.49 17 ΙγΝ SN ₃ Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4 (2-methylpyridin-4-ylmethyl) -1-methyl-1Hpyrrolo [2,3-L] pyridine6-carboxamide (m, 2H), 3.90 (s, 3H), 4.24 (s, 2H), 4.70-4.71 (d, J = 5.4 Hz, 1H), 6, 64-6, 65 (d, J = 3.2 Hz, 1H), 7, 07-7.08 (d, J = 4.5 Hz, 1H), 7.15 (s, 1H), 7.617.67 (m, 3H ), 8.27-8.31 (m, 1H); Mass (m / z): 379.10 (M + H) ⁺ . L L ^ -NMR (DMSO-cA, 4 00 MHz) δ ppm : 1, 22-1.26 (m, 4H), LLH ⁿ 0N 1.61 (m, -1.65 2H), (m, 2H), 1.88-1.94 3.46-3.47 (m, 1H), 3.58 -3, 60 (m, 1H), 3.89 (s, CI Ν - [(IS, 2S) -2- ZN), 4.32 (s, 2H), 4.68-4.69 18 (D, J = 5, 3 Hz, 1H), 6.66-6.66 hydroxycyclohexyl] -4- (d, J = 3.2 Hz, 1H), 7.39-7.41 (2-chloropyridine-5- (d, J = 8, 1 Hz, 1H), 7.66-7.67 ylmethyl) -1-methyl-1H- (d, J = 2.9 Hz, 1H), 7.70-7.73 pyrrolo [2,3-b] pyridine- (m, 1H), 8.25-8.29 (m, 2H), 6-carboxamide 8.43 399, (s, 1H); Mass (m / z): 6 (M + H) ⁺ .

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about spacecraft F-NMR (CDC1 _3, 4, 00 MHz) δ \ m and 1 1 ppm: 1.24-1.26 (m, 4H), Dhd ⁿ bi 1.61-1.65 (m, 2H), 1.88-1.94 AKA (m, 2H), 3.40-3.46 (m, 1H), 11 J Ν - [(IS, 2S) -2- 3.57-3.59 (m, 1H), 3.68 (s, ZN), 3.88 (s, ZN), 4.19 (s, nineteen hydroxycyclohexyl] -4- (4-methoxybenzyl) -1- methyl-1H-pyrrolo [2,3- B] pyridine-6-carboxamide 2H), 4.68-4.70 (d, J = 5.3 Hz, 1H), 6.62-6.63 (d, J = 3, l Hz, 1H), 6.81-6.83 (d, J = 8.3 Hz, 2H), 7.17-7.19 (d, J = 8.3 Hz, 2H), 7.59-7.61 (m, 2H), 8.238.25 ( d, J = 7.8 Hz, 1H); Mass (m / z): 394.3 (M + H) ⁺ . ⁰ CA Y-NMR (DMSO-d _e , 4 00 MHz) δ ppm: 1.21-1.24 (m, 4H), DDD ⁿ OH 1.61-1.66 (m, 2H), 1.92-1.94 1O ^N (m, 2H), 3.46-3.47 (m, 1H), | 1 I 3.57-3.61 (m, 1H), 3.89 (s, N - [(IS, 2S) -2- 3H), 4.06 (s, 2H), 4.32 (s, hydroxycyclohexyl] -4- 2H), 4.69-4.70 (d, J = 5.4 Hz, 20 (2- 1H), 6, 66-6, 67 (d, J = 3.3 Hz, methylsulfanylpyridin5-ylmethyl) -1-methyl-1H- 1H), 7.39-7.41 (m, 1H), 7.63 (s, 1H), 7, 65-7, 66 (d, J = 3.5 pyrrolo [2, 3-b] pyridine- Hz, 1H), 7.97-8.00 (m, 1H), 6-carboxamide 8.24-8.26 (m, 1H), 8.39-8.40 (d, J = 3.9 Hz, 1H), 8.44 (s, 1H); Mass (m / z): 411.3 (M + H) ⁺ . \ ϊ D) Y-NMR (DMSO-de, 4 00 MHz) δ ppm: 1.23-1.27 (m, 4H), ADU ⁿ he 1.63-1.66 (m, 2H), 1.90-1.92 21 L (m, 2H), 2.39 (s, 3H), 3.34- 3.37 (m, 2H), 3.39 (s, 3H), ^ 0 H ₃ C M Ν - [(IS, 2S) -2- 4.35 (s, 2H), 4.71-4.72 (d, J = 5.52 Hz, 1H), 6.73-6.73 (d,

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hydroxycyclohexyl] -4 [4- (2-methylpyridine-3- yl) benzyl] -1-methyl-1Hpyrrolo [2,3-b] pyridine6-carboxamide J = 3.4 Hz, 1H), 7.26-7.29 (m, 1H), 7.29-7.31 (d, J = 8.04 Hz, 2H), 7.38-7.40 (d, J = 8.04 Hz, 2H), 7.57-7.57 (d, J = l, 12 Hz, 1H), 7, 68-7.72 (m, 2H), 8.278.29 ( d, J = 8.16 Hz, 1H), 8.42-8.42 (d, J = 1, 2 Hz, 1H); Mass (m / z): 454.9 (M + H) ⁺ . 22 ⁿ on V) Ν- [(13,23) -2-hydroxycyclohexyl] - 4- (1-methyl-1H-benzimidazol-4-ylmethyl) -1-methyl-1Hpyrrolo [2,3-L] pyridine6-carboxamide ^ -NMR (flMCO-d _6, 4, 00 MHz) δ ppm .: 1,24-1,26 (m, 4H), 1,61-1,65 (m, 2H), 1,89-1 , 98 (m, 2H), 3.43-3.48 (m, 1H), 3.56-3.58 (m, 1H), 3.84 (s, 3H), 3.88 (s, 3H ), 4.62 (s, 2H), 4.69 (brs, 1H), 6.706.71 (d, J = 3.3 Hz, 1H), 7.047.05 (d, J = 6.8 Hz , 1H), 7.167.18 (t, J = 6.8 Hz, 1H), 7.427.44 (d, J = 7.9 Hz, 1H), 7.617.62 (d, J = 3, l Hz, 1H ), 7.64 (s, 1H), 8.23-8.25 (d, J = 7.9 Hz, 1H); Mass (m / z): 418.2 (M + H) ⁺ . 23 _z ⁿ ^ ⁿ Y ^J1 ' ⁿ ' O ΑΛΝ ⁿ on τχ Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4 (2-chloropyridin-5-ylmethyl) -1- (2-fluoroethyl) -1H-pyrrolo [2,3-b] pyridine- ^ -NMR (DMSO-SD, 4 00 MHz) δ ppm: 1.25-1.27 (m, 4H), 1.61-1.65 (m, 2H), 2.03-2.05 (m, 2H), 3.46-3.48 (m, 1H), 3, 58-3, 60 (m, 1H), 4.33 (s, 2H), 4, 64-4, 67 (m, 2H), 4.684.76 (m, 2H), 4, 87-4.89 (m, 1H), 6.17-6.72 (d, J = 3.3 Hz, 1H), 7.40-7.42 (d, J = 8, l Hz, 1H), 7.69 (s, 1H ), 7.73-7.74 (d, J = 3.5 Hz, 1H), 8.26-8.28 (d, J = 7.9 Hz, 1H), 8.44-8.45

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6-carboxamide (d, J = 1, 6 Hz, 2H); Mass (m / z): 431.4 (M + H) ⁺ . 24 N- (2-hydroxy-2- methylpropyl) -4- [4- (thiazol-4-yl) benzyl] -1- methyl-1H-pyrrolo [2,3- B] pyridine-6-carboxamide A-NMR (CDC1 _3, 4, 00 MHz) δ ppm .: 1.31 (s, 6H), 2.87 (brs, 1H), 3,52-3,53 (d, J = 6 , 37 Hz, 2H), 3.89 (s, 3H), 4.31 (s, 2H), 6, 45-6, 46 (d, J = 3.35 Hz, 1H), 7.27-7 , 28 (d, J = 3.14 Hz, 1H), 7.30-7.32 (d, J = 8.01 Hz, 2H), 7.47-7.47 (d, J = l, 64 Hz, 1H), 7.81-7.83 (d, J = 8.04 Hz, 2H), 7.93 (s, 1H), 8.44 (m, 1H), 8.85-8.85 (d, J = 1, 58 Hz, 1H); Mass (m / z): 421.2 (M + H) ⁺ . 25 ⁿ he] QF N - [(IS, 2S) -2-hydroxycyclohexyl] -4 (3-fluorobenzyl) -1-methyl1H-pyrrolo [2,3-b] pyridine-6-carboxamide A-NMR (DMSO-D _6, 4, 00 MHz) δ ppm .: 1,15-1,15 (m, 4H), 1, 63-1, 66 (m, 2H), 1,90-1 , 98 (m, 2H), 3.43-3.50 (m, 1H), 3.59-3.61 (m, 1H), 3.90 (s, 3H), 4.31 (s, 2H ), 4.70-4.72 (d, J = 5.33 Hz, 1H), 6.68-6.67 (d, J = 3.22 Hz, 1H), 7.00-7.04 ( m, 1H), 7.12-7.15 (m, 2H), 7.29-7.34 (m, 1H), 7.66 (s, 2H), 8.26-8.28 (d, J = 7.89 Hz, 1H); Mass (m / z): 382.4 (M + H) +.

Ν- (1hydroxycyclopentylmethyl l) -4- [4- (thiazol-4yl) benzyl] -1-methyl-1Hpyrrolo [2 _g 3-b] pyridine6-carboxamide

A-NMR (DMSO-C ₆ , 400 MHz) δ ppm: 1.23-1.26 (m, 4H),

1.61-1.69 (m, 4H), 3.41-3.42 (m, 2H), 3.88 (s, 3H), 4.33 (s, 2H), 4.70 (s, 1H), 6, 686.69 (d, J = 3.36 Hz, 1H),

7.37-7.39 (d, J = 8.08 Hz, 2H),

7, 67-7.69 (d, J = 5.44 Hz, 2H), 7.89-7.91 (d, J = 8.08 Hz, 2H),

8.09-8.10 (d, J = l, 68 Hz, 1H),

8.49-8.52 (m, 1H), 9.16-9.16 (d, J = 1, 64 Hz, 1H); Mass (m / z): 447.4 (M + H) ⁺ .

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Example 27. No. [(^^) - 2-Hydroxycyclohexyl] -4- (pyridin-3-ylmethyl) -1-methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide

To a solution of N - [(1S, 2S) -2-iugpoKCuiiuKJoiUKCUj] -4- (2-xjopiiupuguii-5-uj \ ieTUj) -1 -methyl-111pyrrolo [2,3-b] pyridine-6-carboxamide (example 18 , 0.064 g, 0.06 mol) in CMecu ethanol (1.5 ml), DMF (1.5 ml) and TEA (0.1 ml) at 25 ° C, 10% Pd / C (0.064 g) was added in one portion and pepemeshuvalu for 8 hours at bapbotupovanuu gas h _2. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using methanolic ammonia: chloroform (3:97) to give the title compound.

Yield: 0.027 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 1.24-1.25 (m, 4H), 1.61-1.65 (m, 2H), 1.88-1, 90 (m, 2H), 3.46-3.47 (m, 1H), 3.57-3.60 (m, 1H), 3.89 (s, 3H), 4.31 (s, 2H) , 4.69-4.70 (d, J = 5.4 Hz, 1H), 6.67-6.68 (d, J = 3.3 Hz, 1H), 7.27-7.30 (m , 1H), 7.64-7.67 (m, 3H), 8.25-8.27 (d, J = 7.9 Hz, 1H), 8.39-8.40 (d, J = 3 , 9 Hz, 1H), 8.57 (s, 1H);

Mass (m / z): 365.3 (M + H) +.

Example 28 N - [(1S, 2S) -2-Hydrocuccucloheccule] -4- (2-cyclopopopulpupuduin-5-ulmethyl) -1-methyl-1H। trrolo [2,3-b] pupudin-6-carboxamide

K suspension N - [(1S, 2S) -2-hydrocuccucloheccule] -4- (2-chloropupuduin-5-ulmethyl) -1-methyl-1Hpuppolo [2,3-b] puppu-6-carboxamide 18 (0pume , 2 g, 0.0005 mol) in 5 ml at 25 ° C in an atmosphere of N _{2 was} added pinacol ester of cyclopropylboronic acid (0.15 g, 0.0009 mol), Pd ₂ dba ₃ (0.0046 g), PCy ₃ (0.0035 g), an aqueous solution of K ₃ PO ₄ (1.7 M, 0.373 g, 0.0017 mol). The reaction mixture was irradiated in a microwave reactor at 140 ° C for 2 h, cooled to room temperature, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using methanolic ammonia: chloroform (1.4: 98.6) to give the title compound.

Yield: 0.050 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 1.21-1.26 (m, 8H), 1.62-1.65 (m, 2H), 1.74-1, 91 (m, 3H), 3.45-3.46 (m, 1H), 3.58-3.61 (m, 1H), 3.89 (s, 3H), 4.31 (s, 2H) , 4.68-4.70 (d, J = 5.3 Hz, 1H), 6.66-6.67 (d, J = 3.2 Hz, 1H), 7.17-7.28 (d , J = 8.0 Hz, 1H), 7.65-7.73 (m, 3H), 8.24-8.25 (d, J = 3.2 Hz, 1H), 8.30 (s, 1H);

Mass (m / z): 405.3 (M + H) ⁺ .

Example 29: No. [(^^) - 2-Hydroxycyclohexyl] -4- (2-fluoropyridin-4-ylmethyl) -1-ethyl-1Hpyrrolo [2,3-b] pyridine-6-carboxamide

This compound was synthesized using a procedure similar to that described in example 1, except for step 4, in which methyl iodide is replaced by ethyl iodide.

Yield: 0.054 g;

Ή-NMR (DMSO, 400 MHz) δ ppm: 1.24-1.27 (m, 4H), 1.41-1.44 (t, 3H), 1.63-1.67 (m , 2H), 2.04-2.15 (m, 2H), 3.53-3.55 (m, 1H), 3.59-3.61 (m, 1H), 4.35-4.41 (t, 2H), 4.72-4.73 (d, J = 5.5 Hz, 1H), 5.55 (s, 2H), 6.686.69 (d, J = 3.4 Hz, 1H) , 7.31 (s, 1H), 7.41 (s, 1H), 7.48-7.50 (d, J = 4.8 Hz, 1H), 7.65-7.66 (d, J = 3.3 Hz, 1H), 8.268.27 (d, J = 3.7 Hz, 1H), 8.29 (s, 1H);

Mass (m / z): 397.3 (M + H) ⁺ .

- 47 035599

Example 30. N - [(1S, 2S) -2-F hydroxycyclohexyl] -4- (2-fluoropyridin-4-ylmethyl) -1-isopropyl-1Hpyrrolo [2,3-b] pyridine-6-carboxamide

This compound was synthesized using a procedure similar to that described in example 1, except for step 4, in which methyl iodide is replaced by isopropyl iodide.

Yield: 0.027 g;

1H NMR (DMSO-06, 400 MHz) δ ppm: 1.23-1.26 (m, 4H), 1.47-1.49 (t, 6H), 1.63-1.67 ( m, 2H), 1.90-1.97 (m, 2H), 3.43-3.48 (m, 1H), 3.49-3.50 (m, 1H), 4.38 (s, 2H), 4.69-4.70 (d, J = 5.4 Hz, 1H), 5.25-5.29 (m, 1H), 6.706.71 (d, J = 3.6 Hz, 1H ), 7.15 (s, 1H), 7.25-7.26 (d, J = 4.7 Hz, 1H), 7.71 (s, 1H), 7.85-7.86 (d, J = 2.3 Hz, 1H), 8.118.13 (d, J = 5.1 Hz, 1H), 8.24-8.25 (d, J = 7.9 Hz, 1H);

Mass (m / z): 411.2 (M + H) +.

Example 31. N - [(1 S ^ S ^ T hydroxycyclohexyl] -4- (2,3-difluorophenylmethyl) -1,3-dimethyl-1Hpyrrolo [2,3-b] pyridine-6-carboxamide

Stage 1. 4-Bromo-1H-pyrrolo [2,3-b] pyridine-3-carboxaldehyde

The title compound was synthesized according to the literature described in US 2009/0298820 A1.

Yield: 0.21 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 7.58-7.59 (d, J = 5.08 Hz, 1H), 8.20-8.21 (d, J = 5.12 Hz, 1H), 8.48 (s, 1H), 10.48-10.49 (d, J = 6.2 Hz, 1H), 13.16 (s, 1H);

Mass (m / z): 225.0 (M + H) +.

Step 2. 4-Bromo-3-hydroxymethyl-1H-pyrrolo [2,3-b] pyridine

To a stirred suspension of 4-bromo-1H-pyrrolo [2,3-b] pyridine-3-carboxaldehyde (0.4 g, 0.0017 mol) in methanol (15 ml) was added sodium borohydride 0.098 g, 0.0026 mol ) to obtain a clear solution. After completion of the interaction, the reaction mixture was concentrated to obtain a residual mass, which was diluted with water (25 ml) and was extracted with ethyl acetate (3x25 ml). The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

Yield: 0.35 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 4.76-4.77 (d, J = 4.82 Hz, 2H), 4.86- (brs, 1H), 7.28-7.29 (d, J = 5.04 Hz, 1H), 7.46-7.48 (d, J = 8 Hz, 1H), 8.02-8.03 (d, J = 5 Hz, 1H), 11.82 (s, 1H);

Mass (m / z): 227.0 (M + H) +.

Step 3. 4-Bromo-3-methyl-1H-pyrrolo [2,3-b] pyridine

To a solution of 4-bromo-3-hydroxymethyl-1H-pyrrolo [2,3-L] pyridine (0.46 g, 0.002 mol) in trifluoroacetic acid (5 ml) was added triethylsilane (0.51 g, 0.004 mol) at room temperature. temperature. The reaction mixture was heated at 65-70 ° C for 2 h, cooled to room temperature and poured into cold water (20 ml), neutralized with NaHCO ₃ and extracted with ethyl acetate (3x25 ml). The organic extracts were combined, washed with saturated brine (15 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

- 48 035599

Yield: 0.4 g;

¹ H-NMR (MeOD, 400 MHz) δ ppm: 2.53 (s, 3H), 7.30-7.32 (d, J = 9.68 Hz, 1H), 7.40-7 , 41 (d, J = 5.6 Hz, 1H), 8.02-8.03 (d, J = 5.47 Hz, 1H);

Mass (m / z): 211.0 (M + H) +.

Step 4. 4-Bromo-3-methyl-1H-pyrrolo [2,3-b] pyridine 7-oxide

The title compound was synthesized from 4-bromo-3-methyl-1H-purrolo [2,3-b] puridine following the procedure outlined in Step 1 of Example 1.

Yield: 1.4 g;

¹ H-NMR (DMSO ^, 400 MHz) δ ppm: 2.4 (s, 3H), 7.23-7.25 (d, J = 6.4 Hz, 1H), 7.30- 7.32 (d, J = 9.6 Hz, 1H), 7.9-8.0 (d, J = 6.4 Hz, 1H), 12.43 (s, 1H);

Mass (m / z): 227.0 (M + H) +.

Step 5. 4-Bromo-3-methyl-1H-pyrrolo [2,3-b] nyridine-6-carbonitrile

The title compound was synthesized from 4-bromo-3-methyl-1H-pyrrolo [2,3-b] pyridine-7 oxide following the procedure outlined in Step 2 of Example 1.

Yield: 0.55 g;

¹ H-NMR (DMSO-dg, 400 MHz) δ ppm: 2.53 (s, 3H), 7.38 (s, 1H), 7.61 (s, 1H), 9.53 (s , 1H);

Mass (m / z): 236, 237.9 (M + H) +.

Step 6. 4-Bromo-3-methyl-1H-pyrrolo [2,3-b] nyridine-6-carboxylic acid

The title compound was synthesized from 4-bromo-3-methyl-1H-nürrolo [2,3-b] nürudin-6carbonitrile following the procedure outlined in Step 3 of Example 1.

Yield: 0.073 g;

¹ H-NMR (DMSO-db, 400 MHz) δ ppm: 2.46 (s, 3H), 7.62 (s, 1H), 7.88 (s, 1H), 12.08 (s , 1H), 13.06 (brs, 1H);

Mass (m / z): 255.0, 256.8 (M + H) +.

Stage 7. Methyl 4-bromo-1,3-dimethyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylate

The title compound was synthesized from 4-bromo-3-methyl-1H-nurrolo [2,3-b] nurudine-6carboxylic acid following the procedure outlined in Step 4 of Example 1.

Yield: 0.061 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 2.5 (s, 3H), 3.89 (s, 3H), 4.01 (s, 3H), 7.17 (s, 1H), 8.06 (s, 1H);

Mass (m / z): 282.8 (M + H) +.

Stage 8. Methyl 1,3-dimethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -III-pyrrolo [2,3EDpyridine-6-carboxylate

The title compound was synthesized from methyl 4-bromo-1,3-dimethyl-3-pyrrolo [2,3EDpyridine-6-carboxylate according to the procedure outlined in Step 5 of Example 1.

Yield: 0.047 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 1.39 (s, 12H), 2.44 (s, 3H), 3.9 (s, 3H), 4.0 (s, 3H), 7.20 (s, 1H), 8.2 (s, 1H);

Mass (m / z): 331 (М + 1) +.

- 49 035599

Stage 9. Methyl 4- (2,3-difluorobenzyl) -1,3-dimethyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylate \

Nc <

The title compound was synthesized from methyl 1,3-dimethyl-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine -6-carboxylate according to the procedure described in step 6 of example 1.

Yield: 0.028d (62%);

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 2.43 (s, 3H), 3.88 (s, 6H), 4.02 (s, 2H), 6.95 (s, 1H), 7.13-7.17 (m, 2H), 7.28-7.33 (m, 1H), 7.49 (s, 1H);

Mass (m / z): 330.9 (M + 1) +.

Step 10 4- (2,3-Difluorobenzyl) -1,3-dimethyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid

The title compound was synthesized from methyl 4- (2,3-difluorobenzyl) -1,3-dimethyl-Spirrolo [2,3-b] pyridine-6-carboxylate following the procedure outlined in Step 7 of Example 1. Yield: 0.019 g (70%);

Mass (m / z): 317.1 (M + 1) +.

Stage 11. No [(^^) - 2-Hydroxycyclohexyl] -4- (2,3-difluorobenzyl) -1,3-dimethyl-III-pyrrolo [2,3 ^ pyridine-6-carboxamide \ N ·

The title compound was synthesized from 4- (2,3-difluorobenzyl) -1,3-dimethyl-Spirrolo [2,3-b] pyridine-6-carboxylic acid following the procedure outlined in Step 8 of Example 1.

Yield: 0.010 g (40%);

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 1.29-1.43 (4H, t), 1.77-1.80 (2H, t), 2.03-2.11 (2H, t), 2.27 (3H, s), 3.51-3.53 (1H, t), 3.67-3.70 (1H, t), 3.84 (s, 3H), 4.46 (s, 2H), 6.60-6.62 (br s, 1H), 6.89 (s, 1H), 7.04-7.16 (m, 2H), 7.28- 7.32 (m, 1H), 7.52 (s, 1H), 8.05-8.07 (br s, 1H);

Mass (m / z): 414.0 (M + 1) +.

Example 32. Racemic trans-M- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1-methyl1H-pyrrolo [2,3-b] pyridine-6-carboxamide

Stage 1. Methyl 4- (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylate

Methyl 4- (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylate was synthesized according to the procedure described in Step 6 of Example 1. The resulting crude compound was added

- 50 035599 was purified by flash chromatography using ethyl acetate: n-hexane (20:80) to afford the title compound.

Yield: 0.29 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 3.84 (s, 3H), 3.86 (s, 3H), 4.28 (s, 2H), 6.67-6 , 68 (d, J = 3.3 Hz, 1H), 7.08-7.12 (t, 2H), 7.32-7.38 (t, 2H), 7.76 (s, 1H), 7.73-7.74 (d, J = 3.2 Hz, 1H);

Mass (m / z): 299.0 (M + H) +.

Stage 2. 4- (4-Fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid coL

Ιλ

Methyl 4- (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylate was converted to 4 (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b ] pyridine-6-carboxylic acid according to the procedure described in step 7 of example 1.

Yield: 0.35 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 3.86 (s, 3H), 4.27 (s, 2H), 6.66-6.67 (d, J = 3, 2 Hz, 1H), 7.08-7.13 (t, 2H), 7.33-7.35 (dd, J = 2.4, 8.2 Hz, 2H), 7.65 (s, 1H ), 7.71-7.72 (d, J = 3.4 Hz, 1H), 12.02 (brs, 1H);

Mass (m / z): 285.0 (M + H) ⁺ .

Step 3. Racemic trans-M- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide.

The title compound was synthesized from 4- (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3b] pyridine-6-carboxylic acid following the procedure outlined in Step 8 of Example 1 using trans-4- hydrochloride aminotetrahydropyran-3-ol (I-21). The resulting crude compound was further purified by flash chromatography using methanol: dichloromethane (1:99) to give the title compound.

Yield: 0.36 g (62%);

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 1.64-1.71 (m, 1H), 1.86-1.89 (m, 1H), 2.89-2, 94 (m, 1H), 3.02-3.07 (m, 1H), 3.58-3.61 (m, 1H), 3.80-3.85 (m, 3H), 3.92 ( s, 3H), 4.28 (s, 2H), 4.99-5.02 (d, J = 5.7 Hz, 1H), 6.65-6.66 (d, J = 3.4 Hz , 1H), 7.08-7.12 (m, 2H), 7.31-7.34 (m, 2H), 7.64-7.67 (m, 2H), 8.42-8.44 (d, J = 8.1 Hz, 1H);

Mass (m / z): 384.3 (M + H) ⁺ .

Example 33. trans-M- (3-Hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1-methyl-III-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-I).

Yield: 0.12 g;

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 1.64-1.70 (m, 1H), 1.86-1.89 (m, 1H), 3.02-3, 07 (m, 2H), 3.58-3.61 (m, 1H), 3.81-3.83 (m, 3H), 3.92 (s, 3H), 4.28 (s, 2H) , 4.99-5.01 (d, J = 5.6 Hz, 1H), 6.65-6.66 (d, J = 3.4 Hz, 1H), 7.08-7.12 (m , 2H), 7.31-7.34 (m, 2H), 7.64-7.67 (m, 2H), 8.42-8.44 (d, J = 8.1 Hz, 1H);

Mass (m / z): 384.3 (M + H) ⁺ .

Chiral HPLC: 99.46% Conditions: CHIRALPAK AD-H 250x4.6 mm 5 μm; Solvent A = 70.0% MEOH, B = 30.0% IPA, C = 0.1% DEA; Constant composition mobile phase flow rate = 0.70 ml / min; T = 25 ° C, retention time = 7.25 min, wavelength = 245 nm.

Example 34. trans-Th3-Hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-II).

Yield: 0.12 g;

1H-NMR (DMSO-de, 400 MHz) δ ppm: 1.64-1.71 (m, 1H), 1.86-1.89 (m, 1H), 3.02-3.07 (m, 2H), 3.58-3.64 (m, 1H), 3.77-3.85 (m, 3H), 3.92 (s, 3H), 4.28 (s, 2H), 4.99-5.01 (d, J = 5.6 Hz, 1H), 6.65-6.66 (d, J = 3.3 Hz, 1H), 7.08-7.12 (m, 2H), 7.31-7.34 (m, 2H), 7.64-7.67 (m, 2H), 8.42-8.44 (d, J = 8.1 Hz, 1H);

Mass (m / z): 384.3 (M + H) ⁺ .

Chiral HPLC: 97.41%, Conditions: CHIRALPAK AD-H 250x4.6 mm 5 μm; Solvent A = 70.0% MEOH, B = 30.0% IPA, C = 0.1% DEA; Constant composition mobile phase flow rate = 0.70 ml / min; T = 25 ° C, retention time = 9.36 min, wavelength = 245 nm.

Example 35. Racemic cis-M- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide

The title compound was prepared according to the experimental procedure,

51 035599 sled in Example 32 using cis-4-aminotetrahydropyran-3-ol (I-20).

Yield: 0.092 g;

1H-NMR (DMSO-06, 400 MHz) δ ppm: 1.58-1.62 (m, 1H), 1.87-1.91 (m, 1H), 3.33-3.42 (m, 1H), 3.50-3.53 (m, 1H), 3.65 (m, 1H), 3.74-3.82 (m, 2H), 3.86 (s, 3H), 4.02-4.05 (m, 1H), 4.28 (s, 2H), 5.25-5.26 (d, J = 5.1 Hz, 1H), 6.66-6.67 ( d, J = 3.3 Hz, 1H), 7.08-7.12 (m, 2H), 7.31-7.34 (m, 2H), 7.66 (s, 1H), 7.68 -7.69 (d, J = 3.3 Hz, 1H), 8.36-8.38 (d, J = 8.3 Hz, 1H);

Mass (m / z): 384.3 (M + H) +.

Example 36. cis-Th3-H hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1-methyl-1 H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-I).

Yield: 0.033 g;

Ή-NMR (DMSO-06, 400 MHz) δ ppm: 1.58-1.62 (m, 1H), 1.87-1.91 (m, 1H), 3.33-3.42 (m, 1H), 3.50-3.53 (m, 1H), 3.65 (m, 1H), 3.74-3.82 (m, 2H), 3.86 (s, 3H), 4.02-4.05 (m, 1H), 4.28 (s, 2H), 5.25-5.26 (d, J = 5.1 Hz, 1H), 6.66-6.67 ( d, J = 3.3 Hz, 1H), 7.08-7.12 (m, 2H), 7.31-7.34 (m, 2H), 7.66 (s, 1H), 7.68 -7.69 (d, J = 3.3 Hz, 1H), 8.36-8.38 (d, J = 8.3 Hz, 1H);

Mass (m / z): 384.3 (M + H) +.

Chiral HPLC: 99.58%, Conditions: CHIRALPAK AD-H, 250x4.6 mm, 5 μm; Solvent A = 30.0% n-heptane, B = 40.0% MEOH, C = 30.0% IPA, D = 0.10% DEA; Constant composition mobile phase flow rate = 0.7 ml / min; T = 25 ° C, retention time = 8.37 min, wavelength = 245 nm.

Example 37. hhc-N- (3-1 'hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1 -methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-II) ...

Yield: 0.031 g;

1H-NMR (DMSO-06, 400 MHz) δ ppm: 1.59-1.62 (m, 1H), 1.87-1.91 (m, 1H), 3.33-3.42 (m, 1H), 3.50-3.53 (m, 1H), 3.65 (m, 1H), 3.74-3.82 (m, 2H), 3.86 (s, 3H), 4.04-4.06 (m, 1H), 4.28 (s, 2H), 5.25-5.26 (d, J = 5.1 Hz, 1H), 6.66-6.67 ( d, J = 3.3 Hz, 1H), 7.08-7.12 (m, 2H), 7.31-7.34 (m, 2H), 7.66 (s, 1H), 7.68 -7.69 (d, J = 3.3 Hz, 1H), 8.36-8.38 (d, J = 8.3 Hz, 1H);

Mass (m / z): 384.3 (M + H) +.

Chiral HPLC: 98.88%, Conditions: CHIRALPAK AD-H, 25x4.6 mm, 5 μm; Solvent A = 30.0% n-heptane, B = 40.0% MEOH, C = 30.0% IPA, D = 0.10% DEA; Constant composition mobile phase flow rate = 0.7 ml / min; T = 25 ° C, retention time = 10.31 min, wavelength = 245 nm.

Examples 38-63. The compounds of examples 38-63 were prepared according to the experimental procedure described in examples 32-37, with some non-critical changes.

Example No. Structure and IUPAC nomenclature Characteristic data and ^ -NMR (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,65-1,71 (m, 1H), 1 86 -1.89 (m, 1H), 2,89-2 , 94 (m, 1H), 3.053.13 (m, 1H), 3.58-3.65 (m, 1H), 3.80-3.84 (m, 3H), 3.93 (s, 3H ), 4.39 (s, 2H), 5.01-5.02 (d, 38 Racemic trans-N- (3- hydroxytetrahydropyran-4yl) -4- (2-fluoropyridine-4ylmethyl) -1-methyl-1Hpyrrolo [2, 3-b] pyridine-6carboxamide J = 5.6 Hz, 1H), 6, 67-6, 68 (d, J = 3.3 Hz, 1H), 7.14 (s, 1H), 7.23-7.24 (d, J = 4.2 Hz, 1H), 7.69-7.69 (d, J = 3.2 Hz, 1H), 7.72 (s, 1H), 8.11-8.12 (d, J = 5.0 Hz, 1H), 8.45-8.47 (d, J = 8, l Hz, 1H); Mass (m / z): 385.3 (M + H) ⁺ .

- 52 035599

39 rfA ¹ ? ⁿ OH - trans-N- (3 - hydroxytetrahydropyran-4yl) -4- (2-fluoropyridine-4ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6carboxamide (isomer-1) A-NMR (DMSO-D _6, 4, 00 MHz) δ ppm. : 1.65-1.71 (m, 1H), 1.86 -1.89 (m, 1H), 2.89-2.94 (m, 1H), 3.033.08 (m, 1H), 3 , 59-3.64 (m, 1H), 3.82-3.85 (m, 3H), 3.93 (s, 3H), 4.39 (s, 2H), 4.99-5.01 (d, J = 5.6 Hz, 1H), 6, 68-6, 69 (d, J = 3.3 Hz, 1H), 7.14 (s, 1H), 7.24-7.25 ( d, J = 4.2 Hz, 1H), 7.69 - 7.70 (d, J = 3.2 Hz, 1H), 7.72 (s, 1H), 8.11-8.12 (d , J = 5.0 Hz, 1H), 8.458.47 (d, J = 8, l Hz, 1H); Mass (m / z): 385.3 (M + H) ⁺ . Chiral HPLC: 99.94%, Method: CHIRAL PAK IC, 250 χ 4.6 mm, 5 μm; Solvent A = 60.0% MeOH, B = 40.0% IPA, C = 0.10% DEA; Constant composition mobile phase flow rate = 0.50 ml / min; T = 25 ° C, retention time = 13, 13 min, wavelength = 300 nm. 40 ... 0 00 ⁿ he and trans-N- (3 - hydroxytetrahydropyran-4- A-NMR (DMSO-D _6, 4, 00 MHz) δ ppm .: 1,65-1,71 (m, 1H), 1 86 -1.89 (m, 1H), 2,88-2 , 93 (m, 1H), 3.023.08 (m, 1H), 3.60-3.64 (m, 1H), 3.82-3.85 (m,

- 53 035599

yl) -4- (2-fluoropyridine-4ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6carboxamide (isomer-11) 3H), 3.93 (s, 3H), 4.39 (s, 2H), 4.99-5.01 (d, J = 5.7 Hz, 1H), 6.68-6.69 (d, J = 3.3 Hz, 1H), 7.14 (s, 1H), 7.24-7.25 (d, J = 4.4 Hz, 1H), 7.69 - 7.70 (d, J = 3.3 Hz, 1H), 7.72 (s, 1H), 8.11-8.12 (d, J = 5.0 Hz, 1H), 8.458.47 (d, J = 8, l Hz, 1H); Mass (m / z): 385.3 (M + H) +. Chiral HPLC: 99.44%, Method: CHIRAL CANCER IC, 250 x 4.6 mm, 5 μm; Solvent A = 60.0% MeOH, B = 40.0% IPA, C = 0.10% DEA; Mobile phase flow rate s constant composition = 0.50 ml / min; T = 25 ° C, time retention = 15.54 min, wavelength = 300 nm. 41 ... 0 Г ^ О vl / j ⁿ he VF cis-N- (3-hydroxytetrahydropyran-4yl) -4- (3,4-difluorobenzyl) -1methyl-1H-pyrrolo [2,3-L] pyridine-6-carboxamide ( isomer-1) Yu-NMR (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,60-1,62 (m, 1H), 1, 84-1,94 (m, 1H), 3,37-3 , 43 (m, 1H), 3.453.53 (m, 1H), 3.65 (m, 1H), 3.74-3.82 (m, 2H), 3.86 (s, 3H), 4, 02-4.07 (m, 1H), 4.30 (s, 2H), 5.28 (m, 1H), 6.69-6.69 (d, J = 3.4 Hz, 1H), 7 , 14 (m, 1H), 7.30-7.43 (m, 2H), 7, 69-7.70 (m, 2H),

- 54 035599

8.36-8.38 (d, J = 8.4 Hz, 1H); Mass (m / z): 401.9 (M + H) ⁺ . Chiral HPLC: 96.12%, Method: CHIRAL CANCER AD-H, 250 x 4.6 mm, 5 μm; Solvent A = 30.0% nheptane, B = 40.0% MeOH, 0 = 30.0% IPA, D = 0.10% DEA; Constant composition mobile phase flow rate = 0.7 ml / min; T = 25 ° C, retention time = 8.65 min, wavelength = 245 nm. 42 teY τι γτ F cis-N- (3 - hydroxytetrahydropyran-4yl) -4- (3,4-difluorobenzyl) -1methylTH-pyrrolo [2,3 - B] pyridine-6-carboxamide (isomer-II) T-NMR (flMCO-d _6, 4, 00 MHz) δ ppm .: 1, 60-1, 62 (m, 1H), 1.85-1.91 (m, 1H), 3,35-3 , 43 (m, 1H), 3.513.53 (m, 1H), 3.65 (m, 1H), 3.74-3.82 (m, 2H), 3.86 (s, 3H), 4, 02-4.07 (m, 1H), 4.30 (s, 2H), 5.26 (s, 1H), 6.69-6.69 (d, J = 3.3Hz, 1H), 7.147 , 14 (d, J = 2.0 Hz, 1H), 7.30-7.43 (m, 2H), 7.677.70 (m, 2H), 8.36-8.38 (d, J = 8 , 4 Hz, 1H); Mass (m / z): 402.0 (M + H) ⁺ . Chiral HPLC: 99.01%, Method: CHIRAL CANCER AD-H, 250 x 4.6 mm, 5 μm; Solvent A = 30.0% nheptane, B = 40.0% MeOH,

- 55 035599

C = 30.0% IPA, D = 0.10% DEA; Constant composition mobile phase flow rate = 0.7 ml / min; T = 25 ° C, retention time = 11.21 min, wavelength = 245 nm. 43 ⁿ he d? F trans-N- (3-hydroxytetrahydropyran-4yl) -4- (2,3-difluorobenzyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1) A-NMR (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,64-1,67 (m, 1H), 1,85-1,89 (m, 1H), 3, 00-3 , 07 (m, 2H), 3.61 (m, 1H), 3.79-3.85 (m, 3H), 3.93 (s, 3H), 4.37 (s, 2H), 4, 99 (s, 1H), 6, 63-6, 64 (d, J = 3.4 Hz, 1H), 7.14-7.20 (m, 2H), 7.30-7.33 (m, 1H), 7.60 (s, 1H), 7, 68-7, 69 (d, J = 3.3 Hz, 1H), 8.43-8.45 (d, J = 8.2 Hz, 1H ); Mass (m / z): 402.0 (M + H) ⁺ . Chiral HPLC: 95.96%, Method: CHIRAL CANCER AD-H, 250 x 4.6 mm, 5 μm; Solvent A = 30.0% nheptane, B = 40.0% MeOH, C = 30.0% IPA, D = 0.10% DEA; Constant composition mobile phase flow rate = 0.70 ml / min; T = 25 ° C, retention time = 6.82 min, wavelength = 245 nm.

- 56 035599

44 A? F trans-N- (3- hydroxytetrahydropyran-4yl) -4- (2,3-difluorobenzyl) -1methyl-1H-pyrrolo [2,3- B] pyridine-6-carboxamide (isomer-II) ^ -NMR (flMCO-d _6, 4, 00 MHz) δ ppm .: 1.65-1.68 (m, 1H), 1, 86-1, 88 (m, 1H), 3, 02-3 , 07 (m, 2H), 3.593.62 (m, 1H), 3.81-3.85 (m, 3H), 3.93 (s, 3H), 4.38 (s, 2H), 4, 99-5.00 (d, J = 5.6 Hz, 1H), 6.636.64 (d, J = 3.3 Hz, 1H), 7.15-7.19 (m, 2H), 7.307 , 32 (m, 1H), 7.60 (s, 1H), 7, 68-7, 69 (d, J = 3.3 Hz, 1H), 8.43-8.45 (d, J = 8 , l Hz, 1H); Mass (m / z): 402.0 (M + H) ⁺ . Chiral HPLC: 99.84%, Method: CHIRAL CANCER AD-H, 250 x 4.6 mm, 5 μm; Solvent A = 30.0% nheptane, B = 40.0% MeOH, 0 = 30.0% IPA, D = 0.10% DEA; Constant composition mobile phase flow rate = 0.70 ml / min; T = 25 ° C, retention time = 9.7 0 min, wavelength = 245 nm. 45 ... 0 / 'ύΆ' ^η t CHLE ⁿ on φ F Racemic cis-N- (3-hydroxytetrahydropyran-4- yl) -4- (2-fluoropyridine-4- ^ -NMR (DMSO-d _6, 4, 00 MHz) δ ppm:.. 1.62 (m, 1H), 1.90 (m, 1H), 3,43-3,43 (m, 2H), 3.57-3.58 (m, 1H), 3.66-3, 80 (m, 2H), 3.87 (m, 3H), 4.05 (m, 1H), 4.40 (s, 2H), 5.255.27 (d, J = 5.2 Hz, 1H),

- 57 035599

ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6carboxamide 6, 69-6, 70 (d, J = 3.3 Hz, 1H), 7.14 (s, 1H), 7.247.25 (m, 1H), 7.71-7.72 (d, J = 3.4 Hz, 1H), 7.75 (s, 1H), 8.11-8.12 (d, J = 5.12 Hz, 1H), 8.37-8.39 (d, J = 8 , 3 Hz, 1H); Mass (m / z): 385.0 (M + H) ⁺ . 46 \ II 0 ° VAA he \ p | F cis-N- (3- hydroxytetrahydropyran-4yl) -4- (2-fluoropyridine-4ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6carboxamide (isomer-1) ^ -NMR (DMSO-L ₆ 4 00 MHz) δ ppm .: 1,60-1,62 (m, 1H), 1, 88-1,92 (m, 1H), 3,41-3 , 46 (m, 2H), 3.53 (m, 1H), 3.66-3.78 (m, 2H), 3.87 (s, 3H), 4.05 (m, 1H), 4, 40 (s, 2H), 5.27-5.28 (d, J = 4.8 Hz, 1H), 6, 69-6, 69 (d, J = 3.2 Hz, 1H), 7.14 (s, 1H), 7.24-7.25 (d, J = 4.4 Hz, 1H), 7.70-7.71 (d, J = 3.2 Hz, 1H), 7.74 ( s, 1H), 8.11-8.12 (d, J = 5.0 Hz, 1H), 8.37-8.39 (d, J = 8.2 Hz, 1H); Mass (m / z): 385, 1 (M + H) ⁺ . Chiral HPLC: 99.97%, Method: CHIRAL CANCER IC, 250 x 4.6 mm, 5 μm; Solvent A = 60.0% nheptane, B = 30.0% ethanol, C = 10.0% IPA; Constant composition mobile phase flow rate = 0.70 ml / min; T = 25 ° C, time

- 58,035,599 retention = 16.43 min, wavelength = 245 nm.

Y-NMR (DMSO-SD, 400 MHz) δ ppm: 1.60-1.62 (m,

1H), 1.85-1.94 (m, 1H),

3.48-3.53 (m, 2H), 3.57- 3.58 (m, 1H), 3, 66- 3.82 (m, 2H), 3.87 (from, ZN), 4.05 (m, 1H), 4.40 (from, 2H), five, , 27-5 , 28 (d,

? Ύ ^Ν Κ ^Ν T CJUJ ⁿ on r F 47 CIS-N- (3 - hydroxytetrahydropyran-4yl) -4- (2-fluoropyridine-4ylmethyl) -1-methyl-1Hpyrrolo [2, 3-b] pyridine-6carboxamide (isomer-11)

J = 4.04 Hz, 1H), 6.696.69 (d, J = 3.04 Hz, 1H), 7.14 (s, 1H), 7.24-7.25 (d, J = 3.8 Hz, 1H), 7,707.71 (d, J = 3, 1 Hz, 1H),

7.74 (s, 1H), 8.11-8.12 (d, J = 5.0 Hz, 1H), 8.378.39 (d, J = 8.2 Hz, 1H);

Mass (m / z): 385.1 (M + H) ⁺ .

Chiral HPLC: 98.87%, Method: CHIRAL CANCER IC, 250 x 4.6 mm, 5 μm; Solvent A = 60.0% nheptane, B = 30.0% ethanol, C = 10.0% IPA; Constant composition mobile phase flow rate = 0.70 ml / min; T = 25 ° C, retention time = 18.43 min, wavelength = 245 nm.

48 bk V- О <0 BH ⁿ he Y-NMR (DMSO-CD, 4 00 MHz) δ ppm: 1.58-1.61 (m, 1H), 1.84 -1.93 (m, 1H), [1 J ^ 01 3.30-3.44 (m, 1H), 3.49-

- 59 035599

Racemic cis-N- (3- hydroxytetrahydropyran-4yl) -4- (2-chloropyridine-5ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6carboxamide 3.52 (m, 1H), 3.54-3.64 (m, 1H), 3.73-3.81 (m, 2H), 3.85 (s, 3H), 4.014.03 (m, 1H), 4.33 (s, 2H), 5, 22-5, 24 (d, J = 5.1 Hz, 1H), 6, 67-6, 68 (d, J = 3.4 Hz, 1H ), 7.23-7.25 (d, J = 7.8 Hz, 1H), 7.567.61 (m, 3H), 8.34-8.36 (d, J = 8.3 Hz, 1H) , 8.43 (s, 1H); Mass (m / z): 401.2 (M + H) ⁺ . 49 V'sA ' ¹ ? VHV ⁿ on cis-N- (3-hydroxytetrahydropyran-4yl) -4- (2-chloropyridine-5ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6carboxamide (isomer-1) T-NMR (DMSO-L ₆ 4 00 MHz) δ ppm:.. 1,59-1, 62 (m, 1H), 1.85 -1.93 (m, 1H), 3,39-3 , 45 (m, 1H), 3.503.53 (m, 1H), 3.55-3.65 (m, 1H), 3.75-3.82 (m, 2H), 3.87 (s, 3H ), 4.054.07 (m, 1H), 4.34 (s, 2H), 5.25-5.27 (d, J = 4.7 Hz, 1H), 6, 69-6, 70 (d, J = 2.5 Hz, 1H), 7.41-7.43 (d, J = 8, l Hz, 1H), 7.707.74 (m, 3H), 8.36-8.38 (d, J = 8, l Hz, 1H), 8.45 (s, 1H); Mass (m / z): 401.2 (M + H) ⁺ . Chiral HPLC: 99.83%, Method: CHIRAL CANCER IC, 2 50 x 4.6 mm, 5 μm; Solvent A = 30.0% nheptane, B = 40.0% ethanol, C = 30.0% IPA; Mobile phase flow rate s

- 60 035599

constant composition = 0.50 ml / min; T = 25 ° C, retention time = 17.02 min, wavelength = 245 nm. 50 ... o /% ΙΑΑ ⁿ on Ια cis-N- (3-hydroxytetrahydropyran-4yl) -4- (2-chloropyridine-5ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6carboxamide (isomer-11) ^ -NMR (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,59-1,62 (m, 1H), 1.85-1.91 (m, 1H), 3,40-3 , 45 (m, 1H), 3.503.53 (m, 1H), 3.55-3.65 (m, 1H), 3.75-3.82 (m, 2H), 3.87 (s, 3H ), 4.024.07 (m, 1H), 4.34 (s, 2H), 5, 25-5, 27 (d, J = 5.2 Hz, 1H), 6, 69-6, 70 (d, J = 3.3 Hz, 1H), 7.41-7.43 (d, J = 8.2 Hz, 1H), 1.107.75 (m, 3H), 8.36-8.38 (d, J = 8.3 Hz, 1H), 8.458.45 (d, J = 1, 8 Hz, 1H); Mass (m / z): 401.2 (M + H) ⁺ . Chiral HPLC: 93.41%, Method: CHIRAL CANCER IC, 250 x 4.6 mm, 5 μm; Solvent A = 30.0% nheptane, B = 40.0% ethanol, C = 30.0% IPA; Constant composition mobile phase flow rate = 0.50 ml / min; T = 25 ° C, retention time = 22.98 min, wavelength = 245 nm.

- 61 035599

51 “A · ¹ ? mLJ ^h oh V F trans-N- (3-hydroxytetrahydropyran-4yl) -4- (3,4-difluorobenzyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-1) ^ -NMR (flMCO-d _6, 4, 00 MHz) δ ppm .: 1,64-1,68 (m, 1H), 1, 87-1,89 (m, 1H), 3,02-3 , 08 (t, J = 10.4 Hz, 1H), 3.36-3.38 (m, 1H), 3.59-3.63 (m, 1H), 3.803.87 (m, 3H), 3.92 (s, 3H), 4.29 (s, 2H), 4.995.00 (d, J = 5.72 Hz, 1H), 6, 67-6, 68 (d, 1H, J = 3, 2 Hz), 7.14 (m, 1H), 7.297.41 (m, 2H), 7.67 (s, 2H), 8.43-8.45 (m, J = 8.15 Hz, 1H) ; Mass (m / z): 401.9 (M + H) ⁺ . Chiral HPLC: 95.32%, Method: CHIRAL CANCER AD-H, 250 x 4.6 mm, 5 μm; Solvent A = 30.0% nheptane, B = 40.0% MeOH, 0 = 30.0% IPA, D = 0.10% DEA; Constant composition mobile phase flow rate = 0.70 ml / min; T = 25 ° C, retention time = 7.04 min, wavelength = 245 nm. 52 ... 0 OUA VF trans-N- (3 - hydroxytetrahydropyran-4- yl) -4- (3,4-difluorobenzyl) -1- ^ -NMR (DMSO-d _6, 4, 00 MHz) δ ppm .: 1.62-1.68 (m, 1H), 1,70-1,72 (m, 1H), 3,05-3 , 08 (t, J = 10.4 Hz, 1H), 3.35-3.38 (m, 1H), 3.58-3.64 (m, 1H), 3.793.87 (m, 3H), 3.92 (s, 3H), 4.29 (s, 2H), 5.01

- 62 035599

methyl-1H-pyrrolo [2,3- B] pyridine-6-carboxamide (isomer-II) (br s, 1H), 6.67-6.68 (d, J = 3.4 Hz, 1H), 7.147.15 (m, 1H), 7.29-7.42 (m, 2H), 7.67 (s, 2H), 8.43-8.45 (m, J = 8.2 Hz, 1H); Mass (m / z): 402.0 (M + H) ⁺ . Chiral HPLC: 97.10%, Method: CHIRAL CANCER AD-H, 2 50 x 4.6 mm, 5 μm; Solvent A = 30.0% nheptane, B = 40.0% MeOH, C = 30.0% IPA, D = 0.10% DEA; Constant composition mobile phase flow rate = 0.70 ml / min; T = 25 ° C, retention time = 9.40 min, wavelength = 245 nm. 53 AND? Racemic trans-N- (3- hydroxytetrahydropyran-4yl) -4- [4- (thiazol-4yl) benzyl] -1-methyl-1Hpyrrolo [2,3-b] pyridine-6carboxamide Yu-NMR (DMSO-L ₆ 4 00 MHz) δ ppm .: 1,64-1,68 (m, 1H), 1, 86-1,89 (m, 1H), 3,02-3 , 07 (m, 1H), 3.343.36 (m, 1H), 3.61 (m, 1H), 3.78-3.85 (m, 3H), 3.92 (s, 3H), 4, 32 (s, 2H), 4.99-5.01 (d, J = 5.52 Hz, 1H), 6.676.69 (m, 1H), 7.36-7.38 (d, J = 8, 08 Hz, 2H), 7, 66-7, 68 (m, 2H), 7.89- 7.91 (d, J = 8.04 Hz, 2H), 8.09-8.09 (d, J = l, 40 Hz, 1H), 8.43-8.45 (d, J = 8.16 Hz, 1H), 9.16-

- 63 035599

9.16 (d, J = 1, 48 Hz, 1H); Mass (m / z): 449.3 (M + H) ⁺ . 54 ο Υο vLJ ^H i _H trans-N- (3-hydroxytetrahydropyran-4yl) -4- [4- (thiazol-4-yl) benzyl] T-methyl THpyrrolo [2,3-b] pyridine-6carboxamide (isomer-1) T-NMR (DMSO-dg, 4 00 MHz) δ ppm: 1.64-1.7 0 (m, 1H), 1.88-1.90 (m, 1H), 3.02-3 , 08 (m, 1H), 3, ΟδΟ, 38 (m, 1H), 3.60-3.64 (m, 1H), 3.81-3.84 (m, ZN), 3.92 (s , 3H), 4.32 (s, 2H), 4.99 (br s, 1H), 6, 67-6, 68 (d, J = 3.23 Hz, 1H), 7.36-7, 38 (d, J = 7.94 Hz, 2H), 7.66-7.67 (d, J = 3.26 Hz, 1H), 7.68 (s, 1H), 7.897.91 (d, J = 7.97 Hz, 2H), 8.08-8.09 (d, J = l, 74 Hz, 1H), 8.41-8.43 (d, J = 8.13 Hz, 1H), 9 , 16-9.16 (d, J = 1, 77 Hz, 1H); Mass (m / z): 449.3 (M + H) ⁺ . Chiral HPLC: 95.45%, Method: CHIRAL CANCER AD-H, 250 x 4.6 mm, 5 μm; Solvent A = 55.0% MeOH, B = 45.0% IPA, 0 = 0.10% DEA; Constant composition mobile phase flow rate = 0.50 ml / min; T = 25 ° C, retention time = 19.60 min, wavelength = 250 pt

- 64 035599

55 LUA Chl trans-N- (3 - hydroxytetrahydropyran-4yl) -4- [4- (thiazol-4yl) benzyl] -1-methyl-1Hpyrrolo [2,3-b] pyridine-6carboxamide (isomer-11) A-NMR (DMSO-L ₆ 4 00 MHz) δ ppm .: 1, 64-1,7 0 (m, 1H), 1, 88-1,90 (m, 1H), 3,02- 3.08 (m, 1H), 3, ΟδΟ, 38 (m, 1H), 3.60-3.64 (m, 1H), 3.81-3.84 (m, 3H), 3.92 ( s, 3H), 4.32 (s, 2H), 4.99 (br s, 1H), 6, 67-6, 68 (d, J = 3.23 Hz, 1H), 7.36-7 , 38 (d, J = 7.94 Hz, 2H), 7.66-7.67 (d, J = 3.26 Hz, 1H), 7.68 (s, 1H), 7.897.91 (d, J = 7.97 Hz, 2H), 8.08-8.09 (d, J = l, 74 Hz, 1H), 8.41-8.43 (d, J = 8.13 Hz, 1H), 9.16-9.16 (d, J = 1, 77 Hz, 1H); Mass (m / z): 449.3 (M + H) ⁺ . Chiral HPLC: 90.82%, Method: CHIRAL CANCER AD-H, 250 x 4.6 mm, 5 μm; Solvent A = 55.0% MeOH, B = 45.0% IPA, 0 = 0.10% DEA; Constant composition mobile phase flow rate = 0.50 ml / min; T = 25 ° C, retention time = 28.34 min, wavelength = 250 nm.

- 65 035599

56 VAXy 010 ⁿ on UA t> \ Racemic trans-N (3-hydroxytetrahydropyran4-yl) -4- [4- (1-methyl-1Hpyrazol-4-yl) benzyl] -1methyl-1H-pyrrolo [2,3b] pyridine -6-carboxamide ^ -NMR (DMSO-L ₆ 4 00 MHz) δ ppm .: 1,64-1,68 (m, 1H), 1, 87-1,90 (m, 1H), 3, 02-3 , 07 (m, 2H), 3.593.62 (m, 1H), 3.80-3.81 (m, 3H), 3.83 (s, 3H), 3.92 (s, 3H), 4, 26 (s, 2H), 4.99-5.01 (d, J = 5.76 Hz, 1H), 6.666.68 (m, 1H), 7.25-7.27 (d, J = 7, 98 Hz, 2H), 7.44-7.46 (d, J = 8.02 Hz, 2H), 7, 66-7, 67 (m, 2H), 7.78 (s, 1H), 8, 05 (s, 1H), 8.42-8.44 (d, J = 8.17 Hz, 1H); Mass (m / z): 446.3 (M + H) ⁺ . 57 \ trans-N- (3-hydroxytetrahydropyran-4yl) -4- [4- (1-methyl-1Hpyrazol-4-yl) benzyl] -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer -1) ^ -NMR (DMSO-L ₆ 4 00 MHz) δ ppm .: 1.61-1.71 (m, 1H), 1, 86-1,89 (m, 1H), 2,89-3 , 02 (m, 1H), 3.33 (m, 1H), 3.58-3.63 (m, 1H), 3.81 (m, 3H), 3.83 (s, 3H), 3, 92 (s, 3H), 4.26 (s, 2H), 5.00-5.01 (d, J = 5.72, 1H), 6.67-6.67 (d, J = 3.36 Hz, 1H), 7.25-7.27 (d, J = 7.92 Hz, 2H), 7.44-7.46 (d, J = 7.93 Hz, 2H), 7, 66 (s , 2H), 7.78 (s, 1H), 8.05 (s, 1H), 8.42-8.44 (d, J = 8.14 Hz, 1H); Mass (m / z): 446.3 (M + H) ⁺ . Chiral HPLC: 99.51%,

- 66 035599

Method: CHIRAL CANCER IC, 2 50 x 4.6 mm, 5 μm; Solvent A = 90.0% MeOH, B = 10.0% IPA, 0 = 0.10% DEA; Constant composition mobile phase flow rate = 0.80 ml / min; T = 25 ° C, retention time = 11.61 min, wavelength = 250 nm. 58 c-Lr ⁿ on ϊ N \ trans-N- (3 - hydroxytetrahydropyran-4yl) -4- [4- (1-methyl-1Hpyrazol-4-yl) benzyl] -1methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-II) ^ -NMR (DMSO-F ₆ 4 00 MHz) δ ppm .: 1, 61-1,71 (m, 1H), 1, 86-1,89 (m, 1H), 2,89-3 , 02 (m, 1H), 3.33 (m, 1H), 3.58-3.63 (m, 1H), 3.81 (m, 3H), 3.83 (s, 3H), 3, 92 (s, 3H), 4.26 (s, 2H), 5.00-5.01 (d, J = 5.72, 1H), 6.67-6.67 (d, J = 3.36 Hz, 1H), 7.25-7.27 (d, J = 7.92 Hz, 2H), 7.44-7.46 (d, J = 7.93 Hz, 2H), 7, 66 (s , 2H), 7.78 (s, 1H), 8.05 (s, 1H), 8.42-8.44 (d, J = 8.14 Hz, 1H); Mass (m / z): 446.3 (M + H) ⁺ . Chiral HPLC: 94.53%, Method: CHIRAL PAK 10, 250 x 4.6 mm, 5 μm; Solvent A = 90.0% MeOH, B = 10.0% IPA, 0 = 0.1% DEA; Constant composition mobile phase flow rate = 0.80

- 67 035599

ml / min; T = 25 ° C, retention time = 13, 14 min, wavelength = 250 nm. 59 sU /? τγ Racemic trans-N- (3- hydroxytetrahydropyran-4yl) -4- (4-methoxybenzyl) -1methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide ^ -NMR (CDCl ₃ , 400 MHz) δ ppm: 1.73-1.89 (m, 2H), 3.21-3.26 (m, 1H), 3.433.52 (m, 2H) , 3.65-3.66 (m, 1H), 3.76 (s, 3H), 3.89 (s, 3H), 4.00-4.08 (m, 2H), 4.22 (s , 2H), 4.65 (m, 1H), 6.46-6.47 (d, J = 3.24 Hz, 1H), 6.79-6.81 (d, J = 8.48 Hz, 2H), 7.13-7.15 (d, J = 8.46 Hz, 2H), 7.27 (s, 1H), 8.01 (s, 1H), 8.118.12 (d, J = 5 , 30 Hz, 1H); Mass (m / z): 396.45 (M + H) ⁺ . 60 ohhy? he IX trans-N- (3 - hydroxytetrahydropyran-4yl) -4- (4-methoxybenzyl) -1methyl-1H-pyrrolo [2,3- B] pyridine-6-carboxamide (isomer-1) ^ -NMR (flMCO-d _6, 4, 00 MHz) δ ppm .: 1,64-1,68 (m, 1H), 1, 86-1, 88 (m, 1H), 3, 05-3 , 07 (m, 1H), 3.583.64 (m, 1H), 3.69 (s, 3H), 3.81-3.83 (m, 4H), 3.91 (s, 3H), 4, 21 (s, 2H), 5.00-5.01 (d, J = 5.73 Hz, 1H), 6.64-6.65 (d, J = 3.31 Hz, 1H), 6, 83 -6.85 (d, J = 8.46 Hz, 2H), 7.91-7.21 (d, J = 8.53 Hz, 2H), 7.61 (s, 1H), 7, 64 - 7.65 (d, J = 3.34 Hz, 1H); 8.41-8.43 (d, J = 8.18 Hz, 1H);

- 68 035599

Weight (m / z): 396, 2 (M + H) ⁺ . Chiral HPLC: 98.31%, Method: CHIRAL CANCER AD-H 250 x 4.6 mm 5 microns; Solvent A = 70.0% MeON, B = 30.0% IPA, C = 0.10% DEA; Speed flow mobile phases with

constant composition = 0.70 ml / min; T = 25 ° C, retention time = 8.86 min, wavelength = 245 nm.

Ή-NMR (DMSO-L ₆ 4 00 MHz) \ j? jO? δ ppm: 1.64-1.68 (m, 1H), 1.86-1.88 (m, 1H), 3.05-3.07 (m, 1H), 3.583.64 (m, 1H), 3.69 (s, 3H), 3.81-3.83 (m, 4H), 3.91 (s, ZN), 4.21 (s, 4JLJ ⁿ he 2H), 5.00-5.01 (d, J = 5.73 Hz, 1H), 6.64- 6.65 (d, J = 3.31 Hz, 1H), trans-N- (3 - 6.83-6.85 (d, J = 8.46 Hz, hydroxytetrahydropyran-4- 2H), 7.91-7.21 (d, yl) -4- (4-methoxybenzyl) -1- J = 8.53 Hz, 2H), 7, 61 (s, methyl-1H-pyrrolo [2,3- 1H), 7, 64 -7, 65 (d, B] pyridine-6-carboxamide J = 3.34 Hz, 1H), 8.41- (isomer-11) 8.43 (d, J = 8.18 Hz, 1H); Mass (m / z): 396.2 (M + H) ⁺ . Chiral HPLC: 95.68%,

Method: CHIRAL CANCER AD-H 250 x 4.6 mm 5 microns; Solvent A = 70.0%

- 69 035599

MeOH, B = 30.0% IPA, C = 0.10% DEA; Constant composition mobile phase flow rate = 0.70 ml / min; T = 25 ° C, retention time = 11.36 min, wavelength = 245 nm. 62 V F trans-N- (3 - hydroxytetrahydropyran-4yl) -4- (3-fluorobenzyl) -1methyl-1H-pyrrolo [2,3- B] pyridine-6-carboxamide (isomer-1) F-NMR (flMCO-d _6, 4, 00 MHz) δ ppm .: 1,64-1,68 (m, 1H), 1, 86-1,89 (m, 1H), 3, 04-3 , 07 (m, 1H), 3.503.53 (m, 1H), 3.81-3.83 (m, 4H), 3.91 (s, 3H), 4.30 (s, 2H), 5, 03-5.04 (d, J = 5.64 Hz, 1H), 6, 67-6, 68 (d, J = 3.34 Hz, 1H), 7.02-7.04 (m, 1H) , 7.12-7.13 (m, 2H), 7.297.32 (m, 1H), 7.66 (s, 2H), 8.45-8.47 (d, J = 8.18 Hz, 1H ); Mass (m / z): 384.3 (M + H) ⁺ . Chiral HPLC: 99.66%, Method: CHIRAL CANCER AD-H 250 x 4.6 mm 5 μm; Solvent A = 100.0% MeOH, B = 0.10% DEA; Constant composition mobile phase flow rate = 0.80 ml / min; T = 25 ° C, retention time = 6.11 min, wavelength = 245 nm.

- 70 035599

63 q.MAXr 'LAD ⁿ on VF trans-N- (3-hydroxytetrahydropyran-4yl) -4- (3-fluorobenzyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide (isomer-II) ^ -NMR (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,64-1,68 (m, 1H), 1, 86-1,89 (m, 1H), 3,04-3 , 07 (m, 1H), 3.503.53 (m, 1H), 3.81-3.83 (m, 4H), 3.91 (s, 3H), 4.30 (s, 2H), 5, 03-5.04 (d, J = 5.64 Hz, 1H), 6, 67-6, 68 (d, J = 3.34 Hz, 1H), 7.02-7.04 (m, 1H) , 7.12-7.13 (m, 2H), 7.297.32 (m, 1H), 7.66 (s, 2H), 8.45-8.47 (d, J = 8.18 Hz, 1H ); Mass (m / z): 384.3 (M + H) ⁺ . Chiral HPLC: 99.72%, Method: CHIRAL CANCER AD-H 250 x 4.6 mm 5 μm; Solvent A = 100.0% MeOH, B = 0.10% DEA; Constant composition mobile phase flow rate = 0.80 ml / min; T = 25 ° C, retention time = 8.07 min, wavelength = 245 nm.

Example 64. Racemic cisA- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide _Λ A.

The title compound was prepared according to the experimental procedure outlined in Step 8 of Example 1 using cis-3-aminotetrahydropyran-4-ol hydrochloride (I-23).

Yield: 0.11 g;

Ή-NMR (DMSOA, 400 MHz) δ ppm: 1.50-1.52 (m, 1H), 1.88-1.91 (m, 1H), 3.15-3.25 (m , 1H), 3.35-3.50 (m, 1H), 3.65 (m, 1H), 3.75-3.86 (m, 2H), 3.90 (s, 3H), 4, 28 (s, 2H), 5.03-5.04 (d, J = 4.3 Hz, 1H), 6.66-6.67 (d, J = 3.2 Hz, 1H), 7.08 -7.12 (m, 2H), 7.31-7.34 (m, 2H), 7.64 (s, 1H), 7.67-7.68 (d, J = 3.3 Hz, 2H ), 8.31-8.33 (d, J = 7.1 Hz, 1H);

Mass (m / z): 384.3 (M + H) +.

Example 65. cis-A (4-Hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-I).

Yield: 0.056 g;

Ή-NMR (DMSOA, 400 MHz) δ ppm: 1.50-1.52 (m, 1H), 1.88-1.91 (m, 1H), 3.22-3.24 (m , 1H), 3.31-3.39 (m, 1H), 3.74-3.76 (m, 2H), 3.81-3.87 (m, 2H), 3.90 (s, 3H ), 4.28 (s, 2H), 5.03-5.04 (m, 1H), 6.66-6.67 (d, J = 3.3 Hz, 1H), 7.08-7, 12 (t, 2H), 7.31-7.34 (m, 2H), 7.64 (s, 1H), 7.67-7.68 (d, J = 3.4 Hz, 1H), 8 , 31-8.33 (d, J = 7.5 Hz, 1H);

Mass (m / z): 384.3 (M + H) +.

Chiral HPLC: 96.53%, Conditions: CHIRALPAK AD-H, 250x4.6 mm, 5 μm; Solvent A = 70.0% MEOH, B = 30.0% IPA, D = 0.10% DEA; Constant composition mobile phase flow rate = 0.6 ml / min; T = 25 ° C, retention time = 7.92 min, wavelength = 245 nm.

Example 66. hhc-N- (4-1 'hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1 -methyl-1 H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-II) ...

Yield: 0.046 g;

1H-NMR (DMSOA, 400 MHz) δ ppm: 1.50-1.52 (m, 1H), 1.88-1.91 (m, 1H), 3.14-3.24 (m , 1H), 3.37-3.42 (m, 1H), 3.75-3.81 (m, 2H), 3.84-3.87 (m, 2H), 3.90 (s, 3H ), 4.28 (s, 2H), 5.03-5.04 (d, J = 4.3 Hz, 1H), 6.66-6.67

- 71 035599 (d, J = 3.3 Hz, 1H), 7.08-7.12 (t, 2H), 7.31-7.34 (m, 2H), 7.64 (s, 1H) , 7.67-7.68 (d, J = 3.3 Hz, 1H), 8.31-8.33 (d,

J = 7.0 Hz, 1H);

Mass (m / z): 384.3 (M + H) +.

Chiral HPLC: 99.19%, Conditions: CHIRALPAK AD-H, 250x4.6 mm, 5 μm; Solvent A = 70.0% MEOH, B = 30.0% IPA, D = 0.10% DEA; Constant composition mobile phase flow rate = 0.6 ml / min; T = 25 ° C, retention time = 11.2 min, wavelength = 245 nm.

Examples 67, 68. Compounds of examples 67, 68 were obtained in accordance with the experimental procedure described in example 64, with some non-critical changes ._______________

Example No. Structure and IUPAC nomenclature Characteristic data 67 ⁿ on XI Racemic cis-N- (4-hydroxytetrahydropyran-3yl) -4- (4-methoxybenzyl) -1methyl-1H-pyrrolo [2,3 - L] pyridine-6-carboxamide A-NMR (DMSO, 400 MHz) δ ppm: 1.50-1.52 (m, 1H), 1.88-1.91 (d, J = ll, l, 1H), 3, 26-3.27 (m, 1H), 3.38-3.41 (m, 1H), 3.70 (s, 3H), 3.84 (s, 2H), 3.86 (s, 3H) , 3.90 (s, 2H), 4.2 (s, 2H), 5.03-5.04 (d, J = 4.43 Hz, 1H), 6, 65-6, 66 (d, J = 3.19 Hz, 1H), 6, 83-6, 85 (d, J = 8.33 Hz, 2H), 7.19-7.21 (d, J = 8.33 Hz, 2H), 7 , 61 (s, 1H), 7.66 (d, J = 3.19 Hz, 1H), 8.30-8.32 (d, J = 7.07 Hz, 1H); Mass (m / z): 396, 2 (M + H) ⁺ . 68 0 ⁿ on TX Racemic cis-N- (4-hydroxytetrahydropyran-3yl) -4- (2-methylpyridin-5ylmethyl) -1-methyl-1Hpyrrolo [2,3-L] pyridine-6carboxamide Mass (m / z): 381.3 (M + H) ⁺

Example 69 (^^) - H4-Hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1-methyl-Spirrolo [2,3-b] pyrudin-6-carboxyamide _ Λ

The title compound was prepared according to the experimental procedure outlined in Step 8 of Example 1, using commercially available (^ (()) - 3-aminotetrahydro-2H-pyran-4-ol.

¹ H-NMR (DMSO0, 400 MHz) δ ppm: 1.50-1.52 (m, 1H), 1.88-1.91 (m, 1H), 3.15-3.25 ( m, 1H), 3.35-3.50 (m, 1H), 3.65 (m, 1H), 3.75-3.86 (m, 2H), 3.90 (s, 3H), 4 , 28 (s, 2H), 5.03-5.04 (d, J = 4.3 Hz, 1H), 6.66-6.67 (d, J = 3.2 Hz, 1H), 7, 08-7.12 (m, 2H), 7.31-7.34 (m, 2H), 7.64 (s, 1H), 7.67-7.68 (d, J = 3.3 Hz, 2H), 8.31-8.33 (d, J = 7.1 Hz, 1H);

Mass (m / z): 384.2 (M + H) +.

Examples 70, 71. The compounds of examples 70-71 were prepared according to the experimental procedure described in example 69, with some non-critical changes.

- 72 035599

Example No. Structure and IUPAC nomenclature Characteristic data 70 hvA ⁿ one XV (3S, 4S) -N- (4-hydroxytetrahydropyran-3yl) -4- (4-methoxybenzyl) -1methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide ^ -NMR (DMSO-L ₆ 4 00 MHz) δ ppm .: 1,48-1,51 (m, 1H), 1, 85-1, 88 (m, 1H), 3,18-3 , 26 (m, 1H), 3.383.52 (m, 1H), 3.60 (m, 1H), 3.77-3.84 (m, 2H), 3.89 (s, 3H), 3, 95 (s, 3H), 4.26 (s, 2H), 5.045.05 (d, J = 4.3 Hz, 1H), 6, 65-6, 66 (d, 1H), 7.267.28 (d , 2H), 7.42-7.44 (d, 2H), 7.66 (s, 1H), 7, 68-7, 69 (d, J = 3.4 Hz, 2H), 8.30- 8.32 (d, J = 7.3

Hz, 1H); Mass (m / z): 396, 2 (M + H) ⁺ 71 V (3S, 4S) -N- (4- hydroxytetrahydropyran-3yl) -4- (2-methylpyridin-5ylmethyl) -1-methyl-1Hpyrrolo [2,3-L] pyridine-6carboxamide ^ -NMR (DMSO-L ₆ 4 00 MHz) δ ppm .: 1,51-1,53 (m, 1H), 1,82-1, 86 (m, 1H), 3,16-3 , 24 (m, 1H), 3.32 (s, 3H), 3.37-3.49 (m, 1H), 3.62 (m, 1H), 3.733.80 (m, 2H), 3, 86 (s, 3H), 4.32 (s, 2H), 5.015.03 (d, J = 4.3 Hz, 1H), 6.61-6.63 (d, 1H), 7.507.55 (m , 2H), 7.69 (s, 1H), 7.70-7.71 (d, J = 3.4 Hz, 2H), 7.80 (s, 1H), 8.28-8.30 ( d, J = 7.3 Hz, 1H); Mass (m / z): 381.3 (M + H) ⁺

Example 72. No. [(^^) - 2-Hydroxycyclohexyl] -4- (2-chloropyridin-5-ylmethyl) -1-methyl-2,3-dihydro1H-pyrrolo [2,3-b] pyridine-6-carboxamide

To a solution of No. [(^^) - 2-hydroxycyclohexyl] -4- (2-chloropyridin-5-ylmethyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide (example 18, 0.38 g, 0.0009 mol) in glacial acetic acid (25 ml) at 25 ° C, sodium cyanoborohydride (0.73 g, 0.0011 mol) was added in portions at 5-10 ° C and heated to room temperature and stirred for 48 including the Reaction mixture was concentrated to obtain a residual mass, which was quenched with ice water (50 ml), podslushivaet alkali solution pH ~ 9 and was extracted with dichloromethane (3x50 ml). The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using methanol: dichloromethane (1.5: 98.5) to afford the title in the connection header.

Yield: 0.15 g;

¹ H-NMR (DMSO ^, 400 MHz) δ ppm: 1.22-1.25 (m, 4H), 1.58-1.64 (m, 2H), 1.85-1.88 (m, 2H), 2.91 (s, 3H), 2.94-2.96 (t, 2H), 3.36-3.45 (m, 2H), 3.46-3.50 (t , 2H), 3.88 (s, 2H), 4.68-4.69 (d, J = 5.4 Hz, 1H), 6.97 (s, 1H), 7.44-7.46 ( d, J = 8.1 Hz, 1H), 7.66-7.69 (d, J = 2.2, 8.1 Hz, 1H), 8.07-8.09 (d, J = 7, 8 Hz, 1H), 8.33-8.33 (d, J = 2.0 Hz, 1H);

Mass (m / z): 400.9 (M + H) +.

- 73 035599

Examples 73-86. The compounds of Examples 73-86 were prepared from the corresponding compounds of the previous examples in accordance with the experimental procedures described in Example 72, with some non-critical changes.

Example No. Structure and IUPAC nomenclature Characteristic data 73 'ΝγΝγζ, χΟ ХЛХ ⁿ on V N- [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridin-4-ylmethyl) -1-methyl-2,3-dihydro-1H-pyrrole [2,3b] pyridine-6-carboxamide ¹ H-NMR (DMS0-F _6, 4, 00 MHz) δ ppm .: 1,22-1,24 (m, 4H), 1.58-1.64 (m, 2H), 1,85- 1.88 (m, 2H), 2.91 (s, 3H), 2.92- 2.96 (t, 2H), 3.36- 3.45 (m, 2H), 3.47- 3, 51 (t, 2H), 3.95 (s, 2H), 4, 68-4, 69 (d, J = 5.4 Hz, 1H), 7.00 (s, 1H), 7.05 (s , 1H), 7.18-7.19 (d, J = 4.7 Hz, 1H), 8.08-8.10 (d, J = 7.7 Hz, 1H), 8.14-8, 15 (d, J = 5.1 Hz, 1H); Mass (m / z): 385.0 (M + H) ⁺ . 74 ίγΧΟ XJXJ ⁴ bn Chp Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4 (2-fluoropyridine-5ylmethyl) -1-methyl-2,3 dihydro-ΙΗ-pyrrole [2,3 - b] pyridine-6- carboxamide Ή-ΗΜΡ (DMSO-sU, 4 00 MHz) δ ppm: 1.22-1.24 (m, 4H), 1.58-1.64 (m, 2H), 1.85-1, 90 (m, 2H), 2.91 (s, 3H), 2.93- 2.97 (t, 2H), 3.35- 3.45 (m, 2H), 3.46-3.48 ( t, 2H), 3.90 (s, 2H), 4.674.68 (d, J = 5.3 Hz, 1H), 6.98 (s, 1H), 7.05 (s, 1H), 7, 10-7.13 (d, J = 2.7.8.4 Hz, 1H), 8.07-8.09 (d, J = 7.8 Hz, 1H), 8, 15 (s, 1H) ; Mass (m / z): 385.0 (M + H) ⁺ . 75 OUJ ⁿ bn XX Ν - [(IS, 2S) -2hydroxycyclohexyl] -1methyl- (6-methylpyridine-Zylmethyl) -2,3-dihydro-1Hpyrrolo [2,3-b] pyridine-6carboxamide Ή-ΗΜΡ (DMSO-F _b , 4 00 MHz) δ ppm: 1.22-1.25 (m, 4H), 1.58-1.64 (m, 2H), 1.85-1 , 88 (m, 2H), 2.42 (s, 3H), 2.91 (s, 3H), 2.94-2.96 (t, 2H), 3.36-3.45 (m, 2H ), 3.46-3.49 (t, 2H), 3.82 (s, 2H), 4.67-4.69 (d, J = 5.4 Hz, 1H), 6.95 (s, 1H), 7.17-7.19 (d, J = 8.0 Hz, 1H), 7.44-7.46 (d, J = 8, l Hz, 1H), 8.07-8.09 (d, J = 7.8 Hz, 1H), 8.33 (s, 1H); Mass (m / z): 381.0 (M + H) ⁺ . 76 κχΧ? XXX ⁿ on N- [(13.23) -2-hydroxycyclohexyl] -4- Ή-ΗΜΡ (DMSO-sU, 4 00 MHz) δ ppm: 1.24-1.27 (m, 4H), 1.58-1.64 (m, 2H), 1.85- 1.91 (m, 2H), 2.90-2.95 (m, 5H), 3.45-3.49 (m, 4H), 3.84 (m, 2H), 4, 68-4, 69 (d, J = 5, 3 Hz, 1H), 6, 97 (s,

- 74 035599

(4-fluorobenzyl) -1-methyl- 2,3-dihydroTH- pyrrolo [2,3-b] pyridine-6carboxamide 1H), 7.10-7.14 (dd, J = 5.5, 8.0 Hz, 2H), 7.22-7.26 (dd, J = 5.5, 8.0 Hz, 2H), 8.078.09 (d, J = 7.7 Hz, 1H); Mass (m / z): 384.2 (M + H) ⁺ . 77 ⁿ he o N - [(IS, 2S) -2-hydroxycyclohexyl] -4 (4-methoxybenzyl) -1methyl-2,3-dihydro-1Hpyrrolo [2,3-b] pyridine-6carboxamide T-NMR (DMSO-T, 4 00 MHz) δ ppm: 1.23-1.30 (m, 4H), 1.58-1.64 (m, 2H), 1.85-1, 89 (m, 2H), 2.88-2.94 (m, 5H), 3.45-3.49 (m, 4H), 3.71 (s, 3H), 3.77 (s, 2H) , 4, 68-4, 69 (d, J = 5.4 Hz, 1H), 6, 84-6, 87 (d, J = 8.5 Hz, 2H), 6.98 (s, 1H), 7.107.12 (d, J = 8.5 Hz, 2H); 8.06-8.08 (d, J = 7.7 Hz, 1H); Mass (m / z): 396.1 (M + H) ⁺ . 78 bXQ VAX ⁿ on vX αχ Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4- (2'-fluoro- [2,5 '] bipyridinyl-5-ylmethyl) -1-methyl-2,3-dihydroTH -pyrrolo [2,3-b] pyridine-6-carboxamide T-NMR (DMSO-T, 40 MHz) δ ppm: 1.23-1.30 (m, 4H), 1.58-1.64 (m, 2H), 1.87-1, 91 (m, 2H), 2.92 (s, 3H), 2.97-3.01 (t, 2H), 3.33- 3.41 (m, 2H), 3.48-3.52 ( m, 2H), 3.91 (s, 2H), 4.674.69 (d, J = 5.3 Hz, 1H), 7.02 (s, 1H), 7.29-7.31 (dd, J = 2.2, 8.4 Hz, 1H), 7.74-7.76 (d, J = 8.0 Hz, 1H), 7.98-8.00 (d, J = 8.0 Hz, 1H), 8.08-8.09 (d, J = 7.7 Hz, 1H), 8.59-8.61 (d, J = 7.8 Hz, 2H), 8.89 (s, 1H ); Mass (m / z): 462.2 (M + H) ⁺ .

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79 z F N - [(IS, 2S) -2- hydroxycyclohexyl] -4 (2,3-difluorobenzyl) -1methyl-2,3-dihydro-1Hpyrrolo [2, 3-b] pyridine-6carboxamide ^ -NMR (DMSO-F _b , 4 00 MHz) δ ppm: 1.25-1.28 (m, 4H), 1.69-1.75 (m, 2H), 1.96 (m , 2H), 2.98 (s, 3H), 3.26- 3.27 (m, 2H), 3.47-3.48 (m, 1H), 3.50-3.52 (m, 1H ), 3.70-3.73 (m, 2H), 3.863.90 (m, 2H), 4.32 (br s, 1H), 6.89-6.91 (m, 1H), 6, 96-7.06 (m, 2H), 7.237.26 (s, 1H), 7.97-7.98 (br s, 1H); Mass (m / z): 402.1 (M + H) ⁺ . 80 {ALA ⁿ on Gn N - [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-methyl-4-pyridinylmethyl) -1-methyl- 2,3-dihydro-1H-pyrrolo [2, 3-b ] pyridine-6carboxamide ^ -NMR (DMSO-F _b , 4 00 MHz) δ ppm: 1.23-1.30 (m, 4H), 1.56-1.60 (m, 2H), 1.79-1 , 87 (m, 2H), 2.33 (s, 3H), 2.67 (s, 3H), 2.91-2.95 (m, 2H), 3.18-3.21 (m, 2H ), 3.32-3.35 (m, 1H), 3.48- 3.55 (m, 1H), 3.95 (s, 2H), 4.51-4.53 (d, J = 4 , 7 Hz, 1H), 6.79-6.81 (m, 1H), 7.09-7.14 (m, 2H), 7.61-7.63 (m, 1H), 8.01 ( broad s, 1H); Mass (m / z): 381.2 (M + H) ⁺ . 81 AALA ⁿ he χχ cis-N- (4-hydroxytetrahydropyran- ^ -NMR (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,47-1,50 (m, 1H), 1,83-1, 87 (m, 1H), 2.91 (s , 3H), 2.92-2.96 (t, 2H), 3.25-3.28 (m, 1H), 3.37-3.39 (m, 1H), 3.48-3.51 (t, 2H), 3.52-3.65 (m, 2H), 3.68-3.79 (m, 2H), 3.90 (s,

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3-yl) -4- (4-fluorobenzyl) - 1-methyl-2,3-dihydro-1Hpyrrolo [2,3-b] pyridine-6carboxamide (isomer-1) 2H), 5.00-5.03 (m, 1H), 7.08-7.14 (m, 2H), 7.317.34 (m, 2H), 7.64 (s, 1H), 8.31 -8.33 (d, J = 6.9 Hz, 1H); Mass (m / z): 386.1 (M + H) ⁺ . 82 ⁿ he V cis-N- (4-hydroxytetrahydropyran3-yl) -4- (4-fluorobenzyl) 1-methyl-2,3-dihydro-1Hpyrrolo [2,3-b] pyridine-6carboxamide (isomer-11) ^ -NMR (flMCO-d ₆ , 4 00 MHz) δ ppm : 1.47-1.50 (m, 1H), 1.83-1.91 (m, 1H), 2.91 (s, 3H), 2.92-2.96 (t, 2H), 3 , 16-3.22 (m, 1H), 3.36- 3.42 (m, 1H), 3.46-3.50 (t, 2H), 3.52-3.66 (m, 2H) , 3.69-3.78 (m, 2H), 3.90 (s, 2H), 5.00-5.03 (m, 1H), 7.08-7.14 (m, 2H), 7 , 31-7.34 (m, 2H), 7.64 (s, 1H), 8.31-8.33 (d, J = 6.9Hz, 1H); Mass (m / z): 386.0 (M + H) ⁺ . 83 ⁿ on Racemic cis-N- (4-hydroxytetrahydropyran3-yl) -4- (4methoxybenzyl) -1-methyl2, 3-dihydro-lH-pyrrolo [2,3-b] pyridine-6carboxamide ^ -NMR (DMSO, 400 MHz) δ ppm: 1.24-1.27 (m, 2H), 1.49-1.51 (m, 1H), 1.83- 1.87 (m, 1H), 3.33-3.37 (m, 1H), 3.38-3.39 (m, 1H), 3.48-3.50 (m, 2H), 3.66- 3.68 (m, 2H), 3.71 (s, 3H), 3.77 (s, 3H), 3.80-3.82 (m, 2H), 4.03 (s, 2H), 5.015 , 02 (d, J = 4.8 Hz, 1H), 6, 85-6.87 (d, J = 8.4 Hz, 2H), 6.97 (s, 1H), 7.117.13 (d, J = 8.2 Hz, 2H), 8.12-8.14 (d, J = 7.5 Hz, 1H); Mass (m / z): 398.3

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(M + H) ⁺ . 84 DDD ⁿ on Ό, (3S, 4S) -N- (4-hydroxytetrahydropyran3-yl) -4- (4-fluorobenzyl) 1-methyl-2,3-dihydro-1Hpyrrolo [2, 3-b] pyridine-6carboxamide Mass (m / z): 386.4 (M + H) ⁺ . 85 IMU ADU ⁿ he XX (3S, 4S) -N- (4-hydroxytetrahydropyran3-yl) -4- (4methoxybenzyl) -1-methyl2, 3-dihydro-lH-pyrrolo [2, 3-b] pyridine-6carboxamide Mass (m / z): 398.3 (M + H) ⁺ . 86 XX (3S, 4S) -N- (4- hydroxytetrahydropyran3-yl) -4- (2-methylpyridin5-ylmethyl) -1-methyl-2,3- Mass (m / z): 383.3 (M + H) ⁺ . dihydro-1H-pyrrolo [2,3- B] pyridine-6-carboxamide

Example 87. ^ [(^^) - 2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride

Stage 1. Ethyl 7- (tert-butoxycarbonyl) -4- (4-fluorobenzyl) -5,8-dihydro-6H- [1,7] naphthyridine-2 carboxylate

To a solution of ethyl 7- (tert-butoxycarbonyl) -4-chloro-5,8-dihydro-6H- [1,7] naphthyridine-2-carboxylate

- 78 035599 (0.2 g, 0.0005 mol, obtained in accordance with patent publication WO 2016/029454 A1), in dry THF (12 ml) under N2 atmosphere was added bis- (tri-tert-butylphosphine) palladium (0 ) (0.015 g, 0.000029 mol) and degassed for 5 min. 4-fluorobenzylzinc chloride (1.5 ml, 0.5 M in THF, 0.0007 mol) was stirred for 2 h, filtered through celite and washed with ethyl acetate (2x20 ml). The filtrate was concentrated in vacuo to give a residue, which was diluted with ethyl acetate (50 ml), washed with water (30 ml), brine (30 ml), and dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

Yield: 0.2 g;

Mass (m / z): 415.1 (M + H) +.

Stage 2.carboxylic acid

7- (tert-Butoxycarbonyl) -4- (4-fluorobenzyl) -5,8-dihydro-6H- [1,7] naphthyridine-2-

To a solution of tert-butyl

2-ethyl 4- (4-fluorobenzyl) -5,8-dihydro-6H- [1,7] naphthyridine-2.7 dicarboxylate (0.2 g, 0.0004 mol) in 1,4-dioxane (10 ml ) at 25 ° C, 10 ml of a saturated aqueous solution of lithium hydroxide (0.1 g, 0.002 mol) was added and stirred for 2 h. The reaction mass was concentrated in vacuo to obtain a residue, which was diluted with ice water (50 ml), acidified with 1N ... HCl, extracted with dichloromethane (3x50 ml). The organic layer was washed with saturated brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

Yield: 0.18 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 1.42 (s, 9H), 2.84 (m, 2H), 3.67 (m, 2H), 4.13 (s , 2H), 4.84 (m, 2H), 7.13-7.26 (m, 4H), 8.02 (s, 1H);

Mass (m / z): 387.0 (M + H) ⁺ .

Stage 3. tert-Butyl 4- (4-fluorobenzyl) -2- (2-hydroxycyclohexylcarbamoyl) -5,8-dihydro-6H [1,7] naphthyridine-7-carboxylate

The title compound was synthesized from 7- (tert-butoxycarbonyl) -4- (4-fluorobenzyl) 5,8-dihydro-6H- [1,7] naphthyridine-2-carboxylic acid following the procedure outlined in Step 8 of Example 1. The resulting crude compound was further purified by flash chromatography using methanol: dichloromethane (1:99) to provide the title compound.

Yield: 0.2 g;

¹ H-NMR (DMSO, 400 MHz) δ ppm: 1.23-1.32 (m, 4H), 1.42 (s, 9H), 1.60-1.64 (m, 2H) , 1.87-1.89 (m, 2H), 2.78 (m, 2H), 3.41-3.53 (m, 2H), 3.61 (m, 2H), 4.05 (s , 2H), 4.60 (m, 2H), 4.66 (m, 1H), 7.12-7.16 (m, 2H), 7.197.23 (m, 2H), 7.62 (s, 1H), 8.20-8.22 (d, J = 7.6 Hz, 1H);

Mass (m / z): 484.3 (M + H) ⁺ .

Stage 4. Hydrochloride # [(^^) - 2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide.

In tert-butyl 4- (4-fluorobenzyl) -2- (2-hydroxycyclohexylcarbamoyl) -5,8-dihydro-6H [1,7] naphthyridine-7-carboxylate, the protecting group was removed with IPA-HCl according to the procedure, described in Step 5 of Preparation 21 to give the title compound as a hydrochloride salt.

Yield: 0.08 g;

¹ H-NMR (DMSO, 400 MHz) δ ppm: 1.23-1.28 (m, 4H), 1.61-1.66 (m, 2H), 1.87-1.89 ( m, 2H), 2.96 (t, 2H), 3.39-3.44 (m, 2H), 3.61 (m, 2H), 4.10 (s, 2H), 4.36 (m , 3H), 7.14-7.18 (m, 2H), 7.21-7.24 (m, 2H), 7.78 (s, 1H), 8.19-8.21 (d, J = 8.0 Hz, 1H), 9.25 (br s, 2H);

Mass (m / z): 384.3 (M + H) ⁺ .

Examples 88-94. Compounds of examples 88-94 were prepared according to the experimental procedures described in example 87, with some non-critical changes.

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Example No. Structure and IUPAC nomenclature Characteristic data 88 89 HCI? --A Ek E HN AG Yu><cDD ⁿ en V1 Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4 (4-chlorobenzyl) -5,6,7,8 tetrahydro [1,7] naphthyridine -2 -carboxamide hydrochloride IP! £ ί] UU ⁿ en V Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4- (3-fluorobenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine -2-carboxamide hydrochloride Ή-NMR (DMSO; 400 MHz) δ ppm: 1.231.26 (m, 4H), 1.61-1.66 (m, 2H), 1.87 1.89 (m, 2H), 2.68 (s, 2H), 2.95 (m, 2H), 3.383.43 (m, 2H), 4.11 (s, 2H), 4.36-4.39 (m, 3H), 7 , 20-7.22 (d, J = 8, l Hz, 2H), 7.38-7.40 (d, J = 8.2 Hz, 2H), 7.80 (s, 1H), 8, 20-8.22 (d, J = 7.8 Hz, 1H), 9.19 (s, 2H); Mass (m / z): 400, 0 (M + H) ⁺ . Ή-NMR (DMSO; 400 MHz) δ ppm: 1.24 1.26 (m, 4H), 1.61-1.65 (m, 2H), 1.871.89 (m, 2H), 2 , 98 (s, 2H), 3.44 (m, 2H), 4.14 (m, 2H), 4.11 (s, 2H), 4.36 (m, 3H), 7.02-7, 09 (m, 2H), 7.37-7.38 (m, 2H), 7.79 (s, 1H), 8.218.23 (d, J = 7.9 Hz, 1H), 9.40 (br .s, 2H); Mass (m / z): 384.0 (M + H) ⁺ . 90 ^{ns |} ? ΓΊ ^Н ОХ »en CA 1 N Al \ N - [(IS, 2S) -2-hydroxycyclohexyl] -4 [4- (1-methyl-1H-pyrazol-4yl) benzyl] -5,6,7,8tetrahydro [ 1,7] naphthyridine -2-carboxamide hydrochloride Ή-NMR (DMSO; 400 MHz) δ ppm: 1.23-1.27 (m, 4H), 1.59-1.65 (m, 2H), 1.871.90 (m, 2H), 3.00 -3.01 (m, 2H), 3.39-3.44 (m, 4H), 3.84-3.86 (m, 3H), 4.08 (s, 2H), 4, 36438 (m, 3H), 7.15-7.17 (d, J = 8.0 Hz, 2H), 7.497.51 (d, J = 8.0 Hz, 2H), 7.81-7.82 (d, J = 1, 2 Hz, 2H), 8.09 (s, 1H), 8.208.22 (d, J = 8.0 Hz, 1H), 9.32 (brs, 2H); Mass (m / z): 446, 0 (M + H) ⁺ . 91 ⁿ aU ^m bn tu Ν - [(IS, 2S) -2hydroxycyclohexyl] -4 (2-fluoropyridine-5- Ή-NMR (DMSO; 400 MHz) δ ppm: 1.24 1.26 (m, 4H), 1.59-1, 66 (m, 2H), 1.87 -1.99 (m, 2H), 2.97-3.00 (s, 2H), 3.36-3.44 (m, 2H), 3.52-3.54 (m, 2H), 4.16 (s, 2H), 4.36 (m, 3H), 7.16-7.18 (m, 1H),

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ylmethyl) -5,6,7,8- tetrahydro [1,7] naphthyridine -2-carboxamide hydrochloride 7.77-7.81 (m, 2H), 8.12 (s, 1H), 8.21-8.23 (d, J = 7.9 Hz, 1H), 9.29 (br s, 2H); Mass (m / z): 385.0 (M + H) ⁺ . 92 HCI μ (А ην VU ^Н 0н N - [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-methoxybenzyl) - 5, 6,7,8-tetrahydro [1,7] naphthyridine -2-carboxamide hydrochloride U-HMP (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,22-1,25 (m, 4H), 1, 60-1, 65 (m, 2H), 1.86 -1 , 88 (m, 2H), 2, ΟδΟ, 01 (m, 2H), 3.35-3.39 (m, 2H), 3.54-3.56 (m, 2H), 3.72 (s , 3H), 4.01 (s, 2H), 4.32 4.34 (brs, 3H), 6.88-6.90 (d, J = 8.4 Hz, 2H), 7.097.11 (d, J = 8.3 Hz, 2H), 7.74 (s, 1H), 8.20-8.22 (d, J = 8.0 Hz, 1H), 9.46 (br s, 2H); Mass (m / z): 396.1 93 94 ^{ns |} ? (L OU ⁿ δΗ V Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4- (2-fluoropyridin-4-ylmethyl) -5, 6,7,8-tetrahydro [1,7] naphthyridine -2- carboxamide hydrochloride ^hci if ΑΊ λ .gsh AAJ ™ Ag π VAA ^H on Ν - [(IS, 2S) -2-hydroxycyclohexyl] -4- (4-pyrazol-1-ylbenzyl) - 5, 6,7,8-tetrahydro [1,7] naphthyridine -2-carboxamide hydrochloride i-NMR (DMSO-F _6L 4 00 MHz) δ ppm: 1.23-1.25 (m, 4H), 1.62-1, 66 (d, 2H), 1.88-1, 91 (d, 2H), 2, Οδ- Ο, 96 (t, 2H), 3.50-3.54 (m, 2H), 3.56-3.58 (m, 2H), 4.24 ( s, 2H), 4.37 (m, 3H), 6.98 (s, 1H), 7.15-7.17 (d, J = 4.7 Hz, 1H), 7.87 (s, 1H ), 8.188.19 (d, J = 5.1 Hz, 1H), 8.23-8.25 (d, J = 8.0 Hz, 1H), 9.33 (brs, 2H); Mass (m / z): 385.2 (M + H) ⁺ . i-NMR (DMSO-SD, 400 MHz) δ ppm: 1.24-1.26 (m, 4H), 1.61-1.65 (m, 2H), 1.87 -1, 89 (m, 2H), 3.003.02 (m, 2H), 3.39-3.44 (m, 2H), 4.15 (m, 2H), 4.11 (s, 2H), 4.36 (m, 3H), 6.53 (s, 1H), 7.297.31 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H), 7.78-7.80 (d, J = 8.3 Hz, 2H), 7.82 (s, 1H), 8.21-8.23 (d, J = 8.0 Hz, 1H), 8.47-8.47 (d, J = 2.0 Hz, 1H), 9.35 (br s, 2H); Mass (m / z): 432.5 (M + H) ⁺ .

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Example 95. N - [(1S.2S) -2-l Chdroxy11I1k1Ohexyl] -4- (4-fluorobe113yl) -7-methyl-5.6.7. (8tetrahydro [1,7] naphthyridine-2-carboxamide

Stage 1. N - [(1S.2S) -2-l A'1roxy11I1k1Ohexyl] -4- (4-fluorobe113yl) -5.6.7. (8-tetrahydro [1.7] 11aphthyridi112-carboxamide

In tert-butyl 4- (4-fluorobenzyl) -2- (2-hydroxycyclohexylcarbamoyl) -5,8-dihydro-6H [1,7] naphthyridine-7-carboxylate, the protecting group was removed using IPA-HCl according to the procedure, described in step 5 of preparation 21, was podslushivaet aqueous ammonia solution to pH ~ 9 and was extracted with dichloromethane (3x50 ml). The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

Yield: 0.05 g;

^X H-NMR (DMSO-06, 400 MHz) δ ppm: 1.24-1.27 (m, 4H), 1.59-1.64 (m, 2H), 1.87-1, 90 (m, 2H), 2.67-2.68 (m, 2H), 2.98-2.99 (m, 2H), 3.35-3.38 (m, 2H), 3.93 ( s, 2H), 4.01 (s, 2H), 4.67-4.68 (d, J = 5.5 Hz, 1H), 7.12-7.22 (m, 4H), 7.59 (s, 1H), 8.12-8.14 (d, J = 8.0 Hz, 1H);

Mass (m / z): 384.1 (M + H) +.

Step 2. No. [(^^) - 2-Hydroxycyclohexyl] -4- (4-fluorobenzyl) -7-methyl-5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide.

To a solution of No. [(^^) - 2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (0.034 g, 0.00008 mol) in 1,2-dichloroethane (5 ml) at 25 ° C paraformaldehyde (0.0034 g, 0.00001 mol), glacial acetic acid (0.008 ml, 0.00013 mol) were added and stirred for 2 h. Sodium triacetoxyborohydride was added (0.056 g, 0.00026 mol) and stirred overnight. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3x50 ml). The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using methanol: dichloromethane (5:95) to give the title compound.

Yield: 0.012 g;

Ή-NMR (DMSO-a6, 400 MHz) δ ppm: 1.23-1.26 (m, 4H), 1.59-1.64 (m, 2H), 1.88-1.91 (m, 2H), 2.36 (s, 3H), 2.67 (m, 2H), 2.78 (m, 2H), 3.34-3.44 (m, 2H), 3.53 ( s, 2H), 4.02-4.16 (m, 2H), 4.67-4.69 (d, J = 5.3 Hz, 1H), 7.13-7.24 (m, 4H) , 7.59 (s, 1H), 8.12-8.14 (d, J = 7.8 Hz, 1H);

Mass (m / z): 398.1 (M + H) +.

Example 96: No. [(^^) - 2-Hydroxycyclohexyl] -4- (4-fluorobenzyl) -7-ethyl-5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide

The title compound was synthesized from # [(^^) - 2-hydroxycyclohexyl] -4- (4fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide following the procedure outlined in Step 2 of Example 95 using acetaldehyde instead of paraformaldehyde. The resulting crude compound was further purified by flash chromatography using methanol: dichloromethane (4:96).

Yield: 0.014 g;

Ή-NMR (DMSO ^ 6, 400 MHz) δ ppm: 1.23-1.26 (m, 4H), 1.28-1.32 (t, 3H), 1.59-1.64 (m, 2H), 1.87-1.90 (m, 2H), 2.42-2.48 (m, 2H), 2.67 (m, 2H), 2.78 (m, 2H), 3.34-3.43 (m, 2H), 3.51 (s, 2H), 4.35-4.41 (t, 2H), 4.674.69 (d, J = 5.3 Hz, 1H) , 7.12-7.22 (m, 4H), 7.58 (s, 1H), 8.12-8.14 (d, J = 7.8 Hz, 1H);

Mass (m / z): 412.0 (M + H) +.

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Example 97. Trans-M- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] 5,6,7,8-tetrahydro [1,7] naphthyridine-2- hydrochloride carboxamide (isomer-II)

Stage 1. Ethyl 7- (tert-butoxycarbonyl) -4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -5,8 dihydro-6H [1,7] naphthyridine -2-carboxylate

To a solution of ethyl 7- (tert-butoxycarbonyl) -4-chloro-5,8-dihydro-6H- [1,7] naphthyridine-2-carboxylate (1.0 g, 0.003 mol) obtained in accordance with the patent WO 2016 / 029454 A1), bis- (pinacolato) dibor (1.1 g, 0.004 mol) and 1,1-bis dichloride complex were added in 1,4-dioxane (20 ml) in a sealed vessel under N ₂ at 25 ° C. - (diphenylphosphino) ferrocene palladium (II) with dichloromethane (0.24 g, 0.0003 mol) and potassium acetate (1.0 g, 0.011 mol). The reaction mixture was heated at 120 ° C for 22 h, cooled to room temperature, diluted with ethyl acetate (50 ml), filtered through a pad of celite and washed with ethyl acetate (50 ml x 2). The filtrate was concentrated in vacuo to provide the title compound.

Yield: 2.5g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 1.15 (s, 12H), 1.29-1.34 (t, 3H), 1.43 (s, 9H), 3 , 07 (m, 2H), 3.593.60 (m, 2H), 4.34-4.36 (q, 2H), 4.59 (m, 2H), 7.94 (s, 1H);

Mass (m / z): 433.1 (M + H) +.

Stage 2. Ethyl 7- (tert-butoxycarbonyl) -4- [4- (thiazol-4-yl) benzyl] -5,8-dihydro-6H-

[1,7] naphthyridine-2-carboxylate

To a solution of ethyl 7- (tert-butoxycarbonyl) 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -5,8 dihydro-6H- [1,7] naphthyridine- 2-carboxylate (0.4 g, 0.0009 mol) in THF (18 ml) under N2, 4- (4-bromomethylphenyl) thiazole (I-14, 0.3 g, 0.0012 mol), cesium carbonate was added (0.9 g, 0.0027 mol) and degassed for 10 min. Then bis- (tri-tert-butyl phosphine) palladium (0) (0.094 g, 0.00018 mol) was added. The reaction mixture was slowly warmed to 40 ° C over 4 h, cooled to room temperature, filtered through celite and washed with ethyl acetate (2 x 20 ml). The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (30:70) to give the title compound.

Yield: 0.1 g;

¹ H-NMR (DMSO-d ^ 400 MHz) δ ppm: 1.29-1.31 (t, 3H), 1.41-1.43 (m, 9H), 2.67 (m, 2H), 2.81 (t, 2H), 4.11 (s, 2H), 4.30-4.32 (q, 2H), 4.58 (m, 2H), 7.25-7.27 (d, J = 7.9 Hz, 2H), 7.72 (s, 1H), 7.93-7.95 (d, J = 8.0 Hz, 2H), 8.13-8.14 ( m, J = 1.4 Hz, 1H), 9.24 (m, 1H);

Mass (m / z): 480.1 (M + n) ⁺ .

Step 3. 7- (tert-Butoxycarbonyl) -4- [4- (thiazol-4-yl) benzyl] -5,8-dihydro-6H- [1,7] naphthyridine-2carboxylic acid

Ethyl 7- (tert-butoxycarbonyl) -4- [4- (thiazol-4-yl) benzyl] -5,8-dihydro-6H- [1,7] naphthyridine-2carboxylate was converted to 7- (tert-butoxycarbonyl) - 4- [4- (thiazol-4-yl) benzyl] -5,8-dihydro-6H- 83 035599

[1,7] naphthyridine-2-carboxylic acid according to the procedure described in step 2 of Example 87.

Yield: 0.05 g;

¹ H-NMR (DMSO-ds, 400 MHz) δ ppm: 1.41 (s, 9H), 2.81 (m, 2H), 3.62 (m, 2H), 4.09 (s , 2H), 4.58 (m, 2H), 7.26-7.27 (d, J = 7.6 Hz, 2H), 7.67 (s, 1H), 7.93-7.95 ( d, J = 7.8 Hz, 2H), 8.13 (s, 1H), 9.18 (s, 1H).

Step 4.trans tert-Butyl 2- (3-hydroxytetrahydropyran-4-ylcarbamoyl) -4- [4- (thiazol-4yl) benzyl] -5,8-dihydro-6H- [1,7] naphthyridine-7-carboxylate (isomer-II)

The title compound was synthesized from 1- (tert-butoxycarbonyl) -4- [4- (thiazol-4yl) benzyl] -5,8-dihydro-6H- [1,7] naphthyridine-2-carboxylic acid according to the procedure described in Step 3 of Example 87 using trans-4-aminotetrahydropyran-3-ol hydrochloride (isomer-II, I-22). The resulting crude compound was further purified by flash chromatography using methanol: dichloromethane (3:97).

Yield: 0.05 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 1.41-1.43 (s, 9H), 1.55-1.62 (m, 1H), 1.65-1, 88 (m, 1H), 2.81 (m, 2H), 3.42-3.62 (m, 4H), 3.78-3.80 (m, 4H), 4.10 (s, 2H) , 4.63 (s, 2H), 4.78 (m, 1H), 7.24-7.26 (d, J = 8.1 Hz, 2H), 7.69 (s, 1H), 7, 93-7.95 (d, J = 8.0 Hz, 2H), 8.12-8.13 (m, J = 1.7 Hz, 1H), 8.41-8.43 (d, J = 8.0 Hz, 1H), 9.18-9.19 (s, J = 1.5 Hz, 1H);

Mass (m / z): 550.9 (M + H) +.

Stage 5.trans-03-Hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer- II).

In trans tert-butyl 2- (3-hydroxytetrahydropyran-4-ylcarbamoyl) -4- [4- (thiazol-4-yl) benzyl] -5,8 dihydro-6H- [1,7] naphthyridine-7-carboxylate (isomer -II) removed the protecting group with IPA-HCl following the procedure outlined in Step 4 of Example 87 to provide the title compound.

Yield: 0.04 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 1.58-1.62 (m, 1H), 1.65-1.88 (m, 1H), 2.99-3, 03 (m, 2H), 3.37-3.57 (m, 4H), 3.78-63.82 (m, 4H), 4.15 (s, 2H), 4.38 (m, 2H) , 4.39 (s, 1H), 7.26-7.28 (d, J = 8.0 Hz, 2H), 7.85 (s, 1H), 7.94-7.96 (d, J = 8.0 Hz, 2H), 8.13-8.14 (d, J = 1.7 Hz, 1H), 8.41-8.43 (d, J = 8.3 Hz, 1H), 9 , 18-9.19 (d, J = 1.4 Hz, 1H), 9.21 (brs, 2H);

Mass (m / z): 450.9 (M + H) +.

Example 98, 99 The compounds of Examples 98 and 99 were prepared according to the experimental procedure described in Example 97, with some non-critical modifications.

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Example No. Structure and IUPAC nomenclature Characteristic data 98 Ά .O Su V IX trans-N- (3- hydroxytetrahydropyran- 4-yl) -4- (4-fluorobenzyl) - 5, 6,7,8- tetrahydro [1,7] naphthyridine n-2-carboxamide hydrochloride (isomer-11) T-NMR (DMSO-B ₆ 4 00 MHz) δ ppm:.. 1,59-1,63 (m, 1H), 1,79- 1,83 (m, 1H), 2,96-2 , 98 (t, 2H), 3.00-3.05 (m, 2H), 3.42-3.59 (m, 2H), 3.78- 3.83 (m, 4H), 4.10 (s, 2H), 4.36 (m, 3H), 7.14-7.19 (m, 2H), 7.21-7.24 (m, 2H), 7.79 (s, 1H), 8.40-8.42 (d, J = 8.3 Hz, 1H), 9.26 (brs, 2H); Mass (m / z): 386, 0 (M + H) ⁺ . 99 md ^ ^HC1, C1 O ^N A N Y trans-N- (3 - gidroksitetragidropiran4-yl) -4- (4-pirazolTilbenzil) -5,6,7,8-tetrahydro- [1,7] naftiridi n-2-carboxamide hydrochloride (isomer-11) T-NMR (DMSO-SD, 4 00 MHz) δ ppm: 1.58-1.67 (m, 1H), 1.80-1.84 (m, 1H), 3.003.05 (m, 2H), 3.30 -3.33 (m, 2H), 3.55-3.59 (m, 2H), 3.78-3.83 (m, 4H), 4.15 (s, 2H) , 4.35-4.37 (m, 3H), 6.53 (s, 1H), 7.30-7.32 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H ), 7.78-7.83 (d, J = 8.3 Hz, 2H), 7.83 (s, 1H), 8.41-8.43 (d, J = 8.3 Hz, 1H) , 8.46-8.47 (d, J = 2.2 Hz, 1H), 9.41 (brs, 2H); Mass (m / z): 434.2 (M + H) ⁺ .

Examples 100-102. The compounds of Examples 100 and 102 were prepared according to the experimental procedure described in Step 8 of Example 1 using cis-3-aminotetrahydropyran-4-ol hydrochloride (I23), followed by preparative chiral HPLC separation.

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Example No. Structure and name by IUPAC nomenclature Characteristic data one hundred on ν A XX OCU E XX cis-N- (4- hydroxytetrahydropyran-3-yl) 4- (4-fluorobenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride (isomer-1) ^ -NMR (flMCO-d _6, 4, 00 MHz) δ ppm .: 1,48-1,50 (m, 1H), 1,85-1,88 (m, 1H), 2.98 (m , 2H), 3.183.20 (m, 2H), 3.43- 3.45 (m, 2H), 3.62 (m, 2H), 3.80-3.82 (m, 2H), 4, 10 (s, 2H), 4.37 (m, 3H), 7.14-7.24 (m, 4H), 7.79 (s, 1H), 8.28-8.30 (d, J = 6.6 Hz, 1H), 9.24 (br s, 2H); Mass (m / z): 386.1 (M + H) ⁺ . 101 UU ⁿ OH cis-N- (4-hydroxytetrahydropyran-3-yl) 4- (4-fluorobenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride (isomer-II) ^ -NMR (DMSO-d _6, 4, 00 MHz) δ ppm .: 1,47-1,50 (m, 1H), 1,85-1,88 (m, 1H), 2.98 (m , 2H), 3.16-3.20 (m, 2H), 3.42-3.46 (m, 2H), 3.71 (m, 2H), 3.80-3.82 (m, 2H ), 4.10 (s, 2H), 4.37 (m, 3H), 7.14-7.24 (m, 4H), 7.79 (s, 1H), 8.288.30 (d, J = 6, 8 Hz, 1H), 9.21 (brs,

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2H); Mass (m / z): 386, 1 (M + H) ⁺ . about ^ -NMR (flMCO-d _6, 4, 00 MHz) δ ppm .: 1.41-1.51 (m, 1H), 1,85-1,88 (m, 1H), 2,99-3 , 00 (m, 2H), 3.14-3.21 (m, τγΑ-0 2H), 3.35-3.45 (m, ⁿ he 1H), 3.71 (m, ZN), TSE 3.80-3.82 (m, 2H), V-na, 4.16 (s, 2H), 4.36- 102 4.38 (m, ZN), 6.54 (s, Racemic cis-N- (4- 1H), 7.29-7.31 (d, hydroxytetrahydropyran-3-yl) - J = 8.3 Hz, 2H), 7.73 4- (4-pyrazol-1-ylbenzyl) - 5, 6,7,8- (s, 1H), 7.78-7.81 (d, J = 8.3 Hz, 2H), 7.85 tetrahydro [1,7] naphthyridine-2- (s, 1H), 8.29-8.30 (d, carboxamide hydrochloride J = 6.9 Hz, 1H), 8.468.47 (d, J = 1, 8 Hz, 1H), 9.41 (br s, 2H); Mass (m / z): 434.2 (M + H) ⁺ .

Example 103. No. [(^^) - 2-Hydroxycyclohexyl] -8- (4-fluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3b] pyridine-6-carboxamide

Stage 1. 2,3-Dihydro [1,4] dioxino [2,3-b] pyridine

A solution of 2,3-dihydroxypyridine (10.0 g, 0.09 mol) in acetonitrile (200 ml) under N2 at 25 ° C was added potassium carbonate (99.4 g, 0.72 mol), 1-bromo-2 β-chloroethane (25.7 g, 0.18 mol), sodium iodide (1.3 g, 0.009 mol) and heated to 100 ° C for 20 h. The reaction mixture was filtered through celite and washed with ethyl acetate (2x50 m). The filtrate was concentrated in vacuo to give the title compound.

Yield: 6.9 g;

1H-NMR (DMSO-de, 400 MHz) δ ppm: 4.22-4.24 (d, 2H), 4.37-4.39 (d, 2H), 6.90-6.95 (m, 1H), 7.26-7.28 (d, J = 0.9, 7.8 Hz, 1H), 7.72-7.73 (d, J = 1.0, 4.4 Hz , 1H);

Mass (m / z): 137.9 (M + H) +.

Stage 2. 2,3-Dihydro [1,4] dioxino [2,3-b] pyridine-5-oxide

The title compound was synthesized from 2,3-dihydro [1,4] dioxino [2,3-b] pyridine following the procedure outlined in Step 1 of Example 1.

Yield: 3.6 g;

1H-NMR (DMSO-dfc 400 MHz) δ ppm: 4.31-4.33 (dd, J = 2.3, 7.9 Hz, 2H), 4.50-4.52 (dd, J = 3.6, 7.9 Hz,

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2H), 6.85-6.89 (d, J = 8.2 Hz, 1H), 6.93-6.95 (d, J = 8.3 Hz, 1H), 7.83-7.85 (d, J = 6.4 Hz, 1H);

Mass (m / z): 154.0 (M + H) +.

Stage 3. 8-Chloro-2,3-dihydro [1,4] dioxino [2,3-b] pyrvdin

Phosphorus oxychloride (45 ml, 8 vol) was added to 2,3-dihydro [1,4] dioxino [2,3-b] pyridine-5oxide (3.5 g, 0.02 mol) under N2 at 0 ° C and then heated to 100 ° C for 7 hours. The reaction mixture was concentrated in vacuo to give the residual compound, which was neutralized with saturated sodium bicarbonate solution pH ~ 8 and was extracted with dichloromethane (3x100 ml). The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (25:75) to give the title compound.

Yield: 1.9 g;

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 4.35-4.36 (d, J = 2.1, 4.1 Hz, 2H), 4.44-4.45 ( d, J = 1.4, 4.0 Hz, 2H), 7.12-7.14 (d, J = 5.2 Hz, 1H), 7.69-7.70 (d, J = 5, 2 Hz, 1H);

Mass (m / z): 171.9 (M + H) +.

Step 4. 8-Chloro-2,3-dihydro [1,4] dioxino [2,3-b] pyridine 5-oxide

The title compound was synthesized from 8-chloro-2,3-dihydro [1,4] dioxino [2,3EDpyridine] following the procedure outlined in Step 1 of Example 1.

Yield: 1.9 g;

¹ H-NMR (DMSO-dg, 400 MHz) δ ppm: 4.43-4.44 (d, J = 2.0, 4.2 Hz, 2H), 4.55-4.56 ( d, J = 2.6, 4.1 Hz, 2H), 7.12-7.14 (d, J = 7.1 Hz, 1H), 7.87-7.89 (d, J = 7, 1 Hz, 1H);

Mass (m / z): 188.0 (M + H) +.

Step 5. 8-Chloro-2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carbonitrile

The title compound was synthesized from 8-chloro-2,3-dihydro [1,4] dioxino [2,3EDpyridine] following the procedure outlined in Step 2 of Example 1.

Yield: 1.6 g;

¹ H-NMR (DMSO ^ ₆ , 400 MHz) δ ppm: 4.47-4.54 (m, 4H), 7.97 (s, 1H);

Mass (m / z): 197.0 (M + H) +.

Step 6. 8-Chloro-2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylic acid

The title compound was synthesized from 8-chloro-2,3-dihydro [1,4] dioxino [2,3EDpyridine-6-carbonitrile using the procedure outlined in Step 3 of Example 1.

Yield: 1.2g;

¹ H-NMR (DMSO-dfo 400 MHz) δ ppm: 4.44-4.51 (m, 4H), 7.71 (s, 1H), 13.17 (s, 1H);

Mass (m / z): 216.0 (M + H) +.

Stage 7. Methyl 8-chloro-2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylate

The title compound was synthesized from 8-chloro-2,3-dihydro [1,4] dioxino [2,3EDpyridine-6-carboxylic acid according to the procedure outlined in Step 4 of Example 1 using potassium carbonate as base. and the reaction mixture was stirred overnight at 25 ° C.

Yield: 1.2g;

¹ H-NMR (DMSOL, 400 MHz) δ ppm: 3.83 (s, 3H), 4.45-4.52 (m, 4H), 7.76 (s, 1H);

Mass (m / z): 230.0 (M + H) +.

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Stage 8. Methyl 8- (4-fluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylate

The title compound was synthesized from methyl 8-chloro-2,3-dihydro [1,4] dioxino [2,3b] pyridine-6-carboxylate following the procedure outlined in Step 1 of Example 87.

Yield: 0.19 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 3.77 (s, 3H), 3.95 (s, 2H), 4.38-4.46 (m, 4H), 7 , 10-7.15 (t, 2H), 7.27-7.30 (t, 2H), 7.49 (s, 1H);

Mass (m / z): 304.0 (M + H) +.

Step 9. 8- (4-Fluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylic acid

The title compound was synthesized from methyl 8- (4-fluorobenzyl) -2,3 dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylate following the procedure outlined in Step 2 of Example 87.

Yield: 0.18 g;

¹ H-NMR (DMSO-de, 400 MHz) δ ppm: 3.94 (s, 2H), 4.37-4.38 (m, 2H), 4.44-4.45 (m, 2H), 7.11-7.15 (t, 2H), 7.27-7.30 (t, 2H), 7.45 (s, 1H);

Mass (m / z): 290.1 (M + H) ⁺ .

Step 10. ^ [(^^) - 2-Hydroxycyclohexyl] -8- (4-fluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3b] pyridine-6-carboxamide.

The title compound was synthesized from 8- (4-fluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylic acid following the procedure outlined in Step 8 of Example 1. The resulting crude the compound was further purified by flash chromatography using methanol: dichloromethane (1.5: 98.5).

Yield: 0.07 g;

1H-NMR (DMSO-de, 400 MHz) δ ppm: 1.21-1.25 (m, 4H), 1.57-1.63 (m, 2H), 1.87-1.89 (m, 2H), 3.35-3.41 (m, 2H), 3.96 (m, 2H), 4.37 (s, 2H), 4.45 (s, 2H), 4.65- 4.66 (d, J = 5.4 Hz, 1H), 7.10-7.15 (m, 2H), 7.26-7.29 (m, 2H), 7.41 (s, 1H) , 7.87-7.89 (d, J = 7.7 Hz, 1H);

Mass (m / z): 386.8 (M + H) ⁺ .

Examples 104-105. The compounds of examples 104-105 were prepared according to the experimental procedure described in example 103, with some non-critical changes.

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Structure and name by

IUPAC characteristic nomenclature data

400 MHz

2.67-2.69

3.41-3.42

N- IS, 2S -2hydroxycyclohexyl] -8- (4methoxybenzyl -2,3dihydro- [1,4] dioxino [2,3-

J = 2.53

4.65-4.67

b] pyridine-6-carboxamide

6, 86-6, 88 d, /, 14- /, 16

J = 8.34 /, 86 - /, 88 (M + H).

N- IS, 2S -2hydroxycyclohexyl] -8- (2chloropyridin-5-ylmethyl) 2,3-dihydro1,4 dioxino 2,3b] pyridine-6-carboxamide

1.23 m, m, 2H

Example 106. No. [(^^) - 2-Hydroxycyclohexyl] -8- [4- (1-methyl-1H-pyrazol-4-yl) benzyl] -2,3 dihydro [1,4] dioxino [2,3- B] pyridine-6-carboxamide

J = 2.59 Hz,

4.45 d,

Stage 1. Methyl 8- (4-chlorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylate

The title compound was synthesized according to the procedure outlined in step 1 of Example 87 with some non-critical modifications.

Yield: 0.19 g;

'h-NMR (DMSO ^, 400 MHz) δ ppm: 3.78 (s, 3H), 3.96 (s, 2H), 4.36-4.46 (dd, J = 3.0 , 5.8 Hz, 4H), 7.26

7.28 (d, 2H), 7.35-7.37 (d, 2H), 7.51 (s, 1H);

Mass (m / z): 320.1 (M + H) ⁺ .

Stage 2. Methyl 8- [4- (1-methyl-1H-pyrazol-4-yl) benzyl] -2,3-dihydro [1,4] dioxino [2,3-b] pyridine

6-carboxylate

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To a solution of methyl 8- (4-chlorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-L] pyridine-6-carboxylate (0.05 g, 0.00015 mol) in THF (8 ml ) in an atmosphere of N _{2 was} added 1-methyl-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (0.14 g, 0.0007 mol) , 1n. cesium carbonate (0.4 ml, 0.0007 mol) and degassed for 10 min. Then bis- (tri-tert-butyl phosphine) palladium (0) (0.016 g, 0.00003 mol) was added. The reaction mixture was slowly heated to 90 ° C over 30 h, cooled to room temperature, filtered through celite and washed with ethyl acetate (2x30 ml). The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using methanol: ethyl acetate (2:98) to give the title compound.

Yield: 0.06 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 3.77-3.84 (t, 6H), 3.94 (s, 2H), 4.39-4.46 (d, J = 2.6 Hz, 4H), 7.217.23 (d, J = 7.9 Hz, 1H), 7.47-7.50 (m, 2H), 7.56 (s, 1H), 7, 80-7.81 (d, J = 4.1 Hz, 2H), 8.08 (s, 1H);

Mass (m / z): 366.3 (M + H) +.

Step 3. 8- [4- (1-Methyl-1H-pyrazol-4-yl) benzyl] -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6carboxylic acid

ABOUT

U ' ⁰ ' 0 ° C

A-1 \

The title compound was synthesized from methyl 8- [4- (1-methyl-N-pyrazol-4-yl) benzyl] 2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylate in accordance with the procedure described in step 2 of example 87.

Yield: 0.043 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 3.84 (s, 3H), 3.93 (s, 2H), 4.39-4.45 (m, 4H), 7 , 21-7.23 (m, 2H), 7.43-7.49 (m, 3H), 7.81 (s, 1H), 8.08 (s, 1H), 12.80 (brs , 1H);

Mass (m / z): 352.3 (M + H) ⁺ .

Stage 4. No. [(^^) - 2-Hydroxycyclohexyl] -8- [4- (1-methyl-1H-pyrazol-4-yl) benzyl] -2,3 dihydro [1,4] dioxino [2,3- b] pyridine-6-carboxamide.

The title compound was synthesized from 8- [4- (1-methyl-N-pyrazol-4-yl) benzyl] -2,3 dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylic acid in following the procedure outlined in Step 8 of Example 1. The resulting crude compound was further purified by flash chromatography using methanol: dichloromethane (3.5: 96.5) to give the pure compound.

Yield: 0.03 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 1.21-1.23 (m, 4H), 1.57-1.62 (m, 2H), 1.82-1, 84 (m, 2H), 3.41-3.50 (m, 2H), 3.84 (s, 3H), 3.94 (s, 2H), 4.38-4.58 (d, 4H) , 4.65-4.67 (m, 1H), 7.20-7.22 (d, J = 7.8 Hz, 2H), 7.42 (s, 1H), 7.47-7.49 (d, J = 7.8 Hz, 2H), 7.80 (s, 1H), 7.87-7.89 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H) ;

Mass (m / z): 449.4 (M + H) ⁺ .

Example 107. H (^^) - 2-Hydroxycyclohexyl] -8- (2,3-difluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxamide

Stage 1. Methyl 8- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -2,3-dihydro [1,4] dioxino [2,3 ^ pyridine-6 -carboxylate

To a stirred mixture of methyl 8-chloro-2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylate (50 mg, 0.21 mmol), bis- (pinacolato) diboron (82, 8 mg, 0.32 mmol) and potassium acetate (40.60 mg, 0.43 mmol) in 1,4-dioxane (10 ml), a dichloro [1,1'-bis (diphenylphosphino) ferrocene complex ] palladium (II) with dichloromethane (17.75 mg, 0.02 mmol) and the mixture was heated at 110 ° C (oil bath temperature) for 7 h. The mixture was cooled to room temperature, diluted with ethyl acetate (30 ml), filtered through celite, washed with brine

- 91 035599 (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude weight of the title compound. Mass (m / z): 322.3 (M + H) +

Stage 2. Methyl 8- (2,3-difluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylate

To a solution of methyl 8- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine- 6-carboxylate (50 mg, 0.15 mmol) in a mixture of 8 ml of THF and 0.8 ml of water in an N2 atmosphere was added 2,3-difluorobenzyl bromide (38.6 mg, 0.18 mmol), cesium carbonate (152.01 mg, 0.46 mmol) and complex [1,1'-bis- (diphenylphosphino) ferrocene] dichloro-palladium (II) with dichloromethane 1: 1 (15.26 mg, 0.01 mmol). The mixture was boiled under reflux for 4 h, cooled to room temperature, filtered through celite and washed with ethyl acetate (2x30 ml). The filtrate was concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (40:60) to give the title compound.

Yield: 56 mg;

Mass (m / z): 322.1 (M + H) ⁺ .

Step 3. 8- (2,3-Dufluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylic acid

To a stirred mixture of 8- (2,3-difluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3EDpyridine-6-carboxylic acid methyl ester (50 mg, 0.15 mmol) in a mixture of THF: water ( 10 ml: 1 ml) was added in portions of NaOH flake (62.3 mg, 1.5 mmol) and then refluxed for 3 h. The reaction mixture was cooled to room temperature and acidified with concentrated HCl (pH ~ 2) and the product was extracted with ethyl acetate (10 mlx4). The combined organic layers were washed with saturated brine (15 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound.

Yield: 27 mg;

Mass (m / z): 308.0 (M + H) +.

Step 4. No. [(^^) - 2-Hydroxycyclohexyl] -8- (2,3-difluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3EDpyridine-6-carboxamide.

To a solution of 8- (2,3-difluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxylic acid (0.01 g, 0.00003 mol) in DMF ( 5 ml) at 25 ° C in an atmosphere of N2, HATU (0.016 g, 0.00004 mol) was added, stirred for 10 min, then (^^) - 2-amino cyclohexanol hydrochloride (0.0041 g, 0.00003 mol) was added and DIPEA (0.023 ml, 0.0001 mol) for 10 min and stirred for 15 h. The reaction mixture was quenched with ice water (20 ml) and extracted with ethyl acetate (3x20 ml). The organic layer was washed with saturated brine (15 ml) and dried over Na ₂ SO ₄ . The organic layer was concentrated in vacuo to give the title compound.

Yield: 0.007 g;

Ή-NMR (CDCl ₃ , 400 MHz) δ ppm: 1.25-1.30 (m, 4H), 1.64-1.67 (m, 2H), 2.00-2.04 ( m, 2H), 2.77-2.80 (m, 1H), 3.42-3.44 (m, 1H), 4.02 (s, 2H), 4.42-4.43 (d, J = 2.52 Hz, 2H), 4.47-4.48 (d, J = 2.22 Hz, 2H), 4.40-4.51 (d, J = 4.38 Hz, 1H), 6.87-6.90 (m, 1H), 6.91-7.08 (m, 2H), 7.30 (s, 1H), 8.41-8.43 (d, J = 8.43 Hz, 1H);

Mass (m / z): 405.1 (M + H) +.

Examples 108-112. The compounds of examples 108-112 were prepared according to the experimental procedure described in example 107 with some non-critical changes.

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Example No. Structure and IUPAC nomenclature Characteristic data / γΧΧ ^{1 n} ° ⁿ 108 and 1 Ν- [(IS, 2S) -2-hydroxycyclohexyl] -8- (1-methyl-1H-pyrazol-4-ylmethyl) -2,3-dihydro- [1,4] dioxino [2,3-b ] pyridine-6-carboxamide ⁰ xx l ₀ XJ ⁿ on TX Mass (m / z): 373.4 (M + H) ⁺ 109 Ν = / Ν- [(IS, 2S) -2-hydroxycyclohexyl] -8- [4 (pyrazol-1-yl) benzyl] -2,3 dihydro- [1,4] dioxino [2,3 - b] pyridine 6-carboxamide ⁰ XX QlA ⁿ έ _Η tx Mass (m / z): 435.3 (M + H) ⁺ 110 N- [(IS, 2S) -2-hydroxycyclohexyl] -8- (2-methylpyridin-5-ylmethyl) - 2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide ⁰ XX С Xj ⁿ 0n Mass (m / z): 384.4 (M + H) ⁺ 111 IX N F N- [(IS, 2S) -2- hydroxycyclohexyl] -8- (2- fluoropyridin-5-ylmethyl) -2,3- Mass (m / z): 388.3 (M + H) ⁺

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N- [(1S hydroxycyclohexyl] -8- (2fluoropyridin-4-ylmethyl) -2,3 dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide dihydro- [1,4] dioxino [2 , 3—

B] pyridine-6-carboxamide

Example 113. trans ^ - (3-Hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) -2,3 dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxamide (isomer-II)

According to the procedure described in Step 10 of Example 103, trans-A (3hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6carboxamide using trans-4-aminotetrahydropyran-3-ol hydrochloride (isomer-II, I-22). The resulting crude compound was further purified by flash chromatography using methanol: dichloromethane (2.5: 97.5) to afford the title compound.

Yield: 0.06 g;

1H-NMR (DMSO-de, 400 MHz) δ ppm: 1.58-1.61 (m, 1H), 1.76-1.89 (m, 1H), 3.36-3.39 (m, 2H), 3.44-3.57 (m, 2H), 3.69-3.78 (m, 2H), 3.96 (s, 2H), 4.37-4.38 (d , J = 2.8 Hz, 2H), 4.38-4.46 (d, J = 2.9 Hz, 2H), 4.93-4.95 (d, J = 5.6 Hz, 1H) , 7.10-7.15 (t, 2H), 7.26-7.29 (m, 2H), 7.42 (s, 1H), 8.08-8.10 (d, J = 8, 1 Hz, 1H);

Mass (m / z): 389.0 (M + H) +.

Example 114-117. The compounds of examples 114-117 were prepared according to the experimental procedure described in example 113, with some non-critical changes.

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Example No. Structure and IUPAC nomenclature Characteristic data 114 _rV XQ yu ⁿ ° ⁿ 'O. (3S, 4S) -N- (4-hydroxytetrahydropyran-3- yl) -8- (4-methoxybenzyl) - 2,3-dihydro- [1,4] dioxino [2,3-b] pyridine-6-carboxamide Mass (m / z): 401.3 (M + H) ⁺ . 115 QCl ^H OH d (3S, 4S) -N- (4-hydroxytetrahydropyran-3yl) -8- (4-fluorobenzyl) -2,3dihydro- [1,4] dioxino [2,3b] pyridine-6-carboxamide Mass (m / z): 389.3 (M + H) ⁺ . 116 117 Yy ⁿ ° ⁿ N CI (3S, 4S) -N- (4-hydroxytetrahydropyran-3yl) -8- (2-chloropyridine-5ylmethyl) -2,3-dihydro- [1,4] dioxino [2,3-b ] pyridine-6-carboxamide guG'y Cd ^{7 n} ° ⁿ T1 (3S, 4S) -N- (4-hydroxytetrahydropyran-3yl) -8- (2-methylpyridine-5ylmethyl) -2,3-dihydro- [1, 4] dioxino [2,3-b] pyridine-6-carboxamide Mass (m / z): 406.7 (M + H) ⁺ . Mass (m / z): 386.3 (M + H) ⁺ .

Example 118. Racemic cis-H4-hydroxytetrahydropyran-3-yl) -8- (4-fluorobenzyl) -2,3 dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxamide

The title compound was prepared according to the experimental procedure from Step 10 of Example 103 using the intermediate cis-3aminotetrahydropyran-4-ol hydrochloride (I-23) and the intermediate obtained in Step 9 of Example 103.

- 95 035599 ¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 1.47-1.57 (m, 1H), 1.81-1.84 (m, 1H), 3.11 -3.19 (m, 1H), 3.44-3.50 (m, 1H), 3.61-3.69 (m, 2H), 3.76-3.79 (m, 2H), 3 , 96 (s, 2H), 4.37 (s, 2H), 4.98-4.99 (d, J = 4.3 Hz, 1H), 7.10-7.15 (t, 2H), 7.26-7.30 (m, 2H), 7.42 (s, 1H), 8.09-8.11 (d, J = 8.1Hz, 1H);

Mass (m / z): 389.3 (M + H) +.

Example 119. Racemic cis-M- (4-hydroxytetrahydropyran-3-yl) -8- (4-methoxybenzyl) -2,3 dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxamide

This compound was obtained in accordance with the experimental procedures described in example 18, with some non-critical changes.

¹ H-NMR (DMSO, 400 MHz) δ ppm: 1.44-1.49 (m, 1H), 1.82-1.84 (m, 1H), 2.67-2.69 ( m, 1H), 3.11-3.16 (m, 1H), 3.60-3.69 (m, 2H), 3.72 (s, 3H), 3.76-3.79 (m, 2H), 3.89 (s, 2H), 4.380-4.385 (d, 2H, J = 2.02 Hz), 4.45-4.46 (d, 2H, J = 2.30 Hz), 4, 98-4.99 (d, 1H, J = 4.86 Hz), 6.86-6.88 (d, 2H, J = 8.35 Hz), 7.15-7.17 (d, 2H, J = 8.26 Hz), 7.38 (s, 1H), 7.96-7.98 (d, 1H, J = 7.76 Hz);

Mass (m / z): 401.2 (M + H) ⁺ .

Example 120. No. [(^^) - 2-Hydroxycyclohexyl] -8- (4-fluorobenzyl) -4-methyl-2H-pyrido [3,2-

b] [1,4] oxazine-6-carboxamide

Stage 1. 2-amino-4-bromopyridin-3-ol hydrobromide

НВг .n nh ₂

To a mechanically stirred suspension of 2-aminopyridin-3-ol (20 g, 0.18 mol) in acetic acid (300 ml) at 5-10 ° C was added dropwise bromine (11.2 ml, 0.21 mol) and the temperature brought to room temperature. The reaction mixture was heated at 120-125 ° C, the temperature was maintained for 12 h and the mixture was concentrated to obtain a crude mass, which was triturated with diethyl ether (3x50 ml) and dried in vacuo to give 2-amino-4-bromopyridin3-ol hydrobromide in the form of a dark brown compound which was used as such without any purification.

Yield: 48.5 g;

Mass (m / z): 189.3, 191.1 (M + H) ⁺ .

Stage 2. 4-Bromo-3- (2-chloroethoxy) pyridin-2-ylamine

Ν NH ₂

Br

To a stirred suspension of 2-amino-4-bromopyridin-3-ol hydrobromide (48 g, 0.17 mol), potassium carbonate (85.8 g, 0.62 mol) and sodium iodide (3.9 g, 0.026 mol) in acetonitrile (500 ml), bromochloroethane (63.5 g, 0.44 mol) was added at room temperature and then the reaction mixture was refluxed for 18 hours. The reaction mixture was concentrated to obtain a residual mass, which was diluted with water (250 ml) and was extracted with ethyl acetate (3x50 ml). The organic layers were combined, washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (20:80) to give 4-bromo -3- (2chloroethoxy) pyridin-2-ylamine.

Yield: 9.3 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 3.84-3.88 (t, J = 5.21 Hz, 2H), 4.24-4.27 (t, J = 4 , 99 Hz, 2H), 4.97 (brs, 2H), 6.79-6.81 (d, J = 5.32 Hz, 1H), 7.63-7.65 (d, J = 5.36 Hz, 1H);

Mass (m / z): 251.0, 253.0 (M + H) ⁺ .

Step 3. 8-Bromo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine

Bg

- 96 035599

A solution of 4-bromo-3- (2-chloroethoxy) pyridin-2-ylamine (9.2 g, 0.036 mol) in DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (2.6 g, 0.065 mol, 60 % oily suspension) in DMF (10 ml) at 15-25 ° C, then sodium iodide (0.5 g, 0.0036 mol) was added and stirred at room temperature for 4 h. The reaction mixture was added to water (250 ml ), was extracted with ethyl acetate (3x50 ml). The organic layers were combined, washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (60:40) to give 8 -bromo-3,4-dihydro-2H-pyrigo [3,2-b] [1,4] oxa-zine.

Yield: 6.3 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 3.56-3.59 (m, 2H), 4.31-4.33 (m, 2H), 4.96 (brs , 1H), 6.77-6.78 (d, J = 5.44 Hz, 1H), 7.46-7.47 (d, J = 5.48 Hz, 1H);

Mass (m / z): 215.1, 217.0 (M + H) +.

Step 4. 8-Bromo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-5-oxide

L

Bg

The title compound was synthesized from 8-bromo-3,4-dihydro-2H-pyrido [3,2ED ^^ oxazine according to the procedure outlined in Step 1 of Example 1.

Yield: 5.2 g;

¹ H-NMR (DMSOL ₆ , 400 MHz) δ ppm: 3.48-3.51 (m, 2H), 4.24-4.26 (m, 2H), 6.77-6.79 (d, J = 7.16 Hz, 1H), 7.56 (br s, 1H), 7.66-7.68 (d, J = 6.96 Hz, 1H);

Mass (m / z): 231.1, 233.0 (M + H) +.

Step 5. 8-Bromo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbonitryl n

Ν N .___- CN o?

Bg

The title compound was synthesized from 8-bromo-3,4-dihydro-2H-pyrido [3,2ED ^^ oxazine ^ -oxide following the procedure outlined in Step 2 of Example 1.

Yield: 1.9 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 3.50-3.52 (t, J = 4.16 Hz, 2H), 4.25-4.27 (t, J = 4 , 20 Hz, 2H), 7.17 (s, 1H);

Mass (m / z): 240.1, 242.0 (M + H) +.

Step 6. 8-Bromo-4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbonitrile

The title compound was synthesized from 8-bromo-3,4-dihydro-2H-pyrido [3,2b] [1,4] oxazine-6-carbonitrile following the procedure outlined in Step 4 of Example 1.

Yield: 0.39 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 3.13 (s, 3H), 3.51-3.53 (t, J = 4.34 Hz, 2H), 4.37- 4.39 (t, J = 4.30 Hz, 2H), 7.12 (s, 1H);

Mass (m / z): 254.0, 256.1 (M + H) +.

Step 7. 8-Bromo-4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxylic acid oγ

Bg

The title compound was synthesized from 8-bromo-4-methyl-3,4-dihydro-2H-pyrido [3,2b] [1,4] oxazine-6-carbonitrile following the procedure outlined in Step 3 of Example 1.

Yield: 0.89 g;

¹ H-NMR (DMSOA, 400 MHz) δ ppm: 3.06 (s, 3H), 3.48 (m, 2H), 4.33 (m, 2H), 7.33 (s, 1H );

Mass (m / z): 273.0, 275.0 (M + H) +.

Stage 8. Methyl 8-bromo-4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxylate

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The title compound was synthesized from 8-bromo-4-methyl-3,4-dihydro-2H-pyrido [3.2b] [1,4] oxazine-6-carboxylic acid following the procedure outlined in Step 4 of Example 1. ...

Yield: 0.6 g;

Ή-NMR (CDCl3, 400 MHz) δ ppm: 3.21 (s, 3H), 3.49-3.52 (t, J = 4.38 Hz, 2H), 3.91 (s, 3H), 4.37-4.39 (t, J = 4.36 Hz, 2H), 7.60 (s, 1H);

Mass (m / z): 287.0, 289.0 (M + H) +.

Stage 9. Methyl 8- (4-fluorobenzyl) -4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxαzine-6carboxylate

Stirred solution of methyl 8-bromo-4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6carboxylate (0.39 g, 0.0013 mol) in dry THF ( 15 ml) was degassed for 2 min and back filled with N ₂ , then bis- (tri-tert-butylphosphine) palladium (0.034 g, 0.000067 mol) and a solution of 4-fluorobenzylzinc chloride (4.1 ml, 0.002 mol, 0 , 5 M in THF). The reaction mixture was boiled under reflux for 3 h, cooled to room temperature, poured into water (50 ml) and extracted with ethyl acetate (3x50 ml). The organic layers were combined, washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was then purified by flash chromatography using ethyl acetate: n-hexane (50:50) to give methyl 8- (4-fluorobenzyl) -4-methyl-3,4-dihydro-2H-pyrido [3,2b] [1,4] oxazine-6-carboxylate.

Yield: 0.39 g;

¹ H-NMR (CDCl3, 400 MHz) δ ppm: 3.19 (s, 3H), 3.45-3.47 (t, J = 4.5 Hz, 2H), 3.84 (s , 3H), 3.87 (s, 2H), 4.28-4.30 (t, J = 4.44 Hz, 2H), 6.93-6.97 (m, 2H), 7.13- 7.16 (m, 1H), 7.24-7.26 (m, J = 7.29 Hz, 2H);

Mass (m / z): 317.0 (M + H) ⁺ .

Step 10.8- (4-Fluorobenzyl) -4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxylic acid

The title compound was synthesized from methyl 8- (4-fluorobenzyl) -4-methyl-3,4-dihydro2H-pyrido [3,2-b] [1,4] oxazine-6-carboxylate following the procedure outlined in Step 7 of Example 1.

Yield: 0.38 g;

¹ H-NMR (DMSO, 400 MHz) δ ppm: 3.04 (s, 3H), 3.42-3.44 (t, J = 3.80 Hz, 2H), 3.81 (s , 2H), 4.27-4.29 (t, J = 3.84 Hz, 2H), 7.04-7.12 (m, 3H), 7.22-7.25 (m, 2H);

Mass (m / z): 303.0 (M + H) ⁺ .

Stage 11. No [(^^) - 2-Hydroxycyclohexyl] -8- (4-fluorobenzyl) -4-methyl-2H-pyrido [3,2b] [1,4] oxazine-6-carboxamide

The title compound was synthesized from 8- (4-fluorobenzyl) -4-methyl-3,4-dihydro-2Hpyrido [3,2-b] [1,4] oxazine-6-carboxylic acid according to the procedure outlined in Stage 8 of Example 1.

Yield: 0.40 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 1.25-1.39 (m, 4H), 1.73-1.76 (m, 2H), 2.00-2.02 (m, 1H), 2.07-2.11 (m, 1H), 3.11 (s, 3H), 3.41-3.48 (m, 3H), 3.70-3.72 (m , 1H), 3.85 (s, 2H), 4.01-4.02 (d, J = 3.26, 1H), 4.28-4.30 (t, J = 4.47 Hz, 2H ), 6.90-6.95 (m, 2H), 7.13-7.17 (m, 2H), 7.33 (s, 1H), 7.75-7.77 (d, J = 6 , 68 Hz, 1H);

Mass (m / z): 400.2 (M + H) ⁺ .

Examples 121-128. The compounds of examples 121-128 were prepared according to the experimental procedure described in example 120, with some non-critical changes.

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Example No. Structure and IUPAC nomenclature Characteristic data 121 1 n O φ F Ν - [(IS, 2S) -2- hydroxycyclohexyl] -8 (3-fluorobenzyl) -4-methyl2H-pyrido [3,2- b] [1,4] oxazine-6carboxamide ¹ H-NMR (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,23-1,33 (m, 4H), 1,57-1, 64 (m, 2H), 1,841,90 ( m, 2H), 3.10 (s, 3H), 3.33-3.35 (m, 2H), 3.47-3.48 (m, 2H), 3.88 (s, 2H), 4 , 29-4.31 (t, J = 4.08, 2H), 4.68-4.69 (d, J = 5.37 Hz, 1H), 7.01-7.06 (m, 4H) , 7.29-7.33 (m, 1H), 7.89-7.91 (d, J = 7.72 Hz, 1H); Mass (m / z): 400, 1 (M + H) ⁺ . 122 1 and О f ' ^N Y ^N Y%' v UM ⁿ on X Ν \ Ν - [(IS, 2S) -2-hydroxycyclohexyl] -8- [4- (1-methyl-1Н-pyrazol-4- yl) benzyl] -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6carboxamide M-NMR (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,23-1,35 (m, 2H), 1,56-1,57 (m, 2H), 1.83 - 1 , 84 (m, 4H), 3.10 (s, 3H), 3.27-3.30 (m, 1H), 3.37-3.47 (m, 3H), 3.84 (s, 5H ), 4.29-4.31 (m, 2H), 4, 68-4, 69 (d, J = 5.40 Hz, 1H), 7.05 (s, 1H), 7.16 -7, 18 (d, J = 7.90 Hz, 2H), 7.44-7.46 (d, J = 8.01 Hz, 2H), 7.95 (s, 1H), 7.89-7.91 (d, J = 7.71 Hz, 1H), 8.06 (s, 1H); Mass (m / z): 462.4 (M + H) ⁺ . 123 । ? ΓΊ C ₀ XJ ⁿ he iQ F Ν - [(IS, 2S) -2-hydroxycyclohexyl] -8 (2-fluoropyridine-4ylmethyl) -4-methyl-2Hpyrido [3.2— b] [1,4] oxazine- 6carboxamide M-NMR (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,58-1,75 (4H, m), 1, 84-1,97 (m, 4H), 3.11 (s , 3H), 3.39-3.40 (m, 1H), 3.46-3.50 (m, 3H), 3.96 (s, 2H), 4.27-4.29 (m, 2H ), 4.68-4.70 (d, J = 5.48 Hz, 1H), 7.12 (s, 1H), 7.16-7.17 (d, J = 4.79 Hz, 1H) , 7.90-7.92 (d, J = 7.7 Hz, 1H), 7.95 (s, 1H), 8.12-8.13 (d, J = 5.09 Hz, 1H); Mass (m / z): 401.0 (M + H) ⁺ .

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124 Ν 2, .Q ° ςιτ ⁿ χ X trans-N- (3 - hydroxytetrahydropyran4-yl) -8- (4-fluorobenzyl) -4methyl-2H-pyrido [3,2— b] [1,4] oxazine-6carboxamide (isomer-11) A-NMR (DMSO-L ₆ 4 00 MHz) δ ppm .: 1,56-1,57 (m, 1H), 1,59-1,60 (m, 1H), 2,993,14 (m , 1H), 3.12 (s, 3H), 3.36-3.37 (m, 1H), 3.46-3.53 (m, 3H), 3.743.83 (m, 3H), 3, 85 (s, 2H), 4.28-4.30 (m, 2H), 4.97-4.98 (d, J = 5.70 Hz, 1H), 7.05-7.12 (m, 3H), 7.22-7.25 (m, 2H), 8.008.02 (d, J = 7.98 Hz, 1H); Mass (m / z): 401.9 (M + H) ⁺ . 125 । ⁰ 0 ° 0N0./U g l lg ^N and ⁿ ° n 01 trans-N- (3-hydroxytetrahydropyran4-yl) -8- (4-methoxybenzyl) -4-methyl2H-pyrido [3,2b] [1,4 ] oxazine-6carboxamide (isomer-11) Mass (m / z): 414.2 (M + H) ⁺ . 126 । ⁰ О V, Ν- [(IS, 2S) -2-hydroxycyclohexyl] -8 (2-chloropyridin-5-ylmethyl) -4-methyl-2Н- A-NMR (DMSO-SD, 400 MHz) δ ppm: 1.25-1.33 (m, 2H), 1.57-1.64 (m, 2H), 1.841.97 (m, 4H), 3.11 (s, 3H), 3.28-3.29 (m, 1H), 3.37-3.38 (m, 1H), 3.423.44 (m, 2H), 3.89 (s, 2H), 4.28-4.29 (m, 2H), 4.68-4.69 (d, J = 5.45 Hz, 1H), 7.10 (s, 1H), 7.41-

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pyrido [3,2- 7.44 (d, J = 8.17 Hz, 1H), B] [1,4] oxazine-6- 7.65-7.68 (dd, J = 2.09, carboxamide 8.12 Hz, 1H), 7.89 -7.91 (d, J = 7.66 HZ, 1H), 8.30- 8.31 (d, J = l, 85 Hz, 1H); Weight (m / z): 41 7.4, 419, 3 (M + H) ⁺ . T-NMR (DMSO-b ₆ , 400 MHz) δ ppm : 1.2E (-1.38 (m, 2H), 1.57-1.64 (m, 2H), 2.33 ι ^χΝ Υ ^{Ν <} τ (m, 1H), 2, 67 -2, 69 (m, Uu ^{n an} 2H), 3.10 (from, ZN), 3.37- 3.38 (m, 2H), 3.47 (m, [1 J, ZN), 3.71 (from, ZN), 3.78 Ν - [(IS, 2S) -2- (s, 2H), 4.30 (m, 2H), hydroxycyclohexyl] -8- 4.68-4.69 (d, J = 5, 2 Hz, (4-methoxybenzyl) -4- 1H), 6.83- -6, 85 (d, J = 8.3 methyl-2H-pyrido [3,2- Hz, 2H), 7.01 (from, 1H), b] [1,4] oxazine-6- 7.10-7.12 (d, J = 8.3 Hz, carboxamide 2H), 7.88- -7.90 (d, J = 7.5 Hz, 1H); Mass (m / z): 412.1 (M + H) +

T-NMR (DMSO-L ₆ 4 00 MHz) δ

N-L (IS, 2S) -2hydroxycyclohexyl] -8 (2-methylpyridine-5ylmethyl) -4-methyl-2Hpyrido [3.2—

b] [1,4] oxazine-6carboxamide

ppm: 1.23-1.30

1.57-1.64

1.86

3, 10

1H)

4H)

2H), 1.841.88-1.97

2H)

ZN)

4.35-4.37

4, 69

7.05

1H)

2.41

ZN)

3, 83

ZN)

3.46-3.48

2H)

2H)

4, 68 (D

1H)

J = 5.24 Hz

1H)

1H)

7.14-7.16

7.46-7.48

7.89-7.91 (d, J = 7.56

8.32

1H);

Hz

1H)

Example 129. No. [(18,28) -2-Hydroxycyclohexyl] -8- [4-pyrazol-1-ylbenzyl] -4-methyl-2H-pyrido [3.2b] [1,4] oxazine-6-carboxamide

Stage 1. Methyl 4-methyl-8- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -3,4-dihydro-2H pyrido [3,2-b] [ 1,4] oxazine-6-carboxylate

The title compound was synthesized from methyl 8-bromo-4-methyl-3,4-dihydro-2Hpyrido [3,2-b] [1,4] oxazine-6-carboxylate following the procedure outlined in Step 5 of Example 1. ...

¹ H-NMR (CDCis, 400 MHz) δ ppm: 1.27 (s, 12H), 3.21 (s, 3H), 3.50-3.52 (m, 2H), 3.91 (s, 3H), 4.37-4.40 (m, 2H), 7.60 (s, 1H);

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Mass (m / z): 335.4 (M + H) ⁺ .

Stage 2. Methyl 8- [4-pyrazol-1-ylbenzyl] -4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6carboxylate

The title compound was synthesized from methyl 4-methyl-8- (4-pyrazol-1-yl-benzyl) -3,4 dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxylate in in accordance with the procedure described in step 6 of example 1.

Yield: 0.14 g;

1H-NMR (CDCl3, 400 MHz) δ ppm: 3.20 (s, 3H), 3.46-3.48 (t, J = 4.5 Hz, 2H), 3.88 (s, 3H), 3.91 (s, 2H), 4.29-4.31 (t, J = 4.5 Hz, 2H), 6.44-6.45 (m, 1H), 7.28-7 , 28 (m, 3H), 7.58-7.60 (m, 2H), 7.70-7.70 (m, 1H), 7.887.88 (d, J = 2.3 Hz, 1H);

Mass (m / z): 365.1 (M + H) ⁺ .

Step 3. 8- [4-Pyrazol-1-ylbenzyl] -4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6carboxylic acid

The title compound was synthesized from methyl 4-methyl-8- (4-pyrazol-1-yl-benzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxylate in in accordance with the procedure described in step 7 of example 1.

Yield: 0.12 g;

¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 3.08 (s, 3H), 3.47-3.49 (m, 2H), 4.02 (s, 2H), 4, 32-4.34 (m, 2H), 6.52 (m, 1H), 7.14 (s, 1H), 7.32-7.34 (d, J = 8.3 Hz, 2H), 7 , 20-7.61 (m, 3H), 8.43-8.44 (d, J = 2.1 Hz, 1H);

Mass (m / z): 351.2 (M + H) ⁺ .

Stage 4. N - [(1S, 2S) -2-F hydroxycyclohexyl] -8- [4-pyrazole-1 -ylbenzyl] -4-methyl-2H-pyrido [3,2b] [1,4] oxazine-6 -carboxamide

The title compound was synthesized from 4-methyl-8- (4-pyrazol-1-yl-benzyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxylic acid in in accordance with the procedure described in step 8 of example 1.

Yield: 0.075 g;

1H-NMR (DMSO-de, 400 MHz) δ ppm: 1.23-1.35 (m, 2H), 1.58-1.64 (m, 2H), 1.85-1.99 (m, 3H), 2.33-2.67 (m, 2H), 3.11 (s, 3H), 3.33-3.49 (m, 3H), 3.90 (s, 2H), 4.31 (m, 2H), 4.68-4.70 (d, J = 5.0 Hz, 1H), 6.52 (s, 1H) 7.09 (s, 1H), 7.33- 7.31 (d, J = 7.9 Hz, 2H), 7.75-7.71 (m, 3H), 7.90-7.92 (d, J = 7.3 Hz, 1H), 8 , 44 (s, 1H);

Mass (m / z): 448.1 (M + H) ⁺ .

Example 130. N - [(1S, 2S) -2-E hydroxycyclohexyl] -4-methyl-8- (1-methyl-1 H-pyrazol-4-ylmethyl) -2Hpyrido [3,2-b] [1, 4] oxazine-6-carboxamide

The title compound was prepared according to the experimental procedures described in Example 129 with some non-critical modifications.

Mass (m / z): 386.3 (M + H) +.

Examples 131-136. The compounds of examples 131-136 were prepared according to the experimental procedure described in example 120, 125, 120, 125, 129 and 130, respectively, with some non-critical changes.

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Example No. Structure and IUPAC nomenclature Characteristic data 131 '5 L and. Racemic cis-N- (4- hydroxytetrahydropyran-3-yl) 8- (4-fluorobenzyl) -4-methyl-2Hpyrido [3,2-b] [1,4] oxazine-6carboxamide Mass (m / z): 402.2 (M + H) ⁺ . 132 ⁿ 0n Racemic cis-N- (4-hydroxytetrahydropyran-3-yl) 8- (4-methoxybenzyl) -4-methyl-2Hpyrido [3,2-b] [1,4] oxazine-6- Mass (m / z): 414.3 (M + H) ⁺ . carboxamide 133 MM ⁿ ° ⁿ TE (3S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) 8- (4-fluorobenzyl) -4-methyl-2Hpyrido [3,2-b] [1,4] oxazine-6carboxamide Mass (m / z): 402.4 (M + H) ⁺ . 134 LqJxJ ^H on ΐΓχ (3S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) 8- (4-methoxybenzyl) -4-methyl-2Hpyrido [3,2-b] [1,4] oxazine-6carboxamide Mass (m / z): 414.7 (M + H) ⁺ . 135 XsAO MM ^{n on} (3S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) 8- (4-pyrazol-1-ylbenzyl) -4methyl-2H-pyrido [3,2— b] [1,4] oxazine-6-carboxamide Mass (m / z): 450.4 (M + H) ⁺ .

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(3S, 4S) -N- (4hydroxytetrahydropyran-3-yl) 4-methyl-8- (1-methyl-1H-pyrazol4-ylmethyl) -2H-pyrido [3,2b] [1,4] oxazine-6- carboxamide

Example 137. N- | (1S, 2S) -2-l Hydroxycyclohexyl

B] pyridine-5-carboxamide

-7- (4-fluorobenzyl) -1 -methyl-1 H-pyrrolo [3,2-

Stage 1. 7-Chloro-1H-pyrrolo [3,2-b] pyridine 4-oxide

The title compound was synthesized from 7-chloro-4-azaindole following the procedure outlined in Step 1 of Example 1.

Yield: 2.36 g;

¹ H-NMR (DMSO-06, 400 MHz) δ ppm: 6.74-6.74 (d, J = 3.16 Hz, 1H), 7.23-7.25 (d, J = 6.6 Hz, 1H), 7.667.67 (d, J = 3.04 Hz, 1H), 8.03-8.05 (s, J = 6.6 Hz, 1H), 12.42 (br. s, 1H);

Mass (m / z): 169.2 (M + H) ⁺ .

Stage 2. 7-Chloro-1H-pyrrolo [3,2-b] pyridine-5-carbonitrile

The title compound was synthesized from 7-chloro-1H-pyrrolo [3,2-b] pyridine 4-oxide following the procedure outlined in Step 2 of Example 1.

Yield: 1.65 g;

1H-NMR (DMSO-ds, 400 MHz) δ ppm: 6.83-6.83 (m, 1H), 7.99-8.01 (m, 2H), 12.52 (brs , 1H);

Mass (m / z): 178.3, 180.2 (M + H) +.

Stage 3. 7-Chloro-1-methyl-1H-pyrrolo [3,2-b] pyridine-5-carbonitrile

The title compound was synthesized from 7-chloro-1H-pyrrolo [3,2-b] pyridine-5carbonitrile following the procedure outlined in Step 4 of Example 1.

Yield: 0.2 g;

1H-NMR (CDCI3, 400 MHz) δ ppm: 4.17 (s, 3H), 6.77-6.78 (d, J = 3.38 Hz, 1H), 7.40-7, 41 (d, J = 3.25 Hz, 1H), 7.47 (s, 1H);

Mass (m / z): 192.1, 194.1 (M + H) ⁺ .

Step 4. 7- (4-Fluorobenzyl) -1-methyl-1H-pyrrolo [3,2-b] pyridine-5-carbonitrile

The title compound was synthesized from 7-chloro-1-methyl-1H-pyrrolo [3,2-L] pyridine-5carbonitrile following the procedure outlined in Step 9 of Example 79.

Yield: 0.13 g;

¹ H-NMR (CDCI3, 400 MHz) δ ppm: 3.90 (s, 3H), 4.45 (s, 2H), 6.76-6.77 (d, J = 3.17 Hz , 1H), 7.02-7.03 (m,

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4H), 7.17 (s, 1H), 7.32-7.32 (d, J = 3.01 Hz, 1H);

Mass (m / z): 266.1, 267.2 (M + H) +.

Step 5. 7- (4-Fluorobenzyl) -1-methyl-1H-pyrrolo [3,2-b] pyridine-5-carboxylic acid

The title compound was synthesized from 7- (4-fluorobenzyl) -1-methyl-N-pyrrolo [3,2 ^ pyridine ^ -carbonitrile according to the procedure outlined in Step 7 of Example 1.

Yield: 0.066 g;

Ή-NMR (DMSOA, 400 MHz) δ ppm: 3.89 (s, 3H), 4.51 (s, 2H), 6.60-6.61 (d, J = 2.31 Hz, 1H), 7.14-7.18 (m, 4H), 7.49-7.51 (m, 2H);

Mass (m / z): 285.1 (M + H) +.

Step 6. N - [(1S, 2S) -2-F hydroxycyclohexyl] -7- (4-fluorobenzyl) -1 -methyl-1 H-pyrrolo [3,2 ^ pyridine-5-carboxamide

The title compound was synthesized from 7- (4-fluorobenzyl) -1-methyl-N-pyrrolo [3,2-pyridine-N-carboxylic acid according to the procedure outlined in Step 8 of Example 1.

Yield: 0.034 g;

Ή-NMR (DMSOA, 400 MHz) δ ppm: 1.25-1.31 (m, 4H), 1.60-1.65 (m, 2H), 1.88-1.93 (m , 2H), 3.38-3.44 (m, 1H), 3.45-3.50 (m, 1H), 3.95 (s, 3H), 4.59 (s, 2H), 4, 70-4.71 (d, J = 5.32 Hz, 1H), 6.64-6.65 (d, J = 3.04 Hz, 1H), 7.16-7.17 (m, 4H) , 7.53 (s, 1H), 7.65-7.66 (d, J = 2.9 Hz, 1H), 8.25-8.27 (d, J = 7.6 Hz, 1H);

Mass (m / z): 382.3 (M + H) +.

Examples 138-142. The compounds of Examples 138-142 were prepared according to the experimental procedure described in Example 137, with some non-critical changes.

Example No. Structure and IUPAC nomenclature Characteristic data ABOUT N JL JL J ^ -NMR (DMSO-de, 4 00 MHz) δ ^he ppm: 1.54-1.60 (m, 1H), / t Υί ''' ⁴ *! 1.62-1.64 (m, 1H), 3.34 (s, 138 IX N Cl ZN), 3.58-3.61 (m, 1H), Racemic cis-N- (3- 3.74-3.83 (m, 5H), 3.99 (s, hydroxytetrahydropyran- 2H), 4.97-4.98 (d, J = 5.71 4-yl) -7- (2-chloropyridine-5- Hz, 1H), 6, 66-6, 67 (d,

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ylmethyl) -1-methyl-1Hpyrrolo [3,2-b] pyridine-5carboxamide J = 3.14 Hz, 1H), 7.47-7.50 (2H, t), 7.58-7, 60 (DD, J = l, 86, 8.3 Hz, 1H), 7.697.70 (d, J = 3.14 Hz, 1H), 8.32-8.32 (d, J = l, 46 Hz, 1H), 8.44-8.46 (d, J = 8.0 Hz, 1H); Mass (m / z): 401.2, 403.2 (M + H) ⁺ . 139 ABOUT AAA n-V ° n / to, N ^ CI N- [(IS, 2S) -2- hydroxycyclohexyl] -7- (2-chloropyridine-5- ylmethyl) -1-methyl-1Hpyrrolo [3,2-b] pyridine-5carboxamide U-HMP (DMSO-F ₆ 4 00 MHz) δ ppm .: 1,23-1,27 (m, 2H), 1, 65-1,74 (m, 2H), 1,88-1 , 97 (m, 4H), 3.42-3.46 (m, 1H), 3.50-3.54 (m, 1H), 3.99 (s, 3H), 4.66 (s, 2H ), 4.69-4.70 (d, J = 5.36 Hz, 1H), 6.666.66 (d, J = 3.09 Hz, 1H), 7.47-7.50 (m, 2H) , 7.58-7.60 (dd, J = 2.07, 8.16 Hz, 1H), 7.68-7.69 (d, J = 3.24 Hz, 1H), 8.25-8 , 27 (d, J = 7.71 Hz, 1H), 8.31-8.32 (d, J = 1, 71 Hz, 1H); Mass (m / z): 399, 3, 401.2 (M + H) ⁺ . 140 he / I XX Racemic cis-N- (4- hydroxytetrahydropyran3-yl) -7- (4- methoxybenzyl) -1-methyl1H-pyrrolo [3,2-b] pyridine 5-carboxamide Mass (m / z): 396.2 (M + H) ⁺ . 141 A ^H on / I A (3S, 4S) -N- (4-hydroxytetrahydropyran3-yl) -7- (4-fluorobenzyl) -1methyl-1H-pyrrolo [3,2 - b] pyridine-5-carboxamide Mass (m / z): 384.4 (M + H) ⁺ . 142 AND nAU he / I XX (3S, 4S) -N- (4- hydroxytetrahydropyran3-yl) -7- (4- methoxybenzyl) -1-methyl1H-pyrrolo [3,2-b] pyridine 5-carboxamide Mass (m / z): 396.4 (M + H) ⁺ .

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Example 143. Determination of EC ₅₀ values of allosteric activity for the muscarinic M1 receptor.

For cellular analysis, a stable CHO cell line expressing the recombinant human muscarinic M1 receptor and the pCRE-Luc reporter system was used. The study provides a non-radioactive method for determining the binding of a compound to GPCR. This particular assay measures the level of 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 transparent bottom plates in Hams F12 medium containing 10% fetal bovine serum (FBS). Cells were kept in serum free medium overnight prior to addition of compounds or standard agonist. Increasing concentrations of test compounds were added to the cells along with the EC _{50 of} acetylcholine in OptiMEM medium. The incubation was continued at 37 ° C in a CO ₂ incubator for 4 hours. The medium was removed and the cells were washed with PBS. The cells were lysed and the luciferase activity was measured using a luminometer. Luminescence units were plotted on a graph of compound concentration using Graphpad software. EC ₅₀ values for compounds were defined as the concentration required to stimulate luciferase activity by 50% in the presence of acetylcholine EC ₅₀ , and the results are presented in table. 1.

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25 362 26 221 27 234 32 486 35 1469 36 3167 37 1251 38 983 39 968 40 755 41 1227 42 2289 43 2531 44 748 45 3148 46 2963 49 1414 50 2916 51 1821 53 31 54 764 55 32 56 38 61 222 72 494 73 786 76 380 77 342 87 241 90 18 97 6 98 109 103 131 104 231 106 fourteen 113 136 120 407 122 85 127 946 129 15 137 641 138 278

Example 144. Pharmacokinetic study in rodents.

Male Wistar rats (260 ± 50 g) were used as experimental animals. The animals were kept separately in polypropylene cages. Two days prior to the study, male Wistar rats were anesthetized with isoflurane for surgical placement of a jugular vein catheter. Rats were randomly divided for oral (3 mg / kg) and intravenous (1 mg / kg) administration (n = 3 per group) and fasted overnight before oral administration (oral). However, the rats intended for intravenous dosing were given food and water ad libitum.

At a predetermined time, blood was drawn through the jugular vein and replaced 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 collected at the following time points: 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. The blood was centrifuged at 4000 rpm for 10 min. Before the study, plasma was separated and stored frozen at -80 ° C. Plasma concentrations of test compounds were quantified using an appropriate LC-MS / MS method using a suitable extraction method. Test compounds were quantified over a calibration range of about 1-1000 ng / ml in plasma. Test samples were analyzed using batch calibration samples and control samples assigned to batch.

Pharmacokinetic parameters Cmax, AUCt, T _1/2 , clearance and bioavailability (F) were calculated from the non-compartmental model using the standard non-compartmental model using Phoenix WinNonlin software version 6,0,4.

table 2

Pharmacokinetic Profile of Test Compounds

Example No. ROA C ^ shah (ng / ml) AUCo-t (nghh / ml) T1 / 2 (h) Clearance (ml / min / kg) F (%) 1 orally (via probe) 373 ± 53 875 ± 215 1.3 ± 0.2 - 59 ± fourteen intravenously (bolus) - 796 ± 41 1.3 ± 0.3 34 ± 3 18 orally (via probe) 887 ± 74 2713 ± 769 3.6 ± 0, 1 - 106 ± thirty intravenously (bolus) - 853 ± 109 1.3 ± 0.2 20 ± 3 73 orally (via probe) 1097 ± 85 1737 ± 296 1.2 ± 0, 1 - 78 ± 13 intravenously (bolus) - 742 ± 40 1.1 ± 0.3 22 ± 1.0 87 orally (via probe) 97 ± 39 219 ± 70 0.7 ± 0.3 - 32 ± ten intravenously (bolus) - 224 ± 66 1.5 ± 0, 1 79 ± 27 103 orally (via probe) 825 ± 41 1093 ± 102 0.5 ± 0.2 - 46 ± 4 intravenously (bolus) - 791 ± eleven 0.7 ± 0, 1 21 ± 0 120 orally (via probe) 69 ± 12 234 ± 76 3.5 ± 3.3 - 13 ± 4 intravenously (bolus) - 593 ± 79 1.2 ± 0.3 28 ± 4 124 orally (via probe) 306 ± 66 526 ± 126 0.50 ± 0, 0 - 22 ± five intravenously (bolus) - 787 ± 130 1.1 ± 0, 1 21 ± 3

Example 145. Study of penetration into the brain of a rodent.

Male Wistar rats (260 ± 40 g) were used as experimental animals. Three animals were housed in separate cages. Throughout the experiment, animals were provided with water and food ad libitum and maintained on a 12 hour light / dark cycle.

Brain penetration in rats was determined discretely. On the day before dosing, male Wistar male rats were acclimated and randomly assigned to groups according to their weight. At each time point (0.50, 1 and 2 h) n = 3 animals were used.

Test compounds were suitably prepared and administered orally at (pure base equivalent) 3 mg / kg. Blood samples were collected by cardiac puncture using isoflurane anesthesia. For the selection of brain tissue, the animals were sacrificed. Plasma was removed prior to analysis and brain samples were homogenized and stored frozen at -20 ° C. The concentrations of the test compounds in plasma and brain were determined by LC-MS / MS.

The test compounds were quantified in plasma and brain homogenate by an appropriate LC-MS / MS method using a suitable extraction method. The test compounds were quantified in plasma and brain homogenate in the calibration range of 1-500 ng / ml. Test samples were analyzed using batch calibration samples and control samples,

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Table 3

Data of hematoencephalic penetration of the test compounds

Example 146. Model of object recognition tasks.

Male Wistar rats (8-10 weeks old) were used as experimental animals. Four animals were housed in separate cages. The day before the experiment, the animals were given 20% less food. Throughout the experiment, water was given in unlimited quantities. The animals were housed on a 12 hour light / dark cycle in a temperature and humidity controlled room. The experiment was carried out in a round or square acrylic arena. Rats were accustomed to separate arenas for up to 1 hour in the absence of any objects on the first day.

One group of 12 rats received vehicle and another group of animals received test compounds prior to familiarization (T ₁ ) and selection (T ₂ ) tests. In step reference (T1), rats were placed individually on an arena for three minutes, during which two identical objects (a1 and a ₂₎ located at a distance of 10 cm from the wall. A long-term memory test was carried out 24 hours after T ₁ . The same rats were housed in the same arena as in trial T ₁ . During the selection stage (T ₂ ), the rats were allowed to explore the arena for 3 min in the presence of a copy of a familiar object (a ₃ ) and one new object (b). During testing, T1 and _T2 study each object (defined as sniffing, licking, chewing or whisker movement with simultaneous nose to the object at a distance of less than 1 cm) were recorded using a stopwatch.

T 1 is the total time spent studying familiar objects (a1 + a ₂ ).

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

Object recognition research was performed as described in Behav. Brain Res. 1988, 31, 47-59.

Table 4

Recognition data of new objects of investigated compounds

Example No. Dose Average study time ± standard error of the mean (sec) Conclusion Familiar an object New object 1 3 mg / kg orally 12.67 ± 0.95 17.98 ± 1.77 Active 18 10 mg / kg orally 8.00 ± 2.88 14.38 ± 1.62 Active 103 3 mg / kg orally 12.20 ± 1.59 19.17 ± 3.01 Active 120 10 mg / kg orally 10.48 ± 1.02 15.43 ± 1.23 Active

Example 147. Model of object recognition tasks execution (combination research).

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

Male Wistar rats (8-10 weeks old) were used as experimental animals. Four animals were housed in separate cages. The day before the experiment, the animals were given 20% less food. Throughout the experiment, water was given in unlimited quantities. Animals were housed on a 12 hour light / dark cycle in a temperature controlled room and

- 110 035599 humidity. The experiment was carried out in an open acrylic arena. The rats were accustomed to separate arenas (open space) for 20 min in the absence of any objects on the first day.

One group of 12 rats received vehicle and another group of animals received a compound of formula (I) or donepezil or a compound of formula (I) and donepezil prior to the familiarization test (T ₁ ) and the selection test (T ₂ ). At the familiarization stage (T ₁ ), the rats were individually placed in the arena for 3 min, during which two identical objects (a ₁ and a ₂ ) were placed at a distance of 10 cm from the wall. A long-term memory test was carried out 24 hours after T ₁ . The same rats were housed in the same arena as in the T ₁ trial. During the selection step (T ₂ ), the rats were allowed to explore the arena for 3 min in the presence of a copy of a familiar object (a ₃ ) and one new object (b). During T ₁ and T ₂ tests, examinations of each object (defined as sniffing, licking, chewing, or moving the vibrissa while pointing the nose towards the object at a distance of less than 1 cm) were recorded using a stopwatch.

T ₁ - the total time spent on the study of familiar objects (a ₁ + a ₂ ).

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

Differentiation Index = time spent with a new object / (time spent with a new and familiar object).

Object recognition research was performed as described in Behav. Brain Res. 1988, 31, 47-59.

Procognitive effects were observed with the combination of the compound of Example 1 and donepezil. The results of this study are shown in FIG. 1.

Claims (9)

CLAIM 1. Compound of formula (I) where ring A is chosen from represents CH ₂ , CHF or CF2; choose from A ¹ R ¹ R ^a is OH; X ^{1 is} independently selected from CH2 and O; a is 0 or 1; R ^{2 is} selected from the group consisting of And ³ represents N or CH; And ⁴ represents CH or CF; R ^b in each occurrence is independently selected from halogen, -O- (C _1-4 ) alkyl, -3- ^ b ^ alkyl, -N (CH ₃ ) ₂ , - (C _1-4 ) alkyl, - (C _{3 -6} ) cycloalkyl, halo (C _1-4 ) alkyl, -OH, -NH2, -CN, phenyl, pyridyl, pyrazolyl, thiazolyl and oxazolyl, where phenyl, pyridyl, pyrazolyl, thiazolyl and oxazolyl are optionally substituted with one or more substituents, selected from the group consisting of halogen, -OH, -NH2, -CN, -O- (C _1-2 ) alkyl, -3- (C _1-2 ) alkyl, - (C _1-2 ) alkyl, or - ( C _3-6 ) cycloalkyl; R ^c represents hydrogen or - (C _1-4 ) alkyl; - 111 035599 X ^{2 is} independently selected from NH, —M- (C _1-2 ) alkyl, O and S; X ^{3 is} independently selected from CH and N; b is 0, 1 or 2; ^^ w <'represents the place of attachment; R ³ represents - (c-Dalkyl, halogen ^ Dalkyl or hydrogen; R ⁴ is hydrogen, - ^ Dalkyl or halogen ^ Dalkyl, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that the compound is selected from the group consisting of: ^ [(^^^ - hydroxycyclohexyl-to-fluoropyridinM-ylmethylM-methyl-III-pyrroloRD- EDpyridine-6-carboxamide; ^ [(^^^ - hydroxycyclohexylN-c-methoxypyridine ^ -ylmethylM-methyl-N-pyrroloREDEDpyridine-6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (2-fluoropyridin-5-ylmethyl) -1-methyl-III-pyrrolo [2,3EDpyridine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -4- (4-thiazol-4-ylbenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide; ^ [(^^^ - hydroxycyclohexyl-pyrazolL-ylbenzylM-methyl-III-pyrroloORD-EDpyridine6-carboxamide; ^ D ^^^ - hydroxycyclohexylN-H-C-methyl-III-pyrazolM-yl ^ enzyldHmethyl-Spyrrolo [2,3-b] pyridine-6-carboxamide; ^ [(^^^ - hydroxycyclohexyl-p-fluoroM-C-methyl-III-pyrazole ^ -yl ^ enzylN-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (2-methylpyridin-5-ylmethyl) -1-methyl-III-pyrrolo [2,3EDpyridine-6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (2-chloropyridin-4-ylmethyl) -1-methyl-III-pyrrolo [2,3EDpyridine-6-carboxamide; ^ [(^^^ - hydroxycyclohexyl-k ^ -difluoropyridine ^ -ylmethylM-methyl-III-pyrroloREDEDpyridine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -4- (benzothiazol-6-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -4- (2'-fluoro [2,5 '] bipyridinyl-5-ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6 - carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -4- (pyridin-4-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide; N - [(1 S, 2S) -2-hydroxycyclohexyl] -4- [2- (1-methyl-III-pyrazol-4-yl) pyridin-5-ylmethyl] -1-methyl III-pyrrolo [2,3- b] pyridine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -4- (2,3-difluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide; ^ [(^^^ - hydroxycyclohexylN-n-methylpyridinM-ylmethylM-methyl-N-pyrroloREDEDpyridine-6-carboxamide; ^ [(^^^ - hydroxycyclohexylN-to-chloropyridine ^ -ylmethylM-methyl-N-pyrroloREDEDpyridine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -4- (4-methoxybenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide; ^ [(^^^ - hydroxycyclohexyl-n-methylsulfanylpyridine ^ -ylmethylM-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -4- [4- (2-methylpyridin-3-yl) benzyl] -1-methyl-1H-pyrrolo [2,3EDpyridine-6-carboxamide; ^ [(^^^ - hydroxycyclohexylN-C-methyl-III-benzimidazole ^ -ylmethylM-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide; ^ [(^^^ - hydroxycyclohexylN-c-chloropyridine ^ -ylmethylM-c-fluoroethyl DSH-pyrroloREDEDpyridine-6-carboxamide; N- (2-hydroxy-2-methylpropyl) -4- [4- (thiazol-4-yl) benzyl] -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -4- (3-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide; N- (1-hydroxycyclopentylmethyl) -4- [4- (thiazol-4-yl) benzyl] -1-methyl-III-pyrrolo [2,3-b] pyridine-6carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -4- (pyridin-3-ylmethyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide; - 112 035599 H - [(AA) -2-hydroxycyclictohexyl | -4- (2-cyc.topropylpyridin-5-ylmethyl) -1-methyl-1H-pyrro.to [2,3b] pyridine-6-carboxamide; H - [(AA) -2-hydroxycyclohexyl | -4- (2- (|) torpyridin-4-ylmethyl) -1-ethyl-1H-pyrrolo [2.3b] pyridine-6-carboxamide; H - [(AA) -2-hydroxycyclohexyl | -4- (2 - (() torpyridin-4-ylmethyl) -1-isopropyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide; H - [(AA) -2-hydroxycyclohexyl | -4- (2.3-di (() torus (() enylmethyl) -1.3-dimethyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide; racemic trans-H- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide; trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1 -methyl-III-pyrrolo [2,3-b] pyridine-6carboxamide (isomer-I and isomer-II); racemic cis-H- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; cis-H- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -1-methyl-III-pyrrolo [2,3-b] pyridine-6carboxamide (isomer-I and isomer-II); racemic trans-H- (3-hydroxytetrahydropyran-4-yl) -4- (2-fluoropyridin-4-ylmethyl) -1-methyl1H-pyrrolo [2,3-b] pyridine-6-carboxamide; trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (2-fluoropyridin-4-ylmethyl) -1 -methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-I and isomer- II); racemic cis-H- (3-hydroxytetrahydropyran-4-yl) -4- (3,4-difluorobenzyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (3,4-difluorobenzyl) -1 -methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-I and isomer-II) ; racemic trans-H- (3-hydroxytetrahydropyran-4-yl) -4- (2,3-difluorobenzyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide; trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (2,3-difluorobenzyl) -1 -methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-I and isomer-II) ; racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (2,3-difluorobenzyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (2,3-difluorobenzyl) -1 -methyl-1H-pyrrolo [2,3 ^ pyridine N-carboxamide (isomer-I and isomer-II); racemic cis-H- (3-hydroxytetrahydropyran-4-yl) -4- (2-fluoropyridin-4-ylmethyl) -1-methyl1H-pyrrolo [2,3-b] pyridine-6-carboxamide; cis-H- (3-hydroxytetrahydropyran-4-yl) -4- (2-fluoropyridin-4-ylmethyl) -1-methyl-1H-pyrrolo [2,3 ^ pyridine ^ -carboxamide (isomer-I and isomer-II ); racemic cis-H- (3-hydroxytetrahydropyran-4-yl) -4- (2-chloropyridin-5-ylmethyl) -1-methyl1H-pyrrolo [2,3-b] pyridine-6-carboxamide; cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (2-chloropyridin-5-ylmethyl) -1-methyl-1H-pyrrolo [2,3 ^ pyridine ^ -carboxamide (isomer-I and isomer-II ); racemic trans-H- (3-hydroxytetrahydropyran-4-yl) -4- (2-chloropyridin-5-ylmethyl) -1-methyl1H-pyrrolo [2,3-b] pyridine-6-carboxamide; trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (2-chloropyridin-5-ylmethyl) -1 -methyl-1H-pyrrolo [2,3 ^ pyridine ^ -carboxamide (isomer-I and isomer-II ); racemic trans-H- (3-hydroxytetrahydropyran-4-yl) -4- (3,4-difluorobenzyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide; trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (3,4-difluorobenzyl) -1 -methyl-1H-pyrrolo [2,3 ^ pyridine N-carboxamide (isomer-I and isomer-II); racemic trans-H- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide; trans-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -1 -methyl-1H-pyrrolo [2,3 ^ pyridine ^ -carboxamide (isomer-I and isomer-II); racemic cis-H- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -1-methyl-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; cis-H- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -1-methyl-III-pyrrolo [2,3 ^ pyridine ^ -carboxamide (isomer-I and isomer-II); racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (1-methyl-1H-pyrazol-4-yl) benzyl] 1 -methyl-1H-pyrrolo [2,3-b] pyridine -6-carboxamide; trans-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (1-methyl-III-pyrazol-4-yl) benzyl] -1-methyl-Spirrolo [2,3-b] pyridine-6 β-carboxamide (isomer-I and isomer-II); racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (1-methyl-1H-pyrazol-4-yl) benzyl] -1methyl-1H-pyrrolo [2,3-b] pyridine- 6-carboxamide; - 113 035599 unc-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (1-methyl-1H-pyrazol-4-yl) benzyl] -1-methyl-1Hpyrrolo [2,3-b] pyridine-6-carboxamide (isomer-I and isomer-II); racemic trans-No. (3-hydroxytetrahydropyran-4-yl) -4- (4-methoxybenzyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide; trans-No. (3-hydroxytetrahydropyran-4-yl) -4- (4-methoxybenzyl) -1 -methyl-1H-pyrrolo [2,3EDpyridine-6-carboxamide (isomer-I and isomer-II); racemic cis-No. (3-hydroxytetrahydropyran-4-yl) -4- (4-methoxybenzyl) -1-methyl-III-pyrrolo [2,3-b] pyridine-6-carboxamide; unc-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-methoxybenzyl) -1 -methyl-1H-pyrrolo [2,3-b] pyridine6-carboxamide (isomer-I and isomer-II); racemic trans-No. (3-hydroxytetrahydropyran-4-yl) -4- (3-fluorobenzyl) -1-methyl-III-pyrrolo [2,3-b] pyridine-6-carboxamide; trans-No. (3-hydroxytetrahydropyran-4-yl) -4- (3-fluorobenzyl) -1 -methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide (isomer-I and isomer-II); racemic cis-N (3-hydroxytetrahydropyran-4-yl) -4- (3-fluorobenzyl) -1-methyl-III-pyrrolo [2,3-b] pyridine-6-carboxamide; cis-N (3-hydroxytetrahydropyran-4-yl) -4- (3-fluorobenzyl) -1-methyl-III-pyrrolo [2,3-b] pyridine-6carboxamide (isomer-I and isomer-II); racemic cis-N (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine-6-carboxamide; cis-N (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1-methyl-III-pyrrolo [2,3-b] pyridine-6carboxamide (isomer-I and isomer-II); racemic trans-No. (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1-methyl-III-pyrrolo [2,3-b] pyridine-6-carboxamide; trans-No. (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1 -methyl-1H-pyrrolo [2,3-b] pyridine-6carboxamide (isomer-I and isomer-II); racemic cis-No. (4-hydroxytetrahydropyran-3-yl) -4- (4-methoxybenzyl) -1-methyl-III-pyrrolo [2,3-b] pyridine-6-carboxamide; cis-No. (4-hydroxytetrahydropyran-3-yl) -4- (4-methoxybenzyl) -1-methyl-1H-pyrrolo [2,3-b] pyridine6-carboxamide (isomer-I and isomer-II); racemic trans-No. (4-hydroxytetrahydropyran-3-yl) -4- (4-methoxybenzyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide; trans-No. (4-hydroxytetrahydropyran-3-yl) -4- (4-methoxybenzyl) -1 -methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-I and isomer-II); racemic cis-N (4-hydroxytetrahydropyran-3-yl) -4- (2-methylpyridin-5-ylmethyl) -1-methyl1I-pyrrolo [2,3-b] pyridine-6-carboxamide; cis-No (4-hydroxytetrahydropyran-3-yl) -4- (2-methylpyridin-5-ylmethyl) -1 -methyl-1H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-I and isomer-II ); racemic trans-No. (4-hydroxytetrahydropyran-3-yl) -4- (2-methylpyridin-5-ylmethyl) -1-methyl1H-pyrrolo [2,3-b] pyridine-6-carboxamide; trans-N (4-hydroxytetrahydropyran-3-yl) -4- (2-methylpyridin-5-ylmethyl) -1-methyl-Spirrolo [2,3-b] pyridine-6-carboxamide (isomer-I and isomer-II ); (3 S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1-methyl-1I-pyrrolo [2,3-b] pyridine6-carboxamide; ^^) - No. (4-hydroxytetrahydropyran-3-yl) -4- (4-methoxybenzyl) -1-methyl-III-pyrrolo [2,3b] pyridine-6-carboxamide; (3S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4- (2-methylpyridin-5-ylmethyl) -1-methyl-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (2-chloropyridin-5-ylmethyl) -1-methyl-2,3-dihydro-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (2-fluoropyridin-4-ylmethyl) -1-methyl-2,3-dihydro-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (2-fluoropyridin-5-ylmethyl) -1-methyl-2,3-dihydro-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -1-methyl- (6-methylpyridin-3-ylmethyl) -2,3-dihydro-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3EDpyridine-6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-methoxybenzyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3EDpyridine-6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (2'-fluoro [2,5 '] bipyridinyl-5-ylmethyl) -1-methyl-2,3-dihydro1I-pyrrolo [2,3-b] pyridine-6-carboxamide; - 114 035599 H - [(^^) - 2-hydroxycyclictohexyl | -4- (2,3-di (|) torbenzyl) -1-methyl-2,3-dihydro-1H-pyrrolo [2,3b] pyridine-6 -carboxamide; H - [(^^) - 2-hydroxycyclohexyl | -4- (2-methyl-4-pyridinylmethyl) -1-methyl-2,3-dihydro-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; cis-H- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1 -methyl-2,3-dihydro-1H-pyrrolo [2,3b] pyridine-6-carboxamide (isomer-I and isomer-II); racemic cis-H- (4-hydroxytetrahydropyran-3-yl) -4- (4-methoxybenzyl) -1-methyl-2,3-dihydro1H-pyrrolo [2,3-b] pyridine-6-carboxamide; ^^) - H- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -1-methyl-2,3-dihydro-Spirrolo [2,3-b] pyridine-6-carboxamide; (3S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4- (4-methoxybenzyl) -1-methyl-2,3-dihydro-1Hpyrrolo [2,3-b] pyridine-6-carboxamide; (3S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4- (2-methylpyridin-5-ylmethyl) -1-methyl-2,3-dihydro1H-pyrrolo [2,3-b] pyridine- 6-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-chlorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-chlorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (3-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride; No. [(^^) - 2-hydroxycyclohexyl] -4- (3-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide; H - [(^^) - 2-hydroxycyclohexyl | -4- [4- (1-methyl-1H-pyrazol-4-yl) benzyl | -5.6.7.8 tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride; No. [(^^) - 2-hydroxycyclohexyl] -4- [4- (1-methyl-1H-pyrazol-4-yl) benzyl] -5,6,7,8tetrahydro [1,7 | on (thyridine-2 -carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (2-fluoropyridin-5-ylmethyl) -5,6,7,8tetrahydro [1,7 | on (thyridine-2-carboxamide hydrochloride; No. [(^^) - 2-hydroxycyclohexyl] -4- (2-fluoropyridin-5-ylmethyl) -5,6,7,8tetrahydro [1,7 | on (thyridine-2-carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-methoxybenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-methoxybenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (2-fluoropyridin-4-ylmethyl) -5,6,7,8-tetrahydro [1,7] on (thyridine-2-carboxamide hydrochloride; No. [(^^) - 2-hydroxycyclohexyl] -4- (2-fluoropyridin-4-ylmethyl) -5,6,7,8-tetrahydro [1,7] on (thyridine-2-carboxamide; No [(^^) - 2-hydroxycyclohexyl] -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -7-methyl-5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide; No. [(^^) - 2-hydroxycyclohexyl] -4- (4-fluorobenzyl) -7-ethyl-5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide; trans-H- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride ( isomer-II); racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -5,6,7,8tetrahydro [1,7 | on (thyridine-2-carboxamide hydrochloride ; cis-H- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride ( isomer-I and isomer-II); racemic trans-Н- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -5,6,7,8tetrahydro [1,7 | on (thyridine-2-carboxamide hydrochloride ; racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -5,6,7,8tetrahydro [1,7 | on (thyridine-2-carboxamide; cis-H- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl] -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer -I and isomer-II); - 115 035599 racemic trans-Н- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl | -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide ; trans-H- (3-hydroxytetrahydropyran-4-yl) -4- [4- (thiazol-4-yl) benzyl | -5.6.7.8-tetrahydro [1.7 | naphthyridine-2-carboxamide (isomer-I and isomer-II ); trans-H- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride (isomer-I and isomer-II); racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride; cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride (isomer-I and isomer-II); racemic trans-H- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride; racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide; cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide (isomer-I and isomer-II); racemic trans-H- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide; trans-H- (3-hydroxytetrahydropyran-4-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide (isomer-I and isomer-II); trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-I and isomer-II); racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride; racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride; cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-I and isomer-II); racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide; trans-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-I and isomer-II); racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide; cis-N- (3-hydroxytetrahydropyran-4-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide (isomer-I and isomer-II); cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride (isomer-I and isomer-II); racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride; racemic trans-H- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride; trans-H- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide hydrochloride (isomer-I and isomer-II); racemic cis-H- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide; cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide (isomer-I and isomer-II); racemic trans-H- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide; trans-H- (4-hydroxytetrahydropyran-3-yl) -4- (4-fluorobenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2carboxamide (isomer-I and isomer-II); racemic cis-H- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride; cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-I and isomer-II); racemic trans-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride; trans-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro [1,7] naphthyridine-2-carboxamide hydrochloride (isomer-I and isomer-II); racemic cis-N- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide; - 116 035599 cis-Н- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro | 1,7 | naphthyridine-2-carboxamide (isomer -I and isomer-II); racemic trans-H- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8tetrahydro [1,7] naphthyridine-2-carboxamide; trans-H- (4-hydroxytetrahydropyran-3-yl) -4- (4-pyrazol-1-ylbenzyl) -5,6,7,8-tetrahydro | 1,7 | naphthyridine-2-carboxamide (isomer-I and isomer-II); H- | (^^) - 2-hydroxycyclohexyl | -8- (4-fluorobenzyl) -2,3-dihydro | 1,4 | dioxino | 2,3-b | pyridine-6carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- (4-methoxybenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- (2-chloropyridin-5-ylmethyl) -2,3-dihydro [1,4] dioxino [2,3L | pyridine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- [4- (1-methyl-1H-pyrazol-4-yl) benzyl] -2,3-dihydro [1,4] dioxino [2,3 -b] pyridine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- (2,3-difluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- (1-methyl-1H-pyrazol-4-ylmethyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine- 6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- [4- (pyrazol-1-yl) benzyl] -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6 -carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- (2-methylpyridin-5-ylmethyl) -2,3-dihydro [1,4] dioxino [2,3L | pyridine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- (2-fluoropyridin-5-ylmethyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- (2-fluoropyridin-4-ylmethyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxamide; trans-N- (3-hydroxyterahydropyran-4-yl) -8- (4-fluorobenzyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine-6-carboxamide (isomer-I and isomer-II); cis-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) -2,3-dihydro | 1,4 | dioxino | 2,3-b | pyridine-6-carboxamide (isomer-I and isomer-II); racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) -2,3-dihydro | 1,4 | dioxino | 2,3-b | pyridine-6-carboxamide; racemic trans-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) -2,3-dihydro | 1,4 | dioxino | 2,3-b | pyridine-6-carboxamide; (^^) - H- (4-hydroxytetrahydropyran-3-yl) -8- (4-methoxybenzyl) -2,3-dihydro | 1,4 | dioxino | 2,3b | pyridine-6-carboxamide; (^^) - H- (4-hydroxytetrahydropyran-3-yl) -8- (4 - (() torbenzyl) -2,3-dihydro | 1,4 | dioxino | 2,3b | pyridine-6-carboxamide; (3 S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -8- (2-chloropyridin-5-ylmethyl) -2,3-dihydro | 1,4 | dioxino | 2,3-b | pyridine-6-carboxamide; (3 S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -8- (2-methylpyridin-5-ylmethyl) -2,3-dihydro | 1,4 | dioxino | 2,3-b | pyridine-6-carboxamide; racemic cis-H- (4-hydroxytetrahydropyran-3-yl) -8- (4-fluorobenzyl) -2,3-dihydro | 1,4 | dioxino | 2,3-b | pyridine-6-carboxamide; racemic cis-H- (4-hydroxytetrahydropyran-3-yl) -8- (4-methoxybenzyl) -2,3-dihydro | 1,4 | dioxino | 2,3-b | pyridine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- (4-fluorobenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- (3-fluorobenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- [4- (1-methyl-1H-pyrazol-4-yl) benzyl] -4-methyl-2H-pyrido [3,2b || 1, 4 | oxazine-6-carboxamide; N - [(1S, 2S) -2-hydroxycyclohexyl] -8- (2-fluoropyridin-4-ylmethyl) -4-methyl-2H-pyrido [3.2b || 1.4 | oxazine-6-carboxamide; racemic cis-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) -4-methyl-2H-pyrido [3.2b || 1.4 | oxazine-6-carboxamide; cis-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) -4-methyl-2H-pyrido (3.2 - ^ (1,4 | oxazine6-carboxamide (isomer-I); racemic trans-H- (3-hydroxytetrahydropyran-4-yl) -8- (4-fluorobenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide; trans-N- (3-hydroxyterahydropyran-4-yl) -8- (4-fluorobenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide (isomer-I and isomer-II); - 117 035599 trans-H- (3-hydroxytetrahydropyran-4-yl) -8- (4-methoxybenzyl) -4-methyl-2H-pyrido [3,2-b | [1,4 | oxazine-6-carboxamide ( isomer-I and isomer-II); racemic trans ^ - (3-hydroxytetrahydropyran-4-yl) -8- (4-methoxybenzyl) -4-methyl-2Hpyrido [3,2-b] [1,4] oxazine-6-carboxamide; racemic cis-No. (3-hydroxytetrahydropyran-4-yl) -8- (4-methoxybenzyl) -4-methyl-2Hpyrido [3,2-b] [1,4] oxazine-6-carboxamide; unc-N- (3-hydroxytetrahydropyran-4-yl) -8- (4-methoxybenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide (isomer-I and isomer-II); No. [(U ^) - 2-hydroxycyclohexyl] -8- (2-chloropyridin-5-ylmethyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide; No. [(U ^) - 2-hydroxycyclohexyl] -8- (4-methoxybenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6carboxamide; No. [(U ^) - 2-hydroxycyclohexyl] -8- (2-methylpyridin-5-ylmethyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide; N - [(1 S, 2S) -2-hydroxycyclohexyl] -8- [4-pyrazol-1-ylbenzyl] -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6- carboxamide; No. [(W ^) - 2-hydroxycyclohexyl] -4-methyl-8- (1-methyl-1H-pyrazol-4-ylmethyl) -2H-pyrido [3.2b] [1,4] oxazine-6-carboxamide ; racemic cis-No. (4-hydroxytetrahydropyran-3-yl) -8- (4-fluorobenzyl) -4-methyl-2H-pyrido [3,2b] [1,4] oxazine-6-carboxamide; racemic cis-No. (4-hydroxytetrahydropyran-3-yl) -8- (4-methoxybenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6-carboxamide; (3 S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -8- (4-fluorobenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6- carboxamide; (3 S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -8- (4-methoxybenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6- carboxamide; ^^) - No. (4-hydroxytetrahydropyran-3-yl) -8- (4-pyrazol-1-ylbenzyl) -4-methyl-2H-pyrido [3,2-b] [1,4] oxazine-6- carboxamide and (3S, 4S) -N- (4-hydroxytetrahydropyran-3-yl) -4-methyl-8- (1-methyl-1H-pyrazol-4-ylmethyl) -2Hpyrido [3,2-b] [1 , 4] oxazine-6-carboxamide, or a pharmaceutically acceptable salt thereof. 3. A pharmaceutical composition for the treatment of a disease or disorder mediated by the muscarinic M1 receptor, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 and pharmaceutically acceptable excipients, wherein the disease or disorder is selected from cognitive disorders , pain or sleep disorder. 4. A combination for treating a disease or disorder mediated by a muscarinic M1 receptor, comprising a therapeutically effective amount of a compound according to claim 1 or 2 and one or more therapeutic agents selected from an acetylcholinesterase inhibitor, wherein the acetylcholinesterase inhibitor is donepezil or a pharmaceutically acceptable salt thereof. 5. The use of a compound according to claim 1 or 2 for the treatment of a disease or disorder mediated by the muscarinic M1 receptor, wherein the disease or disorder is selected from cognitive disorders, pain or sleep disorder. 6. Use according to claim 5, wherein the cognitive disorder is selected from the group consisting of dementia in Alzheimer's disease, dementia in Parkinson's disease, dementia in Huntington's disease, dementia associated with Down's syndrome, dementia associated with Tourette's syndrome, dementia associated with postmenopausal, frontotemporal dementia, Lewy body dementia, vascular dementia, dementia in HIV, dementia in Creutzfeldt-Jakob disease, persistent dementia due to substance use, dementia in Pick's disease, dementia in schizophrenia, senile dementia, and dementia in general disorders organism. 7. The composition of claim 3, wherein the cognitive disorder is selected from the group consisting of Alzheimer's dementia, Parkinson's dementia, Huntington's dementia, Down's syndrome dementia, Tourette's dementia, Tourette's dementia, postmenopausal, frontotemporal dementia, Lewy body dementia, vascular dementia, dementia in HIV, dementia in Creutzfeldt-Jakob disease, persistent dementia due to substance use, dementia in Pick's disease, dementia in schizophrenia, senile dementia, and dementia in general disorders organism. 8. The combination of claim 4, wherein the disease or disorder is selected from the group consisting of Alzheimer's dementia, Parkinson's dementia, Huntington's dementia, Down's syndrome dementia, Tourette's dementia, Tourette's dementia, with postmenopause, frontotemporal dementia, Lewy body dementia, vascular dementia, HIV dementia, dementia with Creutzfeldt-Jakob disease, persistent dementia caused by - 118 035599 use of psychoactive substances, dementia in Pick's disease, dementia in schizophrenia, senile dementia and dementia in general disorders of the body. 9. Use of a compound of formula (I) according to any one of claims 1 or 2 in the manufacture of a medicament for the treatment of a disease or disorder mediated by a muscarinic M1 receptor selected from cognitive disorders, pain and sleep disorders.