HK1195910A

HK1195910A - Novel pyrazine derivatives

Info

Publication number: HK1195910A
Application number: HK14109388.5A
Authority: HK
Inventors: 卡泰丽娜．比桑茨; 巴莱蒂．德瓦苏禄; 尤伟．格雷瑟; 阿尼达．哈斯拉; 保罗．哈巴森; 斯蒂芬．勒韦尔; 马克．罗杰斯-埃文斯
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2011-10-28
Filing date: 2012-10-25
Publication date: 2014-11-28

Description

Novel pyrazine derivatives

The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to compounds which are preferential agonists of cannabinoid receptor 2. The compounds of formula (I) are particularly useful for the treatment or prophylaxis of, for example, pain, in particular chronic pain, atherosclerosis (atherosclerosis), regulation of bone mass (regulation of bone mass), inflammation (inflammation), ischemia (ischemia), reperfusion injury (reperfusion injury), systemic fibrosis (systemic fibrosis), liver fibrosis (1 driver fibrosis), lung fibrosis (1 ng fibrosis), kidney fibrosis (kidney fibrosis), chronic allograft nephropathy (chronic allograft nephropathy), congestive heart failure (congestive heart failure), myocardial infarction (myocardial infarction), systemic sclerosis (systemic sclerosis), glomerulonephropathy (glomerular nephelopathies), thermal injury (burn injury), hypertrophic (scar), gingivitis (scar), and/or scar (1) of the liver.

The invention relates in particular to compounds of the formula (I)

Wherein

R¹Is halophenyl or cycloalkylalkoxy;

R²is cycloalkyl, azetidinyl or difluoroazetidinyl;

R³and R⁴One of which is hydrogen and the other is- (CR)⁵R⁶)-R⁷or-A-R⁷；

Or R²Is cycloalkyl andR³and R⁴Together with the nitrogen atom to which they are attached form a piperidinyl or piperidinylamine;

R⁵and R⁶Independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl and halophenyl;

or R⁵And R⁶Together with the carbon atom to which they are attached form a cycloalkyl or oxetanyl group;

R⁷is cyano, carboxy, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-amino- [1, 2, 4 ]]Oxadiazol-3-yl, 5-alkoxy- [1, 2, 4 ]]Oxadiazol-3-yl, thiazolyl, alkylthiazolyl, pyridyl, alkylaminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, alkoxycarbonyl, dialkylaminocarbonyl, methanesulfonyl-alkyl, 2- [1, 2, 4 ] methyl]Oxadiazol-5-yl) -alkyl, 2-methyl-2H- [1, 2, 4]Triazol-3-yl, 2- (2-methyl-2H- [1, 2, 4 ]]Triazol-3-yl) -alkyl, 2, 4-dihydro- [1, 2, 4]Triazol-3-one-5-yl, 2- (2, 4-dihydro- [1, 2, 4)]Triazol-3-on-5-yl) -alkyl, phenyl, phenylalkyl, pyridylalkyl, pyrazolyl, pyrazolylalkyl, [1, 2, 4]Triazol-1-yl, 2- ([1, 2, 4)]Triazol-1-yl) -alkyl, alkylaminocarbonylalkyl, hydroxyalkylaminocarbonyl, hydroxyalkylaminocarbonylalkyl, haloalkylaminocarbonyl, 5-phenyl-2-methyl-Oxazol-4-yl-alkyl, aminocarbonylalkyl or halogen; and

a is cyclohexyl or thienyl;

with the proviso that when R²Is azetidinyl or difluoroazetidinyl and R⁷Is hydroxyalkyl, haloalkyl, thiazolyl, pyridyl, 2- ([1, 2, 4 ]]Oxadiazol-5-yl) -alkyl, pyridylalkyl, pyrazolylalkyl, 2- ([1, 2, 4 ] methyl]Triazol-1-yl) -alkyl, aminocarbonyl or alkoxycarbonyl, then R⁵And R⁶One is cycloalkyl, cycloalkylalkyl, phenyl, halophenyl or phenylalkyl and the other is hydrogen or alkyl; or then R⁵And R⁶Together with the carbon atom to which they are attached form a cycloalkyl or oxetanyl group;

or a pharmaceutically acceptable salt or ester thereof.

Cannabinoid receptors are a class of cell membrane receptors belonging to the G protein-coupled receptor superfamily. There are currently two known subtypes, known as cannabinoid receptor 1(CB1) and cannabinoid receptor 2(CB 2). The CB1 receptor is expressed predominantly in the central nervous (i.e. amygdala cerebellum, hippocampus) system and in lesser amounts in the periphery. CB2 encoded by the CNR2 gene is expressed predominantly on cells of the immune system, such as macrophages and T-cells (Ashton, J.C. et al, Curr Neuropharmacol2007, 5(2), 73-80; Miller, A.M. et al, Br J Pharmacol2008, 153(2), 299-308; Centonze, D., et al, Curr Pharm Des2008, 14(23), 2370-42), and peripherally in the gastrointestinal system (Wright, K.L. et al, Br J Pharmacol2008, 153(2), 263-70). The CB2 receptor is also widely distributed in the brain, where it is found primarily on microglia rather than neurons (Cabral, g.a. et al Br J Pharmacol2008, 153 (2): 240-51).

Interest in agonists of the CB2 receptor has steadily increased over the past decade (there are currently 30-40 patent applications/years) due to the fact that several of the early compounds have been shown to have beneficial effects in preclinical models of many human diseases, including chronic pain (Beltramo, m.mini Rev Med Chem2009, 9(1), 11-25), atherosclerosis (Mach, f. et al J neuroendinor 2008, 20Suppl1, 53-7), regulation of bone mass (Bab, i. et al Br J Pharmacol2008, 153(2), 182-8), neuroinflammation (Cabral, g.a. et al J leukobio 2005, 78(6), 1192-7), ischemia/reperfusion injury (Pacher, p. et al Br J Pharmacol2008, 153, 252-62), systemic fibrosis (hmetashi, a. atharitis, r 2009-9, gozaz-36; gozaz, E. et al rheumatology (oxford)2009, 48(9), 1050-6), liver fibrosis (Julien, b. et al Gastroenterology2005, 128(3), 742-55; Munoz-Luque, J. et al J Pharmacol Exp Ther2008, 324(2), 475-83).

Ischemia/reperfusion (I/R) injury is the leading cause of tissue damage that occurs in conditions such as stroke, myocardial infarction, cardiopulmonary bypass and other vascular procedures, and organ transplantation, and is the major mechanism of end organ damage that complicates the circulatory shock process of various etiologies. All of these disorders are characterized by an interruption of normal blood supply, resulting in inadequate tissue oxygenation. Reoxygenation, e.g. reperfusion, is the final treatment to restore normal tissue oxygenation. But the lack of oxygen and nutrients from the blood produces a condition in which the restoration of circulation leads to further tissue damage. Reperfusion injury is caused in part by the inflammatory response of the damaged tissue. Leukocytes transported to the area by the newly regurgitated blood release large amounts of inflammatory factors such as interleukins and free radicals in response to tissue damage. The restored blood flow reintroduces intracellular oxygen, which damages cellular proteins, DNA, and plasma membranes.

Remote Ischemic Preconditioning (RIPC) represents a strategy to exploit the body's endogenous protective capacity against damage caused by ischemia and reperfusion. It describes the interesting phenomenon where transient non-lethal ischemia and reperfusion of one organ or tissue confers resistance to subsequent events of "lethal" ischemia reperfusion injury in distant organs or tissues. Despite several hypotheses, the actual mechanism by which transient ischemia and reperfusion of an organ or tissue confers protection is currently unknown.

The fluid hypothesis suggests various intracellular pathways for endogenous substances produced in distant organs or tissues (such as adenosine, bradykinin, opioids, CGRP, endocannabinoids, angiotensin I or some other not yet identified fluid factor) to enter the blood stream and activate their respective receptors in the target tissue and thereby restore cardioprotection involved in ischemic preconditioning.

Recent data indicate that endocannabinoids and their receptors, in particular CB2, may be involved in pretreatment and contribute to the prevention of reperfusion injury through down-regulation of the inflammatory response (pocher, p. et al Br J Pharmacol2008, 153(2), 252-62). In particular, recent studies using CB2 tool agonists have shown the efficacy of this concept for reducing I/R damage in the heart (Defer, n. et al faeb J2009, 23(7), 2120-30), brain (Zhang, m. et al J Cereb Blood Flow Metab2007, 27(7), 1387-96), liver (Batkai, s. et al faeb J2007, 21(8), 1788-.

Furthermore, over the past years, increasing literature has shown that CB2 may also be of interest in subchronic and chronic situations. Specific up-regulation of CB1 and CB2 has been shown to be associated with CB 2-related expression in myofibroblasts, i.e. cells that are responsible for the progress of fibrosis, in animal models of chronic diseases associated with fibrosis (Garcia-Gonzalez, e. et al rheumatology (oxford)2009, 48(9), 1050-6; Yang, Y Y et al Liver Int2009, 29(5), 678-85).

Activation of the CB2 receptor by selective CB2 agonists has in fact been shown to produce an anti-fibrotic effect in diffuse systemic sclerosis (Garcia-Gonzalez, e. et al rheumatogy (oxford)2009, 48(9), 1050-6) and CB2 receptor has been shown to be a key target in experimental dermal fibrosis (akhmmetshina, a. et al Arthritis Rheum2009, 60(4), 1129-36) and in liver pathophysiology, including fibrosis associated with chronic liver disease (Lotersztajn, s. et al gastroentreol Clin Biol2007, 31(3), 255-8; Mallat, a. et al Expert op tar Targets2007, 11(3), 403-9; Lotersztajn, s. et 2008 et al Br J (pha286), 153-9).

The compounds of the present invention bind to and modulate the CB2 receptor and have reduced CB1 receptor activity.

In the present specification, the term "alkyl", alone or in combination, denotes a linear or branched alkyl group having from 1 to 8 carbon atoms, in particular a linear or branched alkyl group having from 1 to 6 carbon atoms, more in particular a linear or branched alkyl group having from 1 to 4 carbon atoms. Straight and branched C₁-C₈Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyl groups, the isomeric hexyl groups, the isomeric heptyl groups and the isomeric octyl groups, in particular methyl, ethyl, propyl, butyl and pentyl groups, more particularly methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl and isopentyl groups. Specific examples of alkyl groups are methyl, ethyl, propyl, isopropyl, tert-butyl and isobutyl.

The term "cycloalkyl", alone or in combination, denotes a cycloalkyl ring having 3 to 8 carbon atoms, and in particular a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. Particular cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl and cyclobutyl are particular examples.

The term "alkoxy", alone or in combination, denotes a group of formula alkyl-O-, wherein the term "alkyl" has the meaning given before, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, especially methoxy and ethoxy.

The term "cycloalkyloxy" or "cycloalkoxy", alone or in combination, denotes a group of the general formula cycloalkyl-O-, wherein the term "cycloalkyl" has the previously given meaning, such as cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.

The term "phenoxy", alone or in combination, denotes a phenyl-O-group.

The term "oxy", alone or in combination, denotes an-O-group.

The term "halogen" or "halo", alone or in combination, denotes fluorine, chlorine, bromine or iodine and especially fluorine, chlorine or bromine and more especially fluorine and chlorine. The term "halo", in combination with another group, means that the group is substituted with at least one halogen, in particular with one to five halogens, in particular one to three halogens. Particular halogens are fluorine and chlorine.

The term "haloalkyl", alone or in combination, denotes an alkyl group substituted with at least one halogen, in particular with one to five halogens, in particular one to three halogens. A particular "haloalkyl" is trifluoromethyl.

The terms "hydroxy" and "hydroxyl", alone or in combination, represent an-OH group.

The term "carbonyl", alone or in combination, denotes a-c (o) -group.

The term "carboxyl (carboxyl)" or "carboxyl (carboxyl)", alone or in combination, denotes a-COOH group.

The term "amino", alone or in combination, denotes a primary amino group (-NH2), a secondary amino group (-NH-) or a tertiary amino group (-N-).

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, and which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. In addition, these salts can be prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to, salts of: primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The compounds of formula (I) may also be present in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula (I) are salts of hydrochloric, hydrobromic, sulfuric, phosphoric and methanesulfonic acids.

By "pharmaceutically acceptable ester" is meant a derivative of the compound of formula (I) which can be derivatized at a functional group to provide a derivative capable of conversion back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ester, methylthiomethyl ester and pivaloyloxymethyl ester. Furthermore, any physiologically acceptable equivalent of a compound of formula (I) that is capable of producing the parent compound of formula (I) in vivo, like metabolically labile esters, is also within the scope of the invention.

If one of the starting materials or the compound of formula (I) contains one or more functional Groups which are unstable or reactive under the reaction conditions of one or more reaction steps, suitable protecting Groups can be introduced before the critical step using methods known in the art (as described, for example, in T.W.Greene and P.G.M.Wutts in "Protective Groups in Organic Chemistry", 3 rd edition, 1999, Wiley, New York). Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are t-butyloxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), benzyloxycarbonyl (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

The compounds of formula (I) may contain several asymmetric centers and may be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

The term "asymmetric carbon atom" means a carbon atom having four different substituents. According to Cahn-Ingold-Prelog Convention, the asymmetric carbon atoms may be in either the "R" or "S" configuration.

The invention relates in particular to compounds of formula (I) wherein:

R¹is halophenyl or cycloalkylalkoxy;

R²is cycloalkyl, azetidinyl or difluoroazetidinyl;

R³and R⁴One of which is hydrogen and the other is- (CR)⁵R⁶)-R⁷；

Or R²Is cycloalkyl and R³And R⁴Together with the nitrogen atom to which they are attached form a piperidinyl group;

R⁵and R⁶Independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;

or R⁵And R⁶Together with the carbon atom to which they are attached form a cycloalkyl group;

R⁷is cyano, carboxy, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-amino- [1, 2, 4 ]]Oxadiazol-3-yl, 5-alkoxy- [1, 2, 4 ]]Oxadiazol-3-yl, thiazolyl, alkylthiazolyl, pyridyl, alkylaminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, alkoxycarbonylDialkylaminocarbonyl, methanesulfonyl-alkyl, 2- [1, 2, 4 ]]Oxadiazol-5-yl) -alkyl, 2-methyl-2H- [1, 2, 4]Triazol-3-yl, 2- (2-methyl-2H- [1, 2, 4 ]]Triazol-3-yl) -alkyl, 2, 4-dihydro- [1, 2, 4]Triazol-3-one-5-yl, 2- (2, 4-dihydro- [1, 2, 4)]Triazol-3-on-5-yl) -alkyl, phenyl, phenylalkyl, pyridylalkyl, pyrazolyl, pyrazolylalkyl, [1, 2, 4]Triazol-1-yl, 2- ([1, 2, 4)]Triazol-1-yl) -alkyl, alkylaminocarbonylalkyl, hydroxyalkylaminocarbonyl or hydroxyalkylaminocarbonylalkyl; with the proviso that when R²Is azetidinyl or difluoroazetidinyl and R⁷Is hydroxyalkyl, haloalkyl, thiazolyl, pyridyl, 2- ([1, 2, 4 ]]Oxadiazol-5-yl) -alkyl, pyridylalkyl, pyrazolylalkyl, 2- ([1, 2, 4 ] methyl]Triazol-1-yl) -alkyl, aminocarbonyl or alkoxycarbonyl, then R⁵And R⁶One is cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl and the other is hydrogen or alkyl;

or a pharmaceutically acceptable salt or ester thereof.

The invention relates in particular to the following:

a compound of formula (I) wherein R¹Is cycloalkylalkoxy;

a compound of formula (I) wherein R¹Is a cyclopropylmethoxy group;

a compound of formula (I) wherein R²Is cycloalkyl or difluoroazetidinyl;

a compound of formula (I) wherein R²Is cyclopropyl or difluoroazetidinyl;

a compound of formula (I) wherein R²Is cycloalkyl, especially cyclopropyl, and R³And R⁴Together with the nitrogen atom to which they are attached form a piperidinyl or piperidinylamine;

a compound of formula (I) wherein R⁵And R⁶Independently selected from hydrogen, alkyl and cycloalkylalkyl;

a compound of formula (I) wherein R⁵And R⁶Independently selected from hydrogen, ethyl, tert-butyl, isobutyl and cyclopropylmethyl;

a compound of formula (I) wherein R⁵And R⁶Independently selected from hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;

a compound of formula (I) wherein R⁵And R⁶Independently selected from hydrogen, ethyl, tert-butyl, isobutyl, cyclopropyl, cyclopropylmethyl and cyclobutylmethyl;

a compound of formula (I) wherein R⁵And R⁶Both are alkyl, in particular both are methyl;

a compound of formula (I) wherein R⁵And R⁶One is alkyl and the other is cycloalkyl or cycloalkylalkyl;

a compound of formula (I) wherein R⁵And R⁶One is methyl and the other is cyclopropyl or cyclopropylmethyl;

a compound of formula (I) wherein R⁵And R⁶One of which is selected from ethyl, tert-butyl, isobutyl and cyclopropylmethyl and the other is hydrogen or ethyl;

a compound of formula (I) wherein R⁵And R⁶One of which is selected from ethyl, tert-butyl, isobutyl, cyclopropylmethyl and cyclobutylmethyl and the other is hydrogen or ethyl.

A compound of formula (I) wherein R⁵And R⁶Together with the carbon atom to which they are attached form a cyclobutyl, cyclohexyl or oxetanyl group, in particular a cyclobutyl or cyclohexyl group;

a compound of formula (I) wherein R⁷Is cyano, carboxy, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-amino- [1, 2, 4 ]]Oxadiazol-3-yl, thiazolyl, alkylthiazolyl, pyridyl, alkylaminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl, 5-methyl-thiazol-2-yl, aminocarbonylalkyl or phenylalkyl;

a compound of formula (I) wherein R⁷Is alkoxyalkyl, aminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl, 5-methyl-thiazol-2-yl, aminocarbonylalkyl, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, hydroxyalkyl or phenylalkyl;

a compound of formula (I) wherein R⁷Is methoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, 5-methyl-thiazol-2-yl, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, aminocarbonylmethyl, hydroxymethyl, methoxyethyl or phenylethyl;

a compound of formula (I) wherein R⁷Is cyano, carboxy, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-amino- [1, 2, 4 ]]Oxadiazol-3-yl, thiazolyl, alkylthiazolyl, pyridyl, alkylaminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl or dialkylaminocarbonyl;

a compound of formula (I) wherein R⁷Is cyano, carboxy, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-amino- [1, 2, 4 ]]Oxadiazol-3-yl, thiazolyl, methylthiazolyl, pyridyl, methylaminocarbonyl, hydroxymethyl, hydroxypropyl, methoxyalkyl, aminocarbonyl or dimethylaminocarbonyl;

a compound of formula (I) wherein R⁷Is alkoxyalkyl, aminocarbonyl or dialkylaminocarbonyl;

a compound of formula (I) wherein R⁷Is methoxycarbonyl, aminocarbonyl or dimethylaminocarbonyl;

the compound of formula (I) is selected from

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-an amide;

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid (cyano-dimethyl-methyl) -amide;

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid [1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclobutyl]-an amide;

6- (3-chloro-phenyl) -5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-an amide;

5-azetidin-1-yl-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]-an amide;

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl) -amide;

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid piperidin-1-ylamide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -2, 2-dimethyl-1-methylcarbamoyl-propyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclobutyl]-an amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-hydroxy-1, 1-dimethyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclobutyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclobutyl]-an amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-1-methyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -2, 2-dimethyl-1-methylcarbamoyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -carbamoyl-phenyl-methyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid piperidin-1-ylamide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-2, 2-dimethyl-propyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -2-cyclopropyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-an amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-cyclopropyl-2-hydroxy-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -carbamoyl-phenyl-methyl) -amide;

(S) -2- [ (5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl) -amino ] -3, 3-dimethyl-butyric acid methyl ester;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -2-cyclopropyl-1-methylcarbamoyl-ethyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -2-cyclopropyl-1-dimethylcarbamoyl-ethyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -3-methyl-1-methylcarbamoyl-butyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-dimethylcarbamoyl-3-methyl-butyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-carbamoyl-2-cyclopropyl-ethyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-carbamoyl-3-methyl-butyl) -amide;

2- [ (5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl) -amino ] -2-ethyl-butyric acid methyl ester;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -2-cyclopropyl-1-methylcarbamoyl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -2-cyclopropyl-1-dimethylcarbamoyl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -3-methyl-1-methylcarbamoyl-butyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-dimethylcarbamoyl-3-methyl-butyl) -amide;

(S) -3-cyclopropyl-2- [ (5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl) -amino ] -propionic acid methyl ester;

(S) -3-cyclopropyl-2- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl ] -amino } -propionic acid methyl ester;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-carbamoyl-2-phenyl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-carbamoyl-2-phenyl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-carbamoyl-2-cyclopropyl-ethyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (S) -cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-an amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (R) -cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-an amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-an amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (R) -cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-an amide;

(S) -2- [ (5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl) -amino ] -3, 3-dimethyl-butyric acid;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-an amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-pyridin-2-yl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((R) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((R) -1-hydroxymethyl-1, 2-dimethyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-hydroxymethyl-1, 2-dimethyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ 1-methyl-1- (4-methyl-thiazol-2-yl) -ethyl ] -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (4-methyl-thiazol-2-yl) -ethyl ] -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (R) -1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-an amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1- (5-amino- [1, 2, 4 ]]Oxadiazol-3-yl) -1-methyl-ethylBase of]-an amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [1- (5-amino- [1, 2, 4 ]]Oxadiazol-3-yl) -1-methyl-ethyl]-an amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-carbamoyl-1-phenyl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-an amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4 [ ] -]Oxadiazol-3-yl) -ethyl]-an amide; and

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]-an amide.

The invention also relates in particular to compounds of formula (I) selected from

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (S) -carbamoyl- (4-fluoro-phenyl) -methyl ] -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -carbamoyl- (4-fluoro-phenyl) -methyl ] -amide;

5-cyclopropyl-6-cyclopropylMethoxy-pyrazine-2-carboxylic acid [ (S) -2-cyclopropyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]-an amide;

(S) -2- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl ] -amino } -4-methyl-pentanoic acid methyl ester;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -3-methyl-1- (2, 2, 2-trifluoro-ethylcarbamoyl) -butyl ] -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -carbamoyl- (4-chloro-phenyl) -methyl ] -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (4-hydroxy-1, 1-dimethyl-butyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1, 1-dimethyl-3-pyridin-4-yl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1, 1-dimethyl-2- (5-methyl-2-phenyl-Oxazol-4-yl) -ethyl]-an amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1, 1-dimethyl-3-pyridin-4-yl-butyl) -amide;

1- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl ] -amino } -cyclobutanecarboxylic acid methyl ester;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl-thiazol-2-yl) -ethyl ] -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl-thiazol-2-yl) -ethyl ] -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-carbamoylmethyl-2-methyl-propyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-carbamoylmethyl-2-methyl-propyl) -amide;

(+) -6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-an amide;

(-) -6-Cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-an amide;

2-cyclopropyl-2- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl ] -amino } -propionic acid methyl ester;

(+) -6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((1R, 2S) -rel-2-carbamoyl-cyclohexyl) -amide;

(-) -5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid cis-2-carbamoyl-cyclohexyl) -amide;

(+) -5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid cis-2-carbamoyl-cyclohexyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl) -amide;

(+) -6-Cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-an amide;

(-) -6-Cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-an amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-carbamoyl-2-methyl-propyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-carbamoyl-cyclohexyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclohexyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-dimethylcarbamoyl-2-methyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-dimethylcarbamoyl-2-methyl-propyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (5-chloro-thiophen-2-yl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclohexyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-methoxy-1, 1-dimethyl-propyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (2-cyclobutyl-1-methylcarbamoyl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (2-cyclobutyl-1-dimethylcarbamoyl-ethyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-cyclobutyl-1-methylcarbamoyl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (3-methoxy-1, 1-dimethyl-propyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-cyclobutylmethyl-2-hydroxy-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-carbamoyl-2-cyclobutyl-ethyl) -amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1, 1-dimethyl-3-phenyl-propyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-cyclobutyl-1-dimethylcarbamoyl-ethyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-carbamoyl-2-cyclobutyl-ethyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-cyclobutylmethyl-2-hydroxy-ethyl) -amide; 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-carbamoyl-1, 1-dimethyl-ethyl) -amide; and

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (2-carbamoyl-1, 1-dimethyl-ethyl) -amide.

The invention relates in particular to compounds of formula (I) selected from

2- [ (5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl) -amino ] -2-ethyl-butyric acid methyl ester; and

(S) -3-cyclopropyl-2- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl ] -amino } -propionic acid methyl ester.

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-cyclobutylmethyl-2-hydroxy-ethyl) -amide; and

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1, 1-dimethyl-3-phenyl-propyl) -amide.

The compounds of formula (I) may be prepared by a process comprising coupling a compound of formula II with an amine of formula III by amide coupling methods known in the art, for example, by means of an amide coupling agent under basic conditions

Wherein R is¹And R²Same as defined before

Wherein R is³And R⁴The same as defined previously, and, if necessary, converting the resulting compound of formula (I) into a pharmaceutically acceptable salt thereof.

The compounds of formula III or II may contain functional groups that will interfere with the coupling procedure described for the amide coupling steps (II to I). In this case, it will be appreciated that either III or II need to be suitably protected by methods known in the art prior to undergoing the amide coupling procedure, and that the compound needs to be deprotected after the coupling step by methods known in the art to give a compound of formula (I).

Coupling agents for the reaction of compounds of the formula II with amines of the formula III are, for example, N, N '-Carbonyldiimidazole (CDI), N, N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] -methylene-bis]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide Hexafluorophosphate (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT), O-benzotriazol-1-yl-N, N' -tetramethylureaTetrafluoroborate (TBTU), or O-benzotriazole-N, N ', N' -tetramethyl-urea-hexafluoro-phosphate (HBTU). Particular coupling agents are TBTU and HATU. Suitable bases include triethylamine, N-methylmorpholine and in particular diisopropylethylamine. An alternative method known in the art may start with the preparation of an acid chloride from II and coupling with an amine of formula III in the presence of a suitable base.

The synthesis of compounds having general structure (I) can be accomplished, for example, according to the following scheme. Unless otherwise indicated, R¹To R⁴As defined above.

According to the procedure according to scheme 1, the compound AA (3, 5-dibromo-2-pyrazinamine, CAN24241-18-7) CAN be used as starting material for the synthesis of compound I-a, wherein R is¹Is a halophenyl radical (R)¹' is a halophenyl group).

Scheme 1

Compound AC can be prepared from AA by coupling with an appropriately substituted aryl-metal species of formula AB, in particular an arylboronic acid or arylboronic acid ester, in the presence of a suitable catalyst, in particular a palladium catalyst and more particularly tetrakis (triphenylphosphine) -palladium (0), and a base such as triethylamine, potassium phosphate, and in particular sodium carbonate, in an inert solvent such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and in particular dimethoxyethane, at a temperature ranging from room temperature to the boiling point of the solvent mixture.

Compounds of general formula AD can be obtained from compounds of general formula AC by palladium (II), in particular palladium (II) acetate catalyzed carbonylation in the presence of a suitable base such as a tertiary amine base, in particular triethylamine, in a suitable solvent such as an alcohol, in particular methanol.

Compounds of general formula AE can be obtained from compounds of general formula AD by reaction with a nitrosating agent, such as a metal nitrite or an organic nitrite, more specifically isoamyl nitrite, in the presence of a bromide ion source, such as hydrobromic acid or more specifically trimethylbromosilane, in a suitable solvent, such as a halogenated hydrocarbon, more specifically dibromomethane.

Saponification of an ester of general formula AE by methods well known to those skilled in the art (i.e., in tetrahydrofuran/ethanol or another suitable solvent at a temperature between 0 ℃ and the reflux temperature of the solvent used, using, for example, aqueous LiOH, NaOH or KOH) gives an acid of general formula AF.

Compound AG can be prepared from AF and the corresponding amine of formula III by a suitable amide bond formation reaction. These reactions are known in the art. For example, coupling agents such as N, N ' -carbonyl-diimidazole (CDI), N, N ' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] -N, N ' -dicyclohexylcarbodiimide]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide Hexafluorophosphate (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT), O-benzotriazol-1-yl-N, N' -tetramethylureaTetrafluoroborate (TBTU), and O-benzotriazole-N, N, N ', N' -tetramethyl-urea-hexafluoro-phosphate (HBTU) can be used to achieve this transition. An alternative method known in the art may start with the preparation of an acid chloride from AF and coupling with an amine of formula III in the presence of a suitable base. The conventional method is to use, for example, 1-chloro-N, 2-trimethylpropenylamine and a base, such as N-ethyl-N-isopropylpropan-2-amine (DIEA), in an inert solvent such as dimethylformamide at room temperature.

The amines III are either commercially available, described in the literature, can be synthesized by the person skilled in the art, or obtained as described in the experimental section.

Compounds I-a wherein R2 is cycloalkyl can be prepared from AG by coupling an appropriately substituted cycloalkyl or cycloalkenyl metal species, particularly a cyclopropyl metal species, such as cyclopropyl zinc (II) chloride, or cyclopropyl boronic acid or cyclopropyl trifluoroborate, with AG in the presence of a suitable catalyst, particularly a palladium catalyst such as tetrakis- (triphenyl-phosphine) palladium, or [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] (3-chloropyridyl) -palladium (II) dichloride or palladium (II) acetate in an inert solvent such as THF or toluene at room temperature to the reflux temperature of the solvent. It will be appreciated by those skilled in the art that for coupling cycloalkyl-or cycloalkenyl-boron species, the addition of a suitable base, such as potassium phosphate, is necessary to start the reaction. In case the practitioner in the art chooses to couple with a cycloalkenyl metal species, such as cycloalkenyl boronate, compound I-a will only be obtained after an additional hydrogenation step, e.g. by hydrogenation with hydrogen in the presence of a palladium catalyst, e.g. palladium on charcoal, in an inert solvent, e.g. ethanol, at suitable temperature and pressure, in particular at ambient temperature and pressure.

Wherein R is²Compounds I-a which are azetidinyl or difluoroazetidinyl may be prepared from AG by reaction with the corresponding azetidine in the presence of a base, in particular DBU or triethylamine, in an inert solvent, in particular DMSO or bisIn an alkane at a temperature in the range of room temperature to 45 ℃.

If one of the starting materials, the compounds of formula III, contains one or more functional Groups that are unstable or reactive under the reaction conditions of one or more reaction steps, suitable protecting Groups (P) can be introduced prior to the critical step using methods well known in the art (as described, for example, in t.w. Greene et al, Protective Groups in Organic Chemistry, John Wiley and Sons inc. new york1999, 3 rd edition). Such protecting groups may be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of formula III contain a chiral center, the pyridines of formula I-a may be obtained as a mixture of diastereomers or enantiomers, which may be separated by methods well known in the art, such as (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization via diastereomeric salts or by enantiomeric separation via specific chromatographic methods using chiral adsorbents or chiral eluents.

After the step according to scheme 2, compound BA (5-chloro-pyrazine-2-carboxylic acid methyl ester, CAN33332-25-1) CAN be used as starting material for the synthesis of compound I-b, wherein R2 is azetidinyl or difluoroazetidinyl (R2)²' is azetidinyl or difluoroazetidinyl). BA is either commercially available or can be synthesized by one skilled in the art as described in the literature.

The compound BB can be prepared from BA by reaction with the corresponding azetidine in the presence of a base, in particular triethylamine, under inert conditionsPolar solvents, especially diIn an alkane at a temperature ranging from room temperature to 45 ℃.

The conversion of compound BB to BC can be achieved by electrophilic aromatic bromination in a suitable solvent, in particular by bromination with N-bromosuccinimide in chloroform at elevated temperature, in particular at 60 ℃, or by using other conditions known in the literature.

Saponification of the ester of formula BC produces the acid of formula BD by methods well known to those skilled in the art-using, for example, aqueous LiOH, NaOH or KOH in tetrahydrofuran/ethanol or any suitable solvent at a temperature from 0 ℃ to the reflux temperature of the solvent employed.

Scheme 2

For R in the formula¹Is cycloalkylalkoxy (R)^aIs cycloalkylalkyl), compound BD can BE converted into compound II-b by reaction with an appropriately substituted primary or secondary alcohol BE in the presence of a base, e.g. potassium hydroxide, with or without an inert solvent, e.g. DMSO, at a temperature in the range from room temperature to the reflux temperature of the solvent, in particular at room temperature.

Alternatively, for wherein R¹Is a halophenyl radical (R)¹'is halophenyl) compound, compound BD can be converted to compound II-b by coupling an appropriately substituted aryl-metal species of formula AB, particularly an arylboronic acid or arylboronic ester, in the presence of a suitable catalyst and more particularly a palladium (II) -dppf (1, 1' -bis (diphenylphosphino) -ferrocene) chloride complex and a base, particularly potassium carbonate, in an inert solvent such as dimethylformamide.

The compound II-b mayTo further refine compound I-b by coupling the compound of formula II-b with an amine of formula III by amide coupling methods known in the art, for example by means of an amide coupling agent under basic conditions. For example, coupling reagents such as N, N ' -Carbonyldiimidazole (CDI), N, N ' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] -N, N ' -dicyclohexylcarbodiimide]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide Hexafluorophosphate (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT), O-benzotriazol-1-yl-N, N' -tetramethylureaTetrafluoroborate (TBTU) or O-benzotriazole-N, N, N ', N' -tetramethyl-urea-hexafluoro-phosphate (HBTU) can be used to achieve this transition. The conventional method is to use, for example, O-benzotriazole-N, N, N ', N' -tetramethyl-ureaHexafluoro-phosphate (HBTU) and a base, for example N-ethyl-N-isopropylpropan-2-amine (DIEA), in an inert solvent such as, for example, dimethylformamide, at room temperature. An alternative method known in the art may start with the preparation of an acid chloride from II-b and coupling with an amine of formula III in the presence of a suitable base.

If one of the starting compounds of formula BE or III contains one or more functional Groups which are unstable or reactive under the reaction conditions of one or more reaction steps, suitable protecting Groups (P) can BE introduced prior to the critical step using methods well known in the art (as described, for example, in T.W.Greene et al, Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York1999, 3 rd edition). Such protecting groups may be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of the formula BE or III contains a chiral center, the pyridines of the formula I-b can BE obtained as a mixture of diastereomers or enantiomers, which can BE separated by methods known in the art, for example (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization via diastereomeric salts or by separation of the enantiomers by special chromatography using chiral adsorbents or chiral eluents.

According to the procedure according to scheme 3, the compound AA (3, 5-dibromo-2-pyrazinamine, CAN24241-18-7) CAN be used as starting material for the synthesis of compounds I-c, wherein R is¹Is cycloalkylalkoxy (R)¹"is cycloalkylalkoxy) and R²Is cycloalkyl (R)²"is cycloalkyl).

For R in the formula¹Is cycloalkylalkoxy (R)¹"is cycloalkylalkoxy and Ra is cycloalkylalkyl) compound AA can BE converted to compound CB by reaction with an appropriately substituted primary or secondary alcohol BE in the presence of a base, e.g. sodium hydride, in the presence or absence of an inert solvent, e.g. DMF, at a temperature in the range from room temperature to the reflux temperature of the solvent, in particular at room temperature.

B of a Compound of the formula CB_ocProtection the compounds of the general formula CC are produced by methods known to the person skilled in the art using, for example, di-tert-butyl dicarbonate in an inert solvent, in particular dichloromethane, in the presence of catalytic amounts of a base, in particular dimethylaminopyridine, if an excess of di-tert-butyl dicarbonate is employed in the reaction.

Scheme 3

Compounds of general formula CD can be obtained from compounds of general formula CC by palladium (II), in particular palladium (II) acetate catalyzed carbonylation in the presence of a suitable base such as a tertiary amine base, in particular triethylamine, in a suitable solvent such as an alcohol, in particular methanol.

Solvolysis of the boc-protected compounds of the general formula CD gives compounds of the general formula CE by methods well known to the person skilled in the art-using, for example, protic solvents, in particular methanol, at elevated temperatures, in particular at reflux temperature.

The compounds of formula CF can be obtained from compounds of formula CE by reaction with a nitrosating agent, such as a metal nitrite or an organic nitrite, more specifically tert-butyl nitrite, in the presence of a bromide ion source, such as hydrobromic acid or more specifically trimethylbromosilane, in a suitable solvent, such as a halogenated hydrocarbon, more specifically dibromomethane.

Wherein R is²Is cycloalkyl (R)²"is cycloalkyl") compound CH can be prepared from CF by coupling an appropriately substituted cycloalkyl or cycloalkenyl metal species CG, particularly cyclopropylboronic acid or cyclopropyltrifluoro-borate, with CF in the presence of a suitable catalyst, particularly a palladium catalyst such as palladium (II) acetate, in the presence of cyclohexylphosphine, in an inert solvent such as toluene, at room temperature to the reflux temperature of the solvent, in the presence of a suitable base such as potassium phosphate. In case the practitioner in the art chooses to couple with a cycloalkenyl metal species, such as cycloalkenyl borate, compound CH will only be obtained after an additional hydrogenation step, for example by hydrogenation with hydrogen in the presence of a palladium catalyst, for example palladium on carbon, in an inert solvent, for example ethanol, at suitable temperature and pressure, in particular at ambient temperature and pressure.

Saponification of the ester of formula CH produces the acid of formula II-c by methods well known to those skilled in the art-using, for example, aqueous LiOH, NaOH or KOH in tetrahydrofuran/ethanol or another suitable solvent at a temperature of 0 ℃ to the reflux temperature of the solvent employed.

Compound II-c can be coupled by a compound of formula II-c with an amine of formula III by amide coupling methods known in the art, for example, by further refinement to compound I-c with the aid of an amide coupling agent under basic conditions. For example, coupling agents such as N, N '-Carbonyldiimidazole (CDI), N, N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] can be used]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide Hexafluorophosphate (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT), O-benzotriazol-1-yl-N, N' -tetramethylureaTetrafluoroborate (TBTU) and O-benzotriazole-N, N; n ', N' -tetramethyl-ureaHexafluoro-phosphate (HBTU) to carry out this conversion. The conventional methods use, for example, O-benzotriazole-N, N, N ', N' -tetramethyl-ureaHexafluoro-phosphate (HBTU) and a base, such as N-ethyl-N-isopropylpropan-2-amine (DIEA), in an inert solvent, such as dimethylformamide, at room temperature. An alternative method known in the art may start with the preparation of an acid chloride from II-c and coupling with an amine of formula III in the presence of a suitable base.

If one of the starting compounds of formula BE, CG or III contains one or more functional Groups which are unstable or reactive under the reaction conditions of one or more reaction steps, suitable protecting Groups (P) can BE introduced before the critical step using methods well known in the art (as described, for example, in T.W. Greene et al, Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York1999, 3 rd edition). Such protecting groups may be removed at a later stage of the synthesis using standard methods known in the art.

If one or more of the compounds of the formulae BE, CG or III contains a chiral center, the pyridines of the formulae I-b can BE obtained as a mixture of diastereomers or enantiomers, which can BE separated by methods known in the art, for example (chiral) HPLC or crystallization. Racemic compounds can be separated into their enantiomers, for example, by crystallization via diastereomeric salts or by separation of the enantiomers by special chromatography using chiral adsorbents or chiral eluents.

The invention also relates to a process for the preparation of a compound of formula (I), said process comprising reacting a compound of formula (A) with a compound of formula NHR³R⁴The amide bond-forming coupling agent and a base,

wherein R is¹To R⁴As defined above.

Examples of amide bond-forming coupling agents are N, N '-carbonyl-diimidazole (CDI), N, N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [ bis (dimethylamino) -methylene ] -carbodiimide]-1H-1, 2, 3-triazolo [4, 5-b]Pyridine compound-3-oxide Hexafluorophosphate (HATU), 1-hydroxy-1, 2, 3-benzotriazole (HOBT), O-benzotriazol-1-yl-N, N' -tetramethylureaTetrafluoroborate salt(TBTU) and O-benzotriazole-N, N, N ', N' -tetramethyl-urea-hexafluoro-phosphate (HBTU).

Examples of suitable bases are tertiary amine bases such as triethylamine, N-methylmorpholine, N, N-diisopropylethylamine or 4- (dimethylamino) -pyridine.

The reaction temperature is, for example, room temperature.

A convenient method is to use, for example, HBTU and a base, for example N-methylmorpholine, in an inert solvent such as, for example, dimethylformamide at room temperature.

The invention further relates to compounds of formula (I) for use as therapeutically active substances.

The invention further relates to pharmaceutical compositions comprising a compound of formula (I) and a therapeutically inert carrier.

A further object of the present invention is the use of a compound of formula (I) for the treatment or prophylaxis of pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.

A further object of the present invention is the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of chronic pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.

The invention also relates to compounds of formula (I) for the treatment or prophylaxis of pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.

The invention relates in particular to compounds of formula (I) for use in the treatment or prevention of ischemia, reperfusion injury, liver fibrosis or kidney fibrosis, in particular ischemia or reperfusion injury.

The invention further relates to compounds of formula (I) prepared by the process according to the invention.

The invention also relates to a method for the treatment or prophylaxis of pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, which method comprises administering an effective amount of a compound of formula (I).

Another embodiment of the present invention provides pharmaceutical compositions or medicaments comprising a compound of the present invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the present invention for preparing such compositions and medicaments. In one example, the compound of formula (I) may be formulated as follows: the galenical administration form is prepared by mixing at ambient temperature, at a suitable pH, and at the desired degree of purity, with a physiologically acceptable carrier, i.e. a carrier which is non-toxic to the recipient at the dosages and concentrations employed. The pH of the formulation depends primarily on the particular use and concentration of the compound, but is preferably anywhere in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH5. In another embodiment, the compounds of formula (I) are sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered herein include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to the practitioner.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if topical treatment is desired, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and the like. Such compositions may contain conventional ingredients of pharmaceutical preparations such as diluents, carriers, pH adjusting agents, sweeteners, fillers, and other active agents.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard c, et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery systems, philiadelphia: lippincott, Williams & Wilkins, 2004; gennaro, Alfonso r., et al Remington: the Science and Practice of pharmacy Philadelphia: lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.handbook of Pharmaceutical excipients Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents (glidants), glidants, processing aids, colorants, sweeteners, flavoring agents, diluents, and other known additives to provide a superior presentation of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the preparation of the pharmaceutical product (i.e., a pharmaceutical product).

The invention will now be illustrated by the following examples which are not to be construed as limiting in nature.

Examples

Abbreviations

MS ═ mass spectrum; EI-electron ionization; ESI ═ electrospray; NMR data were obtained relative to internal standard tetramethylsilane and reference from sample solvent (d)₆DMSO, unless otherwise specified) is given in parts per million (δ); coupling constant (J) in hertz, mp ═ melting point; bp is boiling point; DIEA ═ N-ethyl-N-isopropylpropan-2-amine; DBU ═ 1, 8-diazabicyclo [5.4.0]Undec-7-ene; DMF ═ dimethylformamide; DMSO ═ dimethyl sulfoxide; dppf ═ 1, 1' -bis 2 (diphenylphosphino) ferrocene; HATU 2- (3H- [1, 2, 3)]Triazolo [4, 5-b]Pyridin-3-yl) -1, 1, 3, 3-tetramethylisoureaHexafluorophosphate (V); HBTU ═ O-benzotriazole-N, N' -tetramethyl-urea-hexafluoro-phosphate; HPLC ═ LC ═ high performance liquid chromatography; m-CPBA ═ m-chloroperoxybenzoic acid; rt ═ retention time; TBTU ═ O- (benzotriazol-1-yl) -N, N' -tetramethyl-urea-a tetrafluoroborate salt; TEMPO ═ 2, 2, 6, 6-tetra-methylpiperidine 1-oxyl radical; TBME ═ methyl tert-butyl ether; THF ═ tetrahydrofuran; TFA ═ trifluoroacetic acid; tlc ═ thin layer chromatography; CAN (controller area network)CAS registry number.

Example 1

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

a) 5-bromo-3- (3-chloro-phenyl) -pyrazin-2-ylamine

3, 5-dibromo-2-pyrazinamine (CAN 24241-18-7; 45.1g, 0.178mol) was dissolved in dimethoxyethane (450 mL). To this solution was added 4-chlorophenylboronic acid (27.8g, 0.178mol), sodium carbonate (37.7g, 0.356mol) and tetrakis (triphenylphosphine) -palladium (0) (10.28g, 0.009 mol). The mixture was stirred at 110 ℃ overnight and then cooled to room temperature. Citric acid solution (10%, 200mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed successively with sodium bicarbonate solution (10%, 300mL) and brine (200 mL); combine, treat with charcoal (3.8g), Na₂SO₄Dried and, after filtration, concentrated. The title compound (30.7g, 61%) was isolated by crystallization from the concentrated solution; ms (ei): 285(M + H).

b) 5-amino-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid methyl ester

To a solution of 5-bromo-3- (3-chloro-phenyl) -pyrazin-2-ylamine (5.1g, 18mmol) in methanol (30mL) was added PdCl₂·dppf·CH₂Cl₂(0.51g, 0.6mmol) and triethylamine (5mL) and the mixture was stirred under an atmosphere of 70 bar carbon monoxide at 110 ℃ for 20 hThen (c) is performed. After swelling and cooling the citric acid solution (10%, 150mL), ethyl acetate (300mL) was added and the solids were removed by filtration. The organic phase was separated, stirred with charcoal for 1 hour, over Na₂SO₄Dried and, after filtration, concentrated. The title compound (1.36g, 27%) was isolated by crystallization from the concentrated solution; ms (ei): 263.9(M + H).

c) 5-bromo-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid methyl ester

5-amino-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid methyl ester (18.1g, 61mmo1) was suspended in dibromomethane (190 mL). To the suspension was added isoamyl nitrite (8.8g, 73mmo1) and the mixture was stirred at room temperature for 15 minutes. Bromotrimethylsilane (11.6g, 73mmoD (exothermic reaction) was added dropwise and the resulting solution was stirred at room temperature for 1 hour the mixture was partitioned between water (190mL) and ethyl acetate and the organic phase was MgSO₄Dried, filtered and concentrated in vacuo. The crude material was purified by chromatography (silica gel, 550g, 1: 1 dichloromethane in n-heptane) to give the desired product (11.3g, 54%) as a yellow solid; ms (ei): 328.5(M + H).

d) 5-bromo-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid

To a solution of methyl 5-bromo-6- (3-chloro-phenyl) -pyrazine-2-carboxylate (11.3g, 35mmo1) in THF (170mL) was added 1M lithium hydroxide in water (40mL) and the mixture was stirred at ambient temperature for 1.5 hours. Citric acid solution (10%, 90mL) was added and the organic layer was separated and concentrated in vacuo. The residue was recrystallized from n-heptane to give the title compound (12.0g, quantitative) as a white crystalline solid; ms (esi): 312.5 (M-H).

e) 5-bromo-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

5-bromo-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid (0.200g, 638. mu. mo1) was suspended in dichloromethane (1mL) and 1-chloro-N, N, 2-trimethylpropenylamine (98.0mg, 97.0. mu.l, 734. mu. mol) was added dropwise at room temperature. After stirring for 30 minutes, the brown solution was added dropwise to the α, α, 5-trimethyl-1, 2, 4-A solution of diazole-3-methylamine hydrochloride (CAN 1240526-27-5; 142mg, 797. mu. mol) and ethyldiisopropylamine (206mg, 264. mu.l, 1.59mmol) in DMF (1mL) and the reaction mixture was stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate and 1M citric acid solution; the organic phase was dried over MgSO 4; filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20g, 5% to 50% ethyl acetate in n-heptane) to give the desired product (126mg, 45%) as a white foam; ms (ei): 436.0(M + H).

f)6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

Mixing 5-bromo-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]Amide (0.100g, 229. mu. mol) and tetrakis- (triphenyl-phosphine) palladium (13.2mg, 11.4. mu. mol) were dissolved in THF (2.5 mL). Cyclopropylzinc (II) bromide (0.5M solution in THF, 1800. mu.l, 900. mu. mo1) was added dropwise at 0 ℃ and the reaction mixture was stirred at room temperature for 1.5 hours and at reflux temperature overnight. The mixture was partitioned between water and ethyl acetate and the organic phase was MgSO₄Dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10g, 5% to 40% ethyl acetate in n-heptane) to give the desired product (24mg, 26%) as a white solid; ms (ei): 398.2(M + H). As a by-product, 11mg of 6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid (cyano-dimethyl-methyl) -amide was isolated (example 2).

Example 2

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid (cyano-dimethyl-methyl) -amide

The title compound (11mg, 14%) was isolated as a white solid as a by-product during the preparation of example 1; ms (ei): 341.1(M + H).

Example 3

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid [1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclobutyl]-amides of

a)6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid

5-bromo-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid (example 1d, 0.200g, 638. mu. mol) and [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene](3-Chloropyridyl) -palladium (II) dichloride (22.2mg, 31.9. mu. mol) was dissolved in THF (5mL) and 1, 3-dimethyl-2-imidazolidinone (1 mL). Cyclopropylzinc (II) bromide (0.5M in THF, 3.83mL, 1.91mmol) was added dropwise at room temperature and the reaction mixture was stirred at reflux temperature for 2 hours. More cyclopropyl zinc (II) bromide (0.5M in THF, 1.91mL, 957 μmol) was added and stirring continued at reflux temperature for another 2 hours. The mixture was partitioned between water and ethyl acetate and the organic phase was MgSO₄Dried, filtered and concentrated in vacuo. The crude material was purified by reverse phase chromatography to give the desired product (52mg, 30%) as a pale yellow oil; ms (esi): 273.2 (M-H).

b)6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid [1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclobutyl]-amides of

Analogously to example 1e, 6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid and 1- (5-methyl-1, 2, 4-Oxadiazol-3-yl) -cyclobutylamine hydrochloride (CAN1170897-128-5) the title compound was synthesized as a starting material and isolated as a white solid (43mg, 58%); ms (ei): 410.2(M + H).

Example 4

6- (3-chloro-phenyl) -5- (3, 3-difluoro-aza-asCyclobut-1-yl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]-amides of

Mixing 5-bromo-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]The amide (example 1e, 0.075g, 172. mu. mol) was added to a solution containing 3, 3-difluoroazetidine hydrochloride (77.9mg, 601. mu. mol) and DBU (91.5mg, 89.8. mu.l, 601. mu. mol) in DMSO (1 mL). The reaction mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate and 10% citric acid. The organic phase was washed with MgSO₄Dried, filtered and concentrated in vacuo. The crude material was purified by reverse phase chromatography to give the desired product (8mg, 10%) as colorless oil; ms (esi): 449.1(M + H).

Example 5

5-azetidin-1-yl-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]-amides of

Analogously to example 4, 5-bromo-6- (3-chloro-phenyl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]The title compound was synthesized from the amide (example 1e) and azetidine as starting materials and isolated as a pale yellow oil (29mg, 41%); ms (ei): 413.2(M + H).

Example 6

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl) -amide

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid triethylamine salt (1: 1) (example 3a, 0.77g, 205. mu. mol) was suspended in DMF (770. mu.L). TBTU (78.9mg, 246. mu. mol), DIEA (106mg, 136. mu.l) and α, α -monomethyl-2-thiazolemethylamine hydrochloride (43.9mg, 246. mu. mol) were added and the reaction mixture was stirred at room temperature for 2 hours. Extracting the mixture with ethyl acetate and water; the organic phase was washed with MgSO₄Dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10g, 5% to 50% ethyl acetate in n-heptane) to give the desired product (48mg, 59%) as a white solid; LC-MS (UV peak area, ESI) 94%, 399.1042(M + H).

Example 7

6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid piperidin-1-ylamide

The title compound was synthesized in analogy to example 6, using 6- (3-chloro-phenyl) -5-cyclopropyl-pyrazine-2-carboxylic acid (example 3a) and 1-amino-piperidine as starting materials and isolated as a white solid (29mg, 40%); LC-MS (UV peak area, ESI) 100%, 357.1485(M + H).

Example 8

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -2, 2-dimethyl-1-methylcarbamoyl-propyl) -amide

a)5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid methyl ester

5-chloro-pyrazine-2-carboxylic acid methyl ester (CAN 33332-25-1; 15g, 86.92mmol) was dissolved in dioxaneAlkane (100 mL). To this solution was added 3, 3-difluoroazetidine hydrochloride (CAN 288315-03-7; 13.51g, 104.31mmol), and triethylamine (31.3mL, 226 mmol). The mixture was stirred at 45 ℃ for 22 hours and then cooled to room temperature. Brine solution (100mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed successively with sodium bicarbonate solution (10%, 300mL) and brine (200 mL); with Na₂SO₄Dried and filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 200g, 30% to 50% ethyl acetate in hexanes) to afford the desired product (15g, 75.3%) as a white solid; LC-MS (UV peak area, ESI) 98.6%, 230.4(M + H).

b) 6-bromo-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid methyl ester

To a solution of methyl 5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylate (16.5g, 72.05mmol) in chloroform (200mL) was added N-bromosuccinimide (25.64g, 151.34mmol) portionwise at 60 deg.C and the mixture was stirred at 60 deg.C for 20 hThen (c) is performed. After cooling, water (400mL) was added and the organic phase was separated, washed successively with water (200mL), brine (200 mL); with Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 200g, 50% ethyl acetate in hexanes) to give the desired product (17g, 77.2%) as a light yellow solid; LC-MS (UV peak area, ESI) 97.84%, 308.0(M + H).

c) 6-bromo-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid

To a solution of methyl 6-bromo-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylate (6.0g, 19.48mmol) in THF (20mL) and H2O (10mL) was added lithium hydroxide (1.06g, 25.32mmol) and the mixture was stirred at ambient temperature for 5 hours. The solvent was concentrated in vacuo and the residue was taken up with H₂Dilution with O (30 mL). The aqueous phase was acidified with hydrochloric acid (1M, pH 2-3) and the solid was separated. The solid was triturated with toluene (25mL) and dried in vacuo to give the title compound (4.0g, 70.17%) as a white crystalline solid; LC-MS (UV peak area, ESI) 100%, 294.2(M + H).

d) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid

To a solution of cyclopropyl-methanol (4.96mL, 61.21mmol) in dry dimethyl sulfoxide (90mL) was added potassium hydroxide (5.89g, 107.12mmol) portionwise at ambient temperature. To the mixture was added a solution of 6-bromo-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (9.0g, 30.61mmol) in dimethylsulfoxide (10 mL). The reaction mixture was stirred at ambient temperature for 3 hours. Water (100mL) was added and the aqueous layer was acidified with aqueous hydrochloric acid (10%, pH 3-4) and the solid was filtered. The solid was triturated with toluene (50mL) and dried in vacuo to give the title compound (8.0g, 91.64%) as a white crystalline solid; LC-MS (UV peak area, ESI) 100%, 286.2(M + H).

e) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -2, 2-dimethyl-1-methylcarbamoyl-propyl) -amide

6-Cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 0.1g, 35mmol) was suspended in DMF (3 mL). HBTU (266.14mg, 0.7mmol), DIEA (0.31mL, 1.75mmol) and (S) -2-amino-3, 3, N-trimethyl-butyramide (CAN89226-12-0, 52.82mg, 0.42mmol) were added and the reaction mixture was stirred at ambient temperature for 12 hours. Extracting the mixture with ethyl acetate and water; the organic phase is washed with Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Gemini-NX-C18, 5 μ, 30x100 mm/acetonitrile/0.1% ammonia) to give the desired product (15mg, 10.39%) as a white solid; LC-MS (UV peak area, ESI) 96.48%, 412.6(M + H).

Example 9

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclobutyl]-amides of

Analogously to example 8e, 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 1- (5-methyl-1, 2, 4-Oxadiazol-3-yl) -cyclobutylamine (CAN1170897-128-5, 64.42mg, 0.42mmol) the title compound was synthesized as a starting material and isolated as an off-white solid (25mg, 16.95%); LC-MS (UV peak area, ESI) 99.10%, 421.4(M + H).

Example 10

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-hydroxy-1, 1-dimethyl-propyl) -amide a) 5-bromo-3-cyclopropylmethoxy-pyrazin-2-ylamine

To a solution of cyclopropyl-methanol (16.47mL, 205.62mmol) in dimethyl sulfoxide (200mL) was added sodium hydride (60% in oil, 4.93g, 205.62mmol) at 0 deg.C and the reaction mixture was stirred at 0 deg.C for 2 hours. To the suspension was added 3, 5-dibromo-pyrazin-2-ylamine (20g, 79.09mmol) in dimethylsulfoxide (40mL) and the mixture was stirred at ambient temperature for 12 hours. The mixture was partitioned between water (300mL) and ethyl acetate and the organic phase was taken up with Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was purified by chromatography (silica gel, 500g, 10% ethyl acetate in hexanes) to give the desired product (14g, 72.52%) as a yellow solid; LC-MS (UV peak area, ESI) 94.69%, 244.0(M + H).

b) [ 5-bromo-3- (cyclopropylmethoxy) pyrazin-2-yl ] imidodicarbonic acid di-tert-butyl ester

To a solution of 5-bromo-3-cyclopropylmethoxy-pyrazin-2-ylamine (30g, 122.91mmol) in dichloromethane (200mL) was added di-tert-butyl dicarbonate (67.7mL, 307.26mmol) and 4-dimethylaminopyridine (1.49g, 12.29 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between water (300mL) and dichloromethane and the organic phase was separated, washed with brine, washed with Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was purified by chromatography (silica gel, 600g, 5% -7% ethyl acetate in hexanes) to give the desired product (45g, 82.77%) as a yellow oil; LC-MS (UV peak area, ESI) 94.69%, 445.0(M + H).

c)5- [ bis (tert-butoxycarbonyl) amino ] -6- (cyclopropylmethoxy) pyrazine-2-carboxylic acid methyl ester

To [ 5-bromo-3- (cyclopropylmethoxy) pyrazin-2-yl]Di-tert-butyl imidodicarbonate (20g, 45.05mmol) in methanol (200mL) was added PdCl₂·dppf·CH₂Cl₂(4.04g, 4.95mmol) and triethylamine (9.5mL, 67.57mmol) and the mixture was stirred at 80 ℃ for 5h under an atmosphere of 32 bar carbon monoxide. After expansion and cooling, the solids were removed by filtration. The organic phase was separated, washed with brine (300mL), Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was purified by chromatography (Combi-Flash, 120g, 15% -20% ethyl acetate in hexanes) to give the desired product (14g, 73.68%) as a yellow semisolid; LC-MS (UV peak area, ESI) 96.14%, 424.4(M + H).

d) 5-amino-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid methyl ester

Methyl 5- [ bis (tert-butoxycarbonyl) amino ] -6- (cyclopropylmethoxy) pyrazine-2-carboxylate (15g, 35.46mmol) was suspended in methanol (150mL) and water (225mL), and the mixture was heated at 100 ℃ for 12 hours. After cooling, a white solid formed, filtered and dried in vacuo to afford the title compound (5.7g, 72.15%) as an off-white solid; LC-MS (UV peak area, ESI) 99.68%, 224.2(M + H).

e) 5-bromo-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid methyl ester

5-amino-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid methyl ester (10g, 44.84mmol) was suspended in dibromomethane (150 mL). Trimethylsilyl bromide (14.8mL, 112.11mmol) was added to the suspension followed by tert-butyl nitrite (57.5mL, 448.43mmol) at 0 deg.C and the mixture was stirred at this temperature for 3 hours. The mixture was partitioned between water (190mL) and ethyl acetate, and the organic phase was washed with brine (200mL), Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was purified by chromatography (Combi-Flash, 80g, 20% ethyl acetate in hexanes) to give the desired product (6.3g, 46.6%) as a white solid; LC-MS (UV peak area, ESI) 90.68%, 287.2(M + H).

f) 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid methyl ester

5-bromo-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid methyl ester (5g, 17.42mmol), tripotassium phosphate (12.9g, 60.98mmol) and palladium (II) acetate (389mg, 1.74. mu. mol) were dissolved in toluene (toluene: (TM) (M: (TM))45mL) and water (5mL) and the reaction mixture was degassed with argon for 15 minutes. Cyclopropylboronic acid (2.9g, 34.84mmol) and tricyclohexylphosphine (0.487g, 1.74mmol) were added and the reaction mixture was stirred at 60 ℃ for 16 h. The mixture was partitioned between water and ethyl acetate and the organic phase was washed with brine (100mL), Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was purified by chromatography (Combi-Flash, 80g, 10% -15% ethyl acetate in hexanes) to give the desired product (2.6g, 60.1 l%) as a white solid; LC-MS (UV peak area, ESI) 98.87%, 249.2(M + H).

g) 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid

To methyl 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylate (7g, 28.23mmol) in THF (20mL) and H₂Lithium hydroxide (1.54g, 26.69mmol) was added as a solution in O (10mL) and the mixture was stirred at ambient temperature for 4.5 hours. The solvent was concentrated in vacuo and the residue was taken up with H₂Dilution with O (20 mL). The aqueous phase was acidified with hydrochloric acid (1M, pH 2-3) and the solid was separated. The solid was triturated with toluene (25ml) and dried in vacuo to give the title compound (5.3g, 86.6%) as a white crystalline solid; LC-MS (UV peak area, ESI) 93.2%, 233.2 (M-H).

h) 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-hydroxy-1, 1-dimethyl-propyl) -amide

The title compound was synthesized in analogy to example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and 3-amino-3-methyl-1-butanol (CAN 42514-50-1; 58.46mg, 0.51mmol) as starting materials and isolated as an off-white solid (15mg, 10.9%); LC-MS (UV peak area, ESI) 100%, 320.4(M + H).

Example 11

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclobutyl) -amide

In analogy to example 8e, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and 1-amino-cyclobutanemethanol (CAN180205-34-9, 66.02mg, 0.64mmol) as starting materials and isolated as an off-white solid (50mg, 36.86%); LC-MS (UV peak area, ESI) 97.56%, 318.4(M + H).

Example 12

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclobutyl]-amides of

Analogously to example 8e, 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and 1- (5-methyl-1, 2, 4-Oxadiazol-3-yl) -cyclobutylamine (CAN1170897-128-5, 98.07mg, 0.64mmol) as starting material the title compound was synthesized and isolated as an off-white solid (50mg, 31.67%); LC-MS (UV peak area, ESI) 99.91%, 370.0(M +)H)。

Example 13

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-1-methyl-propyl) -amide

In analogy to example 8e, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and 2-amino-2-methyl-1-butanol (CAN10196-30-2, 64.74mg, 0.64mmol) as starting materials and isolated as an off-white solid (12mg, 8.79%), LC-MS (UV peak area, ESI) 100%, 320.4(M + H).

Example 14

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -2, 2-dimethyl-1-methylcarbamoyl-propyl) -amide

In analogy to example 8e, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and (S) -2-amino-3, 3, N-trimethyl-butyramide (CAN89226-12-0, 106.7mg, 0.64mmol) as starting materials and isolated as an off-white solid (45mg, 29.4%), LC-MS (UV peak area, ESI) 100%, 361.4(M + H).

Example 15

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -carbamoyl-phenyl-methyl) -amide

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) was suspended in DMF (3 mL). TBTU (224.14ng, 0.85mmol), DIEA (0.31mL, 2.24mmol) and (. alpha.S) -a-amino-phenylacetamide (CAN6485-52-5, 51.2mg, 0.51mmol) were added and the reaction mixture was stirred at room temperature for 12 h. Extracting the mixture with ethyl acetate and water; the organic phase is washed with Na₂Dried over SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xbridge-C18, 5 μ, 19x250 mm/acetonitrile/0.1% ammonia) to give the desired product (15mg, 9.58%) as a white solid; LC-MS (UV peak area, ESI) 93.20%, 367.4(M + H).

Example 16

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl) -amide

a) (S) -2- (tert-Butoxycarbonylamino) -3-cyclopropylpropionic acid methyl ester

To (S) -2- (tert-butoxycarbonylamino) -3-cyclopropylpropionic acid (CAN89483-06-7, 6.792g, 30mmol) and K₂CO₃(8.173g, 59mmol) of a mixture in DMF (100mL) was added MeI (10.37g, 73 mmol). The reaction mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated to give the title compound as a yellow oil (6.44g, 89%); ms (ei): 266.2[ M + Na]⁺。

b) (S) -1-cyclopropyl-3-hydroxy-3-methylbut-2-ylcarbamic acid tert-butyl ester

To a solution of methyl (S) -2- (tert-butoxycarbonylamino) -3-cyclopropylpropionate (0.972g, 4mmol) in THF (20mL) at 0 deg.C was added a solution of MeMgBr in diethyl ether (3M, 3.34mL, 10 mmol). The resulting mixture was stirred at 0 ℃ for 3 h. After which it was quenched with water. The mixture was diluted with ethyl acetate (20mL) and brine (20 mL). The organic layer was washed again with brine (20mL), dried over anhydrous sodium sulfate and concentrated to give the title compound as a white solid (0.8g, 82%); ms (ei): 266.2[ M + Na]⁺。

c) (S) -3-amino-4-cyclopropyl-2-methyl-butan-2-ol

A solution of tert-butyl (S) -1-cyclopropyl-3-hydroxy-3-methylbutan-2-ylcarbamate (0.8g, 3mmol) in ethyl acetate was saturated with hydrochloride salt (10mL) and stirred at room temperature for 1 h. After dilution with water (20mL), the layers were separated and the aqueous phase was washed with ethyl acetate (20 mL). Then, the solution was adjusted to pH 8-9 with 1N NaOH and extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound as a yellow oil (0.3g, 64%); ms (ei): 144.2[ M + Na%]⁺。

d) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl) -amide

In analogy to example 15, the title compound was synthesized using 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and (S) -3-amino-4-cyclopropyl-2-methyl-butan-2-ol (60.21mg, 0.42mmol) as starting materials and isolated as a white solid (50mg, 34.72%), LC-MS (UV peak area, ESI) 96.42%, 410.8(M + H).

Example 17

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl) -amide

In analogy to example 15, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and (S) -3-amino-4-cyclopropyl-2-methyl-butan-2-ol (87.83mg, 0.64mmol) as starting materials and isolated as an off-white solid (20mg, 13.03%), LC-MS (UV peak area, ESI) 98.68%, 360.8(M + H).

Example 18

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid piperidin-1-ylamide

In analogy to example 15, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and 1-amino-piperidine (CAN 2213-43-6; 76.9mg, 0.51mmol) as starting materials and isolated as a white solid (17mg, 12.57%); (UV peak area, ESI) 100%; 316.6(M + H).

Example 19

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-2, 2-dimethyl-propyl) -amide

In analogy to example 15, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and 2-amino-3, 3-dimethyl-1-butanol (CAN3907-02-6, 74.8mg, 0.64mmol) as starting materials and isolated as a light yellow sticky solid (40mg, 28.16%); LC-MS (UV peak area, ESI) 89.43%, 334.2(M + H).

Example 20

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -2-cyclopropyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

a) (S) -1-amino-3-cyclopropyl-1-oxoprop-2-ylcarbamic acid tert-butyl ester

A mixture of (S) -2- (tert-butoxycarbonylamino) -3-cyclopropylpropionic acid (CAN89483-06-7, 10g, 44mmol), di-tert-butyl dicarbonate (CAN: 24424-99-5, 14.28g, 66mmol) and pyridine (2.4mL) in acetonitrile (200mL) was stirred at room temperature for 20 minutes. Ammonia (10mL) was added dropwise over 20 min. The resulting reaction mixture was stirred for 4 h. During the removal of most of the solvent under reduced pressure, the product precipitated and the solid was filtered off and washed with acetonitrile (20 mL). The solid was dried under reduced pressure to give the title compound (7.73g, 78%) as a white solid; ms (ei): 251.2[ M + Na ]]⁺。

b) (S) -1-cyano-2-cyclopropylethylcarbamic acid tert-butyl ester

To a solution of tert-butyl (S) -1-amino-3-cyclopropyl-1-oxoprop-2-ylcarbamate (3.7g, 16mmol) and triethylamine (6.55g, 65mmol) in dichloromethane (50mL) was added dropwise trifluoroacetic anhydride (6.81g, 32mmol) at 0 ℃. The resulting mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was washed with water (150mL), citric acid (150mL, 5M) and brine (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the product (3.31g, 97%) as a yellow solid; ms (ei): 233.1[ M + Na]⁺。

c) (S, Z) -1-amino-3-cyclopropyl-1- (hydroxyimino) propan-2-ylcarbamic acid tert-butyl ester

Potassium carbonate (2.18g, 16mmol) was dissolved in water (8mL) and hydroxylamine hydrochloride (1.1g, 16mmol) was added. To this was added a solution of tert-butyl (S) -1-cyano-2-cyclopropylethylcarbamate (3.31g, 16mmol) in ethanol (24mL) and the resulting reaction mixture was stirred for 72 h. After evaporation of the solvent, the residue was dissolved with ethyl acetate (20mL) and then filtered. The filtrate was concentrated to give the crude product as a yellow solid (3.61g, 94%); ms (ei): 244.2[ M + H]⁺。

d) (S) -2-cyclopropyl-1- (5-methyl-1, 2, 4-Oxadiazol-3-yl) ethylcarbamic acid tert-butyl ester

To a solution of acetic acid (0.224g, 4mmol) in DMF (5mL) was added N, N' -carbonyldiimidazole (0.6g, 4mmol) and the mixture was stirred at room temperature for 0.5 h. (S, Z) -1-amino-3-cyclopropyl-1- (hydroxyimino) propan-2-ylcarbamic acid tert-butyl ester (0.84g, 3mmol) was added and the mixture was heated to 120 ℃ and stirred for 4 h. After evaporation of the solvent, the residue was purified by column chromatography (silica gel, 20g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.5 g; 54%) as a yellow solid; ms (ei): 290.1[ M + Na ]]⁺。

e) (S) -2-cyclopropyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethylamine

Reacting (S) -2-cyclopropyl-1- (5-methyl-1, 2, 4-A solution of oxadiazol-3-yl) ethylcarbamic acid tert-butyl ester (0.5g, 2mmol) in saturated hydrochloric acid (10mL) was stirred at room temperature for 1 h. Water (20mL) was then added. The aqueous phase was washed with ethyl acetate (2 × 20mL) and adjusted to pH 9-10 with 2M sodium hydroxide solution. It was then extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (20mL), dried over anhydrous sodium sulfate and concentrated to give the crude product as a white solid (0.25g, 80%); ms (ei): 168.2[ M + H]⁺。

f) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -2-cyclopropyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

Analogously to example 15, 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and (S) -2-cyclopropyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethylamine (88.51mg, 0.53mmol) the title compound was synthesized as a starting material and isolated as a white solid (12mg, 7.8%), LC-MS (UV peak area, ESI) 97.53%, 435.51(M + H).

Example 21

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-cyclopropyl-2-hydroxy-ethyl) -amide

In analogy to example 15, the title compound was synthesized using 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and β -amino-cyclopropaneethanol (CAN776315-67-4, 78.94mg, 0.53mmol 1) as starting materials and was isolated as a light brown solid (20mg, 14.91%); LC-MS (UV peak area, ESI) 97.84%, 368.9(M + H).

Example 22

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -carbamoyl-phenyl-methyl) -amide

In analogy to example 15, the title compound was synthesized using 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and (S) -2-amino-2-phenyl-acetamide (CAN6485-52-5, 52.6mg, 0.53mmol) as starting materials and isolated as a light brown solid (25mg, 17.07%); LC-MS (UV peak area, ESI) 98.31%, 418.0(M + H).

Example 23

(S) -2- [ (5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl) -amino ] -3, 3-dimethyl-butyric acid methyl ester

In analogy to example 6, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and 3-methyl-L-valine methyl ester hydrochloride (1: 1) (CAN63038-27-7) as starting materials and was separated (98mg, 91%) as a pale yellow oil; LC-MS (UV peak area, ESI) 100%, 362.2081(M + H).

Example 24

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -2-cyclopropyl-1-methylcarbamoyl-ethyl) -amide

a) ((S) -2-cyclopropyl-1-methylcarbamoyl-ethyl) -carbamic acid tert-butyl ester

(S) -2- (tert-Butoxycarbonylamino) -3-cyclopropylpropionic acid (2.0g, 8.72mmol) was combined with DMF (30mL) to give a white suspension. TBTU (3.08g, 9.6mmol) and DIEA (5.64g, 7.47ml, 43.6mmol) were added at room temperature followed by methylamine hydrochloride (648 m)g, 9.6 mmol). The suspension was stirred at room temperature for 16 h and concentrated in vacuo to give 8.7g of a pale pink residue, which was suspended in ethyl acetate (150mL) and methanol (5 mL). Ice water and 2N sodium hydroxide solution (35mL) were added and the mixture was stirred for 1 min. The phases were separated, the aqueous phase was extracted with ethyl acetate (70mL), and the organic phases were combined and MgSO₄Dried and concentrated in vacuo. The residue was purified by chromatography (silica gel 0.063-0.200mm, 100g, ethyl acetate/n-heptane 3: 1) to give the desired product (1.2g, 56%) as a white solid; ms (esi): 243.1707(M + H). b) (S) -2-amino-3-cyclopropyl-N-methyl-propionamide hydrochloride (1: 1)

((S) -2-cyclopropyl-1-methylcarbamoyl-ethyl) -carbamic acid tert-butyl ester (1.15g, 4.75mmol) was dissolved in ethanol (10 mL). Adding 4M-HCl at room temperatureA solution in alkane (4.75mL, 19.0mmol) and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo, and the residue was stirred with diethyl ether (10mL) for 1 hour. Filtration and drying of the precipitate gave the desired product (0.79g, 93%) as a white solid; ms (esi): 143.1173(M + H). c) 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -2-cyclopropyl-1-methylcarbamoyl-ethyl) -amide

In analogy to example 6, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and (S) -2-amino-3-cyclopropyl-N-methyl-propionamide hydrochloride (1: 1) (example 24b) as starting materials and isolated as a pale yellow oil (77mg, 89%); LC-MS (UV peak area, ESI) 100%, 359.2081(M + H).

Example 25

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -2-cyclopropyl-1-dimethylcarbamoyl-ethyl) -amide

a) ((S) -2-cyclopropyl-1-dimethylcarbamoyl-ethyl) -carbamic acid tert-butyl ester

(S) -2- (tert-Butoxycarbonylamino) -3-cyclopropylpropionic acid (2.0g, 8.72mmol) was combined with DMF (30mL) to give a white suspension. TBTU (3.08g, 9.6mmol) and DIEA (5.64g, 7.47ml, 43.6mmol) were added at room temperature followed by dimethylamine hydrochloride (782mg, 9.6 mmol). The suspension was stirred at room temperature for 16 h and concentrated in vacuo to give 8.7g of a pale pink residue, which was suspended in ethyl acetate (150mL) and methanol (5 mL). Ice water and 2N sodium hydroxide solution (35mL) were added and the mixture was stirred for 1 min. The phases were separated, the aqueous phase was extracted with ethyl acetate (70mL), and the organic phases were combined and MgSO₄Dried and concentrated in vacuo. The residue was purified by chromatography (silica gel 0.063-0.200mm, 100g, ethyl acetate/n-heptane 3: 1) to give the desired product (1.24g, 56%) as a white solid; GC-MS (EI): 256 (M).

b) (S) -2-amino-3-cyclopropyl-N, N-dimethyl-propionamide hydrochloride (1: 1)

((S) -2-cyclopropyl-1-dimethylcarbamoyl-ethyl) -carbamic acid tert-butyl ester (1.20g, 4.68mmol) was dissolved in ethanol (10 mL). Add 4M HCl at room temperature in twoA solution in alkane (4.68mL, 19.0mmol) and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo, and the residue was stirred with diethyl ether (10mL) for 1 hour. Filtration and drying of the precipitate gave the desired product (0.82g, 91%) as a white solid; ms (esi): 157.1337(M + H).

c) 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -2-cyclopropyl-1-dimethylcarbamoyl-ethyl) -amide

In analogy to example 6, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and (S) -2-amino-3-cyclopropyl-N, N-dimethyl-propionamide hydrochloride (1: 1) (example 25b) as starting materials and isolated as a pale yellow oil (80mg, 86%); LC-MS (UV peak area, ESI) 100%, 373.2231(M + H).

Example 26

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -3-methyl-1-methylcarbamoyl-butyl) -amide

In analogy to example 6, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and (2S) -2-amino-N, 4-dimethyl-pentanamide monohydrochloride (CAN99145-71-8) as starting materials and isolated as an off-white solid (67mg, 87%); LC-MS (UV peak area, ESI) 100%, 361.2232(M + H).

Example 27

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-dimethylcarbamoyl-3-methyl-butyl) -amide

The title compound was synthesized in analogy to example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and (2S) -2-amino-N, 4-trimethyl-pentanamide hydrochloride (1: 1) (CAN207595-81-1) as starting materials and isolated as a yellow solid (68mg, 85%); LC-MS (UV peak area, ESI) 100%, 375.2387(M + H).

Example 28

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-carbamoyl-2-cyclopropyl-ethyl) -amide

In analogy to example 6, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and (S) - α -amino-cyclopropanepropionamide (CAN156077-93-9) as starting materials and was isolated (22mg, 30%) as light yellow oil; LC-MS (UV peak area, ESI) 100%, 345.1929(M + H).

Example 29

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-carbamoyl-3-methyl-butyl) -amide

In analogy to example 6, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and (2S) -2-amino-4-methyl-pentanamide hydrochloride (1: 1) (CAN10466-61-2) as starting materials and isolated as a light yellow colloid (46mg, 62%); LC-MS (UV peak area, ESI) 100%, 347.2081(M + H).

Example 30

2- [ (5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl) -amino ] -2-ethyl-butyric acid methyl ester

In analogy to example 6, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and 2-amino-2-ethyl-butyric acid methyl ester hydrochloride (1: 1) (CAN92398-54-4) as starting materials and isolated as a yellow oil (86mg, 93%); LC-MS (UV peak area, ESI) 100%, 362.2071(M + H).

Example 31

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -2-cyclopropyl-1-methylcarbamoyl-ethyl) -amide

In analogy to example 6, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d) and (S) -2-amino-3-cyclopropyl-N-methyl-propionamide hydrochloride (1: 1) (example 24b) as starting materials and isolated as a white solid (64mg, 89%); LC-MS (UV peak area, ESI) 100%, 410.2001(M + H).

Example 32

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -2-cyclopropyl-1-dimethylcarbamoyl-ethyl) -amide

In analogy to example 6, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d) and (S) -2-amino-3-cyclopropyl-N, N-monomethyl-propionamide hydrochloride (1: 1) (example 25b) as starting materials and isolated as a white solid (63mg, 85%); LC-MS (UV peak area, ESI) 100%, 424.2155(M + H).

Example 33

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -3-methyl-1-methylcarbamoyl-butyl) -amide

In analogy to example 6, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d) and (2S) -2-amino-N, 4-dimethyl-pentanamide monohydrochloride (CAN99145-71-8) as starting materials and isolated as a white solid (59mg, 82%); LC-MS (UV peak area, ESI) 100%, 412.2155(M + H).

Example 34

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-dimethylcarbamoyl-3-methyl-butyl) -amide

In analogy to example 6, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d) and (2S) -2-amino-N, 4-trimethyl-pentanamide hydrochloride (1: 1) (CAN207595-81-1) as starting materials and isolated as a white solid (63mg, 85%); LC-MS (UV peak area, ESI) 100%, 426.2311(M + H).

Example 35

(S) -3-cyclopropyl-2- [ (5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl) -amino ] -propionic acid methyl ester

The title compound was synthesized in analogy to example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and (α S) - α -amino-cyclopropanepropionic acid methyl ester hydrochloride (1: 1) (CAN206438-31-5) as starting materials and was isolated as a yellow oil (80mg, 75%); LC-MS (UV peak area, ESI) 100%, 360.1920(M + H).

Example 36

(S) -3-cyclopropyl-2- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl-pylamino } -propionic acid methyl ester

In analogy to example 6, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d) and (α S) - α -amino-cyclopropanepropionic acid methyl ester hydrochloride (1: 1) (CAN206438-31-5) as starting materials and was isolated as a pale yellow oil (83mg, 82%); LC-MS (UV peak area, ESI) 100%, 411.1836(M + H).

Example 37

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-carbamoyl-2-phenyl-ethyl) -amide

In analogy to example 15, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and (S) -2-amino-3-phenyl-propionamide hydrochloride (1: 1) (CAN5241-58-7, 118.84mg, 0.64mmol) as starting materials and isolated as a colorless viscous solid (60mg, 37.03%); LC-MS (UV peak area, ESI) 100%, 381.4(M + H).

Example 38

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-carbamoyl-2-phenyl-ethyl) -amide

In analogy to example 15, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and (S) -2-amino-3-phenyl-propionamide hydrochloride (1: 1) (CAN5241-58-7, 87.84mg, 0.53mmol) as starting materials and isolated as a colorless viscous solid (75mg, 49.6%); LC-MS (UV peak area, ESI) 100%, 432.2(M + H).

Example 39

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-carbamoyl-2-cyclopropyl-ethyl) -amide

In analogy to example 6, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d) and (S) - α -amino-cyclopropanepropionamide (CAN156077-93-9) as starting materials and isolated as a white solid (40mg, 57%); LC-MS (UV peak area, ESI) 100%, 396.1845(M + H).

Example 40

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (SR) -cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-amides of

a) 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-amides of

Analogously to example 6, 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and α -cyclopropyl-5-methyl-1, 2, 4-Oxadiazole-3-methylamine (CAN1291557-80-6) as starting material the title compound was synthesized and isolated as a pale yellow solid (95mg, 86%); LC-MS (UV peak area, ESI) 100%, 370.1876(M + H).

b) 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (SR) - (cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-amides of

Mixing 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (cyclopropyl- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -methyl]The enantiomers of the amide (example 40a) were separated by chiral HPLC (ChiralPak AD, 10% 2-propanol/n-heptane). The (+) enantiomer was isolated as a colorless viscous oil; LC-MS (UV peak area/ESI) 100%, 370.1874(M + H); the (+) enantiomer of the compound (I) is,

EXAMPLE 41

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (RS) -cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-amides of

Mixing 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (cyclopropyl- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -methyl]Amides (example 40a)The enantiomers of (a) were separated by chiral HPLC (chiralpak ad, 10% 2-propanol/n-heptane). The (-) enantiomer was isolated as a colorless viscous oil; LC-MS (UV peak area/ESI) 100%, 370.1874(M + H); the (-) enantiomer of the compound of formula (I),

example 42

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (SR) -cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-amides of

a) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-amides of

Analogously to example 6, 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d) and α -cyclopropyl-5-methyl-1, 2, 4-Oxadiazole-3-methylamine (CAN1291557-80-6) as starting material the title compound was synthesized and isolated as a white solid (86mg, 83%); LC-MS (UV peak area, ESI) 100%, 421.1792(M + H).

b) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (SR) -cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-amides of

Mixing 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]The enantiomers of the amide (example 42a) were separated by chiral HPLC (ChiralPak AD, 20% ethanol/n-heptane). The (+) enantiomer was isolated as a white solid; LC-MS (UV peak area/ESI) 100%, 421.1794(M + H);

example 43

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (RS) -cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]-amides of

Mixing 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (cyclopropyl- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -methyl]The enantiomers of the amide (example 42a) were separated by chiral HPLC (ChiralPak AD, 20% ethanol/n-heptane). The (-) enantiomer was isolated as a white solid; LC-MS (UV peak area/ESI) 100%, 421.1794 (M)+H)；

Example 44

(S) -2- [ (5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl) -amino ] -3, 3-dimethyl-butyric acid

To a solution of (S) -2- [ (5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl) -amino ] -3, 3-dimethyl-butyric acid methyl ester (58mg, 160 μmol) in THF (3mL) was added lithium hydroxide (30mg, 715 μmol) in water (1mL), and the mixture was stirred at reflux temperature for 3 hours. After cooling, the mixture was poured into water (10mL), acidified with 1N HCl (1mL) and extracted with TBME. The organic phases were combined, dried over Na2S04, filtered and concentrated in vacuo to give the title compound (61mg, quantitative) as a self-colored solid; LC-MS (UV peak area/ESI) 100%, 348.1920(M + H).

Example 45

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

Analogously to example 6, 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and α, α, 5-trimethyl-1, 2, 4-Oxadiazole-3-methylamine hydrochloride (CAN1240526-27-5) as starting material the title compound was synthesized and isolated as a pale yellow solid (64mg, 84%); LC-MS (UV peak area, ESI) 100%, 358.1869(M + H).

Example 46

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-pyridin-2-yl-ethyl) -amide

In analogy to example 15, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and (α S) - α -methyl-2-pyridinemethanamine hydrochloride (1: 1) (100.0mg, 0.64mmol) as starting materials and was isolated as an off-white solid (15mg, 13.03%), LC-MS (UV peak area, ESI) 97.58%, 339.0(M + H).

Example 47

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((R) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -amide

a) (2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -carbamic acid (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexyl ester

α - (trifluoromethyl) -2-pyridinemethylamine (CAN503173-14-6, 2.0g, 11.4mmol) and DIEA (2.94g, 3.97mL, 22.7mmol) were combined with THF (20mL) and cooled with ice to give a pale yellow solution. (-) -Chloroformic acid in THF (20mL)The amount of the polyester (2.73g, 12.5mmol) was 30 minAdded dropwise at 0 ℃ during the course of the clock. The reaction mixture was stirred at 0 ℃ for 4 h. After that, the mixture was poured into ethyl acetate (50mL) and washed with water (2 × 25 mL). The aqueous layer was extracted with ethyl acetate (50mL) in reverse phase. The organic phases were combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (4.1g, quantitative) as a white solid, which was used in the next step without further purification; MS: (EI)359.2(M + H).

b) ((R) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -carbamic acid (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexyl ester

The title compound (1.42g) was isolated by chiral HPLC (ChiralPak AD, ethanol/n-heptane). Separating the (-) -enantiomer; MS: (EI)359.2(M + H).

c) (R) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethylamine

((R) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -carbamic acid (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexyl ester (1200mg, 3.35mmol) was dissolved in dichloromethane (20mL) and cooled to 0 ℃. To this solution was added TFA (4.44g, 3ml, 38.9mmol) at 0 ℃ and then trifluoromethanesulfonic acid (1.69g, 1000. mu.l, 11.3 mmol). The yellow reaction mixture was stirred at 0 ℃ for 8 h and at room temperature for 18 h, after which it was concentrated in vacuo. The residue was poured into ethyl acetate (100mL) and extracted with 1M NaOH (1 × 20 mL). The aqueous phase was extracted with ethyl acetate (100mL), the organic phases were combined, dried over Na2SO4 and concentrated in vacuo. The residue yellow oil was purified by flash chromatography (silica gel, 20g, 0% to 100% ethyl acetate in n-heptane) to give the title compound (0.38g, 65%) as colorless oil; LC-MS (ESI)177.0635(M + H); the (-) enantiomer.

d) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((R) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -amide

In analogy to example 6, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d) and (R) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethylamine (example 47c) as starting materials and was isolated (78mg, 86%) as a white solid; LC-MS (UV peak area, ESI) 100%, 444.1447(M + H).

Example 48

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -amide

a) ((S) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -carbamic acid (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexyl ester

The title compound (1.50g) was isolated by chiral HPLC (ChiralPak AD, ethanol/n-heptane). (ii) separating the (+) -enantiomer; MS: (EI)359.2(M + H).

b) (S) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethylamine

((S) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -carbamic acid (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexyl ester (1200mg, 3.35mmol) was dissolved in dichloromethane (20mL) and cooled to 0 ℃. To this solution, TFA (4.44g, 3ml, 38.9mmol) and then triflic acid (1.69g, 1000. mu.l, 11.3mmol) were added at 0 ℃. The yellow reaction mixture was stirred at 0 ℃ for 8 hours and at room temperature for 23 hours, after which it was concentrated in vacuo. The residue was poured into ethyl acetate (100mL) and extracted with 1M NaOH (1 × 20 mL). The aqueous phase was extracted with ethyl acetate (100mL), the organic phases were combined, dried over Na2SO4 and concentrated in vacuo. The residue yellow oil was purified by flash chromatography (silica gel, 20g, 0% to 100% ethyl acetate in n-heptane) to give the title compound (0.37g, 63%) as colorless oil; ms (ei)177.1(M + H);

c) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -amide

In analogy to example 6, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d) and (R) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethylamine (example 48b) as starting materials and was isolated (66mg, 85%) as a white solid; LC-MS (UV peak area, ESI) 100%, 444.1448(M + H).

Example 49

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethyl) -amide

In analogy to example 6, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and (S) -2, 2, 2-trifluoro-1-pyridin-2-yl-ethylamine (example 48b) as starting materials and isolated as a light yellow colloid (71mg, 85%); LC-MS (UV peak area, ESI) 100%, 393.1524(M + H).

Example 50

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl) -amide

In analogy to example 15, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 2-amino-2-ethyl-N-methyl-butyramide hydrochloride (1: 1) (61.6mg, 0.53mmol) as starting materials and isolated as a colorless viscous solid (30mg, 19.33%), LC-MS (UV peak area, ESI) 96.50%, 412.4(M + H).

Example 51

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((R) -1-hydroxymethyl-1, 2-dimethyl-propyl) -amide

In analogy to example 15, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10 g; 100mg, 0.42mmol) and (2R) -2-amino-2, 3-dimethyl-1-butanol (CAN155158-75-1, 107.06mg, 0.64mmol) as starting materials and isolated as an off-white viscous solid (20mg, 14.04%), LC-MS (UV peak area, ESI) 100%, 334.4(M + H).

Example 52

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-hydroxymethyl-1, 2-dimethyl-propyl) -amide

In analogy to example 15, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10 g; 100mg, 0.42mmol) and (2S) -2-amino-2, 3-dimethyl-1-butanol (CAN956102-64-0, 107.06mg, 0.64mmol) as starting materials and isolated as an off-white viscous solid (25mg, 16.04%), LC-MS (UV peak area, ESI) 90.02%, 334.4(M + H).

Example 53

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl) -amide

In analogy to example 15, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10 g; 100mg, 0.42mmol) and 2-amino-2-ethyl-N-methyl-butyramide (78.2mg, 0.64mmol) as starting materials and isolated as a colorless viscous solid (12mg, 9.44%), LC-MS (UV peak area, ESI) 97.47%, 361.4(M + H).

Example 54

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ 1-methyl-1- (4-methyl-thiazol-2-yl) -ethyl ] -amide

In analogy to example 15, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10 g; 100mg, 0.42mmol) and α, α, 4-trimethyl-2-thiazolemethanamine (CAN859466-62-9, 78.2mg, 0.64mmol) as starting materials and isolated as a colorless viscous solid (12mg, 9.22%), LC-MS (UV peak area, ESI) 99.24%, 373.4(M + H).

Example 55

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (4-methyl-thiazol-2-yl) -ethyl ] -amide

In analogy to example 15, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and α, α, 4-trimethyl-2-thiazolemethanamine (87.28mg, 0.53mmol) as starting materials and isolated as a colorless viscous solid (20mg, 13.47%), LC-MS (UV peak area, ESI) 97.93%, 424.0(M + H).

Example 56

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (R) -1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

Analogously to example 15, 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and (. alpha.R) -alpha, 5-dimethyl-1, 2, 4-Oxadiazole-3-methylamine (CAN1150339-59-5, 66.7mg, 0.52mmol) the title compound was synthesized as a starting material and isolated as an off-white solid (55mg, 39.78%), LC-MS (UV peak area, ESI) 95.17%, 395.4(M + H).

Example 57

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1- (5-amino- [1, 2, 4 ]]Oxadiazol-3-yl) -1-methyl-ethyl]-amides of

a) [1- (5-amino- [1, 2, 4 ]]Oxadiazol-3-yl) -1-methyl-ethyl]-carbamic acid tert-butyl ester

(Z) - [1- (N-hydroxycarbamimidoyl)) -1-methyl-ethyl]Tert-butyl carbamate (CAN1251430-04-2, 5.9g, 27.2mmol) was dissolved in DMF (11.8 mL). To the solution was added piperidine-1-carbonitrile (3.29g, 3.46ml) at room temperature and the reaction mixture was stirred at 130 ℃ for 2.5 h. After cooling, the mixture was added to ice water (400mL) and extracted with ethyl acetate (3 × 200 mL). The organic phases were washed with ice water, combined and washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by chromatography (silica gel, 200g,1: 1 ethyl acetate/n-heptane) to give the title compound (5.0g, 76%) as a white solid; LC-MS (UV peak area, ESI) 83%, 243.1453(M + H).

b)3- (1-amino-1-methyl-ethyl) - [1, 2, 4]Diazole-5-ylamine hydrochloride (1: 1)

Reacting [1- (5-amino- [1, 2, 4 ]]Oxadiazol-3-yl) -1-methyl-ethyl]Tert-butyl carbamate (1.6g, 6.6mmol) was dissolved in ethanol (30 mL). Adding two4M HCl in alkane (6.6mL, 26.4mmol) and the reaction mixture was stirred at room temperature for 16 h. The mixture was placed in vacuo and dried to give the title compound (1.2g, quantitative) as an off-white solid; MS (ESI)143.0927(M + H). c) 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1- (5-amino- [1, 2, 4 ]]Oxadiazol-3-yl) -1-methyl-ethyl]-amides of

Analogously to example 6, 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g) and 3- (1-amino-1-methyl-ethyl) - [1, 2, 4]Oxadiazol-5-ylamine hydrochloride (1: 1) (example 57b) the title compound was synthesized as starting material and isolated as an off-white solid (57mg, 75%); LC-MS (UV peak area, ESI) 100%, 359.1825(M + H).

Example 58

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [1- (5-amino- [1, 2, 4 ]]Oxadiazol-3-yl) -1-methyl-ethyl]-amides of

In analogy to example 6, 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d) and 3- (1-amino-1-methyl-ethyl) - [1, 2, 4 ] were used]Oxadiazol-5-ylamine hydrochloride (1: 1) (example 57b) the title compound was synthesized as starting material and isolated (40mg, 56%) as a white solid; LC-MS (UV peak area, ESI) 100%, 410.1744(M + H).

Example 59

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-carbamoyl-1-phenyl-ethyl) -amide

In analogy to example 15, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and (S) - α -amino- α -methyl-phenylacetamide (CAN30358-55-5, 88.42mg, 0.52mmol) as starting materials and isolated as a white solid (85mg, 56%); LC-MS (UV peak area, ESI) 94.87%, 432.4(M + H).

Example 60

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

a) 2-amino-3-cyclopropyl-2-methyl-propionitrile

To a solution of 1-cyclopropyl-propan-2-one (CAN 4160-75-2; 1.0g, 10.2mmo1) and ammonia (25% in water, 10mL) in ethanol (10mL) was added ammonium chloride (1.63g, 30.6 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Potassium cyanide (1g, 15.30mmol) was added in portions and the reaction mixture was stirred at ambient temperature for 12 h. Ice water (50mL) was added and extracted with ethyl acetate (3 × 50 mL). The organic phases were washed with ice-water, combined and washed with Na₂SO₄Dried and concentrated in vacuo to give the title compound (0.8g, 62.99%) as a yellow oil; NMR (400MHz, DMSO) δ 2.52(bds, 2H); 1.6-1.5(m, 1H); 1.49-1.4(m, 1H); 1.39(S, 3H); 0.85-0.75(m, 1H); 0.49-0.44(m, 2H); 0.16-0.14(m, 2H). b) (1-cyano-2-cyclopropyl-1-methyl-ethyl) -carbamic acid tert-butyl ester

To 2-amino-3-cyclopropyl-2-methyl-propionitrile (1.0 g)6.4mmol) and triethylamine (3.36mL, 19.8mmol) in dichloromethane (20mL) was added di-tert-butyl dicarbonate (CAN24424-99-5, 2.38mL, 9.47 mmol). The reaction mixture was stirred at ambient temperature for 12 hours. The organic phase was washed with ice water, brine and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by chromatography (silica gel, 50g, 1: 9 ethyl acetate/n-hexane) to give the title compound (1.2g, 66%) as a light yellow liquid; LC-MS (UV peak area, ESI) 83%, 225.14(M + H).

c) [ 2-cyclopropyl-1- (N-hydroxycarbamimidoyl) -1-methyl-ethyl ] -carbamic acid tert-butyl ester

Sodium bicarbonate (247.52mg, 2.94mmol) was dissolved in water (2mL) and hydroxylamine hydrochloride (204.747mg, 2.94mmol) was added. To this was added a solution of (1-cyano-2-cyclopropyl-1-methyl-ethyl) -carbamic acid tert-butyl ester (600mg, 2.69mmol) in ethanol (10mL) and the resulting reaction mixture was heated at 80 ℃ for 12 hours. After evaporation of the solvent, the residue was dissolved with ethyl acetate (20mL) and then filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 25g,

3: 7 ethyl acetate/n-hexane) to give the title compound (450mg, 66%) as a white solid; LC-MS (UV peak area, ESI) 100%, 258.4(M + H).

d) 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]-carbamic acid tert-butyl ester

A solution of [ 2-cyclopropyl-1- (N-hydroxycarbamimidoyl) -1-methyl-ethyl ] -carbamic acid tert-butyl ester (300mg, 1.16mmol) in acetic anhydride (10mL) was heated to 120 ℃ and stirred for 4 h. After evaporation of the solvent, the residue was purified by column chromatography (silica gel, 20g, eluting with 20% ethyl acetate in petroleum ether) to give the title compound (0.2 g; 61%) as a colorless viscous liquid; LC-MS (UV peak area, ESI) 90%, 282.2(M + H).

e) 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethylamine

To 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]To a solution of tert-butyl carbamate (0.2g, 0.7mmol) in methanol (5mL) was added hydrochloric acid (4N in bis0.87mL, 3.5mmol) in an alkane and the reaction mixture was stirred at ambient temperature for 4 hours. Water (20mL) was then added. The aqueous phase was washed with ethyl acetate (2 × 20mL) and adjusted to pH 9-10 with 2M sodium hydroxide solution. It was then extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (20mL) and anhydrous Na₂SO₄Dried and concentrated to give the crude product as a white solid (0.1g, 78%); LC-MS (UV peak area, ESI) 80%, 182.0(M + H).

f) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

Analogously to example 15, 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethylamine (86.42mg, 0.52mmol) the title compound was synthesized as starting material and isolated as a white solid (60mg, 38.2%); LC-MS (UV peak area, ESI) 98.77%, 449.4(M + H).

Example 61

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4 [ ] -]Oxadiazol-3-yl) -ethyl]-amides of

Analogously to example 15, 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 1-cyclopropyl-1- (5-methyl- [1, 2, 4mmol) were used]Oxadiazol-3-yl) -ethylamine (88.42mg, 0.52mmol) the title compound was synthesized as starting material and isolated as a white solid (50mg, 32.8%); LC-MS (UV peak area, ESI) 97.16%, 435.2(M + H).

Example 62

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]-amides of

Analogously to example 15, 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.42mmol) and α -cyclopropyl- α, 5-dimethyl-1, 2, 4-Oxadiazole-3-methylamine (CAN1155536-64-3, 106.88mg, 0.64mmol) as starting material the title compound was synthesized and isolated as a white solid (12mg, 7.3%); LC-MS (UV peak area, ESI) 83.46%, 384.0(M + H).

Example 63

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (S) -carbamoyl- (4-fluoro-phenyl) -methyl ] -amide

In analogy to example 15, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.42mmol) and (S) -2-amino-2- (4-fluoro-phenyl) -acetamide (119.2mg, 0.64mmol) as starting materials and was isolated as a white solid (10mg, 6.3%); LC-MS (UV peak area, ESI) 95.12%, 384.8(M + H).

Example 64

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -carbamoyl- (4-fluoro-phenyl) -methyl ] -amide

In analogy to example 15, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and (S) -2-amino-2- (4-fluoro-phenyl) -acetamide (88.4mg, 0.52mmol) as starting materials the title compound was synthesized and isolated as a white solid (20mg, 13.15%); LC-MS (UV peak area, ESI) 99.73%, 436.0(M + H)⁺。

Example 65

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ (S) -2-cyclopropyl-1- (5-methyl-pyrazine 1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) was suspended in DME (3 mL). Diethoxy-phosphoryl carbonitrile (226.0mg, 0.80mmol), DIEA (0.63mL, 4.2mmol) and (S) -2-cyclopropyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethylamine (example 20e, 82.2mg, 0.64mmol) and the reaction mixture was heated at 100 ℃ for 10 minutes under microwave conditions. Extracting the mixture with ethyl acetate and water; the organic phase is washed with Na₂S0₄Dried, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xterra-RP18, 10 μ, 19 × 250 mM/acetonitrile/10 mM ammonium acetate in water) to give the desired product (20mg, 11.72%) as a white solid; LC-MS (UV peak area, ESI) 96.20%, 384.2(M + H).

Example 66

(S) -2- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl ] -amino } -4-methyl-pentanoic acid methyl ester

The title compound was synthesized in analogy to example 6 using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 300mg, 1.05mmol) and L-leucine methyl ester hydrochloride (1: 1) (CAN7517-19-3, 210mg, 1.16mmol) as starting materials and isolated as a light yellow solid (390mg, 90%); LC-MS (UV Peak area, ESI) 100%, 413.1997(M + H)⁺。

Example 67

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -3-methyl-1- (2, 2, 2-trifluoro-ethylcarbamoyl) -butyl ] -amide

a) (S) -2- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl ] -amino } -4-methyl-pentanoic acid

To (1)S) -2- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl]A solution of-amino } -4-methyl-pentanoic acid methyl ester (355mg, 0.86mmol) in THF (18mL) and H2O (6mL) was added lithium hydroxide monohydrate (163mg, 3.87mmol) and the mixture was stirred at reflux temperature for 2H. The mixture was diluted with H2O (10mL), acidified with hydrochloric acid (1N, 5mL) and extracted with ethyl acetate (2 × 25 mL). The organic phases were combined, dried over Na2SO4 and concentrated in vacuo to give the title compound (334mg, 97%) as a white solid; LC-MS (UV Peak area, ESI) 100%, 399.1842(M + H)⁺。

b) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -3-methyl-1- (2, 2, 2-trifluoro-ethylcarbamoyl) -butyl ] -amide

(S) -2- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl ] -amino) -4-methyl-pentanoic acid (40mg, 100. mu. mol) was suspended in DMF (2 mL). TBTU (35.5mg, 110. mu. mol), DIEA (85.9. mu.l, 0.5mmol) and 2, 2, 2-trifluoro-ethylamine hydrochloride (1: 1) (CAN373-88-6, 15mg, 135. mu. mol) were added and the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo; ethyl acetate (3mL) and 2N NaOH solution (2mL) were added, followed by elution with ethyl acetate through ChemElut (10 g). The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 10g, 0% to 100% ethyl acetate in n-heptane) to give the desired product (36mg, 75%) as a white solid; LC-MS (UV peak area, ESI) 100%, 480.2035(M + H).

Example 68

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ (S) -carbamoyl- (4-chloro-phenyl) -methyl ] -amide

Analogously to example 15, a 6-ring was usedPropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and (S) -2-amino-2- (4-chloro-phenyl) -acetamide (67.3mg, 0.52mmol) as starting materials the title compound was synthesized and isolated as a white solid (20mg, 12.6%); LC-MS (UV Peak area, ESI) 100%, 452.2(M + H)⁺。

Example 69

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (4-hydroxy-1, 1-dimethyl-butyl) -amide

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) was suspended in DMF (3 mL). Mukaiyama reagent (CAN878-23-9, 233.8mg, 0.85mmol), DIEA (0.31mL, 2.24mmol) and 4-amino-4-methyl-pentan-1-ol (CAN85054-53-1, 101.33mg, 0.64mmol) were added and the reaction mixture was stirred at room temperature for 12 hours. Extracting the mixture with ethyl acetate and water; the organic phase is washed with Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xterra-RP18, 10 μ, 19 × 250 mM/acetonitrile/10 mM ammonium acetate in water) to give the desired product (100mg, 70.26%) as a colorless viscous liquid; LC-MS (UV peak area, ESI) 96.12%, 334.0(M + H).

Example 70

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1, 1-dimethyl-3-pyridin-4-yl-propyl) -amide

Analogously to example 69, 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Experimental) was usedEXAMPLE 10g, 50mg, 0.21mmol) and 1, 1-dimethyl-3-pyridin-4-yl-propylamine (55mg, 0.32mmol) were used as starting materials to synthesize the title compound and isolated as a white solid (60.0mg, 74%); LC-MS (UV peak area, ESI) 94.93%, 380.0(M + H)⁺。

Example 71

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1, 1-dimethyl-2- (5-methyl-2-phenyl-Oxazol-4-yl) -ethyl]-amides of

In analogy to example 69, 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 50mg, 0.21mmol) and 1, 1-dimethyl-2- (5-methyl-2-phenyl-Oxazol-4-yl) -ethylamine (57.2mg, 0.32mmol) was synthesized as the starting material and isolated as a white solid (75mg, 73.6%); LC-MS (UV Peak area, ESI) 92.82%, 446.8(M + H)⁺。

Example 72

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1, 1-dimethyl-3-pyridin-4-yl-butyl) -amide

The title was synthesized in analogy to example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g10mg, 0.043mmol) and 1, 1-dimethyl-3-pyridin-4-yl-butylamine (12mg, 0.064mmol) as starting materialsCompound and isolated as a white solid (10mg, 59.38%); LC-MS (UV Peak area, ESI) 99.2%, 395.2(M + H)⁺。

Example 73

1- { [ 6-Cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl ] -amino) -cyclobutanecarboxylic acid methyl ester

In analogy to example 6, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 1-amino-cyclobutanecarboxylic acid methyl ester hydrochloride (1: 1) (CAN92398-47-5, 64mg, 0.39mmol) as starting materials the title compound was synthesized and isolated as a white solid (111mg, 80%); LC-MS (UV Peak area, ESI) 100%, 397.1683(M + H)⁺。

Example 74

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl-thiazol-2-yl) -ethyl ] -amide

In analogy to example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.42mmol) and 1-methyl-1- (5-methyl-thiazol-2-yl) -ethylamine (100mg, 0.64mmol) as starting materials the title compound was synthesized and isolated as a white solid (29mg, 18.3%); LC-MS (UV Peak area, ESI) 94.85%, 372.8(M + H)⁺。

Example 75

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl-thiazol-2-yl) -ethyl ] -amide

In analogy to example 15, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 1-methyl-1- (5-methyl-thiazol-2-yl) -ethylamine (82.3mg, 0.526mmol) as starting materials the title compound was synthesized and isolated as a white solid (26mg, 17.5%); LC-MS (UV Peak area, ESI) 86.27%, 423.8(M + H)⁺。

Example 76

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S) -1-carbamoylmethyl-2-methyl-propyl) -amide

The title compound was synthesized in analogy to example 6 using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 50mg, 0.21mmol) and (3S) -3-amino-4-methyl-pentanamide monohydrochloride (CAN173336-51-1, 39mg, 0.24mmol) as starting materials and isolated as a light yellow solid (55mg, 74%); LC-MS (UV peak area, ESI) 98%, 347.2082(M + H)⁺。

Example 77

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((S) -1-carbamoylmethyl-2-methyl-propyl) -amide

With fruitExample 6 the title compound was synthesized in analogy to using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 50mg, 0.21mmol) and (3S) -3-amino-4-methyl-pentanamide monohydrochloride (CAN173336-51-1, 39mg, 0.24mmol) as starting materials and isolated as a white solid (52mg, 74%); LC-MS (UV Peak area, ESI) 100%, 398.1998(M + H)⁺。

Example 78

(+) -6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

By reacting 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]Amide (example 60f) the title compound was isolated by chiral chromatography on ChiralPak AD using heptane/5% 2-propanol as eluent. The (+) -enantiomer is isolated. LC-MS (UV peak area/ESI) 94%, 449.2112(M + H)⁺，

Example 79

(-) -6-Cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Diazol-3-yl) -ethyl radical]-amides of

By reacting 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 2-cyclopropyl-1-methyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]Amide (example 60f) the title compound was isolated by chiral chromatography on ChiralPak AD using heptane/5% 2-propanol as eluent. The (-) -enantiomer was isolated. LC-MS (UV peak area/ESI) 96%, 449.2113(M + H)⁺，

Example 80

2-cyclopropyl-2- { [ 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carbonyl ] -amino) -propionic acid methyl ester

In analogy to example 6, the title compound was synthesized using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 200mg, 0.70mmol) and α -amino- α -methyl-cyclopropaneacetic acid methyl ester hydrochloride (1: 1) (CAN1333675-34-5, 139mg, 0.77mmol) as starting materials and separated (256mg, 89%) as light yellow oil; LC-MS (UV Peak area, ESI) 100%, 411.1838(M + H)⁺。

Example 81

(+) -6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid ((1R, 2S) -re 1-2-carbamoyl-cyclohexyl) -amide

a) 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1R, 2S) -rel-2-carbamoyl-cyclohexyl) -amide

In analogy to example 6, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and (1R, 2S) -rel-2-amino-cyclohexanecarboxamide (CAN24717-01-9, 55mg, 0.39mmol) as starting materials the title compound was synthesized and isolated as a white solid (122mg, 85%); LC-MS (UV Peak area, ESI) 100%, 410.1998(M + H)⁺。

b) (+) -6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1R, 2S) -rel-2-carbamoyl-cyclohexyl) -amide

The title compound was isolated by chiral chromatography of 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1R, 2S) -rel-2-carbamoyl-cyclohexyl) -amide (example 81a) on ChiralPak AD using heptane/20% ethanol as eluent. The (+) -enantiomer is isolated. LC-MS (UV peak area/ESI) 100%, 410.1996(M + H)⁺，

Example 82

(-) -5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid cis-2-carbamoyl-cyclohexyl) -amide

a) 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((1S, 2R) -rel-2-carbamoyl-cyclohexyl) -amide

In analogy to example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 100mg, 0.43mmol) and (1R, 2S) -rel-2-amino-cyclohexanecarboxamide (CAN24717-01-9, 67mg, 0.47mmol) as starting materials the title compound was synthesized and isolated as an off-white solid (155mg, quantitative); LC-MS (UV peak area, ESI) 97%, 359.2078(M + H)⁺。

b) (-) -5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid cis-2-carbamoyl-cyclohexyl) -amide

The title compound was isolated by chiral chromatography of 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((1S, 2R) -rel-2-carbamoyl-cyclohexyl) -amide (example 82a) on ChiralPak AD using heptane/20% ethanol as eluent. The (-) -enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 359.2077(M + H)⁺，

Example 83

(+) -5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid cis-2-carbamoyl-cyclohexyl) -amide

The title compound was isolated by chiral chromatography of 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((1S, 2R) -rel-2-carbamoyl-cyclohexyl) -amide (example 82a) on ChiralPak AD using heptane/20% ethanol as eluent. The (+) -enantiomer is isolated. LC-MS (UV peak area/ESI) 100%, 359.2084(M + H)⁺，

Example 84

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl) -amide

a)2- (3-amino-oxetan-3-yl) -acetamides

To a solution of ethyl 3-amino-3-oxetaneacetate (400mg, 2.51mmol) in toluene (8.0mL) was added ammonium hydroxide in water (25%, 8.0mL, 51.4 mmol). The mixture was stirred in a closed tube at room temperature for 6 days. The solvent was removed in vacuo and the residual water was removed by azeotropic distillation with toluene. The residue was dried under high vacuum at 40 ℃ to give the desired product (290 mg, 89%) as a white solid; GC-MS (ESI), 131.0817(M + H).

b) 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl) -amide

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 50mg, 0.21 mm) was used in analogy to example 6ol) and 2- (3-amino-oxetan-3-yl) -acetamide (31mg, 0.24mmol) as starting materials the title compound was synthesized and isolated as a white solid (30mg, 41%); LC-MS (UV Peak area, ESI) 100%, 347.1710(M + H)⁺。

Example 85

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl) -amide

In analogy to example 6, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 50mg, 0.18mmol) and 2- (3-amino-oxetan-3-yl) -acetamide (example 85a, 25mg, 0.19mmol) as starting materials the title compound was synthesized and isolated as a white solid (37mg, 53%); LC-MS (UV Peak area, ESI) 100%, 398.1641(M + H)⁺。

Example 86

(+) -6-Cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

By reacting 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazole-3-Yl) -ethyl]Amide (example 61) the title compound was isolated by chiral chromatography on ChiralPakAD using heptane/15% 2-propanol as eluent. The (+) -enantiomer is isolated. LC-MS (UV peak area/ESI) 100%, 435.1945(M + H)⁺，

Example 87

(-) -6-Cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -ethyl]-amides of

By reacting 6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]Amide (example 61) the title compound was isolated by chiral chromatography on ChiralPakAD using heptane/15% 2-propanol as eluent. The (-) -enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 435.1945(M + H)⁺，

Example 88

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-carbamoyl-2-methyl-propyl) -amide

In analogy to example 69, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 2-amino-3-methyl-butyramide (CAN13474-14-1, 61.2mg, 0.52mmol) as starting materials the title compound was synthesized and isolated as a white solid (40mg, 49.73%); LC-MS (UV Peak area, ESI) 97.95%, 384.0(M + H)⁺。

Example 89

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-carbamoyl-cyclohexyl) -amide

In analogy to example 69, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 1-amino-cyclohexanecarboxylic acid amide hydrochloride (CAN17704-77-7, 74.73mg, 0.52mmol) as starting materials the title compound was synthesized and isolated as a white solid (100mg, 69.9%); LC-MS (UV Peak area, ESI) 95.07%, 410.0(M + H)⁺。

Example 90

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclohexyl) -amide

In analogy to example 69, 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 1-amino-cyclohexanecarboxylic acid amide hydrochloride (CAN 17704)-77-7, 74.73mg, 0.52mmol) as starting material the title compound was synthesized and isolated as a white solid (100mg, 69.9%); LC-MS (UV Peak area, ESI) 95.07%, 410.0(M + H)⁺。

Example 91

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-dimethylcarbamoyl-2-methyl-propyl) -amide

In analogy to example 69, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 2-amino-3, N-trimethyl-butyramide hydrochloride (CAN1257848-66-0, 75.7mg, 0.52mmol) as starting materials the title compound was synthesized and isolated as a white solid (50.6mg, 34.63%); LC-MS (UV peak area, ESI) 98.97%, 412.0(M + H)⁺。

Example 92

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-dimethylcarbamoyl-2-methyl-propyl) -amide

In analogy to example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 80mg, 0.34mmol) and 2-amino-3, N-trimethyl-butyramide hydrochloride (CAN1257848-66-0, 40.1mg, 0.27mmol) as starting materials the title compound was synthesized and isolated as a white solid (35mg, 28.4%); LC-MS (UV Peak area, ESI) 93.77%, 361.0(M + H)⁺。

Example 93

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (5-chloro-thiophen-2-yl) -amide

In analogy to example 69, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 5-chloro-thiophen-2-ylamine (CAN63806-78-0, 18.6mg, 0.14mmol) as starting materials the title compound was synthesized and isolated as a white solid (12mg, 17.06%); LC-MS (UV Peak area, ESI) 95.2%, 401.2(M + H)⁺。

Example 94

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclohexyl) -amide

In analogy to example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 50mg, 0.214mmol) and (1-amino-cyclohexyl) -methanol hydrochloride (CAN5460-68-4, 22.8mg, 0.17mmol 1) as starting materials the title compound was synthesized and isolated (46mg, 62.32%) as a white solid; LC-MS (UV peak area, ESI) 96.49%, 346.0(M + H) +.

Example 95

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-methoxy-1, 1-dimethyl-propyl) -amide

In analogy to example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 50mg, 0.214mmol) and 3-methoxy-1, 1-dimethyl-propylamine (CAN889765-21-3, 50mg, 0.32mmol) as starting materials the title compound was synthesized and isolated as a white solid (40mg, 56.14%); LC-MS (UV Peak area, ESI) 99.87%, 333.8(M + H)⁺。

Example 96

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (2-cyclobutyl-1-methylcarbamoyl-ethyl) -amide

In analogy to example 69, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 50mg, 0.17mmol) and 2-amino-3-cyclobutyl-N-methyl-propionamide (34mg, 01.7mmol) as starting materials the title compound was synthesized and isolated as a white solid (12mg, 16.15%); LC-MS (UV Peak area, ESI) 99.07%, 422.4(M + H)⁺。

Example 97

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (2-cyclobutyl-1-dimethylcarbamoyl-ethyl) -amide

In analogy to example 69, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 50mg, 01.7mmol) and 2-amino-3-cyclobutyl-N, N-dimethyl-propionamide (36.3mg, 0.17mmol) as starting materials the title compound was synthesized and isolated as a white solid (12mg, 15.63%) (ii) a LC-MS (UV Peak area, ESI) 99.52%, 438.2(M + H)⁺。

Example 98

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-cyclobutyl-1-methylcarbamoyl-ethyl) -amide

In analogy to example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 50mg, 0.21mmol) and 2-amino-3-cyclobutyl-N-methyl-propionamide (41.2mg, 0.32mmol) as starting materials the title compound was synthesized and isolated as a white solid (20mg, 25.16%); LC-MS (UV Peak area, ESI) 99.32%, 373.2(M + H)⁺。

Example 99

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (3-methoxy-1, 1-dimethyl-propyl) -amide

In analogy to example 69, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 50mg, 0.17mmol) and 3-methoxy-1, 1-dimethyl-propylamine (CAN889765-21-3, 27.28mg, 0.175mmol) as starting materials the title compound was synthesized and isolated as a white solid (55.3mg, 67.4%); LC-MS (UV Peak area, ESI) 99.69%, 385.2(M + H)⁺。

Example 100

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-cyclobutylmethyl-2-hydroxy-ethyl) -amide

In analogy to example 69, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 50mg, 0.17mmol) and 2-amino-3-cyclobutyl-propan-1-ol (27.2mg, 0.17mmol) as starting materials the title compound was synthesized and isolated as a white solid (35mg, 50.32%); LC-MS (UV peak area, ESI) 99.21%, 397.2(M + H)⁺

Example 101

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1-carbamoyl-2-cyclobutyl-ethyl) -amide

In analogy to example 69, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 100mg, 0.35mmol) and 2-amino-3-cyclobutyl-propionamide (105.1mg, 0.52mmol) as starting materials the title compound was synthesized and isolated as a white solid (30mg, 21%); LC-MS (UV peak area, ESI) 98.96%, 410.4(M + H)⁺。

Example 102

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (1, 1-dimethyl-3-phenyl-propyl) -amide

Analogously to example 69, using 6-cyclopropyl-methoxy-5- (3,3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 50ng, 0.17mmol) and 1, 1-dimethyl-3-phenyl-propylamine (52.88mg, 0.32mmol) as starting materials the title compound was synthesized and isolated as a white solid (50mg, 54.9%); LC-MS (UV Peak area, ESI) 91.57%, 431.0(M + H)⁺。

Example 103

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-cyclobutyl-1-dimethylcarbamoyl-ethyl) -amide

In analogy to example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 50mg, 0.21mmol) and 2-amino-3-cyclobutyl-N, N-dimethyl-propionamide (54.48mg, 0.32mmol) as starting materials the title compound was synthesized and isolated as a white solid (20mg, 24.3%); LC-MS (UV Peak area, ESI) 100%, 387.2(M + H)⁺。

Example 104

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-carbamoyl-2-cyclobutyl-ethyl) -amide

In analogy to example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 50mg, 0.21mmol) and 2-amino-3-cyclobutyl-propionamide (52.5mg, 0.26mmol) as starting materials the title compound was synthesized and isolated as a white solid (30mg, 39.4%); LC-MS (UV peak area, ESI) 99.04%%, 357.4(M-H)⁺。

Example 105

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-cyclobutylmethyl-2-hydroxy-ethyl) -amide

In analogy to example 69, the title compound was synthesized using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 50mg, 0.21mmol) and 2-amino-3-cyclobutyl-propan-1-ol (38.7mg, 0.3mmol) as starting materials and isolated as a white solid (30mg, 41%); LC-MS (UV Peak area, ESI) 99.69%, 346.2(M + H)⁺。

Example 106

(5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-carbamoyl-1, 1-dimethyl-ethyl) -amide

In analogy to example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 10g, 50mg, 0.21mmol) and 3-amino-3-methyl-butyramide hydrochloride (1: 1) (CAN173336-86-2, 35.8mg, 0.235mmol) as starting materials the title compound was synthesized and isolated as a light yellow solid (56mg, 79%); LC-MS (UV Peak area, ESI) 100%, 333.1926(M + H)⁺。

Example 107

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (2-carbamoyl-1, 1-dimethyl-ethyl) -amide

In analogy to example 6, using 6-cyclopropyl-methoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid (example 8d, 50mg, o.175mmol) and 3-amino-3-methyl-butyramide hydrochloride (1: 1) (CAN173336-86-2, 29.4mg, 0.193mmol) as starting materials the title compound was synthesized and isolated as a white solid (38mg, 57%); LC-MS (UV Peak area, ESI) 100%, 384.1849(M + H)⁺。

Example 108

Pharmacological testing

The following assays were performed to determine the activity of the compounds of formula I:

radioligand binding assays

The affinity of the compounds of the invention for the cannabinoid CB1 receptor was determined using suggested amounts of membrane preparations (Perkin Elmer) of Human Embryonic Kidney (HEK) cells expressing the human CNR1 or CNR2 receptor, each binding 1.5 or 2.6nM [3H ] -CP-55, 940(Perkin Elmer) as radioligand, respectively. Binding was performed in a total volume of 0.2ml of binding buffer (50 mM Tris, 5mM MgCl2, 2.5mM EDTA, and 0.5% (wt/vol) fatty acid free BSA, pH7.4 for CB1 receptor, and 50mM Tris, 5mM MgCl2, 2.5mM EGTA, and 0.1% (wt/vol) fatty acid free BSA, pH7.4 for CB2 receptor, with shaking at 30 ℃ for 1 h. The reaction was terminated by rapid filtration through a 0.5% polyethyleneimine coated micro filter plate (UniFilter GF/B filter plate; Packard). Bound radioactivity was analyzed using non-linear regression analysis (Activity Base, ID Business Solution, Limited) for Ki, and Kd values for [3H ] CP55, 940 were determined from saturation experiments. The compounds of formula (I) show excellent affinity for the CB2 receptor with an affinity of less than 10 μ Μ, more particularly 1nM to 3 μ Μ and most particularly 1nM to 100 nM.

The compounds according to formula I have an activity (Ki) in the above assay of in particular between 0.5nM and 10 μ M, more in particular 0.5nM to 3 μ M and most in particular 0.5nM to 100 nM.

cAMP assay

CHO cells expressing human CB1 or CB2 receptors were seeded 17-24 hours prior to the experiment at 50.000 cells/well in black 96-well plates with clear flat bottom (Corning Costar #3904), in DMEM (Invitrogen No.31331), supplemented with 1 HT, with 10% fetal bovine serum, and in a humidified incubator at 5% CO₂And incubated at 37 ℃. The medium was exchanged with Krebs Ringer Bicarbonate buffer with 1mM IBMX and incubated at 30 ℃ for 30 minutes. The compound was added to a final assay volume of 100. mu.l and incubated at 30 ℃ for 30 minutes. Using the cAMP-Nano-TRF detection kit (Roche Diagnostics), lysis was performed by adding 50. mu.1 lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, 10% NaN)₃) And 50 μ 1 detection solution (20 μ M mAb Alexa700-cAMP 1: 1, and 48 μ M Ruthenium-2-AHA-cAMP) stop the assay and oscillate at room temperature for 2 h. The time-resolved energy transfer was measured by a TRF reader (Evotec Technologies GmbH) equipped with an ND: YAG laser as excitation source. The plate was measured twice, excited at 355nm and emitted at 730 (bandwidth 30nm) or 645nm (bandwidth 75nm) respectively with a 100ns delay and a 100ns gate (gate), for a total exposure time of 10 s. The FRET signal is calculated as follows: FRET-T730-Alexa 730-P (T645-B645), P-Ru 730-B730/Ru645-B645, where T730 is the test well measured at 730nM, T645 is the test well measured at 645nM, and B730 and B645 are buffer controls at 730nM and 645nM, respectively. cAMP content is determined from a function spanning a standard curve from 10. mu.M to 0.13nM cAMP.

EC is determined using Activity Base analysis (ID Business Solution, Limited)₅₀The value is obtained. EC for a broad range of cannabinoid agonists generated from this assay₅₀The values are in agreement with the values disclosed in the scientific literature.

All compounds are EC with less than 3uM₅₀And at least 10-fold selective CB2 agonist relative to CB1 in a corresponding assay.

For example, the following compounds show the following human ECs in the functionalized cAMP assay described above₅₀Value (ND: not measured):

beta-arrestin translocation assay-PathHunter ^TM (DiscoveRx)

The PathHunter. beta. -arrestin CHO-K1CNR1 cell line (Cat #93-0200C2) and the beta-arrestin CHO-K1CNR2 cell line (Cat #93-0706C2) were purchased from DiscoveRxcorporation. Cell lines were engineered to express a β -galactosidase EA fragment fused to a β -arrestin and a ProLink complementary peptide fused to a receptor of interest. PathHunter^TMProtein complementation assay (Discovex Corporation #93-0001) was performed according to the manufacturer's protocol. Assay plates were seeded to contain 7500(CNR1) and 10000(CNR2) cells in 20. mu.L cell plate reagent 2(discover #93-0563R2A) in 384 well plates (Corning Costar #3707, white, clear bottom). At 37 deg.C (5% C0)₂95% relative humidity) was incubated overnight, 5. mu.l of test compound (1% final DMS) was addedO concentration) and incubation continued at 30 ℃ for 90 min. Detection reagents (12. mu.l) were then added and incubation continued at room temperature for 60 min. Then using Victor³A V reader (Perkin Elmer) analyzes the chemiluminescent signal of the plate.

Example A

Film-coated tablets containing the following ingredients can be prepared in a conventional manner:

composition (I)	Each sheet is
			And (3) nucleus:
a compound of formula (I)	10.0mg	200.0mg
			Microcrystalline cellulose	23.5mg	43.5mg
Hydrous lactose	60.0mg	70.0mg
			Polyvinylpyrrolidone (Povidone) K30	12.5mg	15.0mg
Sodium starch glycolate	12.5mg	17.0mg
			Magnesium stearate	1.5mg	4.5mg
(nuclear weight)	120.0mg	350.0mg

Film coating:
			hydroxypropyl methylcellulose	3.5mg	7.0mg
Polyethylene glycol 6000	0.8mg	1.6mg
			Talc	1.3mg	2.6mg
Iron oxide (yellow)	0.8mg	1.6mg
			Titanium dioxide	0.8mg	1.6mg

The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules were then mixed with sodium starch glycolate and magnesium stearate and compressed to obtain 120 or 350mg of cores, respectively. The core is coated with the aqueous solution/suspension of the film coating described above.

Example B

Capsules containing the following ingredients can be prepared in a conventional manner:

composition (I)	Each capsule
		A compound of formula (I)	25.0mg
Lactose	150.0mg
		Corn starch	20.0mg
Talc	5.0mg

The ingredients were sieved and mixed and filled into size 2 capsules.

Example C

The injection solution may have the following composition:

a compound of formula (I)	3.0mg
		Polyethylene glycol 400	150.0mg
Acetic acid	In a proper amount to obtain pH5.0
		Water for injection	Adding to 1.0ml

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (a portion). The pH was adjusted to 5.0 by adding acetic acid. The volume was adjusted to 1.0ml by adding the balance of water. The solution was filtered, filled into vials with the appropriate excess and sterilized.

Claims

1. A compound of formula (I)

Wherein

R¹Is halophenyl or cycloalkylalkoxy;

R²is cycloalkyl, azetidinyl or difluoroazetidinyl;

R³and R⁴In (1)One is hydrogen and the other is- (CR)⁵R⁶)-R⁷or-A-R⁷；

Or R²Is cycloalkyl and R³And R⁴Together with the nitrogen atom to which they are attached form a piperidinyl or piperidinylamine;

R⁷is cyano, carboxy, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-amino- [1, 2, 4 ]]Oxadiazol-3-yl, 5-alkoxy- [1, 2, 4 ]]Oxadiazol-3-yl, thiazolyl, alkylthiazolyl, pyridyl, alkylaminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, alkoxycarbonyl, dialkylaminocarbonyl, methanesulfonyl-alkyl, 2- [1, 2, 4 ] methyl]Oxadiazol-5-yl) -alkyl, 2-methyl-2H- [1, 2, 4]Triazol-3-yl, 2- (2-methyl-2H- [1, 2, 4 ]]Triazol-3-yl) -alkyl, 2, 4-dihydro- [1, 2, 4]Triazol-3-one-5-yl, 2- (2, 4-dihydro- [1, 2, 4)]Triazol-3-on-5-yl) -alkyl, phenyl, phenylalkyl, pyridylalkyl, pyrazolyl, pyrazolylalkyl, [1, 2, 4]Triazol-1-yl, 2- ([1, 2, 4)]Triazol-1-yl) -alkyl, alkylaminocarbonylalkyl, hydroxyalkylaminocarbonyl, hydroxyalkylaminocarbonylalkyl, haloalkylaminocarbonyl, 5-phenyl-2-methyl-Oxazol-4-yl-alkyl, aminocarbonylalkyl or halogen; and is

A is cyclohexyl or thienyl;

with the proviso that when R²Is azetidinyl or difluoroazetidinyl and R⁷Is hydroxyalkyl, haloalkyl, thiazolyl, pyridyl, 2- ([1, 2, 4 ]]Oxadiazol-5-yl) -alkyl, pyridylalkyl, pyrazolylalkyl, 2- ([1, 2, 4 ] methyl]Triazol-1-yl) -alkyl, aminocarbonyl or alkoxycarbonyl, then R⁵And R⁶One is cycloalkyl, cycloalkylalkyl, phenyl, halophenyl or phenylalkyl and the other is hydrogen or alkyl;

or then R⁵And R⁶Together with the carbon atom to which they are attached form a cycloalkyl or oxetanyl group;

or a pharmaceutically acceptable salt or ester thereof.

2. The compound of claim 1, wherein R¹Is cycloalkylalkoxy.

3. The compound of claim 1 or 2, wherein R¹Is cyclopropylmethoxy.

4. A compound according to any one of claims 1 to 3, wherein R²Is cycloalkyl or difluoroazetidinyl.

5. A compound according to any one of claims 1 to 4, wherein R²Is cyclopropyl or difluoroazetidinyl.

6. According to claims 1 to 5The compound of any one of (1), wherein R⁵And R⁶Independently selected from hydrogen, alkyl, cycloalkyl and cycloalkylalkyl.

7. A compound according to any one of claims 1 to 6, wherein R⁵And R⁶Independently selected from the group consisting of hydrogen, ethyl, t-butyl, isobutyl, cyclopropyl, cyclopropylmethyl and cyclobutylmethyl.

8. A compound according to any one of claims 1 to 7, wherein R⁵And R⁶One of which is selected from ethyl, tert-butyl, isobutyl, cyclopropylmethyl and cyclobutylmethyl and the other is hydrogen or ethyl.

9. A compound according to any one of claims 1 to 8, wherein R⁷Is cyano, carboxy, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-amino- [1, 2, 4 ]]Oxadiazol-3-yl, thiazolyl, alkylthiazolyl, pyridyl, alkylaminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl, 5-methyl-thiazol-2-yl, aminocarbonylalkyl or phenylalkyl.

10. The compound according to any one of claims 1 to 9, wherein R⁷Is alkoxyalkyl, aminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl, 5-methyl-thiazol-2-yl, aminocarbonylalkyl, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, hydroxyalkyl or phenylalkyl.

11. The compound according to any one of claims 1 to 10, wherein R⁷Is methoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, 5-methyl-thiazol-2-yl, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, aminocarbonylmethyl, hydroxymethyl, methoxyethyl or phenylethyl.

12. A compound according to any one of claims 1 to 11, selected from

5-azetidin-1-yl-6- (3-chloro)-phenyl) -pyrazine-2-carboxylic acid [ 1-methyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]-an amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1- (5-amino- [1, 2, 4 ]]Oxadiazol-3-yl) -1-methyl-ethyl]-an amide;

6-cyclopropylmethoxy-5- (3, 3-difluoro-azetidin-1-yl) -pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4 [ ] -]Oxadiazol-3-yl) -ethyl]-an amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [ 1-cyclopropyl-1- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -ethyl]-an amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-cyclobutylmethyl-2-hydroxy-ethyl) -amide;

5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-carbamoyl-1, 1-dimethyl-ethyl) -amide; and

13. A compound according to any one of claims 1 to 12, selected from

14. A process for the preparation of a compound according to any one of claims 1 to 13, comprising a compound of formula (a)

And formula NHR³R⁴A compound of (1), an amide bond-forming coupling agent and a base, wherein R¹To R⁴As defined in any one of claims 1 to 11.

15. A compound according to any one of claims 1 to 13, when manufactured according to the process of claim 14.

16. A compound according to any one of claims 1 to 13 for use as therapeutically active substance.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a therapeutically inert carrier.

18. The use of a compound according to any one of claims 1 to 13 for the treatment or prophylaxis of pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.

19. The use of a compound according to any one of claims 1 to 13 for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.

20. A compound according to any one of claims 1 to 13 for use in the treatment or prophylaxis of pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.

21. A method for the treatment or prophylaxis of pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 13.

22. The invention as hereinbefore described.