RU2486186C2 - Type 1 diacylglycerol-o-acyltransferase enzyme inhibitors - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are new triazolopyrimidine derivatives of general formula (I):

wherein R¹ means hydrogen or alkyl; R² means hydrogen; R³ means optionally substituted C_3-8cycloalkyl, optionally substituted bridged monocyclic C₆-cycloalkyl, optionally substituted phenyl, optionally substituted 6-member heterocyclyl containing one or two heteroatoms specified in O and N, etc., a pharmaceutical composition containing them, and using the compounds and composition for inhibiting the enzyme type 1 diacylglycerol-O-acyltransferase (DGAT) for treating type 2 diabetes mellitus, obesity, high plasma triglycerides, metabolic syndrome, etc.

EFFECT: there are presented new triazolopyrimidine derivatives.

11 cl, 73 ex

Description

Field of Invention

Disclosed are compounds that are inhibitors of the enzyme diacylglycerol-O-acyltransferase type 1 (DGAT-1). Also encompassed are methods of using such compounds for inhibiting the activity of type 1 diacylglycerol-O-acyltransferases and pharmaceutical compositions containing such compounds.

State of the art

Triacylglycerides are the main form of energy storage in eukaryotes, and disturbances or imbalances in the metabolism of triacylglycerides are involved in pathogenesis and increase the risk of obesity, insulin resistance, type II diabetes, non-alcoholic obesity of the liver and coronary heart disease (Lewis, et al., Endocrine Reviews 23: 201, 2002). Accumulation of excess triacylglycerides in non-fat tissues such as the liver, muscles, and other peripheral tissues leads to lipid-induced dysfunction in these tissues; thus, a decrease in fat accumulation in non-fat areas appears to be useful in the treatment of lipotoxicity (Unger, R. H. Endocrinology, 144: 5159-5165, 2003). Accumulation of excess triacylglycerides in white adipose tissue (BAT) leads to obesity, a condition associated with reduced life expectancy, type II diabetes, coronary artery disease, hypertension, stroke and the development of certain types of cancer (Grundy, SM Endocrine 13 (2): 155-165, 2000). Obesity is a chronic disease that is very common in modern society, and existing pharmacological treatments are limited, which creates a need for the development of pharmaceuticals for the treatment of obesity that are safe and effective.

Diacylglycerol O-acyltransferases (DGATs) are membrane-bound enzymes that catalyze the final biosynthesis of triacylglycerides. Two enzymes that show DGAT activity have been characterized: DGAT-1 (diacylglycerol-O-acyltransferase type 1) (US Pat. No. 6,100,077; Cases, et al., Proc. Nat. Acad. Sci. 95: 13018-13023, 1998) and DGAT-2 (diacylglycerol-O-acyltransferase type 2) (Cases, et al., J. Biol. Chem. 276: 38870-38876, 2001). DGAT-1 and DGAT-2 have only 12% sequence identity between themselves. It is significant that DGAT-1-negative mice are resistant to diet-induced obesity and have increased sensitivity to insulin and leptin (Smith, et al., Nature Genetics 25: 87-90, 2000; Chen and Farese, Trends Cardiovasc Med. 10: 188, 2000; Chen et al., J. Clin. Invest. 109: 10049, 2002). DGAT-1 deficient mice are protected against liver steatosis, exhibiting increased energy expenditure and reduced levels of triacylglycerides in the tissue. In addition to improved metabolism of triacylglycerides, DGAT-1 deficient mice also have improved glucose metabolism with lower glucose and insulin levels after glucose administration compared to wild-type mice. Partial deficiency of DGAT-1 in heterozygous DGAT-1 +/- animals is sufficient to give an intermediate phenotype for body weight, obesity, and insulin and glucose metabolism compared to wild type and homozygous odnopodnyh animals (Chen and Farese, Arterioscler. Thromb. Vase. Biol. 25: 482-486, 2005), and it was reported that small DGAT-1 inhibitor molecules caused a decrease in body weight in diet-induced obesity mice (DIO) (US 2004/0224997). The phenotypes of DGAT-1 deficient mice and the pharmacological activity of the reported DGAT-I inhibitors suggest that the discovery of small molecules that effectively block the conversion of diacylglycerol to triacylglycerides by inhibiting the DGAT-1 enzyme may be useful in treating obesity and other diseases associated with an imbalance of triacylglycerides.

SUMMARY OF THE INVENTION

One aspect of the invention relates to compounds of formula (I), or a pharmaceutically acceptable salt, prodrug, prodrug salt thereof, or combinations thereof,

or a pharmaceutically acceptable salt, prodrug, prodrug salt thereof, or combinations thereof, in which

R ¹ is hydrogen or alkyl;

R ² is hydrogen, halogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocycle;

R ³ is cycloalkyl, aryl, heteroaryl, heterocycle, - (CR ^a R ^b ) _m —R ⁴ , —C (O) OR ⁵ , —C (R ⁵ ) = NO (R ^y ), —C (O) - R ⁵ or -C (O) -N (R ⁵ ) (R ⁶ );

M = 1, 2, 3 or 4;

R ^a , in each case, is independently hydrogen, halogen, alkyl, alkenyl, haloalkyl, —OR ^7a , —N (R ⁸ ) (R ⁹ ), —C (O) OR ^7b , —C (O) —R ^7b , -C (O) -N (R ⁸ ) (R ⁹ ), - (CR ^c R ^d ) _p -OR ^7a , - (CR ^c R ^d ) _p -N (R ⁸ ) (R ⁹ ), - ( CR ^c R ^d ) _p -C (O) OR ^7b , - (CR ^c R ^d ) _p -C (O) -R ^7b , - (CR ^c R ^d ) _p -C (O) -N (R ⁸ ) (R ⁹ ), aryl, heteroaryl, cycloalkyl or heterocycle;

R ^b , in each case, is independently hydrogen, halogen, alkyl, alkenyl, haloalkyl, —C (O) OR ^7b , —C (O) —R ^7b , —C (O) —N (R ⁸ ) (R ⁹ ), - (CR ^c R ^d ) _p -OR ^7a , - (CR ^c R ^d ) _p -N (R ⁸ ) (R ⁹ ), - (CR ^c R ^d ) _p -C (O) OR ^7b , - (CR ^c R ^d ) _p —C (O) —R ^7b , - (CR ^c R ^d ) _p —C (O) —N (R ⁸ ) (R ⁹ ), aryl, heteroaryl, cycloalkyl or heterocycle;

R^a and R^b can mean together = CH₂;

R ^c and R ^d , in each case, are each independently hydrogen, halogen, alkyl or haloalkyl;

R ^y is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;

R^four denotes hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocycle, provided that when R^four denotes hydrogen, alkyl or halogenated, then at least one R^a denotes -OR^7a, -N (R⁸) (R⁹), -C (O) OR^7b, -C (O) -R^7b, -C (O) -N (R⁸) (R⁹), - (CR^cR^d)_p-OR^7a, - (CR^cR^d)_p-N (R⁸) (R⁹), - (CR^cR^d)_p-C (O) OR^7b, - (CR^cR^d)_p-C (O) -R^7b or - (CR^cR^d)_p-C (O) -N (R⁸) (R⁹); or R^a and R^b together denote = CH₂;

R ⁵ in each case independently means alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;

each cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkyl group of cycloalkylalkyl, aryl group of arylalkyl, heteroaryl group of heteroarylalkyl, and heterocyclic group of heterocycloalkyl represented by R ² , R ³ , R ^a , R ^b , R ⁴ , R ⁵ and R ^y , is independently unsubstituted or additionally substituted with 1, 2, 3, 4, or 5 substituents selected from, but not limited to, alkyl, halogen, haloalkyl, oxo, —OR ¹⁰ , —S (R ¹⁴ ), —S (O) ₂ R ¹⁵ , -S (O) ₂ N (R ¹¹ ) (R ¹² ), -N (R ¹¹ ) (R ¹² ), -C (O) OR ¹⁰ , -C (O) O (trialkylsilylalkyl), -C ( O) N (R ¹¹ ) (R ¹² ), - (CR ^e R ^f ) _q -OR ¹⁰ , - (CR ^e R ^f ) _q -N (R ¹¹ ) (R ¹² ), - (CR ^e R ^f ) _q -C (O) OR ¹⁰ , - (CR ^e R ^f ) _q -C (O) N (R ¹¹ ) (R ¹² ), G ¹ and = NO (R ¹⁰ ),

R ⁶ , R ⁹ and R ¹² , in each case, are each independently hydrogen, alkyl or haloalkyl;

R ^7a , in each case, is each independently hydrogen, alkyl, haloalkyl, —N = C (H) R ^13a , - (CR ^g R ^h ) _r —C (O) OR ¹³ or G ¹ ,

R ^7b and R ¹⁰ , in each case, are each independently hydrogen, alkyl, haloalkyl, - (CR ^g R ^h ) _r —C (O) OR ¹³ or G ¹ ,

R ⁸ and R ¹¹ , in each case, are each independently hydrogen, alkyl, haloalkyl, —S (O) ₂ —R ^13a , —S (O) ₂ —N (R ¹³ ) (R ¹⁴ ), —C (O) OR ¹³ , —C (O) N (R ¹³ ) (R ¹⁴ ) or G ¹ ;

p, q and r, in each case, are each independently 1, 2, 3 or 4;

R ^e , R ^f , R ^g and R ^h , in each case, are each independently hydrogen, halogen, alkyl or haloalkyl;

R ¹⁴ , in each case, independently represents hydrogen, alkyl or halogenated;

R ¹⁵ , in each case, independently represents alkyl, halogenated or G ¹ ;

R ¹³ , in each case, independently represents hydrogen, alkyl, haloalkyl or G ¹ ;

R ^13a , in each case, independently represents alkyl, halogenated or G ¹ ; and

G ¹ , in each case, independently means aryl, heteroaryl, cycloalkyl, heterocycle, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkyl, moreover, aryl, heteroaryl, cycloalkyl, heterocycle, aryl group of heteroalkyl heteroalkyl each independently, unsubstituted or additionally substituted with 1, 2, 3, 4 or 5 substituents selected from, but not limited to, alkyl, halogen, —CN, —NO ₂ , —OH, —O (alkyl), —NH ₂ , -N (H) (alkyl a), -N (alkyl) _2, -C (O) OH, -C (O) O ( alkyl), -C (O) NH _2, -C (O) N (H ) ( alkyl), -C (O) N (alkyl) ₂ , haloalkyl and alkyl substituted with one substituent selected from, but not limited to, —CN, —NO ₂ , —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), -N (alkyl) ₂ , -C (O) OH, -C (O) O (alkyl), -C (O) NH ₂ , -C (O) N (H) (alkyl) and - C (O) N (alkyl) ₂ .

Another aspect of the invention relates to methods for treating various diseases or conditions in a patient, preferably a human, comprising administering to the patient a therapeutically or prophylactically effective amount of a compound of the invention, as disclosed herein, or a pharmaceutically acceptable salt thereof, individually or in combination with a pharmaceutically acceptable carrier. In another aspect, the invention relates to methods for preventing or treating a disease or condition associated with elevated lipid levels, such as plasma lipid levels, especially elevated levels of triacylglycerides, in a patient, in particular a person suffering from such elevated levels, comprising administering to the patient therapeutically or prophylactically an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, as disclosed herein. The invention also relates to compounds having a therapeutic ability to lower lipid levels, especially triacylglyceride levels, in a patient. Accordingly, the compounds and compositions of the invention, individually or together with one or more pharmaceutical agents selected from the group consisting of a DPPIV inhibitor, incretin mimetic, metformin, fenofibrate, rimonabant, sibutramine, orlistat, nicotinic acid and statin, can be used to produce a medicament for treating or preventing the diseases and disorders described herein, in particular for treating or preventing type 2 diabetes, obesity, elevated plasma levels of triglycerides, abolicheskogo syndrome, non-alcoholic steatohepatitis and non-alcoholic fatty liver. The compounds of the invention or their pharmaceutically acceptable salts or compositions, individually or together with one or more pharmaceutical agents, as described herein, can also be used to prepare a medicament for lowering lipid levels in a patient (e.g., mammal, including human), especially levels triglycerides. In another aspect, the invention relates to pharmaceutical compositions comprising one or more compounds of the invention, as disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

For a variable that occurs more than once in any substituent or compound of the invention or any other formulas, its definition in each case is independent of its definition in every other case. Combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds that can be isolated with a useful degree of purity from the reaction mixture.

In the description and appended claims, unless otherwise indicated, the following terms have the following meanings:

The term "alkenyl" as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond, which is formed by the removal of two hydrogen atoms. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3- decentralized.

The term "alkyl" in the framework of the invention means a straight or branched saturated hydrocarbon chain containing from 1 to 10 carbon atoms. The term “lower alkyl” or “C _1-6 alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C _1-3 alkyl” means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms.

Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

The term "alkylene" means a divalent group derived from a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ - and - CH ₂ CH (CH ₃ ) CH ₂ -.

The term "alkynyl" as used herein means a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl” as used herein, means phenyl or bicyclic aryl. Bicyclic aryl is naphthyl or phenyl condensed with monocyclic cycloalkyl, or phenyl condensed with monocyclic cycloalkenyl. Phenyl and bicyclic aryl according to the present invention are unsubstituted or substituted. Bicyclic aryl is attached to the parent molecular group through any carbon atom contained in the bicyclic aryl. Representative examples of aryl include, but are not limited to, bicyclo [4.2.0] octa-1,3,5-trien-7-yl, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl and 5,6,7,8-tetrahydronaphthalenyl.

The term “arylalkyl,” as used herein, means aryl, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl and 3-phenylpropyl.

The term “cycloalkyl” or “cycloalkane” as used herein means monocyclic, bicyclic cycloalkyl or tricyclic cycloalkyl. Monocyclic cycloalkyl is a ring hydrocarbon system containing from three to eight carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl ring, or a bridged monocyclic cycloalkyl in which two non-adjacent carbon atoms of a monocyclic ring are connected by an alkylene bridge containing one, two, three or four carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo [3,1,1] heptane, bicyclo [2,2,1] heptane, bicyclo [2,2.2] octane, bicyclo [3,2,2] nonane, bicyclo [3.3.1] nonane; and bicyclo [4.2.1] nonane. Tricyclic cycloalkyls are illustrated by a bicyclic cycloalkyl fused to monocyclic cycloalkyl or bridged by a bicyclic cycloalkyl in which two non-adjacent carbon atoms of a bicyclic ring system are connected by an alkylene bridge containing from one to four carbon atoms. Representative examples of tricyclic ring systems include, but are not limited to, tricyclo [3.3.1.0 ^3.7 ] nonane and tricyclo [3.3.1.1 ^3.7 ] decane (adamantane). Monocyclic, bicyclic and tricyclic cycloalkyls can be attached to the parent molecular group through any substitutable atom contained in the bicyclic and tricyclic cycloalkyls, and each of them is unsubstituted or substituted.

The term “cycloalkylalkyl” as used herein, means cycloalkyl, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl and cyclohexylmethyl.

The term “cycloalkenyl” or “cycloalkene” as used herein means a monocyclic or bicyclic hydrocarbon ring system. Monocyclic cycloalkenyl contains four, five, six, seven or eight carbon atoms and zero heteroatoms. Four-membered ring systems have one double bond, five- or six-membered ring systems have one or two double bonds, and seven- or eight-membered ring systems have one, two or three double bonds. Monocyclic cycloalkenyl may be attached to the parent molecular group through any substitutable atom contained in monocyclic cycloalkenyl. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group. A monocyclic or bicyclic cycloalkenyl ring may contain one or two alkylene bridges, each of which includes one, two, three or four carbon atoms and each of which binds two non-adjacent carbon atoms in the ring. Bicyclic cycloalkenyl may be attached to the parent molecular group through any substitutable atom contained in the bicyclic cycloalkenyl. Representative examples of bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl and 1,6-dihydropentalene. Monocyclic and bicyclic cycloalkenyl groups according to the present invention may be unsubstituted or substituted.

The term "cycloalkenylalkyl" as used herein means a cycloalkenyl group, as defined herein, appended to the parent molecular group through an alkyl group, as defined herein.

The term "halogen" in the framework of the invention means Cl, Br, I or F.

The term "halogenated" in the framework of the invention means alkyl, as defined here, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heterocycle” or “heterocyclic” as used herein means a monocyclic heterocycle, a bicyclic or tricyclic heterocycle. A monocyclic heterocycle is a three-, four-, five-, six- or seven-membered ring containing at least one heteroatom independently selected from, but not limited to, O, N and S. Three- or four-membered ring contain zero or one a double bond and one heteroatom selected from, but not limited to, O, N and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from, but not limited to, O, N and S. The six-membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from, but not limited to, O, N, and S. The seven-membered ring contains zero, one, two, or three double bonds, and one, two, or three heteroatoms selected from, but not limited to, O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl , isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, ox azolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl tetrahydrothienyl, thiadiazinylinyl, thiadiazolidinyl, thiaolithiol-thiol-azothiol-azothiol-azothiol-thio-thiol-thio-thio-thiol-thio-thiol-thio-di-thiolnedi A bicyclic heterocycle is a monocyclic heterocycle condensed with phenyl, or a monocyclic heterocycle condensed with monocyclic cycloalkyl, or a monocyclic heterocycle condensed with monocyclic cycloalkenyl, or a monocyclic heterocycle which is fused to a monocyclic heterocycle bridged to one, or non-adjacent ring atoms are connected by an alkylene bridge containing one, two, three or even carbon atom. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, and 2,3-dihydro-1H-indolyl. Tricyclic heterocycles are illustrated by a bicyclic heterocycle condensed with phenyl, or a bicyclic heterocycle condensed with monocyclic cycloalkyl, or a bicyclic heterocycle condensed with monocyclic cycloalkenyl, or a bicyclic heterocycle condensed with a monocyclic heterocyclic bicyclic heterocyclic the rings are connected by an alkylene bridge including one, two, three or four carbon atoms Leroda. Examples of tricyclic heterocycles include, but are not limited to, oxa-adamantane and aza-adamantane. Monocyclic, bicyclic and tricyclic heterocycles are linked to the parent molecular group through any carbon atom or any nitrogen atom contained in the rings. The monocyclic, bicyclic and tricyclic heterocycles of the present invention may be unsubstituted or substituted.

The term “heterocycloalkyl” as used herein means a heterocycle, as defined herein, appended to the parent molecular group through an alkyl group, as defined herein.

The term “heteroaryl” as used herein means monocyclic heteroaryl or bicyclic heteroaryl. Monocyclic heteroaryl is a five- or six-membered ring. The five-membered ring contains two double bonds. The five-membered ring may contain one heteroatom selected from O or S; or one, two or three nitrogen atoms and, if necessary, an additional heteroatom selected from oxygen or sulfur; or four nitrogen atoms. The six-membered ring contains three double bonds and one, two, three or four nitrogen atoms. Representative examples of monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiazyl, thiazyl, thiazyl , triazolyl and triazinyl. Bicyclic heteroaryl is illustrated by monocyclic heteroaryl fused with phenyl, or monocyclic heteroaryl fused with monocyclic cycloalkyl, or monocyclic heteroaryl fused with monocyclic cycloalkenyl, or monocyclic heteroaryl fused with monocyclic heteroaryl, monocyclic, or monocyclic. Representative examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, 6,7-dihydro-1,3-benzothiazolyl, imidazo [1,2-α] pyridinyl, indazolyl, indolyl, isoind isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, thiazolo [5,4-b] pyridin-2-yl, thiazolo [5,4-d] pyrimidin-2-yl and 5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroaryl groups of the present invention are linked to the parent molecular group through any carbon atom or any nitrogen atom contained in the rings, and are substituted or unsubstituted.

The term “heteroarylalkyl” as used herein means heteroaryl, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein.

The term “heteroatom” as used herein means a nitrogen, oxygen or sulfur atom.

The term "oxo" in the framework of the invention means a group = O.

The term "trialkylsilyl" as used herein means a group (alkyl) ₃ -Si attached to the parent molecular group through a silicon atom.

The term "trialkylsilylalkyl" as used herein means trialkylsilyl, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein.

The term “mammal” as used herein means humans and animals such as cats, dogs, pigs, cattle, horses, and the like.

The compounds of the invention have the formula (I) as described above.

The specific values of the variable groups in the compounds of formula (I) are as follows. Such values may be used, if necessary, with any of the other values, definitions, claims or embodiments defined above or below.

In the compounds of formula (I), R ¹ is hydrogen or alkyl. Examples of the alkyl group for R ¹ include, but are not limited to, methyl and ethyl.

R ² is hydrogen, halogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocycle, each of the rings denoted by R ² is independently unsubstituted or additionally substituted as described in the brief description. In some embodiments, R ² is hydrogen, halogen, alkyl (e.g. methyl, ethyl, etc.) or haloalkyl. In other embodiments, R ² is hydrogen.

R ³ is cycloalkyl, aryl, heteroaryl, heterocycle, - (CR ^a R ^b ) _m —R ⁴ , —C (O) OR ⁵ , —C (R ⁵ ) = N — 0 (R ^y ), —C (O ) -R ⁵ or -C (O) -N (R ⁵ ) (R ⁶ ); each ring being independently unsubstituted or additionally substituted, and possible substituents, R ^a , R ^b , m, R ⁴ , R ⁵ , R ⁶ and R ^y , are as defined in the short description.

In some embodiments, the implementation of R³ denotes cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl or cycloheptyl) or heterocycle (e.g. morpholinyl or tetrahydro-2H-pyranyl), each of which is independently unsubstituted or additionally substituted, as disclosed in the section "essence of the invention". Particular examples of possible substituents on the ring denoted by R³include, but are not limited to, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), halogen, oxo, -OR¹⁰, -S (R^fourteen), -S (O)₂R^fifteen, -S (O)₂N (R^eleven) (R¹²), -N (R^π) (R¹²), -C (O) OR¹⁰, -C (O) O (trialkylsilylalkyl), -C (O) N (R^eleven) (R¹²), - (CR^eR^f)_q-OR¹⁰, - (CR^eR^f)_q-N (R^eleven) (R¹²), - (CR^eR^f)_q-C (O) OR¹⁰, - (CR^eR^f)_q-C (O) N (R^eleven) (R¹²) and = N-O (R¹⁰), moreover, R¹⁰, R^eleven, R¹², R^fourteen, R^fifteen, R^e, R^f and q as defined in the “Summary of the Invention”. For example, R¹², R^e and R^f, in each case, are each independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl). R¹⁰, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³or phenyl (unsubstituted or substituted as described for G^one in the brief description), and R^g, R^h and R¹³ denote each independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl and the like), and r = 1, 2, 3 or 4, preferably r = 1 or 2. R^eleven, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), where R^13a, R¹³ and R^fourteen have the meanings disclosed in the section "summary of the invention", and q, in each case, means, for example, 1 or 2.

When R ³ is a substituted cycloalkyl or substituted heterocycle, one of the substituents may be attached to the same carbon that is bonded to the alkynyl of general formula (I). Thus, in some embodiments, R ³ is formula (a),

,

,

in which R^1k and R^2k together with the carbon atom to which they are attached form a cycloalkyl ring (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2,2,1] heptyl or cycloheptyl), or a heterocyclic ring (for example tetrahydro-2H-pyranyl), each of which is independently unsubstituted or further substituted, as described in the "Summary of the Invention" and in the previous paragraph, and R^3k denotes -OR¹⁰, -N (R^eleven) (R¹²), -C (O) OR¹⁰ or —C (O) O (trialkylsilylalkyl), where R¹⁰, R^eleven and R¹² have the meanings defined in the section "essence of the invention". R¹²for example, represents hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl). Private example R¹⁰, in each case, independently denotes hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³or phenyl (unsubstituted or substituted as described for G^one in the section "summary of the invention"), with R^g, R^h and R¹³for example, each is independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), and r = 1, 2, 3 or 4, preferably r = 1 or 2. R^elevenfor example, stands for hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R^13a, R¹³ and R^fourteen have the meanings disclosed in the section "essence of the invention". In some embodiments, the implementation of R^3k denotes —OH or —OCH₂COOH. In other embodiments, implementation of R^3k denotes -NH₂ or -N (H) S (O)₂R^13a, and R^13a denotes optionally substituted phenyl.

In other embodiments, implementation of R³ denotes aryl (eg phenyl) unsubstituted or substituted as described in the Summary of the Invention. Examples of possible substituents on aryl denoted by R³include, but are not limited to, alkyl, such as C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), halogen, -OR¹⁰,, -S (R^fourteen), -S (O)₂R^fifteen, -S (O)₂N (R^eleven) (R¹²), -N (R^eleven) (R¹²), -C (O) OR¹⁰, -C (O) O (trialkylsilylalkyl), -C (O) N (R^eleven) (R¹²), - (CR^eR^f)_q-OR¹⁰, - (CR^eR^f)_q-N (R^eleven) (R¹²), - (CR^eR^f)_q-C (O) OR¹⁰, - (CR^eR^f)_q-C (O) N (R^eleven) (R¹²) and G^one, and G^one, R¹⁰, R^eleven, R¹², R^fourteen, R^fifteen, R^e, R^f and q have the meanings defined in the "Summary of the Invention". For example, G^one denotes aryl (for example, phenyl) or heteroaryl, each of which, if necessary, is further substituted, as described in the section "Summary of the invention". R¹², R^e and R^f, in each case, for example, each independently represents hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl). R¹⁰, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl, or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³ or phenyl (unsubstituted or substituted as described for G^one in the section "summary of the invention"), with R^g, R^h and R¹³for example, each is independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), and r = 1, 2, 3 or 4, preferably r = 1 or 2. R^eleven, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R^13a, R¹³ and R^fourteen are as disclosed in the Summary of the Invention, q, in each case, for example, independently means 1 or 2. In some embodiments, R³ denotes phenyl, unsubstituted or additionally substituted, as described in the section "Summary of the invention" and in embodiments.

In other embodiments, implementation, R³ denotes - (CR^aR^b)_m-R^fourwhere R^a, R^b, R^four and m have the meanings defined in the "Summary of the Invention". In other embodiments, implementation, R³ denotes - (CR^aR^b)_m-R^fourwhere R^a and R^b, in each case, are each independently hydrogen, alkyl (e.g., C_1-6 alkyl, such as methyl, ethyl, isopropyl or tert-butyl), alkenyl, halogen or haloalkyl (e.g. trifluoromethyl or difluoromethyl), m = 1, 2, 3 or 4, and R^four denotes cycloalkyl, aryl, heteroaryl or heterocycle, each of which is optionally further substituted as necessary, as described in the "Summary of the Invention". In some embodiments, m = 1 or 2. Examples of a subgroup of compounds described herein include, but are not limited to, compounds in which R³ represents the formula (b)

,

,

in which R^a and R^b, in each case, mean, each independently, hydrogen, halogen, alkyl, such as C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), alkenyl or haloalkyl (e.g. trifluoromethyl or difluoromethyl), R^1k and R^2k together with the carbon atom to which they are attached, form cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl or cycloheptyl) or heterocycle (e.g. tetrahydro-2H-pyranyl), each of which independently unsubstituted or optionally substituted as described for R³ in the "Summary of the Invention", and R^3k denotes -OR¹⁰, -N (R^eleven) (R¹²), -C (O) OR¹⁰ or —C (O) O (trialkylsilylalkyl), wherein R¹⁰, R^eleven and R¹² have the meanings defined in the section "essence of the invention". Examples of possible substituents on the ring that form R^1k, R^2k and carbon atom include, but are not limited to, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), halogen, oxo, -OR¹⁰, -N (R^eleven) (R¹²), -C (O) OR¹⁰, -C (O) O (trialkylsilylalkyl), -C (O) N (R^eleven) (R¹²), - (CR^eR^f)_q-OR¹⁰, - (CR^eR^f)_q-N (R^eleven) (R¹²), - (CR^eR^f)_q-C (O) OR¹⁰, - (CR^eR^f)_q-C (O) N (R^eleven) (R¹²) and = N-O (R¹⁰), moreover, R¹⁰, R^eleven, R¹², R^e, R^f and q have the meanings defined in the "Summary of the Invention". For example, R¹², R^e and R^f, in each case, are each independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl). For example, R¹⁰, in each case, independently denotes hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³ or phenyl (unsubstituted or substituted as described for G^one in the section "summary of the invention"), with R^g, R^h and R¹³for example, each is independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), and r = 1, 2, 3 or 4, preferably r = 1 or 2. R^eleven, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R¹³, R^13a and R^fourteen have the meanings disclosed in the section "summary of the invention", and q, in each case, for example, means 1 or 2.

In other embodiments, implementation of R ³ represents the formula (c)

,

,

in which R^b denotes hydrogen, halogen, alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), alkenyl, -C (O) OR^7bhaloalkyl (e.g. trifluoromethyl or difluoromethyl), aryl (e.g. phenyl), heteroaryl, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or heterocycle (e.g. morpholinyl), each aryl, heteroaryl, cycloalkyl or independently unsubstituted or substituted, as described in the "Summary of the Invention". Examples of possible R substituents^b how rings include, but are not limited to, C_1-6 alkyl, halogen and haloalkyl. R^a stands for OR^7a, N (R⁸) (R⁹) or -C (O) OR^7b, or R^a and R^b together denote = CH₂; R^four denotes hydrogen, alkyl (eg methyl, ethyl, isopropyl or tert-butyl), haloalkyl, cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo [2.2.1] heptyl), aryl (eg phenyl ), heteroaryl or heterocycle (e.g. morpholinyl, tetrahydro-2H-pyranyl), with each of the rings denoted by R^fourmay independently be further substituted as described in the Summary of the Invention, and R^7a, R^7b, R⁸ and R⁹ are as disclosed in the “Summary of the Invention”. For example, R^7a denotes hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³, and R^g, R^h, R¹³ and r, as described in the Summary of the Invention, or phenyl (unsubstituted or substituted, as described in the Summary of the Invention). R^7b, R^g, R^h, R¹³ and R⁹, in each case, for example, each is independently hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl) or haloalkyl (e.g. trifluoromethyl or difluoromethyl). r, for example, means 1 or 2. R⁸for example, stands for hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R¹³, R^13a and R^fourteen are as disclosed in the “Summary of the Invention”.

In another embodiment, R ³ is formula (d)

,

,

in which R^1b denotes hydrogen, alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), alkenyl, halogen, —C (O) OR^7bhaloalkyl (e.g. trifluoromethyl or difluoromethyl), aryl, heteroaryl, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or heterocycle (e.g. morpholinyl), R^1a stands for OR^7a, N (R⁸) (R⁹) or -C (O) OR^7b, and R^2a and R^2b, in each case, are independently hydrogen, halogen, alkyl (eg methyl, ethyl, isopropyl or tert-butyl), alkenyl or haloalkyl (eg trifluoromethyl or difluoromethyl); or R^2b denotes hydrogen, alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), alkenyl, halogen, —C (O) OR^7bhaloalkyl (e.g. trifluoromethyl or difluoromethyl), aryl (e.g. phenyl), heteroaryl, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or heterocycle (e.g. morpholinyl), R^2a stands for OR^7a, N (R⁸) (R⁹) or -C (O) OR^7b, and R^1a and R^1b, in each case, are independently hydrogen, halogen, alkyl (eg methyl, ethyl, isopropyl or tert-butyl), alkenyl or haloalkyl (eg trifluoromethyl or difluoromethyl); each aryl, heteroaryl, cycloalkyl or heterocycle denoted by R^1b and R^2bindependently unsubstituted or substituted as described for R^b in the section "essence of the invention". Examples of possible R substituents^1b or R^2b how rings include, but are not limited to, C_1-6 alkyl, halogen and haloalkyl. R^four denotes hydrogen, alkyl, haloalkyl, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo [2.2.1] heptyl), aryl (e.g. phenyl), heteroaryl or heterocycle (e.g. tetrahydro-2H-pyranyl ), wherein each cycloalkyl, aryl, heteroaryl or heterocycle denoted by R^four, independently, if necessary, additionally substituted, as described in the section "Summary of the invention", and R^7a, R^7b, R⁸ and R⁹ are as disclosed in the “Summary of the Invention”. For example, R^7a, in each case, independently denotes hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³, and R^g, R^h, R¹³ and r have the meanings described in the Summary of the Invention, or phenyl (unsubstituted or substituted as described in the Summary of the Invention). R^7b, R^g, R^h, R⁹, R¹³ and R⁹, in each case, for example, each is independently hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl) or haloalkyl (e.g. trifluoromethyl or difluoromethyl). r, for example, means 1 or 2. R⁸, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R¹³, R^13a and R^fourteen are as disclosed in the “Summary of the Invention”.

In another embodiment, R ³ is —C (O) —R ⁵ , wherein R ⁵ is as described in the Summary of the Invention. For example, R ⁵ is aryl, such as phenyl, unsubstituted or further substituted, as described in the Summary of the Invention.

It should be understood that the present invention contemplates compounds of formula (I) with combinations of the above embodiments, including particular, more specific and preferred embodiments.

Accordingly, one aspect of the invention relates to compounds of formula (I), or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, in which R² denotes hydrogen, halogen, alkyl, or halogenated, R³ denotes aryl (eg phenyl) unsubstituted or substituted as described in the Summary of the Invention. Examples of possible substituents on aryl denoted by R³include, but are not limited to, alkyl, such as C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), halogen, -OR¹⁰,, -S (R^fourteen), -S (O)₂R^fifteen, -S (O)₂N (R^eleven) (R¹²), -N (R^eleven) (R¹²), -C (O) OR¹⁰, -C (O) O (trialkylsilylalkyl), -C (O) N (R^eleven) (R¹²), - (CR^eR^f)_q-OR¹⁰ - (CR^eR^f)_q-N (R^eleven) (R¹²), - (CR^eR^f)_q-C (O) OR¹⁰, - (CR^eR^f)_q-C (O) N (R^eleven) (R¹²) and G^one, and G^one, R¹⁰, R^eleven, R¹², R^fourteen, R^fifteen, R^e, R^f and q are as defined in the Summary of the Invention. For example, G^one denotes aryl (for example, phenyl) or heteroaryl, each of which, if necessary, is further substituted, as described in the section "Summary of the invention". R¹², R^e and R^f, in each case, for example, each is independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl). R¹⁰, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³ or phenyl (unsubstituted or substituted as described for G^one in the section "summary of the invention"), with R^g, R^h and R¹³for example, each is independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), and r = 1, 2, 3 or 4, preferably r = 1 or 2. R^eleven, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R^13a, R¹³ and R^fourteen are as disclosed in the Summary of the Invention, q, in each case, for example, independently 1 or 2. In some embodiments, R³ denotes phenyl, unsubstituted or additionally substituted, as described in the section "Summary of the invention" and in embodiments. In some embodiments, the implementation of R² denotes hydrogen.

Another aspect of the invention relates to compounds of formula (I), or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, in which R³ denotes cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl or cycloheptyl) or heterocycle (e.g. morpholinyl or tetrahydro-2H-pyranyl), each of which is independently unsubstituted or additionally substituted as disclosed in the Summary of the Invention, and R² denotes hydrogen, halogen, alkyl or halogenated. Examples of possible substituents on the ring denoted by R³include, but are not limited to, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), halogen, oxo, -OR¹⁰, -S (R^fourteen), -S (O)₂R^fifteen, -S (O)₂N (R^eleven) (R¹²), -N (R^eleven) (R¹²), -C (O) OR¹⁰, -C (O) O (trialkylsilylalkyl), -C (O) N (R^eleven) (R¹²), - (CR^eR^f)_q-OR¹⁰, - (CR^eR^f)_q-N (R^eleven) (R¹²), - (CR^eR^f)_q-C (O) OR¹⁰, - (CR^eR^f)_q-C (O) N (R^eleven) (R¹²) and = N-O (R¹⁰), moreover, R¹⁰, R^eleven, R¹², R^fourteen, R^fifteen, R^e, R^f and q are as defined in the Summary of the Invention. For example, R¹², R^e and R^f, in each case, are each independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl). R¹⁰, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³or phenyl (unsubstituted or substituted as described for G^one in the section "summary of the invention"), with R^g, R^h and R¹³ denote each independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl, etc.), and r = 1, 2, 3 or 4, preferably r = 1 or 2. R^eleven, in each case, denotes, for example, hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³or -C (O) N (R¹³) (R^fourteen), moreover, R¹³, R^13a and R^fourteen are as disclosed in the Summary of the Invention, and q, for example, is 1 or 2. In some embodiments, R² denotes hydrogen.

From this group of compounds, examples of the subgroup include compounds in which R ³ is formula (a),

,

,

in which R^1k and R^2k together with the carbon atom to which they are attached, form cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl or cycloheptyl) or heterocycle (e.g. tetrahydro-2H-pyranyl), each of which independently unsubstituted or optionally substituted as described in the previous paragraph, R^3k denotes -OR¹⁰, -N (R^eleven) (R¹²), -C (O) OR¹⁰ or —C (O) O (trialkylsilylalkyl), wherein R¹⁰, R^eleven and R¹² have the meanings defined in the "Summary of the Invention" and R² denotes hydrogen, halogen, alkyl or halogenated. R¹²for example, represents hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl). For example, R¹⁰, in each case, independently denotes hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³or phenyl (unsubstituted or substituted as described for G^one in the section "summary of the invention"), with R^g, R^h and R¹³for example, each is independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), and r = 1, 2, 3 or 4, preferably r = 1 or 2. R^elevenfor example, stands for hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R¹³, R^13a and R^fourteen are as disclosed in the “Summary of the Invention”. In some embodiments, the implementation of R² denotes hydrogen. In some embodiments, the implementation of R^3k denotes —OH or —OCH₂COOH. In other embodiments, implementation of R^3k denotes -NH₂ or -N (H) S (O)₂R^13a, and R^13a denotes optionally substituted phenyl.

Another aspect of the invention relates to compounds of formula (I), or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, in which R³ denotes aryl (eg, phenyl), unsubstituted or substituted, as described in the section "Summary of the invention", and R² denotes hydrogen, halogen, alkyl or halogenated. Examples of possible substituents on aryl denoted by R³include, but are not limited to, alkyl, such as C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), halogen, -OR¹⁰, -S (R^fourteen), -S (O)₂R^fifteen, -S (O)₂N (R^eleven) (R¹²), -N (R^eleven) (R¹²), -C (O) OR¹⁰, -C (O) O (trialkylsilylalkyl), -C (O) N (R^eleven) (R¹²), - (CR^eR^f)_q-OR¹⁰, - (CR^eR^f)_q-N (R^eleven) (R¹²), - (CR^eR^f)_q-C (O) OR¹⁰, - (CR^eR^f)_q-C (O) N (R^eleven) (R¹²) and G^one, and G^one, R¹⁰, R^eleven, R¹², R^fourteen, R^fifteen, R^e, R^f and q are as defined in the Summary of the Invention. For example, G^one denotes aryl (for example, phenyl) or heteroaryl, each of which, if necessary, is further substituted, as described in the section "Summary of the invention". R¹², R^e and R^f, in each case, for example, each is independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl). R¹⁰, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³ or phenyl (unsubstituted or substituted as described for G^one in the section "summary of the invention"), with R^g, R^h, R¹³for example, each is independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), and r = 1, 2, 3 or 4, preferably r = 1 or 2. R^eleven, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R¹³, R^13a and R^fourteen are as disclosed in the Summary of the Invention, q, in each case, for example, independently 1 or 2. In some embodiments, R² denotes hydrogen. In some embodiments, the implementation of R³ denotes phenyl, optionally substituted, as described in the "Summary of the Invention" and in Embodiments.

Another aspect of the invention relates to compounds of formula (I), or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, in which R³ denotes - (CR^aR^b)_m-R^four, and R^a, in each case, independently represents hydrogen, halogen, alkyl, alkenyl, halogenated, -OR^7a, -N (R⁸) (R⁹), -C (O) OR^7b, -C (O) -R^7b, -C (O) -N (R⁸) (R⁹), - (CR^cR^d)_p-OR^7a, - (CR^cR^d)_p-N (R⁸) (R⁹), - (CR^cR^d)_p-C (O) OR^7b, - (CR^cR^d)_p-C (O) -R^7b, - (CR^cR^d)_p-C (O) -N (R⁸) (R⁹), aryl, heteroaryl, cycloalkyl or heterocycle; R^b, in each case, independently represents hydrogen, halogen, alkyl, alkenyl, haloalkyl, —C (O) OR^7b, -C (O) -R^7b, -C (O) -N (R⁸) (R⁹), - (CR^cR^d)_p-OR^7a, - (CR^cR^d)_p-N (R⁸) (R⁹), - (CR^cR^d)_p-C (O) OR^7b, - (CR^cR^d)_p-C (O) -R^7b, - (CR^cR^d)_p-C (O) -N (R⁸) (R⁹), aryl, heteroaryl, cycloalkyl or heterocycle, or R^a and R^b together denote = CH₂; each of the rings denoted by R^a and R^bindependently unsubstituted or optionally substituted as described in the Summary of the Invention, R^four denotes hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocycle, each cycloalkyl, aryl, heteroaryl or heterocycle is independently substituted, if necessary, as described in the section "Summary of the invention", provided that when R^four denotes hydrogen, alkyl or halogenated, then at least one R^a denotes -OR^7a, -N (R⁸) (R⁹), -C (O) OR^7b, -C (O) -R^7b, -C (O) -N (R⁸) (R⁹), - (CR^cR^d)_p-OR^7a, - (CR^cR^d)_p-N (R⁸) (R⁹), - (CR^cR^d)_p-C (O) OR^7b, - (CR^cR^d)_p-C (O) -R^7b or - (CR^cR^d)_p-C (O) -N (R⁸) (R⁹), or R^a and Rb together denote = CH₂; R² denotes hydrogen, halogen, alkyl or halogenated, and m, p, R^c, R^d, R^7a, R^7b, R⁸ and R⁹ are as disclosed in the “Summary of the Invention”. In one embodiment, R² denotes hydrogen.

From this group of compounds, examples include compounds in which R³ denotes - (CR^aR^b)_m-R^four, and R^a and R^b, in each case, are each independently hydrogen, alkyl (e.g., C_1-6 alkyl, such as methyl, ethyl, isopropyl or tert-butyl), alkenyl, halogen or haloalkyl (e.g. trifluoromethyl or difluoromethyl), m = 1, 2, 3 or 4, and R^four denotes cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl or cycloheptyl), aryl (e.g. phenyl), heteroaryl or heterocycle (e.g. tetrahydro-2H-pyranyl), each of which if necessary, additionally substituted, as described in the "Summary of the Invention". In some embodiments, implementation, m = 1 or 2.

From this group of compounds, other examples include compounds in which R ³ has the formula (b)

,

,

in which R^a and R^b, in each case, are each independently hydrogen, halogen, alkyl (e.g. C_1-6 alkyl, such as methyl, ethyl, isopropyl or tert-butyl), alkenyl or haloalkyl (e.g. trifluoromethyl or difluoromethyl), R^1k and R^2k together with the carbon atom to which they are attached, form cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl or cycloheptyl) or heterocycle (e.g. tetrahydro-2H-pyranyl), each of which independently unsubstituted or optionally substituted as described for R³ in the section "summary of the invention", R^3k denotes -OR¹⁰, -N (R^eleven) (R¹²), -C (O) OR¹⁰ or —C (O) O (trialkylsilylalkyl), R² denotes hydrogen, halogen, alkyl or halogenated, and R¹⁰, R^eleven and R¹² have the meanings defined in the section "essence of the invention". Examples of possible substituents on the ring that form R^1k, R^2k and carbon atom include, but are not limited to, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), halogen, oxo, -OR¹⁰, -N (R^eleven) (R¹²), -C (O) OR¹⁰, -C (O) O (trialkylsilylalkyl), -C (O) N (R^eleven) (R¹²), - (CR^eR^f)_q-OR¹⁰, - (CR^eR^f)_q-N (R^eleven) (R¹²), - (CR^eR^f)_q-C (O) OR¹⁰, - (CR^eR^f)_q-C (O) N (R^eleven) (R¹²) and = N-O (R¹⁰), moreover, R¹⁰, R^eleven, R¹², R^e, R^f and q are as defined in the Summary of the Invention. R¹², in each case, for example, independently represents hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl). For example, R¹⁰, in each case, independently denotes hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³ or phenyl (unsubstituted or substituted as described for G^one in the section "summary of the invention"), with R^g, R^h and R¹³for example, each is independently hydrogen or C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), and r = 1, 2, 3 or 4, preferably r = 1 or 2. R^eleven, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R¹³, R^13a and R^fourteen are as disclosed in the Summary of the Invention, and q, in each case, for example, independently means 1 or 2. In some embodiments, R² denotes hydrogen.

Other examples of this group of compounds include compounds in which R ³ represents the formula (c)

in which R^b denotes hydrogen, halogen, alkyl (e.g. C_1-6 alkyl, such as methyl, ethyl, isopropyl or tert-butyl), alkenyl, -C (O) OR^7bhaloalkyl (e.g. trifluoromethyl or difluoromethyl), aryl (e.g. phenyl), heteroaryl, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl), or heterocycle (e.g. morpholinyl), each aryl, heteroaryl, cycloalkyl or the heterocycle is independently unsubstituted or substituted, as described in the "Summary of the Invention", R^a stands for OR^7a, N (R⁸) (R⁹) or -C (O) OR^7b, or R^a and R^b together denote = CH₂; R^four denotes hydrogen, alkyl (e.g. C_1-6 alkyl, such as methyl, ethyl, isopropyl or tert-butyl), haloalkyl, cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo [2,2,1] heptyl), aryl (eg phenyl), heteroaryl or a heterocycle (e.g. tetrahydro-2H-pyranyl), with each of the rings denoted by R^fourmay be independently further substituted as described in the Summary of the Invention and in the embodiments, and R^7a, R^7b, R⁸ and R⁹ are as disclosed in the “Summary of the Invention”. Examples of possible R substituents^b how rings include, but are not limited to, C_1-6 alkyl, halogen and haloalkyl. R^7afor example, stands for hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³, and R^g, R^h, R¹³ and r are as described in the Summary of the Invention, or phenyl (unsubstituted or substituted as described in the Summary of the Invention). R^7b, R^g, R^h, R¹³ and R⁹, in each case, for example, each is independently hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl) or haloalkyl (e.g. trifluoromethyl or difluoromethyl). r, for example, means 1 or 2. R⁸for example, stands for hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R¹³, R^13a and R^fourteen are as disclosed in the “Summary of the Invention”.

Other examples of this group of compounds include compounds in which R ³ is formula (d)

,

,

in which R^1b denotes hydrogen, alkyl (e.g. C_1-6 alkyl, such as methyl, ethyl, isopropyl or tert-butyl), alkenyl, halogen, —C (O) OR^7bhaloalkyl (e.g. trifluoromethyl or difluoromethyl), aryl, heteroaryl, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or heterocycle (e.g. morpholinyl), R^1a stands for OR^7a, N (R⁸) (R⁹) or -C (O) OR^7b, and R^2a and R^2b, in each case, are independently hydrogen, halogen, alkyl (eg methyl, ethyl, isopropyl or tert-butyl), alkenyl or haloalkyl (eg trifluoromethyl or difluoromethyl); or R^2b denotes hydrogen, alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), alkenyl, halogen, —C (O) OR^7bhaloalkyl (e.g. trifluoromethyl or difluoromethyl), aryl (e.g. phenyl), heteroaryl, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or heterocycle (e.g. morpholinyl), R^2a stands for OR^7a, N (R⁸) (R⁹) or -C (O) OR^7b, and R^1a and R^1b, in each case, are each independently hydrogen, halogen, alkyl (e.g. C_1-6 alkyl, such as methyl, ethyl, isopropyl or tert-butyl), alkenyl, or haloalkyl (e.g. trifluoromethyl or difluoromethyl); each aryl, heteroaryl, cycloalkyl or heterocycle denoted by R^1b and R^2bindependently unsubstituted or optionally substituted as described for rings denoted by R^b, in the section "essence of the invention". Examples of possible R substituents^1b or R^2b how rings include, but are not limited to, C_1-6 alkyl, halogen and haloalkyl. R^four denotes hydrogen, alkyl, haloalkyl, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo [2.2.1] heptyl), aryl (e.g. phenyl), heteroaryl or heterocycle (e.g. tetrahydro-2H-pyranyl ), and each of the rings denoted by R^fourmay be independently further substituted as described in the Summary of the Invention, and R^7a, R^7b, R⁸ and R⁹ are as disclosed in the “Summary of the Invention”. For example, R^7a, in each case, independently denotes hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), - (CR^gR^h)_r-C (O) OR¹³, and R^g, R^h, R¹³ and r are as described in the Summary of the Invention, or phenyl (unsubstituted or substituted as described in the Summary of the Invention). R^7b, R^g, R^h, R¹³ and R⁹, in each case, for example, each is independently hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl) or haloalkyl (e.g. trifluoromethyl or difluoromethyl). r, for example, means 1 or 2. R⁸, in each case, for example, independently represents hydrogen, C_1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), haloalkyl (e.g. trifluoromethyl or difluoromethyl), -S (O)₂-R^13a, -S (O)₂-N (R¹³) (R^fourteen), -C (O) OR¹³ or -C (O) N (R¹³) (R^fourteen), moreover, R¹³, R^13a and R^fourteen are as disclosed in the “Summary of the Invention”.

Another aspect of the invention relates to compounds of formula (I) or their pharmaceutically acceptable salts, prodrugs, prodrug salts or combinations thereof, in which R ³ is —C (O) —R ⁵ , R ² is hydrogen, halogen, alkyl or haloalkyl , and R ⁵ is as disclosed in the “Summary of the Invention”. For example, R ⁵ is aryl, such as phenyl, optionally further substituted as necessary, as described in the Summary of the Invention. In some embodiments, R ² is hydrogen.

Examples of compounds of the present invention include, but are not limited to, the following compounds:

6 - [(4-aminophenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;

6- (cyclohexylethinyl) -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;

5-methyl-6- (4-phenylbut-1-ynyl) [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;

1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclopentanol;

1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclohexanol;

4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] tetrahydro-2H-pyran-4-ol;

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-cyclopentylbut-3-in-2-ol;

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-phenylbut-3-in-2-ol;

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1,1,1-trifluoro-2-phenylbut-3-in-2- ol;

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1,1-diphenylprop-2-in-1-ol;

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-in-1-ol;

6- (3-cyclohexylprop-1-ynyl) -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopropyl-1-phenylprop-2-in-1-ol;

6 - [(4-methoxyphenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1,1-bis (4-chlorophenyl) prop-2-in-1- ol;

5-methyl-6- (3-morpholin-4-yl-3-phenylprop-1-ynyl) [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (1-methylcyclohexyl) -1-phenylprop-2-in-1- ol;

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (3,4'-dichloro-1,1'-biphenyl-4 -yl) prop-2-yn-1-ol;

1- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -3- (1,1'-biphenyl-4-yl) -4,4 dimethylpent-1-yn-3-ol;

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-hydroxy-2-phenylmethylbut-3-inoate;

N- {1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclohexyl} -3-chlorobenzenesulfonamide;

N- (4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] phenyl} -N '- (3-chlorophenyl) urea;

(1R, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2 , 2,1] heptan-2-ol;

(1Z) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] -4-tert-butylcyclohexanone oxime;

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2- (4-isopropyl-2-methylcyclopentyl) but-3-in-2 -ol;

{[[3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-ynyl] oxy} methyl acetate;

{[[3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-ynyl] oxy} acetic xylate;

{2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] phenyl} methanol;

{3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-hydroxy-1-methylprop-2-ynyl] -2 , 2-dimethylcyclobutyl} acetic acid;

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-cyclobutylbut-3-in-2-ol;

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2- (3-methylcyclobutyl) but-3-in-2-ol;

5-methyl-6- (3-phenylprop-1-ynyl) [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;

6- (3-cyclopentylprop-1-ynyl) -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;

6 - [(1-aminocyclohexyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopentylprop-2-in-1-ol;

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (2,4-dichlorophenyl) prop-2-in-1-ol ;

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopentyl-2-methylbut-3-in-2-ol;

{4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} acetic acid;

{4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} methyl acetate;

(1R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] bicyclo [2.2.1] heptane- 2-ol;

(1R, 2S, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol;

(1R, 2R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,3,3-trimethylbicyclo [2,2,1] heptan-2-ol;

{4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} tert-butyl acetate;

(1S, 2S, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,3,3-trimethylbicyclo [2,2,1] heptan-2-ol;

(1S, 2R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol;

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclopentanol;

1 - [(7-amino [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclopentanol;

1- [3- (7-amino [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclopentanol;

(1R, 2S, 4R) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] -1 7,7-trimethylbicyclo [2.2.1] heptan-2-ol;

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclohexanemethyl carboxylate;

6- [3- (4-methoxyphenoxy) but-1-ynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;

(1R) -3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-in-1-ol;

(1S) -3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-in-1-ol;

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylbut-3-yn-1-ol;

(trans) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclopropaneethyl carboxylate;

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclohexanecarboxylic acid;

1 - [(7-amino-5-ethyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] cyclopentanol;

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-phenylprop-2-in-1-one;

2- {3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxy-1-methylprop-2-ynyl] -2,2-dimethylcyclobutyl} acetamide;

(1R, 2S, 4R) -2 - [(7-amino-5-ethyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol;

1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] cycloheptanol;

{[[3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-cyclopentylprop-2-ynyl] oxy} acetic acid;

({1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] cyclopentyl} oxy) acetic acid;

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-cyclohexylprop-2-in-1-ol;

4- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclohexanemethyl carboxylate;

4- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclohexanecarboxylic acid;

{3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-methyleneprop-2-ynyl] -2,2-dimethylcyclobutyl }acetic acid;

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclopentanemethyl carboxylate;

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclohexan-2- (trimethylsilyl) ethyl carboxylate;

6 - [(4-bromophenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-7-amine;

6 - [(4-chlorophenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-7-amine;

2- {4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] phenyl} -2-methylmethylpropanoate;

1- [4- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) but-3-ynyl] -2-oxocyclopentaneethyl carboxylate;

and their pharmaceutically acceptable salts, prodrugs or salts of prodrugs.

The compounds disclosed herein may contain asymmetrically substituted carbon or sulfur atoms, and accordingly can exist as, and be isolated as, individual stereoisomers (e.g., a single enantiomer or a separate diastereomer), a mixture of stereoisomers (e.g., any mixture of enantiomers or diastereomers) or racemic mixtures thereof. Individual optically active forms of the compounds can be obtained, for example, by synthesis from optically active starting materials, chiral synthesis, enzymatic separation, biotransformation, or chromatographic separation. It should be understood that the present invention encompasses any racemic, optically active, stereoisomeric form or mixtures of these forms in various proportions, which have properties suitable for inhibiting the activity of DGAT-1. If the stereochemistry of the chiral centers in the chemical structures illustrated here is not defined, the chemical structure encompasses compounds containing any stereoisomer of each chiral center in the compound, and mixtures thereof.

The compounds of the invention may exist as geometric isomers. The invention contemplates various geometric isomers and mixtures thereof resulting from the placement of substituents around a carbon-carbon double bond, cycloalkyl group or heterocycloalkyl group. Substituents around a carbon-carbon double bond are defined as having a Z or E configuration, and substituents around a cycloalkyl or heterocycloalkyl are defined as having a trans or cis configuration.

In the framework of the present invention, it should be understood that the compounds disclosed herein may exhibit the phenomenon of tautomerism and that the drawings of the formulas within this description may represent only one of the possible tautomeric forms. It should be understood that the invention encompasses any tautomeric form and should not be limited to any tautomeric form used in the names of the drawings of formulas or compounds.

Synthesis Methods

This invention encompasses compounds of the invention resulting from synthetic processes or metabolic processes. The preparation of compounds of the invention by metabolic processes includes processes that occur in humans or animals (in vivo) or processes that occur in vitro.

The synthesis of compounds of formula (I) in which the groups R ¹ and R ² have the meanings as set forth in the “Summary of the Invention”, unless otherwise indicated, is illustrated by Schemes 1-8.

In the descriptions of the schemes and examples, some abbreviations have the following meanings: DMSO for dimethyl sulfoxide, RP-HPLC for reverse phase preparative high performance liquid chromatography, Boc stands for tert-butoxycarbonyl, and OTs stands for p-tolylsulfonate.

Compounds of the invention were named using ACD / ChemSketch version 5.06 (developed by Advanced Chemistry Development, Inc, Toronto, Ontario, Canada) or were named based on the ACD nomenclature.

Compounds of general formula (I) can be prepared using general procedures as shown in Scheme 1.

Scheme 1

Aromatic halides of the formula (1) in which X^one denotes halogen, can be attached to alkynes of formula (2), in which R¹⁰¹ denotes R³ or trialkylsilyl, such as trimethylsilyl, using Sonogashira coupling reaction conditions. For example, the reaction is usually carried out in the presence of a base, a palladium-based catalyst and copper (I) salts. An example of copper (I) salts that can be used to carry out the coupling reaction is copper (I) iodide. Examples of palladium-based catalysts include, but are not limited to, bis (triphenylphosphine) palladium (II) dichloride and tetrakis (triphenylphosphine) palladium (0). Examples of the base include an organic base such as trialkylamine (e.g. diisopropylethylamine or triethylamine) or inorganic bases such as sodium or potassium salt C_1-6 alcoholate (e.g. sodium methylate), cesium fluoride, sodium, potassium or cesium carbonate, and the like. The reaction is usually carried out at a temperature ranging from about ambient temperature to about 150 ° C, preferably about 50 ° C to about 150 ° C, and more preferably from about 90 ° C to about 120 ° C, in a solvent such as acetonitrile an aromatic hydrocarbon such as toluene, xylene or benzene, water, N, N_-dimethylformamide, dimethyl sulfoxide, dioxane or mixtures thereof.

Compounds of formula (3) in which R ¹⁰¹ is trialkylsilyl can be converted to compounds of formula (3) in which R ¹⁰¹ is hydrogen, for example, by treatment with a base such as potassium carbonate in a solvent such as a mixture of tetrahydrofuran and methanol.

Compounds of formula (3) in which R ¹⁰¹ is hydrogen can be coupled with halides of the formula R ³ -X ² in which X ² is a halide and R ³ is aryl or heteroaryl using Sonogashira coupling reaction conditions as described above.

Intermediates of formula (2) can be purchased or prepared using reaction conditions similar to those known from the literature. For example, alkynes of formula (6), (6a) or (8) in which R ¹⁰² and R ¹⁰³ are each independently aryl, alkyl, haloalkyl, hydrogen, aryl, heteroaryl, cycloalkyl, heterocycle, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkyl, or R ¹⁰² and R ¹⁰³ , together with the carbon to which they are attached, form a cycloalkyl or heterocycle, can be obtained using general procedures, as illustrated in Scheme 2.

Scheme 2

Grignard reagents of formula (5) or (7), in which X ³ is halogen, can be treated with ketones or aldehydes of formula (4) in a solvent such as, but not limited to, tetrahydrofuran and diethyl ether to give alcohols of the formula ( 6). Grignard reagents of formula (7) can be prepared, for example, by reacting haloallylenes of formula (H) CCCH ₂ X ³ with magnesium in the presence of mercury (II) halides in a solvent such as diethyl ether. Compounds of formula (6a) in which R ¹⁰² is hydrogen, aryl, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycle, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkyl can be obtained by oxidation (6), in which R ¹⁰³ is hydrogen, an oxidizing agent, such as, but not limited to, Dess Martin's reagent.

In the presence of a base such as n-butyllithium, the compounds of formula (3a) can be deprotonated and the resulting anion, treated with ketones or aldehydes of formula (4) in a solvent such as, but not limited to, tetrahydrofuran and diethyl ether, gives the compounds of formula (3b) in which R ¹⁰² and R ¹⁰³ are as defined in Scheme 1.

Scheme 3

Alkines of formula (10) in which R¹⁰² and R¹⁰³ are as defined above, can be obtained from compounds of formula (9), in which R¹⁰⁴ denotes an acid protecting group, such as, but not limited to, C_1-6 alkyl, trialkylsilylalkyl, benzyl (substituted or unsubstituted), etc. Such acid-protecting groups can be obtained from the corresponding acids using procedures analogous to those known in the art. For example, 2- (trimethylsilyl) ethyl can be incorporated into the corresponding acid by reacting the acid with 2- (trimethylsilyl) ethanol in the presence of a coupling reagent such as 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride . In the presence of a strong base, such as sodium hydride or lithium diisopropylamide, in a solvent such as, but not limited to, tetrahydrofuran or N, N-dimethylformamide, at a temperature of from about −78 ° C. to about ambient temperature, the protected acids can be deprotonated and the resulting anions can be treated in situ with haloallylenes of formula (H) CCCH₂X³where X³ denotes halogen, at a temperature approximately equal to ambient temperature, to obtain compounds of formula (10).

Scheme 4

Protected acids of formula (13) can be prepared from the corresponding alcohols of formula (11) (a) by treatment with a halide such as trifluoromethanesulfonyl halide, benzenesulfonyl halide or toluenesulfonyl halide, in the presence of an organic base such as pyridine or an inorganic base such as sodium carbonate compounds of formula (12) in which R ¹⁰⁵ is trifluoromethanesulfonyl, benzenesulfonyl or toluenesulfonyl; and (b) reacting a compound of formula (12) with anions formed in situ from (9) as described in Scheme 3.

Scheme 5

Protected acids of formula (17) can be prepared from β-ketoesters of formula (14) as shown in Scheme 5.

Treatment of (14) with phosphorus pentachloride gives the chlorides of formula (15). Hydrolysis of the ester to the corresponding acid, followed by treatment using NaNH₂ in dimethyl sulfoxide gives acids of formula (16), which can be protected to give (17) using methodologies similar to those known in the art.

Scheme 6

Alkines of formula (19) in which R ¹⁰⁶ is alkyl, haloalkyl or halogen can be obtained from the corresponding compounds of formula (18) using procedures similar to those described in J. Chem. Soc, Chem. Commun., 1990, 2, p. 118-119, and Tetrahedron Lett., 1986, 27, p. 5024-5028.

Scheme 7

Alkines of formula (22) can be prepared from the corresponding alcohols of formula (20), as illustrated in Scheme 5.

The conversion of the alcohols of formula (20) to the chlorides of formula (21) can be carried out using procedures similar to those described in JACS, 1957, 79, p.2142-2144. Chloride displacement with NaNH₂ or amines of the formula HNR^elevenR¹²in which R^eleven and R¹² simultaneously does not mean hydrogen, gives amines of the formula (22).

Scheme 8

Condensation of the corresponding β-ketoesters of formula (24) with aminotriazoles of formula (23) at a temperature ranging from about ambient temperature to about the boiling point of the solvent used gives hydroxypyrimidine derivatives of formula (25). Examples of the inert solvent used in this reaction include acetic acid, a lower alcohol solvent such as ethanol, methanol, isopropyl alcohol and the like; aromatic hydrocarbon solvent such as toluene, benzene, chlorobenzene, xylene, etc .; and an ethereal solvent such as tetrahydrofuran, 1,4-dioxane, etc.

Halogen pyrimidine derivatives of formula (26) can be prepared by reaction (25) with an appropriate halogenating reagent, preferably brominating (e.g. phosphorus oxybromide) or a chlorinating agent (e.g. phosphorus oxychloride), in pure form or in the presence of a solvent, and in the presence of a suitable acid scavenger . Examples of an acid scavenger are organic bases such as triethylamine, diisopropylethylamine, dimethylaminopyridine, pyridine, etc .; and inorganic bases such as sodium hydroxide, sodium or potassium bicarbonate, etc. The reaction is preferably carried out at a temperature of from about 25 ° C to about 150 ° C, preferably from about 80 ° C to about 120 ° C. Examples of the solvent include, but are not limited to, aromatic hydrocarbon solvents such as benzene, xylene, chlorobenzene, toluene, etc.

The conversion of compounds of formula (26) to compounds of formula (28) can be carried out by reacting the former with a solution of ammonia in a solvent, such as, but not limited to, methanol. The reaction is usually carried out at from about 60 ° C to about 100 ° C.

Alternatively, the aminotriazoles of formula (23) can be treated with nitriles of formula (27) at a temperature ranging from ambient temperature to the boiling point of the solvent used, to give compounds of formula (28). Examples of the inert solvent used in this reaction include acetic acid, a lower alcohol solvent such as ethanol, methanol, isopropyl alcohol and the like; aromatic hydrocarbon solvent such as toluene, benzene, chlorobenzene, xylene, etc .; and an ethereal solvent such as tetrahydrofuran, 1,4-dioxane, etc.

Iodination of compounds of formula (28) gives compounds of formula (1) in which X ¹ is iodine and can be carried out by reacting (28) with an iodinating reagent. Examples of an iodinating reagent are, for example, IC1 (commercially available or obtained in situ by reaction of sodium iodide and chloramines-T hydrate in the presence of acetic acid), N-iodosuccinimide, iodine, benzyltrimethylammonium dichlorodiodine and the like.

Aminotriazoles of formula (23) are either commercially available or can be prepared by reactions under conditions similar to those known in the art. For example, (23) can be prepared by reacting carboxylic acids of the formula R ² COOH, or their esters, or acid chlorides of these acids, with amino guanidine hydrochloride or amino guanidino bicarbonate.

It should be understood that the synthesis schemes and particular examples illustrated in the synthesis examples section are illustrative and cannot be considered as limiting the scope of the invention as defined in the attached claims. All alternatives, modifications and equivalents of the synthesis methods and particular examples are included in the scope of the claims.

The optimal reaction conditions and reaction times for each individual step may vary depending on the particular reagents used and substituents present in the reagents used. Unless otherwise indicated, solvents, temperatures, and other reaction conditions can be readily selected by one skilled in the art. Specific procedures are described in the Synthesis Examples section. The reactions can be processed in the usual manner, for example, by removing the solvent from the residue, and then purified according to methods known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise indicated, starting materials and reagents are either commercially available or can be obtained by a specialist from commercially available materials using methods described in the chemical literature.

Conventional experiments, including the corresponding manipulation of reaction conditions, reagents and synthesis path sequences, protecting any chemical functional group that cannot be compatible with the reaction conditions, and removing the protective group at an appropriate time in the process reaction sequences, are within the scope of the invention. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are known to those skilled in the art; examples may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis ( 3 ^{rd ed.), John Wiley &} Sons, NY ( 1999), which is incorporated herein by reference. The synthesis of compounds according to the invention can be carried out by methods similar to those described in the synthesis schemes described above, and in particular examples.

Starting materials, if not commercially available, can be obtained in accordance with procedures selected from standard methods of organic chemistry, procedures similar to the methods of synthesis of known structurally similar compounds, or methods similar to the above schemes or procedures described in the synthesis examples section.

If an optically active form of the compound of the invention is desired, it can be obtained by performing one of the procedures described herein using optically active starting material (obtained, for example, by asymmetric induction of a suitable reaction step), or by separating a mixture of stereoisomers of the compound of the invention or intermediates with using a standard procedure (such as chromatographic separation, recrystallization or enzymatic separation).

Similarly, if a pure geometric isomer of a compound of the invention is required, it can be obtained by performing one of the above procedures using a pure geometric isomer as a starting material or by separating a mixture of geometric isomers of a compound of the invention or intermediates using a standard procedure such as chromatographic separation.

Biological data

Inhibition of DGAT-I

The compounds of the invention were identified as inhibitors of DGAT-I easily using the FlashPlate high throughput screening test. In this test, recombinant human DGAT-1 containing the N-terminal His ₆ epitope tag was obtained in a baculovirus expression system. Insect cells (e.g., S f 9 or High Five) were infected for 24-72 hours and collected by centrifugation. Cell pellets were resuspended in homogenization buffer [250 mM sucrose, 10 mM Tris-HCl (pH 7.4), 1 mM EDTA] and lysed using a homogenization apparatus such as a Microfluidizer (single passage, 4 ° C). Cellular detritus was removed by centrifugation at 10,000 × g for 30 minutes, and microsomal membranes were collected by ultracentrifugation at 100,000 × g for 30 minutes.

DGAT-1 activity was determined as follows: test buffer [20 mM HEPES (pH 7.5), 2 mM MgCl ₂ , 0.04% BSA] containing 50 μM enzyme substrate (didecanoyl glycerol) and 7.5 μM radiolabelled substrates acyl-CoA [1- ¹⁴ C] decanoyl-CoA), was added to each well of a phospholipid FlashPlate (PerkinElmer Life Sciences). A small aliquot of the membrane (1 μg / well) was added to start the reaction, which was allowed to proceed for 60 minutes. The reaction was completed after the addition of an equal volume (100 μl) of isopropanol. The plates were sealed, incubated overnight and counted the next morning on a TopCount Scintillation Plate Reader (PerkinElmer Life Science). DGAT-1 catalyzes the transfer of the isotope-labeled decanoyl group to the sn-3 position of didecanoyl glycerol. The obtained radiolabeled tridecanoylglycerol (tricaprine) binds predominantly to a hydrophobic coating on phospholipid FlashPlate. The proximity of the radiolabeled product with the solid scintillator included in the FlashPlate base induced fluorine release from the scintillator, which was measured in the TopCount Plate Reader. Various concentrations (e.g., 0.0001 μM, 0.001 μM, 0.01 μM, 0.1 μM, 1.0 μM, 10.0 μM) of representative compounds of the invention were added to an individual well prior to the addition of membranes. The DGAT-1 inhibition potential for the compounds of the present invention was determined by calculating IC ₅₀ values, defined as the concentration of the inhibitor based on the sigmoid dose-response curve at which enzymatic activity was inhibited by 50%. The compounds of the present invention were effective in inhibiting the activity of DGAT-1 and thus can be used as therapeutic agents for treating conditions and diseases that are associated with the activity of DGAT-1.

Evaluation of the effectiveness of the compounds in reducing chylomicron deviation in DIO or CD1 mice

The purpose of this protocol was to determine the effect of a single administration of a compound on chylomicron deviation induced by a corn oil bolus, either in non-obese mice (CD1 mice, Jackson Laboratories), or in mice that became obese with spontaneous ad libitum high diet fat content (Buhman, KK et al, J Biol Chem. 2002, 277, 25474-25479). Diet-induced obesity (DIO) in rodents reproduces key aspects of human obesity and metabolic syndrome. The DIO mice used in this study showed hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance, and visceral obesity was noted (for DIO mice, see Collins et al., Physiol. Behav. 81: 243-248 , 2004).

Representative compounds of the invention were typically administered in amounts of 0.03 mg / kg, 0.3 mg / kg, 3 mg / kg or 10 mg / kg per os in the form of a formulation in 1% Tween 80 in water one hour before introducing a corn oil bolus. One hour after the administration of the bolus, plasma samples were taken and analyzed for triglycerides. Compounds were believed to be active if pharmacotherapy resulted in a> 30% decrease in plasma triglycerides in drug-treated animals (measured one hour after the administration of a corn oil bolus) relative to control animals receiving only vehicle. In this model, representative compounds resulted in significant decreases in plasma triglycerides relative to control animals receiving only vehicle.

The compounds of the present invention and pharmaceutically acceptable salts can be used as therapeutic agents. Accordingly, an embodiment of this invention includes a method of treating various conditions in a patient (including mammals), which comprises administering to said patient an amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or salt of a prodrug thereof, which is effective in treating the target condition, or the pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for treating, delaying or preventing various conditions in a patient (such as a mammal, preferably a human) that are mediated by DGAT-1, comprising administering to said patient a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt thereof prodrugs, or pharmaceutical composition containing it.

Another aspect of the present invention relates to methods for preventing, delaying or treating obesity and inducing weight loss in a person, which comprises administering to said person a compound of the invention or a pharmaceutically acceptable salt, prodrug, salt of a prodrug thereof, or a pharmaceutical composition containing it. Another aspect of the invention relates to a method for preventing an increase in body weight in humans by administering at least one compound of the invention, or a pharmaceutically acceptable salt, prodrug, salt of a prodrug thereof, or a combination thereof, in an amount that is sufficient to prevent weight gain.

The present invention also relates to the use of the compounds of the invention for the treatment of obesity-related diseases, including associated dyslipidemia and other obesity-related complications, such as, for example, bile cholesterol calculi, gall bladder disease, gout, cancer (e.g., colon , rectum, prostate, breast, ovary, endometrium, cervix, gall bladder and bile duct), menstrual abnormalities, infertility, polycystic ovaries, osteoarthritis and apnea sleep, as well as for many other pharmaceutical applications related to the same, such as regulating appetite and diet, dyslipidemia, hypertriglyceridemia, metabolic syndrome or Syndrome X, type 2 diabetes (non-insulin-dependent diabetes), atherosclerotic diseases such as heart failure, hyperlipidemia , hypercholisterinemia, low levels of HDL, arterial hypertension, cardiovascular disease (including atherosclerosis, coronary heart disease, coronary artery disease and arterial hype hypertension), cerebrovascular disorders such as stroke, and peripheral vascular disease. The compounds of the invention can also be used to treat physiological disorders associated with, for example, regulation of insulin sensitivity, inflammatory response, hepatic steatosis, elevated levels of triacylglycerides in the liver, non-alcoholic obesity of the liver, non-alcoholic steatohepatitis, levels of plasma triacylglycerides, L.P. etc. Metabolic syndrome is characterized by a group of metabolic risk factors in one person. Such factors include, but are not limited to, abdominal obesity, atherogenic dyslipidemia (blood fat disorders such as high triglycerides, low HDL cholesterol and high LDL cholesterol), high blood pressure, insulin resistance (or lack of glucose tolerance), prethrombotic state ( for example, high fibrinogen or plasminogen activator inhibitor-1 in the blood) and a pro-inflammatory state (for example, elevated C-reactive protein in the blood). In one embodiment, the present invention relates to methods for treating the above disorders, comprising the step of administering to the patient one or more compounds of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them. The compounds of the invention, or their pharmaceutically acceptable salts, or pharmaceutical compositions containing them, can also be used in lowering plasma triglycerides. Thus, in one embodiment, the present invention relates to a method for reducing plasma triglycerides in a patient (including a mammal), comprising the step of administering to the patient one or more compounds of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them.

The term "treatment" includes any process, action, application, therapy or the like in which a patient, including a person, is provided with medical care to improve, directly or indirectly, the patient's condition or to slow the development of a condition or disorder in the patient.

The compounds of the invention, or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, may be administered individually or in combination (i.e., used together) with one or more additional pharmaceutical agents. Combination therapy includes the administration of a single pharmaceutical composition containing one or more compounds of the invention, or their pharmaceutically acceptable salts, prodrugs, prodrug salts, and one or more additional pharmaceuticals, as well as the administration of the compounds of the invention, or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs and each additional pharmaceutical, in its own separate pharmaceutical composition. For example, a compound of formula (I), or pharmaceutically acceptable salts, prodrugs, salts of prodrugs, and one or more additional pharmaceuticals thereof, may be administered to a patient together in a single oral composition having a fixed ratio of each active ingredient, such as a tablet or capsule; or each agent may be administered in separate oral dosage formulations.

If separate dosage formulations are used, the compounds of the invention (or their pharmaceutical salts, prodrugs or prodrug salts) and one or more additional pharmaceuticals can be administered at substantially the same time (e.g., simultaneously) or at different times (e.g., sequentially )

For example, the compounds of the invention (or their pharmaceutical salts, prodrugs or prodrug salts) can be used in combination with one of the following more pharmaceuticals, including, but not limited to, anti-obesity agents, including a β-3 agonist such as CL 316,243; CB-1 antagonists and / or inverse agonists (e.g. rimonabant); neuropeptide inhibitors Y5; appetite suppressants such as, for example, sibutramine (Meridia); MCHr1 antagonists and lipase inhibitors, such as, for example, orlistat (Xenical), and a drug compound that modulates digestion and / or metabolism, such as drugs that modulate thermogenesis, fat breakdown, intestinal motility, fat absorption and satiety.

In addition, the compounds of the invention (or their pharmaceutical salts, prodrugs or prodrug salts) can be administered in combination with one or more of the following pharmaceutical agents, including PPAR ligands (agonists, antagonists), insulin secretion enhancing agents (e.g., sulfonylurea and non-sulfonylureas secretion enhancing agents), α-glucosidase inhibitors, insulin sensitizers, compounds that reduce liver glucose production, and derivatives of insulin and insulin. Such agents may be administered before, simultaneously with or after the administration of the compounds of the invention. Insulin and insulin derivatives include both long and short acting forms and formulations of insulin. PPAR ligands may include agonists and / or antagonists of any of the PPAR receptors, or combinations thereof. For example, PPAR ligands can include PPAR-α, PPAR-γ, PPAR-δ ligands, or any combination of two or three PPAR receptors. PPAR ligands include, for example, rosiglitazone, troglitazone and pioglitazone. Sulfonylurea-containing agents include, for example, glyburide, glimepiride, chlorpropamide, tolbutamide and glipizide, α-glucosidase inhibitors include acarbose, miglitol and voglibosis. Insulin sensitizers include PPAR-γ agonists such as glitazones (eg troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone and the like) and other thiazolidinedione and non-thiazolidinedione compounds; biguanides such as metformin and phenformin; protein tyrosine phosphatase-1B inhibitors (PP-1B); dipeptidyl peptidase IV inhibitors (DPP-IV) (e.g. sitagliptin), and 11 beta-HSD inhibitors. Compounds that reduce liver glucose production include glucagon antagonists and metformin, such as Glucophage and Glucophage XR. Drugs that enhance insulin secretion include sulfonylurea and non-sulfonylurea drugs: GLP-1, GIP, PACAP, secretin and its derivatives; nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide. GLP-1 includes derivatives of GLP-1 with longer half-lives than native GLP-1, such as, for example, derivatized with fatty acid GLP-1 and exendin.

The compounds of the invention (or their pharmaceutical salts, prodrugs or prodrug salts) can also be used in the methods of the invention in combination with one or more pharmaceutical agents, including, but not limited to, HMG-CoA reductase inhibitors, nicotinic acid (e.g. Niaspan) fatty acid lowering compounds (e.g. acipimox); lipid-lowering drugs (e.g. stanol esters, sterol glycosides such as tikveside and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), bile acid complexing agents, bile acid reuptake inhibitors, microsomal triacyl glyceride transport inhibitors and fibric acid. HMG-CoA reductase inhibitors include, for example, statin such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, cerivastatin and ZD-4522. Fibric acid derivatives include, for example, clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate, etofibrate and gemfibrozil. Complexing agents include, for example, cholestyramine, colestipol and dialkylaminoalkyl derivatives of cross-linked dextran.

The compounds of the invention (or their pharmaceutical salts, prodrugs or prodrug salts) can also be used in combination with anti-hypertensive drugs, such as, for example, β-blockers and ACE inhibitors. Examples of additional antihypertensive agents for use in combination with the compounds of the present invention include calcium channel blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mibefradil), diuretics (e.g. chlortiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrylic acid, tricrinafen, chlortalidone, furosemide, musolimin, bumetanide, triamtrenene, amiloride, spironolactone), inhibit renin rye, ACE inhibitors (e.g. captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, hinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g. losartan, irbesartan receptortans, vals for example, sitaxssentan, atrsentan, neutral endopeptidase inhibitors (NEPs), vasopepsidase inhibitors (double NEP-ACE inhibitors) (e.g. omapatrilate and hematoprilat) and nitrates.

The compounds of the invention can also be used in conjunction with incretin mimetics, such as, but not limited to, exenatide.

The compounds of the invention (or their pharmaceutical salts, prodrugs or prodrug salts) can be used to achieve the desired pharmacological effect by administering to a patient in an appropriately formulated pharmaceutical composition. The patient, for example, may be a mammal, including a person who needs treatment for a specific condition or disease. Therefore, the present invention includes pharmaceutical compositions that consist of a therapeutically effective amount of a compound (or its pharmaceutical salts, prodrugs or prodrug salts) identified by the methods described herein in combination with a pharmaceutically acceptable carrier. Compounds identified by the methods described herein can be administered with a pharmaceutically acceptable carrier using any of the usual effective effective unit dosage forms, for example, immediate and delayed release formulations, oral, parenteral, topical, and the like.

The pharmaceutical compositions may be formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

The term “pharmaceutically acceptable carrier” as used herein means a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or adjuvant of any type. Examples of therapeutically suitable excipients include sugars; cellulose and its derivatives; oils; glycols; solutions; buffering, coloring, releasing, coating, sweetening, flavoring and flavoring agents; etc. These therapeutic compositions can be administered parenterally, intracisternally, orally, rectally, intravenously or intraperitoneally.

Liquid dosage forms for oral administration of the compounds of the invention include formulations in the form of emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds, liquid dosage forms may contain diluents and / or solvents or emulsifiers. In addition to inert diluents, oral compositions may include wetting, emulsifying, sweetening, flavoring and flavoring agents.

Injectable preparations of the compounds of the invention include sterile injectable, aqueous and oily solutions, suspensions or emulsions, any of which may, if necessary, be formulated with parenterally acceptable diluents, dispersants, wetting or suspending agents. These injectable preparations may be sterilized by filtration through a bacteria-retaining filter or formulated with sterilizing agents that dissolve or disperse in the injectable medium.

Inhibition of DGAT-1 by the compounds of the present invention can be delayed by using a liquid suspension of crystalline or amorphous material with low water solubility. The absorption rate of the compounds depends on their dissolution rate, which, in turn, depends on their crystallinity. Delayed absorption of the parenterally administered compound can be achieved by dissolving or suspending the compound in oil. Injectable depot forms of the compounds can also be prepared by microencapsulation of the compound in biodegradable polymers. Depending on the ratio of the compound to the polymer and the nature of the polymer used, the release rate can be controlled. Injectable depot formulations are also prepared by capturing compounds in liposomes or microemulsions that are compatible with body tissues.

Solid dosage forms for oral administration of the compounds of the invention include capsules, tablets, pills, powders and granules. In such forms, the compound is mixed with at least one inert therapeutically suitable excipient, such as a carrier, excipient, extender, disintegrant, dissolution inhibitor, wetting agent, absorbent, or lubricant. In the case of capsules, tablets and pills, the excipient may also contain buffering agents. Suppositories for rectal administration can be prepared by mixing the compound with a suitable non-irritant excipient that is solid at ordinary temperature but liquid in the rectum.

The compounds of the invention may be microencapsulated with one or more excipients discussed above. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be obtained with coatings and shells, such as enteric and providing controlled release. In these forms, the compounds may be mixed with at least one inert diluent and may optionally include tabletting lubricants and excipients. Capsules may also, if necessary, contain opacifiers that delay the release of compounds in the desired part of the intestine.

Transdermal patches have the added advantage of providing controlled delivery of the compounds of the invention to the body. Such dosage forms are prepared by dissolving or dispensing the compounds in an appropriate medium. Absorption enhancers can also be used to accelerate the movement of compounds through the skin, and the absorption rate can be controlled by controlling the speed of the membrane or dispersing the compounds in a polymer matrix or gel.

The compounds of the invention can be used in the form of pharmaceutically acceptable salts, esters or amides derived from inorganic or organic acids. The term “pharmaceutically acceptable salts, esters and amides” as used herein includes salts, zwitterions, esters and amides of the compounds disclosed herein, which, in the framework of normal medical judgment, are suitable for use in contact with human and animal tissues without undesirable toxicity , irritation, allergic reaction, etc., are commensurate with an acceptable benefit / risk ratio and effective for their intended use.

Pharmaceutically acceptable salts are known in the art. Salts can be prepared by final isolation and purification of the compounds, or by separately reacting the amino group of the compounds with a suitable acid. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate malate, lactate, lactate sulfate , nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, p-toluenesulfonate, undecanoate, chloride, phosphate, bromide and bromide, bromide and . The amino groups of the compounds can also be quaternized with alkyl chlorides, bromides and iodides, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

Base addition salts can be prepared by final isolation and purification of the compounds of the invention by reacting a carboxyl group with a suitable base, such as a metal cation hydroxide, carbonate or bicarbonate, such as lithium, sodium, potassium, calcium, magnesium or aluminum, or an organic primary secondary or tertiary amine. Quaternary amine salts derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N, N-d-phenyl ephenamine and N, N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like are considered to be within the scope of the present invention.

The term “pharmaceutically acceptable ester” as used herein refers to esters of the compounds of the invention that are hydrolyzed in vivo and include those that are readily cleaved in the human body, releasing the parent compound or its salt. Examples of pharmaceutically acceptable, non-toxic esters of the invention include C_1-6 alkyl esters and complex C_5-7 cycloalkyl esters although complex C_1-4 alkyl esters are preferred. Esters of the compounds of the invention can be prepared according to conventional methods. Pharmaceutically acceptable esters can be attached to hydroxyl groups by reacting a compound that contains a hydroxyl group with an acid and an alkyl carboxylic acid such as acetic acid, or with an acid and an aryl carboxylic acid such as benzoic acid. In the case of compounds containing carboxylic acid groups, pharmaceutically acceptable esters are prepared from compounds containing carboxylic acid groups by reacting the compound with a base such as triethylamine and an alkyl halide, alkyl triflate, for example methyl iodide, benzyl iodide, cyclopentyl iodide. They can also be prepared by reacting the compound with an acid, such as hydrochloric acid, and an alkyl carboxylic acid, such as acetic acid, or with an acid and an aryl carboxylic acid, such as benzoic acid.

The term "pharmaceutically acceptable amide" as used herein refers to the non-toxic amides of the invention derived from ammonia, primary C_1-6 alkylamines and secondary di (C_1-6) alkylamines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, primary C_1-3 alkylamides and secondary di (C_1-2) alkylamides are preferred. Amides of the compounds of the invention can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reacting a compound that contains an amino group with an alkyl hydride, aryl acid hydride, acyl halide or aroyl halide. In the case of compounds containing carboxylic acid groups, pharmaceutically acceptable esters are prepared from compounds containing carboxylic acid groups by reacting the compound with a base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyldiimidazole, and alkylamine, dialkylamine, for example with methylamine , diethylamine, piperidine. They can also be prepared by reacting the compound with an acid, such as sulfuric acid, and an alkyl carboxylic acid, such as acetic acid, or with an acid and an aryl carboxylic acid, such as benzoic acid, under dehydrating conditions, such as with the addition of molecular sieves. The composition may contain a compound of the invention in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug” as used herein means those prodrugs of the compounds of the invention which, in the framework of normal medical judgment, are suitable for use in contact with human and animal tissues without undesirable toxicity, irritation, allergic reaction, etc. n., are commensurate with an acceptable benefit / risk ratio and effective for their intended use. The prodrugs of the invention can be rapidly converted in vivo to the parent compound of the invention, for example, by hydrolysis in blood. For a full discussion, see T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, V. 14, A.C.S. Symposium Series, and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

Disorders that may be treated or prevented by the patient by administering to the patient a therapeutically effective amount of a compound (or its pharmaceutical salts, prodrugs or prodrug salts) according to the present invention in such quantity and for such time that is necessary to achieve the desired result. The term “therapeutically effective amount” refers to an amount of a compound of the invention sufficient to effectively alleviate the disorders by inhibiting DGAT-1 in an acceptable benefit / risk ratio applicable to any treatment. The specific therapeutically effective dose level for any given patient may depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the compound used; specific composition used; age, body weight, general health, gender and diet of the patient; time of administration, route of administration, rate of excretion; duration of treatment; and drugs used in combination or concomitant therapy.

The total daily dose of the compounds of the present invention necessary to inhibit the action of DGAT-1 in a single dose or in divided doses may be in amounts, for example, from about 0.01 to 50 mg / kg body weight. In a more preferred range, the compounds of the present invention inhibit the action of DGAT-1 as a single dose or in divided doses of from about 0.05 to 25 mg / kg body weight. Single-dose compositions may contain such amounts or sub-doses thereof of the compounds of the present invention to formulate a daily dose. In general, treatment regimens include administering to a patient from about 1 mg to about 1000 mg of the compounds per day in a single dose or in multiple doses.

Compounds identified by the methods described herein may be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutical agents if the combination does not cause any unacceptable side effects. For example, the compounds of the invention may be combined with an anti-obesity agent or with known anti-diabetic or other agents indicated for this purpose and the like. Thus, the present invention also includes pharmaceutical compositions that consist of a therapeutically effective amount of a compound identified by the methods described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more pharmaceutical agents, as disclosed above.

Examples

Example 1

6 - [(4-aminophenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with commercially available 4-ethynylaniline. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 8.44 (br s, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6 67 (d, J = 8.8 Hz, 2H), 4.51 (br s, 2H), 2.59 (s, 3H). MS (ESI) m / z 265 (M + H) ⁺ .

Example 2

6- (cyclohexylethinyl) -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with commercially available ethynylcyclohexane. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.26 (br s, 2H), 2.79-2.69 (m, 1H), 2.52 ( s, 3H), 1.93-1.81 (m, 2H), 1.63-1.77 (m, 2H), 1.64-1.28 (m, 6H). MS (ESI) m / z 256 (M + H) ⁺ .

Example 3

5-methyl-6- (4-phenylbut-1-ynyl) [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with commercially available but-3-ynylbenzene. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 8.12 (br s, 2H), 7.35-7.29 (m, 5H), 2.97- 2.88 (m, 2H); 2.86-2.78 (m, 2H); 2.39 (s, 3H). MS (ESI) m / z 278 (M + H) ⁺ .

Example 4

1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclopentanol

Example 4A

6-iodo-5-methyl- [1,2,4] triazolo [1,5-α] pyrimidin-7-amine

To a stirred mixture of 3.05 g (20.4 mmol) of 5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-7-amine (prepared as described in Kano; Makisumi; Chem. Pharm. Bull .; 6; 1958; 583, 585) in 50 ml of acetic acid at ambient temperature was added NaI (3.2 g, 21.5 mmol). Then, chloramine-T trihydrate (6.0 g, 21.5 mmol) was added dropwise. The resulting mixture was then stirred for 1 h at ambient temperature. Most of the organic solvent was removed on a rotary evaporator. The mixture was suspended in 40 ml of CH ₃ CN and filtered. The collected solid was washed with diethyl ether and dried in a vacuum oven to afford the title compound as a pale yellow solid (4.93 g, 88% yield).

Example 4B

1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclopentanol

Example 4A (350 mg, 1.27 mmol), bis (triphenylphosphine) palladium (II) dichloride (38 mg, 0.64 mmol) and CuI (21 mg, 0.13 mmol) were hung in a test tube. CH was added₃CN (10 ml) and nitrogen sparged. Then, 1-ethynylcyclopentanol (180 mg, 1.91 mmol) and triethylamine (382 μl, 3.18 mmol) were successively added. The tube was then drowned and heated at 110 ° C for 20 minutes. The reaction mixture was then allowed to cool to ambient temperature and was partitioned between ethyl acetate (15 ml) and brine (10 ml). The aqueous layer was extracted once with ethyl acetate (15 ml). The combined organic layer was dried over MgSO_four and concentrated in vacuo. The residue was purified by reverse phase HPLC (column C-18, eluting with a gradient of 5-100% CH₃CN in 10 mM ammonium acetate)), obtaining the target compound in the form of a white solid (140 mg, 43% yield).^oneH NMR (300 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.14 (br s, 2H), 5.36 (s, 1H), 2.51 (s, 3H), 2.05-1.84 (m, 4H), 1.83-1.62 (m, 4H). MS (ESI) m / z 258 (M + H)⁺.

Example 5

1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclohexanol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with commercially available 1-ethynyl-1-cyclohexanol. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.19 (br s, 2H), 5.53 (s, 1H), 3.29 (s, 3H) 1.96-1.83 (m, 2H); 1.75-1.43 (m, 6H); 1.29-1.10 (m, 2H). MS (ESI) m / z 272 (M + H) ⁺ .

Example 6

4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] tetrahydro-2H-pyran-4-ol

Example 6A

4-Ethinyl-tetrahydro-pyran-4-ol

A solution of ethynyl magnesium chloride in tetrahydrofuran (0.5 m, 12 ml, 6.0 mmol) was added dropwise over 15 minutes with cooling in an ice-water bath to a solution of tetrahydro-4H-pyran-4-one (0.496 g, 5, 0 mmol) in diethyl ether (300 ml). The mixture was stirred at ambient temperature for 1 hour. Then, a saturated aqueous solution of ammonium chloride (10.0 ml) was added, and the mixture was extracted with ether (2 × 20 ml). The ether layers were washed with saturated aqueous sodium chloride (20 ml), then combined, dried over MgSO_four, filtered and concentrated to give 4-ethynyl-tetrahydro-pyran-4-ol in the form of a colorless oil, which solidified upon standing. (0.60 g, yield 96.2%).

Example 6B

4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] tetrahydro-2H-pyran-4-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 6A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 8.31 (br s, 2H), 3.89-3.75 (m, 2H), 3.63- 3.51 (m, 2H), 2.54 (s, 3H), 2.10-1.89 (m, 2H), 1.79-1.63 (m, 2H). MS (ESI) m / z 274 (M + H) ⁺ .

Example 7

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-cyclopentylbut-3-in-2-ol

Example 7A

2-cyclopentylbut-3-in-2-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with 1-cyclopentylethanone.

Example 7B

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-cyclopentylbut-3-in-2-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 7A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.21 (br s, 2H), 2.50 (s, 3H), 2.17-2.03 ( m, 1H), 1.81-1.43 (m, 8H), 1.46 (s, 3H). MS (ESI) m / z 286 (M + H) ⁺ .

Example 8

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-phenylbut-3-in-2-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with commercially available 2-phenyl-3-butyn-2-ol. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.26 (br s, 2H), 7.67 (d, J = 7.5 Hz, 2H), 7 39 (t, J = 7.5 Hz, 2H), 7.28 (m, 1H), 6.16 (s, 1H), 2.54 (s, 3H), 1.75 (s, 3H) . MS (ESI) m / z 294 (M + H) ⁺ .

Example 9

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1,1,1-trifluoro-2-phenylbut-3-in-2- ol

The title compound was prepared according to the procedures described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with 1,1,1-trifluoro-2-phenyl-3-butyn-2-ol commercially available. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 7.88 (s, 1H), 7.79-7.72 (m, 2H), 7.54-7, 42 (m, 3H); 2.60 (s, 3H). MS (ESI) m / z 348 (M + H) ⁺ .

Example 10

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1,1-diphenylprop-2-in-1-ol

The target compound was prepared according to the procedures described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with 1,1-diphenyl-2-propin-1-ol commercially available. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.48 (s, 1H), 8.28 (br s, 2H), 7.68-7.62 (m, 2H), 7.47- 7.21 (m, 6H), 7.04-7.00 (m, 1H), 2.59 (s, 3H). MS (ESI) m / z 356 (M + H) ⁺ .

Example 11

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-in-1-ol

The title compound was prepared according to the procedures described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with commercially available 1-phenyl-2-propin-1-ol. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.28 (br s, 2H), 7.60-7.55 (m, 2H), 7.44- 7.36 (m, 3H), 7.34-7.27 (m, 1H), 6.08 (d, J = 6.1 Hz, 1H), 5.68 (d, J = 6.1 Hz , 1H); 2.50 (s, 3H). MS (ESI) m / z 280 (M + H) ⁺ .

Example 12

6- (3-cyclohexylprop-1-ynyl) -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The title compound was prepared according to the procedures described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with commercially available 3-cyclohexyl-1-propine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.27 (br s, 2H), 2.43 (d, J = 6.8 Hz, 2H), 1 89-1.50 (m, 5H); 1.34-0.99 (m, 6H). MS (ESI) m / z 270 (M + H) ⁺ .

Example 13

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopropyl-1-phenylprop-2-in-1-ol

Example 13A

1-cyclopropyl-1-phenylprop-2-yn-1-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with cyclopropyl (phenyl) methanone.

Example 13B

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopropyl-1-phenylprop-2-in-1-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 13A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.30 (br s, 2H), 7.74-7.68 (m, 2H), 7.44- 7.37 (m, 3H), 7.35-7.27 (m, 1H), 6.69 (t, J = 7.5 Hz, 1H), 2.61 (s, 3H), 3.63 (t, J = 6.4 Hz, 2H); 2.71 (m, 2H). MS (ESI) m / z 320 (M + H) ⁺ .

Example 14

6 - [(4-methoxyphenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with 1-ethynyl-4-methoxybenzene. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (br s, 2H), 8.50 (s, 1H), 7.63 (d, J = 9.2 Hz, 2H), 6 99 (d, J = 9.2 Hz, 2H), 3.80 (s, 3H), 2.61 (s, 3H). MS (ESI) m / z 280 (M + H) ⁺ .

Example 15

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1,1-bis (4-chlorophenyl) prop-2-in-1- ol

Example 15A

1,1-bis (4-chlorophenyl) prop-2-yn-1-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with bis (4-chlorophenyl) methanone.

Example 15B

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1,1-bis (4-chlorophenyl) prop-2-in-1- ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 15A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.31 (br s, 2H), 7.64 (d, J = 8.8 Hz, 4H), 7 42 (d, J = 8.8 Hz, 4H), 7.12 (br s, 1H), 2.56 (s, 3H). MS (ESI) m / z 424 (M + H) ⁺ .

Example 16

5-methyl-6- (3-morpholin-4-yl-3-phenylprop-1-ynyl) [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with 4- (1-phenyl-prop-2-ynyl) -morpholine (prepared as described in Ahn, Jin Hee; Joung, Meyoung Ju; Yoon, Nung Min; J. Org. Chem .; EN; 64; 2; 1999; 488-492). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 7.99-7.94 (m, 1H), 7.74-7.65 (m, 1H), 7, 63-7.42 (m, 4H), 3.81-3.66 (m, 4H), 3.15-2.90 (m, 4H), 2.60 (s, 3H). MS (ESI) m / z 349 (M + H) ⁺ .

Example 17

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (1-methylcyclohexyl) -1-phenylprop-2-in-1- ol

Example 17A

1- (1-methylcyclohexyl) -1-phenylprop-2-in-1-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with (1-methyl-cyclohexyl) benzophenone (prepared as described in Rouzaud, J. et al; BSCFAS ; Bull. Soc. Chim. Fr .; FR; 1965; 2030-2037).

Example 17B

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (1-methylcyclohexyl) -1-phenylprop-2-in-1- ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 17A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.20 (br s, 2H), 7.63-7.56 (m, 2H), 7.42- 7.23 (m, 3H), 2.65 (s, 3H), 1.74-1.46 (m, 4H), 1.46-0.90 (m, 6H), 0.93 (s, 3H). MS (ESI) m / z 376 (M + H) ⁺ .

Example 18

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (3,4'-dichloro-1,1'-biphenyl-4 -yl) prop-2-yn-1-ol

Example 18A

1- (3,4'-dichlorobiphenyl-4-yl) prop-2-in-1-ol

The target compound was prepared according to the procedures described in Example 6 A, replacing the tetrahydro-4H-pyran-4-one used in Example 6 A with 3,4'-dichlorobiphenyl-4-carboxaldehyde (prepared as described in WO2001039773A1).

Example 18B

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (3,4'-dichloro-1,1'-biphenyl-4 -yl) prop-2-yn-1-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 18A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.30 (br s, 2H), 7.68-7.60 (m, 4H), 7.46- 7.39 (m, 4H); 7.13 (m, 1H); 2.56 (s, 3H). MS (ESI) m / z 424, 426, 428 (M + H) ⁺ .

Example 19

1- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -3- (1,1'-biphenyl-4-yl) -4,4 dimethylpent-1-yn-3-ol

Example 19A

3- (biphenyl-4-yl) -4,4-dimethylpent-1-in-3-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with 4-biphenyl-tert-butylketone (prepared as described in Tsuji, Yutaka; Fujio, Mizue; Tsuno, Yuho; Bull. Chem. Soc. Jpn .; 63; 3; 1990; 856-866).

Example 19B

1- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -3- (1,1'-biphenyl-4-yl) -4,4 dimethylpent-1-yn-3-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 19A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.20 (br s, 2H), 7.74-7.63 (m, 6H), 7.51- 7.31 (m, 3H), 6.19 (s, 1H), 2.67 (s, 3H), 1.05 (s, 9H). MS (ESI) m / z 412 (M + H) ⁺ .

Example 20

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-hydroxy-2-phenylmethylbut-3-inoate

Example 20A

2-hydroxy-2-phenylmethylbut-3-inoate

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with methylbenzoyl formate.

Example 20B

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-hydroxy-2-phenylmethylbut-3-inoate

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 20A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.20 (br s, 2H), 7.75-7.22 (m, 5H), 3.68 ( s, 3H); 2.58 (s, 3H). MS (ESI) m / z 338 (M + H) ⁺ .

Example 21

N- {1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclohexyl} -3-chlorobenzenesulfonamide

Example 21A

3-chloro-N- (1-ethynylcyclohexyl) benzenesulfonamide

To a solution of 1-ethynylcyclohexanamine (40 mg, 0.32 mmol) in CH₂Cl₂ triethylamine (68 ml, 0.48 mmol) was added, followed by 3-chlorobenzenesulfonyl chloride (68.2 mg, 0.32 mmol). After 30 minutes, the mixture was partitioned between ethyl acetate and 3N. aqueous solution of HCl. The organic layer was washed with sat. NaHCO₃saline, dried over Na₂SO_four, concentrated in vacuo, obtaining the target compound in the form of a white solid (90 mg, 93% yield).

Example 21B

N- {1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclohexyl} -3-chlorobenzenesulfonamide

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 21A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.17 (s, 1H), 7.80-7.28 (m, 4H), 2.26 (s, 3H), 2.11-1.99 (m, 2H), 1.79-1.38 (m, 6H), 1.32-1.10 (m, 2H). MS (ESI) m / z 445 (M + H) ⁺ .

Example 22

N- {4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] phenyl} -N '- (3-chlorophenyl) urea

To a stirred solution of Example 1 (10 mg, 0.038 mmol) in 1.0 ml of CH₃CN was added 3-chlorophenyl isocyanate (6.4 mg, 0.046 mmol) and triethylamine (8 μl, 0.057 mmol). The resulting mixture was stirred overnight at ambient temperature. The resulting mixture was purified by reverse phase HPLC (column C-18, eluting with a gradient 5-100% CH₃CN in 0.1% trifluoroacetic acid) to give the desired compound in the form of its trifluoroacetic acid salt (3.5 mg, 17.3% yield). MS (ESI) m / z 416, 418 (M + H)⁺.

Example 23

(1R, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2 , 2,1] heptan-2-ol

Example 23A

(1R, 4R) -2-ethynyl-1,7,7-trimethylbicyclo [2.2.1] heptan-2-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with (±) camphor.

Example 23B

(1R, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2 , 2,1] heptan-2-ol

The target compound was obtained according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B, Example 23. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.23 ( broad s, 2H), 5.55 (s, 1H), 2.50 (s, 3H), 2.50 (s, 3H), 2.24-2.14 (m, 2H), 1.96 -1.83 (m, 3H), 1.78-1.63 (m, 3H), 1.54-1.41 (m, 2H), 1.20-1.09 (m, 2H), 1 08 (s, 3H); 0.93 (s, 3H); 0.86 (s, 3H). MS (ESI) m / z 326 (M + H) ⁺ .

Example 24

(1Z) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] -4-tert-butylcyclohexanone oxime

Example 24A

(Z) -4-tert-butyl-2- (prop-2-ynyl) cyclohexanone oxime

A mixture of 4-tert-butyl-2-prop-2-ynyl-cyclohexanone (50 mg, 0.26 mmol) (prepared as described in Dufey, P .; Bull. Soc. Chim. Fr .; 1968, 4653-4662 ) in 1.0 ml of ethanol was heated under reflux with hydroxylamine hydrochloride (25 mg, 0.36 mmol) and pyridine (0.25 ml, excess) for 3 hours. The mixture was then allowed to cool to ambient temperature and partitioned between ethyl acetate and 3n. aqueous solution of HCl. The organic layers were washed with saturated aqueous sodium chloride, dried over MgSO_four, filtered and concentrated to afford the title compound as a pale yellow solid (50 mg, 93% yield).

Example 24B

(1Z) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] -4-tert-butylcyclohexanone oxime

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 24A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.15 (br s, 2H), 3.02-2.90 (m, 1H), 2.80- 2.69 (m, 1H), 2.50 (s, 3H), 2.60-2.22 (m, 2H), 1.93-1.79 (m, 1H), 1.66-0, 95 (m, 3H); 0.87 (s, 9H). MS (ESI) m / z 355 (M + H) ⁺ .

Example 25

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2- (4-isopropyl-2-methylcyclopentyl) but-3-in-2 ol

Example 25A

2- (4-isopropyl-2-methylcyclopentyl) but-3-in-2-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with 1- (4-isopropyl-2-methylcyclopentyl) ethanone (prepared as described in Roger, A. et al. Bull. Soc. Chim. Fr. 1967, 3030-3037).

Example 25B

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2- (4-isopropyl-2-methylcyclopentyl) -but-3-in- 2-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 25A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 8.22 (broad s, 2H), 5.40 (broad s, 1H), 2.50 (s, 3H), 2.14-1.97 (m, 1H), 1.85-1.54 (m, 3H), 1.43 (s, 3H), 1.49-1.13 (m, 3H) , 1.10 and 1.08 (s, 3H total), 0.88 (s, 3H), 0.85 (s, 3H). MS (ESI) m / z 342 (M + H) ⁺ .

Example 26

{[[3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-ynyl] oxy} methyl acetate

Example 26A

2- (1-phenylprop-2-ynyloxy) methyl acetate

To a stirred suspension of NaH (60%, 76 mg, 1.89 mmol) in 5 ml of anhydrous N, N-dimethylformamide was added 1-phenylprop-2-in-1-ol (250 mg, 1.89 mmol). After 15 minutes, methyl bromoacetate (179 μl, 1.89 mmol) was added at ambient temperature. The resulting mixture was stirred at ambient temperature for 90 minutes, after which it was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate (2 × 15 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: hexane (1: 9) to give the title compound as a colorless oil (160 mg, 41% yield).

Example 26B

{[[3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-ynyl] oxy} methyl acetate

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 26A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.44 (s, 1H), 8.44 (br s, 2H), 7.64 (d, J = 6.4 Hz, 2H), 7 , 49-7.35 (m, 3H), 5.72 (s, 1H), 4.41 (q, J = 16.5 Hz, 2H), 3.69 (s, 3H), 2.50 ( s, 3H). MS (ESI) m / z 352 (M + H) ⁺ .

Example 27

{[[3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-ynyl] oxy} acetic acid

Example 26B (60 mg, 0.17 mmol) was stirred in a mixture of methanol / tetrahydrofuran (1 ml, 1: 1, v / v) and 3N was added. aqueous NaOH solution (171 μl, 0.51 mmol). The mixture was stirred at ambient temperature for 5 hours. The volatile organic solvent was evaporated in vacuo and the residue was treated with 1N. NaOH to adjust pH 5. The precipitate formed was collected by filtration and dried in a vacuum oven to afford the title compound (25 mg, 45% yield) as a brown solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.75 (s, 1H), 8.44 (s, 1H), 8.44 (br s, 2H), 7.64 (d, J = 6.8 Hz, 2H), 7.48-7.33 (m, 3H), 5.72 (s, 1H), 4.32 (d, J = 16.6 Hz, 1H), 4.23 ( d, J = 16.6 Hz, 1H), 2.52 (s, 3H). MS (ESI) m / z 338 (M + H) ⁺ .

Example 28

{2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] phenyl} methanol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with (2-ethynylphenyl) methanol. MS (ESI) m / z 280 (M + H) ⁺ .

Example 29

{3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-hydroxy-1-methylprop-2-ynyl] -2 , 2-dimethylcyclobutyl} acetic acid

Example 29A

2- (3- (2-hydroxybut-3-yn-2-yl) -2,2-dimethylcyclobutyl) acetic acid

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with 2- (3-acetyl-2,2-dimethylcyclobutyl) acetic acid (prepared as described in Burgess, K. et al. Tetrahedron Lett. 38, 1997, 1681-1684).

Example 29B

{3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-hydroxy-1-methylprop-2-ynyl] -2 , 2-dimethylcyclobutyl} acetic acid

A mixture of Example 4A (28 mg, 0.1 mmol), Example 29A (21 mg, 0.1 mmol), bis (triphenylphosphine) palladium (II) dichloride (3.5 mg, 0.005 mmol), CuI (1 mg, 0.005 mmol) and triethylamine (28 μl, 0.2 mmol) in acetonitrile (500 μl) were heated at 100 ° C for 5 minutes in a microwave reactor under nitrogen atmosphere. The resulting mixture was purified by reverse phase HPLC (column C-18, eluting with a gradient of 5-100% CH₃CN in 0.1% trifluoroacetic acid), and then purified by flash chromatography on silica gel (eluting with 10% methanol in ethyl acetate) to give the title compound as a white solid (6 mg, 17% yield).^oneH NMR (300 MHz, DMSO-d₆) δ 11.93 (s, 1H), 8.42 (s, 1H), 8.12 (s, 2H), 5.32 (s, 1H), 2.52 (s, 3H), 1.82 -2.32 (m, 6H), 1.42 (s, 3H), 1.12 (s, 6H). MS (ESI) m / z 358 (M + H)⁺.

Example 30

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-cyclobutylbut-3-in-2-ol

The target compound was prepared according to the procedures described in Example 29B, replacing Example 29A with 2-cyclobutylbut-3-yn-2-ol (prepared as described in US Pat. No. 2,779,799) to give a white solid (11 mg, 41%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.16 (s, 2H), 5.39 (s, 1H), 2.52 (s, 3H), 1 58-2.21 (m, 7H); 1.37 (s, 3H). MS (ESI) m / z 272 (M + H) ⁺ .

Example 31

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2- (3-methylcyclobutyl) but-3-in-2-ol

The target compound was prepared according to the procedures described in Example 29B, replacing Example 29A with 2- (3-methylcyclobutyl) but-3-in-2-ol (prepared as described in US Pat. No. 2,779,799) to give a white solid (4 mg, fourteen%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.12 (s, 2H), 5.37 (s, 1H), 2.52 (s, 3H), 1 45-2.38 (m, 6H), 1.34 (d, Hz J = 7.12, 3H); 0.93-1.17 (m, 3H). MS (ESI) m / z 286 (M + H) ⁺ .

Example 32

5-methyl-6- (3-phenylprop-1-ynyl) [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with commercially available prop-2-ynylbenzene. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.27 (s, 2H), 7.21-7.51 (m, 5H), 3.98 (s, 2H), 2.54 (s, 3H). MS (ESI) m / z 264 (M + H) ⁺ .

Example 33

6- (3-cyclopentylprop-1-ynyl) -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with commercially available prop-2-ynylcyclopentane. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 8.12 (s, 2H), 2.51 (s, 3H), 2.08-2.22 (m, 1H), 1.73-1.87 (m, 2H), 1.45-1.70 (m, 4H), 1.27-1.42 (m, 2H). MS (ESI) m / z 256 (M + H) ⁺ .

Example 34

6 - [(1-aminocyclohexyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with commercially available 1-ethynylcyclohexanamine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.49 (br s, 2H), 2.55 (s, 3H), 2.18-2.09 ( m, 1H), 2.07-1.96 (m, 1H), 1.84-1.50 (m, 6H), 1.50-1.33 (m, 1H), 1.26-1, 05 (m, 1H). MS (ESI) m / z 271 (M + H) ⁺ .

Example 35

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopentylprop-2-in-1-ol

Example 35 A

1-cyclopentylprop-2-in-1-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with cyclopentanecarboxaldehyde.

Example 35B

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopentylprop-2-in-1-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 35A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.17 (br s, 2H), 5.37 (d, J = 5.1 Hz, 1H), 4 41-4.34 (m, 1H); 2.50 (br s, 3H); 2.30-2.11 (m, 1H); 1.81-1.40 (m, 8H). MS (ESI) m / z 272 (M + H) ⁺ .

Example 36

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (2,4-dichlorophenyl) prop-2-in-1-ol

Example 36A

The 1- (2,4-dichlorophenyl) prop-2-yn-1-ol target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with 2,4-dichlorobenzaldehyde .

Example 36B

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (2,4-dichlorophenyl) prop-2-in-1-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 36A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.28 (broad s, 2H), 7.82 (d, J = 8.5 Hz, 1H), 7 65 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.5, 2.0 Hz, 1H), 6.40 (d, J = 5.8 Hz, 1H) 5.88 (d, J = 5.8 Hz, 1H); 2.50 (s, 3H). MS (ESI) m / z 348, 350, 352 (M + H) ⁺ .

Example 37

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopentyl-2-methylbut-3-in-2-ol

Example 37A

1-cyclopentyl-1-methylbut-3-in-2-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with cyclopentyl acetone.

Example 37B

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopentyl-2-methylbut-3-in-2-ol

A mixture of Example 4A (28 mg, 0.1 mmol), Example 37A (18 mg, 0.12 mmol), bis (triphenylphosphine) palladium (II) dichloride (3.5 mg, 0.005 mmol), CuI (1 mg, 0.005 mmol) and triethylamine (28 μl, 0.2 mmol) in acetonitrile (500 μl) were heated at 100 ° C for 5 minutes in a microwave reactor under nitrogen atmosphere. The resulting mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO_four, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with ethyl acetate) to give the title compound as a pale yellow solid (9 mg, 30% yield).^oneH NMR (300 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.13 (s, 2H), 5.38 (s, 1H), 2.49 (s, 3H), 1.99-2.20 (m, 1H) 1.80-1.94 (m, 2H), 1.76 (dd, J = 6.27, 2.88 Hz, 2H), 1.49 (s, 3H), 1.37-1.65 (m, 4H); 1.08-1.28 (m, 2H). MS (ESI) m / z 300 (M + H)⁺

Example 38

{4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} acetic acid

Example 43B (5.0 mg) in a mixture of CH ₂ Cl ₂ / trifluoroacetic acid (0.5 ml, 1: 1, v / v) was left at ambient temperature for 2 hours. The solvent was then removed in vacuo to afford the title compound in the form of its trifluoroacetic acid salt (6.0 mg, 100%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 5.65 (br s, 1H), 2.53 (s, 3H), 2.29-2.08 ( m, 2H), 2.05-1.90 (m, 2H), 1.81-1.59 (m, 3H), 1.59-1.44 (m, 2H), 1.41-1, 21 (m, 2H). MS (ESI) m / z 330 (M + H) ⁺ .

Example 39

{4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} methyl acetate

Example 39A

2- (4-ethynyl-4-hydroxycyclohexyl) methyl acetate

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with (4-oxo-cyclohexyl) -acetic acid methyl ester (prepared as described in Suemune, Hiroshi; Oda , Kozo; Sakai, Kiyoshi; Tetrahedron Lett .; 28; 29; 1987; 3373-3376).

Example 39B

{4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} methyl acetate

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 39A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.18 (br s, 2H), 3.58 (s, 3H), 2.53 (s, 3H) 2.27-22.0 (m, 2H), 2.02-1.94 (m, 2H), 1.77-1.65 (m, 3H), 1.58-1.45 (m, 2H), 1.40-1.24 (m, 2H). MS (ESI) m / z 344 (M + H) ⁺ .

Example 40

(1R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] bicyclo [2.2.1] heptane- 2-ol

Example 40A

(1R, 4S) -2-ethynylbicyclo [2.2.1] heptan-2-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with norkamfor.

Example 40B

(1R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] bicyclo [2.2.1] heptane- 2-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 40A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.16 (broad s, 2H), 5.45 (broad s, 1H), 2.51 (s, 3H), 2.42-2.37 (m, 1H), 2.25-2.10 (m, 2H), 2.04-1.92 (m, 1H), 1.80-1.73 ( m, 1H), 1.59-1.45 (m, 1H), 1.39-1.18 (m, 3H). MS (ESI) m / z 284 (M + H) ⁺ .

Example 41

(1R, 2S, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol

Example 41 A

(1R, 2S, 4R) -2-ethynyl-1,7,7-trimethylbicyclo [2.2.1] heptan-2-ol

The target compound was obtained according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A, R - (+) - camphor.

Example 41B

(1R, 2S, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 41A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.23 (br s, 2H), 5.55 (s, 1H), 2.50 (s, 3H) 2.50 (s, 3H), 2.24-2.14 (m, 2H), 1.96-1.83 (m, 3H), 1.78-1.63 (m, 3H), 1 , 54-1.41 (m, 2H), 1.20-1.09 (m, 2H), 1.08 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H ) MS (ESI) m / z 326 (M + H) ⁺ .

Example 42

(1R, 2R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,3,3-trimethylbicyclo [2,2,1] heptan-2-ol

Example 42A

(1R, 2S, 4S) -2-ethynyl-l, 3,3-trimethylbicyclo [2.2.1] heptan-2-ol

The target compound was obtained according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A, (1R) - (-) - fenhon.

Example 42B

(1R, 2R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,3,3-trimethylbicyclo [2,2,1] heptan-2-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 42A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.15 (br s, 2H), 5.30 (s, 1H), 2.52 (s, 3H) 2.02-1.90 (m, 1H), 1.78-1.59 (m, 4H), 1.46-1.31 (m, 1H), 1.19 (s, 3H), 1 14 (s, 3H), 1.12-1.04 (m, 1H), 0.94 (s, 3H). MS (ESI) m / z 326 (M + H) ⁺ .

Example 43

{4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} tert-butyl acetate

Example 43A

2- (4-ethynyl-4-hydroxycyclohexyl) tert-butyl acetate

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with (4-oxo-cyclohexyl) -acetic acid tert-butyl ester (prepared as described in Suemune, Hiroshi ; Oda, Kozo; Sakai, Kiyoshi; Tetrahedron Lett .; 28; 29; 1987; 3373-3376).

Example 43B

{4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} tert-butyl acetate

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 43A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.18 (br s, 2H), 5.65 (s, 1H), 2.50 (s, 3H) , 2.14-2.08 (m, 2H), 2.03-1.94 (m, 2H), 1.77-1.65 (m, 3H), 1.58-1.45 (m, 2H), 1.40-1.28 (m, 2H), 1.39 (s, 9H). MS (ESI) m / z 386 (M + H) ⁺ .

Example 44

(1S, 2S, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,3,3-trimethylbicyclo [2,2,1] heptan-2-ol

Example 44A

(1S, 2S, 4R) -2-ethynyl-1,3,3-trimethylbicyclo [2.2.1] heptan-2-ol

The target compound was obtained according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A, (1S) - (+) - fenhon.

Example 44B

(1S, 2S, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,3,3-trimethylbicyclo [2,2,1] heptan-2-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 44A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.15 (br s, 2H), 5.30 (s, 1H), 2.52 (s, 3H) 2.02-1.90 (m, 1H), 1.78-1.59 (m, 4H), 1.46-1.31 (m, 1H), 1.19 (s, 3H), 1 14 (s, 3H), 1.12-1.04 (m, 1H), 0.94 (s, 3H). MS (ESI) m / z 326 (M + H) ⁺ .

Example 45

(1S, 2R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol

Example 45A

(1S, 2R, 4S) -2-ethynyl-1,7,7-trimethylbicyclo [2.2.1] heptan-2-ol

The target compound was obtained according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A, S - (-) - camphor.

Example 45B

(1S, 2R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 45A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.23 (br s, 2H), 5.55 (s, 1H), 2.50 (s, 3H) 2.50 (s, 3H), 2.24-2.14 (m, 2H), 1.96-1.83 (m, 3H), 1.78-1.63 (m, 3H), 1 , 54-1.41 (m, 2H), 1.20-1.09 (m, 2H), 1.08 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H ) MS (ESI) m / z 326 (M + H) ⁺ .

Example 46

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclopentanol

Example 46A

1- (prop-2-ynyl) cyclopentanol

Magnesium Chips (350 mg, 14.4 mmol) and Hgcl₂ (16 mg, 0.059 mmol) was stirred with 20 ml of anhydrous diethyl ether in a 100 ml round bottom flask. Propargyl bromide (80% in xylene, 2.5 ml, 13.2 mmol) was added. The mixture was stirred for 30 minutes at ambient temperature, after which cyclopentanone (1.0 g, 11.9 mmol) in 10 ml of tetrahydrofuran was added. The resulting mixture was heated under reflux for 2 hours, then allowed to cool to ambient temperature and quenched with a saturated aqueous solution of ammonium chloride (15 ml). The biphasic mixture was extracted with ethyl acetate (50 ml), and the organic layer was washed with brine, dried over Na₂SO_four, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 10% hexanes in ethyl acetate) to give the title compound (800 mg, 54%) as a colorless oil.

Example 46B

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclopentanol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 46A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.15 (br s, 2H), 4.68 (s, 1H), 2.75 (s, 2H) 2.50 (s, 3H); 1.80-1.52 (m, 8H). MS (ESI) m / z 272 (M + H) ⁺ .

Example 47

1 - [(7-amino [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclopentanol

The target compound was prepared according to the procedures described in Example 4B, replacing Example 4A used in Example 4B with commercially available 6-bromo [1,2,4] triazolo [1,5-α] pyrimidin-7-amine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (s, 1H), 8.40 (br s, 2H), 8.32 (s, 1H), 5.34 (s, 1H) 2.50 (s, 3H); 2.07-1.63 (m, 8H). MS (ESI) m / z 244 (M + H) ⁺ .

Example 48

1- [3- (7-amino [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclopentanol

The target compound was prepared according to the procedures described in Example 4B, replacing Example 4A with commercially available 6-bromo- [1,2,4] triazolo [1,5-α] pyrimidin-7-amine, and replacing the 1-ethynylcyclopentanol used in Example 4B, Example 46A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 8.35 (br s, 2H), 8.34 (s, 1H), 4.68 (s, 1H) 2.71 (s, 2H); 2.50 (s, 3H); 1.80-1.53 (m, 8H). MS (ESI) m / z 258 (M + H) ⁺ .

Example 49

(1R, 2S, 4R) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] -1 , 7,7-trimethylbicyclo [2.2.1] heptan-2-ol

Example 49A

(1R, 2S, 4R) -1,7,7-trimethyl-2- (prop-2-ynyl) bicyclo [2.2.1] heptan-2-ol

The target compound was obtained according to the procedures described in Example 46A, replacing the cyclopentanone used in Example 46A, R - (+) - camphor.

Example 49B

(1R, 2S, 4R) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] -1 , 7,7-trimethylbicyclo [2.2.1] heptan-2-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 49A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.14 (br s, 2H), 4.56 (s, 1H), 2.73 (s, 2H) 2.53 (s, 3H), 2.01-1.90 (m, 1H), 1.73-1.59 (m, 2H), 1.52-1.32 (m, 3H), 1 09 (s, 3H), 1.16-1.02 (m, 1H), 0.91 (s, 3H), 0.82 (s, 3H). MS (ESI) m / z 340 (M + H) ⁺ .

Example 50

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclohexanemethyl carboxylate

Example 50A

1- (prop-2-ynyl) cyclohexanemethyl carboxylate

To a solution of diisopropylamine (879 μl, 6.22 mmol) in anhydrous tetrahydrofuran (12 ml) at -40 ° C under nitrogen was added 1.6 M n-butyllithium in hexane (3.9 ml, 6.22 mmol), followed by by adding hexamethylphosphoramide (4 ml). The mixture was cooled to −78 ° C. and a solution of cyclohexanemethyl carboxylate (807 μl, 5.65 mmol) in tetrahydrofuran (4 ml) was added, keeping the temperature below -70 ° C. After 15 minutes, propargyl bromide (80% w / w in xylene, 2.5 ml, 22.6 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 30 minutes, it was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water (× 4), dried over MgSO ₄ , filtered and concentrated to give 900 mg of an intermediate in the form of a light brown oil.

Example 50B

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclohexanemethyl carboxylate

A mixture of Example 4A (28 mg, 0.1 mmol), Example 50A (36 mg, 0.2 mmol), bis (triphenylphosphine) palladium (II) dichloride (3.5 mg, 0.005 mmol), CuI (1 mg, 0.005 mmol) and triethylamine (28 μl, 0.2 mmol) in acetonitrile (500 μl) were heated in a sealed tube under nitrogen at 90 ° C in an oil bath for 3 hours. The resulting mixture was purified by reverse phase HPLC (column C-18, eluting with a gradient 5-100% CH₃CN in 10 mM aqueous solution of ammonium acetate), obtaining the target compound in the form of a light pink solid (8 mg, 24% yield).^oneH NMR (300 MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.10 (s, 2H), 3.67 (s, 3H), 2.48 (s, 3H), 2.73 (s, 2H), 2.00 -2.15 (m, 2H); 1.17-1.68 (m, 8H). MS (ESI) m / z 328 (M + H)⁺.

Example 51

6- [3- (4-methoxyphenoxy) but-1-ynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 50B, replacing Example 50A with 1- (but-3-yn-2-yloxy) -4-methoxybenzene (prepared as described in Harfenist; J. Org. Chem .; 37; 1972; 841). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.28 (s, 2H), 7.05-7.08 (m, 2H), 6.81-6, 92 (m, 2H), 5.27 (q, J = 6.44 Hz, 3H), 3.70 (s, 3H), 2.38 (s, 3H), 1.69 (d, J = 6 44 Hz, 3H). MS (ESI) m / z 324 (M + H) ⁺ .

Example 52

(1R) -3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-in-1-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with commercially available (S) -1-phenyl-2-propin-1-ol. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.28 (br s, 2H), 7.60-7.55 (m, 2H), 7.44- 7.36 (m, 3H), 7.34-7.27 (m, 1H), 6.08 (d, J = 6.1 Hz, 1H), 5.68 (d, J = 6.1 Hz , 1H); 2.50 (s, 3H). MS (ESI) m / z 280 (M + H) ⁺ .

Example 53

(1S) -3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-in-1-ol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with commercially available (R) -1-phenyl-2-propin-1-ol. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.28 (br s, 2H), 7.60-7.55 (m, 2H), 7.44- 7.36 (m, 3H), 7.34-7.27 (m, 1H), 6.08 (d, J = 6.1 Hz, 1H), 5.68 (d, J = 6.1 Hz , 1H); 2.50 (s, 3H). MS (ESI) m / z 280 (M + H) ⁺ .

Example 54

4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylbut-3-yn-1-ol

The target compound was obtained as described in Example 50B, replacing Example 50A with 1-phenyl-3-butyn-1-ol. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 8.09 (s, 2H), 7.20-7.49 (m, 5H), 5.67 (d, J = 4.07 Hz, 1H), 4.75-4.97 (m, 1H), 2.89 (dd, J = 6.27, 1.53 Hz, 2H), 2.35 (s, 3H ) MS (ESI) m / z 294 (M + H) ⁺ .

Example 55

(trans) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclopropaneethyl carboxylate

Example 55A

(trans) -2 - (- 1-hydroxyprop-2-ynyl) cyclopropaneethyl carboxylate

A solution of 2-formyl-1-cyclopropaneethyl carboxylate (mainly trans, 331 μl, 2.5 mmol) in tetrahydrofuran (5 ml) was cooled to -70 ° C. Ethyl magnesium bromide (0.5 M in tetrahydrofuran, 5 ml, 2.5 mmol) was added dropwise to this solution under a nitrogen atmosphere and stirred at -70 ° C for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO_four, filtered and concentrated, obtaining 419 mg of the target compound (yield 100%, crude) in the form of a light yellow oil.

Example 55B

(trans) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclopropaneethyl carboxylate

A mixture of Example 4A (28 mg, 0.1 mmol), Example 55A (20 mg, 0.12 mmol), bis (triphenylphosphine) palladium (II) dichloride (3.5 mg, 0.005 mmol), CuI (1 mg, 0.005 mmol) and triethylamine (28 μl, 0.2 mmol) in acetonitrile (500 μl) were heated in a sealed tube under nitrogen at 90 ° C in an oil bath for 1.5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO_four), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with ethyl acetate) to give the title compound as a white solid (2 mg, 6% yield).^oneH NMR (500 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.26 (s, 2H), 5.67 (dd, J = 13.73, 6.10 Hz, 1H), 4.39-4.65 (m, 1H), 4.07 (q, J = 7.02 Hz, 2H), 2.47 (s, 3H), 1.69-1.86 (m, 2H), 1.19 (t, J = 7 , 02 Hz, 2H), 1.03-1.14 (m, 2H). MS (ESI) m / z 316 (M + H)⁺.

Example 56

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclohexanecarboxylic acid

To a solution of Example 69 (83 mg, 0.2 mmol) in tetrahydrofuran (2 ml) was added tetrabutylammonium fluoride (1M in tetrahydrofuran, 500 μl, 0.5 mmol) at ambient temperature and stirred at ambient temperature for 24 hours. The reaction was quenched with 2n. HCl (3 ml). After 5 minutes, pH ~ 4-5 was adjusted using a saturated solution NaHCO₃, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO_four), filtered and concentrated in vacuo to afford the title compound as an off-white solid (63 mg, 100%).^oneH NMR (300 MHz, DMSO-D₆) δ 12.53 (s, 1H), 8.40 (s, 1H), 8.09 (s, 2H), 2.70 (s, 2H), 2.49 (s, 3H), 2.01 -2.14 (m, 2H); 1.20-1.65 (m, 8H). MS (ESI) m / z 314 (M + H)⁺.

Example 57

1 - [(7-amino-5-ethyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] cyclopentanol

Example 57A

5-ethyl- [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

A mixture of 3-oxopentannitrile (1.0 g, 10.3 mmol) and 3-amino-1,2,4-triazole (0.91 g, 10.8 mmol) in 10 ml of acetic acid was heated in a closed tube at 150 ° C for 24 hours. The reaction mixture was allowed to cool to ambient temperature, and the solvent was removed in vacuo. The solid was removed by filtration. The filtrate partially solidified upon standing at ambient temperature, and the solid was collected by filtration to obtain the desired compound (200 mg, 12% yield).

Example 57B

5-ethyl-6-iodo- [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4A, replacing 5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-7-amine used in Example 4A, Example 57A.

Example 57C

1 - [(7-amino-5-ethyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] cyclopentanol

The target compound was prepared according to the procedures described in Example 4B, replacing Example 4A used in Example 4B with Example 57B. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.44 (s, 1H), 8.12 (br s, 2H), 5.37 (s, 1H), 2.84 (q, J = 7.5 Hz, 2H), 2.05-1.62 (m, 8H), 1.24 (t, J = 7.5 Hz, 3H). (MS (ESI) m / z 272 (M + H) ⁺ .

Example 58

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-phenylprop-2-in-1-one

Example 11 (35 mg, 0.153 mmol) was suspended in 1.0 ml of CH ₂ Cl ₂ . Dess-Martin reagent (100 mg, 0.235 mmol) was then added. The resulting milk mixture was stirred at ambient temperature for 5 hours. The solvent was removed in vacuo, the residue was suspended in a mixture of DMSO / methanol (1.5 ml, 1: 1, v / v) and filtered through celite. The filtrate was purified using reverse phase HPLC (C-18 column, eluting with a gradient of 5-100% CH ₃ CN in 10 mM ammonium acetate (aqueous solution)) to give the desired compound (5 mg, 14%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.84 (br s, 2H), 8.50 (s, 1H), 8.25-8.18 (m, 2H), 7.79- 7.58 (m, 3H); 2.67 (s, 3H). MS (ESI) m / z 278 (M + H) ⁺ .

Example 59

2- {3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxy-1-methylprop-2-ynyl] - 2,2-dimethylcyclobutyl} acetamide

Example 59A

2- (3- (2-hydroxybut-3-yn-2-yl) -2,2-dimethylcyclobutyl) acetamide

To a mixture of Example 29A (84 mg, 0.4 mmol), ammonium chloride (32 mg, 0.6 mmol), O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (154 mg, 0.48 mmol) in N, N-dimethylformamide was added N, N-diisopropylethylamine (348 μl, 2.0 mmol). The reaction mixture was stirred at ambient temperature overnight. It was partitioned between ethyl acetate and saturated NaHCO₃. The organic phase was washed twice with brine, dried (MgSO_four), filtered and concentrated in vacuo to give the intermediate compound in the form of a white solid (50 mg, 60% yield).

Example 59B

2- {3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxy-1-methylprop-2-ynyl] -2,2-dimethylcyclobutyl} acetamide

The target compound was obtained as described in Example 29B, replacing Example 29A with Example 59A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 7.94 (s, 2H), 7.18 (s, 1H), 6.61 (s, 1H), 5 30 (s, 1H), 2.52 (s, 3H), 1.79-2.15 (m, 5H), 1.58-1.75 (m, 1H), 1.42 (s, 3H) ), 1.13 (s, 3H), 1.10 (s, 3H). MS (ESI) m / z 357 (M + H) ⁺ .

Example 60

(1R, 2S, 4R) -2 - [(7-amino-5-ethyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol

The title compound was prepared according to the procedures described in Example 4B, replacing Example 4A with Example 57B, and replacing the 1-ethynylcyclopentanol used in Example 4B with the product of Example 41A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.44 (s, 1H), 8.18 (br s, 2H), 5.57 (s, 1H), 2.83 (q, J = 7.5 Hz, 2H), 2.29-2.14 (m, 1H), 1.96-1.82 (m, 2H), 1.78-1.64 (m, 2H), 1.55 -1.41 (m, 1H), 1.24 (t, J = 7.5 Hz, 3H), 1.18-1.09 (m, 1H), 1.08 (s, 3H), 0, 93 (s, 3H); 0.86 (s, 3H). MS (ESI) m / z 340 (M + H) ⁺ .

Example 61

1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] cycloheptanol

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with commercially available 1-ethynylcycloheptanol. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.15 (br s, 2H), 5.41 (s, 1H), 2.50 (s, 3H) 2.08-1.97 (m, 2H); 1.87-1.76 (m, 2H); 1.71-1.46 (m, 8H). MS (ESI) m / z 286 (M + H) ⁺ .

Example 62

{[[3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-cyclopentylprop-2-ynyl] oxy} acetic acid

To a stirred solution of Example 35B (20 mg, 0.074 mmol) in 0.5 ml of anhydrous N, N-dimethylformamide was added NaH (60%, 4.0 mg, 0.096 mmol). The resulting mixture was stirred for 20 minutes, after which tert-butyl bromoacetate (11 μl, 0.074 mmol) was added, and stirring was continued for 2 hours. The reaction mixture was then partitioned between ethyl acetate (10 ml) and brine (10 ml), the organic layer was dried over MgSO_four, filtered, evaporated to dryness in vacuo. The residue was treated with 1.0 ml of 4N. HCl in 1,4-dioxane for 3 hours. The organic solvent was then removed on a rotary evaporator, and the residue was purified using reverse phase HPLC (column C-18, eluting with a gradient of 5-100% CH₃CN in 10 mM ammonium acetate (aqueous solution)) to give the desired compound (5 mg, 21% yield).^oneH NMR (300 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.15 (broad s, 2H), 4.79-4.60 (m, 2H), 4.34 (d, J = 7.1 Hz, 1H) 2.54 (s, 3H); 2.25-2.15 (m, 1H); 1.81-1.38 (m, 8H). MS (ESI) m / z 330 (M + H)⁺.

Example 63

({1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] cyclopentyl} oxy) acetic acid

The target compound was prepared according to the procedures described in Example 62, replacing Example 35B with Example 4B. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 8.36 (br s, 2H), 6.27-6.23 (m, 1H), 3.91 ( s, 1H), 2.52 (s, 3H), 2.60-2.39 (m, 4H), 1.97-1.86 (m, 4H). MS (ESI) m / z 298 (M-H ₂ O) ⁺ .

Example 64

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-cyclohexylprop-2-in-1-ol

Example 64A

1-cyclohexylprop-2-in-1-ol

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with cyclohexane with carboxaldehyde.

Example 64B

3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-cyclohexylprop-2-in-1-ol

The title compound was prepared as described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with Example 64A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.19 (s, 2H), 5.30 (d, J = 5.09 Hz, 1H), 4.39 -4.24 (m, 1H), 2.52 (s, 3H), 2.01-0.96 (m, 11H). MS (ESI) m / z 286 (M + H) ⁺ .

Example 65

4- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclohexanemethyl carboxylate

Example 65A

4-formylcyclohexanemethyl carboxylate

4-hydroxymethyl-1-cyclohexanecarboxylic acid (1.58 g, 10 mmol) was dissolved in a saturated solution of HCl in methanol (20 ml). This solution was heated in an oil bath (70-80 ° C) for 3 hours. The reaction mixture was concentrated in vacuo and evaporated together with ethyl acetate to give 1.8 g of an oil (> 100%). Half of this charge (~ 5 mmol) in tetrahydrofuran (15 ml) was treated with Dess-Martin periodate (2.8 g, 6.6 mmol) at ambient temperature for 1 hour. The resulting mixture was concentrated and purified by flash chromatography on silica gel (eluting with 20-40% ethyl acetate in Hexane) to give the title compound as a colorless oil (540 mg, 64% yield).

Example 65B

4- (1-hydroxyprop-2-ynyl) cyclohexanemethyl carboxylate

The target compound was prepared according to the procedures described in Example 6A, replacing the tetrahydro-4H-pyran-4-one used in Example 6A with Example 65A.

Example 65C

4- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclohexanemethyl carboxylate

The title compound was prepared as described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with Example 65B. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.00 (s, 2H), 5.33 (d, J = 4.41 Hz, 1H), 4.30 -4.44 (m, 1H), 3.60 (s, 3H), 2.60-2.72 (m, 1H), 2.49 (s, 3H), 1.21-2.15 (m , 9H). MS (ESI) m / z 344 (M + H) ⁺ .

Example 66

4- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclohexanecarboxylic acid

To a solution of Example 65C (26.5 mg, 0.077 mmol) in a mixture of tetrahydrofuran (0.5 ml) / methanol (0.5 ml) was added 2N. NaOH (77 μl, 0.154 mmol). The reaction mixture was stirred at ambient temperature overnight and neutralized with 2n. HCl (0.154 mmol). This mixture was purified by reverse phase HPLC (C-18 column, eluting with a gradient of 5-100% CH ₃ CN in 10 mM ammonium acetate (aqueous solution)) to obtain the target compound in the form of a white solid (10 mg, 40% - exit). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.31 (s, 2H), 5.31 (s, 1H), 4.37 (d, J = 5, 43 Hz, 1H), 2.49 (s, 3H), 2.48-2.50 (m, 1H), 1.26-2.13 (m, 9H). MS (ESI) m / z 330 (M + H) ⁺ .

Example 67

{3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-methyleneprop-2-ynyl] -2,2-dimethylcyclobutyl }acetic acid

Example 67A

2- (3- (but-1-en-3-yn-2-yl) -2,2-dimethylcyclobutyl) acetic acid

To a stirred solution of Example 29A (253 mg, 1.2 mmol) in 5 ml of CH ₂ Cl _{2 was} added triethylsilane (250 μl, 1.6 mmol) followed by trifluoroacetic acid (116 μl, 1.6 mmol). The resulting mixture was stirred at ambient temperature overnight. Volatile organic components were removed in vacuo and the residue was evaporated with toluene (2 × 10 ml). The obtained target compound was used without further purification.

Example 67B

{3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-methyleneprop-2-ynyl] -2,2-dimethylcyclobutyl }acetic acid

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 67A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.86 (br s, 2H), 6.07-5.96 (m, 2H), 2.67- 2.11 (m, 5H), 2.52 (s, 3H), 1.94-1.87 (m, 1H), 1.41 (s, 3H), 1.26 (s, 3H). MS (ESI) m / z 340 (M + H) ⁺ .

Example 68

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclopentanemethyl carboxylate

Example 68A

1- (prop-2-ynyl) cyclopentanemethyl carboxylate

The target compound was prepared according to the procedures described in Example 50A, replacing the cyclohexanemethyl carboxylate with cyclopentane methyl carboxylate.

Example 68B

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclopentanemethyl carboxylate

The title compound was prepared as described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with Example 68A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 8.13 (s, 2H), 3.66 (s, 3H), 2.82 (s, 2H), 2 46 (s, 3H), 1.96-2.17 (m, 2H), 1.54-1.83 (m, 6H). MS (ESI) m / z 314 (M + H) ⁺ .

Example 69

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclohexan-2- (trimethylsilyl) ethyl carboxylate

Example 69A

Cyclohexane-2- (trimethylsilyl) ethyl carboxylate

To a mixture of cyclohexanecarboxylic acid (1.28 g, 10 mmol), 2- (trimethylsilyl) ethanol (1.3 g, 11 mmol), 1-ethyl-3- [3- (dimethylamino) propyl] -carbodiimide hydrochloride (2, 11 g, 11 mmol) in dichloromethane, 4-dimethylaminopyridine (123 mg, 1.0 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 days. It was partitioned between ethyl acetate and 2n. HCl. The organic phase was washed with brine, saturated NaHCO₃saline, dried over MgSO_four, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 0-20% ethyl acetate in hexane) to give the title compound as a colorless oil (1.7 g, 75% yield).

Example 69B

1- (prop-2-ynyl) cyclohexane-2- (trimethylsilyl) ethyl carboxylate

The target compound was obtained as described in Example 50A, replacing the cyclohexanemethyl carboxylate used in Example 50A with Example 69A (39% yield).

Example 69C

1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclohexan-2- (trimethylsilyl) ethyl carboxylate

The target compound was obtained as described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with Example 69B (39% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 8.10 (s, 2H), 4.07-4.20 (m, 2H), 2.70 (s, 2H), 2.47 (s, 3H), 2.00-2.18 (m, 2H), 1.19-1.67 (m, 8H), 0.86-0.99 (m, 2H) , -0.01 (s, 9H). MS (ESI) m / z 414 (M + H) ⁺ .

Example 70

6 - [(4-bromophenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with commercially available 1-bromo-4-ethynylbenzene. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (s, 2H), 8.45 (s, 1H), 7.65 (s, 4H), 2.61 (s, 3H). MS (ESI) m / z 328 (M + H) ⁺ .

Example 71

6 - [(4-chlorophenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-7-amine

The target compound was prepared according to the procedures described in Example 4B, replacing 1-ethynylcyclopentanol used in Example 4B with commercially available 1-chloro-4-ethynylbenzene. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.51 (s, 2H), 8.45 (s, 1H), 7.68 - 7.76 (m, 2H), 7.45-7, 54 (m, 2H); 2.61 (s, 3H). MS (ESI) m / z 283 (M + H) ⁺ .

Example 72

2- {4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] phenyl} -2-methylmethylpropanoate

Example 72A

5-methyl-6 - ((trimethylsilyl) ethynyl) - [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

A mixture of Example 4A (275 mg, 1.0 mmol), ethynyltrimethylsilane (283 μl, 2.0 mmol), bis (triphenylphosphine) palladium (II) dichloride (35 mg, 0.05 mmol), CuI (10 mg, 0, 05 mmol) and triethylamine (279 μl, 2 mmol) in acetonitrile (4 ml) were heated at 90 ° C under an atmosphere of nitrogen for 1 hour. The resulting mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO_four), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with ethyl acetate) to give the title compound as a pale yellow solid (123 mg, 50% yield).

Example 72B

6-ethynyl-5-methyl- [1,2,4] triazolo [1,5-a] pyrimidin-7-amine

A mixture of Example 72A (122 mg, 0.5 mmol), potassium carbonate (138 mg, 1.0 mmol) in a mixture of methanol / tetrahydrofuran / H ₂ O (3 ml / 3 ml / 0.5 ml) was stirred at ambient temperature within 1.5 hours. The reaction mixture was acidified with 1N. HCl. The solid was filtered off, washed with water and ethyl acetate to obtain the desired compound in the form of an off-white solid (35 mg, 40% yield).

Example 72C

2- {4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] phenyl} -2-methylmethylpropanoate

A mixture of Example 72B (17 mg, 0.1 mmol), 2- (4-bromophenyl) -2-methylmethylpropanoate (38 mg, 0.15 mmol), bis (triphenylphosphine) palladium (II) dichloride (3.5 mg, 0.005 mmol), CuI (1 mg, 0.005 mmol) and triethylamine (28 μl, 0.2 mmol) in acetonitrile (500 μl) were heated at 95 ° C in a nitrogen atmosphere for 1 hour. The resulting mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO_four, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with ethyl acetate) to give the title compound as a white solid (16 mg, 45% yield).^oneH NMR (300 MHz, DMSO-d₆) δ 8.44 (s, 3H), 7.64 (d, J = 8.48 Hz, 2H), 7.36 (d, J = 8.48 Hz, 2H), 3.61 (s, 3H ), 2.60 (s, 3H), 1.52 (s, 6H). MS (ESI) m / z 350 (M + H)⁺.

Example 73

1- [4- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) but-3-ynyl] -2-oxocyclopentaneethyl carboxylate

The target compound was prepared according to the procedures described in Example 4B, replacing the 1-ethynylcyclopentanol used in Example 4B with 1-but-3-ynyl-2-oxo-cyclopentanecarboxylic acid ethyl ester (prepared as described in Belotti, D .; Cossy, J .; Pete, JP; Portella, C; J. Org. Chem .; 51; 22; 1986; 4196-4,200). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.18 (br s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 2 87 (t, J = 6.8 Hz, 2H), 2.76-2.68 (m, 2H), 2.58-2.23 (m, 6H), 2.50 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). MS (ESI) m / z 356 (M + H) ⁺ .

It should be understood that the foregoing detailed description and accompanying examples are merely illustrative and should not be construed as limiting the scope of the invention. Various changes and modifications, including but not limited to those related to chemical structures, substituents, derivatives, intermediates, syntheses, compositions and / or methods of using the invention, can be made without departing from the spirit of the present invention and its scope.

Claims (11)

1. The compound having the formula (I)

or its pharmaceutically acceptable salts, in which
R ¹ is hydrogen or alkyl;
R ₂ is hydrogen;
R ³ is monocyclic C ₃ -C ₈ cycloalkyl optionally substituted with 1 or 2 substituents selected from the group consisting of —OR ¹⁰ , —N (R ¹¹ ) (R ¹² ) and - (CR ¹¹ R ¹² ) C (O) OR ¹⁰ ,
bridged monocyclic cycloalkyl, optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C ₁ -C ₆ -alkyl and —OH, wherein the bridged monocyclic cycloalkyl is monocyclic C ₆ -cycloalkyl in which two non-adjacent carbon atoms of a monocyclic ring are connected by an alkylene bridge containing one carbon atom,
phenyl optionally substituted with 1 substituent independently selected from the group consisting of halogen, —OR ¹⁰ , —N (R ¹¹ R ¹² ), - (CR ^e R ^f ) _q —OR ¹⁰ and - (CR ¹¹ R ¹² ) C (O) OR ¹⁰ , a six-membered monocyclic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, wherein said heterocycle may be substituted with 1 substituent selected from the group consisting of —OH,
- (CR ^a R ^b ) _m -R ⁴ , or
-C (O) -R ⁵ ;
m is 1 or 2;
R ^a in each case independently denotes
hydrogen, C ₁ -C ₆ alkyl, halogen-C ₁ -C ₆ alkyl, -OR ^7a , -C (O) OR ^7b or
phenyl optionally substituted with 1 substituent selected from the group consisting of halogen;
R ^b in each case independently represents hydrogen or —OH; or
R ^a and R ^b may together mean = CH ₂ ;
R ⁴ is
C ₁ -C ₆ -alkyl, monocyclic C ₃ -C ₆ -cycloalkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C ₁ -C ₆ -alkyl, oxo, -OR ¹⁰ , - C (O) OR ¹⁰ , C (O) O (trimethylsilylethyl), - (CR ¹¹ R ¹² ) C (O) OR ¹⁰ , - (CR ^e R ^f ) _q -C (O) N (R ¹¹ ) (R ¹² ), G ¹ and = NO (R ¹⁰ ),
bridged monocyclic cycloalkyl, optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C ₁ -C ₆ alkyl and —OH, wherein the bridged monocyclic cycloalkyl is monocyclic C ₆ cycloalkyl in which two non-adjacent carbon atoms of a monocyclic ring are connected by an alkylene bridge containing one carbon atom, phenyl, optionally substituted by 1 or 2 substituents independently selected from the group consisting of C ₁ -C ₆ -alkyl, halogen and G ¹ , or a six-membered monocyclic heterocycle containing two heteroatoms selected from the group consisting of O and N,
provided that when R ⁴ is C ₁ -C ₆ alkyl, then by
at least one R ^a is —OR ^7a ;
R ⁵ in each case independently represents phenyl;
R ^7a in each case independently denotes hydrogen, - (CR ^g R ^h ) _r —C (O) OR ¹³ or G ¹ ,
R ^7b in each case independently represents C ₁ -C ₆ alkyl,
R ¹⁰ in each case independently represents hydrogen, C ₁ -C ₆ -alkyl or - (CR ^g R ^h ) _r -C (O) OR ¹³ ;
R ¹¹ in each case independently represents hydrogen, C ₁ -C ₆ alkyl, —S (O) ₂ —R ^13a or —C (O) N (R ¹³ ) (R ¹⁴ );
R ¹² in each case independently represents hydrogen or C ₁ -C ₆ alkyl;
R ¹³ in each case independently represents hydrogen, C ₁ -C ₆ alkyl or G ¹ ;
R ^13a in each case independently denotes G ¹ ;
R ¹⁴ in each case independently represents hydrogen;
q and r in each case are 1;
R ^e , R ^f , R ^g and R ^h in each case independently represent hydrogen, - and
G ¹ in each case independently represents phenyl, optionally substituted with 1 substituent selected from the group consisting of halogen and —O (C ₁ -C ₆ alkyl),
wherein the halogen is Cl, Br, I or F. 2. The compound according to claim 1 or its pharmaceutically acceptable salt, in which R ³ denotes a monocyclic C ₃ -C ₈ cycloalkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of -OR ¹⁰ , -N ( R ¹¹ ) (R ¹² ) and - (CR ¹¹ R ¹² ) C (O) OR ¹⁰ . 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in which R is a bridged monocyclic cycloalkyl, optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C ₁ -C ₆ alkyl and he. 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in which R ³ is phenyl, optionally substituted with 1 substituent selected from the group consisting of halogen, —OR ¹⁰ , —N (R ¹¹ ) (R ¹² ), - (CR ^e R ^f ) _q -OR ¹⁰ and - (CR ¹¹ R ¹² ) C (O) OR ¹⁰ . 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in which R ³ is a six-membered monocyclic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, wherein said heterocycle may be substituted with 1 substituent selected from the group consisting of -OH. 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ³ is - (CR ^a R ^b ) _m —R ⁴ . 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in which R ³ is —C (O) —R ⁵ . 8. The compound according to claim 1, selected from the group consisting of the following compounds:
6 - [(4-aminophenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;
6- (cyclohexylethynyl) -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;
5-methyl-6- (4-phenylbut-1-ynyl) [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;
1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclopentanol;
1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclohexanol;
4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] tetrahydro-2H-pyran-4-ol;
4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-cyclopentylbut-3-in-2-ol;
4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-phenylbut-3-in-2-ol;
4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1,1,1-trifluoro-2-phenylbut-3-in-2- ol;
3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1,1-diphenylprop-2-in-1-ol;
3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-in-1-ol;
6- (3-cyclohexylprop-1-ynyl) -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;
3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopropyl-1-phenylprop-2-in-1-ol;
6 - [(4-methoxyphenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;
3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1,1-bis (4-chlorophenyl) prop-2-in-1- ol;
5-methyl-6- (3-morpholin-4-yl-3-phenylprop-1-ynyl) [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;
3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (1-methylcyclohexyl) -1-phenylprop-2-in-1- ol;
3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (3,4'-dichloro-1,1'-biphenyl-4 -yl) prop-2-yn-1-ol;
1- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -3- (1,1'-biphenyl-4-yl) -4,4 dimethylpent-1-yn-3-ol;
4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-hydroxy-2-phenylmethylbut-3-inoate;
N- {1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclohexyl} -3-chlorobenzenesulfonamide;
N- {4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] phenyl} -N '- (3-chlorophenyl) urea;
(1R, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2 , 2,1] heptan-2-ol;
(1Z) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] -4-tert-butylcyclohexanone oxime;
4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2- (4-isopropyl-2-methylcyclopentyl) but-3-in-2 -ol;
{[[3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-ynyl] oxy} methyl acetate;
{[[3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-ynyl] oxy} acetic acid;
{2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] phenyl} methanol;
{3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-hydroxy-1-methylprop-2-ynyl] -2 , 2-dimethylcyclobutyl} acetic acid;
4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2-cyclobutylbut-3-in-2-ol;
4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -2- (3-methylcyclobutyl) -but-3-in-2-ol;
5-methyl-6- (3-phenylprop-1-ynyl) [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;
6- (3-cyclopentylprop-1-ynyl) -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;
6 - [(1-aminocyclohexyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;
3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopentylprop-2-in-1-ol;
3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1- (2,4-dichlorophenyl) prop-2-in-1-ol ;
4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-cyclopentyl-2-methylbut-3-in-2-ol;
{4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} acetic acid;
{4 - [{7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} methyl acetate;
(1R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] bicyclo [2.2.1] heptane- 2-ol;
(1R, 2S, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol;
(1R, 2R, 43) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,3,3-trimethylbicyclo [2,2,1] heptan-2-ol;
{4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -4-hydroxycyclohexyl} tert-butyl acetate;
(1S, 2S, 4R) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,3,3-trimethylbicyclo [2,2,1] heptan-2-ol;
(1S, 2R, 4S) -2 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol;
1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclopentanol;
1 - [(7-amino [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) ethynyl] cyclopentanol;
1- [3- (7-amino [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclopentanol;
(1R, 2S, 4R) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] -1 7,7-trimethylbicyclo [2.2.1] heptan-2-ol;
1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) prop-2-ynyl] cyclohexanemethyl carboxylate;
6- [3- (4-methoxyphenoxy) but-1-ynyl] -5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-7-amine;
(1R) -3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-in-1-ol;
(1S) -3- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylprop-2-in-1-ol;
4- (7-amino-5-methyl [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) -1-phenylbut-3-yn-1-ol;
(trans) -2- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclopropaneethyl carboxylate;
1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclohexanecarboxylic acid;
1 - [(7-amino-5-ethyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] cyclopentanol;
3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-phenylprop-2-in-1-one;
2- {3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxy-1-methylprop-2-ynyl] -2,2-dimethylcyclobutyl} acetamide;
(1R, 2S, 4R) -2 - [(7-amino-5-ethyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] -1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol;
1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] cycloheptanol;
{[[3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-cyclopentylprop-2-ynyl] oxy} acetic acid;
({1 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] cyclopentyl} oxy) acetic acid;
3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-cyclohexylprop-2-in-1-ol;
4- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclohexanemethyl carboxylate;
4- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-hydroxyprop-2-ynyl] cyclohexanecarboxylic acid;
{3- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) -1-methyleneprop-2-ynyl] -2,2-dimethylcyclobutyl } acetic acid;
1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclopentanemethyl carboxylate;
1- [3- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) prop-2-ynyl] cyclohexan-2- (trimethylsilyl) ethyl carboxylate;
6 - [(4-bromophenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-7-amine;
6 - [(4-chlorophenyl) ethynyl] -5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-7-amine;
2- {4 - [(7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) ethynyl] phenyl} -2-methylmethylpropanoate; and
1- [4- (7-amino-5-methyl [1,2,4] triazolo [1,5-α] pyrimidin-6-yl) but-3-ynyl] -2-oxocyclopentaneethyl carboxylate; or a pharmaceutically acceptable salt thereof. 9. The use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disorder selected from the group consisting of type 2 diabetes, obesity, elevated plasma triglycerides, metabolic syndrome, non-alcoholic steatohepatitis and non-alcoholic liver obesity. 10. A pharmaceutical composition for inhibiting the enzymes diacylglycerol 0-acyltransferase type 1 (DGAT-1), comprising a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable carrier. 11. The use of the pharmaceutical composition of claim 10 for the manufacture of a medicament for treating a disorder selected from the group consisting of type 2 diabetes, obesity, elevated plasma triglycerides, metabolic syndrome, non-alcoholic steatohepatitis and non-alcoholic liver obesity.