KR100373993B1 - Benzocycloalkylazorethion Derivatives as Dopaminebeta-hydroxylase Inhibitors - Google Patents

Abstract

The present invention provides a compound of formula (I) which is a dopamine β-hydroxylase inhibitor and its pharmaceutically acceptable salts, isomers and mixtures of these isomers; And a method of using and preparing the benzocycloalkylazorethione compound:

[Formula I]

In the above formula,

n is 0, 1 or 2;

t is 0, 1, 2 or 3;

R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy;

R ² is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (a), (b) and (c):

The benzocycloalkyl moiety of the compound is indanyl, 1,2,3,4-tetrahydronaphthalenyl and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, wherein benzo is optionally 1 To two substituents);

The azorethione moiety of the compound is 2-thioxo-2,3-dihydro-1H-imidazol-3-yl, 5-thioxo-4,5-dihydro-1H- [1,2,4] Triazol-4-yl and 5-thioxo-4,5-dihydro-1H- [1,2,4] triazol-1-yl, which are optionally substituted with 1 to 3 substituents .

Description

Benzocycloalkylazorethion Derivatives as Dopamine Beta-hydroxylase Inhibitors

Dopamine is a catecholamine neurotransmitter found primarily in the central nervous system with specific dopaminergic receptors. Norepinephrine is a circulating catecholamine that acts as an adrenergic receptor isolated from the peripheral nervous system. Dopamine β-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine and is found in both the central nervous system and peripheral sympathetic neurons. Inhibition of DBH simultaneously increases the level of dopamine by blocking the metabolism of dopamine and decreases the level of norepinephrine by blocking the synthesis of norepinephrine. Thus, drugs that inhibit DBH are useful for treating diseases associated with reduced dopamine levels (eg, Parkinson's disease), and diseases associated with elevated norepinephrine levels (eg, hypertension, congestive heart failure, etc.). It is useful for treating. Fusaric acid, a DBH inhibitor, reduces the tremor and other abnormalities associated with Parkinson's disease. Fusaric acid also lowers blood pressure in hypertensive patients; The release of Norrepinephrine from the adrenal gland and thereby poorness is also observed. Other more selective DBH inhibitors are known but often have drawbacks.

The present invention relates to novel benzocycloalkylazorethion dopamine β-hydroxylase inhibitors and methods of using and preparing the inhibitors.

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts, individual isomers and mixtures of these isomers:

[Formula I]

In the above formula,

n is 0, 1 or 2;

t is 0, 1, 2 or 3;

R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy;

R ² is bonded at the α-, β- or γ- position and is a group selected from the following general formulas (a), (b) and (c):

R ⁴ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ (where q is 0, 1, 2, 3 or 4, R ⁹ is carboxy, (C _1-4 ) alkyloxycarbonyl , Carbamoyl, or aryl and heteroaryl (these groups are optionally hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazo-5-yl, carboxy and (C _1-4 ) alkyloxycarbo Is further substituted with 1 or 2 substituents independently selected from yl), and R ⁵ is hydro or -NHR ¹⁰ , wherein R ¹⁰ is hydro, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _{1- 4} ) Groups selected from alkanoyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, aroyl or heteroaroyl (wherein the aroyl or heterocyclic aroyl thing optionally hydroxy, (C _1-4) al Oxy, cyano, 1H- tetrazol-5-yl, carboxy and (C _1-4) is further substituted with one to two substituents independently selected from alkyloxycarbonyl) or -C (NR ¹¹⁾ NHR ¹² Wherein R ¹¹ and R ¹² are independently hydro, acetyl or t-butoxycarbonyl; or

R ⁴ and R ⁵ are each hydro and R ³ is —NHR ¹⁰ , wherein R ¹⁰ is as defined above; or

R ⁵ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁴ is (C _1-4 ) alkyl, di (C _{1- 4} ) alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, formyl, 1-hydroxy (C _1-4 ) alkyl or -CH ₂ NHR ¹³ , wherein R ¹³ is hydro, (C _1-4 ) alkyl, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkyl Carbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, carboxy (C _1-4 ) alkyl, (C _1-4 ) alkyloxycarbonyl (C _1-4 ) alkyl, carbamoyl (C _1-4 ) alkyl, aroyl, hetero A group selected from aroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl (the aroyl or heteroaroyl is optionally hydroxy, (C _1-4 ) alkyloxy, cyano, 1H Tetrazol-5-day, carboxy Or (C _1-4) is further substituted with one to two substituents independently selected from alkyloxycarbonyl) or -C (NR ¹¹⁾ NHR ¹² (wherein, R ¹¹ and R ¹² are as defined above)) Or; or

R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁴ is hydro, (C _1-4 ) alkyl or —C (O) R ¹⁴ , wherein , R ¹⁴ is amino, hydroxy, (C _1-4 ) alkyloxy, 2- (dimethylamino) ethylamino, 4-methylpiperazin-1-yl, 2- (dimethylamino) ethylmercapto, 4- ( Methylsulfonylamino) anilino or 1H-tetrazol-5-ylamino), and R ⁵ is cyano, hydroxymethyl, 1H-tetrazol-5-yl, 4,5-dihydroimidazole-2 -Yl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1 -Ylmethyl, -C (O) R ¹⁴ , wherein R ¹⁴ is as defined above, -C (NH) NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are independently hydro, (C _1-4 ) alkyl or trifluoro (C _1-4) alkyl) or -CH ₂ NR ¹⁰ R ¹⁷ (wherein, R ¹⁰ is as defined above, R ¹⁷ is hydro or (C _1-4) Kill a) or; or

R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above, and R ⁴ and R ⁵ are independently di (C _1-4 ) alkylaminomethyl, piperidine -1-ylmethyl, morpholin-4-ylmethyl or hydroxymethyl;

R ⁶ is hydro, 2-carboxyethyl, 2-carbamoylethyl or 2- (C _1-4 ) alkyloxycarbonylethyl;

R ⁷ is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperidin-1-ylmethyl, 4- (C _1-4 ) alkylpipepe Rajin-1-ylmethyl or —CH ₂ NR ¹⁰ R ¹⁷ wherein R ¹⁰ and R ¹⁷ are as defined above;

R ⁸ is hydro, 2-carboxyethyl, 2-carbamoylethyl, 2- (C _1-4 ) alkyloxycarbonylethyl or —NHR ¹⁰ , wherein R ¹⁰ is as defined above.

Another aspect of the invention is a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient mixed with a compound of formula (I) or each isomer thereof, a mixture of isomers thereof, or a pharmaceutically acceptable salt or salt thereof in a therapeutically effective amount .

Another aspect of the invention comprises administering to a animal in need of such treatment a therapeutically effective amount of a compound of formula (I), or each isomer thereof, a mixture of isomers, or a pharmaceutically acceptable salt or salts thereof. It is a method for treating diseases that can be alleviated by inhibiting β-hydroxylase.

Another aspect of the invention is a process for the preparation of compounds of formula (I), which is disclosed in the detailed description of the invention.

Another aspect of the invention relates to a compound of formula (II): and a pharmaceutically acceptable salt, each isomer, and a mixture of isomers thereof:

[Formula II]

In the above formula,

n is 0, 1 or 2;

t is 0, 1, 2 or 3,

R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy;

R ¹⁸ is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (d), (e) and (f):

R ²⁰ is hydro, R ¹⁹ is hydro or — (CH ₂ ) _q R ⁹ (where q is 0, 1, 2, 3 or 4, R ⁹ is carboxy, (C _1-4 ) alkyloxycarbonyl , Carbamoyl or aryl and heteroaryl (this group is optionally hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazo-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl Is further substituted with 1 or 2 substituents independently selected from: and R ²¹ is -NR ²⁵ R ²⁶ , wherein R ²⁵ is hydro or (C _1-4 ) alkyl, and R ²⁶ is L-alanyl, L-arginyl, L-asparaginyl, L-α-aspartyl, L-β-aspartyl, L-cysteinyl, L-glutaminyl, L-α-glutamyl, L -γ-glutamyl, N- (C _1-4 ) alkanoyl-L-α-glutamyl,-(C _1-4 ) alkanoyl-L-γ-glutamyl, glycyl, L-histidyl, L Isoleucine, L-leucine, L-lysyl, L-methionyl, L-ornithynyl, L-phenylalanyl, L-prolyl, L-seryl, L-threonyl, L-tryptophil , L-tyrosyl, L-valyl, 1-amino-cyclopropylcarbonyl, 1-aminocyclobutylcarbonyl, 1-aminocyclopentylcarbonyl or 1-aminocyclohexylcarbonyl); or

R ²⁰ and R ²¹ are each hydro and R ¹⁹ is —NR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ are as defined above; or

R ²¹ is hydro, R ¹⁹ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above, and R ²⁰ is —CH ₂ NR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ is as defined above; or

R ¹⁹ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ²⁰ is hydro, (C _1-4 ) alkyl or —C (O) R ¹⁴ , wherein , R ¹⁴ is amino, hydroxy (C _1-4 ) alkyloxy, 2- (dimethylamino) ethylamino, 4-methylpiperazin-1-yl, 2- (dimethylamino) ethylmercapto, 4- (methyl Sulfonylamino) anilino or 1H-tetrazol-5-ylamino), R ²¹ is -CH ₂ NR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ are as defined above;

R ²² is hydro, 2-carboxyethyl, 2-carbamoylethyl or 2- (C _1-4 ) alkyloxycarbonylethyl;

R ²³ is —CH ₂ NR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ are as defined above;

R ²⁴ is —NR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ are as defined above.

Another aspect of the invention is a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients mixed with a compound of Formula II or each isomer thereof, a mixture of isomers thereof, or a pharmaceutically acceptable salt or therapeutically effective amount thereof. .

Another aspect of the invention comprises administering to a animal in need of such treatment a therapeutically effective amount of a compound of formula (II), or each isomer thereof, a mixture of isomers, or a pharmaceutically acceptable salt or salts thereof. It is a method for treating diseases that can be alleviated by inhibiting β-hydroxylase.

Another aspect of the invention is a process for the preparation of compounds of formula II, which is disclosed in the detailed description of the invention.

Another aspect of the present invention relates to a compound of formula III and a pharmaceutically acceptable salt thereof, each isomer and a mixture of these isomers:

[Formula III]

In the above formula,

n is 0, 1 or 2,

t is 0, 1, 2 or 3,

R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy;

R ²⁷ is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (g), (h) and (i):

R ⁴ is hydro, R ³ is hydro or —NHR ¹⁰ where R ¹⁰ is hydro, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carbamoyl, (C _{1- 4} ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) alkylamino (C _{1- 4} ) a group selected from alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, aroyl or heteroaroyl (wherein aroyl or heteroaroyl is optionally hydroxy, (C _1-4) ) Is further substituted with 1 to 2 substituents independently selected from alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl) or -C (NR ¹¹ ) NHR ¹² , wherein R ¹¹ and R ¹² are independently hydro, acetyl or t-butoxycarbonyl; or

R ⁵ is hydro, R ⁴ is (C _1-4 ) alkyl, di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, 1-hydroxy ( C _1-4 ) alkyl or —CH ₂ NHR ¹³ wherein R ¹³ is hydro, (C _1-4 ) alkyl, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carba Moyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) Alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, carboxy (C _1-4 ) alkyl, (C _1-4 ) alkyloxycarbonyl (C _1-4 ) alkyl, carbamoyl (C _1-4 ) alkyl, aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl group (Aroyl, Heteroaroyl, aryl and heteroaryl are optionally independently selected from hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl 1 to 2 substitutions Is further substituted) or -C (NR ¹¹ ) NHR ¹² , wherein R ¹¹ and R ¹² are as defined above; or

R ⁴ is hydro, (C _1-4 ) alkyl or —C (O) R ¹⁴ wherein R ¹⁴ is amino, hydroxy, (C _1-4 ) alkyloxy, 2- (dimethylamino) ethylamino, 4 -Methylpiperazin-1-yl, 2- (dimethylamino) ethylmercapto, 4- (methylsulfonylamino) anilino or 1H-tetrazol-5-ylamino), R ⁵ is hydroxymethyl, 1H-tetrazol-5-yl, 4,5-dihydroimidazol-2-yl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazine -1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1-ylmethyl, -C (O) R ¹⁴ , wherein R ¹⁴ is as defined above, -C (HH) NR ¹⁵ R ¹⁶ wherein R ¹⁵ and R ¹⁶ are independently hydro, (C _1-4 ) alkyl or trifluoro (C _1-4 ) alkyl) or —CH ₂ NR ¹⁰ R ¹⁷ , wherein R ¹⁰ is as defined above And R ¹⁷ is hydro or (C _1-4 ) alkyl); or

R ⁴ and R ⁵ are independently di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl or hydroxymethyl;

R ⁶ is hydro, 2-carboxyethyl, 2-carbamoylethyl or 2- (C _1-4 ) alkyloxycarbonylethyl;

R ⁷ is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperidin-1-ylmethyl, 4- (C _1-4 ) alkylpipepe Rajin-1-ylmethyl or —CH ₂ NR ¹⁰ R ¹⁷ wherein R ¹⁰ and R ¹⁷ are as defined above;

R ²⁸ is (C ^2-6 ) alkyl {where alkyl is —N (R ²⁹ ) ₂ , —C (O) OR ³⁰ , —PO (OR ³⁰ ) ₂ , —SO ₃ R ³⁰ , SO ₂ NHR ³⁰ and Further substituted with one or two substituents independently selected from -OR ³⁰ , wherein each R ²⁹ is independently hydro, acetyl or trifluoroacetyl, and each R ³⁰ is independently hydro or (C _1-5 ) Alkyl)}.

Another aspect of the invention is a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient mixed with a compound of Formula III or each isomer thereof, a mixture of isomers thereof, or a pharmaceutically acceptable salt or therapeutically effective amount thereof. .

Another aspect of the invention comprises administering to a animal in need of such treatment a therapeutically effective amount of a compound of formula III, or each isomer thereof, a mixture of isomers, or a pharmaceutically acceptable salt or salts thereof. It is a method of treating diseases by alleviating by inhibiting β-hydroxylase.

Another aspect of the invention is a method for preparing a compound of formula III, which is disclosed in the detailed description of the invention.

Another aspect of the invention is a compound of the general formula: (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine:

Another aspect of the invention relates to a process for the synthesis of (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine, which is disclosed in the detailed description of the invention. .

Justice

As used herein, "alkyl" refers to a straight or branched saturated hydrocarbon radical having 1 to the indicated carbon atom number (e.g., (C _1-4 ) alkyl is methyl, ethyl, prop-1-yl , Prop-2-yl, but-1-yl, but-2-yl, 2-methylpropyl and 1,1-dimethylethyl radical).

"Trifluoroalkyl" means an allyl radical as defined above having from 1 to the indicated carbon atom number and comprising a trifluoromethyl group (eg, trifluoro (C _1-4 ) alkyl is trifluoro Methyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1--yl, 1,1,1-trifluoroprop-2-yl and the like).

"Alkoxyoxy" means an -OR radical, where R is alkyl having from 1 to the indicated carbon atom number (eg, (C _1-4 ) alkyloxy is methoxy, ethoxy, prop-1- Yloxy, prop-2-yloxy, but-1-yloxy, but-2-yloxy, 2-methylprop-1-yloxy and 2-methylprop-2-yloxy) .

“Aryl,” as used in aryl or aryl (C _1-4 ) alkyl, is an organic radical derived from an aromatic hydrocarbon having 6 to 14 carbon atoms, such as a monocycle or a condensed carbocycle aromatic ring (eg, phenyl , Naphthyl, anthracenyl, phenanthrenyl and the like), and may be optionally further substituted with 1-2 substituents independently selected from halo and cyano.

"Aroyl" means the radical -C (O) R, where R is aryl as defined above (eg, benzoyl, etc.).

“Heteroaryl” as used in heteroaryl or heteroaryl (C _1-4 ) alkyl contains 5 to 14 atoms, of which 1 to 5 atoms are selected from aromatic hydrocarbons which are heteroatoms selected from N, O or S As the organic radicals derived, monocyclic or condensed carbocycle aromatic rings (eg thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, benzo [b] thienyl, iso Benzofuranyl, furinyl, isoquinolinyl, pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, and the like), and 1 to 2 independently selected from halo and cyano Optionally substituted with three substituents.

"Heteroaryl" means a radical -C (O) R, wherein R is heteroaryl as defined above (eg, nicotinoyl, 2-furanoyl, picolinoyl, etc.).

"Carbamoyl" as used in carbamoyl, (C _1-4 ) alkylcarbamoyl, di ((C _1-4 ) alkylcarbamoyl or carbamoyl (C _1-4 ) alkyl means aminocarbonyl. .

“Alkanoyl” means a radical —C (O) R having from 1 to the indicated carbon atom number (eg, formyl, acetyl, propionyl, butyryl, etc.).

"Halo" means fluoro, chloro or bromo.

"Leaving group" has the meaning commonly associated with it in synthetic organic chemistry, i.e. represents an atom or group substitutable under alkylation conditions, and halo and alkane- or arerensulfonyloxy such as mesyloxy, ethanesulfonyloxy, benzenesul Phonyloxy, trifluoromethanesulfonyloxy, tosyloxy and the like.

"Animal" includes non-human mammals such as humans, dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, and deer, and non-mammals such as poultry and the like.

"Disease" includes any unhealthy condition of an animal and a portion thereof, and refers to an unhealthy condition that is caused or accompanied by a medical or veterinary treatment performed on the animal, i. Include.

"Pharmaceutically acceptable" means that it is generally useful for preparing pharmaceutical compositions that are safe, nonpolar, and which are undesirable from a biological or any aspect, and include those useful in veterinary as well as human pharmaceutical use.

"Pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable and has the desired pharmacological activity as defined above. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, formic acid, acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentapropionic acid, glycolic acid, pyruvic acid, lactic acid, mal Lonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene -1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, lauryl sulfuric acid, gluconic acid And organic acids such as glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. It includes acid addition salts.

Pharmaceutically acceptable salts also include base addition salts which are formed when the acidic protons present can react with an inorganic base or an organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

A "therapeutically effective amount" means an amount that is effective enough to treat the disease when administered to treat the disease.

“Treatment” of a disease includes (1) preventing the disease from occurring in an animal that may already be exposed to the disease but has not yet experienced or exhibited the symptoms of the disease; (2) inhibiting the disease, ie stopping the development of the disease; Or (3) alleviating the disease, ie, reducing the disease.

Compounds of formula (I) wherein R ³ , R ⁵ or R ⁸ are amino or R ⁴ , R ⁵ or R ⁷ are aminomethyl can be reacted with amino acids to produce compounds of formula (II). Suitable amino acids are L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamine, L-glutamic acid, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine , L-methionine, L-ornithine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine or L-valine and 1-amino-1-cyclopropanecarboxylic acid, 1- Achiral cycloamino acids such as amino-1-cyclobutanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid (cycloleucine) or 1-amino-1-cyclohexanecarboxylic acid. Amino acid groups impart hydrophilicity to molecules. Hydrophilicity increases the water solubility of the molecule. The amide bond is then degraded by in vivo proteolytic reactions. Thus, the compound of formula II is a water soluble prodrug for a compound of formula I wherein R ³ , R ⁵ or R ⁸ is amino or R ⁴ , R ⁵ or R ⁷ is aminomethyl.

Compounds of formula (I) wherein R ³ , R ⁵ or R ⁸ are hydro are (C _2-6 ) alkyl {where alkyl is —N (R ²⁹ ) ₂ , —C (O) OR ³⁰ , —PO (OR ³⁰ ) _Is further substituted with one or two substituents independently selected from ₂ , -SO ₃ R ³⁰ , SO ₂ NHR ³⁰ , -SO ₂ NHR ³⁰ and -OR ³⁰ , wherein each R ²⁹ is independently hydro, acetyl or tri Fluoroacetyl, and each R ³⁰ is independently hydro or (C _1-5 ) alkyl) to form a dithio bond. Substituted alkyl groups impart hydrophilicity to the molecule. Hydrophilicity increases the water solubility of the molecule. Dithio bonds are then degraded by chemical, enzymatic or metabolic conversion in vivo. Thus, the compound of formula III is a water soluble prodrug for a compound of formula I wherein R ³ , R ⁵ or R ⁸ is hydro.

Compounds of formulas (I), (2) and (3) are benzocycloalkylazorethions in which the benzocycloalkyl moiety of the molecule is of the general formula:

(1) The group of the following general formula wherein n is 0 and the monovalent carbon is at the 1- or 2-position (ie α- or β-position) is optionally substituted indan-1-yl or indan-2- Each is called work:

(2) groups of the following general formula where n is 1 and monovalent carbon is in the 1- or 2-position (ie, α- or β-position) are each optionally substituted 1,2,3,4-tetra Hydronaphthalen-1-yl or 1,2,3,4-tetrahydronaphthalen-2-yl:

And (3) groups having the following general formula wherein n is 2 and monovalent carbon is at the 5-, 6- or 7-position, respectively, is optionally substituted 6,7,8,9-tetrahydro-5H-benzo Cyclohepten-5-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl or 6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl.

The monovalent carbon of the benzocycloalkyl group may be a chiral center. Thus, the compounds of formula (I) and the particular compounds used in their synthesis may exist as one of the pairs of enantiomers with opposite chirality or as mixtures of these enantiomers. Compounds of formulas (II) and (3) each contain one or two chiral centers. Compounds of formulas (II) and (3) having two chiral centers have two pairs of enantiomers (ie, four diastereomers) and may exist as any one of these enantiomers or as a mixture thereof. The enantiomers are characterized by the absolute configuration of their chiral centers and are described as R-batch or S-batch by the rules of Cahn, Ingold and Prelog. When two chiral cores exist, the coordination of each chiral center is appropriately denoted by R or S. Conventions for stereochemical nomenclature, methods for determining stereochemistry, and methods for separating stereoisomers are known in the art (eg, "Advanced Organic Chemistry", 3rd Ed., March, Jerry, John Wiley & Sons, New York, 1985). Unless stated otherwise, examples, descriptions, or naming of specific chiral compounds of Formulas (I), (II), (III), (1-6), (8-32), (44-46), and (48) in the specification or claims refer to each and every enantiomer It is intended to include mixtures, racemates or other mixtures.

The azorethione moiety (ie, the R ² , R ¹⁸ and R ²⁷ groups of formulas I, II and III, respectively) of the molecule is an imidazole rethion or triazorethion group. For example, R ² is specifically defined as follows:

(1) the group of the following general formula (a):

1,3-dihydroimidazole-2-thione when forming a major name, and 2-thioxo-2,3-dihydro-1H-imidazolyl when forming a prefix to a main name .

(2) the group of the following general formula (b):

2,4-dihydro [1,2,4] triazole-3-thione when forming the principal name, 5-thioxo-4,5-dihydro-1H- when used as a prefix to the principal name It is called [1,2,4] triazolyl.

(3) the group of the following general formula (c):

2,4-dihydro [1,2,4] triazole-3-thione when forming the principal name, 5-thioxo-4,5-dihydro-1H when forming a prefix to the principal name -[1,2,4] triazolyl.

Certain R ² and R ¹⁸ groups are tautomeric equilibrated between thioxo and mercapto tautomers (ie the group of formula (a) wherein R ³ is hydro). Compounds of formula (I) or (II) containing a group that may exist as one of the tautomers are named, illustrated, or otherwise described herein as thion or thioxo substituted derivatives. However, it will be understood that mercapto tautomers are also included in this naming, example, and description.

Compounds of formulas (I), (II) and (III) are named by AUTONOM version 1.0 by Beilstein-Institut and Springer-Verlag Berlin Heidelberg, a fully automatic computerized system for naming the IUPAC system directly from the structural diagrams of organic compounds. For example, a compound of Formula I wherein n is 1, t is 0, R ² is bonded at the β-position and is a group of general formula (a), i.e., wherein R ⁵ is aminomethyl 5-aminomethyl-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydro-imidazole-2-thione, 3- when R ⁵ is carboxy It is named (1,3,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid:

Compound of formula (I) wherein n is 1, t is 0, R ² is bonded at the β-position and is a group of general formula (b) is 5-aminomethyl-4- (1,2 when R ⁶ is aminomethyl; , 3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3-thione.

Compound of formula (I) wherein n is 1, t is 0, R ² is bonded at the β-position and is a group of formula (c) is 4-amino-2- (1,2,3 when R ⁷ is amino , 4-tetrahydro-naphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3-thione and when R ⁷ is acetylamino N- [1- (1 , 2,3,4-tetrahydronaphthalen-2-yl) -5-thioxo-4,5-dihydro [1,2,4] triazol-4-yl] acetamide.

wherein n is 1, t is 0, R ¹⁸ is bonded to the β-position and R ²¹ of formula (d) is L-α-aspartylaminomethyl, i.e. -N- [3- (1,2,3,4-tetrahydronaphthalene-2S-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] succinic acid do:

n is 1, t is 0, R ²⁷ is bonded to the β-position and is a group of formula (g) wherein R ⁵ is aminomethyl and R ²⁸ is 2-amino-2-carboxyethyl A compound of formula (III) having the general formula: 2-amino-3- [5-aminomethyl-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1H-imidazol-2-yldi Sulfanyl] propionic acid is named:

Currently Preferred Embodiments:

While the range of compounds presented by the present invention is disclosed in the Summary of the Invention, certain compounds of formulas (I), (II) and (III) are preferred. Preferred compounds of formula (I) are represented by formula (I) wherein R ² is of formula (a). Preferred compounds of formula (a) are those in which R ² is bonded to the benzocycloalkyl moiety of the molecule at the β-position, preferably n is 0 or 1, R ⁵ is di (C _1-4 ) alkylaminomethyl, Pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1-ylmethyl Or —CH ₂ NHR ¹⁰ . Most preferred compounds of formula (a) are those in which R ² is bonded at the β-position, n is 0, t is 2, each R ¹ is preferably fluoro at 5- and 7-positions, R ⁵ is —CH ₂ NHR ¹⁰ , wherein R ¹⁰ is hydro, carbamoyl or (C _1-4 ) alkanoyl, preferably acetyl, especially their S-enantiomers.

Compounds of formula I, wherein R ² is of formula (b), are represented by compounds of formula I (b). Preferred compounds of formula (b) are those in which R ² is bonded at the β-position, preferably n is 0 or 1 and R ⁷ is di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-yl Methyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1-ylmethyl or -CH ₂ NHR ¹⁰ phosphorus will be. Most preferred compounds of formula (b) are those wherein R ² is bonded at the β-position, n is 0, t is 2, each R ¹ is preferably fluoro at the 5- and 7-positions, R ⁶ is di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1-ylmethyl or —CH ₂ NHR ¹⁰ , in particular their S-enantiomers.

Compounds of formula I, wherein R ² is of formula (c), are represented by compounds of formula I (c). Preferred compounds of formula I (c) are those in which R ² is bonded at the β-position, preferably n is 0 or 1 and R ⁸ is —NH ₂ . Most preferred compounds of formula (c) are those in which R ² is bonded at the β-position, n is 0, t is 2, each R ¹ is preferably fluoro at the 5- and 7-positions, R ⁶ is —NH ₂ , especially their S-enantiomers.

Preferred compounds of formula II are those wherein R ¹⁸ is a group of formula (d) and is bonded at the β-position, preferably n is 0 or 1 and R ²¹ is —CH ₂ NHR ²⁶ . Most preferably, R ¹⁸ is a group of formula (d) and is bonded at the β-position, n is 0 or 1, t is 2, and each R ¹ is preferably fluorine at 5- or 7-positions. And R ²¹ is —CH ₂ NHR ²⁶ , wherein R ²⁶ is preferably arginyl, α-aspartyl, β-aspartyl, histidyl or ornitinyl.

Preferred compounds of formula III are those in which R ²⁷ is a group of general formula (g) and is bonded at the β-position, preferably n is 0 or 1 and R ⁵ is di (C _1-4 ) alkylaminomethyl, pyrroli Din-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1-ylmethyl or- CH ₂ NHR ¹⁰ . Most preferably, R ²⁷ is a group of formula (g) and is bonded at the β-position, n is 0 or 1, t is 2, and each R ¹ is preferably fluorine at 5- or 7-positions. And R ⁵ is di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl , 4- (C _1-4 ) alkylpiperazin-1-ylmethyl or -CH ₂ NHR ¹⁰ and R ²⁸ is ethyl, 1,1-dimethylethyl and propyl (these groups include carboxy, methoxycarbonyl, amino And 1-2 substituents independently selected from trifluoroacetylamino), and preferably (R) -2-amino-2-methoxycarbonylethyl, (R) -2-amino 2-carboxyethyl, (R) -2-trifluoroacetylamino-2-methoxycarbonylethyl, 2-aminoethyl, (S) -2-amino-2-carboxy-1,1, -dimethylethyl Or 3-amino-3-carboxy-prop-1-yl. .

Pharmacology and uses

Compounds of the invention are inhibitors of dopamine β-hydroxylase. Thus, the compounds of the present invention are useful for treating diseases ameliorable by inhibition of dopamine β-hydroxylase. For example, as long as the compounds of the present invention inhibit norepinephrine biosynthesis, they are useful for treating diseases caused or exacerbated by sympathetic nervous conditions. In particular, since the compounds of the present invention are peripheral vasodilators, they are useful as post-load reducing agents in treating congestive heart failure. Moreover, the compounds of the present invention reduce the levels of norepinephrine, thus alleviating the adverse effects on the myocardial layer produced by sympathetic nervous activity in congestive heart failure. Thus, the compounds of the present invention treat congestive heart failure because they reduce cardiac function by initially improving cardiovascular output by reducing postload and delaying cardiac function by decreasing the level of norepinephrine in myocardial tissue. Useful for

Dopamine β-hydroxylase inhibitory properties of test compounds can be determined by in vitro assays known in the art that rely on DBH-catalytic conversion of thyrine to octopamine and inhibition of DBH activity by test compounds, It is specifically described in Example 63. Dopamine β-hydroxylase inhibitory properties of test compounds may also be determined by in vivo assays known in the art that depend on dopamine and norepinephrine tissue concentrations and the effect of the test compound on it (eg, BA Berkowitz et al., 1988, J. Pharm. Exp Ther. 245, 850-857), Example 64. The blood pressure lowering properties of the test compounds are determined by in vivo assays using spontaneous hypertension rats, which are described in detail in Example 65.

Dosing and Pharmaceutical Compositions

In general, the compounds of the present invention will be administered in a therapeutically effective amount in any useful and acceptable method known in the art, and will be administered alone or as a mixture with other compounds of the invention or as a mixture with other therapeutic agents. . The therapeutically effective amount can vary greatly depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compound used and other factors. The therapeutically effective amount ranges from about 0.1 mg (0.1 mg / kg body weight) to 30 mg / kg body weight per day. Preferably the therapeutically effective amount is about 0.1 to 10 mg / kg / day. Therefore, the therapeutically effective amount for 70 kg of human is 7.0 to 2100 mg / day, preferably 70 to 700 mg / day.

Those skilled in the art of treating the disease will be able to reliably determine the therapeutically effective amount of a compound of the present invention according to personal knowledge and the disclosure herein without unnecessary experimentation. In general, the compounds of the present invention will be administered as pharmaceutical compositions in one of the following routes: oral, systemic (eg, through the skin, intranasally or by suppository) or parenteral (eg, intramuscularly, Intravenously or subcutaneously). The compositions may take the form of tablets, pills, capsules, semisolids, powders, delayed release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition, and are generally mixed with one or more pharmaceutically acceptable excipients Consisting of the compounds of the present invention. Acceptable excipients are nontoxic administration aids and do not adversely affect the therapeutic effect of the compound of formula (I). Such excipients can be any of solids, gases, semisolids, and for aerosol compositions can be gaseous excipients generally known in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dry skim milk, and the like. do. Liquid and semisolid excipients can be selected from water, ethanol, glycerol, propylene glycol and various oils (including petroleum oils, animal oils, vegetable oils or synthetic oils, such as peanut oil, soybean oil, mineral oil, castor oil, etc.). . Preferred liquid carriers, especially carriers for injectable solutions, include water, saline, aqueous dextrose and glycols.

Compressed gases may be used to disperse the compounds of the present invention in aerosol form. Suitable inert gases for this purpose are nitrogen, carbon dioxide, nitrogen oxides and the like. Other suitable pharmaceutical carriers and combinations thereof are described in A.R. Alfonso Remington's Pharmaceutical Science 1985, 17th ed., Easton, Pa. Mack Publishing Company.

The amount of the compound of the invention in the composition can vary greatly depending on the type of combination, the size of the unit dosage form, the type of excipient, and other factors known to those skilled in the pharmaceutical art. In general, the final composition will comprise from 10 to 90% by weight of the present compound and the remaining amount of excipients and excipients.

The pharmaceutical composition is preferably administered in a single dosage form for continuous treatment, or in any amount in a single dosage form, especially when relieving symptoms. Exemplary pharmaceutical combinations comprising a compound of Formula (I) are described in Example 67.

chemistry:

Compound of Formula (I):

The process for the preparation of compounds of Formula I (a) wherein R ³ , R ⁴ and R ⁵ are each hydro is shown in Scheme I below:

[Reactivity I]

Wherein L is a leaving group, R ³¹ is alkyl, preferably methyl or ethyl and each n, t and R 1 are as defined above for formula (I).

Compounds of formula (I) wherein R ³ , R ^4, and R ⁵ are each hydro are used as the compounds of formula 2, usually with alcohols (e.g., methanol, ethanol, any suitable mixture of suitable alcohols, etc.), preferably By reacting with thiocyanic acid in a suitable solvent such as methanol). The reaction is carried out in potassium thiocyanate in the presence of an aqueous acid (eg, dilute hydrochloric acid, phosphoric acid or sulfuric acid, etc.) for 1-5 hours at 50-100 ° C., typically 70-90 ° C., preferably liquid 80 ° C. Do it using

The compound of formula 2 can be prepared by the reductive amination of the dialkyloxyacetaldehyde, preferably dimethoxyacetaldehyde or diethoxyacetaldehyde using the compound of formula 3. The reductive amination reaction is carried out in the presence of a chemical reducing agent (eg, sodium cyanoborohydride, etc.) or by catalytic hydrogenation (eg, methanol, ethanol, ethyl acetate, any mixture of suitable solvents, etc.) , H _2, palladium on carbon, H _2, ^Raney? performs writing because nickel, etc.). Optionally, water is removed from the reaction mixture in a standard manner (eg, by use of a desiccant such as molecular sieve or by azeotropy). A more detailed description of this paragraph and the reaction steps disclosed in that paragraph is given in Example 9. In contrast, the compound of formula 2 reductively aminations the compound of formula 7 with 2,2-dialkyloxyethylamine, preferably 2,2-dimethoxyethylamine or 2,2-diethoxyethylamine. Can be prepared (see Example 12 for more details):

The compound of formula 3 may be purchased commercially or by reacting the compound of formula 5 with the appropriate azide salt in a suitable solvent (eg, dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), etc.). It can be prepared by obtaining and then reducing the azide of general formula (4). The reaction with the azide salt is carried out at 50-90 ° C., typically 50-60 ° C., preferably at about 50 ° C. for 12-18 hours. Reduction of the compound of formula 4 can be carried out by catalytic hydrogenation (eg H ₂ , palladium on 10% carbon, etc.) in a suitable solvent (eg ethyl acetate, ethanol, etc.). A more detailed description of the reaction steps disclosed in this paragraph is given in Example 8.

The compound of formula 5 is prepared by treating the compound of formula 6 with an appropriate formulation to produce leaving group L. For example, a compound of formula 5 wherein L is mesyloxy is a compound of formula 6 in a suitable solvent (eg, in any mixture of diethyl ether, tetrahydrofuran (THF), methylene chloride, suitable solvent) Can be prepared by reacting with methanesulfonyl chloride. The reaction is carried out in the presence of triethylamine for 3 to 15 hours at −20 to 5 ° C., typically at −25 to −5 ° C., preferably at about −10 ° C. (see Example 7 for more details). .

Another method for preparing compounds of Formula I (a) wherein R ³ , R ⁴ and R ⁵ are each hydro is shown in Scheme II below:

Scheme II

Wherein R ³¹ is alkyl, preferably methyl or ethyl and each n, t and R ¹ are as defined in formula I above.

Compounds of formula (I) wherein R ³ , R ⁴ and R ⁵ are each hydro may be selected from compounds of the general formula 9 in suitable solvents (eg, DMF, DMSO, 1,3-dimethyl-3,4,5,6-tetra). Hydro-2 (1H) -pyrimidinone (DMPU), etc.) to react with 2,2-dialkyloxyethylamine, preferably 2,2-dimethoxyethylamine or 2,2-diethoxyethylamine to The compound of formula 8 is obtained and then prepared by subjecting the compound of formula 8 to ring closure by treatment with acid (eg hydrochloric acid). The reaction with the amine is carried out at 20 to 90 ° C., typically at 70 to 90 ° C., preferably at about 85 ° C. for 1 to 2.5 hours. Treatment with acid and the resulting ring closure reaction are carried out at 20 to 90 ° C., typically at 70 to 85 ° C., preferably at about 80 ° C. for 3 to 72 hours. A detailed description of the reaction steps disclosed in this paragraph is provided in Example 11.

The compound of formula 9 reacts the compound of formula 3 with 1,1′-thiocarbonyldiimidazole in a suitable solvent (eg, ethyl acetate, acetonitrile, acetone, methylene chloride, any mixture of suitable solvents, etc.) I can manufacture it. The reaction is carried out at 0 to 50 ° C., typically 10 to 30 ° C., preferably at about 20 ° C. for 3 to 18 hours (see Example 10 for more details).

The process for the preparation of compounds of formula (I) wherein R ³ is-(CH ₂ ) _q R ⁹ is shown in Scheme III:

Scheme III

Wherein L is a leaving group and each n, t, R ¹ , R ⁴ , R ⁵ and R ⁹ are as defined in formula (I).

Compounds of formula (I) wherein R ³ is-(CH ₂ ) _q R ⁹ (Formula 10) are prepared by alkylating the compound of formula 11 with an alkylating agent of formula L- (CH ₂ ) _q R ⁹ It can be prepared by producing a dazolium salt and then sulfiding. Alkylation is carried out in a suitable solvent (eg acetonitrile, DMF, THF, any mixture of suitable solvents), preferably in acetonitrile or DMF, from 0 to 160 ° C., typically at about 25 to reflux temperature. To 16 hours. The sulfidation reaction is carried out at 50 to 125 ° C., typically from 80 to 100, using lac sulfur in a suitable weak base (eg triethylamine, pyridine, any mixture of weak bases, preferably a mixture of triethylamine and pyridine). At 1O < 0 > C, preferably at 90 < 0 > C, the internal content of the compound of formula 11 is aminoaryl or alkylsulfonate (e.g. o-mesitylenesulfonyl-hydroxylamine, o-methanesulfonylhydroxylamine or o-hydroxylamine Sulfonic acid) to give the corresponding 3-aminoamidazolium salt, which can then be prepared by sulfiding. The reaction with a sulfonate is 0-40 ° C., typically 10-30 ° C., preferably in a suitable solvent (eg acetonitrile, methylene chloride, THF, any mixture of suitable solvents, preferably acetonitrile). Is carried out at 20 ° C. for 0.5 to 18 hours. A more detailed description of the reaction steps disclosed in this paragraph is provided in Example 15.

Compounds of formula 11 can be prepared by reacting the corresponding compounds of formula 5 with a suitably substituted imidazole in a suitable solvent (eg DMF, DMSO, acetonitrile, etc.). The reaction is carried out at 50 to 100 ° C., preferably at about 85 ° C. for 8 to 24 hours (see Example 13 for more details). In a similar manner, a compound of formula 11 wherein n is 1 and the imidazole portion of the molecule is attached at the β-position is suitably substituted 2-bromo-1,2,3,4-tetrahydronaphthalene-1- One can be prepared by reacting with a suitably substituted imidazole and reducing it. The reduction reaction is carried out by contact hydrogenation (for 1 to 24 hours at 15 to 100 psi, typically 40 to 60 psi, preferably about 50 psi, in a suitable acidic solvent such as sulfuric acid, acetic acid, any mixture of acids, etc.). For example, H ₂ , palladium hydroxide) can be carried out.

Alternatively, the compound of formula 11 can be prepared by treating the corresponding compound of formula I with Raney nickel. Treatment with Raney Nickel is carried out in a suitable solvent (eg ethanol, methanol, acetic acid, water, any mixture of suitable solvents, etc.) from 0 to 100 ° C., typically from 25 to 80 ° C., preferably from about 80 ° C. to 0.25 to Run for 4 hours (see Example 14 for more details).

Wherein R ³ and R ⁴ are hydro and R ⁵ is di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, R ^{4 is} And N, N-disubstituted methyleneammonium salts (e.g., N, N-dimethylmethyleneammonium chloride, N, N-diethylmethyleneammonium chloride, etc.) with appropriately substituted compounds of formula 11 wherein R ⁵ is all hydro; N-di (C _1-4 ) alkylmethyleneammonium salts, 1-methylenepiperidinium chloride, 4-methylenemorpholinium chloride, etc.) can be prepared by alkylation and sulfidation. The alkylation is carried out at 50 to 100 ° C., typically 80 to 100 ° C., preferably at about 95 ° C., in a suitable solvent (eg DMF, DMPU, acetonitrile, any mixture of suitable solvents, etc., preferably DMF). To 18 hours.

Compounds of formula (I) wherein R ³ is hydro may be selected from the group of the formula 11 in a suitable solvent (e.g., 1,2-dimethoxyethane, THF, 2-methoxyethyl ether, etc.) By reacting with lithium, lithium diisopropylamide (LDA, etc.) to produce and sulfide the corresponding 2-imidazolides. The reaction with a base cools the solution of the compound of formula 12 to 0 to -78 ° C, typically -50 to -78 ° C, preferably about -78 ° C, adds a base, and the reaction is 0.25 to 3 Do this by letting it happen for a time. The sulfidation reaction is carried out at 0 to -78 ° C, typically -50 to -78 ° C, preferably about -78 ° C for 2 to 18 hours. A detailed description of the reaction steps disclosed in this paragraph is provided in Example 16.

The process for the preparation of compounds of formula (I) wherein R ³ and R ⁴ are hydro and R ⁵ is amino is shown in Scheme IV below:

Scheme IV

Wherein n, t and R ¹ are as defined in formula (I).

Compounds of formula (I) wherein R ³ and R ⁴ are hydro and R ⁵ is amino (Formula 12) react the compound of Formula 13 with an alkali base (eg potassium hydroxide or sodium hydroxide) to rearrange the rearrangement. Can be prepared. The reaction with the base and the subsequent rearrangement are carried out at 0 to 40 ° C., typically at 10 to 30 ° C., preferably at about 20 ° C. for 0.1 to 2 hours.

The compound of formula 13 can be prepared by reacting the compound of formula 9 with aminoacetonitrile hydrochloric acid in a suitable solvent such as triethylamine, triethylamine in acetonitrile, dimethylformamide or dimethylsulfoxide. have. The reaction is carried out at 20 to 100 ° C., typically at 10 to 30 ° C., preferably at about 20 ° C. for 12 to 24 hours. A more detailed description of the reaction step in this paragraph is provided in Example 17.

Formula I (R ³ is hydro, R ⁴ is hydro, (C _1-4 ) alkyl or (C _1-4 ) alkyloxycarbonyl, and R ⁵ is cyano or (C _1-4 ) alkoxycarbonyl. The process for preparing the compound of a) is shown in Scheme V below:

Scheme V

Wherein L is a leaving group (eg halo, alkyloxy, acyloxy, aryloxy, etc.), R ³² is cyano or (C _1-4 ) alkyloxycarbonyl, and R ³³ is (C _1-4 ) Alkyl or (C _1-4 ) alkyloxycarbonyl, each n, t and R ¹ are as defined in formula (I) above.

R ³ is hydro, R ⁴ is hydro, (C _1-4 ) alkyl or (C _1-4 ) alkyloxycarbonyl, and R ⁵ is cyano or (C _1-4 ) alkyloxycarbonyl Formula 14) The compound of Formula I (a) reacts a compound of Formula 16 with a compound of Formula R ³³ C (O) L to produce a compound of Formula 15, wherein the compound of Formula 15 is reacted with thiocyanic acid. Can be prepared by reaction. The reaction of the general formula R ³³ C (O) L with a compound is carried out in the presence of a base (eg t-butoxylated potassium, LDA, etc.) in a suitable solvent (eg THF, 1,2-diethoxyethane, diethyl ether, And any mixture of suitable solvents).

For example, a compound of Formula 15 wherein R ⁴ is hydro is reacted by reacting the compound of Formula 16 with alkyl or arylformates (eg, ethyl formate, phenyl formate, etc.) in the presence of t-butoxylated potassium. It can manufacture. The reaction with formate is carried out at −40 to 65 ° C., typically at −30 to 0 ° C., preferably at −15 ° C. for 3 to 24 hours (see Example 24 for more details). Compounds of formula 15 wherein R ⁴ is (C _1-4 ) alkyl are substituted with compounds of formula 16 in the presence of LDA (C _2-5 ) alkanoic acid or anhydrides (e.g. acetyl chloride, propionyl chloride, acetic anhydride, etc.). It can be prepared by reacting with). The reaction with acid chlorides or anhydrides is carried out at -78 to -15 ° C, typically at -50 to -78 ° C, preferably at about -78 ° C for 1 to 24 hours (see Example 25 for more details). . The reaction with thiocyanic acid is carried out using potassium thiocyanate in the presence of aqueous acid at 50-100 ° C., typically 75-95 ° C., preferably about 85 ° C. for 1-5 hours.

The compound of formula 16 may be prepared by heating the compound of formula 17 in n-butyl formate for 3 to 24 hours at a temperature of 70 to 105 ° C, preferably about 105 ° C. Alternatively, the compound of formula 16 can be prepared by reacting the compound of formula 17 with acetic anhydride in a suitable solvent (eg methylene chloride, dichloromethane, THF, etc.). The reaction with formic acid anhydride is carried out at −15 to 25 ° C., preferably at about 0 ° C. for 0.5 to 3 hours.

Compounds of formula 17 wherein R ³² is ethoxycarbonyl can be prepared by reductive amination of ethyl glyoxalate with the compound of formula 3. Reductive amination is carried out in a suitable solvent (eg methanol, ethanol, ethyl acetate, any mixture of suitable solvents, etc.) in the presence of a chemical reducing agent (eg sodium cyanoborohydride, sodium borohydride, etc.). Optionally, water is removed from the reaction mixture by standard methods (eg, by use of a desiccant such as molecular sieve or by azeotropy). See Example 23 for a detailed description of the reaction steps disclosed in this and previous paragraphs.

Compounds of formula 17 wherein R ³² is cyano may be prepared by reacting a compound of formula 3 with formaldehyde sodium bisulfite complex and potassium cyanide in a suitable solvent (eg, water, aqueous ethanol, etc.). The reaction is carried out at 50 to 80 ° C., typically 50 to 60 ° C., preferably 50 ° C. for 0.5 to 2 hours (see Example 19 for more details).

The process for the preparation of compounds of formula (I) wherein R ³ and R ⁵ are hydro and R ⁴ is formyl is shown in Scheme VI below:

Scheme VI

Wherein n, t and R ¹ are as defined in formula (I).

Compounds of formula (I) wherein R ³ and R ⁴ are formyl (formula 18) are prepared by oxidizing the compound of formula (19). The oxidation reaction is carried out at 0 to 80 ° C. using a suitable oxidizing agent (eg, lead tetraacetate, periodic acid, etc.) in a suitable solvent (eg acetic acid-benzene, acetic acid-toluene, acetic acid, any mixture of suitable solvents, etc.), Typically at 20-40 ° C., preferably at about 25 ° C. for 0.25-4 hours.

Compounds of formula 19 are prepared by reacting compounds of formula 9 with D-(+)-glucosamine. The reaction is carried out in a suitable solvent, typically an alcohol (eg ethanol, methanol, any mixture of suitable alcohols, etc.), preferably ethanol, 50 to 80 ° C., typically 70 to 80 ° C., preferably about 80 ° C. At 1-2 hours. A more detailed description of this paragraph and the reaction steps disclosed in that paragraph is provided in Example 22.

Compounds of formula (I), in which R ³ and R ⁴ are hydro and R ⁵ is hydroxymethyl, are formulated in a suitable solvent (e.g. ethyl acetate, THF, dioxane, any mixture of suitable solvents, preferably ethyl acetate) The compound of 3 or its acid addition salt can be prepared by reacting with thiocyanic acid and dihydroxyacetone, and then treating the reaction mixture with sulfuric acid (purity with sulfuric acid increases the purity). The reaction is carried out for 0.5 to 3 hours at 20 to 50 ° C. under nitrogen using potassium thioisocyanate in the presence of an acid (eg glacial acetic acid, propionic acid, etc., preferably glacial acetic acid) (see Example 18 for more details). .

Compound of formula (b):

R ⁷ is hydro, aminomethyl, (C _1-4 ) alkylaminomethyl, di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholine- The process for the preparation of the compound of formula (b), which is 4-ylmethyl, piperazin-1-ylmethyl or 4- (C _1-4 ) alkylpiperazin-1-ylmethyl, is shown in Scheme VII below:

Scheme VII

Wherein R ³⁴ is hydro, aminomethyl, (C _1-4 ) alkylaminomethyl, di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, Morpholin-4-ylmethyl, piperazin-1-ylmethyl or 4- (C _1-4 ) alkylpiperazin-1-ylmethyl, or protected derivatives thereof, each n, t and R ¹ are As defined in I.

R ⁷ is hydro, aminomethyl, (C _1-4 ) alkylaminomethyl, di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholine- Compounds of formula (I) wherein 4-ylmethyl, piperazin-1-ylmethyl or 4- (C _1-4 ) alkylpiperazin-1-ylmethyl (formula 20) are compounds of formula 21 or these The protected derivative of may be converted to a base (eg sodium ethoxyoxide, t-butoxylated) in a suitable solvent, typically an alcohol (eg ethanol, t-butanol, isopropanol, any mixture of suitable alcohols, etc.), preferably ethanol. It is prepared by reacting with potassium, etc.) to carry out the ring closure reaction and then removing any protecting groups present. The reaction with the base and thus the ring closure reaction is carried out at 0 to 75 ° C., preferably at about 20 ° C. for 1 to 24 hours. Deprotection can be carried out by treatment with an acid in a suitable solvent (eg 15% anhydrous hydrogen chloride in ethyl acetate, trifluoroacetic acid in methylene chloride, etc.).

The compound of formula 21 may be selected from the group consisting of hydrazide of formula H ₂ NHNC (O) R ³⁴ or a protected derivative thereof in a suitable solvent (eg DMF, ethyl acetate, any mixture of suitable solvents, etc.). Prepared by reacting with. The reaction is carried out at 50 to 100 ° C., typically 70 to 90 ° C., preferably at about 80 ° C. for 1 to 4 hours.

Hydrazide of formula H ₂ NHNC (O) R ³⁴ is reacted with hydrazine by reaction of the corresponding methyl aminoacetate or a protected derivative thereof in a suitable solvent (eg, methanol, ethanol, DMF, any mixture of suitable solvents, etc.). It can manufacture. The reaction is carried out at 20-80 ° C., typically 50-70 ° C., preferably at about 65 ° C. for 48-96 hours. Suitable methyl aminoacetates can be purchased commercially or readily prepared by methods known in the art of organic synthesis. For example, protected derivatives of methylaminoacetate can be prepared by esterifying N- (t-butoxycarbonyl) glycine. Other aminoacetates may be formulated with the corresponding methyl chloroacetate in a suitable solvent (e.g. acetonitrile, ethanol, DMF, any mixture of suitable solvents, etc.), in which the general formulas NHR ³⁶ R ³⁷ where R ³⁶ and R ³⁷ are independently (C _1-4) alkyl or or with _{- (CH 2) 4 -,} - (CH 2) 5 -, - (CH 2) 2 -O- (CH 2) 2 - or ^{_{- (CH 2) 2 -NR 38}} - (CH ₂ ) _2- , wherein R ³⁸ can be prepared by reacting with an amine of hydro or (C _1-4 ) alkyl. The reaction is carried out at 0 to 100 ° C., typically 65 to 95 ° C., preferably at about 80 ° C. for 1 to 48 hours. See Example 25 for a more detailed description of this paragraph and the reaction steps disclosed in that paragraph.

Compound of Formula I (c):

The process for the preparation of compounds of formula I (c) wherein R ⁷ is hydro is shown in Scheme VIII:

Scheme VIII

Wherein n, t and R ¹ are as defined in formula (I) above.

Compounds of formula I (c) wherein R ⁷ is hydro (formula 22) may be prepared by reacting a compound of formula 23 with a suitable base (eg, 10% sodium hydroxide, t-butoxylate, etc.). The reaction with the base and thus the ring closure reaction is carried out at 20 to 100 ° C., typically at 50 to 90 ° C., preferably at about 70 ° C. for 1 to 24 hours.

Compounds of formula 22 are isothiocyanates (e.g. trimethylsilyl isothiocyanates) in a suitable solvent (e.g. toluene, 1,2-dimethoxyethane, any mixture of suitable solvents, etc.) And the like). The reaction is carried out at 20 to 110 ° C., typically 50 to 90 ° C., preferably at about 70 ° C. for 18 to 24 hours. Compounds of Formula 24 are prepared by reacting a compound of Formula 7 with formic acid hydrazide and then reducing in a suitable solvent (eg, ethanol, isopropanol, etc.). The reaction with hydrazide is carried out at 20-100 ° C., typically 60-90 ° C., preferably about 75 ° C., in the presence of an acid (eg hydrochloric acid, p-toluene sulfonic acid, boric acid, trifluoroacetic acid, etc.). It is carried out for 1 to 5 hours. The reduction reaction is carried out in a suitable solvent, typically an alcohol (eg ethanol, any suitable mixture of alcohols, etc.), preferably ethanol, with a chemical reducing agent (eg lithium borohydride, sodium borohydride, sodium cyanoborohydride). Ride, etc.) may be carried out at 20 to 80 ℃ for 8 to 24 hours. See Example 27 for a detailed description of this paragraph and the reaction steps disclosed in that paragraph.

Compounds of formula (I) wherein R ⁷ is amino react the compound of formula 5 with 1,2,4-triazol-4-ylamino to produce the corresponding 4-aminotriazolium salts, which are then sulfided to It can manufacture. The reaction with 4-amino [1,2,4] triazole is carried out at 50 to 100 ° C., typically at 80 to 90 ° C., preferably at about 90 ° C. for 1 to 8 hours. The anti-sulfurization reaction is carried out for 1 to 8 hours at 50 to 125 DEG C, typically 80 to 100 DEG C, preferably about 90 DEG C, using Lac sulfur in the presence of a weak base (e.g. triethylamine etc.) See Example 28 for details.

Other Methods for Making Compounds of Formula (I):

R ⁵ is a compound R ⁵ is cyano Hydra prematurity derivative of a compound of Formula I Formula I (e.g., tributyltin azide, triphenylsilyl azide, t--butyldiphenylsilyl azide, etc.) to give It can manufacture. The reaction is carried out at 100 to 150 ° C., typically 120 to 140 ° C., preferably at about 130 ° C. for 2 to 18 hours (see Example 21 for more details).

R ⁵ is carbamoyl compounds of formula I can be R ⁵ is prepared to write because the hydrolysis of a compound of formula (I) cyano. The hydrolysis is carried out using aqueous hydrochloric acid at 100 to 140 ° C., typically at 125 to 135 ° C., preferably at about 130 ° C. for 2 to 18 hours. 5,6-difluoroindan-2-yl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl-carboxamide having a melting point of at least 280 ° C. as described above Is prepared. Compounds of formula (I) wherein R ⁵ is -C (NH) NR ¹⁵ R ¹⁶ comprise a compound of formula (I) wherein R ⁵ is cyano in a suitable solvent (eg toluene, benzene, Etc.) can be prepared by reacting with a reagent of the general formula (CH ₃ ) ₂ AlNR ¹⁵ R ¹⁶ . The reaction is carried out at 20 to 130 ° C., typically 60 to 100 ° C., preferably at 80 ° C. for 1 to 18 hours. The reagent of general formula -C (NH) NR ¹⁵ R ¹⁶ is prepared by reacting an amine of general formula NHR ¹⁵ R ¹⁶ with trimethylaluminum. 5- (aminoiminomethyl) -1- (5,6-difluoroindanyl-2-yl) -1,3-dihydroimidazole-2-thione and 1- (5,6) -Difluoroindan-2-yl) -5- [imino- (2,2,2-trifluoroethylamino) methyl] -1,3-dihydroimidazole-2-thione (melting point: 199- 200 ° C.).

Compounds of formula (I) wherein R ⁵ is 4,5-dihydroimidazol-2-yl can be prepared by reacting a compound of formula (I) wherein R ⁵ is cyano with ethylenediamine. The reaction can be carried out by heating the reaction to 100 to 250 ° C., typically 180 to 220 ° C., preferably about 200 ° C. for 1 to 3 hours in the presence of p-toluenesulfonic acid. 1,2,3,4-tetrahydronaphthalen-2-yl-5- (4,5-dihydroimidazol-2-yl) -1,3-dihydroimidazol-2-thione as described above (Melting point: 130-145 ° C.) is prepared.

Compounds of formula (I) wherein R ³ and R ⁴ are hydro and R ⁵ is aminomethyl may be prepared by reducing compounds of formula (I) wherein R ⁵ is cyano. The reduction reaction is carried out in a chemical reducing agent (eg lithium aluminum hydride, THF in a suitable solvent (eg THF, 1,2-dimethoxyethane, 2,2-dimethoxyethyl ether, any suitable mixture of suitable solvents, etc.). Borane, aluminum hydride and the like) is used at 0-65 ° C., typically 0-20 ° C., preferably at about 0 ° C. for 1-5 hours (see Example 20 for more details).

A preferred process for preparing compounds of formula (I) wherein R ³ and R ⁴ are hydro and R ⁵ is aminomethyl is shown in Scheme IX:

Scheme IX

Wherein R ³⁵ is hydro, (C _1-4 ) alkyl or trifluoro (C _1-4 ) alkyl, each n, t and R ¹ are as defined in formula (I) above.

Acid addition salts of compounds of formula (I) wherein R ³ and R ⁴ are each hydro and R ⁵ is aminomethyl (formula 25) may be selected from R ⁵ as formylaminomethyl, (C _1-4 ) alkylcarbonylaminomethyl or tri The corresponding compounds of formula I, which are fluoro (C _1-4 ) alkylcarbonyl-aminomethyl (formula 26), can be prepared by catalytic hydrolysis. The hydrolysis is carried out in a suitable solvent, typically an alcohol (eg isopropanol, ethanol, methanol, any suitable mixture of alcohols, etc.), preferably isopropanol, at 62-82 ° C. under nitrogen, preferably at reflux temperature of 0.5-4 ° C. Run for hours.

Pharmaceutically acceptable acid addition salts of compounds of formula (I) wherein R ³ and R ⁴ are each hydro and R ⁵ is aminomethyl are pharmaceutically acceptable acids (eg 2 to 8 equivalents of concentrated hydrochloric acid, preferably About 4 equivalents). In contrast, the acid addition salt form of the compound of formula 25 is converted to the corresponding free base form by reaction with an acceptable inorganic and organic base, followed by reaction with a suitable pharmaceutically acceptable acid to form a pharmaceutically acceptable acid addition salt. You can switch. A detailed description of this paragraph and the reaction steps disclosed in that paragraph is provided in Example 31.

Compounds of formula (I) wherein R ⁵ is formylaminomethyl, (C _1-4 ) alkylcarbonylaminomethyl or trifluoro (C _1-4 ) alkylcarbonylaminomethyl, are compounds in which R ⁵ is hydroxymethyl (formula 27) Corresponding compounds of formula I can be prepared by reacting with primary amines of the general formula H ₂ NC (O) R ³⁵ (eg formamide, acetamide, trifluoroacetamide, etc.). The reaction is carried out by adding the compound of formula 27 to the amide and then heating the mixture at 150 to 190 ° C. under a nitrogen stream for 0.5 to 2 hours. The amide is formamide, and the reaction is preferably performed at 170 to 175 ° C. for about 1 hour. Similarly, using urea instead of primary amines can be performed to prepare compounds of formula I, wherein R ⁵ is ureidomethyl. A more detailed description of the reaction steps disclosed in this paragraph is provided in Example 29.

Preferred methods for the preparation of compounds of formula 26 include those of the compounds of formula 27, wherein ammonium salts of the formula NH ₄ ⁺ -OC (O) R ³⁵ (eg ammonium formate, ammonium acetate, ammonium trifluoroacetate, etc.) And ammonium formate). For example, the compound of formula 27 can be reacted with ammonium formate to provide a compound of formula 24 wherein R ³⁵ is hydro. The reaction is carried out in the pure state or in formamide, preferably in formamide for 1 to 2 hours at 100 to 180 ° C., preferably 120 to 150 ° C. (see Example 30 for more details). .

R ³ and R ⁴ are hydro, R ⁵ is aminomethyl, (C _1-4 ) alkylaminomethyl, di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperidine-1 The compound of formula I wherein -ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl or 4- (C _1-4 ) alkylpiperazin-1-ylmethyl is a compound wherein R ⁵ is hydroxymethyl A compound of formula I is converted to a compound of formula 28 and the compound of formula 28 is an amine of formula HNR ³⁶ R ³⁷ , wherein R ³⁶ and R ³⁷ are independently (C _1-4 ) alkyl or together-( _{CH 2) 4 -, - (} CH 2) 5 -, - (CH 2) 2 -O- (CH 2) 2 - or ^{_{- (CH 2) 2 -NR 38}} - (CH 2) 2 - , and wherein R ³⁸ can be prepared by reacting with hydro or (C _1-4 ) alkyl:

Wherein L is a leaving group and n, t and R ¹ are as defined in formula (I) above. Conversion of the compound of formula 28 to a suitable leaving group (eg methanesulfonyl chloride, thionyl chloride, phosphorus, oxy) in a suitable solvent (eg methylene chloride, chloroform, THF, any suitable mixture of suitable solvents, etc.) Phosphorus chloride, etc.). The reaction with amines is carried out at −10 to 20 ° C. for 1 to 4 hours in a suitable solvent (eg THF, 1,2-dimethoxyethane, acetonitrile, suitable mixture of suitable solvents, etc.). A more detailed description of the reaction steps disclosed in this paragraph is provided in Example 32.

Compounds of formula (I) wherein R ⁴ is aminomethyl can be prepared by reacting a compound of formula (I) wherein R ⁴ is formyl with hydroxylamine hydrochloric acid to produce the corresponding oxime and then reduction. The reaction with hydroxylamine hydrochloric acid is carried out in the presence of a suitable base (e.g. sodium hydroxide, sodium acetate, etc.), of a suitable solvent, typically an alcohol (e.g., ethanol, methanol, any suitable mixture of alcohols, etc.) or of alcohol and water. In a mixture (eg ethanol / water (1: 1), etc.) it is carried out at 20-100 ° C., typically 50-70 ° C., preferably at about 60 ° C. for 1-8 hours. Reduction of the oxime is -50 to 50 ° C., typically -20 to 20 ° C., using chemical reducing agents (eg lithium aluminum hydride, etc.) in a suitable solvent (eg THF, any mixture of suitable solvents, etc.) Preferably at about 0 ° C. A more detailed description of the reaction steps disclosed in this paragraph is provided in Example 47.

Compounds of formula (I) wherein R ⁴ is -CH ₂ NHR ¹⁰ , wherein R ¹⁰ is as defined in formula (I) above, are compounds of formula (I) wherein R ⁴ is formyl to the amine of formula NH ₂ R ¹⁰ (eg, t-butyl ester hydrochloric acid, glycineamide hydrochloric acid, phenethylamine, methyl 4- (2-amino-ethyl) benzoate and the like). The reductive amination is chemically carried out in a suitable solvent (eg, THF, water, ethyl acetate, alcohol, any suitable mixture of solvents, etc.), typically alcohol (eg, ethanol, methanol, any suitable mixture of alcohols, etc.). a reducing agent (e.g., sodium cyanoborohydride in hydride, sodium borohydride, etc.) or catalytic hydrogenation in the presence of the (top, for example, H _2, carbon palladium, H _2, ^Raney? nickel) 20 to 100 ℃ by, preferably Is carried out at about 50 ° C. for 1 to 8 hours (see Example 48 for more details).

Compounds of formula (I) wherein R ⁴ is 1-hydroxy (C _1-4 ) alkyl can be used to prepare the corresponding compounds of formula (I) wherein R ⁴ is formyl with suitable alkylating agents (eg, methylmagnesium chloride, ethylmagnesium chloride, n-propylmagnesium chloride). And the like). The alkylation reaction is carried out in the pure state at −20 to 60 ° C., typically 0 to 25 ° C., preferably about 0 ° C. (see Example 40 for more details).

Is a compound of Formula I wherein R ³ , R ⁵ or R ⁸ is -NHC (NR ¹¹ ) NHR ¹² or R ⁴ , R ⁵ or R ⁷ is -CH ₂ NHC (NR ¹¹ ) NHR ¹² , wherein R ¹¹ is hydro, Acetyl or t-butoxycarbonyl, and R ¹² is acetyl or t-butoxycarbonyl), wherein R ³ , R ⁴ , R ⁵ , R ⁷ or R ⁸ is amino or aminomethyl Compounds of I are suitably substituted amidines (eg, N ^1- (t-butoxycarbonyl) methylthioamidine, N ¹ , N ² -di (t-butoxycarbonyl) methylthioamidine, N ¹ , N ² -di (acetyl) methylthioamidine and the like). The reaction is carried out at 0 ° C. to reflux temperature, typically 20 ° C. to reflux temperature, preferably in a suitable solvent (eg THF, methanol, ethanol, DMF, water, any suitable mixture of suitable solvents, etc., preferably THF). Is carried out at about 50 ° C. under inert atmosphere for 1 to 24 hours (see Example 49 for more details).

A compound of Formula I wherein R ³ , R ⁵ or R ⁸ is -NHC (NR ¹¹ ) NHR ¹² or R ⁴ , R ⁵ or R ⁷ is -CH ₂ NHC (NR ¹¹ ) NHR ¹² , wherein R ¹¹ and R ¹² is hydro a) compounds of formula (I) R ¹¹ and / or R ¹² is an acetyl or a t- butoxycarbonyl the appropriate acid with the appropriate co-solvent in the corresponding compound, optionally, (e. g., ethanol) of formula (I) (e.g., Trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfuric acid and the like, preferably TFA). The acid treatment is carried out at 0-120 ° C., typically 0-80 ° C., preferably at about 25 ° C. for 0.5-12 hours (see Example 50 for more details).

Wherein R ³ and R ⁵ are hydro and R ⁴ is di (C _1-4 ) alkylalminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, R ³ , R Compounds of formula I, wherein ⁴ and R ⁵ are each hydro, can be prepared by alkylating with an appropriate N, N-disubstituted methyleneammonium salt. The alkylation is carried out at 50 to 130 ° C., typically 80 to 110 ° C., preferably at about 95 ° C. in a suitable solvent (eg DMF, acetonitrile, any suitable mixture of suitable solvents, etc., preferably DMF). To 24 hours.

Compounds of formula I wherein R ⁴ is hydro, R ⁵ is di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, and R ³ is not hydro to ⁵ is alkylated with an appropriately the corresponding compound N, N- disubstituted methylene ammonium salt of about one equivalent of the dihydro-formula (I) can be produced. The alkylation is carried out at 0 ° C. to reflux temperature, typically 25 to 100 ° C., preferably about 80, in a suitable solvent (eg DMF, DMPU, acetonitrile, any suitable mixture of suitable solvents, etc., preferably DMF). It is carried out for 1 to 24 hours at ℃ (see Example 35 for more details).

Compounds of formula I wherein R ³ and R ⁴ are hydro and R ⁵ is di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl are compounds in which R ⁵ is hydro Thioprotected derivatives of the corresponding compounds of formula I (such as their 3- (imidazol-2-ylthio) propionate derivatives) are alkylated with about 1 molar equivalents of an appropriate N, N-disubstituted methyleneammonium salt. It may then be prepared by deprotection. The alkylation is carried out at 50 to 130 ° C., preferably 80 to 100 ° C. for 1 to 24 hours in a suitable solvent (eg DMF, DMPU, acetonitrile, preferably any suitable mixture of suitable solvents and the like, DMF). The deprotection reaction can be carried out at 0 to 50 ° C., preferably at about 25 ° C., using a suitable base (eg sodium alkoxide, such as sodium ethoxylate, sodium hydroxide, potassium hydroxide, etc., preferably sodium ethoxide). Can be.

Suitable thio protected derivatives can be prepared by reacting a compound of formula (I) wherein R ³ is hydro with ethyl acetate to produce 3- (imidazol-2-ylthio) propionate derivatives. The protecting step is from 0 ° C. to reflux temperature in the presence of a suitable solvent, typically an alcohol (eg methanol, ethanol, any suitable mixture of suitable alcohols, etc.), preferably an acid (eg anhydrous hydrochloric acid) in ethanol. , Typically at 50 ° C. to reflux, preferably at about 80 ° C.

Compounds of formula I wherein R ³ is hydro and R ⁴ and R ⁵ are di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, respectively, are R ⁴ and R Protected derivatives of the corresponding compounds of formula I, wherein each of ⁵ is hydroalkylated, are suitably alkylated with 2 to 15 molar equivalents, typically 5 to 10 molar equivalents, preferably about 7 molar equivalents of N, N-disubstituted methyleneammonium salts After deprotection can be prepared. The alkylation reaction is carried out in a suitable solvent (eg DMF, DMPU, acetonitrile, any suitable mixture of suitable solvents, etc., preferably DMF) from 50 to 130 ° C., typically from 90 to 110 ° C., preferably about 100 Run at 1 ° C. for 1 to 24 hours (see Example 36 for more details).

R ⁴ and / or R ⁵ is tetrahydro-methyl compounds of formula I can be prepared to write because reduction of the ethoxycarbonyl compound of formula I in the R ⁴ and / or R ^5. The reduction reaction is carried out in a suitable solvent (eg THF, diglyme, dioxane, a suitable mixture of suitable solvents, etc., preferably THF), with a chemical reducing agent (eg sodium borohydride, calcium borohydride, lithium borohydride, Sodium borohydride), such as lithium aluminum hydride, preferably in the presence of calcium chloride, for 1 to 72 hours at -20 ° C to reflux temperature, typically 0 to 80 ° C, preferably about 50 ° C. (See Example 33 for more details).

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ are aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl, wherein aroyl, hetero Aroyl, aryl and heteroaryl are further substituted with 1H-tetrazol-5-monosubstituent) wherein the compound of formula (I) is further substituted with cyano substituents with aroyl, heteroaroyl, aryl and heteroaryl substituents The corresponding compounds of formula (I) can be prepared by reacting with hydrazonic acid derivatives such as tributyltin azide. The reaction is carried out in the pure state or in a suitable solvent (eg xylene, toluene, benzene, any suitable mixture of suitable solvents, etc., preferably xylene), 80-150 ° C., typically 80-130 ° C., preferably reflux Run at temperature for 4 to 24 hours (see Example 39 for more details).

R ⁵ or R ⁴ and R ⁵ are both 1H-tetrazol-5-yl-aminocarbamoyl, 2- (dimethylamino) ethylcarbamoyl, 4-methylpiperazin-1-ylcarbonyl, methylsulfonylanilino Compounds of formula (I), which are carbonyl or 2- (dimethylamino) ethylmercaptocarbonyl, may be substituted with compounds of formula (I) wherein R ⁵ or R ⁴ and R ⁵ are carboxy, or acid derivatives thereof, Amino-1H-tetrazole, 2- (dimethylamino) teramine, 4-methylpiperazine, 4-methylsulfonylaminoaniline or 2-dimethylaminoethanethiol hydrochloric acid). For example, compounds of formula I wherein R ⁵ is 1H-tetrazol-5-ylcarbamoyl can be prepared by converting the corresponding carboxylic acid into an acid halide and reacting the acid halide with 5-amino-1H-tetrazole. have. The reaction with 5-amino-1H-tetrazole is from 0 to 40 ° C., typically from 20 to 30 ° C., preferably from about 25 ° C. in a suitable solvent (eg, pyridine, DMF, any suitable mixture of suitable solvents, etc.). It is carried out for 1 to 24 hours at ℃ (see Example 41 for more details).

Compounds of formula I wherein R ⁵ is 2- (dimethylamino) ethylcarbamoyl, 4-methylpiperazin-1--ylcarbonyl or 2- (dimethylamino) ethylmercaptocarbonyl are suitable solvents (eg, THF, The corresponding carboxylic acid in methylene chloride, DMF, any suitable mixture of suitable solvents, etc. may be added to a coupling agent (e.g., 1,1'-carbonyldiimidazole, dicyclohexylcarbodiimide, benzotriazol-1-yloxytrippy) It can be prepared by treatment with lollydinophosphonium hexafluorophosphate (PyBOP, etc.) followed by reaction with a suitable amine or thiol. The reaction with the amine or thiol is carried out at 0 to 80 ° C., typically 20 to 30 ° C., preferably at about 25 ° C. for 1 to 24 hours (see Example 42 for more details).

Compounds of formula (I) wherein R ³ , R ⁶ or R ⁸ are 2- (C _1-4 ) alkyloxycarbonylethyl represent compounds of formula (I) wherein R ³ , R ⁶ or R ⁸ are each hydrophobic (C _1-4 Can be prepared by reaction with alkyl acrylates (eg, methyl acrylate, ethyl acrylate, etc.). The reaction is carried out in the presence of a base (e.g., sodium ethoxylate, benzyltrimethylammonium hydroxide, sodium hydroxide, etc.), in a suitable solvent (e.g., ethanol, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, etc.). ) At 50 to 100 ° C., preferably at 80 ° C. for 1 to 6 hours (see Example 34 for more details).

Compounds of formula (I) in which R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ substituents are further substituted with carboxy or carboxy substituents may be selected from R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ can be produced by substituent is (C _1-4) decomposing the corresponding compound of the formula alkyloxycarbonyl or (C _1-4) allyloxy is further substituted with a carbonyl substituent group I singer. The hydrolysis involves the addition of an aqueous base (eg potassium hydroxide, sodium hydroxide, lithium hydroxide, etc.) in a suitable solvent, typically an alcohol (eg ethanol, methanol, isopropanol, any suitable mixture of alcohols, etc.), preferably ethanol. 20-120 ° C., typically using aqueous acids (eg hydrochloric acid, trifluoroacetic acid, sulfuric acid, hydrobromic acid, etc.) or in a suitable solvent (eg methylene chloride, ethyl acetate, dioxane, DMF, THF, etc.) For 4 to 24 hours at 90 to 110 ° C., preferably at about 100 ° C. (see Example 37 for more details).

Compounds of formula I wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ substituents are further substituted with carbamoyl or carbamoyl substituents are R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ Or a corresponding compound of formula (I) wherein R ⁸ is a group further substituted with a carboxy or carboxy substituent. The amination can be prepared by converting the carboxylic acid to the corresponding acid chloride and then reacting the acid chloride with aqueous ammonium hydroxide. The conversion of the acid to acid chloride is carried out in a suitable solvent (eg DMF, methylene chloride, dichloroethane, any suitable mixture of suitable solvents, etc., preferably DMF) with a suitable chloride (eg thionyl chloride, oxalyl chloride, Phosphorus pentachloride, etc.) at 10 to 40 ° C., typically 15 to 30 ° C., preferably at about 20 ° C. for 2 to 18 hours. The reaction between acid chloride and aqueous ammonium hydroxide is carried out at 0 to 50 ° C., typically at 20 to 30 ° C., preferably at about 25 ° C. for 0.5 to 24 hours. A detailed description of the reaction steps disclosed in this paragraph is provided in Example 38.

^{R 3, R 4, R 5} , R 6, R 7 or R ⁸ is (C _1-4) alkyloxycarbonyl or (C _1-4) is more compounds of formula I the group is substituted by alkoxycarbonyl Compounds of formula (I) in which R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ are further substituted with carboxy or carboxy substituents can be prepared by reaction with (C _1-4 ) alcohols. The reaction is carried out at 20 to 110 ° C., preferably at about 85 ° C. for 8 to 72 hours.

R ¹⁰ is (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di ( C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 Compounds of formula (I) which are alkanoyl, aroyl or heteroaroyl may be prepared by appropriate acylating agents (e.g., compounds of formula (I) wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ is amino or , Acyl halides such as dimethylcarbamyl chloride, benzoyl chloride, nicotinyl chloride and the like, anhydrides such as acetic anhydride, activated esters such as methyl chloroformate and the like) or protected derivatives thereof. The reaction is -10 to 40 ° C., typically 15 to 35 ° C., preferably about 15 ° C. in a suitable solvent (eg, methylene chloride, THF, pyridine, water, any mixture of suitable solvents, etc., preferably pyridine). Run at 25 ° C. for 0.5-8 hours (see Example 44 for more details).

In contrast, R ¹⁰ is carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl , (C _1-4) alkylamino (C _1-4) alkanoyl, di (C _1-4) alkylamino (C _1-4) alkanoyl, aroyl or heterocyclic aroyl those compounds of formula (I) R ^3, Corresponding compounds of formula (I) wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ are amino or aminomethyl may be substituted with appropriate acids (eg picolinic acid or the like) or protected derivatives thereof (eg N- (t -Butoxycarbonyl) glycine and the like). The reaction is carried out in a non-nucleophilic base (eg N, N-diisopropyl) in a suitable solvent (eg DMF, DMPU, acetonitrile, THF, methylene chloride, any suitable mixture of suitable solvents, etc., preferably DMF). Ethylamine (DIEA), N, N-dicyclohexylmethylamine, etc., preferably DIEA) and suitable coupling agents (e.g., PyBOP, 1,1'-carbonyldiimidazole, dicyclohexylcarbodiimide, etc.) Preferably in the presence of PyBOP) at −20 to 80 ° C., typically 0 to 30 ° C., preferably at about 25 ° C. (see Example 45 for more details).

Alternatively, a compound of formula I wherein R ³ , R ⁵ or R ⁸ is -NHR ¹⁰ or R ⁴ , R ⁵ or R ⁷ is -CH ₂ NHR ¹⁰ wherein R ¹⁰ is (C _1-4 ) alkylcarbamoyl Can be prepared by reacting the corresponding compound of formula (I) wherein R ³ , R ⁴ , R ⁵ , R ⁷ or R ⁸ is amino or aminomethyl with (C _1-4 ) alkyl isocyanate . The reaction is carried out at 0 ° C. to reflux temperature in the presence of a base (eg triethylamine, pyridine, etc.) in a suitable solvent (eg THF, benzene, methylene chloride, any suitable mixture of suitable solvents, etc., preferably THF), Typically at 25-80 ° C., preferably at about 50 ° C. (see Example 46 for more details).

R ¹ is hydroxy and / or R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ is aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 Compounds of formula I wherein alkyl, wherein aroyl, heteroaroyl and heteroaryl are further substituted with one or two hydroxy substituents, are those wherein R ¹ is methoxy and / or R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ is aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl (where aroyl, heteroaroyl, aryl and heteroaryl are May be prepared by demethylation of the compound of formula (I) which is further substituted with one or two methoxy substituents). The demethylation is carried out at -10 to 20 ° C using boron tribromide in a suitable solvent (e.g. methylene chloride, 1,2-dichloroethane, nitromethane, any suitable mixture of suitable solvents, preferably methylene chloride), Typically at −5 to 5 ° C., preferably at about 0 ° C. for 0.5 to 4 hours. A more detailed description of the reaction steps disclosed in this paragraph is provided in Example 43.

The compounds of formula (I) react as their respective stereoisomers by reacting their racemic mixtures with optically active dissociating agents to produce diastereomeric compound pairs, separating the diastereomers and separating optically pure enantiomers. It can manufacture. Decomposition of the enantiomers can be carried out using covalent diastereomeric derivatives of the formula (I), but preference is given to using degradable complexes (eg crystalline diastereomeric salts). When the compound of the formula (I) contains a basic amine group, the crystalline diastereomeric salt may be used as a disintegrating agent with optically active acids (e.g. tartaric acid, mandelic acid, malic acid, 2-arylpropionic acid, generally camphorsulfonic acid, etc.) Can be prepared.

Diastereomers have distinct physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) and can be easily separated by taking advantage of these dissimilarities. Diastereomers can be separated using chromatography or separation / decomposition techniques, preferably based on solubility differences. The optically pure enantiomer is then recovered with the disintegrant using any physical means that does not cause racemization. A more detailed description of techniques for separating stereoisomers of compounds from racemic mixtures is described by Jean Jacques, Andre Collet, Samuel H. Wielen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

In summary, aspects of the invention relate to methods of preparing compounds of Formula I, and pharmaceutically acceptable salts, each isomer, a mixture of isomers thereof:

[Formula I]

In the above formula,

n is 0, 1 or 2;

t is 0, 1, 2 or 3,

R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy;

R ² is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (a), (b) and (c):

R ⁴ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ (where q is 0, 1, 2, 3 or 4, R ⁹ is carboxy, (C _1-4 ) alkyloxycarbonyl , Carbamoyl, or aryl and heteroaryl (this group is optionally hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazo-5-yl, carboxy and (C _1-4 ) alkyloxycarbo Is further substituted with 1 or 2 substituents independently selected from yl), and R ⁵ is hydro or -NHR ¹⁰ , wherein R ¹⁰ is hydro, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _{1- 4} ) Groups selected from alkanoyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, aroyl or heteroaroyl (wherein the aroyl or heterocyclic aroyl thing optionally hydroxy, (C _1-4) alkyl When, cyano, 1H- tetrazol-5-yl, carboxy and (C _1-4) is further substituted with one to two substituents independently selected from alkyloxycarbonyl) or -C (NR ¹¹⁾ NHR ¹² Wherein R ¹¹ and R ¹² are independently hydro, acetyl or t-butoxycarbonyl;

R ⁴ and R ⁵ are each hydro and R ³ is —NHR ¹⁰ , wherein R ¹⁰ is as defined above; or

R ⁵ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁴ is (C _1-4 ) alkyl, di (C _{1- 4} ) alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, formyl, 1-hydroxy (C _1-4 ) alkyl or -CH ₂ NHR ¹³ , wherein R ¹³ is hydro, (C _1-4 ) alkyl, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkyl Carbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, carboxy (C _1-4 ) alkyl, (C _1-4 ) alkyloxycarbonyl (C _1-4 ) alkyl, carbamoyl (C _1-4 ) alkyl, aroyl, hetero Groups selected from aroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl (the aroyl, heteroaroyl, aryl and heteroaryl are optionally hydroxy, (C _1-4 ) alkyl Oxy, cyano, 1H-tetra 5-yl, carboxy and or (C _1-4) is further substituted with one to two substituents independently selected from alkyloxycarbonyl) or -C (NR ¹¹⁾ NHR ¹² (wherein, R ¹¹ and R ¹² Is as defined above); or

R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁴ is hydro, (C _1-4 ) alkyl or —C (O) R ¹⁴ , wherein , R ¹⁴ is amino, hydroxy, (C _1-4 ) alkyloxy, 2- (dimethylamino) ethylamino, 4-methylpiperazin-1-yl, 2- (dimethylamino) ethylmercapto, 4- ( Methylsulfonylamino) anilino or 1H-tetrazol-5-ylamino), and R ⁵ is cyano, hydroxymethyl, 1H-tetrazol-5-yl, 4,5-dihydroimidazole-2 -Yl, pyrrolidin-1-ylmethyl, piperidin--1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin- 1-ylmethyl, —C (O) R ¹⁴ , wherein R ¹⁴ is as defined above, —C (NH) NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are independently hydro, (C _{1- 4)} alkyl or trifluoro (C _1-4) alkyl) or -CH ₂ NR ¹⁰ R ¹⁷ (wherein, R ¹⁰ is as defined above, R ¹⁷ is hydro or (C _1-4) Kill a) or; or

R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above, and R ⁴ and R ⁵ are independently di (C _1-4 ) alkylaminomethyl, piperidine -1-ylmethyl, morpholin-4-ylmethyl or hydroxymethyl;

R ⁶ is hydro, 2-carboxyethyl, 2-carbamoylethyl or 2- (C _1-4 ) alkyloxycarbonylethyl;

R ⁷ is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperidin-1-ylmethyl, 4- (C _1-4 ) alkylpipepe Rajin-1-ylmethyl or —CH ₂ NR ¹⁰ R ¹⁷ wherein R ¹⁰ and R ¹⁷ are as defined above;

R ⁸ is hydro, 2-carboxyethyl, 2-carbamoylethyl, 2- (C _1-4 ) alkyloxycarbonylethyl or-NHR ¹⁰ , wherein R ¹⁰ is as defined above.

The manufacturing method includes the following processes:

(a) reacting a compound of formula 3, wherein n, t and R ¹ are as defined in Formula I above, with dialkyloxyacetaldehyde in the presence of a chemical reducing agent or by catalytic hydrogenation; Treatment with cyanic acid yields a compound of formula I wherein R ² is a group of formula (a) and R ³ , R ⁴ and R ⁵ are each hydro:

or

(b) each of n, t and R ¹ is reacted with thiocyanic acid and dihydroxyacetone with a compound of formula 3 or an acid addition salt thereof as defined in formula (I), and then optionally the reaction mixture is treated with sulfuric acid To obtain a compound of formula I wherein R ³ and R ⁴ are hydrogen and R ⁵ is hydroxymethyl; or

(c) reacting a compound of formula 5, wherein n, t and R ¹ are as defined in Formula I above, with 1,2,4-triazol-4-ylamino and then sulfiding To obtain a compound of formula I wherein ² is a group of formula (c) and R ⁸ is amino:

or

(d) Compounds of the following general formula (7) wherein each n, t and R ¹ are as defined in formula (I) above are reacted with 2,2-dialkyloxyethylamine in the presence of a chemical reducing agent or by contact hydrogen; And reacted with thiocyanic acid to give a compound of formula I wherein R ² is a group of formula (a) and R ³ , R ⁴ and R ⁵ are each hydro:

or

(e) reacting a compound of formula 9 (wherein each of n, t and R ¹ are as defined in formula I) with 2,2-dialkyloxyethylamine and treating with acid to give R ² general Or a compound of formula I wherein R ³ , R ⁴ and R ⁵ are each hydro:

or

(f) reacting a compound of formula 9 with aminoacetonitrile hydrochloric acid followed by treatment with a base wherein R ² is a group of formula (a), R ³ and R ⁴ are each hydro and R ⁵ is amino To obtain; or

(g) reacting and oxidizing a compound of formula 9 with D-(+)-glucosamine to afford a compound of formula I wherein R ² is formula (a), R ³ and R ⁵ are each hydro and R ⁴ is formyl do or; or

(h) a compound of Formula 9 is represented by Formula H ₂ NHC (O) R ³⁴ , wherein R ³⁴ is hydro, aminomethyl, (C _1-4 ) alkylaminomethyl, di (C _1-4 ) alkylaminomethyl , Pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl or 4- (C _1-4 ) alkylpiperazin-1-yl Is reacted with a hydrazide or a protected derivative thereof, followed by a base and, if necessary, deprotection so that R ² is a group of formula (b) and R ⁶ is hydro and R ⁷ is hydro, aminomethyl , (C _1-4 ) alkylaminomethyl, di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazine To obtain a compound of formula I which is -1-ylmethyl or 4- (C _1-4 ) alkylpiperazin-1-ylmethyl; or

(i) reacting and sulfiding a compound of formula 11 (wherein each n, t, R ⁴ and R ⁵ are as defined in formula I above) with a strong base to yield a compound of formula I wherein R ³ is hydro; do or:

or

(j) a compound of formula 11 wherein each n, t and R ¹ are as defined in formula I above, a compound of formula L- (CH ₂ ) _q R ⁹ , wherein L is a leaving group, each q and R ⁹ are as defined in formula I) and the reaction was, sulfide by R ² is a group of formula (a) R ³ is - (CH _{2) q} R ⁹ the obtained compounds of formula (I), or; or

(k) reacting a compound of Formula 11, wherein R ⁴ and R ⁵ are each hydro and each n, t and R ¹ are as defined in formula I above, reacts with amino aryl- or alkylsulfonate to R ² To obtain a compound of formula (I) wherein is a group of formula (a) and R ³ is amino; or

(1) reacting a compound of Formula 11, wherein R ⁴ and R ⁵ are each hydro and each n, t and R ¹ are as defined in Formula I above with an appropriate N, N-disubstituted methylene ammonium salt And sulfided to give R ² a group of formula (a) and R ⁵ is di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl To obtain; Or (m) a compound of formula 16 wherein R ³² is cyano or (C _1-4 ) alkyloxycarbonyl and each n, t and R ¹ are as defined in formula (I) After reacting with a compound of R ³³ C (O) L and treating with thiocyanic acid, R ² is a group of formula (a), R ² is hydro, R ⁵ is cyano or (C _1-4 ) alkoxycarbo Or a compound of formula I wherein R ⁴ is hydro, (C _1-4 ) alkyloxycarbonyl or (C _1-4 ) alkyl;

or

(n) A compound of formula 24, wherein n, t and R ¹ are as defined in formula I above, is reacted with isothiocyanate and treated with a base so that R ² is represented by formula (c) Or a compound of formula I wherein R ⁸ is hydro;

or

(o) a compound of formula (I) wherein R ⁵ is hydroxymethyl is a compound of formula H ₂ N (O) R ³¹ or an ammonium salt of formula NH ₄ ⁺ -OC (O) R ³¹ , wherein R ³¹ is hydrogen R ⁵ is formylaminomethyl, (C _1-4 ) alkylcarbonyl-aminomethyl or trifluoro (C ₁ ), and reacted with (C _1-4 ) alkyl or trifluoro (C _1-4 ) alkyl). _-4 ) Obtain a compound of formula (I) which is alkylcarbonylaminomethyl, and optionally further hydrolyze the compound to give an acid addition salt of the compound of formula (I) wherein R ³ and R ⁴ are each hydro and R ⁵ is aminomethyl To obtain; or

(p) reacting a compound of formula I wherein R ⁵ is hydroxymethyl with urea to obtain a compound of formula I wherein R ⁵ is ureidomethyl; or

(q) reacting a compound of Formula I wherein R ⁵ is cyano with a hydrazonic acid derivative to obtain a compound of Formula I wherein R ⁵ is 1H-tetrazol-5-yl; or

(r) reducing the compound of formula I wherein R ⁵ is cyano to afford a compound of formula I wherein R ⁵ is aminomethyl; or

(s) hydrolyzing the compound of formula I wherein R ⁵ is cyano to obtain a compound of formula I wherein R ⁵ is carbamoyl; or

(t) reacting a compound of formula I wherein R ⁵ is cyano with ethylenediamine to give a compound of formula I wherein R ⁵ is 4,5-dihydroimidazol-2-yl; or

(u) reacting a compound of formula (I) wherein R ⁵ is cyano with a compound of formula (CH ₃ ) ₂ AlNR ¹⁵ R ¹⁶ , wherein R ⁵ is -C (NH) NR ¹⁵ R ¹⁶ , and R ¹⁵ and R ¹⁶ are Obtaining a compound of formula I as defined in I; or

(v) reducing the compound of formula I wherein R ⁵ or R ⁴ and R ⁵ are both ethoxycarbonyl to obtain a compound of formula I wherein R ⁵ or R ⁴ and R ⁵ are all hydroxymethyl; or

(w) converting a compound of formula (I) wherein R ⁵ is hydroxymethyl, to a compound of formula 28, wherein n, t and R ¹ are as defined in formula (I): The compound is synthesized with a common stone HNR ³⁶ R ³⁷ wherein R ³⁶ and R ³⁷ are independently (C _1-4 ) alkyl or together — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, — (CH ₂ ) ₂ -O- (CH _{2) 2} - or ^{_{- (CH 2) 2 -NR 38}} - (CH 2) 2 - , and wherein R ³⁸ is reacted with an amine of the hydro or (C _1-4) alkyl) R ⁵ Valent aminomethyl, (C _1-4 ) alkylaminomethyl, di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl To obtain a compound of formula (I) which is piperazin-1-ylmethyl or 4- (C _1-4 ) alkylpiperazin-1-ylmethyl:

or

(x) reacting a compound of formula (I) wherein R ⁴ is formyl with hydroxylamine hydrochloric acid and reducing to form a compound of formula (I) wherein R ⁴ is aminomethyl; or

(y) reacting a compound of formula I wherein R ⁴ is formyl with an amine of the general formula NH ₂ R ¹⁰ in the presence of a chemical reducing agent or by catalytic hydrogenation, wherein R ⁴ is —CH ₂ NHR ¹⁰ wherein R ¹⁰ is formula I To form a compound of formula (I); or

(z) alkylating a compound of formula I wherein R ⁴ is formyl to produce a compound of formula I wherein R ⁴ is 1-hydroxy (C _1-4 ) alkyl; or

(aa) a compound of formula (I) wherein R ³ , R ⁵ or R ⁶ is amino or R ⁴ , R ⁵ or R ⁸ is aminomethyl is reacted with an appropriately substituted amidine so that R ³ , R ⁵ or R ⁶ is- NHC (NR ¹¹ ) NHR ¹² or R ⁴ , R ⁵ or R ⁸ is —CH ₂ NHC (NR ¹¹ ) NHR ¹² , R ¹¹ is hydro, acetyl or t-butoxycarbonyl and R ¹² is acetyl or to yield the corresponding compound of formula I that is t-butoxycarbonyl; or

(bb) R ³ , R ⁵ or R ⁶ is -NHC (NR ¹¹ ) NHR ¹² or R ⁴ , R ⁵ or R ⁸ is -CH ₂ NHC (NR ¹¹ ) NHR ¹² and R ¹¹ is hydro, acetyl or a compound of formula (I) wherein t-butoxycarbonyl and R ¹² is acetyl or t-butoxycarbonyl is reacted with an acid so that R ³ , R ⁵ or R ⁶ is -NHC (NH) NH ₂ or R ⁴ , R To yield a compound of Formula I wherein ⁵ or R ⁸ is -CH ₂ NHC (NH) NH ₂ ; or

(cc) acylating a compound of formula (I) wherein R ³ , R ⁵ or R ⁶ is amino or R ⁴ , R ⁵ or R ⁸ is aminomethyl with an appropriate acylating agent or a protected derivative thereof, followed by deprotection if necessary R ³ , R ⁵ or R ⁶ is -NHR ¹⁰ or R ⁴ , R ⁵ or R ⁸ is -CH2NHR ¹⁰ , and R ¹⁰ is (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) Alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) Groups selected from alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, aroyl and heteroaroyl (the aroyl or heteroaroyl Is optionally further substituted with 1 to 2 substituents independently selected from (C _1-4 ) alkyloxy, cyano, carboxy and (C _1-4 ) alkyloxycarbonyl); or

(dd) reacting a compound of formula I wherein R ³ , R ⁵ or R ⁶ is amino or R ⁴ , R ⁵ or R ⁸ is aminomethyl, reacts with (C _1-4 ) alkyl isocyanate to R ³ , R ⁵ or R To yield a compound of Formula I wherein ⁶ is -NHR ¹⁰ or R ⁴ , R ⁵ or R ⁸ is -CH ₂ NHR ¹⁰ and R ¹⁰ is (C _1-4 ) alkylcarbamoyl; or

(ee) The compounds of formula (I) wherein R ³ , R ⁴ and R ⁵ are each hydroalkylated with an appropriate N, N-disubstituted methyleneammonium salt so that R ³ and R ⁵ are each hydro and R ⁴ is di (C _{1- 4} ) to yield a compound of formula I which is alkylaminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl; or

(ff) R ⁵ is di (C _1-4 ) alkylaminomethyl, piperidine by alkylating a compound of formula (I) wherein R ⁴ is hydro and not R ³ is hydrolyzed with an appropriate N, N-substituted methyleneammonium salt To yield the corresponding compound of formula I which is -1-ylmethyl or morpholin-4-ylmethyl; or

(gg) protecting a compound of formula (I) wherein R ³ is hydro, protecting with a thiol protecting group, alkylating with an appropriate N, N-substituted methyleneammonium salt and deprotecting so that R ³ and R ⁴ are each hydro and R ⁵ is di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl or R ³ is hydro and R ⁴ and R ⁵ are both di (C _1-4 ) alkylaminomethyl To yield a compound of formula (I) which is piperidin-1-ylmethyl or morpholin-4-ylmethyl; or

(hh) A compound of formula (I) or an acid derivative thereof, wherein R ⁵ or R ⁴ and R ⁵ are both carboxy, is reacted with a suitable amine or thiol so that both R ⁵ or R ⁴ and R ⁵ are 1H-tetrazol-5-yl -Aminocarbamoyl, 2- (dimethylamino) ethylcarbamoyl, 4-methylpiperazin-1-ylcarbonyl, methylsulfonylanilinocarbonyl or 2- (dimethylamino) ethylmercaptocarbonyl To produce a compound; or

(ii) reacting a compound of formula (I) wherein R ³ , R ⁶ or R ⁸ is hydro with (C _1-4 ) alkyl acrylate, where R ³ , R ⁶ or R ⁸ is 2- (C _1-4 ) alkyloxy To yield a compound of formula I that is carbonylethyl; or

(jj) R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ are (C _1-4 ) alkyloxycarbonyl or a group further substituted with a (C _1-4 ) alkyloxycarbonyl substituent Hydrolyzing the compound of formula I to produce a compound of formula I wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ are groups further substituted by carboxy or carboxy substituents; or

^{(kk) R 3, R 4} , R 5, R 6, R 7 or R ⁸ is carboxy or O more compounds of the substituted group, the formula I in carboxy substituent folk by ^{R 3, R 4, R 5} , R 6 , Yields a compound of formula I wherein R ⁷ or R ⁸ is a group further substituted with carbamoyl or carbamoyl substituent; or

(ll) a compound of formula (I) wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ is further substituted with a carboxy or carboxy group to react with (C _1-4 ) alcohol to give R ³ , R ^{4, R 5, R 6,} R 7 or R ⁸ is (C _1-4) alkyloxycarbonyl or (C _1-4) create a more compounds of formula I the group is substituted by alkoxycarbonyl group, or; or

(mm) R ¹ is methoxy and / or R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ is aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4) alkyl (wherein, aroyl, heteroaryl, aroyl, aryl and heteroaryl are further substituted by 1 to 2 methoxy-ethoxy substituent) by a demethylating a compound of formula (I) R ¹ is hydroxy, and / or or R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ are aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl, wherein aroyl, hetero Aroyl, aryl and heteroaryl are further substituted with 1 to 2 hydroxy substituents); or

(nn) R ³ , R ⁵ , R ⁶ or R ⁸ is -NHR ¹⁰ , or R ³ , R ⁵ or R ⁷ is -CH ₂ NHR ¹⁰ , wherein R ¹⁰ is aroyl, heteroaroyl, aryl ( Hydrazoic acid is a compound of formula I selected from C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl, wherein aroyl, heteroaroyl, aryl and heteroaryl are further substituted with cyano substituents. Reacted with a derivative so that R ¹⁰ is aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl, where aroyl, heteroaroyl, aryl and heteroaryl are 1H-tetra Further substituted with zol-5-yl substituents); or

(oo) reacting the corresponding non-salt form of the compound of formula I with a pharmaceutically acceptable inorganic or organic acid or base to produce a pharmaceutically acceptable salt; or

(pp) reacting the corresponding acid addition salt or form of base addition salt of the compound of formula I with a suitable base or acid, respectively, to produce a free acid or free base; or

(qq) The mixture of stereoisomers of the compound of formula (I) is separated to form a single stereoisomer.

Compound of Formula 3:

A preferred process for the preparation of each (S) -enantiomer of the compound of formula 3 wherein n is 1 and the amine is bonded at the β-position is shown in Scheme X below:

Scheme X

Wherein t and R ¹ are as defined in formula (I) above.

The compound of formula 3 wherein n is 1 and the amine is bonded at the β-position can be prepared as each (S) -enantiomer (formula 3 (a)) by hydrolyzing the compound of formula 29. The hydrolysis is carried out in a suitable solvent, typically an alcohol (eg methanol, ethanol, isopropanol), preferably in an aqueous base (eg lithium hydroxide monohydrate, sodium hydroxide, aluminum hydroxide, potassium carbonate, etc., preferably hydroxide). Lithium monohydrate) may be used at 25 to 100 ° C., preferably at reflux for 0.5 to 5 hours.

The compound of formula 29 is prepared by hydrogenolysis of the compound of formula 30. The hydrogenolysis is carried out by (i) hydrogenating the compound of formula 30 until the conversion to the corresponding 1-naphthol is completed, (ii) adding sulfuric acid and continuing the hydrogenation reaction This can be accomplished in a two step process to produce compounds of. The hydrogenation of the compound of formula 30 to 1-naphthol is carried out in acetic acid or trifluoroacetic acid (TFA), preferably in acetic acid, in the presence of a suitable catalyst (e.g., a Perman catalyst, palladium on carbon, etc., preferably a Perman catalyst). At a pressure of 1 to 130 psig and a temperature of 10 to 30 ° C. for 0.5 to 4 hours. The hydrogenation of 1-naphthol is carried out by adding 1 to 10 equivalents of sulfuric acid or perchloric acid, preferably 4 to 6 equivalents, and maintaining the hydrogenation for 3 to 120 hours under the same conditions. Alternatively, the hydrocracking reaction is carried out in a one step process involving the hydrogenation of compound 30 in the presence of a suitable catalyst in perchloric acid in sulfuric acid or acetic acid. Single process hydrolysis is carried out for 3 to 120 hours at a pressure of 1 to 130 psig and a temperature of 10 to 30 ° C.

Compounds of Formula 30 are prepared by intramolecular Friedel-Crafts reaction of compounds of Formula 31. The reaction converts the compound of formula 31 to the corresponding acid chloride and treats the acid chloride with the appropriate Lewis acid (eg ammonium chloride, hydrogen fluoride, etc., preferably ammonium chloride) to give the compound of formula 30 By doing so. Conversion to acid chloride is carried out at 0 to 10 ° C., preferably at 5 to 10 ° C., using an appropriate chlorinating agent in methylene chloride (eg phosphorus pentachloride, thionyl chloride, oxalyl chloride, preferably phosphorus pentachloride). At 0.5 to 2 hours. Treatment with Lewis acid and the resulting ring closure reaction are carried out at 0 to 10 ° C., preferably at 5 to 10 ° C. for 1 to 3 hours. Preferably, the crude product is separated by recrystallization from methanol / water or isopropanol / water mixture; It is then crystallized from the toluene / heptane mixture if necessary.

The compound of formula 31 is prepared by hydrogenolysis of the compound of formula 32. The hydrocracking reaction is carried out with a suitable catalyst (e.g., 20% palladium hydroxide on carbon (Perman's catalyst), paradium on carbon, etc., preferably Perman's catalyst) and 1-5 equivalents, preferably 1.5-2 equivalents, sulfuric acid in glacial acetic acid. It is carried out by hydrogenation for 2 to 48 hours at a pressure of 1 to 60 psig and a temperature of 5 to 30 ° C. in the presence of.

Compounds of Formula 32 are prepared by subjecting optionally substituted benzene to Friedel-Craft alkylation with N- (trifluoroacetyl) -L-aspartic anhydride. The alkylation is preferably from 25 to 40 ° C., preferably in the presence of Lewis acids (eg aluminum chloride, tin chloride, hydrogen fluoride, etc., preferably aluminum chloride) in a suitable solvent (eg methylene chloride, preferably methylene chloride). Preferably at reflux for 2 to 5 hours.

N- (trifluoroacetyl) -L-aspartic anhydride is prepared by reacting L-aspartic acid with trifluoroacetic anhydride (TFAA). Since the reaction is exothermic, it should be carried out under conditions capable of dissipating heat when using more than 100 g of reactant. For example, a convenient method of carrying out the reaction is to heat 2 to 4 equivalents, preferably 2.3 to 2.5 equivalents of TFAA to 30 to 40 ° C., preferably to reflux, followed by one equivalent of L-aspartic acid. The reaction proceeds easily, but at a rate such that the heat generated by the reaction can be dispersed by reflux. L-aspartic acid is preferably added to TFAA for 30-60 minutes as a solution in TFA.

Scheme XIII can be carried out except that D-aspartic acid is used instead of L-aspartic acid to prepare (R) -enantiomer of the compound of formula 3 (a). A more detailed description of the reaction step for Scheme XII is provided in Example 6.

Compound of Formula 6:

Compounds of formula 6 can be prepared by reducing the corresponding compounds of formula 7. The reduction reaction is carried out in sodium borohydride or a suitable solvent (eg diethyl ether, THF, 1,2-) in a suitable solvent, typically an alcohol (eg ethanol, methanol, isopropanol, a suitable mixture of alcohols of a suitable solvent, etc.). Dimethoxyethane, any suitable mixture of suitable solvents, etc.) using a chemical reducing agent such as lithium aluminum hydride at 0-80 ° C. for 1-2 hours (see Example 1 for more details).

Another method for preparing a compound of Formula 6 wherein n is 0 or 1 and hydroxy is bonded to the β-position is shown in Scheme XI below:

Scheme XI

Wherein n is 0 or 1 and t and R ¹ are as defined in formula (I) above.

Compounds of formula (6) wherein n is 0 or 1 and hydroxy is bonded to the β-position (Formula 6 (b)) are reacted with 3-chloroperoxybenzoic acid (m-CPBA) It can be prepared by producing the epoxide of formula 33 and then reducing the epoxide to produce the corresponding β-alcohol. The reaction with m-CPBA is carried out in a suitable solvent (eg benzene, methylene chloride, chloroform, any suitable mixture of suitable solvents, etc.) at 0-20 ° C., preferably at about 0 ° C. for 0.5-5 hours. Reduction of the epoxide can be carried out by catalytic hydrogenation (eg H ₂ , 10% palladium on carbon, etc.) in a suitable solvent (eg ethyl acetate, ethanol, isopropanol, any suitable mixture of suitable solvents, etc.). .

The compound of formula 34 may be prepared at a temperature of 20 to 110 ° C., typically using p-toluenesulfonic acid, with the α-alcohol of formula 6 (a) in a suitable solvent (eg benzene, toluene, dichloroethane, methylene chloride, etc.) At 60 to 100 ° C., preferably at about 80 ° C. for 1 to 5 hours. A detailed description of this paragraph and the reaction steps disclosed in that paragraph is provided in Example 2.

Compounds of formula (I) can be prepared from each stereoisomer of the starting material as their respective stereoisomers. Starting materials can be prepared as individual stereoisomers by any of the degradation methods described above or by any method known to those skilled in the art. For example, compounds of formula 6 can be prepared as individual stereoisomers by kinetic enzymatic digestion using suitable enzymes (eg, pig pancreatic lipase, Candida silindadracea, pancreatin, etc.).

In contrast, certain starting materials in the process for preparing compounds of formula I can be prepared as their respective stereoisomers by chiral synthesis. For example, compounds of formula 6 can be prepared as their respective stereoisomers by chiral reduction of the corresponding compound of formula 7. The compound of formula 6, wherein hydroxy is bonded at the α-position, reacts the corresponding compound of formula 7 with (S) -1-aza-2-boro-3-oxo-4,4-diphenyl [3.3.0] in THF. ] Reduced with borohydride in the presence of bicyclooctane to prepare as (R) -enantiomer. Similarly, (S) -enantiomers can react with compounds of Formula 7 in the presence of (R) -1-aza-2-boro-3-oxo-4,4-diphenyl [3.3.0] bicyclooctane. It can be prepared by reducing.

Compounds of formula 6 wherein hydroxy is bonded at the β-position can be prepared by reducing the corresponding compounds of formula 7 with lithium aluminum hydride in the presence of (1R, 2S) -N-methylephedrine and 2-ethylaminopyridine. Can be. Similarly, (S) -enantiomers can be prepared by reducing the compound of formula 7 in the presence of (1R, 2S) -N-methylephedrine and 2-ethylaminopyridine.

Compound of formula 7:

Compounds of formula 7 may be purchased commercially or readily prepared for those skilled in the art. For example, suitable compounds of Formula 7 can be prepared by oxidizing the available compounds of Formula 6. Oxidation of the compound of formula 6 can be carried out using a suitable oxidizing agent (eg, des-martin reagent) in a suitable solvent (eg, THF, in methylene chloride).

The compound of formula 7 wherein n is 0 or 1 and oxo is bonded at the α-position is shown in Scheme XII:

Scheme XII

Wherein n is 0 or 1 and t and R ¹ are as defined in formula (I) above.

Compounds of formula 7 wherein n is 0 or 1 and oxo is bonded at the α-position (formula 7 (a)) are suitable solvents (e.g. methylene chloride, carbon disulfide, nitrobenzene, any suitable mixture of suitable solvents) Etc.) may be prepared by reacting a compound of formula 35 with Lewis acid (eg, aluminum chloride, aluminum bromide, boron trifluoride, hydrogen fluoride, etc.). The reaction is carried out in the presence of carbon disulfide at 20 to 45 ° C., typically at 30 to 45 ° C., preferably at about 45 ° C. for 1 to 8 hours.

The compound of formula 35 is selected from 20 to 40 ° C., typically from 10 to 30 ° C., preferably from about 20 ° C. to 2 to 18 in a suitable solvent (eg methylene chloride, dichloroethane, any suitable mixture of suitable solvents, etc.). The compound of formula 36 can be prepared by reaction with a chlorinating agent (e.g., oxalyl chloride, tinoyl chloride, phosphorus pentachloride, etc., preferably oxalyl chloride) over time. A detailed description of this paragraph and the reaction steps disclosed in that paragraph is provided in Example 1.

The compound of formula 36 wherein n is 0 reacts with ethylacrylate and bromo- or urodobenzene optionally substituted in a suitable solvent (eg DMF, dimethylacetamide, DMPU, any suitable mixture of suitable solvents, etc.). Can be prepared by reduction and hydrolysis. The reaction with ethylacrylate is carried out at 70 to 110 ° C., typically 80 to 100 ° C., preferably at about 90 ° C. in the presence of a suitable palladium catalyst (eg bis (triphenylphosphine) palladium (II) chloride). To 72 hours. The reduction reaction can be carried out by catalytic hydrogenation under standard conditions. The hydrolysis can be carried out using an aqueous base in a suitable solvent such as aqueous sodium hydroxide in ethanol, aqueous sulfuric acid in dioxane and the like.

Similarly, a compound of formula 36 wherein n is 1 is reacted with 3-butan-1-ol optionally substituted bromo- or iodobenzene in a suitable solvent (eg, DMF and triethylamine, etc.), It can be prepared by reduction and oxidation. The reaction with 3-butyn-1-wool is carried out at 80 to 90 ° C., preferably at about 85 ° C., for 4 to 24 hours in the presence of a suitable palladium catalyst (eg, bis (triphenylphosphine) palladium (II) chloride). Perform. The oxidation reaction can be carried out using a suitable oxidizing agent (eg potassium dichromate (VI), potassium permanganate, etc.).

The process for preparing the compound of formula 7 wherein n is 1 and oxo is bonded to the β-position is shown in Scheme XIII below:

Scheme XIII

Wherein t and R ¹ are as defined in formula (I).

Compound of formula 7 wherein n is 1 and oxo is bonded at the β-position (formula 7 (b)) converts the compound of formula 38 to the corresponding acid chloride (formula 37) and converts the acid chloride to Lewis It can be prepared by reaction with ethylene in the presence of an acid (eg, aluminum chloride, boron trifluoride, aluminum bromide, etc.). Conversion to acid chloride is carried out using a suitable chloride (eg, thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc.) in a suitable solvent (eg methylene chloride, dichloroethane, any suitable mixture of suitable solvents, etc.). It is carried out at 40 ° C., typically at 20 to 30 ° C., preferably at about 20 ° C. for 2 to 18 hours. The reaction with ethylene is carried out in a suitable solvent (e.g. methylene chloride, carbon disulfide, any suitable mixture of suitable solvents, etc.) at a rate sufficient to maintain the reaction mixture below -40 ° C, preferably below -60 ° C. Acid chloride is added and the mixture is bubbled with ethylene gas for 0.1 to 0.5 hours at -78 to -40 ° C, typically -60 to -78 ° C, preferably about -78 ° C.

The process for the preparation of compounds of formula 7 wherein n is 2 and oxo is bonded at the β-position is shown in Scheme XIV:

Scheme XIV

Wherein t and R ¹ are as defined in formula (I).

Compounds of formula 7 wherein n is 2 and oxo is bonded to the β-position react the compound of formula 39 with sodium nitrite in a suitable solvent (eg, acetic acid-water, trifluoroacetic acid-water, acetic acid-ethanol, etc.). Can be prepared. The reaction is carried out at −15 to 20 ° C., typically at −10 to 0 ° C., preferably at about 0 ° C. for 1 to 18 hours.

The compound of formula 39 is reacted with trimethylsilyl cyanide (TMSCN) and zinc chloride in a suitable solvent (e.g. methylene chloride, any suitable mixture of suitable solvents, etc.) with compound of formula 7 (c) It is prepared by producing and reducing the compound. The reaction with TMSCN is carried out at 0-20 占 폚, typically 10-20 占 폚, preferably about 20 占 폚 for 1-18 hours. The reduction is carried out using a chemical reducing agent in a suitable solvent. A detailed description of this paragraph and the reaction steps disclosed in that paragraph is provided in Example 4.

The process for preparing the compound of formula 7 wherein n is 2 and oxo is bonded at the γ-position is shown in Scheme XV:

Scheme XV

Wherein t and R ¹ are as defined in formula (I).

Compound 7 of Formula 7 wherein n is 2 and oxo is bonded at the γ-position (Formula 7 (e)) is subjected to ring closure by treating the compound of Formula 42 with sodium ethoxylate to obtain a compound of Formula 41. The compound of formula 41 can then be hydrolyzed to give the corresponding acid and decarboxylated. The reaction with sodium ethoxylated and thus the ring closure reaction is carried out in a suitable solvent (e.g. toluene, ethanol, any suitable mixture of suitable solvents, etc.) from 80 to 110 ° C, typically from 90 to 110 ° C, preferably about 100 ° C. Perform on Hydrolysis is carried out by heating in an aqueous base or acid. The decarboxylation reaction is carried out at 80 to 125 ° C., typically at 90 to 110 ° C., preferably at about 100 ° C. for 4 hours. The compound of formula 42 may be prepared by reducing the compound of formula 43. The reduction reaction can be carried out by catalytic hydrogenation (eg H ₂ , palladium on carbon, etc.).

Compounds of formula 43 can be prepared by reacting optionally substituted dibromo or diiodo benzene with ethylacrylate. The reaction with ethylacrylate is 75 to 130 in the presence of a suitable palladium catalyst (eg bis (triphenylphosphine) palladium (II) chloride, etc.) in a suitable solvent (eg DMF, any suitable mixture of suitable solvents, etc.). At 72 ° C., typically at 85 ° C.-105 ° C., preferably at about 95 ° C. for 72-168 hours. A detailed description of this paragraph and the reaction steps disclosed in that paragraph is provided in Example 5.

Process for the preparation of the compound of formula II:

The process for the preparation of compounds of Formula II wherein R ¹⁸ is a group of formula (d) and R ²¹ is —CH ₂ NR ²⁵ R ²⁶ is shown in Scheme XVI:

Scheme XVI

Wherein n, t, R ¹ , R ²⁵ and R ²⁶ are as defined in Formula II above.

Compounds of formula II wherein R ¹⁸ is a group of formula (d) and R ²¹ is —CH ₂ NR ²⁵ R ^{26 may be selected} from R in a suitable solvent (eg, DMF, methylene chloride, THF, any suitable mixture of suitable solvents, etc.). ⁵ can be prepared by removing all the protecting groups present after the compound of formula I (a) a -CH ₂ NR ²⁵ reaction with a protected derivative of L- amino acids. Reactions with L-amino acids include non-nucleophilic bases (eg DIEA, N, N-dicyclohexylmethylamine, etc.) and peptide coupling agents (eg PyBOP, benzotriazol-1-yloxy (dimethylamino)- Phosphonium hexafluorophosphate, N, N-dicyclohexylcarbodiimide, bromotris (pyrrolidin-1-yl) phosphofonium hexafluorophosphate, etc.) in the presence of 20 to 80 ° C., preferably about It is carried out at 20 ° C. for 8 to 24 hours (see Example 51 for details).

Protected L-amino acids are prepared by reacting a suitable L-amino acid with a suitable protecting group (eg, di-t-butyldicarbonate, 9-fluorenylmethylsuccinimidylcarbonate, etc.). For example, protected derivatives of L-lysine are prepared by reacting L-lysine with di-t-butyldicarbonate in a suitable solvent (eg, THF, DMF, any suitable mixture of suitable solvents, etc.). The reaction is carried out at 0 to 20 ° C., preferably at about 20 ° C. for 8 to 48 hours. Removal of the protecting group can be carried out by acid hydrolysis (eg 15% hydrogen chloride) in a suitable solvent (eg ethyl acetate, 1,2-dimethoxyethane, any suitable mixture of suitable solvents, etc.). The 9-fluorenylmethoxycarbonyl protecting group can be removed with piperidine in DMF. Carbobenzyloxy protecting groups can be removed by hydrogenation with palladium on carbon.

Similarly, compounds of formula II wherein R ¹⁸ is a group of formula (d) and R ²⁰ is -CH ₂ NR ²⁵ R ²⁶ are derived from compounds of formula I (a) wherein R ⁴ is -CH ₂ NR ²⁵ Manufacture. Compounds of formula II wherein R ¹⁸ is a group of formula (d) and R ²¹ is -NR ²⁵ R ²⁶ are prepared from compounds of formula I (a) wherein R ⁵ is -NHR ²⁵ . Compounds of formula II wherein R ¹⁸ is a group of formula (e) and R ²³ is -CH ₂ NR ²⁵ R ²⁶ are prepared from compounds of formula I (b) wherein R ⁷ is -CH ₂ NHR ²⁵ . Compounds of formula II wherein R ¹⁸ is a group of formula (d) and R ¹⁹ is —NR ²⁵ R ²⁶ are prepared from compounds of formula I (a) wherein R ³ is —NHR ²⁵ . Compounds of formula II wherein R ¹⁸ is a group of formula (f) and R ¹⁵ is -NR ²⁵ R ²⁶ are prepared from compounds of formula I (c) wherein R ⁸ is -NHR ²⁵ .

Process for preparing compound of formula III:

The process for the preparation of compounds of formula III wherein R ²⁷ is a group of formula (g) is shown in Scheme XVII:

Scheme XVII

Wherein n, t, R ¹ and R ²⁸ are as defined in formula III.

Compounds of formula III wherein R ²⁷ is a group of formula (g) (formula 46) are those in which R ³ is hydrophilic in a suitable solvent (e.g., ethyl acetate, ethylenedichloride, THF, any suitable mixture of suitable solvents, etc.) It may be prepared by reacting a compound of Formula I (a) with a compound of Formula 47 and then removing all existing protecting groups. The reaction with the compound of formula 47 is carried out at 20 to 110 ° C, preferably at about 80 ° C for 1 to 4 hours.

The compound of formula 47 may be a compound of formula X-SR ²⁸ (where X is halo) or a protected derivative thereof in a suitable solvent (eg ethylenedichloride, carbon tetrachloride, 1,1,1,2-tetrachloroethane Etc.) to react with potassium phthalimide. The reaction is carried out at −30 to 20 ° C., preferably at about −20 ° C. for 1 to 3 hours. Compounds of formula X-SR ²⁸ can be readily prepared by those skilled in the art. For example, a compound of the general formula X-SR ²⁸ wherein X is bromo and R ²⁸ is 2-t-butoxycarbonyl-2- (t-butoxycarbonylamino) ethyl is N- ( t-butoxycarbonyl) cysteine can be prepared by reaction with bromine in a suitable solvent (eg dichloroethane, etc.). The reaction is carried out at −40 to 20 ° C., preferably at about −23 ° C. for 1 to 3 hours. A detailed description of the reaction steps initiated by Scheme XVII is provided in Example 52.

Similarly, compounds of formula III wherein R ²⁷ is a group of formula (h) are prepared from compounds of formula I (b). Compounds of formula III wherein R ²⁷ is formula (i) are prepared from compounds of formula 1 (c) wherein R ⁸ is hydro.

Example 1

5,6-difluoro-1-hydroxyindane

The following is a method for preparing a compound of Formula 6 wherein n is 0, t is 2 and R ¹ is fluoro.

3- (3,4-difluorophenyl) propionic acid (80.0 g, 0.43 mol) was dissolved in 3 drops of DMF and 350 ml methylene chloride. Oxalyl chloride (75 ml, 0.860 mol) was added and the mixture was stirred at room temperature under nitrogen for about 3 hours. Excess oxalyl chloride was removed by evaporation and the residue was co-evaporated twice with 200 ml of carbon tetrachloride to give 95.0 g of oily residue.

Aluminum chloride (200 g) was suspended in 800 ml of disulphide carbon and the suspension was cooled to 0 ° C. A residue solution in 300 ml of carbon disulfide was added to the suspension for 20 minutes and the mixture was stirred at reflux for 4 hours. The mixture was poured into 2 kg of crushed ice and the aqueous layer was extracted with ethyl acetate (3 x 300 ml). Both the carbon disulfide layer and the ethyl acetate extract were dried over magnesium sulphate, filtered and collected. The solvent was removed by evaporation and the residue was recrystallized from isopropyl ether to give 54.3 g of 5,6-difluoroindan-1-one in the solid state. The mother liquor was purified by column chromatography on silica gel (elute: 10% ethyl acetate / hexane) to give 5.2 g of 5,6-difluoroindan-1-one.

5,6-Difluoroindan-1-one (59.3 g, 0.353 mol) was dissolved in 1 L of ethanol and sodium borohydride (6.68 g, 0.176 mol) was added. The mixture was stirred for 48 hours and ethanol was removed by evaporation under reduced pressure. The residue was partitioned between diethyl ether and water and the mixture was acidified with 1N hydrochloric acid. The mixture was dried over magnesium sulfate and filtered. The solvent was evaporated to give 5,6-difluoro-1-hydroxyindane in oil state (59.6 g).

Using the other starting material instead of 3- (3,4-difluorophenyl) propionic acid and performing as in Example 1 to prepare the following compounds of the general formula 6:

Replacement with 3- (3,5-difluorophenyl) propionic acid to give 5,7-difluoro-1-hydroxy-indane (melting point: 102-103 ° C.);

Replacement with 4- (2,4-difluorophenyl) butyric acid to give 5,7-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene in oil state;

Replacement with 4- (3,4-difluorophenyl) butyric acid to give 6,7-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene in oil state;

Replacement with 4- (4-fluorophenyl) butyric acid to give 7-fluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene in oil state;

Replacement with 4- (3-fluorophenyl) butyric acid to give oily 6-fluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene;

Substituted with 4- (3,5-difluorophenyl) butyric acid to give 6,8-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene (melting point: 102-103 ° C.) It was.

Example 2

5,6-difluoro-2-hydroxyindane

The following is a method for preparing a compound of Formula 6 wherein n is 0, t is 2 and R ¹ is 5- or fluoro at the 6-position.

5,6-difluoro-1-hydroxyindane (59.8 g, 356 mmol) prepared in Example 1 was dissolved in 600 ml of benzene, and p-toluenesulfonic acid monohydrate (3.36 g, 17.66 mmol) was Added. The mixture was heated to 120 ° C., distilled for about 2 hours and cooled. Saturated sodium bicarbonate solution was added and the benzene layer was dried over magnesium sulfate. The benzene layer was filtered and the filter residue was washed with diethyl ether.

The benzene / diethylether mixture was cooled to 0 ° C. and m-CPBA (75.5 g, 0.35 mol) was added for 15 minutes. The mixture was stirred at rt for 5 h. Diethyl ether was removed on a rotary evaporator, methylene chloride was added and the mixture was stirred for 2 hours. Additional m-CPBA (30.0 g, 0.14 mol) was added and the mixture was stirred for 2 hours. The mixture was cooled to 0 ° C. and potassium iodide (45 g) in 150 ml water was added. The mixture was stirred for about 15 minutes and sodium thiosulfate (40 g) in 150 ml water was added. Cugelor distillation (boiling point 60-90 ° C. [0.1 mm]) afforded 30 g of impure 1,2-epoxy-5,6-difluoroindan as an oil.

Impure 1,2-epoxy-5,6-difluoroindan was dissolved in 100 ml of ethanol and hydrogenated with 10% palladium on carbon (450 mg) for 15 hours. The mixture was filtered and evaporated to give 5,6-difluoro-2-hydroxyindane (2.7Z g, 15.0 mmol) (melting point: 57-58 ° C.). Compounds of the following general formula 6 were prepared in the same manner as in Example 2, using another starting material instead of 5,6-difluoro-1-hydroxyindane:

5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxy, replaced by 5,7-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene Obtaining naphthalene (melting point: 93-94 ° C.);

Replacement with 4,6-difluoro-hydroxyindan to give 4,6-difluoro-2-hydroxyindan (melting point: 52-56 ° C.);

6,7-difluoro-1,2,3,4-tetrahydro-2 in oily state, replacing 6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene -Obtain hydroxynaphthalene;

6,8-difluoro-1,2,3,4-tetrahydro-2-hydroxy, replacing 6,8-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene Naphthalene was obtained.

Example 3

(R) -5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene

t is 2 and R ¹ is fluoro at the 5- and 7-positions.

A mixture of 3,5-difluorophenylacetic acid (100 g, 0.58 mmol) and thionyl chloride (113.7 M, 100 ml, 1.37 mol) was stirred at rt for 15 h. Evaporation gave 3,5-difluorophenylacetyl chloride as an oily residue. A stirred suspension of aluminum chloride (154 g, 1.16 mmol) in 1 L of methylene chloride was cooled to -65 ° C and acid chloride in 200 ml of methylene chloride was added dropwise so that the reaction temperature did not exceed -60 ° C. Ethylene gas was bubbled through the suspension at high speed at −65 ° C. for 10 minutes. The reaction mixture was warmed to 0 ° C. for 2 hours, then cooled to −10 ° C. and treated with 500 ml of water. The organic layer was separated, washed with 100 ml of aqueous sodium chloride and dried over magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was distilled under vacuum (boiling point 90-110 ° C. [0.1-0.7 mm]) to give a clear distillate. 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-one (73.56 g, 0.342 mol) as a white solid by redistillation (boiling point 100-105 ° C. [0.3 mm]) 46 ° C.) was obtained.

A solution of (1R, 2S) -N-methylephedrine (81.3 g, 0.454 mol) in 1.2 L of anhydrous diethyl ether was added to lithium aluminum hydride (1.0 M in diethyl ether, 416 ml, 0.416 mol) for 45 minutes. Was added. The mixture was heated at reflux for 1 hour and then cooled to room temperature. A solution of 2-ethylaminopyridine (110.7 g, 0.907 mol) in 100 ml anhydrous diethyl ether was added over 45 minutes. The mixture was heated at reflux for 1 h and then cooled to -65 ° C. A solution of 5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-one (23.0 g, 0.107 mol) in 100 ml of diethylether so that the reaction temperature does not exceed -60 ° C. Was added drop wise. The mixture was stirred at -65 ° C to -68 ° C for 3 hours so that the reaction temperature did not exceed -60 ° C. The mixture was stirred at -65 to -68 ° C for 10 minutes, warmed to -20 ° C, and 3.0 L of 3N hydrochloric acid was added so that the reaction temperature did not exceed 35 ° C. The diethyl ether layer was separated, washed with 200 ml of saturated sodium chloride and dried over magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. Crystallize from 20 ml of diethyl ether and 200 ml of hexane and dry under vacuum to give (R) -5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene (10.87 g , 0.05 mol) (melting point: 85 ° C) was obtained. [a] _D ²⁵ = + 36.03 ° (c = 1.59, CHCl ₃ ).

Compounds of the following general formula 6 were prepared in the same manner as in Example 3 using another starting material instead of 3,5-difluorophenylacetic acid:

Substitution with 3-fluorophenylacetic acid gave (R) -7-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, melting point: 59-61 ° C., [α] _D ²⁵ = + 48.8 ° (c = 2.0, CHCl ₃ );

Substitution with 4-fluoro wasteniylacetic acid afforded (R) -6-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, [α] _D ²⁵ = + 49.2 ° (c = 1.84 , CHCl ₃ );

Substitution with phenylacetic acid to give (R) -1,2,3,4-tetrahydro-2-hydroxynaphthalene in oil state, [α] _D ²⁵ = + 62.2 ° (c = 1.6, CHCl ₃ );

Substitution with 1,3-difluorophenylacetic acid gave (R) -6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene. Melting point: 88-92 ° C., [α] _D ²⁵ = + 39.0 ° (c = 2.2, CHCl ₃ ).

(S) -5,7-difluoro-1,2,3,4 as described in Example 3, using (1R, 2S) -N-methylephedrine instead of (1S, 2R) -N-methylephedrine Tetrahydro-2-hydroxynaphthalene (melting point: 84-85 ° C., [α] _D ²⁵ = + 37.4 ° (c = 2.6, CHCl ₃ )) was obtained.

Using other starting materials instead of 3,5-difluorophenylacetic acid and reducing without using (1R, 2S) -N-methylephedrine or 2-ethylaminopyridine, was carried out as in Example 3 Compounds were prepared:

Replacement with 4-bromophenylacetic acid to give 6-bromo-1,2,3,4-tetrahydro-2-hydroxynaphthalene in oil state;

Replacement with 4-chlorophenylacetic acid to give 6-chloro-1,2,3,4-tetrahydro-2-hydroxynaphthalene in oil state;

Substitution with 3-chlorophenylacetic acid to give 7-chloro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, melting point: 79-81 ° C;

Replacement with 3,5-dichlorophenylacetic acid to give 5,7-dichloro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, melting point: 84-86 ° C .;

Replacement with 3,5-difluorophenylacetic acid to give 5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene;

Replacement with 3,4-difluorophenylacetic acid to give 6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene;

Replacement with 3,4-dichlorophenylacetic acid to give 6,7-dichloro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, melting point: 103-105 ° C;

Substitution with 4-fluorophenylacetic acid gave 6-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene.

Example 4

1,3-difluoro-6,7,8,9-tetrahydro-5H-benzocycloheptene

The following is a method for preparing a compound of Formula 6 wherein t is 2 and R ¹ is fluoro at the 1- and 3-positions.

5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-one (4.0 g, 22.0 mmol), zinc iodide (22.0 mg, 68.9 mmol) and trimethylsilyl cyanide (3.23 ml, 24.2 mmol) was stirred for 18 h at room temperature under argon. TMSCN was evaporated under reduced pressure and the residue (6.13 g) was dissolved in 45 ml of anhydrous diethyl ether. Lithium aluminum hydride (1.0M, 24.2 ml, 24.2 mmol) in diethyl ether was added to the solution at a rate to maintain gentle reflux. The mixture was stirred at rt for 1 h and 0.84 ml of water, 0.84 ml of 15% sodium hydroxide and 1.63 ml of additional water were added successively. The aqueous layer was stirred for 10 minutes, filtered and extracted with diethyl ether. The combined extracts were dried over magnesium sulfate and concentrated to give 4.21 g of residue. The residue was purified by flash chromatography (elution: 10% methanol / methylene chloride) to give 1-aminomethyl-5,7-difluoro-1-hydroxy-1,2,3,4-tetrahydronaphthalene (3.67 g , 17.2 mmol) was obtained.

1-aminomethyl-5,7-difluoro-1-hydroxy-1,2,3,4-tetrahydro-naphthalene (3.58 g, 16.8 mmol) and sodium nitrate in 8 ml of acetic acid and 20 ml of water (2.32 g, 33.6 mmol) was heated to −5 ° C., then warmed to rt and stirred for 18 h. The solvent was removed by evaporation and 3.14 g of the residue was purified by flash chromatography (elution: 50% hexanes / methylene chloride) to give 1.8 g of residue. A mixture of the above purified residue and LAH (9.2 ml 9.2 mmol) in THF was stirred at 0 ° C. for 18 hours and 0.64 ml of water, 0.64 ml of 15% sodium hydroxide and 1.3 ml of additional water were added successively. . The THF layer was dried over magnesium sulfate and concentrated to give 1.8 g of residue. Purification by flash chromatography (elution; methylene chloride) gave 1.3-difluoro-6,7,8,9-tetrahydro-6-hydroxy-5H-benzocycloheptene (1.4 g, 7.06 mmol). .

Example 5

1,3-difluoro-6,7,8,9-tetrahydro-7-hydroxy-5H-benzocycloheptene

The following is a method for preparing a compound of Formula 6 wherein t is 2 and R ¹ is fluoro at the 1- and 3-positions.

1,2-dibromo-3,5-difluorobenzene (24.7 g, 91.6 mmol), bis (triphenylphosphine) palladium (II) chloride (2.57 g, 3.66 mmol) and tri in 300 ml DMF A mixture of ethylamine (51.0 ml, 366 mmol) was stirred under argon at about 85 ° C. for 15 minutes. Hydrazine hydrate (366 μl, 7.54 mmol) was added and the mixture was stirred for an additional 10 minutes. Ethylacrylate (39.7 ml, 366 mmol) was added and the mixture was stirred at about 85 ° C. for about 144 hours under argon. The solvent was removed by evaporation under reduced pressure, and the residue was dissolved in 1.0 L of ethyl acetate. The ethylacrylate solution was washed three times with water and dried over magnesium sulfate. The solvent was evaporated to afford crude ethyl 3- {3,5-difluoro-2- [2- (ethoxycarbonyl) vinyl] phenyl} acrylate (36 g).

Ethyl 3- {3,5-difluoro-2- [2- (ethoxycarbonyl) vinyl] phenyl} acrylate (5.7 g, 18.4 mmol) in 250 ml of ethyl acetate was dissolved on 10% palladium on carbon. Hydrogenated at 60 psi for 4 hours and the mixture was filtered through celite. The solvent was evaporated to afford ethyl 3- {3,5-difluoro-2- [2- (ethoxycarbonyl) ethyl] phenyl} propionate (5.73 g, 22.4 mmol) as a colorless oil.

T-Butoxylated potassium (167 ml, 0.167 mol) in DMF was added to 400 ml of toluene and DMF was removed by evaporation. Ethyl 3- {3,5-difluoro-2- [2- (ethoxycarbonyl) ethyl] phenyl} propionate (5.65 g, 18.0 mmol) was added and the mixture was added at 8 ° C. under argon. Stir for hours. The mixture was cooled to 0 ° C., acidified by addition of 11.5 ml of acetic acid, washed three times with water and dried over magnesium sulfate. Evaporate solvent to ethyl 1,3-difluoro-6,7,8,9-tetrahydro-7-oxo-5H-benzo-cyclohepten-6-carboxylate and ethyl 1,3-difluoro-6 , 7,8,9-tetrahydro-7-oxo-5H-benzocyclohepten-8-carboxylate (4.3 g) was obtained.

The carboxylate isomer (4.2 g) was dissolved in 20 ml of acetic acid and 10 ml of 9N hydrochloric acid and the solution was refluxed for 10 hours. The mixture was cooled to room temperature and extracted with diethyl ether (1 × 200 ml and then 1 × 50 ml). The extracts were combined and mixed with 120 ml of 10% aqueous sodium carbonate. The organic layer was dried over magnesium sulfate and the solvent was removed by evaporation. The residue was purified by flash chromatography (elution: 50% methylene chloride / hexane) to give 1,3-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one (1.5 g, 7.6 mmol) was obtained.

1,3-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one (1.5 g, 7.6 mmol) is dissolved in 30 ml of dry THF and the solution is 0 under argon. Cool to C and add 1M LAH (7.5 ml, 7.5 mmol) in THF for 2 minutes. The mixture was stirred at 0 ° C. for 1 hour and 0.28 ml of water, 0.28 ml of 15% aqueous sodium hydroxide and 0.9 ml of water were added in sequence. The mixture was stirred for 5 minutes, filtered, washed with ethyl acetate and dried over magnesium sulfate. The solvent was evaporated to afford 1,3-difluoro-6,7,8,9-tetrahydro-7-hydroxy-5H-benzocycloheptene (1.55 g, 7.8 mmol) in oil state.

Example 6

(S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid

The following is a method for preparing a compound of Formula 3 wherein n is 1, t is 2 and R ¹ is fluoro at 5- and 7-positions.

(a) Trifluoroacetic anhydride (7.7 kg, 5.3 L, 37.5 mmol) was heated to reflux and a solution of L-aspartic acid (2.0 kg, 15.0 mol) in 9 L trifluoroacetic acid (gradual to 65 ° C) Heated to and stirred for 3 hours) to reflux TFAA for 30 minutes. The mixture was upstream and 9 L of TFA were removed. The remaining mixture was added to 8 L of cold hexane under nitrogen. The hexane mixture was stirred for 3 hours in an ice bath to afford crystalline material. The material was separated by filtration and the filtered residue was washed with about 25 liters of hexane. Drying to constant weight in a vacuum oven at 50 ° C. under nitrogen bleed gave N- (trifluoroacetyl) -L-aspartic anhydride (2.9 kg, 13.7 mol) (melting point: 140-141 ° C., [α]) _D = -27.4 ° (c = 3.28, THF)).

(b) A solution of 1,3-difluorobenzene (2.3 kg, 20.0 mol) in 5 L methylene chloride was added N- (trifluoroacetyl) -L-aspartic anhydride in 25 L methylene chloride. (4.2 kg, 20.0 mol) and aluminum chloride (7.4 kg, 55.5 mol) were added. The temperature of the reaction mixture was gradually increased for 1.5 hours and held at reflux for 3 hours. The mixture was cooled down and added with shaking 10 L of water and 20 L of 6N hydrochloric acid. The methylene chloride layer was separated, washed sequentially with water and brine, and the volatiles were distilled off under atmospheric pressure.

The article was dissolved in 40 L of toluene and 8 L of volatiles were removed by distilling the mixture in vacuo. The solution was heated to 50 ° C. and 8 L of hexane was added. The mixture was cooled to 30 ° C. and 90 L of hexane was added. The mixture was stirred at 25 ° C. for 3 hours to afford crystalline material. The material was separated by filtration and the filtered residue was washed with hexane (3 x 10 L). Dry to constant weight in vacuum oven at room temperature under nitrogen bleed to afford (S) -2-[(trifluoroacetyl) amino] -4- (2,4-difluorophenyl) -4-oxobutanoic acid (5.2 kg , 16.0 mol) (melting point: 82.4-84.0 ° C., [α] _D = + 15.2 ° (c = 0.956, CH ₃ OH)).

(c) (S) -2-[(trifluoroacetyl) amino] -4- (2,4-difluorophenyl) -4-oxobutanoic acid (4.8 kg, 14.7 mol) in 5 L of acetic acid And a mixture of activated carbon Darco ^® (0.4 kg) was stirred at room temperature for 1 hour. The mixture was filtered over a Perman catalyst (0.5 kg, 50% wet) and washed with 15 L glacial acetic acid. The mineral acid (1.2 L, 21.8 mol) in 1 L glacial acetic acid was filtered through the mixture and washed with 2.8 L glacial acetic acid. The reaction vessel was purged three times with vacuum / pressure using nitrogen and then purged six times with hydrogen at 10 psig. The mixture was stirred vigorously for 24 hours under hydrogen at atmospheric temperature. The reaction vessel was then purged with Salsa and the mixture was filtered over 4.6 kg of sodium acetate trihydrate. The filter was washed with 10 liters of glacial acetic acid. Glacial acetic acid was removed by distillation of the mixture in vacuo.

The residue was partitioned between 20 liters of methylene chloride and 40 liters of water. The aqueous layer was extracted with 10 L of methylene chloride and the combined methylene chloride was washed with 10 L of water. The methylene chloride mixture was then dried over sodium sulfate (10 kg) and filtered. The solvent was removed in vacuo and the residue was dissolved in 5 L of methylene chloride. The solution was added to 15 l of hexane under nitrogen such that the temperature of the hexane mixture was within 0-5 ° C. The mixture was allowed to stand for 1 hour to give crystalline material. The material was separated by filtration and the filter residue was washed with 10 L of hexane. (S) -2-[(trifluoroacetyl) amino] -4- (2,4-difluorophenyl) butanoic acid (3.3 kg, 10.4 mol) was dried to constant weight in vacuo at 25 ° C. with nitrogen bleed. Was obtained (melting point: 62-83.5 ° C). Analytically pure samples have a melting point of 86-89 ° C. [a] _D = + 6.8 ° (c = 0.995, CH ₃ OH)).

(d) A suspension of phosphorus pentachloride (2.2 kg, 10.6 mol) in 12 liters of methylene chloride was cooled to 5 ° C. and (S) -4-[(2,4-difluorophenyl) in 12 liters of methylene chloride -2 [(trifluoroacetyl) amino] butanoic acid (3.1 kg, 9.9 mol) was added over 20 minutes. Thin layer chromatography of the fractions quenched with methanol confirmed that butanoic acid was converted to the corresponding acid chloride.

The mixture was stirred for 30 minutes and added to a slurry of aluminum chloride (4.3 kg) in 38.8 L of methylene chloride at a rate such that the slurry temperature was maintained at 1-5 ° C. The reaction mixture was stirred for 1 hour and added to 28 kg of ice and 5.3 kg of concentrated hydrochloric acid. The mixture was stirred for 1 hour and the temperature was raised to 20 ° C.

The aqueous layer was separated and extracted with methylene chloride (2 x 15 L). The methylene chloride layer was washed once with water and combined with the methylene chloride extract. The combined methylene chloride was washed with water. The pH of the aqueous phase was adjusted to 6 by addition of aqueous sodium bicarbonate solution. The methylene chloride layer was washed sequentially with water and brine. Methylene chloride was dried over sodium sulfate and filtered. The mixture was concentrated by evaporation at atmospheric pressure and the residue dissolved in 15 liters of methanol. The methanol solution was distilled off to remove residual methylene chloride and 9.9 L of water were added. The mixture was warmed to 56 ° C., cooled to room temperature and stirred for about 12 hours. Crystalline material was produced and separated by filtration. The filtered residue was washed with 15 L of water. The separated material was dried to constant weight with nitrogen bleed at room temperature under vacuum.

The material was dissolved in 5 L of toluene at a temperature of 90 ° C. and mixed with 10 L of heptane at 80 ° C. The temperature of the mixture was gradually reduced for 1.5 hours. The mixture was then stirred at 5 ° C. for about 12 hours to afford crystalline material. The material was separated by filtration and the filtered residue was washed with 15 L of heptane. (S) -5,7-difluoro-2-[(trifluoroacetyl) amino] -3,4-dihydro- (2H) -naphthalene-1 by drying to a constant weight with nitrogen bleed under vacuum at room temperature -On (2.0 kg, 6.8 mol) was obtained (melting point: 142.4-144.6 ° C., [α] _D = -59.4 ° (c = 0.994, CH ₃ OH)).

(e) (S) -5,7-difluoro-2-[(trifluoroacetyl) amino] -3,4-dihydro- (2H) -naphthalen-1-one (1.1) in 11 L of TFA kg, 3.8 mol) and a reaction vessel with a mixture of Perman catalyst (0.55 kg, 50% wet) were vacuum / pressure purged eight times with nitrogen and then purged eight times with 11 psig of hydrogen. The mixture was stirred vigorously for 24 h under hydrogen (125 psig) at room temperature. Thin layer chromatography showed that naphthalen-1-one was dissolved in (S) -1-hydroxy-5,7-difluoro-2-[(trifluoroacetyl) amino] -3,4-dihydro- (2H)-. It was confirmed that it was converted to naphthalene.

(f) 1 L of TFA-rich sulfuric acid (1.1 L, 19.4 mol) was added and the mixture was stirred for 24 h at room temperature under hydrogen (125 psig). The reaction vessel was then purged with nitrogen and the mixture was filtered through celite and washed with 11 L of TFA. The filtrate was mixed with 2.8 kg of sodium acetate trihydrate and 80 L of water. The mixture was cooled to 10 ° C. to obtain crystalline material. The material was isolated by filtration and the filtered residue was washed with 10 liters of ice water. Drying gave (S) -5,7-difluoro-2-[(trifluoroacetyl) amino] -1,2,3,4-tetrahydronaphthalene (0.8 kg, 2.9 mol) (melting point: 159.9-160.9 ° C., [α] _D = -56.0 ° (c = 1.01, CH ₃ OH)).

(g) (S) -5,7-difluoro-2-[(trifluoroacetyl) amino] -1,2,3,4-tetrahydronaphthalene (20.8) in 187 ml of methanol and 21 ml of water. g, 74.5 mmol) was added lithium hydroxide monohydrate (7.8 g, 0.2 mol). The mixture was stirred at reflux for 30 minutes and diluted with 200 ml of methanol. The diluted mixture was then washed with 60 ml of water, 24.8 ml of concentrated hydrochloric acid and 4.2 g of activated carbon Darco ^. Mixed with. The mixture was stirred for 30 minutes and filtered through celite. The filtrate was distilled until the head temperature reached 75 ° C. The remaining mixture was cooled down and left for about 60 hours. The mixture was cooled in an ice bath to afford crystalline material. The material was isolated by filtration and the filter residue was washed with water. Drying in vacuo at room temperature under nitrogen stream to afford (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid (14.8 g, 67.6 mol) It was. Melting point: 280 ° C. or higher, [α] _D = -66.2 ° (c = 0.162, CH ₃ OH)).

Example 7

(R) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate

The following is a process for the preparation of a compound of formula 5 wherein n is 1, t is 2, R ¹ is fluoro at 5- and 7-positions and L is methoxy.

(R) -5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene (59.0 g, 0.32 mol) and triethylamine (13.8 M, 74.2) prepared in Example 3 ml, 0.53 mol) was cooled using methanol / ice bath. Methanesulfonyl chloride (12.9 M, 37.2 ml, 0.48 mol) was added under argon for 5-10 minutes and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between water and ether, the ether layer was separated and the aqueous layer was extracted with ether. The combined ether layers were washed once each with 1N hydrochloric acid, saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. Evaporation gave (R) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate (87.12 g) as a gray solid. Melting point: 79-80 ° C., [α] _D = + 16.77 ° (c = 2.0, CHCl ₃ )).

(R) -5,7-Difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene was carried out in the same manner as in Example 7, except that another starting material was used. The compounds of were prepared:

Replacement with 1,2,3,4-tetrahydro-2-hydroxynaphthalene to give 1,2,3,4-tetrahydro-maphthalen-2-yl methanesulfonate;

Replacement with (R) -1,2,3,4-tetrahydro-2-hydroxynaphthalene yields (R) -1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;

(S) -5-fluoro-1,2,3,4-tetrahydronaphthalene-2, replaced by (R) -5-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene Obtaining one methanesulfonate;

(S) -6-fluoro-1,2,3,4-tetrahydronaphthalene-2, replaced by (R) -6-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene Obtaining one methanesulfonate;

(S) -7-fluoro-1,2,3,4-tetrahydronaphthalene-2, replaced by (R) -7-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene Obtaining one methanesulfonate;

2-6,7--dichloro-1,2,3,4-tetrahydronaphthalen-2-yl methane, replacing 6,7-dichloro-1,2,3,4-tetrahydro-2-hydroxynaphthalene Obtaining sulfonate;

(-)-6,7-difluoro-1,2,3,4 by replacing (-)-6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene Obtaining tetrahydronaphthalen-2-yl methanesulfonate;

6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl, substituted by 6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene Obtaining methanesulfonate;

(R) -5,7-difluoro-1,2,3,4 by replacing with (S) -5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene Obtaining tetrahydronaphthalen-2-yl methanesulfonate;

5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl, substituted by 5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene Obtaining methanesulfonate;

6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl, substituted by 6,8-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene Obtaining methanesulfonate;

(S) -6,8-difluoro-1,2,3,4 by replacing with (R) -6,8-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene Obtaining tetrahydronaphthalen-2-yl methanesulfonate;

6,8-difluoro-1,2,3,4-tetrahydro by replacing 6,8-difluoro-1,2,3,4-tetrahydro-2-hydroxy-7-methoxynaphthalene -7-methoxynaphthalen-2-yl methanesulfonate;

Replacement with 2-hydroxyindan to give indan-2-yl methanesulfonate;

Replacement with 4,6-difluoro-2-hydroxyindan to give 4,6-difluoroindan-2-yl methanesulfonate;

Replacement with 5,6-difluoro-2-hydroxyindan to give 5,6-difluoroindan-2-yl methanesulfonate;

Replacement with 5,6-difluoro-1-hydroxyindan to give 5,6-difluoroindan-1-yl methanesulfonate;

Substitution with 5,7-difluoro-2-hydroxyindan yielded 5,7-difluoroindan-1-yl methanesulfonate.

Example 8

(S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid

The following is a method for preparing a compound of Formula 3 wherein n is 1, t is 2 and R ¹ is fluoro at 5- and 7-positions.

(S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate (54.0 g) and lithium azide prepared in Example 7 above in 400 ml of DMF (15.8 g, 0.322 mol) was stirred under argon at 50 ° C. for 16 h. The reaction was stopped using 200 ml of water and the mixture was extracted with 1 L of pentane. The extract was washed with 50 ml of water and dried over magnesium sulfate. Evaporation at 35 ° C. under reduced pressure gave (S) -2-azido-5,7-difluoro-1,2,3,4-tetrahydronaphthalene (59.8 g) as a yellow residue.

The azide residue was dissolved in 1.2 L of ethyl acetate, hydrogenated over 10% palladium on carbon (6 g), and hydrogen was refilled every hour to remove the nitrogen gas generated. The mixture was filtered through celite and stirred with ether-based hydrogen chloride (1 N, 250 ml) to afford crystalline material. The material was separated by filtration for 4 hours, and the filtered residue was washed with ethyl acetate. The residual solvent was removed in vacuo to afford (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid (48.2 g, 0.22 mol) as a white solid. Melting point: 280 ° C. or higher, [α] _D = −60.15 ° (c = 2.7, CH ₃ OH)).

(R) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate was carried out in the same manner as in Example 8 except that another starting material was used instead of The compound of formula 3 was prepared:

1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate was replaced with 1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid, melting point: 239-242 ° C .;

Substituted by (R) -1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate to obtain (S) -1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid, melting point : 241-244 ° C .;

(S) -5-fluoro-1,2,3,4-tetrahydronaphthalene in place of (R) -5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate Obtaining 2-ylamine hydrochloric acid, melting point: 280 캜 or higher;

(S) -6-fluoro-1,2,3,4-tetrahydronaphthalene in place of (R) -6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate Obtaining 2-ylamine hydrochloric acid, melting point: 264-265 ° C .;

(S) -7-fluoro-1,2,3,4-tetrahydronaphthalene in place of (R) -7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate Obtaining 2-ylamine hydrochloric acid, melting point: 280 캜 or higher;

6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid replaced by 6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate Obtained melting | fusing point: 280 degreeC or more;

(-)-6,7-difluoro-1,2,3 replacing (-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate To obtain 4-tetrahydronaphthalen-2-ylamine hydrochloric acid;

6,7-difluoro-1,2,3,4-tetrahydronaphthalene-2 in place of 6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate To obtain monoamine hydrochloric acid;

(S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate replaced by (R) -5,7-difluoro-1,2,3 , 4-tetrahydronaphthalen-2-ylamine hydrochloric acid was obtained, melting point: 280 DEG C or higher;

5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2 in place of 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate To obtain monoamine hydrochloric acid;

6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2 in place of 6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate To obtain monoamine hydrochloric acid;

(S) -6,8-difluoro-1,2,3 replacing (R) -6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate To obtain 4-tetrahydronaphthalen-2-ylamine hydrochloric acid;

6,8-difluoro-7-methoxy-1,2 by replacing 6,8-difluoro-1,2,3,4-tetrahydro-7-methoxynaphthalen-2-yl methanesulfonate Obtaining 3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid;

Replacement with 2-indan-2-yl methanesulfonate to obtain indan-2-ylamine hydrochloric acid;

Replacement with 4,6-difluoroindan-2-yl methanesulfonate to give 4,6-difluoroindan-2-ylamine;

Replacement with 5,6-difluoroindan-2-yl methanesulfonate to give 5,6-difluoroindan-2-ylamine hydrochloric acid, melting point: 280 ° C or higher;

Replacement with 5,6-difluoroindan-1-yl methanesulfonate to obtain 5,6-difluoroindan-1-ylamine hydrochloric acid;

Substitution of 5,7-difluoroindan-1-yl methanesulfonate gave 5,7-difluoroindan-1-ylamine hydrochloric acid.

Example 9

5,7-difluoro-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione

The following description is a process for the preparation of compounds of formula I (a) wherein n is 1, t is 2 and R ³ , R ⁴ and R ⁵ are each hydro and R ¹ is fluoro at the 5- and 7-positions; .

(S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (2.05 g, 11.2 mmol) prepared in Example 8, and dimethoxyacetaldehyde in 50 mL of ethanol (1.73 g, 13.1 mmol) was hydrogenated with 10% palladium on carbon (500 mg) for 18 hours. The mixture was filtered and concentrated by evaporation. The residue was mixed with 30 mL of 1N hydrochloric acid and potassium thiocyanate (1.57 g, 16.2 mmol) in 20 mL of ethanol and the mixture was heated at 70-80 ° C. for 18 hours. The mixture was cooled in an ice bath to afford crystalline material, which was separated by filtration. Recrystallization from ethyl acetate / hexanes gave 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (1.27 g, 4.76 mmol) (melting point 250-251 ° C.).

The procedure was the same as in Example 9, except that (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-ylamine was replaced with another starting material. Formula I compounds were prepared:

1- (7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1 in place of 7-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine , 3-dihydroimidazole-2-thione (melting point 215-217 ° C.) was obtained;

1- (6,7-difluoro-1,2,3,4-tetrahydronaphthalene- in place of 6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine 2-yl) -1,3-dihydroimidazol-2-thione242-2 43 ° C.) was obtained;

1- (6,8-difluoro-1,2,3,4-tetrahydronaphthalene- in place of 6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine 2-yl) -1,3-dihydroimidazole-2-thione (melting point 250-251 ° C.) was obtained;

1- (1,2,3,4-tetrahydro-5-methoxynaphthalen-2-yl) -1 substituted with 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine , 3-dihydroimidazole-2-thione (melting point 250-251 ° C.) was obtained;

1- (1,2,3,4-tetrahydro-6-methoxynaphthalen-2-yl) -1 in place of 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine , 3-dihydroimidazole-2-thione (melting point 226-227 ° C.) was obtained;

1- (1,2,3,4-tetrahydro-7-methoxynaphthalen-2-yl) -1 in place of 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine , 3-dihydroimidazole-2-thione (melting point 271-273 ° C.) was obtained;

1- (1,2,3,4-tetrahydro-8-methoxynaphthalen-2-yl) -1 in place of 8-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine , 3-dihydroimidazole-2-thione (melting point 249-257 ° C.) was obtained;

1- (6,8-difluoro-1,2,3,4 by replacing 6,8-difluoro-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine -Tetrahydro-7-methoxynaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (melting point 228-230 ° C.) was obtained;

1- (1,2,3,4-tetrahydro-5-methoxynaphthalen-1-yl) -1, substituted with 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylamine , 3-dihydroimidazole-2-thione (melting point 176-177 ° C.) was obtained;

1- (1,2,3,4-tetrahydro-6-methoxynaphthalen-1-yl) -1 in place of 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylamine , 3-dihydroimidazole-2-thione (melting point 190-192 ° C.) was obtained;

1- (1,2,3,4-tetrahydro-7-methoxynaphthalen-1-yl) -1 in place of 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylamine , 3-dihydroimidazole-2-thione (melting point 142-143 ° C.) was obtained;

1- (4,6-difluoroindan-2-yl) -1,3-dihydroimidazole-2-thione (melting point 185-186) in place of 4,6-difluoroindan-2-ylamine C) was obtained;

1- (5,6-difluoroindan-2-yl) -1,3-dihydroimidazole-2-thione (melting point 255-257) in place of 5,6-difluoroindan-2-ylamine C) was obtained;

Substitution with 5-methoxyindan-1-ylamine gave 1- (5-methoxyindan-1-yl) -1,3-dihydroimidazole-2-thione (melting point 195-196 ° C.);

(+)-1- (4,6-difluoroindan-1-yl) -1,3-dihydroimidazole- replaced by (-)-4,6-difluoroindan-1-ylamine 2-thione (melting point 191-193 ° C.) was obtained;

(-)-1- (4,6-difluoroindan-1-yl) -1,3-dihydroimidazole- replaced by (+)-4,6-difluoroindan-1-ylamine 2-thione (melting point 181-191 ° C.) was obtained;

1- (5,6-difluoroindan-1-yl) -1,3-dihydroimidazole-2-thione (melting point 183-187) in place of 5,6-difluoroindan-1-ylamine C) was obtained; And

1- (5,7-difluoroindan-1-yl) -1,3-dihydroimidazole-2-thione (melting point 212-215) in place of 5,7-difluoroindan-1-ylamine C) was obtained.

Example 10

(-)-6,7-fluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene

The following description is a process for the preparation of compounds of formula 9 wherein n is 1, t is 2 and R ¹ is fluoro at the 6- and 7-positions.

(-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (0.56 g, 3.06 mmol) prepared in Example 8, and 1,1 in 15 mL of ethyl acetate A mixture of '-thiocarbonyldiimidazole (0.82 g, 4.59 mmol) was stirred until the reaction was complete. The solvent was removed by evaporation. Purification of the residue by column chromatography on silica gel (elution: 5% acetone / methylene chloride) gave (-)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydro Naphthalene (0.55 g, 2.42 mmol) ([α] _D ²⁵ -15.5 °, (c = 1.0, CH ₃ OH) was obtained.

The procedure was the same as in Example 10 except that (-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine was replaced with another starting material. The compound of formula 9 was prepared:

2-isothiocyano-1,2,3,4-tetrahydronaphthalene was obtained as an oil by substitution with 1,2,3,4-tetrahydronaphthalen-2-ylamine; And

(+)-6,7-difluoro-2-isothiocyano- in place of (+)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine 1,2,3,4-tetrahydronaphthalene (melting point 206-207 ° C) was obtained.

Example 11

(-)-6,7-difluoro-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione

The following description is a process for the preparation of compounds of formula I (a) wherein n is 1, t is 2 and R ³ , R ⁴ and R ⁵ are each hydro and R ¹ is fluoro at the 5- and 7-positions; .

(-)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene (0.49 g, 2.2 mmol) and 2,2- in DMF prepared in Example 10 A mixture of dimethoxyethylamine (0.23 g, 2.2 mmol) was heated at 85 ° C. for 2.5 h under argon. The solvent was removed under reduced pressure and the residue was dissolved in 2-3 mL of ethanol and 20 mL of 4N hydrochloric acid. The solution was heated and cooled at 85 ° C. for approximately 48 hours to afford crystalline material. The material was separated by filtration and dried. Purification by column chromatography on silica gel (elution: 3% methanol / methylene chloride) (-)-6,7-difluoro-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (0.225 g, 0.84 mmol) (melting point 200-205 ° C., [α] _D ²⁵ -15.5 °, (c = 0.6, CH ₃ Cl / CH ₃ OH)) Obtained.

(+)-(6,7-fluoro-1- (1,2,3,4-tetrahydronaphthalene) to (+)-6,7-difluoro-2-isothio

The process was carried out as in Example 11 except that cyano-1,2,3,4-tetrahydronaphthalene was replaced with (+)-6,7-difluoro-1- (1,2 , 3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione- (0.225 g, 0.84 mmol) (melting point 206-207 ° C., [α] _D ²⁵ 86.98, (c = 1.06, 2: 1 CHCl ₃ / CH ₃ OH).

Example 12

1- (4,6-difluoroindan-1-yl) -1,3-dihydroimidazole-2-thione

The following description is a process for the preparation of compounds of formula I (a) wherein n is 0, t is 2, R ¹ is fluoro at the 4- and 6-positions and R ³ , R ⁴ and R ⁵ are each hydro .

Of 4,6-difluoroindan-1-one (11.3 g, 67.26 mmol), 2,2-dimethoxyethylamine (7.07 g, 67.26 mmol) and sodium cyanoborohydride (4.23 g) in 75 mL methanol The mixture was heated under moderate reflux and stirred under nitrogen for approximately 18 hours. Additional sodium cyanoborohydride (2.12 g) was added and the mixture was heated at 65 ° C. for 20 hours. The solvent was removed by evaporation. Purification of the residue by column chromatography on silica gel (elution: 2.5% methanol / methylene chloride) gave 4.6-difluoroindan-1-yl)-(2,2-dimethoxyethyl) amine.

(4,6-difluoroindan-1-yl)-(2,2-dimethoxyethyl) amine (11.68 g, 45.9 mmol), potassium thiocyanate (4.46 g, 45.9 mmol) in 21.6 mL of 12 N hydrochloric acid A mixture of 86 mL of ethanol and 86 mL of water was heated at 80-85 ° C. for 15 hours. The mixture was cooled in an ice bath and diluted with water to afford crystalline material. The material was separated by filtration and the filter residue was washed with cold ethanol (2 x 25 mL) and 50 mL diethyl ether. Drying afforded 1- (4,6-difluoroindan-1-yl) -1,3-dihydroimidazole-2-thione (5.65 g, 22.2 mmol) (melting point 205-207 ° C).

A compound of the general formula I was prepared by following the same procedure as in Example 12 except for replacing with another starting material for 4,6-difluoroindan-1-one:

1- (1,2,3,4-tetrahydronaphthalen-1-yl) -1,3-dihydroimidazol-2-thione, replacing 1,2,3,4-tetrahydronaphthalen-1-one (Melting point 188-189 ° C.) was obtained;

1- (6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -1, substituted with 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-one 3-dihydroimidazole-2-thione (melting point 190-192 ° C.) was obtained;

1- (5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -1, substituted with 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-one, 3-dihydroimidazole-2-thione (melting point 176-177 ° C.) was obtained;

1- (7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -1, replacing 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-one, 3-dihydroimidazole-2-thione (melting point 142-143 ° C.) was obtained;

Substitution with indan-2-one gave 1- (indan-2-yl) -1,3-dihydroimidazole-2-thione (melting point 210-211 ° C.); And

Substitution with indan-1-one gave 1- (indan-1-yl) -1,3-dihydroimidazole-2-thione (melting point 136-137 ° C.).

Example 13

1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole

The following description is a method for producing the compound of formula 11 wherein n is 1 and t is 0.

A mixture of 1,2,3,4-tetrahydronaphthalen-2-yl metasulfonate (15.74 g, (69.6 mmol) prepared in Example 7 and imidazole (23.68 g, 349 mmol) in 100 mL of DMF was added under argon. Heated for 24 h at 80-90 ° C. The solvent was removed by rotary evaporation under vacuum The residue was dissolved in 500 mL of ethyl acetate and the solution washed with water (5 × 250 mL) The combined aqueous layers were extracted with 500 mL of ethyl acetate. The extract was then washed with water (5 × 250 mL) The combined ethyl acetate extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by rotary evaporation Column chromatography on silica gel (elute: 5%). Purification of the residue by methanol / methylene chloride) gave 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole (5.18 g, 26.1 mmol) (melting point 93-95 ° C.).

4-methylimidazole instead of imidazole and 2-bromo-1,2,3,4-tetranaphthalen-1-one instead of 1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate The procedure was followed as in Example 13 except for the reduction followed by the reduction to give 1- (1,2,3,4-tetrahydronaphthalen-2-yl) -4-methylimidazole.

Example 14

(S) -H- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,3-dihydro-1H-imidazol-4-yl Methyl] formamide

The following description is a process for the preparation of compounds of formula 11 wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁴ is hydro.

Formamide prepared in Example 29, (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2 , 3-dihydro-1H-imidazol-4-ylmethyl] -formamide (1.38 g, 4.27 mmol) and activated Raney ^? The mixture of nickel (11 g) was stirred rapidly at 80 ° C for 1 hour. The mixture was filtered through silite and the filtrate was evaporated to give a white solid (0.98 g). The solid was recrystallized from ethyl acetate / methanol to give (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,3-dihydro -1H-imidazol-4-ylmethyl] formamide (melting point 194-195 ° C.) was obtained.

(S) -N- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already The compound of Formula 11 was prepared as in Example 14 except that the dazol-4-ylmethyl] formamide was replaced with another starting material;

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) 1,3-dihydroimidazole-2-thione hydrochloric acid Alternatively (S)-[3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,3-dihydro-1H-imidazol-4-yl Methyl] amine (melting point 273-274 ° C.) was obtained; And

1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydro-imidazole-2-thione in place of 1- (5,7 -Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole was obtained.

Example 15

3-amino-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione

The following description is a process for the preparation of compounds of formula I (a) wherein n is 1, t is 0, R ³ is amino and R ⁴ and R ⁵ are each hydro.

1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole (198 mg, 1 mmol) prepared in Example 13, and O-mesitylenesulfonylhydroxyamine (215 mg, 1 mmol) in acetonitrile ) Was stirred for 18 h under argon. The reaction mixture was diluted with diethyl ether to give a precipitate of oil. The solvent was decanted off and the residue was washed with diethyl ether (2 × 10 mL). The residual solvent was evaporated in vacuo. The residue and a mixture of lac sulfur (32 mg, 1.0 mmol) in 1 mL of pyridine and 0.5 mL of triethylamine were heated under argon at approximately 90 ° C. for 4 hours. The solvent was removed by evaporation and the residue co-evaporated with toluene. The residue was purified by column chromatography on silica gel eluting with methylene chloride to give 3-amino-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole- 2-thione (5.18 g, 26.1 mmol) (melting point 187-189 ° C.) was obtained.

As in Example 15, except that O-mesitylenesulfonatehydroxyamine and / or 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole are replaced with other starting materials The process proceeded to afford the compound of formula I:

Quaternary-butyl 3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole, substituted by quaternary-butyl bromoacetate -1-yl acetate (melting point 167-169 ° C.) was obtained;

Methyl 4- [3- (1,2,3,4-tetrahydronaphthalene in place of methyl 4-bromobutylate and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole -2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] butyrate;

5- [3- (1,2,3,4-tetrahydro by replacing methyl 5-bromomethylpicolinate and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole Naphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl] picolinate was obtained as an oil;

Methyl 4- [3- (1,2,3,4-tetrahydro replaced by methyl 4-bromomethylbenzoate and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole Naphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl] benzoate (melting point 133-135 ° C.) was obtained;

Methyl 3- [3- (1,2,3,4-tetrahydro replaced by methyl 3-bromomethylbenzoate and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole Naphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl] benzoate (melting point 130-132 ° C.) was obtained;

3- (3,4-dimethoxybenzyl) -1- (1, replacing 3,4-dimethoxybenzyl chloride and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole 2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (melting point 129-131 ° C.) was obtained;

Methyl 4- [3- (1,2,3, substituted with methyl 4-bromomethylbenzoate and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) -4-methylimidazole 4-tetrahydronaphthalen-2-yl) -5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl] benzoate (melting point (140-141 ° C.) was obtained). ;

3- (6-dimethylaminopyridazin-3-yl) in place of 6-dimethylamino-3-bromopyridazine and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (melting point 198-199 ° C.) was obtained;

3- (2-phenylethyl) -1- (1,2,3,4 by replacing 2-bromoethylbenzene and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole -Tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (melting point 140-142 ° C.) was obtained;

Methyl 4- (2- [3- (1,2) by substitution with methyl 4- (2-bromoethyl) benzoate and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole , 3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imadizol-1-yl] ethyl} benzoate (melting point 159-161 ° C.) was obtained;

4- [3- (1,2,3,4-tetra by replacing 4- (2-bromoethyl) benzoic acid and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole Hydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylethyl] benzoic acid (melting point 227-230 ° C.) was obtained;

3- [2- (3, substituted with 3,4-dimethoxy-1- (2-bromoethyl) benzene and 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole 4-dimethoxyfetyl) ethyl] -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydro-imidazole-2-thione (melting point 97-101 ° C.) Obtained;

4- (2-bromoethyl) benzoic acid and (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) imidazole replaced by (S) -4- {2- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already Dazol-1-yl] ethyl} -benzoic acid (melting point 222-224 ° C.) is obtained, treated with potassium hydroxide in methanol, evaporated to dryness and recrystallized from methanol / isopropanol to give potassium (S) -4- {2- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] Ethyl} benzoate (melting point> 280 ° C.) was obtained;

4- (2-bromoethyl) -1-cyanobenzene and (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) imidazolo Alternatively (S) -3- [2- (4-cyanophenyl) ethyl] -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1 , 3-dihydroimidazole-2-thione (melting point 130-133 ° C.) was obtained;

4- (2-bromoethyl) benzene and (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) imidazole for (S) -3- (2-phenylethyl) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (Melting point 131-133 ° C.) was obtained;

3- [2- (4-cyanophenyl) ethyl by replacing 4- (2-promoethyl) -1-cyanobenzene and 1-1,2,3,4-tetrahydronaphthalen-2-yl) imidazole ] -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (melting point 169-170 ° C.) Obtained;

4- (2-Bromoethyl) benzoic acid and (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,3- Substituted with dihydro-1H-imidazol-4-ylmethyl] formamide (S) -4- {2- [4-formylaminomethyl-3- (5,7-difluoro-1,2, 3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] ethyl} benzoic acid was obtained;

Ethyl 3-bromopropionate and (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,3-dihydro (S) -3- [4-formylaminomethyl-3- (5,7-difluoro-1,2,3,4-tetra) replaced by -1H-imidazol-4-ylmethyl] formamide Hydronaphthalen-2-yl) -2-thioxo-2,3-dihydro = 1H-imidazol-1-yl] propionate was obtained.

Example 16

1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione

The following description is a process for the preparation of compounds of formula I (a) wherein n is 1, t is 0 and R ³ , R ⁴ and R ⁵ are each hydro.

A solution of 1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole (1.6 g, 8.1 mmol) prepared in Example 13 in 30 mL of THF was cooled to -78 ° C and n-butyllithium (6 mL, 9.7 mmol) was added over 15 minutes. The mixture was stirred at -78 ° C for 1 hour and Lark sulfur (0.34 g, 10.5 mmol) was added. The mixture was stirred at −78 ° C. for an additional 2 hours and then warmed to room temperature. The mixture was poured into 100 mL of water to afford crystalline material. The material was separated by filtration, washed with ethyl ether and dried. The filtrate was extracted with methylene chloride (2 x 100 mL) and the extract was washed with brine, dried over magnesium sulfate and concentrated by evaporation. The residue was purified by column chromatography on silica gel (elution: 1.5% methanol with 2% concentrated ammonium hydroxide) .The crystals were combined to give 1- (1,2,3,4-tetrahydronaphthalen-2-yl. ) -1,3-dihydroimidazole-2-thione (0.81 g, 3.5 mmol) (melting point 233-234 ° C.) was obtained.

Example 17

5-amino-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione

The following description is a process for the preparation of compounds of formula I (a) wherein n is 1, t is 0, R ³ and R ⁴ are hydro and R ⁵ is amino.

2-isothiocyano-1,2,3,4-tetrahydronaphthalene (1.92 g, 10.1 mmol) prepared in Example 10, of aminoacetonitrile hydrochloric acid (0.94 g, 10.1 mmol) in 1.41 mL of triethylamine The mixture was heated at 60 ° C. for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography (elution: 3% methanol in methylene chloride then methylene chloride).

The purified residue was recrystallized from ethyl acetate / hexanes. The residue (1.06 g) and 44 mL of 0.1 N potassium hydroxide were stirred under nitrogen for 15 minutes. The residue was separated by filtration, washed with water, air dried and then stirred with methylene chloride. Filtration and drying afforded 5-amino-1-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (melting point 169-171 ° C.).

Example 18

(S) -5-hydroxymethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione

The following description is a process for the preparation of compounds of formula I (a) wherein n is 1, t is 2 and R ¹ is fluoro at the 5- and 7-positions and R ⁵ is hydroxymethyl.

Potassium thiocyanate (15.9 g, 162.6 mmol) was dried by heating to 175 ° C. under nitrogen and then cooled to 35 ° C. using several nitrogen purging under vacuum. (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine prepared in Example 6 in 540 mL of dihydroxyacetone (15.9 g, 176.7 mmol) and ethyl acetate. A mixture of hydrochloric acid (30.0 g, 137.0 mmol) was added to dry potassium thiocyanate. The reaction vessel was purged with nitrogen and 40.83 g of glacial acetic acid was added. The reaction mixture was stirred at 35 ° C. for 2 hours and 100 mL of 1.0 M sulfuric acid was added. The mixture was stirred for 15 minutes and then cooled in an ice bath and 2.5M sodium hydroxide was added until the mixture was at pH 7. The organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate solution and then with 50 mL brine. The organic layer was concentrated to 480 mL by distillation and the mixture was cooled to 6 ° C. and left for 12 hours to give crystalline material. The material was separated by filtration, the filter residue was washed with cold ethyl acetate and the separated material was dried.

The material was dissolved in 650 mL of ethyl acetate and 25 mL of water. The mixture was distilled until 500 mL of volatiles were removed. The mixture was cooled to room temperature and stirred for 45 minutes to yield crystalline material. The material was separated by filtration and the filtration residue was washed with cold ethyl acetate. (S) -5-hydroxymethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-di by drying with nitrogen bleed in vacuo Hydroimidazole-2-thione (30.4 g, 107.4 mol) (melting point 206-207 ° C. [α] _D -40 ° (c = 0.682, CH ₃ OH) was obtained.

(S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid to (S) -6,7-dichloro-1,2,3,4-tetrahydro The procedure was similar to that of Example 18, except that it was replaced with naphthalen-2-ylamine hydrochloric acid to give (S) -5-hydroxymethyl-1- (6,7-dichloro-1,2,3, 4-tetrahydronaphthalen-2-yl) -1,3-dihydro-imidazole-2-thione (melting point 247-248 ° C.) was obtained.

Example 19

(S) -5-cyano-1- (5,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione

The description below describes compounds of formula I (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions, R ³ and R ⁴ are each hydro and R ⁵ is cyano; It is a manufacturing method.

(S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid (50.3 g, 0.23 mol) herbicided in Example 8, and sodium hydroxide in 450 mL of water ( 10.0 g, 0.25 mol) was heated to 50 ° C. followed by addition of formaldehyde sodium bisulfite complex (30.8 g, 0.23 mol). The mixture was stirred for 30 minutes and potassium cyanide (15.0 g, 0.23 mol) was added. The mixture was heated to 80 ° C., stirred for 1 h, cooled to rt and extracted with ethyl acetate. Evaporation gave an oil residue (51.3 g). Purification by column chromatography on silica gel (elution: 5% methanol / methylene chloride) (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamino) acetonitrile (39.4 g) and (S)-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (7.12 g) were obtained. The recovered starting material was circulated again and the obtained product was combined to give (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamino) acetonitrile (44.8 g, 0.20 mol). (Melting point 73-76 ° C., [α] _D ²⁵ = −58.04 ° (c = 1.6, CHCl ₃ )).

A solution of (S)-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamino) acetonitrile in butyl formate (8.7 M, 240 mL, 2.10 mol) was refluxed. Heated and stirred under nitrogen for 19 h. The solvent was removed under reduced pressure, toluene was added and then evaporated. Dried to give (S) -N- (cyanomethyl) -N- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) formamide as an oil residue (53.2 g Obtained). A stirred mixture of formamide (53.2 g) and ethyl formate (12.4 M, 48.7 mL, 604 mol) in anhydrous THF was cooled to -15 ° C. A solution of potassium quaternary-butoxide in THF (1.0 M, 302 mL, 0.302 mol) was added over 20 minutes and the mixture was stirred for 18 hours. Evaporate solvent to potassium (S) -N- (1-cyano-2-oxyvinyl) -N- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) Formamide was obtained as a residue.

Potassium (S) -N- (1-cyano-2-oxyvinyl) -N- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) formamide and 1N A mixture of 0.99 L hydrochloric acid and potassium thiocyanate (78.1 g, 0.80 mol) in 0.497 L of methanol was heated to 85 ° C. and stirred for 135 minutes. The mixture was then cooled in an ice bath to form a precipitate and collected as a slurry. Purification by column chromatography on silica gel packed with hexane (elution: 10% acetone / methylene chloride) gave (S) -5- (1-cyano- (5,7-difluoro-1,2,3, 4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazol-2-thione (18.1 g, 0.06 mol) (melting point 241-249 ° C., [α] _D ²⁵ = -69.1 ° (c = 1.20) , DMSO) was obtained.

The process was carried out as in Example 19, except that (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid was replaced with another starting material. The following compounds of formula I were obtained:

5-cyano-1- (5,7-difluoro-1,2,3,4 by replacing 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine -Tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (melting point 255 ° C.) was obtained;

(R) -5-cyano-1- (5,7-difluoro by replacing with (R) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine -1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione was obtained;

(S) -5-cyano-1- (7-fluoro-1,2,3 as an alternative to (S) -7-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine , 4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione was obtained;

(S) -5-cyano-1- (6-fluoro-1,2,3 replaced by (S) -6-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine , 4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione was obtained;

(S) -5-cyano-1- (5-fluoro-1,2,3 as an alternative to (S) -5-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine , 4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione was obtained;

(S) -5-cyano-1- (1,2,3,4-tetrahydronaphthalen-2-yl substituted by (S) -1,2,3,4-tetrahydronaphthalen-2-ylamine ) -1,3-dihydroimidazole-2-thione was obtained;

5-cyano-1- (6,7-difluoro-1,2,3,4 by replacing 6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine -Tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione was obtained;

(S) -5-cyano-1- (6,7-difluoro by replacing with (S) -6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine -1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione was obtained;

5-cyano-1- (5,6-difluoroindan-2-yl) -1,3-dihydroimidazole-2-thione, substituted with 5,6-difluoroindan-2-ylamine Obtained.

Example 20

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thioxo Hydrochloric acid

The preparation of compounds of formula (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions, R ³ and R ⁴ are hydro, and R ⁵ is aminomethyl It is a way.

(S) -5-cyano-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimime prepared in Example 19 Dazol-2-thione (5.0 g, 0.017 mol) was stirred in an ice bath under argon in 75 mL of THF, and a solution of LAH solution (1.0 M, 34.3 mL, 34.3 mmol) in THF was added dropwise over 10 minutes. The mixture was cooled to 0 ° C., then stirred for 30 minutes to warm up to room temperature and left to stand for 1.5 hours. After the mixture was cooled to 0 ° C., a sufficient amount of saturated sodium potassium tartarate solution was added to the mixture to allow for free stirring. An additional 30 ml of saturated sodium potassium tartarate solution and 10% methanol in 200 ml methylene chloride were added, the mixture was stirred for 15 minutes, and then 100-150 ml of water was added. The organic layer was separated and the aqueous layer was extracted twice with 10% methanol (2x125 mL) in methylene chloride. The combined extracts were washed with 75 ml of water, dried over magnesium sulphate and evaporated to concentrate into a residue (5.2 g). Column chromatography on silica gel (elution: 5% methanol / methylene chloride) to give (S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2 -Yl) -1,3-dihydroimidazole-2-thione (2.92 g, 10.0 mmol) was obtained.

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione It was dissolved in methanol and treated with 1.5 equivalents of anhydrous hydrogen chloride in ethyl ether. Co-evaporate with ethyl acetate to remove solvent (S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3 -Dihydroimidazole-2-thione hydrochloric acid (mp 245 ° C., [α] _D ²⁵ = 11.30 ° (c = 0.5, DMSO)) was obtained.

As disclosed in Example 20, but including (S) -5-cyano-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-di Other starting materials were used in place of hydroimidazole-2-thione to give the compound of formula

5-cyano-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione using 5- Aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (mp 172-178 ° C.) And 5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp 265 -270 ° C),

(R) -5-cyano-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione Using (R) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2- Obtaining thion hydrochloric acid,

(S) -5-cyano-1- (7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione ( S) -5-aminomethyl-1- (7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp 237- 247 ° C.),

(S) -5-cyano-1- (6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione ( S) -5-aminomethyl-1- (6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp240- 249 ° C.),

(S) -5-cyano-1- (5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione ( S) -5-aminomethyl-1- (5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp 273- 276 ° C.),

(S) -5- using (S) -5-cyano-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione Aminomethyl-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp 255-258 ° C.) was obtained,

5-cyano-1- (6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione using 5- Aminomethyl-1- (6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp 260-263 ° C. (Decomposition)),

(S) -5-cyano-1- (6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione Using (S) -5-aminomethyl-1- (6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2- Thion hydrochloric acid (mp253-270 ° C.) was obtained,

5-aminomethyl-1- (5,6-di using 5-cyano-1- (5,6-difluoroindan-2-yl) -1,3-dihydroimidazole-2-thione Fluoroindan-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp 280 DEG C or higher (decomposition)) was obtained.

Example 21

1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5 (1H) -tetrazol-5-yl-1,3-dihydroimidazole-2 -Tion

The following is a process for the preparation of compounds of formula (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ³ is 1H-tetrazol-5-yl.

5-cyano-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2- prepared in Example 19 Thion (0.554 g, 1.9 mniol) was stirred for 2.5 h at 130 ° C. in a nitrogen atmosphere of 1.6 ml tributyltin azide and then 10 ml toluene was added. After the mixture was cooled to room temperature, about 5 ml of diethyl ether was added. The mixture was cooled to 0 ° C. and then treated with 10 mL of 1N hydrogen chloride in diethyl ether for about 15 minutes. The mixture was poured into a solution of potassium fluoride monohydrate (15.0 g) in 15-20 mL of water and 75 mL of ethyl acetate. The ethyl acetate layer was extracted with 2N sodium hydroxide and the aqueous layer was washed six times with methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated to yield 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5 (1H) -tetrazol-5-yl-1,3-dihydro Imidazole-2-thione (0.57 g, 1.7 mmol, mp 214-215 ° C.) was obtained.

5-cyano-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-as disclosed in Example 21 2-thione was used as another starting material to obtain a compound of formula

1- (5,6-difluoroindan-2 using 5-cyano-1- (5,6-difluoroindan-2-yl) -1,3-dihydroimidazole-2-thione -Yl) -5 (1H) -tetrazol-5-yl-1,3-dihydroimidazole-2-thione (mp 142-147 ° C.),

5-cyano-1- (6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione using 1- (6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5 (1H) -tetrazol-5-yl-1,3-dihydroimidazol-2-thione (mp 195-212 ° C) was obtained.

Example 22

3- (1,2,3,4-tetrahydronaphthalene-yl) -2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde

The following is a method for preparing a compound of formula (a) wherein n is 1, t is 0, R ³ and R ⁵ are each hydro and R ⁴ is formyl.

Homogeneous a mixture of 2-isothiocyano-1,2,3,4-tetrahydronaphthalene (1.89 g, 10 mmol) and D-(+)-glucosamine (1.78 g, 10 mmol) prepared as in Example 10 After stirring at 90 ° C. until addition, 0.8 ml of acetic acid are added. The mixture was stirred at 90 ° C. for 30 minutes and then cooled. Solvent was removed by rotary evaporation and the residue was co-evaporated with toluene (2 × 25 mL). The residue was dissolved in acetic acid and heated at 90-100 ° C. for 30 minutes. The mixture was cooled and triturated with acetone to afford crystalline material. The material was isolated by filtration and the filter residue was washed with acetone. Dried to 4- (1R, 2R, 3S, 4) -tetrahydroxybut-1-yl) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydro Imidazole-2-thione (1.48 g, 4.23 mmol) was obtained.

4- (1R, 2R, 3S, 4) -tetrahydroxybut-1-yl) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) in 15 mL 33% acetic acid / benzene A suspension of -1,3-dihydroimidazole-2-thione (0.252 g, 0.72 mmol) and lead tetraacetate (0.851 g, 1.92 mmol) was stirred until the mixture was homogeneous and for 30 minutes. The reaction mixture was poured into 125 mL of saturated sodium carbonate solution and the mixture was filtered. The organic layer was separated, dried over magnesium sulfate and concentrated. The residue was dissolved in 40 mL of THF and 2 mL of sulfuric acid (6% SO ₂ ). Evaporate the solvent to 3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde (0.15 g, 0.59 mmol, mp 206-210 ° C.).

As disclosed in Example 22, but with (S) -2-isothiocyano-5,7-difluoro-1,2 for 2-isothiocyano-1,2,3,4-tetrahydronaphthalene (S) -3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2, using 3,4-tetrahydronaphthalene, 3-dihydro-1H-imidazole-5-carbaldehyde (mp> 285 ° C.) was obtained.

Example 23

Ethyl [(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) (formyl) amino] acetate

The following is a method for preparing a compound of Formula 17 wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ³² is ethoxycarbonyl.

5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (6.0 g, 32.8 mmol) and ethyl glyoxylate as prepared in Example 8 in 300 ml ethanol ( 4.6 g, 36.0 mmol) was hydrogenated over 10% palladium on carbon (0.75 g) for 10 hours. The mixture was filtered and evaporated to concentrate. The residue was purified by column chromatography on silica gel (elution: 30% ethyl acetate / hexane) to give ethyl [(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl as oil). ) Amino] acetate (7.5 g, 27.9 mmol) was obtained.

A solution of ethyl [(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) amino] acetate (715 g, 25.6 mmol) in 20 mL methylene chloride under argon atmosphere was heated to about 0 ° C. Cooled to. Acetic formic anhydride (9.7 mL, 67.3 mmol) was cooled to 0 ° C. and added for 5-10 minutes. The mixture was cooled at 0 ° C. for 2 hours and then allowed to warm to room temperature. The solvent was removed by coevaporation with toluene (3 x 50 mL). The residue was crystallized under high vacuum to give ethyl [(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) (formyl) amino] acetate (7.68 g, 25.0 mmol). .

As disclosed in Example 23, 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine was used as another starting material to obtain a compound of formula

Ethylene [(6,8-difluoro-1,2,3,4-tetrahydronaphthalene- using 6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine 2-yl) (formyl) amino] acetate was obtained,

4,6-difluoroindan-2-ylamine was used to give ethyl [(4,6-difluoroindan-2-yl)-(formyl) amino] acetate,

5,7-difluoroindan-2-ylamine was used to give ethyl [(5,7-difluoroindan-2-yl)-(formyl) amino] acetate,

5,6-Difluoroindan-2-ylamine was used to give ethyl [(5,6-difluoroindan-2-yl)-(formyl) amino] acetate.

Example 24

Ethyl 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate

Following is a compound of formula (a) wherein n is 1, t is 0, R ¹ is fluoro at the 5- and 7-positions, R ³ and R ⁴ are hydro and R ⁵ is ethoxycarbonyl It is a manufacturing method.

Ethyl [(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-(formyl) amino] acetate (7.58 g, 24.7 mmol) prepared in Example 23 in 60 mL THF. ) And ethyl formate (5.91 mL, 72.7 mmol) were cooled to -10 ° C under argon. Potassium t-butoxide (4.08 g, 36.4 mmol) in 45 mL THF was added and the mixture was stirred at -10 ° C for 2 h. The mixture was then warmed to room temperature and stirred for a further 4 hours. The solvent was removed by evaporation and the residue was dissolved in 75 mL of 1N hydrochloric acid and 50 mL of ethanol. Potassium thiocyanate (2.65 g, 75 mmol) was added and the mixture was stirred at 85 ° C for 15 h. The mixture was cooled down, diluted in 125 mL of water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and removed by rotary evaporation of ethyl acetate. The residue was purified by column chromatography on silica gel (elute: 2.5% methanol / methylene chloride) to give ethyl 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)- 2-Tioxo-2,3-dihydro-1H-imidazole-4-carboxylate (8.07 g, 24.6 mmol, mp 159-161 ° C.) was obtained.

As described in Example 24, but using ethyl [(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-(formyl) amino] acetate as another starting material A compound of formula 1 was obtained:

Ethyl 3- (6,8-difluoro-1 using ethyl [(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-(formyl) amino] acetate , 2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate (mp 187-189 ° C.) was obtained,

Ethyl 3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2- using ethyl (1,2,3,4-tetrahydronaphthalen-2-yl)-(formyl) aminoacetate Thioxo-2,3-dihydro-1H-imidazole-4-carboxylate (mp 70-72 ° C.) was obtained,

Ethyl 3- (7-fluoro-1,2,3,4-tetra using ethyl (7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-(formyl) aminoacetate Hydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate,

Ethyl 3- (4,6-difluoroindan-2-yl) -2-thioxo-2, using ethyl [(4,6-difluoroindan-2yl)-(formyl) amino] acetate 3-dihydro-1H-imidazole-4-carboxylate was obtained,

Ethyl 3- (5,7-difluoroindan-2-yl) -2-thioxo-2, using ethyl [(5,7-difluoroindan-2yl)-(formyl) amino] acetate 3-dihydro-1H-imidazole-4-carboxylate was obtained,

Ethyl 3- (5,6-difluoroindan-2-yl) -2-thioxo-2, using ethyl [(5,6-difluoroindan-2yl)-(formyl) amino] acetate 3-dihydro-1H-imidazole-4-carboxylate was obtained.

Example 25

Ethyl 3- (1,2,3,4-tetrahydronaphthalen-2-yl) -5-methyl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate

The following is a process for preparing the compound of formula (a) wherein n is 1, t is 0, R ³ is hydro, R ⁴ is methyl and R ⁵ is ethoxycarbonyl.

Under argon a solution of diisopropylamine (1.54 mL, 11 mmol) in 30 mL of dry THF was cooled to 0 ° C. and n-butyllithium (6.25 mL, 10 mmol) was added. The mixture was cooled to -78 ° C and ethyl [(1,2,3,4-tetrahydronaphthalen-2-yl)-(formyl) amino] acetate (1.33 g) prepared as in Example 23 in 20 mL THF. , 5.0 mmol) was added for 15 minutes. The mixture was stirred at -78 ° C for 1 hour and acetyl chloride (0.427 mL, 6.0 mmol) was added for 5 minutes. The mixture was stirred at −78 ° C. for 3 hours and then warmed at room temperature for 1 hour. The solvent was removed by evaporation and the residue was dissolved in 25 mL of 1N hydrochloric acid and 25 mL of ethanol. Potassium thiocyanate (1.94 g, 20 mmol) was added and the mixture was stirred at 75-80 ° C. for 18 hours. The mixture was cooled, diluted with water and extracted twice with ethyl acetate. Ethyl acetate was concentrated to a thick oil. The residue was purified by column chromatography on silica gel (elute: 2% methanol / methylene chloride) and triturated with ethyl acetate / isopropyl ether to yield ethyl 3- (1,2,3,4-tetrahydronaphthalene-2 as a pale yellow solid. -Yl) -5-methyl-2-thioxo-1,3-dihydro-1H-imidazole-4-carboxylate (mp 225-227 ° C.) was obtained.

As disclosed in Example 25, but using ethyl [(1,2,3,4-tetrahydronaphthalen-2-yl)-(formyl) amino] acetate and / or acetyl chloride as other starting materials, Compound was obtained:

Ethyl 3- (1,2,3,4-tetrahydronaphthalen-2-yl) -5-prop-2-yl-2-thioxo-1,3-dihydro-1H using isobutyryl chloride -Imidazole-4-carboxylate (mp 195-197 ° C.) was obtained,

Ethyl 3- (1,2,3,4-tetrahydronaphthalen-2-yl) -5- (1,1-dimethylethyl) -2-thioxo-1,3-dihydro- using trimethylacetyl chloride 1H-imidazole-4-carboxylate was obtained with foam,

Ethyl 3- (5,7-difluoro-1,2 using ethyl (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) (formyl) -aminoacetate , 3,4-tetrahydronaphthalen-2-yl) -5-methyl-2-thioxo-1,3-dihydro-1H-imidazole-4-carboxylate (mp 207-209 ° C.) was obtained,

Ethyl 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5-ethoxycarbonyl-2-thioxo-1, using ethyl oxalyl chloride, 3-dihydro-1H-imidazole-4-carboxylate (mp 160-161 ° C.) was obtained.

Example 26

5-aminomethyl-4- (1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3-thione

The following is a method for preparing a compound of Formula (b) wherein n is 1, t is 0 and R ⁷ is aminomethyl.

2-isothiocyano-1,2,3,4-tetrahydronaphthalene (0.19 g, 1.0 mmol) and (t-butyloxycarbonyl) aminoacetyl-hydra prepared in Example 10 in 5 mL of DMF. A mixture of zide (0.19 g, 1.1 mmol) was heated at 80 ° C. for 2.5 h under nitrogen. Solvent was removed by rotary evaporation. The residue was stirred at room temperature under nitrogen and 4.5 mL of sodium ethoxide (prepared in 0.46 g of sodium and 45 mL of ethanol) was added. The reaction mixture was refluxed under nitrogen for about 24 hours, cooled and filtered. The solvent was removed by rotary evaporation and the residue dissolved in water. The solution was acidified to pH 3 with 10% hydrochloric acid and then filtered. Water was evaporated under reduced pressure to afford 5- (t-butyloxycarbonyl) aminomethyl-4- (1,2,3,4-tetrahydro-naphthalen-2-yl) -2,4-dihydro [1,2 , 4] triazole-3-thione (0.203 g, 0.56 mmol) was obtained.

Anhydrous hydrogen chloride (4.22 g) was aerated into 15 mL of ethyl acetate in an ice-methanol bath. 5- (t-butyloxycarbonyl) aminomethyl-4- (1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3 -Thione (0.178 g, 0.49 mmol) was added and the mixture was stirred at room temperature. Ether was added and the mixture was filtered under nitrogen. The solvent was evaporated under reduced pressure to afford 5-aminomethyl-4- (1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3-thione Hydrochloric acid (0.125 g, 0.41 mmol, mp 279-281 ° C.) was obtained.

As disclosed in Example 26, but using 2-isothiocyano-1,2,3,4-tetrahydronaphthalene and / or (t-butyloxycarbonyl) aminoacetylhydrazide as another starting material A compound of formula 1 was obtained:

5- (4-methylpiperazin-1-yl) -4 using 2-isothiocyano-1,2,3,4-tetrahydronaphthalene and 4-methylpiperazin-1-ylacetylhydrazide -(1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3-thione (mp 217-218 ° C) was obtained,

(S) using (S) -5,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene and (t-butyloxycarbonyl) aminoacetylhydrazide -5-Aminomethyl-4- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole- 3-thione and (S) -5-aminomethyl-4- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1, 2,4] triazole-3-thione hydrochloric acid (mp> 280 ° C.) was obtained.

Example 27

2- (1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3-thione

The following is a method for preparing a compound of Formula 1 (c) wherein n is 1, t is 0 and R ⁸ is hydro.

1,2,3,4-tetrahydronaphthalene-one (3.5 g, 24.0 mmol) and form hydrazide (1.56 g, 26.0 mmol) in 25 mL of methanol and 1 drop of concentrated hydrochloric acid were added at 70 DEG C for 1 hour. Heated. The mixture was cooled to room temperature to give crystalline material. The material was isolated by filtration and washed with ethanol. Drying gave 2-formylhydrazono-1,2,3,4-tetrahydronaphthalene (3.5 g, 8.7 mmol).

A mixture of 2-formylhydrazono-1,2,3,4-tetrahydronaphthalene (3.0 g, 16.0 mmol) and sodium borohydride in 25 ml of ethanol was stirred at room temperature for 20 hours. The mixture was quenched with water and then extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (elute: 2% methanol / methylene chloride) to give 2-formylhydrazo-1,2,3,4-tetrahydronaphthalene (2 g, 10.7 mmol).

A mixture of 2-formylhydrazo-1,2,3,4-tetrahydronaphthalene (2.0 g, 10.7 mmol) and trimethylsilyl isothiocyanate (2.8 g, 21.0 mmol) in 20 mL toluene Stirring at 占 폚 gave crystalline material. Filtration and drying gave N-[(1,2,3,4-tetrahydronaphthalen-2-yl) (aminothio-carbonyl) amino] formamide (0.6 g, 2.4 mmol).

A solution of N-[(1,2,3,4-tetrahydronaphthalen-2-yl) (aminothiocarbonyl) amino] formamide (0.6 g, 2.4 mmol) in 10 ml of 10% sodium hydroxide was dried at 70 ° C. Heated for 30 minutes. The solution was cooled, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate / hexanes and filtered to give 2- (1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3-thione (0.25 g, 1.06 mmol, mp 200.5 ° C.) was obtained.

Example 28

4-amino-2- (1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3-thione

The following is a method for preparing a compound of formula (c) wherein n is 1, t is 0 and R ⁸ is amino.

2-bromo-1,2,3,4-tetrahydronaphthalene (1.06 g, 5 mmol) and 4-amino [1,2,4] triazole (2.1 g, 25 mmol) in 8 mL DMF at 90 ° C. Heat and stir for 2 hours. Solvent was evaporated off and the residue was dissolved in 5 ml pyridine. Lark Sulfur (0.16 g, 5 mmol) and 2.5 ml of triethylamine were added and the mixture was heated at about 90 ° C. and stirred under argon for 4 hours. The solvent was removed by evaporation and the residue was removed by coevaporation with toluene (x2). Purification by flash chromatography (elution: 3-5% methanol / methylene chloride) gave 4-amino-2- (1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1 , 2,4] triazole-3-thione (0.35 g, 1.42 mmol, mp 147-150 ° C.) was obtained.

Example 29

(S) -N- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already Dazol-4-yl] methyl] formamide

Below is a process for the preparation of compounds of formula (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁵ is formylaminomethyl.

Formamide (250 mL, 6.3 mol) was heated to 175 ° C. and (S) -5-hydroxymethyl-1- (5,7-difluoro-1,2,3, as prepared in Example 18, 4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (25.0 g, 88.3 mmol) was added in portions for 30 minutes and the reaction mixture was stirred for 1 hour under a nitrogen sweep. The mixture is cooled to 50 ° C. and 2.5 g of activated carbon, Darco ^? Was added. The mixture was cooled to 30 ° C., filtered through celite and washed with 25 ml of formamide. The filtrate was heated to 95 ° C. and then 1 L of water was added dropwise. The mixture was cooled and stirred at room temperature for 12 hours. The mixture was cooled to 0 ° C. to obtain crystalline material. The material was isolated by filtration and dried.

The material was stirred with about 5 times weight of 70% THF / 30% hexane for 5 minutes. The material was isolated by filtration and the filter residue was washed with 50% THF / 50% hexanes. Dried to constant weight to form (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-di Hydro-1H-imidazol-4-ylmethyl] formamide (19.5 g, 62.7 mmol, mp 245-246 ° C., [α] _D + 48.9 ° (c = 0.613, DMSO)) was obtained.

As disclosed in Example 29, but with (S) -5-hydroxymethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3- Dihydroimidazole-3-thione or formamide was used as another starting material to obtain a compound of formula (a):

(S) -5-hydroxymethyl-1- (6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione is used To (S) -N- [3- (6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H- Imidazol-4-ylmethyl] formamide was obtained,

(S) -5-ureidomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole using urea -2-thione (mp). 258-260 ° C., [α] _D + 34.3 ° (c = 0.574, DMSO) was obtained.

Example 30

(S) -N- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already Dazol-4-yl] methyl] formamide

Below is a process for the preparation of compounds of formula (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁵ is formylaminomethyl.

(S) -5-hydroxymethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3- prepared as in Example 18 A mixture of dihydroimidazole-2-thione (1.0 g, 3.5 mmol) and ammonium formate (10 g, 158.6 mmol) was stirred at about 125 ° C. for 1 hour. The mixture was then heated to about 138 ° C. and stirred for an additional 35 minutes. The mixture was diluted with 25 mL of water and cooled to room temperature. The mixture was aged for about 18 hours to give crystalline material. The material was isolated by filtration and the filter residue was washed with water. Dried to constant weight to form (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-di Hydro-1H-imidazol-4-ylmethyl] formamide (0.92 g, 2.96 mmol) was obtained.

As disclosed in Example 30, (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl using ammonium formate as ammonium acetate ) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] acetamide (mp 275.5-276 ° C. (decomposition), [α] _D + 41.3 ° (c = 1.00, DMSO) ) Was obtained.

Example 31

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid

The following is a process for the preparation of compounds of formula (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁵ is aminomethyl.

(S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2- as prepared in Example 30 in 400 ml isopropanol A mixture of thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] formamide (19.1 g, 59.0 mmol) and 25 mL concentrated hydrochloric acid (12.0 M, 25 mL, 300 mmol) was added for 12 minutes. Heated to reflux and stirred for 1 hour 40 minutes. The mixture was distilled off to remove 150 mL of isopropanol. The mixture was gradually cooled to rt and stirred for 3 h 45 min. The material was isolated by filtration and the filter residue was washed with 75 ml of isopropanol. (S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1, by vacuum drying with nitrogen bleed at 110-125 ° C., 3-dihydroimidazole-2-thione hydrochloric acid (15.6 g, 47.1 mmol, mp 251.9 ° C., [α] _D + 10.2 ° (c = 0.500, DMSO)) was obtained.

As disclosed in Example 31, but with (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2, 3-dihydro-1H-imidazol-4-ylmethyl] formamide was used as another starting material to obtain a compound of formula

(S) -N- [3- (6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole- (S) -5-aminomethyl-1- (6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-di with 4-ylmethyl] formamide Hydroimidazole-2-thione hydrochloric acid (mp 190 ° C. (decomposition) was obtained,

(S) -4- {2- [4-formylaminomethyl-3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2 (S) -4-12- [4-aminomethyl-3- (5,7-difluoro-1,2, using 3,3-dihydro-1H-imidazol-4-yl] ethyl} benzoic acid 3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-yl] ethyl} benzoic acid hydrochloric acid (mp246-248 ° C) was obtained,

(S) -3- [4-formylaminomethyl-3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3- (S) -3- [4-aminomethyl-3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene using dihydro-1H-imidazol-4-yl] propionic acid -2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-yl] propionic acid hydrochloric acid (mp 191 ° C.) was obtained.

Example 32

(S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5-pyrrolidin-1-ylmethyl-1,3-dihydroimime Dozol-2-thione

The following formula (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions, R ³ and R ⁴ are hydro and R ⁵ is pyrrolidin-1-ylmethyl ) Is a method for producing a compound.

(S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-prepared as in Example 18 in 20 mL of THF and 1 drop of DMF. A solution of 5-hydroxymethyl-1,3-dihydroimidazole-2-thione (140 mg, 0.47 mmol) was cooled at a temperature of 0-5 ° C. and thionyl chloride (13.7 M, 109 μl, 1.49 mmol) was added. Dropwise addition under nitrogen atmosphere. The mixture was stirred at RT for 0.5 h, refluxed for 0.5 h and again at RT for 0.5 h. The mixture was then cooled to a temperature of 0-5 ° C. and pyrrolidine (12.0 M, 818 μl, 9.8 mmol) was added dropwise. The mixture was stirred at reflux for 1.5 h. Solvent was removed by evaporation and the residue was diluted with water. Ethyl acetate was added to the diluent and the mixture was titrated to pH 7. The ethyl acetate layer was dried and concentrated by evaporation. The residue was purified by column chromatography to give (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydro-5- (Pyrrolidin-1-ylmethyl) -imidazol-2-thione (100 mg. 0.29 mmol [α] _D -10.96 ° (c = 1.3, DMSO)) was obtained.

(S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3 by treating with 2 molar equivalents of 1M anhydrous hydrogen chloride in diethyl ether -Dihydro-5- (pyrrolidin-1-ylmethyl) -imidazol-2-thione hydrochloric acid (100 mg, 0.26 mmol, mp 187-189 ° C.) was obtained.

As disclosed in Example 32, but including (S) -5-hydroxymethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3- Dihydroimidazole-2-thione was used as another starting material to obtain a compound of formula

(S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5- (methylaminomethyl) -1,3-di with methylamine Hydroimidazole-2-thione (mp 250-260 ° C.) and (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5- ( Methylaminomethyl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp 250 ° C., [α] _D + 7.7 ° (c = 2.4, DMSO)) was obtained,

(S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5- (dimethylaminomethyl) -1,3-di with dimethylamine Hydroimidazole-2-thione and (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5- (dimethylaminomethyl) -1, 3-dihydroimidazole-2-thione hydrochloric acid (mp 207-208) was obtained,

Using piperidine (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5- (piperidin-1-ylmethyl) -1,3-dihydroimidazole-2-thione and (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5- (pi Ferridin-1-ylmethyl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp 169-170) was obtained,

(S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5- (morpholin-4-ylmethyl) -1 using morpholine , 3-dihydroimidazole-2-thione (mp 198-201 ° C., [α] _D ²⁵ = -7.56 ° (c = 2.38, DMSO)) and (S) -1- (5,7-difluoro -1,2,3,4-tetrahydronaphthalen-2-yl) -5- (morpholin-4-ylmethyl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp 182-184 ° C.) Obtained,

(S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5- (4-methylpiperazin-1 using 1-methylpiperazine -Ylmethyl) -1,3-dihydroimidazole-2-thione and (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)- 5- (4-Methyl-piperazin-1-ylmethyl) -1,3-dihydroimidazole-2-thione hydrochloric acid (mp 237-245) was obtained.

Example 33

1- (1,2,3,4-tetrahydronaphthalen-2-yl) -4,5-di (hydroxymethyl) -1,3-dihydroimidazole-2-thione

The following is the preparation of compounds of formula I (a) wherein n is 1, t is 0, R ³ is hydro and R ⁴ and R ⁵ are hydroxymethyl, respectively.

Sodium borohydride (0.22 g, 5.8 mmol) and anhydrous calcium chloride (0.34 g, 3.1 mmol) in 10 ml of dry THF were stirred at about 25 ° C. for 1 hour, then prepared as in Example 25 in 10 ml of dry THF. Ethyl 3- (1,2,3,4-tetrahydronaphthalen-2-yl) -5-ethoxycarbonyl-2-thiox-1,3-dihydro-1H-imidazole-4-carboxylate (0.37 g, 1 mmol) was added. The mixture was stirred at 50 ° C. for about 72 hours and concentrated. The residue was treated with 20 ml 10% sodium hydroxide and 50 ml ethyl acetate, filtered and the aqueous phase was extracted again with ethyl acetate (3 x 50 ml). The combined extracts were dried (MgSO ₄ ) and concentrated. The residue was stirred with methylene chloride / methanol (93: 7) and the mixture was filtered. The aqueous phase was evaporated to dryness and the residue was stirred with methanol. The methanol mixture was filtered and then combined with methylene chloride / methanol filtrate. The combined mixture was concentrated and the residue was purified by flash chromatography, eluting with methylene chloride / methanol (93: 7 to 96: 4) on silica gel to give 1- (1,2,3,4-tetrahydronaphthalene-2- Il) -4,5-di (hydroxymethyl) -1,3-dihydroimidazole-2-thione (35 mg, 0.12 mmol) was obtained: melting point 199 to 200 ° C.

Example 34

Ethyl 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] propionate

The following is the preparation of compounds of formula I (a) wherein n is 1, t is 0, R ³ is 2-ethoxycarbonylethyl and R ⁴ and R ⁵ are each hydro.

1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (1.3 g, 5.6 mmol) prepared as in Example 9 in 14 ml ethanol. ) And a mixture of ethyl acrylate (3.1 ml, 28.2 mmol) and 1.28 ml N-benzyltrimethylammonium hydroxide (2.8 mmol) in methanol were heated at 80 ° C. for 2 hours under nitrogen. The mixture was cooled and concentrated by rotary evaporator. The residue was purified by chromatography, eluting with hexanes / ethyl acetate (3: 1) on silica gel to give ethyl 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) 2-thioxo- 2,3-dihydroxy-1H-imidazol-1-yl] propionate (1.2 g, 3.7 mmol) was obtained: melting point 71-73 ° C.

Proceed as in Example 34, but replacing 1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione with different starting materials Obtain the compound of I:

t-butyl 4- (1,2,3,4-tetrahydronaphthalen-2-yl) -5-thioxo-1,5-dihydro [1,2,4] triazol-3-ylmethylaminofo Substituted with mate ethyl-3- [4- (1,2,3,4-tetrahydronaphthalen-2-yl) -3- (t-butoxycarbonylaminomethyl) -5-thioxo-1,5 -Dihydro [1,2,4] triazol-1-yl] propionate was obtained;

(S)-(1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazol-2-thione, replacing (S ) -3- [3- (5Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl ] -Propionate was obtained: melting point 105-107 ° C.

Example 35

Ethyl 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -4-dimethylaminomethyl 2-thioxo-2,3-dihydro-1H-imidazol-1-yl] Propionate

The following is the preparation of compounds of formula I (a) wherein n is 1, t is 0, R ³ is 2- (ethoxycarbonyl) ethyl, R ⁴ is hydro and R ⁵ is dimethylaminomethyl.

Ethyl 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole prepared as in Example 34 in 7 ml DMF. A mixture of -1-yl] propionate (0.5 g, 1.5 mmol) and N, N-dimethylmethylene ammonium chloride (0.17 g, 1.8 mmol) was heated at 80 ° C. for 16 hours under nitrogen. This mixture was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried (NaSO ₄ ), filtered and concentrated. The residue was purified by column chromatography eluting with ethyl acetate / hexanes on silica gel to give ethyl 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -4-dimethylaminomethyl-2- Thioxo-2,3-dihydro-1H-imidazol-1-yl] propionate (277 mg, 0.7 mmol) was obtained: melting point 128-130 ° C.

Proceed as in Example 35, but with ethyl 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole- 1-yl] propionate is methyl 4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -5-methyl-2-thioxo-2,3-dihydro-1H- Methyl 4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -4-dimethylamino-5-methyl-2-thiooxo by replacing with imidazol-1-ylmethyl] benzoate -2,3-dihydro-1H-imidazol-1-ylmethyl] benzoate was obtained as a foam.

Example 36

1- (1,2,3,4-tetrahydronaphthalen-2-yl) -4,5-di (dimethylamino) -1,3-dihydroimidazole-2-thione

The following is the preparation of compounds of formula I (a) wherein n is 1, t is 0, R ³ is hydro and R ⁴ and R ⁵ are each dimethylaminomethyl.

1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (1 g, 4.3 mmol) prepared as in Example 9 in 20 ml of ethanol. And a mixture of hydrochloric acid (IN in ether, 8.7 ml, 8.7 mmol) was heated at 80 ° C. for about 5 hours under nitrogen. The mixture was cooled, concentrated and partitioned into saturated sodium bicarbonate solution and methylene chloride. The organic layer was separated, dried (K ₂ CO ₃ ), filtered and concentrated. The residue was purified by column chromatography eluting with methylene chloride / methanol (99: 1) on silica gel to give ethyl 3- [1- (1,2,3,4-tetrahydronaphthalen-2-yl) imidazole-2 -Yl-thio] propionate (1.36 g, 4.1 mmol) was obtained.

Ethyl 3- [1- (1,2,3,4-tetrahydronaphthalen-2-yl) -imidazol-2-ylthio] propionate (1.36 g, 4.1 mmol) and N, N in 25 ml DMF The dimethylmethylene ammonium chloride (1.66 g, 17.7 mmol) mixture was heated at 100 ° C. for about 22 hours under nitrogen. The reaction mixture was cooled to about 90 ° C. and additionally N, N-dimethylmethylene ammonium chloride (0.83 g, 8.8 mmol) was added. The mixture was heated for 31.5 hours and then partitioned between sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with brine, dried (K ₂ CO ₃ ), filtered and concentrated. The residue was purified by column chromatography eluting with 5-10% methanol in methylene chloride on silica gel to give ethyl 3- [1- (1,2,3,4-tetrahydro-naphthalen-2-yl) -4,5 -Di (dimethylaminomethyl) imidazol-2-ylthio] propionate (0.55 g, 1.2 mmol) was obtained.

Ethyl 3- [1- (1,2,3,4-tetrahydronaphthalen-2-yl) -4,5-di (dimethylaminomethyl) imidazol-2-yl-thio] propionate in 5 ml of ethanol (0.55 g, 1.2 mmol) and sodium ethoxide (3.5 ml of a solution prepared from 450 mg of sodium in 45 ml of ethanol, 1.4 mmol) were heated at about 25 ° C. for 1.75 h. The mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried (K ₂ CO ₃ ), filtered and concentrated. The residue was purified by column chromatography eluting with methylene chloride / methanol (97: 3) on silica gel to give 1- (1,2,3,4-tetrahydronaphthalen-2-yl) -4,5-di (dimethyl Amino) -1,3-dihydro-imidazole-2-thione (0.24 g, 0.7 mmol) was obtained: melting point 182-184 ° C.

Example 37

3- (5-7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid

The preparation of compounds of formula I (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions, R ³ and R ⁴ are hydro, and R ⁵ is carboxy to be.

Ethyl 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2- prepared as in Example 24 in 130 ml ethanol / water (10: 3) -2- Thioxo-2,3-dihydro-1H-imidazole-4-carboxylate (4.6 g, 13.6 mmol) and potassium hydroxide (3.14 g, 47.6 mmol) were stirred at 85-90 ° C. for 5 hours. The solvent was removed by evaporation and the residue was dissolved in water. The solution was acidified to pH 1 with 1N hydrochloric acid to give crystalline material. The material was separated by filtration to give 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imide Dazole-4-carboxylic acid (3.86 g, 12.5 mmol) was obtained; Melting point 250 to 252 ° C.

Proceed as in Example 37, but with ethyl 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro- 1H-imidazole-4-carboxylate was replaced with a different starting material to afford the compound of formula I (a):

Ethyl 3- (1,2,3,4-tetrahydronaphthalen-1-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate in place of ethyl 3- (1 , 2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid was obtained: melting point 231 to 332 ° C. (decomposition);

By replacing with ethyl 3- (7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate Ethyl 3- (7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid was obtained: Melting point 207 to 209 ° C;

Ethyl 3- (6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate 3- (6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4- A carboxylic acid was obtained (melting point 207-208 ° C.), treated with potassium hydroxide in methanol, evaporated to solid and recrystallized from methanol / isopropanol to give potassium 3- (6,8-difluoro-1,2,3,4-tetra Hydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate was obtained: melting point 160 to 163 ° C;

3- (4,6-di by replacing with ethyl 3- (4,6-difluoroindan-1-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate Obtain fluoroindan-1-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid, treat with potassium hydroxide in methanol, evaporate to dryness and recrystallize from methanol / isopropanol To obtain potassium 3- (4,6-difluoroindan-1-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate: melting point 163-173 ° C .;

3- (5,7-di by replacing with ethyl 3- (5,7-difluoroindan-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate Fluoroindan-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (melting point 230-232 ° C.) was treated with potassium hydroxide in methanol, evaporated to dryness And recrystallized from methanol / isopropanol to give potassium 3- (5,7-difluoroindan-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate. Melting point 170 to 174 ° C;

3- (5,6-di by replacing with ethyl 3- (5,6-difluoroindan-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate Fluoroindan-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid was obtained: melting point 233 to 234 ° C;

Methyl 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl] benzoate and hydroxide 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl] benzoic acid substituted by sodium Obtained: melting point 252-254 ° C;

Methyl 4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl] benzoate and hydroxide 4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl] benzoic acid substituted with sodium Obtained: melting point 211-212 ° C;

Methyl 4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] butyrate to replace 4 -[3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] butyric acid was obtained: Melting point 156 To 158 ° C;

Replaced with Methyl 5- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl] piconate And recrystallized from a solution of hydrochloric acid in ethanol to give 5- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-1 -Ylmethyl] picolinic acid hydrochloric acid was obtained: melting point 204 to 205 캜;

By replacing methyl 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1yl] propionate 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] propionic acid was obtained: melting point 167 to 168 ° C;

Methyl 4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1 ylmethyl] benzo 4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1- Monomethyl] benzoic acid was obtained: melting point 181 to 182 ° C;

Ethyl 3- [4- (1,2,3,4-tetrahydronaphthalen-2-yl) -3- (t-butoxycarbonylaminomethyl) -5-thioxo-1,5-dihydro [1 3- [4- (1,2,3,4-tetrahydronaphthalen-2-yl) -3- (t-butoxycarbonyl in place of 2,4] triazol-1-yl] propionate Aminomethyl) -5-thioxo-1,5-dihydro [1,2,4] triazol-1-yl] propionic acid was obtained: melting point 76-78 ° C .;

Ethyl (S) -3- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H- (S) -3- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2- replacing imidazol-1yl] propionate Thioxo-2,3-dihydro-1H-imidazol-1-yl] propionic acid was obtained: melting point 182-184 ° C .;

Ethyl 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -4-dimethylamino-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1yl ] 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -4-dimethylaminomethyl-2-thioxo-2,3-dihydro-1H- in place of propionate Imidazol-1-yl] propionic acid was obtained: melting point 171 to 174 ° C;

Methyl (S) -4- {2- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4- (S) -4- {2- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3 substituted with yl-methylamino] ethyl} benzoate -Dihydro-1H-imidazol-4-ylmethylamino] ethyl} benzoic acid hydrochloric acid was obtained: melting point 240 to 241 ° C; And

Ethyl (S) -3- [4-formylaminomethyl-3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1-thioxo-2,3 (S) -3- [4-formylaminomethyl-3- (5,7-difluoro-1,2,3,4- in place of -dihydro-1H-imidazol-1yl] propionate Tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] -propionic acid was obtained.

Proceed as in Example 37, but with ethyl 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro- 1H-imidazole-4-carboxylate was replaced with different starting materials and acid catalyzed hydrolysis was performed to give the compound of formula I (a):

with t-butyl-3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1ylacetate and trifluoroacetic acid Subsequently, 3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl-acetic acid was obtained: Melting point 228 To 230 ° C .;

t-butyl- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-yl 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H- in place of methylaminoacetate and hydrochloric acid Imidazol-4-ylmethylaminoacetic acid hydrochloric acid was obtained: melting point 214-216 ° C .;

t-butyl (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo- in place of dazol-4-ylmethylaminoacetate and hydrochloric acid 2,3-dihydro-1H-imidazol-4-ylmethylaminoacetic acid hydrochloric acid was obtained: melting point 214 ° C. (eff.); And t-butyl 1- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethylaminoacetate and hydrochloric acid Subsequently 1- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-yl-methylaminoacetic acid hydrochloric acid was obtained. : Melting point 208 to 211 ° C.

Example 38

4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] butyramide

The following is the preparation of compounds of formula I (a) wherein n is 1, t is 0, R ³ is 4- (carbamoyl) propyl and R ⁴ and R ⁵ are each hydro.

4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H- prepared as in Example 37 in 10 ml of methylene chloride. A mixture of imidazol-1-yl] butyric acid (100 mg, 0.32 mol), oxalyl chloride (2M, 0.32 ml, 0.64 mol) and 5 drops of DMF was stirred for 2 hours. The solvent and excess oxalyl chloride were removed by evaporation and the residue was treated with 5 ml of 30% aqueous ammonium hydroxide and stirred for 16 hours. The mixture was poured into aqueous sodium bicarbonate and extracted with methylene chloride. The extract was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography, eluting with methylene chloride / methanol (99: 1 to 96: 4) on silica gel to give 4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl)- 2-Tioxo-2,3-dihydro-1H-imidazol-1-yl] butyramide (70 mg, 0.22 mmol) was obtained as a foam.

Proceed as in Example 38, but with 4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-1 -Yl] butyric acid was replaced with a different starting material to afford the compound of formula

4- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylethyl] benzoic acid replacing 4 -[3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-ylethyl] benzamide was obtained: Melting point 158 to 160 ° C; And

3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] propionic acid in place of 3- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] propionamide was obtained: Melting point 180 To 181 ° C.

Example 39

3- [2- (4 (1H) -tetrazol-5-ylphenyl) ethyl] -1- (1,2,1,4-tetrahydronaphthalen-1-yl) -1,3-dihydroimidazole 2-thione

The following general formula (a) wherein n is 1, t is 0, R ³ is 2- (4 (1H) -tetrazol-5-ylphenyl) ethyl, and R ⁴ and R ⁵ are each hydro; Preparation of compounds.

3- [2- (4-cyanophenyl) ethyl] -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3 prepared as in Example 15 in 3 ml of xylene -Dihydroimidazole-2-thione (0.5 g, 1.4 mmol) was heated at 120 ° C. under nitrogen for about 16 hours. The mixture was purified by chromatography, eluting with methylene chloride / methanol on silica gel, and the purified product was recrystallized from ethyl acetate / methanol to 3- [2- (4 (1H) -tetrazol-5-ylphenyl) ethyl]- 1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (0.5 g, 1.4 mmol) was obtained: melting point 218-220 ° C.

Example 40

(S) -4- (1-hydroxy) ethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole 2-thione

The following is the preparation of compounds of formula I (a) wherein n is 1, t is 0, R ³ and R ⁵ are hydro and R ⁴ is 1-hydroxyethyl.

(S) -3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-di prepared as in Example 22 Hydro-1H-imidazole-5-carbaaldehyde (178 mg, 0.6 mmol) was stirred at about 0 ° C. for 1 hour and further at about 25 ° C. for 1 hour. The mixture was treated with 5 ml of dilute sulfuric acid and extracted with ethyl acetate (2 ×). The combined extracts were dried (MgSO ₄ ) and concentrated and the residue was purified by flash chromatography, eluting with methylene chloride / methanol (98: 2) on silica gel. The purified residue was further purified by preparative thin layer chromatography, eluting with methylene chloride / methanol (95: 5) on silica gel to give (S) -4- (1-hydroxy) ethyl-1- (5, 7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (22 mg, 0.1 mmol) was obtained: Melting point 210-211 ℃.

Proceed as in Example 40, but replacing methylmagnesium chloride with n-propylmagnesium chloride (S) -4- (1-hydroxy) but-1-yl-1- (5,7-difluoro- 1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione was obtained: melting point 154-156 캜.

Example 41

N-1H-tetrazol-5-yl-3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro -1H-imidazole-4-carboxamide

The preparation of compounds of formula I (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁵ is 1H-tetrazol-5-yl-carbamoyl to be.

3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H- prepared as in Example 37 Imidazole-4-carboxylic acid (1 g, 3.33 mmol) was dissolved in 15 ml of oxalyl chloride, and one drop of DMF and this solution was stirred under nitrogen for 3 hours. Excess oxalyl chloride was removed by rotary evaporator and the residue was co-evaporated with carbon tetrachloride (2 × 25 ml). The residue was cooled at 0 ° C. and anhydrous 5-amino-1H-tetrazole (0.85 g, 10 mmol) and 25 ml pyridine were added. The mixture was allowed to warm to rt and then stirred for 16 h. The solvent was removed by evaporation and the residue coevaporated with toluene. The residue was purified by column chromatography on silica gel filled with 5% methanol / methylene chloride containing 1% acetic acid to yield 0.9 g of impure product. The impure product was dissolved in aqueous potassium carbonate and the solution extracted with ethyl acetate. The aqueous layer was acidified to give a solid material. The material was isolated by filtration, and N-1H-tetrazol-5-yl-3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo -2,3-dihydro-1H-imidazole-4-carboxamide (0.54 g, 1.56 mmol) was obtained as a light orange solid: 228-230 ° C.

Example 42

(4-methylpiperazin-1-yl) [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-di Hydro-1H-imidazol-4-yl] methanone

The following compounds of formula I (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁵ is 4-methyl-piperazin-1-ylcarbonyl Is manufactured.

3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-1,3-di in 6 ml of THF as prepared in Example 37 A mixture of hydro-1H-imidazole-4-carboxylic acid (0.75 g, 2.42 mmol) and 1,1'-carbonyldiimidazole (0.43 g, 2.65 mmol) was stirred under argon at room temperature for about 18 hours. N-methylpiperazine (0.29 ml, 2.65 mmol) was added and the mixture was stirred at room temperature under argon for about 18 hours. The mixture was partitioned between methylene chloride and water. The methylene chloride layer was washed four times with water, dried over magnesium sulfate and concentrated by evaporation. The residue was recrystallized from ethyl acetate / methanol (4-methylpiperazin-1-yl) [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)- 2-thioxo-2,3-dihydro-1H-imidazol-4-yl] methanone (0.68 g, 1.76 mmol) was obtained; 248 to 250 ° C.

Proceed as in Example 42, but with 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-1,3-dihydro-1H -Imidazole-4-carboxylic acid and / or N-methylpiperazine were replaced with different starting materials to give the compounds of the general formula (I):

Replaced with 3- (6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-1,3-dihydro-1H-imidazole-4-carboxylic acid (4-methylpiperazin-1-yl) [3- (6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3- Dihydro-1H-imidazol-4-yl] methanone was obtained as an oil;

3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-1,3-dihydro-1H-imidazole-4-carboxylic acid and N N- (2-dimethylaminoethyl) -3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-ti substituted by, N-dimethylethylenediamine Oxo-2,3-dihydro-1H-imidazole-4-carboxamide was obtained: melting point 125 ° C .;

3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-1,3-dihydro-1H-imidazole-4-carboxylic acid and p N- [4- (methylsulfonylamino) phenyl] -3- (5,7-difluoro-1,3,3,4-tetrahydronaphthalen-2-yl) in place of -methylsulfonylaminoaniline 2-Tioxo-1,3-dihydro-1H-imidazole-4-carboxamide was obtained: melting point 225 to 230 ° C;

3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-1,3-dihydro-1H-imide in the presence of dichlorohexylcarbodiimide 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-1,3 substituted with dazol-4-carboxylic acid and dimethylaminoethanethiol hydrochloric acid -Dihydro-1H-imidazole-4-carbothioic acid S- (2-dimethylaminoethyl) ester was obtained: melting point 204-206 ° C .; And

3- (6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-1,3-dihydro-1H-imide in the presence of dichlorohexylcarbodiimide 3- (6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-1,3 substituted with dazol-4-carboxylic acid and dimethylaminoethanethiol hydrochloric acid -Dihydro-1H-imidazole-4-carbothioic acid S- (2-dimethylaminoethyl) ester was obtained: Melting point 275-277 ° C.

Example 43

3- (3,4-dihydroxybenzyl) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione

The following is the preparation of compounds of formula I (a) wherein n is 1, t is 0, R ³ is 3,4-dihydroxybenzyl and R ⁴ and R ⁵ are each hydro.

3- (3,4-dimethoxybenzyl) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydro prepared as in Example 15 in 10 mldml methylene chloride Imidazole-2-thione (900 mg, 2.37 mol) was cooled to 0 ° C. under nitrogen and boron tribromide (1M, 7.1 ml, 7.1 mmol) was added dropwise in addition to 10 ml of methylene chloride. The mixture was cooled to rt, stirred for 16 h and slowly added to water. The organic layer was separated, washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography, eluting with methylene chloride / methanol (96: 4) on silica gel, and then crystallized from methanol / ethanol / hexanes to give 3- (3,4-dihydroxybenzyl) -1- ( 1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (520 mg) was obtained: melting point 173-174 ° C.

Proceed as in Example 43, but with 3- (3,4-dimethoxybenzyl) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole- 2-thione was replaced with a different starting material to afford the compound of formula I:

3- [2- (3,4-dimethoxyphenyl) ethyl] -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione Alternatively 3- [2- (3,4-dihydroxyphenyl) ethyl] -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2 -Thione was obtained: melting point165 to 167 ° C;

Substituted with 1- (5-methoxyindan-1-yl) -1,3-dihydroimidazol-2-thione 1- (5-hydroxyindan-1-yl) -1,3-dihydroimide Dazol-3-thione was obtained: Melting point 208-209 ° C.

1- (1,2,3,4-tetrahydro-6-methoxynaphthalen-1-yl) -1,3-dihydroimidazol-2-thione in place of 1- (1,2,3,4 -Tetrahydro-6-hydroxynaphthalen-1-yl) -1,3-dihydroimidazole-2-thione was obtained: melting point 213-215 캜.

1- (1,2,3,4-tetrahydro-5-methoxynaphthalen-1-yl) -1,3-dihydroimidazol-2-thione in place of 1- (1,2,3,4 -Tetrahydro-5-hydroxynaphthalen-1-yl) -1,3-dihydro-imidazole-2-thione was obtained: melting point 188 to 190 ° C.

1- (1,2,3,4-tetrahydro-7-methoxynaphthalen-1-yl) -1,3-dihydroimidazol-2-thione in place of 1- (1,2,3,4 -Tetrahydro-7-hydroxynaphthalen-1-yl) -1,3-dihydroimidazole-2-thione was obtained: melting point 195-196 ° C.,

1- (1,2,3,4-tetrahydro-5-methoxynaphthalen-2-yl) -1,3-dihydroimidazole-2-thione in place of 1- (1,2,3,4 -Tetrahydro-5-hydroxynaphthalen-2-yl) -1,3-dihydro-imidazole-2-thione was obtained: melting point 263-265 캜.

1- (1,2,3,4-tetrahydro-6-methoxynaphthalen-2-yl) -1,3-dihydroimidazole-2-thione in place of 1- (1,2,3,4 -Tetrahydro-6-hydroxynaphthalen-2-yl) -1,3-dihydro-imidazol-2-thione was obtained: melting point 240-241 ° C.

1- (1,2,3,4-tetrahydro-7-methoxynaphthalen-2-yl) -1,3-dihydroimidazole-2-thione in place of 1- (1,2,3,4 -Tetrahydro-7-hydroxynaphthalen-2-yl) -1,3-dihydroimidazole-2-thione was obtained: melting point 248-250 ° C.

1- (1,2,3,4-tetrahydro-8-methoxynaphthalen-2-yl) -1,3-dihydroimidazole-2-thione in place of 1- (1,2,3,4 Tetrahydro-8-hydroxynaphthalen-2-yl) -1,3-dihydroimidazole-2-thione was obtained: melting point 274-276 ° C.

1- (6,8-difluoro-1,2,3,4-tetrahydro-7-methoxynaphthalen-2-yl) -1,3-dihydroimidazole-2-thione in place of 1- (6,8-difluoro-1,2,3,4-tetrahydro-7-hydroxynaphthalen-2-yl) -1,3-dihydroimidazole-2-thione was obtained: melting point 258 to 260 ° C.

Example 44

(S) -N- [3- (5,7-Difluoro-1,2,3,4-tetrahydro-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole -4-ylmethyl] -4-butylbenzamide

Below is the preparation of compounds of formula I (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁵ is 4-butylbenzoylaminomethyl.

(2) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydro-2-yl) -1 prepared as in Example 31 in 10 ml of anhydrous pyridine , 3-dihydroimidazole-2-thione (0.30 g, 1 mmol) and 4-butylbenzoyl chloride (0.21 ml, 1.1 mmol) were stirred under argon at about 0 ° C. for 1 hour and at about 25 ° C. for an additional 2 hours. Was stirred. The mixture was concentrated and the residue was treated with water. The mixture was extracted with ethyl acetate (3 ×) and the combined extracts were dried (MgSO ₄ ) and concentrated. The residue was recrystallized from ethyl acetate to give (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydro-2-yl) -2-thioxo-2,3 -Dihydro-1H-imidazol-4-ylmethyl] -4-butylbenzamide (0.25 g, 0.55 mmol) was obtained: melting point 242-243 ° C.

Proceed as in Example 44, but with (S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydro-2-yl) -1,3-di Hydroimidazole-2-thione and / or 4-butylbenzoyl chloride were replaced with different starting materials to afford the following compounds of formula (I);

(S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3 substituted with nicotinoyl chloride -Dihydro-1H-imidazol-4-ylmethyl] -nicotinamide was obtained: melting point 218-221 ° C .;

(S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-di replaced by benzoyl chloride Hydro-1H-imidazol-4-ylmethyl] benzamide was obtained: melting point 260-261 ° C .;

(S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydro-2-yl) -2-thioxo-2,3- replaced by dimethylcarbamyl chloride Dihydro-1H-imidazol-4-ylmethyl] dimethylcarbamide was obtained: melting point 218-221 ° C .;

(S) -3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro by substitution with methyl chloroformate -1H-imidazol-4-ylmethyl] carbamate was obtained; Melting point 220 to 222 ° C;

(S) -3-amino-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and acetic anhydride in place of N- [3 -(1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-yl] acetamide was obtained: Melting point 196 to 200 ℃; And

(S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2, substituted with 2-furancarboxylic acid chloride, 3-dihydro-1H-imidazol-4-ylmethyl] -2-furancarboxamide was obtained: melting point 227-231 ° C .; And

4-amino-2- (1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3-thione and acetic anhydride, replacing N -[1- (1,2,3,4-tetrahydronaphthalen-2-yl) -5-thioxo-4,5-dihydro-1H- [1,2,4] triazol-4-yl] Acetamide was obtained: melting point 199 to 201 ° C.

Example 45

(S) -N- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already Dazol-4-ylmethyl] picolinamide

Below is the preparation of compounds of formula (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁵ is picolinoylaminomethyl.

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimime prepared in Example 31 A mixture of dozol-2-thiene (295 mg, 1 mmol), picolinic acid (l23 mg, 1 mmol) and PyBOP (620 mg, 1.2 mmol) in 10 ml of dry DMF was stirred at about 25 ° C. for 5 minutes under argon to give N, N- Diisopropylethylamine (0.58 ml, 3.3 mmol) was added. The mixture was stirred for about 12 hours and 10 ml of water was added. The aqueous layer was extracted with ethyl acetate (3 × 10 ml) and the combined extracts were washed with water, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel eluting with hexane / THF (1: 1 to 8: 2) to give (S) -N- [3- (5,7-difluoro-1,2,3, 4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] picolinamide (80 mg, 0.2 mmol) was obtained. Melting point 216-217 캜.

Proceed as in Example 45, but replacing the other starting material instead of picolinic acid to obtain a compound of formula

(S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl using N- (t-butoxycarbonyl) glycine and deprotecting ) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] aminoacetamide with a melting point of 144-153 ° C .;

(S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl using N- (t-butoxycarbonyl) glycine and deprotecting ) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] -2-amino-2-methylpropionamide trifluoroacetate, having a melting point of 158 ° C .;

(S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2 using 5-butylpicolinic acid , 3-dihydro-1H-imidazol-4-ylmethyl] -5-butylpicolinamide was obtained. Melting point 99 to 104 ° C.

Example 46

(S) -N- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already Dazol-4-ylmethyl] ethylcarbamide

Below is the preparation of compounds of formula (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁵ is ethyluridomethyl.

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimime prepared in Example 31 A mixture of dazol-2-thiene (294 mg, 1 mmol) and ethyl isocyanate (0.16 ml, 2 mmol) in 10 ml of THF was stirred at about 50 ° C. under argon for about 60 hours. The mixture was filtered and the filtered solid was recrystallized from ethyl acetate / methanol (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) 2-Tioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] ethylcarbamide (110 mg, 0.3 mmol) with a melting point of 219 to 220 캜 was obtained.

Example 47

4-aminomethyl-1- (1,2,3,4, -tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione

Below is the preparation of compounds of formula (a) wherein n is 1, t is 0, R ³ and R ⁵ are each hydro and R ⁴ is aminomethyl.

3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4-carbaldehyde (0.25 g, 1.0 mmol), A mixture of 2 mL of ethanol and 2 mL of water of hydroxylamine hydrochloric acid (0.09), 1.3 mmol, and sodium hydroxide (0.064 g, 1.6 mmol) was stirred at 60 ° C. for 1 hour. The mixture was cooled to give crystalline material. The material was isolated by filtration and drying. The filtrate was stirred with ethyl acetate to give more crystalline material. The material was isolated by filtration and drying. The crystalline material was mixed to form 1- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde oxime ( 0.186 g, 0.68 mmol) was obtained.

3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-5- in 20 ml of THF prepared as in Example 22 A suspension of carbaldehyde oxime (0.158 g, 0.58 mmol) was cooled at 0 ° C. and LAH (1.0 M, 1.16 ml, 1.16 mmol) in THF was slowly added. The mixture was stirred at 0 ° C. for 1 h and saturated ammonium chloride, water and ethyl acetate were added. The aqueous worms were separated with acetyl acetate and extracted. The combined ethyl acetate was dried over magnesium sulfate and concentrated by evaporation. Purification of the residue by flash chromatograph (elute: 3 to 10% methanol / methylene chloride) was carried out with 4-aminomethyl-1- (1,2,3,4-tetrahydro-naphthalen-2-yl) -1,3 -Dihydroimidazole-2-thione, melting | fusing point 197-200 degreeC was obtained.

Example 48

(S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -4- (2-phenylethyl) aminomethyl-1,3-dihydroimime Dozol-2-thione

Below is the preparation of compounds of formula (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁴ is 2- (phenyl) ethylaminomethyl.

As prepared in Example 22, (S) -3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3- Dihydro-1H-imidazole-5-carbaldehyde (147 mg, 0.5 mmol), a mixture of phenethylamine (75 μl, 0.6 mmol) and sodium cyanoborohydride (47 mg, 0.75 mmol) in 10 ml methanol Was stirred at about 60 ° C. for 2 hours. The mixture was concentrated and the residue was purified by flash chromatograph on silica gel eluting with methylene chloride / methanol (97: 3). The purified product was concentrated, converted to hydrochloride and recrystallized from ethyl acetate / methanol (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) 4- (2-phenylethyl) aminomethyl-1,3-dihydroimidazole-2-thione hydrochloric acid (68 mg, 0.2 mmol) with a melting point of 227-229 ° C. was obtained.

Proceed as in Example 48, but with (S) -3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-di Other starting materials were substituted for hydro-1H-imidazole-5-carbaldehyde and / or phenethylamine to give the compound of formula

3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde And t-butyl 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3- replacing glycine t-butyl ester hydrochloric acid To obtain dihydro-1H-imidazol-5-ylmethylaminoacetate;

(S) -3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-5 T-butyl (S) -3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2 in place of -carbaldehyde and glycine t-butyl ester hydrochloric acid -Thioxo-2,3-dihydro-1H-imidazol-5-ylmethylaminoacetate;

3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde and glycine t-butyl ester hydrochloric acid Substitutes t-butyl 3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-5-ylmethylaminoacetate and;

(S) -3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro- in place of glycineamide hydrochloric acid 1H-imidazol-5-yl-methylaminoacetamide, having a melting point of 212 to 213 ° C .;

Methyl (S) -4- {2- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2 by replacing methyl 4- (2-aminoethyl) benzoate hydrochloric acid -Yl) -2-thioxo-2,3-dihydro-1H-imidazol-5yl-methylamino] ethyl} benzoate with a melting point of 159-160 ° C. was obtained.

Example 49

^{(S) -N 3 - [3-} (5,7- difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro -1H- Imidazol-4-ylmethyl] -N ¹ , N ² -di (t-butoxycarbonyl) formamidine

Where n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁵ is N ¹ , N ² -di (t-butoxycarbonyl) amidinoaminomethyl It is a manufacturing method of the compound of (a).

(S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5-aminomethyl-1,3-di as prepared in Example 31 A mixture of hydroimidazole-2-thione (0.6 g, 2 mmol) and N ¹ , N ² -di (t-butoxycarbonyl) methylthioamidine (0.65 g, 2.2 mmol) in 15 ml of THF and 0.3 ml The water was stirred at about 50 ° C. under argon for 4 hours. The mixture was concentrated and the residue was mixed with 5% aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the extract was dried over (MgSO ₄ ) and concentrated. The residue in methylene chloride / methanol (99: 1) and purified by flash chromatography on silica gel, eluting with ^{(S) -N 3 - [3-} ( 5,7-difluoro-1,2,3,4-in Tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] -N ¹ , N ² -di (t-butoxycarbonyl) formamidine (0.54 g, 1 mmol) and a melting point of 155 ° C. were obtained.

Proceed as in Example 49, however, another starting material was substituted for N ¹ , N ² -di (t-butoxycarbonyl) methylthioamidine to obtain a compound of Formula 1

N ^1, N ² - di (acetyl) methyl, replacing thio amidine ^{(S) -N 3 - [3-} (5,7- difluoro-1,2,3,4-tetrahydronaphthalen-2 Il) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] -N ¹ , N ² -di (acetyl) formamidine, having a melting point of 213 to 214 ° C .;

N ¹ - (t- butoxycarbonyl) by replacing the methylthio amidine ^{(S) -N 3 - [3-} (5,7- difluoro-1,2,3,4-tetrahydro-naphthalene -2 -Yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] -N ^1- (t-butoxycarbonyl) formamidine with a melting point of at least 280 ° C was obtained.

Example 50

^{(S) -N 3 - [3-} (5,7- difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro -1H- Imidazol-4-ylmethyl] formamidine

Following is the preparation of compounds of formula (a) wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ⁵ is amidinoaminomethyl.

Carried out (S) of the trifluoroacetic acid in 20ml As prepared in Example 50 -N ³ - [3- (5,7- difluoro-1,2,3,4-tetrahydronaphthalen-2-yl ) -2-Tioxo-2,3-dihydro-1 H-imidazol-4-ylmethyl] -N ¹ , N ² -di (t-butoxycarbonyl) formamidine (0.34 g, 0.6 mmol) The solution was stirred at about 25 ° C. for 1.5 hours. The mixture was concentrated and the residue was mixed with 100 ml of diethyl ether. Diethyl ether was poured off and the residue was mixed with 100 ml of diethyl ether. The mixture was filtered and the filtered residue was dissolved with ethyl acetate. The solution was concentrated, emptied and the resulting foam was treated with diethyl ether. The mixture was filtered ^{(S) -N 3 - [3-} (5,7- difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3- Dihydro-1H-imidazol-4-ylmethyl] formamidine trifluoroacetate (0.28 g, 0.6 mmol) with a melting point of 103 ° C. was obtained.

Example 51

2S-amino-3- (3H-imidazol-4-yl) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2R-yl) -2- Thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] propionamide hydrochloric acid

Wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions, R ¹⁸ is a group of formula (d), and R ²¹ is L-histidylaminomethyl It is the recipe of.

As prepared in Example 31, (R) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3- Dihydroimidazole-2-thione (0.55 g, 1.86 mmol), (s) -2- (t-butoxycarbonyl) amino-3- (3-t-butoxycarbonyl-3H-imidazole-4 A mixture of -yl) propionic acid (0.76 g, 1.86 mmol) and PyBOP (1.07 g, 2.05 mmol) in 6.2 ml of DMF was stirred until uniform under argon. Diethylisopropylethylamine (1.07 ml, 6.15 mmol) was added and the mixture was stirred for about 18 hours. The mixture was separated between water and ethyl acetate and the organic layer was washed twice with water, dried over magnesium sulfate and concentrated by evaporation. The residue was purified by column chromatography (elution: 5% methanol / methylene chloride) to give 2S- (t-butoxycarbonyl) amino-3- (3-t-butoxycarbonyl-3H-imidazole- as a foam. 4-yl) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2R-yl) -2-thioxo-2,3-dihydro-1H- Imidazol-4-ylmethyl] propionamide (1.003 g) was obtained.

2S- (t-butoxycarbonyl) amino-3- (3-t-butoxycarbonyl-3H-imidazol-4-yl) -N- [3- (5,7-difluoro-1 45 ml of 30% anhydrous of 2,3,4-tetrahydronaphthalene-2R-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] propionamide (0.935 g) Dissolve in hydrogen chloride / ethyl acetate and stir the mixture for 18 hours to afford crystalline material. Separation of material by filtration and drying at 60 ° C. under vacuum to 2S-amino-3- (3H-imidazol-4-yl) -N- [3- (5,7-difluoro-1,2,3 , 4-tetrahydronaphthalene-2R-yl) -2-tyloxo-2,3-dihydro-1H-imidazol-4-ylmethyl] propionamide hydrochloric acid (0.655 g, 1.24 mmol) with a melting point of 228 ° C. It was.

Proceed as in Example 51, but with (R) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3- Dihydroimidazole-2-thione and / or (s) -2- (t-butoxycarbonyl) amino-3- (3-t-butoxycarbonyl-3H-imidazol-4-yl) propionic acid The compound of formula 2 was obtained:

5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and / or (s 3S-amino-N- [3- (5,7-difluoro-1,2,3,4 by replacing t-butoxycarbonyl-2-t-butoxycarbonylaminopropionic acid) -Tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-yl-methyl] succinic acid hydrochloric acid, melting point 220 deg.

5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (s)- 2-S-amino-N- [3- (5,7-difluoro-1,2,3,4 by replacing 3- (t-butoxycarbonyl-3- (t-butoxycarbonylamino) propionic acid -Tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-yl-methyl] succinic acid hydrochloric acid, melting point 220 deg.

5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (s)- 2S, 5-diamino-N- [3- (5,7-difluoro-1,2,3,4-tetrahydro, replacing 2,5-di (t-butoxycarbonylamino) valeric acid Naphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] valeramide hydrochloric acid, melting point 212-216 degreeC,

5-aminomethyl-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (s) -2,5-di (t- Butoxycarbonylamino) valeric acid replaces 2S, 5-diamino-N- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3- Dihydro-1H-imidazol-4-ylmethyl] valeramide hydrochloric acid, having a melting point of 191 to 205 캜;

5-aminomethyl-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (s) -2- (t-butoxycarbo 2S-amino-N- [3- (1,2,3,4-tetrahydronaphthalen-2-yl) -2-ti as a substituted for niyl-5- (t-butoxycarbonyl) guanidinovaleric acid Oxo-2,3-dihydro-1H-imidazol-4-ylmethyl] -5-guanidinovaleramide hydrochloric acid with a melting point of 160 ° C. was obtained;

3-amino-1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (s) -2- (t-butoxycarbonyl ) Amino-3- (3-t-butoxycarbonyl-3H-imidazol-4-yl) propionic acid to replace 2S-amino-3- (3H-imidazol-4-yl) -N- [3- Obtained (1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] propionamide hydrochloric acid, melting point 197-205 degreeC and;

5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (s)- 2-S-amino-3- (3H-imidazole-4 in place of 2- (t-butoxycarbonyl) amino-3- (3-t-butoxycarbonyl-3H-imidazol-4-yl) propionic acid -Yl) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already To obtain dazol-4-ylmethyl] propionamide hydrochloric acid, melting point 195 to 238 ° C,

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (s) -2- (t-butoxycarbonyl-amino-3- (3-t-butoxycarbonyl-3H-imidazol-4-yl) propionic acid to replace 2S-amino-3- (3H- Imidazol-4-yl) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2S-yl) -2-thioxo-2,3-dihydro -1H-imidazol-4-ylmethyl] propionamide hydrochloric acid, melting point 225 DEG C, was obtained;

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (s) -4-acetylamino-4-t-butoxycarbonylbutyric acid to replace 2S-aacetylamino-4- [3- (5,7-difluoro-1,2,3,4-tetra Hydronaphthalene-2S-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethylaminocarbonyl] butyric acid with a melting point of 159 ° C .;

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (S) -2,5-di (t-butoxycarbonylamino) pentanoic acid to replace 2S, 5-diaminoN- [2- (5,7-difluoro-1,2,3,4 -Tetrahydronaphthalene-2S-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] valeramide hydrochloric acid, melting point 233-237 degreeC is obtained;

(R) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (S) -2,5-di (t-butoxycarbonylamino) pentanoic acid to replace 2S, 5-diamino-N- [3- (5,7-difluoro-1,2,3, 4-tetrahydronaphthalene-2R-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] valeramide hydrochloric acid, having a melting point of 128 to 150 占 폚;

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (S) -3- (t-butoxycarbonyl) -2- (t-butoxycarbonylamino) propionic acid to replace 3S-amino-N- [3- (5,7-difluoro-1, 2,3,4-tetrahydronaphthalene-2S-yl) -2-thioo-2,3-dihydro-1H-imidazol-4-yl-methyl] succinic acid hydrochloric acid, melting point 194 ° C. was obtained;

(R) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione and (S) -3- (t-butoxycarbonyl) -2- (t-butoxycarbonylamino) propionic acid to replace 3S-amino-N- [3- (5,7-difluoro-1, 2,3,4-tetrahydronaphthalene-2R-yl) -2-thioo-2,3-dihydro-1H-imidazol-4-yl-methyl] succinic acid hydrochloric acid, melting point 193 ° C. was obtained;

4-amino-2- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3- 2S, 5-diamino-N- [1- (5,7-difluoro-1,2,3,2-substituted by replacing thion and (S) -2,5-di (t-butoxycarbonylamino) valeric acid 3,4-tetrahydronaphthalen-2-yl) -5-thioxo-4,5-dihydro-1H- [1,2,4] triazol-4-yl] valeramide hydrochloric acid;

4-amino-2- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3- Thion and (S) -2-di (t-butoxycarbonyl) amino-3- (3-t-butoxycarbonyl-3H-imidazol-4-yl) propionic acid in place of 2S-amino-3- (3H-imidazol-4-yl) -4-yl) -N- [1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5-ti Oxo-4,5-dihydro-1H- [1,2,4] triazol-4-yl] propionamide hydrochloric acid, having a melting point of 221 to 224 ° C .;

(S) -5-methylaminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione And (S) -3- (t-butoxycarbonyl) -2- (t-butoxycarbonylamino) propionic acid to replace 3S-amino-N- [3- (5,7-difluoro-1 , 2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-yl-methyl] N-methylsuccinic acid hydrochloric acid;

4-amino-2- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3- 2S-amino-N- [1- (5,7-difluoro-) in place of ionic and (S) -3- (t-butoxycarbonyl) -3- (t-butoxycarbonylamino) propionic acid 1,2,3,4-tetrahydronaphthalen-2-yl) -5-thioxo-4,5-dihydro-1H- [1,2,4] triazol-4-yl] succinic acid hydrochloric acid, melting point 193-196 ° C. was obtained.

Example 52

2R-amino-3- [1- (4,6-difluoroindan-1-yl) -1-H-imidazol-2-yldisulfanyl] propionic acid hydrochloric acid

Where n is 0, t is 2, R ¹ is fluoro at the 5- and 7-positions, R ²⁷ is a group of formula (g), R ⁴ and R ⁵ are each hydro and R ²⁸ is 2- A preparation of the compound of formula 3 which is amino-2-carboxyethyl.

(R, R ')-3,3'-disulfanylbis [t-butyl-2- (t-butoxy-carbonyl) aminopropionate (1.06 g, 2.0 mmol) in 5 ml ethylenedichloride The solution of was cooled to -23 ° C under argon. Bromine (51.3 μl, 1.0 mmol) was added dropwise and the mixture was stirred for about 20 minutes and then diluted by the addition of 2 ml of ethylenedichloride. A suspension of potassium phthalimide (370 mg, 2.0 mmol) in 5 ml of ethylenedichloride was cooled to about −23 ° C. and then warmed to room temperature for at least 45 minutes. The mixture was filtered and concentrated in vacuo. The residue was dissolved in benzene. Purification by chromatography gave (R) -N- [2- (t-butoxycarbonyl) ethylsulfanyl] phthalimide (684 mg) as an oil.

(R) -N- [2- (t-butoxycarbonylamino) -2- (t-butoxycarbonyl) -ethylsulfanyl] phthalimide in 8 ml of ethyl acetate prepared in Example 9 660 mg, 1.61 mmol) and 1- (4,6-difluoroindan-1-yl) -1,3-dihydroimidazole-2-thione (400 mg, 1.59 mmol) were refluxed under argon for 1 hour. Heated. The mixture was cooled at room temperature to give crystalline precipitate and then the solvent was removed by evaporation under reduced pressure. The remaining semisolid was triturated with benzene and the benzene mixture was filtered. The benzene solution was concentrated by evaporation. Purification of the residue by chromatography was performed using t-butyl 2R- (t-butoxycarbonyl) amino-3- [1- (4,6-difluoroindan-1-yl) -1-H-imidazole- 2-yldisulfanyl] propionate (672 mg) was obtained.

T-butyl-2R- (t-butoxycarbonyl) amino-3- [1- (4,6-difluoroindan-1-yl) -1-H-imidazole in 15 ml of trifluoroacetic acid A mixture of -2-yldisulfanyl] propionate (672 mg) and 15 ml of methylene chloride was stirred at room temperature under nitrogen atmosphere for 2 hours. The solvent was removed by evaporation and the residue was co-evaporated with ethyl acetate (2 x 50 ml).

Treatment with hydrogen chloride on ether gives 2R-amino-3- [5-aminomethyl-1- (4,6-difluoroindan-1-yl) -1H-imidazol-2-yldisulfanyl] propionic acid hydrochloric acid as a solid

(768 mg, 1.74 mmol) and melting points of 147-154 ° C. were obtained.

Proceed as in Example 52, but with (R, R ')-3,3'-disulfanylbis [t-butyl-2- (t-butoxy-carbonyl) aminopropionate and / or 1- ( Instead of 4,6-difluoroindan-1-yl) -1,3-dihydroimidazol-2-thione, another starting material was substituted to obtain a compound of formula

(R, R ')-3,3'-disulfanylbis [t-butyl-2- (t-butoxy-carbonyl) aminopropionate to replace methyl 2R-amino-3- [5-amino Methyl-1- (4,6-difluoroindan-1-yl) imidazol-2-yl-disulfanyl] propionate hydrochloric acid, having a melting point of 155 to 157 ° C .;

Methyl 2-2- (aminoethyldisulfanyl) -1- (4,6-difluoroindan by replacing 3,3'-disulfanylbis [2- (t-butoxycarbonyl) aminomethyl] -1-yl) imidazole hydrochloric acid, melting point 175-177 ° C .;

Methyl 2- (trifluoroacetyl) amino-3- as an oil, replacing (R, R ')-3,3'-disulfanylbis [methyl-2- (trifluoroacetyl) aminopropionate] To obtain [1- (4,6-difluoroindan-1-yl) imidazol-2-yl-disulfanyl] propionate;

(R, R ')-3,3'-disulfanylbis [t-butyl-2- (t-butoxy-carbonyl) amino-propionate to replace methyl 2R-amino-3- [1- Obtaining (4,6-difluoroindan-2-yl) imidazol-2-yl-disulfanyl] propionic acid hydrochloric acid, melting point 145-150 ° C .;

2R-amino-3- [1- (4,5-difluoroindan) in place of 1- (4,5-difluoroindan-2-yl) -1,3-dihydroimidazol-2-thione 2-yl) -1H-imidazol-2-yl-disulfanyl] propionic acid hydrochloric acid, melting point 140 占 폚 was obtained;

2R-amino-3- [substituted 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1H-imidazol-2-yldisulfanyl] propionic acid hydrochloric acid with a melting point of 130 ° C. was obtained;

2R-amino-3- [1 by replacing 1- (6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2 thion -(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1H-imidazol-2-yldisulfanyl] propionic acid hydrochloric acid, having a melting point of 141 ° C .;

2R-amino-3- [1 by replacing 1- (6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2 thion -(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1H-imidazol-2-yldisulfanyl] propionic acid hydrochloric acid, having a melting point of 130 ° C .;

2R- by replacing 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-1,3-dihydroimidazole-5-carboxylic acid Amino-3- [5-carboxy-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) imidazol-2-yldisulfanyl] propionic acid hydrochloric acid, melting point 129 To 138 ° C .;

1- (4,5-difluoroindan-2-yl) -1,3-dihydroimidazole-2-thione and (S, S ')-4,4'-disulfanylbis [t-butyl 2S-amino-4- [1- (4,5-difluoroindan-2-yl) imidazol-2-yl-disulfanyl, replacing 2- (t-butoxycarbonyl) aminobutyrate] ] Butyric acid hydrochloric acid, melting | fusing point 146 degreeC is obtained;

1- (4,5-difluoroindan-2-yl) -1,3-dihydroimidazole-2-thione and 3,3'-disulfanylbis [2- (t-butoxycarbonyl) Aminoethyl] was substituted to give 2- (2-aminoethyldisulfanyl) -1- (4,5-difluoroindan-2-yl) imidazol-2-yl] imidazole hydrochloric acid, melting point 59 ° C. and;

1- (4,5-difluoroindan-2-yl) -1,3-dihydroimidazole-2-thione and (S, S ')-3,3'-disulfanylbis [t-butyl 2S-amino-3- [1- (4,5-difluoroindan-2-yl) -1-H-imide, replacing 2- (t-butoxycarbonyl) amino-3-methylbutyrate] Dazol-2-yl-disulfanyl] -3-methylbutyric acid, melting point 143-149 ° C .;

1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -5 (1H) -tetrazol-5-yl-1,3-dihydroimidazole-2 2- (2-aminoethyldisulfanyl) -1- (5,7-difluoro as a substitute for -thione and 3,3'-disulfanylbis [2- (t-butoxycarbonyl) aminoethyl] Rho-1,2,3,4-tetrahydronaphthalen-2-yl) -5 (1H) -tetrazol-5-yl-1,3-dihydroimidazole hydrochloric acid with a melting point of 165 ° C. was obtained;

(S) -5- (t-butoxycarbonyl) aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-di 2R-amino in place of hydroimidazole-2-thione and (R, R ')-3,3'-disulfanylbis [t-butyl-2- (t-butoxycarbonyl) aminopropionate] -3- [5-Aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1H-imidazol-2-yldisulfanyl] propionic acid hydrochloric acid A melting point of 179 to 180 ° C. is obtained;

Example 53

N- (trifluoroacetyl) -L-aspartic anhydride

L-aspartic acid in trifluoroacetic anhydride (7.7 kg, 5.3 L, 37.5 mol) was heated at reflux and 9 L of trifluoroacetic acid (gradual heating to 65 ° C. and stirred for 3 h) (2.0 kg, 15.0 mol) was added to reflux trifluoroacetic anhydride for 30 minutes. The mixture was distilled off and 9 L of trifluoroacetic acid was removed. The remaining mixture was added to cold hexane under 8 L of nitrogen. The hexane mixture was stirred for 3 hours in an ice bath to give crystalline material. The material was isolated by filtration and the filtrate residue was washed with about 25 liters of hexane. N- (trifluoroacetyl) -L-aspartic anhydride (2.9 kg, 13.7 mol), melting point 140 to 141 DEG C, [α] _D -27.4 by drying in a vacuum oven at 50 DEG C under nitrogen gas bleed (C = 3.28, THF) was obtained.

Example 54

(S) -2-[(trifluoroacetyl) amino] -4- (2,4-difluorophenyl) -4-oxobutanoic acid

Below is the preparation of compounds of formula 31 wherein n is 1, t is 2 and R ¹ is fluoro at the 2- and 4-positions.

A solution of 1,3-difluorobenzene (2.3 kg, 20.0 mol) in 5 L of methylene chloride as prepared in Example 53 was added N- (trifluoroacetyl) -L-aspartic anhydride (4.2 kg). , 20.0 mol) and aluminum chloride (7.4 kg, 55.5 mol) in 25 L methylene chloride. The temperature of the reaction mixture was gradually increased for 1.5 hours and maintained at reflux for an additional 3 hours. The mixture was cooled and 10 L of water and 20 L of 6N hydrochloric acid were added with good stirring. The methylene chloride layer was separated, washed with water and washed with brine, and the volatiles were removed by distillation at atmospheric pressure.

The residue was dissolved in 40 L of toluene and 8 L of volatility was removed by distillation of the mixture in vacuo. The solution was heated at 50 ° C. and 8 L of hexane was added. The mixture was stirred at 25 ° C. for 3 hours to afford crystalline material. The material was isolated by filtration and the filter residue was washed with hexane (3 × 10 L). Dry in a vacuum oven at room temperature under nitrogen bleed to give (S) -2-[(trifluoroacetyl) amino] -4- (2,4-difluorophenyl) -4-oxobutanoic acid (5.2 kg , 16.0 mol), melting point 82.4 to 84.0 ° C. [α] _D + 15.2 ° (C = 0.956, CH ₃ OH) was obtained.

Example 55

(S) -2-[(trifluoroacetyl) amino] -4- (2,4-difluorophenyl) butanoic acid

Following is the preparation of compounds of formula 30 wherein n is 1, t is 2 and R ¹ is fluoro at the 2- and 4-positions.

(S) -2-[(trifluoroacetyl) amino] -4- (2,4-difluorophenyl) -4-oxobutanoic acid (4.8 kg, 14.7 mol) as prepared in Example 54 and Activated carbon in 5 liters of acetic acid, Darco ^? (0.4 kg) of the mixture was stirred at rt for 1 h. The mixture was filtered over a Perman catalyst (0.5 kg, 50% humidity) and washed with 15 L of glacial acetic acid. Sulfuric acid (1.2 L, 21.8 mol) in 1 L glacial acetic acid was filtered in the mixture and washed with 2.8 L glacial acetic acid. The reaction vessel is vacuum / pressure of 10 psig purged three times with nitrogen and then six times with nitrogen. The mixture was stirred vigorously for 24 hours at room temperature under atmospheric pressure under nitrogen. The reaction vessel was purged with nitrogen and then the mixture was filtered with 4.6 kg sodium acetate trihydrate. The filtrate was washed with 10 L glacial acetic acid. Glacial acetic acid was removed by distilling the mixture in vacuo.

The residue was placed between 10 L methylene chloride and 40 L water. The aqueous layer was extracted with 10 L of methylene chloride and the mixed methylene chloride was washed with 10 L of water. The methylene chloride mixture was dried over sodium sulfate (10 kg) and filtered. The solvent was removed in vacuo and the residue was dissolved in 5 liters of methylene chloride. The solution was added at a rate equal to a temperature between 0 and 5 ° C. with a hexane mixture remaining under 15 L of hexane under nitrogen. The mixture was held for 1 hour to obtain crystalline material. The material was separated by filtration and the filter residue was washed with 10 L of hexane. Dry in vacuo with nitrogen bleed at 25 ° C. in constant quantity to afford (S) -2-[(trifluoroacetyl) amino] -4- (2,4-difluorophenyl) butanoic acid (3.3 kg, 10.4 mol). Obtained. Melting point 62-83.5 ° C. Analytical pure samples had melting points of 86-89 ° C. [a] _D + 6.8 ° (C = 0.995, CH ₃ OH).

Example 56

(S) -5,7-difluoro-2-[(trifluoroacetyl) amino] -3,4-dihydro-1 (2H) -naphthalenone

The following is a method for preparing a compound of Formula 29 wherein n is 1, t is 2 and R ¹ is fluoro at the 5- and 7- positions.

A suspension of phosphorus pentachloride (2.2 kg, 10.6 mol) in 12 l of methylene chloride was cooled to 5 ° C and (S) -4- (2,4-difluorophenyl) -2- in 12 l of methylene chloride prepared in Example 55. [(Trifluoroacetyl) amino] butanoic acid (3.1 kg, 9.9 mol) is added over 20 minutes. Thin layer chromatography of the methanol-quenched aliquot confirms the conversion of butanoic acid to the corresponding chlorate.

The mixture is stirred for 30 minutes and an aluminum chloride slurry (4.3 kg) in 38.8 L of methylene chloride is added at a rate such that the temperature of the slurry is maintained at 1-5 ° C. The reaction mixture is stirred for 1 hour and 28 kg of ice is added followed by 5.3 kg of concentrated hydrochloric acid. The mixture is stirred for 1 hour and the temperature is raised to 20 ° C.

The aqueous layer is separated and extracted with methylene chloride (2 x 15 L). The methylene chloride layer is washed once with water and combined with the methylene chloride extract. The combined methylene chloride is washed with water. Aqueous sodium bicarbonate solution is added to adjust the pH of the aqueous layer to 6. The methylene chloride layer is washed with water followed by brine. Methylene chloride is dried over magnesium sulfate and filtered. The mixture is concentrated by evaporation under atmospheric pressure and the residue is dissolved in 15 liters of methane. The methanol solution is distilled to remove residual methylene chloride and 9.9 L of water are added. The mixture is warmed up to 56 ° C., cooled to room temperature and stirred for about 12 hours. Crystalline material is obtained and separated by filtration. The filter residue is washed with 15 liters of water. The separated material is dried with nitrogen bleed at room temperature under vacuum to constant mass.

The material is dissolved in 5 l of toluene at a temperature of 90 ° C. and combined with 10 l of heptane at a temperature of 80 ° C. The temperature of the mixture is slowly lowered for 1.5 hours. The mixture is then stirred at 5 ° C. for about 12 hours to yield crystalline material. The material is filtered off and the filter residue is washed with 15 liters of heptane. (S) -5,7-difluoro-2-[(trifluoroacetyl) amino] -3,4-dihydro- (2H) -naphthalene-1 by drying with nitrogen bleed at room temperature under vacuum to constant mass -On (2.0 kg, 6.8 mol) is obtained (melting point 142.4-144.6 ° C., [α] _D -59.4 °, c = 0.994, CH ₃ OH).

Example 57

(S) -5,7-difluoro-2-[(trifluoroacetyl) amino] -1,2,3,4-tetrahydronaphthalene

The following is a method for preparing a compound of Formula 28 wherein n is 1, t is 2 and R ¹ is fluoro at the 5- and 7- positions.

(S) -5,7-difluoro-2-[(trifluoroacetyl) amino] -3,4-dihydro- (2H) -naphthalen-1-one prepared in Example 56 in 11 L of TFA. (1.1 kg, 3.8 mo1) and a reaction vessel containing a mixture of Perman's catalyst (0.55 kg, 50% humidity) are vacuum / pressurized to 11 psi eight times with nitrogen followed by eight times with hydrogen. The mixture is stirred vigorously for 24 h under hydrogen (125 psig) at room temperature. Thin layer chromatography gave naphthalen-1-one as (S) -1-hydroxy-5,7-difluoro-2-[(trifluoroacetyl) amino] -3,4-dihydro- (2H). Verify that you switched to naphthalene.

Sulfuric acid (1.1 L, 19.4 mol) in 1 L of TFA is added and the mixture is then further stirred at room temperature under hydrogen (125 psig) for 24 h. The reaction vessel is washed with nitrogen and the mixture is filtered over celite and washed with 11 liters of TFA. The filtrate is combined with 2.8 kg of sodium acetate trihydrate and 80 l of water. The mixture is cooled to 10 ° C. and crystalline material is obtained. The material is separated by filtration and the filter residue is washed with 10 liters of ice water. Drying affords (S) -5,7-difluoro-2-[(trifluoroacetyl) amino] -1,2,3,4-tetrahydronaphthalene (0.8 kg, 2.9 mol) (melting point 159.9 -160.9 ° C., [α] _D -56.0 °, c = 1.01, CH ₃ OH).

Example 58

(S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid

The following is a method for preparing a compound of Formula 3 wherein n is 1, t is 2 and R ¹ is fluoro at the 5- and 7-positions.

Lithium hydroxide monohydrate (7.8 g, 0.2 mol) was prepared in Example 57 in 187 mL methanol and 21 mL water (S) -5,7-difluoro-2-[(trifluoroacetyl) amino]-. To a solution of 1,2,3,4-tetrahydronaphthalene (20.8 g, 74.5 mmol). The mixture is stirred at reflux for 30 minutes and diluted with 200 mL of methanol. The diluted mixture was then washed with 60 mL of water, 24.8 mL of concentrated hydrochloric acid and activated carbon, DARCO ^? (Darco ^? ) Combine with 4.2 g. The mixture is stirred for 30 minutes and filtered through celite. The filtrate is distilled until the top temperature reaches 75 ° C. The remaining mixture is cooled down and left for about 60 hours. The mixture is then cooled in an ice bath to yield crystalline material. The material is filtered off and the filter residue is washed with water. (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloric acid (14.8 g, 67.6 mol) was dried in a stream of nitrogen until constant mass under vacuum at room temperature. ) Is obtained (melting point of 280 ° C. or higher, [α] _D −66.2 °, c = 0.162, CH ₃ OH).

Example 59

(S) -5-hydroxymethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione

The following is a method for preparing a compound of Formula 27 wherein n is 1, t is 2 and R ¹ is fluoro at the 5- and 7- positions.

Potassium thiocyanate (15.9 g, 162.6 mol) is dried by heating to 175 ° C. under nitrogen and cooled to 35 ° C. with several nitrogen washes under vacuum. (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl prepared in Example 58 in dihydroxyacetone (15.9 g, 176.7 mmol) and 540 mL ethyl acetate A mixture of amine hydrochloric acid (30.0 g, 137.0 mmol) is added to anhydrous potassium thiocyanate. The reaction vessel is washed with nitrogen and 40.83 g of ice cold acetic acid are added. The reaction mixture is stirred at 35 ° C. for 2 hours and 100 mL of 1.0 M sulfuric acid is added. The mixture is stirred for 15 minutes, then cooled in an ice bath and 2.5 M sodium hydroxide is added until the pH of the mixture is 7. The organic layer is washed with 50 mL of saturated aqueous sodium dicarbonate and then with 50 mL of brine. The organic layer is concentrated to 480 mL by distillation and the mixture is cooled to 6 ° C. and left for 12 hours to afford crystalline material. The material is separated by filtration, the filter residue is washed with cold ethyl acetate and the separated material is dried.

The material is dissolved in 650 mL of ethyl acetate and 25 mL of water. The mixture is distilled until 500 mL volatiles are removed. The mixture is cooled to room temperature and stirred for 45 minutes to yield crystalline material. The material is separated by filtration and the filter residue is washed with cold ethyl acetate. (S) -5-hydroxymethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-di by drying with nitrogen bleed under vacuum Hydroimidazole-2-thione (30.4 g, 107.4 mol) is obtained (melting point 206-207 ° C, [α] _D -40 °, c = 0.682, CH ₃ OH).

Example 60

(S) -N- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already Dazol-4-ylmethyl] formamide

The following is a method for preparing a compound of Formula 26 wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ² is hydrogen.

Formamide (250 mL, 6.3 mol) was heated to 175 ° C. and (S) -5-hydroxymethyl-1- (5,7-difluoro-1,2,3,4- prepared in Example 59. Tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione (25.0 g, 88.3 mmol) is added several times for 30 minutes and the reaction mixture is stirred for 1 hour under a nitrogen sweep. The mixture was cooled to 50 ℃ and activated carbon, ^Darko? 2.5 g are added. The mixture is cooled to 30 ° C., cooled through celite and washed with 25 mL of formamide. The filtrate is heated to 95 ° C. and 1 L of water is added dropwise. The mixture is cooled and then stirred for 12 hours at room temperature. The mixture is cooled to 0 ° C. to obtain crystalline material. The material is separated by filtration and dried.

The material is stirred for 5 minutes to be about 5 times the weight of (70% THF) / (30% hexanes). The material is separated by filtration and the filter residue is washed with (50% THF) / (50% hexanes). Dry to a constant mass to give (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-di Hydro-1H-imidazol-4-ylmethyl] formamide (19.5 g, 62.7 mmol) is obtained (melting point 245-246 ° C., [α] _{D +} 48.9 °, c = 0.613, DMSO).

The process was carried out similarly as in Example 60, except that formamide was replaced with urea (S) -5-ureidomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydro Naphthalen-2-yl) -1,3-dihydroimidazol-2-thione is obtained (melting point 258-260 ° C., [α] _{D +} 34.3 °, c = 0.574, DMSO).

Example 61

(S) -N- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already Dazol-4-ylmethyl] formamide

The following is a method for preparing a compound of Formula 26 wherein n is 1, t is 2, R ¹ is fluoro at the 5- and 7-positions and R ² is hydrogen.

(S) -5-hydroxymethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydro prepared in Example 59 The mixture of imidazole-2-thione (1.0 g, 3.5 mmol) and ammonium formate (10 g, 158.6 mmol) is stirred at about 125 ° C. for 1 hour. The mixture is heated to about 138 ° C. and further stirred for 35 minutes do. The mixture is diluted with 25 mL of water and cooled to room temperature. Aging of the mixture for about 18 hours yields a crystalline material. The material is separated by filtration and the filter residue is washed with water. Dry to a constant mass to give (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-di Hydro-1H-imidazol-4-ylmethyl] formamide (0.92 g, 2.96 mmol) is obtained.

The process was carried out similarly as in Example 61, except that ammonium formate was replaced with ammonium acetate to give (S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydro-naphthalene 2-yl) -1-thioxo-2,3-dihydro-1H-imidazol-4-ylmethylacetamide is obtained (melting point 275.5-276 ° C. (decomposition), [α] _{D +} 41.3 °, c = 1.00, DMSO).

Example 62

(S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2,3-dihydro-2-thioxo-1H -Imidazole hydrochloric acid

The following is a method for preparing a compound of Formula 25 wherein n is 1, t is 2 and R ¹ is fluoro at the 5- and 7- positions.

(S) -N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo- prepared in Example 60 in 400 mL of isopropanol A mixture of 2,3-dihydro-1H-imidazol-4-ylmethyl] formamide (19.1 g, 59.0 mmol) and 25 mL (12.0 M, 25 mL, 300 mmol) of concentrated hydrochloric acid was refluxed for about 12 minutes. Heat and stir for 1 hour 40 minutes. The mixture is distilled off to remove 150 mL of isopropanol. The mixture is gradually cooled to room temperature and stirred for 3 hours 45 minutes. The material is separated by filtration and the filter residue is washed with 75 mL of isopropanol. (S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-dried with nitrogen bleed under vacuum at 110-125 ° C. 1,3-dihydroimidazole-2-thione hydrochloric acid (15.6 g, 47.1 mmol) is obtained (melting point 251.9 ° C., [α] _{D +} 10.2 °, c = 0.500, DMSO).

Example 63

In vitro dopamine β-hydroxylase inhibition

The following describes an in vitro test to identify compounds that inhibit dopamine β-hydroxylase (DBH). This test relies on the DBH-catalytic transfer of tyramine to octopamine and the inhibition of DBH activity by the test compound.

Bovine adrenal DBH (13.8 mUnits / mL), Cu ²⁺ (2 mM), ascorbic acid (10 mM), catalase (200 μg / mL) and test compound in 0.65 mL of 50 mM sodium acetate buffer (pH 4.5). The mixture is incubated at 37 ° C. for 10 minutes. Tyramine is added and the reaction mixture is incubated at 37 ° C. for 10 minutes. The reaction is quenched with 0.1 mL of concentrated ammonium hydroxide. The octopamine product is oxidized p-hydroxybenzaldehyde by adding 0.2 mL of 2% sodium metaperiodate and incubated for an additional 4 minutes. Excess sodium metaperiodate is reduced to 0.2 mL of 10% sodium disulfate and measured spectrophotometrically at a wavelength of 330 nm.

Optionally, a mixture comprising bovine adrenal DBH (0.02 mUnits / mL), 0.125 M sodium acetate, 10 mM fumarate, 0.5 μM CuSO ₄ , 100 μg / mL catalase and 10 mM tyramine Cu ²⁺ (2 mM) Incubate at 5 ° C. for 5 minutes and add N, N-dimethyl-1,4-phenylenediamine (DMPD) to initiate the reaction. Absorbents are continuously monitored at a wavelength of 515 nm by spectrophotometry.

Test compound is tested at various ranges of concentration and the concentration of test compound required for 50% inhibition of DBH activity is interpolated (ID ₅₀ ).

The compound of the present invention is tested and found to have DBH inhibitory activity while carrying out the process as in Example 63. For example, 5- (S) -aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl) -1,3-dihydroimidazole 2-thione hydrochloric acid has an ID ₅₀ of 8.5 nm.

Example 64

Inhibition of dopamine β-hydroxylase in vivo

The following describes an in vivo test to identify compounds that inhibit dopamine β-hydroxylase (DBH). This test depends on the concentration of dopamine and norepinephrine tissue and the effect of the test compound on excitation.

Male rats of normal blood pressure or congenital hypertension are administered orally or intravenously with vehicle (1-10 mL / kg) or test compound (0.3-100 mg / kg). Some rats are administered 1-2 times daily for up to 24 days. After 2-12 hours of final dosing, the rats are anesthetized with halotane and the neck cut off. Selected tissues (eg cerebral cortex, spinal cord, mesenteric artery and left ventricle) are rapidly collected and weighed and placed in 0.4 mL of cold perchloric acid. Tissue concentrations of dopamine and norepinephrine are determined by HPLC and electrochemical detection.

Test compounds are tested in a wide range of dosages and their effects are compared to controls. DBH inhibition is defined as a statistically effective value (p ≦ 0.05) as a decrease in norepinephrine concentration, at the same time as an increase in dopamine concentration and an increase in dopamine: noepinephrine ratio.

Performing as in Example 64, the compound of the present invention is tested and confirmed to have DBH inhibitory activity. 5- (S) -aminomethyl- for dopamine and norepinephrine (g / g of tissues) and dopamine: norepinephrine (g / g) in the left ventricle of congenital hypertensive rats following three oral administrations for 12 hours. The effect of 1- (5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid is summarized in the following table. . Values are expressed as mean (9 rats / group) ± standard deviation.

Example 65

Hypotensive effect

The following describes a test to identify compounds that lower blood pressure.

Anesthetize male rats with high blood pressure and insert cannula into the femoral or carotid artery while continuing to monitor blood pressure. Rats are allowed to recover from anesthesia for 30 to 60 minutes and baseline blood pressure levels are obtained. Rats are administered vehicle (10 mL / kg) or test compound (0.3-30 mg / kg) by oral or intravenous administration followed by 4-6 hours.

Test compounds are tested in a wide range of doses and the blood pressure drop effect is defined as a statistically effective value (p ≦ 0.05) compared to vehicle treated rats.

While performing as in Example 65, the compound of the present invention is tested and confirmed to have blood pressure lowering activity. For example, 5- (S) -aminomethyl-1- (5,7-difluoro-1,2 for changes in mean arterial blood pressure over 4 hours after oral administration (mg / kg) once prior to administration. The effects conferred to the limited congenital hypertensive rats of, 3,4-tetrahydro-naphthalen-2-yl) -1,3-dihydroimidinezol-2-thione hydrochloric acid are summarized in the following table.

Example 66

toxicity

5- (S) -aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid Does not induce mutations in comprehensive tests. The lethal dose of the compound is at least 1000 mg / kg in mice, at least 2500 mg / kg and at least 400 mg / kg in rats and dogs, respectively.

Example 67

The following shows a pharmaceutical formulation containing a compound of formula (1).

Formulations for Oral Administration

Representative solutions for oral administration contain:

Intravenous Formulation

Representative solutions for intravenous administration contain:

Tablet formulation

Representative tablet forms of the compound of formula 1 contain:

A pharmaceutical formulation containing a compound of Formula 2 or Formula 3 can be prepared while performing as in Example 67.

Claims (37)

A compound of formula (I), a pharmaceutically acceptable salt thereof, a mixture of each isomer and an isomer thereof, or a prodrug thereof: [Formula I] In the above formula, n is 0, 1 or 2; t is 0, 1, 2 or 3; R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy; R ² is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (a), (b) and (c): Wherein R ⁴ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ where q is 0,1, 2, 3 or 4 and R ⁹ is carboxy, (C _1-4 ) alkyl Oxycarbonyl, carbamoyl; Or substituted or substituted with 1 or 2 substituents independently selected from hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazo-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl Unsubstituted aryls and heteroaryls (wherein "aryl" includes monocyclic or condensed carbocycle aromatic rings as organic radicals derived from aromatic hydrocarbons containing 6 to 14 carbon atoms, and "heteroaryl" is 5 Organic radicals derived from aromatic hydrocarbons containing from 14 to 14 atoms, wherein 1 to 5 of these are heteroatoms selected from N, O or S, monocycles or condensed heterocycles and condensed carbocycles Cyclic aromatic ring); and R ⁵ is hydro or —NHR ¹⁰ wherein R ¹⁰ is hydro, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl; carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alka Noyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl; or hydroxy, (C _1-4 ) alkyloxy, Aroyl and heteroaroyl, unsubstituted or substituted with 1 to 2 substituents independently selected from cyano, 1H-tetrazol-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl "Aroyl" is -C (O) R, where R is "aryl" as defined above, "heteroaroyl" is -C (O) R ', wherein R' is "heteroaryl" as defined above) Or -C (NR ¹¹ ) NHR ¹² , wherein R ¹¹ and R 12 are independently hydro, acetyl or t-butoxycarbonyl; or R ⁴ and R ⁵ are each hydro and R ³ is —NHR ¹⁰ , wherein R ¹⁰ is as defined above; or R ⁵ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁴ is (C _1-4 ) alkyl, di (C _{1- 4} ) alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, formyl, 1-hydroxy (C _1-4 ) alkyl or -CH ₂ NHR ¹³ wherein R ¹³ is hydro, (C _1-4 ) alkyl, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkyl Carbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, carboxy (C _1-4 ) alkyl, (C _1-4 ) alkyloxycarbonyl (C _1-4 ) alkyl, carbamoyl (C _1-4 ) alkyl; Or a group selected from aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl (wherein aroyl, heteroaroyl, aryl and heteroaryl are as defined above, Further substituted with 1 to 2 substituents independently selected from hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl Unsubstituted) or -C (NR ¹¹ ) NHR ¹² , wherein R ¹¹ and R ¹² are as defined above; or R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁴ is hydro, (C _1-4 ) alkyl or —C (O) R ¹⁴ , wherein , R ¹⁴ is amino, hydroxy, (C _1-4 ) alkyloxy, 2- (dimethylamino) ethylamino, 4-methylpiperazin-1-yl, 2- (dimethylamino) ethylmercapto, 4- ( Methylsulfonylamino) anilino or 1H-tetrazol-5-ylamino), and R ⁵ is cyano, hydroxymethyl, 1H-tetrazol-5-yl, 4,5-dihydroimidazole-2 -Yl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1 -Ylmethyl, -C (O) R ¹⁴ , wherein R ¹⁴ is as defined above, -C (NH) NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are independently hydro, (C _1-4 ) alkyl or trifluoro (C _1-4) alkyl) or -CH ₂ NR ¹⁰ R ¹⁷ (wherein, R ¹⁰ is as defined above, R ¹⁷ is hydro or (C _1-4) Kill a) or; or R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above, and R ⁴ and R ⁵ are independently di (C _1-4 ) alkylaminomethyl, piperidine -1-ylmethyl, morpholin-4-ylmethyl or hydroxymethyl; R ⁶ is hydro, 2-carboxyethyl, 2-carbamoylethyl or 2- (C _1-4 ) alkyloxycarbonylethyl; R ⁷ is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin -1-ylmethyl or —CH ₂ NR ¹⁰ R ¹⁷ wherein R ¹⁰ and R ¹⁷ are as defined above; R ⁸ is hydro, 2-carboxyethyl, 2-carbamoylethyl, 2- (C _1-4 ) alkyloxycarbonylethyl or -NHR ¹⁰ , wherein R ¹⁰ is as defined above, Provided that when R ² is a general formula (a) bonded at the α-position, R ³ is hydrogen, R ⁴ is hydrogen and R ⁵ is —COR ¹⁴ , wherein R ¹⁴ is amino, hydroxy or lower alkyloxy ) Or when R ³ is hydrogen and both R ⁴ and R ⁵ are -COR ¹⁴ (R ¹⁴ is lower alkyloxy). The method of claim 1, R ² is a group of formula (a), (b) or (c) bonded to the β-position. The method of claim 2, R ² is a group of formula (a) bonded at the β-position, n is 0 or 1, R ⁵ is di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperi Din-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1-ylmethyl or —CH ₂ NHR ¹⁰ . The method of claim 3, wherein n is 1, t is 2 and each R ¹ is fluoro. The method of claim 4, wherein Compound wherein R ⁵ is aminomethyl, i.e. 5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole -2-thione and its pharmaceutically acceptable salts; A compound wherein R ⁵ is ureidomethyl, ie 5-ureidomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydro Imidazole-2-thione and its pharmaceutically acceptable salts; or A compound in which R ⁵ is acetylaminomethyl, ie N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3- Dihydro-1H-imidazol-4-ylmethyl] acetamide and pharmaceutically acceptable salts thereof. The method of claim 2, R ² is a group of formula (b) bonded at the β-position, n is 0 or 1 and R ⁷ is di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperi Din-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1-ylmethyl or —CH ₂ NHR ₁₀ . The method of claim 6, n is 1, t is 2 and each R ¹ is fluoro. The method of claim 7, wherein A compound wherein R ⁶ is hydro and R ⁷ is aminomethyl, i.e. 5-aminomethyl-4- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-'2, 4-dihydro [1,2,4] triazole-3-thione and its pharmaceutically acceptable salts. The method of claim 2, R ² is a group of formula (c) bonded at the β-position, n is 0 or 1 and R ⁸ is amino. The method of claim 9, n is 1, t is 2 and each R ¹ is fluoro at positions 5 and 7, ie 4-amino-2- (5,7-difluoro-1,2,3,4- Tetrahydronaphthalen-2-yl) -2,4-dihydro [1,2,4] triazole-3-thione. A compound which is a prodrug of a compound of claim 1, a pharmaceutically acceptable salt, each isomer or mixture of isomers thereof as a compound of formula II: [Formula II] In the above formula, n is 0, 1 or 2; t is 0, 1, 2 or 3; R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy; R ¹⁸ is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (d), (e) and (f); R ²⁰ is hydro, R ¹⁹ is hydro or-(CH ₂ ) _q R ⁹ [where q is 0, 1, 2, 3 or 4 and R ⁹ is carboxy, (C _1-4 ) alkyloxycarbonyl , Carbamoyl; Or further substituted with 1 or 2 substituents independently selected from hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazo-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl Unsubstituted aryl and heteroaryl (wherein “aryl” is an organic radical derived from an aromatic hydrocarbon containing 6 to 14 carbon atoms, including monocycle or condensed carbocycle aromatic rings, and “heteroaryl” Is an organic radical derived from an aromatic hydrocarbon containing 5 to 14 atoms, wherein 1 to 5 atoms are hetero atoms selected from N, O or S, monocycle or condensed heterocycle and condensed carbocycle Phosphorus heterocycle aromatic ring); and R ²¹ is -NR ²⁵ R ²⁶ , wherein R ²⁵ is hydro or (C _1-4 ) alkyl, and R ²⁶ is L-al Ranyl, L-arginyl, L-asparaginyl, L-α-aspartyl, L-β-aspartyl, L-cysteinyl, L-glutaminyl, L-α-glutamyl, L-γ- Glutamyl, N- (C _1-4 ) alkanoyl-L-α-glutamyl, N- (C _1-4 ) alkanoyl-L-γ-glutamyl, glycyl, L-histidyl, L-iso Leucyl, L-leucine, L-lysyl, L-methionyl, L-ornithynyl, L-phenylalanyl, L-prolyl, L-seryl, L-threonyl, L-tryptiphyl, L-tie Rosyl, L-valyl, 1-amino-cyclopropylcarbonyl, 1-aminocyclobutylcarbonyl, 1-aminocyclopentylcarbonyl or 1-aminocyclohexylcarbonyl); or R ²⁰ and R ²¹ are each hydro and R ¹⁹ is —NR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ are as defined above; or R ²¹ is hydro, R ¹⁹ is hydro or — (CH ₂ ) _q R ⁹ (where q and R ⁹ are as defined above) and R ₂₀ is —CH ₂ HR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ is as defined above; or R ¹⁹ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ²⁰ is hydro, (C _1-4 ) alkyl or —C (O) R ¹⁴ , wherein , R ¹⁴ is amino, hydroxy (C _1-4 ) alkyloxy, 2- (dimethylamino) ethylamino, 4-methylpiperazin-1-yl, 2- (dimethylamino) ethylmercapto, 4- (methyl Sulfonylamino) anilino or 1H-tetrazol-5-ylamino), R ²¹ is -CH ₂ NR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ are as defined above; R ²² is hydro, 2-carboxyethyl, 2-carbamoylethyl or 2- (C _1-4 ) alkyloxycarbonylethyl; R ²³ is —CH ₂ NR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ are as defined above; R ²⁴ is —NR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ are as defined above. The method of claim 11, R ¹⁸ is a group of formula (d) bonded at the β-position, n is 0 or 1, t is 2, each R ²¹ is fluoro, and R ²¹ is —CH ₂ NHR ²⁶ . The method of claim 12, R ¹ is fluoro at positions 5 and 7 and R ²⁶ is L-arginyl, L-α-aspartyl, L-β-aspartyl, L-histidyl or L-orninitinyl. The method of claim 13, A compound in which R ²⁶ is L-α-aspartyl, ie 3S-amino-N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2- Thioxo-2,3-dihydro-1H-imidazol-4-yl-methyl] succinic acid and its pharmaceutically acceptable salts; A compound wherein R ²⁶ is L-histidinyl, ie 3S-amino-3- (3H-imidazol-4-yl) -N- [3- (1,2,3,4-tetrahydronaphthalen-2-yl ) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] propionamide and pharmaceutically acceptable salts thereof; or A compound in which R ²⁶ is L-ornithynyl, ie 2S, 5-diamino-N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)- 2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl] valeramide and pharmaceutically acceptable salts thereof. A compound which is a prodrug of a compound of claim 1 as a compound of formula III, a pharmaceutically acceptable salt thereof, each isomer or a mixture of isomers thereof: [Formula III] In the above formula, n is 0, 1 or 2; t is 0, 1, 2 or 3; R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy; R ²⁷ is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (g), (h) and (i): Wherein R ⁴ is hydro, R ⁵ is hydro or —NHR ¹⁰ where R ¹⁰ is hydro, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carbamoyl, ( C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) alkylamino ( C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl; or hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazol-5-yl Aroyl and heteroaroyl, wherein "aroyl" is unsubstituted or substituted with 1 to 2 substituents independently selected from carboxy, and carboxy and (C _1-4 ) alkyloxycarbonyl. Wherein R is “aryl” as defined above “heteroaroyl” is —C (O) R ′ wherein R ′ is “heteroaryl” as defined above or —C (NR ¹¹ ) NHR ¹² (wherein, R ¹¹ and R ¹² are independently hydro, acetyl or a t- butoxycarbonyl- A) or; or R ⁵ is hydro, R ⁴ is (C _1-4 ) alkyl, di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, 1-hydroxy ( C _1-4 ) alkyl or —CH ₂ NHR ¹³ wherein R ¹³ is hydro, (C _1-4 ) alkyl, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carba Moyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) Alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, carboxy (C _1-4 ) alkyl, (C _1-4 ) alkyloxycarbonyl (C _1-4 ) alkyl, carbamoyl (C _1-4 ) alkyl; or a group selected from aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl (the aroyl , Heteroaroyl, aryl and heteroaryl are as defined above and are hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazol5-yl, carboxy and (C _1-4 ) alkyloxycarbo Independent from Neil Is one to two substituents further substituted or is unsubstituted) or -C (NR ¹¹⁾ NHR ¹² (where, R ¹¹ and R ¹² are as defined above)), or; or R ⁴ is hydro, (C _1-4 ) alkyl or —C (O) R ¹⁴ wherein R ¹⁴ is amino, hydroxy, (C _1-4 ) alkyloxy, 2- (dimethylamino) ethylamino, 4 -Methylpiperazin-1-yl, 2- (dimethylamino) ethylmercapto, 4- (methylsulfonylamino) anilino or 1H-tetrazol-5-ylamino), R ⁵ is hydroxymethyl, 1H-tetrazol-5-yl, 4,5-dihydroimidazol-2-yl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazine -1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1-ylmethyl, -C (O) R ¹⁴ , wherein R ¹⁴ is as defined above, -C (NH) NR ¹⁵ R ¹⁶ wherein R ¹⁵ and R ¹⁶ are independently hydro, (C _1-4 ) alkyl or trifluoro (C _1-4 ) alkyl) or —CH ₂ NR ¹⁰ R ¹⁷ , wherein R ¹⁰ is as defined above And R ¹⁷ is hydro or (C _1-4 ) alkyl); or R ⁴ and R ⁵ are independently di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl or hydroxymethyl; R ⁶ is hydro, 2-carboxyethyl, 2-carbamoylethyl or 2- (C _1-4 ) alkyloxycarbonylethyl; R ⁷ is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperidin-1-ylmethyl, 4- (C _1-4 ) alkylpipepe Rajin-1-ylmethyl or —CH ₂ NR ¹⁰ R ¹⁷ wherein R ₁₀ and R ¹⁷ are as defined above; R ²⁸ is (C _2-6 ) alkyl wherein alkyl is —N (R ²⁹ ) ₂ , —C (O) OR ³⁰ , —PO (OR ³⁰ ) ₂ , —SO ₃ R ³⁰ , SO ₂ NHR ³⁰ and Further substituted with one or two substituents independently selected from -OR ³⁰ , wherein each R ²⁹ is independently hydro, acetyl or trifluoroacetyl, and each R ³⁰ is independently hydro or (C _1-5 ) Alkyl). The method of claim 15, R ²⁷ is a group of formula (g) bonded at the β-position, n is 0 or 1, t is 2, and each R ¹ is fluoro. The method of claim 16, R ²⁸ is a group selected from ethyl, 1,1-dimethylethyl and propyl, wherein these groups are further substituted with one or two substituents independently selected from carboxy, methoxycarbonyl, amino and trifluoroacetylamino ) Compound. Parkinson's disease, hypertension or congestion, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, each isomer or mixture of isomers thereof, or one or more pharmaceutically acceptable excipients thereof Pharmaceutical composition for treating heart attack. [Formula I] In the above formula, n is 0, 1 or 2; t is 0, 1, 2 or 3; R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy; R ² is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (a), (b) and (c): Wherein R ⁴ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ where q is 0, 1, 2, 3 or 4 and R ⁹ is carboxy, (C _1-4 ) alkyl Oxycarbonyl, carbamoyl; Or substituted or substituted with 1 or 2 substituents independently selected from hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazo-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl Unsubstituted aryl and heteroaryl (wherein “aryl” is an organic radical derived from an aromatic hydrocarbon containing 6 to 14 carbon atoms and includes a monocycle or condensed carbocycle aromatic ring, and “heteroaryl” is Organic radicals derived from aromatic hydrocarbons containing 5 to 14 atoms, wherein 1 to 5 atoms are hetero atoms selected from N, O or S, monocycles or condensed heterocycles and condensed carbocycles a heterocycle group selected from and a ring); and, R ⁵ is hydro or -NHR ¹⁰ [where, R ¹⁰ is hydro, (C _1-4) alkanoyl, Triple Oro (C _1-4) alkanoyl, carbamoyl, (C _1-4) alkyloxycarbonyl, (C _1-4) alkyl carbamoyl, di (C _1-4) alkyl carbamoyl, amino (C _{1- 4} ) alkanoyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, or hydroxy, (C _1-4 ) Aroyl and heteroaroyl, optionally substituted with 1 to 2 substituents independently selected from alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl (Wherein "aroyl" is -C (O) R, wherein R is "aryl" as defined above, "heteroaroyl" is -C (O) R ', wherein R' is "hetero as defined above Aryl "or -C (NR ¹¹ ) NHR ¹² , wherein R ¹¹ and R ¹² are independently hydro, acetyl or t-butoxycarbonyl; R ⁴ and R ⁵ are each hydro and R ³ is —NHR ¹⁰ , wherein R ¹⁰ is as defined above; or R ⁵ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁴ is (C _1-4 ) alkyl, di (C _{1- 4} ) alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, formyl, 1-hydroxy (C _1-4 ) alkyl or -CH ₂ NHR ¹³ , wherein R ¹³ is hydro, (C _1-4 ) alkyl, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkyl Carbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, carboxy (C _1-4 ) alkyl, (C _1-4 ) alkyloxycarbonyl (C _1-4 ) alkyl, carbamoyl (C _1-4 ) alkyl; or aroyl, Groups selected from heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl (the aroyl, heteroaroyl, aryl and heteroaryl are as defined above, hydroxy, ( C _1-4 ) alkyl Or further substituted with 1 to 2 substituents independently selected from oxy, cyano, 1H-tetrazol-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl) or -C (NR ¹¹ ) NHR ¹² , wherein R ¹¹ and R ¹² are as defined above; or R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁴ is hydro, (C _1-4 ) alkyl or —C (O) R ¹⁴ , wherein , R ¹⁴ is amino, hydroxy, (C _1-4 ) alkyloxy, 2- (dimethylamino) ethylamino, 4-methylpiperazin-1-yl, 2- (dimethylamino) ethylmercapto, 4- ( Methylsulfonylamino) anilino or 1H-tetrazol-5-ylamino), and R ⁵ is cyano, hydroxymethyl, 1H-tetrazol-5-yl, 4,5-dihydroimidazole-2 -Yl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1 -Ylmethyl, -C (O) R ₁₄ , wherein R ₁₄ is as defined above, -C (NH) NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are independently hydro, (C _1-4 ) alkyl or trifluoro (C _1-4) alkyl) or -CH ₂ NR ¹⁰ R ¹⁷ (wherein, R ¹⁰ is as defined above, R ¹⁷ is hydro or (C _1-4) A reel), or; or R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above, and R ⁴ and R ⁵ are independently di (C _1-4 ) alkylaminomethyl, piperidine -1-ylmethyl, morpholin-4-ylmethyl or hydroxymethyl; R ⁶ is hydro, 2-carboxyethyl, 2-carbamoylethyl or 2- (C _1-4 ) alkyloxycarbonylethyl; R ⁷ is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin -1-ylmethyl or —CH ₂ NR ¹⁰ R ¹⁷ wherein R ¹⁰ and R ¹⁷ are as defined above; R ⁸ is hydro, 2-carboxyethyl, 2-carbamoylethyl, 2- (C _1-4 ) alkyloxycarbonylethyl or —NHR ¹⁰ , wherein R ¹⁰ is as defined above. The method of claim 18, The compound, 5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione or pharmaceutically thereof Acceptable salts; 5-ureidomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-1-thione; N- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4- Ylmethyl] acetamide; 5-aminomethyl-4- (5,7-difluoro-1,2,3,4-tetrahydronaphth-2-yl) -2,4-dihydro [1,2,4] triazole- 3-thione and its pharmaceutically acceptable salts; 4-amino-2- (5,7-difluoro-1,2,3,4-tetrahydronaphth-2-yl) -2,4-dihydro [1,2,4] triazole-3 -Thione; or 3S-amino-N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already Dazol-4-yl-methyl] succinic acid or a pharmaceutically acceptable salt thereof, 2S-amino-3- (3H-imidazol-4-yl) -N- (3- (1,2,3,4- Tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-1-yl] propionamide or a pharmaceutically acceptable salt thereof, or 2S, 5-diamino-N -[3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazol-4-yl A prodrug pharmaceutical composition selected from the group consisting of the compounds of claims 11 and 15 comprising methyl] valeramide or a pharmaceutically acceptable salt thereof. A process for preparing a compound of formula (I) and a pharmaceutically acceptable salt thereof, each isomer, mixture of isomers, or prodrugs thereof; [Formula I] [In the above formula, n is 0, 1 or 2; t is 0, 1, 2 or 3, R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy; R ² is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (a), (b) and (c): Wherein R ⁴ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ where q is 0, 1, 2, 3 or 4 and R ⁹ is carboxy, (C _1-4 ) alkyl 1 independently selected from oxycarbonyl, carbamoyl, or hydroxy, (C _1-4 ) alkyloxy, cyano, 1H-tetrazo-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl Aryl and heteroaryl substituted or unsubstituted with two substituents (wherein "aryl" is an organic radical derived from an aromatic hydrocarbon containing 6 to 14 carbon atoms, including monocyclic or condensed carbocycle aromatic rings) "Heteroaryl" is a free radical derived from an aromatic hydrocarbon containing 5 to 14 atoms, wherein 1 to 5 atoms are hetero atoms selected from N, O or S, monocycle or condensed hetero Cycles and condensed carbocycles Rosa and a group selected from the cycle comprises an aromatic ring)], R ⁵ is hydro or -NHR ¹⁰ [where, R ¹⁰ is hydro, (C _1-4) as alkanoyl, trifluoro (C _1-4) Alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, or hydroxy, (C _1-4 ) alkyloxy, cyano, 1H Aroyl and heteroaroyl (wherein "aroyl", unsubstituted or substituted with 1 to 2 substituents independently selected from -tetrazol-5-yl, carboxy and (C _1-4 ) alkyloxycarbonyl) Is -C (O) R, wherein R is "aryl" as defined above. "Heteroaroyl" is -C (O) R ', wherein R' is "heteroaryl" as defined above. or -C (NR ¹¹⁾ NHR ¹² (wherein, R ¹¹ and R ¹² are independently Jethro, acetyl or t- butoxycarbonyl is - or; R ⁴ and R ⁵ are each hydro and R ³ is —NHR ¹⁰ , wherein R ¹⁰ is as defined above; or R ⁵ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁴ is (C _1-4 ) alkyl, di (C _{1- 4} ) alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, formyl, 1-hydroxy (C _1-4 ) alkyl or -CH ₂ NHR ¹³ , wherein R ¹³ is hydro, (C _1-4 ) alkyl, (C _1-4 ) alkanoyl, trifluoro (C _1-4 ) alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkyl Carbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl, (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, carboxy (C _1-4 ) alkyl, (C _1-4 ) alkyloxycarbonyl (C _1-4 ) alkyl, carbamoyl (C _1-4 ) alkyl; or aroyl, Groups selected from heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl (the aroyl, heteroaroyl, aryl and heteroaryl are as defined above, hydroxy, ( C _1-4) al Oxy, cyano, 1H- tetrazol-5-yl, carboxy and or (C _1-4) alkyloxycarbonyl optionally substituted further by 1 to 2 substituents independently selected from is unsubstituted), or -C ( NR ¹¹ ) NHR ¹² , wherein R ¹¹ and R ¹² are as defined above; or R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁴ is hydro, (C _1-4 ) alkyl or —C (O) R ¹⁴ , wherein , R ¹⁴ is amino, hydroxy, (C _1-4 ) alkyloxy, 2- (dimethylamino) ethylamino, 4-methylpiperazin-1-yl, 2- (dimethylamino) ethylmercapto, 4- ( Methylsulfonylamino) anilino or 1H-tetrazol-5-ylamino), and R ⁵ is cyano, hydroxymethyl, 1H-tetrazol-5-yl, 4,5-dihydroimidazole-2 -Yl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin-1 -Ylmethyl, -C (O) R ¹⁴ , wherein R ¹⁴ is as defined above, -C (NH) NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are independently hydro, (C _1-4 ) alkyl or trifluoro (C _1-4) alkyl) or -CH ₂ NR ¹⁰ R ¹⁷ (wherein, R ¹⁰ is as defined above, R ¹⁷ is hydro or (C _1-4) Kill a) or; or R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above, and R ⁴ and R ⁵ are independently di (C _1-4 ) alkylaminomethyl, piperidine -1-ylmethyl, morpholin-4-ylmethyl or hydroxymethyl; R ⁶ is hydro, 2-carboxyethyl, 2-carbamoylethyl or 2- (C _1-4 ) alkyloxycarbonylethyl; R ⁷ is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl, 4- (C _1-4 ) alkylpiperazin -1-ylmethyl or —CH ₂ NR ¹⁰ R ¹⁷ wherein R ¹⁰ and R ¹⁷ are as defined above; R ⁸ is hydro, 2-carboxyethyl, 2-carbamoylethyl, 2- (C _1-4 ) alkyloxycarbonylethyl or —NHR ¹⁰ , wherein R ¹⁰ is as defined above] (a) reacting a compound of formula 3, wherein n, t and R ¹ are as defined in Formula I above, with dialkyloxyacetaldehyde or catalytic hydrogenation in the presence of a chemical reducing agent: Treatment with thiocyanic acid yields a compound of formula I wherein R ² is a group of formula (a) and R ³ , R ⁴ and R ⁵ are each hydro: or (b) reacting a compound of formula 3 (each n, t and R ¹ as defined in formula I) or an acid addition salt thereof with thiocyanic acid and dihydroxyacetone, and optionally reacting the reaction mixture with sulfuric acid Treatment yields a compound of formula I wherein R ³ and R ⁴ are hydrogen and R ⁵ is hydroxymethyl; or (c) reacting a compound of formula 5, wherein n, t and R ¹ are as defined in Formula I above, with 1,2,4-triazol-4-ylamino and then sulfiding to R To obtain a compound of formula I wherein ² is a group of formula (c) and R ⁸ is amino: or (d) reacting or catalyzing a compound of formula 7, wherein n, t and R ¹ are as defined in Formula I above, with 2,2-dialkyloxyethylamine in the presence of a chemical reducing agent Treatment with thiocyanic acid after the hydrogenation reaction yields a compound of formula I wherein R ² is a group of formula (a) and R ³ , R ⁴ and R ⁵ are each hydro: or (e) compounds of the following formula 9 (to wherein each n, t and R ¹ are as defined in Formula I) is reacted with a 2,2-alkyl-oxy-ethyl amine, by treatment with an acid R ² is Or a compound of formula (I) wherein R ₃ , R ₄ and R ₅ are each hydro: or (f) reacting a compound of formula 9 with aminoacetonitrile hydrochloric acid followed by treatment with a base wherein R ₂ is a group of formula (a), R ³ and R ⁴ are each hydro and R ⁵ is amino To obtain; or (g) a compound of formula (I) wherein R ² is a group of formula (a), R ³ and R ⁵ are each hydro and R ⁴ is formyl, by reacting and oxidizing the compound of formula 9 with D-(+)-glucosamine To obtain; or (h) a compound of Formula 9 is represented by Formula H ₂ NHC (O) R ³⁴ , wherein R ³⁴ is hydro, aminomethyl, (C _1-4 ) alkylaminomethyl, di (C _1-4 ) alkylaminomethyl , Pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl or 4- (C _1-4 ) alkylpiperazin-1-yl Is reacted with a hydrazide or a protected derivative thereof, followed by a base and, if necessary, deprotection so that R ² is a group of formula (b) and R ⁶ is hydro and R ⁷ is hydro, aminomethyl , (C _1-4 ) alkylaminomethyl, di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazine To obtain a compound of formula I which is -1-ylmethyl or 4- (C _1-4 ) alkylpiperazin-1-ylmethyl; or (i) reacting and sulfiding a compound of formula 11 (wherein each n, t, R ⁴ and R ⁵ are as defined in formula I above) with a strong base to yield a compound of formula I wherein R ³ is hydro; do or: or (j) a compound of Formula 11 wherein each n, t and R ¹ are as defined in Formula I above, a compound of Formula L- (CH ₂ ) _q R ⁹ , wherein L is a leaving group, each q and R ⁹ are as defined in formula I) and the reaction was, sulfide by R ² is a group of formula (a) R ³ is - (CH _{2) q} R ⁹ the obtained compounds of formula (I), or; or (k) reacting a compound of Formula 11, wherein R ⁴ and R ⁵ are each hydro and each n, t and R ¹ are as defined in formula I above, reacts with amino aryl- or alkylsulfonate to R ² To obtain a compound of formula (I) wherein is a group of formula (a) and R ³ is amino; or (l) reacting a compound of formula 11, wherein R ⁴ and R ⁵ are each hydro and each n, t and R ¹ are as defined in Formula I above with the appropriate N, N-disubstituted methylene ammonium salts And sulfided to give R ² a group of formula (a) and R ⁵ is di (C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl To obtain; or (m) a compound of formula 16 wherein R ³² is cyano or (C _1-4 ) alkyloxycarbonyl and each n, t and R ¹ are as defined in formula (I); ^{Reacted with} a compound of ³³ C (O) L and treated with thiocyanic acid, where R ² is a group of formula (a), R ³ is hydro, R ⁵ is cyano or (C _1-4 ) alkyloxycarbo Or a compound of formula I wherein R ⁴ is hydro, (C _1-4 ) alkyloxycarbonyl or (C _1-4 ) alkyl; or (n) A compound of formula 24, wherein n, t and R ¹ are as defined in formula I above, is reacted with isothiocyanate and treated with a base so that R ² is represented by formula (c) Or a compound of formula I wherein R ⁸ is hydro; or (o) a compound of formula (I) wherein R ⁵ is hydroxymethyl is a compound of formula H ₂ N (O) R ³¹ or an ammonium salt of formula NH ₄ ⁺ -OC (O) R ³¹ , wherein R ³¹ is hydrogen R ⁵ is formylaminomethyl, (C _1-4 ) alkylcarbonyl-aminomethyl or trifluoro (C ₁ ), and reacted with (C _1-4 ) alkyl or trifluoro (C _1-4 ) alkyl). _-4 ) Obtain a compound of formula (I) which is alkylcarbonylaminomethyl, and optionally further hydrolyze the compound to give an acid addition salt of the compound of formula (I) wherein R ³ and R ⁴ are each hydro and R ⁵ is aminomethyl To obtain; or (p) reacting a compound of formula I wherein R ⁵ is hydroxymethyl with urea to obtain a compound of formula I wherein R ⁵ is ureidomethyl; or (q) reacting a compound of Formula I wherein R ⁵ is cyano with a hydrazonic acid derivative to obtain a compound of Formula I wherein R ⁵ is 1H-tetrazol-5-yl; or (r) reducing the compound of formula I wherein R ⁵ is cyano to afford a compound of formula I wherein R ⁵ is aminomethyl; or (s) hydrolyzing the compound of formula I wherein R ⁵ is cyano to obtain a compound of formula I wherein R ⁵ is carbamoyl; or (t) reacting a compound of formula I wherein R ⁵ is cyano with ethylenediamine to give a compound of formula I wherein R ⁵ is 4,5-dihydroimidazol-2-yl; or (u) reacting a compound of formula (I) wherein R ⁵ is cyano with a compound of formula (CH ₃ ) ₂ AlNR ¹⁵ R ¹⁶ , wherein R ⁵ is -C (NH) NR ¹⁵ R ¹⁶ , and R ¹⁵ and R ¹⁶ are Obtaining a compound of formula I as defined in I; or (v) reducing the compound of formula I wherein R ⁵ is or both R ⁴ and R ⁵ are ethoxycarbonyl to obtain a compound of formula I wherein R ⁵ or both R ⁴ and R ⁵ are hydroxymethyl; or (w) converting a compound of formula (I) wherein R ⁵ is hydroxymethyl, to a compound of formula 28, wherein n, t and R ¹ are as defined in formula (I): The compound of formula HNR ³⁶ R ³⁷ , wherein R ³⁶ and R ³⁷ are independently (C _1-4 ) alkyl or together is-(CH ₂ ) ₄ -,-(CH ₂ ) ₅ -,-(CH ₂ ) ₂ -O- (CH _{2) 2} - or ^{_{- (CH 2) 2 -NR 38}} - (CH2) 2- , and wherein R ³⁸ is reacted with an amine of the hydro or (C _1-4) alkyl) R ⁵ Valent aminomethyl, (C _1-4 ) alkylaminomethyl, di (C _1-4 ) alkylaminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl To obtain a compound of formula (I) which is piperazin-1-ylmethyl or 4- (C _1-4 ) alkylpiperazin-1-ylmethyl: or (x) reacting a compound of formula I wherein R ⁴ is formyl with hydroxylamine hydrochloric acid and reducing to yield a compound of formula I wherein R ⁴ is aminomethyl; or (y) reacting a compound of formula (I) wherein R ⁴ is formyl with an amine of the general formula NH ₂ R ¹⁰ in the presence of a chemical reducing agent or catalytic hydrogenation, wherein R ⁴ is —CH ₂ NHR ¹⁰ wherein R ¹⁰ is Obtaining a compound of formula (I) as defined in I; or (z) alkylating a compound of formula I wherein R ⁴ is formyl to yield a compound of formula I wherein R ⁴ is 1-hydroxy (C _1-4 ) alkyl; or (aa) a compound of formula (I) wherein R ³ , R ⁵ or R ⁶ is amino or R ⁴ , R ⁵ or R ⁸ is aminomethyl is reacted with an appropriately substituted amidine so that R ³ , R ⁵ or R ⁶ is- NHC (NR ¹¹ ) NHR ¹² or R ⁴ , R ⁵ or R ⁸ is —CH ₂ NHC (NR ¹¹ ) NHR ¹² , wherein R ¹¹ is hydro, acetyl or t-butoxycarbonyl, and R ¹² is acetyl Or t-butoxycarbonyl) to yield the corresponding compound of formula (I); or (bb) R ³ , R ⁵ or R ⁶ is -NHC (NR ¹¹ ) NHR ¹² or R ⁴ , R ⁵ or R ⁸ is -CH ₂ NHC (NR ¹¹ ) NHR ¹² , wherein R ¹¹ is hydro, acetyl Or t-butoxycarbonyl, and R ¹² is acetyl or t-butoxycarbonyl), reacting with a acid so that R ³ , R ⁵ or R ⁶ is -NHC (NH) NH ₂ or R ⁴ To obtain a compound of formula I wherein R ⁵ or R ⁸ is —CH ₂ NHC (NH) NH ₂ ; or (cc) acylating a compound of formula (I) wherein R ³ , R ⁵ or R ⁶ is amino or R ⁴ , R ⁵ or R ⁸ is aminomethyl with an appropriate acylating agent or a protected derivative thereof, followed by deprotection if necessary R ³ , R ⁵ or R ⁶ is -NHR ¹⁰ or R ⁴ , R ⁵ or R ⁸ is -CH ₂ NHR ¹⁰ [wherein R ¹⁰ is (C _1-4 ) alkanoyl, trifluoro (C _{1 -4} ) alkanoyl, carbamoyl, (C _1-4 ) alkyloxycarbonyl, (C _1-4 ) alkylcarbamoyl, di (C _1-4 ) alkylcarbamoyl, amino (C _1-4 ) alkanoyl , (C _1-4 ) alkylamino (C _1-4 ) alkanoyl, di (C _1-4 ) alkylamino (C _1-4 ) alkanoyl; Or aroyl and heteroaroyl, unsubstituted or substituted with 1 to 2 substituents independently selected from (C _1-4 ) alkyloxy, cyano, carboxy and (C _1-4 ) alkyloxycarbonyl , "Aroyl" is -C (O) R, wherein R is "aryl" as defined above "heteroaroyl" is -C (O) R ', wherein R' is "heteroaryl" as defined above Is a group selected from or (dd) reacting a compound of formula I wherein R ³ , R ⁵ or R ⁶ is amino or R ⁴ , R ⁵ or R ⁸ is aminomethyl, reacts with (C _1-4 ) alkyl isocyanate to R ³ , R ⁵ or R To obtain a compound of formula I wherein ⁶ is -NHR ¹⁰ or R ⁴ , R ⁵ or R ⁸ is -CH ₂ NHR ¹⁰ and R ¹⁰ is (C _1-4 ) alkylcarbamoyl; or (ee) The compounds of formula (I) wherein R ³ , R ⁴ and R ⁵ are each hydroalkylated with an appropriate N, N-disubstituted methyleneammonium salt so that R ³ and R ⁵ are each hydro and R ⁴ is di (C _{1- 4} ) obtaining a compound of formula I which is alkylaminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl; or (ff) R ⁴ is hydro and R ⁵ is di (C _1-4) alkyl aminomethyl, by appropriately N, N- alkylated-disubstituted methylene ammonium salt of a compound of formula (I) R ³ is other than a dihydro-piperidin- To yield the corresponding compound of formula I which is 1-ylmethyl or morpholin-4-ylmethyl; or (gg) protecting a compound of formula (I) wherein R ³ is hydro with a thiol protecting group, alkylating with an appropriate N, N-disubstituted methyleneammonium salt and deprotecting so that R ² and R ⁴ are each hydro and R ⁵ is C _1-4 ) alkylaminomethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl or R ³ is hydro and both R ⁴ and R ⁵ are di (C _1-4 ) alkylaminomethyl, Obtaining a compound of formula I that is piperidin-1-ylmethyl or morpholin-4-ylmethyl; or (hh) R ⁵ or R ⁴ and R ⁵ both to the carboxy compound or an appropriate amine or thiol, and reacting the acid derivatives thereof of formula I R ⁵ or R ⁴ and R ⁵ 1H- tetrazol-5-ylcarbamoyl To obtain a compound of formula (I) which is 2- (dimethylamino) ethylcarbamoyl, 4-methylpiperazin-1-ylcarbonyl, or 2- (dimethylamino) ethylmercapto; or (ii) reacting a compound of formula (I) wherein R ³ , R ⁶ or R ⁸ is hydro with (C _1-4 ) alkyl acrylate, where R ³ , R ⁶ or R ⁸ is 2- (C _1-4 ) alkyloxy Obtaining a compound of formula I that is carbonylethyl; or (jj) R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ are (C _1-4 ) alkyloxycarbonyl or a group further substituted with a (C _1-4 ) alkyloxycarbonyl substituent Hydrolysis of a compound of formula (I) to yield a compound of formula (I) wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ are groups further substituted by carboxy or carboxy substituents; or ^{(kk) R 3, R 4} , R 5, R 6, R 7 or R ⁸ is carboxy or O more compounds of formula I, wherein the group substituted by a carboxy substituent folk by ^{R 3, R 4, R 5} , R 6 To obtain a compound of formula (I) wherein R ⁷ or R ⁸ is a group further substituted with carbamoyl or carbamoyl substituents; or (ll) A compound of formula (I) wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ is further substituted with a carboxy or carboxy group, reacts with (C _1-4 ) alcohol to give R ³ , R ^{4, R 5, R 6,} R 7 or R ⁸ is (C _1-4) alkyloxycarbonyl or (C _1-4) to give a further compound of formula (I) substituted by a group of the alkyloxycarbonyl group, or; or (mm) R ¹ is methoxy and / or R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ is aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4), allyl (wherein, aroyl, heteroaryl, aroyl, aryl and heteroaryl are as defined above, the first to be further substituted with two methoxy substituents) to the demethylating a compound of formula (I) R ¹ is Hydroxy and / or R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ are aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl ( Wherein aroyl, heteroaroyl, aryl and heteroaryl are as defined above and are further substituted with 1 to 2 hydroxy substituents); or (nn) R ³ , R ⁵ , R ⁶ or R ⁸ is -NHR ¹⁰ , or R ⁴ , R ⁵ or R ⁷ is -CH ₂ NHR ¹⁰ , wherein R ¹⁰ is aroyl, heteroaroyl, aryl ( C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl, aroyl, heteroaroyl, aryl and heteroaryl are as defined above and further substituted with cyano substituents) The compound is reacted with a hydrazoic acid derivative so that R ¹⁰ is aroyl, heteroaroyl, aryl (C _1-4 ) alkyl and heteroaryl (C _1-4 ) alkyl, wherein aroyl, heteroaroyl, aryl and hetero Aryl is as defined above and is further substituted with 1H-tetrazol-5-yl substituent) to obtain a compound of formula (I); or (oo) reacting the corresponding non-salt form of the compound of formula I with a pharmaceutically acceptable inorganic or organic acid or base to obtain a pharmaceutically acceptable salt; or (pp) reacting the corresponding acid addition salt or form of base addition salt of the compound of formula I with a suitable base or acid, respectively, to give a free acid or free base; or (qq) separating the mixture of stereoisomers of the compound of formula I to obtain a single stereoisomer; or (rr) reacting a protected derivative of L-amino acid with a compound of formula (I) or a pharmaceutically acceptable salt, each isomer or mixture of isomers thereof to form the prodrug of formula (II); [Formula I] [In the above formula, Each n, t and R ¹ are as defined in formula (II) of claim 11; R ² is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (a), (b) and (c): R ⁴ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ where q and R ⁹ are as defined above and R ⁵ is —NHR ¹⁰ where R ¹⁰ is as defined above ); Or R ⁴ and R ⁵ are each hydro and R ³ is —NHR ¹⁰ , wherein R ¹⁰ is as defined above; or R ⁵ is hydro, R ³ is hydro or — (CH ₂ ) _q R ⁹ (where q and R ⁹ are as defined above) and R ⁴ is —CH ₂ NHR ¹⁰ where R ¹⁰ is defined above Or as; or R ³ is hydro or — (CH ² ) ^q R ⁹ where q and R ⁹ are as defined above and R ⁴ is hydro, (C _1-4 ) alkyl or —C (O) R ¹⁴ , wherein , R ¹⁴ is amino, hydroxy, (C _1-4 ) alkyloxy, 2- (dimethylamino) ethylamino, 4-methylpiperazin-1-yl, 2- (dimethylamino) ethylmercapto, 4- ( Methylsulfonylamino) anilino or 1H-tetrazol-5-ylamino; R ⁵ is —CH ₂ NHR ¹⁰ , wherein R ¹⁰ is as defined above; R ⁶ is hydro, 2-carboxyethyl, 2-carbamoylethyl or 2- (C _1-4 ) alkyloxycarbonylethyl; R ⁷ is —CH ₂ NHR ¹⁰ , wherein R ¹⁰ is as defined above; R ⁸ is —NHR ¹⁰ , wherein R ¹⁰ is as defined above; or (ss) a compound of formula 47 wherein R ²⁸ is as defined in formula III or a protected derivative thereof is reacted with a compound of formula I or a pharmaceutically acceptable salt thereof, each isomer or mixture of isomers And if necessary, deprotection to form the prodrug of Formula III of claim 15: [Formula I] [In the above formula, Each n, t and R ¹ are as defined above; R ² is bonded at the α-, β- or γ-position and is a group selected from the following general formulas (a), (b) and (c): R ³ , R ⁷ and R ⁸ are hydro, R ⁴ , R ⁵ and R ⁶ are as defined in formula III]. Compounds having the general formula: (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamine: (a) reducing the compound of formula 7 (b) in the presence of 2S-dimethylamino-1R-phenylpropanol and 2-ethylaminopyridine to produce the (R) -enantiomer of formula 6 (c); : (b) treating (R) -enantiomer of formula 6 (c) with methanesulfonyl chloride and reacting with an azide salt to produce (S) -enantiomer of formula 4 (a): (c) including reducing, Method for preparing the S-enantiomer of the general formula 3 (a): Wherein t is 0, 1, 2 or 3; R ¹ is independently halo, hydroxy or (C _1-4 ) alkyloxy. The method of claim 18, A pharmaceutical composition wherein said compound is a compound as defined in any one of claims 1, 2, 11, 14, and 15. The method of claim 1, R ² is bonded at the β- or γ-position. The method of claim 3, wherein R ⁵ is ureidomethyl, aminomethyl or acetylaminomethyl. The method according to any one of claims 4, 7, and 16, Wherein said fluoro is at positions 5 and 7. The method of claim 5, (S) -5-aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione hydrochloric acid ; (S) -5-ureidomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazole-2-thione ; or (S) -N- [3- (5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-already Compound which is dazol-4-ylmethyl] acetamide The method of claim 8, (S) -5-aminomethyl-4- (5,7-difluoro-1,2,3,4-tetrahydronaphth-2-yl) -2,4-dihydro [1,2,4 ] Triazole-3-thione hydrochloric acid. The method of claim 10, (S) -4-amino-2- (5,7-difluoro-1,2,3,4-tetrahydronaphth-2-yl) -2,4-dihydro [1,2,4] Compound that is triazole-3-thione. The method of claim 11, R ¹⁸ is a group of formula (d) bonded at the β-position. The method of claim 14, 3S-amino-N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2S-yl) -2-thioxo-2,3-dihydro-1H-already Dazol-4-yl-methyl] succinic acid hydrochloric acid; 2S-amino-3- (3H-imidazol-4-yl) -N- [3- (1,2,3,4-tetrahydronaphthalene-2S-yl) -2-thioxo-2,3-di Hydro-1H-imidazol-1-yl] propionamide dihydrochloric acid; or 2S, 5-Diamino-N- [3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2S-yl) -2-thioxo-2,3-dihydro- 1H-imidazol-4-ylmethyl] valeramide-2 hydrochloride. The method of claim 15, R ²⁷ is a group of formula (g) bonded at the β-position. The method of claim 17, R ²⁸ is (R) -2-amino-2-methoxy-carbonylethyl, (R) -2-amino-2-carboxyethyl, (R) -2-trifluoroacetylamino-2-methoxycarbon Nylethyl, 2-aminoethyl, (S) -2-amino-2-carboxy-1,1-dimethylethyl or 3-amino-3-carboxyprop-1-yl. The method of claim 20, Step (rr) further reacts the compound of formula (II) in corresponding non-salt form with a pharmaceutically acceptable inorganic or organic acid or base to produce a pharmaceutically acceptable salt, or to correspond to a compound of formula (II) Further reacting the acid addition salt or base addition salt form with a suitable base or acid, respectively, to form a free acid or free base, or separating a mixture of stereoisomers of a compound of Formula II to produce a single stereoisomer. How to include. The method of claim 20, Step (ss) further reacts the corresponding non-salt form of the compound of formula III with a pharmaceutically acceptable inorganic or organic acid or base to produce a pharmaceutically acceptable salt, or Further reacting the acid addition salt or base addition salt form with a suitable base or acid, respectively, to produce a free acid or free base, or separating a mixture of stereoisomers of a compound of Formula III to produce a single stereoisomer. How to include. The method of claim 22, t is 2; The method of claim 22, R ¹ is fluoro present in positions 5 and 7.