UA68384C2 - Thiazolo-, oxazolo- and selenazolo[4,5-c]quinoline-4-amines and analogs thereof - Google Patents

Abstract

Thiazolo-, oxazolo- and selenazolo[4,5-c]quinoline-4-amines and analogs thereof are described including methods of manufacture and the use of novel intermediates. The compounds are immunomodulators and induce cytokine biosynthesis, including interferon and/or tumor biosynthesis, necrosis factor, and inhibit the T-helper type 2 immune response. The compounds are further useful in the treatment of viral and neoplastic diseases.

Description

Description of the invention

This invention relates to oxazolo, thiazolo and selenazolo|4,5-c|quinoline-, tetrahydroquinoline-4-amines and their 2 heteroanalogues, as well as intermediate compounds used in their preparation. The invention also relates to pharmaceutical compositions containing the aforementioned compounds, as well as the use of these compounds as immunomodulators and for stimulating cytokine biosynthesis, including α-interferon biosynthesis and/or biosynthesis

A tumor necrosis factor.

Prerequisites for the creation of the invention and prior art 70 The first plausible synthesis of the 1H-imidazo|4,5-c|quinoline system was described by VasKtap ei ai., U. Ogu. Spent 15, 1278-1284 (1950), which describes the synthesis of 1-(6b-methoxy-8-quinolinyl)-2-methyl-1H-imidazo|4,5-c|quinoline for use as an antimalarial agent. Later, the syntheses of various substituted 1H-imidazo|4,5-c|quinolines were described. For example, m.)aiip ey aЙ, 9. May. Spent 11, pp. 87-92 (1968), synthesized 1-(2-(4-piperidyl)ethyl|-1H-imidazo|4,5-c|Yiquinoline for use as an anticonvulsant "12 cardiovascular agent. Also, Vagapom ei aii.,, Spet. Arvz. 85, 94362 (1976), and Vegepui ei ai., 5.

Neijegosusiis Spet. 18, 1537-1540 (1981), described some 2-oxoiimidazo|4,5-c|quinolines.

In subsequent reports, 1H-imidazo|4,5-c|quinolin-4-amines and their 1- and 2-substituted derivatives were obtained for use as antiviral agents, bronchodilators and immunomodulators. Among them should be mentioned US patents 4,689,338; 4698348; 4929624; 5037986; 5266675; 5268376; 5346905; 5389640; 5605899; 5352784; 5DAv1B5Z and 5482936. Zpepei AI., US patent Mo4038396 and 4131677, describe some oxazolo- and thiazolopyridines that have anti-inflammatory, analgesic and antipyretic properties.

Description of the invention

The presented invention relates to the compound of formula I:

MN se sh. M o

U-k street TV m " in d) in which:

Cu is selected from the group consisting of oxygen, sulfur and selenium; at

EC" is selected from the group containing c - hydrogen; 325 - alkyl; ke, -alkyl-OH; -haloalkyl; -alkenyl; "-alkyl-X-alkyl; -alkyl-X-alkenyl; but) c -alkenyl-X-alkyl; : » -alkenyl-X-alkenyl; -alkyl-M(Co)"; -alkyl-M»u3; -apKt-O-C(0)-M(B c)"; b - heterocycle;

Ge | -alkyl-X-heterocycle; -alkenyl-X-heterocycle; o -aryl; o 20 -alkyl-X-aryl; -alkenyl-X-aryl;

T" -heteroaryl; -alkyl-X-heteroaryl; and -alkenyl-X-heteroaryl; 25 Ez and K4 each independently:

HF) - hydrogen; -x-alkyl; o - halogen; -haloalkyl; 60 -M(Bvu; or when taken together, Kz and K4 form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;

X is selected from the group containing -О-, -5-, -МКв-, -С(0)-, -Ч(О)0-, -ОС(О)- and a bond; and each Kv, independently, H or C..8 alkyl; because under the condition that when K. is sulfur, Kz is not -MN";

or a pharmaceutically acceptable salt thereof.

In a second aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (a) and a pharmaceutically acceptable excipient:

МН, мя

U- street ZY

Moscow) in which:

Cu is selected from the group consisting of oxygen, sulfur and selenium;

EC" is selected from the group containing -hydrogen; -alkyl; -alkyl-OH; -haloalkyl; -alkenyl; -alkyl-X-alkyl; -alkyl-X-alkenyl; -alkenyl-X-alkyl; -alkenyl-X-alkenyl; -alkyl-M(Co)"; ch -alkyl-M»u3; -alyl-O-C(O)-M(B do: i) -heterocycle; -alkyl-X-heterocycle; -alkenyl-X-heterocycle; "g zo -aryl; -alkyl-X-aryl; co-alkenyl-X-aryl; c -heteroaryl; -alkyl-X-heteroaryl; and co-alkenyl-X-heteroaryl; "at

Ez and Ku each independently: -hydrogen; -x-alkyl; - halogen; "-haloalkyl; with c -ShkKoe)";

And or when taken together, Kz and K4 form a fused aromatic, heteroaromatic, cycloalkyl, or y? heterocyclic ring;

X is selected from the group containing -О-, -5-, -МКв-, -С(О)-, - (О)О-, -ОС(О)- and a bond; and each Kb, independently, H or C. in alkyl;

Ge" or its pharmaceutically acceptable salt.

Compounds of formula (a) are used to stimulate the biosynthesis of certain cytokines in animals, including humans. Cytokines that can be stimulated by the compounds of the invention include, but are not limited to 2) interferon, in particular, A-interferon and o-tumor necrosis factor. The invention also relates to a method of 50p stimulation of cytokine biosynthesis in animals, which consists in prescribing an effective amount of the composition to the animal, which includes an effective amount of the compound of formula (a). Since the compounds of the invention are able to stimulate biosynthesis

And" cytokine they can be used in the treatment of a variety of conditions, including viral diseases and neoplasms, and the invention further relates to a method of treating such conditions in subjects by administering to the subject a therapeutically effective amount of a composition containing a compound of formula I(a) .

Another aspect of the present invention relates to intermediate compounds of formula I: (F) l» Ex

And U-v

And: 60 av in which

Cu is selected from the group consisting of oxygen, sulfur and selenium;

EC" is selected from the group containing 65 -hydrogen; -alkyl;

-alkyl-OH; -haloalkyl; -alkenyl; -alkyl-X-alkyl; -alkyl-X-alkenyl; -alkenyl-X-alkyl; -alkenyl-X-alkenyl; -alkyl-M(Co)"; 70 -apkip-Mz, -alkyl-O-C(O)-M(K 5)"; -heterocycle; -alkyl-X-heterocycle; -alkenyl-X-heterocycle; -aryl; -alkyl-X-aryl; -alkenyl-X-aryl; -heteroaryl; -alkyl-X-heteroaryl; -alkenyl-X-heteroaryl; -3025SNU"; and -Сн.-о-с(0)-СН";

Ez and Ku each independently: -hydrogen; c -x-alkyl; o - halogen; -haloalkyl; -ShckKoe)"; or when taken together, K3 and K4 form a fused aromatic, heteroaromatic, cycloalkyl or "E zo heterocyclic ring;

X is selected from the group containing -O-, -5-, -МКв-, -С(О0)-, -С(О)О- and a bond; and so each Kb, independently, H or C. 8 alkyl. with

Detailed description of the invention

This invention includes compounds of formula I, pharmaceutical compositions containing compounds of formula (a) and co-therapeutic methods of using compounds of formula (a), as well as intermediate compounds of formula II, which are used in the preparation of compounds of formula | and I(a).

The terms "alkyl" and "alkenyl" as used herein, unless otherwise indicated, refer to branched or unbranched hydrocarbon groups or cyclic groups (ie, cycloalkyl and cycloalkenyl) containing from 1 to 20, preferably from 1 to 10, most preferably from 1 to 8 carbon atoms. Typical alkyl groups "

There are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. Examples of cyclic groups are cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, and adamantyl. The prefix "alk," when used, for example, for "alkoxy" and the like, also ;" also means the same thing.

The term "aryl" refers to a carbocyclic aromatic ring or ring system. The aryl group is preferably a six-membered ring such as phenyl or an aromatic polycyclic system such as

Ge» naphthyl. More preferably, the aryl group is phenyl, which may be unsubstituted or substituted with one or more substituents as indicated below. Examples of other suitable aryl groups are biphenyl, co-fluorenyl and indenyl. 2) The term "heteroaryl" refers to an aromatic ring or ring system containing one or more

The number of heteroatoms in which the heteroatoms are selected from nitrogen, oxygen, and sulfur. Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, tetrazolyl, imidazo, and the like. In the case when K" and Ku" taken together and i" form a 5- or b-membered heteroaromatic ring, the heteroatoms are nitrogen, oxygen or sulfur and the ring may contain one or more of such atoms. Preferably, the heteroatom is nitrogen or sulfur. Predominantly heteroaromatic rings are formed from K with and K as shown in the following formulas, where the two lines show how

They are condensed. " pada ime) i- M 2 M ra "" V V s 5 ho 5

The terms "heterocyclic" and "heterocycle" mean non-aromatic rings or ring systems containing one or more ring heteroatoms (eg, O, 5, M). Examples of heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidino, piperazino, thiazolidinyl, imidazolidinyl, and the like. for All of the above-mentioned rings and ring systems may be substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, alkylthio, hydroxy, halogen, haloalkyl, polyhaloalkyl, perhaloalkyl (e.g., trifluoromethyl), trifluoroalkyl (e.g., trifluoromethoxy), nitro, amino, alkylamino, dialkylamino, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, nitrite and alkoxycarbonyl.

Substituents are mainly Si. alkyl, C 1 -C 6 oxy, halogen, amino, alkylamino, dialkylamino, hydroxy, C. 4 alkoxymethyl and trifluoromethyl.

The term "halogen" means a halogen atom, such as, for example, fluorine, chlorine, bromine or iodine.

The invention includes the compounds described herein in any of their pharmaceutically acceptable forms, including isomers, such as diastereomers and enantiomers, salts, solvates, polymorphs, and the like.

As stated above, compounds of the formula ! and Ma) capable of forming "pharmaceutically acceptable salts".

Pharmaceutically acceptable acid additive salts of compounds of the formula! and Ma) include salts derived from non-toxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphoric, and the like, as well as salts derived from non-toxic organic /5 Acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted carboxylic acids, hydroxycarboxylic acids, alkanedionic acids, aromatic acids, aliphatic and aromatic sulfonic acids and others.

Such salts also include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrophosphate, dihydrophosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, hydroxynaphthoate, xinafoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Amino acid salts, such as arginates and the like, gluconates, galacturates are also provided (see, for example, Vegde 5M, ей ай., сч "Рпаптасецииса! Зай(8," 9. Rpagt. Zsi. 1977;66:1).

Acid-addition salts of compounds are obtained as a result of the interaction of a free base with a sufficient amount of the desired (8) acid with the release of a salt using generally accepted methods. The free base can be obtained as a result of the interaction of the salt with the base and the release of the base using generally accepted techniques.

Preferred compounds of the formula | and (a) there are those in which Ki is oxygen or sulfur. Predominantly, Co substituents are C-10 alkyl and alkoxyalkyl, with C-4 alkyl being particularly preferred.

Mostly K»z and Ku; taken together form a fused benzene or pyridine ring, which may be substituted or unsubstituted. co

The most preferred compounds are compounds of formula III or IM:

MN" p

M

M Y U-yu (Se)

B Go)

In which C is as defined above and K is hydrogen, alkyl, alkoxy, alkylthio, hydroxy, halogen, haloalkyl, polyhaloalkyl, perhaloalkyl (e.g., trifluoromethyl) , trifluoroalkoxy

Me (e.g., trifluoromethoxy), nitro, amino, alkylamino, dialkylamino, alkylcarbonyl, alkenylcarbonyl, o arylcarbonyl, heteroarylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, nitrile, and alkoxycarbonyl. o Examples of the compounds of the invention include: o 2-methylthiazolo|4,5-siquinolin-4-amine; thiazolo|4,5-c|quinoline-4-amine; i» 2-ethylthiazoloi|4,5-c|quinolin-4-amine; 2-propylthiazolo|4,5-c|quinoline-4-amine; 2-pentylthiazolo|4,5-s|quinoline-4-amine; 59 2-butylthiazolo|4,5-siquinolin-4-amine;

HF) 2-(1-methylethyl)thiazolo|4,5-c)quinolin-4-amine; 2-(2-phenyl-1-ethenyl)thiazolo|4,5-c)quinolin-4-amine; where 2-(2-phenyl-1-ethyl)thiazolo|4,5-c|quinolin-4-amine; 2-(4-aminothiazolo|4,5-c|quinolin-2-yl)-1,1-dimethylethyl carbamate; 6o 2-(ethoxymethyl)thiazolo|4,5-c|quinolin-4-amine; 2-(methoxymethyl)thiazolo|4,5-c|quinolin-4-amine; 2-(2-methylpropyl)thiazoloyl|4,5-c)quinolin-4-amine; 2-benzylthiazolo|4,5-c|quinoline-4-amine; 8-methyl-2-propylthiazoloi|4,5-c|quinolin-4-amine; bo (4-aminothiazolo|4,5-c|quinolin-2-yl)umethanol;

2-methyloxazoloi|4,5-s|quinolin-4-amine; 2-ethyloxazolo|4,5-s|quinolin-4-amine; 2-butyloxazolo|4,5-c|quinoline-4-amine; 2-propylthiazolo|4,5-c)quinoline-4,8-diamine; 2-propyloxazolo|4,5-s|quinoline-4-amine; 8-bromo-2-propylthiazolo|4,5-c|quinoline-4-amine; 7-methyl-2-propylthiazolo|4,5-c|quinolin-4-amine; 2-butyl-7-methyloxazolo!|4,5-c|quinolin-4-amine; 70 7-methyl-2-propyloxazolo|4,5-c)quinolin-4-amine; 7-fluoro-2-propyloxazoloi|4,5-s|quinolin-4-amine; 7-fluoro-2-propylthiazolo[4,5-c]quinolin-4-amine; 2-propyl-7-(trifluoromethyl)thiazolo[4,5-c]quinolin-4-amine; 2-(4-morpholino)thiazolo|4,5-c|quinolin-4-amine; 2-(1-pyrrolidino)thiazolo|4,5-c|quinolin-4-amine; 2-butylthiazolo|4,5-cI(1,5|Inaphthyridin-4-amine; 2-propylthiazolo|4,5-C|1,5|Inaphthyridin-4-amine; 7-chloro-2-propylthiazolo|4, 5-c) quinoline-4-amine; 7-methoxy-2-propylthiazolo|4,5-c|quinolin-4-amine; and their pharmaceutically acceptable salts, especially their hydrochloride salts.

Preparation of compounds

The compounds of the invention can be obtained according to Reaction Scheme I, in which К. К", Kz and К; are as stated above.

At stage (1) of Reaction Scheme I, the compound of the formula M reacts with a carboxylic acid or its equivalent to give the compound of the formula MI. Suitable carboxylic acid equivalents are acid anhydrides, acid chlorides, orthoethers and 1,1-dialkoxyalkanoates. The carboxylic acid or its equivalent is chosen so as to i) provide the desired Co substituent in the compound of formula MI. For example, triegylorthoformate will provide a compound of formula MI in which Co is hydrogen and acetic anhydride will provide a compound of formula MI in which Co is methyl.

The reaction can proceed in the absence of a solvent, in the presence of an acid such as polyphosphoric acid or, preferably, in the presence of a carboxylic acid of the formula CoC(O)OH. The reaction takes place with sufficient heating to separate the alcohol or water formed as a result of the reaction. Compounds of formula M are known or can be prepared using generally known methods (see, for example,

She Ategisap SPpetisa! ZosieMu, 69, pp. 36b5-371 (1947); Her special year. AI., Zupipevziz, pp. 656-658 (1992); Adieeg hey. aiYi.,, dotsgpa! ой (She Spetisa! bosieeiu, 1794-1797 (1960); 55

Spetieee, 583, pp. 150-160 (1953); and beat her. ai., diviiv Iieridz Appaiep deg Spetie, 593, pp. 91-126 (1955). "at

At stage (2) of the reaction scheme | the compound of the formula MI is oxidized to obtain the M-oxide of the formula I.

Oxidation is carried out using generally accepted oxidizing agents that can lead to formation

M-oxides. Mostly, the reaction consists in the interaction of a solution of a compound of the formula M! in chloroform with

with chloroperoxybenzoic acid at room temperature and pressure. Alternatively, oxidation can be carried out using peracetic acid in a suitable solvent such as ethyl or methyl acetate. in s At stage (3) of the reaction scheme | The M-oxide of formula II is aminated to give a compound of formula I. Step (3) involves (ii) reaction of a compound of formula II with an adilating agent and then (ii) reaction of the product with an aminating agent. ;" Part (i) of stage (3) involves the reaction of the M-oxide of the formula II with an adilating agent. Suitable adilating agents are alkyl or arylsulfonyl chlorides (eg, benzenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred. Para-toluenesulfonyl chloride is the most

Ge" preferred. Part (iii) of stage (3) involves the reaction of the product of part () with an excess of aminating agent.

Ammonia (eg, in the form of ammonium hydroxide) and ammonium salts (eg, ammonium bicarbonate, ammonium bicarbonate, ammonium phosphate) are suitable aminating agents. Ammonium hydroxide is preferred. The reaction is mainly carried out by dissolving or suspending the M-oxide of the formula !! in an inert solvent such as dichloromethane or 50 chloroform, the aminating agent is added to the solution or suspension and then the acylating agent is added. The product or its pharmaceutically acceptable salt can be isolated using well-known methods. Alternatively, step (3) can be carried out by (i) reaction of the M-oxide of formula II with isocyanate and then (ii) hydrolysis of the resulting product. Part ()) involves the reaction of M-oxide with an isocyanate in which the isocyanate group is linked to the carbonyl group. Preferably, the isocyanate is trichloroacetyl isocyanate and an aroyl isocyanate such as benzoyl isocyanate. The reaction of isocyanate with M-oxide is carried out mainly in an anhydrous medium by adding isocyanate to a solution of M-oxide in an inert solvent such as dichloromethane.

F) Part (Her) includes hydrolysis of the product from part (Her). Hydrolysis can be carried out using conventional methods such as heating in the presence of water or a lower alcohol, optionally in the presence of a catalyst such as an alkali metal or ammonium alcoholate. 60 b5

The reaction scheme of mothers about battles, i

YES, -- To AI

Woo HE Woo ! With va vi in

In M p o

MN; m to vv

Va

AND

Compounds of the invention in which K. is oxygen or sulfur and Kz and K; together forming, optionally, a substituted aromatic ring, can be obtained according to Reaction Scheme HER, in which K and Co" are as indicated above.

At stage (1) of reaction scheme I! Z-aminoquinolin-4-ol or Z-aminoquinolin-4-thiol of the formula Mi! reacts with a carboxylic acid or its equivalent to give an oxazolo- or thiazolo|4,5-c|quinoline of the formula MI. Suitable equivalents of the carboxylic acid are acid anhydrides, acid chlorides, orthoethers, and 1,1-dialkoxyalkanoates. The carboxylic acid or its equivalent is chosen to provide the desired

EK" substitute in the compound of formula MIII. For example, triethyl orthoformate will provide a compound of formula MIP in which Co is hydrogen and acetic anhydride will provide a compound of formula MI in which Co is methyl. The reaction can proceed in the absence of a solvent, in the presence of an acid, such as polyphosphoric acid, or preferably in the presence of a carboxylic acid of the formula K»C(FO)OH. The reaction is carried out with sufficient heating to separate the alcohol or water formed as a result of the reaction. 3-Aminoquinoline-4-ols and 3-aminoquinoline-4-thiols of the formula Mi! are i) known or can be obtained using known methods.

At stage (2) of Reaction Scheme II, oxazolo- or thiazolo|4,5-syquinoline of formula MI is oxidized to obtain oxazolo- or thiazolo|4,5-syquinoline-5M-oxide of formula IX, which is an analogue of formula II. Oxidation is carried out using generally accepted oxidizing agents capable of leading to the formation of M-oxides. Preferably, the reaction consists in the interaction of a solution of the compound of the formula MI in chloroform with 3-chloroperoxybenzoic acid CO at room temperature and pressure. Alternatively, the oxidation can be carried out using peracetic acid in a suitable solvent such as ethyl or methyl acetate.

At stage (3) of Reaction Scheme II, the M-oxide of formula IX was aminated to obtain oxazolo|4,5-c)quinolin-4-amine of formula I or thiazolo|4,5-c|quinolin-4-amine of formula IM, both of which are analogs of formula I. Stage (3) includes (iii) reaction of the compound of formula IX with an adilating agent and then (ii) reaction of the product with an aminating agent.

Part (th) of stage (3) involves the reaction of the M-oxide of the formula IX with the adilating agent. Alkyl or arylsulfonyl chlorides (eg, benzenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride) are suitable adilating agents. Arylsulfonyl chlorides are preferred. Para-toluenesulfonyl chloride is most preferred. Part (ii) of stage (3) involves the reaction of the product of part (ii) with an excess of aminating agent. Ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate) are suitable aminating agents. Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving or suspending the M-oxide of formula IX in an inert solvent such as dichloromethane or chloroform, adding an aminating agent to the solution or suspension, and then adding an acylating agent. The product or a pharmaceutically acceptable salt thereof can be isolated using generally known methods.

Ge» Alternatively, stage (3) can be carried out by (iii) reaction of M-oxide of formula IX with isocyanate and then (ii) hydrolysis of the resulting product. Part ()) involves the reaction of M-oxide with an isocyanate in which the isocyanate group is bound to the carbonyl group. Preferably, the isocyanate is trichloroacetyl isocyanate and 2) aroyl isocyanates such as benzoyl isocyanate. The reaction of isocyanate with M-oxide is carried out mainly in an anhydrous medium by adding isocyanate to a solution of M-oxide in an inert solvent such as dichloromethane. co Part (Her) includes hydrolysis of the product from part (Her). Hydrolysis can be carried out using conventional methods such as heating in the presence of water or a lower alcohol, optionally in the presence of a catalyst such as an alkali metal alcoholate or ammonium.

F) name) 60 b5

Reaction scheme |! Opi M

M ev, KG v v, ii Y pd

ZY vn E her

In In KU

UP University of Applied Sciences their b)

M

M we

With | acting in

W (VO)

IM (Viev)

Compounds of the invention in which Ku is sulfur can be prepared according to Reaction Scheme I, in which Co", Kz and Ku are as defined above.

At stage (1) of Reaction Scheme III, the compound of formula X reacts with an acyl halide of formula K»C(О0)7, in which K» is as defined above and 7 is chlorine or bromine, as a result of which an amide of formula XI is formed. The reaction can be carried out by controlled addition of the acyl halide (eg dropwise) to a solution or suspension of a compound of formula X in a suitable solvent such as pyridine or dichloromethane in the presence of a tertiary amine.

At stage (2) of Reaction scheme I, the amide of the formula Xi reacts with phosphorus pentasulfide, resulting in the formation of the compound of the formula XII. The reaction can be carried out by adding phosphorus pentasulfide to a solution or suspension of a compound of formula XI in a suitable solvent such as pyridine and heating the resulting mixture.

Stages (3) and (4) of the reaction scheme NO can be carried out similarly to stages (2) and (3) of the reaction scheme I, as a result of which, accordingly, the M-oxide of the formula Xi is formed, which is an analogue of the formula I and the compound of the formula KHIM, which is an analogue of formula I, respectively. AND

Her reaction scheme! o s bottoms and in, Yu | In her lies;

Vu on V Her on Z ve v m Ge) x hi KhP iy ; "; at. M

KU in -9. DE d-k o, s vya Ku y 5

In V

;" hu x

Compounds of the invention in which Ku is sulfur and Kz and K4 together form, optionally, a substituted aromatic ring,

Can be obtained according to the reaction scheme of IM, in which K and Ko are as defined above.

He" At stage (1) of the reaction scheme IM 3-aminoquinolin-4-ol of the formula XM reacts with an adihal of the formula K"C(O)4, in which K o" is as defined above and 7 is chlorine or bromine, as a result of which is formed with M-(4-hydroxyquinolin-3-yl)iamide of the formula HMI. The reaction can be carried out by controlled addition of 2) acyl halide (for example, dropwise) to a solution or suspension of a compound of formula XM in a suitable solvent, such as dichloromethane in the presence of a tertiary amine. co In stage (2) of the reaction scheme IM M-(4-hydroxyquinolin-3-yl)lamide of the formula XM! reacts with phosphorus pentasulfide to obtain thiazolo|4,5-s|yquinoline of the formula KhMiII. The reaction can be carried out by adding phosphorus pentasulfide to a solution or suspension of a compound of formula HMI in a suitable solvent such as pyridine and heating the resulting mixture.

Stages (3) and (4) of Reaction scheme IM can be carried out similarly to stages (2) and (3) of Reaction scheme II, respectively, obtaining thiazolo|4,5-c|quinoline-5M-oxide of the formula XM, which is an analogue formulas I and

F) thiazolo|4,5-c|quinolin-4-amine of formula IM, which is an analogue of formula I, respectively. name) 60 b5

The reaction scheme of MI (c) had M

МН и 2 M са M х ги ноя о -. | in» s Za z 5 on on

And: In K

ХУ ХМ ХУП

()

MN

0. I

M -- M

M M

In in (0 | U-th

From 5 x 5

In Vt M Khush

Substituents in the 2-position can be introduced by the reaction of the compound of formula XIX:

M i »-sv,

B V

20 B. xx in which Ku is oxygen or sulfur and K is as above, with a lithiation agent such as lithium diisopropylamide or n-butyllithium in a polar aprotic solvent to give a compound with a lithiated methyl group in the 2-position. The lithiated compound can react with an acceptable reagent containing a leaving group capable of replacing lithium in the methyl group in the 2 position. Examples of suitable reagents are He) halides such as methyl iodide or chloromethyl methyl ether, aldehydes such as benzaldehyde and ketones such as acetone. The compounds can be oxidized and aminated using the methods described above to give compounds of formula 111 or M. Some compounds of formula | can be obtained directly from other compounds of formula I. For example, nitration of 2-propylthiazolo|4,5-c|quinoline-4-amine gives 8-nitro-2-propylthiazolo|4,5-c|quinoline-4-amine and ( g) reduction of the nitro compound leads to the production of 2-propylthiazolo|4,5-c|quinoline-4,8-diamine. co

Pharmaceutical compositions and biological activity

The pharmaceutical compositions of the invention contain a therapeutically effective amount of the compound of formula (a) together with a pharmaceutically acceptable carrier. with

The term "therapeutically effective amount" as used herein means an amount of a compound capable of producing a desired therapeutic effect, such as cytokine biosynthesis, antitumor activity, and/or antiviral activity. Although the exact amount of a compound used in a pharmaceutical composition of the invention will vary according to factors known to one skilled in the art, such as the physical and chemical nature of the compound, as well as the nature of the carrier, the intended dosage regimen, and the condition to be treated, it provides , that from the composition of the invention will contain a sufficient amount of the active ingredient to obtain doses that lie in the interval from about 100ng/kg to about 5Omg/kg, preferably from about 1Okg/kg to about 5mg/kg: of the compound. Any commonly known dosage forms can be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, mucosal patches, and the like. Dosage forms will also depend on the characteristics of the compound being prescribed. b For example, some compounds of formula (a), especially those in which K. is sulfur, tend to have relatively low oral bioavailability and are easily absorbed when injected into the blood. Such properties make such compounds (ee) particularly suitable for the treatment of conditions where local administration of compounds with immunomodulatory properties is desirable, such as asthma, basal cell carcinoma, cervical intraepithelial neoplasia, etc.

Compounds of the invention show stimulation of the production of certain cytokines in experimental (ee) studies according to the Test Method shown below. These results showed that the compounds are

HT" that when used as immune response modifiers can modulate the immune response in several different ways, making them useful for use in the treatment of a variety of diseases.

Cytokines, the biosynthesis of which is stimulated by the appointment of the compounds according to the invention are mainly α-interferon (o-IFN) and/or o-tumor growth factor (0-FRP), as well as some interleukins (IL). Cytokines whose biosynthesis can be stimulated by the compounds of the invention include o-IFN, o-FRP, IL-1, 6, 10 and 12, and (F) various other cytokines. Among other effects, cytokines inhibit the production of viruses and the growth of malignant ones

GI cells, which makes possible the use of compounds in the treatment of malignant formations and viral diseases.

In addition to the ability to stimulate the production of cytokines, the compounds of the invention show their activity in other aspects of the natural immune response. For example, the activity of natural killer cells can be stimulated, leading to the corresponding cytokine induction. The compounds can also activate macrophages, which in turn stimulate the secretion of nitric oxide and the production of additional amounts of cytokines. Further, the compounds can induce the proliferation and differentiation of B-lymphocytes and can be used to stimulate the maturation of dental cells. 65 The compounds of the invention also have efficacy prior to the acquisition of an immune response. For example, although it is not believed that the target compounds either directly act on T cells or that cytokines directly stimulate T cells,

the production of T helper type 1 (TA1) cytokine y-IFN is directly stimulated and the production of T helper type 2 (TA2) cytokines IL-4, IL-5 and IL-13 is inhibited when the compounds are administered. This activity means that the compounds are used in the treatment of diseases where increased regulation of the TN1 response and/or is desired

Decreased regulation of TN2 response. In view of the ability of the compounds of formula Ia to inhibit the TN2 immune response, the compounds can be used in the treatment of atopies, for example, atopic dermatitis, asthma, allergies, allergic rhinitis and systemic lupus erythematosus; as an auxiliary vaccine to increase cell-mediated immunity; and possibly for the treatment of recurrent fungal diseases and chlamydia.

The effects of modifying the immune response of the compounds can be used to treat a wide range of diseases. Because they are able to stimulate cytokines such as o-IFN and/or o-FRP, the compounds are particularly useful for the treatment of viral diseases and neoplasms. This immunomodulatory activity means that the compounds of the invention are useful in the treatment of diseases such as, but not limited to, viral diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis

C, herpes simplex type | and type II, molluscum contagiosum, HIV, CMV, HPV, cervical intraepithelial 75 neoplasia, human papillomavirus and related neoplasia; fungal diseases, for example, Candida, aspergillus, cryptococcal meningitis; neoplastic diseases, for example, basal cell carcinoma, advanced cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma and other cancers; parasitic diseases, for example, pneumocystosis, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosomiasis, leishmaniasis; and bacterial infections, for example, tuberculosis, avian tuberculosis. Additional diseases and conditions that may be treated using the compounds of the invention include eczema, eosinophilia, primary thrombocythemia, leprosy, multiple sclerosis, Ommen syndrome, rheumatoid arthritis, systemic lupus erythematosus, discoid lupus, Bowen's disease, papular

Bowenoids and strengthening and stimulation of wound healing, including chronic wounds. Ha

Accordingly, the invention provides a method of stimulating cytokine biosynthesis in animals, which consists in administering to the animal an effective amount of the compound of formula Ia. An amount of a compound effective for stimulating the biosynthesis of i) a cytokine is an amount sufficient to produce one or more types of cells, such as monocytes, macrophages, dendritic cells and B cells, an amount that increases the level of one or more cytokines, such such as, for example, o-IFN, o-FRP, IL-1, 6, 10 and 12 compared to the usual level of such "I cytokines. The amount determined will vary depending on factors known in the art, but doses of from about 100ng/kg to about 5mg/kg, preferably from about 1mg/kg to about 5mg/kg, are expected. The invention also provides a method of treating viral infections in animals, which consists in administering to the animal an effective amount of the compound of formula Ia. An amount effective to treat or inhibit viral infection is an amount sufficient to reduce one or more manifestations of viral infection, such as viral damage, viral burden, viral production rate, and mortality, as compared to (Ce) untreated control animals . The amount determined will vary depending on factors known in the art, but doses of from about 100 ng/kg to about 5 ug/kg, preferably from about 1 ug/kg to about 5 mg/kg, are expected. "

Compounds of the invention may be administered to a subject as a single therapeutic agent, or 470 may be formulated as a combination with one or more other agents. Examples of suitable agents that may be used in combination with immune response modifying compounds include, but are not limited to, analgesics, antibacterials, anti-inflammatory agents, antitumor agents, antiviral agents, bronchodilators, narcotics, and steroids.

The following examples illustrate the invention, but should not be construed as limiting it.

EXAMPLES

Ge) Example 1 2-Methylthiazolo|4,5-cYquinoline-5M-oxide (ee) bo o sh | and "with"

Part A

A suspension of 3-aminoquinoline-4-thiol (approximately 12g) in a mixture of acetic anhydride (150ml) and acetic acid 59 (300ml) was heated under reflux overnight. The reaction mixture was filtered off

GF) finely dispersed solid substance. The filtrate was evaporated under vacuum. The residue was diluted with ethanol and then boiled for 30 minutes. The solution was concentrated under vacuum and the residue was diluted with water. The aqueous residue was basified using sodium hydroxide and then extracted with diethyl ether. The ether extracts were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated to obtain 12.8 g of crude product. The sample (800 mg) was recrystallized from hexane to obtain 2-methylthiazolo|4,5-c|quinoline in the form of a yellow residue, mp. 95.5-97.57C. Analysis: calculated for C 44NaMeoz: 900,65,97; 9oH, 4.03; 90M, 13.99; found: 90, 65,96; 95Н, 4.16; 95M, 14.08.

Part B 2-Methylthiazolo|4,5-c|quinoline, (5.0g, 25mmol), 3-chloroperbenzoic acid (9.5g 50-6095) and dichloromethane bo (1500ml) were combined and stirred at room temperature for C hours The reaction solution was diluted with dichloromethane (ZOO ml) and then extracted with aqueous sodium carbonate solution to remove acids. The organic layer was washed with water, diluted with ethyl acetate to remove the turbidity, dried over magnesium sulfate and then concentrated under vacuum to obtain 4.5 g of crude product. A small portion was recrystallized from methanol to give a yellow residue of 2-methylthiazolo|4,5-c|quinoline-5M-oxide hydrate, mp. 150-1607C. Analysis:

Calculated for С.44Ni8М2О50.75Н20: 902, 57.50; 9оН, 4.17; 90M, 12.19; Found: 90, 57,58; 9oH, 4.10; 95M, 11.93.

Example 2 2-Methylthiazolo|4,5-c)quinolin-4-amine 170 МН; x IZ

Zach | y t 2-Methylthiazoloi|4,5-c|quinoline-5M-oxide (1.5 g, b, ummol) was added to a mixture of dichloromethane (10 ml) and ammonium hydroxide (25 ml). With vigorous stirring, a solution of tosyl chloride (2.0 g, 10.4 mmol) in dichloromethane (1 mL) was added to the reaction mixture. The reaction mixture was refluxed with the addition of dichloromethane and ammonium hydroxide until TLC showed that the reaction was complete. Dichloromethane was distilled from the mixture and the yellow product was filtered from the aqueous residue. The solid was washed with water and then dried to give 1.2 g of crude product. The solid was dissolved in dilute hydrochloric acid. The solution was triturated with charcoal and then filtered. The filtrate was basified with dilute sodium hydroxide. The resulting residue was separated by filtration, washed with water, dried and then recrystallized from a mixture of methanol/dichloromethane to obtain 0.46 g of 2-methylthiazolo|4,5-c|quinoline-4-amine in the form of a white powder, Tpl. 184-1877"S. Analysis: Calculated for sch

C11NoMz: dos, 61.37; UoN, 4.21; 95M, 19.52; Found: 95C, 61.32; 95Н, 4.52; 90M, 19.68. Go)

Example C 2-Methylthiazolo|4,5-s|quinolin-4-amine Alternative synthesis

Trichloroacetyl isocyanate (2.0 mL, 16.6 mmol) was added to a suspension of 2-methylthiazolo|4,5-s)|quinoline-5M-oxide (3.03 g, 14.0 mmol) in dichloromethane (150 mL). With 3o The reaction mixture was stirred at room temperature for about 50 minutes. Dichloromethane (ee) was concentrated under vacuum to give crude M-(2-methylthiazolo|4,5-c)quinolin-4-yl)utrichloroacetamide. The amide was dissolved in methanol and then sodium methoxide (2595 mL of sodium methoxide in methanol) was added. The reaction mixture was boiled for 40 minutes, then the methanol was evaporated under vacuum. The resulting brown solid (se) was washed with water and dried to give 2.85 g of crude product. This material was triturated with charcoal and then recrystallized from ethyl acetate to give 2-methylthiazolo|4,5-c|quinolin-4-amine as a solid, and

Tpl. 184-186С2С. Analysis: Calculated for C44NoMaz: 95, 61.37; 9оН, 4.21; 90M, 19.52; Found: 90, 61.48; 9оН, 4.17; oh, 19.60.

Example 4 « 20 2-Methylthiazoloi|4,5-s|quinoline-4-amine hydrochloride sh-v

Concentrated hydrochloric acid (0.2 ml 12.1 M) was added to a solution of 2-methylthiazolo|4,5-c)quinolin-4-amine c (0.5 g) in methanol (1 bml). Isopropanol (1 bml) was added and the reaction mixture was then heated to reflux removing most of the methanol. The resulting residue was separated by filtration, washed with isopropanol and dried to obtain 2-methylthiazolo|4,5-c|quinoline-4-amine hydrochloride as a solid, mp. 323-3257"С. Analysis: Calculated for SpNoM zone: boss, 52.48; 90Н, 4.00; 90М, 16.69;

FO Found: 90, 52.46; 9oH, 4.08; 95M, 16.52.

Example 5 (ee) Thiazolo[4,5-c)quinoline-4-amine hydrochloride hydrate o Part A 3-Aminoquinoline-2-thiol (approximately 18.5g) was added to triethyl orthoformate (26.0ml). The reaction mixture was heated on a steam bath for 20 minutes. Formic acid (400 Oml) was added and the reaction mixture was heated

T" under reflux overnight. The main mass of formic acid was evaporated under vacuum. The residue was combined with ethanol and boiled for 30 minutes. Ethanol was evaporated under vacuum. The residue was suspended in water and then basified by adding sodium hydroxide. A precipitate was formed.

The solid was extracted with several portions of dichloromethane. The extracts were combined, dried over magnesium sulfate, and then concentrated to obtain a yellow solid, which was recrystallized from hexane (F) to obtain 13.1 g of thiazolo|4.5-s)|quinoline in the form of a yellow crystalline substance, mp. 104-106".

GI Part B

Peracetic acid (2 mL of 3295 in acetic acid, 100 mmol) was added to a suspension of thiazolo|4,5-c|quinoline (12.5 g, b7 mmol) in methyl acetate (30 mL). The reaction mixture was heated under reflux overnight and then cooled to room temperature. The precipitate was separated by filtration and then suspended in water (100 mL). An aqueous solution of sodium bicarbonate (10 Oml) was added to the suspension and the mixture was stirred for an hour. The solid substance of thiazolo|4,5-quinoline-5M-oxide was separated by filtration, washed with water and dried. 65 Part B

Trichloroacetyl isocyanate (0.72 ml, b,Omol) was added to a suspension of thiazolo|4,5-c|quinoline-5M-oxide (1.10 Hg,

5.A4 mmol) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 45 minutes and then the dichloromethane was evaporated under vacuum to give crude

M-(thiazolo|4,5-c|quinolin-4-yl)utrichloroacetamide. The amide was combined with 2M ammonia in methanol and stirred at room temperature for 2 hours. Methanol was evaporated under vacuum. The residue was suspended in water, combined with sodium carbonate and then stirred for 10 minutes. The brown solid was collected, washed with water and dried. The solid substance was suspended in water, hydrochloric acid (1O0Oml bM) was added and the mixture was heated on a steam bath. The mixture was filtered, then the filtrate was left to cool slowly to room temperature. The obtained residue was separated by filtration and then dried to obtain 0.75 g of 7/0 Brown residue. This material was dissolved in water (1O0Oml) under heating. Coal was added and the mixture was heated with stirring for 5 minutes. The mixture was filtered through a layer of Celite. The filtrate was heated on a steam bath to remove most of the water and then allowed to cool to room temperature. The precipitate was separated by filtration and dried to obtain 0.30 g of thiazolo|4,5-s|quinolin-4-amine hydrochloride hydrate in the form of white crystals, Tpl. 284-2857S. Analysis: Calculated for C 1087M3ZONSIPNO: 95С, 46.97; 95Н, 3.94; Ohm, 16.43; Found: 90, 46,96; 95Н, 3.99; 95M, 16.34.

Example 6

Thiazoloi|4,5-c) quinoline-4-amine

MN

- M her » y: 5

Part A Gee!

Thiazoloi|4,5-c|quinoline-2-thiol (8.7 g, 0.04 mol) was suspended in a solution of sodium hydroxide (1.4 g, 0.04 mol) in water. A few drops of 5095 sodium hydroxide were added to the suspension until most of the solid matter was dissolved. Hydrogen peroxide (13.5 ml 3095, 000.08 mol) was added dropwise within 30 minutes, maintaining the temperature of the reaction mixture in the range of 25-35"C using a cold water bath. The bath was removed and the reaction mixture was stirred for 15 minutes. Dropwise to the reaction mixture sulfuric acid (2.5 g 95.9890) was added to the mixture. After 30 minutes, the reaction mixture was basified (pH0-9.5) with sodium hydroxide 50905. The reaction mixture was acidified (pH2.5) with hydrochloric acid, while a yellow-brown solid substance was formed . The mixture was then heated on a steam bath for 15 minutes and the precipitate dissolved. The solution was allowed to cool to room temperature and a precipitate formed. The mixtures were basified (pHO) 5095 with sodium hydroxide. The resulting oily product was extracted with ethyl acetate. The extracts were combined, washed with brine, and dried over magnesium sulfate and then concentrated under vacuum to obtain 3.3g of thiazolo|4.5-s|quinolinui «0 in the form of a yellow-brown solid, mp 104.4-1057 C. Analysis: Calculated for S.oneMe»z: dos, 64.19;

BACKGROUND, 3.25; 95M, 15.04; Found: 95, 64.15; 9оН, 3.26; 9oM, 14.9.

Part B «

Peracetic acid (4.7 ml 3295) was added to a solution of thiazolo|4,5-cIquinoline (2.8 g) in methyl acetate. A precipitate formed after a few minutes. The reaction mixture was heated to boiling and then diluted by adding 1Oml - s of methyl acetate. Most of the sediment dissolved. After 1 hour, another 3.0 ml of peracetic acid was added. and The reaction mixture was heated overnight and then allowed to cool to room temperature. ,» Methyl acetate and acetic acid were azeotroped from heptane. The resulting oily product was suspended in water.

The mixture was basified with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water, dried over magnesium sulfate, and then concentrated under vacuum (o) to give 0.6 bg of thiazolo|4,5-c|quinoline-5M-oxide as an orange solid, mp. 178.4"C (difference).

Part B (ee). . at

A solution of tosyl chloride (0.3 g) in water was added dropwise to a cooled (57) suspension (95) of thiazolo|4,5-c|quinoline-5M-oxide (0.3 g) in a mixture of ammonium hydroxide (5 ml) and dichloromethane ( 5 Oml). The temperature was maintained at 4-6°C during the addition. After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours. Analysis using thin-layer chromatography showed the presence of starting material. The reaction mixture was cooled and 1 equivalent of tosyl chloride was added.

The reaction mixture was stirred at room temperature for 20 hours. Dichloromethane was evaporated under vacuum. The residue was suspended in a small amount of water. The mixture was filtered. The isolated solid was washed with water, dried and then recrystallized from isopropanol to obtain 0.2 g of thiazolo|4,5-c|quinoline-4-amine as an orange powder, mp. 172.47 (distinction). Analysis: Calculated for SionNUMa3: dos, 59.68; 90N. 3.50; 95M, 20.88; Found: 95, 59,82; 95Н, 3.20; 90M, 19.50. ime) Example 7 2-Ethylthiazolo|4,5-s|quinoline-5M-oxide 5) o i | m, in so 65 Part A

Under nitrogen, 2-methylthiazolo|4,5-c|quinoline (1.0g, 10,00mmol, Example 2 or 3) was placed in a dried flask. Anhydrous tetrahydrofuran (5 Oml) was added and the reaction mixture was cooled to -787C in a dry ice bath. Lithium diisopropylamide (w/ml 1.5M in hexane, 10.00 mmol) was added dropwise. 30 minutes later, methyl iodide (0.95 mL, 15.0 mmol) was added. After 40 minutes, the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with water and then extracted with diethyl ether (25 Oml). The extract was washed with water (3 x 100 ml), dried over magnesium sulfate and then concentrated under vacuum to obtain 2.8 g of brown oil. This material was purified using high resolution rare earth chromatography and a 3:1 hexane-ethyl acetate mixture as eluent to give 1.47 g of 2-ethylthiazolo|4,5-c|quinoline as a yellow oil.

Part B 70 C-Chloroperbenzoic acid (0.44g) was added to a solution of 2-ethylthiazolo|4,5-phenol (0.53g) in chloroform (20ml). The reaction mixture was stirred at room temperature for 2 hours and then diluted with dichloromethane (20ml), washed with sodium bicarbonate, washed with water (3x100ml), dried over magnesium sulfate and then concentrated under vacuum. The obtained yellow solid was recrystallized from ethyl acetate to obtain 0.32 g of 2-ethylthiazolo|4,5-s|quinoline-OM-oxide as a solid, mp. 12870. Analysis: 75 Calculated for С42НиоМ2О: 950. 62.59 95Н, 4.38; 9oM, 12.16; Found: 90, 62.59; 90Н, 4.27; 95M, 12,12.

Example 8 2-Ethylthiazolo|4,5-s|quinoline-4-amine

MH,

M k sh | ply

Part A

Trichloroacetyl isocyanate (0.5 ml, 4.3 mmol) was added to a suspension of 2-ethylthiazolo|4,5-c|quinoline-5M-oxide ch 29 (0.90 g, 3.9 mmol) in dichloromethane (bOml). The reaction mixture was stirred at room temperature for 30. (In minutes) and then concentrated under vacuum to obtain 1.80 g

M-(2-ethylthiazoloi|4,5-c|quinolin-4-yl)utrichloroacetamide as a yellow solid.

Part B

M-(2-Ethylthiazoloi|4,5-c)quinoline-4-yl trichloroacetamide (0.40g) was suspended in a solution of ammonia in methanol C 30 (20ml 2M) and then stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was washed with water and then dried to obtain 0.19 g of the crude product, which was recrystallized from a mixture of ethyl acetate/hexane to obtain 2-ethylthiazolo|4,5-c|quinolin-4-amine as a yellow-brown residue, mp 170-1727S. Analysis: Calculated for C 412H414Ma3Z: 90, 62.85; 90Н, 4.83; 95M, at 18.32; Found: 90, 62.58; 9oH, 4.78; 90M, 18.08. 3o Example 9 ee, 2-Ethylthiazoloi|4,5-c)Yquinolin-4-amine Alternative synthesis

Part A

Propionyl anhydride (200 ml) was added to a suspension of 3-amino-quinoline-4-thiol (15 g) in propionic acid (100 ml). The reaction mixture was refluxed overnight and then filtered to remove the precipitate. The filtrate was concentrated under vacuum. The residue was taken up in dichloromethane (200 mL), washed with sodium bicarbonate, then water, and then dried over magnesium sulfate. The solution was filtered through a layer of silica gel using first a 1:1 mixture of ethylacetate texane and then ethyl acetate as eluent. The filtrate was evaporated to give 2.6 g of 2-ethylthiazolo|4,5-s|quinoline as a yellow oil.

Part B 35 Peracetic acid (7/4 ml 3295) was added to a solution of 2-ethylthiazolo|4,5-c|quinoline (5g) in ethyl acetate

F (100 ml). The reaction mixture was stirred at room temperature for 2 days. The obtained residue (oo) was separated by filtration, washed with hexane and dried to obtain 34 g of 2-ethylthiazolo|4,5-c|quinoline-5M-oxide.

Mn Part B (oo) 20 Trichloroacetyl isocyanate (b.5ml, 54mmol) was added to a suspension of 2-ethylthiazolo|4,5-c|quinoline-5M-oxide

Their (9.Og, 39.mmol) in dichloromethane (500ml). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to give crude

M-(2-Ethylthiazolo|4,5-cIquinoline-4-yl-trichloroacetamide. This material was added to a solution of ammonia in methanol (Bbbml 2M) and stirred at room temperature for about 2 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in dichloromethane, washed with sodium bicarbonate (2x15Oml)

HF) was then dried over magnesium sulfate with water (33x150 ml) and then concentrated under vacuum. Remainder

HF was recrystallized from 1,2-dichloroethane to obtain a yellow-brown residue. This material was suspended in water, one equivalent of concentrated hydrochloric acid was added, and the mixture was heated until the solid dissolved. The solution was triturated with charcoal and then filtered. The filtrate was cooled and then alkalized with sodium carbonate. The obtained residue was separated by filtration, washed with water and then recrystallized from 1,2-dichloroethane to obtain 2-ethylthiazolo|4,5-c)quinolin-4-amine as a yellow residue,

Tpl. 169-1717S. Analysis: Calculated for SiONi4Maz: 95, 62.85; 95Н, 4.83; 9oM, 18.32; Found: 90, 62.79; 9oH, 4.86; 9oM, 18.22. b Example 10 2-Ethylthiazolo|4,5-s|quinoline-4-amine hydrochloride

Concentrated hydrochloric acid (18.5 mmol) was added to a solution of 2-ethylthiazolo|4,5-c)quinolin-4-amine (4.25 g) in hot isopropanol. The reaction mixture was heated under reflux until the volume decreased and water was released. The reaction mixture was cooled to room temperature. The precipitate was separated by filtration and then dried to give 2-ethylthiazolo|4,5-cIquinolin-4-amine hydrochloride as a solid, mp. 268-27070. Analysis: Calculated for С42НпМ3ЗО NS: 95, 54.23; 9oH, 4.55; 95M, 15.81; Found: 95C, 54.25; 9oH, 4.63; house, 15.71.

Example 11 2-Propylthiazolo|4,5-s|quinoline-5M-oxide still dk IM b rr yez 5 -dy

Part A

We used the general method of Example 7 Part A, 2-methylthiazolo|4,5-s|quinoline (2.50g, 12.5mMmol) reacted first Kk! lithium diisopropylamide and then Kk! with ethyl iodide, obtaining 0.28 g of 2-propylthiazolo|4,5-s|quinoline in the form of a yellow crystalline substance, Tpl. 547C. Analysis: Calculated for

Si3Nl12M": 90, 68.39; 9oH, 5.30; 95M, 12.27; Found: 90, 68,41; 9oH, 5.19; 90M, 12.31.

Part B

The general method of Example 7 Part B was used, 2-propylthiazolo|4,5-phenol (1.05g, 4.bmmol) was oxidized with 3-chloroperbenzoic acid to obtain 0.65g of 2-propylthiazolo|4,5-s|quinoline-5M-oxide in the form of a yellow solid, Tpl. 12370. Analysis: Calculated for С413Н42М2О5: 90, 63.91; 99H, 4.95; 90M, 11.47;

Found: 90, 63.53; 9oH, 4.88; 95M, 11.44. see

Example 12 about 2-Propylthiazolo|4,5-c)quinoline-4-amine

M sleigh to | yes With 5 so

The general procedure of Example 8 was used, 2-propylthiazolo|4,5-c|quinoline-5M-oxide (0.63g) was reacted with trichloroacetylisocyanate and the resulting intermediate amide was hydrolyzed using a solution of ammonia in methanol, obtaining 0.22g of 2-propylthiazolo|4 ,5-c|quinolin-4-amine in the form of white crystals, Tpl. 140-14276.

Analysis: Calculated for C44H413Ma35: 95, 64.17; 9oH, 5.38; 9oM, 17.27; Found: 90, 64,31; 9oH, 5.39; 90M, 17.13. oh

Example 13 2-Propylthiazolo|4,5-c)quinoline-4-amine

Alternative Synthesis Using the general procedure of Example 9 Part A, a suspension of 3-aminoquinoline-4-thiol (15g) in butanoic acid was reacted with butanoic anhydride to give 2-propylthiazolo|4,5-c|quinoline. in the form of yellow oil. :z» Part B

The general method of Example 9 Part B was used, 2-propylthiazolo|4,5-phenol (46g) was oxidized with peracetic acid to obtain 2-propylthiazolo|4,5-c|quinoline-5M-oxide in the form of a yellow crystalline substance. b 15 Part B

Ammonium hydroxide (50ml) was added to a solution of 2-propylthiazolo|4,5-s|quinoline-5M-oxide (20g) in chloroform (ee) (500ml). The reaction mixture was cooled in an ice bath and then a solution of tosyl chloride (16 g) in chloroform was added dropwise. The reaction mixture was refluxed for 2 hours and then diluted with chloroform and water. The layers were separated. The organic layer was washed with an aqueous solution of sodium bicarbonate, (ee) 50 was dried over magnesium sulfate and then concentrated under vacuum. The residue was recrystallized from

HT» of 1,2-dichloroethane, obtaining 2-propylthiazolo|4,5-s|quinolin-4-amine in the form of a yellow-brown solid,

Tpl. 140-1427S. Analysis: Calculated for С13Н.3М3: 90, 64.17; 9oH, 5.38; 95M, 17.27; Found: 95C, 64.10; he, 5.47; 9oM, 17.29.

Example 14 2-Propylthiazolo|4,5-c)|quinoline-4-amine hydrochloride

GF) The general method of Example 10 was used, 2-propylthiazolo|4,5-c|quinolin-4-amine (1.75 g) was subjected to 7 reactions with 1 equivalent of concentrated hydrochloric acid, obtaining 2-propylthiazolo|4,5-c|quinoline- 4-amine hydrochloride in the form of an almost white crystalline substance, Tpl. 234-2377"S. Analysis: Calculated for

SizNizM3ZO NOI: 95, 55,81; 9oH, 5.04; 90M, 15.02; Found: 90, 55,86; 9oH, 5.02; 95M, 14.99. Example 15 2-Pentylthiazolo|4,5-s|quinoline-5M-oxide and uoiate of 65 g

Part A

Using the general procedure of Example 7, Part A, 2-methylthiazolo|4,5-phenol (2.0 g, 1 mmol) was reacted first with lithium diisopropylamide (5.bml 2M in benzene) and then with 1-iodobutane (1.vml) to give 1.1 g of 2-pentylthiazolo|4,5-c)quinoline in the form of a yellow solid, Tpl. 62-6476.

Part B

Peracetic acid (1.50ml of 32905 in acetic acid) was added to a suspension of 2-pentylthiazolo|4,5-c|quinoline (125g) in methyl acetate (5bOml). The reaction mixture was boiled for two hours. The reaction mixture was allowed to cool to room temperature and then diluted with dichloromethane and washed first with 7/0 sodium bicarbonate and then with water. The organic layer was dried over magnesium sulfate and then concentrated in vacuo to give 1.20 g of a pale yellow solid. This material was recrystallized from ethyl acetate to obtain 0.90 g of 2-pentylthiazolo|4,5-c|quinoline-BM-oxide in the form of white crystals, mp 142-1447S. Analysis: Calculated for Si5BNieM2O5: 95С, 66.14; 95Н, 5.92; 9oM, 10.19; Found: 90, 65,63; 9oH, 5.83; 90M, 10.28.

Example 16 2-Pentylthiazolo|4,5-s|quinoline-4-amine

M mya i

I swear to them

From 5

Trichloroacetyl isocyanate (0.5 ml) was added to a solution of 2-pentylthiazolo|4,5-c|quinoline-5M-oxide (0.78 g) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for about 75 minutes and then concentrated in vacuo to give crude

M-(2-pentylthiazolo|4,5-c|quinolin-4-yl)utrichloroacetamide. The amide was combined with a solution of ammonia in methanol (40 ml of 2M solution). Dichloromethane was added to the resulting solution. The completion of the reaction was monitored by thin-layer chromatography, the reaction mixture was concentrated under vacuum. The residue was mixed with i) dichloromethane and sodium bicarbonate. The organic layer was separated, washed with sodium bicarbonate then water, dried over magnesium sulfate and then concentrated under vacuum to give a white solid. This material was recrystallized from ethyl acetate to give 2-pentylthiazolo|4,5-c|quinolin-4-amine in the form of almost white crystals, mp 119-121 "С. Analysis: Calculated for С.5Н4и7Ма35: 95, 66.39; 90Н, 6.31; 90М, 15.48;

Found: 90, 66,21; 9oH, 6.35; 95M, 15.39. co

Example 17 c 2-Butylthiazoloi|4,5-c|quinoline-5IM-oxide o, (ge) iy | UA i-o zkh 5

Part A «

The general procedure of Example 7 was used. Part A, 2-methylthiazolo|4,5-c)quinoline (2.50 g, 12.5 mmol) was reacted first with lithium diisopropylamide (7.0 ml of 2M in benzene) and then with 1- iodopropane (Z,Og) . obtaining 1.19 g of 2-butylthiazolo|4,5-s|quinoline in the form of a yellow oil. and Part B

The general method of Example 15 Part B was used, 2-butylthiazolo|4,5-c)quinoline (1.33g) was oxidized with peracetic acid to obtain 0.5g of 2-butylthiazolo|4,5-c|quinoline-5M-oxide as a solid , Tpl. b 133-13576.

Example 18 c 2-Butylthiazolo|4,5-c|quinoline-4-amine o Her" i

M z

So Ge | photo from

The general procedure of Example 16 was used, 2-butylthiazolo|4,5-s|quinoline-5M-oxide /(0.50 g) was converted into an amide and then hydrolyzed to obtain 0.25 g of 2-butylthiazolo|4,5-s|quinoline-4 -amine in the form of a yellow crystalline substance, Tpl. 149-1517S. Analysis: Calculated for C145NibMa3e: оС, 65.34; 95Н, 5.87; 90M, at 16.33; Found: 90, 64,88; 90Н, 5.84; 90M, 16.03. име) Example 19 2-(1-Methylethyl)thiazolo|4,5-c|quinoline-5M-oxide 60 0) "ме M, и 5 и и 65 Part A

The general method of Example 7 was used. Part A, 2-methylthiazolo|4,5-phquinoline (1.50g, 7.5mmol)

was reacted first with lithium isopropylamide (15.00 ml of 2M in benzene) and then with methyl iodide (2.4 ml), obtaining 0.97 g of 2-(1-methylethyl)thiazolo|4,5-c)quinoline in the form of a yellow oil.

Part B

The general method of Example 15, Part B was used, 2-(1-methylethyl)thiazolo|4,5-s|quinoline (0.95g) was oxidized with peracetic acid, obtaining 0.84g of 2-(1-methylethyl)thiazolo|4,5-s |quinoline-5M-oxide in the form of a yellow solid, Tpl. 161-16276.

Example 20 2-(1-Methylethyl)thiazolo|4,5-c|quinolin-4-amine 76 ME; and: 5

Using the general procedure of Example 16, 2-(1-methylethyl)thiazolo|4,5-c|quinoline-bM-oxide (0.84 g) was converted into an amide and then hydrolyzed to obtain 0.16 g of 2-(1-methylethyl)thiazolo| 4,5-s|quinoline-4-amine in the form of a yellow residue, Tpl. 163-1657S. Analysis: Calculated for С43Н43Ма35: 90, 64.17; UoN, 5.38; 90M, 17.27;

Found: 90, 63.49: 90Н, 5.36; 95M, 17.09.

Example 21 2-(2-Phenyl-1-ethenyl)thiazolo|4,5-s|quinoline-5M-oxide i schu zyd s r o

Part A

Using the general procedure of Example 7, Part A, 2-methylthiazolo|4,5-c|quinoline (5.0g, 25mmol) was reacted first with lithium diisopropylamide (15.0ml of 2M in benzene) and then with benzaldehyde (3.vml) g zo obtaining 5,Zg 1-phenyl-2-thiazolo|4,5-s|)quinolin-2-yl-1-ethanol in the form of a solid substance, Tpl. 147-1487S.

Part B so

Concentrated hydrochloric acid was added dropwise to a suspension of 1-phenyl-2-thiazolo|4,5-c|quinolin-2-yl-1-ethanol (2.16g) in water (400ml) until all solids were dissolved.

The reaction mixture was heated on a steam bath during the addition, heating continued until TLC showed that all starting materials had reacted. The reaction mixture was allowed to cool to room temperature and a precipitate formed. The reaction mixture was neutralized with sodium carbonate. Dichloromethane was added and stirred until all the precipitate was dissolved. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, dried over magnesium sulfate and then concentrated under vacuum to give 2.2 g of a green solid. This material was recrystallized from ethyl acetate to give 1.55 g of 2-(2-phenyl-1-ethenyl)thiazolo|4,5-c|quinoline as green crystals. Analysis: with c Calculated for: Si8H41oM»z: 90, 74.97; UoN, 4.19; 90M, 9.71; Found: 90, 74.89; 90Н, 4.17; 95M, 9.72.

Part B; » Peracetic acid (1.32ml of 3290 in acetic acid) was added to a suspension of 2-(2-phenyl-1-ethenyl)thiazolo|4,5-c)quinoline (1.20g) in methyl acetate (50ml). A precipitate was formed.

Ethanol was added to the reaction mixture until all the precipitate was dissolved. The reaction mixture was heated with reflux

Ge" in the refrigerator overnight and then cooled to room temperature. The resulting residue was separated by filtration, dried, and then recrystallized from a mixture of methanol/dichloromethane to give 2-(2-phenyl-1-ethenyl)thiazolo|4,5-c|quinoline-5M-oxide as a yellow solid, mp. 268-270". Analysis:

Ha Calculated for: С43Н12М2О5: 90, 71.03; 90Н, 3.97; 95M, 9.20; Found: 95C, 69.94; 9oH, 3.87; 9oM, 9.05.

Example 22 c 2-(2-Phenyl-1-ethenyl)thiazolo|4,5-c)quinolin-4-amine i» h dn M bu z 5 o The general method of Example 16 was used, 2-(2-phenyl-1 -ethenyl)thiazolo|4,5-s|quinoline-5M-oxide (0.67g) ime) was converted into trichloroacetamide, then hydrolyzed to obtain 0.43g of 2-(2-phenyl-1-ethenyl)thiazolo|4,5-s |quinolin-4-amine in the form of a yellow crystalline substance, Tpl. 239-24G6. 60 Analysis: Calculated for C/8H4izMa35: 95, 71.26; 9oH, 4.32; 9oM, 13.85; Found: 90C, 70.73; 9oH, 4.15; 95M, 13.68.

Example 23 2-(2-Phenyl-1-ethyl)thiazoloi|4,5-s|quinoline-oM-oxide b5 what. M, y 5 -zh3X »

Part A

A small amount of catalyst (596 palladium on activated carbon) was added to a suspension of 2-(2-phenyl-1-ethenyl)thiazolo|4,5-siquinoline (1.1b6g, Example 21 Part B) in acetic acid (200ml). Mixtures 70 were regenerated in a Parr apparatus at a hydrogen pressure of 50 psi (3.5 kg/cm?) for 1 day. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, washed with sodium bicarbonate, then with water, dried over magnesium sulfate, and then concentrated under vacuum to obtain 0.8 g of 2-(2-phenyl-1-ethyl)thiazoloin|4,5-siquinoline in the form of an oily solid.

Part B

The general method of Example 15 was used, Part B, 2-phenylethylthiazolo|4,5-s|quinoline (0.90 OHg) was oxidized with peracetic acid to obtain 0.6g of 2-(2-phenyl-1-ethyl)thiazolo|4,5-s| quinoline-5M-oxide in the form of orange crystals, Tpl. 165-16970. Analysis: Calculated for С.8Н.иМ2О5: 90, 70.56; 90Н, 4.60; Fo!chCh, 9.14;

Found: 90, 69.59; 95Н, 4.50; 95M, 9.04.

Example 24 2-(2-Phenyl-1-ethyl)thiazolo|4,5-c|quinolin-4-amine

MN" in: y - va - sch o

The general method of Example 16 was used, 2-(2-phenyl-1-ethyl)thiazolo|4,5-c|quinoline-5M-oxide (0.63 g) was converted into trichloroacetamide, then hydrolyzed to obtain 0.21 g of 2-(2-phenyl -1-ethyl)thiazolo|4,5-s|quinolin-4-amine in the form of a yellow crystalline substance, Tpl. 158-15976. Analysis: Calculated for Su8NiBIM5: 90, 70.79; 9oH, 4.95; 9o0M, 13.75; Found: 900. 70.29; 9oH, 4.90; 95M, 13.66.

Example 25 with 2-Methyl-1-(thiazolo|4,5-c|quinolin-2-yl)-2-propanol-5M-oxide co (c) zh k (he) z ke He;

Part A «

Under argon, anhydrous tetrahydrofuran (150 mL) was added to a dry flask containing 2-methylthiazolo|4,5-c|quinoline (8.40 g). The reaction mixture was cooled to -78°C in a dry ice bath. Lithium diisopropylamide (2 mL of 2.0 M in benzene) was added dropwise. After approximately 50 minutes, acetone (5 mL) was added and the reaction mixture was allowed to warm to 0°C. WITH. After a few hours, the reaction mixture was quenched with water, diluted with chloroform and then washed with water. The organic layer was dried over magnesium sulfate and then concentrated under vacuum. The residue was suspended in water (2000 ml) and the mixture was heated. Hydrochloric acid (6M) was slowly added until the entire solid the substance did not dissolve. Charcoal was added and the mixture was heated at

Ge") with stirring for about 5 minutes. The mixture was filtered to remove carbon. The filtrate was neutralized with sodium carbonate and then extracted with chloroform. The chloroform extract was washed several times with water, dried over magnesium sulfate, and then concentrated under vacuum to obtain 8.0 g of a light brown solid. This material was recrystallized from a mixture of dichloromethane/hexane to obtain 5.0 g of 2-methyl-1-(thiazolo|4,5-c|quinolin-2-yl)-2-propanol in the form of a yellow crystalline substance, Tpl. 155-15770. bo Analysis: Calculated for C 45Н414М2О5: 90, 65.08; 90Н, 5.46; 90M, 10.84; Found: 95C, 64.97; 90Н, 5.33; 9oM, "from" 10.90.

Part B

Peracetic acid (4 vml 3290 in acetic acid) was added to a suspension of 2-Methyl-1-(thiazolo[4,5-c)quinolin-2-yl)-2-propanol (3.0g) in methyl acetate (200ml). The reaction mixture was refluxed overnight, cooled to room temperature, and then concentrated under

F, vacuum. The residue was dissolved in dichloromethane and then combined with sodium bicarbonate and intensively stirred. The resulting residue was separated by filtration and then dissolved in a mixture of methanol/dichloromethane. This solution was concentrated under vacuum. The residue was combined with dichloromethane and then filtered to remove undissolved material. The filtrate was concentrated under vacuum to obtain 2.6 bg of the desired M-oxide. A small portion (0.2 g) was recrystallized from a methanol/water mixture to obtain 2-methyl-1-(thiazolo|4,5-c|quinolin-2-yl)-2-propanol-5M-oxide as a solid, mp. 187-18976.

Analysis: Calculated for С45Н14М2025011/3Н250: 90, 59.98; 9оН, 5.27; 90M, 9.99; Found: 90, 60.09; 9oH, 5.03; home, 10.00. 65 Example 26 2-(4-Aminothiazolo|4,5-c|quinolin-2-yl)-1,1-dimethylethyl carbamate

MN;

M xx 5 o y

Trichloroacetyl isocyanate (3.2 ml) was added to a solution of 2-methyl-1-(thiazolo|4,5-c|quinolin-2-yl)-2-propanol-5M-oxide (2.4 g) in dichloromethane (250 ml). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue 70 was stirred with a solution of ammonia in methanol (15O0ml 2M) for 2 hours. Methanol was removed under vacuum.

The residue was suspended in a mixture of dichloromethane and ethyl acetate and then washed with sodium bicarbonate.

The undissolved material was separated by filtration, washed with water, washed with dichloromethane and then recrystallized from a methanol/dichloromethane mixture to give 1.6 g of 2-(4-aminothiazolo|4,5-c|quinolin-2-yl)-1,1-dimethylethyl carbamate in in the form of a solid substance, Tpl. 222-22376. 72 Analysis: Calculated for Si5BNIiveMiO: 96, 56.94; 90Н, 5.09; 90M, 17.70; Found: 90, 56,71; 9oH, 5.08; 95M, 17.52.

Example 27 2-(Ethoxymethyl)thiazolo|4,5-s|quinoline-5M-oxide o vuva M ; She and

Part A ch 29 Ethoxyacetyl chloride (bml, 53.8mmol) was added to a suspension of 3-aminoquinoline-4-thiol (4.6g, 26.1mmol) in Ge)ethoxyacetic acid (50ml). The reaction mixture was heated at 60°C overnight. The reaction mixture was concentrated under vacuum by removing a portion of ethoxyacetic acid. The residue was combined with water (100 mL) and a precipitate formed. The mixture was basified with 5095 sodium hydroxide. The precipitate was filtered off, washed with water and then dried to give 2 -(ethoxymethyl)thiazolo|4,5-s|quinoline as a loose green solid.

Part B (he)

Peracetic acid (1.0 mL of 32905 in acetic acid) was added to a solution of 2-(ethoxymethyl)thiazolo|4,5-c|quinoline (1.0 g) in ethanol. The reaction mixture was stirred at room temperature for 1 week. The reaction mixture was concentrated under vacuum and then azeotroped from heptane to remove acetic acid. The residue was dissolved in (se) dichloromethane, washed with sodium bicarbonate, washed with water, dried over magnesium sulfate and then concentrated under vacuum. The residue was recrystallized by Kk! isopropanol, obtaining 2-(ethoxymethyl)thiazolo|4,5-s|quinoline-5M-oxide in the form of a yellow crystalline substance, Tpl. 138-1407S. Analysis:

Calculated for С43Н12М2О»25: 90, 59.98; 90Н, 4.65; 9oM, 10.76; Found: 90, 59.85; 9UoN, 4.66; 90M, 10.71.

Example 28 " du 2 Ethoxymethyl)hiazolo5-sequinolin-1-amine with C Hr

15 Trichloroacetyl isocyanate (0.7 ml) was added to a solution of 2-(ethoxymethyl)thiazolo|4,5-c|quinoline-2M-oxide (1.0 g) in dichloromethane (5 g). The reaction mixture was stirred at room temperature for 2 hours and then (ee) concentrated under vacuum to give M-(2-(ethoxymethyl)thiazolo|4,5-c)quinolin-4-yl)utrichloroacetamide. The amide was taken up in methanol and then combined with 1 equivalent of sodium methoxide. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The reaction mixture was repeated (ee) 20 a second time using 2 g of M-oxide. The products were combined and recrystallized from isopropanol to give

GT" 2,251. 2-(ethoxymethyl)thiazolo|4,5-c|quinolin-4-amine in the form of a light yellow residue, M.P. 149-151 "S. Analysis:

Calculated for SizNizM3O5: 95, 60.21; 95Н, 5.05; 9oM, 16.20; Found: 90, 59,86; 90Н, 4.97; 95M, 16,16.

Example 29 2-(Methoxymethyl)thiazolo|4,5-c|quinoline-57mM-oxide that M o 0 Mo zh 5 yu y vo Part A

Methoxyacetyl chloride (1.9ml) was added to a mixture of 3-aminoquinoline-4-thiol (2.8g) in methoxyacetic acid (15ml). The reaction mixture was heated at approximately 1407C for 1 hour and then allowed to cool to room temperature. The reaction mixture was diluted with a small amount of water, basified with 1095 sodium hydroxide and then extracted with dichloromethane (300 ml). The extract was washed with sodium bicarbonate, washed with water, dried over magnesium sulfate and then concentrated under vacuum to give the crude product as a dark oil. The oil was dissolved in dichloromethane and then transferred to a layer of silica gel. Silica gel was eluted with a mixture of 11 hexane:ethyl acetate. The eluent was concentrated under vacuum to obtain 2.3 g of 2-(methoxymethyl)thiazolo|4,5-c|quinoline as an orange solid.

Part B

The general method of Example 27 Part B was used, 2-(methoxymethyl)thiazolo|4,5-c|quinoline (1.7g) was oxidized to obtain 1.8g of 2-(methoxymethyl)thiazolo|4,5-c|quinoline-5M-oxide in the form of a yellow residue, Tpl. 151-1537S. Analysis: Calculated for C12Ni0M2O5: 90, 58.52; 95Н, 4.09; 90M, 11.37; Found: 90C, 57.95; 9BN, 3.98; 9oM, 11.3.

Example 30 70 2-(Methoxymethyl)thiazolo|4,5-c|quinolin-4-amine

MN;

And M still it

The general procedure of Example 28 was used, 2-(methoxymethyl)thiazolo|4,5-c|quinoline-bOM-oxide (1.3 g) was reacted with the formation of trichloroacetamide and then it was hydrolyzed to obtain 2-(methoxymethyl)thiazolo|4,5 -c|quinoline-4-amine in the form of a light yellow residue, Tpl. 183-18570. Analysis:

Calculated for С42Н44М5О5: 95, 58.76; 95Н, 4.52; 95M, 17.13; Found: 95, 58,69; UoN, 4.34; 95M, 17.14.

Example 31 2-(2-Methylpropyl)thiazolo|4,5-s|quinoline-5M-oxide o, z M

ИЙ | Moscow State University 5 sem o

Part A

3-Aminoquinoline-4-thiol (4.6g) was added to polyphosphoric acid (80g). Isovaleric acid (3.5 ml) was added and the reaction mixture was heated at 1407C for 2 hours. The reaction mixture was poured into a mixture of ice and water (30 ml). The mixtures were filtered through a pad of Celite to remove some insoluble materials. The filtrate was basified with 50% sodium hydroxide while the mixture was cooled with ice and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and then concentrated under vacuum to obtain an oil. Oil (U) was dissolved in dichloromethane and then placed on a layer of silica gel and eluted with a mixture of 1:1 ethyl acetate:hexane.

The eluent was concentrated under vacuum to obtain 2-(2-methylpropyl)thiazolo|4,5-c|quinoline. co

Part B "o

The general method of Example 27, Part B was used, 2-(2-methylpropyl)thiazolo|4,5-s|quinoline (5.2g) was oxidized to obtain 2.5g of 2-(2-methylpropyl)thiazolo|4,5-s|quinoline -5M-oxide in the form of a yellow solid.

Example 32 2-(2-Methylpropyl)thiazolo|4,5-c|quinolin-4-amine «

MN; with c и " И | or и? C 5 (o) The general method of Example 28 was used, 2-(2-methylpropyl)thiazolo|4,5-c)|quinoline-5M-oxide (2.5Hg) was subjected to a reaction with the formation of trichloroacetamide and then hydrolyzed to give 2-(2-methylpropyl)thiazolo|4,5-c|quinolin-4-amine as light yellow plates, mp 123-12570.Analysis: (95) Calculated for C.44Ni5Ma3: 90, 65.34; 9oH, 5.87; 90M, 16.33; Found: 95, 64.87; 95H, 5.79; 9oM, 16.18. so 50 Example 33 2-Benzylthiazolo|4,5-s| quinoline-OMmM-oxide chz" that M, and 5 0 - (F, Part A ka Thionyl chloride (1.5g) was added dropwise to a cooled solution of phenylacetic acid (2g) in dichloromethane (1Oml). This mixture was left to stir at room temperature within 1 hour, obtaining a solution containing phenylacetyl chloride. Triethylamine (4.3 mL) was added to a suspension of 3-aminoquinolin-4-ol in dichloromethane (1 mL), and the resulting mixture was cooled in an ice bath. Phenyl acetyl chloride solution was added dropwise to the cooled mixture. the mixture was left to stir at room temperature overnight. The resulting cloudy oil was diluted with water (1 Oml) and then stirred rapidly for 1 hour.

The reaction mixture was filtered. Thin layer chromatography showed that both the isolated solid and the filtrate 65 contained the desired product. The filtrate was diluted with dichloromethane and water. The dichloromethane layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The residue was combined with the previously isolated solid and recrystallized from a mixture of 80:20 isopropanol/water to give 1.3 g

M-(4-hydroxyquinolin-Z3-yl)uphenylacetamide as a residue, Tpl, 253-2557"C. Analysis: Calculated for:

С17Н44М2О»: dos, 73.37; ON, 5.07; 90M, 10.07; Found: 95, 73,16; 95Н, 5.03; 9oM, 10.07.

Part B

Phosphorus pentasulfide (1.6 g) was added to a suspension of M-(4-hydroxyquinolin-3-yl)urenylacetamide (1.0 g) in pyridine. The reaction mixture was heated under reflux until the reaction was complete. The reaction mixture was concentrated under vacuum and then azeotroped with water to remove most of the pyridine. The residue was combined with water, neutralized with sodium carbonate and then extracted with dichloromethane. The 7/0 extract was washed with water, dried over magnesium sulfate, and then concentrated under vacuum to give 2-benzylthiazolo|4,5-c)quinoline as a solid.

Part B

The general method of Example 27 Part B was used, 2-benzylthiazolo|4,5-phenol (3.3g) was oxidized to obtain 2.1g of 2-benzylthiazolo|4,5-quinoline-5M-oxide in the form of a yellow solid, mp. 185-18670.

Analysis: Calculated for С.47Н412М2О5: 95, 69.84; 95Н, 4.14; 90M, 9.58; Found: 90, 69.51; 90Н, 4.06; 9oM, 9.55

Example 34 2-Benzylthiazolo|4,5-s|quinoline-4-amine hydrochloride

MN

Koh

Shauna

Trichloroacetylisocyanate (1.2 mL, 10.3 mmol) was added to a solution of 2-benzylthiazolo|4,5-cIquinoline-2M-oxide (2.0 g, 6.8 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated to give crude M-(2-benzylthiazolo|4,5-cIquinolin-4-yl)utrichloroacetamide. Amide d) was dissolved in methanol. Sodium methoxide (1 equivalent) was added. The reaction mixture was heated on a steam bath for 30 minutes and then allowed to cool to room temperature. The obtained residue was separated by filtration and then suspended in a mixture of methanol and isopropanol. Hydrochloric acid (1 equivalent) was added and all solids dissolved. A white solid was crystallized. This material was isolated by nitration, washed with isopropanol and then dried to obtain -1.5 g of 2-benzylthiazolo|4,5-c|quinoline-4-amine hydrochloride, Tpl. 152-15570. Analysis: Calculated for: С 47Н13М3МО NS: dos, 62.28; UoN, 4.30; 90M, 12.82; Found: 90, 62.05; 90Н, 4.23; 90М, 12.82. at

Example 35 8-Methyl-2-propylthiazolo (4,5-s) quinoline-5M-oxide f (se) sha M dra y 5 « - s Part A:z» Catalyst (0.10g 1095 platinum on charcoal) was added to a solution of b-methyl-3-nitroquinolin-4-ol (1 g) in ethanol (25 ml) and ammonium hydroxide (0.5 ml). The mixtures were reconstituted in a Parr apparatus at room temperature under a hydrogen atmosphere. The reaction mixture was filtered to remove the catalyst and then concentrated under vacuum. b 15 The residue was combined with water and heated. Hydrochloric acid was added dropwise until all solids were dissolved. Activated carbon was added to the solution. The mixture was filtered. Hydrochloric acid (2ml 12M) was added to the nitrate. This was recrystallized three times to obtain 0.50 g of 3-amino-6-methylquinolin-4-ol hydrochloride, mp. 2310". Analysis: Calculated for C10NioMoOp Its: 95, 57.02; 9oN, 5.26; 90M, 13.30; Found: dos, 56.92; UoN, 5.16; 90M, 13.24. so 7 Part B

HT» Triethylamine (11.4 bml) was added to a suspension of 3-amino-b6-methylquinolin-4-ol hydrochloride in dichloromethane (400 ml). Butyryl chloride (4.4 bml) was added. The reaction mixture was heated on a steam bath for 30 minutes.

The solution was diluted with sodium bicarbonate and then filtered. The filtrate was washed with bicarbonate and then concentrated under vacuum. The residue was recrystallized by Kk! receiving isopropanol

Z-butyramido-b-methylquinolin-4-ol hemihydrate in the form of a solid substance, Tpl. 274-2777S. Analysis: Calculated

HF) for C44NivM20501/2H50: 90, 66.39; 9oH, 6.76; 90M, 11.06; Found: 90, 66.56; 9oH, 6.46; 95M, 11.03. 7 Part B

Phosphorus pentasulfide (12.9 g) was added to a mixture of 3-butyramido-b6-methylquinolin-4-ol hemihydrate (7.12 g) in pyridine. The reaction mixture was boiled for 90 minutes, combined with a mixture of ice and sodium carbonate, and then extracted with dichloromethane. The extract was concentrated under vacuum. The residue was diluted with toluene and then concentrated under vacuum to give a crude solid. This material was purified using column chromatography, eluting with 2090 dichloromethane in ethyl acetate to give 8-methyl-2-propylthiazolo|4,5-c)quinoline as a yellow solid.

Part D. The general method of Example 7 was used. Part B, 8-methyl-2-propylthiazolo|4,5-c)quinoline (4,O)

oxidized using 3-chloroperbenzoic acid to give 4.19 g of crude product, which was recrystallized from isopropanol to give 2.0 g of 8-methyl-2-propylthiazolo|4,5-c|quinoline-5M-oxide as a solid. Tpl. 143-1457S. Analysis: Calculated for С 14Н414М2О5: 90, 65.09; 95Н, 5.46; 90M, 10.84;

Found: 90, 64,86; 9oH, 5.40; 95M, 10.88.

Example 36 8-Methyl-2-propylthiazolo|4,5-s|quinoline-4-amine

MN" in Kk 70 vna

The general method of Example 28 was used, 8-methyl-2-propylthiazolo|4,5-c|quinoline-5M-oxide 7/5 was converted into M-(8-methyl-2-propylthiazolo|4,5-c)quinoline-4 -ilutrichloroacetamide and then hydrolyzed to obtain 1.32 g. 8-methyl-2-propylthiazolo|4,5-c|quinolin-4-amine in the form of a crystalline substance, Tpl. 1147-1490. Analysis:

Calculated for C.44Ni5Ma3: 90, 63.54; 9oH, 5.87; 90M, 16.33; Found: 95, 64,97; 95Н, 5.76; 9oM, 16.25.

Example 37 (4-Aminothiazolo|4,5-s|quinolin-2-yl)umethanol

MN;

M U to on p 29 Part A Ge)

Triethylamine (7.3ml) was added to a suspension of 3-aminoquinolin-4-ol (5g) in dichloromethane (50ml). The mixture was cooled in an ice bath and then acetoxyacetyl chloride (Zml) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The resulting finely dispersed residue was diluted with water (1 Oml), quickly stirred for 20 minutes and then isolated by filtration. TLC showed that both the solid and the filtrate contained the desired product. The filtrate was concentrated under (ee) vacuum. The residue was mixed with water and then filtered. The combined solids were recrystallized from a mixture of 80:20 isopropanol/water to give M-(4-hydroxyquinolin-3-ylluacetoxyacetamide, mp 224-22576.

Part B d o)

We used the general method of Example 33 Part B, M-(4-hydroxyquinolin-3-yl)uacetoxyacetamide ! - ! ! (Ce) (5.3g) was reacted with phosphorus pentasulfide to obtain 2.9g of thiazolo|4,5-c)|quinolin-2-ylmethylacetate as a solid.

Part B

Using the general procedure of Example 27 Part B, thiazolo|4,5-c|quinolin-2-ylmethylacetate (2.8 g) was oxidized with peracetic acid to give thiazolo|4,5-c)quinolin-2-ylmethylacetate-5M-oxide in in the form of a yellow-brown crystalline substance. c Part G:c» Trichloroacetylisocyanate (0.b5ml) was added to a solution of thiazolo|4,5-c|quinolin-2-ylmethylacetate-5M-oxide (1.0g) in dichloromethane (50ml). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was dissolved in methanol. Sodium methoxide (1 equivalent) was added and the reaction mixture was stirred at room temperature overnight. The obtained residue was separated by filtration and dried to obtain 0.68 g of (4-aminothiazolo (|4,5-c|quinolin-2-yl)umethanol in the form of a white solid (ee) substance, mp. 247-249"C. Analysis: Calculated for C414NoM3O5: 90, 57.13; 90H, 3.92; 95M, 18.17; Found: 95C, 56.85; 9oH, 3.96; 9oM, 17.83. (95)

Example C8 (ee) 20 2-Methyloxazolo|4,5-c|quinolin-4-amine

МН с»

M | p level

GF) Part A

3-Aminoquinoline-4-yl (bg) was refluxed with acetic anhydride (8eq) until TLC showed that the reaction was complete. The reaction mixture was cooled, diluted with ice and water, basified with 1095 sodium hydroxide and then extracted with dichloromethane. Extract 60 was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under vacuum. The residue was purified by column chromatography (silica gel was eluted with a mixture of methanol/ethyl acetate) to obtain 5.1 g of 2-methyloxazolo|4,5-s|quinoline.

Part B

A mixture of 2-methyloxazolo|4,5-c|quinoline (5.0 g), peracetic acid (BEC) and ethanol was stirred at room temperature. After 2 hours, a smaller portion of peracetic acid (2 eq) was added and the contents were stirred for another 3 hours. The reaction mixture was concentrated under vacuum. The residue was azeotroped with heptane to obtain 4.2 g of 2-methyloxazolo|4,5-s|quinoline-5M-oxide.

Part B

Trichloroacetylisocyanate (3.bml) was slowly added to a cooled mixture of 2-methyloxazolo!|4,5-c|quinoline-5M-oxide (4.0g) and dichloromethane. The reaction mixture was stirred for several hours and then concentrated under vacuum to obtain crude

M-2-methyloxazolo|4,5-s|quinolin-4-yl)utrichloroacetamide. This material was combined with a solution of ammonia in methanol (2M) and stirred for 1 hour. The reaction mixture was concentrated under vacuum, diluted with water and then extracted 7/0 with dichloromethane. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under vacuum. The residue was purified by column chromatography (silica gel was eluted with a mixture of ethyl acetate/hexane) to obtain 1.2 g of 2-methyloxazolo|4,5-s|quinoline-4-amine as a solid substance, Tpl. 195-1977C. Analysis: Calculated for

C11NeoMzO: 95С, 66.32; 9oH, 4.55; 95M, 21.09; Found: 90, 65,96; 9oH, 4.44; 90M, 20.68.

Example 39 2-Ethyloxazolo|4,5-c)quinoline-4-amine

ME"

M | In summer

Part A

3-Aminoquinolin-4-ol hydrochloride (bg) was refluxed with propionic anhydride (vec) until TLC showed that the reaction was complete. The reaction mixture was cooled, the solution was diluted with ice and water, basified with 1095 sodium hydroxide and then extracted with dichloromethane. Go)

The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under vacuum. The residue was purified by column chromatography (silica gel was eluted with a mixture of methanol/ethyl acetate) to obtain 4.0 g of 2-ethyloxazolo|4,5-s|quinoline.

Part B h 2-Ethyloxazolo|4,5-c|quinoline, (3.5g), peracetic acid (4.5ml 3295 in acetic acid) and methyl acetate c (40ml) were combined and heated at 507C for several hours. The reaction mixture was concentrated under vacuum.

The residue was suspended in hexane and then filtered to obtain 2.5 g of 2-ethyloxazolo|4,5-s|quinoline-5M-oxide U as a solid. (uh)

Part One! - ! (Se)

Trichloroacetyl isocyanate (2 ml) was slowly added to a cooled mixture of 2-ethyloxazolo!|4,5-s|quinoline-5M-oxide (2.5 g) and dichloromethane. The reaction mixture was stirred for several hours and then concentrated under vacuum to obtain crude

M-(2-ethyloxazolo|4,5-s|quinolin-4-yl)utrichloroacetamide. This material was combined with a solution of ammonia in methanol (2M) and stirred for 1 hour. The reaction mixture was concentrated under vacuum, diluted with water and then extracted with dichloromethane. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under vacuum. The residue was purified using a column; from" chromatography (silica gel was eluted with a mixture of ethyl acetate/hexane) obtaining 2-ethyloxazolo|4,5-c|quinolin-4-amine in the form of a solid, Tpl. 175-1787"S. Analysis: Calculated for

С12Н44М3О: boss, 67.59; UoN, 5.20; 90M, 19.71; Found: 90, 67,19; 9о0Н, 4.86; 95M, 20.43. b 15 J Example 40 2-Butyloxazolo|4,5-s|quinoline-5H-oxide so that Cho z o (95) o 50

Part A 3-Aminoquinolin-4-ol hydrochloride (1.97 g, 10.0 mmol), triethylamine (1.01 g, 10.1 mmol) and valeric anhydride (9.3 g, 50.0 mmol) were combined and then boiled were kept for 18 hours. The reaction mixture was cooled to room temperature and then poured onto ice. The mixture was adjusted to pH 12 1095 with sodium hydroxide. Mixture 22 was stirred until all the ice had melted and then extracted with diethyl ether. Ether extracts

F! combined, dried over magnesium sulfate and then concentrated under vacuum to give a yellow-brown solid. This material was purified by flash chromatography and eluted with a 3:2 mixture of ethylacetate and dichloromethane to obtain 1.45 g of 2-butyloxazolo|4,5-s|quinoline.

Part B 60 Peracetic acid (1.6g, b.Hmmol 3295 in acetic acid) was added with stirring to a solution of 2-butyloxazolo|4,5-c|quinoline (1.4g, b.2mmol) in ethanol (5bOml). The reaction mixture was stirred at room temperature for 3 days and then quenched with saturated potassium carbonate solution. The layers were separated. The organic layer was concentrated under vacuum to give a yellow-brown solid. This material was suspended in diethyl ether and then filtered to obtain 0.6 mg of 2-butyloxazolo|4,5-s|quinoline-5M-oxide, mp. 120-12126. bo Analysis: Calculated for C 14H44MoOdo: bos, 69.41; 90Н, 5.82; 90M, 11.56; Found: 90, 69.22; 90Н, 5.76; 9oM,

11.59.

Example 41 2-Butyloxazolo!|4,5-c|quinolin-4-amine tw: y M de ia, y ho) 70 In a nitrogen atmosphere, trichloroacetyl isocyanate (0.bg, 3.4 mmol) was added with stirring to a solution of 2- butyloxazolo|4,5-c|quinoline-5M-oxide (0.55g, 2.27mmol) in anhydrous dichloromethane (20ml). The reaction mixture was left at room temperature for 2 h and then concentrated under vacuum to give crude M-(2-butyloxazolo|4,5-c|quinoline-4-yl-trichloroacetamide) as an oil. The oil was taken up in methanol (25 mL). Methoxide was added to the solution. sodium (0.49 g 2595, 2.27 mmol). The reaction mixture was boiled at 75 for 2 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water.

The ethyl acetate layer was concentrated in vacuo to give an orange solid. This material was purified using flash chromatography, eluting first with ethyl acetate and then with 30906 dichloromethane in ethyl acetate to give 0.15 g of 2-butyloxazolo|4,5-c|quinoline-4-amine, Tpl. 96-98". Analysis: Calculated for

Si4NuBMZO: boss, 69.69; UoN, 6.27; 9oM, 17.41; Found: 90, 69.23; 90Н, 6.06; 95M, 17.07.

Example 42 2-Propylthiazolium,5-sequinoline-4,8-diamine mM, and to

M

Part A

Potassium nitrate (0.46g, 4.52mmol) was added to a solution of 2-propylthiazolo|4,5-c|quinolin-4-amine (1g, 4.11mmol, t 3o Example 12) in sulfuric acid (1Oml). The reaction mixture was stirred at room temperature for 30 (ee) minutes, then poured onto ice, neutralized (pH-7) with ammonium hydroxide (150 mL) and then extracted with dichloromethane. The extract was washed with sodium bicarbonate, dried over magnesium sulfate, and then concentrated under vacuum to give a yellow solid. This material was recrystallized from a mixture of isopropanol/water to give 0.84 g of 8-nitro-2-propylthiazolo|4,5-c|quinoline as a yellow solid,

Tpl. 228-230"С. Analysis: Calculated for С.43Н12М4О0255: 90, 54.15; 9оН, 4.20; 95М, 19.43; Found: 95С, 54.22;

UN, 4.05; 95M, 19.04.

Part B

The catalyst (0.13 g of palladium on charcoal) was added to a solution of 8-nitro-2-propylthiazolo|4,5-c|quinoline (1.31 g) in ethanol. The mixtures were reconstituted in a Parr apparatus under a hydrogen atmosphere. The reaction mixture was filtered to remove the catalyst and the sediment on the filter was washed with ethanol. The filtrate was concentrated under vacuum at 507 and then c dried in a nitrogen atmosphere to obtain 2-propylthiazolo|4,5-c|quinoline-4,8-diamine in the form of a yellow crystalline substance, Tpl. 190-1927С, Analysis: Calculated for С13Н44М/З: 90, 60.44; 95Н, 5.46; 90M, 21.69; Found: 95C, 60.11; 95Н, 5.45; 95М, 21.96.

Example 43 y y y y b 2-Propyloxazolo|4,5-c)quinolin-4-amine

MN; (uh)

M M o what ra i o o 50 s"

Part A

A mixture of 3-aminoquinolin-4-ol hydrochloride (1.97g, 10.00mmol), butanoic anhydride (3.15g, 20mmol) and pyridine (25ml) was heated under reflux overnight. The reaction mixture was cooled and then poured onto ice. The mixture was basified (pH11) with 1 M sodium hydroxide and then extracted with diethyl ether (100 ml). The precipitate was removed by filtration. The ether extracts were combined, dried over magnesium sulfate, and then concentrated to give 1.1 g of 2-propyloxazolo|4,5-c|quinoline as an off-white solid.

Part B in 33-Chloroperbenzoic acid (1.Oeq. booo) was added with stirring to a solution of 2-propyloxazolo|4,5-cIquinoline (1.0 g, 4.7 mmol) in chloroform (30 mL). The reaction mixture was stirred at room temperature overnight and then quenched with saturated potassium carbonate solution. The layers were separated.

The aqueous layer was extracted with dichloromethane. The organic layers were combined and concentrated. The resulting crude product was purified by flash chromatography, eluting with a mixture of 8:2 ethyl acetate:dichloromethane, 65 to give 1.0 g of 2-propyloxazolo|4,5-s|quinoline-2M-oxide as a yellow-brown solid.

Part B

Trichloroacetylisocyanate (0.9g, 5.25mMmol) was added with stirring to a solution of 2-propyloxazolo|4,5-c|quinoline-27M-oxide (0.8g, 3, 5mmol) in dichloromethane (30ml). The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated under vacuum to give crude

M-(2-propyloxazolo|4,5-c|quinoline-4-yl trichloroacetamide. The amide was dissolved in methanol (50ml) and then combined with sodium methoxide (1.0eq 2595 in methanol) and boiled for 2 hours. The reaction mixture was concentrated under vacuum. The residue was taken up in a mixture of diethyl ether and water. The ether layer was separated and concentrated to give a yellow-brown solid. This material was purified by flash chromatography using two columns (the first was eluted with 8:2 ethyl acetate:dichloromethane; the second 1:11 7/0 ethyl acetate dichloromethane) obtaining 0.1 g of 2-propyloxazolo|4,5-c)quinolin-4-amine in the form of a yellow powder, Tpl. 159.0-160.07С. Analysis: Calculated for С.3Н/3зМ3О: 906, 68.71; 9oH, 5.77; 90M, 18.49; Found: 90, 68.03; 9oH, 5.77; 9ChoM, 18,14.

Example 44 8-Bromo-2-propylthiazolo|4,5-s|quinoline-4-amine

MH m ra with 5 t of 2-Propylthiazolo|4,5-c|quinolin-4-amine (1.0 g, 0.41 mmol) was combined with acetic acid (15 ml) and heated at 60"C. It was added dropwise bromine (0.10 ml, 1.94 mmol) and the reaction mixture was stirred at 60"C for 18 hours. The reaction mixture was diluted with water and the resulting residue was separated by filtration, obtaining 0.25 g..- CM of 8-bromo-2-propylthiazolo|4,5-cyquinoline-4-amine in the form of a yellow solid, Tpl. 177-1802C. Analysis: d)

Calculated for С43Н412ВгМ35: 90, 48.46; 90Н, 3.75; 95M, 13.04; Found: 90C, 47.98; 9oH, 3.95; 90M, 12.70.

Example 45 7-Methyl-2-propylthiazolo|4,5-c|quinoline-4-amine

MN" in

From kt, d) that | photo from p

Part A and

Diethyl ethoxymethylmalonate (37, vml, 187mmol) and m-toluidine (20,00ml, 187mmol) were combined and heated at 1007 for about 3 hours. The reaction mixture was allowed to cool to room temperature and a solid precipitated from it. Dauter A (350ml) was added and the reaction mixture was boiled for approximately 130 minutes. The reaction mixture was allowed to cool to room temperature. The resulting residue was isolated by filtration, washed with acetone and dried to obtain ZZg ethyl 4-hydroxy-7-methyl-3-quinolinecarboxylate in the form of a yellow-brown powder. :z» Part B

Ethyl 4-hydroxy-7-methyl-3-quinolinecarboxylate (32g, 138mmol) was suspended in sodium hydroxide (50O0ml of 1095 aqueous solution) and then boiled for about 30 minutes. The reaction mixture was left to cool for 15 minutes to room temperature and then acidified with concentrated hydrochloric acid. The resulting residue was separated by filtration, washed well with water and then dried to give (ee) 4-hydroxy-7-methyl-3-quinolinecarboxylic acid (28g). A portion of (253) was recrystallized twice from MM-dimethylformamide to give a loose white solid, mp. 264-2657"С. Analysis: Calculated for

C11NoMO»z: 90, 65.02; 9oH, 4.46; 95M, 6.89; Found: 95C, 65.22; 90Н, 4.42; 9oM, 6.88. so 7 Part B

HT» 4-Phydroxy-7-methyl-3-quinolinecarboxylic acid (32 g) was placed in a round-bottomed flask and then heated in a Bud metal bath at 3107°C for several minutes until all solids melted into a light brown liquid. viscous liquid and gas evolution was not complete. The reaction mixture was allowed to cool to room temperature. The crude solid was recrystallized from a mixture of ethyl acetate/ethanol to give 9.8 g of 7-methyl-4-quinolinol. During the recrystallization, a portion of the solid was not

HF) dissolved, this material was separated by filtration and then recrystallized to obtain 1.1 g of 7-methyl-4-quinolinol in the form of yellow-brown plates, Tpl. 233-2357S. Analysis: Calculated for C 0NoMoO: dos, 75.45; UoN, 5.70; 90M, 8.80; Found: 90, 75.23; 90Н, 5.54; 95M, 8.76.

Part G bo Nitric acid (bml 7095) was slowly added to a hot (12572) solution of 7-methyl-4-quinolinol (10.5g) in propionic acid (125ml). The reaction mixture was stirred for approximately 1.5 hours and then allowed to cool to room temperature. The resulting residue was separated by filtration, washed well with ethanol and water and then dried to give 6.9 g of 7-methyl-3-nitro-4-quinolinol as a pale yellow solid. because Chastinad

7-Methyl-3-nitro-4-quinolinol (11.8g, 5mmol), methanol (ca. 300ml), ammonium hydroxide (BOml) and palladium on charcoal (1g 1095) were combined. The mixture was placed in a Parr apparatus with a hydrogen pressure of 35-4Opsi (2.4-2.8Kg/cm) and hydrogenated for about 1 hour. Was the reaction mixture filtered through a layer of Celite? and the residue was washed well with methanol. The filtrate was triturated with charcoal and then concentrated in vacuo to give a loose pale green solid. This material was triturated with acetonitrile to obtain /8.5 g

Z-amino-7-methyl-4-quinolinol.

Part E

Under a nitrogen atmosphere, triethylamine (0.7 mL, 5.1 mmol) was added to a suspension of 3-amino-7-methyl-4-quinolinol 70 (800 mg, 4.0 mmol) in dichloromethane (30 mL). Butyryl chloride (0.53 mL, 5.1 mmol) was added. The reaction mixture was stirred at room temperature for about 2 hours. Thin-layer chromatography (silica gel eluted with a mixture of 9:1 dichloromethane:methanol) showed the presence of the starting material. The reaction mixture was heated to boiling and then left for about 30 minutes. Another solvent was added and the reaction mixture was heated at boiling for an hour, thin-layer chromatography showed the absence of starting material. 75 The resulting residue was separated by filtration and then washed with dichloromethane and water to give bB5Omg of M-(4-hydroxy-7-methylquinolin-4-yl)butyramide as a pale pink-yellow-brown solid.

Part E is in a nitrogen atmosphere, phosphorus pentasulfide (1.15 g, 2.mmol) was added to the mixture

M-(4-hydroxy-7-methylquinolin-4-yl)butyramide (b3Omg, 2.bmmol) in pyridine (2O0ml). The reaction mixture was heated to boiling. The reaction mixture turned dark yellow and all solids dissolved. The reaction mixture was boiled for about 2 hours and then allowed to cool to room temperature. The reaction mixture was extracted with water, aqueous sodium bicarbonate and dichloromethane. The organic layer was triturated with a saturated solution of copper sulfate, dried over magnesium sulfate, and then concentrated under vacuum to obtain an oil. The oil was dried under high vacuum to give 410 mg of 7-methyl-2-propylthiazolo|4,5-s|quinoline su as an orange solid.

Part G i)

C-Chloroperbenzoic acid (2.4g 57-8695) was added to a mixture of 7-methyl-2-propylthiazolo|4,5-c|quinoline (2g) and chloroform (100ml). The reaction mixture was left to stir at room temperature for 2 hours.

Thin layer chromatography showed the absence of starting materials, but showed the presence of two products. "I The reaction mixture was stirred at room temperature for another hour and then it was extracted with dichloromethane and an aqueous solution of sodium bicarbonate. The organic layer was dried with magnesium sulfate and then concentrated under vacuum to give a yellow-orange oil. The oil was dried under high vacuum to give 2.1 g of 7-methyl-2-propylthiazolo|4,5-c|quinoline-5M-oxide as a solid. Part C under a nitrogen atmosphere, trichloroacetyl isocyanate (1.4 mL, 12.mmol) was added to a mixture of 7-methyl-2-propylthiazolo|4,5-c|quinoline-5M-oxide (2.1g, 8.mmol) and dichloromethane (100ml). The resulting dark brown solution was allowed to stir at room temperature for about 2 hours.

The reaction mixture was concentrated under vacuum to obtain

M-(7methyl-2-propylthiazolo|4,5-c|quinolin-4-yl)utrichloroacetamide in the form of oil. The oil was combined with methanol and sodium methoxide (1.9 mL of 2595 in methanol, 8.1 mmol) and then stirred at room temperature for 40.1 hours. The obtained residue was separated by filtration and then recrystallized twice from isopropanol to obtain 50 mg of 7-methyl-2-propylthiazolo|4,5-c|quinoline-4-amine in the form of a yellow-brown powder, Tpl. ts 186-1877S. Analysis: Calculated for C 445Ni5Maz: 90, 65.34; 90Н, 5.87; 90M, 16.33; Found: 95, 64,95; 9oH, "» 5.77; 96M, 16.08.

Example 46 2-Butyl-7-methyloxazolo!|4,5-s|quinolin-4-amine

Ge" MN" so Dr yZ 0 (95) at 50

Part A i» Under a nitrogen atmosphere, a mixture of 3-amino-7-methyl-4-quinolinol (5g, 28.7mmol) and valeric anhydride (28ml, 143.5mmol) was boiled for about 20 hours. The reaction mixture was left to cool to room temperature, then it was basified with 1095 sodium hydroxide and stirred for another hour at room temperature. The reaction mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and then concentrated under vacuum to obtain a dark brown liquid. The liquid was purified by column chromatography (silica gel was eluted with a mixture of 3:2 ethyl acetate:dichloromethane) to give 4.7 g of a dark brown almost solid substance. A portion (approximately 7000 mg) was purified by column chromatography (silica gel was eluted with a mixture of 95:5 dichloromethane:methanol) to obtain 2-butyl-7-methyloxazolo|4,5-c|quinoline, 60 Tpl. 52-5570. Analysis: Calculated for C45NivM2O: оС, 74.97; 9оН, 6.71; 95M, 11.66; Found: 90, 74,80; UN, 6.73; 9oM, 11.53.

Part B

C-Chloroperbenzoic acid (4.6 g 57-8690) was added to a solution of 2-butyl-7-methyloxazolo|4,5-c|quinoline (3.9 g, 16.2 mmol) in chloroform (100 ml). The reaction mixture was left to stir at room temperature 65 for 4 hours. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and then concentrated under vacuum to obtain 4.2 g of 2-butyl-7-methyloxazolo|4,5-c|quinoline-5M-oxide in the form of a dark brown-orange oil.

Part B under a nitrogen atmosphere, trichloroacetyl isocyanate (2.Oml, 24mmol) was added to a mixture of 2-butyl-7-methyloxazolo|4,5-c|quinoline-0M-oxide (4.2g, 1bmmol) and dichloromethane (100Oml). The reaction mixture was allowed to stir at room temperature for about 3 hours, then it was concentrated under vacuum. The resulting residue was taken up in methanol and then combined with sodium methoxide (3.7 ml of 25 95 in methanol, 1 mmol). The reaction mixture was stirred at room temperature overnight. The methanol was evaporated and the resulting residue was purified by column chromatography (silica gel eluted with 7/0 buffer 95:5 dichloromethane:methanol) to give a brown solid. This solid was recrystallized from acetonitrile to give 5500 mg of 2-butyl-7-methyloxazolo|4,5-c|quinolin-4-amine as a good yellow-brown residue, mp 187-1887S. Analysis: Calculated for С 15Н.47М3О0.1Н20: 95С, 70.07; UN, 6.74; 95M, 16.34; Found: 95, 70.07; 95Н, 6.49; 90M, 16.58.

Example 47 7-Methyl-2-propyloxazolo|4,5-c)quinolin-4-amine

MN; we

Dee -

Part A

Under a nitrogen atmosphere, a mixture of 3-amino-7-methyl-4-quinolinol (3.4 g, 20 mmol) and butanoic anhydride (1 bml) was heated under reflux overnight. The reaction mixture was allowed to cool to room temperature and then poured onto ice. The pH of the mixture was adjusted to 12 by adding 10905 sodium hydroxide and then extracted with dichloromethane. The extract was dried over magnesium sulfate and then concentrated under vacuum. (3

The residue still contained anhydride, so 1095 sodium hydroxide was added to it and stirred for 1 hour at room temperature. The mixtures were extracted with dichloromethane. The extract was dried over magnesium sulfate and then concentrated under vacuum to give a brown oil. The oil was purified by column chromatography (silica gel was eluted with a mixture of 3:2 ethyl acetate:dichloromethane) to obtain 3.1 g of 307-methyl-2-propyloxazolo|4,5-c|quinoline in the form of a light brown oil, which solidified on standing. Tpl. (ee) 65-687C. Analysis: Calculated for С45Н414М2О: 90, 74.31; 90N. 6.24; 90M, 12.38; Found: 90, 73.69; 9oH, 6.07; oh, 12.15. co

Part B d o)

C-Chloroperbenzoic acid (3.8 g 57-8690) was added to a solution of 7-methyl-2-propyloxazolo|4,5-c|quinoline (Zg) in chloroform (10 Oml). The reaction mixture was allowed to stir at room temperature overnight. oh

The reaction mixture was washed twice with sodium bicarbonate, dried over magnesium sulfate, and then concentrated under vacuum to obtain 3.1 g of 7-methyl-2-propyloxazolo|4,5-c|quinoline-5M-oxide as a pale orange solid. "

Part B with and and under a nitrogen atmosphere, trichloroacetyl isocyanate (2.3 mL, 19.2 mmol) was added to a solution of 7-methyl-2-propyloxazolo|4,5-cIquinoline-20M-oxide (3.1 g, 12.8 mmol) in dichloromethane (10 Oml). The reaction mixture was allowed to stir at room temperature for 3 hours and then the solvent was removed under vacuum.

Methanol (100 mL) was added to the resulting orange residue, followed by sodium methoxide (2.9 mL of 2590 in methanol, 12.8 mmol). The reaction mixture was stirred at room temperature overnight. b 15 The resulting residue was separated by filtration and then recrystallized from isopropanol to obtain 4500 mg of 7-methyl-2-propyloxazolo|4,5-c|quinoline-4-amine as a white solid, mp. 188-18920. (ee) Analysis: Calculated for C 15Ni5М3ОО0.2НіЁо: 95, 68.66; 90Н, 6.34; 90M, 17.16; Found: 90, 68.44; 9BN, 6,11; with om, 17.42.

Example 48 (ee) 20 7-Fluoro-2-propyloxazolo|4,5-c|quinoline-4-amine

I" M

3-fluoroaniline (50.0 g, 0.45 mol) and diethylethoxymethylmalonate (9 mL, 0.45 mmol) were combined under nitrogen and heated at 100°C for 3 hours. The reaction mixture was allowed to cool. to room temperature and it solidified at 60. Douterm A (200 ml) was added and the reaction mixture was heated at 240°C for 4 hours. The reaction mixture was allowed to cool to room temperature. The resulting residue was separated by filtration, washed with hexane and then dried in a vacuum to obtain 7/1.50 g of ethyl 7-fluoro-4-hydroxy-3-quinolinecarboxylate.

Part B 65 A suspension of ethyl 7-fluoro-4-hydroxy-3-quinolinecarboxylate (b5g, 0.28 mol) in 1095 sodium hydroxide (250 ml) was boiled for 3 hours, resulting in the formation of a solution. The reaction mixture was allowed to cool to room temperature and then it was filtered through a paper filter under vacuum. The filtrate was acidified with concentrated hydrochloric acid. The resulting residue was collected, washed with water and then dried to obtain 53.5 g of 7-fluoro-4-hydroxy-3-quinolinecarboxylic acid as a white solid.

Part B 7-Fluoro-4-hydroxy-3-quinolinecarboxylic acid (25g) was placed in a round-bottomed flask and heated to 330-350", during which carbon dioxide began to be released and the material turned into a liquid. After about 2 minutes, another 25g of 7- of fluoro-4-hydroxy-3-quinolinecarboxylic acid. Heating was continued for another 4-6 minutes, during which no further evolution of carbon dioxide was observed. The solution was allowed to cool 7/0 to room temperature. The resulting solid was separated by filtration to give 35.6 g of 7- fluoro-4-quinolinol as a pink solid.

Part G

Nitric acid (2O0ml 7095) was added to a hot (12572) solution of 7-fluoro-4-quinolinol (35g, 214mmol) in propionic acid (200ml). The reaction mixture was stirred at 1257C for about 1.5 hours and then allowed to cool to room temperature. The resulting yellow precipitate was separated by filtration, washed with water, and then with ethanol, and then recrystallized from a mixture of M,M-dimethylformamide/water to obtain 18 g of 7-fluoro-3-nitro-4-quinolinol.

Parts

A mixture containing 7-fluoro-33-nitro-4-quinolinol (17 g, 81.7 mmol), ammonium hydroxide (80 mL), methanol (200 mL), and palladium on carbon (1 g 1095) was maintained in a Parr apparatus under a hydrogen atmosphere with pressure of about ZOpsi (2.1 kKg/cm2) for 1 hour. The reaction mixture was filtered to remove the catalyst. The filtrate was triturated with charcoal then concentrated in vacuo to give a dark yellow-brown solid which became very dark brown on drying. The solid was dissolved in methanol, then hydrochloric acid in diethyl ether was added. A gray precipitate formed immediately. The suspension was stirred at room temperature for several hours. The precipitate was separated by filtration and washed well with ether to give 6.6 g of 3-amino-7-fluoro-4-quinolinol hydrochloride. i9 )

Part E

Under a nitrogen atmosphere, 3-amino-7-fluoro-4-quinolinol hydrochloride (3.4 g, 19.1 mmol), triethylamine (2.9 mL, 21.00 mmol) and butanoic anhydride (15.6 mL, 95 .5 mmol) and boiled for about 18 hours. "I The reaction mixture was poured onto ice and basified to approximately pH 12 with 1095 sodium hydroxide. The resulting suspension was stirred until all the ice had melted and then extracted with dichloromethane. The extract was dried over magnesium sulfate and then concentrated under vacuum to obtain an oil. The oil was purified by column chromatography (silica gel was eluted first with dichloromethane and then with a 9:1 mixture of dichloromethane:methanol) to give 2,bg 7-fluoro-2-propyloxazolo|4,5-c|quinoline in the form of a light brown so 3z5 solid . Gee)

Part E 7-Fluoro-2-propyloxazolo|4,5-c|quinoline, (2.6g, 11.3mmol), 3-chloroperbenzoic acid (3.3g 57-8690) and chloroform (90ml) were combined and stirred at room temperature for about 3 hours. "

Thin-layer chromatography (silica gel was eluted with a mixture of 95:5 dichloromethane:methanol) showed the presence of starting materials. Another 0.5 equivalents of 3-chloroperbenzoic acid was added and the reaction mixture was stirred at room temperature for another 2 hours, after which thin-layer chromatography showed the absence of starting materials. The reaction mixture was diluted with dichloromethane and then washed twice with sodium bicarbonate. "» The organic layer was dried over magnesium sulfate and then concentrated under vacuum to obtain 2.8 g of 7-fluoro-2-propyloxazolo|4,5-s|quinoline-5M-oxide as a yellow-orange oily solid.

Part Z

Ge") under a nitrogen atmosphere, trichloroacetyl isocyanate (2.Oml, 17 mmol) was added to a solution of 7-fluoro-2-propyloxazolo|4,5-c|quinoline-5M-oxide (2.8g, 11.3 mmol) in dichloromethane ( 5 Oml). The reaction mixture was stirred at room temperature for 3 hours and then dichloromethane was removed under vacuum. The residue was dissolved in methanol and then combined with sodium methoxide (2.4 ml of 2595 in methanol, 11.3 mmol). The reaction mixture was stirred at room temperature overnight, then filtered to remove a small amount of solid matter. The filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, dried over

HT" with magnesium sulfate and then concentrated under vacuum to give a brown oil. The oil was purified by column chromatography (silica gel was eluted with a mixture of 95:5 dichloromethane.methanol) to obtain a light brown sticky solid. This material was recrystallized from acetonitrile to obtain 200 mg of T-fluoro-2-propyloxazolo!|4,5-c|quinoline-4-amine in the form of a red powder, mp. 184-187". Analysis: Calculated for C13Hl12EMa3O: 90, 63.67; UoH, 4.93; 90M, 17.13; Found: 95, 63.43; 95H, 4.57; 9o0M, 16.74. iF ) Example 49 ko 7-Fluoro-2-propylthiazolo|4,5-c|quinoline-4-amine

MN;

M

"J

With Z

Part A 65 Under nitrogen, triethylamine (b4ml, 46.2mmol) was added to a suspension of 3-amino-7-fluoro-4-quinolinol hydrochloride (3g, 14.00mmol) in tetrahydrofuran (50ml). Butyryl chloride (1.bml, 15.4mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 4 hours.

An aqueous solution of sodium bicarbonate was added and the reaction mixture was allowed to stir at room temperature for approximately 1 hour. The resulting biphasic mixture was filtered to remove the solid,

The solid was washed with diethyl ether to obtain a slightly pink powder. The tetrahydrofuran layer was concentrated under vacuum to give a dark pink solid. This solid was triturated with ether and then dried. The solids were combined to obtain Z,Og

IM-(7-fluoro-4-hydroxyquinolin-3-yl)butanamide. A 300 mg portion was recrystallized from a mixture of ethyl acetate/ethanol to obtain a light gray loose solid, mp. 306-3087C. Analysis: Calculated for С 43Н43ЕМ»О: 9осС, 7/0 82.90; zhoN, 5.28; volume, 11,28; Found: dos, 62.95; 9oH, 5.34; 90M, 11,14.

Part B under a nitrogen atmosphere, phosphorus pentasulfide (4.7g, 10.5mmol) was added to the mixture

IM-(7-fluoro-4-hydroxyquinolin-3-yl)butanamide (2.6g, 10.bmmol) and pyridine (8Oml). The reaction mixture was boiled for 2 hours and then allowed to cool to room temperature. The reaction mixture was extracted with 7/5 sodium bicarbonate/dichloromethane. The organic layer was separated, washed twice with water, dried over magnesium sulfate, and then concentrated under vacuum to give a red solid. This material was recrystallized from methanol to give 1.8 g of 7-fluoro-2-propylthiazolo|4,5-c|quinoline as a red lamellar residue.

Part B

C-Chloroperbenzoic acid (2.1g 57-8695) was added to a solution of 7-fluoro-2-propylthiazolo|4,5-c|quinoline (1.8g, 7.mmol) in chloroform (50ml). The reaction mixture was stirred at room temperature. Thin-layer chromatography (silica gel was eluted with a mixture of 95:5 dichloromethane:methanol) showed the presence of starting materials, so another 0.5 equivalent of 3-chloroperbenzoic acid was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed twice with sodium bicarbonate, dried over magnesium sulfate, and then concentrated under vacuum to obtain 1.8 g of 7-fluoro-2-propylthiazolyl|4,5-s|quinoline-5M-oxide as a pale orange solid. and)

Part G under a nitrogen atmosphere, trichloroacetyl isocyanate (1.2 mL, 10 4 mmol) was added to a mixture of 7-fluoro-2-prolylthiazolo|4,5-c|quinoline-bM-oxide (1.8 g, b, 0 mmol) and dichloromethane (5 0 mL ). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to give

M-(7-fluoro-2-propylthiazolo|4,5-c|quinoline-4-yl-trichloroacetamide) in the form of an orange oil. The oil was dissolved in methanol and then combined with sodium methoxide (1.5 ml of 25 wt.90 in methanol) The reaction mixture was allowed to stir at room temperature for 3 hours. The resulting residue was separated by filtration and then recrystallized first from acetonitrile and then from methanol to give 1.1 g of 7-fluoro-2-propylthiazolo|4,5-c|quinoline-4- amine in the form of a yellow-brown powder, melting point 192.5-193.570. Analysis: "o

Calculated for C43Ni12EMa3: 90, 59.75; 9oH, 4.63; 95IR, 16.08; Found: 95C, 59.55; 9oH, 4.69; 90M, 16,12.

Example 50 2-Propyl-7-(trifluoromethyl)thiazolo|4,5-c|quinolin-4-amine

MN; "di M

TU - p. 8

IS

2" p

IS

Part A

In a nitrogen atmosphere, a mixture of 3-trifluoromethyl)aniline (4 0 mL, 0.32 mmol) and diethyl ethoxymethyl malonate was heated

Me. at 1007C for 3 hours. The reaction mixture was allowed to cool to room temperature after which

Go! solution of solids, which gave 102 g of diethyl 2-13-(trifluoromethyl)aniline methylene malonate as a cream-colored solid. o Part B

Go! 20 Under a nitrogen atmosphere, a mixture of diethyl 2-13-(trifluoromethyl)anilino|methylene)malonate (80g, 0.24mol) and douter A was heated to 240°C and then stirred for 3 hours. The reaction mixture was allowed to cool to

T" at room temperature and then stirred for 16 hours. The solids were isolated by filtration and then washed with hexane to obtain 47.5 g of ethyl 4-hydroxy-7-(trifluoromethyl)-3-quinolinecarboxylate as an off-white solid.

Part B

HF) Mixtures of ethyl 4-hydroxy-7-trifluoromethyl)-3-quinolinecarboxylate (43.4 g, 0.521 mol) and 109 g of sodium hydroxide (15 0 ml) were heated to boiling. Most of the ester did not dissolve, so methanol (150 ml) was added to facilitate dissolution. After boiling for 2 hours, a solution was obtained. The solution was refluxed for another 2 hours and then allowed to cool to room temperature overnight. 60 Methanol was removed under reduced pressure and the resulting aqueous solution was acidified with concentrated hydrochloric acid. The obtained residue was separated by filtration, washed with water and then dried in a vacuum at 1207C for 24 hours, obtaining 38.5 g of 4-hydroxy-7-trifluoromethyl)-3-quinolinecarboxylic acid in the form of a white solid.

Part G bo 4-hydroxy-7-trifluoromethyl)-3-quinolinecarboxylic acid (34.1 g,

0.132mol) and then heated in a bath with Wood's metal for 5 minutes during which carbon dioxide was released and the material turned from a solid to a liquid. After 5 minutes, the gas was no longer released, so the flask was removed from the bath and left to cool to room temperature. The resulting solid

The substance was separated by filtration, obtaining 27.75 g of 7-trifluoromethyl)-4-quinolinol.

Parts

A mixture of 7-(trifluoromethyl)-4-quinolinol (22.7 g, 0.10 bmol) and propionic acid (106 mL) was heated to 12076.

Nitric acid (1 Oml 70905) was added dropwise and heating was continued for another 2 hours. The reaction mixture was allowed to cool to room temperature. The obtained residue was separated by 7/0 filtration, then washed with water and diethyl ether, obtaining 13.3 g

C-nitro-7-trifluoromethyl)-4-quinolinol as an off-white solid.

Part E

Methanol (4 Oml), ammonium hydroxide (1 Oml),

C-nitro-7-(trifluoromethyl)-4-quinolinol (12.8g, 49.bmmol) and palladium on charcoal (1.0g 1095). The mixture was kept in a 75 Parr apparatus under a hydrogen atmosphere at a pressure of 40 psi (2.bkg/cm?) for 4 hours. The mixtures were filtered and the catalyst was washed with methanol and dichloromethane. The combined organic extracts were concentrated in vacuo to give a green solid. The solid was dissolved in methanol and then combined with 1M hydrochloric acid in anhydrous diethyl ether (1500ml). A precipitate formed immediately. The reaction mixture was left to stir for 16 hours. The precipitate was separated by filtration, washed with diethyl ether and then dried in a vacuum at 807°C to obtain 9.3 g of 3-amino-7-trifluoromethyl)-4-quinolinol hydrochloride as an off-white solid.

Part E

Butyryl chloride (1.5 ml, 14.5 mmol) was added dropwise to a mixture of 3-amino-7-"-trifluoromethyl)-4-quinolinol hydrochloride (3.5 g, 13.2 mmol), triethylamine (6.1 ml, 43, bmmol) and anhydrous tetrahydrofuran (ZOml). p

The reaction mixture was left to stir for 16 hours. A small amount of aqueous sodium bicarbonate solution was added and the reaction mixture was stirred for 0.5 hours. Tetrahydrofuran was removed under i9) vacuum. The resulting solid was mixed with diethyl ether, separated by filtration, washed with water and diethyl ether, and then dried in a vacuum at 80°C overnight to obtain 3.Zg

I-(4-hydroxy-7-(trifluoromethyl)quinolin-3-yl|Ibrutanamide in the form of a cream-colored solid substance. "I

Part Z

A mixture of M-(4-hydroxy-7-(trifluoromethyl)quinolin-3-yl|bsuthanamide (3.0g, 10.05mmol), phosphorus pentasulfide (4.5g, 10.005mmol) and pyridine (30ml) was boiled for E hours. The solution was allowed to cool to room temperature and then diluted with dichloromethane and aqueous sodium bicarbonate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, and then concentrated in vacuo to give a yellow solid. This material was triturated with o-hexane and then isolated by filtration to give 1.7 g of 2-propyl-7-"(trifluoromethyl)thiazolo|4,5-c|quinoline. as a yellow-brown solid. The hexane filtrate was concentrated to give additional 0, 6 g of the product in the form of a yellow solid.

Part C

C-Chloroperbenzoic acid (193g, b.8v8mol) was added to a mixture of CH with 2-propyl-7-trifluoromethyl)thiazolo|4,5-c|quinoline (2.0g, 6./5mmol) in chloroform (30ml). The resulting solution was left to stir for 24 hours. The reaction mixture was diluted with an aqueous sodium bicarbonate solution and then extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, and then concentrated under vacuum to obtain 1.98 g of 2-propyl-7-(trifluoromethyl)thiazolo|4,5-s|quinoline- 0M-oxide in

Appearance of a yellow solid.

Ge") Part under a nitrogen atmosphere, trichloroacetyl isocyanate (0.75 ml, 6 b, 24 mmol) was added to a mixture of 2-propyl-7-"(trifluoromethyl)thiazolo|4,5-c|quinoline-5M-oxide (1.3 g, 4.1 mmol) and anhydrous dichloromethane (20 ml). The resulting solution was left to stir at room temperature for 16 hours. The solvent was removed under reduced pressure. The obtained residue was dissolved in methanol (40 ml) and then combined with sodium methoxide CO (1.4 ml of 2595 in methanol, 6.24 mmol). The resulting solution was left to stir at room temperature

Chl" for 16 hours during which a precipitate was formed. The precipitate was separated by filtration, washed with a small amount of methanol and then dried for 16 hours in a vacuum at 80"C, obtaining 0.96 g of 2-propyl-7-"(trifluoromethyl)thiazolo|4,5-c|quinoline-4-amine in the form of a white of solid matter, Tpl. 215-1676.

Analysis: Calculated for С 145Н412РзМ3З: 90, 54.01; 95Н, 3.89; 95M, 13.50; Found: 90, 53,82; 95Н, 3.66; 9oM, 13.37. iF) Example 51 ko 2-(Methylsulfonyl)thiazolo|4,5-s|quinoline-5IM-oxide 6o i | In zo sn also K 2-p3

Part A 65 M7-(2-methylpropyl)quinoline-3,4-diamine (54g, 25mmol) was combined with carbon disulfide (U9ml, 150mmol) and ethanol (55ml) and then heated under reflux on a steam bath for 2 hours . The obtained residue was separated by filtration, washed with ethanol and then dried in air to obtain 44 g of crude product. A portion (1 g) was dissolved in a hot dilute solution of sodium hydroxide and then quenched with acetic acid. The precipitate was separated by filtration while still hot, washed with hexane and then stirred in air to obtain thiazolo|4,5-s|quinoline-2-thiol as a solid, Tpl. 282-284". Analysis:

Calculated for SloNeM.52: 90, 55.02; 9оН, 2.77; 90M, 12.83: Found: 95, 54.96; 95Н, 2.69; 90M, 12.74.

Part B

Sodium methoxide (15.8ml 2595 in methanol, bbmmol) and methyl iodide (3.9ml, bZmmol) were added to a solution of thiazolo|4,5-cIquinoline-2-thiol (13.65g, bZmmol) in methanol (1bOml). The reaction mixture was heated on a steam bath /o0 for 1 hour. The solvent was removed under vacuum. The resulting light-green-yellow solid was suspended in water, isolated by filtration and washed with water to obtain 9.8 g of crude product. A portion (1 g) was recrystallized from methanol to obtain 2-(methylthio)thiazolo|4,5-c|quinoline in the form of a solid substance,

Tpl. 116-1192C, Analysis: Calculated for C14NaMoZ»o: 90, 56.87; 9oH, 3.47; 90M, 12.06; Found: 95C, 57.09; 90Н, 3.57; 9o0M, 12.04.

Part B

Peracetic acid (27.8 ml 3296, 132 mmol) was added to a mixture of 2-(methylthio)thiazolo|4,5-c|quinoline (7.7 g,

33 mmol) and acetic acid (10 Oml). The reaction mixture was heated at about 607C for about 4 hours and then at room temperature overnight. The obtained yellow precipitate was separated by filtration, obtaining 5.bg of the crude product. The filtrate was concentrated under vacuum, then the residue was diluted with toluene (100 ml). Toluene was removed under vacuum to give another 4 g of crude product. Portion (g) was recrystallized from M,M-dimethylformamide to obtain 2-(methylsulfonyl)thiazolo|4,5-c|quinoline-b0M-oxide in the form of a yellow solid, mp. 245-2477S. Analysis: Calculated for C 44H8 M2Oz3Z: 90, 47.13; 9oH, 2.88; Ohm, 9.99; Found: 95, 47.08; 90Н, 3.08; 95M, 10,14.

Example 52 2-(4-Morpholino)thiazolo|4,5-s|quinoline-5M-oxide o o, g M

M Uk

With 5 K/ « 2-(« (Methylsulfonyl)thiazolo|4,5-c|quinoline-5M-oxide (2.5g, 8.9mmol) and morpholine (u75Oml) were combined and then heated on a steam bath for 9 hours. The resulting residue was separated by filtration to give 0.9 g of the crude product as a yellow solid. The filtrate was cooled in an ice bath.

The obtained residue was separated by filtration to obtain 0.8 g of the crude product as a yellow (ee) solid. The two portions were combined and then a portion (0.5 g) was recrystallized from methanol to obtain 2-(4-morpholino)thiazolo|4,5-c|quinoline-OM-oxide as a solid, mp. 241-2427"S. Calculated for her

Si4NizM30»: 95C, 58.52; ON, 4.56; 9oM, 14.62; Found: 90, 58.24; 90Н, 4.38; 95M, 14.43.

Example 53 2-(4-Morpholino)thiazolo|4,5-c)quinolin-4-amine «

MN"

At about, with "M i

And" more

Ammonium hydroxide (13ml) was added to a mixture of 2-(4-morpholino)thiazolo|4,5-c|quinoline-bM-oxide (1.2g, 4.2mmol) and dichloromethane (24ml). The mixture was cooled and then slowly added tosyl chloride (0.88g, 4.bmol)

Me. in dichloromethane (1 Oml). The reaction mixture was warmed to room temperature and then stirred overnight.

Go! The organic phase was separated, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, and then concentrated under vacuum to give the crude product as a yellow solid. o This material was purified by column chromatography, then dissolved in hydrochloric acid and

Go! 20 was precipitated with sodium hydroxide. The precipitate was separated by filtration and then recrystallized twice from methanol to obtain 0.26 g of 2-(4-morpholino)thiazolo|4,5-c|quinoline-4-amine as a solid, mp. і" 225-227". Analysis: Calculated for C 145Н44МАО5: 90, 58.72; 95Н, 4.93; 90М, 19.57; Found: 90С, 58.47; 95Н, 4.63; dom, 19, 23.

Example 54 59 2-(1-Pyrrolidino)thiazolo|4,5-c)quinolin-4-amine

MN; at 60 o'clock

Part A 2-(Methylsulfonyl)thiazolo|4,5-c|quinoline-5M-oxide (2.5g, 8.bmmol) and pyrrolidine (70ml) were combined and then boiled on a steam bath for 3 days. The resulting yellow precipitate was separated by filtration to obtain 0.4 g of 2-(1-pyrrolidino)thiazolo|4,5-c|quinoline-56M-oxide. The filtrate was cooled in an ice bath. 65 The resulting residue was separated by filtration to obtain 0.7 g of 2-(1-pyrrolidino)thiazolo|4,5-cquinoline-2M-oxide in the form of a yellow solid. The two portions were combined.

Part B

Ammonium hydroxide (12ml) was added to a mixture of 2-(1-pyrrolidino)thiazolo|4,5-c|quinoline-5M-oxide (0.8g, 2.95 mmol) and dichloromethane (50ml). The mixture was cooled and then tosyl chloride (0.6 mg, 3.2 mmol) in dichloromethane (1 mL) was slowly added. The reaction mixture was warmed to room temperature and then stirred overnight.

The organic phase was separated, washed with a saturated aqueous solution of sodium bicarbonate and then concentrated under vacuum to give the crude product as a yellow solid. This material was purified by column flash chromatography, then suspended in hot methanol, cooled and isolated by filtration of 0.14 g of 2-(1-pyrrolidino)thiazolo|4,5-c|quinoline-4-amine as a solid, mp . 259-26170. Analysis: Calculated for С45Н14МА: 90, 62.20; 90Н, 5.22; 9o0M, 20.49; Found: 95C, 61.76; 9oH, 5.25; 9oM, 20.72.

Example 55 2-Propylthiazolo|4,5-c|quinoline-4-amine xynofoate on MH - 4 M and 5 2-Propylthiazolo|4,5-c|quinoline-4-amine (3.0g, 12.mmol) and 1-hydroxy-2-naphthoic acid (2.3 g, 12.3 mmol) were dissolved separately in methanol using dichloromethane if necessary. The two solutions were combined and the total volume of the solution was reduced. The obtained residue was separated by filtration to obtain 3.bg 2-propylthiazolo|4,5-c|quinolin-4-amine xinofoate in the form of a colorless crystalline substance, Tpl. 185-189" (decomposes). Analysis: Calculated for С 25Н21М3О3: 90, 66.80; 95Н, 4.91; 95М, 9.74; Found: 90, 66.71; 95Н, 5.07; 95М, 9 , 78. see

Example 56 o 2-Propylthiazolo|4,5-c)|quinoline-4-amine. C-hydroxy-2-naphthoate

ХК он зи

SS 7 oyu «t hy ook ky 8 t so

A solution of 3-hydroxy-2-naphthoic acid (1.9 g, 7 mmol) in methanol (30 mL) was added to a solution of 2-propylthiazolo|4,5-c|quinoline-4-amine (2.4 g, 10 mmol) in hot methanol (70 ml). A precipitate formed immediately.

The mixtures were heated for another 5 minutes and then allowed to cool to room temperature. The precipitate was separated by filtration, washed with methanol and dried to obtain 4.0 g of the product in the form of a yellow-brown powder. This material was recrystallized from a mixture of methanol/dichloromethane to give 3.2 g of 2-propylthiazolo|4,5-siquinolin-4-amine 3-hydroxy-2-naphthoate as a white powder. Calculated for

Со4Но»3М3О38: 95С, 66.80; OBN, 4.91; 9oM, 9.74; Found: oS, 66.28; 9UoN, 4.92; 9oM, 9.59.

Example 57 "2-Butylthiazoloi|4,5-s|1,5)Inaphthyridine-5M-oxide with c ocia Kk, z" - | f o

Part A

Me. A mixture containing 3-nitro|1,5|inaphthyridin-4-ol (7.5g), methanol (200Oml), ammonium hydroxide (5Oml) and 590

Go! platinum on charcoal (0.75 g) was kept in the Parr apparatus for b hours. The reaction mixture was filtered to remove the catalyst and then filtered a second time using Celite). The filtrate was concentrated under vacuum to give 6.1 g of 3-amino/1,5|inaphthyridin-4-ol as a brown solid. because o Part B

Valeril chloride (4.3 g, Zbmmol) was added dropwise to a suspension of 3-amino/1,5|naphthyridin-4-ol (5.2 g,

T» 32mmol) in pyridine (10Oml). The reaction mixture was boiled for 2 hours. Pyridine was removed. The resulting residue was transferred to hot water and then left to cool. The resulting gray precipitate was separated by filtration, washed well with hot water then dried to obtain /--2.3 gH 29 M-(4-hydroxy|1,5|naphthyridin-3-yl)pentamide as a gray solid.

GF) Part B

Phosphorus pentasulfide (4.2g, 9U4mmol) was added to a suspension of M-(4-hydroxy|1,5)inaphthyridin-3-yl)upentamide de (2.3g, 9.4mmol) in pyridine (150ml). The reaction mixture was boiled for 2 hours. Pyridine was removed. The resulting residue was transferred to a mixture of water, 1095 sodium carbonate and 1095 sodium hydroxide (an amount sufficient to obtain 60 pHN»8) and then extracted twice with dichloromethane. The dichloromethane extracts were combined, washed with a saturated aqueous solution of sodium chloride, dried and then concentrated under vacuum. The residue was diluted with toluene and then concentrated under vacuum to obtain 2 g of black syrup. This material was purified using silica gel column chromatography to afford 1.4 g of 2-butylthiazolo|4,5-s|(1,5|Inaphthyridine as an amber liquid. High Resolution Mass Spectrometry (RE): Calculated for 69 Si3H1z3M38 (M) 243.0830; Found 243.0825.

Part G

A solution of 3-chloroperbenzoic acid (1.1 g 57-8690) in chloroform (5 Oml) was added dropwise to a solution of 2-butylthiazolo|4,5-cI(1,5|Inaphthyridine (1.4 g, 5.8 mmol) in chloroform (100 mL). The reaction mixture was stirred at room temperature for 2.5 hours and then diluted with dichloromethane, washed twice with 1095 sodium hydroxide, washed with saturated aqueous sodium chloride solution, dried and concentrated under vacuum to give a light yellow syrup which solidified on standing. The material was purified by column chromatography on silica gel to give 1.2 g of a pale yellow solid. 5M-oxide, melting point 65-697 C. Analysis: Calculated for С 13Н43М3О5: 95С, 60.21;

UN, 5.05; UM, 16.20; Found: 95, 60.43; 95Н, 5.17; 90M, 16,18. High Resolution Mass Spectrometry (HRMS): Calculated for C4z3NisM3O5 (M") 259.0779; Found 259.0789.

Example 58 2-Butylthiazolo|4,5-s|(/1,5Inaphthyridin-4-amine

ME in M

I | t yZ 5 y

A solution of /2-butylthiazolo|4,5-c|(/1,5|Inaphthyridine-5M-oxide (0.5 g, 1.0 mmol) in dichloromethane (100 ml) was cooled in an ice bath. A solution of trichloroacetyl isocyanate (0, 4g, 2.1mmol) in dichloromethane (25ml). The reaction mixture was stirred at room temperature for 8 hours. By adding ammonia in methanol, the reaction mixture was made basic and then left overnight. The reaction mixture was further diluted with dichloromethane and then washed twice with 1095 sodium hydroxide, washed saturated aqueous CM sodium chloride solution, dried and concentrated under vacuum to give 0.bg of a pale yellow solid. This o material was purified by column chromatography on silica gel and then recrystallized from acetonitrile (dml) to give 0.15 g of 2-butylthiazolo|4, 5-si(1,5)naphthyridine-4-amine in the form of white crystals,

Tpl. 136-138"С. Analysis: Calculated for С43Н14МАЗ: 90, 60.44; 95Н, 5.46; 90М, 21.69; Found: 95С, 60.12; УоН, 5.42; 90М, 21.51. High-resolution mass spectrometry (HRMS) Calculated for С 13Н44МА5 (М"). 258.0941 "

Found: 258.0939. NMR chemical shifts in SOSIzZ (m.h.) 8.637 dd (IN, |- 3.6; 1.2 Hz), 8.048 dd (1Н, и-8.5; со 1.2 Hz), 7.48 bdd (1Н , i-8.55 3.6Hz), 5.91 shes (2H), 3.196t (2H, |-7Hz), 1.918 quintet (2H, |-7Hz), 1.509 sextet (2H, |Y-7Hz), 1.003 t (ZH, iY-7Hz). me)

Example 59 so 2-Propylthiazolo|4,5-si(1,5|Inaphthyridine-5M-oxide o. M (Se) 1 dra se r « du Part A z

The general procedure of Example 57 was used, Part B, 3-amino|1,5|Inaphthyridin-4-ol (1.8 g, 11.2 mmol) was reacted with butyryl chloride (1.3 g, 12.3 mmol) to give 1.2 g :z» M-(4-hydroxy/1,5)naphthyridin-3-yl)butanamide in the form of a coal-gray solid, Mpl. 236070.

Part B

Using the general procedure of Example 57, Part B, M-(4-hydroxy/1,5)naphthyridin-3-yl)butanamide y - y b (1.27, 5.2 mmol) was reacted with phosphorus pentasulfide (2.3 g, 52 mmol) ) obtaining 0.9 g of 2-propylthiazolo|4,5-s|(1,5Inaphthyridine in the form of an amber-colored syrup. (ee) Part B

We used the general method of Example 57 Part G, 2-propylthiazolo|4,5-s|(/1,5|naphthyridine (0.9Hg,

C, mmol) was oxidized to obtain 0.7 g of 2-prolylthiazolo|4,5-s|(/1,5|Inaphthyridine-5M-oxide in the form of a pale yellow (ee) 50 solid, melting point 139-1427С. Analysis : Calculated for C 12Н14М3О5: 90, 58.76; 95Н, 4.52; 9оM, 17.13;

GT" Found: 95C, 58.66; 95Н, 4.59; 90M, 17.16. High-resolution mass spectrometry: (EI) calculated for

SLANp"O5 (M) 245.0623; Found 245.0612.

Example 60 2-Propylthiazolo|4,5-si(/1,5)naphthyridine-4-amine

ME" o Tue still Dr bo still

The general method of Example 58 was used, 2-propylthiazolo|4,5-s|(/1,5|Inaphthyridine-5M-oxide (0.5g, 2mmol) was aminated to obtain 0.2g of 2-propylthiazolo|4,5-s|1 ,5|naphthyridine-4-amine in the form of an ivory-colored residue, M.P. 135-136". Analysis: Calculated for С42Н42МАЗ: 90, 58.99; 95Н, 4.95; 90М, 22.93;

Found: 95C, 59.06; 95H, 4.96: 95M, 22.97. High Resolution Mass Spectrometry (HRMS) Calculated for 65 С12Н12М.5 (М") 244.0783; Found 244.0785.

Example 61

2-Propylpyrido3,4-hy|(1,9)hiazole-5M-oxide

Ex. 5

Part A

A suspension of 3-nitropyridin-4-ol (1.0g, 7.1mmol) in methanol (110ml) and a small amount of Raney nickel was charged to a Parr flask and hydrogenated for 4 hours. The reaction mixture was acidified with a solution of hydrochloric acid in ethanol and then filtered to remove the catalyst. The filtrate was filtered again at 70 using Celite. The filtrate was concentrated under vacuum to obtain 1.2 g of 3-aminopyridin-4-ol in the form of a brown powder, Tpl. 199-20076.

Part B

N,M-Diisopropylethylamine (33ml, 180mmol) was added to a suspension of 3-aminopyridin-4-ol (8.5g, 4bmmol) in dichloromethane (1000ml). A solution of butyryl chloride (5.4 g, 5 Bimol) in dichloromethane (100 ml) was added dropwise. 75 The reaction mixture was stirred at room temperature for 3 hours and then at reflux for 3 hours. The reaction mixture was filtered to remove the black precipitate. The filtrate was concentrated under vacuum. The resulting light brown residue was triturated with hot ethyl acetate (2500 ml) and then left overnight. The mixture was filtered to remove solids (9.1 g) and the solids were washed with fresh ethyl acetate. The filtrate was concentrated under vacuum to obtain 13 g of light amber syrup. The syrup was dissolved in water and then extracted twice with ethyl acetate. The extracts were combined, washed with a saturated aqueous solution of sodium chloride, dried and then concentrated under vacuum to obtain 2.5 g of amber-colored syrup. This material was purified by column chromatography to give 1.2 g of M-(4-hydroxypyrid-3-yl)butanamide as a light amber syrup which solidified on standing.

Part V Ge!

Using the general procedure of Example 57, Part B, M-(4-hydroxypyrid-3-yl)butanamide (1.1 g, b, mmol) was reacted with phosphorus pentasulfide (2.7 g, b mmol) to give b4g of 2-propylpyrido. C3,4-41(/1,3)hiazole in the form of an amber-colored syrup, which solidified on standing, Tpl. 44-47".

Part G

The general method of Example 57 was used. Part D, 2-propylpyrido/3,4-41|(1,3-Ithiazole (0.4g, "Ж 2.2mmol)) was oxidized to obtain 0.2g of 2-propylpyrido/3,4-411,9| thiazole-5M-oxide as an ivory-colored residue after crystallization from ethyl acetate (/ml), mp 137-1397 C. Analysis: Calculated for Со9NiоМ2О5: содос, 55.65; 9оН, 5.19; 90М, 14, 42; Found: 95С, 55.47; 95Н, 5.25; 9о0М, 14.34. со

Example 62 2-Propylpyrido3,4-si|(1,3)thiazol-4-amine trifluoroacetate so ve (se) - M

Fe ra at 5 "

A solution of trichloroacetylisocyanate (0.11g, 0.bmmol) in dichloromethane (5 ml) was added dropwise to a cooled (ice bath) solution of 2-propylpyrido3,4-4111,3hiazole-5M-oxide (0.1g, 0.bmmol) in C with dichloromethane (20 ml). The reaction mixture was stirred at room temperature for 5 hours. Trichloroacetyl isocyanate (0.2 g) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was rapidly heated to boiling and then allowed to stir at room temperature for approximately 3 hours. Ammonia was bubbled through the reaction mixture, which was then allowed to stir at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane, washed twice with 1095 ia sodium hydroxide, washed with a saturated aqueous solution of sodium chloride, dried and then concentrated under vacuum to obtain an amber-colored syrup. The reaction was repeated again. The products were combined to obtain 0.1 g of amber syrup. This material was purified by semi-preparative HPLC o using a Gilson system (Kaipip Misgovog C18 column, 21.4525 Ohm, particle size 8 microns, BOA pores, o 20 1Oml/min., eluent gradient from 2-9595 V in 25 min., retention at 9595 In the course of 5 min., where A-0.1956 trifluoroacetic acid/water and B-0.195 trifluoroacetic acid/acetonitrile, a peak was recognized at 254 nm for the starting

T" of the fractional collection). Fractions of semi-preparative HPLC were analyzed using LC-ARSI/MS and suitable fractions were lyophilized to obtain the desired product in the form of a trifluoroacetate salt, Tpl. 160-16270. Analysis:

Calculated for СоН.и«М3зЗАСЕзС(О0)2Н: 95С, 42.99; 95Н, 3.94; 90M, 13.67; Found: 90, 42.84; 95Н, 3.98; 9oM, 22 13.52. High-resolution mass spectrometry: (EI) calculated for C 9H414Ma35 (Mk) 193.0674; Found

F! 193.0681.

Example 63 o 7-Chloro-2-propylthiazolo|4,5-s)|quinoline-4-amine

MH bo nia, and fo si v5 Part A 7-Chloro-4-hydroxyquinoline (35g, 0.195 mol; obtained from Algissy, Mim/acKee, UMI) and nitric acid (35O0ml

7090) were combined and boiled for 75 minutes. The reaction mixture was poured hot onto ice. The resulting dark yellow precipitate was separated by filtration and then washed 3 times with boiling ethyl acetate to give 17.3 g of 7-chloro-3-nitro-4-hydroxyquinoline as a pale yellow solid.

Part B 7-Chloro-3-nitro-4-hydroxyquinoline (4.48g, 20mmol), tin(II) chloride dihydrate (22.6g, 1000mmol) and ethanol (200ml) were combined and then boiled for 4 hours . The reaction mixture was cooled to room temperature and then poured into water (250 ml). The pH of the mixture was adjusted to neutral by adding saturated sodium bicarbonate solution and then filtered to remove tin salt. The filtrate was extracted with ethyl acetate. The combined 7% organic fractions were dried over magnesium sulfate, filtered and then concentrated under vacuum to obtain 1.8 g of 3-amino-7-chloro-4-hydroxyquinoline as a green powder.

Part B

Under a nitrogen atmosphere, butyryl chloride (0.7 bml, 7.mmol) was added dropwise to the mixture

of 3-amino-7-chloro-4-hydroxyquinoline (1.3g, b/mmol), triethylamine (30ml, 21.5mmol) and anhydrous 7/5 tetrahydrofuran (20ml). The reaction mixture was kept at room temperature overnight. The obtained residue was separated by filtration, washed with water, then with tetrahydrofuran and then dried under vacuum to obtain 1.05 g of M-(7-chloro-4-hydroxyquinolin-3-yl)butanamide in the form of a yellow-brown powder.

Part G

A mixture of //M-(7-chloro-4-hydroxyquinolin-3-yl)/butanamide (0.9g, 34mol), phosphorus pentasulfide (1.51g, 34mmol) and pyridine (25ml) was refluxed in an atmosphere nitrogen for 2.5 hours and then allowed to cool to room temperature. The reaction mixture was partitioned between dichloromethane (100ml) and saturated sodium bicarbonate solution (1000ml). The aqueous layer was extracted with dichloromethane (2x1O00Oml).

The organic fractions were combined, washed with water, dried over magnesium sulfate, filtered and then concentrated under vacuum to obtain a crude product. This material was purified by silica gel chromatography (97:3 dichloromethane:methanol, 10g io) to give 0.62g of 7-chloro-2-propylthiazolo[4,5-c)quinoline as a golden yellow solid. at

C-chloroperbenzoic acid (0.7g 57-8690) was added portionwise to a mixture of 7-chloro-2-propylthiazolo|4,5-c|quinoline (0.5g, 1.9mmol) and chloroform (20ml). After 2 hours at room temperature, 3-chloroperbenzoic acid (0.2 g) was added and the reaction mixture was left at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane and then washed twice with saturated sodium bicarbonate solution. The organic fractions were dried over magnesium sulfate, filtered, and then concentrated under vacuum to give 0.52 g of 7-chloro-2-propylthiazolo|4,5-c|quinoline-5M-oxide as an orange solid. co

Part E Ge) trichloroacetyl isocyanate (0.32 ml, 2.7 mmol) was added to a mixture of 7-chloro-2-propylthiazolo|4,5-s|quinoline-5M-oxide (0.50 g, 1.8 mmol) and dichloromethane under a nitrogen atmosphere (20 ml). The reaction mixture was left at room temperature for 2 hours and then concentrated under vacuum. The obtained oily residue was dissolved in methanol (1 ml), sodium methoxide (1 ml 2595, 4.4 mmol) was added and the reaction mixture was left at room temperature for 2.5 days. The obtained residue was separated by filtration and washed (PE) with hexane to obtain 0.28 g of the desired product in the form of a golden-yellow powder. A portion of 5mg was recrystallized from methanol to give //7-chloro-2-prolylthiazolo|4,5-c|quinolin-4-amine in the form of "» golden-yellow crystalline substance, M.P. 159-16070. IN nNMR (ZOOMHc, DMSO -dv) 65 7.82 (d, U-8.5Hz, 1H), 7.60 (d, |-2.0Hz, 1), 7.27 (dd, |-8.5, 21Hz, 1), 7, 10 (s, 2H), 3.16 (t, )-7.4Hz, 2H), 1.87 (sextet, |Е7.АХц, 2H), 1.02 (t, )57.4Hz, ZN); MU ( EI) t/e 277.0441 (277.0440 calculated for SizN.»SiIM35).

Ge) Example 64 with 7-Methoxy-2-propylthiazolo|4,5-s|quinoline-4-amine

MN; I M (95) M Where (ee) iz" Her

Part A

3-Methoxyaniline (12.3 g, 0.1 mol) and diethyl ethoxymethylene malonate (21.6 g, 0.1 mol) were combined and heated at 259 at 1202C for 3 hours. The reaction mixture was allowed to cool to room temperature and then

HF) was kept under vacuum overnight, obtaining 28.5 g of diethyl 2-I33-(methoxyanilino)methylene|malonate in the form of an orange oil. o Part B

Dowtherm A (-7200ml) was loaded into a flask equipped with a stirrer, a nitrogen inlet, a Dean-Stark nozzle and a 60° refrigerator. The solvent was heated to intense boiling and then 2-13-"methoxyanilino)methylene|malonate (20.0 g, bvmmol) was added. The reaction mixture was heated for 0.5 g and the brown solution was allowed to cool to room temperature. The obtained residue was separated by filtration, washed with acetone and then dried in air to obtain 12.5 g of ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate in the form of a yellow powder. because Part B

A suspension of ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (12.0g, 4v8mmol) in 1095 sodium hydroxide/water (200ml) was boiled for 1.5h. The reaction mixture was left to cool to room temperature and then acidified (pH-Z3) by dropwise addition of concentrated hydrochloric acid. The resulting residue was separated by filtration, washed twice with water and then dried overnight in a vacuum at 80"C to obtain 10.4 g of 4-hydroxy-7-methoxyquinoline-3-carboxylic acid.

Part G

A suspension of 4-hydroxy-7-methoxyquinoline-3-carboxylic acid (4.0 g) in deuterium A (75 ml) was boiled for 2 h. The resulting brown solution was left to slowly cool to room temperature. The obtained 7/0 residue was separated by filtration and then dried in a vacuum at 80"C for 2.5 days to obtain 3.1 g of 7-methoxyquinolin-4-ol as a light yellow-brown solid.

Parts

A mixture of 7-methoxyquinolin-4-ol (5.0g, 28.5mmol) and propionic acid (50ml) was heated to boiling. Nitric acid (3.2ml 70906, 5Omol) was added dropwise over 15 minutes. The reaction mixture was boiled with 7/5 Reflux for 2 h and then allowed to cool to room temperature. The resulting residue was filtered off, washed with cold ethanol, then hexane, and then dried to give 3.9 g of 7-methoxy-3-nitroquinolin-4-ol as a gray solid.

Part E

7-Methoxy-3-nitroquinolin-4-ol (4.5g, 20.4mmol), methanol (250ml), ammonium hydroxide (5ml) and palladium on carbon (400mg 1095) were combined. The mixture was kept in the Parr apparatus at a hydrogen pressure of 40 Opsi (2.8 Kg/cm2) for 2 hours. The reaction mixture was filtered. The filtrate was concentrated under vacuum to give a green solid. This material was dissolved in methanol (200ml) and then hydrochloric acid in diethyl ether (75ml) was added.

The resulting residue was filtered off and dried to give 2.6 g of 3-amino-7-methoxyquinolin-4-ol hydrochloride as a pink solid. Ha

Part E

Butyryl chloride (0.6 mL, b mmol) was added dropwise to the solution containing i9)

3-amino-7-methoxyquinolin-4-ol hydrochloride (1.0 g, 5.2 mmol), triethylamine (2.35 mL, 16.8 mmol), dichloromethane (30 mL), and N,M-dimethylformamide (1 mL). The reaction mixture was kept at room temperature overnight.

M,M-Dimethylformamide was removed in vacuo and the resulting solid was partitioned between dichloromethane (100 mL) and water (100 mL). The organic fraction was washed with water, dried over magnesium sulfate, filtered and then concentrated under vacuum to obtain 0.8 mg of M-(4-pdroxy-7-methoxyquinolin-3-yl)butanamide as a yellow-brown solid. co

Part Z

Under a nitrogen atmosphere, a mixture of M-(4-hydroxy-7-methoxyquinolin-3-yl)butanamide (0.66 g, 2.54 mmol), pyridine CO (2 O mL), and phosphorus pentasulfide (1.13 g, 2.54 mmol) was heated under reflux refrigerator and then cooled to room temperature. The reaction mixture was filtered. The filtrate was partitioned between dichloromethane (100ml) and saturated sodium bicarbonate solution (1000ml). The aqueous fraction was extracted by adding dichloromethane (100 ml).

The organic fractions were combined, washed with water, dried over magnesium sulfate, filtered and then concentrated under vacuum to obtain a solid. This material was purified by chromatography on silica gel (15 g of 5" was eluted with a mixture of 95:5 dichloromethane:methanol) to obtain 045 g and c of 7-methoxy-2-propylthiazolo|4,5-c|quinoline in the form of a pale yellow powder. ц Part C "» Using the method of Example 63 Part D, 7-methoxy-2-propylthiazolo|4,5-c|quinoline (0.40g, 1.55mmol) was oxidized to give 7-methoxy-2-propylthiazolo|4,5- c|quinoline-5M-oxide as an orange solid.

Part

Ge") Using the method of Example 63 Part EE, the M-oxide from Part D was reacted with trichloroacetyl isocyanate and the resulting amide hydrolyzed to give 190 mg of the desired product as an off-white solid. The analytical sample was obtained as a result of crystallization from methanol, obtaining (95) 7-methoxy-2-propylthiazolo|4,5-c|quinolin-4-amine in the form of an almost white residue, mp. 152-1542S. "H NMR (SO0MHC, so 50 DMSO-av) 5 7.67 (d, 9U-8.7Hz, 1H), 7.06 (d, i-2.4Hz, 1H), 6.91 (dd, )- 8.7, 2.5Hz, 1H), 6.82 (s, 2H), 3.86 (s, ЗН), 3.11 (t, )-7.4Hz, 2H), 1.85 (sextet, |-7.4 Hz, 2H), 1.01 (t, )|-7.4Hz, ZN); MS (EI) t/e 273.0934 i" (273.0936 calculated for С.445Н4и5М3О5).

STIMULATION OF INTERFERON (9) IN HUMAN CELLS

Human blood cells were used to evaluate interferon stimulation by the compounds of the invention. 2o The study is based on the measurement of interferon secretion in the culture medium. The content of interferon was measured using a biological sample.

Obtaining blood cells for culture medium Whole blood was collected by venipuncture in EDTA vacutainer flasks. Peripheral blood mononuclear cells (PBMC) were separated from the whole blood mass using either I esoRKER; tm Vgapa Seyi Zeragaiop Tyrez 60 (received from Vesiop Oiskipzop), or RisoiI-Radoie solution? (obtained from Ripaptasia KV Vioiesppolodu Ips,

Rivsaiamau, M). MKPC was suspended to a concentration of 1x105/ml in ERMI 1640 medium (obtained from

SIVS(O), Ogapa IviIapa, MU), which contained 25MM NEREZ (M-2-hydroxyethylpiperazine-M'-2-ethanesulfonic acid) and

I-glutamine (195 penicillin-streptomycin solution was added) with the addition of 1095 heat-inactivated (5672 for 30 minutes) embryonic calf serum. A 200-μl portion of the MKPC suspension was added to a 96-well (flat bottom) plate containing a sterile tissue culture (Vesiop Oiskipzop I arzhmage, I ipsoip Ragk, MU).

Preparation of compounds

Compounds were dissolved in ethanol, dimethylsulfoxide or tissue culture water, then diluted with tissue culture water, 0.01M sodium hydroxide or 0.01M hydrochloric acid (the choice of solvent depends on the chemical characteristics of the compound to be studied). The concentration of ethanol or DMSO should not exceed the final concentration of 190 after addition to the culture wells. The compounds were initially tested at concentrations ranging from about 0.1 µg/ml to about 5 µg/ml. Compounds that showed activity at a concentration of 0.5 μg/ml were then studied at a wider range of values.

Incubation 70 The solution of the test compounds was added in a volume (less than or equivalent to 5 Ωcl) to the wells containing 200 μl of diluted blood or MKPC medium. Solvent and/or medium was added to control wells (wells without test compounds) and, if necessary, the final volume in each well was adjusted to 250 μl. The plates were covered with plastic film, gently mixed and then incubated for 48 hours at 37"C in an atmosphere containing 595 carbon dioxide.

Separation

After incubation, the plates were covered with parafilm and then centrifuged at 1000 rpm for 10 to 15 minutes at 4"C in a Juatop EC Mode! SKO-5000 centrifuge. The medium (approximately 200 μl) was removed from 4-8 wells and combined in 2 ml sterile chilled bottles. Samples were stored at -70"C until analysis.

Analysis/calculation of interferon

The content of interferon was determined by a bioassay in which human A549 cells isolated from female breast carcinoma caused by encephalomyocarditis were used. Details of the biosample method are described by 0. I. Vgeppap and Y.. N.

Ktgopepregd in "Atsiotaiei Vioazzau ipiepegopz ov Misgo-ievi Riafev", Vioyespppidtsev, ipe/)shu, 78, 1983, incorporated herein by reference. Briefly, the method is as follows: diluted interferon and AB49 cells were incubated at 37"C for 12-24 hours. The incubated cells were infected with the sch ov encephalomyocarditis virus. The infected cells were incubated for some time at 377"C before determining the viral cytopathic effect. The viral cytopathic effect was determined by measuring i) spectrophotometric absorption. The results were expressed in the form of an alpha ratio of units/ml based on the values obtained for MIN NI IR-I. standard Interferon was determined as essentially all interferon alpha by staggered neutralization studies with rabbit anti-human E interferon (beta) and goat anti-human interferon (alpha) using A5b49 monolayers of encephalomyocarditis virus cells. co

The compounds of the invention were tested for their ability to induce interferon in human cells using the test method described above. The results are shown in the table below, in which "" means that the compound induces α-interferon, in particular, at this concentration, "- means that the compound does not induce α-interferon, in particular, at this concentration, and "ж-" means that the results are questionable, in particular, at this concentration. -1151 do not conduct did not conduct|did not conduct, 41111215 where conducted did not conduct did not conduct

I" 5 1-1 811-111 not conducted not conducted not conducted. 12 (kr xx not conducted not conducted not conducted.

F 4 1-1 111 not conducted not conducted not conducted. 16 1-10 1-0 not conducted not conducted not conducted! so 8 1-1 1119 not carried out not carried out ZO POLE in 110111 days was not conducted not conducted. in 1-10 0-0 not conducted not conducted not conducted 82 1-11 1 he conducted not conducted did not conduct! about from 1-11. not carried out not carried out not carried out) name) in the 7th century in Rlorvorova oo | in | in 1777-1171 the 1st did not conduct it did not conduct it! 177-17-11. -11 conducted not conducted not conducted 17771111 133 conducted not conducted not conducted by it was not carried out! 4911-1111 was not carried out it was not carried out it was not carried out it was not carried out it was not carried out

CYTOKINE STIMULATION IN HUMAN CELLS

Human blood cells were used to evaluate cytokine stimulation by the compounds of the invention.

The study is based on measuring the secretion of α-interferon and α-tumor necrosis factor (IFN and FRN, respectively) in the culture medium, as described by Tezieptap em oai. in "SuyukKipe Ipdysiop bu "Zhe

Ittypotoatsiags Ipidcytoad apa 5-27609", Proceedings of Geocosmology. 58, 365-372 (Zerietrieg, 1995).

Obtaining blood cells for culture medium

Whole blood was collected by venipuncture in EDTA vacutainer flasks from healthy human donors. Peripheral blood mononuclear cells (PBMCs) were separated from the whole blood mass by centrifugation using Nizioradoet-1077 (Zidta SPetisai5, Zi Yotsiz, MO). MKPC was suspended to obtain a concentration of 3-4x10b/ml in ERMI 1640 medium containing 1095 embryonic calf serum, 2MM

I-glutamine and 190 penicillin/streptomycin solution (CRMI complete). The ICP suspension was added to a 48-well flat-bottom plate containing a sterile tissue culture (Soviag, Satrgidde, MA og Vesiop bisKipzop

I armage, I ipsoip Ragk, MU), containing equal volumes of KRMI complete medium containing the test compound. at

Preparation of compounds

The compounds were dissolved in dimethylsulfoxide (DMSO). The concentration of DMSO should not exceed the final concentration of 195 after addition to the culture wells. The compounds were mainly studied at concentrations ranging from about 0.12 to ZOμM.

Incubation 09

The solution of the test compound was added in bOmK to the first well containing complete KRMI and a series of 3-9 dilutions was made. The MCPC suspension was added to the wells in equal volumes, bringing the concentration of the tested compounds to the desired range (0.12-3ΩμM). The final concentration of the MCPC suspension is 1.5-2 x109 cells/ml. The plates were covered with a sterile plastic film, carefully mixed and then incubated for (Ce) 18-24 hours at 37"C in an atmosphere containing 595 carbon dioxide.

Separation

After incubation, plates were centrifuged for 5-10 minutes at 700 rpm (5200 x 9) at 4 rpm.

The cell culture supernatant was removed using a sterile polypropylene pipette and transferred to a sterile polypropylene flask. The samples for analysis were stored at a temperature from -30 to -10°C. The samples were analyzed for the content of os-interferon either by the EP IZA method, or biosamples or for the content of o-factor "» of tumor necrosis by the EG IZA method. Analysis of interferon bioassay

The interferon content was determined by the bioassay method, which used human A5bB49 cells isolated from female breast carcinoma caused by encephalomyocarditis. Details of the bioassay method are described in 0.1. me) Vgeppap and G.N. Ktopepreg in "Aziotaei Vioazzau ipiebegopz v Misgo-iezi Ria(ev), Vioyesppidnev, ipe/9Oshu, p. 78, 1983, incorporated herein by reference. A brief method is as follows: Ab549 cells were incubated with diluted sample or standard interferon at 37 "C for 24 hours. Incubated cells were infected with encephalomyocarditis virus. Infected cells were incubated for another 24 hours at 377C with 20°C before determining the viral cytopathic effect. The viral cytopathic effect was determined by the degree of crystal violet staining after visual analysis of the plates. The results were expressed as » alpha ratio of units/ml based on the values obtained for MIN NI IR-I standard.

Analysis of the content of o-interferon and tumor necrosis factor 5 by the EGISA method

The concentration of a-interferon was determined by the EGISA method using the Nitap Miyi-Zresiez kit from 22 RVI Viotedis) I Abogaiyugiev, Mem Vgypvuisk, MU, according to the attached instructions.

GF) The concentration of o-tumor necrosis factor (TNF) was determined by the EGISA method, the kits were obtained from Sepgute,

Satrgidde, MA; KO bBuvietv, Mippearoiis, MM; or RIagtipdep, Zap Oiedo, SA, according to the attached instructions.

In the tables below, "y" means that the compound induces a cytokine, in particular, at that concentration, "-" 60 means that the compound does not induce a cytokine, in particular, at that concentration, and "-" means that the results are equivocal, in particular, at this concentration. bo Concentration (µm) Concentration (µm)

11 house odt tt vazi to zo om | from | duty | 383 | then | zo a r v syu 1 1511-11 m 1-11 i 1 1-1 in 1-11 -1-1-1-1-1 1

You tt e I O OEU EP FIELD FIELD WITH FIELD NN SHEU SHE to syu 1-1 1-1 kr in 1-11 in zr

ПНИ ЦЦ ЦЦ ЦЦ VEU PE ПР ОЧНЯ ПОХНУ OUN PERUN ОЧН

The presented invention has been described with reference to some of its embodiments. The foregoing detailed description and examples are provided for clarity of understanding only and should not be construed as limiting. It should be readily apparent to one skilled in the art that many changes may occur in the described embodiments without departing from the spirit and scope of the invention. Thus, the scope of the invention should not be limited to the essential details of the compositions and chemical structures described herein, but rather to the details of the claims that follow.

Claims (25)

The formula of the invention 1. Oxazolo-, thiazolo-, and selenazoloi|4,5-s|quinolin-4-amines of the formula (1): Mn; (о, о M | у в, а и 1 t КЗ с Кк, со in which со Ку is selected from the group containing oxygen, sulfur and selenium; EK" is selected from the group containing (Ce)-hydrogen; -alkyl ; -alkyl-OH; « -haloalkyl; -alkenyl; - c -alkyl-X-alkyl; h -alkyl-X-alkenyl; ,» -alkenyl-X-alkyl; -alkenyl-X-alkenyl; -alkyl-H (Co)"; (o) -alkyl-M 3; o -alkyl-O-C(O)-M(K 5)"; -heterocyclyl; i95) -alkyl-X-heterocyclyl; so 50 -alkenyl-X-heterocyclyl; -aryl; I"-alkyl-X-aryl; -alkenyl-X-aryl; -heteroaryl; -alkyl-X-heteroaryl and o-alkenyl-X-heteroaryl; Ez and K4 each independently: where is hydrogen; -x-alkyl; 60 - halogen; -haloalkyl; -M(Kv)2; or when taken together, K3 and K4 form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring; 65 X is selected from the group containing -O-, -5-, -МКв-, -Ф(0)-, -ЧШЧЧО)0-, -ОС(О)- and a bond; and each Kv, independently, H or S. valkil; under the condition that when K. is sulfur, Kz is not -MN"; or pharmaceutically acceptable salts thereof 2. The compound according to item 1, in which K. is oxygen or sulfur. 3. A compound according to point 1, in which Kz and K; taken together form a substituted or unsubstituted benzene ring. 4. Compound according to point 2, in which Kz and Ku; taken together form a substituted or unsubstituted benzene ring. 5. A compound according to point 1, in which K»z and Ku; taken together form a substituted or unsubstituted pyridine 7/o Ring. 6. A compound according to point 2, in which K»z and Ku; taken together form a substituted or unsubstituted pyridine ring. 7. The compound according to item 1, in which K" is Si. by far 8. The compound according to point 2, in which K" is S. dalkil. 9. The compound of claim 1, wherein Cu is sulfur. 10. Compound according to point 9, in which Kz and Ku; taken together form a substituted or unsubstituted benzene ring. 11. The compound according to clause 10, in which K» is Si .dalkyl. 12. The compound according to clause 10, in which K» is n-propyl. 13. The compound according to item 1, which is 2-n-propylthiazolo|4,5-c|quinolin-4-amine or a pharmaceutically acceptable salt thereof. 14. The compound according to point 1, selected from the group containing: 2-methylthiazolyl|4,5-c|quinolin-4-amine; thiazolo|4,5-c|quinoline-4-amine; ch 2-ethylthiazoloi|4,5-s|quinolin-4-amine; 2-propylthiazolo|4,5-c|quinoline-4-amine; i) 2-pentylthiazolo|4,5-c|quinolin-4-amine; 2-butylthiazolo|4,5-c|quinoline-4-amine; 2-(1-methylethyl)thiazolo|4,5-c)quinolin-4-amine; 2-(2-phenyl-1-ethenyl)thiazolo[4,5-c]quinolin-4-amine; 2-(2-phenyl-1-ethyl)thiazolo|4,5-c|quinolin-4-amine; so 2-(4-aminothiazolo|4,5-c|quinolin-2-yl)-1,1-dimethylethyl carbamate; c 2-(ethoxymethyl)thiazolo|4,5-c|quinolin-4-amine; 2-(methoxymethyl)thiazolo|4,5-c|quinolin-4-amine; so 2-(2-methylpropyl)thiazoloyl|4,5-c)quinolin-4-amine; "o 2-benzylthiazolo|4,5-s|quinoline-4-amine; 8-methyl-2-propylthiazoloi|4,5-c|quinolin-4-amine; (4-aminothiazolo|4,5-c|quinolin-2-yl)umethanol; 2-methyloxazoloi|4,5-s|quinolin-4-amine; "2-ethyloxazolo|4,5-s|quinolin-4-amine; with c 2-butyloxazolo|4,5-c|quinolin-4-amine; . 2-propylthiazolo|4,5-c)quinoline-4,8-diamine; and?" 2-propyloxazolo|4,5-s|quinoline-4-amine; 8-bromo-2-propylthiazolo|4,5-c|quinoline-4-amine; 7-methyl-2-propylthiazolo|4,5-c|quinolin-4-amine; He» 2-butyl-7-methyloxazolo!|4,5-c|quinolin-4-amine; 7-methyl-2-propyloxazolo|4,5-c)quinolin-4-amine; so 7-fluoro-2-propyloxazoloi|4,5-s|quinolin-4-amine; 2) 7-fluoro-2-propylthiazolo[4,5-c]quinolin-4-amine; 2-propyl-7-(trifluoromethyl)thiazolo[4,5-c]quinolin-4-amine; so 2-(4-morpholino)thiazolo|4,5-c|quinolin-4-amine; 2-(1-pyrrolidino)thiazolo|4,5-c|quinolin-4-amine; 2-butylthiazolo|4,5-s|(1,5|Inaphthyridin-4-amine; 2-propylthiazolo|4,5-s|1,5|Inaphthyridin-4-amine; 7-chloro-2-propylthiazolo|4 ,5-c) quinoline-4-amine; 7-methoxy-2-propylthiazolo|4,5-c|quinolin-4-amine; F) and their pharmaceutically acceptable salts. ka 15. A pharmaceutical composition containing a therapeutically effective amount of the compound of formula (1): Mn, (), 60 M tes -v r e 'Ez 65 i, in which Cu is selected from the group consisting of oxygen, sulfur and selenium; EC" is selected from the group containing -hydrogen; -alkyl; -alkyl-OH; -haloalkyl; -alkenyl; -alkyl-X-alkyl; 70 - alkyl-X-alkenyl; -alkenyl-X-alkyl; -alkenyl-X-alkenyl; -alkyl-M(Co)"; -alkyl-M»z; -alkyl-O-C(O)-M(K 5)"; -heterocyclyl; -alkyl-X-heterocyclyl; -alkenyl-X-heterocyclyl; -aryl; -alkyl-X-aryl; -alkenyl-X-aryl; -heteroaryl; -alkyl-X-heteroaryl and -alkenyl-X-heteroaryl; each Ez and Ku independently: o - hydrogen; -x-alkyl; - halogen; -haloalkyl; "r - ShkKoe)"; or when taken together, Kz and Kl form a fused aromatic, heteroaromatic, cycloalkyl or co-heterocyclic ring; c X is selected from the group containing -О-, -5-, -МКв-, -С(0)-, - Ч(О)0-, -ОС(О)- and a bond; and each Kb, independently, H or S. dalkil; SO or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. co 16. A method of stimulating cytokine biosynthesis in a mammal, in which the composition according to item 15 is administered to the mammal. 17. The method according to item 16, in which the cytokine is 5:-IFN. 18. The method according to item 16, in which the cytokine is 5-TNF. " 19. The method according to item 16, in which the composition is administered locally. from the village 20. The method of treating a viral disease in a mammal, in which the composition according to item is administered to the mammal 15. ;" 21. The method according to item 20, in which the composition is administered locally. 22. The method of treating a neoplastic disease in a mammal, in which the composition according to item 15 is administered to the mammal. Ge" 23. The method according to item 22, in which the composition is administered locally. 24. Oxazolo, thiazolo, and selenazolo|4,5-s|quinoline-5o-oxides of the formula (11): so o: (I), o u Fo 70 | o-t to v, c» Ka Kk, in which Ku is selected from the group containing oxygen, sulfur and selenium; (F) EC" is selected from the group containing r - hydrogen; -alkyl; in -alkyl-OH; -haloalkyl; -alkenyl; -alkyl-X-alkyl; -alkyl-X-alkenyl; 65 - alkenyl-X-alkyl; -alkenyl-X-alkenyl; -alkyl-M(Co)"; -alkyl-M»u3; -alkyl-O-C(O)-M(K 5)"; -heterocyclyl; -alkyl-X-heterocyclyl; -alkenyl-X-heterocyclyl; -aryl; -alkyl-X-aryl; 70 -alkenyl-X-aryl; -heteroaryl; -alkyl-X-heteroaryl; -alkenyl-X-heteroaryl; -5025СНзи -Сн.-о-с(0)-СН"; Ez and Ku each independently: -hydrogen; -x-alkyl; - halogen; -haloalkyl; -MZh(Kv)2; or when taken together, K3 and K4 form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring; X is selected from the group containing -O-, -5-, -МКв-, -С(О)-, - Ф(О)О- and a bond; and sch each Kb, independently, H or S. dalkil. 25. The compound according to item 24, selected from the group containing: i) 2-methylthiazolo|4,5-c|quinoline-5M-oxide; 2-ethylthiazoloi|4,5-s|quinoline-5M-oxide; 2-propylthiazolo|4,5-s|quinoline-5M-oxide; "g zo 2-pentylthiazolo|4,5-s|quinoline-5M-oxide; 2-butylthiazolo|4,5-s|quinoline-5M-oxide; co 2-(1-methylethyl)thiazolo|4,5-c|quinoline-5M-oxide; c 2-(2-phenyl-1-ethenyl)thiazolo|4,5-c|quinoline-5M-oxide; 2-phenylethylthiazolo|4,5-s|quinoline-5M-oxide; so 2-methyl-1-thiazolo|4,5-c|quinolin-2-yl-2-propanol-5M-oxide; "o 2-(ethoxymethyl)thiazolo|4,5-c|quinoline-5M-oxide; 2-(Methoxymethyl)thiazolo|4,5-c|quinoline-5M-oxide; 2-(2-methylpropyl)thiazolo|4,5-c|quinoline-5M-oxide; 2-benzylthiazolo|4,5-s|quinoline-5M-oxide; « 8-methyl-2-propylthiazolo|4,5-c|quinoline-5M-oxide; with c 2-butyloxazolo|4,5-c|quinoline-5M-oxide. ;" Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2004, M 8, 15.08.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. (22) (ee) (95) o 50 s» F) ime) 60 b5