HRP20010127A2 - Oxamides as impdh inhibitors - Google Patents

Description

OXAMIDES AS IMPDH INHIBITORS

Description of the invention

The proposed invention relates to new oxamide derivatives, processes for their production, pharmaceutical preparations containing these derivatives, and the use of these derivatives as medicines. In particular, the proposed invention relates to new oxamide derivatives that are inhibitors of inosine monophosphate dehydrogenase (IMPDH).

Inosine monophosphate dehydrogenase (IMPDH) is an enzyme involved in the de novo synthesis of guanine nucleotides. The enzyme catalyzes the NAD-dependent oxidation of inosine-5'-monophosphate (IMP) to xanthosine-5'-monophosphate, which is the rate-limiting step in the synthesis of guanine nucleotides. As a result of the enzyme's key role in the biosynthesis of guanine nucleotides, the enzyme represents an important target for the development of inhibitors to be used as therapeutic agents in the treatment of IMPDH-related processes.

De novo synthesis of guanine nucleotides is particularly important for B- and T-lymphocytes to obtain sufficient amounts of nucleotides to support a proliferative response to a mitogen or antigen [Wu, I.C., Persp. in Drug Discovery and Design., 2, 185-204, (1994)]. Therefore, inhibition of IMPDH is an interesting target for selective inhibition of the immune system. IMPDH inhibitors are known [Pankiewicz, K.W., Exp. Opin. Ther. Patents., 9, 55-65, (1999)], and the noncompetitive inhibitor mycophenolic acid (MPA) has been shown to inhibit the response of B- and T-cells to a mitogen or antigen [Allizon, A.C. and Eugui, E.M., Transplant. Proc., 25, 8-18, (1993)]. MPA is therefore useful as an immunosuppressant.

IMPDH is also known to have a role in other rapidly proliferating cells, such as tumor cell lines, indicating that inhibition of IMPDH is a target in cancer chemotherapy [Nagai, M. et al., 51, 3886-3890, (1990 )].

IMPDH inhibition has also been shown to play a role in viral replication in some cell lines that support viral replication [Pankiewicz, K.W., Exp. Opin. Ther. Patents., 9, 55-65, (1999)]. Ribavirin, for example, is a broad-spectrum antiviral agent approved by the U.S. for use as an aerosol for children with serious respiratory infections due to respiratory syncytial virus. Food and Drug Administration, and is also used as an agent for the treatment of patients infected with the hepatitis C virus when used in combination with interferon [Patterson, J.L. and Fernandez-Larsson, R., Rev. Infect. Dis., 12, 1139-1146, (1990); McHutchison, J.G. et al., New. English J. Med., 339, 1549-1550, (1998)]. Ribavirin is converted in cells to ribavirin 5' monophosphate, which is an IMPDH inhibitor.

In addition, the IMPDH inhibitors ribavirin and MPA have been shown to inhibit the replication of the yellow fever virus (RNA virus), while MPA has been shown to inhibit the replication of the hepatitis B virus (DNA virus) in vitro, supporting a wide range of antiviral activity as an inhibitor [ Neyts , J. et al., Antiviral Res., 30, 125-132, (1996); Gong. Z.I. et al., J. Viral Hepatitis., 6, 229-236, (1999)]. In addition, MPA has also been shown to enhance the antiviral effects of nucleoside analogs in vitro and in animal models [Neyts, J. and De Clercq, E., Inter. Antiviral News., 7, 134-136, (1999)]. Together, these observations indicate that IMPDH inhibitors are useful as broad-spectrum antiviral agents.

IMPDH inhibitors may therefore have therapeutic potential as immunosuppressants, anticancer agents, and antiviral agents. Specifically, such compounds can be used in the treatment of transplant rejection, cancer treatment and as antiviral agents in the treatment of viral diseases, such as retrovirus and hepatitis C virus infections (alone or in combination with other antiviral agents such as interferon or its derivatives, such as polyethylene glycol conjugates).

The new oxamide derivatives provided by the proposed invention are compounds of the general formula (I):

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where

R 1 represents heterocyclyl;

R 2 represents hydrogen, unsubstituted lower alkyl, lower alkoxy, halogen, hydroxy or cyano;

R 3 represents hydrogen, unsubstituted lower alkyl, lower alkoxy, halogen, or cyano;

R 4 represents hydrogen, lower alkyl, lower cycloalkyl, aryl, or heterocyclyl;

R 5 represents hydrogen, unsubstituted lower alkyl, lower alkoxy, halogen, or cyano;

R 6 represents hydrogen, unsubstituted lower alkyl, lower alkoxy, halogen, or cyano;

R7 represents hydrogen, or unsubstituted lower alkyl;

R 8 represents hydrogen, or unsubstituted lower alkyl;

or R4 and R5 together with the nitrogen atom to which they are attached represent heterocyclyl;

and their pharmaceutically acceptable salts.

The oxamide derivatives provided by the proposed invention are inhibitors of the enzyme inosine monophosphate dehydrogenase (IMPDH). They can be used as drugs, particularly for the treatment of immune-mediated conditions or diseases, viral diseases, bacterial diseases, parasitic diseases, inflammation, inflammatory diseases, hyperproliferative vascular diseases, tumors, and cancer. They may be used alone or in combination with another therapeutically active agent, such as, for example, an immunosuppressant, a chemotherapeutic agent, an antiviral agent, an antibiotic, an antiparasitic agent, an anti-inflammatory agent, an antifungal agent, and/or an anti-vascular hyperproliferative agent. .

In particular, the compounds of the present invention and compositions containing them can be used as chemotherapeutic agents, inhibitors of viral replication and modulators of the immune system, and can be used to treat viral diseases such as retrovirus and hepatitis C virus infections (alone or in combination with other antiviral agents, such as interferon or its derivatives, such as conjugates with polyethylene glycol), inflammatory diseases such as osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, and adult respiratory distress syndrome, hyperproliferative vascular diseases such as restenosis, stenosis and arteriosclerosis, cancer , for example lymphoma and leukemia, and as immunosuppressants in the treatment of autoimmune diseases, host-to-graft disease and transplant rejection.

Compounds of the present invention that have antiviral effects and/or immunosuppressive properties are particularly useful for the treatment of HCV infection.

As used herein, the term "lower alkyl" means a straight or branched alkyl group having up to 10 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, eg methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and 1,1-dimethylethyl; and which is optionally substituted with, e.g., one or more cyano, halogen, carboxyl, hydroxyl, lower alkoxy, lower cycloalkyloxy, aryloxy, heterocyclyloxy, heterocyclyl-(lower alkoxy)-aryl-amino-oxalyl-oxy, lower alkoxy-carbonyl , aryl, aryl-carbonyl-amino-aryl, lower alkyl-carbonyl-amino-aryl, heterocyclyl, lower alkyl-heterocyclyl, lower cycloalkyl, lower alkenyl, lower alkynyl, amino, mono- or di-(lower alkyl)amino, lower cycloalkyl amino, aryl amino, heterocyclyl-amino, lower alkyl-aryl-lower alkyl-amino, lower alkoxy-carbonyl-amino, lower alkenyl-carbonyl-amino, lower alkyl-carbonyl-amino, di-(aryl)-lower alkyl- carbonyl-amino, lower alkyl-sulfonyl-lower alkyl-carbonyl-amino, lower cycloalkyl-lower alkyl-carbonyl-amino, heterocyclyl-lower alkyl-carbonyl-amino, lower alkoxy-lower alkyl-carbonyl-amino, di-aryl-lower alkyl-carbonyl-amino, aryl-carbonyl-amino, lower alkyl-aryl-carbonyl-amino, tri-(lower alkyl)-aryl-carbonyl-amino, mono- or di-(lower alkoxy)-aryl-carbonyl-amino, di-(lower alkyl)- amino-aryl-carbonyl-amino, lower alkyl-carbonyl-amino-aryl-carbonyl-amino, heterocycl1-aryl-carbonyl-amino, lower cycloalkyl-carbonyl-amino, mono- or tetra-(lower alkyl)-lower cycloalkyl-carbonyl -amino, heterocyclyl-carbonyl-amino, mono- or di-(lower alkyl)-heterocyclyl-carbonyl-amino, tri-(lower alkyl)-aryl-oxalyl-amino, lower alkyl-carbamoyl, or aryl-carbamoyl, thio, lower alkyl thio, lower cycloalkyl thio, aryl thio, heterocyclyl thio, lower alkyl sulfonyl, lower cycloalkyl sulfonyl, aryl sulfonyl, heterocyclyl sulfonyl.

Where there is more than one substituent, they may be the same or different, for example tri-fluoromethyl, triphenylmethyl, 1-[1-methyl-1-[methylformyl]-2-phenyl] ethyl, or 2-[1-hydroxyl- 3-cyclohexyl].

The term "unsubstituted lower alkyl" means an alkyl group as defined above in which no substituents are present.

The term "lower alkenyl" means an alkenyl group containing from 2 to 7 carbon atoms, eg allyl, vinyl and butenyl.

The term "lower alkynyl" means an alkynyl group containing from 2 to 7 carbon atoms, eg propargyl or butynyl.

The term "lower cycloalkyl", alone or in combination as "lower cycloalkyl-lower alkyl", means a cycloalkyl group containing 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl and adamantyl, and which can optionally be substituted, for example, with one or more lower alkyl, carboxyl, hydroxyl or aryl, or optionally benz-fused, for example, to aryl. Where there is more than one substituent, the substituents may be the same or different. Examples of lower cycloalkyl-lower alkyl groups are cyclopropylmethyl, 2-cyclobutyl-ethyl and 3-cyclohexyl-propyl.

The term "halo" means fluorine, chlorine, bromine or iodine. The term "lower alkoxy" means an optionally substituted lower alkyl group as defined above, which is attached via an oxygen atom, eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like. Suitable substituents are those which can be used for "lower alkyl".

The term "aryl", alone or in combination as "aryl-lower alkyl", means phenyl or naphthyl, optionally benz-fused, e.g. benz-fused to a lower cycloalkyl ring, and/or optionally substituted e.g. with one or more halogen, or other substituents such as cyano, carboxyl, lower alkyl-thio, nitro, oxo, hydroxyl, lower alkoxy, lower cycloalkyloxy, aryloxy, heterocyclyl oxy, lower alkyl-heterocyclyl, heterocyclyl, lower alkoxy-carbonyl, lower alkyl-carbonyl , heterocyclyl-carbonyl, lower alkyl-heterocyclyl-carbonyl, sulfamoyl, lower alkyl- sulfamoyl, thio, lower alkyl thio, lower cycloalkyl thio, aryl thio, heterocyclyl thio, lower alkyl-sulfonyl, lower cycloalkyl sulfonyl, aryl sulfonyl, heterocyclyl-sulfonyl , amino, mono- or di-(lower alkyl) amino, lower alkyl-sulfonyl-amino, di-(lower alkyl)-heterocyclyl-amino, lower alkyl-carbonyl-amino, (lower alkyl-carbonyl) (lower alkyl)- amino, lower alkoxy-carbonyl-amino, aryl-carbonyl-amino, mono- or di-(lower alkyl)-carbamoyl, aryl-carbamoyl, n lower alkyl, aryl-lower alkyl, amino-lower alkyl, heterocyclyl-lower alkyl, lower alkoxy-carbonyl-lower alkyl, lower alkyl-sulfamoyl-lower alkyl, aryl-sulfonyl-amino-lower alkyl, lower alkyl-sulfonyl-amino- lower alkyl, lower alkoxy-carbonyl-amino-lower alkyl, heterocyclyl-oxy-carbonyl-amino-lower alkyl, aryloxy-carbonyl-amino-lower alkyl, lower alkyl-carbonyl-amino-lower alkyl, lower alkoxy-carbonyl-(lower alkyl)-amino-lower alkyl, lower alkyl-carbamoyl-lower alkyl, lower alkyl-aryl-carbonyl-amino-lower alkyl, aryl-carbamoyl -lower and alkyl, lower cycloalkyl-carbonyl-amino-lower alkyl, heterocyclyl-carbonyl- amino-lower alkyl, or aryl-carbonyl-amino-lower alkyl. Where there is more than one substituent, the substituents may be the same or different, for example 1-(3-methoxy-4-oxazolyl)phenyl, 1-(3-chloro-4-methoxy)phenyl, 1-(3-chloro- 4-methyl)phenyl and 1-(3-fluoro-4-methyl)phenyl.

The same substituents listed above apply to all terms containing the phrase "optionally substituted phenyl...".

The term "aryloxy" means an aryl group as defined above, which is linked through an oxygen atom, eg, phenoxy, and the like.

As used herein, the term "heterocyclyl", alone or in combination as "heterocyclyl-lower alkyl", means a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system containing one or more heteroatoms selected from nitrogen, sulfur and oxygen; and which is connected to the rest of the molecule via a carbon atom (C-linked), or a nitrogen atom (N-linked) in the ring system, and which is, if necessary, substituted in the same way as the aryl group defined above and/or with oxido. Where there is more than one substituent, the substituents may be the same or different.

Examples of heterocyclyl groups are oxazolyl, isoxazolyl, furyl, tetrahydrofuryl, 1,3-dioxolanyl, dihydropyranyl, thienyl, pyrazinyl, isothiazolyl, isoquinolinyl, indolyl, indazolyl, quinolinyl, dihydro-oxazolyl, pyrimidinyl, benzofuranyl, tetrazolyl, pyrrolidinonyl, (N-oxide )-pyridinyl, pyrrolyl, triazolyl eg 1,2,4-triazolyl, pyrazolyl, benzotriazolyl, piperidinyl, morpholinyl, thiazolyl, pyridinyl, dihydrothiazolyl, imidazolidinyl, pyrazolinyl, benzothienyl, piperazinyl, imidazolyl, thiadiazolyl eg 1,2,3- thiadiazolyl, and benzo-thiazolyl.

Any functional (ie, reactive) group present in the side chain may be protected with a protecting group known as such, as described, for example, in "Protective Groups in Organic Synthesis", 2nd ed., T.W. Greene and P.G.M. Wuts, John Wiley & Sons, New York, NY, 1991. For example, the amino group can be protected with tert-butoxycarbonyl, formyl, trityl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetene, 2-(biphenylyl)isopropoxy - by a carbonyl or isobornyloxycarbonyl group or in the form of a phthalimido group; or the hydroxyl group may be protected with tert-butyldimethylsilyl, tetrahydropyranyl, 4-methoxy-benzyl, or benzyl; or the carboxyl group may be protected in the form of an ester, for example as a methyl or tert-butyl ester. The protecting group can be retained in the terminal compound or, if necessary, removed by methods known in the art.

The compounds of this invention may have one or more asymmetric carbon atoms and therefore may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In addition, where the compound of the invention contains an olefinic double bond, it may have an (E) or (Z) configuration. Also, each chirality center can have an R or S configuration. All such isomeric forms of these compounds are covered by the proposed invention.

Examples of compounds of formula (I) are shown below in Tables 1a and 1b:

Table 1a

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Table 1b

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Preferred compounds of formula (I) are those in which at least one of R2, R3, R5 and R6 is not hydrogen.

In addition, preferred compounds of formula (I) are those in which R 1 represents an optionally substituted oxazole ring.

In particular, preferred compounds of formula (I) are those having the general formula:

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in which they are

R2 to R8 defined as in claim 1, i

R 9 is hydrogen, lower alkyl, or aryl-lower alkyl;

R10 is hydrogen.

More preferably, preferred compounds of formula (I) are those conforming to general formula (IX) wherein

R 2 is methoxy or chlorine;

R 3 is hydrogen;

R 4 is heterocyclyl, aryl, or optionally substituted lower branched chain alkyl;

R 5 is hydrogen;

R 6 is hydrogen;

R 7 is hydrogen;

R 8 is hydrogen;

R 9 is hydrogen;

R10 is hydrogen.

In particular, preferred compounds of formula (I) are also those which conform to the general formulas:

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in which they are

R2, R3, R5, R6, R7, R9 and R10 as defined above,

R11 and R13 represent H or lower alkyl, m is 1 to 5 and

R 12 is heterocyclyl or aryl, provided that R 12 is not 4-fluorophenyl.

Particularly preferred compounds of formulas (XIa or XIb) are those in which

R2 represents methoxy,

R3, R5, R6, R9, R10, R11 and R13 represent hydrogen and where

R 12 represents optionally substituted phenyl and optionally substituted heteroaryl, provided that R 12 does not represent 4-fluorophenyl.

Examples of such compounds are given in Table Ic.

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Particularly preferred compounds of formula (I) are also those which conform to the general formula

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in which they are

R2, R3, R5, R6, R7, R9 and R10 as defined above,

R11, R13, R14, R15, R16, R17 and R18 represent H or lower alkyl and

R 19 is alkyl, cycloalkyl, heterocyclyl alkyl or aryl alkyl.

Particularly preferred compounds of formula (XII) are those in which

R 2 represents methoxy, and

R3, R5, R6, R9, R10, R11 and R13 represent hydrogen.

Examples of such compounds are listed below in Table Id.

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Particularly preferred compounds of formula (I) are also those which conform to the general formula

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in which they are

R2, R3, R5. R6, R7, R9 and R10 defined as above,

R11, R13, R14, R15, R16, R17 and R18 represent H or lower alkyl and

R 20 is alkyl, cycloalkyl, aryl, heterocyclyl.

Particularly preferred compounds of formula (XIII) are those in which

R 2 represents methoxy, and

R3, R5, R6, R9, R10, R11 and R13 represent hydrogen.

Examples of such compounds are listed below in Table 1e.

Table 1e

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Particularly preferred compounds of formula (I) are also those which conform to the general formula

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in which they are

R2, R3, R5, R6, R7, R9 and R10 as defined above,

R11 and R13 represent H or lower alkyl,

n is 0 or l,

Ra, Rb represent lower alkyl or Ra and Rb taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocycle, and

R 12 is heterocyclyl, aryl or lower cycloalkyl, and

Z is O, S or NR28, where

R28 represents H or lower alkyl.

Further preferred compounds of formula XVIII are those conforming to the general formulas:

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in which they are

R2, R3, R5, R6, R7, R9 and R10 as defined above,

R11 and R13 represent H or lower alkyl,

n is 0 or 1,

m is 1 to 5, and

R 12 is heterocyclyl, aryl or lower cycloalkyl.

Particularly preferred compounds of formula (XIV) are those in which

R 2 represents methoxy and

R3, R5, R6, R9, R10, R11 and R13 represent hydrogen.

Examples of such compounds are listed below in Table If1.

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Further preferred compounds of formula (XVIII) are those conforming to the general formula

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in which they are

R2, R3, R5, R6, R7, R9 and R10 as defined above,

R11 and R13 represent H or lower alkyl,

n = 0 or 1,

Ra, Rb represent lower alkyl or Ra and Rb taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocycle, and

R 12 is heterocyclyl, aryl or lower cycloalkyl.

Particularly preferred compounds of formula (XIX) are those in which

R 2 represents methoxy, and

R3, R5, R6, R9, R10, R11 and R13 represent hydrogen.

Examples of such compounds are listed below in Table 1f2.

Table 1f2

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Further preferred compounds of formula (VIII) are those conforming to the general formula

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in which they are

R2, R3, R5, R6, R7, R9 and R10 as defined above,

R11, R13 and R28 represent H or lower alkyl,

n is 0 or 1,

Ra, Rb represent lower alkyl or Ra and Rb taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocycle, and

R 12 is heterocyclyl, aryl or lower cycloalkyl.

Particularly preferred compounds of formula (XX) are those in which

R 2 represents methoxy, and

R3, R5, R6, R9, R10, R11 and R13 represent hydrogen or methyl.

Examples of such compounds are listed below in Table 1f3.

Table 1f3

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Particularly preferred compounds of formula (I) are also those which conform to the general formula

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in which they are

R2, R3, R5, R6, R7, R9 and R10 as defined above,

R11 and R13 represent H or lower alkyl,

n = 0 or 1,

R21 is optionally substituted alkyl, cycloalkyl, phenyl, heterocyclyl, optionally substituted cycloalkyl alkyl, phenyl alkyl or heterocyclyl alkyl,

optionally substituted alkyl carbonyl, cycloalkyl carbonyl, phenyl carbonyl, heterocyclyl carbonyl,

optionally substituted alkyl sulfonyl, cycloalkyl sulfonyl, phenyl sulfonyl, heterocyclyl sulfonyl.

Particularly preferred compounds of formula (XV) are also those in which

R 2 represents methoxy, and

R3, R5, R6, R9, R10, R11 and R13 represent hydrogen.

Examples of such compounds are listed below in Table 1g.

Table 1g

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Particularly preferred compounds of formula (I) are also those which conform to the general formula

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in which they are

R2, R3, R5, R6, R7, R9 and R10 as defined above,

R22, R23, R24, R25 and R26 represent H or lower alkyl,

R27 is alkyl, aryl or heterocyclyl, alkoxy, aryloxy, heterocyclyloxy.

Particularly preferred compounds of formula (XVI) are those in which

R 2 represents methoxy, and

R3, R5, R6, R9, R10, R13, R22, R23, R24, R25 and R26 represent hydrogen.

Examples of such compounds are listed below in Table 1h.

Table 1h

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Particularly preferred compounds of formula (I) are also those which conform to the general formula

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in which they are

R2, R3, R5, R6, R7 and R10 as defined above,

R11 and R13 represent H or lower alkyl and

R 12 is heterocyclyl, aryl or lower cycloalkyl.

Particularly preferred compounds of formula (XVII) are those in which

R 2 represents methoxy, and

R3, R5, R6, R9, R10, R11 and R13 represent hydrogen, and where

R12 is optionally substituted phenyl or

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where R21 is defined as above.

Examples of such compounds are listed below in Table 1i:

Table 1i

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The compounds of formulas (IV) and (VIII), which are intermediates in the previous procedures, are new and are also provided by the proposed invention.

Reaction scheme A

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According to reaction scheme A, the first step involves coupling a compound of formula (II) with an activated oxalyl derivative, such as methyl chloroxoacetate, to give a compound of formula (III). The reaction can be carried out in the usual way, preferably in an organic solvent which is inert under the reaction conditions and in the presence of an organic base at approx. 0°C to approx. room temperature. Suitable solvents include halogenated hydrocarbons, eg dichloromethane. As examples of suitable organic bases which can be used, mention may be made of pyridine and tri(lower alkyl)-amines, eg triethylamine.

Subsequent hydrolysis of the compound of formula (III) to give the acid compound of formula (IV) can be carried out by treatment with a solution of an alkali metal hydroxide, such as sodium hydroxide, in a suitable solvent system, such as aqueous methanol.

Alternatively, a compound of formula (II) can be coupled with tert-butyl chloroxoacetate and then treated with an acid to remove the tert-butyl group, thereby giving a compound of formula (IV).

A compound of formula (IV) is then coupled with an amine compound of formula (V) using standard peptide coupling reagents such as hydroxybenzotriazole in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride to give an oxamide compound of formula (I ).

After this coupling step, the R group of the resulting compound can be further modified by techniques known in the art, for example, functional groups can be changed and/or linked to other groups.

Reaction scheme B

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According to reaction scheme B, the first step involves coupling a compound of formula (VI) with an activated oxalyl derivative, such as methyl chloroxoacetate, to give a compound of formula (VII). The reaction is carried out in the manner described above for the formation of the compound of formula (III) from the compound of formula (II).

The compound of formula (VII) is then hydrolysed, thereby obtaining the acidic compound of formula (VIII) in the manner described above for the hydrolysis of the compound of formula (III).

Alternatively, the compound of formula (VI) can be coupled with tert-butyl chloroxoacetate and then treated with acid to remove the tert-butyl group, thereby obtaining the compound of formula (VII).

The compound of formula (VIII) is then coupled with the amine compound of formula (V), thereby obtaining the oxamide compound of formula (IX), under the conditions described above for the coupling of the compound of formula (IV) with the compound of formula (V).

After this coupling step, the R groups in the resulting compound can be further modified by techniques known in the art, for example, the functional groups can be changed and/or can be linked to further groups.

Reaction scheme C

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Alternatively, compounds of formula (I) are prepared by coupling a compound of formula (II) with the oxalic acid of a compound of formula (X) using standard peptide coupling reagents, such as hydroxybenzotriazole in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride , which gives the oxamide compound of formula (I).

After this coupling step, the groups in the resulting compound can be further modified by techniques known in the art, for example, functional groups can be changed and/or can be linked to other groups.

As mentioned above, the compounds of formula (I) and their salts are inhibitors of the IMPDH enzyme in vitro and in vivo, and can be used to suppress or prevent IMPDH-mediated conditions or diseases.

IMPDH activity can be assayed using an adapted method described by Carr [S. Carr et al., J. Biol Chem. 268, p. 27286 (1993)], which publication is incorporated herein as a reference. IMPDH activity was measured spectrophotometrically by observing the increase in absorbance at 340 nm due to the formation of NADH (e 340 is 6220 M-1 cm-1) due to the reduction of NAD. The IMPDH reaction mixture contained 0.1 M Tris pH 8.0, 0.1 M KCl, 1 mM DTT, 3 mM EDTA, 100 mM IMP, and 100 mM NAD. The reaction was initiated by the addition of IMPDH (human type II) to the final concentration of IMPDH tetramer in the experiment between 1 nM and 5 nM. The initial rate was measured by the linear increase in absorbance at 340 nm at 37°C for 45 minutes. The reading was performed using a Spectromax 190 spectrophotometer (Molecular Devices) in a 96-well format plate with a final reaction volume of 200 μl.

For the inhibition assay experiment, the compound was dissolved in DMSO to a final concentration of 10 mM and added to the initial reaction mixture as 5 µL, yielding a final DMSO concentration of 2-5%. Enzyme reaction initiated by addition of IMPDH and initial rates were measured as above. IC50 determinations were performed by measuring initial rates in the presence of 10 inhibitor concentrations and comparing with a 4-parameter curve obtained by Softmax software (Molecular Devices).

The preferred compounds of the invention tested in the above experiment have an IC50 value of up to 500 nM, ie. 0.5 μM.

Specific examples of IC50 values for preferred compounds of formula (I) are shown below in Table 2:

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Compounds of formula (I) which are acidic may form pharmaceutically acceptable salts with bases such as alkali metal hydroxides, eg sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides, eg calcium hydroxide, barium hydroxide and magnesium hydroxide, and the like; with organic bases, for example with N-ethyl piperidine, dibenzylamine, and the like. Those compounds of formula (I) which are basic can form pharmaceutically acceptable salts with inorganic acids, for example with hydrohalic acids such as hydrochloric acid and hydrobromic acid, with sulfuric acid, with nitric acid and with phosphoric acid, and the like, and with organic acids such as which are, for example, acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid and p-toluene sulfonic acid, and the like. The formation and isolation of such salts can be carried out according to methods known in the art.

The oxamide derivatives provided by the proposed invention (ie compounds of formula (I) and their pharmaceutically acceptable salts) can be used as drugs, for example in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered enterally, such as orally, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, as solutions, emulsions or suspensions, or nasally, eg in the form of nasal sprays. They can also be administered rectally, eg in suppository form, or parenterally, (eg intramuscularly, intravenously, or subcutaneously), eg in the form of injectable solutions.

For the production of pharmaceutical preparations, oxamide derivatives can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used as such a carrier for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient, the preparation can be produced without a carrier, which is generally required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sugar, sucrose, invert sugar, glucose and the like. Suitable carriers for the production of injection solutions are, for example, water, salt solution, alcohols, polyols, glycerin, vegetable oils and the like. Natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable carriers for the production of suppositories. The pharmaceutical compositions of the present invention may also be provided as sustained release formulations or as other suitable formulations.

Pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, dyes, spices, salts for adjusting osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically active substances, such as an immunosuppressant, a chemotherapeutic agent, an antiviral agent, an antibiotic, an anti-parasitic agent, an anti-fungal agent, an anti-inflammatory agent and/or an anti-vascular hyperproliferative agent. A preferred agent that can be used with the compounds of the proposed invention is interferon or its derivatives, as conjugates with polyethylene glycol.

Medicines containing the compound of formula (I) or its salts and a therapeutically acceptable carrier, as well as the process for the production of such medicines are also subject of the proposed invention. This process involves bringing a compound of formula (I) or a pharmaceutically acceptable salt thereof into a galenic form for administration together with a therapeutically inert carrier material and, optionally, with one or more additional therapeutically active substances.

A further subject of the invention includes the use of the oxamide derivatives provided by the invention for the treatment of an immune-mediated condition or disease, viral disease, bacterial disease, parasitic disease, inflammation, inflammatory disease, hyperproliferative vascular disease, tumor, or cancer. The dosage can be varied within wide limits and, of course, is adapted to individual requirements in each individual case.

Favorable dosage amounts in monotherapy and/or in combination therapy are between approx. 0.01 and approx. 100 mg/kg body weight per day (preferably 0.5 - 75 mg/kg/day), applied approx. 1-5 times a day. The active substance can be combined with a carrier material. A typical preparation contains approx. 5% - 95% active compound (w/w) (preferably approx. 20% - 80% active compound). Daily dosing can be given as a single dose or in divided doses.

The compounds and preparations of the proposed invention can be used in monotherapy and/or in combined therapy, i.e. the treatment can be associated with the application of one or more additional therapeutically active substances. When the treatment is carried out by combination therapy, such treatment can be simultaneous or sequential as far as the oxamide derivative of the proposed invention is concerned. Thus, simultaneous application, as used herein, includes administration of the combined agents, either simultaneously, together, or before, or one after the other.

It is understood that the treatment mentioned here refers to treatment extended to prophylaxis as well as treatment of existing conditions. Treatment of a disease or condition, as used herein, also includes the prevention, inhibition, regression, prevention of development, mitigation or amelioration of the disease or condition, or its clinical symptoms. The term "subject" as used herein refers to beings, including humans and other mammals.

The following examples illustrate the proposed invention.

As for the starting materials, these are known compounds, some of which can be obtained from commercial suppliers. Other starting materials, which are known, and their analogues can be produced by methods known in the art. Examples of compounds obtainable from commercial suppliers and directions for the synthesis of other compounds and their analogs are provided below.

Compounds of formula (II) and compounds of formula (VI) were obtained from commercial suppliers (eg 4-(5-oxazolyl)-aniline, Maybridge Catalog No. DFP 00120), or were prepared by adapted methods described in published patent application WO 974002, or are produced by adapted methods given in Palacz et al., FEBS Lett., 1984, 176(2), 365-370.

Compounds of formula (V) were obtained from commercial suppliers (eg, tert-butylamine, Aldrich Catalog No. B8,920-5; cumylamine, TC1-US Catalog No. C1293), or were prepared by adapted methods given in Kazuo Achiwa et al., Chem. . Pharm. Bull., 1998, 46(4), 697-670.

Compounds of formula (X) were prepared by adapted methods given in Minisca et al., J. Org. Chem., 1995, 60 (17), 5430-5433.

Examples of commercially available reagents include those used in Examples 7, 10, and 11, (2-methoxy-4-nitrobenzoic acid, Aldrich Catalog No. 42,291-6; tert-butylacetic acid, Aldrich Catalog No. B8,840-3; and p -tolualdehyde, Aldrich catalog number T3.560-2).

Where indicated, NMR spectra were recorded on a Bruker DRKS 400 MHz spectrometer with the sample temperature set at 300 K.

Where marked with "(M+;EI)", mass spectra were recorded under electron impact (EI) conditions on a THERMOQUEST MAT95 S with a source temperature of 200°C. Other mass spectra were recorded under electrospray ionization spectrum (ESI) conditions, on one of the following devices:

a) THERMOQUEST SSQ 7000 [solvent 0.085% TFA in 90% acetonitrile/water; flow rate 100 microliters/minute; capillary 250°C; spray voltage 5KV; thrust gas 80 psi], or

b) LC-MS system (liquid chromatograph coupled to mass spectrum) THERMOQUEST TSQ 7000 ELECTROSPRAY or MICROMASS PLATFORM ELECTROSPRAY [solvent 0.1% TFA in water or 0.085% TFA in 90% acetonitrile/water or 0.085% TFA in acetonitrile].

Unless otherwise stated, mass spectroscopy values reported in the MS (ES) column refer to (M+H)+ values, regardless of whether a value is reported as (M+;EI).

Example 1

N-tert-butyl-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide

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Example 1, alternative synthesis

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A solution of 26 mg (0.1 mmol) N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalic acid, 15 mg (0.2 mmol) tertiary butylamine, 28 mg (0.15 mmol) l- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 15 mg (0.11 mmol) of 1-hydroxy-7-azabenzotriazole in 1 ml of dimethylformamide were mixed for 4 hours at room temperature and then diluted with ethyl acetate and washed with 2M hydrochloric acid, saturated sodium bicarbonate and water. The resulting solution is dried over magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether/petrol (1:1) and collected by filtration to give 11 mg of N-tert-butyl-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 318.0 [M+H] + .

The starting material was produced as follows:

i) 5.7 g (30 mmol) of 3-methoxy-4-(5-oxazolyl)aniline and 3.33 g (33 mmol) of triethylamine are dissolved in 50 ml of dichloromethane and the solution is cooled to 0°C. A solution of 3.86 g (31.5 mmol) of methyl oxalyl chloride in 10 ml of dichloromethane was added drop by drop and the resulting mixture was stirred for 1 hour, then washed with 2M hydrochloric acid. The precipitated solid was collected by filtration and washed with dichloromethane and water to give 6,2 methyl N-[3-methoxy-4-(5-oxazolyl)phenyl]-oxalamate as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ: 3.88 (3H, s), 3.94 (3H, s), 7.48 (1H, s), 7.58 (1H, dd), 7, 65 (IH, d), 7.68 (IH, d)), 8.39 (IH, s), 10.92 (IH, s).

ii) 6.2 g (22.46 mmol) of methyl N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalate and 1.2 g (30 mmol) of sodium hydroxide are refluxed for 2 hours in 240 ml of methanol/ of water (1:1) and then cooled, filtered and acidified with 2M hydrochloric acid. The precipitated solid was collected by filtration and washed with water, acetone and diethyl ether to give 5.1 g of N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalic acid as a pale yellow solid. MS: m/e 262.9 [M+H] + .

Alternatively, N-tert-butyl-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide can be prepared as follows:

A solution of 95 mg (0.5 mmol) 3-methoxy-4-(5-oxazolyl)-aniline, 73 mg (0.5 mmol) N-tert-butyloxalic acid, 134 mg (0.7 mmol) 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 75 mg (0.55 mmol) of 1-hydroxy-7-aza-benzotriazole in 4 ml of dichloromethane are stirred for 18 hours at room temperature. The resulting mixture is washed with 2M hydrochloric acid and saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness. The residue was triturated with petrol and collected by filtration to give 128 mg of N-tert-butyl-N'-[3-methoxy-4-(5-oxazolyl)phenyl]-oxalamide as a pale yellow solid. MS: 318 [M+H] + .

Example 2

Tert-butyl [3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]-amino]benzyl] carbamate

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A mixture of 2.04 g (7.79 mmol) of N-(3-methoxy-4-(5-oxazolyl)phenyl]oxalic acid, prepared as described above in Example 1, 1.9 g (8.56 mmol) tert-butyl (3-aminobenzyl)carbamate, 1.8 g (9.4 mmol) of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride and 1.3 g (9.6 mmol) of 1-hydroxy-7 -azabenzotriazole in 30 ml of dimethylformamide was stirred for 20 hours at room temperature. (5-Oxazolyl)anilino]oxalyl]amino]benzyl]-carbamate as a white solid MS: m/e 466 M+.

Example 3

N-[3-(aminomethylphenyl]-N' [3-methoxy-4-(5-oxazolyl)phenyl]-oxalamide trifluoroacetate

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15 mg (0.032 mmol) of tert-butyl [3-[[[3-methoxy-4-(5-oxazolyl)aniline]oxalyl]amino]benzyl]carbamate, prepared as described above in Example 2, was dissolved in 1 ml of dichloromethane and 1 ml of trifluoroacetic acid at room temperature for 5 minutes. The solution was evaporated to dryness, the residue was triturated with diethyl ether and collected by filtration to give 11 mg of N-[3-(aminomethylphenyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide trifluoroacetate as white solid MS: m/e 408 [M+H+MeCN]+.

Example 4

N-[3-(benzamidomethyl)phenyl]-N'-{3-methoxy-4-(5-oxazolyl)-phenyl]oxalamide

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29 mg (0.21 mmol) of benzoyl chloride is added to a solution of 100 mg (0.21 mmol) of N-[3-(aminomethyl)phenyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl ]oxalamide trifluoroacetate, prepared as described above in Example 3, and 46 mg (0.46 mmol) of triethylamine in a mixture of 2 ml of dimethylformamide and 5 ml of dichloromethane, and stirred for 18 hours at room temperature. The solution is washed with 2M hydrochloric acid and saturated sodium bicarbonate, then dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using ethyl acetate/petrol (2:1) as eluent. After trituration with diethyl ether, 45 mg of N-[3-(benzamidomethyl)phenyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide was obtained as a white solid. MS: m/e 471.0 [M+H] + .

Example 5

N-[3-[(benzenesulfonamido)methyl]phenyl]-N' -[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide

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Analogous to the procedure described in example 4, but by replacing benzoyl chloride with phenylsulfonyl chloride, N-[3-[(benzenesulfonamido)methyl]phenyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl] was obtained oxalamide as a white solid. MS: m/e 507 [M+H] + .

Example 6

Methyl [3-[[[3-methoxy-4-(5-oxazolyl]anilino]oxazolyl]-aminobenzyl]carbamate

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Analogous to the procedure described in example 4, but replacing benzoyl chloride with methyl chloroformate, methyl [3-[[[3-methoxy-4-(5-oxazolyl]anilino]oxazolyl]-aminobenzyl]carbamate was obtained as a white solid. MS : m/e 425 [M+H]+.

Example 7

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A mixture of 371 mg (1 mmol) of N-[4-(bromoacetyl)-3-methoxy-phenyl]-N'-tert-butyloxalamide and 315 mg (5 mmol) of ammonium formate was refluxed for 4 hours in 10 ml of formic acid and then cool and evaporate to dryness. The residue was dissolved in ethyl acetate, washed with 2M sodium hydroxide and dried over magnesium sulfate. The solution was evaporated to dryness and the residue was chromatographed on silica gel using ethyl acetate/petrol (7:18) as eluent. After trituration with diethyl ether/petrol (1:1), 65 mg of N-tert-butyl-N'-[3-methoxy-4-(4-oxazolyl)phenyl]oxalamide was obtained as a white solid. MS: m/e 318 [M+H] + .

The starting material was produced as follows:

i) A mixture of 3.94 g (20 mmol) of 2-methoxy-4-nitro-benzoic acid, 3.9 g (40 mmol) of N,O-dimethyl-hydroxylamine hydrochloride, 5.73 g (29.92 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.37 g (22 mmol) of 1-hydroxybenzotriazole hydrate and 5.06 g (44 mmol) of N-ethylmorpholine in 50 ml of dichloromethane were stirred for 3 hours at room temperature and then is washed with 2M hydrochloric acid and with saturated bicarbonate. The resulting solution was dried over magnesium sulfate, evaporated to dryness and the residue triturated with diethyl ether and collected by filtration to give 3.95 g of N,O-dimethyl 2-methoxy-4-nitrobenzohydroxamate as a white solid.

1H NMR (400 MHz, CDCl3) δ: 3.37 (3H, s), 3.48 (3H, s), 3.97 (3H, s), 7.45 (1H, d), 7.80 ( 1H, d), 7.91 (1H, dd).

ii) A mixture of 1.2 g (5 mmol) of N,0-dimethyl 2-methoxy-4-nitrobenzohydroxamate and 4.75 g (25 mmol) of tin(II) chloride in 40 ml of ethanol is heated for 30 minutes at 80°C and then cooled and evaporated to dryness. The residue was dissolved in dichloromethane, washed with 2M sodium hydroxide and the organic phase was dried over magnesium sulfate and evaporated to dryness to give 960 mg of N,O-dimethyl 4-amino-2-methoxybenzohydroxamate as a white solid.

1H NMR (400 MHz, CDCl3) δ: 3.25 (3H, s), 3.62 (3H, s), 3.79 (3H, s), 6.22 (1H, d), 6.28 ( 1H, dd), 7.09 (1H, d).

iii) A mixture of 700 mg (3.33 mmol) N,O-dimethyl 4-amino-2-methoxybenzohydroxamate, 483 mg (3.33 mmol) N-tert-butyloxalic acid, 600 mg (3.92 mmol) 1- hydroxybenzotriazole hydrate and 960 mg (5.01 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 15 ml of dichloromethane are stirred for 3 hours at room temperature and then washed with 2M hydrochloric acid and with saturated sodium bicarbonate. The organic phase is dried over magnesium sulfate, evaporated to dryness and the residue is chromatographed on silica gel using ethyl acetate/petrol (3:1) as eluent to give 960 mg of N,O-dimethyl 4-[[(tert-butylamino) oxalyl]amino]-2-methoxybenzohydroxamate as a white solid.

1H NMR (400 MHz, CDCl3) δ: 1.46 (9H, s), 3.25-3.4 (3H, br, s,), 3.45-3.65 (3H, br, s,) , 3.89 (3H, s), 7.08 (1H, dd), 7.29 (1H, d), 7.44 (1H, s), 7.53 (1H, d), 9.40 ( 1H, s).

iv) 3.1 ml (4.34 mmol) of 1.4 M methylmagnesium bromide in tetrahydrofuran was added portionwise over 1 hour to a solution of 337 mg (1 mmol) of N,O-dimethyl-4-[[(tert -butylamino)oxalyl]amino]-2-methoxybenzohydroxamate in 10 ml of dry tetrahydrofuran. The resulting solution was diluted with diethyl ether and washed with 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, evaporated to dryness and the residue was chromatographed on silica gel using ethyl acetate/petrol (3:7) as eluent to give 255 mg of N-(4-acetyl-3-methoxyphenyl)-N' -tert-butyloxalamide as a white solid.

1H NMR (400 MHz, CDCl3) δ: 1.45 (9H, s), 2.61 (3H, s), 3.96 (3H, s), 7.03 (1H, dd), 7.43 ( 1H, s), 7.64 (1H, d), 7.82 (1H, d), 9.47 (1H, s).

v) 320 mg (0.85 mmol) of phenyltrimethylammonium tribromide was added portionwise over 10 minutes to a stirred solution of 247 mg (0.85 mmol) of N-(4-acetyl-3-methoxyphenyl)-N'-tert-butyloxalamide in 5 ml of dry tetrahydrofuran. After 15 minutes, a further 100 mg (0.26 mmol) of phenyltrimethylammonium tribromide was added. The obtained suspension is diluted with diethyl ether, washed with water and the organic phase is dried over magnesium sulfate. Evaporation gives a gum which is chromatographed on silica gel using first 0.5% methanol in dichloromethane and then 1% methanol in dichloromethane for washing. The product was dissolved in diethyl ether/petrol (2:1) and the resulting crystals were collected by filtration to give 135 mg of N-[4-(bromoacetyl)-3-methoxyphenyl]-N'-tert-butyloxalamide as a white solid.

1H NMR (400 MHz, CDCl3) δ; 1.44 (9H, s), 3.99 (3H, s), 4.61 (2H, s), 7.06 (1H, dd), 7.42 (1H, s), 7.68 (1H , d), 7.93 (1H, d), 9.51 (1H, s).

Examples 8-11

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Example 8

Tert-butyl[2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl-amino]-2-methyl]propyl]carbamate

77 mg (0.87 mmol) tert-butyl (2-amino-2-methylpropyl) carbamate, 207 mg (1.05 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 166 mg (1.08 mmol ) of 1-hydroxy-7-azabenzotriazole and 200 mg (0.76 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalic acid are dissolved in 5 ml of dichloromethane and 5 ml of dimethylformamide and stirred for 16 hours at room temperature. The mixture is then diluted with 50 ml of dichloromethane and washed with a 10% citric acid solution and sat. NaCl solution. The organic layer is then dried with anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed on silica gel using 30% ethyl acetate in hexane as eluent to give 165 mg of tert-butyl [2-[[[3-methoxy-4-(5-oxazolyl)-anilino]oxalyl]amino]-2 -methylpropyl]carbamate as a yellow solid.

1H NMR (400 MHz, d6 DMSO) δ: 1.35 (s, 6H), 1.45 (s, 9H), 3.25 (d, 2H), 3.95 (s, 3H), 7.25 (t, 1H), 7.55 (s, 1H), 7.70 (m, 2H), 7.80 (s, 1H), 8.25 (s, 1H), 8.50 (s, 1H) , 10.8 (s, 1H).

Example 9

N-(2-amino-1,1-dimethylethyl)-N'-[3-methoxy-4-(5-oxazolyl)-phenyl]oxalamide trifluoroacetate (1:1)

26 mg (0.29 mmol) of tert-butyl [2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methylpropyl]carbamate is dissolved and mixed in 10 ml of 1:1 mixture of 1,1,1-trifluoroacetic acid and dichloromethane. After 1 hour, the mixture is co-evaporated with toluene three times and with dichloromethane twice. The obtained gum is then triturated with 40-60 petroleum ether, which gives 124 mg of N-(2-amino-1,1-dimethylethyl)-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide trifluoroacetate (1:1) as yellow solids.

1H NMR (400 MHz, d6 DMSO) δ: 1.40 (s, 6H), 3.20 (m, 2H), 3.90 (s, 3H), 7.50 (s, 1H), 7.60 -7.74 (m, 2H), 7.80 (s, 1H), 7.90 (s (br), 3H), 8.30 (s, 1H), 8.40 (s, 1H), 10 ,80 (s, 1H).

The previously described salt of trifluoroacetic acid is partitioned between a saturated solution of sodium hydrogen carbonate and ethyl acetate. The organic layer is then dried with magnesium sulfate, filtered and evaporated to give the free base used in Example 10.

Example 10

N-(3-methoxy-4-(5-oxazolyl)phenyl]-N'-[2-(3,3-dimethylbutyramido)-1,1-dimethylethyl]oxalamide

30 mg (0.09 mmol) N-(2-amino-1,1-dimethyl-ethyl)-N'-(3-methoxy-4-oxazol-5-yl-phenyl)-oxalamide, 52 mg (O, 45 mmol) of tert-butylacetic acid, 86 mg (0.45 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 69 mg of HOAt are dissolved and stirred for 16 hours in 2 ml of dimethylformamide. After 16 hours of stirring, the mixture is diluted with 10 ml of dichloromethane and washed with a 10% solution of citric acid in water, with a saturated solution of sodium hydrogen carbonate and with sat. NaCl solution. The organic solution was then dried with solid magnesium sulfate, filtered and evaporated to give N-(3-methoxy-4-(5-oxazolyl)phenyl]-N'-[2-(3,3-dimethylbutyramido)-1, 1-dimethylethyl]oxalamide as pale yellow solid, MS: m/e 431.3 [M+H]+.

Example 11

N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[2-(4-methylbenzyl-amino)-1,1-dimethylethyl]oxalamide

30 mg (0.09 mmol) N-(2-amino-1,1-dimethyl-ethyl)-N'-(3-methoxy-4-oxazol-5-yl-phenyl)-oxalamide, 11.3 mg ( 0.095 mmol) of 4-methylbenzaldehyde and 30 mg (0.14 mmol) of sodium triacetoxyborohydride were dissolved for 16 hours in 2 ml of a 5% acetic acid/dichloromethane mixture. The reaction mixture is then diluted with 8 ml of dichloromethane and washed with water, with saturated sodium hydrogen carbonate and with salt solution. The resulting organic solution is then dried with magnesium sulfate, filtered and evaporated to give N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[2-(4-methylbenzyl-amino)-1, of 1-dimethylethyl]oxalamide as a yellow solid, MS: m/e 437.3 [M+H]+.

Example 12

2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methylpropionic acid

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A mixture of 161 mg (0.446 mmol) of methyl 2-[[3-methoxy-4-(5-oxazolyl)anilinoxalyl]amino]-2-methylpropionate and 56 mg (1.33 mmol) of lithium hydroxide hydrate in 3 ml of methanol and 0 .5 ml of water is heated for 2 hours at 50°C and then diluted with water and washed with diethyl ether. The aqueous phase was acidified to pH 2 with 2M hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (120:15:3:2) as eluent. After trituration with ether, 70 mg of 2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methyl-propionic acid was obtained as a white solid. MS: m/e 247.9 [M+H] + .

Example 13

N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1-methyl-1-(phenyl-carbamoyl)ethyl]oxalamide

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A solution of 30 mg (0.086 mmol) 2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methylpropionic acid, 16 mg (0.172 mmol) aniline, 18 mg (0.132 mmol) 1-Hydroxy-7-azabenzotriazole and 25 mg (0.131 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 2 ml of dimethylformamide were mixed for 18 hours at room temperature and then diluted with ethyl acetate and washed with 2M hydrochloric acid. and with saturated sodium bicarbonate. The organic phase is dried over magnesium sulfate and the residue after evaporation is triturated with diethyl ether and collected by filtration, which gives 20 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1-methyl- 1-(phenylcarbamoyl)ethyl]-oxalamide as a white solid. MS: m/e 423.0 [M+H] + .

Example 14

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A mixture of 30 mg (0.086 mmol) 2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methylpropionic acid, 12 mg (0.178 mmol) methylamine hydrochloride, 18 mg (0.132 mmol ) l-hydroxy-7-azabenzotriazole, 25 mg (0.131 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 22 mg (0.218 mmol) of triethylamine in 2 ml of dimethylformamide were mixed for 18 hours at room temperature. and then diluted with ethyl acetate and washed with 2M hydrochloric acid and saturated sodium bicarbonate. The organic solution was dried over magnesium sulfate, evaporated to dryness and the residue chromatographed on silica gel using dichloromethane/methanol (24:1) as eluent. After trituration with ether, 17 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1-methyl-1-(methylcarbamoyl)ethyl]-oxalamide were obtained as a white solid. MS: m/e 361.0 [M+H] + .

Example 15

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A solution of 740 mg (1.81 mmol) of methyl 2-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]phenyl]acetate and 152 mg (3.62 mmol) of lithium hydroxide hydrate in 10 ml of methanol, 10 ml of 1,4-dioxane and 5 ml of water is stirred for 18 hours at room temperature. The solvent is removed by evaporation and the residue is dissolved in water. The aqueous solution is washed with diethyl ether and acidified with citric acid solution. The solid that precipitates is collected by filtration and washed with water, ethanol, and diethyl ether to give 414 mg of 2-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino] phenyl]-acetic acid as a white solid. MS: m/e 396.0 [M+H] + .

Example 16

N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[3-[(phenyl-carbamoyl)methyl]phenyl]oxalamide

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A solution of 30 mg (0.076 mmol) of 2-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]phenyl]acetic acid and 11 mg (0.096 mmol) of N-ethylmorpholine in 1 ml of dimethylformamide is cooled to 0°C and a solution of 12 mg (0.088 mmol) of isobutyl chloroformate in 1 ml of dichloromethane is added. The resulting mixture was stirred for 30 minutes at 0°C and then a solution of 7 mg (0.075 mmol) of aniline in 1 ml of dichloromethane was added and the stirring was continued for another hour at 0°C. After 18 hours at room temperature, the mixture was evaporated to dryness and the residue was chromatographed on silica gel using dichloromethane/methanol (19:1) as eluent. 3 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[3-[(phenylcarbamoyl)-methyl]phenyl]oxalamide were obtained as a white solid; m/e 471.0 [M+H]+.

Example 17

N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[3-[(methylcarbamoyl)-methyl]phenyl]oxalamide

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A mixture of 30 mg (0.076 mmol) 2-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]phenyl]acetic acid, 22 mg (0.115 mmol) 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride, 14 mg (0.092 mmol) of 1-hydroxy-benzo-triazole hydrate, 26 mg (0.385 mmol) of methylamine hydrochloride and 52 mg (0.452 mmol) of N-ethylmorpholine in 1 ml of dimethyl 1-formamide were mixed for 18 h. hours at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (1:19) as eluent. 15 mg of N-[3-methoxy-4-(5-oxazolyl)-phenyl]-N'-[3-[(methylcarbamoyl)-methyl]phenyl]oxalamide were obtained as a white solid. MS: m/e 409 [M+H] + .

Example 18

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20 mg (0.043 mmol) of tert-butyl [3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]phenyl]carbamate was dissolved for 10 minutes in a mixture of 1 ml of dichloromethane and 1 ml of trifluoroacetic acid. acid at room temperature. The solvent was removed by evaporation and the residue was triturated with diethyl ether. The resulting solid was collected by filtration to give 18 mg of N-(3-aminophenyl)-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide trifluoroacetate as a white solid. MS: m/e 394.0 [M+H+MeCN] + .

Example 19

N-[3-(benzamidophenyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]-oxalamide

[image]

A mixture of 30 mg (0.064 mmol) N-(3-aminophenyl)-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide trifluoroacetate, 9 mg (0.074 mmol) benzoic acid, 15 mg (0.078 mmol ) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 15 mg (0.096 mmol) of 1-hydroxybenzotriazole hydrate and 22 mg (0.19 mmol) of N-ethylmorpholine in 0.5 ml of dimethylformamide were mixed for 18 hours at room temperature and then it is diluted with ethyl acetate and washed with a 10% solution of citric acid, with saturated sodium bicarbonate and water. The organic phase is dried over magnesium sulfate, evaporated to dryness and the residue is chromatographed on silica gel using dichloromethane/methanol (19:1) as eluent. Trituration with diethyl ether/petrol (1:1) gave 12 mg of N-[3-(benzamidophenyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]-oxalamide as a white solid. MS : m/e 457.0 [M+H]+.

Example 20

N-[3-(methanesulfonamido)phenyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide

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12 mg (0.011 mmol) of methanesulfonyl chloride was added to a solution of 50 mg (0.011 mmol) of N-(3-aminophenyl)-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide trifluoroacetate and 32 mg ( 0.317 mmol) of triethylamine in 0.5 ml of dimethylformamide. The resulting solution is left for 18 hours at room temperature and then diluted with ethyl acetate and washed with a 10% solution of citric acid, with saturated sodium bicarbonate and water. The organic phase is dried over magnesium sulfate, evaporated to dryness and the residue is chromatographed on silica gel using ethyl acetate/petrol (1:1) for elution. 5 mg of N-[3-(methanesulfonamido)phenyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide were obtained as a white solid. MS: m/e 431.0 [M+H] + .

Example 21

N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide

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A mixture of 44 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl-2-(4-nitrophenyl)ethyl]-oxalamide and 90 mg (0.5 mmol) of stannous (II) chloride is mixed and heated for 5 hours at 85°C in 2 ml of ethanol and 1 ml of 1,4-dioxane. The resulting solution was cooled, diluted with ethyl acetate and washed with 2M sodium hydroxide. The organic phase is dried over magnesium sulfate, evaporated to dryness and the residue is chromatographed on silica gel using ethyl acetate/petrol (2:1) as eluent. After trituration with petroleum, 31 mg of N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)-phenyl]oxalamide were obtained as a white solid. MS: m/e 409 [M+H] + .

Example 22

N-[2-(4-benzamidophenyl)-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide

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A mixture of 30 mg (0.074 mmol) N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide, 10 mg (0.082 mmol ) of benzoic acid, 14 mg (0.092 mmol) of 1-hydroxybenzotriazole hydrate, 21 mg (0.11 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 18 mg (0.16 mmol) of N-ethylmorpholine in 2 ml. of dichloromethane is stirred for 18 hours at room temperature and then diluted with dichloromethane and washed with 2M hydrochloric acid and with saturated sodium bicarbonate. The organic phase is dried over magnesium sulfate, evaporated to dryness and the residue is chromatographed on silica gel using ethyl acetate/petrol (2:1) as eluent. 9 mg of N-[2-(4-benz-amidophenyl)-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)-phenyl]oxalamide were obtained as a white solid. MS: m/e 513 [M+H] + .

Example 23

N-[2-(4-acetamidophenyl)-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide

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A mixture of 30 mg (0.074 mmol) N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]-oxalamide, 8 mg (0.078 mmol) of acetic anhydride and 17 mg (0.15 mmol) of N-ethylmorpholine in 1 ml of dichloromethane are mixed for 2 hours at room temperature. The solvent was removed by evaporation and the residue was triturated with diethyl ether and collected by filtration to give 14 mg of N-[2-(4-acetamidophenyl)-1,1-dimethylethyl]-N'-[3-methoxy-4-(5 -oxazolyl)phenyl]-oxalamide as a white solid. MS: m/e 451 [M+H] + .

Example 24

N2-[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]-N-1,3-dimethyl-L-valinamide

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290 mg (0.75 mmol) of N-[[3-methoxy-4-(5-oxazolyl)-anilino]oxalyl]-3-methyl-L-valine methyl ester in 3 ml of methanol and 1 ml of IM aqueous sodium hydroxide is heated gently and leave the resulting solution for 18 hours at room temperature. The mixture is diluted with water, washed with diethyl ether and the aqueous phase is acidified with 2M hydrochloric acid. The solution is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate, evaporated to dryness and the residue is chromatographed on silica gel using ethyl acetate/acetic acid (99:1) for elution. After trituration with diethyl ether, 110 mg of N2-[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]-N-13-dimethyl-L-valinamide was obtained as a white solid. MS: m/e 376.0 [M+H] + .

Example 25

Tert-butyl [3-[[[4-(5-oxazolyl)anilino]oxalyl]amino]-benzyl]carbamate

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Analogous to the procedure described in example 1, but replacing 3-methoxy-4-(5-oxazolyl)aniline with 4-(5-oxazolyl)-aniline, and N-tert-butyloxalic acid with N-[3-[(tert-butoxyformamido) )methyl]phenyl]oxamic acid, tert-butyl [3-[[[4-(5-oxazolyl)anilino]oxalyl]amino]-benzyl]-carbamate was obtained as a white solid.

1H NMR (400 MHz, DMSO) δ: 1.4 (9H, s), 4.1 (2H, d), 7.02 (1H, d), 7.32 (1H, t), 7.40 ( 1H, t), 7.63 (1H, s), 7.69 (1H, d), 7.70-7.79 (3H, m), 7.97 (2H, d), 8.43 (1H , s), 10.82 (1H, s), 10.99 (1H, s).

The starting material was produced as follows:

i) 586 mg (4.78 mmol) of methyl oxalyl chloride is added to a solution of 1 g (4.5 mmol) of tert-butyl (3-aminobenzyl)-carbamate and 508 mg (5.03 mmol) of triethylamine in 10 ml of dichloromethane. . The resulting solution is stirred for 30 minutes at room temperature and then washed with a 5% solution of citric acid and with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate and the solvent was removed by evaporation, yielding 1.5 g of methyl N-[3-[(tert-butoxyformamido)methyl]phenyl]oxamate as a viscous gum.

1H NMR (400 MHz, CDCl3) δ: 1.43 (9H, s), 3.96 (3H, s), 4.31 (2H, d) 4.9-5.0 (br, s, 1H) , 7.11 (1H, d), 7.33 (1H, t), 7.51 (1H, s), 7.52 (1H, d), 8.86 (br, s, 1H).

ii) A mixture of 1.232 g (4 mmol) of methyl N-[3-[(tert-butoxyformamido)methyl]phenyl]oxamate and 0.24 g (6 mmol) of sodium hydroxide in 15 ml of methanol/water (2:1) was mixed for 2 hours at room temperature. The solvent was removed by evaporation and the residue was dissolved in water and diethyl ether. The aqueous layer was acidified with citric acid and washed twice with ethyl acetate. The combined organic solutions were dried over magnesium sulfate and the solvent was removed by evaporation to give 670 mg of N-[3-[(tert-butoxy-formamido) methyl] phenyl] oxamic acid as a white solid.

1H NMR (400 MHz, DMSO) δ: 1.48 (9H, s), 4.17 (2H, d), 7.09 (1H, d), 7.36 (1H, t), 7.49 ( 1H, t), 7.64 (1H, d), 7.74 (1H, s), 10.75 (1H, s).

Example 26

Tert-butyl [2-[[[4-(5-oxazolyl)anilino]oxalyl]amino]-benzyl]carbamate

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Analogously to the procedure described in example 25, but by replacing N-[3-[(tert-butoxyformamido)methyl]phenyl]oxamic acid with N-[2-[tert-butoxyformamido)methyl]phenyl]oxamic acid, tert-butyl [ 2-[[[4-(5-oxazolyl)-anilino]oxalyl]amino]benzyl]carbamate as a white solid MS: m/e 437.0 [M+H] + .

Example 27

tert-butyl [4-[[[4-(5-oxazolyl]anilino]oxalyl]amino]-benzylcarbamate

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Analogous to the procedure described in example 25, but by replacing N-[3-[(tert-butoxyformamido)methyl]phenyl]oxamic acid with N-[4-[tert-butoxyformamido)methyl]phenyl]-oxamic acid, tert -butyl [4-[[[4-(5-oxazolyl)anilino]oxalyl]amino]-benzyl]carbamate as a white solid. MS: m/e 436.6 [M+H] + .

Example 28

N-tert-butyl-N'-[4-(5-oxazolyl)phenyl]oxalamide

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Analogously to the procedure described in example 25, but by replacing 3-methoxy-4-(5-oxazolyl) aniline with 4-(5-oxazolyl) aniline, N-tert-butyl-N'-[4-(5- oxazolyl)phenyl]oxalamide as a pale yellow solid. MS: m/e 329.0 [M+H+MeCN] + .

Example 29

N-[3-(aminomethylphenyl]-N'-[4-(5-oxazolyl)phenyl]oxalamide trifluoroacetate

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Analogous to the procedure described in example 25, but replacing tert-butyl [3-[[[3-methoxy-4-(5-oxazolyl)-aniline]oxalyl]amino]benzyl]carbamate with tert-butyl [3-[[ [4-(5-oxazolyl)oxalyl]amino]benzyl]carbamate gave N-[3-(aminomethylphenyl]-N'-[4-(5-oxazolyl)phenyl]-oxalamide trifluoroacetate as a white solid. MS: m /e 336 [M]+.

Examples 30-193

Analogously to the procedure described in Example 1, starting with N-[3-methoxy-4-(5-oxazoyl)phenyl oxalamic acid (prepared as described in Example 1, paragraphs (i) and (ii) ) and with the appropriate amine compounds the compounds shown in table 3 were also produced:

Table 3

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Examples 194-214

Analogously to the procedure described in Example 4, starting with N-[3-(aminomethyl)phenyl]-N'-[3-methoxy-4-(5-oxazolyl)-phenyl]oxalamide trifluoroacetate (prepared as described in Example 3 ) and with the corresponding carboxylic acid derivative, the compounds shown in Table 5 were also produced:

Table 5

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Examples 215-301

Analogous to the procedure described in Example 10, starting with N-[2-amino-1,1-dimethyl)-N'-(3-methoxy-4-oxazol-5-ylphenyl]oxalamide (prepared as described in Example 9 ) and with the corresponding carboxylic acid, the compounds shown in Table 4 were also produced:

Table 4

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Examples 302-315; 438-458 and 653-663

Typical methods used to prepare the compounds of Table Ic are described below.

Example 440

N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl-2-(1-oxido-4-pyridyl)ethyl]oxalamide

30 mg (0.1 mmol) of 60% 3-chloroperoxybenzoic acid is added to a mixed solution of 20 mg (0.051 mmol) of N-[3-methoxy-4-(5-oxazolyl)-phenyl]-N'-[1 ,1-dimethyl-2-(4-pyridyl)ethyl]oxalamide in 1 ml of dichloromethane. The mixture is stirred for 1 hour and then diluted with ethyl acetate, washed with sodium bisulfite solution, sodium bicarbonate solution and salt solution. The organic solution was dried over magnesium sulfate, evaporated to dryness and the residue triturated with diethyl ether to give 13 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl -2-(1-oxido-4-pyridyl)ethyl]oxalamide as a white solid. MS: m/e 411 [M+H] + .

The starting material was produced as follows:

i) A solution of 17.4 g (0.115 mol) of alpha, alpha-dimethyl-4-pyridineethanol in 115 ml of acetic acid is added dropwise to a mixture of 115 ml of acetic acid, 58 ml of concentrated sulfuric acid and 6.8 ml ( 0.126 mmol) of acetonitrile with cooling in an ice/salt bath. The resulting mixture is stirred for 2 hours at room temperature, the pH is raised to 10 by the addition of 6M sodium hydroxide solution while cooling with ice. The slurry is filtered, washed with ethyl acetate and the aqueous filtrate is extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/methanol (1:19), (1:9) and (3:17) for gradient elution. 1.87 g of N-[1,1-dimethyl-2-(4-pyridyl)ethyl]acetamide were obtained as an orange oil.

1H NMR (400 MHz CDCl3) δ: 1.29 (6H, s), 1.91 (3H, s), 3.11 (2H, s), 5.10 (IH, br, s,), 7, 07 (2H, d), 8.50 (2H, d).

ii) A solution of 1.8 g (9.3 mmol) of N-[1,1-dimethyl-2-(4-pyridyl)ethyl]acetamide, 2.66 g (9.3 mmol) of titanium(IV) isopropoxide and 2.56 g (14 mmol) of diphenylsilane in 10 ml of tetrahydrofuran were stirred for 20 hours at room temperature. The obtained mixture is chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (60:18:2:3) for washing. The product is dissolved in 20 ml of concentrated hydrochloric acid and 50 ml of methanol and evaporated to dryness. The residue was evaporated five times with toluene to give 620 mg of alpha,alpha-dimethyl-4-pyridineethylamine hydrochloride (1:1) as a pale brown solid.

1H NMR (400 MHz DMSO) δ: 1.31 (6H, s), 3.26 (2H, s), 8.02 (2H, d), 8.4-8.6 (3H, br, s) , 8.88 (2H, d).

iii) A mixture of 100 mg (0.45 mmol) alpha/alpha-dimethyl-4-pyridineethylamine hydrochloride (1:1), 120 mg (0.45 mmol) N-[3-methoxy-4-(5-oxazolyl) phenyl]oxalic acid, 105 mg (0.68 mmol) of 1-hydroxybenzotriazole hydrate, 105 mg (0.54 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 127 mg (1.1 mmol) of N-ethyl -morpholine in 4 ml of dichloromethane is stirred for 20 hours at room temperature and then diluted with ethyl acetate and washed with water and sat. NaCl solution. The organic solution was dried over magnesium sulfate, evaporated to dryness and the residue was chromatographed on silica gel using ethyl acetate/methanol (19:1) as eluent. After trituration with diethyl ether, 32 mg of N-[3-methoxy-4-(5-oxazolyl)-phenyl]-N'-[1,1-dimethyl-2-(4-pyridyl)ethyl]-oxalamide were obtained as white solid substances. MS: m/e 395 [M+H] + .

Example 455

2-[2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methylpropyl]-5-benzofurancarboxylic acid

A solution of 68 mg (0.12 mmol) of benzyl 2-[2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl] amino]-2-methyl-propyl]-5-benzofurancarboxylate in 10 ml tetrahydrofuran is hydrogenated for 4 hours with 20 mg of 10% palladium on charcoal. The obtained suspension is filtered, evaporated to dryness and the residue is triturated with diethyl ether, which gives 41 mg of 2-[2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methylpropyl ]-5-benzofurancarboxylic acids as white solids. MS: m/e 477.9 [M+H] + .

The starting material was produced as follows:

i) A solution of 1.976 g (22.46 mmol) of isobutyric acid in 8 ml of anhydrous tetrahydrofuran is added to a stirred suspension of 1.078 g (26.95 mmol) of 60% sodium hydride and 2.268 g (22.46 mmol) of diisopropylamine in 40 ml of anhydrous tetrahydrofuran in a nitrogen atmosphere and the mixture is heated for 15 minutes under reflux. When cooled to 0°C, a solution of 14.04 ml (22.46 mmol) of 1.6M butyllithium in hexane was added while maintaining the temperature at 0-5°C. After 5 minutes at 0°C, the mixture is heated for 20 minutes at 30-35°C, cooled to 0°C, and a solution of 5.3 g (22.46 mmol) of 2-(bromo-methyl)-5 -benzofurancarbonitrile in 15 ml of anhydrous tetrahydrofuran while maintaining the temperature at 0°C. The suspension is stirred for 5 minutes at 0°C and then heated for 20 minutes at 30-35°C before being cooled to 15°C and quenched by careful addition of 50 ml of water and diluted with 50 ml of diethyl ether. The aqueous phase is separated, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The organic phase is dried over magnesium sulfate, evaporated to dryness and the residue is chromatographed on silica gel using ethyl acetate/petrol (1:2) for elution. 670 mg of 5-cyano-alpha,alpha-dimethyl-2-benzofuranpropionic acid were obtained as a white solid.

1H NMR (400 MHz CDCl3) δ: 1.23 (6H, s), 3.01 (2H, s), 6.46 (1H, s), 7.38 (1H, d), 7.42 (1H , d), 7.75 (1H, s).

ii) A mixture of 652 mg (2.68 mmol) of 5-cyano-alpha, alpha-dimethyl-2-benzofuranpropionic acid, 732 mg (2.68 mmol) of diphenylphosphoryl azide and 269 mg (2.66 mmol) of triethylamine in 8 ml tert-butanol is refluxed for 8 hours and then evaporated to dryness and the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, evaporated to dryness and chromatographed on silica gel using ethyl acetate/petrol (2:3) as eluent to give 225 mg of a white solid which was suspended in 10 ml of 2M sodium hydroxide solution and stirred. and reflux for 20 hours. The resulting suspension is cooled, evaporated to dryness and 5 ml of ethylene glycol and 400 mg of potassium hydroxide are added. It is heated for 20 minutes at 190°C and then 2 ml of water is added and after 20 minutes another 15 ml of water is added and the heating is continued for another 20 minutes until a permanent paste is obtained which is cooled and dissolved in 20 ml of water. By adding concentrated hydrochloric acid, the pH is adjusted to 2 and then 25 ml of dioxane, 3 g (21.74 mmol) of potassium carbonate and 1.5 g (6.88 mmol) of di-tert-butyl dicarbonate are added and the mixture is stirred for 24 hours . The solvent was removed by evaporation and the residue was dissolved in diethyl ether and water. The aqueous phase is separated, acidified with 2M hydrochloric acid and extracted with diethyl ether. The organic phase was dried over magnesium sulfate and evaporated to dryness, yielding 106 mg of 2-[2-(tert-butoxyformamido)-2-methylpropyl]-5-benzofurancarboxylic acid as a colorless gum.

iii) A mixture of 105 mg (0.32 mmol) of 2-[2-(tert-butoxyformamido)-2-methylpropyl]-5-benzofurancarboxylic acid, 80 mg (0.53 mmol) of benzyl bromide, and 200 mg (1, 45 mmol) of potassium carbonate in 4 ml of dimethylformamide is stirred for 1 hour at room temperature and then diluted with diethyl ether and water. The organic phase is washed twice with water, dried over magnesium sulfate, evaporated to dryness and the residue is chromatographed on silica gel using ethyl acetate/petrol (1:5) for elution. 104 mg of benzyl 2-[2-(tert-butoxyformamido)-2-methylpropyl]-5-benzofurancarboxylate were obtained as a colorless gum.

1H NMR (400 MHz CDCl3) δ: 1.39 (6H, s), 1.50 (9H, s), 3.23 (2H, s), 4.49 (1H, s), 5.41 (2H , s), 6.52 (1H, s), 7.34-7.52 (6H, m), 8.02 (1H, d), 8.30 (1H, s).

iv) 103 mg (0.24 mmol) of benzyl 2-[2-(tert-butoxyformamido)-2-methylpropyl]-5-benzofurancarboxylate were dissolved in 5 ml of trifluoroacetic acid/dichloromethane (1:1) for 10 minutes and then evaporated to dryness and the residue dissolved in 1 ml of dimethylformamide and added to a stirred solution of 66 mg (0.25 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalic acid, 115 mg (1 mmol ) N-ethylmorpholine, 45 mg (0.29 mmol) of 1-hydroxybenzotriazole hydrate and 70 mg (0.37 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 2 ml of dimethylformamide and the resulting mixture was stirred for 18 hours at room temperature. After dilution with ethyl acetate, the organic solution was washed with 2M hydrochloric acid, saturated sodium bicarbonate solution and water, dried over magnesium sulfate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/petrol (45:55) as eluent. . After trituration with diethyl ether, 81 mg of benzyl 2-[2-[[[3-methoxy-4-(5-oxazolyl)-anilino]oxalyl]amino]-2-methylpropyl]-5-benzofuran-carboxylate were obtained as a white solid . MS m/e 568 [M+H]+.

Example 443

2-[3-[2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]-amino]-2-methylpropyl]phenoxy]acetic acid

A solution of 45 mg (0.081 mmol) of benzyl 2-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methylpropyl]phenoxy]acetate in 5 ml of ethanol/tetrahydrofuran (1 :1) is hydrogenated for 5 hours with 4 mg of 10% palladium on charcoal as a catalyst. The resulting suspension is filtered, evaporated to dryness and triturated with diethyl ether, which gives 29 mg of 2-[3-[2-[[[3-methoxy-4-(5-oxazolyl)amino]-2-methylpropyl]phenoxy] acetic acid as a white solid. MS: m/e 468 [M+H] + .

The starting material was prepared as follows: i) 8 mg (0.2 mmol) of 60% sodium hydride was added to a stirred solution of 85 mg (0.2 mmol) of N-[2-(3-hydroxy-phenyl)- of 1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)-phenyl]oxalamide in 1 ml of dimethylformamide. After 10 minutes, 55 mg (0.24 mmol) of benzyl bromoacetate was added and the mixture was stirred for 4 hours at room temperature. The resulting solution is diluted with ethyl acetate, washed twice with water, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using ethyl acetate/petrol (2:1) as eluent. 51 mg of benzyl 2-[3-[2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methyl-propyl]phenoxy]acetate were obtained as a white solid. MS: m/e 558 [M+H] + .

Analogously to the procedure described in Example 1, starting with N-[3-methoxy-4-(5-oxazolyl)phenyl oxalamic acid, prepared as described in Example 1, paragraphs (i) and (ii)/ and with the appropriate amine, additional compounds shown in Table 1c were also produced.

Table 1c

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Examples 316-330

Analogously to the procedure described in Example 11, starting with N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide, produced as was described in Example 21, and with the corresponding aldehyde, the compounds shown in Table 1d were also produced.

Table 1d

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Examples 331-395 and 596-597

Analogously to the procedure described in Example 22, starting with N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide, prepared as was described in Example 21, and with the appropriate carboxylic acid, the compounds shown in Table 1e were produced.

Table 1e

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Examples 396-406; 433-437; 542-595 and 635-650

Typical methods used to prepare compounds from Tables 1f1, 1f2 and 1f3 are described below:

Example 398

N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl-3-(4-nitrophenoxy)propyl]oxalamide

(i) A mixture of 0.5 g (3.94 mmol) of 2,4,4-trimethyl-5,6-dihydro-1,3(4H)oxazine and 0.5 g (3.6 mmol) of 4-nitrophenol it is heated for 6 hours at 180C in a nitrogen atmosphere. The resulting mixture was cooled and purified by chromatography on silica gel using ethyl acetate for washing. 524 mg of N-[1,1-dimethyl-3-(4-nitrophenoxy)propyl]acetamide were obtained.

(ii) 693 mg (2.61 mmol) of N-[1,1-dimethyl-3-(4-nitro-phenoxy)propyl]acetamide, 815 mg (2.87 mmol) of titanium isopropoxide and 719 mg (3.91 mmol) of diphenylsilane is dissolved in 8 ml of tetrahydrofuran and left for 18 hours at room temperature. The resulting solution was dissolved in ethyl acetate and saturated sodium bicarbonate solution, filtered and the organic phase was extracted twice with 2M hydrochloric acid. The combined acid extracts were basified with 2M sodium hydroxide solution, extracted with ethyl acetate and the organic extracts were dried over magnesium sulfate, filtered and evaporated to dryness to give 266 mg of 1,1-dimethyl-3-(4-nitrophenoxy)propylamine. 1,1-Dimethyl-3-(4-nitrophenoxy)propylamine is then coupled with N-[3-methoxy-4-(5-oxazolyl)phenyl oxalamic acid analogously to the procedure described in Example 1 to give N-[ 3-Methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl-3-(4-nitrophenoxy)-propyl]oxalamide as a pale yellow solid. MS: m/e 469 [M+H] + .

Example 433

4-[3-[[[3-methoxy-4-(5-oxalzolyl)anilino]oxalyl]amino]-3-methylbutoxy]benzoic acid

A solution of 650 mg (1/17 mmol) of benzyl 4-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-3-methyl-butoxy]benzoate in 20 ml of tetrahydrofuran is hydrogenated 48 hours with 65 mg of 10% palladium on charcoal as a catalyst, then after 24 hours another 65 mg of catalyst is added and again after 44 hours. The obtained suspension is filtered, evaporated to dryness and the residue is triturated with diethyl ether, which gives 415 mg of 4-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-3-methyl -butoxy]benzoic acid as a white solid. MS: m/e 468 [M+H] + .

The starting material was produced as follows:

i) A mixture of 1.14 g (5 mmol) of benzyl 4-hydroxybenzoate and 800 mg (6.3 mmol) of 2,4,4-trimethyl-5,6-dihydro-1,3(4H)-oxazine is mixed and heated for 3 hours at 180°C. Another 600 mg (4.72 mmol) of oxazine is added and heating is continued for another 21 hours. The resulting mixture was cooled and chromatographed on silica gel using ethyl acetate/petrol (3:1) for elution. 1.52 g of benzyl 4-(3-acetamido-3-methylbutoxy)benzoate were obtained as a white solid.

1H NMR (400 MHz CDCl3) δ: 1.43 (6H, s), 1.94 (3H, s), 2.26 (2H, t), 4.14 (2H, t), 5.36 (2H , s), 5.65 (1H, s), 6.91 (2H, d), 7.35-7.52 (5H, m), 8.05 (2H, d).

ii) A solution of 1.5 g (4.23 mmol) benzyl 4-(3-acetamido-3-methylbutoxy) benzoate, 1.166 g (6.35 mmol) diphenylsilane and 1.2 g (4.23 mmol) titanium( IV) isopropoxide in 4 ml of tetrahydrofuran is mixed for 6 hours at room temperature. The resulting mixture is diluted with diethyl ether/2M sodium hydroxide solution, filtered and the organic phase is extracted twice with 2M hydrochloric acid. The combined aqueous extracts are basified with 2M sodium hydroxide solution and extracted with ether. The organic extracts were dried over magnesium sulfate and evaporated to dryness to give 1.16 g of benzyl 4-(3-amino-3-methyl-butoxy)benzoate as a pale colored gum.

1N NMR (400 MHz CDCl3) δ: 1.22 (6H, s), 1.92 (2H, t), 4.08 (2H, t), 5.36 (2H, s), 6.90 (2H , d), 7.33-7.48 (5H, m), 8.05 (2H, d).

iii) A solution of 873 mg (3.33 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalic acid, 500 mg (3.27 mmol) of 1-hydroxybenzotriazole hydrate, 1.2 g (3 .83 mmol) of benzyl 4-(3-amino-3-methylbutoxy) benzoate and 1 g (5.22 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml of dimethylformamide were stirred for 24 hours at room temperature. The resulting mixture was diluted with ethyl acetate and washed with 2M hydrochloric acid, with saturated sodium bicarbonate solution and water and then dried over magnesium sulfate, evaporated to dryness and chromatographed on silica gel using ethyl acetate/petrol (2:1) for elution. After trituration with diethyl ether, 765 mg of benzyl 4-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-3-methyl-butoxy]benzoate were obtained as a white solid. MS: m/e 558 [M+H] + .

Example 434

Analogous to the procedure described in example 433, but replacing benzyl 4-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]-oxalyl]amino]-3-methylbutoxy]benzoate with benzyl 2-[3 -[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-3-methyl-butoxy]benzoate, 2-[3-[[[3-methoxy-4-(5-oxazolyl) )anilino]oxalyl]amino]-3-methylbutoxy]benzoic acid as a white solid. MS: m/e 468 [M+H] + .

The starting material was produced as follows:

i) A solution of 917 mg (3.5 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalic acid, 650 mg (4.66 mmol) of 3-amino-3-methyl-1-butanol hydrochloride (1:1), 612 mg (4 mmol) of 1-hydroxybenzotriazole hydrate, 690 mg (6 mmol) of N-ethylmorpholine and 960 mg (5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml of dimethylformamide it is stirred for 20 hours at room temperature. The resulting mixture was diluted with ethyl acetate and washed with 2M hydrochloric acid, with saturated sodium bicarbonate solution and water and then dried over magnesium sulfate, evaporated to dryness and chromatographed on silica gel using ethyl acetate/petrol (3:1) for elution. 410 mg of N-(3-hydroxy-1,1-dimethylpropyl)-N'-[3-methoxy-4-(5-oxazolyl)-phenyl] oxalamide were obtained as a pale yellow solid. MS: m/e 348 [M+H] + .

ii) A solution of 48 mg (0.276 mmol) of diethyl azodicarboxylate in 2 ml of tetrahydrofuran is added to a mixture of 72 mg (0.275 mmol) of triphenylphosphine, 57 mg (0.25 mmol) of benzyl salicylate and 87 mg (0.25 mmol) of N- (3-hydroxy-1,1-dimethylpropyl)-N'-[3-methoxy-4-(5-oxazolyl)-phenyl]oxalamide and left for 1 hour at room temperature. The resulting mixture was chromatographed twice on silica gel using first ethyl acetate/petrol (1:1) and then methanol/dichloromethane (1:49) for washing. 29 mg of benzyl 2-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]-amino]-3-methylbutoxy]benzoate were obtained as a colorless gum. MS: m/e 558 [M+H] + .

Example 435

3-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-3-methylbutoxy]benzoic acid

Analogously to the procedure described in example 433, but by replacing benzyl 4-hydroxybenzoate with benzyl 3-hydroxybenzoate, 3-[3-methoxy-4-(5-oxazolyl)-anilino]oxalyl]amino]-3-methylbutoxy was obtained ]benzoic acid as a white solid. MS: m/e 468.

Example 553

4-[2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methylpropoxy]benzoic acid

Analogous to the procedure described in example 433, but replacing benzyl 4-[3-[[[3-methoxy-4-(5-oxazolyl)anilino]-oxalyl]amino]-3-methylbutoxy]benzoate with benzyl 4-[2 -[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methyl-propoxy]benzoate, 4-[2-[[[3-methoxy-4-(5-oxazolyl) anilino]oxalyl]amino]-2-methylpropoxy]benzoic acid as a white solid. MS: m/e 454 [M+H] + .

The starting material was produced as follows:

(i) A solution of 0.280 g (4 mmol) of 2,2-dimethylaziridine (Cairns, J. Am. Chem. Soc. 1941, 63, 871) and 9 g (40 mmol) of benzyl 4-hydroxybenzoate in 30 ml of chloroform is heated 3 hours under reflux. The reaction mixture is allowed to cool and diluted with dichloromethane. The solution was washed with 2M sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Column chromatography of the residue using dichloromethane:methanol:acetic acid:water (240:12:3:2) gave benzyl 4-(2-amino-2-methylpropoxy)benzoate (0.300 g, 1 mmol, 25%).

(ii) Benzyl 4-(2-amino-2-methylpropoxy)benzoate is coupled with N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalic acid analogously to the procedure described in Example 433, paragraph (iii) , giving benzyl 4-[2-[[[3-methoxy-4-(5-oxazolyl)anilino]oxalyl]amino]-2-methylpropoxy]benzoate as a white solid.

Example 561 was prepared analogously to the procedure described in Example 433, paragraphs (i) and (ii), wherein benzyl 4-hydroxybenzoate was replaced by 3-cyanophenol.

Examples 585, 588 and 589 were prepared from the compounds of Examples 583, 587 and 586 by reaction of the nitrile substituent with trimethylsilyl azide and dibutyltin oxide according to the method described by S.J. Wittenberger and B.G.J. Donner, J. Org. Chem., 1993, 58, 4139-4141.

For examples in Table 1f1 containing unprotected hydroxyl or amino groups, suitable protecting groups such as benzyl for hydroxyl and benzyloxycarbonyl for amino or similar groups, which are mentioned above and are well known in the art, are used.

Table 1f1

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Examples 615-631 and 664-670

Example 615

N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl-2-(phenylthio)ethyl]oxalamide

(i) A mixture of 2 g (17.7 mmol) of 2,4,4-trimethyl-2-oxazoline and 1.95 g (17.7 mmol) of thiophenol is heated for 18 hours at 120°C. After cooling, the resulting solid was triturated with diethyl ether/petrol (1:2) and filtered to give 2.55 g of N-[1,1-dimethyl-2-(phenylthio)ethyl]acetamide as a white solid.

(ii) A solution of 2.5 g (11.2 mmol) of N-[1,1-dimethyl-2-(phenylthio)ethyl]acetamide, 3.18 g (11.2 mmol) of titanium isopropoxide and 3.09 g (16.8 mmol) of diphenylsilane in 12 ml of tetrahydrofuran was stirred for 18 hours at room temperature. The resulting mixture was chromatographed on silica gel using 3%, 6% and 10% methanol in dichloromethane for elution. 2 g of 1,1-dimethyl-2-(phenylthio)ethylamine were obtained as a pale orange oil. 1,1-dimethyl-2-(phenylthio)ethylamine is then coupled with N-[3-methoxy-4-(5-oxazoyl)phenyl oxalamic acid analogously to the procedure described in Example 1, thereby obtaining N-[3- methoxy-4-(5-oxazolyl)-phenyl]-N'-[1,1-dimethyl-2-(phenylthio)ethyl]oxalamide. MS: m/e 426 [M+H] + .

Example 616 was prepared analogously to the method described in Example 615, but using 4-benzyloxythiophenol instead of thiophenol and removing the protecting group using a mixture of hydrogen bromide in acetic acid.

Additional compounds listed in Table 1f2 were produced analogously to the procedure described for Example 615 by reacting the corresponding thiol with 2,4,4-trimethyl-2-oxazoline or 2,4,4-trimethyl-5,6-dihydro-1,3( 4H)oxazine and, where necessary, by removing the protective groups with the usual . methods.

Table 1f2

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Examples 632-634

The compounds in table lf3 were prepared analogously to the procedure described for example 398 in table lf1 by replacing 4-nitrophenol with the corresponding aniline and reacting with 2,4,4-trimethyl-2-oxazoline or 2,4,4-trimethyl-5,6 -dihydro-1,3(4H)oxazine and, where necessary, deprotection by conventional methods. Table 1f3

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Examples 407-414, 459-541 and 651-652

Typical methods used for the production of compounds from Table 1g are described below.

Example 408

N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[2-[4-(4-methoxy-phenyl)-1-piperazinyl]-1,1-dimethylethyl]oxalamide

(i) A mixed solution of 3.23 g (16.8 mmol) of 1-(4-methoxyphenyl)piperazine, 2.00 g (16.8 mmol) of 2-methyl-2-nitropropan-1-ol and 5.34 g (50.4 mmol) of sodium carbonate in 40 ml of n-butanol is refluxed for 16 h. The reaction mixture is allowed to cool and diluted with 100 ml of dichloromethane. The solution is filtered and concentrated in vacuo. The residue was purified by vacuum chromatography on silica gel using petroleum ether/ethyl acetate (10:1) as eluent to give 1.86 g (6.34 mmol, 38%) of 1-(4-methoxy-phenyl)-4- (2-methyl-2-nitropropyl)piperazine as a white solid.

(ii) A solution of 1.86 g (6.34 mmol) of 1-(4-methoxyphenyl)-4-(2-methyl-2-nitropropyl)piperazine and 0.5 g of palladium on activated carbon in 50 ml of ethanol is mixed 48 hours at room temperature in a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 1.59 g (6.04 g mmol, 95%) of 2-[4-(4-methoxyphenyl)-piperazin-1-yl)-1,1- of dimethylethylamine as a clear oil. 2-(4-(4-Methoxyphenyl)-piperazin-1-yl)-1,1-dimethylethylamine is then coupled with N-[3-methoxy-4-(5-oxazoyl)phenyl oxalamic acid analogously to the procedure described in to example 1, which gives N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[2-[4-(4-methoxyphenyl)-1-piperazinyl]-1,1-dimethylethyl]oxalamide as a white solid. MS: m/e 508 [M+H] + .

Examples 407, 409, 410, 411, 412 and similar structures were prepared by an analogous procedure by replacing 1-(4-methoxyphenyl) piperazine with an appropriately substituted piperazine.

Examples 413 and 414 were prepared by an analogous procedure by replacing 1-(4-methoxyphenyl)piperazine with t-butyl-1-piperazinecarboxylate to give 4-(2-amino-2-methyl-propyl)piperazine-1-carboxylic acid t-butyl ester which is then linked to N-[3-methoxy-4-(5-oxazoyl)phenyl oxalamic acid. The resulting product is then deprotected to give N-[3-methoxy-4-(5-oxazolyl)-phenyl]-N'-[1,1-dimethyl-2-(1-piperazinyl)ethyl]oxalamide which can used to produce examples 413, 414 and various other N-acyl and N-sulfonyl derivatives, such as those shown in Table 1g, using the appropriate acylating or sulfonylating reagents.

Example 489

N-[2-[4-(cyclohexylmethyl)-1-piperazinyl]-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide

A mixed solution of 48 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl-2-(1-piperazinyl)ethyl]-oxalamide (1.2 mmol) and 13 mg of cyclohexanecarboxaldehyde (1.2 mmol) in 1 ml of a mixture of 5% acetic acid/dichloromethane was mixed with a solution of 38 mg of sodium triacetoxyborohydride (1.8 mmol) in 1 ml of a mixture of 5% acetic acid/dichloromethane. After stirring overnight at room temperature, the reaction mixture was diluted with 10 ml of dichloromethane and washed with 8 ml of sodium bicarbonate solution and then with 8 ml of water. The organic layer was then evaporated and purified by vacuum chromatography on a silica gel column eluting with 5% methanol/dichloromethane, which after evaporation of the fractions gave 14.3 mg (0.3 mmol, 25%) of N-[2-[4-( cyclohexylmethyl)-1-piperazinyl]-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 498.2 [M+H] + .

Other N-alkylated compounds shown in table 1g were produced by analogous methods.

Table 1g

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Examples 415-420

Analogous to the procedure described in example 4, starting with N-[3-(aminomethylphenyl]-N'-[3-methoxy-4-(5-oxazolyl)-phenyl]oxalamide and the chloride of the corresponding carboxylic acid, the compounds shown in table 1h were produced .

Table 1h

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Examples 421-427 and 598-614

Typical methods used to prepare the compounds shown in Table 1b are described below.

Examples 421 and 423 were prepared by reacting N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl-2-(4-piperidinyl)ethyl]oxalamide with the appropriate acylating agent.

Example 424 was prepared analogously to the procedure described in Example 1, starting with N-[3-methoxy-4-(5-oxazoyl)-phenyl oxalamic acid, prepared as described in Example 1, parts (i) and (ii) , and the corresponding amine.

Example 422

N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl-2-(phenylthio)ethyl]oxalamide

(i) A mixture of 2 g (17.7 mmol) of 2,4,4-trimethyl-2-oxazoline and 1.95 g (17.7 mmol) of thiophenol is heated for 18 hours at 120°C. When cooled, the resulting solid was triturated with diethyl ether/petrol (1:2) and filtered to give 2.55 g of N-[1,1-dimethyl-2-(phenylthio)ethyl]acetamide as a white solid.

(ii) A solution of 2.5 g (11.2 mmol) of N-[1,1-dimethyl-2-(phenylthio)ethyl]acetamide, 3.18 g (11.2 mmol) of titanium isopropoxide and 3.09 g (16.8 mmol) of diphenylsilane in 12 ml of tetrahydrofuran was stirred for 18 hours at room temperature. The resulting mixture is chromatographed on silica gel using 3%, 6% and 10% methanol in dichloromethane for elution. 2 g of 1,1-dimethyl-2-(phenylthio)ethylamine were obtained as a pale orange oil. 1,1-dimethyl-2-(phenylthio)ethylamine is then coupled with N-[3-methoxy-4-(5-oxazoyl)phenyl oxalamic acid analogously to the procedure described in Example 1, thereby obtaining N-[3- methoxy-4-(5-oxazolyl)-phenyl]-N'-[1,1-dimethyl-2-(phenylthio)ethyl]oxalamide. MS: m/e 426 [M+H] + .

Example 427 was prepared analogously to the method described for Example 422, but using 4-benzyloxythiophenol instead of thiophenol and removing the protecting group using a mixture of hydrogen bromide in acetic acid.

Example 607 was prepared starting with benzofuran-3-acetic acid ethyl ester by alkylating iodomethane using potassium tertiary butoxide as base followed by alkaline hydrolysis, Curtius reaction, hydrolysis in ethylene glycol and water at 180°C. The resulting amine is then coupled with N-[3-methoxy-4-(5-oxazoyl)phenyl oxalamic acid as described in Example 1.

Example 426 was prepared analogously to the procedure described for Example 408 in Table 1g using tetrahydroquinoline instead of 1-(4-methoxyphenyl)piperazine.

Example 610

N-[2-[1-(methanesulfonyl)-4-piperidinyl]-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide

14 mg (0.12 mmol) of methanesulfonyl chloride is added to a solution of 40 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl-N'-[1,1-dimethyl-2 -(4-piperidinyl)ethyl]-oxalamide in 1 ml of dichloromethane and then 17 mg (0.15 mmol) of N-ethylmorpholine was added and the mixture was stirred for 4 hours at room temperature. The resulting solution is diluted with ethyl acetate, washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate, evaporated to dryness and the residue is triturated with diethyl ether. 23 mg of N-[2-[1-(methanesulfonyl)-4-piperidinyl]-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide were obtained as a white solid. MS m/e 479 [M+H]+.

The starting material was produced as follows:

i) A solution of 4.65 g (31 mino l) of alpha, alpha-dimethyl-4-pyridineethylamine, 15.6 g (0.154 mol) of triethylamine and 13.5 g (61.9 mmol) of di-tert-butyl dicarbonate in 100 ml of methanol was stirred for 2 days at room temperature and then evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, evaporated to dryness and chromatographed on silica gel using ethyl acetate/petrol (2:1) as eluent. 2.12 g of tert-butyl [1,1-dimethyl-2-(4-pyridyl)ethyl]carbamate were obtained as a pale orange solid.

1N NMR (400 MHz CDCl3) δ: 1.29 (6H, s), 1.49 (9H,,s), 3.04 (2H,s), 4.30 (1H, br,s), 7, 10 (2H,,d), 8.52 (2H,,d).

ii) 2.1 g (8.4 mmol) of tert-butyl (1,1-dimethyl-2-(4-pyridyl)ethyl]carbamate in 20 ml of methanol is hydrogenated with 400 mg of 10% palladium on charcoal as a catalyst 6 days at 70°C and under 7 bar.The obtained suspension is filtered, evaporated to dryness and the residue is triturated with diethyl ether/petrol (1:9), which gives 1.2 g of tert-butyl [1,1-dimethyl -2-(4-piperidinyl)ethyl]carbamate as a white solid.

1H NMR (400 MHz CDCl3) δ: 1.18 (6H, s), 1.28-1.41 (2H, m), 1.37 (9H, s), 1.52-1.69 (3H, m), 1.75-1.83 (2H, d), 2.74-2.84 (2H, t), 3.12-3.21 (2H, d), 6.40-6.48 ( 1H, br, s), 8.60-8.95 (1H, br, s).

iii) A solution of 1.2 g (4.68 mmol) of tert-butyl [1,1-dimethyl-2-(4-piperidinyl)ethyl]carbamate, 945 mg (9.36 mmol) of triethylamine and 2.33 g ( 9.36 mmol) of N-(benzyloxycarbonyloxy)succinimide in 20 ml of dichloromethane was stirred for 18 hours at room temperature and then washed with a 10% solution of citric acid and with a saturated solution of sodium bicarbonate. The organic phase is dried over magnesium sulfate, evaporated to dryness and the residue is chromatographed on silica gel using ethyl acetate/petrol (1:2) for elution. 1.89 g of benzyl 4-[2-(tert-butoxyformamido)-2-methylpropyl]-1-piperidinecarboxylate were obtained.

1N NMR (400 MHz CDCl3) δ: 1.15-1.32 (2H, m), 1.29 (6H, s), 1.42 (9H, s), 1.49-1.78 (5H, m), 2.75-2.90 (2H, m), 4.05-4.16 (2H, m), 4.41 (1H, br, s), 5.12 (2H, s), 7 .37-7.42 (5H, m).

iv) A solution of 1.79 g (4.6 mmol) of benzyl 4-[2-(tert-butoxyformamido)-2-methylpropyl]-1-piperidinecarboxylate in 6 ml of trifluoroacetic acid/dichloromethane (1:1) is stirred for 5 minutes at room temperature and then evaporated to dryness. The residue was dissolved in 20 ml of dichloromethane together with 1.2 g (4.58 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalic acid, 1.1 g (5.74 mmol) of 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.32 g (11.5 mmol) of N-ethylmorpholine and 1.1 g (6.9 mmol) of 1-hydroxy-7-azabenzo-triazole. After stirring overnight, the solution is diluted with ethyl acetate, washed with 10% citric acid solution and saturated sodium bicarbonate solution, dried over magnesium sulfate, evaporated to dryness and chromatographed on silica gel using ethyl acetate/petrol (1: 1) for rinsing. 1.14 g of benzyl 4-{2-[[[3-methoxy-4-(5-oxazolyl)phenylamino]oxalyl]amino]-2-methyl-propyl}-1-piperidinecarboxylate were obtained as a white foam. MS: m/e 535 [M+H] + .

v) A solution of 1.1 g (2.05 mmol) of benzyl 4-{2-[[[3-methoxy-4-(5-oxazolyl)phenylamino]oxalyl]amino]-2-methylpropyl}-1-piperidinecarboxylate in 25 ml of methanol is hydrogenated for 4 hours with 100 mg of 10% palladium on charcoal as a catalyst. The resulting suspension was filtered and evaporated to dryness, yielding 732 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl-2-(4-piperidinyl)ethyl] oxalamide as a white solid. MS: m/e 401 [M+H] + .

Example 616 was prepared starting from the ethyl ester of benzofuran-3-acetic acid by alkylation of iodomethane using potassium tertiary butoxide as a base followed by alkaline hydrolysis, Curtius reaction, hydrolysis in ethylene glycol and water at 180°C. The resulting amine is then coupled with N-[3-methoxy-4-(5-oxazoyl)phenyl oxalamic acid as described in Example 1.

Example 619

N-[2-[1-(methanesulfonyl)-4-piperidinyl]-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide

14 mg (0.12 mmol) of methanesulfonyl chloride was added to a solution of 40 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)-phenyl-N'-[1,1-dimethyl- 2-(4-piperidinyl)ethyl]oxalamide in 1 ml of dichloromethane and then 17 mg (0.15 mmol) of N-ethylmorpholine was added and the mixture was stirred for 4 hours at room temperature. The resulting solution is diluted with ethyl acetate, washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate, evaporated to dryness and the residue is triturated with diethyl ether. 23 mg of N-[2-[1-(methanesulfonyl)-4-piperidinyl]-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl] oxalamide were obtained as a white solid. MS m/e 479 [M+H]+.

The starting material was produced as follows:

i) A solution of 4.65 g (31 mmol) of alpha, alpha-dimethyl-4-pyridineethylamine, 15.6 g (0.154 mol) of triethylamine and 13.5 g (61.9 mmol) of di-tert-butyl dicarbonate in 100 ml of methanol was stirred for 2 days at room temperature and then evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, evaporated to dryness and chromatographed on silica gel using ethyl acetate/petrol (2:1) as eluent. 2.12 g of tert-butyl [1,1-dimethyl-2-(4-pyridyl)ethyl]carbamate were obtained as a pale orange solid.

1N NMR (400 MHz CDCl3) δ: 1.29 (6H, s), 1.49 (9H, s), 3.04 (2H, s), 4.30 (1H, br, s), 7.10 (2H, d), 8.52 (2H, d).

ii) 2.1 g (8.4 mmol) of tert-butyl [1,1-dimethyl-2-(4-pyridyl) ethyl] carbamate, in 20 ml of methanol, was hydrogenated for 6 days with 400 mg of 10% palladium at coal as a catalyst at 70°C and 7 bar. The obtained suspension is filtered, evaporated to dryness and the residue triturated with diethyl ether/petrol (1:9), which gives 1.2 g of tert-butyl [1,1-dimethyl-2-(4-piperidinyl)ethyl]carbamate as white solids.

1N NMR (400 MHz DMSO) δ: 1.18 (6H, s), 1.28-1.41 (2H, m), 1.37 (9H, s), 1.52-1.69 (3H, m), 1.75-1.83 (2H, d), 2.74-2.84 (2H, t), 3.12-3.21 (2H, d), 6.40-6.48 ( 1H, br, s), 8.60-8.95 (1H, br, s).

iii) A solution of 1.2 g (4.68 mmol) of tert-butyl [1,1-dimethyl-2-(4-piperidinyl)ethyl]carbamate, 945 mg (9.36 mmol) of triethylamine and 2.33 g ( 9.36 mmol) of N-(benzyloxycarbonyloxy)succinimide in 20 ml of dichloromethane was stirred for 18 hours at room temperature and then washed with a 10% solution of citric acid and with a saturated solution of sodium bicarbonate. The organic phase is dried over magnesium sulfate, evaporated to dryness and the residue is chromatographed on silica gel using ethyl acetate/petrol (1:2) for elution. 1.89 g of benzyl 4-[2-(tert-butoxyformamido)-2-methylpropyl]-1-piperidinecarboxylate were obtained.

1H NMR (400 MHz CDCl3) δ: 1.15-1.32 (2H, m), 1.29 (6H, s), 1.42 (9H, s), 1.49-1.78 (5H, m), 2.75-2.90 (2H, m), 4.05-4.16 (2H, m), 4.41 (1H, br, s), 5.12 (2H, s), 7 .27-7.42 (5H, m).

iv) A solution of 1.79 g (4.6 mmol) of benzyl 4-[2-(tert-butoxyformamido)-2-methylpropyl]-1-piperidinecarboxylate in 6 ml of trifluoroacetic acid/dichloromethane (1:1) is stirred for 5 minutes at room temperature and then evaporated to dryness. The residue was dissolved in 20 ml of dichloromethane together with 1.2 g (4.58 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalic acid, 1.1 g (5.74 mmol) of 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.32 g (11.5 mmol) of N-ethyl-morpholine and 1.1 g (6.9 mmol) of 1-hydroxy-7-azabenzo-triazole. After stirring overnight, the solution is diluted with ethyl acetate, washed with 10% citric acid solution and saturated sodium bicarbonate solution, dried over magnesium sulfate, evaporated to dryness and chromatographed on silica gel using ethyl acetate/petrol (1: 1) for rinsing. 1.14 g of benzyl 4-{2-[[[3-methoxy-4-(5-oxazolyl)phenylamino]-oxalyl]amino]-2-methylpropyl}-1-piperidinecarboxylate were obtained as a white foam MS: m/e 535 [M+H]+.

v) A solution of 1.1 g (2.05 mmol) of benzyl 4-{2-[[[3-methoxy-4-(5-oxazolyl)phenylamino]oxalyl]amino]-2-methyl-propyl}-1- of piperidinecarboxylate in 25 ml of methanol is hydrogenated for 4 hours with 100 mg of 10% palladium on charcoal as a catalyst. The resulting suspension was filtered and evaporated to dryness, yielding 732 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N'-[1,1-dimethyl-2-(4-piperidinyl)ethyl] oxalamide as a white solid. MS: m/e 401 [M+H] + .

The remaining examples in Table 1b were produced analogously to the methods described above, according to the structure, or by methods previously described for related structures.

Table 1b

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Examples 428-432;

Examples 428, 431 and 432 in Table 1 were prepared analogously to the procedure described for Example 408 in Table 1g but using N-[3-methoxy-4-(4-oxazoyl)phenyl oxalamic acid or N-[3-methoxy-4 -(2-methyl-4-oxazoyl)phenyl oxalamic acid instead of N-[3-methoxy-4-(5-oxazoyl)phenyl oxalamic acid for the coupling step.

Examples 429 and 430 in table li were produced analogously to the procedures described for the preparation of compounds from table 1f.

Table 1i

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In the proposed description, the term "comprising" means "including or consisting of" and "comprising" means "including or consisting of".

The features disclosed in the previous description, or in the following patent claims, or in the attached drawings, expressed in specific forms or terms of meaning for the implementation of the described function, or method or for the process by which the described result is achieved, if appropriate can be separated, or in any which combination of such features, to apply to realize the invention in its different form.

Claims (77)

1. Compounds of general formula (I): [image] indicated by that R 1 represents heterocyclyl; R 2 represents hydrogen, unsubstituted lower alkyl, lower alkoxy, halogen, hydroxy or cyano; R 3 represents hydrogen, unsubstituted lower alkyl, lower alkoxy, halogen, or cyano; R 4 represents hydrogen, lower alkyl, lower cycloalkyl, aryl, or heterocyclyl; R 5 represents hydrogen, unsubstituted lower alkyl, lower alkoxy, halogen, or cyano; R 6 represents hydrogen, unsubstituted lower alkyl, lower alkoxy, halogen, or cyano; R7 represents hydrogen, or unsubstituted lower alkyl; R 8 represents hydrogen, or unsubstituted lower alkyl; or R4 and R5 together with the nitrogen atom to which they are attached represent heterocyclyl; and their pharmaceutically acceptable salts. 2. Compounds according to claim 1, characterized in that at least one of R2, R3, R5 and R6 is not hydrogen. 3. Compounds according to claim 1 or claim 2, characterized in that R1 represents an optionally substituted oxazole ring. 4. Compounds according to any preceding claim, characterized in that R1 represents an optionally substituted oxazole ring, in accordance with the general formula: [image] in which they are R 2 to R 8 are defined as in claim 1, and R 9 is hydrogen, lower alkyl, or aryl-lower alkyl; R10 is hydrogen. 5. Compounds according to claim 4, characterized in that R9 represents methyl, ethyl or benzyl. 6. Compounds according to claim 4, characterized in that R9 and R10 represent hydrogen. 7. Compounds according to claim 1 or 2, characterized in that R1 represents triazolyl. 8. Compounds according to any preceding claim, characterized in that R 2 represents lower alkyl. 9. Compounds according to claim 8, characterized in that R2 represents methoxy. 10. Compounds according to any preceding claim, characterized in that R4 represents a lower alkyl group which is branched. 11. Compounds according to any preceding claim, characterized in that R7 represents hydrogen. 12. Compounds according to any preceding claim, characterized in that R8 represents hydrogen. 13. A compound according to any one of claims 1, 2, 3, 4, or 6, characterized in that it is selected from: [image] [image] or a pharmaceutically acceptable salt thereof. 14. Compounds according to claim 1 formula [image] characterized in that R 2 , R 3 , R 5 , R 6 , R 7 , R 9 and R 10 are as defined above, R 11 and R 13 are H or lower alkyl, m is 1 to 5 and R is heterocyclyl or aryl, provided that R 12 is not 4-fluorophenyl. 15. Compounds according to claim 14, characterized in that R2 represents methoxy, R3, R5, R6, R9, R10, R11 and R13 represent hydrogen and where R12 represents optionally substituted phenyl and optionally substituted heteroaryl, provided that R12 does not represent 4-fluorophenyl. 16. Compounds according to claim 14, characterized in that they are selected from: Table 1c [image] [image] [image] [image] 17. Compounds according to claim 1 of the formula [image] characterized in that R2, R3, R5, R6, R7, R9 and R10 are as defined above, R11, R13, R14, R15, R16, R17 and R18 represent H or lower alkyl and R 19 is alkyl, cycloalkyl, heterocyclyl alkyl or aryl alkyl. 18. Compounds according to claim 17, characterized in that R2 represents methoxy, and R3, R5, R6, R9, R10, R11 and R13 represent hydrogen. 19. Compounds according to claim 17 or 18, characterized in that they are selected from: Table 1d [image] [image] 20. Compounds according to claim 1 of the formula [image] indicated that R2, R3, R5. R 6 , R 7 , R 9 and R 10 as defined above, R 11 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 represent H or lower alkyl and R 20 is alkyl, cycloalkyl, aryl, heterocyclyl. 21. Compounds according to claim 20, characterized in that R2 represents methoxy, and R3, R5, R6, R9, R10, R11 and R13 represent hydrogen. 22. Compounds according to claim 20 or 21, characterized in that they are selected from: Table 1e [image] [image] [image] [image] [image] [image] 23. Compounds according to claim 1 of the formula [image] characterized in that R2, R3, R5, R6, R7, R9 and R10 are as defined above, R11 and R13 represent H or lower alkyl, n is 0 or 1, Ra, Rb represent lower alkyl or Ra and Rb taken together with the carbon atom to which they are attached form a -3- to 7-membered carbocycle, and R12 is heterocyclyl, aryl or lower cycloalkyl, and Z is O, S or NR28, where R28 represents H or lower alkyl. 24. Compounds according to claim 23 of the formula [image] characterized in that R2, R3, R5, R6, R7, R9 and R10 are as defined above, R11 and R13 are H or lower alkyl, n = 0 or 1, (CH2)m, m = 1 to 5, and R12 is heterocyclyl/aryl or lower cycloalkyl. 25. Compounds according to claim 23 or 24, characterized in that R2 is methoxy, and R3, R5, R6, R9, R10, R11 and R13 represent hydrogen. 26. Compounds according to claims 23 to 25, characterized in that they are selected from: Table 1f1 [image] [image] [image] [image] [image] [image] [image] 27. Compounds according to claim 23 of the formula [image] indicated by the fact that they are R2, R3, R5, R6, R7, R9 and R10 as defined above, R11 and R13 represent H or lower alkyl, n = 0 or 1, Ra, Rb represent lower alkyl or Ra and Rb taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocycle, and R 12 is heterocyclyl, aryl or lower cycloalkyl. 28. Compounds according to claim 27, characterized in that R2 represents methoxy, and R3, R5, R6, R9, R10, R11 and R13 represent hydrogen. 29. Compounds according to claim 23, 27 or 28, characterized in that they are selected from: Table 1f2 [image] [image] 30. Compounds according to claim 23 of the formula [image] indicated by the fact that they are R2, R3, R5, R6, R7, R9 and R10 as defined above, R11, R13 and R28 represent H or lower alkyl, n = 0 or 1, Ra, Rb represent lower alkyl or Ra and Rb taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocycle, and R 12 is heterocyclyl, aryl or lower cycloalkyl. 31. Compounds according to claim 30, characterized in that R2 represents methoxy, and R3, R5, R6, R9, R10, R11 and R13 represent hydrogen or methyl. 32. Compounds according to claim 23, 30 or 31, characterized in that they are selected from: Table 1f3 [image] 33. Compounds according to claim 1 of the formula [image] indicated by the fact that they are R2, R3, R5, R6, R7, R9 and R10 as defined above, R11 and R13 represent H or lower alkyl, n = 0 or 1, R21 is optionally substituted phenyl alkyl, optionally substituted phenyl carbonyl, optionally substituted phenyl sulfonyl. 34. Compounds according to claim 33, characterized in that R2 represents methoxy, and R3, R5, R6, R9, R10, R11 and R13 represent hydrogen. 35. Compounds according to claim 33 or 34, characterized in that they are selected from: Table 1g [image] [image] [image] [image] [image] [image] [image] [image] 36. Compounds according to claim 1 of the formula [image] indicated by the fact that they are R2, R3, R5, R6, R7, R9, R10 and R13 are defined as above, R22, R23, R24, R25 and R26 represent H or lower alkyl, R27 is alkyl, aryl or heterocyclyl, alkoxy, aryloxy, heterocyclyloxy. 37. Compounds according to claim 36, characterized in that R2 represents methoxy, and R3, R5, R6, R9, R10, R13, R22, R23, R24, R25 and R26 represent hydrogen. 38. Compounds according to claim 36 or 37, characterized in that they are selected from: Table 1h [image] 39. Compounds according to claim 1 of the formula [image] wherein R 2 , R 3 , R 5 , R 6 , R 7 and R 10 are as defined above, R 11 and R 13 are H or lower alkyl, and R 12 is heterocyclyl, aryl or lower cycloalkyl. 40. Compounds according to claim 39, characterized in that R2 represents methoxy, and R3, R5, R6, R9, R10, R11 and R13 represent hydrogen, and where R12 is optionally substituted phenyl or [image] where R21 is defined as above. 41. Compounds according to claim 39 or 40, characterized in that they are selected from: Table 11i [image] 42. Compounds according to claim 1, characterized in that they are selected from: Table 1b [image] [image] [image] 43. Process for the production of compounds of formula (I) according to any claim from 1 to 42 and their pharmaceutically acceptable salts, characterized in that it includes a general reaction scheme [image] wherein R1 to R8 are defined as in claim 1, and if necessary, converting the compound of formula (I) into a pharmaceutically acceptable salt. 44. Compound formula [image] indicated that R1, R2, R3, R5, R6 and R7 are defined as in claim 1. 45. Process for the production of compounds according to claim 4 and their pharmaceutically acceptable salts, characterized in that it includes the general reaction scheme: [image] wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are defined as in claim 1, R 9 and R 10 are defined as in claim 4, and, if necessary, converting the compound of formula (IX) into a pharmaceutically acceptable salt. 46. Compounds of the general formula [image] characterized in that R2, R3, R5, R6 and R7 are defined as in claim 1, R9 and R10 are defined as in claim 4. 47. Process for the production of compounds of formula (I) according to any claim from 1 to 42 and their pharmaceutically acceptable salts, characterized in that it includes the general reaction scheme: [image] where R1 to R8 are defined as in claim 1, and, if necessary, converting the compound of formula (I) into a pharmaceutically acceptable salt. 48. Compounds according to any of claims 1 to 42 and their pharmaceutically acceptable salts, characterized in that they are produced in accordance with a process according to claim 43 or claim 47 or in accordance with a process equivalent to them. 49. Compounds according to claim 4 and their pharmaceutically acceptable salts, characterized in that they are produced in accordance with the process according to claim 45 or in accordance with a process equivalent to it. 50. A pharmaceutical preparation, characterized in that it contains a compound according to any of claims 1 to 42, 48 or 49, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or auxiliary agent, and, if necessary, one or more additional therapeutically active substances. 51. Pharmaceutical preparation according to claim 50, characterized in that it contains one or more additional therapeutically active substances that are immunosuppressant, chemotherapeutic agent, antiviral agent, antibiotic, anti-parasitic agent, antifungal agent, anti-inflammatory agent and/or agent against vascular hyperproliferation. 52. Pharmaceutical preparation according to claim 51, characterized in that one or more additional therapeutically active substances are interferon or its derivative. 53. A compound according to any of claims 1 to 42, 48 or 49, or its pharmaceutically acceptable salt, or a preparation according to any of claims 50 to 52, indicated to be used in therapy. 54. Compound according to claim 53, characterized in that it is used in monotherapy. 55. Compound according to claim 53, characterized in that it is used in combined therapy. 56. A method for the production of a drug, characterized in that the compound according to any of claims 1 to 42, 48 or 49, or its pharmaceutically acceptable salt is brought into a galenic form for application together with a pharmaceutically acceptable carrier, diluent or auxiliary agent, and, if necessary, with one or more additional therapeutically active substances. 57. The method according to claim 56, characterized in that one or more additional therapeutically active substances is an immunosuppressant, a chemotherapeutic agent, an anti-viral agent, an antibiotic, an anti-parasitic agent, an anti-fungal agent, an anti-inflammatory agent and/or an anti-vascular hyperproliferation agent . 58. The method according to claim 57, characterized in that one or more additional therapeutically active substances are interferon or its derivative. 59. A method for treating an immune-mediated condition or disease, viral disease, bacterial disease, parasitic disease, inflammation, inflammatory disease, hyperproliferative vascular disease, tumor or cancer in a subject, comprising the step of administering to the subject a therapeutically effective amount of the compound according to any of claims 1 to 42, 48 or 49, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any of claims 50 to 52. 60. A method for treating an immune-mediated condition or disease, viral disease, bacterial disease, parasitic disease, inflammation, inflammatory disease, hyperproliferative vascular disease, tumor or cancer in a subject, comprising the step of administering to the subject (a) a therapeutic an effective amount of a compound according to any one of claims 1 to 42, 48 or 49, or a pharmaceutically acceptable salt thereof, and (b) simultaneous or sequential administration to the subject of one or more additional therapeutically active substances. 61. The method according to claim 60, characterized in that one or more additional therapeutically active substances are selected from the group consisting of an immunosuppressant, a chemotherapeutic agent, an anti-viral agent, an antibiotic, an anti-parasitic agent, an anti-inflammatory agent, an anti-fungal agent and an agent against vascular hyperproliferation. 62. The method according to claim 61, characterized in that one or more additional therapeutically active substances are interferon or its derivative. 63. Use of a compound according to any one of claims 1 to 42, 48 or 49, or a pharmaceutically acceptable salt thereof, characterized in that it is used for the treatment or prevention of IMPDH-mediated diseases. 64. The use of a compound according to any claim 1 to 42, 48 or 49, or a pharmaceutically acceptable salt thereof, alone, or simultaneously, or sequentially with one or more additional therapeutically active substances, characterized in that it is used for a treatment method, in particular for the treatment of immune-mediated conditions or diseases, viral diseases, bacterial diseases, parasitic diseases, inflammation, inflammatory diseases, hyperproliferative vascular diseases, tumors or cancer. 65. Use of a compound according to any of claims 1 to 42, 48 or 49, characterized in that it is used for the production of a drug used in a method of treatment, in particular for use in the treatment of immune-mediated conditions or diseases, viral diseases, bacterial diseases, parasitic diseases, inflammation, inflammatory diseases, hyperproliferative vascular diseases, tumors or cancer. 66. Use according to claim 65, characterized in that it is a drug for simultaneous or sequential application with one or more additional therapeutically active substances. 67. The use of a compound according to any one of claims 1 to 42, 48 or 49, characterized in that it, in combination with one or more additional therapeutically active substances, is used for the production of a drug used in a treatment method, especially for use in treatment immune-mediated conditions or diseases, viral diseases, bacterial diseases, parasitic diseases, inflammation, inflammatory diseases, hyperproliferative vascular diseases, tumors or cancer. 68. Use according to any one of claims 63 to 67, characterized in that it is for the treatment of an immune-mediated condition or disease, in particular for the treatment of autoimmune disease, host graft rejection disease, or graft rejection. 69. Use according to any of claims 63 to 67, characterized in that it is a viral disease, in particular the treatment of a viral disease, wherein the virus is orthomoxovirus, paramyxovirus, herpesvirus, retrovirus, flavirus, pestivirus, hepatotrophic virus, buniavirus, Hantaan virus, Caraparu virus, human papilloma virus, encephalitis virus, arena virus, reovirus, vesicular stomatitis virus, rhinovirus, enterovirus, Lassa fever virus, togavirus, poxvirus, adenovirus, rubella virus, rubella virus, or hepatitis virus. 70. Use according to claim 69, characterized in that it is a hepatitis C virus. 71. Use according to claim 69, characterized in that it is the HIV virus. 72. Use according to any of claims 63 to 67, characterized in that it is for the treatment of hyperproliferative vascular disease, in particular for the treatment of hyperproliferative vascular disease where the hyperproliferative vascular disease is restenosis, stenosis or arteriosclerosis. 73. The use of any of claims 63 to 67, characterized in that it is for the treatment of inflammation or an inflammatory disease, in particular for the treatment of an inflammatory disease, where the inflammatory disease is osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, or adult respiratory distress syndrome. 74. The use according to any of claims 63 to 67, characterized in that it is for the treatment of a tumor or cancer, in particular for the treatment of cancer, where the cancer is lymphoma or leukemia. 75. Use according to any claim 63 or 65 to 74, characterized in that one or more additional therapeutically active substances are an immunosuppressant, a chemotherapeutic agent, an anti-viral agent, an antibiotic, an anti-parasitic agent, an anti-inflammatory agent, an anti-fungal agent, and against vascular hyperproliferation. 76. Use according to claim 75, characterized in that one or more additional therapeutically active substances are interferon or its derivative. 77. Invention, characterized in that it is in accordance with the above description.