RU2339633C2 - Compounds of (2-carboxyamido)(3-amino)thiophene - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: in compound of general formula I

or its pharmaceutically acceptable salts or N-oxides R1 stands for

, R2 stands for

R3 stands for C_0-4alkyl.

EFFECT: possibility to use compounds in elaboration of anti-cancer pharmaceutical preparations.

11 cl, 1 tbl, 20 ex

Description

The present invention is directed to 2,3-substituted thiophenes. Specifically, the present invention is directed to (2-carboxamido) (3-amino) thiophenes, which are inhibitors of the c-Kit proto-oncogen (also known as Kit, CD-117, stem cell factor receptor, mast cell growth factor receptor).

It is believed that the c-Kit proto-oncogen is of great importance in embryogenesis, melanogenesis, hematopoiesis and pathogenesis of mastocytosis, tumors of the gastrointestinal tract and other solid tumors, as well as some leukemias, including AML. Accordingly, it is desirable to develop new compounds that are inhibitors of the c-Kit receptor.

Many modern methods of treating hyperproliferative disorders (cancer) use compounds that inhibit DNA synthesis. By the mechanism of action, such compounds are toxic to cells, in particular, rapidly dividing tumor cells. Thus, their extensive toxicity can be a problem for the patient. However, other approaches to anticancer agents that are acting differently than inhibiting DNA synthesis have been investigated in an attempt to enhance the selectivity of the anticancer effect and thereby reduce adverse side effects.

It is known that cells can become cancer due to the transformation of part of their DNA into an oncogen (i.e., a gene that, when activated, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant protein tyrosine kinases that can cause cell transformation. With an excellent pathway, overexpression of normal proto-oncogenic tyrosine kinase can also lead to proliferative disorders, sometimes leading to a malignant phenotype. Alternatively, co-expression of the tyrosine kinase receptor and its similar ligand within the same cell type can also lead to malignant transformation.

Receptor tyrosine kinases are large enzymes that are embedded in the cell membrane and have i) an extracellular binding domain for growth factors such as the KIT ligand (also known as stem cell factor (SCF), Steele factor (SLF) or mast cell growth factor ( MGF)), ii) the transmembrane domain, and iii) the intracellular part, which functions as a kinase that phosphorylates specific tyrosine residues in proteins. The binding of the KIT ligand to the KIT tyrosine kinase leads to homodimerization of the receptor, activation of the KIT tyrosine kinase activity, and subsequent phosphorylation of various protein substrates, many of which are intracellular signal transmission effectors. These phenomena can lead to increased cell proliferation or stimulate an increase in cell survival. With some receptor kinases, receptor heterodimerization may also occur.

It is known that such kinases are often aberrantly expressed in common human cancers, such as breast, head and neck cancers, gastrointestinal cancers, such as colon cancer, colon and stomach cancers, leukemia and cancer of the ovary, bronchi, lung or pancreas glands. Kit kinase expression has been documented for a wide variety of human cancers, such as mastocytosis / mast cell leukemia, stromal gastrointestinal tumors (GIST), small cell lung carcinoma (SCLC), synonasal natural T-killer cell lymphoma, testicular carcinoma (Seminoma) malignant melanoma, ovarian carcinoma, lymphatic vesicle carcinoma, acute myelogenous leukemia (AML), breast carcinoma, pediatric acute T-cell lymphoblastic leukemia, an hyosarcoma, anaplastic large cell lymphoma, endometrial carcinoma and prostate carcinoma. KIT kinase activity is included in the pathophysiology of many of these and additional tumors, including breast carcinoma, SCLC, GIST, embryonic cell tumors, mast cell leukemia, neuroblastoma, AML, melanoma and ovarian carcinoma.

Some mechanisms of KIT activation in tumor cells have been reported, including activating mutations, autocrine and paracrine activation of the receptor kinase through its ligand, loss of protein tyrosine phosphatase activity, and cross-activation of other kinases. It is believed that transformation mechanisms initiated by activating mutations include dimer formation and an increase in the internal activity of the kinase domain, both of which lead to complex ligand-independent kinase activation and possibly altered substrate specificity. More than thirty activating mutations of the Kit protein are associated with malignant tumors with a high degree of malignancy in humans.

Accordingly, it is recognized that receptor tyrosine kinase inhibitors are useful as selective mammalian cancer cell growth inhibitors. For example, Gleevec ^™ (also known as imatinibmesylate or STI571), a 2-phenylpyrimidine tyrosine kinase inhibitor that inhibits the kinase activity of the BCR-ABL hybrid gene product, has recently been approved by the US Food and Drug Administration for the treatment of CML. Gleevec ^™ in addition to inhibiting BCR-ABL kinase also inhibits KIT kinase and PDGF receptor kinase, although it is ineffective against all mutant isoforms of KIT kinase. The growth of MO7e of human leukemic cells stimulated by a Kit ligand is inhibited by Gleevec ^™ , which also induces apoptosis under these conditions. In contrast, GM7S-stimulated human leukemic cell growth MO7e is not affected by Gleevec ^™ . Further, in recent clinical trials using Gleevec ^TM for the treatment of patients with GIST, a disease in which KIT kinase is involved in cell transformation, many patients show a marked improvement.

These studies showed how KIT kinase inhibitors can treat tumors whose growth depends on the activity of KIT kinase. Other kinase inhibitors have shown even greater selectivity for kinases. For example, the Tarceva ^™ 4-anilinoquinazoline compound, with high efficiency, inhibits only the EGF kinase receptor, despite the fact that it can inhibit the signaling of other receptor kinases, probably due to the fact that these receptors are heterodimerized with the EGF receptor.

Although anticancer compounds, such as those described above, make a significant contribution to this area, there remains a need for improved anticancer pharmaceuticals and it is desirable to develop new compounds with improved selectivity and efficacy or with reduced toxicity or side effects.

Published application No. WO00 / 27820 describes amide derivatives of N-aryl (thio) anthranilic acid. In published application No. WO99 / 32477 and US patent No. 6140351 described derivatives of orthoanthranilamide. Published application No. WO00 / 27819 describes anthranilic acid amides. In published applications Nos. WO02 / 00651 and WO01 / 19798, factor Xa inhibitors are described. Published application No. WO01 / 07050 describes ORL-1 nociceptin receptor agonists. US Pat. No. 5,968,965 describes farnesyl protein inhibitors. In published application No. WO01 / 64642 and US patent No. 6376515 described benzamides. Published application No. WO01 / 05763 and US Pat. No. 6,410,561 describe compounds active against the muscarinic receptor. US patent No. 6410561 describes amide derivatives.

Published application No. WO02 / 066470 describes substituted alkylamine derivatives. Published application No. WO02 / 068406 describes derivatives of substituted amines. Published application No. WO02 / 055501 describes derivatives of substituted arylamines.

In US patent No. 6207693 and 6316482 and European patent No. EP0832061 described benzamide derivatives with antagonistic activity against vasopressin.

The present invention relates to compounds represented by formula (I):

or a pharmaceutically acceptable salt or N-oxide thereof, wherein R1 is

R2 is

and R3 is C _0-4 alkyl useful for treating tumors.

The present invention relates to a compound represented by formula (I):

or a pharmaceutically acceptable salt or N-oxide thereof, wherein R1 is

R2 is

and R3 is C _0-4 alkyl.

; и другие переменные являются такими, как описано выше для формулы (I).In one embodiment, the present invention is directed to a compound represented by formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2 is

; and other variables are as described above for formula (I).

; R3 представляет собой водород; и другие переменные являются такими, как описано выше для формулы (I).In one embodiment of this embodiment, the present invention is directed to a compound represented by formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2 is

; R3 is hydrogen; and other variables are as described above for formula (I).

; R3 представляет собой С_0-4алкил, и другие переменные являются такими, как описано для формулы (I).In a second embodiment, the present invention is directed to a compound represented by formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2 is

; R3 is C _0-4 alkyl, and other variables are as described for formula (I).

; R3 представляет собой водород; и другие переменные являются такими, как описано выше для формулы (I).In one embodiment of the second embodiment, the present invention is directed to a compound represented by formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2 is

; R3 is hydrogen; and other variables are as described above for formula (I).

; R3 представляет собой С_0-4алкил, и другие переменные являются такими, как описано выше для формулы (I).In a third embodiment, the present invention is directed to a compound represented by formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2 is

; R3 is C _0-4 alkyl, and other variables are as described above for formula (I).

; R3 представляет собой водород; и другие переменные являются такими, как описано выше для формулы (I).In one embodiment of the third embodiment, the present invention is directed to a compound represented by formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2 is

; R3 is hydrogen; and other variables are as described above for formula (I).

; R3 представляет собой С_0-4алкил, и другие переменные являются такими, как описано выше для формулы (I).In a fourth embodiment, the present invention is directed to a compound represented by formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2 is

; R3 is C _0-4 alkyl, and other variables are as described above for formula (I).

The present invention is also directed to a method for treating hyperproliferative disorders, including breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, cancer of the ovaries, bronchi, lungs and pancreas, synonasal lymphoma of natural killer / T cells, testicular cancer (seminoma) , thyroid carcinoma, malignant melanoma, lymphoid carcinoma, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma or prostate carcinoma, by introducing an effect vnogo amount of a compound represented by formula (II) or a pharmaceutically acceptable salt thereof:

where R11 represents aryl, C _3-6 cycloalkyl or heterocyclyl, each of which is optionally substituted with 1-6 independent halogen atoms; hydroxy; nitro; amino; acyl; substituted acyl; acylC _1-6 alkylsulfinyl; acylC _1-6 alkylsulfonyl; acyloxy; C _1-6 alkylamino C _1-6 alkylcarbamoyloxy; aryl; cyano; heterocyclyl; C _2-6 alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl substituted aryl; C _2-6 alkynyl optionally substituted with amino, acylamino or substituted acylamino; C _1-6 alkyl optionally substituted with a halogen atom, amino, C _1-6 alkylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acyl C _1-6 alkanoyloxy, acyl substituted with acyl, acyl C _1-6 alkoxyimino, aryl or acyl substituted aryl; C _1-6 alkylthio optionally substituted with acyl or substituted acyl; alkoxy optionally substituted with aryl, substituted aryl, hydroxy, acyloxy, amino, lower alkylamino, protected amino, heterocyclyl, acyl substituted pyridyl, substituted acyl substituted pyridyl, halogen, atsilS _1-6 alkylamino, N-protected atsilS _1-6 alkylamino, N- acylC _1-6 alkyl-N-lower alkylamino, acyl substituted by acyl, acylamino, substituted acylamino, C _1-6 alkylhydrazinocarbonylamino, hydroxyimino, acylC _1-6 alkoxyimino, substituted acylC _1-6 alkoxyimino, acylC _1-6 alkoxy, guany N-protected guanidino; or C _2-6 alkenyloxy optionally substituted with acyl or acyl substituted by substituents;

R21 represents hydrogen; lower alkyl optionally substituted with hydroxy, aryl or acyl; or cyclo (lower) alkyl;

R31 represents hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; C _1-6 alkyl optionally substituted with hydroxy or C _1-6 alkoxy; C _1-6 alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or C _1-6 alkylthio; nitro; amino; acyl; substituted acyl; or C _3-6 cycloalkyloxy;

R41 is hydroxy; halogen; nitro; amino; protected amino; C _1-6 alkylamino; acyloxy; amino C _1-6 alkylamino; N-protected amino C _1-6 alkylamino; C _1-6 alkoxy optionally substituted with hydroxy, aryl substituted with aryl, acyl substituted with acyl, amino, C _1-6 alkylamino, acylamino substituted with acylamino, a protected amino group, heterocyclyl or guanidino; C _1-6 alkylthio, optionally substituted with acyl, substituted acyl, amino, C _1-6 alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl, hydroxy, C _1-6 alkylsulfonyloxy, arylsulfonyloxy, arC _1-6 alkoxy, or substituted arC _{1 -6} alkoxy; C _1-6 alkyl substituted with acyl substituted with acyl, amino, lower alkylamino, acylamino substituted with acylamino, protected amino, heterocyclyl, hydroxy, C _1-6 alkylsulfonyloxy or arylsulfonyloxy; C _2-6 alkenyl optionally substituted with acyl; C _2-6 alkynyl optionally substituted with hydroxy, amino, protected amino, C _1-6 alkylsulfonyloxy or arylsulfonyloxy; amino C _1-6 alkylsulfonyl; N-protected amino C _1-6 alkylsulfonyl; C _1-6 alkylaminosulfonyl; heterocyclylsulfonyl; amino C _1-6 alkylsulfinyl; N-protected amino C _1-6 alkylsulfinyl; piperidyloxy; or N-protected piperidyloxy;

R51 represents hydrogen, C _1-6 alkyl, C _1-6 alkoxy or halogen;

A is a single bond, O or NH;

E represents C _1-6 alkylene, C _2-6 alkylene,

or E represents a group of the formula -G-J-, in which

G represents C _1-6 alkylene and

, где R₆₁ представляет собой водород или N-защитную группу;J represents O or

Where R ₆₁ represents hydrogen or an N-protecting group;

X represents —CH = CH—, —C = N— or S, and

Y represents CH or N.

The compounds of formula (II) are described in US patent No. 6054457.

In one embodiment, the present invention is directed to a method for the treatment of hyperproliferative diseases, including breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, cancer of the ovary, bronchi, lung and pancreas, synonasal lymphoma of natural killer / T cells, testicular cancer ( seminoma), thyroid carcinoma, malignant melanoma, lymphoid carcinoma, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma or prostate carcinoma, by means of giving an effective amount of the compound represented by formula II, or a pharmaceutically acceptable salt thereof, wherein X is S, and other variables are as described for formula II.

In one embodiment of this embodiment, the present invention is directed to a method for treating hyperproliferative diseases, including breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, cancer of the ovary, bronchi, lung and pancreas, sinonasal lymphoma of natural killer / T cells , testicular cancer (seminoma), thyroid carcinoma, malignant melanoma, lymphoid carcinoma, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma or carcinoma representative gland, by administering an effective amount of a compound represented by formula II, or a pharmaceutically acceptable salt thereof, wherein X is S; R11 is an optionally substituted aryl, and other variables are as described for formula II.

In yet another embodiment of this embodiment, the present invention is directed to a method for treating hyperproliferative diseases, including breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, cancer of the ovary, bronchi, lung and pancreas, sinonasal lymphoma of natural killers / T- cells, testicular cancer (seminoma), thyroid carcinoma, malignant melanoma, lymphoid carcinoma, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma or carcinoma of the Yelnia cancer, by administering an effective amount of a compound represented by the formula II, or a pharmaceutically acceptable salt thereof, wherein X represents S; R11 is an optionally substituted heterocyclyl, and other variables are as described for formula II.

In yet another embodiment of this embodiment, the present invention is directed to a method for treating hyperproliferative diseases, including breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, cancer of the ovary, bronchi, lung and pancreas, sinonasal lymphoma of natural killers / T- cells, testicular cancer (seminoma), thyroid carcinoma, malignant melanoma, lymphoid carcinoma, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma or carcinoma of the Yelnia cancer, by administering an effective amount of a compound represented by the formula II, or a pharmaceutically acceptable salt thereof, wherein X represents S, Y represents N, and the other variables are as described for formula II.

The present invention is also directed to a method for treating hyperproliferative diseases, including breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, cancer of the ovary, bronchi, lung and pancreas, natural killer / T cell synonasal lymphoma, testicular cancer (seminoma) , thyroid carcinoma, malignant melanoma, lymphoid carcinoma, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma or prostate carcinoma, by administering an effect of tive amount of a compound represented by formula III:

Where

R12 represents aryl, C _3-6 cycloalkyl or heterocyclyl, each of which is optionally substituted with 1-6 independent halogen atoms; hydroxy; nitro; a protected amino group, amino; acyl; substituted acyl; acylC _1-6 alkylsulfinyl; acylC _1-6 alkylsulfonyl; acyloxy; C _1-6 alkylamino C _1-6 alkylcarbamoyloxy; aryl; cyano; heterocyclyl; C _2-6 alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl substituted aryl; C _2-6 alkynyl optionally substituted with amino, acylamino or substituted acylamino; C _1-6 alkyl optionally substituted with halogen, amino, C _1-6 alkylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acylC _1-6 alkanoyloxy, acyl substituted with acyl, acyl C _1-6 alkoxyimino, aryl or acyl substituted aryl; C _1-6 alkylthio optionally substituted with acyl or substituted acyl; alkoxy optionally substituted with aryl, substituted aryl, hydroxy, alkoxy, amino, lower alkylamino, protected amino, heterocyclyl, acyl substituted pyridyl, substituted acyl substituted pyridyl, halogen, atsilS _1-6 alkylamino, N-protected atsilS _1-6 alkylamino, N-atsilS _1-6 alkyl-N-lower alkylamino, acyl substituted with acyl, alkylamino, substituted alkylamino, C _1-6 alkylhydrazinecarbonylamino, hydroxyimino, acylC _1-6 alkoxyimino, substituted acylC _1-6 alkoxyimino, acylC _1-6 alkoxy, guanidino or N -protected guanidino; or C _2-6 alkenyloxy optionally substituted with acyl or acyl substituted by substituents;

R22 represents hydrogen; C _1-6 alkyl optionally substituted with hydroxy, aryl or acyl; or C _3-6 cycloalkyl;

R32 represents hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; C _1-6 alkyl optionally substituted with hydroxy or C _1-6 alkoxy; C _1-6 alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or C _1-6 alkylthio; nitro; amino; acyl; substituted acyl; or C _3-6 cycloalkoxy;

A1 is a single bond, O or NH;

E ₁ represents C _1-6 alkylene, C _2-6 alkenyl,

or E ₁ represents a group of formulas, -G1-J1-, in which

иG1 represents C _1-6 alkylene or

and

, где R₆₂ представляет собой водород или N-защитную группу;J1 represents O or

Where R ₆₂ represents hydrogen or an N-protecting group;

X ₁ represents —CH = CH—, —C = N— or S; and

Y ₁ represents aryl, optionally substituted with 1-6 independent acyls, substituted with amino C _1-6 alkanoyl, protected by amino and nitro groups, amino and nitro or diamino substituents; or Y1 is a conjugated heterocyclyl optionally substituted with 1-6 halogens, acyl, C _1-6 alkoxy, hydroxy, guanidino, mercapto, acylamino, amino, heterocyclyl, cyanamino, aminoC _1-6 alkyl (C _1-6 alkyl) amino, C _1-6 alkylamino, C _1-6 alkylamino (C _1-6 alkylamino), substituted heterocyclyl, C _1-6 alkylhydrazino, aryloxy, C _1-6 alkylthio, aryl, protected amino group, N-protected C _1-6 alkylamino ( C _1-6 alkyl) amino, N-protected amino C _1-6 alkyl (N'-C _1-6 alkyl) amino, amino C _1-6 alkyl (N-C _1-6 alkyl) amino, C _1-6 alkylamino ( C _1-6 alkyl) (N-C _1-6 alkyl) amino or C _1-6 a alkoxy (C _1-6 alkyl) amino substituents, or C _1-6 alkyl substituent optionally substituted with aryl, arC _1-6 alkoxy, cyano, hydroxyimino, mercapto, C _1-6 alkylamino, acyloxy, halogen, C _1-6 alkoxy, protected hydroxy, hydroxy, C _1-6 alkoxyaryl, protected amino, amino, heterocyclyl or substituted heterocyclyl substituents;

provided that Y ₁ is phenyl optionally substituted with C _1-6 alkyl or aryl,

And ₁ is a simple bond and

. E ₁ represents

.

The compounds of formula (III) are described in US patent No. 6316482.

In one embodiment, the present invention is directed to a method for the treatment of hyperproliferative diseases, including breast cancer, head cancer or neck cancer, gastrointestinal cancer, leukemia, cancer of the ovary, bronchi, lung and pancreas, synonasal lymphoma of natural killer / T cells, testicular cancer ( seminoma), thyroid carcinoma, malignant melanoma, lymphoid carcinoma, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma or prostate carcinoma, by means of giving an effective amount of the compound represented by formula III, or a pharmaceutically acceptable salt thereof, wherein X ₁ is S, and other variables are as described for formula III.

In the present invention, “C _0-4 alkyl” means an alkyl having 0-4 carbon, i.e. 0, 1, 2, 3 or 4 carbon, in an unbranched or branched structure. Carbon-free alkyl is hydrogen if alkyl is an end group. Alkyl having no carbon is a direct bond if the alkyl is a bridging group.

In the present invention, unless otherwise indicated, “alkyl”, “alkenyl” and “alkynyl” include branched and unbranched structures. Lower alkyls, alkenyls and alkynyls have 1-6 carbons. Higher alkyls, alkenyls and alkynyls have more than 6 carbons.

In the present invention, unless otherwise indicated, the terms "aryl" and "ar" are well known to chemists and include, for example, phenyl and naphthyl, as well as phenyl with one or more short alkyl groups (tolyl, xylyl, mesityl, cumenyl, di ( tert-butyl) phenyl). Phenyl, naphthyl, tolyl and xylyl are preferred. “Substituted aryl” is aryl substituted with suitable substituents, such as, for example, acyl, substituted acyl, N-protected piperazinylsulfonyl, piperazinylsulfonyl, NC _1-6 alkylpiperazinylsulfonyl, hydroxyC _1-6 alkyl, heterocyclyl, halo, nitro, nitro _1-6 alkylamino, cyano or C _1-6 alkoxy.

In the present invention, unless otherwise indicated, “heterocyclyl” is well known to chemists and contains at least one N, S or O heterocyclic atom and includes saturated, unsaturated, partially saturated, mono- and polycyclic heterocyclic groups, such as e.g. pyrrolyl, pyrrolynyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, indolyl, isoindino, isoindol yl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, pyranyl, furyl, 1H-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, benzazuranazoles, thiazylazoylazothiazylazothiazylazothiazylazothiazylazothiazylazothiazylazothiazylazothiazylazothiazothiazylazothiazylazothiazylazothiazylazothiazylazothiazylazothiazylazothiazylazothiazylazothiazylazothiazylazothiazylazothiadediolazothiales benzodioxyl and the like. Such heterocyclyls are suitably substituted with lower alkyl or oxo substituents.

In the present invention, unless otherwise indicated, “acyl” includes, for example, carboxy, esterified carboxy, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, aroyl, heterocyclylcarbonyl and the like. The esterified carboxy includes substituted or unsubstituted lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, dimethylaminopropylcarbonylcarbonyl, substituted or unsubstituted aryloxycarbonyl such as phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl; substituted or unsubstituted ar (lower) alkoxycarbonyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, 3-methoxy-4-nitrobenzyloxycarbonyl and N-containing heterocyclylcarbonyl, such as N-methylpiperidyloxycarbonyl.

In the present invention, unless otherwise indicated, “halogen” is fluoro, chloro, bromo or iodo.

In the present invention, unless otherwise indicated, “C _1-6 alkyl hydrazino” may be 2-mono- or 2,2-di (C _1-6 alkyl) hydrazino, such as 2-methylhydrazino, 2,2-dimethylhydrazino, 2 ethyl hydrazino, 2,2-diethyl hydrazino or the like.

In the present invention, unless otherwise indicated, “C _1-6 alkylaminoC _1-6 alkyl” includes, for example, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl or the like.

“C _1-6 alkanoyl” includes substituted or unsubstituted alkanoyls such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like.

“Aroyl” includes benzoyl, naphthoyl, toluoyl, di (tert-butyl) benzoyl and the like.

In the present invention, unless otherwise indicated, the "N-protecting group" in the "protected amino group" includes substituted or unsubstituted lower alkanyl (such as, for example, formyl, acetyl, propionyl, trifluoroacetyl), phthaloyl, lower alkoxycarbonyl (such as tert- butoxycarbonyl, tert-amyloxycarbonyl), substituted or unsubstituted aralkyloxycarbonyl (such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), 9-fluorenylmethoxycarbonyl, substituted or unsubstituted arenesulfonyl (benzenesulfonyl, tosyl). Phthaloyl, tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl are preferred.

In the present invention, unless otherwise indicated, the "N-protecting group" in the "protected guanidino" includes lower alkoxycarbonyl (such as tert-butoxycarbonyl, tert-amyloxycarbonyl).

In the present invention, unless otherwise indicated, a “hydroxy protecting group” includes substituted or unsubstituted arylmethyl (eg, benzyl, lower alkoxybenzyl), acyl or substituted silyl (eg, tert-butyldiphenylsilyl).

The above formulas I, II and III are shown without specific stereochemistry in some positions. The present invention includes all stereoisomers of the compounds represented by formulas I, II, and III, and their pharmaceutically acceptable salts. Further, mixtures of stereoisomers are also included, as are isolated specific stereoisomers. During the synthesis used to prepare such compounds, or using racemization or epimerization known to those skilled in the art, the result of such techniques may be a mixture of stereoisomers.

The present invention also encompasses a pharmaceutical composition comprising a compound of formula I in combination with a pharmaceutically acceptable carrier.

Preferably, the composition comprises a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of formula I as described above (or a pharmaceutically acceptable salt or N-oxide thereof).

However, within this preferred embodiment, the present invention encompasses a pharmaceutical composition for treating a disease by inhibiting the c-Kit kinase, which may be a wild-type or mutant form of a protein, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound represented by formula I as described above (or a pharmaceutically acceptable salt or N-oxide thereof).

The compounds and compositions of the present invention are effective for the treatment of mammals, such as, for example, humans.

The term "pharmaceutically acceptable salts" means salts derived from pharmaceutically acceptable non-toxic bases or acids. If the compound of the present invention is acidic, its corresponding salt can be easily obtained from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (I and II), ferric, ferrous, lithium, magnesium, manganese (I and II), potassium, sodium, zinc and the like salts thereof. Salts of ammonium, calcium, magnesium, potassium and sodium are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as natural or synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N ', N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, trimethylamine, trimetrilomethyltrimethimetrimetrometrin like these are.

If the compound of the present invention is basic, its corresponding salt can be easily obtained from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, e.g. succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, methanesulfonic and tartaric acids.

The pharmaceutical compositions of the present invention or used in the methods of the present invention include a compound represented by formulas I, II or III (or a pharmaceutically acceptable salt or N-oxide thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Compositions include compositions suitable for oral, rectal, local and parenteral (including subcutaneous, intramuscular and intravenous) administration, despite the fact that the most convenient route of administration in each case will depend on the specific organism and the nature and severity of the conditions in which active Ingredients. The pharmaceutical compositions can be presented in the form of suitable unit dosage forms and prepared by one of the methods well known in the pharmaceutical field.

In practice, the compound represented by Formula I, or pharmaceutically acceptable salts or N-oxides thereof of the present invention can be combined as active ingredients in admixture with pharmaceutical carriers in accordance with generally accepted methods for the preparation of pharmaceutical compositions. The carrier may take a wide variety of forms depending on the preparation of the forms desired for administration. For example, oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration, such as capsules, sachets or tablets, each of which contains a predetermined amount of the active ingredient. Further, the compositions can be presented in the form of a powder, granules, solution, suspension in an aqueous liquid, in a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. In addition to the usual dosage forms described above, the compound represented by formula I, or a pharmaceutically acceptable salt or N-oxide thereof, can also be administered via controlled release means and / or delivery devices. Compositions can be obtained by any pharmaceutical method. In general terms, such methods include the step of incorporating into the active ingredient a carrier which comprises one or more necessary ingredients. In general, compositions are prepared by uniformly and thoroughly mixing the active ingredients with liquid carriers or finely divided solid carriers, or both. The product can then be easily shaped to be suitable for administration.

Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt or N-oxide thereof represented by formulas I, II or III. The compounds represented by formulas I, II or III, or pharmaceutically acceptable salts or N-oxides may also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical compositions of this invention include a pharmaceutically acceptable liposome formulation containing a compound of formulas I, II or III, or a pharmaceutically acceptable salt or N-oxide thereof.

The pharmaceutical carrier used may be, for example, solid, liquid or gaseous. Examples of solid carriers include lactose, white clay (kaolin), sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are sugar syrup, peanut butter, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

In preparing compositions for oral dosage forms, any conventional pharmaceutical agents may be used. For example, water, glycols, oils, alcohols, flavors, colorants, and the like. can be used to formulate liquid oral preparations, such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used to formulate solid oral preparations such as powders, capsules and tablets. Tablets and capsules are the preferred oral dosage units due to their ease of use, whereby solid pharmaceutical carriers are used. Optionally, tablets may be coated using standard aqueous or anhydrous techniques.

A tablet containing a composition of the invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compression in a suitable machine, the active ingredient in free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface-active or dispersing agent, or other such excipients. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binders, for example, starch, gelatin or acacia; and lubricants, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby ensure sustained activity over time. For example, substances such as glycerol monostearate or glycerol distearate can be used for time delays.

In hard gelatin capsules, the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. In soft gelatin capsules, the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Molded tablets may be prepared by molding in a suitable apparatus a mixture of powdered substances moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient.

For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the active substance mixed with an appropriate and suitable carrier compound, the amount of which may vary from about 5 to about 95 percent of the total composition. A unit dosage form usually contains from about 1 mg to about 2 g of the active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active substance in water. Suitable surfactants may include, for example, hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, or mixtures thereof in oil. Further, a preservative may be included to prevent the growth of harmful microorganisms.

Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the compositions may be presented in the form of sterile powders for the immediate preparation of such sterile injectable solutions or dispersions. In all cases, the final injection form must be sterile and must be an effective fluid for easy syringe collection. Pharmaceutical compositions must be stable during manufacture and storage; thus, it is preferable that there is protection against the contaminating activity of microorganisms such as bacteria and fungi. The carrier may contain a solvent or dispersion medium, for example, water, ethanol, a polyol (i.e. glycerin, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention can be presented in a form suitable for topical application, such as, for example, aerosol, cream, ointment, lotion, powder or the like. Further, the compositions may be in a form suitable for transdermal administration. These compositions can be prepared using the compound represented by formula I of the present invention or a pharmaceutically acceptable salt or N-oxide thereof by conventional processing methods. As an example, a cream or ointment is prepared by mixing a hydrophilic substance or water together with from about 5 wt.% To about 10 wt.% Of the compound, to obtain a cream or ointment having the desired consistency.

The pharmaceutical compositions of this invention may be presented in a form suitable for rectal administration, wherein the carrier is solid. Mixed forms of dosage suppositories are preferred. Suitable carriers include cocoa butter and other commonly used agents. It is convenient to form suppositories by mixing the first composition with a softened or molten carrier (s), followed by cooling and molding in templates.

In addition to the above carrier ingredients, the pharmaceutical compositions described above may include, as appropriate, one or more additional carrier ingredients, such as diluents, buffers, flavorings, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like. In addition, other adjuvants may be included to render the finished form isotonic with the blood of the intended recipient. Compositions containing the compound described by Formula I, or a pharmaceutically acceptable salt or N-oxide thereof, can also be prepared as a concentrated powder or liquid.

For treatment under the conditions described above, a dosage level of usually from about 0.01 mg / kg to about 150 mg / kg body weight per day, or alternatively from about 0.5 mg to about 10 mg per patient per day, is generally used. For example, it is possible to effectively use in the treatment of breast cancer, head and neck cancer, and gastrointestinal cancer, such as colon, rectal, or stomach cancer, from about 0.01 to 100 mg of substance per kilogram of body weight per day, or, alternatively, about from 0.5 mg to about 7 g per patient per day.

Similarly, it is possible to effectively use in the treatment of leukemia, cancer of the ovary, bronchus, lung and pancreas from about 0.01 to 100 mg of substance per kilogram of body weight per day or, alternatively, from about 0.5 mg to about 7 g per patient day.

In the treatment of mastocytosis / mast cell leukemia, gastrointestinal stromal tumors (GIST), small cell lung carcinoma (SCLC), natural killer / T cell synonasal lymphoma, textuloma cancer (seminoma), thyroid carcinoma, malignant melanoma carcinoma, ovarian carcinoma, carcinoma of the ovary acute myeloid leukemia (AML), breast carcinoma, pediatric T-cell acute lymphoblastic leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma and prostate carcinoma glands, it is possible to effectively use from about 0.01 to 100 mg of substance per kilogram of body weight per day or, alternatively, from about 0.5 mg to about 7 g per patient per day.

It is clear, however, that the specific dosage level for specific different patients will depend on many factors, including age, body weight, general health, gender, diet, time of administration, route of administration, rate of excretion, combination of medications and the severity of the particular disease being treated.

The compounds of the present invention or their pharmaceutically acceptable salts or N-oxides can also be effectively administered in combination with other compounds for treating cancer. For example, cytotoxic agents and angiogenesis inhibiting agents may be beneficial co-agents with the compounds of the present invention. Accordingly, the present invention includes compositions comprising compounds represented by Formula I, or pharmaceutically acceptable salts or N-oxides and cytotoxic agents or angiogenesis inhibiting agents thereof. Each can be in a therapeutically effective amount, in each case, the joint effect can overcome the cancer resistance to monotherapy treatment. Amounts of some may also be subtherapeutic, minimizing adverse effects in specific sensitive patients.

Cancer treatment is known to depend on the type of cancer. For example, lung cancer is treated with the first course of therapy differently than colon cancer or breast cancer is treated. In comparison, in lung cancer, for example, the first course of therapy differs from the second course of therapy, which, in turn, differs from the third course of therapy. Newly diagnosed patients can be treated in a regimen containing cisplatin. Upon failure, they switch to a second course of therapy, such as a taxon. Finally, if this is not enough, they switch to an EGFR tyrosine kinase inhibitor as a third course of therapy. Further, the approved regulatory process differs from country to country. Accordingly, the accepted treatment regimen may vary from country to country. However, the compounds of the present invention or their pharmaceutically acceptable salts or N-oxides may be advantageously co-administered in combination or combination with other such compounds for the treatment of cancer. Such other compounds include, for example, a variety of cytotoxic agents (alkylators, topoisomerase DNA inhibitors, antimetabolites, tubulin binding agents); angiogenesis inhibitors; and various other therapies include kinase inhibitors such as Tarceva, monoclonal antibodies, and anti-cancer vaccines. Other such substances that can be advantageously co-administered with the compounds of the present invention include doxorubicin, vincristine, cisplatin, carboplatin, gemcitabine and taxanes. Thus, the compositions of the present invention include a compound according to Formula I, or a pharmaceutically acceptable salt or N-oxide thereof, and an antineoplastic, antitumor, antiangiogenic or chemotherapeutic agent.

The compounds of the present invention or their pharmaceutically acceptable salts or N-oxides can also be effectively administered in combination with other therapeutic compounds, regardless of cancer therapy. For example, therapeutic agents effective in improving adverse side effects may be beneficial co-agents with the compounds of the present invention.

Examples of the present invention are summarized in the table.

R1

Project 1 Project 2 Project 3 Project 4 R2

Project 11 Ex.5 Ex.6 Ex 7

Project 12 Project 9 Project 10 Ex 8

I. Bench Analysis of Activated c-Kit Kinase

A cDNA encoding the tyrosine kinase Kit domain is isolated from K562 cells and cloned into a baculovirus expression vector to express the protein as a GST (glutathione S-transferase) protein in insect cells. After purification, the enzyme is incubated with ATP to generate a tyrosine phosphorylated, activated form of the enzyme, which is used in kinase assays to determine the ability of the compounds to inhibit phosphorylation of an exogenous substrate through the Kit tyrosine kinase domain.

Phosphorylation of c-Kit Protein

The following reagents are used:

Column Buffer:

50 mM HEPES pH 7.4 125 mM NaCl

10% glycerin

1 mg / ml BSA

2 mm DTT

200 μm NaVO ₃

Phosphorylation Buffer:

50 mM HEPES pH 7.4

125 mM NaCl

24 mM MgCl ₂

1 mM MnCl ₂

1% glycerin

200 μm NaVO ₃

2 mm DTT

2 mm ATP

75 .mu.l of the protein tyrosine kinase purified GST-Kit (approximately 150 ug) was incubated with 225 ul of phosphorylation buffer for 1 hour at 30 ^° C in a cold room for desalting column (e.g., Pharmacia PD-10 column) is equilibrated using 25 ml buffer for the column. Phosphorylated protein is applied to the column, followed by the application of a sufficient amount of buffer for the column to 2.5 ml in total (in this case, 2.2 ml). The phosphorylated Kit protein is then eluted with 3.5 ml of column buffer and collected in a tube containing 3.5 ml of glycerol (final concentration is 50% glycerol). After mixing, aliquots are stored at ^-20 ° C or -70 ° ^C.

Assay of c-Kit kinase activity

Kinase activity is determined by an ELISA-based analytical method that measures the ability of Kit to phosphorylate an exogenous substrate (poly Glu: Tyr) from tyrosine residues in the presence of ATP. Phosphorylation of the substrate is recorded by quantifying the degree of antibody binding, which recognizes only phosphorylated tyrosine residues in the substrate, followed by incubation with Kit. The antibody used has a reporter enzyme (e.g., horseradish peroxidase, HRP) covalently attached so that binding of the antibody to the phosphorylated substrate can be quantified by incubation with the corresponding HRP substrate (e.g., ABTS).

The following starting reagents are used:

13.3 μg / ml PGT stock solution: 66.7 μl 10 mg / ml PGT is added to 50 ml PBS.

1X wash buffer: dilute 20X wash buffer (KPL # 50-63-00) to 1X with H ₂ O.

Analysis buffer:

50 mM Hepes, pH 7.4

125 mM NaCl

24 mM MgCl ₂

1 mM MnCl ₂

1% glycerin

200 μm vanadate - add immediately before use

2 mm DTT - add immediately before use

Assay buffer + ATP: Add 5.8 μl of 75 mM ATP to 12 ml of assay buffer.

Activated GST-c-kit (TK): Dilute 1: 500 in assay buffer.

Blocking buffer:

PBS containing 0.5% Tween-20, 3% BSA

200 μm vanadate - add immediately before use

pY20-HRP:

6.2 μl of stock solution of 100 μg / ml Y20-HRP is added to 10 ml of blocking buffer.

ABTS substrate: KPL 3 50-66-06, used as provided.

Analysis technique

Each well of 94-well Immulon-4 microtiter plate were coated with 75 ul of 13.3 mg / ml stock solution PGT, incubated overnight at ³⁷ ° C and washed once with 250 .mu.l of 1X Wash Buffer.

To the wells for negative control add 50 μl of assay buffer (without ATP), all other wells contain 50 μl of assay buffer + ATP. 10 μl of 5% DMSO is added to the wells for positive and negative control, other wells contain 10 μl of test compounds (at concentrations between 10 nM and 100 μm) dissolved in 5% DMSO.

Add 30 μl of activated GST-c-kit to initiate analysis by incubation at room temperature for 30 minutes and then stop by adding 50 μl / well of 0.5 M EDTA. The plate is washed 3 times with 1X wash buffer and then 75 μl of phosphotyrosine-specific antibody-HRP conjugate (e.g. pY20-HRP, Calbiochem) is added in blocking buffer. The plate was incubated at room temperature for two hours and then washed three times with 1X wash buffer. Next, 100 μl of ABTS substrate was added, the plate was incubated at room temperature for 30 minutes, and the reaction was stopped by adding 100 μl of 1% SDS. The reaction is quantified by measuring the absorbance at 405/490 nm on a microtiter plate reader.

Comparison of the analytical signals obtained in the presence of the compound with the signals from the controls in the presence and absence of ATP without the addition of the compound makes it possible to evaluate the degree of inhibition of kinase activity determined in the range of compound concentrations. These inhibition values are used to construct a sigmoidal dose-response inhibition curve to determine IC ₅₀ values (i.e., the concentration of a compound that reduces kinase activity to 50% of the control activity).

The compounds of this invention reduce the ability of the Kit to phosphorylate poly (Glu: Tyr) in the above assay, thus demonstrating direct inhibition of the tyrosine kinase activity of the c-Kit receptor. IC ₅₀ values in this assay are between 9 nM and 388 nM.

The compounds of the present invention surprisingly and unexpectedly show improved c-Kit inhibition activity in accordance with the above assay than the closest similar thiophene compounds in this field (IC ₅₀ values in this assay for compounds of the present invention are lower than IC ₅₀ values in this assay for known nearest compounds thiophene). Additionally, the compounds of the present invention are surprisingly and unexpectedly more chemically stable than many of their respective regioisomers.

experimental part

The compounds of the examples of the present invention are obtained in accordance with the following methods:

With reference to the scheme given below for example 1, type 3 anilides can be obtained directly from esters, such as compound 1, under Weinreb amidation conditions, and under these conditions, these esters react with anilines, as demonstrated by example of compound 2 in the presence of alkylaluminum reagents such as, but not limited to trimethylaluminum or chlorodimethylaluminum in a neutral solvent such as toluene or dichloromethane ( Synthetic Communications , (1982), 12, 989).

Compounds, such as 3, bearing a primary functional amino group, can further react with aldehydes under reduced conditions to give secondary amines, such as the compound of Example 1, for example, in the presence of a mixture of triethylsilane and trifluoroacetic acid or other reagents, such as, but not limited to them) sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and hydrogen.

EXAMPLE 1

N- (4-trifluoromethoxyphenyl) -3 - [(quinolin-4-ylmethyl) amino] thiophene-2-carboxamide

The compound of example 1 is obtained in accordance with the following procedure:

Part 1:

N - (4-trifluoromethoxyphenyl) -3-aminothiophene-2-carboxamide: To a stirred solution of 4-trifluoromethoxyaniline (7.8 g, 44.5 mmol) in toluene (50 ml) under nitrogen atmosphere was added trimethylaluminum (2M in toluene, 26 7 ml, 53.4 mmol). The mixture was stirred at room temperature for 16 hours. Methyl 3-amino-2-thiophenecarboxylate (7g, 44.5 mmol) and the resulting solution was stirred at reflux (oil bath temperature: 130 ° ^C) under a nitrogen atmosphere for 24 hours. After cooling to room temperature, a saturated sodium bicarbonate solution (100 ml) was carefully added dropwise and the mixture was stirred at room temperature for 30 minutes. The product was extracted with dichloromethane (3 × 100 ml), the organic layer was dried over Na ₂ SO ₄ and concentrated to give an oil, which was then triturated with hexane / ethyl acetate to give N - (4-trifluoromethoxyphenyl) -3-aminothiophen-2-carboxamide in the form of a brown solid.

¹ H-NMR (400 MHz / CD ₃ OD): δ = 6.65 (d, J = 5.6Hz, 1H), 7.23 (d, J = 8.4Hz, 2H), 7.39 (d , J = 5.2Hz, 1H); 7.67 (d, J = 9.2Hz, 2H). MS (ES ⁺ ): 303 [MH ⁺ ].

Part 2:

N - (4-trifluoromethoxyphenyl) -3 - [(quinolin-4-ylmethyl) amino] thiophene-2-carboxamide: Solution of N - (4-trifluoromethoxyphenyl) -3-aminothiophene-2-carboxamide (1 g, 3.31 mmol ) and quinoline-4-carboxaldehyde (347 mg, 2.21 mmol) in a mixture of trifluoroacetic acid: dichloromethane (1: 1, 30 ml) are heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and triethylsilane (0.71 ml, 4.42 mmol) was added. The resulting solution was further stirred at reflux for 16 hours under nitrogen. After cooling to room temperature, the reaction mixture was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (3 × 100 ml) and saturated sodium bicarbonate solution (50 ml). The organic layers are dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (20-30% ethyl acetate in hexane) to give the compound of Example 1 as a pale yellow solid, melting point 168-170 ° ^C.

¹ H-NMR (400 MHz / CD ₃ OD): δ = 5.01 (d, J = 6.2Hz, 2H), 6.56 (d, J = 5.4Hz, 1H), 7.12 (s , 1H), 7.22 (d, J = 8.7Hz, 2H), 7.25 (s, 1H), 7.44 (d, J = 4.3Hz, 1H), 7.58 (d, J = 9.0Hz, 2H), 7.62 (d, J = 8.2Hz, 1H), 7.76 (t, J = 8.3Hz, 1H), 8.02 (d, J = 7.5Hz, 2H), 8.17 (d, J = 8.3Hz, 1H), 8.86 (d, J = 4.5Hz, 1H). MS (ES ⁺ ): 444 [MH ⁺ ].

¹³ C-NMR (400 MHz / CDCl ₃ ): δ = 45.9 101.4, 117.9, 118.9, 119.5, 121.9, 122.0, 122.6, 126.5, 127 , 2, 129.1, 129.7, 130.6, 136.8, 144.5, 145.4, 148.3, 150.7, 155.9, 163.8. Analysis. Calculated for C ₂₂ H ₁₆ F ₃ N ₃ O ₂ S: C, 59.59; H, 3.64; N, 9.48; F, 12.85; S, 7.23. Found: C, 59.59; H, 3.67; N, 9.46; F, 13.01; S, 7.23.

EXAMPLE 2

N - (4-bromo-3-methylphenyl) -3 - [(quinolin-4-ylmethyl) amino] thiophene-2-carboxamide

The compound of Example 2 was prepared according to the procedure described above for Example 1 using 4-bromo-3-methylaniline instead of 4-trifluoromethoxyaniline. MS (ES ⁺ ): 452, 454 [MH ⁺ ].

EXAMPLE 3

N - (2,2,3,3-tetrafluorobenzodioxan-6-yl) -3 - [(quinolin-4-ylmethyl) amino] thiophen-2-carboxamide

The compound of Example 3 was prepared according to the procedure described above for Example 1, using 6-amino-2,2,3,3-tetrafluorobenzodioxane instead of 4-trifluoromethoxyaniline. MS (ES ⁺ ): 490 [MH ⁺ ].

EXAMPLE 4

N - (4-chlorophenyl) -3 - [(quinolin-4-ylmethyl) amino] thiophen-2-carboxamide

The compound of Example 4 was prepared according to the procedure described above for Example 1 using 4-chloroaniline instead of 4-trifluoromethoxyaniline. MS (ES ⁺ ): 394, 396 [MH ⁺ ].

EXAMPLE 5

Methylamide 4 - {[2- (4-bromo-3-methylphenylcarbamoyl) thiophen-3-ylamino] methyl} pyridine-2-carboxylic acid

To a stirred solution of N - (4-bromo-3-methylphenyl) -3-aminothiophene-2-carboxamide (1 eq., Obtained as described above for example 1, part 1, using 4-bromo-3-methylaniline instead of 4- trifluoromethoxyaniline) in THF at ⁰ ° C in an open flask was added 2- (N-methylcarbamoyl) pyridine-4-carboxaldehyde (prepared as described in published PCT № WO 01/23375) (1,1 eq.) in THF and 4M H ₂ SO ₄ (0.1 eq.) and the mixture was stirred for 30 min at ⁰ ° C was added portionwise sodium borohydride (1 eq.), the mixture was allowed to warm to room temperature and stirred for 2 hours. Water is then added, the mixture is made basic to pH 12 with a 2M sodium hydroxide solution, and the resulting product is extracted with ethyl acetate. The combined extracts were washed with water, then with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to obtain a yellow semi-solid, which was purified by column chromatography, eluting with a 95: 5 hexane: ethyl acetate mixture, with a gradually increasing gradient to 50:50, MS (ES ⁺ ): 459, 461 [MH ⁺ ].

EXAMPLE 6

Methylamide 4 - {[2- (2,2,3,3-tetrafluorobenzodioxan-6-ylcarbamoyl) thiophen-3-ylamino] methyl} pyridine-2-carboxylic acid

The compound of example 6 was prepared according to the procedure described above for example 5 using N - (2,2,3,3-tetrafluorobenzodioxan-6-yl) -3-aminothiophen-2-carboxamide (prepared as described above for example 1 , part 1, using 6-amino-2,2,3,3-tetrafluorobenzodioxane instead of 4-trifluoromethoxyaniline). MS (ES ⁺ ): 497 [MH ⁺ ].

EXAMPLE 7

4 - {[2- (4-Chlorophenylcarbamoyl) thiophen-3-ylamino] methyl} pyridine-2-carboxylic acid methylamide

The compound of Example 7 was prepared according to the procedure described above for Example 5 using N - (4-chlorophenyl) -3-aminothiophen-2-carboxamide (prepared as described above for Example 1, part 1, using 4-chloroaniline instead of 4 trifluoromethoxyaniline). MS (ES ⁺ ): 401, 403 [MH ⁺ ].

EXAMPLE 8

N - (4-chlorophenyl) -3 - [(1H-pyrrolo [2,3-b] pyridin-3-ylmethyl) amino] thiophene-2-carboxamide

Part 1:

7-azaindole-3-carboxaldehyde: Phosphorus oxychloride (36.5 ml) was added dropwise to a cooled DMF solution (40 ml), keeping the temperature below 10 ^C. The resulting solution was further cooled ^to 5 ° C and slowly over 30-40 minutes, a solution of 7-azaindole in DMF (40 ml), keeping the temperature below 25 ^C. The mixture was heated to 95 ^{° C} for 48 hours, then cooled to 35 ^{° C} and carefully, with stirring for one hour, cold saturated sodium bicarbonate solution (800 ml) is added. The mixture was extracted with ethyl acetate (4 × 500 ml) and the combined extracts washed with water (500 ml) and brine (500 ml), then dried (MgSO ₄ ), filtered and concentrated in vacuo to a dark brown semi-solid. This crude product was purified using column chromatography, eluting with a 50:50 ethyl acetate: hexane mixture, gradually increasing the gradient to 90:10.

¹ H-NMR (400MHz / D ₆ -DMSO): δ = 7.25 (m, 1H), 8.38 (m, 2H), 8.42 (s, 1H), 9.92 (s, 1H) 12.62 (br s, 1H). MS (ES ⁺ ): 147 [MH ⁺ ].

Part 2:

N - (4-chlorophenyl) -3 - [(1H-pyrrolo [2,3-b] pyridin-3-ylmethyl) amino] thiophene-2-carboxamide: prepared according to the procedure described above for example 5 using N - (4-chlorophenyl) -3-aminothiophene-2-carboxamide (obtained as described in example 1, part 1, using 4-chloroaniline instead of 4-trifluoromethoxyaniline) and 7-azaindole-3-carboxaldehyde (example 8, part 1) instead of 2- ( N- methylcarbamoyl) pyridin-4-carboxaldehyde. MS (ES ⁺ ): 383, 385 [MH ⁺ ].

EXAMPLE 9

N - (4-bromo-3-methylphenyl) -3 - [(1H-pyrrolo [2,3-b] pyridin-3-ylmethyl) amino] thiophen-2-carboxamide

The compound of example 9 was prepared according to the procedure described in example 5 using N - (4-bromo-3-methylphenyl) -3-aminothiophene-2-carboxamide (prepared as described in example 1, part 1, using 4-bromine -3-methylaniline instead of 4-trifluoromethoxyaniline) and 7-azaindole-3-carboxaldehyde (Example 8, part 1) instead of 2- ( N- methylcarbamoyl) pyridine-4-carboxaldehyde. MS (ES ⁺ ): 441, 443 [MH ⁺ ].

EXAMPLE 10

N - (2,2,3,3-tetrafluorobenzodioxan-6-yl) -3 - [(1H-pyrrolo [2,3-b] pyridin-3-ylmethyl) amino] thiophene-2-carboxamide

The compound of Example 10 was prepared according to the procedure described in Example 5 using N - (2,2,3,3-tetrafluorobenzodioxan-6-yl) -3-aminothiophen-2-carboxamide (prepared as described in Example 1, part 1, using 6-amino-2,2,3,3-tetrafluorobenzodioxane instead of 4-trifluoromethoxyaniline) and 7-azaindole-3-carboxaldehyde (Example 8, part 1) instead of 2- ( N- methylcarbamoyl) pyridine-4-carboxaldehyde. MS (ES ⁺ ): 479 [MH ⁺ ].

EXAMPLE 11

N - {[2- (4-trifluoromethoxyphenylcarbamoyl) thiophen-3-ylamino] methyl} pyridine-2-carboxylic acid methylamide

The compound of Example 11 was prepared according to the procedure described above for Example 5 using N - (4-trifluoromethoxyphenyl) -3-aminothiophen-2-carboxamide (prepared as described above for Example 1). MS (ES ⁺ ): 451 [MH ⁺ ].

EXAMPLE 13

N - (4-trifluoromethoxy) phenyl-3 - [(1 H -pyrrolo [2,3-b] pyridin-4-ylmethyl) amino] thiophen-2-carboxamide

Part 1:

4-chloro-1 H- pyrrolo [2,3-b] pyridine: 7-oxide 1 H -pyrrolo [2,3- b ] pyridine is slowly added to 200 ml of POCl ₃ and the resulting mixture is stirred at 80 ^about C in overnight. Then the excess POCl _{3 was} removed in vacuo, the residue was treated with 500 ml of H ₂ O and made basic with a saturated aqueous solution of K ₂ CO ₃ (aq) before extraction with EtOAc (2 × 300 ml). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-chloro-1 H -pyrrolo [2,3-b] pyridine (12.9 g, 76%). MS (ES ⁺ ): 153 [MH ⁺ ].

Part 2:

4-iodo-1 H -pyrrolo [2,3- b ] pyridine: To a solution of 4-chloro-1 H -pyrrolo [2,3-b] pyridine (12.9 g, 84.3 mmol) and NaI (40 g, 168 mmol) in acetonitrile (150 ml) acetyl chloride (12.6 ml, 176 mmol) is slowly added. The mixture was stirred at ⁸⁰ ° C for 4 days and then the excess acetonitrile was removed in vacuo. 300 ml of a 10% aqueous solution of K ₂ CO ₃ (aq) was added to the residue and the mixture was extracted with CH ₂ Cl ₂ (3 × 100 ml). The combined organic extracts were washed with 10% aqueous sodium bisulfite and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude product (22.2 g). To a solution of this crude product in THF (150 ml) was added 1M NaOH (100 ml). The mixture was stirred at room temperature for 2 hours before evaporating the solvent in vacuo, diluting with water and extracting CH ₂ Cl ₂ . The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting brown solid was purified by silica gel chromatography and recrystallized from acetonitrile to give pure 4-iodo-1 H -pyrrolo [2,3- b ] pyridine (9.75 g, 48%). MS (ES ⁺ ): 245 [MH ⁺ ].

Part 3:

1 H -pyrrolo [2,3- b ] pyridin-4-carbonitrile: To a solution (4.7 g, 19.3 mmol) of 4-iodo-1 H -pyrrolo [2,3- b ] pyridine in degassed DMF ( 25 ml) add Pd ₂ (dba) ₃ (10 mg), dppf (15 mg), degassed H ₂ O (2 ml) and Zn (CN) ₂ (1.4 g, 11.6 mmol). The mixture was stirred at 90 ° ^C under a nitrogen atmosphere for 20 hours, then cooled to ⁷⁰ ° C and 75 ml of 4: 1: 4 mixture of saturated NH ₄ Cl: NH ₄ OH: H ₂ O. The mixture was stirred at ⁵ ° C. within 20 minutes, the resulting precipitate was filtered off, washed with 75 ml of a 4: 1: 5 mixture of saturated NH ₄ Cl: NH ₄ OH: H ₂ O, 500 ml of H ₂ O and 100 ml of toluene, then dried in vacuum to obtain 2.06 g (74%) 1 H -pyrrolo [2,3- b ] pyridin-4-carbonitrile. MS (ES +): 143 [MH ⁺ ].

¹ H-NMR (400MHz, D ₆ -DMSO): δ = 6.65 (d, 1H, J = 3.2Hz), 7.56 (d, 1H, J = 4.8Hz), 7.84 (d , 1H, J = 4.0Hz), 8.40 (d, 1H, J = 4.8Hz).

Part 4:

1 H -pyrrolo [2,3- b ] pyridin-4-carboxaldehyde: To a solution (200 mg, 1.4 mmol) 1 H -pyrrolo [2,3- b ] pyridin-4-carbonitrile in THF (7 ml) at ^-78 ° C under nitrogen was added Dibal-H (1.0M in toluene, 3.07 mL, 3.07 mmol). The reaction mixture was stirred at ^-78 ° C for 1 hr, warmed to 55 ^C and stirred for an additional 2 hours. An additional one equivalent of Dibal-H (1,4 ml, 1.4 mmol) and the mixture was stirred at 55 ^{° C} for 2 hours. The mixture was cooled to 5 ^° C, acidified with 2M HCl and stirred for 15 minutes. The mixture was then neutralized with saturated aqueous NaHCO ₃ , extracted with CH ₂ Cl ₂ (5 × 25 ml), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 1 N -pyrrolo [2,3-b] pyridine- 4-carboxaldehyde (107 mg, 52%). MS (ES +): 146 [MH ⁺ ].

¹ H-NMR (400MHz, D ₆ -DMSO): δ = 7.22 (d, 1H, J = 3.6Hz), 7.57 (d, 1H, J = 4.8Hz), 7.67 (d , 1H, J = 2.4Hz), 8.61 (d, 1H, J = 5.2Hz), 10.42 (s, 1H).

Part 5:

Methyl 3 - [(1 H -pyrrolo [2,3-b] pyridin-4-ylmethyl) amino] thiophene-2-carboxylate: Solution of 3-aminothiophen-2-carboxylic acid methyl ester (110 mg, 0.701 mmol) and 1 H-pyrrolo [2,3- b] pyridine-4-carboxaldehyde (107 mg, 0.736 mmol) in a mixture of TFA / CH ₂ Cl ₂ (2 ml / 2 ml) was stirred ^at 50 ° C for 3 hours. The solution was cooled ^to 0 ° C and added dropwise triethylsilane (0.224 mL, 1.40 mmol). Then the mixture is stirred at 50 ^about C for 4 hours and treated with 2n. aqueous NaOH solution (to pH 6) and then a saturated aqueous NaHCO ₃ solution (to pH 8). The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 10 ml). The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient from 20% EtOAc / hexanes to 70% EtOAc / hexanes) to give methyl 3 - [(1 H -pyrrolo [2,3- b ] pyridin-4-ylmethyl) amino] thiophen-2 β-carboxylate (98 mg, 49%). MS (ES +): 287 [MH ⁺ ].

¹ H-NMR (400MHz, D ₆ -DMSO): δ = 3.75 (s, 3H), 4.84 (d, 2H, J = 4.4Hz), 6.74 (dd, 1H, J = 2 , 8Hz and 2.0 Hz), 6.70 (d, 1H, J = 5.6Hz), 7.01 (d, 1H, J = 4.8Hz), 7.51 (t, 1H, J = 2 4Hz), 7.61 (d, 1H, J = 5.2Hz), 8.18 (d, 1H, J = 4.8Hz).

Part 6:

N - (4-trifluoromethoxy) phenyl-3 - [(1 H -pyrrolo [2,3- b ] pyridin-4-ylmethyl) amino] thiophen-2-carboxamide: To a solution of 4-trifluoromethoxyaniline (0.381 ml, 1.74 mmol) in anhydrous toluene (5 ml), AlMe ₃ (2.0 M in toluene, 0.520 ml, 1.4 mmol) was added and the solution was stirred at room temperature overnight. Methyl-3 - [(1 H-pyrrolo [2,3-b] pyridin-4-ylmethyl) amino] thiophene-2-carboxylate (100 mg, 0.348 mmol) and the mixture was stirred at 130 ^{° C} overnight before cooling to room temperature and treatment with 15 ml of a saturated aqueous solution of NaHCO ₃ . After stirring for 1 hour, the mixture was filtered, the filtered layers were separated, and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 10 ml). The isolated solid was dissolved in 15 ml of CH ₂ Cl ₂ and all organic solutions (toluene and CH ₂ Cl ₂ ) were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient from 20% EtOAc / hexanes to 50% EtOAc / hexanes) to give N - (4-trifluoromethoxy) phenyl-3 - [(1 H -pyrrolo [2,3- b ] pyridin-4- ilmethyl) amino] thiophene-2-carboxamide (93 mg, 62%). MS (ES +): 432 [MH ⁺ ].

¹ H-NMR (400MHz, D ₆ -DMSO): δ = 4.81 (d, 2H, J = 6.4Hz), 6.62 (dd, 1H, J = 3.6 and 1.6Hz), 6 78 (d, 1H, J = 5.6Hz), 6.99 (d, 1H, J = 4.8Hz), 7.31 (d, 2H, J = 8.8Hz), 7.45 (dd, 1H, J = 2.8 and 3.2Hz), 7.59 (d, 1H, J = 5.6Hz), 7.79 (ddd, 2H, J = 8.8, 3.2 and 2.0Hz) 8.08 (t, 1H, J = 6.4Hz), 8.15 (d, 1H, J = 4.8Hz), 9.54 (s, 1H).

The following analogs are prepared using methyl 3 - [(1 H -pyrrolo [2,3-b] pyridin-4-ylmethyl) amino] thiophene-2-carboxylate (Example 13, Part 5) and a suitable aniline, in accordance with the procedure described above for example 13, part 6.

EXAMPLE 14

N - (4-chlorophenyl) -3 - [(1 H -pyrrolo [2,3- b ] pyridin-4-ylmethyl) amino] thiophene-2-carboxamide

(5.1 mg, 4%). MS (ES +): 383 [MH ⁺ ].

EXAMPLE 15

3 - [(1 H -pyrrolo [2,3- b ] pyridin-4-ylmethyl) amino] - N - (2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6 -yl) thiophene-2-carboxamide

(19.4 mg, 16%). MS (ES +): 479 [MH ⁺ ].

EXAMPLE 16

4-methyl- N - (4-trifluoromethoxyphenyl) phenyl-3 - [(quinolin-4-ylmethyl) amino] thiophen-2-carboxamide

Prepared in accordance with the procedure described for example 13, parts 5 and 6, using methyl 3-amino-4-methylthiophene-2-carboxylate, quinoline-4-carboxaldehyde and 4- (trifluoromethoxy) aniline as starting materials. MS (ES +): 458 [MH ⁺ ], 459 [MH ²⁺ ].

¹ H-NMR (400MHz, CDCl ₃ ): δ = 2.15 (d, 2H, J = 1.2Hz), 5.01 (d, 2H, J = 7.2Hz), 6.98 (d, 1H , J = 1.2Hz), 7.17-7.24 (m, 3H), 7.51-7.54 (m, 3H), 7.58 (ddd, 1H, J = 8.0, 6, 4 and 1.2Hz), 7.74 (ddd, 1H, J = 8.0, 6.8 and 1.2Hz), 7.86 (br.s, 1H), 7.97 (dd, 1H, J = 8.8 and 0.8Hz), 8.16 (d, 1H, J = 8.0Hz), 8.89 (d, 1H, J = 4.8Hz).

The following compounds of the examples are prepared in a similar manner using in each case a suitable aniline.

EXAMPLE 17

N - (4-chlorophenyl) -4-methyl-3 - [(quinolin-4-ylmethyl) amino] thiophene-2-carboxamide

MS (ES +): 408, 410 [MH ⁺ ].

EXAMPLE 18

N - (4-bromo-3-methylphenyl) -4-methyl-3 - [(quinolin-4-ylmethyl) amino] thiophene-2-carboxamide

MS (ES +): 467, 469 [MH ⁺ ].

EXAMPLE 19

4-methyl-3 - [(quinolin-4-ylmethyl) amino] - N - (2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) thiophen-2- carboxamide

MS (ES +): 503 [MH ⁺ ].

EXAMPLE 20

3 - {[(1-oxidoquinolin-4-yl) methyl] amino} - N - [4- (trifluoromethoxy) phenyl] thiophene-2-carboxamide

Part 1:

Quinolin-4-ylmethanol

A solution of quinoline-4-carbaldehyde (0.50 g, 3.24 mmol) in methanol (5 ml) was cooled ^to 0 ° C then added in portions sodium borohydride (0.11 g, 2.91 mmol). After stirring for 1 hour at 0 ° ^C was added dropwise 2M aqueous HCl solution to adjust rN≈5. Then, methanol was evaporated in vacuo and the aqueous phase was neutralized by the addition of a saturated aqueous solution of NaHCO ₃ . The aqueous solution was extracted with CH ₂ Cl ₂ (3 ×) and the combined organic extracts were washed with saturated aqueous NaHCO ₃ and brine. The organic solution was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give quinolin-4-ylmethanol as a yellow solid. MS (ES +): 160 [MH ⁺ ].

¹ H-NMR (400MHz, CDCl ₃ ): δ = 2.41 (br s, 1H), 5.25 (br s, 2H), 7.75 (ddd, 1H, J = 4.4, 1 , 2 and 1.2Hz), 7.58 (ddd, 1H, J = 8.4, 7.2 and 1.2Hz), 7.73 (ddd, 1H, J = 8.4, 6.8 and 1 6Hz), 7.97 (ddd, 1H, J = 8.4, 1.2 and 0.4Hz), 8.14 (ddd, 1H, J = 8.0, 1.2 and 0.4Hz), 8.90 (d, 1H, J = 4.4Hz).

Part 2:

(1-oxidoquinolin-4-yl) methanol

To a solution of quinolin-4-ylmethanol (0.20 g, 1.26 mmol) in CH ₂ Cl ₂ (10 ml) which was cooled ^to 0 ° C, was added m -hlorperbenzoynuyu acid (57-86% w / w in H ₂ O, 0.50 mg) in one portion. The reaction mixture was allowed to warm slowly to room temperature while stirring. After 17.5 hours, the resulting solid was filtered off and washed with CH ₂ Cl ₂ to give (1-oxidoquinolin-4-yl) methanol as a white solid. MS (ES +): 176 [MH ⁺ ].

Part 3:

Quinoline-4-Carbaldehyde 1-Oxide

To a vigorously stirred suspension of (1-oxidoquinolin-4-yl) methanol (0.10 g, 0.57 mmol) in acetonitrile (10 ml), Dess-Martin periodinan (0.47 g, 0.63 mmol) was added. After 1 hour, a 2M aqueous NaOH solution (2 ml) and ethyl acetate (105 ml) were added and the reaction mixture was stirred for 5 minutes. The layers were then separated and the organic phase was washed with saturated aqueous NaHCO ₃ , brine and dried over MgSO ₄ , filtered and concentrated in vacuo to a light yellow solid. MS (ES +): 174 [MH ⁺ ].

(This intermediate can also be prepared as described in Heterocycles (2003), 60 (4), 953).

Part 4:

3 - {[(oxidoquinolin-4-yl) methyl] amino} - N - [4- (trifluoromethoxy) phenyl] thiophen-2-carboxamide

A solution of 1-quinoline-4-carboxaldehyde oxide (0.12 g, 0.69 mmol), 3-amino N - [4- (trifluoromethoxy) phenyl] thiophene-2-carboxamide (0.21 g, 0.69 mmol ), dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was heated ^at 50 ° C for 2 hours, then cooled to room temperature, treated trietisilanom (0.22 mL, 1.38 mmol) and stirred ^at 50 ° C for another 2 hours. After this time, the mixture was diluted with water (40 ml), made basic (pH 9) with a 2M aqueous NaOH solution and extracted with ethyl acetate (3 × 20 ml). The extracts were washed with water (30 ml) and brine (30 ml), then dried (MgSO ₄ ) and concentrated in vacuo to give a crude product. This product is chromatographed on silica gel, eluting with 15% acetonitrile / CH ₂ Cl ₂ , and then the isolated material is purified by crystallization from acetonitrile to give 3 - {[(1-oxoquinolin-4-yl) methyl] amino} - N - [4- (trifluoromethoxy) phenyl] thiophene-2-carboxamide. MS (ES +): 460 [MH ⁺ ].

¹ H-NMR (400MHz, D ₆ -DMSO): δ = 5.00 (s, 2H), 6.87 (d, 1H, J = 5.6Hz), 7.25-7.40 (m, 3H ), 7.65 (d, 1H, J = 5.3Hz), 7.73-7.91 (m, 4H), 8.04 (t, 1H, J = 6.4Hz), 8.30 (d , 1H, J = 7.1Hz), 8.56 (d, 1H, J = 6.3Hz), 8.61 (d, 1H, J = 8.3Hz), 9.60 (s, 1H).

Claims (11)

1. The compound represented by formula (I)

(I) or a pharmaceutically acceptable salt or N-oxide thereof, wherein R1 is

R2 is and

R3 is C _0-4 alkyl. 2. The compound according to claim 1 or its pharmaceutically acceptable salt or N-oxide, where R2 is.

3. The compound according to claim 1 or its pharmaceutically acceptable salt or N-oxide, where R2 represents

and R3 is hydrogen. 4. The compound according to claim 1 or its pharmaceutically acceptable salt or N-oxide, where R2 represents

. 5. The compound according to claim 1 or its pharmaceutically acceptable salt or N-oxide, where R2 represents

and R3 is hydrogen. 6. The compound according to claim 1 or its pharmaceutically acceptable salt or N-oxide, where R2 represents

7. The compound according to claim 1 or its pharmaceutically acceptable salt or N-oxide, where R2 represents

and R3 is C _0-4 alkyl. 8. The compound according to claim 1 or its pharmaceutically acceptable salt or N-oxide, where R2 is

and R3 is hydrogen. 9. The compound according to claim 1 or its pharmaceutically acceptable salt or N-oxide, where R2 represents

and R3 represents C ₀ - ₄ alkyl. 10. The compound according to claim 1, selected from N- (4-trifluoromethoxyphenyl) -3 - [(quinolin-4-ylmethyl) amino] thiophene-2-carboxamide; N- (4-bromo-3-methylphenyl) -3 - [(quinolin-4-ylmethyl) amino] thiophen-2-carboxamide; N- (2, 2, 3, 3-tetrafluorobenzodioxan-6-yl) -3 - [(quinolin-4-ylmethyl) amino] thiophen-2-carboxamide; N- (4-chlorophenyl) -3 - [(quinolin-4-ylmethyl) amino] thiophen-2-carboxamide; 4 - {[2- (4-bromo-3-methylphenylcarbamoyl) thiophen-3-ylamino] methyl} pyridine-2-carboxylic acid methylamide; methylamide 4 - {[2- (2, 2, 3, 3-tetrafluorobenzodioxan-6-ylcarbamoyl) thiophen-3-ylamino] methyl} pyridine-2-carboxylic acid; 4 - {[2- (4-chlorophenylcarbamoyl) thiophen-3-ylamino] methyl} pyridine-2-carboxylic acid methylamide; N- (4-chlorophenyl) -3 - [(1H-pyrrolo [2,3-b] pyridin-3-ylmethyl) amino] thiophen-2-carboxamide; N- (4-bromo-3-methyl phenyl) -3 - [(1H-pyrrolo- [2,3-b] pyridin-3-ylmethyl) amino] thiophen-2-carboxamide; N- (2, 2, 3, 3-tetrafluorobenzodioxan-6-yl) -3 - [(1H-pyrrolo [2, 3-b] pyridin-3-ylmethyl) amino] thiophen-2-carboxamide; N - {[2- (4-trifluoromethoxyphenylcarbamoyl) thiophen-3-ylamino] methyl} pyridine-2-carboxylic acid methylamide; N- (4-trifluoromethoxy) phenyl-3 - [(1H-pyrrolo- [2,3-b] pyridin-4-ylmethyl) amino] thiophen-2-carboxamide; N- (4-chlorophenyl) -3 - [(1H-pyrrolo- [2,3-b] pyridin-4-ylmethyl) amino] thiophen-2-carboxamide; 3 - [(1H-pyrrolo [2,3-b] pyridin-4-ylmethyl) amino] -N- (2, 2, 3, 3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6- il) thiophene-2-carboxamide; 4-methyl-N- (4-trifluoromethoxyphenyl) phenyl-3 - [(quinolin-4-ylmethyl) amino] thiophen-2-carboxamide; N- (4-chlorophenyl) -4-methyl-3 - [(quinolin-4-ylmethyl) amino] thiophene-2-carboxamide; N- (4-bromo-3-methylphenyl) -4-methyl-3 - [(quinolin-4-ylmethyl) amino] thiophene-2-carboxamide; 4-methyl-3 - [(quinolin-4-ylmethyl) amino] -N- (2, 2, 3, 3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) thiophen-2- carboxamide; 3 - {[(1-oxidoquinolin-4-yl) methyl] amino} -N- [4- (trifluoromethoxy) phenyl] thiophene-2-carboxamide or a pharmaceutically acceptable salt or N-oxide thereof. 11. The compound of formula (I), which is N- (4-trifluoromethoxyphenyl) -3 - [(quinolin-4-ylmethyl) amino] thiophen-2-carboxamide or a pharmaceutically acceptable salt or N-oxide thereof.