 2-amino-4,5-trisubstituted thiazolyl derivatives
专利摘要:
Compounds of formula (I ′), N-oxides thereof, pharmaceutically acceptable for the manufacture of a medicament for the prophylaxis or treatment of inflammatory and / or autoimmune diseases mediated through TNF-α and / or IL-12 Use of salts, quaternary amines and stereochemically isomeric forms: Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; Aminocarbonyl; Hydroxy, carboxyl, cyano, amino, amino substituted with piperidinyl, amino substituted with C 1-4 alkyl substituted with piperidinyl, mono- or di (C 1-6 alkyl) amino, C 1- 6 alkyloxycarbonyl, C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl a C 1-6 alkyl substituted with; Cyano; Amino; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Amino-S (= 0) 2 —; Mono- or di (Ci_ 6 alkyl) amino-S (= 0) 2 ; -C (= NR x ) NR y R z ; Q is optionally substituted C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl ; Q is a radical of the formula: L is optionally substituted phenyl or optionally substituted monocyclic 5 or 6-membered partially saturated or aromatic heterocycle or bicyclic partially saturated or aromatic heterocycle; Aryl is optionally substituted phenyl. 公开号:KR20040031712A 申请号:KR10-2003-7017268 申请日:2002-08-09 公开日:2004-04-13 发明作者:러브크리스토퍼존；반로멘가이로살리아유진；도욘줄리안조지피에르-올리비에르；본가르츠쟌-피에르안드레마르크；반데르아아마르셀요셉마리아；헨드리크스로버트요셉마리아；부이즌스터스피터야코부스요하네스안토니우스；쿠이만스루드위그파울；반데르마에센넬레；코에세만스에르윈；보엑크스구스타프마리아 申请人:얀센 파마슈티카 엔.브이.； IPC主号:
专利说明:
2-amino-4,5-trisubstituted thiazolyl derivatives} [2] WO 99/64418 describes aryl-pyridyl thiazoles as TNF-α inhibitors. [3] WO 02/34748 relates to imidazopyridyl derivatives as anticancer agents. [4] Compounds of the present invention are distinguished from the prior art by their structure, pharmacological activity, and potency. [1] The present invention relates to 2-amino-4, 5-trisubstituted thiazolyl derivatives having pre-inflammatory (pro-inflammatory) cytokine production inhibitory properties, in particular TNF-α and / or IL-12 inhibitory properties. The present invention further relates to methods of preparation thereof and pharmaceutical compositions comprising the same. The invention also relates to the use of 2-amino-4, 5-trisubstituted thiazolyl derivatives for the manufacture of a medicament for the prevention or treatment of diseases mediated through TNF-α and / or IL-12, in particular IL-12. It is about. [5] The present invention provides a compound of formula (I ′), N-oxides, pharmaceuticals thereof for the manufacture of a medicament for the prevention or treatment of inflammatory and / or autoimmune diseases mediated through TNF-α and / or IL-12 Pertaining to the use of acceptable salts, quaternary amines and stereochemically isomeric forms: [6] [7] Where [8] Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; Aminocarbonyl; Hydroxy, carboxyl, cyano, amino, amino substituted with piperidinyl, amino, mono- or di (C 1-6 alkyl) amino, aminocarbonyl substituted with C 1-4 alkyl substituted with piperidinyl , Mono- or di (C 1-6 alkyl) aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl C 1-6 alkyl; PolyhaloC 1-4 alkyl; Cyano; Amino; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Amino-S (= 0) 2 —; Mono- or di (Ci_ 6 alkyl) amino-S (= 0) 2 ; Or -C (= NR x ) NR y R z ; [9] R x is hydrogen, C 1-6 alkyl, cyano, nitro or —S (═O) 2 —NH 2 ; [10] R y is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; [11] R Z is hydrogen or C 1-6 alkyl; [12] Q is C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl, wherein Each ring system is halo; hydroxy; cyano; carboxyl; azido; amino; mono- or di (C 1-6 alkyl) amino; C 1-6 alkylcarbonylamino; C 1-6 alkyl; C 2- 6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl, hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-4 alkyl) substituted C 1-6 alkyl amino C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; arylC 1-6 alkyloxy; aryloxy; polyhaloC 1-6 Alkyl; polyhaloC 1-6 alkyloxy; polyhaloC 1-6 alkylcarbonyl; Het; C 1-4 alkyl-S (= 0) n -or R 1 HN-S (= 0) n- Optionally substituted with up to 3 substituents independently selected from: [13] Q is a radical of the formula: [14] [15] Wherein X and Y are each independently O, NR 3 , CH 2 or S, wherein R 3 is hydrogen or C 1-4 alkyl; [16] q is an integer from 1 to 4; [17] Z is O or NR 4, wherein R 4 is hydrogen or C 1-4 alkyl; [18] r is an integer from 1 to 3; [19] n is an integer of 1 or 2; [20] R 1 is hydrogen or a radical of formula (a-1) [21] Indicates [22] (Wherein A is a divalent radical of formula -CR 2a = -N- with O, S or CR 2a bonded to N of formula (a-1), where R 2a is hydrogen, C 1-6 Alkyl or C 1-6 alkyloxy))); [23] L is halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; -C (= NR x ) NR y R z is phenyl substituted with up to 4 respective substituents independently selected from; [24] L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (C 1- 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; Monocyclic 5 or 6-membered partially saturated or aromatic heterocycle or bicy, which may be optionally substituted with up to 3 respective substituents independently selected from -C (= NR x ) NR y R z A partially saturated or aromatic heterocycle of the click; [25] Het is that each ring system is halo; Hydroxy; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Or monocyclic 5 or 6-membered, which may be optionally substituted with up to 3 respective substituents independently selected from mono- or di (C 1-4 alkyl) amino-C (═O) —NH— Partially saturated or aromatic heterocycle or bicyclic partially saturated or aromatic heterocycle; [26] Aryl is halo, hydroxy, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, cyano, nitro, amino, mono- or di (C 1 Phenyl optionally substituted with up to 5 substituents each independently selected from -6 alkyl) amino. [27] The present invention relates to compounds of formula (I), N-oxides, pharmaceutically acceptable salts, quaternary amines and stereochemically isomeric forms thereof: [28] [29] Where [30] Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; Aminocarbonyl; Hydroxy, carboxyl, cyano, amino, amino substituted with piperidinyl, amino, mono- or di (C 1-6 alkyl) amino, aminocarbonyl substituted with C 1-4 alkyl substituted with piperidinyl , Mono- or di (C 1-6 alkyl) aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl C 1-6 alkyl; PolyhaloC 1-4 alkyl; Cyano; Amino; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Amino-S (= 0) 2 —; Mono- or di (Ci_ 6 alkyl) amino-S (= 0) 2 ; Or -C (= NR x ) NR y R z ; [31] R x is hydrogen, C 1-6 alkyl, cyano, nitro or —S (═O) 2 —NH 2 ; [32] R y is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; [33] R Z is hydrogen or C 1-6 alkyl; [34] Q is C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl, wherein Each ring system is halo; hydroxy; cyano; carboxyl; azido; amino; mono- or di (C 1-6 alkyl) amino; C 1-6 alkylcarbonylamino; C 1-6 alkyl; C 2- 6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl, hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-4 alkyl) substituted C 1-6 alkyl amino C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; arylC 1-6 alkyloxy; aryloxy; polyhaloC 1-6 Alkyl; polyhaloC 1-6 alkyloxy; polyhaloC 1-6 alkylcarbonyl; Het; C 1-4 alkyl-S (= 0) n -or R 1 HN-S (= 0) n- Optionally substituted with up to 3 substituents independently selected from: [35] Q is a radical of the formula: [36] [37] Wherein X and Y are each independently O, NR 3 , CH 2 or S, wherein R 3 is hydrogen or C 1-4 alkyl; [38] q is an integer from 1 to 4; [39] Z is O or NR 4, wherein R 4 is hydrogen or C 1-4 alkyl; [40] r is an integer from 1 to 3; [41] n is an integer of 1 or 2; [42] R 1 is hydrogen or a radical of formula (a-1) [43] Indicates [44] (Wherein A is a divalent radical of formula -CR 2a = -N- with O, S or CR 2a bonded to N of formula (a-1), where R 2a is hydrogen, C 1-6 Alkyl or C 1-6 alkyloxy))); [45] L is halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; -C (= NR x ) NR y R z is phenyl substituted with up to 4 respective substituents independently selected from; [46] L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (C 1- 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; Monocyclic 5 or 6-membered partially saturated or aromatic heterocycle or bicy, which may be optionally substituted with up to 3 respective substituents independently selected from -C (= NR x ) NR y R z A partially saturated or aromatic heterocycle of the click; [47] Het is that each ring system is halo; Hydroxy; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Or monocyclic 5 or 6-membered, which may be optionally substituted with up to 3 respective substituents independently selected from mono- or di (C 1-4 alkyl) amino-C (═O) —NH— Partially saturated or aromatic heterocycle or bicyclic partially saturated or aromatic heterocycle; [48] Aryl is halo, hydroxy, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, cyano, nitro, amino, mono- or di (C 1 Phenyl optionally substituted with up to 5 substituents each independently selected from -6 alkyl) amino; [49] Provided that the compound is 1, 2-dihydro-5- [2- [(4-methoxyphenyl) amino] 5-methyl-4-thiazolyl] -6-methyl-2-oxo-3-pyridinecarbonitrile. With the proviso that when the bicyclic aromatic heterocycle in the L definition represents imidazopyridyl, the imidazopyridyl is unsubstituted. [50] As used above or below, C 1-4 alkyl as a group or part of a group is a straight or branched chain saturated hydrocarbon radical having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, 1- Methylethyl, butyl and the like; C 1-6 as a group or part of a group is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms, for example a group defined in C 1-4 alkyl and pentyl, hexyl, 2-methyl Butyl and the like; C 2-6 alkenyl as a group or part of a group is a straight or branched chain hydrocarbon radical having 2 to 6 carbon atoms and 1 double bond, for example ethenyl, propenyl, butenyl, pentenyl, Hexenyl, 3-methylbutenyl and the like; C 2-6 alkynyl as a group or part of a group is a straight or branched chain hydrocarbon radical having 2 to 6 carbon atoms and 1 triple bond, for example ethynyl, propynyl, butynyl, pentynyl, Hexynyl, 3-methylbutynyl and the like; C 3-6 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Monocyclic or bicyclic partially saturated heterocycles represent a ring system consisting of one or two rings and comprising at least one hetero atom selected from O, N or S, and at least one double bond (However, the ring system is not an aromatic system); Monocyclic or bicyclic aromatic heterocycles represent aromatic ring systems consisting of one or two rings and comprising at least one hetero atom selected from O, N or S; The term aromatic is well known to those skilled in the art and refers to a cyclically bonding system of 4n '+ 2 electrons (Wickel's law) with π-electrons such as 6, 10, 14 and the like. [51] L or Q radicals as described above for the compounding of formula (I) or (I ′) may be suitably bonded to the remainder of the molecule of formula (I) or (I ′) via any ring carbon or heteroatom. . For example, when Q is pyridyl, it may be 2-pyridyl, 3-pyridyl or 4-pyridyl. [52] The line drawn by the ring system states that the bond can be connected to any suitable ring atom. If the ring system is a bicyclic ring system, the bond may be bonded to the appropriate ring atom of either ring. [53] As used above, the term (= O) forms a carbonyl moiety when attached to a carbon atom, forms a sulfoxide moiety when attached to a sulfur atom, and when two of the terms are attached to a sulfur atom, Form a sulfonyl moiety. [54] The term halo is a generic term for fluoro, chloro, bromo and iodo. As used above and below, polyhaloC 1-4 alkyl or polyhaloC 1-6 alkyl as a group or part of a group is mono- or polyhalosubstituted C 1-4 alkyl or C 1-6 Alkyl, eg methyl, substituted with one or more fluoro atoms, eg difluoromethyl or trifluoromethyl. When more than one halogen atom is bonded to an alkyl group within the definition of polyhaloC 1-4 alkyl or polyhaloC 1-6 alkyl, they are the same or different. [55] When a variable is formed more than once in any configuration, each definition is independent. [56] Some of the compounds of formula (I) and their N-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more chirality centers and may exist in stereochemically isomeric forms. [57] As used above or below, the term “stereochemically isomeric form” is intended to be possessed by a compound of formula (I) or (I ′) and its N-oxides, addition salts, quaternary amines, or physiologically functional derivatives thereof. Define all possible stereoisomeric forms. Unless otherwise stated or indicated, the chemical names of compounds represent mixtures of all possible stereochemically isomeric forms, said mixtures being 10% free of all diastereomers and enantiomers and substantially free isomers of the underlying molecular structure. Each of the individual isomeric forms of formula (I) or (I ′) and its N-oxides, salts, solvates or quaternary amines which are less than, preferably less than 5%, in particular less than 2% and most preferably less than 1% It contains. Stereochemically isomeric forms of the compounds of formula (I) or (I ') are expressly included within the scope of the present invention. [58] For therapeutic use, the salts of the compounds of formula (I) or (I ') are salts in which the counterions are pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention. [59] Pharmaceutically acceptable acid and base addition salts mentioned above or below include therapeutically active non-toxic acid and base addition salt forms which compounds of formula (I) or (I ') can form. Pharmaceutically acceptable acid addition salts can be readily obtained by treating the base form with such a suitable acid. Suitable acids include, for example, inorganic acids, such as hydrochloric acid, such as hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and pseudo acids; Or organic acids, such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (ie ethanedioic acid), malonic acid, succinic acid (ie butanedioic acid), maleic acid, fumaric acid, malic acid (ie hydride) Oxybutanedioic acid), tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and similar acids. [60] Conversely, the salt form can be converted to the free base form by treatment with a suitable base. [61] Compounds of formula (I) or (I ') containing acidic protons can also be converted to their non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic acids. Suitable base salt forms are, for example, ammonium salts, alkali and alkaline earth metal salts, for example lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases such as primary, secondary and tertiary aliphatic and Aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butyl Amines, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinucilidine, pyridine, quinoline and isoquinoline; Benzatin, N-methyl-D-glucamine, hydravamine salts, and salts with amino acids such as arginine, lysine and the like. [62] Conversely, the salt form can be converted to the free acid form by treatment with an acid. [63] The term addition salt as used above also includes solvates which the compounds of formula (I) or (I ′) and salts thereof can form. Such solvates are, for example, hydrates, alcoholates and the like. [64] The term "quaternary amine" as used above means that the compound of formula (I) or (I ') is substituted with the basic nitrogen of the compound of formula (I) or (I') with a suitable quaternizing agent, for example optionally Quaternary ammonium salts which can be formed by reaction between alkyl halides, aryl halides or arylalkyl halides, for example methyl iodide or benzyl iodide, are defined. Other reactants with good leaving groups can also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterions of choice can be introduced using ion exchange resins. [65] The present compound is meant that the N-oxide form includes compounds of formula (I) or (I ') in which one or several tertiary nitrogen atoms are oxidized to so-called N-oxides. [66] Some of the compounds of formula (I) or (I ') may also exist in tautomeric forms. Such forms are not expressly represented in the above formula but are included within the scope of the present invention. [67] Examples of partially saturated heterocycles, in particular monocyclic or bicyclic, include pyrrolinyl, imidazolinyl, pyrazolinyl, 2, 3-dihydrobenzofuranyl, 1,3-benzodioxolinyl, 2, 3-dihydro-1, 4-benzodioxyyl, indolinyl, and the like. [68] Particularly examples of monocyclic or bicyclic aromatic heterocycles include azetyl, oxetylideneyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, Thiazolyl, thiadiazolyl, oxdiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, Indolizinyl, indolyl, isoindoleyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, Pyridinyl, quinolinyl, isoquinolinyl, cynolinyl, quinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, pteridinyl, benzopyranyl, pyrrolopyridyl, tier Nopyridyl, furopyridyl, isothiazolopyridyl, thiazole Pyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furypyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isox Isazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl, Isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl, thia Zolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadizolo Pyrazinyl, thiadiazolopyrazinyl , Triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl , Imidazothiazolyl, imidazoimidazolyl, isoxazolotriazinyl, isothiazolo triazinyl, pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl, Thiadiazolotriazinyl, triazolotriazinyl. [69] One aspect of interest of the present invention is [70] Q is C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl, wherein Each ring system is halo; hydroxy; cyano; carboxyl; azido; amino; mono- or di (C 1-6 alkyl) amino; C 1-6 alkylcarbonylamino; C 1-6 alkyl; C 2- 6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl, hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-4 alkyl) substituted C 1-6 alkyl amino C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; arylC 1-6 alkyloxy; aryloxy; polyhaloC 1-6 Alkyl; polyhaloC 1-6 alkyloxy; polyhaloC 1-6 alkylcarbonyl; C 1-4 alkyl-S (═O) n -or R 1 HN-S (= 0) n -respectively Optionally substituted with up to 3 substituents independently selected); [71] Q is a radical of the formula: [72] [73] Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; Aminocarbonyl; Hydroxy, carboxyl, amino, cyano, mono- or di (C 1-6 alkyl) amino, aminocarbonyl, mono- or di (C 1-6 alkyl) aminocarbonyl, C 1-6 alkyloxycarbonyl , C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl a C 1-6 alkyl substituted with; PolyhaloC 1-4 alkyl; Cyano; Amino; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyloxycarbonyl, C 1-6 alkyloxycarbonyloxy; AminoS (═O 2 ) —; Mono- or di (C 1-6 alkyl) amino-S (= O 2); A compound of formula (I) or formula (I ′) wherein -C (═NR x ) NR y R z . [74] Another aspect of interest of the invention is that Q is C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, Indazolyl, or imidazopyridyl, wherein each ring system is halo; hydroxy; cyano; carboxyl; azido; amino; mono- or di (C 1-6 alkyl) amino; C 1-6 alkylcarbo Nylamino; C 1-6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl; hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1- 4 alkyl) amino C 1-6 alkyl substituted with; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; aryl C 1-6 alkyl, Oxy; aryloxy; polyhaloC 1-6 alkyl; polyhaloC 1-6 alkyloxy; polyhaloC 1-6 alkylcarbonyl; Het or C 1-4 alkyl-S (═O) n Each optionally substituted with up to 3 substituents independently selected); Q is C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl, wherein Each ring system is halo; hydroxy; cyano; carboxyl; azido; amino; mono- or di (C 1-6 alkyl) amino; C 1-6 alkylcarbonylamino; C 1-6 alkyl; C 2- 6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl, hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-4 alkyl) substituted C 1-6 alkyl amino C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; arylC 1-6 alkyloxy; aryloxy; polyhaloC 1-6 Optionally substituted with up to 3 substituents each independently selected from alkyl; polyhaloC 1-6 alkyloxy; polyhaloC 1-6 alkylcarbonyl; or C 1-4 alkyl-S (═O) n And compounds of formula (I) or (I '). [75] Also of interest in the present invention are compounds of formula (I) or (I ') that satisfy one, or possibly more, of the following conditions: [76] a) L is halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; Or 3-halophenyl or 3-cyanophenyl substituted with one, two, or three respective substituents independently selected from -C (= NR x ) NR y R z , in particular L is 3-halophenyl or 3-cyanophenyl; [77] L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; Or monocyclic 5 or 6-membered partially saturated or aromatic heterocycle or bi, which may be optionally substituted with up to 3 respective substituents independently selected from -C (= NR x ) NR y R z Cyclic partially saturated or aromatic heterocycle; [78] b) L is halo for each ring system; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; Or monocyclic 5 or 6-membered partially saturated or aromatic heterocycle or bi, which may be optionally substituted with up to 3 respective substituents independently selected from -C (= NR x ) NR y R z Cyclic partially saturated or aromatic heterocycle; [79] c) Q is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl, wherein each ring system is halo ; Hydroxy; cyano; carboxyl; azido; amino; mono- or di (C 1-6 alkyl) amino; C 1-6 alkylcarbonylamino; C 1-6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl, hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-4 alkyl) C 1-6 alkyl substituted with amino; C 1-6 Alkyloxy; C 1-6 alkylthio; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; arylC 1-6 alkyloxy; aryloxy; polyhaloC 1-6 alkyl; polyhalo C 1-6 alkyloxy; polyhaloC 1-6 alkylcarbonyl; may be optionally substituted with up to 3 substituents independently selected from Het or C 1-4 alkyl-S (═O) n −) Or; [80] d) Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl, aminocarbonyl; Hydroxy, cyano, amino, amino substituted with piperidinyl, C 1-4 alkyl substituted amino, mono- or di (C 1-6 alkyl) amino, aminocarbonyl, mono- substituted with piperidinyl or di (C 1-6 alkyl) aminocarbonyl, C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl a C 1-6 alkyl substituted with; PolyhaloC 1-4 alkyl; Cyano; Amino; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkylcarbonyloxy; AminoS (═O 2 ) —; Mono- or di (C 1-6 alkyl) amino-S (= O 2); -C (= NR x ) NR y R z . [81] Another particular aspect of the present invention is a compound of formula (I) or (I ') which satisfies one, or possibly more, of the following conditions: [82] a) L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; A bicyclic partially saturated or aromatic heterocycle other than 3,4-dihydro-benzoxazin-3-one, which may be optionally substituted with up to 3 respective substituents independently selected from; [83] b) L is halo for each ring system; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; A bicyclic aromatic heterocycle, which may be optionally substituted with up to 3 respective substituents independently selected from Het-NH-; [84] c) L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; A 6-membered partially saturated or aromatic heterocycle, which may be optionally substituted with up to 3 respective substituents independently selected from; [85] d) L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; A 6-membered aromatic heterocycle, which may be optionally substituted with up to 3 respective substituents independently selected from; [86] e) L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; A 5-membered partially saturated or aromatic heterocycle, which may be optionally substituted with up to 3 respective substituents independently selected from; [87] f) L is halo for each ring system; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; 5-membered aromatic heterocycle, which may be optionally substituted with up to 3 respective substituents independently selected from. [88] One aspect of interest of the present invention relates to compounds of formula (I) or (I ') wherein L is optionally substituted pyridyl, more particularly optionally substituted 3-pyridyl, most particularly unsubstituted 3-pyridyl will be. [89] Another aspect of interest of the invention is Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl, aminocarbonyl; Hydroxy, cyano, amino, amino substituted with piperidinyl, C 1-4 alkyl substituted amino, mono- or di (C 1-6 alkyl) amino, aminocarbonyl, mono- substituted with piperidinyl or di (C 1-6 alkyl) aminocarbonyl, C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl a C 1-6 alkyl substituted with; PolyhaloC 1-4 alkyl; Cyano; Amino; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkylcarbonyloxy; AminoS (═O 2 ) —; Mono- or di (C 1-6 alkyl) amino-S (= O 2); And to compounds of formula (I) or (I ') wherein -C (= NR x ) NR y R z . [90] Another aspect of interest of the invention is that Z is halo, in particular fluoro; C 1-6 alkyl, especially methyl; C 1-6 alkyl substituted with amino, in particular —CH 2 —NH 2 ; C 1-6 alkyl substituted with hydroxy, especially —CH (OH) CH 3 ; C 1-6 alkyl substituted with amino substituted with piperidinyl, especially 4-piperidinylaminomethyl; With regard to compounds of formula (I) or (I ') which are C 1-6 alkyl substituted with amino substituted with C 1-4 alkyl substituted with piperidinyl, in particular 1-methyl-4-piperidinylaminomethyl will be. A further aspect of interest of the present invention relates to compounds of formula (I) or (I ′), wherein Z is fluoro, methyl or —CH (OH) CH 3 . [91] Another further aspect of interest in the present invention is that Z is fluoro, methyl or CH (OH) CH 3 and L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; A compound of formula (I) or (I ') which is a bicyclic aromatic heterocycle, which may be optionally substituted with up to three respective substituents independently selected from Het-NH-. [92] Another further aspect of interest of the invention is that Q is benzthiazolyl; Pyridyl substituted with halo or C 1-6 alkyl; Phenyl or halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxycarbonyl, hydroxy, C 1-6 alkyloxy, C 1-6 alkylthio, 1-methyl-2 -Phenyl substituted with one, two or three substituents selected from imidazolyl; Z is halo; Cyano; C 1-6 alkylcarbonyl; Aminocarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl; Hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-6 alkyl) amino, piperidinyl-amino, 1-methyl-4-piperidinyl-amino, or a C 1-substituted with morpholinyl 6 alkyl; L is pyridyl; Pyridyl substituted with amino; 3-halophenyl; Imidazopyridyl; Imidazothiazolyl; Pyrimidinyl; It relates to a compound of formula (I) or (I ') which is furanyl. [93] Another further aspect of interest of the invention is that Q is phenyl, 3-trifluoromethyl-phenyl, 3-trifluoromethyl-4-fluoro-phenyl, 4-trifluoromethyl-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-methyl-phenyl, 3-hydroxy-phenyl, 4-hydroxy -Phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-dimethoxy-phenyl, 3,4, 5-trimethoxy-phenyl, 3-methylthio-phenyl, 4-methylphenyl, 2 , 3-dichloro-phenyl, 3-methyl-4-fluoro-phenyl, 3-ethyloxycarbonyl-phenyl, 4-ethyloxycarbonyl-phenyl, 6-benzothiazolyl, 6-chloro-pyridi-2 -Yl, 6-methyl-pyridin-2-yl, 5-chloro-pyridin-3-yl, 3-trifluoromethyl-4-methoxy-phenyl; Z is bromo, chloro, fluoro, acetyl, aminocarbonyl, ethyloxycarbonyl, morpholinylethyl, morpholinylmethyl, di (methyl) aminoethyl, di (methyl) aminomethyl, ethylaminomethyl, 4 -Piperidinylaminomethyl, 1-methyl-4-piperidinylaminomethyl, -CH (OH) CH 3 , aminomethyl, hydroxymethyl, methoxymethyl, cyano, methyloxycarbonyl, methyl; L is 2-amino-5-pyridyl, 3-fluoro-phenyl, 3-pyridyl, 4-pyridyl, 3-imidazopyridyl, imidazothiazol-5-yl, 5-pyrimidinyl, A compound of formula (I) or (I ') that is 5-fluoro-pyridin-3-yl, 3-furanyl. [94] Still another aspect of interest of the present invention is that Q is phenyl, 3-trifluoromethyl-phenyl, 3-trifluoromethyl-4-fluoro-phenyl, 4-trifluoromethyl- Phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 4-fluorophenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-methyl-phenyl, 4-methoxy-phenyl, 3-methyl Thio-phenyl, 4-methyl-phenyl, 2,3-dichloro-phenyl, 3-methyl-4-fluoro-phenyl, 3-ethyloxycarbonyl-phenyl, 4-ethyloxycarbonyl-phenyl, 6-benzo Thiazolyl, 2-chloropyridin-5-yl, 2-methyl-pyridi-5-yl, 5-chloro-pyrididi-3-yl; Z is fluoro, 4-piperidinylaminomethyl, 1-methyl-4-piperidinylaminomethyl, morpholinylmethyl, -CH (OH) CH 3 , aminomethyl, hydroxymethyl, methyl; L is 2-amino-5-pyridyl, 3-fluorophenyl, 3-pyridyl, 5-fluoro-pyridin-3-yl, 3-furanyl, imidazothiazol-5-yl ) Or (I '). [95] Preferred compounds of formula (I) or (I ') are compounds 1, 4 and 14 (see Table 1). [96] In general, a compound of formula (Ia) wherein Z is halo is a compound of formula (I) wherein the intermediate of formula (II) represents the halo-R (III), wherein R represents the remainder of the Can be prepared by reacting a halo-introducing reagent) with an appropriate solvent, such as N, N-dimethylformamide, optionally in the presence of a suitable base, such as 2, 6-lutidine. Suitable halo-introducing reagents are, for example, 1-chloro-pyrrolidinedione, 1-bromo-pyrrolidinedione or Selectfluor R (1 (chloromethyl) -4-fluoro-1, 4-diazoniabicyclo [2.2.2octane, bis [tetrafluoroborate (1-)]). [97] [98] Compounds of formula (Ia-1), wherein Z is fluoro, are compounds of formula (Ia-1) wherein intermediates of formula (IV), wherein W 1 represents a suitable leaving group, for example chloro, Intermediates and suitable fluoro-introducing reagents such as Selectfluor R ; And in the presence of a suitable solvent such as N, N-dimethylformamide or an alcohol such as ethanol. [99] [100] Alternatively, the compound of formula (I-a-1) may be prepared by reacting the intermediate of formula (XX) with the intermediate of formula (V) in the presence of a suitable solvent such as tetrahydrofuran. [101] [102] Z is a compound of C 1-6 alkyloxycarbonyl or C 1-6 alkylcarbonyl is a Z of the formula (I) Compounds of formula (Ib) is the intermediate of formula (V) an intermediate of formula (VI) Phenyl N, N, N-trimethylammonium trihalide, such as phenyl N, N, N-trimethylammonium tribromide, or benzyltrimethylammonium dichloroiodate, and the like, and suitable solvents such as tetrahydrofuran or alcohols, For example, it can manufacture by reacting in presence of methanol, ethanol, etc. [103] [104] A compound of formula (Ic), wherein Z is C 1-6 alkyl or cyano, is a compound of formula (I) wherein Z b is an intermediate of formula (VII), wherein W 2 is an appropriate leaving group, for example halo, Bromo) may be prepared by reacting the intermediate of formula (V) with an appropriate solvent, such as alcohol, such as ethanol. [105] [106] Compounds of formula (Ic) also contain compounds of formula (VII ') with intermediates of formula (V) and Br 2 or phenyl trimethyl ammonium tribromide and suitable solvents such as methylene chloride, tetrahydrofuran and alcohols such as It can be prepared by reacting in the presence of ethanol. [107] [108] Z C -C 1-6 alkyl wherein Z is C 1-6 alkyl substituted with amino, mono- or di (C 1-6 alkyl) amino, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl A compound of formula (Id) which is a compound of formula (I) is a compound of formula (VIII) wherein W 3 represents a suitable leaving group such as halo, eg chloro, It can be prepared by reacting the intermediate with an appropriate base such as NaHC0 3 , and a suitable solvent such as acetonitrile. [109] [110] Z is piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl carbonyl compound of the CH 2 CH 2 -Z d of the formula (I) of the formula (Ie) is a compound of the substituted intermediate of formula (XVII) Can be prepared by reacting an intermediate of formula (XVIII) with H 2 , a suitable catalyst such as Pt / C, and a suitable solvent such as alcohol such as methanol. [111] [112] Z is a compound of formula (If) Compounds of the alkyl of the formula (I) substituted with amino substituted with 4-piperidinyl is, for the general formula (XIX) (where, P is a suitable protective group, for example C 1- 6 alkyloxycarbonyl or benzyloxycarbonyl) can be prepared by deprotection in the presence of a suitable acid such as hydrochloric acid. [113] [114] The use of protecting groups is described in [Protective Groups in Organic Chemistry (JWF McOmie, Plenum Press (1973)) and [Protective Groups in Organic Synthesis'2 nd ( TW Greene & PGM Wutz, Wiley Interscience (1991)). [115] Compounds of formula (I) may be converted to one another according to functional group transformation reactions known in the art, including those described below. [116] Compounds of formula (I) can be converted to the corresponding N-oxide form according to known methods of converting trivalent nitrogen to its N-oxide form. The N-oxidation reaction mentioned can usually be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali peroxide metals or alkali peroxide metals such as sodium peroxide, potassium peroxide; Suitable organic peroxides include, but are not limited to, peroxide acids such as benzenecarboperoxoacid or halosubstituted benzenecarboperoxoic acid (e.g. 3-chlorobenzene-carboperoxoic acid), peroxoalkanoic acid (e.g. peroxoacetic acid) , Alkylhydroperoxides such as t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane and mixtures of such solvents. [117] Compounds of formula (I) in which L is substituted with amino are reacted with C 1-6 alkylcarbonyl chloride in a suitable solvent such as pyridine to formula (I) where L is substituted with C 1-6 alkylcarbonylamino. It can be converted into a compound of. [118] Compounds of formula (I) wherein Q is substituted with cyano are converted to compounds of formula (I) wherein Q is substituted by carboxyl by reacting with a suitable acid, such as concentrated hydrochloric acid, in the presence of a suitable reaction inert solvent such as water. Can be. [119] Compounds of formula (I), in which L is substituted with C 1-6 alkyl-C (= 0) -NH-, react with an appropriate acid, for example hydrobromic acid, in the presence of a suitable solvent, for example It can be converted into a compound of formula (I) substituted with. [120] Compounds of formula (I) wherein Z is cyano can be reacted in a mixture of H 2 SO 4 / H 2 0 to convert to compounds of formula (I), wherein Z is aminocarbonyl. [121] Compounds of formula (I), wherein Z is cyano, are suitable reducing agents, for example H2And suitable catalysts such as Raney Nickel, and suitable solvents such as tetrahydrofuran, NH3, Alcohols such as CH3Reacted in the presence of 0H to form a compound of formula (I) wherein Z is -CH2-NH2 Is). [122] Compounds of formula (I) wherein Z is C 1-6 alkyloxycarbonyl are compounds of formula (I) in the presence of a suitable reducing agent such as LiAlH 4 , and a suitable solvent such as tetrahydrofuran Wherein Z is -CH 2 -OH. [123] Compounds of formula (I), wherein Z is C 1-6 alkyloxycarbonyl, are suitable reducing agents such as NaBH 4 or LiAlH 4 , and suitable solvents such as tetrahydrofuran or diethyl In the presence of an ether it can be converted to a compound of formula (I) wherein Z is C 1-5 alkylyl-CHOH-. [124] Compounds of formula (I), wherein Z is C 1-6 alkyl substituted with amino, are piperidine or C 1-4 alkyl substituted piperidine and H 2 , a suitable catalyst, for example palladium on charcoal Reacted in the presence of a suitable catalyst such as a thiophene solution, and a suitable solvent such as an alcohol such as methanol, for example, a compound of formula (I) wherein Z is piperidine or C 1-4 And C 1-6 alkyl substituted with amino substituted with alkyl substituted piperidine. [125] Compounds of formula (I), wherein Z is C 1-6 alkyl substituted with amino, are formulated with paraform and H 2 , a suitable catalyst, eg palladium on charcoal, a suitable catalyst poison, eg thiophene solution And in the presence of a suitable solvent such as an alcohol such as methanol to convert into a compound of formula (I), wherein Z is C 1-6 alkyl substituted with dimethylamino. [126] In the following paragraphs several methods for producing the intermediates in the above production process are described. Many intermediates and starting materials are compounds that are commercially available or can be prepared according to conventional reaction methods commonly known in the art. [127] Intermediates of formula (II) may be prepared by reacting the intermediate of formula (IV) with the intermediate of formula (V) in the presence of a suitable solvent such as an alcohol such as ethanol. [128] [129] Intermediates of formula (II) also contain intermediates of formula (X) with intermediates of formula (V) and phenyl N, N, N trimethylammonium trihalides, such as phenyl N, N, N-trimethylammonium tribromide, or benz It can be prepared by reacting in the presence of one N, N, N-trimethylammonium dichloroiodate, and the like, and a suitable solvent, for example tetrahydrofuran. [130] [131] Intermediates of formula (IV) may be prepared by reacting L with intermediates of formula (XI), wherein W 1 is as defined above in the presence of C (= S) 2 and AlCl 3 . [132] [133] Intermediates of formula (IV-a), which are intermediates of formula (IV), wherein W 1 is bromo, may also comprise intermediates of formula (X) with N, N, N trimethylbenzeneaminium tribromide and a suitable solvent, eg For example, it may be prepared by reacting in the presence of tetrahydrofuran and an alcohol such as methanol. [134] [135] Intermediates of formula (V) may be prepared by reacting the intermediate of formula (XII) in the presence of a suitable base such as sodium hydroxide with a suitable solvent such as alcohol such as ethanol. [136] [137] Intermediates of formula (V) also contain the intermediate of formula (XIII) in the presence of benzoyl isothiocyanate and a suitable base such as sodium hydroxide and a suitable solvent such as tetrahydrofuran, or an alcohol such as ethanol. It can be prepared by reaction under. [138] [139] Intermediates of formula (XII) may be prepared by reacting the intermediate of formula (XIII) with benzoyl isothiocyanate in the presence of a suitable solvent such as tetrahydrofuran. [140] [141] Intermediates of formula (VII-a), wherein the intermediate of formula (VII), wherein Z b is C 1-6 alkyl, the intermediate of formula (X ′) is a leaving group-introducing reagent of formula (XIV), eg For example, Br 2 , wherein R ′ represents the remainder of the leaving group introducing reagent, may be prepared by reacting with a suitable acid, such as acetic acid or hydrobromic acid in water. [142] [143] Intermediates of formula (VII) of the formula The intermediates intermediates of formula (VII ') of the formula (VII-b) (wherein, Z b represents the cyano) (here, Z b represents the cyano) ( Intermediates of VII-b) can be prepared by reacting the intermediate of formula (VII'-a) with the intermediate of formula (XIV) in the presence of a suitable solvent, for example methylene chloride. [144] [145] Intermediates of formula (X ′) may be prepared by reacting L in the presence of an intermediate of formula (XV), wherein W 1 is as defined above, in the presence of AlCl 3 and a suitable solvent such as methylene chloride. . [146] [147] Intermediates of formula (VIII) are formulated as intermediates of formula (XVI), wherein W 2 and W 3 are as defined above and intermediates of formula (V) with a suitable solvent such as an alcohol such as methanol. It can be prepared by reacting in the presence. [148] [149] Intermediates of formula (XVI-a), which are intermediates of formula (XVI), wherein W 2 represents bromo, are prepared by reacting the intermediate of formula (XXI) with Br 2 in the presence of a suitable acid such as acetic acid, for example. It can manufacture. [150] [151] Intermediates of Formula (XXI), wherein W 3 represents chloro and C 1-6 alkyl represents-(CH 2 ) 2- , the intermediate of Formula (XXI-a) converts the intermediate of Formula (XXII) to HCl It can be prepared by reaction with. [152] [153] Intermediates of formula (XVII) can be prepared by reacting the intermediate of formula (I-a) with nBuLi in the presence of N, N-dimethylformamide and tetrahydrofuran. [154] [155] Intermediates of formula (XIX) are compounds of formula (Id-1) wherein intermediates of formula (Id), wherein Z represents C 1-6 alkylNH 2 , are represented by intermediates of formula (XXIII) with H 2 , It can be prepared by reacting in the presence of a suitable catalyst such as palladium on charcoal, a suitable catalyst poison such as thiophene solution, and a suitable solvent such as alcohol such as methanol. [156] [157] Compounds of the present invention exhibit cytokine production regulatory activity, in particular cytokine production inhibitory activity, more particularly proinflammatory cytokine production inhibitory activity. Cytokines are secreted polypeptides that modulate interactions between cells in an immune or inflammatory response and thus affect the actions of other cells. Examples of cytokines are interleukin-1 (IL-1) to interleukin-23 (IL-23), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor-beta (TNF-β). The compounds also exhibit inhibitory activity against the production of chemotactic cytokines or chemokines leading to trafficking and activation of leukocytes. Chemokine production inhibited by a compound of formula (I) or (I ') is MCP-1 production (monocytic chemotactic protein 1). [158] Cytokine production specifically inhibited by compounds of formula (I) or (I ') is TNF-α and / or interleukin-12 (IL-12) production. [159] TNF-α is produced mainly by monocytes, macrophages, T and B lymphocytes, neutrophils, mast cells, tumor cells, fibroblasts, keratinocytes, astrocytes, microglia, smooth muscle cells and others. This proinflammatory cytokine is settled at the apex of the proinflammatory cascade; It plays an important role in the cytokine network with respect to the pathogenesis of many infectious, inflammatory and autoimmune diseases. Excessive or unregulated TNF-α production can lead to rheumatoid arthritis, ankylosing spondylitis, spondyloarthropathies, systemic lupus erythematosus, osteoarthritis, gouty arthritis, juvenile arthritis and other arthritis symptoms, polychondritis, scleroderma, Wegener's granulomatosis, dermatitis, Stevens-Johnson syndrome, idiopathic sprue, endocrine eye disease (endocrine opthalmopathy), Graves' disease, alveolitis, chronic irritable pneumonia, primary cholangiocytosis, uveitis, dry keratoconjunctivitis and spring keratoconjunctivitis, allergic rhinitis, swelling, eosinophilic, Syndrome, eosinophilic pneumonia, parasite infection, bronchopulmonary aspergillosis, nodular polyarthritis, eosinophil granulomas, eosinophil-related diseases affecting the airway caused by half the drug, sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxin shock syndrome, brain malaria, adult respiratory distress syndrome, bronchitis (acute, arachidic acid, Tar, chronic, croup, pneumonia bronchitis), chronic obstructive airway or lung disease, pulmonary fibrosis, pneumoconiosis (aluminosis, carbonosis, asbestosis, asthma (pulmonary pulmonary disease), eyelashes missing, iron syndrome, silicosis, tobacco poisoning Ailments, tuberculosis), tuberculosis, silicon pneumonia, exacerbation of airway hyperresponsiveness to other drug treatments (such as aspirin or β-agonist therapy), ischemic sarcoidosis, bone absorption disease, meningitis, reperfusion injury, graft versus host Reaction, allograft rejection, transplant rejection, fever and myalgia due to infection, for example, influenza, cachexia (eg, bacterial, viral or parasitic infections or loss or decline of the function of body fluids or other organs, or malignant) Cancer; malaria and spring cachexia; cachexia and urinary cachexia caused by pituitary, thyroid or thymic dysfunction; secondary from cachexia secondary to acquired immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS) Consecutive complexes), diabetes, cancer, angiogenesis, lymphoma, Kawasaki disease, Beget syndrome, aphtha ulceration, skin-related diseases such as psoriasis, edema, burns, dermatitis, keloid formation, scar tissue formation, leprosy nodules, Crohn's disease, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, heartburn, asthma (endogenous, exogenous, allergic, non-atopic, exercise-induced and occupational and bacterial infection-induced asthma), whispering infant syndrome (wheezy infant syndrome), multiple sclerosis, Parkinson's disease, pancreatitis, heart disease, congestive heart failure, myocardial infarction, acute liver failure, therapies-related syndromes including glomerulonephritis, YARISHHECHES HEIMER RESPONSE and IL-2 infusion, anti-CD3 antibody injection Has been implicated in mediating or aggravating a number of diseases, including syndromes, hemodialysis, yellow fever. TNF-α has been shown to activate HIV (human immunodeficiency virus) replication in monocytes and / or macrophages. Therefore, inhibiting TNF-α production or activity helps to limit HIV progression. TNF-α can also be used for other viral infections, such as type 1 herpes simplex virus, type 2 simple herpes virus, varicella-zoster virus, Epstein-Barr virus, human herpes virus ( and the human herpes virus) -6, -7 and -8 C hepatitis, CMV (cytomegalovirus (cytomegalovirus)), influenza and herpes virus infections, and a bottle of Mad Dog false non gigwanyeom important role in containing the. [160] IL-12 is produced primarily by monocytes, macrophages and dendritic cells in response to bacteria, bacterial products (lipopolysaccharides) and immune signals. IL-12 production is regulated by other cytokines and endogenous mediators produced during inflammatory and immune responses. IL-12 plays an important role in the immune system. Evidence from animal models and human disease suggests that IL-12's ability to induce inappropriate and prolonged production of IL-12 and the production of T helper 1 cell responses can lead to chronic inflammatory diseases such as rheumatoid arthritis, collagen-induced arthritis, allergies. Motivation for causing and maintaining sexual encephalitis, colitis, inflammatory bowel disease, Crohn's disease and multiple sclerosis, and for causing autoimmune diseases such as diabetes, or graft-versus-host disease, shock or musculoskeletal and connective tissue disease Suggested that Side effects also include pulmonary edema, including anemia (hemolytic, plastic, pure red blood cells, idiopathic hypothyroidism), neutropenia, lymphopenia, hepatomegaly, including monocyte cell infiltration and interstitial cell infiltration. Excess IL-12 production may accelerate the inflammatory progression of a disease, such as, for example, rheumatoid arthritis, or the onset of the disease, or increase the severity of the disease. [161] Inhibition of TNF-α and / or IL-12 production by a compound of formula (I) or (I ′) is of interest and is potent and less non-toxic for nonspecific immunosuppression in the treatment of chronic inflammatory and autoimmune diseases. Adult alternatives (eg corticosteroids) may be provided. Co-regulation of TNF-α and IL-12 production may improve the disease to be treated more than mono-therapy. Therapeutic efficacy in parallel with the inhibition of both the immune and inflammatory parts of the disease can provide additional near miss benefits. The compounds may also be directed for use as a co-treatment medication for use with immunosuppressive and / or anti-inflammatory drugs as adjuvant of the therapeutic efficacy of the drug, thereby reducing the potential side effects of the drug by reducing the necessary dosage. Surface inhibitory and / or anti-inflammatory drugs are for example cyclopeptides, cyclopeptides or macrolides. Inhibitory or anti-inflammatory drugs such as drugs belonging to the class of cyclosporine, such as cyclosporin A or G, Tacrolimus substance, ascomycin, rapamycin, glucocorticosteroid drugs such as budesonide, beclomethasone, fluticasone, mometasone. [162] Compounds of formula (I) are useful for preventing or treating cytokine mediated diseases and for inhibiting, inhibiting or antagonizing the production or activity of proinflammatory cytokines such as TNF-α and / or IL-12. [163] TNF-α and / or IL-12 mediated diseases are cytokines themselves, or cytokines that cause another cytokine, such as IL-1 or IL-6, or certain mediators released by TNF-α. And / or any and all diseases and disorders upon which IL-12 acts. [164] Due to cytokine production inhibitory activity, in particular its proinflammatory cytokine production inhibitory activity, more particularly its TNF-α and / or IL-12 inhibitory activity, even more particularly its IL-12 inhibitory activity, The compounds of '), their N-oxides, pharmaceutically acceptable salts, quaternary amines and stereoisomeric forms are cytokine mediated diseases, in particular excessive or uncontrolled proinflammatory cytokines such as TNF-α and / or It is useful for the treatment or prevention of diseases or conditions associated with the production of IL-12, such as inflammatory diseases or autoimmune diseases. Diseases or disorders associated with excessive or uncontrolled production of proinflammatory cytokines include rheumatoid arthritis, ankylosing spondylitis, spondyloarthropathies, systemic lupus erythematosus, osteoarthritis, gouty arthritis, juvenile arthritis and other joint abnormalities, polychondritis, scleroderma , Wegener's granulomatosis, dermatitis, Stevens-Johnson syndrome, idiopathic sprue, endocrine eye disease (endocrine opthalmopathy), Graves' disease, alveolitis, chronic irritable pneumonia, primary cholangiocytosis, uveitis, dry keratoconjunctivitis and spring keratoconjunctivitis, allergic Rhinitis, pemphigus, eosinophilia, Löpler syndrome, eosinophilic pneumonia, parasitic infection, bronchopulmonary aspergillosis, nodular polyarteritis, eosinophil granulomas, eosinophil-related diseases caused by drug reactions and affecting the airways, sepsis, Septic shock, endotoxin shock, gram-negative sepsis, toxin shock syndrome, brain malaria, adultity Respiratory distress syndrome, bronchitis (acute, arachidonic acid, Qatar, chronic, croup, pulmonary pathogenic bronchitis), chronic obstructive airway or lung disease, pulmonary fibrosis, pneumoconiosis (aluminosis, carbonosis, asbestosis, asthma (pulmonary) lung (syndrome) , Exaggerated eyelashes, ironosis, silicosis, tobacco intoxication, mumps, tuberculosis, silicosis, worsening of airway hyperresponsiveness to other drug treatments (eg aspirin or β-agonist therapy), ispasarcoidosis, bone Malabsorption disease, meningitis, reperfusion injury, graft versus host reaction, allograft rejection, transplant rejection, musculoskeletal disease and connective tissue disease, fever and myalgia caused by infection, for example influenza, cachexia (e.g., bacteria, viruses or Malignant cancer due to parasitic infection or loss of function of body fluids or other organs, or malignant cancer; malaria and spring cachexia; cachexia and urinary cachexia caused by pituitary, thyroid or thymic dysfunction; acquired AIDS, ARC (AIDS-related complex), diabetes mellitus, cancer, angiogenesis, lymphoma, Kawasaki disease, Beget syndrome, aphtha ulceration, skin-related diseases, such as cachexia secondary to immunodeficiency (AIDS) For example, psoriasis, edema, burns, dermatitis, keloid formation, scar tissue formation, leprosy nodules, Crohn's disease, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, heartburn, asthma (endogenous, exogenous, allergic, non- Atopic, exercise-induced and occupational and bacterial infection-induced asthma), whisker infant syndrome, multiple sclerosis, Parkinson's disease, pancreatitis, heart disease, congestive heart failure, myocardial infarction, acute liver failure, glomerulonephritis, yarisi Therapy-Related Syndromes Including Hexheimer's Response and Syndrome Associated with IL-2 Infusion, Anti-CD3 Antibody Infusion, Hemodialysis, Yellow Fever, HIV or Other Viral Infections, eg, 1 Type simple herpes virus, type 2 simple herpes virus, varicella-zoster virus, Epstein-Barr virus, human herpes virus-6, -7 and-8 hepatitis C, CMV (cytomegalovirus (cytomegalovirus)), influenza and herpes virus infection, false Mad Dog disease and non gigwanyeom, blood follicle (angiofollicular) lymphoid hyperplasia, anemia (haemolytic, aplastic, pure red cell, idiopathic thrombocytopenia that ), Treatment of pulmonary edema, including neutrophil leukopenia, lymphocytopenia, hepatobiliary device including monocyte infiltration and stromal cell infiltrates; Or useful for the prevention of the disease. In particular, the compounds of formula (I) or (I ') can be used for the treatment of rheumatoid arthritis, Crohn's disease, irritable bowel syndrome, colitis, psoriasis or multiple sclerosis. [165] Inhibitory activity of cytokine production of a compound of formula (I) or (I ′) For example, inhibition of TNF-α and / or IL-12 production is demonstrated in an in vitro test “Inhibition of cytokine production in human whole blood cultures”. Can be. Appropriate in vivo tests include "Measurement of LPS-Lilacpolysaccharides and Serum Cytokines in Anti-CD3 Immunized Mice", "Inhibition of LPS-galactosamine-induced Shock in Mice", "Inhibition of Collagen Induced Shock in Mice" to be. [166] Compounds of formula (I) or (I ') may also inhibit interleukin-6 (IL-6). [167] The compounds can serve as intermediates for the preparation of further thiazolyl derivatives. [168] With respect to the pharmacological properties described above, the compounds of formula (I) or (I ′) or subgroups thereof, N-oxides, pharmaceutically acceptable salts, quaternary amines and stereoisomeric forms thereof can be used as medicaments. Can be. In particular, the compounds can be used for the production of medicaments for the treatment or prevention of cytokines, more particularly TNF-α and / or IL-12 mediated diseases such as inflammatory and autoimmune diseases. [169] With regard to the usefulness of the compounds of formula (I) or (I '), cytokines, more particularly humans suffering from TNF-α and / or IL-12 mediated diseases such as inflammatory and autoimmune diseases, Provided are methods for treating or preventing warm blooded animals. The method comprises administering an effective amount of a compound of formula (I) or (I '), an N-oxide form, a pharmaceutically acceptable salt, a quaternary amine or a possible stereoisomeric form to a warm blooded animal, including a human, preferably Includes oral administration. [170] The present invention relates to cytokines, more particularly TNF-α and / or IL-12 mediated diseases, for example, comprising a therapeutically effective amount of a compound of formula (I) or (I ′) and a pharmaceutically acceptable carrier or diluent Provided are compositions for preventing or treating inflammatory and autoimmune diseases. [171] The compounds of the present invention or subgroups thereof can be formulated in various pharmaceutical forms for administration purposes. As suitable compositions, all the compositions mentioned may generally be used as systemic administration medicaments. To prepare a pharmaceutical composition of the present invention, the active ingredient is mixed in an intimate mixture with an effective amount of a particular compound, any additional salt form, and a pharmaceutically acceptable carrier, the carrier depending on the form of preparation required for administration. Various forms can be taken. Such pharmaceutical compositions are particularly preferably in single dose form suitable for oral, rectal, transdermal or parenteral injection. For example, in preparing the compositions in oral dosage form, in the case of oral liquid preparations such as suspending agents, syrups, ericses, emulsions and solutions, any of the usual pharmaceutical media such as water, glycols, oils, alcohols and the like Can be used; In the case of powders, pills, capsules, tablets and the like, solid carriers such as starch, sugars, kaolin, lubricants, binders, and disintegrants can be used. Because of the ease of administration, tablets and capsules appear in the form of the most useful oral dosage units, in which case solid pharmaceutical carriers are suitably applied. For parenteral compositions, the carrier generally contains at least a high proportion of sterile water, although other ingredients, such as ingredients to aid dissolution, are included. Injectable solutions can be prepared, for example, with a carrier comprising saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In a composition suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable humectant, which are optionally mixed in small proportion with a suitable additive of any property, which is an additive that does not significantly affect the skin. Said addition may facilitate the administration to the skin and / or assist in the preparation of the desired composition. These compositions can be administered in a variety of ways, such as transdermal patches, spot-ons, ointments. The compounds of the present invention may also be administered by oral inhalation or insufflation by methods and formulations using techniques for administration of this route. As such, the compounds of the present invention may generally be administered to the lungs in the form of solutions, suspensions or dry powders, with solutions being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or sparging is suitable for the administration of the compounds of the invention. [172] To aid in solubility of the compound of formula (I), suitable components, such as cyclodextrin, may be included in the composition. Suitable cyclodextrins are α-, β-, γ-cyclodextrin or ethers and mixed ethers thereof, wherein at least one hydroxy group of the anhydroglucose unit of the cyclodextrin is C 1-6 alkyl, in particular methyl, ethyl or iso Propyl, such as randomly methylated β-CD, hydroxyC 1-6 alkyl, in particular hydroxyethyl, hydroxy-propyl or hydroxybutyl, carboxyC 1-6 alkyl, in particular carboxymethyl or carboxy-ethyl; C 1-6 alkylcarbonyl, especially acetyl). In particular the complexants and / or solubilizers are β-CD, randomly methylated β-CD, 2, 6-dimethyl-β-CD, 2-hydroxyethyl β-CD, 2-hydroxyethyl-γ-CD, 2 Notable are -hydroxypropyl-γ-CD and (2-carboxymethoxy) propyl-β-CD, and especially 2-hydroxypropyl-β-CD (2-HP-β-CD). [173] The term mixed ether refers to cyclodextrin derivatives in which at least two cyclodextrin hydroxy groups are etherified with different groups such as hydroxy-propyl and hydroxyethyl. [174] The average molecular substitution (M. S.) is used as a measure of the average number of alkoxy units per mole of anhydrous glucose. Average degree of substitution (D. S.) refers to the average number of hydroxy substituted per anhydroglucose. M. S. and D. S. values can be measured by various analytical techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values can be obtained for one given cyclodextrin derivative. Preferably, M. S. ranges from 0. 125 to 10 and D. S. ranges from 0. 125 to 3 as determined by mass spectrometry. [175] Other suitable compositions for oral or rectal administration include particles consisting of a solid dispersion comprising a compound of formula (I) or (I ') and one or more suitable pharmaceutically acceptable water soluble polymers. [176] As used herein, the term “solid dispersion” refers to the active ingredient (s) and cyclodextrin, where one component is the other component or ingredients (in addition to pharmaceutically acceptable formulations generally known in the art). A solid state (as opposed to liquid or gaseous), comprising at least two components, dispersed somewhat uniformly, for example, by including plasticizers, preservatives, and the like. If the mentioned dispersions of the above components are entirely physicochemically homogeneous or homogeneous or consist of one phase as defined in thermodynamics, such solid dispersions will be referred to as "solid solutions" below. Solid solutions are preferred physical systems because the components in them show generally easy bioavailability for the organisms to which they are administered. The advantage of this may be explained that the solid solution mentioned can easily form a liquid solution when contacted with a liquid medium such as gastrointestinal juice. The ease of dissolution may be due, at least in part, to the fact that the energy required to dissolve the component from the solid solution is less than that required to dissolve the component from the crystalline or microcrystalline solid phase. [177] The term "solid dispersion" also includes dispersions which are less homogeneous overall than solid solutions. Such dispersions are not physicochemically overall homogeneous or contain one or more phases. For example, the term “solid dispersion” may also refer to a compound of formula (I), either intangible, microcrystalline or crystalline, or to an insoluble, microcrystalline or crystalline water soluble polymer, or both water soluble polymers, or compounds of formula (I). Or to a system with domains or small portions dispersed somewhat uniformly in another phase comprising a solid solution comprising a compound of formula (I) or (I ′) and a water soluble polymer. The domains mentioned are the parts in the solid dispersion that are distinguished by some physical properties, are small in size, and are uniformly and randomly dispersed through the solid dispersion. [178] Various techniques exist for preparing solid dispersions, including melt-extrusion, spray-drying, freeze-drying and solution-evaporation, with the latter being preferred. [179] a) dissolving the compound of formula (I) and the water soluble polymer in a suitable solvent, optionally at elevated temperature: [180] b) optionally evaporate the solvent by heating the resulting solution under a) under vacuum. The solution can also be poured over a large surface to form a thin film from which the solvent can be evaporated. [181] In the spray-drying technique, the two components are also dissolved in a suitable solvent and the resulting solution is sprayed through the nozzle of the spray dryer and then the solution is evaporated from the resulting droplets at elevated temperature. [182] A preferred technique for preparing a solid dispersion is a melt-extrusion method comprising the following steps: [183] a) mixing the compound of formula (I) and a suitable water soluble polymer, [184] b) optionally admixing the mixture so obtained with the additives, [185] c) heating and blending the blend so obtained until a homogeneous melt is obtained. [186] d) forcing the so obtained melt through one or more nozzles; [187] e) Cool until the melt solidifies. [188] The terms "melt" and "melting" are to be interpreted broadly. These terms not only refer to the transformation from the solid phase to the liquid state, but also to the change to the free or rubber state, in which one component of the mixture may be included somewhat uniformly in the other component. In special cases, one component will melt and the remaining component (s) will dissolve in the melt to form a solution, which, upon cooling, can form a solid solution with advantageous dissolution properties. [189] After preparing the solid dispersion as described above, the obtained product may optionally be milled and sieving. [190] The solid dispersion product may be milled or ground to particles having a particle size of less than 600 μm, preferably less than 400 μm, most preferably less than 125 μm. [191] Particles prepared as described above may be formulated in conventional pharmaceutical form, such as tablets and capsules, by conventional techniques. [192] Those skilled in the art will appreciate the parameters of the techniques for preparing the solid dispersions described above, such as the most appropriate solvents, operating temperatures, types of equipment used, mixing and milling rates, spray-drying rates, freezing rates, sublimation rates, It will be appreciated that efficiency in melt-extrusion can be optimized. [193] The water-soluble polymer in the particles has an apparent viscosity of 1 to 5000 mPa · s, more preferably 1 to 700 mPa · s, most preferably 1 to 100 mPa · s when dissolved in an aqueous solution of 2% (w / v) at 20 ° C. It is a polymer having. For example, the water-soluble polymer may be alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, carboxyalkyl cellulose, alkali metal salt of carboxyalkyl cellulose, carboxyalkylalkyl cellulose, carboxyalkyl cellulose ester, starch, pectin, chitin derivative, Di-, oligo- and polysaccharides such as trehalose, alginic acid or alkali metal and ammonium salts thereof, carrageenan, galactomannan, tragacanth, aga-agar, arabic gum, guar gum and xanthan gum, polyacrylic acid and Salts thereof, polymethacrylic acid and salts thereof, methacrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate, combinations of polyvinyl alcohol and polyvinylpyrrolidone Water, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and ethyl And a copolymer of an oxide and propylene oxide. Preferred water-soluble polymers are hydroxypropyl methylcelluloses. [194] One or more cyclodextrins may also be used as water soluble polymers in the preparation of the above mentioned particles as described in WO 97/18839. Cyclodextrins include pharmaceutically acceptable unsubstituted and substituted cyclodextrins, more particularly α, β or γ cyclodextrins or pharmaceutically acceptable derivatives thereof, known in the art. [195] Substituted cyclodextrins that can be used to prepare the particles described above include the polyethers described in US Pat. No. 3,459,731. Further substituted cyclodextrins are those in which one or more cyclodextrin hydroxy groups have hydrogen in C 1-6 alkyl, hydroxyC 1-6 alkyl, carboxyC 1-6 alkyl, or C 1-6 alkyloxycarbonylC 1-6 Ether or substituted ethers thereof substituted with alkyl. In particular such substituted cyclodextrins have hydrogen in one or more cyclodextrin hydroxy groups, C 1-4 alkyl, hydroxyC 2-4 alkyl or carboxyC 1-2 alkyl or more particularly methyl, ethyl, hydroxyethyl, hydroxy Ether substituted with propyl, hydroxybutyl, carboxymethyl or carboxyethyl. [196] Useful ones include, for example, β-cyclodextrin ethers, such as Drugs of the Future, Vol. 9, No. 8, p577-578 by M. Nogradi (1984)], dimethyl-β-cyclodextrins and polyethers, such as hydroxypropyl β-cyclodextrin and hydroxyethyl β-cyclodextrin. Such alkyl ethers may be methyl ethers having a degree of substitution of about 0.125 to 3, for example 0.3 to 2. Such hydroxypropyl cyclodextrins can be formed, for example, from the reaction of β-cyclodextrin and propylene oxide and can have an MS value of about 0.125 to 10, such as about 0.3 to 3. [197] Another suitable form of cyclodextrin is sulfobutylcyclodextrin. [198] The ratio of the compound of formula (I) or (I ') to the water soluble polymer can be very wide. For example, it may be applied in a ratio of 1/100 to 100/1. The range of interest of compounds of formula (I) or (I ′) versus cyclodextrin is in the range of about 1/10 to 10/1. More preferred ratios range from about 1/5 to 5/1. [199] It may be easy to prepare compounds of formula (I) or (I ') in the form of nanoparticles having surface modifiers adsorbed on their surface in an amount sufficient to maintain an effective average particle size at 1000 nm. Useful surface modifiers include those that are physically adsorbed to the surface of a compound of formula (I) or (I ′) but do not chemically bind to the compound. [200] Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular oligomers, natural salt products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. [201] Another interesting method of formulating a compound of formula (I) or (I ') is to incorporate the compound of formula (I) or (I') into a hydrophilic polymer and as a coating film on a number of small beads This mixture is applied to prepare the obtained pharmaceutical composition which can be easily prepared and suitable as a pharmaceutical dosage formulation for oral administration. [202] The beads comprise a central, round or spherical core, a coating film of hydrophilic polymer and a compound of formula (I) or (I ') and optionally a seal-coating layer. [203] Suitable materials as cores in the beads vary as long as they are pharmaceutically acceptable and have the appropriate size and firmness. Examples of such materials are polymers, inorganic materials, organic materials, and saccharides and derivatives thereof. [204] Particular preference is given to formulating the above-mentioned pharmaceutical compositions in unit dose form for easy and uniform administration. As used herein, unit dosage form refers to fully discrete units suited in a single dose, each unit comprising a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. . Examples of such unit dosage forms are tablets (including multi-layered or coated tablets), capsules, pills, powder packets, suppositories, wafers, injectable solutions or suspensions, and complexes thereof. [205] The compounds of the present invention are orally active compounds and are preferably administered orally. [206] The exact dose and frequency of administration will depend in particular on the compound of formula (I) or (I ') used, in particular the condition to be treated, the severity of the condition to be treated, age, weight, sex, extent of disease, general physical condition of the particular patient as well as the individual This is by means of other ingestible medicaments, which are well known to those skilled in the art. The effective daily dose can also be reduced or increased by evaluation of the response of the subject to be treated and / or the physician's prescription of a compound of the invention. [207] Compounds of formula (I) or (I ') may also be used in other conventional anti-inflammatory or surface inhibitors such as steroids, cyclooxygenase-2 inhibitors, non-steroid-anti-inflammatory agents, TNF-α antibodies, For example, acetyl salicylic acid, bufexamark, diclofetac potassium, sulindac, diclofenac sodium, ketorolac tromethamol, tolmethine, ibuprofen, naproxen, naproxen sodium, thiapropenic acid, flurbiprop Pens, mefenamic acid, niflumic acid, meclofenamate, indomethacin, proglumetacin, ketoprofen, nabumethone, paracetamol, pyricampam, tenoxycam, nimesulide, phenylbutazone, tramadol, Beclomethasone dipropionate, betamethasone, beclomethasone, buscesonide, fluticasone, mometasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcisolone, celecoxib, ropeco B, infliximab, leflunomide, etanercept, CPH 82, methotrexate, sulfasalazine, antilymphozymic immunoglobulin, antithyroid immunoglobulin, azathioprine, cyclosporine, tacrolimus substance, ascomycin, rapamycin , Muromonab-CD3 can be used in combination. [208] Accordingly, the present invention relates to the combination of a compound of formula (I) or (I ') with another anti-inflammatory or surface inhibitor. The said combination can be used as a medicine. The present invention also provides a combination of (a) a compound of formula (I) or (I ') as a combined medicament for simultaneous, separate or sequential use in the treatment of a disease associated with excessive or unregulated cytokine production, and (b) It relates to a product comprising another anti-inflammatory or surface inhibitory compound. Different drugs can be combined in a single formulation with a pharmaceutically acceptable carrier. [209] Experiment [210] Hereinafter, "DMF" defines N, N-dimethylformamide, "DIPE" is diisopropyl ether, and "THF" defines tetrahydrofuran. [211] A. Preparation of Intermediate Compounds [212] Example A1 [213] a) intermediate 1 [214] Manufacture [215] AlCl 3 (50 g) was added in small portions to a solution of imidazo [1,2-a] pyridine (0.05 mol) in CS 2 (250 ml). The mixture was warmed to ± 40 ° C. Then chloroacetyl chloride (0.11 mol) in CS 2 (50 ml) was added dropwise and the resulting reaction mixture was stirred overnight and refluxed. The reaction mixture was cooled and then cooled on ice / ethanol-bath and decomposed by the dropwise addition of ice water. CH 3 0H (100 ml) was added dropwise and the reaction mixture was stirred for 3 hours at room temperature. The resulting precipitate was filtered off and dried (vacuum). Yield: 7.3 g of intermediate 1 (63%). [216] b) intermediate 2 [217] [218] 1- (6-amino-3-pyridinyl) ethanone hydrobromide (0.007 mol) was converted to THF, p. a. (50 ml) / CH30H, p. a. (10 ml) and the mixture was stirred at room temperature. N, N, N-trimethylbenzenealuminum tribromide (0.007 mol) was added in small portions and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was stirred in 2-propanone / 2-propanol, filtered and dried. Yield: 1.85 g of intermediate 2 (88.6%). [219] Example A2 [220] a) intermediate 3 [221] [222] Manufacture [223] A mixture of 2-bromo-1- (3-pyridinyl) ethanone hydrobromide (0.0030 mol) and [3- (trifluoromethyl) phenyl] thiourea (0.0030 mol) in ethanol (30 ml) was added for 4 hours. Stirred and refluxed, then cooled with stirring. The mixture was filtered and the filter residue was washed with ethanol followed by 2-propanone. The residue was dissolved in CH 3 0H / CH 2 Cl 2 / (H 2 0 / Na 2 CO 3 / NaOAc) and stirred for 10 minutes until almost all material was dissolved. Separate layers The aqueous phase was extracted with CH 2 Cl 2 (the remaining solid material was dissolved) (x 4). The combined organic layers were dried (MgSO 4 ), filtered and the solvent was evaporated. Yield: 0.84 g of Intermediate 3 (88%; mp: 204-206 ° C). [224] b) intermediate 4 [225] [226] Manufacture [227] 1- (3-fluorophenyl) ethanone (0.0082 mol) in THF (50 ml) was stirred at room temperature. N, N, N-trimethylbenzenealuminum tribromide (0.0082 mol) was added in small portions for 1 hour. The precipitate formed was filtered off and washed. The filtrate was stirred at room temperature. [4-fluoro-3- (trifluoromethyl) phenyl] thiourea (0.0082 mol) was added. The mixture was stirred for 18 hours. The solvent was evaporated. The residue was crystallized from CH 3 CN (25 ml). The precipitate was filtered off, washed with DIPE and dried. Yield: 1.7 g. This fraction was recrystallized from CH 3 CN (25 ml). The precipitate was filtered off, washed with DIPE and dried. Yield: 1.3 g of intermediate 4. [228] c) intermediate 5 [229] [230] Manufacture [231] A solution of Intermediate 14 (0.005 mol) (prepared according to Example A8b), [3 (trifluoromethyl) phenyl] thiourea (0.005 mol) in methanol (50 ml) was stirred for 14 hours and refluxed. The reaction mixture was cooled down. The precipitate was filtered off and dried. Yield: 1.5 g of intermediate 5. [232] Example A3 [233] a) intermediate 6 [234] [235] Manufacture [236] A solution of benzoyl isothiocyanate (0.068 mol) in THF (50 ml) was added dropwise to a solution of 4-fluoro-3-methyl-benzeneamine (0.068 mol) in THF (150 ml). The reaction mixture was stirred at rt overnight. The solvent was evaporated. The residue was suspended in DIPE, filtered, washed and dried (vacuum). Yield: Intermediate 6. [237] b) intermediate 7 [238] [239] Manufacture [240] A mixture of intermediate 6 (0.055 mol) and NaOH 1M (0.06 mol) in EtOH (500 ml) was stirred for 1 hour and refluxed. The reaction mixture was cooled down and the solvent was evaporated. The residue was suspended in H 2 0, filtered, washed and dried (vacuum). Yield: 9.8 g of intermediate 7 (97%). [241] Example A4 [242] Intermediate 8 [243] [244] Manufacture [245] THF p. a. A mixture of benzoyl isothiocyanate (0.027 mol) in (10 ml) was added to THF p. a. To a mixture of 6-benzothiazolamine (0.027 mol) in (80 ml) was added dropwise. The mixture was stirred at rt for 2 h. The solvent was evaporated. EtOH (100 ml) was added to the residue. The mixture was warmed up. NaOH 1M p. a. (0.027 mol) was added dropwise. The mixture was stirred while bringing the temperature to room temperature. The precipitate was filtered off and dried. Yield: 4 g. The filtrate was evaporated. Yield: 5 g F1. The filtrate precipitate and F1 were mixed and stirred in water. The precipitate was filtered off and dried. Yield: 5 g of intermediate 8 (88%). [246] Example A5 [247] a) intermediate 9 [248] [249] Manufacture [250] A mixture of imidazo [1,2-a] pyridine (0.42 mol) in CH 2 Cl 2 (1000 ml) was cooled to 5 ° C. (ice / EtOH). AlCl 3 (150 g) was added in small portions (the temperature was raised to 30 ° C.). A mixture of propanoyl chloride (0.84 mol) in CH 2 Cl 2 (500 ml) was added dropwise at 10 ° C. over 30 minutes. The mixture was stirred for 48 hours, refluxed and cooled. Ice / MeOH (1000 ml) was added dropwise. The mixture was stirred for 4 hours. The organic layer was separated and the solvent was evaporated. The residue was stirred in 2-propanone, filtered and dried in vacuo at 40 ° C. Yield: 64.79 g of intermediate 9 (73%). [251] b) intermediate 10 [252] [253] Manufacture [254] 48% HBr in H 2 0 (50 ml) was added to the mixture of intermediate 9 (0.095 mol) in HOAc (150 ml). The mixture was warmed to 70 ° C. Br 2 (0.095 mol) was added dropwise. The mixture was stirred at 70 ° C. for 14 hours and then cooled. The solvent was evaporated. The residue was evaporated together with EtOH / toluene. The residue was stirred in 2-propanone. The precipitate was filtered off and dried in vacuo at 40 ° C. The residue (12.682 g) was stirred in 2-propanone while refluxing. EtOH was added until the reaction mixture became homogeneous. The mixture was cooled. The precipitate was filtered off and dried at 50 ° C. in vacuo. Yield: 100% of intermediate 10. [255] Example A6 [256] Intermediate 11 [257] [258] Manufacture [259] Reaction under N 2 atmosphere. A mixture of sodium-oxo-3-pyridinepropanenitrile ion (1-) (0.005 mol) in CH 2 Cl 2 , pa was stirred at −70 ° C. Br 2 (0.005 mol) in CH 2 Cl 2, pa (10 ml) was added dropwise at −70 ° C. for 30 minutes. The mixture was allowed to warm to room temperature. The mixture was stirred at 20 ° C. overnight. CH 2 Cl 2 (100 ml) was added. The mixture was filtered and the filtrate was evaporated (at low temperature). Yield: 1 g (91%) of intermediate 11. [260] Example A7 [261] Intermediate 12 [262] [263] Manufacture [264] The compound 99 (0.0141 mol) mixture in tetrahydro (125 ml) was stirred on isopropanol / CO 2 under N 2 while cooling the bath. Tetrahydro (100 ml) was added and stirring continued until the temperature reached -78 ° C. nBuLi was added dropwise. After addition, the reaction mixture was further stirred at −78 ° C. for at least 1 hour before DMF (1 lml) was added dropwise. After addition, stirring was continued for an additional 1 hour at -78 ° C. Ayr, the reaction mixture was allowed to reach -15 ° C and 100 ml of HCI 1N + 100 ml of ice water were added dropwise. After addition, stirring was continued for 30 minutes and then extracted with 500 ml of ethyl acetate. K 2 CO 3 was added to the separated aqueous layer until the pH reached approximately 9 and the mixture was extracted again with 100 ml of ethyl acetate. The combined organic layers were dried (MgSO 4 ), filtered and evaporated. The residue was stirred in 50 ml of boiling acetonitrile / CH 2 Cl 2 3/1. The residue was filtered off, washed with acetonitrile and dried at 50 ° C. (vacuum). Yield: 3.08 g of intermediate 12. [265] Example A8 [266] a) intermediate 13 [267] [268] Manufacture [269] [270] (0.14 mol) and HCl 12 N (240 ml) were stirred and refluxed. Solvent was evaporated and the residue was dissolved in ice / CH 2 Cl 2 . The mixture was alkalized with Na 2 CO 3 . The organic layer was separated, washed with H 2 O, dried, filtered and evaporated. The residue was purified over Si0 2 (eluent: CH 2 Cl 2 / CH 3 0H). Desired fractions were evaporated. Yield: 15 g of intermediate 13. [271] b) intermediate 14 [272] [273] Br 2 (0.08 mol) was added dropwise to the mixture of intermediate 13 (15 g) and acetic acid (60 ml) and stirring continued overnight at room temperature. The solvent was evaporated and the residue was crystallized from diisopropyl ether. The precipitate was filtered off and dried. Yield: 14 g of intermediate 14. [274] Example A9 [275] Intermediate 15 [276] [277] Manufacture [278] A solution of compound 93 (0.00122 mol) and 1-t-butoxycarbonyl-4-piperidinone (0.3 g) in thiophene solution (0.1 ml) and methanol (50 ml) was added with Pd / C 10% (0.1 g). ) Was hydrogenated to H 2 (1 equiv). The catalyst was filtered off. The filtrate was evaporated and evaporated with toluene. The residue was purified on silica gel using CH 2 Cl 2 / MeOH 96/4 as eluent. The desired fractions were combined and evaporated. The solid was crystallized from 10 ml of diisopropyl ether, filtered off, washed and dried at 50 ° C. (vacuum). Yield: 0.276 g of intermediate 15. [279] B. Preparation of Final Compound [280] Example B 1 [281] a) compound 1 [282] [283] Manufacture [284] Intermediate 3 (0.016 mol) was dissolved in DMF (40 ml), cooled to 5 ° C. and then 1- (chloromethyl) -4-fluoro-1, 4-diazoniabicyclo [2.2. 2] Octane bis [tetrafluoroborate (1 − )] (= Selectfluor R ) (0.017 mol) was added in 1 minute. The reaction mixture was stirred and slowly warmed to room temperature and stirred for an additional 24 hours. NH 3 / MeOH-solution and H 2 O were added with rapid stirring and cooling and the mixture was stirred for 6 hours. The mixture was poured into H 2 0 (100 ml), filtered and washed with H 2 0. The residue was flash column chromatography on silica gel (eluent: THF / hexane 20/80). The product fractions were recovered and the solvent was evaporated. The residue was dried (24 h vacuum at 20 ° C.). Yield: 2.19 g of compound 1 (40%; mp 208-210 ° C). [285] b) compound 2 [286] [287] Manufacture [288] Intermediate 3 (0.0026 mol) was dissolved in DMF (10 ml) and then cooled to 0 ° C. 1-chloro-2, 5-pyrrolidinedione (0.0026 mol) was added in one shot. The reaction mixture was stirred for 2 hours and allowed to warm to room temperature. The solvent was evaporated. The residue was triturated under water + Na 2 CO 3 (solution), filtered, washed with water, CH 3 CN and dissolved in ethanol (150 ml). The solution was filtered and the filtrate was acidified with HCl / 2-propanol (pH = 1). The solvent was evaporated. Yield: 0.30 g of compound 2 (29%). [289] To prepare 5-bromo derivatives, such as compound 99, 1-bromo-2, 5-pyrrolidinedione can be used. [290] c) compound 3 [291] [292] Manufacture [293] In DMF (50ml) [294] [295] (0.03 mol, crude residue comprising Br) (prepared according to A2a) was stirred until dissolved. Selectfluor R (0.003 mol) was added in small portions and the mixture was stirred overnight at room temperature. The solvent was evaporated and coevaporated with toluene. The residue was stirred in toluene. The precipitate was filtered off and dried. Yield: 1.2 g. The filtrate was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / MeOH 98/2; 90/10). The desired fractions were recovered and the solvent was evaporated. The residue was recrystallized from CH 3 CN. The precipitate was filtered off and dried. Yield: 0.34 g. This fraction was dried overnight (80-90 ° C .; vacuum). Yield: 0.3 g of compound 3. [296] Example B2 [297] a) compound 5 [298] [299] Manufacture [300] 1- (3-pyridinyl) -1, 3-butanedione (0.01 mol) in THF (200 ml) was stirred. N, N, N-trimethylbenzenealuminum tribromide (0.01 mol) was added in small portions at 20 ° C. The mixture was stirred for 45 minutes. EtOH (100 ml) was added and the mixture was stirred for 15 minutes. [3- (trifluoromethyl) phenyl] thiourea (0.01 mol) was added. The mixture was stirred at 20 ° C. overnight; Stir and reflux. The mixture was stirred for 1 hour. The precipitate was filtered off and dried. Yield: 0.6 g. The filtrate solvent was evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried. Yield: 1. 5 g of compound 5 (34%). [301] b) compound 6 [302] [303] Manufacture [304] A mixture of 2-bromo-1- (3-pyridinyl) -1-propaneone hydrobromide (0.005 mol) and [3- (trifluoro) phenyl] thiourea (0.005 mol) in EtOH (50 ml) was added for 8 hours. Stirred and refluxed. The reaction mixture was cooled down, filtered, washed with EtOH and 2-propanone and dried (60 ° C. vacuum, 16 h). Yield: 1.52 g of compound 6 (73%). [305] c) compound 7 [306] [307] Manufacture [308] Intermediate 11 (0.007 mol) and (4-fluorophenyl) thiourea (0.008 mol) mixture in ethanol (150 ml) was stirred for 4 hours, refluxed and stirred at 20 ° C. overnight. The precipitate was filtered off, washed with 2-propanol and dried. Yield: 0.8 g of compound 7 (30%). [309] d-1) Compound 8 [310] [311] Manufacture [312] It was stirred at sodium β-oxo-3-pyridinepropanenitrile ion (1 − ) (0.029 mol) in CH 2 Cl 2 , pa (100 ml) at −60 ° C. Br 2 (0.029 mol) solution in CH 2 Cl 2 , pa (20 ml) was added in small portions at −60 ° C. and the reaction mixture was allowed to warm to room temperature. (4-fluorophenyl) thiourea (0.029 mol) in CH 2 Cl 2 , pa (50 ml) was added. Ethanol (100 ml) was added and the reaction mixture was stirred overnight. The solvent was evaporated. The residue was stirred in 2-propanol, filtered, stirred in NH 4 0H, filtered and dried. Yield: 4.2 g of compound 8. [313] d-2) Compound 96 [314] [315] To a stirred mixture of sodium P-oxo-3-pyridinepropanenitrile ion (1 − ) (0.088 mol) and tetrahydrofuran (250 ml) under N 2 atmosphere was added small amounts of phenyl trimethyl ammonium tribromide ((0.088 mol)). After addition, the reaction mixture was further stirred for 3 h at room temperature (4-fluoro-3-trifluoromethyl-phenyl) thiourea (0.084 mol) was added followed by ethanol (100 ml). The reaction mixture was further stirred for 3 h at rt, refluxed for 3 h and further stirred for 16 h at rt Tetrahydrofuran (150 ml) was added and stirring continued for 1 h. The residue was washed with tetrahydrofuran The residue was stirred with boiling acetonitrile (75 ml) / H 2 0 (100 ml) / saturated aqueous NaHC0 3 solution (50 ml) for 30 minutes The mixture was filtered at 35 ° C. And the residue was washed with acetonitrile-H 2 0 (1/2). Washed with H 2 0, ethanol and diisopropyl ether The residue was dried (vacuum) at 60 ° C. Yield: 11,74 g of compound 96. [316] Example B3 [317] Compound 9 [318] [319] Manufacture [320] In CH 3 CN (25ml) [321] [322] (Intermediate 5; prepared according to A2.c) (0.025 mol), N-methylmethanamine hydrochloride (0.003 mol) and NaHCO 3 (0.01 mol) mixture were stirred overnight at 50 ° C. Additional N-methylmethanamine hydrochloride (0.012 mol) and NaHC0 3 (0.0125 mol) were added and the mixture was stirred at 70 ° C. for 48 hours (in a pressure tube). The mixture was cooled. The solvent was evaporated. The residue was dissolved in CH 2 Cl 2 and washed with H 2 O. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / MeOH 98/2). The desired fractions were recovered and the solvent was evaporated. The residue was triturated under diPE. The precipitate was filtered off and dried. Yield: 0.1 g of compound 9. [323] Example B4 [324] Compound 10 [325] [326] Manufacture [327] H 2 SO 4 / H 2 0 90/10 (50 ml) was stirred in the reaction flask. Compound 84 (prepared according to B2.c) (0.0082 mol) was then added in small portions at 20 ° C. The reaction mixture was heated to 70 ° C. and then stirred at 20 ° C. overnight. The mixture was reheated and stirred at 70 ° C. for 1 hour and 20 ° C. for 3 hours. The mixture was poured on ice and the mixture was alkalized with NH 4 OH (dark) and left overnight. The precipitate was filtered off, washed with H 2 O and dried. The residue was crystallized with DMF / methanol, filtered and dried. Yield: 1.5 g of compound 10. [328] Example B5 [329] Compound 11 [330] [331] Manufacture [332] A mixture of compound 8 (prepared according to B2.d) (0.014 mol) in NH 3 / CH 3 0H (150 ml) and THF (50 ml) was hydrogenated at 14 ° C. with Raney Nickel (catalyst amount). After uptake of H 2 (2 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in 2-propanol, filtered and dried. Yield: 2.8 g. A portion (0.5 g) of this fraction was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 0H 97/3). The product fractions were recovered and the solvent was evaporated. The residue was dried. Yield: 0.4 g of compound 11. [333] Example B6 [334] Compound 13 [335] [336] Manufacture [337] LiAlH 4 (0.007 mol) was suspended in THF (100 ml) and stirred at room temperature. Compound 12 (prepared according to B2.a) (0.0034 mol) was added and the mixture was stirred for 2 hours at room temperature. H 2 0 (5 ml) was added dropwise. NaOH (1N; 10 ml) was added dropwise. H 2 0 (50 ml) was added dropwise. The mixture was filtered over decalite. The solvent was evaporated. The residue was dissolved in CH 2 Cl 2 and H 2 O. The separated layer was washed with H 2 O, dried and filtered. The solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / MeOH 99/1). The desired fractions were recovered and the solvent was evaporated. The residue was triturated. The precipitate was filtered off and dried. Yield: 0.1 g of compound 13. [338] Example B7 [339] Compound 14 [340] [341] Manufacture [342] NaBH 4 (0.015 mol) was added slowly to a mixture of compound 5 (prepared according to B2.a) (0.0034 mol) in methanol (100 ml) at 20 ° C. for 30 minutes. The mixture was stirred overnight. Additional NaBH 4 (0.5 g) was added dropwise at 20 ° C. Again the mixture was stirred at 20 ° C. overnight. The reaction mixture was filtered, washed with water and dried. Yield: 1.6 g of compound 15. [343] Example B8 [344] a) compound 89 [345] [346] Manufacture [347] Compound 93 (0.2 g; 0.0005 mol), 1-methyl-4-piperidinone (O. lg), Pd / C 10% (O.1 g), thiophene solution (0.1 ml) and methanol (50 ml) The mixture was stirred for 7 days at room temperature under H 2 (0.0005 mol). 1-methyl-4-piperidinone was added several times. The catalyst was filtered off and the residue was filtered over silica gel (eluent: CH 2 Cl 2 / CH 3 0H / CH 3 0H-NH 3 95/5/0 to 90/10/0 to 90/5/0). The desired fractions were recovered and the solvent was evaporated. The residue was purified by column chromatography (eluent: CH 2 Cl 2 / CH 3 0H-NH 3 95/5). The desired fractions were recovered and the solvent was evaporated and the residue dried. Yield: 0.044 g of compound 89. [348] b) Compound 90 and Compound 91 [349] [350] [351] Manufacture [352] A mixture of compound 93 (0.5 g; 0.00135 mol), paraform (0.85 g), Pd / C 10% (0.9 g), thiophene solution (1 ml) and methanol (50 ml) was added at room temperature to H 2 (0.0027). mol). After 24 hours the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (eluent: CH 2 Cl 2 / CH 3 0H-NH 3 : 98/2 to 95/5). Two fractions (F1, F2) were recovered. The solvent of F1 was evaporated and the residue was stirred in diisopropyl ether, filtered and dried. Yield: 0.069 g of compound 90. The solvent of F2 was evaporated and the residue was stirred in diisopropyl ether, filtered and dried. Yield: 0.023 g of compound 91. [353] Example B9 [354] Compound 100 and Compound 101 [355] [356] [357] Manufacture [358] A mixture of intermediate 12 (0.000 8 mol) and morpholine (0.006 mol) in methanol (50 ml) was hydrogenated using Pt / C 5% as catalyst for 4 days at room temperature. After H 2 (1 equiv) uptake, the catalyst was filtered off and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / MeOH 95/5) to give two fractions. Two fractions were recovered and the solvent was evaporated to give residues I and II. Residue I was stirred in diisopropyl ether. The precipitate was filtered off and dried. Yield 0.079 g of compound 100. Residue II was dried. Yield: 0.056 g of compound 101. [359] Example B 10 [360] Compound 88 [361] [362] Manufacture [363] To a stirred solution of intermediate 15 (0.0005 mol) in isopropanol (10 ml) was added HCl 6 N in isopropanol (2 ml). The reaction mixture was stirred at 100 ° C. for 3 1/2 hours and cooled to room temperature. The solvent was evaporated. The residue was stirred in 10 ml of saturated NaHC0 3 aqueous solution + 5 ml of H 2 0 for 1 hour. The precipitate was filtered off, washed with H 2 O and dried at 50 ° C. Yield: 0.170 g of compound 88. [364] Table 1 lists the compounds of formula (I) prepared according to one of the above examples (Example No.). [365] Table 1 : [366] [367] Table 2 lists the experimental (experimental) and theoretical (theoretical) elemental analysis values for carbon (C), hydrogen (H), and nitrogen (N) for the compounds prepared in the experimental section. [368] TABLE 2 [369] [370] NMR Spectrum Decoding for Compounds 46 and 100 [371] Compound 46: [372] [373] Compound 100: [374] [375] C. Pharmacological Examples [376] Example C. 1: Inhibition of TNF-α Production in Human Blood in Vitro [377] Human whole blood stimulation [378] Peripheral blood was drawn from a healthy male donor into a heparinized (12. 5 U heparin / ml) syringe. Blood samples were diluted three-fold in RMPI 1640 medium (Life Technologies, Belgium) supplemented with 2 mM L-glutamine, 100 U / ml penicillin and 100 g / ml spreptomycin and 300 μl fractions were collected in 24-well multi-disc plates ( Nunc, Roskilde, Denmark). Before stimulating the blood sample by adding 100 μl lipopolysaccharide at a final concentration of 100 ng / ml, either 100 μl of drug solvent (dimethyl sulfoxide in RPMI 1640 at final concentration of 0.02%) or an appropriate dose of 100 μl First incubated with 6% CO 2 atmosphere moistened with test compound (at 37 ° C. for 60 minutes). After 6 hours, the cell-free supernatant solution was collected by centrifugation and stored at −20 ° C. until the presence of TNF-α was tested. [379] Example C. 2: Inhibition of IL-12p40 Production in Human Blood in Vitro [380] Human whole blood stimulation [381] Peripheral blood was drawn from a healthy male donor into a heparinized (12. 5 U heparin / ml) syringe. Blood samples were diluted three-fold in RMPI 1640 medium (Life Technologies, Belgium) supplemented with 2 mM L-glutamine, 100 U / ml penicillin and 100 g / ml spreptomycin and 300 μl fractions were collected in 24-well multi-disc plates ( Nunc, Roskilde, Denmark). Before stimulating the blood sample by adding 100 μl lipopolysaccharide at a final concentration of 100 ng / ml, either 100 μl of drug solvent (dimethyl sulfoxide in RPMI 1640 at final concentration of 0.02%) or an appropriate dose of 100 μl The incubation with the test compound was first incubated in a humidified 6% CO 2 atmosphere (37 ° C. for 60 minutes). After 24 hours, the cell-free supernatant solution was collected by centrifugation and stored at −20 ° C. until the presence or absence of IL-12p40 was tested. [382] Example C. 3: Cytokine Measurement [383] Cytokine protein concentrations were measured by Sandwich ELISA as described in Van Wauwe et al. (1996, Inflamm Res, 45, 357-363). Murine monoclonals used as capture antibodies against human cytokines from R & D Systems (Abingdon, United Kingdom) were obtained and encoded with MAB210 and MAB61 for TNF-α and IL-12 P40, respectively. Biotinylated goat polyclonal antibodies used to detect human cytokines were obtained from R & D Systems (BAF210, BAF219). Cytokine levels were calculated from standard curves using recombinant cytokines supplied by R & D Systems. [384] Table 3 lists the percent inhibition of TNF-α and IL-12 production at test doses 10-6 , 1 × 10 −7 or 1 × 10 −8 for the compounds of the present invention. [385] TABLE 3 [386]
权利要求:
Claims (16) [1" claim-type="Currently amended] Compounds of formula (I ') for the manufacture of a medicament for the prevention or treatment of inflammatory and / or autoimmune diseases mediated through TNF-α (tumor necrosis factor-alpha) and / or IL-12 (interleukin 12) , The use of N-oxides, pharmaceutically acceptable salts, quaternary amines and stereochemically isomeric forms thereof: Where Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; Aminocarbonyl; Hydroxy, carboxyl, cyano, amino, amino substituted with piperidinyl, amino, mono- or di (C 1-6 alkyl) amino, aminocarbonyl substituted with C 1-4 alkyl substituted with piperidinyl , Mono- or di (C 1-6 alkyl) aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl C 1-6 alkyl; PolyhaloC 1-4 alkyl; Cyano; Amino; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Amino-S (= 0) 2 —; Mono- or di (Ci_ 6 alkyl) amino-S (= 0) 2 ; Or -C (= NR x ) NR y R z ; R x is hydrogen, C 1-6 alkyl, cyano, nitro or —S (═O) 2 —NH 2 ; R y is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; R Z is hydrogen or C 1-6 alkyl; Q is C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl, wherein Each ring system is halo; hydroxy; cyano; carboxyl; azido; amino; mono- or di (C 1-6 alkyl) amino; C 1-6 alkylcarbonylamino; C 1-6 alkyl; C 2- 6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl, hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-4 alkyl) substituted C 1-6 alkyl amino C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; arylC 1-6 alkyloxy; aryloxy; polyhaloC 1-6 Alkyl; polyhaloC 1-6 alkyloxy; polyhaloC 1-6 alkylcarbonyl; Het; C 1-4 alkyl-S (= 0) n -or R 1 HN-S (= 0) n- Optionally substituted with up to 3 substituents independently selected from: Q is a radical of the formula: Wherein X and Y are each independently O, NR 3 , CH 2 or S, wherein R 3 is hydrogen or C 1-4 alkyl; q is an integer from 1 to 4; Z is O or NR 4, wherein R 4 is hydrogen or C 1-4 alkyl; r is an integer from 1 to 3; n is an integer of 1 or 2; R 1 is hydrogen or a radical of formula (a-1) Indicates (Wherein A is a divalent radical of formula -CR 2a = -N- with O, S or CR 2a bonded to N of formula (a-1), where R 2a is hydrogen, C 1-6 Alkyl or C 1-6 alkyloxy))); L is halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; -C (= NR x ) NR y R z is phenyl substituted with up to 4 respective substituents independently selected from; L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; Monocyclic 5 or 6-membered partially saturated or aromatic heterocycle or bicy, which may be optionally substituted with up to 3 respective substituents independently selected from -C (= NR x ) NR y R z A partially saturated or aromatic heterocycle of the click; Het is that each ring system is halo; Hydroxy; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Or monocyclic 5 or 6-membered, which may be optionally substituted with up to 3 respective substituents independently selected from mono- or di (C 1-4 alkyl) amino-C (═O) —NH— Partially saturated or aromatic heterocycle or bicyclic partially saturated or aromatic heterocycle; Aryl is halo, hydroxy, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, cyano, nitro, amino, mono- or di (C 1 Phenyl optionally substituted with up to 5 substituents each independently selected from -6 alkyl) amino. [2" claim-type="Currently amended] The compound of claim 1, wherein Q is C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazo Pyridyl, wherein each ring system is halo; hydroxy; cyano; carboxyl; azido; amino; mono- or di (C 1-6 alkyl) amino; C 1-6 alkylcarbonylamino; C 1- 6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl; hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-4 alkyl) amino C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; arylC 1-6 alkyloxy; aryloxy; poly HaloC 1-6 alkyl; polyhaloC 1-6 alkyloxy; polyhaloC 1-6 alkylcarbonyl; C 1-4 alkyl-S (═O) n -or R 1 HN-S (= O) is optionally substituted with up to 3 substituents each independently selected from n- ; Q is a radical of the formula: Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; Aminocarbonyl; Hydroxy, carboxyl, amino, cyano, mono- or di (C 1-6 alkyl) amino, aminocarbonyl, mono- or di (C 1-6 alkyl) aminocarbonyl, C 1-6 alkyloxy carbonyl , C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl a C 1-6 alkyl substituted with; PolyhaloC 1-4 alkyl; Cyano; Amino; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyloxycarbonyl, C 1-6 alkyloxycarbonyloxy; AminoS (═O 2 ) —; Mono- or di (C 1-6 alkyl) amino-S (= O 2); -C (= NR x ) NR y R z The use of a compound. [3" claim-type="Currently amended] 3. The compound of claim 1 or 2, wherein L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; Or monocyclic 5 or 6-membered partially saturated or aromatic heterocycle or bi, which may be optionally substituted with up to 3 respective substituents independently selected from -C (= NR x ) NR y R z Use of a compound that is a cyclic partially saturated or aromatic heterocycle. [4" claim-type="Currently amended] The compound of claim 1, wherein Z is halo; C 1-6 alkyl; C 1-6 alkyl substituted with amino; C 1-6 alkyl substituted with hydroxy; 4-piperidinylaminomethyl; Use of a compound that is 1-methyl-4-piperidinylaminomethyl. [5" claim-type="Currently amended] Compounds of formula (I), N-oxides, pharmaceutically acceptable salts, quaternary amines and stereochemically isomeric forms thereof: Where Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; Aminocarbonyl; Hydroxy, carboxyl, cyano, amino, amino substituted with piperidinyl, amino, mono- or di (C 1-6 alkyl) amino, aminocarbonyl substituted with C 1-4 alkyl substituted with piperidinyl , Mono- or di (C 1-6 alkyl) aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl C 1-6 alkyl; PolyhaloC 1-4 alkyl; Cyano; Amino; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Amino-S (= 0) 2 —; Mono- or di (Ci_ 6 alkyl) amino-S (= 0) 2 ; Or -C (= NR x ) NR y R z ; R x is hydrogen, C 1-6 alkyl, cyano, nitro or —S (═O) 2 —NH 2 ; R y is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; R Z is hydrogen or C 1-6 alkyl; Q is C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl, wherein Each ring system is halo; hydroxy; cyano; carboxyl; azido; amino; mono- or di (C 1-6 alkyl) amino; C 1-6 alkylcarbonylamino; C 1-6 alkyl; C 2- 6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl, hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-4 alkyl) substituted C 1-6 alkyl amino C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; arylC 1-6 alkyloxy; aryloxy; polyhaloC 1-6 Alkyl; polyhaloC 1-6 alkyloxy; polyhaloC 1-6 alkylcarbonyl; Het; C 1-4 alkyl-S (= 0) n -or R 1 HN-S (= 0) n- Optionally substituted with up to 3 substituents independently selected from: Q is a radical of the formula: Wherein X and Y are each independently O, NR 3 , CH 2 or S, wherein R 3 is hydrogen or C 1-4 alkyl; q is an integer from 1 to 4; Z is O or NR 4, wherein R 4 is hydrogen or C 1-4 alkyl; r is an integer from 1 to 3; n is an integer of 1 or 2; R 1 is hydrogen or a radical of formula (a-1) Indicates (Wherein A is a divalent radical of formula -CR 2a = -N- with O, S or CR 2a bonded to N of formula (a-1), where R 2a is hydrogen, C 1-6 Alkyl or C 1-6 alkyloxy))); L is halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; -C (= NR x ) NR y R z is phenyl substituted with up to 4 respective substituents independently selected from; L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; Monocyclic 5 or 6-membered partially saturated or aromatic heterocycle or bicy, which may be optionally substituted with up to 3 respective substituents independently selected from -C (= NR x ) NR y R z A partially saturated or aromatic heterocycle of the click; Het is that each ring system is halo; Hydroxy; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Or monocyclic 5 or 6-membered, which may be optionally substituted with up to 3 respective substituents independently selected from mono- or di (C 1-4 alkyl) amino-C (═O) —NH— Partially saturated or aromatic heterocycle or bicyclic partially saturated or aromatic heterocycle; Aryl is halo, hydroxy, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, cyano, nitro, amino, mono- or di (C 1 Phenyl optionally substituted with up to 5 substituents each independently selected from -6 alkyl) amino; Provided that the compound is 1, 2-dihydro-5- [2- [(4-methoxyphenyl) amino] 5-methyl-4-thiazolyl] -6-methyl-2-oxo-3-pyridinecarbonitrile. With the proviso that when the bicyclic aromatic heterocycle in the L definition represents imidazopyridyl, the imidazopyridyl is unsubstituted. [6" claim-type="Currently amended] The compound of claim 5, wherein Q is C 3-6 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazo Pyridyl, wherein each ring system is halo; hydroxy; cyano; carboxyl; azido; amino; mono- or di (C 1-6 alkyl) amino; C 1-6 alkylcarbonylamino; C 1- 6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl; hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-4 alkyl) amino C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; arylC 1-6 alkyloxy; aryloxy; poly HaloC 1-6 alkyl; polyhaloC 1-6 alkyloxy; polyhaloC 1-6 alkylcarbonyl; C 1-4 alkyl-S (═O) n -or R 1 HN-S (= O) is optionally substituted with up to 3 substituents each independently selected from n- ; Q is a radical of the formula: Z is halo; C 1-6 alkyl; C 1-6 alkylcarbonyl; Aminocarbonyl; Hydroxy, carboxyl, amino, cyano, mono- or di (C 1-6 alkyl) amino, aminocarbonyl, mono- or di (C 1-6 alkyl) aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxy, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl a C 1-6 alkyl substituted with; PolyhaloC 1-4 alkyl; Cyano; Amino; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyloxycarbonyl, C 1-6 alkyloxycarbonyloxy; AminoS (═O 2 ) —; Mono- or di (C 1-6 alkyl) amino-S (= O 2); -C (= NR x ) NR y R z . [7" claim-type="Currently amended] 6. The compound of claim 5, wherein L is each ring system halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; Or monocyclic 5 or 6-membered partially saturated or aromatic heterocycle or bi, which may be optionally substituted with up to 3 respective substituents independently selected from -C (= NR x ) NR y R z Compounds that are cyclic partially saturated or aromatic heterocycles. [8" claim-type="Currently amended] 8. The compound of any one of claims 5 to 7, wherein L is each ring system is halo; Hydroxy; Mercapto; Amino; Cyano; Carboxyl; Mono- or di (Ci_ 6 alkyl) amino; C 1-6 alkyl; Hydroxy, C 1-4 alkyloxy, amino or mono- or di (C 1-6 alkyl) C 1-6 alkyl substituted with amino; PolyhaloC 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; Aminocarbonyl; Mono- or di (Ci_ 6 alkyl) aminocarbonyl; C 1-6 alkyl-C (═O) —NH—; C 1-6 alkyloxy-C (═O) —NH—; H 2 NC (= 0) -NH-; Mono- or di (C 1-4 alkyl) amino-C (═O) -NH—; Het-NH-; Or partly of 6-membered partially saturated or aromatic heterocycle or bicyclic, which may be optionally substituted with up to 3 respective substituents independently selected from -C (= NR x ) NR y R z Compounds that are saturated or aromatic heterocycles. [9" claim-type="Currently amended] 6. The compound of claim 5, wherein Q is benzthiazolyl; Pyridyl substituted with halo or C 1-6 alkyl; Phenyl or halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxycarbonyl, hydroxy, C 1-6 alkyloxy, C 1-6 alkylthio, 1-methyl-2 -Phenyl substituted with one, two or three substituents selected from imidazolyl; Z is halo; Cyano; C 1-6 alkylcarbonyl; Aminocarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl; Hydroxy, C 1-6 alkyloxy, amino, mono- or di (C 1-6 alkyl) amino, piperidinyl-amino, 1-methyl-4-piperidinyl-amino, or a C 1-substituted with morpholinyl 6 alkyl; L is pyridyl; Pyridyl substituted with amino; 3-halophenyl; Imidazopyridyl; Imidazothiazolyl; Pyrimidinyl; A compound that is furanyl. [10" claim-type="Currently amended] 10. The compound of any one of claims 5, 7-9, wherein Z is halo; C 1-6 alkyl; C 1-6 alkyl substituted with amino; C 1-6 alkyl substituted with hydroxy; 4-piperidinylaminomethyl; 1-methyl-4-piperidinylaminomethyl. [11" claim-type="Currently amended] The compound of any one of claims 5-10, wherein L is 3-pyridyl. [12" claim-type="Currently amended] The compound according to any one of claims 5 to 10 for use as a medicament. [13" claim-type="Currently amended] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 5 to 10 as an active ingredient. [14" claim-type="Currently amended] A method for preparing a pharmaceutical composition according to claim 13, characterized in that the pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound according to claim 5. [15" claim-type="Currently amended] a) the intermediate of formula (II) is reacted with a halo-introducing reagent of formula halo-R (III) in the presence of a suitable solvent, optionally in the presence of a suitable base: b) the intermediate of formula (IV) with the intermediate of formula (V) and the presence of a suitable fluoro-introducing reagent; And in the presence of a suitable solvent; c) reacting the intermediate of formula (XX) with the intermediate of formula (V) in the presence of a suitable solvent; d) reacting the intermediate of formula (VI) with the intermediate of formula (V) in the presence of a suitable halo-introducing reagent and a suitable solvent; e) reacting the intermediate of formula (VII) with the intermediate of formula (V) in the presence of a suitable solvent; f) reacting the compound of formula (VII ') with the intermediate of formula (V) in the presence of Br 2 and a suitable solvent; g) reacting the intermediate of formula (VIII) with the intermediate of formula (IX) in the presence of a suitable base and a suitable solvent; h) reacting the intermediate of formula (XVII) with the intermediate of formula (XVIII) in the presence of H 2 , a suitable catalyst, and a suitable solvent; i) deprotecting the intermediate of formula (XIX) in the presence of a suitable acid; If desired, the compounds of formula (I) are converted to one another according to known transformation reactions, and if desired, the compounds of formula (I) are treated with acids to convert to therapeutically active non-toxic acid addition salts. Or by treating with a base to convert to a therapeutically active non-toxic base addition salt, or, conversely, treating an acid addition salt form with alkali to convert to a free base, or treating a base addition salt with an acid to free acid. To switch; A process for preparing a compound according to claim 5, characterized in that if desired, the stereochemically isomeric form, quaternary amine or N-oxide form is prepared: a) b) c) d) e) f) g) h) i) Where L and Q are as defined in claim 5; R represents the remainder of the halo-introducing reagent; W 1 represents an appropriate leaving group; Z a represents C 1-6 alkyloxycarbonyl or C 1-6 alkylcarbonyl; Z b represents C 1-6 alkyl or cyano; W 2 represents an appropriate leaving group; Z is C -C 1-6 alkyl, amino, mono- or di (C 1-6 alkyl) amino, piperidinyl, piperazinyl, morpholinyl, represents a C 1-6 alkyl substituted with thiomorpholinyl ; W 3 represents an appropriate leaving group; Z d represents piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; P represents an appropriate protecting group. [16" claim-type="Currently amended] A product comprising a combination of (a) a compound as defined in claim 5 and (b) another anti-inflammatory or immunosuppressive compound, for use in the treatment of an inflammatory or autoimmune disease simultaneously, separately or sequentially.
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同族专利:
公开号 | 公开日 US20040254191A1|2004-12-16| PL368130A1|2005-03-21| WO2003015773A2|2003-02-27| NZ530950A|2006-03-31| NO20040632L|2004-03-11| IL160329A|2010-05-31| HU0401748A2|2004-12-28| IL160329D0|2004-07-25| AU2002324045C1|2008-05-29| ZA200401162B|2005-07-27| JP4388805B2|2009-12-24| BR0211887A|2004-09-21| WO2003015773A3|2003-12-18| HK1069997A1|2010-02-05| EA200400306A1|2004-08-26| CN1541097A|2004-10-27| CN100496493C|2009-06-10| UA82176C2|2008-03-25| HRP20040097B1|2013-10-11| HU0401748A3|2011-03-28| CA2451980C|2012-12-11| ES2407807T3|2013-06-14| EP1418909B1|2013-02-20| CA2451980A1|2003-02-27| MXPA04001399A|2004-05-27| US20070203189A1|2007-08-30| EA007717B1|2006-12-29| US7232838B2|2007-06-19| US7803823B2|2010-09-28| AU2002324045B2|2007-10-04| KR20100076043A|2010-07-05| EP1418909A2|2004-05-19| KR101034489B1|2011-05-17| KR100979988B1|2010-09-03| NO327409B1|2009-06-22| HRP20040097A2|2004-06-30| JP2005501099A|2005-01-13|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
2001-08-13|Priority to EP01203087.0 2001-08-13|Priority to EP01203087 2002-08-09|Application filed by 얀센 파마슈티카 엔.브이. 2002-08-09|Priority to PCT/EP2002/008955 2004-04-13|Publication of KR20040031712A 2010-09-03|Application granted 2010-09-03|Publication of KR100979988B1
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申请号 | 申请日 | 专利标题 EP01203087.0|2001-08-13| EP01203087|2001-08-13| PCT/EP2002/008955|WO2003015773A2|2001-08-13|2002-08-09|2-amino-4,5-trisubstituted thiazolyl derivatives and their use against autoimmune diseases| 相关专利
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