TW200837061A - Triazoles useful in the treatment of inflammation - Google Patents

Abstract

There is provided compounds of formula I, wherein W is an optionally substituted aryl or heteroaryl group, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a lipoxygenase (e.g. 15-lipoxygenase) is desired and/or required, and particularly in the treatment of inflammation.

Description

200837061 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel vw cuts. Compounds which are used to treat oxygenase activity and are therefore generally used for the treatment of secondary diseases and inflammation are not invented. The present invention also relates to the use of such compounds as W-Leh, the composition of the 苴 苴 蕴 韦 关 3 / 、 , , , , , , , , , , , , , , , , , , , , , , , , , , Clothing

[Prior Art] Background of the Invention "Benbei is an inflamed disease/disease. A major problem associated with the treatment of existing inflammatory conditions is the lack of efficacy and/or the prevalence of side effects (real or perceived). Asthma is an adult that affects 6% to 8% of the industrialized world.

: 〗 〖Sexual inflammatory disease. Among children, the incidence is even higher, which is close to 10% in most countries. Asthma is the most common cause of hospitalization for children under the age of fifteen. The treatment of the disease is based on the severity of the symptoms. Mild conditions are not treated or treated with only inhaled beta-agonists. Patients with more severe asthma are typically treated with anti-inflammatory compounds in a general manner. #YmJE is a asthmatic disease in treatment, at least in part due to the fact that it has been less than a few, and the maintenance of treatment (mainly inhaled corticosteroids) 6 200837061 / % risk. These include the risk of growth delays and loss of bone density in children, resulting in unnecessary morbidity and mortality. It has been developed as an alternative to steroids, leukotriene receptor antagonists (LTRas). These drugs can be administered orally, but are significantly less effective than inhaled steroids and generally do not satisfactorily control airway inflammation. This combination of factors results in at least 50% of all asthma patients not being adequately treated. There is a similar pattern in the treatment of over-breaking disease, in which the medicinal substance T is used to treat many diarrhea symptoms but is not fully utilized due to the side effects. Rhinitis, conjunctivitis, and dermatitis may have allergenic ingredients, but may also occur in the absence of essential allergies. Indeed, such non-allergic symptoms are difficult to treat in many situations. Spastic obstructive pulmonary disease (c〇pD) is a common disease affecting 6% to 8% of the world's population. The disease can be fatal and the morbidity and mortality due to this condition is considerable. Currently, there are no known pharmacological therapies that can alter the course of COPD. Other chronic inflammatory diseases that may be mentioned include: # (a) Pulmonary fibrosis (this is more common than c〇pD$, "but a serious disease with a very poor prognosis. There is no cure for treatment) (b) Inflammatory bowel disease (a family of people with a high rickets rate*. Today only use the symptoms of these diseases); and (rheumatoid arthritis and osteoarthritis (commonly disabled joints) Inflammatory disease. Now there is no cure for the management of the filament 7 200837061 and only moderately effective treatment.) Inflammation is also a common cause of pain. Inflammatory pain can be caused by many reasons, such as infection, surgery Surgery or other trauma. Moreover, some of the first malignant tumors have inflammatory components added to the patient's symptoms. Therefore, a novel and/or alternative anti-inflammatory treatment is beneficial to all of the above patient populations. In particular, for the treatment of An effective anti-inflammatory drug that has an inflammatory disease (such as asthma) without real or perceived side effects has a true and substantial need to meet clinical needs. The mammalian lipoxygenase is a structurally related family of enzymes that catalyze the oxidation of arachidonic acid. Three human lipoxygenases are known which catalyze the insertion of molecular oxygen at the carbon sites 5, 12 and 15 into arachidene. The enzymes are therefore named 5-, 12- and 15-lipoxygenase, respectively. The arachidonic acid metabolite formed after lipoxygenase action is known to have pro-inflammat〇 Ry) significant pathophysiological activity of the effect. For example, the major product of the action of 5-lipoxygenase on arachidonic acid is further transformed into various physiologically and pathophysiologically important metabolites by many enzymes. These most important (leukotrienes) are strong bronchoconstrictors. Great efforts have been made in the development of drugs that inhibit the effects of these metabolites and on the biological methods by which they are formed. _lipoxygenase inhibitor, inhibitor of FLAP (pentasoxygenase-activating protein) and leukotriene receptor antagonist (LTRas) as described above. Another type of metabolism of arachidonic acid It is cyclooxygenase 8 200837061 (cyclooxygenase). The arachidonic acid metabolites produced by this method include prostaglandins, lipoproteins and prostacyclin, all having physiological or pathophysiological activity. In particular, prostate PGEs are a pro-inflammatory mediator that also induces fever and pain. As a result, many drugs have been developed to inhibit the formation of PGE2, including "NSAIDs" (non-steroidal anti-inflammatory drugs) and Coxibs, (selective cyclooxygenase-2 inhibitors). These kinds of compounds play a significant role by inhibiting one or several cyclooxygenases. As a result, in general, agents that block the formation of arachidonic acid metabolites may be advantageous in the treatment of inflammation. Prior Art International Patent Application WO 00/034269 discloses compounds comprising various guanamines containing 1,2,3-oxadiazol-4-carboxylate containing thiourea. This document does not mention or suggest the use of such compounds for the treatment of inflammation. _ Heteroaryl-based compounds including triterpenoids have been disclosed in some publications. For example, the international patent application WO 2 5/007625 discloses three. Anti-tuberculosis compounds of the class; international patent application W〇2〇〇4/106324 specifically discloses triazoles used as herbicides; international patent applications 02/070483 and W〇〇3//〇163〇4 disclose various A triazole-containing triazole is disclosed in US Patent No. 2002/0091 16 and International Patent Application No. WO 99/32454; International Patent Application No. WO 01/21160 discloses Including triazole antiviral compounds. No. 1 (State_Unsubstituted), 2,3-triazole-4-carboxylic acid 9 200837061 Acid amines are not disclosed for the treatment of inflammation and/or as inhibitors of lipoxygenase. All of the patents WO 2004/080999, WO 2006/0:32851 and WO 2006/032852 disclose various melamine pyrazoles for the treatment of inflammation. However, no disclosure or suggestion is made in any of these documents. 2,3_Disa_4_oleic acid amines. International Patent Application WO 97/30034 discloses various 4-aminoquinazoline derivatives useful as antitumor agents. This document does not disclose or suggest the absence of such substituents. The compound does not mention or suggest the use of the compound for the treatment of inflammation. International Patent Application WO 2004/096795 discloses various heterocyclic species (including a steroid) as inhibitors of protein kinases, international patent application WO 02/092573 discloses various heterocyclics for use as inhibitors of, in particular, JNK3 protein kinases and International Patent Application No. 1/55 丨 15 discloses various activators useful as cysteine proteases (caSpases) and An adenine amide of an inducer of apoptosis. The use of these documents can be used for the treatment of 4 inch cancers. The use of these compounds as inhibitors of lipoxygenase is not disclosed or suggested in any of these documents. International Patent Application w〇97/19〇 62 discloses various heterocyclic compounds for the treatment of skin = related diseases and refers to the use of such compounds for the treatment of various diseases. However, this document does not mention or suggest 3-meramine-based saliva. JP Patent No. 10195063 discloses various uses as leukotriene antagonists, and thus can be used to treat inflammatory < 2 ethynyl ruthenium (IV) organisms. However, this 200837061 document does not mention or suggest compounds without such substituents. International Patent Application No. W〇2〇04/〇41789 discloses various compounds useful as protein kinase inhibitors (and thus useful in the treatment of, in particular, autoimmune diseases). However, there is no disclosure of triazoles in this document. 4_ Carboxylic acid amides. International Patent Applications WO 03/068767, WO 03/037274, WO 96/18617, WO 2005/009954, WO 2005/009539, WO 2004/108133, and WO 2004/ 1063 05 all disclose various &% treatment The compounds, including the three classes. However, none of these documents specifically disclose i (Nl. unsubstituted 1,2,3-triazole-4-carboxylic acid decylamines. [Description of the disclosure] The invention provides a compound of formula I,

Wherein W represents an aryl or heteroaryl group, optionally substituted with one or more substituents selected from the group consisting of: 1) G1; 2) an aryl or heteroaryl group, both of which are optionally selected by one or more Substituting from A1, -11 200837061 N3, -N02 and -S(0)pR6e2 substituents; and 3) heterocycloalkyl groups, optionally containing one or more selected from the group consisting of A2, -N〇2 and =〇 Substituent substitution; represents halogen, -R3a, -CN, _C(0)R3b, _C(0)0R3c, _C(0)N(R4a)R5a, -N(R4b)R^b, -N(R3d) C(0)R4c, -N(R3e)C(0)N(R4d)R5d, -N(R3f)C(0)R4e, -N3, -N02, ·N(R3g)S(0)2N(R4f ) R5f λ .〇R3h x -〇C(0)N(R4g)R5g - 0S(0)2R31, _S(0)mR3j, _N(R3k)S(0)2R3m, -0C(0)R3n, - 10 OC(〇)OR3p, -S(〇)2N(R4h)R5h, one s(0)20H, -P(0)(OR4i)(〇R' or -C(0)N(R3q)S(0) 2R3r; R3a represents a C16 alkyl group optionally substituted with one or more substituents selected from the group consisting of z, F, Ci, _N(R6b)R6c, _N3, =0 and -OR6d;

Ra, Rk, R3h, and R4a to R4h independently represent H, z or a Ci6 alkyl group optionally substituted with one or more halogen atoms or -QRW; R3d to R3g, R3k, R3q, R5a, R5b, R5d and R5f To R5h independently represent H or, as desired, one or more halogen atoms or _〇R6d, alkaloid, or any of R4a and R5a, R and R5b, R4d and R5d, R4f and R5f, R4g and R5g, and R4h and R5h, may be bonded together to form a 3 to 6-membered ring which, in addition to the nitrogen atom to which these substituents must be attached, optionally contains further heteroatoms (eg, nitrogen) Or oxygen), and the ring is optionally substituted with a C16 alkyl group substituted with one or more fluorine atoms as desired; 3, R3m, r3p and R3r independently represent z or optionally one or more selected from B a substituent substituted with a Cl_6 alkyl group; an eve 12 200837061 % R41 and R5· independently represent H or optionally a CVJ group substituted by a poly- or a multi-substituent; Each occasion·· :)) a heterocyclic ring b) aryl or heteroaryl group substituted with one or more substituents selected from A3 and = hydrazine, both of which are required It is required to be substituted with one or more substituents selected from VIII, N3, -N〇2 and _S(〇)qR7e; AA, A3 and A4 independently represent halogen, _R6a, _CN, -# or -OR6d; Each of the occasions referred to herein, independently, represents H or, optionally, a Cw alkyl group substituted with one or more substituents selected from B3, R, R6e and R7e independently represent one Or a plurality of c16 alkyl groups substituted with a substituent selected from the group; or R6b* may be bonded together to form a 3 to 6 member ring which, in addition to the nitrogen atom to which the substituents must be attached, Containing further heteroatoms (eg, nitrogen or oxygen), and the ring is optionally substituted with a Cle6 alkyl group substituted with or substituted with one or more fluorine atoms; β1, B2, B3, and B4 independently represent ρ, a, -OCH3, _〇CH2CH3, -〇chf2, _OCH2Cf3, -0CF3 or -〇CF2CF3; and 111,? And 9 independently represent hydrazine, 1 or 2, or a pharmaceutically acceptable salt thereof, with the following restrictions: (A) when W represents a phenyl group substituted with a G1 substituent at the ortho position, 'G1 represents R3a , R3a represents a Z-substituted ethynyl group, Z Table 13 200837061 shows a 2-thiazolyl group substituted by a4 at the 4-position, and a4 represents R6a, then R6a does not represent a cyclobutyl group; (B) when W represents 4 - 6-terpenyl group substituted by G1, G1 represents -N(R4b)R5b, R5b represents H and r# represents z, then Z does not represent 3_rat I phenyl, such compounds and salts are described later It is called "the compound of the present invention". [Embodiment]

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional methods, for example, by reacting a compound of formula I with an acid or a base form with one or more equivalents of a suitable acid or base, optionally in a solvent, or in a salt. Do not dissolve in the towel of the towel, and then remove the solution or the salt by using standard techniques (for example, by vacuum drying or filtration). The salt may also be exchanged for the compound of the invention in the form of a salt. The relative ions and the other-opposite ions are prepared, for example, using a suitable ion exchange resin. The compound of the present invention may contain a double bond and thus may have E (trans) and smooth, tender / (page) for each double bond. What are the isomers. All such structures and mixtures thereof* are included in the scope of the invention β. ', the compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures 35 thereof are included Within the scope of the invention. "The compounds of the invention may also contain - or more, thus exhibiting optical and/or non-mirror nine atoms and may be separated using conventional techniques, such as tomography::structures can be + again, crystal. Various stereopsis 14 200837061 Lying can be separated by conventional (e.g., fractional crystal 丨hplc technique) or a mixture of other compounds. Or the desired optical isomer may be reacted by a suitable optically active starting material under conditions which do not cause racemization or differential anamorphism (ie, 'chiral pool Uhiralp(K)1). The reaction of a suitable starting material with a 'chiral auxiliary' which can be subsequently removed at an appropriate stage, for example by hydrazine with pure chiral (h〇m〇chirai) acid (ie analytical 'including kinetic analysis'' The non-imagewise isomerized derivative is then separated by conventional methods such as chromatography, or by reaction with a suitable tweezing agent, (iv) all skilled in the art (4): two. All stereoisomers and mixtures thereof are included in the ferrules of the present invention. = unless otherwise indicated 'otherwise the k-based group as defined herein (as it is, if the fly field has a sufficient number (ie the lowest one) of the carbon atoms, it is branched, and/or braided (hence, in the alkane) Base = October form, (4) h ring-burning group). In the step of step _, when t has a sufficient number (that is, the lowest four) of carbon atoms, the slave atoms can also be Department: Clothing. Further, unless otherwise indicated, the alkyl groups may also be 2 or or 'when there are sufficient numbers (ie, the lowest two) of carbon atoms, otherwise indicated 'otherwise' , for example, or a C2-q alkynyl group). The term "halogen", when used by Toda Shinji + + π " when used herein, includes fluorine, chlorine, indifferent and oxime = the heterocyclic group mentioned includes monocyclic or bicyclic heterolyl groups ("groups are At least one of the steps (eg, one to 15 200837061 atoms in the ring system are non-carbon (ie, heteroatoms), and wherein the total number of atoms in the ring system is between three and twelve (eg, in five) Further, the heterocycloalkyl groups may be saturated or contain one or more double and/or pendant unsaturated groups to form, for example, c:2-q heterocycloalkenyl (where q The C 2 q heterocyclic compound group which may be mentioned as the upper limit of the range or the C 3 _ q 杂 快 基 group D includes 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3 η]heptyl, 6·azabicyclo[3.2.1]octyl, 8-azabicyclo-[3.2.1]octyl, aziridinyl, azetidinyl, dihydropiperidyl, dihydropyridine Base, ruthenyl (including 2,5-dihydroindenyl), dioxolane (including monooxylanyl), dioxanyl (including iota, 3-di) Engaged in the United States and 1,4-two hires Alkyl), dithianyl (including 1,4-dioxanyl), dithiolanyl (including 1,3-dithiolanyl), imidazolium Base, imidazolinyl, ifolin, 7-oxabicyclo[2·2·1]heptyl, 6-oxabicyclo-[3.2.1]octyl, oxetanyl, ethylene oxide , piperidinyl, piperidinyl, piperidyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinacridyl, sulfolanyl, 3-ring Sulfenyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydropyridyl, thietanyl, thiopyranyl, tetrahydrothiophenyl, thiofenofin, trithiazide (trithianyl), (including 1,3,5-trithiaalkyl), tropanyl, etc. The substituent on the heterocycloalkyl group may, where appropriate, be located inclusive of a hetero atom Further, in the case of any atom in the ring system, further, in the case where the other substituent is another cyclic compound, the cyclic compound may be via a single atom on the heterocyclic group. The formation of the so-called "spiro" 16 200837061 compound. The point of attachment of the heterocyclic compound can be via a hetero atom (such as a nitrogen atom), or a 7 atom or any of the ring system. The atom on the stone counter%. It can also be in the N- or S-oxidized form. The aryl group which may be mentioned as a heteroalkyl group includes c6 i "exemplified that the group may be a monocyclic, bicyclic or -10) group group. A - J and have a stone in the 6 and 14 An atom, wherein at least one of the rings is aromatic. C ^ ^ 曰, 鼓美笨望 m-square C6·] 4-aryl group includes phenyl,

^ Examples U, 3, 4 · tetrahydronaphthyl, hydroquinone, fluorenyl and 10,000. The point of attachment to the aryl group can be passed through any of the oxime systems. However, when the aryl group is bicyclic or: r, punctate, they are attached to the remainder of the molecule via the atoms of the aromatic ring. The heteroaryl group which may be mentioned by μ includes those members having between 5 and 1G between 5 and ΐ4. The groups are monocyclic, bicyclic: two% 'with the proviso that at least one of the rings is aromatic and at least = (for example one to four) the atoms in the ring system are non-carbon (ie: Hetero atom). Heteroaryl groups which may be mentioned include acridinyl, benzimidazolyl, benzodi〇xanyl, benzodioxoyl, benzodiacylpentenyl (benz〇di〇) X〇iyl)(包# !,3_benzodioxolyl), benzofuranyl, benzofurazyl, :==zozolyl, benzothiadiazolyl ( Package # 2,3 benzothiadiazolyl), benzo- 4 (including benzo-di-(diyl)), benzo- morphine, 3,4-dihydro JH-M-benzopyrene Phenyl), benzoxazolyl, benzimidyl, benzofolin, benzoseladiazinyl (benz〇selenadiaz〇iyi) including 2,1,3-benzoselenadiazolyl, Benzothiophenyl, carbazolyl, benzodiazepine 17 200837061 hydroquinone, porphyrinyl, furyl, imidazolyl, imidazo[l,2-a]acridinyl, oxazolyl, porphyrin , mercapto, isobenzofuranyl, isobenzodihydrol 11 hexanyl, isoindolyl, isodecyl, isoquinolyl, isothiazolyl, isothiochroman , Isozolyl, acridinyl (including hydrazine, 5_ acridine and 1,8-acridinyl), oxadiazolyl (including Oxadiazolyl, I, 2,4- oxadiazolyl palate and I, 3,4- oxadiazolyl palate), _ oxazolyl, coffee farming yl, thiazol brown

Or morphine, morphine, acridinyl, fluorenyl, pyridyl, pyrazolyl, morphine, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinacyl, tonlin a tetrahydroiso(tetra)yl group (including 1>2,3,4-tetrahydroisowalinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolyl (including -tetrahydro) Quinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetras-succinyl (3)-succinyl, decyl-saltyl and (1)-disodium sulphate, thiobenzodihydro Mercapto, D-septyl, triazolyl (including hydrazine, tris-s, 1,2,4, tri- s- and tri-sal), and the like. The heteroaryl group = substituent (where appropriate) may be located in the ring system including the hetero atom = atom. The point of attachment of the heteroaryl group may include any atom of a hetero atom (such as a nitrogen atom) via a ring, or any atom which may be part of the ring system in the fused ring of the fused stone present in the ^^ knife . When the 'quasi-group' is a bicyclic or tricyclic ring, they are attached to the rest of the molecule via the aryl group: the original form of -. _乜7 may be mentioned in N- or S-oxidation. , nitrogen and sulfur. For the avoidance of doubt, phosphorus, antimony, boron, pound, selenium and preferably, in the case where the multiple substitutions of the compounds of the invention 18 200837061 are the same, the individual substituents are true. The characteristics are not interdependent in any way. For example, in the form of f in which w is substituted with two or more substituents, the substituents may be the same or different. For example, when w is two

When substituted with a substituent, and the substituents are all _c(〇)R3b, wherein R3b is a CM alkyl group, and each alkyl group may be the same or different. Similarly, when more than one substituent, as defined herein, is substituted, the knowledge of the individual substituents is not considered interdependent. For example, when one substituent represents _(〇)R and the other substituent represents _c(〇)〇r3c, and the R3b and white form are not substituted by -ORW of the C1_6 alkyl group, the properties of the two groups are not Considered to be interdependent. Compounds of the invention which may be mentioned include those wherein: W is not substituted by phenyl, 4Η·[1,2,4]trisyl-4-yl kappa or a group; W does not represent pyrimidinyl (eg 5-pyrimidinyl) a group; W does not represent a carbazolyl group; W does not represent a pyridyl group (eg, a 2-pyridyl group); w does not indicate that a 6-membered ring is aromatic and a 5-membered ring is non-aromatic "6,5-bicyclo-rich W represents a 2_ porphyrinyl or anthracene-isoindolyl group, a basin C (〇)N(R4a)R5a and an A, R3d)(0)W group is substituted (for example Where:: position), and when R3d and R4a each represent chlorine, then R5a and: when?) indicate/not indicate a group (for example, a cyclosyl group or a group such as a P group); 4-6 When w represents 2, a fixed group or a 2, fluorenyl group, the group is substituted (for example, at the 4 position), then, the heteroaryl group of the heteroaryl group does not indicate as needed. 19 200837061 Substituted 4·pyrazolyl . "Another compound of the invention which may be mentioned includes such hairs. :: (for example, when W is a phenyl group) in the ortho position: relative to the compound of formula I -I solid α W relapping group is selected from: When the C(9)- group is substituted, it replaces 1) G1; 2) a square or heteroaryl group, and the second is ^ white and one or more selected from Ν3, Ν02 and a substituent substituted with -S(0)pR6e;

3) a heterocycloalkyl group which is optionally substituted by one or more substituents of a2, -N02 and =, wherein the heteroaryl or heterocycloalkyl group does not comprise a nitrogen atom and (1) -R3a, -CN , -C(0)R3b, τ(〇)〇ρ, _c(〇)N(R4a)= :, -N〇2, -0R3h, _〇C(〇)N(R4g)R5g, _〇s( 〇) 2R3i, (1)), -〇c(〇)Rh, _oc(〇)〇r3p, _s(9)2N(R4h)R5h, _s(〇)2:, _p(0)(0R4i)(0R5i) or -c( o) N(R3q)s(o)2R3r. 2 Other compounds of the invention which may be mentioned include those wherein W (for example when phenyl is) is in the ortho position (relative to w to the compound of formula I 2_N(H)C(0)-based When substituted, the substituent is selected from: 1) G1; 2) aryl or heteroaryl, both of which are optionally selected from one or more selected from the group consisting of A1, -N3, -N0ja-S ( 0) a pR6e2 substituent substituted; and 3) a heterocyclic alkyl group, which is optionally substituted by one or more substituents selected from the group consisting of (7) and ==〇, 20 200837061 wherein 八1 and 八2 independently Represents -1^, -〇>1, -:^(1161))11" or -〇1^(1 and (}1 represent halogen, -CN, -C(0)R3b, -C(0)0R3c , _C(0)N(R4a)R5a, Lai N(R4b)R51?, -N(R3d)C(0)R4e, -N(R3e)C(0)N(R4d)R5d, _N(R3f) C(Q)〇4e, -N3, -N02, -N(R3g)S(0)2N(R4f) R5f ... 0C(0)N(R4^)R5gx .0S(0)2R3K .N(R3k)s (〇) 2R3m> .〇C(〇)R3n ^ -〇C(0)OR3p, -S(0)2N(R4h)R5h, _s(〇)2〇h,.p(〇)(〇R4i)( 〇R' or -C(〇)N(R3q)S(〇)2R3r.

Another compound of the invention which may be mentioned includes those wherein R4b and R5b are not bonded as defined herein. Another compound of the present invention which may be further included includes: wherein R6a represents an acyclic c 6 alkyl group substituted with one or more substituents selected from B4 as desired; R represents a C1-3 alkyl group or a Cs_6 alkyl group, Both of them are optionally substituted by a substituent selected from y; one A represents _, -CN, _N(R6b)R6e or _〇rw; :z represents a heteroaryl group, which does not represent a thiazolyl group (e.g., h thiazolyl); when the field represents a heteroaryl group (e.g., thiazolyl (e.g., 2-thiazolyl)), the 5 hexyl group is substituted by one or the guest, 4 XT ', a group, and A4 in A. '3 N02 and _S(〇)qR7e substitution 3a 八中 A 不, -CN, _N(R6b)R6c or ·〇Ιι6(ι ; R table does not need to be one or more selected from F, α, _ =0 and -OR6d , , c1-6 alkyl substituted with -ν3, a substituent of the body; when W represents a hetero group u 1 group); 'base 蚪, it does not represent a quinazolinyl group (For example, when 6-quinazoline is substituted at the unbonded position (for example, when 6-quinazoline is used, then the group 21 200837061 is as G1, for example, when G1 represents -N(R4b)R5b); R4b represents Η Or Cw burned by one or more halogen atoms or -R6d as needed. ; G1 represents _ prime, -R3a, -CN, -C(0)R3b, -C(0)0R3c, -C(0)N(R4a)R5a, -N(R3d)C(0)R4e, -N (R3e)C(0)N(R4d)R5d, _N(R3f)C(0)R4e, -N3, -N02, -N(R3g)S(0)2N(R4f)R5f, -OR3h, -OC (0)N(R4g)R5g, -OS(0)2R3i, -S(0)mR3j, -N(R3k)S(0)2R3m, -0C(0)R3n, -OC(0)OR3p, -S (0) 2N(R4h)R5h, -S(0)20H, -#P(0)(0R4i)(0R5i) or -C(0)N(R3q)S(0)2R3r. Preferred compounds of the invention Including W such as phenyl, naphthyl, fluorenyl, fluorenyl, fluorenyl, sulfhydryl, stilbene, stilbene, stimulating, stimulating, sputum Base, ° ratio σ base (eg 2 -σ than mercapto, 3-pyridyl or 4-pyridyl), carbazolyl, fluorenyl, porphyrin, isoindolyl, oxonyl, Quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolyl, quinidine-1, benzofuranyl, isophenyl And furyl, benzopyranyl, benzothienyl, morphine, pyridinyl, pyridinyl, oxazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl (eg 2_quinoxalinyl), 1,3-benzene Dibenzocycloxyl, benzofluorenyl, 1,4-benzoxanyl, 1,3,4-didecyl or 1,3,4_嗟Base group, group. Particularly preferred values for W include thiazolyl (e.g., 2-thiazolyl), 1,3-benzodioxolyl, glucosyl (e.g., 2-pyrimidyl) or, if desired, substituted Preferably, the substituted 啥_琳基 (eg 22 200837061 2-quinoxaolinyl), preferably 咗啾 r r 土 ( (eg 4 - 喧 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基And more preferably, it has a cost or a ratio of pyridine (for example, 3-pyridyl or, more preferably, 2- to thiol). Preferred compounds of the invention include those wherein R and R3q independently represent Η; R and R3r independently represent z'j: ζ矣-- from 甘//, TZ, such as phenyl) , a heteroaryl group (for example, ti is more than a pyridyl group), and thereafter a group of 乂 乂 俊 as defined herein

R or C1-6 (eg C1·3)alkyl (eg methyl) is optionally substituted by one or more fluorine atoms (thus forming, for example, a trifluoromethyl group); R and R (when expressed as needed When substituted, the substituents are independently substituted with one or more fluorine atoms to replace the .η λ sheet, 7 士 C, such as Cw) alkyl; and the non-aryl or heteroaryl group is optionally selected from the group consisting of Substituted by a substituent of A4; A6 AA * A4 independently represents halogen (for example, chlorine or any rR7e represents an optionally substituted u group, then the alkyl group is optionally substituted, eg Cw An alkyl group; a ring to a 6-membered ring, which optionally contains additional heteroatoms (see milk extraction) and is optionally substituted with the clay 2, _CF3 or = ( (and thus forms, for example, 吼嘻σ定美, 旅基基, 福福林基或(四)基的 (e.g., 4-methyl)yl)^ Β, Β2, Β3, and Β4 independently represent F or a; P and q independently represent 2. More preferred compounds of the invention include those wherein 23 200837061 W is optionally substituted with between 1 and 4 substituents (e.g., aryl or G1); G1 represents N3 or, more preferably, _, -R3a, -CN , -C(0)R3b, -C(0)OR3c, -C(0)N(R4a)R5a, -N(R4b)R5b, -N(R3d)C(〇)R4c, -N(R3e)C (0) N(R4d)R5d, -N(R3f)C(0)0R4e, -N02, _N(R3g)S(0)2N(R4f)R5f, -〇R3h, _OC(〇)N(R4g) R5g, - 0S(0)2R3i, -S(0)mR3j or -S(0)2N(R4b)R5h ; when any R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R4g and R5g, Or 11411 and RU pairs, when bonded together, they form a 5_ to the Bulu ring, which optionally contains further heteroatoms in addition to the nitrogen atom and is optionally substituted with methyl, _CHF2, -CF3 or =〇 (Thus it forms, for example, a pyridine group, a piperidinyl group, a phenylephrine group or a piperage group (for example, a 4-methylpipedyl group) ring). Another preferred compound of the present invention includes the same: wherein R3a represents a C 1.6 alkyl group substituted with one or more substituents selected from the group consisting of F and 〇R6d; _ 任 -R3b, R3C, R3h, R4a to R4h, R5a, R5b, R5d, R5f to R5h independently represent H or optionally substituted C_4 alkyl or related pair (ie, R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R4g and R5g And R4h and R5h) may be bonded together as defined above; R3d to R3g independently represent Α·4 (e.g., C1_2) alkyl (e.g., methyl) or, more particularly, hydrazine;

Rl and independently represent a C 1.4 alkyl group substituted with one or more β1 substituents as desired; β represents F (thus Rh and R3) may represent a ch3 or cf3 group); 24 200837061 when any RR31>, R3C When R3h, R" to R4h, R5a, R5b, R5d, R5f are not calcined to the scale, preferred substituents include _〇ch3 and especially F. Another preferred compound of the invention includes such Wherein: when W is substituted, it is substituted with one to three substituents selected from (1); R represents, for example, a c12) alkyl group substituted with one or more fluorine atoms (eg, isopropyl or more specifically , methyl or ethyl); R is not hydrogen or optionally substituted by one or more fluorine atoms, c1-4 (for example, ♦ D alkyl (such as methyl or ethyl) (thus forming, for example, _CF3 group R and R independently represent a Ci 2 alkyl group (e.g., methyl or ethyl); G represents F, C1, -CH3, -CH2CH3, -CHF2, -CF3, -CH2CF3, CN N(CH3)2 , -N(CH2CH3)2, -n02, -〇h, -OCH3, -OCH2CH3, -〇ch2CF3, -CHF2, -〇cf3, and 曙〇cf2cf3. Preferred substituents on w include: Need And aryl (e.g., phenyl); -N(R3f)C(〇)〇R4e; preferably, -S(0)2N (R4h% R5h; or preferably, halogen (e.g., bromine or preferably , fluoro or chloro); -R3a; -OR3h; -N02 ; represents n-propyl, ethyl or, more preferably, isopropyl or, preferably, methyl, such groups, if desired, one or more The fluorine atom is substituted (thus forming, for example, 25 200837061 -cf3 group); R3f represents Η; R3h represents trifluoromethyl, ethyl, propyl (eg, n-propyl), butyl (eg, tert-butyl) Or more preferably, methyl; R4e represents a Cm alkyl group (e.g., a third-butyl group), which group may be substituted with - or a plurality of halogen atoms but is preferably unsubstituted; R and R5h independently represent H, Methyl or ethyl.

Thus, preferred substituents on W include phenyl, bromo, ethyl, propyl, -NHC(0), tert-butyl, ethoxy, propoxy (eg, propyl), Butoxy (eg n-butoxy), trifluoromethoxy, especially 疋S(〇)2NH2, _S(〇)2N(CH3)H, _S(0)2N(CH3)2, ^〇)2n (ch2ch3) 2, isopropyl and more particularly, i, chloro, methyloxy, hydrazine 2 and trifluoromethyl. Preferred compounds of the invention include those wherein: W is a 5-membered monocyclic ring or a 9-membered bicyclic ring or, more preferably, a bicyclic ring; a 6-membered monocyclic ring or a member of the group W is a monocyclic 5-member j-Rolagan & a person., 衣守, which contains at least one hetero atom (for example: thioaryl ring, therefore, I group (such as thiazol-2-yl) group; ϊ W is a single 6- Chang has four ni: , exhibits a 'phenyl group or preferably contains one as a heterozygous; § 2 ^ ^ as in the case, a heteroaryl group than a mercapto group; for example, nitrogen), therefore Formed when T is a phenyl group 2- or 4-position) 'which is via at least one substituent (eg, at or, preferably, at least two (eg, 3 - or better, one or three) 26 200837061

Substituent. Preferred positions include 2- and 3-, 3- and 5-, 2- and 6- or more preferably 2- and 5-, 3- and 4- or more, when substituted by two substituents. Ground, 2- and 4-positions. When substituted with three substituents, and the first two substitutions are based on the 2_ and 4-positions, the third substituent is preferably at 6_ or better, 3 or %. Preferred substituents at the 2-position of the phenyl ring include _s(〇)2NH2, _S(0)2N(CH3)H, -S(0)2N(CH3)2, isopropyl, preferably. , trifluoromethyl, methoxy, -N〇2 and more preferably, fluorine, chlorine and methyl. Preferred substituents at the 4-position of the phenyl group include methyl, trifluoromethoxy or, more preferably, -s(o)2nh2, _s(o)2N(Ch3)h, _s(〇) 2N(CH3)2, ·S(〇)2N(CH2CH3)2, preferably, -N〇2 and more preferably, halogen (e.g., bromine or, preferably, fluorine and chlorine) and trifluoromethyl. Other preferred substituents at the 3, 5 and 6 positions include fluorine, chlorine, bromine, methyl I, ethyl, isopropyl, trifluoromethyl and methoxy; In the o-, m- or, more preferably, the position adjacent to the point of the 3-acid amine group of the monocyclic ring-bonding compound, the position is substituted (the restriction is that the p-position is not a hetero atom) When i W is a 9-membered bicyclic ring, it is a kind of one kind in which one ring (connected to three female base circles) is aromatic, the case ^ μ L bei is, for example, stupid, and the second is non-aro a family, such as a 5_membered ring, an example of 匕3 — or two swarf sheep, such as an oxygen heteroatom, thus forming, for example, a...

乳... The pentyl pentenyl group (di_W (for example, [1,3]- pentylpentenyl) is preferably unsubstituted; it may be substituted, but when W is a 10-shell bicyclic ring, it is two rings ( For example, nitrogen) /, singly, is aromatic and the group preferably contains a ' or a 聋f 27 200837061. These heteroatoms are preferably in the first ring of the double ring (ie, its linkage To the amidino group of the compound of formula I. The groups are preferably attached via a 2-, 3- or 4-position of the heteroaryl group and are unsubstituted or, more preferably, via - or more For example, one) is selected from a trifluoromethyl group and, preferably, a halogen (such as gas or chlorine) is attached to, for example, a 6-, 7- or 8-position (with the limitation that the substituent is not attached to the aromatic ring) Substituent substitution of an atom. For the avoidance of doubt, when a phenyl ring is substituted, the relative position of the substituent refers to the relative position of the substituent relative to the point of attachment of the phenyl ring. For example, 2-, 3-, and 4 - Positions refer to o-, m-, and p-substituents, respectively (and the 5 and 6 positions, respectively, refer to the alternative inter- and ortho-substituents).

#W When substituted with a substituted heterocyclic, aryl or heteroaryl group, the preferred value for the heterocycloalkyl, aryl or heteroaryl group includes 1- as desired. More than private! ^ ^ Each base, 1-pipeline, defensin, ^ piperage, ten base (such as 4 "bow buki"), hire two wow, 曙〇 sit , phenyl, fluorene (for example, 3 _ group) " time base (for example, 3 Μ )) ... ratio. (eg 2 "specification base", tetrasyl, oxime, succinyl, (tetra) thiophene Base and three filaments (eg mountain. Sancha _3 base). Preferred substituents on such groups include fluoro, chloro, methyl, trimethyl, methoxy, trimethoxy and/or, when the group is heterocycloalkyl, = 〇 . The best value of Ζ includes the (4) base that is replaced as needed (for example, 4 orders of soil) 腭! Base, hire 嗤基, 啥 基 (for example, 啥琳基), 吼. Sit (e.g., 3 to saliva), disulfanyl, sulphate, and more particularly, phenyl and fluorenyl (e.g., phenyl). Preferred substituents on the fluorene group include apo-, chloro, methyl, trifluoromethyl, methoxy, tri- 28 200837061 fluoromethoxy and/or 'when z represents a heterocycloalkyl group Preferred compounds of the invention also include those wherein when W represents a fluorenyl group, it is unsubstituted or substituted with a sulfafluoride or chloro) substituent, for example at the 6,8 position; When W represents a fluorenyl group, it may be substituted by two substituents, or may be substituted by one substituent, for example, at the point of attachment of a phase group (to a tris-tris-amino group) Position, the substituent is selected from the group consisting of bromine, ruthenyl, methyl, ", propyl, methoxy, ethoxy; propoxy (eg / n-propoxy), butoxy (eg, positive _ Butoxy), benzene tert-butyl or, more preferably, chlorine, gas and trifluoromethyl; (0) when W represents a phenyl group, it is unsubstituted or more preferably, such as 1 to 3 substituents Substituent; when W represents a (iv) group (eg, (tetra)-2-yl) group, it is preferably substituted, for example, at the 5-position 'with at least one (eg, one) chloro group; when w is a spur bite (eg, mouth bite) 2_ a group) which is unsubstituted or substituted, for example, at a wide position by at least one (for example, one) methyl group; when W represents benzodioxolyl (benz〇di〇x〇iyi) (e.g., benzoindole, 3]dioxol-5)), which is preferably unsubstituted. Higher compounds of the invention may be mentioned, including: wherein W represents substituted 吼唆a 2 - group, preferably at least one (for example one or two) selected from the group consisting of nitro, methyl, ethyl, propyl, methoxyethoxy, propoxy (eg, n-propyl) Substituent substitution of oxy), butoxy (eg n-butoxy), -N(H)C(0)0 tert-butyl, chloro, I and trifluoromethyl; 29 200837061 The substituted pyridyl group is preferably substituted with at least one (e.g., one or two) substituents selected from the group consisting of methyl, methoxy, and phenyl groups. Substituted positions include 2-, 5-, and 6-positions. Preferred compounds of the invention include those wherein W represents 2-chloro-4,6-monofluorophenyl, 4-fluoro-3-methylphenyl, 2 , 3,4-trifluorophenyl, 2,3-dichlorophenyl, 2-chloro-5-A Phenyl, 3,5-diphenylphenyl, 2,4-bis(trifluoromethyl)phenyl, 2-fluoro-5-methylphenyl, 2-aero-6-trifluoromethylphenyl, 5-Chloro-2-mercaptophenyl, 2-methylamine sulfonylphenyl, 2-dimethylamine sulfonylphenyl, 2,4,6-^difluorophenyl, 3,5-di Fluorophenyl, 3,4-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-fluoro-5 -trifluoromethylphenyl, 3-fluoro-4-methylphenyl, 3-chloro-4-methylphenyl, 3-fluoro-5-trifluoromethylphenyl, 4-gas-2-methyl Phenylphenyl, 3-trifluoromethyl-4-methylphenyl, 3,4-dichlorophenyl, 4-trifluorodecyloxyphenyl, 5-fluoro-2-methylphenyl, 4- Chloro-3-trifluoromethylphenyl, 2,6·dioxa-4-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3-chloro- 2-methylphenyl, 4-fluoro-3-trifluorodecylphenyl, _ 2,6-diisopropylphenyl, 3,5-bis(trifluoromethyl)phenyl, 2-fluoro- 6-trifluoroanthracene basic group, 5-> odor 0 is more than fluoren-2-yl, 5-nitroindole 11-denyl, 6-methyl hydrazine. _ 2-yl, 6-bromoindole-2-yl, 4-trifluoromethylpyridin-2-yl, 4-methylpyridin-2-yl, 5-methylpyridin-2-yl, 5 -ethyl-6-methylpyridin-2-yl, 3-chloro-5-trifluoromethylpyridin-2-yl, 5,6-dimethylpyridine-2-yl, % decyloxypyridine _ 2 -yl,5,6-dimethoxyindole-2-yl, 6-methyl σ-bityl, 4,6-dimethylpyridin-2-yl, 3,5-dichloropyridine-2- , 3-methoxypyridin-2-yl, 5-butoxy σ, butyl-2-yl, 5-ethoxyindole, butyl-2-yl, propoxydin-2-yl, 5- Propyl. Ratio α _2 _ base, 5-ethyl σ ϋ 基, 6 — trifluoromethyl 吼 一 30 200837061 2 · base, 5- (NH_C (0) third - butyl ratio bit-2- , 2,5-dichloro, butyl-3-yl, 5-methylindole, 3-yl, 6-methoxy-5-methyl D, -3-yl, 5-phenylindole Benzo-3-yl, 5-chlorothiazol-2-yl, benzo[1,3]dioxocyclopentenyl, thiophene-2-yl or 4-methyltr-butyl-2-yl However, more preferred compounds of the invention include those wherein W represents quinolin-4-yl, unsubstituted phenyl, 4-isopropylphenyl, 4-diethylamine sulfonylphenyl, Quinoxaline-2-yl, 4-amine fluorenylphenyl, 4-methylamine sulfonylphenyl, 4-dimethylamine sulfonylphenyl, 2,4-dichloro-6- Methylphenyl, 8-fluoroindole-3-yl, 8-oxoline-3-yl,

2-fluoro-6-difluoromethylphenyl, preferably 啥琳_3_yl, 6-fluoroindan-3-yl, 7-fluoroquinolin-3-yl, 2,4-diindole Oxyphenyl, 4-chloro-2,5-dimethoxyphenyl, 2,4,6-dichlorophenyl, 2-trifluoromethylphenyl, 4-nitrophenyl or, more preferably , 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 4-fluorophenyl, 2,3,4-trichlorophenyl, 3,4-diphenyl, 2-chloro Phenyl, 2,4,5-trichlorophenyl, 2,4-dimethylphenyl, 2,5-dichlorophenyl, 'chloro-3-methylphenyl, 'chloromethoxyphenyl 2,4-Dichloromethylphenyl, 2-nitro-4-pyridylphenyl, 4fluoro-2-difluoromethylphenyl, 4-branched 2-trifluoromethyl stupyl, 4· Gas-octafluorophenyl, trifluoromethylphenyl, %chloropyridinyl 1, 5-fluoropyridin-2-yl or 5-trifluoromethylindol-2-yl. The compound of the examples described later. The compounds of the present invention which are well known to those skilled in the art of the stomach include the compounds of the present invention which can be used according to familiar practice (for example, as described later). Compounds According to another aspect of the present invention, there is provided a process for the preparation of a method comprising: & protection and/or protection 31 200837061 (e.g., s曰), a reaction with a compound of the formula

II wherein w 1C is derogatory, which is under coupling conditions, for example, at about room temperature or above (for example, eve to 40-1 8 ° C), if necessary in a suitable base (eg, sodium hydrazine, sodium hydride) Sodium, potassium carbonate, pyrrolidine pyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylamine bite, triisopropylamine, diisopropylethylamine, 1, diazepine-bicyclo[ 5·4·〇]11___ene, sodium hydroxide, &amp; ethyl diisopropylamine, N-(methyl polystyrene)-4-(decylamino)pyridine, φ butyl Lithium (for example, ... second- or third-butyl-lithium) or a mixture thereof, a suitable solvent (for example, tetrahydrofuran, pyridine, toluene, dichlorodecane, chloroform, acetonitrile, monomethylcarbamide, dimethyl Sulfoxide, water or triethylamine) and suitable coupling agents (eg 1, 1, carbonyl diimidazole, N, N, dicyclohexylcarbodiimide, dimethylaminopropyl)-3-ethylcarbamate Imine (or its hydrochloride), N,N'-disuccinimide carbonate, benzotriazol-1-yloxy ginseng (dimethylamine 袅Guanglin hexafluorophosphate, 2-(1Η) -benzotriazole_;1_yl hm3-tetramethyl fluorene Fluorophosphate, benzotriazol-1-yloxyl η, pyrrolidinyl hexafluorophosphate φ acid, bromine-cis-pyrrolidinium hexafluorophosphate, 2-(1Η-benzotriazole) _:μ base)-1,1,3,3-tetradecylurea iron tetrafluorocarbonate, 1-cyclohexylcarbodiimide _ 3-propoxy fluorenyl polystyrene, 0-(7-oxygen Heterobenzotriazole 4-base)_Ν,Ν,Ν',ν'-tetramethyluronium hexafluorophosphate or 〇-benzotris-l-yl_^ tetradecylurea rust tetrafluoroboron In the presence of a salt, alternatively, the third-strand-4-carboxylic acid may first be treated with an appropriate reagent by the presence of a suitable solvent (for example, dichloromethane, THF, toluene or benzene) and a suitable catalyst (for example, DMF). For example, grasshopper chlorine, sulfoxide, etc.) are activated by treatment, 32 200837061 leads to the formation of individual ruthenium chloride. This activated intermediate can then be combined with the compound of formula II under standard conditions (eg such Condition) The reaction of the skilled person is that when the compounds are essentially liquid, they can act as both solvent and reactants in this reaction. Alternatives to this step include 1, 2, 3-three. Oxazole-4-carboxylic acid t The reaction of a protected derivative (for example, ethyl vinegar) with a hydrazine compound of the formula </ RTI> </ RTI> the compound can first be used, for example, in an inert atmosphere and in the presence of a suitable solvent (for example, methylene chloride) with a suitable reagent (for example, top three) Aluminum) treatment.

(η) 1,2,3-oxadiazol-4-carboxylic acid decylamine, or a derivative of its N-protected (for example, triazole nitrogen), reacted with a compound of formula m,

W III where L is not properly leaving the base. For example, _ prime (such as chlorine, bromine and iodine), - 〇s 〇 2Cf3, -B (oh) 2, · barrier % (the towel RZ is cj base and relatively sulfhydryl or butyl), -Pb (0C (0)CH3)3, -Bi(W)2, -Bi(W)2(〇C(〇)CH3)2, _Bi(w)2(〇c(〇)CF3)2 or ·physical muscle), And W as defined above (and wherein the compound of formula m comprises more than one w group, preferably all of the same), for example in a catalyst comprising (preferably) Pd or Cu, and, for example, hydrating In the presence of potassium or sodium, potassium carbonate, potassium second butoxide and lithium N,N-diisopropylguanamine. Catalysts which may be mentioned include Pd2(dba)3 (parabens (diphenylmethyleneacetone dipalladium (palladium)), and the bases which may be mentioned include carbonic acid planers, and the ligands which may be mentioned include 2, 2, (Phenylphosphino)-1,1'-binaphthyl and solvents which may be used include toluene. These reactions can be carried out at elevated temperatures (for example, about argon) in an inert atmosphere (for example, argon). a compound of formula IV,

Irw where W is as defined above, or a % N-protected derivative, and a suitable source of sulphur nitrogen ions (eg, sodium azide or azide) The skilled person knows the reaction under the conditions. The reaction can be carried out under standard 1,3-dipole% addition reaction conditions (e.g., 誃~ et al., described in Katritzky AR·specialist 'Summers 2003, 60 (5), 1 1225-1239), for example ' The reaction can be carried out in the absence of a solvent or in the presence of a suitable solvent (e.g., water, methanol, ethyl, monomethylammoniumamine, dichloromethylbenzene or a mixture thereof) (d) (n-city, a t). , ... or above (for example between 40 and 8. (iv) - 纟 or its protected 彳 $ biological and - test mixture), such as 雔 ^ _ Tian A k field test (or such as double (dimethyl hydrazine) Base) potassium guanamine, sodium decylamine, sodium hydride, the first = Dingsa knows 4, 士^又,一丞j ―一·斤一～丁己钾 or organic lithium base, such as 正-BuLi, 弟一-BuLi , Di Er-BuLi, one heart can be a lithium isopropyl amide or 2,2,6,6-tetramethylpiperidine lithium (the organic lithium base as needed JV, such as lithium complexing agent such as ether (eg dimethyl ethane ethane) or amine (eg tetramethylethylenediamine (TMEDA), (-) cinnabarine or i 3_dimercapto _3 $ soil 5 J,6-tetrahydro-2 (m) _ feeding 嗣 (read U) 4, etc.)) the reaction in the presence of the reaction of the compound of V ^

V W-N=C=0 34 200837061 wherein w is as defined above, followed by stopping the reaction with a suitable proton source such as water or a saturated aqueous NH4CI solution. Those skilled in the art should be aware that the three-salt possible nitrogen atom in the three-bite system needs to be used as a protecting group directly to the group (for example, SEM).

CH2〇C2H4Si(CH3)3) group) protection. The reaction can be carried out in the presence of a suitable solvent such as a polar aprotic solvent (e.g., tetrahydroanion or diethylhydrazine) at SUB-ambient tempemures such as 〇〇c to _78.完成 is carried out under an inert atmosphere (if appropriate) by deprotection of the N-protecting group under standard conditions (for example in the case of SEM groups, using conditions such as in the presence of a fat ethanol solution). (V) - a compound of formula VI,

N

VI. A reaction of a compound according to the above formula (IV), for example, in a coupling strip: for example, as described above with respect to step (1) of the above method. Preferred conditions include the reaction in the presence of a solvent but without a coupling reagent. In this case, the compound of the formula II can also be used in excess.

1,2,3-triazole-4's carboxylic acid is commercially available (eg, derived from a cut U: chemical), or may be derived from sources of propyl and azide ions, such as, for example, and These are prepared as described above for the preparation of the compound of formula t (square/έτν (iii)). Compounds of formula 1 can be prepared: 35 200837061 化合物 The compound of formula III as described in relation to ammonia, or preferably its protected derivative, 虱^, f M4 organism (eg benzylamine), as before Said that the preparation of the compound of the formula I; or the preparation of the method (method step (Π)) (11) by the reduction of the compound of the formula VII, w-no7 VII, as defined above, in the standard Under reducing conditions, for example, by the presence of decahydrol W (for example, ethanol) under reflux, (IV) water tin (II) chloride catalyst (for example, in the illusion of carbon, a source of helium hydrogen such as hydroquinone or Primary hydrogen-hydrogen (eg from citric acid), optionally hydrogenated in the presence of a solvent such as an alcohol solvent (eg methanol). 1,2,3-triazole·4-carboxylic acid guanamine can be obtained by hydrazine Preparation of a 2,3-triazole-4-carboxylic acid, or a derivative thereof, with ammonia, for example, under the reaction conditions such as those described above for the preparation of the compound of formula I (step (1) of the above process).戈化化5 can be prepared by reacting a propiolic acid with a hydrazine compound as defined above, For example, the reaction conditions are prepared, for example, as described above for the preparation of the compound of formula I (step (i) of the above process). The compound of formula VI can be present under dimerization conditions, for example, in the presence of sulfoxide or chloroform chloride. The preparation is carried out from hydrazine, 2,3-triazolecarboxylic acid, if necessary in the presence of a suitable solvent and a catalyst, for example as defined by the reference. Other di-polymerization agents include carbodiimides such as anthracene, 3-dicyclohexylcarbodiimide or diammonium propyl)-3-ethylidenecarbodiimide (EDC1, or its hydrochloride), as needed Ground in the presence of a suitable base (eg 4_36 200837061 dimethylaminopyridine). Compounds of the formula ¥, ¥ and νπ are commercially available, and those which have been removed from the literature may be obtained by analogy with the methods described herein, or by conventional synthetic procedures, according to standard techniques, using appropriate The reagents and reaction conditions are obtained from the available starting materials. In this regard, the skilled person is particularly aware of Comp · Λ 4 · T r 〇 s t know Τ 1 · and · Fleming "Comprehensive Organic

Synthesis", pergam〇n, i99i. Substituents on w as defined above, if present, may be utilized by those skilled in the art after or during such methods for preparing compounds of formula I The method is modified one or more times. Examples of the method include substitution, reduction, oxidation, burning, deuteration, hydrolysis, esterification, and etherification. The precursor group can be changed at any time during the reaction sequence. a group, or a group as defined in the formula J. In the case where the substituent on w represents a group, the group may be converted to or after the method described above for the preparation of the compound of formula I. One or more times. • Suitable reagents include NiC!2 (for conversion to chlorine groups). In this regard, the artist can also refer to AR Katritzky, 〇Meth_cohn and cw

Rees' "Comprehensive Organic Functional Group Transformations" ’ Pergamon Press, 1995. Other transformations which may be mentioned include the conversion of a halo group (preferably iodine or bromine) to a cyano or 1-alkynyl group (for example by means of a compound with a source of a cyano anion (for example sodium, potassium, copper) (1) or resignation) or with 丨-alkyne, if appropriate. The post-reaction can be carried out by suitably coupling the catalyst (for example with a catalyst of a copper base and/or a copper matrix) and a suitable base (for example tris(Ci4 alkyl)amine example 37 200837061 such as triethylamine, tributylamine or ethyldiisopropylamine) Implemented in existence. Further, the amine group and the hydroxyl group can be introduced according to standard conditions using reagents known to those skilled in the art. The compounds of the present invention can be isolated from their reaction mixtures using conventional techniques. It will be appreciated by those skilled in the art that in the above and described methods, the functional groups of the intermediate compound may need to be protected by a protecting group. For example, triazole nitrogen or (when there is a _N(R4b)R5b substituent on W) _N(R4b)R5b gas # group may need to be protected. Suitable nitrogen-protecting groups include those which form the following: (i) a urethane group (ie, an alkoxy- or aryloxy-carbonyl group); (ii) a guanamine group (eg, B) (in) an N-institutional group (benzoinyl or SEM group); (lv) an N-continuary group (eg, an arylsulfonyl group); (ν)Ν- a phosphinyl group and a fluorenyl-phosphonium group (for example, a diarylphosphinyl group and a diarylphosphonium group); or a (Vi) fluorene-fluorenyl group (for example, a fluorenyl-trimethyl fluorenyl group) ). Further protecting groups for the triazole nitrogen include a mercapto group which can be protected under standard conditions, for example using a bite hydrochloride at elevated temperatures, for example, in a sealed container at 2 〇〇〇c Microwave irradiation. The protection and deprotection of the B% group can occur before or after the reaction in the above scheme. The protecting group can be removed according to techniques well known to those skilled in the art and as described hereinafter. For example, the protected compound/intermediate 38 200837061 described herein can be chemically converted to an unprotected compound using standard deprotection techniques. The type of chemistry involved will indicate the need and type of protecting group and the order in which the synthesis is completed. The use of protecting groups is fully described in "Protective Groups in Organic Chemistry" M ^ J WF McOmie, ed., Plernim Press (1973), and "Protective Groups in Organic Synthesis (Protective Groups in 0rganic Synthesis", 3rd edition,

W. Greene &amp; P.G.M. Wutz, Wiley-Interscience (1999). Pharmaceutical and pharmaceutical uses, the compounds of the invention are effective because of their pharmacological activity. The specialized compound is therefore indicated as a medicine you ^, horse booty. According to another aspect of the present invention, there is provided a compound as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament.

Although the compound γI of the present invention is icy-acting, it has a music activity, and may be present or coated with a certain compound of the present invention - commercially acceptable (for example, "protected" organism, which may not Having the sputum, sputum, sputum, sputum activity, but can be parenterally or orally administered (which may have some pharmacologically identifiable compounds. The "activity", the compound:, = limit The condition is that the activity is lower than the "prodrug," Lin Mingwei of the compound of the present invention, and thus can be described as being within the scope of the present invention. The jinliangliang is included in the "pre-drug of the compound of the present invention", and is administered after the administration. In the time (in the oral or parenteral (for example, about 1 small W to form the compound of the present compound 39 200837061, experimentally - measurable amount. Special rLit compounds especially because they can inhibit lipoxygenase (and the monthly 匕 _) is active and effective, that is, they prevent the regulation of the effect of the complex of the 15_ 5 = 酶 zymase enzyme-particulate compound, for example, the test can be made in the following test Cool 'month The chemistries are therefore useful in the treatment of such conditions in which it is desirable to inhibit the milk licking enzyme 'and the specifics of the lipoxygenase. The compounds of the invention are therefore expected to be useful in the treatment of inflammation. Those skilled in the art should be aware of the terminology. In local or systemic protection, (4) ^ ^ any ^ # % μ is a characteristic symptom, which can be mediated by physical "two: chronic diseases" such as those mentioned above, &quot; or external: the chemical and // or a physiological response (such as a partial allergic reaction). = Reaction 'The harmful agent used to destroy, dilute or separate the two, and the second weave, by, for example, heat, swelling, pain, redness, Increased vascular enlargement or blood flow, area affected by leukocyte invasion, loss of function, and/or any other symptoms known to be associated with inflammatory symptoms. 'L 孓 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此, any symptoms associated with the inflammatory component associated with it, and or any symptoms characterized by inflammation, including acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and others An inflammatory form known to the skilled artisan. For the purposes of the present invention, the term thus also includes sense of pain and/or fever. Thus, the compounds of the invention may be used for the treatment of asthma, chronic obstructive pulmonary disease (CODD), Pulmonary fibrosis, allergic disease, rhinitis, 200837061 ι fire f intestinal disease, ulcer, inflammatory pain, fever, arteriosclerosis, coronary artery disease, vasculitis, pancreatitis, arthritis, osteoarthritis, Rheumatism is inflammation, conjunctivitis, iritis, scleritis, uveal layer &amp;, traumatic 痊 '悤 skin k wet treatment, psoriasis, stroke, diabetes, autoimmune disease, Alzheimer's disease, multiple Sclerosis, sarcoma-like disease, Hodgkin's disease and other malignancies' and other diseases associated with inflammatory components. The compounds of this month may also have an effect on the inflammatory mechanism.

• J is on the eve of the eve and the bone loss of the physiotherapy. Symptoms that may be mentioned in this method include osteoporosis, osteoarthritis, Paget, s disease, and/or periodontal disease. The compound of Formula 1 and its pharmaceutically acceptable salt can therefore also be used to increase the onset of pain in the treatment of the genitals, the degree of menstruation, and the reduction of fracture occurrence and/or recovery. Anti-Treatment The compounds of the present invention show both. The treatment of the above symptoms and / or pre-explosive is not another invention _ such as a lipoxygenase): there are: a treatment and lipoxygenase (for example (&quot;J&quot; 15· hope and / or need Her oxygenase side: special: two = its: like::::: acceptable salt 'administered to suffer from these symptoms or to the; "patients'' including mammals (including the term "effective amount," The amount of the compound that confers on the treatment of the patient's 200837061 treatment effect. The effect can be objective (that is, can be measured by some test or marker) I subjective (that is, the indication or feeling of the effect given by the subject) Effect) The compound of the present invention will normally be administered orally, intravenously, subcutaneously, frequently, rectally, transdermally, intranasally, intratracheally, tracheally, sublingually, in a pharmaceutically acceptable dosage form, Administration by any other parenteral route or by inhalation. The compounds of the present invention may be administered alone, but are preferably administered by known pharmaceutical formulations, and (4) administered to a drug delivery tablet, capsule or _ a suppository for rectal administration, with (4) intestinal or intramuscular administration Bacterial solution, etc. The formulations may be prepared according to the standard and/or by (4) practiced according to the invention, according to the invention, another -,,, w/-g, Cl W , and bar = the formula defined above a compound, or a pharmaceutically acceptable salt thereof, S'7K, which may be admixed with an adjuvant, diluent or carrier. Further, a method of preparing a pharmaceutical preparation as defined above, comprising A compound of formula I: or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. The compound of the invention may also be formulated with other therapeutic/oral treatments as defined herein ( For example, NSAIDs, kexibs, u〇x alcohols, analgesics, 5 B匕ϋ, anti-proteins, inhibitors, FLAP (5-lipoxygenase inhibitors, and leukotriene receptors) Agent (LTRas), 42 200837061 / or other combination of therapeutic agents useful for treating inflammation. According to another aspect of the present invention, there is provided a combination product comprising: (A) - a species as defined above without limitations a compound of the formula, or a pharmaceutically acceptable salt thereof; and (Β) another for treatment An inflamed therapeutic agent, each of which is formulated with an adjuvant, a release agent or a carrier which is acceptable for the drug. The therapeutic agent commissure 1 is therefore also present in a separate formulation wherein the formulations comprise: a compound comprising a compound of the invention and at least one of the other therapeutic agents, the second combination formulation is present (ie, formulated) (ie, including the hair A single formulation of sulphate S and other therapeutic agents is present. Therefore, it is further provided: (1) A medical medicinal formulation 'which includes a s ▲ species as defined by the description but without restrictions For the first time, it is acceptable for the salt, another therapeutic agent for the treatment of inflammation, and the medicine / ^ ^ Baile acceptable adjuvant, diluent or carrier; and (2) a part containing the component Kits: (a) A pharmaceutical formulation comprising a compound of formula j as defined by the description without its limitations, a barium acceptable salt, and a T-medical Adjuvant, diluent or carrier blend; and (b) - Medical preparations, their agents, 锸#, and other medically acceptable sputum 】 therapeutic agents for the treatment of inflammation, / adult injuries (a) and (b) each encounter with others Another form of co-injection 43 is provided in 200837061. The compound of formula 1 as defined above, in combination with a force-limiting condition, or a pharmaceutically acceptable salt thereof, may be used as a diluent or Carrier. A commercially acceptable adjuvant, administration: a combination of ', we mean that the two components are suitable for joining each other in the foregoing:: By making the two components "in progress," combined to make a backup: Method 'We include two sets of parts that are later used in combination with each other in a combination therapy (ie, independent of each other); or "combined packaging" used in combination therapy in combination therapy. The separate parts are packaged and present together. ^ The compound can be administered at varying doses. Oral, pulmonary, and intracranial; at a dose of about 1 mg/kg body weight per day (mg/kg coupon/eight: about 100 *克/kg/day 'preferably about 〇·〇ι to about 10 millimeters of material/day' and more (four) °, 1 to about 5.00 mg / kg / day for example, for oral administration, typical composition The ground contains between about 〇〇2, Γ〇0 gram, and preferably between about 1 milligram and about 100 milligrams. Intravenously, the preferred dose will be during the fixed rate perfusion: 1 to about 10 mg, kg, the range of hours. Favorably, ° early Each dose may be administered, or the total dose may be administered in two separate doses of 44,370,361, three, or four separate doses. In any event, the physician, or the skilled person, may determine the actual drug that is most suitable for the individual patient. Quantity, which may vary depending on the route of administration, the type and severity of the symptoms to be treated, and the particular patient's breed, age, sex, kidney function, liver function, and response to be treated. Examples; of course, there may be individual examples in which higher or lower dosage ranges are valuable, and such are within the scope of the invention. The compounds of the invention may have the advantage that they are lipoxygenases, and that they are known An effective and/or selective inhibitor of 15 _lipoxygenase. The compounds of the invention may also have advantages: they may be more effective, less toxic, longer acting, more effective, than compounds known in the prior art. Produces fewer side effects, absorbs more than and/or has better pharmacokinetic profiles than compounds known in the prior art (eg, higher oral bioavailability) And/or lower clearance rate, exceeding and/or having other effective pharmacological, physical, or chemical properties, whether or not used in the instructions. _ Bioassay used in assays with lipid hydrase synthesizing polyunsaturated The fatty acid (including the 1,4-cis-pentadiene configuration) is oxidized to its corresponding peroxy or trans-base derivative. In this particular analysis, the lipoxygenase is a purified human lipoxygen. The synthase and fatty acid are arachidonic acid. The analysis was done at room temperature (2〇_22〇c) and the following was added to each well of the 96 well microplate: 〇35 μl phosphate buffered saline (8) (1) 1174); b) Inhibitor (ie compound) or vehicle (〇·5 μl dms〇); 45 200837061 'Lengzhi 1 5-month 曰oxygenase concentration in pBS 1 〇χ Solution. The plates were incubated for 5 minutes at room temperature; d) 5 microliters of 〇125 福 peanut tetrazoic acid in PBS. The plate is then incubated for 10 minutes at room temperature; e) the enzyme reaction is terminated by the addition of 100 microliters of methanol; and f) 15-peroxyhydroxyeicosatetraenoic acid or 15-hydroxy-eicosatetraene The amount of acid was measured by reverse phase HPLC. The invention is illustrated by the following examples, in which the following abbreviations are used: aq. Water DMAP DMF 4_Dimethylaminopyridine monomethylmethalamine dmso monomethine EtOAc ethyl acetate MS mass spectrometry NMR nuclear magnetic resonance Pd_C in activity Palladium on carbon PyBrop bromotripyrrolidinium hexafluorophosphate rt room temperature TBTU 〇-benzotriazol-1-yl-N,N,N,, fluoroborate THF Tetrahydrofuran is specified in the following synthesis Starting materials and from, for example, Sigma-Aldrich Fine Chemicals. One or more of the compounds of the examples described hereinafter are described in U.S. Pat. All tautomeric forms of the compounds of the examples described hereinafter should be considered as being disclosed. Synthesis of intermediate 1,2,3-triazole-4-carboxyindole Propelleric acid (1·55 ml, 1/?6 g, 25 mmol), azide in a sealed bottle at 80 °C A mixture of tridecyl decane (8.4 ml, 7.3 g, ο mmol) and MeOH (10 mL) for 3 h. After cooling to &quot;, the resulting white solid was filtered, washed with Et.sub.2 (2.times.s. a · 】 HNMR ( DMSO-d6, 400MHz) δ 13.30 ( br. s, 2H) , 〇 y 8.4ο (s, 1H) 〇h『2- 甲甲石日基1乙气基基小i 2,3 - Three n all NaH (6 〇% suspension in mineral oil, 11 gram, 28 4 Yuan Mo) was added to 1,2,3-triazole (1.90 g, 27.0 mmol) in THF ( The solution in 3 ml) and the mixture were stirred at rt for 1 hour. The mixture was cooled in an ice bath and 2-(trimethyl)-ethoxymethyl chloride (5 g, 30 mmol) was added dropwise. The mixture was heated to rt and was quenched at rt for 8 hours. The precipitate was filtered and concentrated, and then re-dissolved in EqO (50 mL) water (20 mL) in a washing solution, dried (ΝΜ〇4) and concentrated to yield Color oil (5.7 g). According to NMR spectroscopy, the oil was the title product: a mixture of the isomers 2-[2-(trimethylglycosyl)ethoxy fluorenyl]·1&gt; 2,3_trisole (3··1). The mixture was used without further purification.

H NMR (CDC13 5 400 MHz), δ 7 76-7 7W 〇 /·/0 /·μ (m, 2H), 5·71 200837061, 0·〇2 (s, 9H). (s ' 2H), 3.54 ( t, 2H), 〇 · 94 ( t, 2H) aryl is a synthetically known non-commercially available aromatic amine based on the synthesis of intermediates (eg, For example, those described later) are synthesized. Butylaminoquinoxaline

Rape at 150. (: a mixture of 2_chloropin (1.1 g, (4) millimolar) and benzylamine (6 ml) was heated for 6 hours. After cooling, the mixture was poured into NaH2P〇4 (saturated aqueous solution, (50 liters) and extracted with EtOAc (3×20 mL). EtOAc (EtOAc) NMR ( DMSO-d6, 400MHz) δ 8.37 ( s, iH) , 81 〇 ( t 1H) '7.76 (d'lH) '7.54-0 7.25 (m,7H), 4.63(d 2H) 〇(b ) 2 - A certain quinine hindrance stirs 2-benzylaminoquinoline (13 g, 5 · 5 mmol), ammonium formate (3.13 g, 49.7 mmol) and Pd_c (1%) The title compound (278 mg, 25%) of an orange oil was obtained from EtOAc (EtOAc). DMSO-d6,400MHz) δ 8·26 ( s,1H), 7.74 ( d, 1Η), 7.55-7.46 (m, 2H), 7.3〇 (ddd, lH), 6.95 (s, 48 200837061 % 2H) 〇 4 dichloro-o-helium jasmine is heated under reflux to 4-chloro-2-methoxy-1-nitrogen a mixture of benzene (938 mg, 5. 〇 millimol), tin (II) chloride dihydrate (3. 38 g, 15 mmol) and EtOH (25 mL) for 18 hours. After cooling to rt, Join

NaOH (aq, 4M, 50 mL). The mixture was extracted with Et 2 〇 (3 x 20 mL) and dried (NaJO 4 ) and concentrated. The title compound (5 11 mg, 65%) of a red oil was purified by chromatography. 4 NMR (DMSO-d6, 400 MHz) δ 6·78 (1H, d), 6.67 (1H, dd) </ </ RTI> </ RTI> 6.7 (1H, d) </ RTI> 4.82 (2 Η, s), 3.75 (3H, s). 14-Dichloro-m-methylideneamine This intermediate is prepared from 1,3-dichloro-2-indolyl-4-nitrost (1·〇3 g, 5 mmol) according to the above procedure. Light red oil that solidifies when left to stand. Produced 617 mg (70%). NMR (DMSO-d6, 400 MHz), δ 7.05 (1H, d), 6.64 (1H, d), 5.44 (2H, s), 2.32 (3H, s). 4-Amino-N,N-diethyl sulfonamide was cooled in an ice bath with a solution of diethylamine (5.2 g, 710 mmol) in pyridine (i 5 mL) and small during 10 min. Partially added N-acetamidosulfonium chloride (10 g, 43 mmol). The mixture is at 110. (: Mix for 4 hours and concentrate to give a brown oil. Add EtOH (15 ml), water (25 ml) and HCl (concentrated aqueous solution, 25 ml) and at 100. (The mixture is stirred for 3 hours. Cool to rt Thereafter, the pH was adjusted to ~1 Torr by the addition of NaOH (aq, 49 200837061 4%). The brown sediment was filtered, the knees were washed with water, dried and recrystallized from EhO/conne to give the title product (6·〇克) , 62%) of yellow crystals. 4 NMR (DMSO-d6, 400MHz) δ 7.39 ( dd, 2 Η), 6.61 ( dd, 2H), 5.94 (s, 2H), 3.05 (q, 4H), 1.01 (t, 6H). Amino-N-A is a smile (a) A base of 4-nitrate is stirred under rt with 4-nitrobenzenesulfonate (ΐ·2〇g, 5.42 mmol) ), ♦ methylamine (2M in THF, 2.7 ml, 5.4 mmol), DMaj&gt; (66 mg, 〇·54 mmol), triethylamine (〇.87 ml, 6 23) Mixture of millimolar and CH2C12 (50 ml) for 15 min. Dilute the mixture with CH.sub.2Cl.sub.2 (. And concentration. by chromatography (dissolution) Purification of EtOAc / EtOAc (EtOAc) (EtOAc) ·95·7·76 (1Η, br. s), 2·47 (3Η, s). (b) N-decyl-4-nitrobenzenesulfonate at normal pressure and normal temperature A mixture of guanamine (337 mg 1,56 houser), Pd-C (10% Pd, 100 mg) and a few drops of DMF in Me〇H (20 mL) was hydrogenated for 3 days. Concentration to give the title product (2 </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt;

(1H,q),6·61 ( 2H,ddd),5.91 ( 2H,s), 2 32 ( 3H d) 0 4 -amino-N,N-methylmethicone (a) -Methyl-4-Shischwitt stupid broth face sub-title compound is used according to the above procedure using an excess of triethylamine (丨W 宅, 12.45 耄 Mo) from 4-nitrobenzene sulfonium chloride (12 gram grams) , $ millimolar) and dimethylamine hydrochloride (5 〇 8 mg, 6. 23 mmol) prepared. 818 mg (66%) of pale yellow needles were produced.

4 NMR (DMSO-d6,400ΜΗΖ) δ 8.43 ( 2Η,ddd),8 〇〇(2H,ddd) ,2_67 ( 6H,s ) 〇(b ) 4-amino-N,N-dimethyl stony The title compound was prepared from N,N-dimethyl-4-nitrobenzamide (767 mg, 3.33 mmol) by hydrogenation according to the previous procedure. Yield 608 mg (91%) of a brown solid. iH NMR (DMSO-d6, 400 MHz) δ 7·33 (2H, ddd), 6·62 (2 Η, ddd), 6.2-5.8 (2Η, br.s), 2·48 (6Ή, s). 3-amino-6-fluoroquinoline, 3-amino-7-fluoroquinoline, 3-amino-8-fluoroquinoline and amino-8-chloroquineline according to the following step (a) To (f) preparation. (a) 2-"(4-Fluoroamino)methylene-1propanediquinone λ pain 4 - aniline (4.26 liters '45 mmol) and 2-ethoxy fluorenylmalonate A mixture of diethyl ester (14.59 g, 67.5 mmol) was stirred at i3 (rc) for 18 h. After cooling to rt, solid was recrystallised from acetone/water to give sub-title compound (9. 84 g &lt;78%) Glossy beige solid. MNMmDMSO-d〆400ΜΗζ) δ 10.67( 1Η,s), 8.31( 1Η, 51 200837061 s) ' 7.45-7.39 ( 2H,m),7·21 ( 2H,t), 4.25-4.05 (4H, m),1·25 (6H,t) 0 竺2 1 (3_-fluoroanilinyl i propylene dioxime 匕 匕 标题 标题 标题 标题 titled compound from 3-fluoroaniline (1.83 g, 16.5 m) Preparation of MeOH (DMSO-d6, 400 MHz) δ 10.66 (1H, d), 8.38 (1H, d) '7·46_7·33 ( 2Η, except for the use of the crude product without further purification. m), 7·21 (1Η, dd), 6.97 (1Η, _dt), 4.2GU5 (4H, m), 1.3-1.2 (6H, m). 2-.1 (2-fluoroanilino) The base i-malonate di-curie title compound was prepared according to the above procedure from fluoroaniline <5 gram, 45 mM 0 11.68 g (92%) of a white cottony solid was obtained. WNMRC DMSO-d, 400 MHz) δ 11·05 (1 Η, d), 8.62 (1 Η, d), 7.79 (1 Η, dt), 7·49 ( 1Η, ddd), 7.40 (1Η, ddd), 7.33 (1H, ddd). 4.37 ( 2H,q),4·28 ( 2H,q),1.42 (3H,t),1.41 ( 3H,t) 〇• 2- [(2- gasoamine) 砟methyl 1 malonate II The ethyl ester subtitle compound was prepared from 2-chloroaniline (4·74 mL, 45 mmol) according to the procedure above. A white solid of I2·66 g (%) was produced. H NMR (DMSO-d6, 400 ΜΗζ), δ 11.17 (1Η, d), 8.51 (1Η, d), 7·65 (1H, d), 7·55 (1H, d), 7.40 (1H, dd) , 7.16 (lH, dd), 4_23 (2H, q), 4.14 (2H, q), 1.27 (3H, t), 1.26 (3H, t). (b) 6-Fluoro-4-pyridin-3-oxoacetate 52 200837061 2-[(4-Fluoroanilino)methylene]malonate diethyl ester (9 83 g, 34·9 ¢: Moore, see step (a) above) added to Dowtherm®® (5 ml). The mixture was heated to 22 ° C and maintained at this temperature for 15 hours, cooled to ft., then filtered and filtered, Et.sub.2 /Heptane (2: washed and dried to give 4.15 g (51%) of white solid. 4 NMR (DMSO-d6, 400MHz) δ 12.43 ( 1H, s), 8·56 ( 1H, s), 7·80-7.58 (3Η, πι), 4.20 ( 2H, q), ΐ · 28 (3Η , 〇. 7 -Fluor-4 - 噎 噎 -3 - #酸匕酷_ The subtitle compound is from the crude 2-[(3-fluoroanilino)-methylene]malonate according to the above procedure. (See step (a) above). Yield 2 46 g (66% of one step) of white solid. lHNMR (DMS0_d6, 400 ΜΗζ) δ12·32 (1H, s), 8.60 (1H, s) ' 8.14 (1Η 'd), 7·67 (1Η, dd), 7.45 (1Η, dd), 4.22 ( 2H,q),1·28 ( 3H,t ). 8-fluoro-4-hydroxyquina- The ethyl 3-carboxylate subtitle compound was obtained from diethyl 2-[(2-fluoroanilino)-methylene-yl]malonate (11.67 g, 41.4 mmol) according to the above procedure; see step (a) above Preparation: 6:: πg (63%) of a white solid. 1H NMR (DMSO-d6 '400 ΜΗζ) δ 12.45 (1 Η, s), 8.37 (1) , s), 7.94 ( lH, d), 7.64 ( lH, ddd), 7.39 ( lH, ddd), 4.22 ( 2H, q), 1 · 28 ( 3H, t). 8- gas _ 4 · hydroxyquinoline The title compound of -3-3⁄4 acid ethyl ester was obtained from diethyl 2-[(2-chloroanilino)-methylene]malonate according to the above procedure (12·64 g, 42 5 mmol); Step 53 200837061 1 a)) Prepared to give 7.94 g (74%) of a white solid. lHNMR (DMS0 々 ΜΗζ ) δ 11.89 (1 Η, s), 8.41 (1 Η, ) 8, 11 ( , dd ), 7.88 (1Η, dd), 7·41 (1Η, t), 4·22 ( 2H, q), 1.28 ( 3H, t) (C) Ethyl carboxylate 6-fluoro-4-hydroxyquinoline _3_Carboxylic acid ethyl ester (41S g, 17.6 mmol; see step (b) above) and P〇Cl3 (5.40 g, 35·2 mmol) mixed at 1 °c After 3 minutes, after cooling, the mixture fj was poured into ice (~5 gram) and neutralized with ammonia (2 liters of saturated aqueous solution). The mixture was extracted with CH2C12 (3 x 30 liters) and the combined extracts were made with ammonia ( q 2M '2 liters) was washed: and concentrated to give a sub-title compound (4 29 g 'quantitative yield) of glossy flakes. Old NMR (DMSO-d6, 400MHz) δ 9.22 ( 1H, s), 8.33 ( 1H, dd) ' 8.16 ( lH,dd), 8.02 ( lH,ddd), 4.54 (2H,q), 1·50 ( 3H , t) ethyl porphyrin-3-carboxylate ethyl 7-fluoro-4-hydroxyquinolin-3-carboxylic acid ethyl ester (2.45 g, 10.0 mmol; see step (b) above) and P〇Cl3 ( A mixture of 3 ml) was stirred at 100 ° C for 20 minutes, cooled and concentrated. The residue was washed with heptane (3 χ 3 mL) and dried. 2.26 g (89%) of a white solid was obtained. NMR (CDC13,400ΜΗζ) δ 9·52 ( 1Η, s), 8.73 ( 1Η, dd), 8.32 ( lH, dd), 7.82 ( lH,ddd) , 4.57 (2H,q), 1·51 ( 3Ή,t) ethyl chloro-S-fluoroquinoline-3-carboxylic acid ethyl ester 54 200837061 8-fluoro-4·hydroxyquinoline-3-carboxylic acid ethyl ester (6.11 g, 26·〇 mmol; see above A mixture of step (b)) and P0C13 (20 ml) was stirred at 100 ° C for 3.5 hours, cooled and concentrated to give a yellow semi-solid (9.85 g) which was used without purification. NMR (CDC13, 400 MHz) δ 9.58 (1 Η, s), 8.46 (1 Η, d), 8.04-7.90 (2 Η, m), 4·60 (2H, q), 1·54 (3H, t). Ethyl 4,8-dichloroquinolin-3-carboxylate ethyl 8-chlorohydroxyquinoline-3-carboxylate (7.94 g, 31.5 mmol; cf see step (b) above) and P〇Cl3 ( A mixture of 6 ml) was stirred at 10 ° C for 30 minutes, cooled and concentrated. The crude material was recrystallized from EtOAc. 5.46 grams (68%) of white flakes were produced. 'H NMR (CDC13, 400MHz) δ 9·23 ( 1H, s), 8.34 ( 1H, dd) ' 8·16 ( 1Η, dd) , 7·81 ( 1Η, dd) , 4·44 (2Η, q ), 1·39 (3Η, t). (d) 6-fluoroquinoline-3-carboxyl ginseng Xijing at room temperature and normal temperature 4-chloro-6-fluoroindolin-3-acid ethyl ester (4.2 g, _ 17.6 耄 Moar; see The above step (C)) and a mixture of Pd_c (10% Pd, 100 gram) in acetic acid (10 liters) were hydrogenated for 18 hours. The mixture was filtered through Celite 9 and washed with EtOAc (3 mL). The filtrate was concentrated and the residue was crystallised from EtOAc EtOAc (EtOAc) iHNMR (DMSO-d6, 400MHz) δ 9.28 ( 1H, s), 9 〇 2 ΠΗ, s), 8.18 ( 1H, dd), 8.06 (1 Η, dd), 7. 84 (1 η, m), 4.42 ( 2H, q), 1.39 ( 3h, t). 55 200837061 _7-fluoroquinoline-3-carboxys sub-titled compound according to the above procedure from 4-chloro-7-fluoroquinoline-3-carboxylic acid ethyl acetate (1.50 g, 5.91 mmol; see above Step (c)) Preparation. The green crude product was used without purification. 4 NMR (DMSO-d6, 400MHz) δ 9.33 ( 1H,d), 9·07 ( 1H, dd) ' 8·36 ( 1H,dd),7·88 ( 1H,dd),7·69 ( 1H, Dt), 4·42 ( 2H, q), 1·39 ( 3H, t). G-fluoroquinoline _3-carboxy S# _ sub-title compound from ethyl 4-chloro-8-fluoroquinoline-3-carboxylate (9·65 g of crude material by hydrogenation for 48 hours according to the above procedure; See step (c) above for preparation. Brown oil was used without purification. lHNMR (DMS〇-d6, 400MHz) δ 9·33 (1Η, d), 9.07 (1Η, dd), 8.06 (lH, dd), 7.78-7.65 ( 2H, m), 4.42 ( 2Η, q), 1.39 (3H,t) 〇多-鼠啥琳_ 3 -Weinic acid acetoin title compound was obtained from 4,8-dichloroquinoline-3-carboxylic acid, ethyl ester (5.15 g) by hydrogenation according to the above procedure for 2 hours. , 2 〇 1 mmol; see the above step (c)). The product was purified by chromatography (eluent Et EtOAc / heptane). Yield 717 mg (15%) of a white solid. H NMR ( DMSO-d6 ' 400 MHz ) δ9·41 (ΐΗ, (1), 9·09 (1Η, d), 8.23 (1Η, dd), 8.12 (1Η, dd), 7.71 (1Η, t ), 4·44 ( 2H,q),1·4〇( 3h,t). (e ) 6-fluorophthalocyanine-3-acid by adding NaOH (aq, 2M, 8 ml, 16 mmol) To 6_Fluor 56 200837061 啥 叛 叛 叛 ( (927 mg, 4.23 mmol; see step (d) above), MeOH (15 ml) and dioxane (ml) mixture. Stir at rt The mixture was acidified with EtOAc (EtOAc (EtOAc)EtOAc. W NMR ( DMSO-d6, 400 MHz) δ 9.26 ( 1H, d), 8.96 ( 1H, d) ' 8·15 ( 1H, dd), 8·01 ( 1H, dd), 7·81 ( 1H, ddd) The 7-fluoroquina-3-carboxyindole subtitle compound was prepared from ethyl 7-fluoroquinoline-3-carboxylate (crude material; see above ((1)) according to the above procedure. 176 mg. % white solids after two steps. 4 NMR (DMSO-d6, 400 MHz) δ 13.83-13.26 (1H, br.s), 9·33 ( 1H 'd) ' 9.03 ( 1H,d), 8.33 ( 1H,dd),7.86 (1H,dd) , 7.67 ( 1H,dt). 8-fluoroquino-3.carboxyindole• 'Subtitle compound based on The above procedure was prepared from ethyl 8-fluoroquinoline-3-carboxylate (9. 6 g of crude material; see step (d) above) to yield 3 - (10) g (60% over three steps) of pale yellow solid. 1H NMR (DMSO-d6,400MHz), δ 9.30 ( 1H,d), 9.01 (1Η' dd) ' 8.00 ( 1Η' dd) ' 7.74·7 62 ( 2Η, (7). 8 -Chloropurine-3-peracid The title compound was prepared according to the procedure above from ethyl <RTI ID=0.0># </RTI> </RTI> chloroquinoline <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; -d6,400MHz) δ 13.7 ( 1H,s),9·40 ( 1H, d),9·06 ( 1Η,d), 8.22 ( 1Η,dd),8·10 ( 1Η,dd), 7.69 ( 1H , t) 〇(f) 3-amino-6-1.唼呲6-fluoroindol-3-lowic acid (595 mg '3_11 mmol); see step (Ο) above, azide phosphate II Phenyl ester (991 mg, 3.6 mmol), triethylamine (3 64 mg, 3.6 mmol) and anhydrous THF (15 mL) _ The mixture was heated under reflux for 2 hours. Water (5 ml) and the mixture were heated under reflux for 2 hours. After cooling to rt, the mixture was extracted with EtOAc (3×15 mL) The residue was recrystallized from EtOAc (EtOAc:EtOAc) !HNMR( DMSO-cV 400MHz) δ 8·4〇( 1H,d),7 79( 1H, dd) ' 7·38 ( 1H ' dd ) ' 7·17 ( 1H,dt) , 7·09 ( 1H , d), 5.82 ( 2H, s) 〇 Xin 3 -Amino-7-fluoro oxime sub-title compound is based on the above procedure from 7-fluoroquinoline _3_carboxylic acid (i72 housek, 〇·90 mmol) Ear; see step (e) above for preparation. A milligram (29%) of a yellow solid was produced. NMR ( DMSO-d6, 400 MHz) δ 8.46 (m,d), 7 69 (m, dd), 7.49 (1H, dd), 7.31 (1H, dd), 7 l9 (iH,d), 5,63 ( 2H,s) 〇3 -Amino-8-fluoroindole 58 200837061 The subtitle compound is based on the above procedure from 8-fluoroquinoline, 3-carboxylic acid (i gram, 5.23 mmol; see Prepared in the above step (e)). A yellow solid of π mg (13%) was produced. W NMR ( DMSO-d6, 400 MHz) δ 8·42 (1H, d), 7 % (m, dd), 7.29 (1H, ddd), 7.13 (1H, dd), 7〇5 (m, dd), 5.85 ( 2H, s). The 3-amino-8-chloroindole ▲ subtitle compound was prepared according to the procedure above from &lt;RTI ID=0.0&gt;&gt; Yellow solid. NMR (DMSO-d6,400ΜΗζ) δ 8.53 ( 1Η ^ d) , 7.59 ( 1Η » dd) '7.46(1H'dd) '7.33(lH't) 7ΐ8(ΐΗ,(4), 5.89 ( 2Η , s) amidino-5,6-dimethyl gas a certain hip hop (a) IAiU gas base-6-nitrate ^^ under (four) 2-bromo-3-methoxy D bite (4·45 Gram, 23 7 mmol) added to a mixture of fuming _3 and concentrated H2S〇4 (1: Bu 18 ml). Mix the mixture for 24 hours at W and then pour into ice water (15 liters) The precipitate formed by the hydrazine was washed with water (3 ml) and dried in vacuo to yield 3.54 g (64%) of pale yellow solid, which was essentially pure. ^nmrcdmso-^^oomhz Δ841(ά, 1Η) 5 7 g〇(d&gt; 1H) ' 4·06 ( s, 3H). (b) Nitropyridine 59 200837061 Sodium methoxide (927 μl of 30% solution in MeOH, 5 · 2 mM) added to 1 2 · bromo-3-methoxy-6-nitropyridine (750 mg, 3.22 mmol), DMSO (6 Mixture of ML) and Me〇H (9 ml). Stir the mixture at rt for 90 minutes, then at 24 ° C for 24 hours and at rt for 24 hours. The mixture was poured into ice (1 50 mL) and neutralized. The precipitate was washed with water (1 mL) EtOAc (EtOAc)jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1H),7·55 (d,1Η),3·97 (s·3Η),3·94 (s,3Η). (c) 1. Amino-5,6-dimethyl gas is more difficult 2,3-Dimethoxy-6-stone succinyl hydrazide (450 mg, 2.44 mmol), Pd_c (1 〇%, 1 〇〇 mg), 仏 (10) (1) at systemic pressure and system temperature The mixture was stirred for 3 hours with EtOAc (EtOAc). 400MHz) δ 7·05 ( d,1H), 5.92 ( d, 1H), 5.36 ( br.s. 2H), 3.75 (s, 3H) 3.60 (s, 3H). 2·amine _3 4 5_methyl chloride 吼 ^ 1 / odor - methoxy group 吼 ° (1 · 20 grams, 5.15 millimoles), 2

The amine water sigma (6 liters) and pd-C (1 〇%, 4 〇〇 mg) were filtered at Et 〇 H 3 . The material was concentrated in vacuo. Water (2 ml) and hydrazine were added; (saturated 4 and aqueous solution &apos; 10 mL) and the mixture was extracted with CHC1S (2×50 mL). 5 Dry: ^(Na1S〇6) The combined extracts were concentrated in vacuo to give a mixture of title 6 (40 liters). After 200837061 product (61 5 mg' 96%) of a low melting colorless solid. </ RTI> <RTIgt; 2-Amino-3-methyl a pyridinium by a step similar to the above 2-amino-5,6-dimethoxypyridine, step (c) 'using 3·methoxynitropyridine (1598)克, 1〇·4 mmol) was prepared in place of 2,3-dimethoxy-6-stone. Yield: 961 g (74%) of white needles. • lH NMR (DMSO-d6, 400MHz) δ 7·49 ( dd, 1H), 6 舛 (dd, 1H), 6·49 ( dd, 1H), 5·60 ( br.s, 2H), 3 % (s,3H) 〇2 -Amino-5-Ethene 吼n(a) 2 -Wang-3 - Ethene 咐, 〇 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2.00 g, 11.5 mmol, 峨 烧 (3.12 g, 20 mmol) and a mixture of k2C03 (2.99 g, 18 mmol) in DMF (17 mL) for 11 min. The mixture was concentrated in 窆 and the residue was dissolved in Et EtOAc (1 mL) and water (50 liters). The aqueous phase was extracted with EtOAc (EtOAc (EtOAc)EtOAc. %) of brown oil. H NMR (DMSO-d6, 400 MHz) δ 7.95 (dd, 1H), 7. 51 (dd, 1H), 7.39 (dd, 1H), 4.15 (q, 2H), 1.36 (t, 3H). (b) 2 di-ethoxy _6-nitro p specific ratio 61 200837061 by a procedure similar to the above 2-bromo-3-methoxy-6-nitropyridine, using 2-bromo-3- Ethoxypyridine (1.827 g, 9.04 mmol) was prepared instead of 2·bromo-3-methoxypyridine. Yield: 1.53 g (68%) of a pale yellow solid. lU NMR ( DMSO-d6 ^ 400ΜΗζ) δ 8.39 ( d ^ 1H), 7.79 ( d, 1H) , 4.33 ( q, 2H) , 1.42 ( t, 3H) 〇 (c ) 2 -amino _ 5 _ 乙乳The base p is 0 by a step similar to the above 2-amino-5-methoxypyridine, using 2-® bromo-3-ethoxy-6-nitropyridine (1.50 g, 6.08 mmol) Ear) Prepared instead of 2-bromo-3-methoxy-6-nitropyridine. Yield: 836 mg (100%) of a yellow oil. NMR ( DMSO_d6,400ΜΗζ) δ 7.62 ( d,1Η),7·09 ( dd, 1Η),6·40 ( d,1H), 5.42 ( br s,2H),3·91 ( q,2H), 1.26 (t, 3H). 2 _月安基_ 5 _ propyl oxygen mouth ratio mouth (a) 2 - &gt; odor _ 3 propoxy mouth ratio mouth ^ by a step similar to the above 2-bromo-3-ethoxy pyridine, Prepared using 1-iodopropane instead of iodoethane. Yield · 2.26 g (91%) of light brown oil. 1H NMR (DMSO-d6, 400MHz) δ 7.95 ( dd, 1H) , 7.51 ( dd, 1H) , 7.39 ( dd, 1H) , 4_06 ( t, 2H) , 1.82-1.70 ( m, 2H) ,1·01 (t, 3H). (b) 2 _ &gt; Odor-6 Shishaw·3 -propoxy; 口 口 口 口 by using a procedure similar to the above 2-bromo-3-indolyl-6-nitropyridine using 2-bromo- 3-propoxypyridine (2.20 g, 10.2 mmol) was prepared in place of 2-bromo-3- 62 200837061 decyloxypyridine. Yield: 1.58 g (59%) of a pale yellow solid. NMR ( DMSO-d6 &gt; 400ΜΗζ) δ 8.38 ( d ^ 1Η), 7·79 ( d, 1Η), 4·23 ( t, 2H), 1·87-1·75 (ηι, 2H), 1· 02 ( t,3H) 〇(c ) 2 _Amino-5-propoxy. The ratio of 2-bromo-6-nitro-3-propoxyacridine (1.55 g, 5.94 mmol) was used instead of 2 by the procedure similar to the above 2-amino-5-methoxypyridine. Preparation of bromine_3_methoxy-6.nitroacridine. Yield: 913 mg (100%) of a white solid. • NMR ( DMSO_d6, 400MHz) δ 7.62 ( d,1Η), 7.09 ( dd, 1H), 6·40 ( d,1H), 5.41 ( br. s, 2H), 3.81 ( t, 2H), 1.71-1.59 ( m, 2H) , 0.94 ( t, 3H). 2 _Amino-5 _ butyl lactylation than the oral (a) 2-bromo-3-butoxy 0 ratio bite by a procedure similar to the above 2-bromo-3-ethoxypyridine, using 1- Iodine is prepared in place of iodoethane. Yield: 2.185 g (95%) of a yellow oil. 4 NMR (DMSO-d6, 400MHz) δ 7.94 ( dd, 1H), 7·51 ( dd, 1Η), 7.39 ( dd, 1H) , 4.06 ( t, 2H) , 1.77-1 · 68 ( m, 2H) , 1.53-1.40 (m, 2H), 0.94 (t, 3H) (b) 2-bromo-3-butoxy-6-nitroacridine by similar to the above 2-bromo-3-methoxy- The procedure for 6-nitropyridine was prepared using 2-bromo-3-butoxypyridine (2.10 g, 9.13 mmol) instead of 2-bromo-3-methoxypyridine. Yield · 1.04 g (41%) of a pale yellow solid. NMR ( DMSO-d6,400 ΜΗζ) δ 8.39 ( d,1 Η) , 7·80 ( d, 63 200837061 1H), 4.28 (t, 2H), 1.82-1.67 (m, 2H),, 2H), 0.96 (t , 3H). (c) Butoxy-pyrrolidine using a step similar to the above 2-amino-5-methoxypyridine, using 2_bromo-3-butoxynitroacridine (1〇3 g, 3.74 m Mole) was prepared instead of 2-bromo-3-indolyl nitropyridine. Yield ····························· , 2H), 3·81 (ί, 2Η), 1.68-1.58 (m, 2H), 1·47-1·34 (ιη, 2H), 〇.92(t, 3H). L-amino-5 _ B. Bi-ha will add diethyl ether (24 ml of iM solution in hexane, 24 mmol) to 2_amino _5_ bromo. Bite (2·〇克, 116 毫Mol) and Pd(dppf)Cl2_CH2Cl2 (225 mg, 〇·28 mmol) in degassed dioxane (45 mL). The mixture was stirred at rt for 2 h, then _ The mixture was stirred at rt for 7 hrs under argon. The mixture was poured into EtOAc (aq. sat. The title compound (1.40 g, 99%). 7.74 ( s, 1H), 7·25 ( dd, 1Η), 6.40 ( d, 1Η), 5.67 ( br, s, 2 Η), 2·39 ( q, 2 Η ), 1·1 〇 ( t, 3H) 〇 64 200837061 * Surface 2-amino-5-propyl screen ^^ Bromine at 0cC under argon atmosphere A solution of magnesium propylate (6 ml of a 2 M solution in diethyl ether, 12 mmol) added to zinc chloride (methane in diethyl ether, 6 ml '6 mmol). Diluted solution of 4-dioxane (10 ml) and transferred to 2-amino-5-bromopyridine (516 mg, 3 mmol) and Pd(dppf)Cl2-CH2Cl2 (55 mg, 〇·〇7 mM Ear) suspension in ι, 4- 2 (5 ml). Heat the mixture under reflux for 2 Torr. After cooling to rt, pour the mixture into water (50 mL) and add

NaHC03 (aq, 1M; 20 mL). The mixture was extracted with EtOAc (3×50 mL) andEtOAc····································· NMR (CD3〇D, 4〇〇MHz) δ 7_74 ( d,1H), 7.43 ( d, 1H), 6·62 ( d,1H), 2.43 ( t,2H),1·55-1·62 ( m, 2H), 0.91 (t, 3H) 〇2-amino-5-butyl valence is used in a similar manner to the 2-amino-5-propyl hydrazine step described above, using chlorinated butyl ( Prepared in place of 2M in THF, 12 mL·24 mmol, instead of magnesium bromobromide. The crude product was purified by EtOAc (EtOAc) elute H NMR (DMSO-d6 &gt; 400 MHz), δ 7.71 (d, 1H), 7_21 (dd, 1H), 6.37 (d, 1H), 5·61 (br·s, 2H), 2.37 (t, 1H) ) ' 1.46(p, 2H), 1.25-1.30 (m, 2H), (K88(t, 3H). 2-Amino-5-ethyl-6-methylpyridine 65 200837061

It is a step similar to the above 2-amino-5-ethylindole ratio, using 2-amino-5-bromo-6-methyl acridine (2.00 g, 10.7 mmol) instead of 2_ Preparation of amino bromide. The crude product was purified by chromatography (EtOAc /EtOAc) Yield: 0.74 g (51%). 4 NMR ( DMSO-d6, 400 MHz) δ 7.06 (d, 1H), 6_21 (d, 1H), 5.51 (s, 2H), 2·40 (q, 2H), 2.21 (s, 3H), 1.06 (t , 3H) 〇2-amino-5,6-lutidine 2 -amino-5 · -6 -methyl 0 ratio (5 6 1 mg, 3 · 〇 millimol), K2C〇 A solid mixture of 3 (1.24 g, 9.0 mmol) and Pd(dppf)Cl2-CH2Cl2 (245 mg, 0·30 mmol) was added to the trimethyloxohydrocarbon terpolymer (boroxine) (377 mg, 3. 0 millimoles) and water (i ml) in a solution of 1,4-dihydroalkane (1 ml). The mixture was heated under reflux for 3 hours. After cooling to rt, the mixture was poured into water (5 mL) and mixture was extracted with diethyl EtOAc (3 <RTIgt; The material was purified by chromatography (EtOAc /EtOAc) Yield: 244 mg (67%). !H NMR ( DMSO-d6 ^ 400ΜΗζ) , δ 7·〇9 ( d,1H) , 6.18 (d,lH), 5.50 ( br.s, 2H), 2.18 (s, 3H), 2.03 (s, 3H) ).

Examples 1 to 6Q General Procedure Method A TBTU (1.1 mmol) was added to 1,2,3-triazole-4-carboxylic acid (113 mils, 2008, 370, 621, ι·〇 millimoles) and A solution of isopropylethylamine (258 g, 2 mmol) in anhydrous DMF (1 mL) and a mixture of sb. Add the relevant aromatic amine (13 mmol) and stir at the indicated temperature: the compound is allowed to pass for the indicated period of time. The resulting mixture was concentrated and water (2 Torr) was added to the residue. The mixture was extracted with Et 〇Ae (3 x 2 G mL): the combined extracts <dry air) were washed with water (20 ml) and concentrated. The residue was purified by chromatography (EtOAc EtOAc /EtOAc)

Method B A mixture of 1,2,3-triazole-the present carboxylic acid (65 mg, 〇.5 〇 millimol), s〇ci2 (i ml) and DMF (1 drop) was heated at 40 cc for 2 hours. The mixture was concentrated and the residue was dried in vacuo. The mixture was stirred at the indicated temperature: a mixture of solid, _ (83 mg, 〇·68 mmol) and related arylamine (Mole) in CH2C12 (5 liter) over a specified period of time and then concentrated. The residue was dissolved in Et EtOAc (2 mL), washed with EtOAc (aq. The residue was purified by chromatography (EtOAc EtOAc/EtOAc)

Method C oxaloquinone chloride (0.58 ml, 6.6 mmol) was added dropwise to '2'3d4_(tetra) (678 mg, 6 Q mmol), dmf (I liter) and THF under argon at 〇 °C. (30 liters) in a mixture. The mixture was mixed for 2 hours and transferred dropwise to the relevant aromatic amine (2.2 moles) and DIPEA (0.76 ml '4.4 mmol) in THF (Im). 〇 oc solution. The mixture was stirred under wc π for 30 minutes and twisted to the specified temperature for a specified period of time. Force heat ^ After cooling to rt, pour the mixture into EtOAc (30 mL) and water (3 〇 Ί 毛 毛Divided organic phase and concentrated. The residue was purified by chromatography (eluent (10) Ae / EtOAc, EtOAc EtOAc)

EXAMPLES (Ex· ) 1 to 6Q Ex Name Preparation from Aromatic Amines ---~~--- Reaction Conditions Yield (%) Method Time h Temperature °r 1 1,2,3-Tris--4-carboxylic Acid喧琳-3_基基胺三-Amino 啥琳 A 18 20 9 2 1,2,3-triazole-4-carboxylic acid (2-chloro-4_fluoro-phenyl) guanamine 2-chloro- 4-aniline A - 18 20 4 3 1,2,3-trimethyl-4-deoxalate (2,4-dichlorophenyl) decylamine 2,4-dichloro-aniline A 18 20 5 4 1,2 ,3-triterpene·4_carboxylic acid (4-fluorophenyl)-brown knee 4-fluoroaniline A 18 20 6 5 1,2,3-three-sodium -4-sodium sulphate 4-Aminoquinoline A 144 22 10 6 1,2,3_Trisin·4·Resinated chlorophenyl) decylamine 2,3,4-tris-aniline A 120 22 14 7 1,2,3 -Triazole_4_carboxylic acid (5-chlorosyl)decylamine 2-amino-5-chloro ° ° ° A 18 20 1 68 200837061 8 1,2,3-triazole-4-carboxylic acid benzene Acrylamine aniline A 18 20 23 9 1,2,3-triazole-4-carboxylic acid (3,4-dichlorophenyl) decylamine 3,4-dichloroaniline A 18 20 33 10 1,2, 3-triazole-4-carboxylic acid (2-dichlorophenyl) decylamine 2-chloroaniline A 18 20 8 11 1,2,3-triazole-4-carboxylic acid (5-trifluorodecyl-pyridine -2-yl) guanamine 2-amino _5_difluoroantimonyl than bit B 72 20 44 12 1,2,3-triazole-4-hypoacid (2,4,5-trichloroaniline-2-yl) decylamine 2,4,5-trichloroaniline A 18 50 8 13 1,2 ,3-triazole-4-carboxylic acid (2,4-dimethylphenyl)decylamine 2,4-dimethylaniline A 18 22 76 14 1,2,3-triazole-4-carboxylic acid (2 ,5-dichlorophenyl)guanamine 2,5-dichloroaniline A 18 22 19 15 1,2,3-triazole-4-carboxylic acid (5-fluoropyridin-2-yl)nonanamine 2-amine Base-5-port ratio B 18 20 23 16 1,2,3-triazole-4·carboxylic acid (2,4-dimethoxyphenyl)decylamine 2,4-dimethoxy-aniline A 48 22 19 17 1,2,3_Triazole-4-carboxylic acid (4-chloro-2,5-dimethoxyphenyl) decylamine 4-chloro-2,5-dimethoxyaniline A 24 601 35 18 1,2,3-triazole-4-carboxylic acid (4-chloro-3-indolyl-phenyl)decylamine 4-chloro-p-anisidine A 24 601 47 69 200837061 19 1,2, 3-triazole-4-carboxylic acid (4-isopropylphenyl) decylamine p-isopropylaniline A 24 601 53 20 1,2,3-triazole-4·carboxylic acid (4-diethylamine sulfonate Mercapto-phenyl) decylamine 4-amino-N,N-diethylbenzamine xanthine A 18 80 25 21 1,2,3-triazole-4-carboxylic acid quinone scare ^ - 2 - Alkylamine 2-Aminoguanidine A 18 80 4 22 1,2,3-Triazole-4-carboxylic acid 4-Aminesulfonylphenyl)decylamine 4-aminobenzene-continuous indoleamine A 24 601 7 23 1,2,3·triazole-4·carboxylic acid (4-chloro-2-methoxy-benzene Alkylamine 4-chloro-o-methoxyaniline A 24 85 33 24 1,2,3-triazole-4-carboxylic acid (2,4-dichloro-3-methyl-phenyl)-bristamine 2 ,4·di-m-toluidine A 24 85 27 25 1,2,3-triazole-4-carboxylic acid (4-methylamine sulfonyl-phenyl) decylamine 4-amino-N- Methylbenzene-sulfonamide A 24 85 31 26 1,2,3-triazole-4-carboxylic acid (4-didecylaminesulfonyl-phenyl)decylamine 4-amino-N,N- Dimethylbenzene-continued amine A 24 85 23 27 1,2,3-triazole-4-carboxylic acid (2,4·di-nitro-6-methyl-phenyl)-bristamine 2,4-dichloro -6-mercaptoaniline A 48 85 24 28 1,2,3-triazole-4-carboxylic acid (6-fluoroindol-3-yl)guanamine 3 -amino-6-gas - 喧琳 A 18 85 26 29 1,2,3-triazole-4-carboxylic acid (8-fluoroquinolin-3-yl)decylamine 3-amino-8-gas_ 喧琳 A 18 85 46 s 70 200837061 30 1, 2,3-triazole-4·carboxylic acid (8-chloroquinolin-3-yl)guanamine 3 -amino-8-chloro_ A 18 85 8 31 1,2,3-triazole-4-carboxylic acid (7-fluoroindol-3-yl)guanamine 3-amino-7-gas- A 18 85 60 32 1,2,3-triazole-4-carboxylate Acid (2-chloro-4,6-dimorph-phenyl)-trending 2-chloro-4,6-difluoroaniline C 16 60 28 33 1,2,3-triazole-4-carboxylic acid (2, 3-dichlorophenyl)guanamine 2,3-dichloro-aniline A 2 80 29 34 1,2,3-triazole-4-carboxylic acid (5-chloroindole-2-yl)-nonylamine 2 -amino-5-chloroσ stopper B 18 80 5 35 1,2,3-triazole-4-carboxylic acid (5-bromo-pyridin-2-yl)-nonylamine 2-amino-5 - &gt; odor ratio 16 A 16 60 35 36 1,2,3_triazole-4-carboxylic acid [2,4-bis(trifluoromethyl)phenyl]decylamine 2,4·double (three Fluorine-fluorenyl)aniline C 2 60 3 37 1,2,3·triazole-4-carboxylic acid (5-nitropyridin-2-yl)nonanyl 2-amino-5-nitrol ratio bite A 96 100 16 38 1,2,3-Triazole-4-carboxylic acid [2-(methylaminesulfonyl)-phenyl] indigoamine 2-aminomethylbenzene-sulfonamide A 72 100 15 39 1,2,3-Tris-sodium-4-di-weilic acid (2,4,6-trifluorophenyl)decylamine 2,4,6-trifluoro-aniline C 1/3 (20 minutes) 20 21 40 1,2,3-triazole-4-carboxylic acid (6-methyl 2-amino-6·methyl A 20 100 33 71 200837061 oxy acridine-2-yl) decylamino group ° pyridine 41 1, 2,3-triazole"4.carboxylic acid (6-bromopyridin-2-yl)decylamine 2-amino-6- &gt; odor _ pyridine A 16 80 7 42 1,2,3-triazole-4-carboxylic acid (2,6-dichloro-4-phenylphenyl)-bristamine 2,6-dichloro-4-fluoroaniline B 16 60 25 43 1,2,3-triazole-4-carboxylic acid (4-trifluoromethyl-pyridin-2-yl) decylamine 2-amino-benzotrifluoromethyl ratio biting A 3 80 6 44 1,2, 3-triazole-4-carboxylic acid (4-mercaptopyridin-2-yl)guanamine 2-amino-4-methyl σ ratio bite 67 67 33 45 1,2,3-triazole-4- Carboxylic acid (2,5-dichloroσ ratio bit-3-yl) S-cetoamine 3-amino-2,5-dichloropyridine A 48 80 9 46 1,2,3-triazole-4-carboxylic acid (5-methylpyridin-2-yl)decylamine 2-amino-5-mercaptopyridine A 67 80 25 47 1,2,3-triazole-4-carboxylic acid (5-ethyl-6-methyl ^ σ -2 -2 - - - 酿 酿 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 3-chloro-5-trifluoromethylpyridin-2-yl) decylamine 2-amino-3-chloro-5·trifluoromethyl-mouth ratio A 67 80 3 49 1,2,3-triazole 4-carboxylic acid (2,6-dichloro-4-difluorodecylphenyl) decylamine 2,6-dichloro-4trifluorodecyl-aniline C 15 60 15 50 1,2,3-three Oxazole-4-carboxylic acid (5,6-dimercaptopyridin-2-yl)nonan-2-amino-5,6-dimethyl oxime A2 70 20 37 72 200 837061 51 1,2,3-triazole-4·carboxylic acid (5-methyl-indole-3-yl)decylamine 3-amino-5-methylindole A 48 80 43 52 1,2, 3-triazole-4-carboxylic acid (5-methoxy-indolepyrimidin-2-yl)-bristamine 2-amino-5-methoxyacridine A 44 80 59 53 1,2,3- Triazole-4-carboxylic acid (5,6-dimethoxy-pyridin-2-yl) decylamine 2-amino-5,6-dimethoxy oxime bit A 66 80 43 54 1,2,3 -Triazole-4-carboxylic acid (6-methyl-π ratio sigma-2-yl)charamin 2-amino-6-methyl bite A 67 80 48 55 1,2,3-triazole- 4-carboxylic acid (4,6-dimethoxy-pyridin-2-yl) decylamine 2-amino-4,6-dimercaptopyridine A 67 80 45 56 1,2,3-triazole-4 -carboxylic acid (3,5-dichloro-0-pyridin-2-yl)-bristamine 2-amino-3,5-dichloropyridine A 67 80 4 57 1,2,3-triazole-4- Carboxylic acid (4-mercaptopyrimidin-2-yl)guanamine 2-amino-4-methyl oxime C 1 68 6 58 1,2,3-triazole-4-carboxylic acid (pyrimidin-2-yl醯amine 2-amine cleavage C 18 25 6 59 1,2,3-triazole-4-carboxylic acid (3-methoxy-pyridin-2-yl) decylamine 2-amino-3-oxo Base ratio 48A 48 100 41 60 1,2,3-triazole-4-carboxylic acid (5-butoxy-acridin-2-yl) decylamine 2-amino-5- 44 定 A A 44 80 36 61 {6-[(1,2,3-Tris--4-carbonyl)amino] acridine-3-yl}amine (6-Amino-bite-3- Base)-amino hydrazine A 44 80 26 73 200837061 carboxylic acid tert-butyric acid tert-butyl ester 62 1,2,3-triazole-4-carboxylic acid [2-(N,N-didecyl) Acesulfonyl) phenyl]-nonylamine 2-amino-indole, hydrazine-dimethylbenzenesulfonamide A 66 80 12 63 1,2,3-triazole-4-carboxylic acid (5-ethoxy Base-Acridine·2·yl) guanamine 2-amino-5-ethoxyl ratio A 66 80 42 64 1,2,3-triazole-4-carboxylic acid (5-propoxy-oxime)咬-2-yl) guanamine 2-amino-5-propoxy group 唆A 66 80 40 65 1,2,3-triazole-4-carboxylic acid (6-decyloxy-5-methyl Acridine-3-yl) decyl 3-amino-6-methoxy-5-methylindole A 48 80 42 66 1,2,3-triazole-4-carboxylic acid (5-phenyl- Τι比σ _ 3 -yl) acid amine 3-amino-5-phenylpyridine A 48 80 22 67 1,2,3-triazole-4-carboxylic acid (5-propyl_TJ ratio σ- 2-based) 2-amino-5-propyl σ 唆A1 18 25 16 68 1,2,3-triazole-4-carboxylic acid (5-ethyl ° ratio σ- 2 -yl) Amine amine 2-amino-5-ethyl guanidine A 18 80 59 69 1,2,3-triazole-4-carboxylic acid 6-Trifluoromethylpyridin-2-yl)guanamine 2-amino-6-difluoromethyl-acridine B 18 60 7 1 The reaction mixture was heated at the specified temperature for 3 days at rt before the specified time. . 74 1

Substitution of TBTU with bromotripyrrolidinyl squarroperaphosphate (PyBroP, 470 mg, 1.0 mM) Table 2- Physical properties of the compounds of Examples 1-69 200837061

Ex. MW MS (M+l), m/z 4 NMR (DMSO-d6, 400MHz), δ 1 239.24 240 14·9 ( br · s, 1H), 10.92 ( s, 1H), 9·22 (d , 1H) , 8.84 ( d, 1H), 8.61 ( br · s, 1H), 7.97 ( t, 2H), 7.68 ( t, 1H) , 7.59 ( t, 1H) 2 240.63 241 9.17 ( s, 1H) , 8.42 ( dd,1H), 8.26. ( s,1H) , 7.13 ( dd,1H), 7.00 ( ddd,1H) 1 3 257.08 257 9·29 ( s,1H),8.55 ( s,1H),7.89 ( d,1H) ,7·69 ( d,1H) , 7.43 (dd,1H) 4 206.18 207 10.45 ( s,1H) , 8.80 ( s,1H), 7.81-7.77(m,2H),7.17-7.11( m, 2H) 5 239.24 240 10.73 ( s,1H) , 8.89 ( d,1H), 8.69 ( s,1H) , 8.18 ( d,1H), 8.05 ( d,1H) , 8.00 ( d,1H), 7.81 ( t,1H) , 7.67 ( t,1H) 6 291.52 291 10.13 ( s,1H) , 8.64 ( s,1H), 7.92 ( s,1H) , 7.71 ( s,1H) 7 223.62 224 10.41 ( br_ s, 1H), 8.67 ( s, 1H), 8.42 ( d,1H) , 8.18 ( d,1H), 7.96 ( dd,1H) 8 188.19 189 10.36 ( s,1H) , 8.50 ( s,1H), 7.92 ( s ,1H) , 7.79 ( d,2H), 7.3 1 ( t,2H) ,7·07 ( t,1H) 75 20083706 1

9 257.08 257 10.73 ( s,1H) ,8·55 ( s,1H), 8.18 ( d,1H) , 7.92 ( s,1H), 7.82 ( dd,1H) ,7·58 ( d,1H) 10 222.63 223 9.88 ( s,1H), 8.59 ( s,1H),7·94 (d,1H) , 7.54 ( dd,1H) &gt; 7.37 (dt,1H) , 7.22 ( dt,1H) 11 257.18 258 8.67 ( m,1H) , 8.44 ( m,2H), 8.12 ( dd,1H) 2 12 291.52 291 10.00 ( s,1H), 8.63 ( br · s,1H), 8.23 ( s,1H) ,7.99 ( s,1H 13 216.24 217 9.77 ( s,1H), 8.46 ( s,1H), 7.29 (d,1H) , 7.04 ( s,1H) , 6.98 (d,1H) , 2.25 ( s,3H) ,2·18 ( s,3H) 14 257.08 257 9·93 ( s,1H), 8.64 ( s,1H), 8.08 (d,1H) , 7.59 ( d,1H) , 7.31 (dd,1H) 15 207.17 208 15.73 ( br · s,1H) , 10.35 ( br· s, 1H), 8.69 ( br· s,1H), 8·40 ( d, 1H) , 8_13·8.21 ( m,1H) , 7.82 (ddd,1H) 16 248.24 249 9.29 ( s,1H), 8.53 ( s,1H),7_98 (d,1H) ,6_67 ( d,1H) ,6·53 (dd,1H) ,3.87 ( s,3H) ,3.75 (s,3H) 17 282.69 283 9·46 ( 1H, s), 8.60 ( 1H, br· s), 8.14 ( 1H, s), 7.23 ( 1H, s ), 3.89 (3H, s), 3.81 (3H, s) 76 200837061 18 236.66 237 10.44 ( 1H, s) , 8.51 ( 1H, s), 7.81 ( 1H, d) , 7.66 ( 1H, dd), 7.35 ( 1H,d) , 2.32 ( 3H,s) 19 230.27 231 10.28 ( 1H,s) , 8.48 ( 1H,s), 7.69 ( 2H,d) ,7.19 ( 2H,d), 2.85 ( 1H, 七重峰),1·20 ( 3H, s) , 1·18 ( 3H,s) 20 323.38 324 10.79 ( s,1H) , 8.57 ( s,1H), 8.03 ( d,2H) , 7.74 ( d,2H), 3.13 ( q,4H) , 1.03 ( t,6H) 21 240.23 241 15.85 ( br.s,1H) , 11.10 ( br.s, 1H), 9.67( s,1H), 8.77( s,1H), 8.10 ( Dd,1H),8.96 ( dd,1H), 7·85 ( dt,1H) ,7.77 ( dt,1H) 22 267.27 268 15.9-15.6( 1H,br. s),10.71 ( 1H, s),8· 56( 1H,s),8.00( 2H,d), 7.79 ( 2H,d) ,7.27 ( 2H,s ) 23 252.66 253 15.9-15.6 ( 1H,br· s),9·48 ( 1H, s), 8·63 ( 1H, s), 8·21 ( 1H, d), 7·21 ( 1H, d) , 7.06 ( 1H, dd), 3.95 ( 3H, s) 24 271.11 271 15.9-15.7 ( 1H, br · s), 9.94 ( 1H, s), 8.63 ( 1H, s), 7.88 ( 1H, d), 7.50 ( 1H, d) , 2 .48 ( 3H,s) 25 281.30 282 15.8-15.7( 1H ^ br. s), 10.78 ( 1H, s), 8.58 ( 1H, s), 8.04 ( 2H,d), 7·76 ( 2H,d) , 7.33 ( 1H, q), 2.41 ( 3H,d) 77 200837061 26 295.32 296 15.9-15.7 ( 1H, br · s), 10.85 ( 1H, s), 8.61 ( 1H, s), 8, 12 ( 2H, d), 7.73 ( 2H,d) , 2.61 ( 6H,s) 27 271.11 271 15.8-15.6( 1H,br. s),10.16( 1H, s),8·51 ( 1H,s), 7.56 ( 1H, d), 7.43 ( 1H,d) , 2.23 ( 3H,s) 28 257.23 258 15.91-15.67 ( 1H,br. s ) ,10.97 (1H,s ) , 9.20 ( 1H,d ) ,8.87 (1H,d) , 8.73 - 8.54 ( 1H, br · s), 8.02 ( 1H, dd), 7.79 ( 1H, dd), 7·56 ( 1H, ddd ) 29 257.23 25 8 15.97-15.65 ( 1H, br · s ) , 11.04 (1H, s) , 9.28 ( 1H, d) , 8.94 (1H, dd), 8.74 - 8.54 ( 1H, br. s), 7.80 ( 1H, br · d), 7.58 ( 1H, ddd ), 7.49 ( 1H , dd) 30 273.68 274 15.95-15.60 ( 1H, br · s ) , 11, 06 (1H, s) , 9.33 ( 1H, d) , 8.96 (1H, d), 8.69 - 8.54 ( 1H, br · s) , 7.96 ( 1H, dd), 7.84 ( 1H, dd), 7.57 ( 1H, t) 31 257.23 258 16.26-15.24 ( 1H, b r· s ) , 10.95 (1H, s) , 9·25 ( 1H, d) , 8·90 (1H, d), 8.65: 8.57 ( 1H, br· s), 8.08 ( 1H &gt; dd ), 7 · 72 ( 1H, dd), 7.75 ( 1H, dt) 32 258.61 259 15.73 ( br. s, 1H), 10.26 ( s, 1H), 8.55 ( br · s, 1H) , 7 · 54-7 · 44 ( Ιι, 78 200837061

2H) 33 257.08 25 7 15.81 ( br_ s,1H), 10.07( s,1Η), 8.63 ( s,1H) ,7·94 ( dd,1H), 7.51 ( dd,1H) , 7.42 ( dd,1H) 34 229.65 230 8.46 ( br. s, 1H) , 7.39 ( s, 1H) 2 3 5 268.07 268 15.83 ( br. s, 1H), 10.43 ( s, 1H), 8.69 ( s, 1H) , 8.51 ( d, 1H), 8.14 (d,1H), 8.11(dd,1H) 36 324.18 325 15.87( br· s,1H),10.15( s,1H), 8.69 ( s,1H),8·23_8·11 ( m, 3H) 37 234.17 235 16.40-15.17 ( br. s, 1H), 11.07-10.93 (br· s, 1H), 9.22 ( d, 1H), 8.82 - 8.73 (br. s, 1H) , 8.68 ( dd &gt; 1H), 8.40 ( dd, 1H) 38 281.29 282 16.29-15.29 ( br · s, 1H ) , 10.84 (s, 1H) , 8.62 ( s, 1H) ^ 8.55 (dd, 1H), 7·87·7· 79( br. s,1H), 7.82 ( dd,1H), 7.70 ( ddd,1H ), 7.34 ( ddd,1H),2·46 ( br. s,3H ) 39 242.16 243 15.78 ( br. s,1H ), 10.22( s,1H), 8.54 ( s,1H),7.3 7-7.26 ( m,2H) 40 219.20 220 15.88-15.70 ( br. s ^ 1H), 9.88-9.75 (br· s,1H) , 8·73_8·62 ( br_ s, 1H) , 7.77-7.75 ( m, 2H) , 6_60 (dd, 1H) , 3.87 ( s, 3H) 41 268.07 268 15.74 ( br. s, 1H) , 10.61 ( br · s, 1H) , 8.70 ( s, 1H) , 8.17 ( d, 79 200837061

1H) , 7.81 ( dd, 1H) , 7.43 ( d, 1H) 42 275.07 275 15.72 ( br. s, 1H), 10.37 ( s, 1H), 8.54 ( s, 1H) , 7_66 ( d, 2H) 43 257.17 258 15.82( br· s,1H), 10.74( s,1H), 8.72 ( s,1H) , 8.69 ( d,1H), 8.49 ( s,1H) ,7·57 ( d,1H) 44 203.20 204 15.85 :15.61( br. s,1H),10·10-9_91 (br· s,1H),8.65 ( s,1H) ^ 8.22 (d,1H) ,8.06 ( dd,1H) , 7.68 (dd,1H) , 2.28 ( s, 3H) 45 258.06 258 16,09-15.58 ( br. s ^ 1H ) , 10.07 (s, 1H), 8.74 - 8.62 ( br. s, 1H), 8.52 ( d, 1H) , 8.38 ( d,1H) 46 203.20 204 15.81-15.67 ( br· s,1H ) ,10.00 (br· s,1H),8.67 ( s,1H) &gt; 8.23 (d,1H) ,8.02 ( dd,1H) ,7.03 (dd,1H) , 2.36 ( s,3H) 47 231.25 232 15.77 ( br. s,1H) , 9.94 ( br· s, 1H) , 8.66 ( s,1H) , 7.94 ( d, 1H) , 7.61 ( d , 1H) , 2.60 ( q, 2H), 2.43 ( s, 3H), 1.17 ( t, 3H) 48 291.92 292 15.93-15.66 ( br. s, 1H), 10.99-10.83 (br· s, 1H) , 8.89 (m, 1H), 8.70-8.57 ( br · s, 1H) , 8.61 ( d, 1H) 49 325.07 3 25 15.78 ( bT· s,1H) , 10.66 ( br. s, 1H), 8.57 ( br. s, 1H), 8.07 ( s, 80 200837061

2H) 50 217.23 218 15·83 ( br. s, 1H) , 9.92 ( br. s, 1H) , 8.63 ( s, 1H) , 7.79 ( d, 1H), 7.58 ( d, 1H), 7.58 ( d, 1H), 2.39 ( s, 3H), 2.23 ( s, 3H) 51 203.20 204 15.94-15.51 ( br. s, 1H ) , 10.59 (s, m) , 8.79 ( d, m) , 8.55 (br· s,1H),8.16 ( m,1H),8·07 (m,1H) ,2.30 ( s,3H) 52 219.20 220 16.20-15.27 ( br· s,1H ) ,10.09 (br. s,1H), 8.63( s,1H), 8.11-8.07 (m,2H), 7.50 ( dd,1H) ^ 3.83 (s,3H) 53 249.23 250 15.98-15.46 ( br. s &gt; 1H) ^9.81-9.58 (br. s ^ 1H) ^ 8.71-8·53 ( br · s, 1H), 7.65 ( d,1H), 7.38 ( d,1H) , 3.89 ( s,3H), 3.78 ( s,3H) 54 203.20 204 16.29- 15.28( br· s,1H), 10.21-9.87 (br· s,1H),8·67 ( s,1H),7.99 (d,1H) ,7·74 ( dd,1H) ,7·04 (d ,1H) ,2.44 ( s,3H) 55 217.23 218 15.93-15.58( br · s,1H),10.01-9.72 (br· s,1H) ,8.66 (s,1H) ,7.84 ( s,1H) ,6 ·89 (s,1H) ,2·88 ( s,3H) ^ 2.84 (s,3H) 56 258.06 258 15.91-15.56( br. s,1H),10.79-10.69 81 200837 061

(br. s,1H) , 8.62 - 8.51 ( br. s 5 1H) , 8.55 ( d,1H) , 8.36 ( d, 1H) 57 204.19 205 15.23 ( br. s,1H) , 10.37 ( br. s, 1H), 8.61 ( br. s, 1H), 8.58 ( d, 1H) , 7.16 ( d, 1H) , 2.45 ( s, 3H) 58 190.16 191 15.7 ( br_ s, 1H), 10.47 ( s, 1H), 8.74 ( d,2H) , 8.65 ( s,1H), 7.28 ( dd,1H) 59 219.20 220 15.83-15.51 ( br · s,1H),10.07-10.00 (br· s,1H) ,8.66-8.43 ( br · s, 1H), 8·01 ( dd, 1H), 7.52 ( dd, 1H) , 7.28 ( dd, 1H) , 3.85 ( s, 3H) 60 261.28 262 16.23-15.42 ( br. s, 1H), 10.27 -9.90 (br· s,1H) , 8.63 (s,1H) , 8.10-8.06 ( m,2H), 7.50 ( dd,1H),4.05 ( dd,2H), 1.76-1.66( m,2H),1.51 -1.38( m, 2H) , 0·95 ( t,3H) 61 304.30 305 16.13-15.32 ( br. s,1H), 10.25-9.97 (br· s,1H) ,9.54 ( s,1H) ,8· 63 (s,1H) , 8.44 ( d,1H) , 8.07 (d,1H) , 7.90 ( dd,1H) , 1.48 (s,9H) 62 295.32 296 16.10-15.58 ( br· s,1H ) ,10.90 ( s,1H),8.73-8.55 ( br· s,1H), 82 200837061 8.62 ( dd,1H),7·8 3 ( dd,1Η), 7.76 ( ddd,1H),7.3 8(ddd,1H ), 2·69 ( s,6H) 63 233.23 234 15.97-15.52( br· s,1H),10.27-9.90 (br. s, 1H), 8.63 ( s, 1H), 8.10-8.05 (m, 2H), 7.50 ( dd, 1H) , 4.10 (q, 2H) , 1.34 ( t, 3H) 64 247.25 248 15.93-15.34 ( br. s,1H), 10.19-9.93 (br· s,1H) , 8.63 (s,1H) , 8.10-8.05 ( m,2H), 7.50 ( dd ^ 1H) , 4.00 ( t,2H), 1.77-1.70 ( m,2H), 0.99 ( t,3H) 65 233.23 234 15.91-15.36 ( br · s,1H ) , 10.42 (s,1H), 8.51 ( br · s,1H),8·38 (d,1H) , 7·94 ( d,1H) , 3.87 (s,3H) , 2·16 ( s,3H) 66 265.27 266 16.28-15.10 ( br. s,1H ) , 10.76 (s,1H) ,9.03 ( d,1H ), 8.63 (d,1H), 8.58 ( br. s,1H) , 8.51 (dd,1H) , 7.74 - 7.68 (m, 2H), 7.54-7.40 ( m,3H) 67 231.25 232 15.74 ( br. s , 1H) , 10.07 ( br · s, 1H) , 8.64 ( s, 1H) , 8.22 ( d, 1H) , 8·08 ( d, 1H) , 7.70 ( dd, 1H) , 2.54 ( q , 2H ) , 1.58-1.63 (m,2H) ,0.90 ( t,3H) 68 217.23 218 15.76 ( br· s,1H) ,10.09 ( br· s, 1H ), 8.66 ( s, 1H) , 8.24 ( d, 83 200837061 1H), 8.09 ( d,1H), 7.73 ( dd, 1HQ j 2.6i ( q &gt;2H)^|&gt;2〇( t,3H) 8.52 ( d,1H),8·43 (br s,1H), (dd,1H)丄丄[4 ( d,1H) 1 is performed in CDC13, 400 MHz 2 is performed in CD3OD, 4〇〇mHz is implemented Example 70-78

(a) $2 base ethoxymethyl 1-1,2,3:^_^4_carboxylic acid aryl amide amine butyl lithium (U Μ, ML, 17 mM in hexane Mohr) is added dropwise to 1-[2_(trimethyl sulphate) ethoxymethyl b, % 3 4 (3:1 mixture of isomers, prepared as previously described, 3 〇〇 mg, 15 Milliol) Cool to -20oC in THF (20 mL). Stir the mixture for 30 minutes at _2〇〇c and cool to _78〇Ce dropwise

A solution of chlorate (-&gt; millimolar) in THF (5 mL) and a mixture of &lt;1&gt; Et2(R) (20 mL) and NH4C1 (1 mL of a saturated aqueous solution) were added and the layers were separated. Extract the aqueous phase and dry with Et2〇 (2x2() mL)

(The mixture was concentrated and concentrated. The residue was purified by chromatography (EtOAc EtOAc / EtOAc) toield toield of the subtitle product ( intermediate (a) 32 to 4 〇).

Stirring at the rt of 3-(2-trimethyldecylethoxymethyl)β1,2,3•三坐4竣|^ arylamine (1()亳莫耳) and (2 in (10)η 7 84 200837061 Sacrifice, 1 _5 liters) mixture for 2 〇 minutes and concentrated. The residue was purified by chromatography (eluent Et EtOAc / hexane) to afford white or yellow powder of the title product (Examples 32 (b) to 4 (b)). Interstitials and Examples f, (b) 70 to 78 • Steps -------- Name the aryl isocyanate yield in step (a) % 70 (a) 3-[2-(Trimethoate) Ethoxymethyl]-1,2,3-triwax-4-weilic acid 2,4,6-trichlorophenylguanamine 2,4,6-trichlorophenyl-isocyanate (b) 1,2,3-triazole-4-carboxylic acid (2,4,6-trichlorophenyl)decylamine 56 71 (a) 3-[2-(trimethylsulfonyl)ethoxymethyl -1,2,3-triazole-4-carboxylic acid 2-(trifluoromethyl)phenyl decylamine 2_(trifluoromethyl)-phenylisocyanate 59 (b) 1,2,3 Triazol-4-carboxylic acid 2-(trifluoromethyl)phenyl decylamine 39 72 (a) 3-[2-(tridecyl)ethoxyindolyl]_1,2,3-triazole 4-carboxylic acid 4-nitrophenyl decylamine 4-nitrophenyl-isocyanate 59 (b) 1,2,3-triazole-4-carboxylic acid 4-nitrophenyl octaamine 58 73 (a 3-[2-(Trimethyl decyl)ethoxy fluorenyl]-1,2,3-triazole-4-carboxylic acid 2-nitro-4-(trifluoromethyl)phenyl decylamine 2- Nitro-4-(trifluoromethyl)-phenylisocyanate 34 85 200837061 (b) 1,2,3-triazole-4-carboxylic acid 2-nitro-4-(trifluoromethyl)phenylhydrazine Amine 74 74 (a) 3-[2-(trimethyl)ethoxy oxime -1,2,3-tris--4-dicarboxylic acid 4-fluoro-2-(trifluoromethyl)phenyl decylamine 4·fluoro-2-(trifluoromethyl)-phenylisocyanate 48 ( b) 1,2,3-triazole-4-carboxylic acid 4-fluoro-2-(trifluoromethyl)phenyl decylamine 39 75 (a) 3-[2-(trimethyldecyl)ethoxymethyl -1,2,3-triazole-4-carboxylic acid 4-chloro-2-(trifluoromethyl)phenyl decylamine 4-chloro-2-(trifluoromethyl)-phenylisocyanate 38 ( b) 1,2,3-triazole-4-carboxylic acid 4-chloro-2-(trifluoromethyl)phenyl decylamine 76 76 (a) 3-[2-(tridecyl)ethoxy Methyl]-1,2,3·triazole-4-carboxylic acid 4-chloro-2-fluorophenylguanamine 4-chloro-2-fluorophenylisocyanate 3 8 (b) 1,2 , 3-triazole-4-carboxylic acid 4-chloro-2-phenylphenylguanamine 55 77 (a) 3-[2-(trimethylsulfonyl)ethoxymethyl]·1,2,3-tri Oxazole-4-carboxylic acid 2-chloro-4-(trifluoromethyl)phenyl decylamine 2-chloro-4-(trifluoromethyl)-phenylisocyanate 42 (b) 1,2,3-triazole 4-carboxylic acid 2-chloro-4-(trifluoromethyl)phenyl decylamine 73 86 200837061

78 U) 3_[2-(Trimethyl)ethoxymethyl 2-fluoro-6·(trifluoroindolyl)-, 2,3-triazole-4-carboxylic acid 2-yl)phenyl Isocyanate-6-(difluoromethyl)phenyl-carboxamide (b) 1,2,3 -trim-4 -teric acid 2-fluoro-6-(trifluoromethyl)phenyl decylamine 60 Table 4 - Physical properties of intermediates (a) 70 to 78 and examples (b) 70 to 78

Ex. Step MW MS (M++1), m/z lU NMR (DMSO-d6, 400 MHz), δ 70 (a) 421.78 421 10.83 (s, 1H), 8.48 (s, 1H), 7.86 (s, 2H) &gt; 6.01 (s, 2H), 3·59 ( t, 2H), 0·08 ( t, 2H), -0.09 ( s, 9H) (b) 291.52 291 15.60 ( br. s, 1H), 10.39 ( s, 1H) , 8.5 ( s. 1H), 7.80 ( s, 2H) 71 (a) 386.44 387 10.58 ( s, 1H), 8.41 ( s, 1H), 7.88-7.74 ( m, 2H), 7.64 -7.49 ( m,2H),6·00 ( s, 2H) , 3.58 ( t,2H), 0.82 ( t,2H), -0.08 ( s,9H) (b) 256.19 257 15.77 ( br. s,1H ), 9.97 ( s, 1H) , 8.57 ( s, 1H) , 7.84 - 7.71 ( m, 3H) , 7.49 ( t, 1H) 87 200837061 72 (a) 363.44 364 12.00 ( s, 1H), 8.49 ( s,1H), 8.30 ( d,1H) ,7.99 (d,1H) ,6_02 ( s,2H), 3.59 ( t,2H),0.82 ( t,2H), -0.10 ( s,9H) (b) 233.19 234 15.80 ( br. s, 1H), 11.02 ( s, 1H) , 8.62 ( s, 1H), 8.26 (d, 2H), 8.13 (d, 2H) 73 (a) 431.44 431 11.36 ( s, 1H) , 8.50 ( s, 1H), 8.38 ( d, 1H) , 8.19 (dd, 1H), 7.90 ( d, 1H), 5.97 ( s, 2H), 3.57 ( t, 2H), 0.82 ( t,2H), -0.09 ( s,9H) (b) 301.19 302 15.94 ( br. s,1H),11·66 ( s, 1H) , 8.71 ( s,1H), 8.63( d,1H) , 8.45( d,1H), 8.19 ( dd,1H) 74 (a) 404.43 405 10.55 ( br. s,1H), 8.34 ( s, 0.67H) , 8.25 ( s, 033H), 7.77-7.52 ( m, 3H), 5.96( s,2H), 5.68( s,1H), 3.55 ( t,2H), 0.80 ( t,2H), -0_07 ( s,3H), -0.09 ( s,6H) (b) 274.18 275 15·74 ( br· s,1H), 10.04 ( s, 1H) , 8.54 ( s,1H) ^ 7.80-7.60 ( m,3H) 88 200837061 75 (a) 420.89 421 10.63 ( br. s,1H) , 8.40 ( s, 1H) , 7.11 ( d,1H) , 7.86 (dd,1H),7·59 ( d,1H), 5_99( s,2H),3.57( t,2H), 0.81(t,2H ), -0.08 ( s, 9H) (b) 290.63 291 15.79 ( br. s, 1H), 10.03 ( s, 1H ) ; 8_58 ( s, 1H ) , 7·87 (d, 1H), 7·83 ( m,2H) 76 (a) 370.88 371 10.62( s,1H)° 8.45( s. 1H), 7.70-7.54( m,2H), 7.36( ddd, 1H ) ,6.00 ( s,2H ) ,3.58 (t , 2H) , 0.81 ( t, 2H), 0.09 ( s, 9H) (b) 240.63 241 15.74 ( br. s, 1H ) , 10.12 (s, 1H) , 8.55 ( s 1H), 7.75( t,1H), 7.55 ( dd,1H), 7.32 ( ddd,1H) 77 (a) 420.89 421 10.72 ( br. s,1H), 8.50 ( s, 1H) , 8.32 ( s, 1H ) ^ 7.88-7.78( m,2H),6.01 ( s,2H), 3·59 ( t,2H),0.83 ( t,2H), -0·08 ( s,9H) (b) 290.63 291 15.88 ( Br· s,1H),:10.05 ( s, 1H ) , 8.68 ( s,1H ) , 8.32 (d,1H) , 8·02 ( d,1H), 7.80 ( dd ^ 1H) 89 200837061 78 ( a) 404.43 405 10.64( s' 1H), 8.46( s,1H), 7.80-7.65 ( m,3H),6·〇〇( s, 2H), 3.56 ( t,2H),〇_81 7ΤΓ 274.18 275 ----- (t,2H),-0·09 ( s"9H) 15.73 ( br. s,m),l〇_2〇( s, 1H) ' 8.52(s' 1H),773_ 7.60 ( m,3H ) Example 7 9 - 1 0 S -~~-_ General procedure

Butyllithium (1.6 在 in hexane, 900 μl, 1.5 mmol) (iv) Add to / Example of three W-based) ethoxylated hydrazine, 2,3·tris-salt (isomer: ear 1: Compound 'prepared as described above, 21 〇 microliters '299 mg.. 5 isocyanate r (2:: min, cooled to _78 ° c and added dropwise to the relevant lower molars) 4THF (5 The solution in ML) and /:::30 minutes, soaked to rt and then stirred under η (16) in the mixture of 16% of the mixture and ^^ from ~Γ) ° after GhC for 4h , concentrated residue: production: = liquid (10) one, TM pure

90 200837061 Trifluorophenyl) decylamine isocyanate 81 1,2,3 · triazole-4-carboxylic acid (2-chloro-5-methylphenyl) decylamine 2-chloro-5-nonylphenyl isocyanate 21 82 1,2,3-triazole-4-carboxylic acid (3,5-dichlorophenyl) decylamine 3,5-dichlorophenyl-isocyanate 23 83 1,2,3-triazole-4-carboxylate Acid (2-fluoro-5-nonylphenyl) decylamine 2-fluoro-5-mercapto-phenylisocyanate 14 84 1,2,3-triazole-4·carboxylic acid (2-chloro-6-three Fluoromethylphenyl)guanamine 2-chloro-6-difluoro-methylphenylisocyanate 2828 85 1,2,3-triazole-4-carboxylic acid (5-chloro-2-indenyl) Phenyl) decylamine 5-chloro-2-methyl-phenylisocyanate 28 86 1,2,3·triazole-4-carboxylic acid (3,5-difluorophenyl)decylamine 3,5-difluoro Phenyl-isocyanate 22 87 1,2,3-triazole-4-carboxylic acid (3,4-difluorophenyl) decylamine 3,4-difluorophenyl-isocyanate 29 88 1,2,3-three Oxazole-4-carboxylic acid (2-fluoro-3-trifluoromethylphenyl)decylamine 2-fluoro-3-difluoromethyl-phenylisocyanate 19 89 1,2,3-triazole-4-carboxylate Acid (2,5-difluorophenyl)decylamine 2,5-difluorophenyl-isocyanate 34 90 1,2,3-triazole-4-carboxylic acid (2-fluoro·5-trifluoromethylbenzene base) Amine 2-fluoro-5-difluoromethyl-phenylisocyanate 29 91 1,2,3-di-sodium-4-decanoic acid (3-fail-4-methylphenyl)decylamine 3-fluoro-4 -methyl-phenylisocyanate 27 92 1,2,3-triazole-4-carboxylic acid (3-chloro-4-methylphenyl)decylamine 3-chloro-4-methyl-phenylisocyanate 26 93 1,2,3-triazole-4-carboxylic acid (3-fluoro-5-trifluoromethylphenyl)decylamine 3-fluoro-5-trifluoromethyl-phenylisocyanate 29 94 1,2, 3-difluorene-4-weilic acid (4-chloro-2- 4-chloro-2-methyl-phenyliso 27 91 200837061 methylphenyl) guanamine cyanate 95 1,2,3-triazole 4-carboxylic acid (4-methyl-3-trifluoromethylphenyl) decylamine 3-trifluoromethyl-4. nonylphenyl isocyanate 18 18 96 1,2,3-triazole 4-carboxylic acid (4-trifluoromethoxyphenyl)decylamine 4-trifluoromethoxyphenyl isocyanate 10 97 1,2,3-triazole-4-carboxylic acid (5-fluoro-2- Methylphenyl) decylamine 5-fluoro-2-methyl-phenylisocyanate 23 98 1,2,3-triazole-4-carboxylic acid (benzo[d][l,3]dioxolene (di oxo 1)-5-yl)decylamine 3,4-methylenedioxy-phenylisocyanate 20 99 1,2,3-triazole-4-carboxylic acid (4-gas-3-trifluoromethyl) Phenyl phenyl) guanamine 4- -3-trifluoro-methylphenyl-isocyanate 15 100 1,2,3-triazole-4-carboxylic acid (3-chloro-4-fluorophenyl)decylamine 3-chloro-4- Gas-phenyl isocyanate 32 101 1,2,3 -Tris(R)-4 ·Weric acid (3-trifluoromethylphenyl)decylamine 3-trifluoromethyl-phenylisocyanate 22 102 1,2,3 - Triazole-4-carboxylic acid (3-chloro-2-methylphenyl) decylamine 3-chloro-2-indolyl-phenyl isocyanate 21 103 1,2,3-triazole-4-carboxylic acid ( 4-fluoro-3-trifluoromethylphenyl)decylamine 4-fluoro-3-tris-decylphenylisocyanate 4104 1,2,3-triazole-4-carboxylic acid (2, 6-diisopropylphenyl)guanamine 2,6-diisopropyl-phenyl-isocyanate 25 105 1,2,3-triazole-4-carboxylic acid [3,5·bis(trifluoromethyl) Phenyl]decylamine 3,5-bis(trifluoro-indolyl)-phenylisocyanate 25 Table 6 - Physical Properties of Examples 79-105

Ex. M.W MS (M++l), NMR (DMSO-d6,400MHz), m/z δ 92 200837061

79 220.20 221 10.41 ( s,1Η) ,8·55 ( s,1H), 7.78( d,1H),7.71-7.65( m,1H), 7.16(dd,1H) 80 242.16 243 10.44 ( s,1H) , 8.62 ( s, 1H), 7.53-7.36 ( m, 2H) 81 236.66 237 9.82 ( s &gt; 1H), 8·60 ( br · s, 1H), 7·82 ( br · s, 1H), 7.43 ( d,1H), 7.06 ( dd,1H) , 2·32 ( s,1H) 82 257.08 257 10.79 ( s,1H), 8.59 ( br· s,1H), 8.00-7.95 ( m &gt; 2H), 7.32 ( dd, 1H) 83 220.20 221 15.74 ( br · s, 1H), 9.96 ( s, 1H), 8.56 ( br. s ^ 1H), 7.55 ( d, 1H), 7.18 ( dd, 1H), 7.03 7.07( m,1H), 2.30 ( s,3H) 84 290.63 291 10.09 ( s,1H), 8.68 ( br · s,1H), 8.38 ( d,1H) , 7.84 ( d,1H), 7_62 ( dd, 1H) 85 236.66 237 9.93 ( s, 1H), 8.55 ( br · s, 1H), 7.63 ( dd, 1H). 7.32 ( d,1H), 7.21 ( dd ^ 1H) , 2_25 ( s· 3H) 86 224.17 225 10.82 ( s,1H) , 8·58 ( s,1H). 7.63 ( d,2H) , 6.95 ( dd,1H) 87 224.17 225 10.75 ( s,1H) , 8.63 ( s,1H), 8·05 ( ddd,1H) , 7.76-7.70 ( m, 1H) , 7.49 ( Dd,1H) 88 274.17 275 10.38 ( s,1H) , 8.59 ( s,1H), 8.00 ( dd,1H), 7.64 ( dd,1H), 7.44 ( dd,1H) 93 200837061

89 224.17 225 10.14 ( s,1H),8·66 ( br· s,1H), 7.73-7.78 ( m,1H),7.39-7.47( m, 1H) , 7.13-7.20 ( m,1H) 90 274.17 275 10.33 ( s,1H) , 8.65 ( s,1H), 8.23 ( d,1H), 7.75-7.69 ( m,1H), 7.63 ( dd,1H) 91 220.20 221 10.42 ( s,1H) ,8·44 ( s,1H), 7.63 ( d,1H) ,7·44 ( d,1H), 7.14 ( dd,1H) 92 236.66 237 10.58 ( s,1H) ,8·60 ( s,1H), 8.06 ( d, 1H) , 7.74 ( dd, 1H), 7.38 ( d, 1H) 93 274.17 275 15.47 ( br · s, 1H), 10.97 ( s, 1H), 8.60 ( s, 1H) , 8.17 ( s, 1H), 8.05 ( d,1H) , 7.36 ( d,1H) 94 236.66 237 9.94 ( s,1H) ,8·52 ( s,1H), 7.49 ( d,1H) ,7_37 ( d,1H), 7.27 ( dd,1H ), 2.25 ( s, 3H) 95 270.21 271 10.68 ( s, 1H) , 8_55 ( s, 1H), 8 · 25 ( d, 1H) , 7.99 ( d, 1H), 7.41 ( d, 1H) 96 272.18 273 15.71( br. s,1H), 10.63( s' 1H), 8.55 ( s,1H) , 7.93 ( d,2H), 7.37 ( d,2H) 97 220.20 221 9.85 ( s,1H),8·55 ( Br· s,1H), 7.48 ( ddd,1H), 7.30 ( dd,1H), 6.99 ( ddd· ,1H) , 2.25 ( s,3H) 98 232.20 233 10.30 ( s,1H),8.48 ( br· s,1H), 94 200837061 7.46 ( d,1H) ,7·27 ( dd,1H), 6.88 ( d , 1H) , 6.00 ( s, 3H) 99 190.63 291 15.82 ( br. s, 1H), 10.92 ( s, 1H), 8 · 59 ( s, 1H), 8.46 ( d, lH), 8.16 (dd, 1H) ),7·73 ( d,1H) 100 240.62 241 10.68 ( s,1H) ,8·56 ( s,1H), 8.12 ( dd,1H), 7.81 ( ddd,1H), 7.41(dd,1H) 101 256.18 257 10.77 ( s,1H) , 8.57 ( s,1H), 8·31 ( s,1H) , 8.11 ( d,1H), 7.59 ( dd,1H) , 7.45 ( d,1H) 102 236.66 237 10.19 ( s,1H),8·53 ( br· s,1H), 7.42-7.34 ( m,2H), 7.25 (dd,1H) 103 274.17 275 15.87( br· s,1H), 10.90( s,1H), 8.65 ( s,1H) , 8.42 ( dd,1H), 8.28-8.20 ( m,1H), 7.59 ( dd,1H) 104 272.35 273 9.89 ( s,1H) , 8.47 ( s,1H), 7.27 ( dd, 1H) , 7.20 ( d, 2H), 3·08 (seven peaks, 2H), 1.13 ( d, 12H) 105 324.18 325 11.15 ( s, 1H) , 8.48 ( s, 1H), 8.40 ( s, 2H) , 7.90 ( s,1H), 6.02 ( s,2H) ,3.59 ( dd,2H), 0 .82 ( s, 2H) , -0.11 ( s, 9H) Example 106 The title compound of the Example was tested in the above biological test and found to show IC5 of 10 μΜ or less. . For example, representative compounds of the following examples show the following IC5Q values: 95 200837061 Examples Examples Examples Examples Examples Examples Examples Examples Examples Examples Examples Examples 1 : 1400 ηΜ 6 : 330 Μ Μ 7 : 1800 η Μ 9 : 1600 η Μ 12 : 760 η Μ 18 : 950 η Μ 35 : 810 η Μ 36 · · 1160 η Μ 73 : 3800 η Μ 75 : 250 η Μ 76 : 530 η Μ 82 : 4100 η Μ 91 : 9400 η Μ

[Simple description of the diagram] None [Main component symbol description]

Claims (1)

200837061 X. Applying for a patent: 1 · A compound of formula I, Wherein w represents an aryl or heteroaryl group, which are optionally substituted by one or more substituents selected from the group consisting of: 1) G1; 2) aryl or heteroaryl, both of which are optionally one or more a substituent selected from the group consisting of VIII, -N3, -N02*-S(0)pR6e; and 3) a heterocycloalkyl group, optionally containing one or more selected from the group consisting of a2, -N3, -N〇2 Substituted with a substituent of =0; G1 represents _, -R3a, -CN, -C(0)R3b, -C(0)0R3c, -C(0)N(R4a)R5a, -N(R4b)R5b -N(R3d)C(0)R4c, -N(R3e)C(0)N(R4d)R5d, -N(R3f)C(0)OR4e, -N3, -N02, -N(R3g)S (0) 2N(R4f)R5f, -OR3h, -0C(0)N(R4g)R5g, -0S(0)2R3i, -S(0)mR3j, -N(R3k)S(0)2R3m, -0C (0) R3n, -OC(0)OR3p, -S(0)2N(R4h)R5h, -S(0)20H, -P(0)(0R4i)(0R5i) or -C(0)N(R3q S(0)2R3r; R3a represents a Cu alkyl group optionally substituted with one or more substituents selected from the group consisting of Z, F, Cb-N(R6b)R6e, -N3, =0 and -OR6d; R3b, R3c, R3h, R3n and R4a to R4h independently represent Η, Z or as desired 97 200837061 R h independently of C14 alkyl; Ci 6 alkyl R3d to m substituted by one or more halogen atoms or -〇R6d R3k, R3q, R5a, R5b R5d and R5f ^ H shown or optionally substituted with one or more of Southern Shi atom or a substituted or _〇R6d r and R5a, c and R5b, R4 ^ R5d, R4 ^ R5f, R4 Ruler, R5h pair ' can be bonded to form a 3- to 6-membered oxime, :: except: these substituents must be attached to their nitrogen atom as needed: the step-by-step heteroatom, and the ring Replacing with cv6 alkyl substituted by hydrazine or, if desired, by a gas atom; Γ: R3j, R3m, R3P and R3r independently represent z or CV6 optionally substituted with or substituted by substituents derived from B丨Alkyl; a R41 and R5i independently represent H or, as desired, substituted by one or more substituents, c"alkyl; taken as z: a) optionally selected from one or more selected from 八3 and =〇 a substituent substituted with a ^^/3⁄4 b) aryl or heteroaryl group, both of which are optionally substituted by one or more substituents selected from the group consisting of A4, N3, -N〇2 and ·S(〇)qR7e AA, A3 and A4 independently represent spectrin, -R6a, _CN, -N(R6b)|^6c or -OR6d; R to R6d independently represent hydrazine or optionally one or more substituents selected from B3 Substituting (^_6 alkyl; R6a, R6e and independently representing an alkyl group substituted with one or more substituents selected from B4; or 98 200837061 ❶ and R6e may be bonded together to form 3- to 6-member ring, the ring In addition to the nitrogen atom to which these substituents must be attached, further heteroatoms are optionally included, and the ring is optionally substituted with a fluorene or a C 6 alkyl group substituted with one or more fluorine atoms as desired; B1, B2 B3 and B4 independently represent f, CBu·0€Η3, -〇ch2CH3, -〇CHF2, -〇CH2CF3, -〇CF3 or -OCF2CF3; and m, P and q independently represent 〇, 1 or 2, _ Or a pharmaceutically acceptable salt thereof, wherein the conditions are: (A) When W represents a phenyl group substituted with a g1 substituent at the ortho position, G1 represents R3a, and R3a represents z-substituted ethynyl, z Represents a 2-mercapto group substituted by a4 at the 4_ position, and A4 represents R6a, then R6a does not represent a cyclobutyl group; (B) when W represents a 6-quinazolinyl group substituted by G1 at the 4-position, G1 represents 'N(R4b)R5b, R5b represents H and represents Z, then Z does not represent 3-chloro-φ4-fluorophenyl. 2. According to the compound of claim i, wherein W represents , left-substituted phenyl, naphthyl, π-l-butyl, anthracene, porphinyl, fluorenyl, sulfenyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, alumina Mercapto, porphyrin, isoindolinyl, oxonyl, quinolinylfluorene, 2,3,4·tetrahydroquinolyl, isoquinolinyl, iota, 2,3,4- Tetrahydroisoquinoline tertinophthyl, benzofuranyl, isobenzofuranyl, benzohydropyranylbenzothiophenyl, morphine, pyrimidinyl, pyridyl, oxazolyl, benzene Salicyl, quinazolinyl, quinacridyl, 1,3-benzodioxolyl 99, 200837061 (benz〇di〇x〇lyl), benzofluorenyl, M•benzone A benzodioxanyl, U, 4_-diazolyl or 13 4 thiadiazolyl group. 3. A compound according to item 2 of the scope of the patent application, wherein w ^ indicates that the substituted sigma saponin 1 ^ ^ l3 · benzodioxolyl, pyrimidinyl, quinoxalinyl, Quinolinylphenyl or 0 to ° base. 4. A compound according to item 3 of the patent application, wherein | represents a substituted quinolinol group, a quinolyl group, a phenyl group or an acridinyl group. The compound according to any one of claims 4 to 4, wherein W is substituted with 1 and 4 substituents selected from the group consisting of aryl and hydrazine 1 as needed. The compound according to any one of claims 5 to 5, wherein, when w is substituted, it is substituted with one to three substituents selected from G1. 7. A compound according to any one of claims 6 to 6, wherein G1 represents halogen, -R3a, CN, c(〇)R3b, _c(〇)〇r3c, ·C(0)N(R) R , -N(R4b)R5b , -N(R3d)C(0)R4c , . N(R^)C(0)N(R,RW,_N(R3f)c(〇)〇R4e, n〇2 , _ N(Rk)S(0)2N(R, RH, -〇R3h, -〇c(〇)N(R4g)R5g, ·0S(0)2R3j, -S(0)mR3j or -s(〇 2N(R4b)R5h. 8. The compound according to any one of claims 1 to 7 wherein any of R4a and R5a, r41&gt; and R5b, R4d and R5d, R4f and R5f, R4g and R5g Or R4h and p, bonded together, when they form a 5 to 6 member ring, 'the ring optionally contains a further heteroatom in addition to the nitrogen atom and is optionally substituted with methyl, -CHF2, -CF3 or =0 100. The compound according to any one of claims 1 to 8, wherein R3a represents a Cle6 alkyl group substituted with one or more substituents selected from F and _〇rw as needed. A compound according to claim 9 wherein R3b represents a cU3 alkyl group substituted with one or more fluorine atoms as needed. The compound of any one of clauses 1 to 10, wherein R3b, R3c, R3h, R4a to R4h, R5a, r51&gt;, R5d, R5f to R5h independently represent H or an optionally substituted Cw alkyl group or The related pairs are bonded together. 12. A compound according to the scope of the patent application, wherein the compound is not hydrogen or a c14 alkyl group substituted by one or more fluorine atoms as required. 13. According to the scope of application patent u or 12 The compound of the formula wherein R4a and R4b independently represent a Cu alkyl group. The compound according to any one of claims 1 to 13, wherein R3d to R3g independently represent a Cm alkyl group or a hydrazine. The compound of any one of claims 1 to 14, wherein R31 and R3" independently represent C?-4 alkyl substituted by one or more 81 substituents as needed. The compound of any one of the preceding claims, wherein Β1 represents f. 17. The compound according to any one of claims 16 to 16, wherein the desired substituent on W is an aryl group (see patent application) Depending on any of the range 1 to 15 and timing), _N(R3f)c (〇)〇R4e, _S(0)2N(R4h)R5h, halogen, _R3a, -〇R3h or _N〇2. 101 200837061 u λ 18. According to the compound of claim 7 of the patent application, the substituents as needed are halogen, -R3a, -OrM or -Ν〇2. 19. A compound according to claim 17 wherein the optional substituent on w is phenyl, bromo, ethyl, propyl, -NHC ((^q tert-butyl, ethoxy, Propoxy, butoxy, trifluoromethoxy, _S(0)2NH2, -S(〇)2N(CH3)H ' -s(o)2n(ch3)2 , _ s(o)2n( Ch2ch3) 2, isopropyl, fluoro, chloro, methyl, methoxy, or trifluoromethyl. ί 20 · A compound according to claim 18 or 19 of the patent application, wherein The group is a compound of the formula I as defined in any one of claims 1 to 2, or a pharmaceutical thereof, according to the fluorine, chlorine, sulfhydryl, decyloxy, hydrazine, or trifluoromethyl group. An acceptable salt, which is used as a medicine. 疋 "But the salt of formula I without its limitations A drug for the activity of lipoxygenase. The use of the item, wherein the lipoxygen is a pharmaceutical formulation comprising one according to Application 2. A "compound, or a salt thereof" as defined in any one of the items, is admixed with a pharmaceutically acceptable adjuvant, diluent or carrier. Any of the compounds or their pharmaceutically acceptable substances which are desirable and/or need to be inhibited 25· According to the patent application scope 23 S# is 1 5 lipoxygenase. Use of 23 or 24 items, wherein the 102 200837061 disease is inflammatory and/or inflammatory. %·According to the use of the scope of the patent application, in which the inflammatory disease;: qi and disease obstructive lung disease, pulmonary fibrosis, allergic disease, rhinitis, inflammatory bowel disease, ulceration, inflammatory pain , fever, arteries, sputum arterial disease, vasculitis, smear inflammation, arthritis, bone and joint human λ, ,, ouguan, inflammation, conjunctivitis, iritis, membranous inflammation, uveitis, trauma , dermatitis, moist treatment, psoriasis, stroke, diabetes, self ^ Immune disease, Alzheimer's disease, multiple sclerosis, sarcoma-like disease, Hodgkin's disease or another malignant tumor. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> % defined in any of the negatives without its restriction strips, "Do not, or a pharmaceutically acceptable salt thereof. 28. A combination product, which contains - as defined in any one of 20" or a pharmaceutically acceptable salt thereof; (A) a compound of the formula I according to the scope of the patent application but without the limitation thereof, and an acceptable adjuvant, dilution (B) - for the treatment of inflammation The ingredients (A) and (B) are each blended with a medicinal agent or a carrier. μ "...the combined product of item 28, 1 package of human _ commercial drug formulation, including according to the application, /, 匕Each of the patents defined in paragraphs 1 to 20 of the patent scope, but without its restrictions, is a compound of the formula I, or a potable salt of the formula, and another may be used for the substance. Therapeutic agents, and pharmaceuticals can be used as an adjuvant, diluent or carrier. 3. A kit comprising the following components (4) according to Article 28 of the scope of the patent application: U) A pharmaceutical formulation comprising a definition but not defined in any of items 1 to 20 of the scope of the patent application. a compound of formula I or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable adjuvant, dilution or carrier blend; A pharmaceutical formulation comprising another therapeutic agent for treating inflammation which is admixed with a pharmaceutically acceptable adjuvant, diluent or carrier, each of which is suitable for sharing with another The form of the offer is provided. 3 1 _ a method for preparing a compound according to the formula 1 defined in claim j, which comprises: (i) 1,2,3-triazole_4_carboxylic acid, or N-protection thereof / or 〇_protected derivative, reacted with a compound of formula II, WNH2 II wherein W is as defined in claim 1; (ii) 1,2,3-triazole-4-carboxylic acid hydrazine Amine, or an N-protected derivative thereof, is reacted with a compound of formula III, wherein W-L1 III wherein L1 represents a suitable leaving group and W is as defined in claim 1; (Hi) Compound IV, 104 IV 200837061 Wherein W is as defined in claim i, or its N-protected derivative', and a suitable reagent for providing a source of azide ions; (IV) a reaction of a diazole, or a protected derivative thereof, with a suitable base, followed by a reaction with a compound of formula V, WN=C=0 v wherein W is as defined in item i of the scope of the patent , then stop the reaction with an appropriate proton source; or (V) - a compound of formula VI, 〇 VI 反应 A reaction with a compound of formula II as defined above. ▲ 32. A method for preparing a pharmaceutical formulation as defined in the Japanese Patent Publication No. F 2235, which comprises carrying out a compound of the formula 1 as defined in the items 至γ of the first to second paragraphs of the patent application, or a pharmaceutical thereof A combination of an adjuvant, diluent or carrier that is acceptable for I '/, W can be accepted. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The salt is combined with other therapeutic agents useful for treating inflammation, and at least one pharmaceutically acceptable adjuvant, diluent or carrier. 11. National style: None 106