TW200924772A - Heterobicyclic-substituted quinolones useful as nitric oxide synthase inhibitors - Google Patents

Abstract

Novel compounds and pharmaceutical compositions, certain of which have been found to inhibit inducible NOS synthase have been discovered, together with methods of synthesizing and using the compounds including methods for the treatment of iNOS-mediated diseases in a patient by administering the compounds.

Description

200924772 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention discloses novel heterobicyclic substituted quinolone compounds and compositions and their use as medicaments for the treatment of diseases. The present invention also provides a method for inhibiting nitric oxide synthase in a human or animal article for the treatment of diseases. [Prior Art] Nitric oxide (NO) involves the regulation of many physiological processes and the pathophysiology of many diseases. In many tissues and cell types, nitric oxide is synthesized from L-arginine by three different subtypes (is〇f〇rm) of 〇 NO synthase (NOS). Two of these subtypes, endothelium (eNOS) and neuronal NOS (nNOS), are expressed in a constitutive manner and are protein-dependent. Endothelial NOS is expressed by endothelial tissues and other cell types and is involved in cardiovascular homeostasis. Neuronal NOS is composed in the central and peripheral nervous system 'where NO is a neurotransmitter. Under normal physiological conditions, these constituent forms of N〇s produce low, short-lived NOs that accommodate the increase in intracellular calcium concentration. The role of these low levels of N〇 is to regulate blood pressure, platelet adhesion, gastrointestinal motility, bronchial muscle tone and neurotransmission. Conversely, 'the third subtype of NOS, which induces NOS (iNOS), is actually a calcium-dependent enzyme' that is not present in quiescent cells, but is actually in all nucleated mammalian cells. Express rapidly and respond to irritants such as endotoxins and/or cytokines. The inducible subtype is neither blocked by calcium nor blocked by a calmodulin antagonist. It contains several closely associated auxiliary factors ' including FMN, FAD and tetrahydrobiopterin. The inducible isoform of nitric oxide synthase (NOS2 or iNOS) is actually expressed in all nucleated mammalian cells upon contact with an inflammatory cytokine or lipopolysaccharide. The iNOS synthase is a homodimer composed of a 130 kDa subunit. Each subunit includes the addition of the 6 200924772 oxidase domain and the reductase domain. Importantly, the dimer formation of the iNOS synthase requires enzymatic activity. If the dimer formation mechanism is disrupted, the production of nitric oxide by the inducible NOS enzyme will be inhibited. The presence of iNOS in macrophages and lung epithelial cells is of interest. If present, the NO synthesized by iN〇s is 100-1000 times that synthesized by the constitutive enzyme, and thus continues for several stages. The NO produced by hydrazine and the resulting NO-derived metabolites (e.g., peroxynitrite) cause cytotoxicity and tissue damage that trigger the pathophysiology of many diseases, disorders, and conditions. ^ Nitric oxide produced by the inducible form of NOS is involved in the pathogenesis of inflammatory diseases. In animal experiments, hypotension induced by lipopolysaccharide or tumor necrosis factor alpha can be reversed by a 1 〇 3 inhibitor. The state leading to cytokine-induced hypotension includes septic shock, blood dialysis, and interleukin treatment in cancer patients. iNOS inhibitors have been shown to be effective in the treatment of cytokine-induced hypotension, enteritis, cerebral ischemia, osteoarthritis, asthma and neuropathy such as diabetic neuropathy and post-pampoo neuralgia. In addition, a large amount of nitric oxide in inflammatory tissues has been shown to induce local pain and enhance central and peripheral stimuli. • Because nitric oxide produced by the inflammatory response is thought to be synthesized by iN〇s© The inhibition produces a cake for the patient's towel and a therapeutic analgesic effect. Nitric oxide and NO activity and expression are involved in neuropathic pain and post-constrained neuralgia, and the treatment options for status are also most unclear (Wu CL and Raja SN, "/面.2〇〇8 jan;9 (1 S_ l): S19-30). The iNOS inhibition shows hope for treating such debilitating diseases. By the method of the examples' - some recent studies on the administration of iN〇s to sputum in rats indicate that the role of peripherally expressed iNOS in the pain state of inflammatory components and the potential value of the state in this state are - In one study, rats administered the iNOS inhibitor GW27415 24 24 hours after the injection of Freund's complete adjuvant (FCA) in the hind paw showed the accumulation of guacamera in inflammatory paws. It was shown that in fact iNOS inhibition and attenuated hypersensitivity to pain and water abdomen were in a dose-dependent manner. (De Alba J et al., 2006 Jan; 120(l-2): 170-81). In another study, evidence of local NOS expression and NO effects in chronic constrictive injury (CCI) of neuropathic pain was demonstrated (Levy D and Zochodne DW, five wr«yWewrosci.. 1998 May; 10 ( 5): 1846-55) and administration of GW274150 after chronic stenotic injury surgery significantly reversed the hypersensitivity response to CCI-associated pain (De Alba J et al, J 2006 Jan; 120(l-2): 170-81). As described above, 'iNOS selective and non-selective inhibitors.' are well known in the art, and have been studied for the treatment of iNOS mediated diseases and conditions including pain. In the event that excess NO is detrimental, the logical iN〇S inhibitor will reduce the production of NO, thereby alleviating inflammation, pain and other NO-mediated diseases. However, so far, no inhibitors have entered the market, and the reasons for this are not detailed here. The earliest compounds were not of the type of active site inhibitor, resulting in unacceptable side effects. Since the important physiological roles played by the constituent N〇s subtypes (especially eN〇s) become clearer, later compounds are designed to have subtype selectivity to ensure that iNOS inhibition has minimal for eN〇s The possible role of the activity. Other agents fail to have pharmacokinetic characteristics suitable for oral agents with good patient compliance. There is also a need for selective, effective, pharmacologically suitable iN〇s inhibitors. SUMMARY OF THE INVENTION It has been discovered that novel compounds and pharmaceutical compositions capable of inhibiting inducible N〇s synthase, as well as methods of synthesizing and using these compounds, include mediated by iNOS in patients treated with the compound The method of illness. These compounds have also been shown to have utility as _ anti-inflammatory agents. Finally, the chemical ages disclosed in the present invention exhibit good metabolic stability. 200924772 In the examples of the present invention, the 'compound has the structural formula ι:

Wherein: R is selected from the group consisting of a stilbene, a silk, a dilute group, an aminoalkyl group, a mercaptoalkyl group, an alkynyl group, a decylamino group, a wind group, an amino group, an aryl group, an aryl group, an aryl group, and an oxy group. Arylamino, arylaminomorphyl aryl sulfide, silk, cyclofilament, vinegar, shout, dentate, acne oxy, halo-heteroaryl, heteroarylalkyl, heteroarylamino, hetero An arylaminoalkyl group, a heterocycloalkyl group, a heterocycloalkylalkyl group, a decyl group, a hydrogen, an imido group, a sulfur, a sulfonate, a thioguanamine group, and a thioanthrylamino group, wherein any group thereof Optionally substituted; R2 is selected from decyl, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkylamino, alkynyl, alkylimino, arylamino, amino, aryl, thiol , cyano, cycloalkyl, ester, flavonol, heteroaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; or, optionally, R2 may be bonded to R1 to form a heterocyclic ring An alkyl group, which may be optionally substituted. Φ R3 is selected from the group consisting of aryl, amino, arylalkyl, aryl, cycloalkyl, haloalkyl, heteroarylalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and A, B , C and D are each independently selected from the group consisting of an aryl group, an alkoxy group, a decyl group, a aryl group, an alkylamino group, a aryl group, a decylamino group, an amino group, an aminosulfuryl group, an aryl group, an aryl alkoxy group, Arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halogen, haloalkoxy, haloalkyl, heteroaryl, heteroaryl, heteroarylamino, heterocycloalkyl, fluorenyl, Hydrogen, imino, sulfur, sulfate, and sulfonium amino, any of which may be optionally substituted; or, optionally, two or more of A, b, C, and D may be combined to form an aryl group, a ring A heteroaryl or heterocycloalkyl group, any of which may be optionally substituted. The specific compounds disclosed herein may have useful iNOS inhibitory activity and may be used to treat or test iNOS-transformed silkworms on 200924772. Thus, in a broad sense, the specific embodiments also provide pharmaceutical compositions comprising one or more of the compounds disclosed herein and a pharmaceutically acceptable carrier, and methods of making and using the compounds and compositions . Particular embodiments provide methods of inhibiting iNOS. Other embodiments provide treatment of iNOS mediated diseases in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound and composition of the invention. Also provided is the use of a particular compound disclosed herein for the preparation of a medicament for treating a disease and condition ameliorated by inhibition of iNOS. In a further embodiment, the compound has the structural formula π

Or a salt, ester or prodrug thereof, wherein: X1 is selected from the group consisting of CR4 and hydrazine; X2 is selected from the group consisting of CR5 and hydrazine; X3 is selected from the group consisting of CR6 and hydrazine; and R4-R6 are independently selected from the group consisting of hydrogen, dentate, cyano, and lower alkyl. , lower _alkyl, lower haloalkoxy, lower alkynyl, lower cycloalkyl, lower aryl, lower heteroaryl, (CH2)mOR12, (CH2)mSR13 and (CH2)mN(R14)R15 ' Any group may be substituted with a group selected from the group consisting of methyl, ethyl, halogen, perfluoromethyl and perfluoromethoxy; R7 is selected from lower alkyl, -(CH2)n-lower cycloalkyl , _(CH2)n-lower heterocycloalkyl, -(CH2)n-lower aryl and -(CH2)n-lower heteroaryl, any of which may optionally be selected from one of the following or 200924772 Group substitution: methyl, ethyl, halogen, perfluoromethyl and perfluoromethoxy; R8, R9, R10 and R11 are independently selected from hydrogen, lower alkyl and halogen; R12 and R13 are independently selected From hydrogen, halogen, lower alkyl, lower cycloalkyl, lower aryl, lower heteroaryl, lower heterocycloalkyl and lower heterocycloalkylalkyl, any of which may be optionally selected from one or two of the following Substituted by a group : methyl, ethyl, halogen, perfluoromethyl and perfluorodecyloxy; R14 and R15 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, lower aryl, lower heteroaryl a base, a lower heterocycloalkyl group and a lower heterocycloalkylalkyl group, any of which may be optionally substituted with one or two groups selected from the group consisting of methyl, ethyl, arginyl, perfluoromethyl and Alternately methoxy; or R14 and R15 are taken together with the atom to which they are attached to form an optionally substituted 3-7 membered heterogeneous > base moiety; and m and η are independently 〇4. In a further embodiment, R10 and R11 are hydrogen. In a further embodiment, in a further embodiment, © X2 is CR5; and X3 is CR6. In a further embodiment, R5 and R6 are hydrogen. In a further embodiment, R9 is selected from the group consisting of fluorine and hydrogen. In a further embodiment, R9 is hydrogen. In a further embodiment: R4 is selected from the group consisting of hydrogen, halogen, cyano, lower alkyl, lower halogen, lower halooxy, (CH2)m〇R12, (CHASR13 and (CH2)mN(R14)R15 Any of which may be optionally substituted with two groups selected from the lower group of 200924772: methyl, hexyl, sulphin, perfluoromethyl and all-gas methoxy; and R14 and R15 are independently selected From hydrogen and lower alkyl; or "4 and Rls are taken together with the nitrogen to which they are attached to form an optionally substituted 3-5 membered heterocycloalkyl moiety. In a particular embodiment: r7 is selected from the group consisting of lower alkyl and - ( Any of the CHA-lower ring building groups' may be optionally substituted with one or two groups selected from the group consisting of methyl, ethyl, „, 千代 methyl and all-gas methoxy; and η is 0 or 1. In a further embodiment, X1 is Ν. In a further embodiment, X1 is CH. In a further embodiment, a compound selected from Examples i to 88 and 9〇95 is provided. Further implementation of the financial resources, the application of the compound described in the Dijon scarf as a drug is provided. In the example, the application according to the patent application in the patent application is provided as a treatment and the application of the lion to the iNGS is further provided. Further provided is a compound according to the item i according to the scope of the patent application. And a pharmaceutical composition of a pharmaceutically acceptable carrier. Further provided is a method for inhibiting the sensation, comprising contacting _S with a compound as described in claim i. Further providing a method for treating iNOS mediated diseases, Including administering a therapeutically effective amount of a root spray to a patient in need of treatment thereof, the compound of claim i. Further providing a method of treating iNOS mediated diseases, including administration: 200924772 ... therapeutically effective i: root shot §f The compound described in the scope of the patent; and the additional therapeutic agent. As described below, the meaning of the following terms is indicated. In the scope of the numerical value, the labeling method used is "from call to n2", wherein % and叱疋Number, the material has the 'the purpose of this notation is to reduce the range between the body and the number. The range can be a complete or continuous value in the interval and includes the end value By the method of the embodiment, the range "6 carbons from 2 sides, refers to two, three, four, five and six carbons, 〇 because of the carbon sap sands." Below, via the method of the present, the range '1 to 3 μΜ (micromolar), ', which means including 1 μΜ, 3 μΜ, and all significant figures between the ranges (eg U55 μΜ) , 2"啪, 2娜μΜ, etc.) The term "about" as used herein refers to a change in the number given, indicating that the value is a variable within the margin of error. If no specific margin of error is given (4) as in the data thief The standard deviation of the average values given, the term "about," should be understood to include a given numerical value and a valid number in the range above or below the numerical value. The term "mercapto" as used herein, when taken alone or when combined, means that the carbonyl group is attached to an alkenyl group, an alkyl group, an aryl group, a cycloalkyl group, a heteroaryl group, a heterocyclic ring or any other group, and the atom attached to the group is carbon. "B-based" refers to the ~c(o)ch3 group. "Alkylcarbonyl," or "alkan〇yl," refers to an alkyl group attached to the parent molecular moiety through a number of groups. Examples of such groups include methyl groups and ethyl groups. The thiol group includes a fluorenyl group, a carboxyl group, and an aryl group. The term "alkenyl" as used herein, when taken alone or in combination, refers to a straight or branched hydrocarbon having one or more double bonds and containing from 2 to 20 carbon atoms. In a particular embodiment, the alkenyl group contains from 2 to 6 complex atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions. For example, acetylene [«Η^ΟΗϋ^)]. An example of a suitable alkenyl group is 13 200924772, including ethylene, propylene, 2, methyl propyl, bismuth, and the like. Unless otherwise stated, the term "dilute group" includes "alkenylene" groups. The term "alkoxy" as used herein, when taken alone or in combination, refers to an alkyl ether group wherein the term alkyl is as defined below. Examples of the alkyl group include methoxy, ethoxy, η propoxy, isopropoxy, η-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. The term "alkyl" as used herein, when taken alone or in combination, refers to a straight or branched alkyl group containing from 1 to 2 carbon atoms. In a particular embodiment, the alkyl group comprises up to 1 carbon atom. In a further embodiment the alkyl group comprises from 1 to 6 carbon atoms. The alkyl group can be optionally substituted as defined herein. Examples of oxy groups include methyl, ethyl, n-propyl, isopropyl n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, fluorene Base and so on. The term "alkylene" as used herein, when used alone or in combination, refers to a saturated aliphatic group that is bonded at two or more positions derived from a straight or branched saturated hydrocarbon, unless otherwise stated, the term "hospital base" "Includes "alkylene" groups. As used herein, the term "alkylamino", when used alone or in combination, means that the alkyl group is attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or di-alkylated, and the resulting groups are, for example, fluorenyl-methylamino, hydrazine-ethylamino, hydrazine, hydrazine-dimethylamino, ν, Ν-ethylmethylamino. And the like, as used herein, the term "alkylidene", when used alone or in combination, refers to a chain-dense group in which one carbon atom of a carbon-carbon double bond belongs to the parent moiety attached to the bond-dense group. The term "alkylthio", when used alone or in combination, refers to an alkyl sulfide (RS-) group 'wherein the alkyl group is as defined above' wherein the sulfur may be mono- or di-oxidized. Examples of the alkyl group-containing sulfur bond group include methyl sulfide, ethyl sulfide, η-propyl sulfur, isopropyl sulfide, η-butyl sulfide, isobutyl sulfide, sec-butyl sulfide, t-butyl sulfide, and sulfur-burning sulfur.醯, 乙烧醯, etc. The term "alkynyl" as used herein, when taken alone or in combination, refers to a straight or branched hydrocarbon group, which has two or more triterpenes and contains from 2 to 20 carbons. Atom. In a particular embodiment, the fast radical comprises from 2 to 6 carbon atoms. In an advanced embodiment, the radical comprises from 2 to 4 Carbon atom. The term "alkynylene" refers to a carbon-carbon triple bond, such as ethynylene-OC-, attached at two positions. Examples of silk include ethynyl, propyl-based, and -propynyl-l-butynyl, 2-butyryl, 3-methyl-1butynyl, 2-hexyl, etc. Unless otherwise indicated, the term "alkynyl" includes "alkynylene" As used herein, the terms "amido", and "carbam〇yl", in a single (Q alone or in combination, means that the amino group is attached to the parent molecular moiety through a carbonyl group (as described below). And vice versa. The term "C-protonyl" as used herein, when used alone or in combination, refers to a _c(=〇)_nr2 group (r is described below). The term "Ν" as used herein. -Amidino", when used alone or in combination, refers to a RC(=0)NH- group (R, as used herein, as the term "acylamino" as used herein, refers to a thiol group, either alone or in combination. The amino group is attached to the parent moiety. An example of an "acylamino" is an ethylamino group (CH3C(0)NH-). The term "amino" is used herein. By singly or in combination, _nrr, wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, decyl, isoalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, any of which The group itself may be optionally substituted. In addition, R and R' may be combined to form a heterocyclic compound, wherein each group may be optionally substituted. The term "aryl" as used herein, when used alone or in combination, refers to a , two or three ring carbocyclic aromatic systems 'where such polycyclic systems are fused together. The term "aryl" refers to, for example, phenyl, naphthyl, anthryl and phenanthryl. "Arylkenkenyl" or "aralkenyl", when taken alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group. As used herein, the term "arylalkoxy" or "aralkoxy", 15 200924772, when used alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group. The term 'arylalkyl' or 'aralkyl', when used alone or in combination, refers to an aryl group attached to the parent molecular moiety through a siloxane group. The term "arylalkynyl" as used herein. "" or "aralkynyl", when used alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group. As used herein, the term "arylalkanoyl", or "aralkanoyl" or "aroyl" is used alone or in combination to mean thiol derived from aryl. Substituted alkane carboxylic acid 'e.g. benzamidine, naphthyl 'phenethyl hydrazine, 3-phenylpropene fluorene (hydrogenated cinnamyl), 4 phenyl butyl ketone, (2-naphthyl) ethyl ketone, 4-gas hydrogenation Cinnamon-based and the like. The term "aryloxy" as used herein, when used alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxygen. The terms described herein are the terms "benzo" and "stupid," either alone or When combined, it refers to a divalent group derived from benzene 〇Η4=. Examples include benzothiophene and benzimidazole. As used herein, the term "carbamate", when used alone or in combination, refers to an ester of carbamic acid (-NHCOO-) which can be attached to the parent molecule from the nitrogen or acid end, optionally as described herein. Substitutes. The term "ammonium amide" as used herein refers to the term 0 (: (0) position, group, where R and R' are as defined herein, alone or in combination. -Aminoguanidino", when taken alone or in combination, means 难0€(0 is difficult, □ group, wherein R and R' are as defined herein. The term "carbonyl" as used herein includes thiol when alone [< (_, when bound, refers to -C(O)- 〇 as used herein, the term "carix Xyl" or "carboxy xy", refers to 200924772 or minus "carboxy sulfonium salt" anion For example, in a buffer acid salt. "Armium," refers to RC(9)~group' wherein R is as defined herein. "C-stable group" refers to a distressed group, wherein R is as defined herein. The term "cyano", when used alone or in combination, refers to -CN. The term "cycloalkyl", or "carbocyclic," as used herein, means saturated or alone or when combined. a partially saturated monocyclic, bicyclic or bicyclic, pendant group wherein each ring moiety comprises from 3 to 12 carbon atoms in the ring minus 'the silk group is optionally silk-filled _, optionally in accordance with The definitions herein are substituted. In a particular embodiment, the cycloalkyl group will comprise from 5 to 7 carbon atoms. Such ring pendant groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ring. Heptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H., fluorenyl, etc. The "bicyclic" and "tricyclic" described herein include two Ring-equilibrated ring systems, such as decahydroxanthene, octagonal arsenic, and polycyclic (multi-centered) saturated or partially non-existing types. The latter isomers are generally exemplified by bicyclic [1,1 , 1] pentane, camphor, adamantamine, and bicyclo[3,21] octyl. The term "vinegar" as used herein, when used alone or in combination, refers to a carboxy group attached to two carbon atoms. The term 'goods', when used alone or in combination, refers to the attachment of oxygen to two carbon atoms. The terms "self" or "self" described herein are either alone or In the meantime, it refers to fluorine, gas, moisture and iodine. The term "by alkoxy" as used herein, alone or in combination, means that the alkyl group is attached to the parent molecular moiety through an oxygen atom. The term "dentate alkyl" as used herein. ''In the case of singly or in combination, refers to an alkyl group as defined above wherein one or more hydrogens are replaced by a halogen. In particular, it refers to monohaloalkyl, dihaloalkyl and polyhaloalkyl. By way of example, single A haloalkyl group may contain an iodo, bromo, oxo or fluoro atom in the base map. 17 200924772 The binary and multi-ship bases have two jerseys. , Difluoromethyl, Trifluoromethyl, Methyl, Dimethyl, Trimethyl, Pentafluoroethyl, Heptafluoropropyl, Difluoromethyl, Dichlorofluoromethyl, Difluoro A group, a difluoropropyl group, a dichloroethyl group, and a dichloropropyl group. Examples include fluoromethyl H:FH-), difluoromethyl (-CFr_), chloromethane, and the like. The term "hybrid" as used herein, when used alone or in combination, refers to a stable straight bond or a bond or cyclonic acid group' or a combination thereof. Fully saturated or unsaturated to 3 to 3, including a fixed number of carbon atoms and one to three heteroatoms selected from 〇, N and S, wherein the nitrogen pure atom is optionally oxidized and the nitrogen hetero atom is optionally Was Ji Wei. The hetero atom Ό, N and s are located anywhere inside the filament. More than two heteroatoms can be joined together, such as _CH2 NH 〇CH3.

Q The term "heteroaryl" as used herein, when taken alone or in combination, refers to a 3 to 7 membered unsaturated heteromonocyclic ring, or a slightly monocyclic, bicyclic or tricyclic ring system in which at least one fused ring is aromatic. Containing at least one atom selected from the group consisting of ruthenium, S and N. In a particular embodiment, the heteroaryl will contain from 5 to 7 carbon atoms. The term also refers to a fused polycyclic ring system in which a heterocyclic ring is fused to an aromatic ring wherein the heteroaryl ring is fused to other heteroaryl rings, wherein the heteroaryl ring is fused to a heterocycloalkyl group, or wherein the heteroaryl ring and ring are fused. The base is slightly combined. Examples of the hetero group include β-pyrrolyl, pirolidol, miso, hydrazino, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, Furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, benzodiazepine, isothiazolyl, fluorenyl, iso-β-decyl, °5丨°Qin, Benzene-flavored β-sodium, sulfinyl, iso-indolyl, aboline, sulphate, sulphonyl, benzotriazolyl, benzodioxolyl, benzopyran Base, phenylpropionazolyl, oxadioxalyl, benzothiazole, benzothiadiazine, benzofuranyl, benzothienyl, chromone, oxaphthalene, benzo " Bisyl, tetrahydro of aryl, tetrahydroindenyl, tetrahydroisoindolyl, thienopyrimidinyl, furopyridinyl, pyrrolopyridyl, etc. Tricyclic heterocyclic group sleepy 18 200924772 Example Including the base, stupid silk (benzi homogenate, light Wei, dibenzo-based) biting group, phenanthryl, oxime, etc. The terms "heterocyclic," and "heterocyclic" as used herein. , exchangeable, in separate By binding is meant a saturated, partially saturated or fully unsaturated monocyclic, bicyclic or tricyclic brinic group comprising at least one heteroatom as a member of a ring, wherein each of said heteroatoms may be independently selected from the group consisting of nitrogen oxides and sulfur In a particular embodiment, the heterocyclic pendant includes i to 4 heteroatoms as members of the ring. In further embodiments, the heterocyclic alkyl group comprises from 1 to 2 heteroatoms as a ring. In a particular embodiment, the heterocycloalkyl group comprises from 3 to 8 heteroatoms in each ring. In a further embodiment, the heterocyclic filaments comprise 3 to 3 in each ring. In the additional embodiment, the heterocyclic alkyl group includes 5 to 6 heteroatoms in each ring. "Heterocyclic alkyl" and "heterocyclic" include milled, sulfoxide, tertiary nitrogen. a N-oxide of a member ring, and a carbon ring fused and benzo fused system. Additionally, the two terms also include systems wherein the heterocycle is fused to an aryl group, as described herein, or with The heterocyclic group is fused. Examples of the heterocyclic group include aziridine, 0-butyridyl, 1,3-benzodioxole Alkenyl, dihydroisoindolyl, dihydroisoquinolyl, dihydroisomeric 1# base, dihydro benzodioxin, dihydro [1,3] 嗔峻 [4,5 7]" Ratio of decyl, benzoxanthyl, bishydroindolyl, dihydropyridinyl, 1,3-dioxyl, 1,4-dioxyl, 1,3-dioxolane a base, an isoindoline, a morpholinyl group, a fluorene group, a pyridyl group, a tetrahydropyridyl group, an acridinyl group, a thio-allinyl group, etc. The heterocyclic group may be optionally selected. Substituted, unless specifically prohibited. The term "mercapto" as used herein, when used alone or in combination, refers to two amino groups joined by a single bond, such as -NN-. The term "hydroxy" as used herein is used alone or in combination. The term "hydroxyalkyl" as used herein, when taken alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group. 200924772 The term "imino" as used herein, when used alone or in combination, refers to =N_. The term "iminohydroxy" as used herein, when used alone or in combination, refers to =n(〇h) and 吟~ The phrase "in the main chain" refers to the longest continuous chain or carbon atom _, which is One point is attached to any of the formulas described herein. The term "isocyanoquinone" refers to an -NCO group. The term "isothiocyanato," refers to a _NCS group. The term "atomic straight chain" refers to the longest straight chain of an atom, independently selected from carbon 'nitrogen, gas, and sulfur. The term "lower" is used alone or in combination Unless otherwise specified, it is meant to contain from 1 to 6 carbon atoms. The term "lower, aryl", when used alone or in combination, refers to phenyl or naphthyl, which may be optionally substituted as described herein. a lower fresh base, when used alone or in combination, refers to a monocyclic heterocyclic ring containing a five or six membered ring, wherein one to four of the members may be heteroatoms selected from 0, s and fluorene or 2) bicyclic The aryl group wherein each fused ring includes a five- or six-membered ring, includes one to four heteroatoms selected from the group consisting of 0, S and fluorene. The term "lower cyclofilament" as used herein, when taken alone or in combination, refers to a monocycloalkyl group having a three to six membered ring. Lower cycloalkyl groups can be unsaturated. Examples of lower cycloalkyl groups include cyclopropylcyclobutyl, cyclopentyl and cyclohexyl. The term "lower heterocyclic compound" as used herein, alone or in combination, refers to a monocyclic heterocyclic ring having a three to six membered ring. The cycloalkyl group, one to four of which may be a hetero atom selected from the group consisting of ruthenium, s and osmium. Examples of the lower heterocyclic thiol group include a fluorenyl group, an imidazolidinyl group, a pyrazolidinyl group, an acridinyl group, and the like. And a morpholinyl group. The lower heterocycloalkyl group may be unsaturated. The term "lower amino group" as used herein, when used alone or in combination, means _Nrr', wherein R and R, independently 20 200924772, are selected from hydrogen. , lower calcining groups and lower calcining groups, any of which may be optionally substituted. Further, R and R of the lower amino group may be bonded to a five- or six-membered heterocycloalkyl group, each of which can be optionally substituted. The term "thioacetal" as used herein, when taken alone or in combination, refers to an RS-group, wherein R is as defined herein. The term "Jingji" as used herein, when used alone or in combination, means -N〇2. The term oxygen or "oxa" as used herein, when used alone or in combination, means _ 〇 ^ 3 The term "oxo" as used herein is used alone or in combination. The term "perhaioaikoxy" as used herein, refers to an alkoxy group in which all of the hydrogen atoms are replaced by a halogen atom, either alone or in combination. The term "perhaloaikyi" as used herein. When used alone or in combination, refers to a sapon group in which all of the hydrogen atoms are replaced by a drawn atom. The terms "acid salt", "supply acid" and "base" as used herein, refer to the 4 〇 311 group when used alone or in combination. And its negative example, because sulfonic acid is used for salt formation. The term "sulfanyl" as used herein, when used alone or in combination, means that the term "sulfinyl" as used herein, when used alone or in combination, means "(). The term "continuous base" as used herein refers to _$(〇)2_, alone or in combination. δδ'Ή-ammonium sulfonate, refers to the RS(=0)2NR'- group, wherein amps and Hans, as defined herein. The term "S-ammoxime" refers to an OSH^NRR' group, wherein as defined herein. The terms "thia" and "thio" as used herein, when used alone or in combination, refer to each group or ether 'where oxygen is replaced by sulfur. The oxidized derivative of the thio group ( That is, sulfinyl and fluorenyl are included within the definition of thia or thio. The term "thiol" as used herein, when used alone or in combination, refers to a -SH group. 21 200924772 The term " "Thiocarbonyl" includes thioaldehyde-C(S)H and a combined C(S)- group, alone or in combination. The term '*Ν-thioamino group' refers to R〇C(S) An NR,- group, wherein R and R' are as defined herein. The term "oxime-thiocarbamyl" refers to a -C(S)NRR, group, wherein R and R' are as defined herein. The term "thiocyanate" refers to a -CNS group. The term "trihalomethoxy" refers to an X3CO- group wherein X is a halogen. The term "trisubstituted nonylalkyl" as used herein, when taken alone or in combination, is substituted with a triple free valency group, the substituents being given under the definition of a substituted amino group herein. Examples include triterpene.矽alkyl, tert-butyldimethylformamidinyl, triphenylcarbenyl, etc. Any definition herein may be used in conjunction with other definitions to indicate a composite structural group. By agreement, the back of any such definition The unit is attached to the parent moiety. For example, a complex group alkylamino group represents an alkyl linkage attached to the parent moiety through an amino group, and the term alkoxyalkyl refers to an oxy group attached to the parent molecular moiety through a siloxane group. When defined as "null," it means that the group does not exist. 〇 The term "optionally substituted" means that the aforementioned group may or may not be substituted. When substituted, the substituent of the "optionally substituted" group may include, without limitation, one or more substituents which, when taken alone or in combination, are independently selected from the group consisting of the following groups or a group of a particular specified series Group: lower alkyl lower alkenyl, lower alkynyl, lower alkanol, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower alkenyl, lower alkynyl, lower homodentate Base, lower homodentate alkoxy, lower ring, phenyl, aryl, aryloxy, lower alkoxy, lower i alkoxy, oxo, lower alkoxy, carbonyl, carboxyl, lower alkane Carbonyl group, lower carboxy ester, lower decylamino group 22 200924772 "b〇xamido", cyano group, hydrogen, dentate, thiol, amino lower grade aminoarylamino group, aryl group, nitro group, thiol, lower order wire Sulfur, low-grade self-sulfenyl sulphur low-grade all-tooth sulphur-based sulphur, aryl sulphur, sulphuric acid vinegar, hepta, trisubstituted methyl ketone, n3, SH, _, c (〇) cH3, c〇2CH3, 2 bite Based on 1 基 ° 夫 喃 、, lower urethane and lower urea. Two substituents can be attached to form a zero To a three-, five-, six-, or seven-membered carbocyclic or heterocyclic ring, for example, to form a dioxane or an ethylene standard dioxygen. The optionally substituted base circle may be unsubstituted (eg, -CH2CH3), completely Substituted (eg, _CF2CF3), monosubstituted (eg, even CH2F) or any grade of substitution between a complete substitution and a monosubstituted (eg, (8). When no substitution conditions are stated, 'arms and filaments #纹“substituted, when, specifically refers to the substitution H, additionally 'different optional substituents for a particular moiety are as desired; in some cases, the optional substitution is defined as the following phrase Optionally, where β is used alone and without a digital indication, unless otherwise defined, the term R or R, refers to a moiety selected from the group consisting of hydrogen, silk, cyclofilament, heterofilament, aryl, Heteroaryl and heterocycloalkyl, optionally substituted with any fine oxime. Such "R," M is understood to be optionally substituted as defined herein. Whether or not the R group has a digital designation, including R, R, and Rn © (where n = (l, 2, 3, ... η)), each R group, each substitution The radical and each term should be understood to be independent of the other groups in the selected group. Any variable, substituent or term (eg, aryl 'heterocycle, R, etc.) should occur more than once in a formula or non-patent structure. The definition of each occurrence is independent of the definition at every other occurrence. Those skilled in the art will further appreciate that a particular group may be attached to the parent molecule or may occupy at either end of the listed chain group. Thus, by way of example only, an asymmetric group such as €(〇)1^(11)_ can be attached to the parent moiety on a carbon or nitrogen atom. Asymmetric centers are present in the disclosed compounds. These centers are indicated by the designation of the substituents in the chiral sub-box by the symbol "R" or "s" according to 23 200924772. It is to be understood that the invention includes all stereochemically isomeric forms, including diastereomeric enantiomers and epimers, as well as d.isomeric n and 1,4-(tetra) and mixtures thereof. The compound _ xiang body (four) body can be synthesized by commercially available raw materials containing chiral centers, or prepared by separation or recrystallization of a mixture of corresponding product products. The separation method includes chromatographic techniques and direct chromatography through a chiral column. The corresponding body or any other suitable method known in the art is isolated. The starting compounds of a particular stereochemical nature are either commercially available or can be made or solved by techniques well known in the art. Additionally, the compounds disclosed herein may be geometric isomers. The invention includes all cis, trans, syn, anti, ipsilateral (E) and ipsilateral (z) isomers, and the appropriate mixtures thereof. Additionally, the compounds may be tautomers, and all tautomers are provided by the present invention. Additionally, the compounds disclosed herein may be unsolvated and pharmaceutically acceptable (eg, water, ethanol, etc.) The solvated form is carried out. Generally, the solvated form is equivalent to the unsolvated form.

The term "bond" refers to a covalent bond between two atoms or two moieties that are considered part of a larger substructure when the atoms are bonded by a bond. Unless otherwise specified, the key can be a single key, a double key, or a triple key. A dashed line between two atoms in the depicted molecule indicates that there may or may not be additional bonds at that position. The term "disease" as used herein refers to the synonymous 'and can be used interchangeably with the terms "condition," and "state as in medical conditions", all of which reflect the abnormal state of the human or animal body. Or its normal function of damage, the term is typically demonstrated by distinguishing between signs and symptoms, and causing a human or animal to suffer a shortened life duration or reduced quality of life. The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic state or disease as described herein. Such administration involves the administration of these therapeutic agents in a large number of co-existing manners, e.g., a single capsule having a defined ratio or plurality of active ingredients, having separate capsules for each active ingredient. Additionally, such administration also includes the use of each type of therapeutic agent in a sequential manner. In each case the treatment will provide a beneficial effect of the drug combination in the state or disease described herein. As used herein, "iNOS inhibitor" refers to a compound having an IC5Q of iNOS activity of no greater than about 100 μΜ and typically no greater than about 50 μΜ, which is measured in the iN〇s assay generally described below. “ICso” is reduced The concentration of the enzyme activity (e.g., iNOS) to half the maximum level of inhibitor. The compounds disclosed herein are found to exhibit inhibition of iNOS. In a particular embodiment, the compound exhibits EC?0 for iNOS. Greater than about 1 μμΜ; in further embodiments, the compound will exhibit an EC% of no greater than about 5 μΜ for iNOS; in still further embodiments, the compound will exhibit an EQ0 of no greater than about 1 μΜ for iNOS; In still further embodiments 'the compound will exhibit an EC50 of no greater than about 200 η 针对 for iNOS, as measured in the iNOS assay generally described below. The phrase "therapeutically effective" is determined in the treatment of the disease or condition. The amount of active ingredient used. This amount will achieve the purpose of reducing or eliminating the disease or condition. The term "therapeuticly acceptable" means suitable for use in contact with the tissue of a patient. Compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are free of abnormal toxicity, irritation, and allergic reactions, are equally effective at a reasonable benefit/risk ratio' and their intended use. As used herein, reference to a patient's "treatment" refers to prevention. The term "patient," refers to all animal sputum patients including humans, including humans, cows, dogs, cats, sheep, pigs, and rabbits. Preferably, the patient is a human. More Active Compounds β Certain compounds disclosed herein can be used as Drugs in Hydmtysis in Drug and Pmdmg Metabolism: Chemist^ Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. 25 200924772

Described in Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein refer to structurally modified forms of the compounds which are readily chemically altered under physiological conditions to provide the compounds. Additionally, prodrugs can be converted to the compounds by chemical or biochemical methods in an in vitro environment. For example, a prodrug can be slowly converted to the compound when placed in a transdermal patch memory with a suitable leaver or chemical reagent. Prodrugs are often useful because, in some cases, they can be administered more readily than the compound or parent drug. For example, they are bioavailable by oral administration and the parent drug is not. The prodrug may also have a better solubility in the pharmaceutical composition than the parent drug. A wider variety of prodrug derivatives are known in the art, such as those derivatives which rely on hydrolytic cleavage or oxidative initiation of prodrugs. For example, without limitation, a prodrug is administered as an ester ("prodrug"), but it is subsequently metabolically hydrolyzed to a carboxylic acid, i.e., an active substance. Further examples include peptidyl derivatives of the compounds.

The compounds disclosed herein can exist in the form of a therapeutically acceptable salt. The present invention includes the form of the salt of the above compound 'including an add addition salt. Suitable salts include those formed with organic or inorganic acids. Such acid addition salts are normally pharmaceutically acceptable. However, salts of 'non-pharmaceutically acceptable salts can be used in the preparation and purification of the compounds in question. A basic addition salt can also be formed which is pharmaceutically acceptable. For the preparation of salts and the selection of well-prepared records, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002). The term "therapeutic" is used herein. Accepted salts" represent salts or zwitterionic forms of the compounds disclosed herein which are water soluble or oil soluble or dispersible and are therapeutically acceptable as defined herein. The salt can be prepared in the final isolation and purification of the compound, or by reaction of a suitable compound in a free domain form with a suitable acid, representative acid addition salts including acetate, adipic acid, alginic acid Salt, L-ascorbic acid, aspartate 'benzoate, 26 200924772 phenyl acid salt (benzoate), heavy fermentation m $ acid orphan, butyrate, camphorate, camphor sulfonate ,lemon

Acid salt, every sugar acid salt, formic acid, sleep? 1:+π A τ acid solanic acid, gentisate, glutarate, glycerol phosphate, glycolate, hemisulfate, electrolysis, ortho-heptanoate, hexanoate, benzoguanamine acetate , hydrochloride hydrogen chloride hydroquinone, 2_hexyl citrate (ethyl ethyl citrate), lactate, maleic acid I propionate, DL-mandelate, (3) trimethylbenzene Hetero-salt, carboxylate, naphthyl-salt salt, cigarette bribery: 2, naphthalene salt, oxalate, di-naphthyl salicylate, pectinate, persulfate, 3_Pyrylpropionate (3 phenyipr〇pri〇nate), carbamate, quaternary acid salt, pivalate, propionate, pyroglutamate, _salt, acid salt, tartaric acid

Salt, L-tartrate, tri-gas acetate, Sandon acetate, sulphate, glutamic acid, bicarbonate, p-toluene (P. A) and ten-hetero. Earning, the domain of the finely divided compound can be quaternized, using the following groups: vapor, trim and moth of methyl, ethyl, propyl and butyl; dimercapto, di Sulfates of benzyl, dibutyl and pentyl; vapors, bromides and iodides of mercapto, ethyl, propyl and ketone groups; and bromides of benzyl and phenethyl groups. Examples of the acid which can be used to form the therapeutically acceptable addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Salts can also be formed by the coordination of the compounds with soil or metal ions. Accordingly, the present invention relates to sodium, potassium, magnesium and calcium salts of the disclosed compounds, and the like. Domain addition salts are prepared by reaction of a carboxy group with a suitable domain in the final isolation and purification of the compound: a bicarbonate of a hydroxide, carbonate or metal cation or aqueous ammonia or an organic primary, secondary or tertiary amine. The cations of the therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and im- and non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, three Ethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-didecylaniline 'methylation', melon bite, guanidine methylmorpholine, dicyclohexylamine, procaine, Dibenzylamine, anthracene, fluorene diphenyl phenylethylamine, 1-diphenyl 27 200924772 A typical organic amine formed by the addition of a methylamine and an N,N'c ethylenediamine Including ethylene diamine tea test, ethanolamine, diethanolamine, beta melon bite and call. Although the compound of the present invention is administered as a raw chemical, it may also be used as a pharmaceutical formulation. Accordingly, the pharmaceutical formulations provided herein comprise one or more specific compounds disclosed herein or one or more pharmaceutically acceptable salts, esters, prodrugs, guanamine or solvates thereof, and also include one or A plurality of pharmaceutically acceptable carriers thereof and optionally one or more additional therapeutic ingredients. The carrier must be compatible with the other ingredients of the dosage form and not deleterious to the recipient thereof, in the sense that the recited body is "acceptable," depending on the selected dosage form. Route of administration. Any well-known technic acid carrier and excipients, such as in scjences, can be used if suitable and known in the art. The musical compositions disclosed herein can be prepared by any method known in the art. For example, by conventional methods: mixing, dissolving, drying, grinding, emulsifying, encapsulating, entrapping or compressing, the dosage forms include those suitable for oral, parenteral (including subcutaneous, Intradermal, intramuscular, venous, internodal, and intravital), intraperitoneal, refractory, percutaneous, rectal, and topical (including dermal, buccal, sublingual Administration and intraocular administration, although the optimally conjugated administration surface may depend, for example, on the recipient's state of affairs and dosage. The dosage form may be formed into a unit dosage form and may be prepared by any method known in the art of pharmacy. These methods comprise associating a compound of the present invention, or a pharmaceutically acceptable salt thereof, vinegar, a captanamine, a prodrug or a solvate ("active ingredient") with a carrier constituting one or more complexing agents (let _〇η) In general, the preparation is prepared by uniformly bringing the active ingredient into association with a liquid carrier or a finely distributed solid carrier or both, and if necessary, making the product The dosage form of the compound disclosed herein may be a separate unit such as a capsule, a creme, or a tablet, each unit containing a predetermined amount of active ingredient; for example, a powder or granule; For example, a solution or suspension in an aqueous or non-aqueous liquid; or, for example, an oil-in-water liquid latex or a water-in-oil liquid latex. The active ingredient may also be a bolus, a syrup or a plaster. Pharmaceutical preparations include tablets, pushOfit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The tablets may be compressed or Type manufacturing 'optionally having one or more compounding agents. Compressed tablets may be prepared by compressing the active ingredient (in a free-flowing form such as a powder or granules), optionally with a dry agent, inertly diluted on a suitable machine. The agent or the lubricant, the surfactant or the dispersing agent are mixed together. The molded tablet may be prepared by molding a mixture of the powdered compound and an inert liquid diluent in a suitable machine to manufacture the beta tablet. A garment or score and may be formulated to provide sustained or controlled release of the active ingredient. The dosage of all oral dosage forms should be suitable for the method of administration. The push-fit capsule can contain the active ingredient and be mixed There are fillers such as lactose, a dry agent such as a powder and/or a lubricant such as talc or stearic acid, and optionally a stabilizer. In the soft capsule, the active ingredient can be scaled at the age of the body. Towels, such as fatty oil, © 丝^似液县 glycol. In addition, a stabilizer can be added. The dragee core can be suitably coated. For this purpose, the thief may be condensed, which may optionally contain gum arabic, talcum powder 'polyethylene slip fine, poly slow epoxide gel polyethylene glycol and/or dioxin, lacquer solution and suitable Organic reagent or solvent mixture. Dyestuffs or pigments may be added to the tablets or sugar-coated coatings to characterize the different combinations of active compounds. The chemodes can be formulated in a parenteral dosage form which can be annotated, for example by bolus injection or serial injection. Note _ Caisaki into a single __ as in the An Lai or in multi-dose packaging, and protective agents - from the addition. The composition may form a suspension in oil or water, or may contain a g&suppressive agent and/or dispersant. The dosage form can be placed in a unit dose or multi-dose package, such as a sealed ampoules and vials, and can be given in the form of a final or in a cold-recorded (green) condition, which only needs to be added immediately prior to use. The human is poured in a sterile liquid, such as saline or sterile water for injection. The temporary injection solution and mixing can be prepared from the above-mentioned no-ends, granules and tablets. Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injectable solutions of the active ingredient 'which can & contain antioxidants, buffers, sulphur dichlorochloride and solutes which render the dosage form The amount of money that is infiltrated by the employee; the job also contains a water-containing and non-aqueous g-free suspension of a lipophilic solvent or carrier containing (iv) a buoyant and a nougmented surface, including a fat-aged such as sesame oil < Fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may contain substances which increase their viscosity, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain a suitable stabilizer or a reagent which increases the solubility of the compound to prepare a 126 degree concentrated solution. In addition to the aforementioned dosage forms, the compounds may also be formulated in a dosage form. Such long acting dosage forms can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. For example, the compound can therefore be formulated with a suitable polymeric or hydrophobic material (for example an emulsion in an acceptable oil 0) or an ion exchange resin, or for example a slightly soluble derivative or, for example, a slightly soluble salt. . For oral or sublingual administration, the composition can be formulated into tablets, lozenges, pastilles or gels formulated according to conventional methods. The active ingredient is included in the case of sucrose and gum arabic or tragacanth. The compounds may also be formulated for rectal administration such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol or other glycerides. 30 200924772 The specific compounds disclosed herein can be administered by topical administration by non-systemic administration. It involves applying the disclosed compound to the epidermis or oral vestibule and dropping the compound into the ear, eyes and nose so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration. Suitable dosage forms for external use include liquid or semi-liquid preparations which are suitable for penetration through inflammatory sites of the skin, such as gels, elixirs, lotions, creams, ointments or liquorices, to provide suitable fit to the eyes, ears Or drops administered by the nose. The administration of the active ingredient for external use may include, for example, 0.001% to 10% W/W (by weight) of the dosage form. In a particular embodiment, the active ingredient can comprise as much as 10% w/w. In other embodiments, it can include less than 5% w/w. In a particular embodiment, the active ingredient can include from 2% w/w to 5% w/w. In other embodiments, it may include from 1% to 1% w/w of the dosage form. Gels for topical or transdermal administration generally comprise a mixture of volatile solvents, a non-volatile solvent and water. In a particular embodiment, the volatile solvent component of the buffered solvent system can comprise a lower (C1-C6) alkyl alcohol, a lower alkyl glycol, and a lower ethylene glycol polymer. In a further embodiment, the volatile solvent is ethanol. The volatile solvent component is considered to act as a permeation enhancer, although it provides a cooling effect when it is volatilized. The non-volatile reagent portion of the buffer solvent system is selected from the group consisting of lower alkenyl alcohols and lower ethylene glycol polymers. In a particular embodiment, propylene glycol is used. The non-volatile reagent de-malts the volatile reagent and reduces the vapor pressure of the buffered solvent system. The amount of the non-volatile solvent component and the volatile solvent is determined by the pharmaceutical compound or the drug used. When the amount of non-volatile solvent in the system is too small, the pharmaceutical composition may crystallize due to evaporation of the volatile solvent, although an excess thereof may result in loss of bioavailability due to too little release of the drug from the solvent mixture. The buffer component of the buffered solvent system can be selected from any buffer system commonly used in the art; water is used in certain embodiments. The usual 31 200924772 ratio of ingredients is about 20% non-volatile solvent, about 40% volatile solvent, and about 4% water. There are several kinds of external raw materials which can be added to the external component. These include, but are not limited to, chelating agents and gelling agents. Suitable gelling agents include, when not limited to, semi-synthetic cellulose derivatives (such as hydroxypropyl methylcellulose) and synthetic polymers, as well as cosmetic agents. Lotions include those suitable for application to the skin and eyes. The eye wash may comprise a sterile aqueous solution optionally comprising a bactericide, which may be prepared in a manner similar to the preparation of drops. Lotions and elixirs for application to the skin may also include agents which rapidly dry and cool the skin, such as alcohol or acetonide, and/or moisturizers such as glycerin or oils such as castor oil or peanut oil. An emulsion, ointment or paste is a topical semisolid dosage form of the active ingredient. The active ingredient may be mixed with an oily or non-oily base, either separately or in solution, in a water-mixed or non-nuclear towel, with the aid of a suitable machine. The substrate may comprise hydrocarbons such as hard, soft or lye, glycerin, bee, metal soap; (iv); oils of natural origin such as almonds, jade, peanuts, ramie or tax oil; lanolin or its derivatives Or a fatty acid such as stearic acid or oleic acid and an alcohol such as propylene glycol or a gel. The jumper may be any suitable indicator of an active agent such as an anionic, cationic or non-example surfactant such as sorbitan or polyoxyethylene. Fine as a woven gum, a fiber-reading organism or a domain former such as bismuth citrate, and other components such as lanolin may also be included. Drops may include sterile aqueous or oily solutions or suspensions which may be prepared by dissolving the active ingredient in a suitable aqueous solution which is dissolved by a bactericide and/or fungicide and/or any other suitable The fine towel in the mosquito includes a surfactant formed by the mouth of the liquid and then passed through the ship; and transferred to a suitable pocket, which is sealed and sealed by the same S or at 98-100 C. In addition, the solution can be sterilized by filtration and transferred to the container by aseptic processing. Among the drops suitable for 32 200924772 Examples of bactericidal and/or fungicidal agents are phenylmercuric nitrate or acetate (0.002 〇 / 〇), stupid gas (0.01%) and gas hexidine (〇. 〇1%). Suitable solvents for the preparation of oily solutions include glycerin, alkenyl alcohol and propylene glycol. Formulations for external use in the mouth (for example, buccally or sublingually) include lozenges comprising the active ingredient, based on the taste of, for example, sucrose and acacia or tragacanth, and comprising the active ingredient, gelatin-based and glycerin or sucrose and Lozenges of Arabian cockroaches. For inhaled dosage forms, the compound is released by either an insufflator, a spray pack or other convenient means of releasing the spray. The pressurized pack may contain a suitable propellant such as di-dioxane, tri-fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. With regard to pressurized aerosols, the dosage unit can be ascertained by providing a valve to release the amount measured. Further, for administration by inhalation or inhalation, the compound according to the invention may be formulated in the form of a dry powder component, for example a powder mixture of the compound and a suitable powder base such as lactose or starch. Unit dosage forms, such as capsules, cartridges, gelatin or blister packs, can be administered with the aid of an inhaler or insufflator. Preferred unit dosage forms include an effective dose, as described below, or a suitable effective fraction thereof. It will be understood that for the dosage form in question, in addition to the above ingredients, the above dosage forms may include other conventional agents in the art, for example those suitable for oral administration may comprise a flavoring agent. The compound can be administered orally or by injection at a dose of from 5 to 5 mg/kg per day. The rhythmic dose ranges from about 5 mg to about days. The tablet or other form of the form provided in the monomer unit may suitably contain a certain amount of the compound or the same compound in the amount of the seed, for example, containing 5 mg to · ng of the unit, the oil version g To 2〇〇mg. 33 200924772 The amount of active ingredient that is combined with the carrier to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. The compounds can be administered in a variety of ways, such as orally or by injection. The precise amount of the compound administered to the patient is the responsibility of the physician. The specific dosage level for a particular patient will depend on a variety of factors, including the activity of the particular compound administered, age, weight, general health, sex, diet, administration. Time, route of administration, rate of excretion, combination of drugs, the precise condition being treated, and the severity of the condition or condition being treated. The route of administration also varies depending on the state and its severity. In a particular example, it is suitable to administer at least one of said compounds (or pharmaceutically acceptable guanidinium salts, esters or prodrugs thereof) and another therapeutic agent in combination therewith only by the method of the examples, if one is accepted One side effect caused by a patient of the compound is hypertension, and the anti-hypertensive agent should be administered in combination with the initial therapeutic agent. Alternatively, the effects of the compounds described herein may be enhanced by the administration of an adjuvant by only the methods of the examples (ie, the adjuvant itself has only minimal therapeutic effect, but is used in combination with another therapeutic agent, for all of the patient's The therapeutic effect has been improved). Alternatively, the benefit of a patient may be increased by the combined administration of one of the compounds described herein and another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. Providing another therapeutic agent for diabetes may also enhance the therapeutic benefit in the treatment of diabetes comprising one of the compounds described herein by the method of the examples only. In any event, the overall benefit obtained by a patient regardless of the disease, condition or condition being treated can be a synergistic benefit for both therapeutic agents or patients. Specific, non-limiting examples of possible combination therapies include the use of the compounds of the invention and: a) corticosteroids including betamethasone dipropionate (both enhanced and non-reinforced), betamethasone valerate, chloride propionate Bisoned pine, diacetonate, halobutyrol propionate, ansinide, diazepam 34 200924772 dexosimethasone, fluocinolone acetononide, fluocinolone, hacicinide Diclofenac and fluoxetine; b) Non-steroidal anti-inflammatory includes difenfen, germination ibuprofen and beta-roxicam; muscle relaxants and other agents Combination, including Cyclobenzaprine, Baclofen, Cyclobenzaprine/Lidocaine, Paxafen/Cyclobenzaprine, and Cyclobenzaprine/Lidocaine/Hydrazine ibuprofen; d) Anesthetics and Combination with other agents, including lidocaine, lidocaine/deoxy-D-glucose (anti-viral), prilocaine, and Enna emulsion [local anaerobic eutectic mixture (2.5% lidocaine and 2.5%) Amphetamine; an emulsion in which the oil phase has a weight of 1:1 of lidocaine and prilocaine a ratio of eutectic mixture. The eutectic mixture has a melting point below room temperature and both local anesthetics are present as liquid rather than crystals); e) tanning agents and their association with other agents, including Tacrox glyceryl ether and guaiacol glyceryl ether / ketoprofen / Cyclobenzaprine; f) antidepressants including tricyclic antidepressants (eg amitriptyline, doxepin, desipramine) , imipramine, amoxapine, clomipramine, nortriptyline, and protriptyline), selective ash/norepinephrine reuptake inhibitors including (eg duloxetine and rice nitrogen) Flat), and selective norepinephrine heavy Wei-suppressive (eg, nisol, maprotiline, and rexixi (1), selective serotonin-suppressed lakes (eg, fluorine and flu (4)); Anticonvulsant and its combination, including gabapentin, carbamazepine, felacetic acid, lamo sylvestre, vinegar, sputum carbene, oxetzepine, carbamezipine, manicheamide mexiletine Gabapentin River Leding, gabapentin / carbamazepine and carbamazepine / Cyclobenzaprine; h) antihypertensive drugs including 1) Classes of thieves include butylamine, tramadol, morphine, fentanyl, and carbaryl, and x) topical anti-irritants include menthol, wintergreen oil, bartan, oil reduction and Turpentine; k) Partially large classes include CB positions in the selection and surface (2) _ subject anti-agents include the selection of steep and non-selective HiR and postal ligands; and other ligands such as the pepper field. 35 200924772 In summary, the combination therapeutics (at least one of which is a compound disclosed herein) can be administered in any order or simultaneously. If administered simultaneously, the combination therapeutic agent may be provided in a single, multiple or multiple forms of silk (only by remuneration, transfer or silk removal. One of the therapeutic agents may be administered in multiple doses, or both may be administered in multiple doses. Not simultaneously, the time between the multiple doses can be any time interval from a few minutes to four weeks. Thus, in another aspect, certain embodiments provide treatment for iNOS mediated in a human or animal article in need of such treatment. A method of treating a condition comprising administering to the article a quantitative amount of an effective compound disclosed herein to reduce or prevent the condition in the article from at least one additional agent for treating the condition known in the art In a related aspect, certain embodiments provide a therapeutic composition comprising at least one compound disclosed herein in combination with one or more additional agents for treating an iNOS mediated disorder. Nitric oxide synthase-mediated diseases, disorders and conditions are useful, especially as inhibitors of nitric oxide synthase. Studies in iN〇s knockout mice have found that during microvascular changes following injury, axons and Zhao fats fail and are cleared before regeneration. 'Nitric oxide promotes the development of neuropathic pain D, Kubes p And 2001 May; 60(5): 411-21)» The compound of the present invention has neuropathy or inflammatory pain such as reflex sympathetic dystrophy/burning (nerve damage), peripheral neuropathy (including diabetic nerve; Kem) TS, 2) Peru 2007; 2007: 95103), stubborn cancer pain, complex regional pain syndrome, and compression neuropathy (carpal canal syndrome) are useful. The compounds can also be used to treat acute blistering. Rash (vesicular therapy) related pain, post-herpetic neuralgia (ΡΗΝ;) and associated pain syndrome such as eye pain. The compound is further used as an analgesic for the treatment of pain such as surgical painless or therapeutic fever Antipyretic drugs. Pain indications include, without limitation, postoperative pain, toothache/extraction, cancer pain, myalgia, breast pain, skin damage pain, low back pain, various surgical procedures including heart surgery 36 200924772, Headaches of various etiology include migraine, etc. The compounds can also be used to treat headache-associated conditions such as tactile allodynia and hyperalgesia. The pain can be a causal (nociceptive or neuropathic pain) Acute and/or chronic pain. The nitric oxide inhibitors of the present invention are also useful in the traditional administration of non-steroidal anti-inflammatory drugs, morphine or fentanyl opiate preparations and/or other narcotic analgesics. The compounds of the present invention are useful for the treatment and prevention of opiate resistance in patients requiring prolonged opiate analgesics, benzodiazepine resistance in patients receiving benzodiazepines, and others Addictive reactions, such as nicotine addiction, alcoholism, and eating disorders. In addition, the methods and compounds of the present invention are useful for treating and preventing drug withdrawal symptoms, such as treating and preventing symptoms of opioid, alcohol, or tobacco addiction. Further, the compounds of the invention can be used to treat insulin resistance and other metabolic diseases such as atherosclerosis typically associated with amplifying inflammatory signals. The invention includes methods of treating and preventing a disease or condition of a smoking system using a selective iNOS inhibitor, including the use of a medicament for the prevention and treatment of a disease or condition of a respiratory system, including: asthma states including allergens Asthma, exercise-induced wheezing, pollution-induced asthma, cold-induced asthma, and virus-induced asthma; chronic obstructive pulmonary disease including chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis) ), emphysema, asthmatic bronchitis, and running disease; and other lung diseases including inflammation include bronchiectasis fibrocystic disease, peg〇n fander, s disease, peasant lungs, Acute respiratory distress syndrome, pneumonia, aspiration or inhalation injury, pulmonary lipid embolism, pulmonary acidosis inflammation, acute pulmonary edema, acute mountain sickness, acute pulmonary hypertension, neonatal persistent pulmonary hypertension, perinatal inhalation Syndrome, neonatal hyaline disease, acute private 37 200924772 embolism, heparin From the reaction, sepsis, status asthmaticus, and hypoxia. A condition or condition that can be advantageously treated with a compound of the invention includes inflammation. An additional advantage of the compounds of the invention as anti-inflammatory agents is that their deleterious effects are significantly reduced. The sigma is used to treat arthritis (Cuzz〇crea s, ^ 2006; 12 (27): 3551-7G) 'including but not limited to rheumatoid arthritis (Ma Yi Yang et al, plus melon - /. 2_ Jun 18. [Internet publishing prior to printing]), spinal rickets, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatoid arthritis, enteropathic arthritis, nerve joints Inflammation, psoriasis, inflammation and septic arthritis. The compounds are also useful in the treatment of osteoporosis and other phase diseases. The compound also treats gastro-intestinal diseases such as malignant esophagitis, diarrhea, enteritis, Crohn's disease, gastrin occupational collaterals, and ulcerative colitis. The compounds are also useful in the treatment of pneumonia, such as silkworm and fibrocystic vesicle-associated pneumonia. Additionally, the compounds of the invention may be used in organ transplant patients alone or in combination with conventional immunomodulators. Wealth, this hair _ all kinds of _ 槪 槪 和 and white mad wind. The compound of the present invention is also treated with _injury in vascular disease: vascular disease migraine, nodular periarteritis, thyroiditis, aplastic anemia, Hodgkin's disease, edematous sclerosis (sdenKloma), rheumatic fever Diabetes mellitus, neuromuscular junction diseases including myasthenia gravis, white matter including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, becher's syndrome, polymyositis, tendinitis, Periodontitis, hypersensitivity, swelling after injury, ischemia include myocardial ischemia, cardiovascular ischemia, cardiac arrest, and ischemia. The compounds of the invention are useful in the treatment of specific diseases and conditions of the nervous system. Mesenteric neonatal disorders that are inhibited by nitric oxide include cortical filaments including Alzheimer's disease, stroke-induced central nervous system damage, ischemia including cerebral ischemia (local cerebral ischemia), thrombosis, and Whole heart ischemia (such as cardiac arrest) and trauma. Application of oxidative inhibition of neurotoxicity 38 200924772 Sexual disorders include hypoxia, hypoglycemia, neurodegenerative or neurological necrosis caused by epilepsy, and medianic sacral nervous system (CNS) injury (eg spinal cord and craniocerebral injury), hyperbaric oxygen spasm Acid and toxicity, dementia such as Alzheimer's disease, and aids-related dementia, cachexia, Westdenham's chorea, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Cole Other symptoms and anxieties associated with Saco's disease, cerebrovascular related dullness, sleep disorders, schizophrenia, depression, depression, or premenstrual syndrome (PMS). In addition, the compounds of the present invention are also useful for inhibiting N-arginine production of N〇, including systemic hypotension associated with septicemia and/or toxic sepsis induced by various sputum factors; application of cytokines such as TNF, IL_1 and IL-2 (4) treatment; and as an adjuvant for the immunosuppression of transplanted ovum. These compounds are also useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome and atherosclerosis. Other conditions or conditions treated by the compounds of the invention include the prevention and treatment of hyperproliferative diseases, particularly cancer. Blood and non-hematological malignancies that can be treated or prevented include, but are not limited to, multiple bone tumors, acute or chronic leukemia including acute lymphocytic white disease (AT T ), chronic lymphocytic leukemia (CLL), and chronic Zhao cells Leukemia (CML), lymphoma including © Hodgkin's (H°d_) lymphoma and non-Hodgkin's lymphoma (low, medium and high), as well as brain, head and neck, breast, lung, reproduction Solid tumors and malignant tumors of the upper, upper digestive tract, pancreas, liver, kidney, bladder, prostate, and colorectum. The compounds and methods can be used to treat fibrosis, for example, with radiation therapy. The compounds and methods can be used to treat patients with adenomatous polyps, including patients with familial adenoid polyposis (FAP). Additionally, the compounds and methods can be used to prevent the risk of polyp formation of FAP. The compounding seam of the present invention is sufficient for treating eye diseases such as glaucoma, retinal ganglion degeneration, ocular ischemia, corneal neovascularization, optic neuritis, retinitis, retinopathy such as cyan 39 200924772 retinal age of light eye / or diabetes Inflammation and pain associated with paralytic disease, uveitis, diurnal eyesight, dry eye, Sygmy's syndrome, allergic conjunctivitis, chronic eye conditions, and acute ocular tissue damage. The compounds are also useful in the treatment of post-operative inflammation or pain such as ocular surgery (e.g., cataract surgery). Further, the compounds of the present invention are useful for the treatment of menstrual warts, dysmenorrhea, premature labor, gingivitis 'viscous bursitis, skin-associated conditions such as psoriasis, genital warts, burns, sunburn, dermatitis, adrenitis, liver fire, and the like. The compounds of (4) provide the benefits of inhibition-nitric oxide inhibition to treat other conditions including diabetes (type I and type π) power failure, myocarditis dysplasia, and aortic aneurysm. The compounds are also used in combination therapy, local or complete treatment in place of other conventional anti-inflammatory therapies' such as combination, non-steroidal anti-inflammatory drugs, cox_2 selective inhibitors, 5_lipoxygenase inhibitors, ltb4 and coffee Engage in enzyme inhibition. Secret_Compound # can also be used to prevent tissue damage when used in combination with antibacterial and antiviral drugs. In addition to use in the treatment of humans, the compounds and dosage forms are also useful in mammals for the introduction of animals and farm animals, including mammals, weeds, and the like. More preferred animals include horses, dogs, and juveniles. All references, patents or applications in the United States or abroad to which the application is applied are hereby incorporated by reference in its entirety. If there is any *, the contents of this article shall prevail. [Embodiment] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A ship synthesis method for preparing a compound The following scheme can be used to carry out the present invention. 40 200924772 Option 1

a

R1〇3

Reagents: (8) xylene, 0 唆 reflux, 3-18 hours. (b) (i) Br2, AcOH, 25-50 ° C, 5-18 hours. (ii) Acetone, 25 ° C, 2 hours. (c) Selective fluorescer (Selectfluor®), ACN, 60 ° C, 6 hours or S02C12, DCM (20 mL) 0 ° C ~ RT, 2 hours. (6) H2S04, 40 ° C, 2-18 hours. (e) NaH, DMF, RT, 2-18 hours or 220 ° C, 2-5 minutes or propylene glycol 190 ° C, 100 minutes or sodium bicarbonate, propylene glycol, 10 ° C, 45 minutes. (f) PPA, 120 ° C, 2 hours. (g) HATU, DIEA, DMF, RT, 18-30 hours. (h) AcOH, 60 ° C, 18-40 hours. 41 200924772 Option 2

Ο

Reagents: (a). (i) m-CPBA, 25 ° C, 16 hours. (ii) P0C13,11 (TC, 2 hours. (b) Dihydropyran, p-TsOH 80 ° C, 1 hour. (6) Cyclopropylboronic acid, Pd2(dba)3, C26H36NP, Cs2C03, toluene, 12 (TC , 2 hours. (6) HQ sounds 0, RT, 10 minutes. (e) Nal, TMSC1, ACN, reflux, 18 hours. (f) KF 'Cul ' TMSi-CF3 ' DMF ' 55 ° C ' 18 42 200924772 hours. (g) Zinc isopropyl bromide, Pd(PPh3)4 'THF 'reflow' for 18 hours or Et2Zn 'Pd(dppf)Cl2, 1,4-dioxane, refluxed for 18 hours. (h) Pair -Methoxybenzylamine, 100 ° C, 72 hours. (i) (1) HBr / AcOH, 18 hours, 50 ° C. (ii) succinic anhydride, NMP (2 mL), 200 ° C (MW), 30 min. 1 Rhh-NH-Rh», 70-110 ° C, 24 hours. (k) NaH, DMF, RT, 2-18 hours or 220 ° C, 2-5 minutes or propylene glycol 190 ° C, 100 minutes or carbonated Sodium hydrogenate, propylene glycol, l ° ° C, 45 minutes. (1) Hydrazine hydrate, EtOH, RT, 4.5 hours.

Option 3

43 200924772

Reagents: (8) xylene, acridine reflux, 3.18 hours. (8) H2S〇4, 40〇c, 2_18 hours. (c) PC15, P0C13, 100 ° C, 2 hours. (d) MeONa, MeOH, reflux, 6 hours. (e) NBS, benzamidine peroxide, CCI4, refluxed for 24 hours. (f) NaH, DMF,; 25 ° C, 1 - 5 hours. (g) PPA, 120 ° C ' 2 hours. (8) (1) m-CPBA, 25 ° C ' 16 hours. (ii) POBr3 'DCM, 25 ° C, 4 hours. (1) THF/H20/cHC1, 60 ° C, 18 hours. 1 Pd(0)(tBu3P)2, 44 200924772

Zn(CN) 2, DMA, 110 ° C, 24 hours. (k) Pd/C, H2 (50 psi), AcOH, 1 hour. Intermediate oxime synthesis Intermediate 1

4-(Bromoindenyl)-7,8-difluoroquinolinone 〇 F π Step 1: Ν-(2,3-difluorophenyl)-3-oxetamine

A solution of methyl 3-oxobutanoate (300 g, 2.4 mol) in xylene/pyridine (900 ml / 20 ml) was heated to reflux for 0.5 h. Then, 2,3-difluoroaniline (145 g, 1.1 mol) was added dropwise to the above reaction mixture. The mixture was refluxed and stirred for 30 hours. At this point no further progress was observed by HPLC. The solution was allowed to cool and extracted with 500 mL of 20% aqueous NaOH. At this time, the precipitated salt was removed by filtration. The aqueous layer was separated and made to be weakly acidic using a high concentration of HC1. The resulting precipitate was collected by filtration and air-dried to obtain 149 g (yield: 62%) of N-(2,3-difluorophenyl)-3-oxetamine as a brown solid. hNMRpOOMHz, DMSO-dfi) δ 9.48 (s,1H) ' 8.10 (m ' 1H),7·04 (m,1H) ' 6.92 (m,1H),3.64 (s,2H),2,34 (s, 3H). Step 2: 4-Bromo-indole-(2,3-difluorophenyl)-3-oxetamine 45 200924772

To a solution of N-(2,3-difluorophenyl)-3-oxetamine (111 g, .52 mol) in AcOH (500 mL), EtOAc (EtOAc) The mixture was stirred at room temperature for 22 hours. Then, 50 ml of acetone was added thereto. Once the reaction was completed by HPLC, 170 ml of water was added dropwise to the mixture. The mixture produces seeds and the crystals form rapidly. The mixture was cooled and the solid was collected by filtration and dried in vacuo to give <RTI ID=0.0>0> The purity is 99%.

MJJt: 4-(bromodecyl)·7,8-difluoroquinolin-2(1H)-one

0

Q 4-Bromo-N-(2,3 difluorophenyl)-3-oxetamine (79 g) was dissolved in a high concentration of h2s〇4 (4 mL) and heated to 40. The solution was stirred at 40 ° C for 20 hours. After cooling to room temperature, the solution was poured into 2000 g of H2 crucible/ice. After simmering and using H2 〇 苏 鳢 鳢. Then, it was washed with an aqueous solution of 5% by volume of acid gas, followed by water washing, and dried in vacuo to obtain 59 g of 4·(methane)·7,<2>difluoroquinolin-2(1Η)-one as an off-white solid ( 80%). iHNMR (300 MHz, DMSad6) δ 12 Q7 (s ' 1H) ' 7.72 (m, 1H), 7.37 (m, 1H), 6.78 (s ' 1H), 4.89 (s, 2H). LCMS: 274 (M+H)+ 〇 Intermediate 2 4-(bromomethyl K7,8-difluoro-3-methylquinolinone 46

Br 200924772 As described for Intermediate 1, 4-(bromomethyl)-7,8-difluoro-3-methylquinoline-2(1 H)-one uses 2·methyl-3 Oxo Ethyl butyrate and 2,3-difluoroaniline are synthesized as raw materials. 1H NMR (300 MHz 'DMSO-sentence δ 12 07 (s, 1 Η), 7.68 (m, 1 Η), 7.30 (m, 1 Η), 4.90 (s, 2H), 2.14 (s, 3H). lCMS: 287 ( M+H), intermediate 3 o 4-(bromomethyl)_3,7,8-trifluoroquinolin-2(1H)-one

Step F: 4-bromo-N-(2,3-difluorophenyl)-2-fluoro-3-oxetamine

Heating ACN-N-(2'3-difluorophenyl)-3-oxetamine (3. gram, 10.9 亳mol) and selective fluorinating agent (Selectfluor®) (4.60 g, 13.00) A mixture of millimoles) is 18 hours to 50 °C. The reaction mixture was cooled to room temperature and the solvent was removed. The residue was partitioned between DCM and water. Purification by flash chromatography on a hydrazine gel gave 1.2 g of 4-bromo-2-fluoro-N-(2,3-carbophenyl)-3-oxetamine as a yellow solid. Step 2: 4-(Bromomethyl)-3,7,8-trifluoroquine##(1Η)_明 47

200924772 As described for the third step of intermediate 1, 4_(bromomethyl)_3,7,8-trifluoroquinolin-2(1H)- Ming uses 4-winter 2-fluoro-N-(2' 3 -Fluorophenyl)_3_oxetamine as a raw material for synthesis. 1H NMR (300 MHZ ' DMSO 〇 δ 12·65 (s, 1 Η) ' 7.73 (m ' 1 Η ) ' 7.43 (m, 1 Η) ' 4.89 (s ' 2 Η ) 〇 ± ΜΜΛ 4 ~ (bromomethyl) - 7 'Difluoro-2-methoxyquinoline

F complex Lf:: 7,8-difluoro ice methylquinoline_2(1Η)-one ◎ As described in the third step of intermediate 鳢1, 7,8-difluoro ice methylquinoline-2 (1Η The ketone was synthesized using 1SK2, 3-fluorophenyl)-3-oxetamine as a starting material.

F Shame "U:: 2-gas-7,8-difluoro 4-methylquinoline pCl5 (1 g) was added to p〇ci3 (302.1 g) in 7,8-difluoro-4-methylquinin -2 (1H)-嗣 (14 g) solution' and heat for 2 hours to l〇〇eC. The mixture was concentrated and the residue was dissolved in EtOAc EtOAc (EtOAc) EtOAc (EtOAc) 7, '8-two gas ~ 4 ~ methyl 啥 'forest white solid. Step 3: 7'-Difluoro-2-methoxy 4-methylquinoline

A mixture of 2_gas-7,8-difluoro-4-methylquinine (14 g) and MeONa (7.1 g) in MeOH (25 mL) was refluxed for 6 hours. The residue was purified by flash chromatography on silica gel eluting with 1:1 EtOAc/EtOAc to afford 13 g (94%) of 7? <» Step 4: 4-(Bromomethyl)·7,8-difluoro-2-methoxyquinoline

C8 (10 ml) of 7,8-difluoro-2-methoxyindolemethylquineline (4.39 g, 21.00 mmol), NBS (7.4 g, 41.57 mmol), and BPO ( A mixture of 350 mg, 2.13 mmol) was returned to the sea for 24 hours. TLC (EtOAc/PE = 1:10) followed the course of the reaction. The residue was purified by flash chromatography on EtOAc EtOAc (EtOAc) eluting A quinolinol white solid. NMR NMR (300 MHz, DMSOO δ 7.68 (m, 1H), 7.28 (m '1H), 6.92 (s, 1H), 4.66 (s ' 2H), 4.06 (s, 3H). Intermediate 艚 5 _ ..- 4·(Bromomethyl)·8-1 quinoline-2(1H)-one 49 200924772

As described for Intermediate 1, the ' 4-(bromomethyl)·8-fluoroquinolin-2(1H)-one was synthesized using 2-fluoroaniline as a starting material. LCMS: 255 (M+H)+. Middle 艚6

4-(Mide methyl)-3-chloro-7,8-difluoroquinolin-2(1H)-one

MJ, ± : 4-bromo-2-a-N-(2 ′ 3-difluorophenyl)·3·oxetamine

To a solution of 4-bromo-N«(2' 3-difluorophenyl)-3-oxobutamine in DCM (40 mL), EtOAc (EtOAc) (2,92 g, 10,00 mmol, 1.00 eq.) in solution while maintaining the temperature at 〇. The resulting solution was stirred at room temperature for 2 hours. 100 ml of DC1V was used [diluted solution was prepared and washed with h20 and dried by Na2S〇4. & The residue was purified by flash chromatography on a silica gel (using 2 〇: 1 PE:Et〇Ac solvent system) to obtain 2.88 g (crude product) 4_bromo-2·gas·N_(2 , 3c fluorophenyl) 3 butyl amide white solid. Star: 4-(bromomethyl)-gas-7,8-difluoroquinoline·2(1Η)-one

Or

F 50 200924772 As described in the third day of Intermediate 1, 4·(Met's methyl > 3 Lu 7 ' 8_ 2 gas 嫉 2 (1 Η) · ketone using 4H gas · Ν (2, 3- fluoro Synthesis of 3-oxetamine as a starting material. LCMS: 307 (M+H)+. ±MMl 4-(bromomethyl)_7_氡_8-fluoroquinolin-2(1H)-one

As described for the intermediate 1, 4-(bromomethyl)-7-gas-8-fluoroquinoline-2(1H)-one was synthesized using 3-gas _2·fluoroantamine as a starting material. LCMS: 2905 (M+H)+. The above-described methods and/or intermediates are selectively described by the skilled artisan using the methods well known in the art by the following examples, or alternatively, U.S. Patent Application Serial No. 11/ filed on Feb. 23, 2007. The method disclosed in 678,572, the disclosure of which is hereby incorporated by reference herein in its entirety in its entirety, the disclosure of the disclosure of the disclosure of -((2-isopropyl-1Η-imidazo[4,5-b]pyrazin-1-yl)methyl)啥琳_2(1Η)-ketone

51 200924772 Step 1: 2-isopropyl-1H-imidazo[4 ' 5-b]pyrazine

1 '2-Diaminopyrazine (1.1 g, 1 〇 mmol) was transferred into a 4 〇 ml capless bottle. To this was added 2-propanecarboxylic acid (0,88 g, 1 mL), followed by polyphosphoric acid (4 mL, EtOAc), EtOAc, EtOAc, EtOAc. The reaction mixture was heated and mixed at 12:2 for 2 hours. The viscous mixture thickened and became uniform during the first 30 minutes at 120C. 12〇. After 2 hours, the hot reaction mixture was poured into a stirred and cooled Na〇H solution (33 mL, <3N, 0.1 mole). The pH of the solution was adjusted (using a NaOH solution or polyphosphoric acid as needed) to 7.5. After 30 minutes at pH 7.5, the RT slurry was filtered. The filtered solids were then washed with HiO (2 X 5 mL) and dried in vacuo to afford 4 g of 2~isopropyl-1H-imidazo[4 ' 5-b]pyrazine as a pale brown solid. (M+H)+. ϋ 2 steps: 7,8-difluoro 4-((2-isopropyl-1Η-imidazo[4,5-b]pyrazine-1-yl)methyl)quinoline

To a solution of 2-isopropyl-1,1-imidazo[4,5-b]pyrrole (162 mg, 1.0 mmol) was added DMF (2 ml of μM to give a dark solution of β and then NaH (92 mg, 60) %'2.3 mmol). After settling (~5 minutes), add 4-(Meta-methyl)-7' 8-difluoroindole-2(1H)-copper (intermediate 1 '246) Mg, 〇.9〇mmol.) After 1 hour at RT, 'Add MeOH (1 mL). Reverse 52 200924772 Phase HPLC purification of the crude mixture to give 75 mg of 7,8-difluoro~4-((2-) propyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)porphyrinone white solid. 4 NMR (400 MHz 'CD3OD; TFA salt) δ 8.52 (d, 1H), 8.37 (d,1H) ' 7.86 (m ' 1H), 7.30 (m, 1H), 5.96 (s ' 2H), 5.58 (s, 1H) ' 3.35 (m ' 1H), 1.42 (d ' 6H). LCMS : 356 (M+H)+ 〇f Example 2 4-((2-Cyclobutyl-3H-flavored[4,5-b]e than -3-yl)methyl)-7 '8 -Difluorophthalene-2 (1H)-

Φ as described in Example 1 'Use 4_(Moline methyl)-7' difluoroantimonin (intermediate 1) and 2-cyclobutyl-[4' 5-b]"tfc To synthesize 4-((2-cyclobutyl-3H-flavored [4,5-b]°tb -3-yl)methyl)_7,8-difluoroindole 1 -2 (1H)· Hey. 1H NMR (400 MHz, DMSO-d^; TFA salt) δ 8.32 (d,1H) ' 8.14 (d,1H), 7.85 (m ' 1H) ' 7.38 (m, iH), 7.34 (m,1H), 5.73 (s, 2H), 5.22 (s ' 1H), 3.84 (m ' 1H) ' 2.5-1.8 (m, 6H). LCMS: 367 (M+H)+ e Example 3 7,8-Difluoro-ice ((2-(oxazo-3-yl)-3H-isoxazo[4' 5-b] acridine-3 -yl)methyl)quinoline-2(1H)-one 53 200924772

As described in Example i, 4_(漠代曱基)-7,8-difluoroquinolin-2(1H)-one (Intermediate 1) and 2-(Huanxuan-3-Cong)-Xun The rice is sitting and [4 '5-7]° is used as a raw material to synthesize 7,8-difluoro 4-((2_(pentan-3-yl)-3H-milymium [4,5-b]pyridine _3_yl)methyl)porphyrin_2(1H)_copper. 1H NMR (400 MHz, DMSO-mountain; TFA salt) δ 8.32 (d ' 1 Η), 815 (d, 1 Η), 7.91 (m, 1 Η), 7 38 (m, 1 Η) ' 7.35 (m, 1 Η), 5.82 (s, 2Η), 5.29 (s ' 1Η), 3.88 (m ' 1Η), ! 9-1 6 (m, 4H), 0.78 (t ' 6H). LCMS: 383 (M+H)+. Example $ 4-((2-Cyclobutyl-7-methyl_3H- miso[4,5-b]° pyridine-3-yl)methyl)·7,8-difluoroquinoline • 2 (111) - Ming

4- As described in Example 1, 4-(bromomethyl)-7'8~difluoroquinolin-2 (1Η> ketone (Intermediate 1) and 2-cyclobutyl-7-methyl-3H were used. Synthesis of 4-((2-cyclobutyl-7-methyl-3H-imidazo[4,5-7]pyridinyl)methyl) by the use of sulphur and [4 '5-7] ° pyridine · 7,8-Difluoroquino-2 (1H)-Ming. 丨HNMR (400 MHz, DMSO-mountain; 叮8 salt) δ 12 02 (s '1H) ' 8.13 (d, 1H), 7.85 (m , (1,1H) 2> j 8 (m, 6H). LCMS: 381 (M+H)+, 7.8-difluoro-4- Example 5 Methyl-2-(pentyrim-3-yl)-3H-imidazole [4,5_b]pyridine each) fluorenyl) o quinoline-2(1H)-one

'Use bromomethylamino-7' 8-difluoroindene-2(1Η)-one (intermediate 1) and 7-mercapto-2-(pentyl)- as described in Example Synthesis of 7 ' 8-difluoro- 4-((7-methyl-2-(pentane)-3H-imidazolium μ) by using pyridine-[4,5-b]e as a starting material 5-b]pyridine each)methyl)porphyrinone. LCMS: 397 (M+H)+.

Example 6 4-((7-Gas-2-cyclobutyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8.difluoroquinoline-2 (1 H) -ketone

Step 1: 2-cyclobutyl-3H-imidazo[4,5-blpyridine 4-oxide O' 55 200924772 2-Cyclobutyl-3H-imidazo[4,5-b] in a 1 liter flask Propylene (300 ml) was added to pyridine (9.5 g, 55 mmol). The reaction solution was stirred while adding m-benzoic acid (15 g, 72% '62 mmol). After 16 hours at RT, the slurry was filtered. The filtered solid was washed with acetone (5 mL) and dried in vacuo to give <RTI ID=0.0>>丨H NMR (400 MHz, D20) δ 7.98 (m, 1 Η), 7.51 (m, 1 Η), 7.06 (m, 1H) s 3.64 (m, 1H), 2.3-1.7 (m, 6H). LCMS: 190 (M+H)+. Ά1±.: 7-Gas-2-cyclobutyl-3H-imidazo[4,5-b]pyridine

To a solution of 2·cyclobutyl-3H-carbazolo[4,5-b]pyridinium oxide (8·5 g, 45 mmol) in a 200 ml flask was added a tris-oxygen scale (5 mL, 330 mmol). The reaction solution was heated to reflux. After 2 hours at ll ° C, the solution was cooled to 40 ° C and concentrated to give a residue. The residue was dissolved in DCM (300 mL) and a pH 9 of phosphate buffer (400 mL, 1 N K2HP 〇4). The organic layer was separated and dried (MgSO.sub.4), filtered and concentrated. Purification by hydrazine gel chromatography (50% to 75% EtOAc/hexanes) afforded 7 g of 7- s.丨HNMR (400 MHz, DMSOO δ 13.14 (s, 1H), 8.15 (d, 1H), 〇 7.28 (d '1H), 3·72 (m, 1H), 2.5-1.8 (m, 6H). LCMS: 208 (M+H)+. Step 3: 4·((7-Chloro-2-cyclobutyl-indole-imidazo[4,5-b]pyridine-3-yl)methyl)J7,8- Difluoroquinolinone 56 200924772

As described in Example 2, the second less than 'Use 4_(bendoyl)-7'8-difluoroindoleone (Intermediate 1) and 7-Galy-2-cyclobutyl-3H-imidazo[4 ,5-7]pyridine as raw material to synthesize 4-((7-chloro-2-cyclobutyl-3H-imidazo[4,5-b]e than bit _3_yl)methyl)-7 '8_ Difluoropyrene-2(1H)-嗣. 1H NMR (400 MHz, DMSOO δ 12.〇2 (s ' 1Η) ' 8.21 (d ' 1Η), 7.82 (m, 1Η) ' 7.44 (d ' ^ 1Ή) ' 7.37 (m,1H) ' 5.73 (s ' 2H), 5.22 (s ' 1H), 3.86 (m ' 1H), 2.5-1.8 (m, 6H). LCMS: 401 (M+H) + ° Example 7 4-((2-cyclobutyl-) 7-(Dimethylamino)-3H-methanol 0 sits and [4 ' 5-b]° bites 3-yl) fluorenyl)-7 ' 8-difluoroquinolin-2(1H)-嗣

Step 1: 2-cyclobutyl-N,N-dimethyl-3H-mithio[4,5-punching ratio -7-amine

Add 7-gas-2-cyclobutyl·3Η-^β to a 4 ml vial and add [4'5-7]° to the bite (0.21 g 'L0 mmol) to add dimethylamine (2 ml of 2 ml in THF). The solution). The vial was sealed and the reaction mixture was heated. After 24 hours at 11 ° C, the reaction mixture was cooled to a white solid. The slurry was diluted with Et20 57 200924772 (10 ml) and filtered. The solid was triturated with HzO (5 mL), filtered, and dried in vacuo to give <RTI ID=0.0>>&&&&&&&&&&&&&& -amine. 1 NMR (400 MHz, DMSO-d6) δ 12,38 (s, 1 Η), 7.79 (d, 1 Η), 6.20 (d, 1 Η), 3.60 (m, 1H), 3.30 (s, 6H) ' 2.4- 1.8 (m ' 6H). LCMS: 217 (M+H)+. Step 2: 4-((2-Cyclobutyl-7-(dihydroamino)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-7,8-difluoroquine Porphyrin-2 (1Η> ketone

As described in step 2 of Example 1, 'Using 4-(indiyl)-7' 8-difluoroquino*#-2(1Η)-one (Intermediate 1) and 2-cyclobutyl-hydrazine Synthesis of 4-((2-cyclobutyl-7-(dimethylamino)-3H-imidazole) by using hydrazine-dimethyl-3-hydrazino-imidazo[4,5-b]pyridin-7-amine as starting material [4,5-b]pyridin-3-yl)indolyl-7,8-difluoroquinolinone. 1HNMR (400 MHz, DMSO-d^: TFA salt) δ 12.09 (s, 1 Η) ' 7.95 (d, 1 Η), 7.75 (m, 1 Η), 6.59 (d ' 1 Η) ' 5.69 (s ' 2 Η) , 5.15 (s, 1H), 3.77 (m ' 1H), 3.55 (s, 6H), 2.4-1.8 (m, 6H). LCMS: 410 (M+H)+. Example 8 4-((2-Cyclobutyl-7-(pyrrolidin-1-yl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-7,8- Difluoroquinolinone 58 200924772

Ίί 0 as described in Example 7 'Using 4·(bromomethyl)·7,8-difluoroquinolin-2(1Η)-one (Intermediate 1) and 2-cyclobutyl-7-(° Synthesis of 4-((2-cyclobutyl-7-decarrolidin-1-yl)-3H-isoxazole by using bromo-[4,5-b]pyridine as a starting material [4,5-b]pyridin-3-yl)methyl)-7,8-difluoroquinolin-2(1Η)-one. 1H NMR (400 MHz, DMSO-A; TFA salt) δ 12.05 (s, 1 Η), 7.95 (d ' φ 1H), 7.72 (m, 1H), 7.41 (m '1H), 6.50 (d, 1H), 5·70 (s, 2H), 5.11 (s, 1H), 3.95 (s, 4H), 3.74 (m, 1H) ' 2.4-1.8 (m ' 10H). LCMS: 436 (M+H)+. Example 9 4-((2-Cyclobutyl-7-(ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl)indolyl)-7,8-difluoroquinolinone

4- 4-((7-Chloro-2-cyclobutyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7' 8-difluoroquine in a 4 mL vial To the linoleone (60 mg, 0.15 mmol) was added ethylamine (2 mL, 70% wt. After 4 hours at 7 ° C, the solution was concentrated to give a crystallite crystals crystals crystals _3H_imidazo[,5-pyridin-3-yl)methyl)-7,8-difluoroquinolin-2(1H)-one. 1η NMR (400 MHz, CD3〇D; TFA salt) δ 7.90 (d,1H), 59 200924772 7.78 (m,1H),7.32 (m ' 1H), 6.75 (d,1H), 5.76 (s ' 2H) , 5.42 (s, 1H), 3.81 (m, 1H), 3.30 (m ' 1H) ' 1.9-2.6 (m, 6H), 1.39 (t, 3H). LCMS: 410 (M+H) + 〇 Example 10 4-((2-cyclobutyl-7-(methylaminomethane)[4,5-b]° ratio base) methyl)-7 ' 8-Difluoroquinoline-2(1Η)-_

'Use 4-((7-gas-2-cyclobutyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8-difluoro as described in Example 9. Synthesis of 4-((2-cyclobutyl-7-(indolyl)-3H-imidazo[4,5-pyridin-3-yl)methyl)-7,8 from quinoline and methylamine - Difluoroquinolin-2(1H)-one. 4 NMR (400 MHz, CD3OD; TFA salt) δ 7.90 (d, 1H), 7.78 (m, 1H), 7.33 (m, 1H), 6.75 (d ' 1H), 5.78 (s ' 2H) ' 5.42 (s , 1H), 3.81 (m ' 1H) ' 2,92 (s, 3H), 2.6-1.9 (m, 6H). LCMS: 396 (M+H) + <"&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& -yl)methyl)·7,8-difluoroquinolinone 200924772

'Using 4-(bromomethyl)-7' 8-difluoxetine-2(1H)-one (Intermediate 1) and 2-cyclobutyl-N-ethyl-N as described in Example 7. Synthesis of 4-((2-cyclobutyl-7-(ethyl(methyl)amino)-3H-imidazole by using -methyl-3H-imidazo[4' 5-b]pyridine-7-amine as starting material [4,5-7] "Bitter-3-yl)methyl)-7,8-difluoroquinolin-2(1H)-one. 1H NMR (400 MHz, CD3OD; TFA salt) δ 7.83 (d ' 1H) ' 7.78 (m, 1H), 7.34 (m, 1H), 6.72 (d, 1H), 5.78 (s, 2H), 5.40 (s ,1H), 4,30 (m,2H),3.80 (m,1H) ' 3.60 (m,2H) ' 3.31 (d,3H) ' 2.6-1.9 (m,6H) ' 1.42 (t,3H) 〇 LCMS: 424 (M+H) + 〇 Example 12 4-((2-cyclobutyl-7-methoxy-3H--e-s-[4,5-b]° 唆-3-yl) A Base)-7' 8-difluoroporphyrin-2(1H)-one

As described in Example 1, 4-(deuterated methyl)-7,8-difluoroindole-2(1H)-net (intermediate 1) and 2-cyclobutyl-7-methoxy- were used. 3H is fed and [4,5-b]e is synthesized as a raw material to synthesize 4_((2_cyclobutyl-7-methoxy-3H-imidazo[4,5-b]pyridin-3-yl) Methyl)-7 ' 8-dioxaporphyrin-2(1H).one. 1H NMR (400 MHz, DMSO-d^; TFA salt) δ 8.05 (d ' 1 Η), 7.65 (m, 1 Η) ' 7.21 (m ' 1H), 6.82 (d, 1H), 5.58 (s, 2H) ' 5.11 (s,1H) ' 3.90 (s ' 3H) ' 3.68 (m ' 1H) ' 61 200924772 2.4-1.6 (m,6H). LCMS: 397 (M+H)+. Example 13 4-((2-Cyclobutyl-7-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine·3·yl)methyl)-7,8-difluoroquinoline -2(1H)-ketone

Cf3 Step 1: Cyclobutyl-7-Moth-3H-Feeding β and [4,

7-Gas-2-cyclobutyl-3H-imipo[4,5-b]e ratio bite (5.2 g, 25.12 mmol) in NCN (200 mL) Nal (11.2 g, 74.67 mmol) A mixture of (CH3)3SiCl (8.1 g, 75.00 mmol) was refluxed for 18 hours. The mixture was concentrated and diluted with 250 mL EtOAc. Adjust the pH to 9 by adding NaOH (2 N). The resulting solution was extracted using 200 ml of EtOAc. The combined organic layers were concentrated and purified by flash chromatography (eluent eluting with 50:1 〇DCM/MeOH) to afford 51 g (67%) of 2-cyclobutyl-7-- 3H-Mi Jun and [4,5-7] ° bite white solid. LCMS: 300 (M+H)+.笫2_Jl : 2-cyclobutyl-7-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine

KF (170 mg, 2.93 mmol) and cu1 (570 mg, 300 mmol) were added to a closed tube at 62 200924772, and heated under reduced pressure while slowly shaking until a uniform light green powder was obtained. Add 2-cyclobutyl-7-disc-3H-mimi" and [4,5-b]n ratio bite (580 mg ' 1.94 mmol), DMF (10 ml) and TMSi-CF3 (710 mg' 5.00 After millimolar), the suspension was vigorously stirred at 55 ° C for 18 hours. The reaction mixture was poured into aqueous ammonia (12% <RTI ID=0.0>> The mixed organic layer was washed with brine (2 x 50 mL) dried and evaporated. The residue was purified by flash chromatography on EtOAc EtOAc (EtOAc): LCMS: 242 (M+H)+. φ Step 3: 4-((2-Cyclobutyl-7-(trifluoromethyl)-3H-imidazo[4,5-pyridin-3-yl)methyl)-7,8-difluoro Quinolinone

'Use 2-cyclobutyl-7-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine and 4-(bromomethyl)-7' 8 as described in Example 1. -Difluoroquinolone (Intermediate 1) as a starting material for the synthesis of 4-((2-cycloindoleyl-7-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-3- Methyl)-7,8-difluorophosphonate-2(1H)-one. 1H NMR (400 MHz 'DMSOO δ 8.47 (d ' 1H), 7.84 (m, 1H), 7.62 (d, 1H) ' 7.39 (m, 1H), 5.78 (s, 2H) ' 5.22 (s ' 1H), 3.91 (m ' 3H), 1.80-2.45 (m, 6H). LCMS: 435.2 (M+H)+. Example 14 7,8-Difluoro-4_(〇isobutyl-1H-imidazo[4 ,5-b]"Bai-1-yl)methyl)quinoline 2(1H)· 63 200924772

'Using 4·(bromomethyl)-7,8-difluoroquinolin-2(1H)-one (Intermediate 1) and 2-isobutyl-1H-imiphthene as described in Example 1 Synthesis of 7,8-difluoro-4-((2-isobutyl-1H- miso[4,5-b]0-pyridin-1-yl)methyl by 4'-5-7 pyrazine ) pout-2 (1H)-ketone. 1H NMR (400 MHz 'DMSO-de; HC1 salt) δ 8.52 (d ' 1H), 8.33 (d, 1H), 7.82 (m ' 1H) ' 7.40 (m ' 1H), 5.85 (s, 2H) ' 5.37 (s, 1H), 2.82 (d, 2H), 2.26 (m, 1H), 0.95 (d ' 6H). LCMS: 370 (M+H)+. Example 15 4-((2-Cyclopentyl-1H-imidazo[4' 5-b]pyrazin-1-yl)methyl)-7' 8-difluorogold--2(1H>- ketone

'Use 4-(bromomethyl)-7,8-difluoroquinolin-2(1H)-one (Intermediate 1) and 2-cyclopentyl-1H-imidazo[4] as described in Example 1. '5-b]pyrazine was used as raw material to synthesize 4-((2-cyclopentyl-1H-imidazo[4,5-b]pyrazine)methyl)-7,8-difluoroquinoline-2 (1H)-ketone. 1H NMR (400 MHz, DMSO-de; HC1 salt) δ 8.52 (d ' 1H), 8.33 (d ' 1H), 7.88 (m, 1H) ' 7.41 (m, 1H), 5.89 (s, 2H), 5.39 (s, 1H) ' 3.49 (m, 1H), 2.5-1.5 (m, 8H). LCMS: 382 (M+H)+. 200924772 Example 16 7,8-Difluoro-4-((2-(3-mercaptobutan-2-yl)-1Η-imidazo[4,5-b]pyridin-1-yl)methyl Quinoline-2(1H)-one

'Using 4-(extended methyl)-7'-8-difluoroquinolin-2(1H)-one (Intermediate 1) and racemic 2-(3-methylbutane-- as described in Example 1 Synthesis of 7 ' 8-difluoro-4-((2-(3-methylbutan-2-ylimidate) by 2-yl)_1H-imiphtho[4,5-b]° And a racemic mixture of [4,5-b]"pyrazine-1-yl)methyl)indole-2(111)-one. WNMRGOOMHz 'DMSO-d^ ; TFA salt 'racemic mixture) δ 8.52 (d,1H), 8.33 (d ' 1H) ' 7.88 (m,1H), 7.41 (m,1H), 5.88 (m, 2H), 5.32 (s ' 1H), 2.99 (m,1H), 2.09 (m, 3H), 1.28 (d, 3H), 0.96 (d, 3H) ' 0, 84 (d ' 3H). LCMS: 384 (M+H)+. The two enantiomers were separated on a chiral HPLC to give Examples 17 and 18. Example 1 叾 First eluting enantiomer: 4 NMR (400 MHz, DMSO-dfi; TFA salt) δ 8.52 (d, 1H), 8.33 (d '1H), 7.88 (m '1H), 7.41 (m ' 1H), 5.88 (m, 2H), 5.32 (s, 1H), 2.99 (m ' 1H), 65 200924772 2.09 (m, 3H), 1.28 (d ' 3H), 0, 96 (d, 3H), 0, 84 (d ' 3H). LCMS: 384 (M+H)+. Example 18 Second eluting enantiomer: NMR (400 MHz, DMSO-d6; TFA salt) δ 8.52 (d, 1H), 8.33 (d, 1H), 7.88 (m, 1H), 7.41 (m,1H), 5.88 (m,2H),5,32 (s,1H),2.99 (m,1H), 2.09 (m,3H),1.28 (d ' 3H) ' 0.96 (d ' 3H) ' 0.84 (d ' 3H). LCMS: 384 (M+H)+. Example 19 4-((2-(Cyclobutylmethyl)-1Η-imidazo[4,5-b]pyran-1-yl)methyl)-7' 8-difluoroquinoline-2 (1H) -ketone

'Use 4-(bromomethyl)-7,8.difluoroquinolinone (Intermediate 1) and 2-(cyclobutylmethyl)-1Η-imidazo[4,5-b as described in Example 1. Pyrazine is used as a starting material to synthesize 4-((2-(cyclobutylmethyl)-1Η-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinine_ 2(1H)-ketone. LCMS: 382 (M+H)+. Example 20 4-((2-Butyl-1H-indazolo[4 '5-7]-pyrazine-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one 200924772

As in Example 1, '4' (Moline methyl)-7'-8-difluoroquinolin-2(1H)-one (Intermediate 1) and 2-butyl-1H-sphere ice and [4' 5_b]° is used as a starting material to synthesize 4-((2-butyl-1H-isoxazo[4' 5-b]pyrazin-1-yl)methyl)·7,8·difluoroquinoline· 2 (1 Η) ketone. 4 丽11 (400 MHz, DMSO-d6; HC1 癯) δ 8.50 (d '1H) ' 8.32 (d,1H) ' 7.82 (m,1H), 7.40 (m, 1H), 5.85 (s, 2H), 5·39 (s ' 1H), 2 95 (t ' 3H), L78 (m, 3H), 1.37 (m, Ο 3H), 0.86 (t, 3H) ° LCMS : 370 (M+H)+. Example 21 4-((2-(3,3->methylcyclobutyl)_1H_imipo[4,5?> 嗓-1-yl)methyl)·7,8-II Fluoroquinoline-2(1H)-one

4-(Bromomethyl)-7,8-difluoroquinolin-2(1H)-one (Intermediate 1) and 2-(3,3-dimethylcyclobutyl) were used as described in Example 1. )_1H_Mijun and [4,5-7]pyrazine as raw materials to synthesize 4-((2-(3, 3-dimethylcyclobutyl)_1H-imidazo[4 ' 5-b]" Pyrazin-1-yl)methyl)·7,8-difluoroquinoline-2(111)-one. 1H NMR (400 MHz, DMSO-de; HC1 salt) δ 8.52 (d ' 1 Η), 8.32 (d ' 1 Η) ' 7.81 (m, 1H), 7.39 (m, 1H) ' 5.78 (s ' 2H) ' 5.36 (s, 1H) ' 3.92 (m ' 1H), 2.25 (t, 2H), 2.05 (t, 2H) ' U6 (s, 3H), 1.09 (s, 3H). LCMS: 396 (M+H)+. 67 200924772 4-((2-sec-butyl-1H_imipo[4,5-bHazine-7-yl)methyl)_7,8-difluoroquinolin-2(1H)-

'Use 4-(bromomethyl)-7,8-difluoroquinolin-2(1H)-one (intermediate oxime 1) and 2 sec-butyl-1H-imiline as described in Example 1. Synthesis of 4-((2-sec-butyl-1H-imidazo[4,5-b]pyrazine-1-yl)methyl)-7,8-di by [4'5-7]°Bistazine Fluoroquinolone. 1H NMR (400 MHz, CD3OD; TFA salt, racemic mixture) δ 8.58 (d, 1H), 8.36 (d, 1H), 7.85 (m, 1H), 7.26 (m '1H), 5.94 (s ' 2H ) ' 5.59 (s,ih),3,10 (m,1H),2.1-1.7 (m, 2H) , 1.40 (d,3H),0 90 〇,3H) : LCMS : 370 (M+H)+ . 4-((2-Cyclobutyl milano[4 ′ 5 -7]pyridin-1-yl)methyl)-7,8-difluoromethylmethyl phthalocyanine. -2(1H)-鲖

As described in Example 1, 'Using 4·(10)-substituted methyl)·7'8·υ-methyl °Ι: *#·2(1Η)-ketone (intermediate 2) and 2-cyclobutanthine-flavor Synthesis of 4-((2·cyclobutyl-1Η- 68 200924772 imidazo[4,5-b]pyrazine-1-yl)methyl)-7,8- by saliva[4 '5_b] scales Difluoro-3.methylquinolin-2(1H)-one. 1H NMR (400 MHz, DMSO-d^; TFA salt) δ 12.20 (s, 1H), 8.43 (d, 1H), 8.30 (d, 1H), 7.50 (m ' 1H), 7.10 (m ' 1H), 5.70 (m, 2H), 3.72 (m ' 1H), 1.8-2.4 (m ' 9H)» LCMS : 397 (M+H) + 〇 Example 24 4-((2-cyclobutyl-1H-imidazolium) [4,5-b]pyrazin-1-yl)indolyl-3'7' 8-trifluoroquinolin-2(1H)-one

o using the method described in Example 1 'Using 4·(代代methyl)_3 ' 7,8-trifluoroquinolinone (Intermediate 3) and 2-cyclobutyl-speaking-imiphthene[4 '5-7 Pyrazine is used as a raw material to synthesize 4-((2_cyclobutyl-1H-imidazo[4,5-b]pyrazine small) fluorenyl)·3 ' 7,8-trifluoroquinoline-2 ( 1H)-ketone. LCMS: 386 (M+H) + </RTI> Example 25 4-((7-bromo-2-cyclobutyl-3 oxime, &lt;RTIgt; ' 8-difluoroquinoline-2 (1H&gt; ketone

69 200924772 Step 1: 7-Bromo-2-cyclobutyl-3H-imidazo[4,5-b]pyridine

N Η POBr3 (4.0 g, 13.95 mmol) was slowly added to DCM (50 mL), 2-cyclobutyl-3H-imidazo[4,5-b]pyridine 4-oxide (1.62 g, 8.56). Millimol) of the stirred solution. After 4 hours the reaction was quenched with EtOAc (EtOAc)EtOAc. The organic layer was combined and dried (Na2SO4) filtered and concentrated. The product was purified using automated flash column chromatography (Si02) to afford 7-bromo-2-cyclobutyl-3H-imidazo[4,5-b]pyridine as a white solid. 1H NMR (400 MHz, DMSOO δ 7.49 (d, 1H), 6.87 (d, 1H), 3.21-3.12 (m, 1H), 1.84-1.69 (m, 4H), 1.49-1.37 (m, 1H), 1.30- 1.21 (m,1H). LCMS: 254.1 (M+H)+. Step 2: 4-((7-bromo-2-cyclobutyl-3H-imidazo[4,5-b]pyridine-3- Methyl)-7,8-difluoro-2-indolylquinoline

As described in the second step of Example 1, 7-bromo-2-cyclobutyl-3H.imidazo[4,5-b]pyridine and 4-(bromomethyl)-7,8-difluoro- 2-methoxyquinoline (Intermediate 4) was synthesized as a starting material 4-((7-Demo-2-cyclobutyl-3H-Miso-[4' 5-b]°tb--3-yl) A Base)-7 '2-difluoro_2·methoxyoxin&lt;»〗 ΗΝΜΚ (400 MHz, DMSO-d6) δ 8.09 (d '1Η) ' 8.07-8.05 (m,1Η) ' 7.70-7.63 (m,1Η), 7.58 (d ' 1H), 5.92 (s,2H), 5.84 (s,1H) ' 3.89 (s ' 3H), 3.84 (m,1H), 2.45-2.37 (m,2H), 2.19-2.11 (m, 2H) ' 2.01-1.80 (m, 2H). LCMS: 461.1 (M+H). 200924772 Step 3: 4-((7-Methyl-2-cyclobutyl-3H-imidazo[4'5-7]-bite each base)methyl)_7' 8-difluoroquinoline·2(1Η) _ketone

4-((7-De-2-3⁄4 butyl-3Η-ρ half beat [4 ' 5-b]e ratio _3-yl) fluorenyl)-7,8-difluoromethoxyquinoline (11 mg, mmol) was dissolved in 1 ml of THF/H20/cHC1 solution (2: i: iv/v). The mixture was stirred at 60 ° C overnight and then purified using reverse phase HPLC to give 4-((7, 2 - cyclobutyl-3H-imidazo[4,5-b]pyridin-3-yl)indolyl)- 7 ' 8-difluoroquinoline-2 (1Η)-_.丨η (400 MHz, DMSOO δ 12.08 (s, 1H), 8.12 (d, 1H), 7.84-7.80 (m, 1 Ή), 7.59 (d, 1H) ' 7.41-7.34 (m ' 1H), 5.71 (s ' 2H), 5.21 (s ' 1H) ' 3.85 (quint, 1H), 2.54-2.37 (m, 2H), 2.28-2.18 (m, 2H), 2.06-1.82 (m ' 2H). LCMs : 447.1 (M +H)+ 〇Example 26 © 2-cyclobutyl·3·((7,8-difluoro-2-oxo-dihydroquinolinyl) fluorenyl)-3H-mimi-[4 , 5-b] pyridine-7-carbonitrile

Step 1: 2-cyclobutyl-3-((7' 8-difluoro-2-methoxyquinolinyl)methyl)·3Η_imidazo[4' 5-b]pyridine-7- Formonitrile 71 200924772

4-((7-Bromo-2-cyclobutyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8-difluoro·2·methoxyquinoline (15.8 mg, 0.063 mmol) was dissolved in dimethylacetamide (700 μL). To the solution were added zinc (2 mg, 0.031 mmol), Pd(0)(tBu3P)2 (3 mg, 0.006 mmol) and Zn(CN)2. The reaction mixture was degassed and stirred at 100 ° C overnight. Further, Zn(CN) 2 (4 mg) and Pd(0)(tBu3P) 2 (3 mg) were added to the mixture, and the resulting solution was further stirred at 110 ° C for 4 hours. The crude reaction mixture was diluted with MeOH, filtered and purified with reversed phase HPLC to afford 2- <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; -3H-imidazo[4,5-b]pyridine-7-carbonitrile.屯NMR (400 MHz 'DMSO-de) δ 8.41 (d,1H), 8.10-8.04 (m, 1H), 7.77 (d,1H) ' 7.71-7.64 (m ' 1H) ' 6.52 (s ' 1H), 5.98 (s, 2H), 3.95-3.87 (m, 4H), 2.54-2.40 (m, 2H) ' 2.21-2.14 (m ' 2H), 2.02-1.80 (m, 2H)»LCMS : 406.2 (M+H + 〇 Step 2: 2-cyclobutyl-3-((7,8-difluoro-2-oxo-bu 2-dihydroquinin-4-yl)methyl)-3H-imidazole [4,5-b]pyridine-7-carbonitrile

As described in step 3 of Example 25, 'Using 2-cyclobutyl-3·((7'8-difluoro-2-methoxyquinolin~4-yl)methyl)-3Η- miso and [4 Synthesis of 5-cyclobutyl-3-(7' 8-difluoro-2-oxo 72 200924772 -1 '2-dihydroquinolin-4-yl group by 5-b]e )methyl)_3H-imidazo[4,5-b]pyridine-7-carbonitrile. LCMS: 392.2 (M+H)+ «&gt; Example 27 4-((7-(Aminomethyl)-2-cyclobutyl·3Η-imiphtho[4,5-b]n ratio bite-3 -yl)methyl)-7' 8-dioxaquinoline-2(1H)-one

Φ 2-Cyclobutyl-3-((7,8-difluoro-2-indolyloxyquinolin-4-yl)methyl)-acetic acid (3 ml) in a nitrogen (50 psi) atmosphere 3H-Imidazo[4,5-b]pyridine-7-carbonitrile (40 mg, 0.099 mmol) and 10% Pd/C (cat) for 1 hour. The reaction product was filtered through celite and concentrated. LCMS: 410.2 (M+H). The crude product in a mixture of THF (2 mL), water (0.5 mL) and EtOAc (EtOAc) The mixture was concentrated to give 4-((7-(aminomethyl)-2-cyclobutyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8-difluoroquinoline -2(1H)-one. 1H NMR (4〇〇0 MHz, CD30D) δ 8.69 (d ' 1Η), 7.89-7.83 (m ' 1Η), 7.76 (d ' 1Η), 7.37-7.30 (m, lH), 6.08 (s, 2H) '5.72(1H), 4.80(s'2H)'4.344.24(m'lH), 2.85-2.74(m, 2H), 2.56-2.45 (m,2H), 2.32-2.00(m ' 1H),2 ,12-2.02(m,1H)» LCMS : 396.2(M+H), cautious example 28 4-((7-gas-2-isobutyl-3H-imidazo[4' 5-b]pyridine- 3-yl)methyl)-7,8-difluoroquinolin-2(1H)-one 73 200924772

As described in Example 6, 7·chloro-2-isobutyl-3H-imidazo[4,5-b]acridine and 4-(bromoindolyl)-7,8-difluorophosphate were used. 2(1Η)-ketone (intermediate 1:) is used as a raw material to synthesize 4-((7_gas_2_isobutyl-3Η_味峻[4,5-7])) 7 ' 8-Difluoroquinolin-2(1Η)-one. 1H NMR (400 MHz, MeOH-Mountain) M.27 (d, 1H), 7.88-7.84 (m, 1H), 7.46 (d, 1H) s 7.32_7.26 (m s)

1H), 5.90 (s, 2H), 5.53 (s, 1H) ' 2.88 (d ' 2H), 2.28-2.18 (m ' 1H), 1.00 (d, 6H) ° LCMS : 403.KM+H) Example 29 4-((7-(dimethylaminoisobutyl-3H-imidazo[4,5-7] ° bite each base) methyl)_7 '8·difluoroquinolin-2(1Η)-one

As described in Example 7, 4-(bromomethyl)-7,8-difluoroquinoline-2 (1Η&gt; Lang 1 (intermediate 1) and 2-isobutyl-anthracene, fluorene-dimethyl Synthesis of 4-((7-(dimethylamino)-2-isobutyl-3H-imidazo[4' 5-7) by using 3-indene-imidazo[4' 5-b]-bite-7-amine as starting material ] bite each base) methyl)_7,8-difluoroporphyrin-2 (1H&gt;-ketone. 1H NMR (4〇〇MHz ' MeOH-dO δ 7.85 (d,1H) ' 7.80-7.76 (m ' 1H), 7.37-7.30 (m,1H) ' 6.74 (d ' 1H) ' 5.84 (s ' 2H) ' 5.42 (s ' 2H), 4.87 (s, 6H), 2.75 (d, 2H), 2.32 - 2.24 (m, 1H), 1.04 (d, 6H). LCMS: 412.2 (M+H) +. 74 200924772 Example 30 4-((8-cyclohexyl-9H_嘌呤-9-yl)methylhydrazine, 8-difluoroquinoline-2(1H)-one a

As described in Example 1, 4_(演代曱基&gt;7,8·difluoroquinolin-2(1H)-one (intermediate 1) and 8-cyclobutyl-9H-catch were used as raw materials. Synthesis of 4-((8-cyclobutyl-9H-indol-9-yl)indenyl)-7,8-difluoroquinolin-2(1Η)-_.lH NMR (400 MHz 'DMSO-mountain; TFA salt ) δ 12.10 (s ' 1Η), 9.17 (s ' 1Η) ' 8 87 (s, 1Η), 7.81 (m, 1Η), 7.38 (m, 1Η), 5.73 (s ' 2H), 5.28 (s, 1H) ), 3 89 (m ' 1H) ' 2.5-1.8 (m, 6H). LCMS: 368 (M+H) +. Example 4-((8-cyclobutylmethyl-N-N--9)曱)),7,8-difluoroquinolin-2(1H)-one

4-(Bromomethyl)-7,8-difluoroquinolin-2(111)-one (intermediate oxime and 8·cyclobutyl-6-methyl-9H-oxime) was used as described in Example 1.吟 is used as a raw material to synthesize 4_((8_cyclobutyl_6_methyl_9H_嘌呤_9.yl)methyl)-7,8.difluoroquinoline_2(1Η), 〇Wnmr (400 MHz , DMSO-d^ ; HC1 salt) δ 8.98 (s ' 1H), 7.81 (m ' 1H) ' 7.38 (m, 1H), 5 77 (s, 2H), 5 35 (s, 1H), 3.93 (m , 1H), 2.88 (s, 3H) ' 2.5-1.8 (m, 6H). LCMS: 382 (M+H) +. 75 200924772 Example 32

8_Fluoro_4_((2.isobutyl-1H-flavored [4,5-b]&quot; behavidin) methyl)Shilin-2(1H)-one as described in Example i Using 4-(indiylthio)-8-fluoroquinolin-2(1Η)-one (intermediate 5) and 2-isobutyl-1Η-imidazo[4' 5-b]pyrazine Starting material to synthesize 8-fluoro-ice ((2-isobutyl-1 Η-imidazo[4,5-b]pyrazine)methyl)quinoline-2 (1H&gt;• ketone. lHNMR (400 MHz, MeOH_) Mountain) δ 8.69 (d,1H) ' 8.57 (d,1H) ' 7.84 (d ' 1H), 7.51 (dd,1H), 7.40-7.35 (m ' 1H),6 〇7 (s,2H),5.85 (s,1H),3.10 (d,2H), 2.31 (m,1H),1.07 (d, 6H) 〇LCMS : 352.2 (M+H)

Example M

4-((2-cyclobutyl- hydrazino[4'-batchazine-1·yl)methyl)·8·fluoroquinone-2 (1H&gt; ketone as described in Example 1, using 4·( Bromomethyl)·8-fluorodeanline-2 (1Η&gt;·one (intermediate 5) and 2-cyclobutyl-1H-mythracene [4,5-hour azine as raw material to synthesize 4-( (2-Cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)fluorobenzolinium. 1H (400 MH2, DMSad6) δ 11.83 (s, 1H), 8.50 (d,1H) ' 8.30 (d ' 1H) ' 7.78 (d ' 1H),7.51 (dd ' 1H) ' 200924772 7.30-7.25 (m,1H) ' 5.76 (s ' 2H) ' 5.35 (s, speak ), 3 93 (m, Qiu, 2 51 2 4〇(m, 2H) ' 2.32-2.20 (m, 2H) ' 2.07-1.86 (m, 2H) e LCMS : 35〇2 (M+H)+.

‘ 8-Difluoro fluoro ((2-phenyl-1H-miso-pyrene-μ,5-7)pyridinium)-methyl)喧琳2(10)阙

笫1 step: 2·phenyl-1H-imidazo[4 ′ 5 7] sigh

As described in Example i帛i, the use of benzoic acid as a starting material to synthesize 2^1 Η 坐 and [4 ‘5-7] pyrazine. LCMS: 197 (Μ+Η)+. 2 steps* 7 ’ — Fluoride ice ((2·Phenyl·1Η- miso and [4 ’ 5 7]吼” Qin Xiaoji) methyl)喧琳 Φ -2(1Η&gt;·ketone

To a 8 ml vial was added 2-phenyl-1 quinone-imidazole [4,5 -7] hydrazine (28 mg, 0.14 mmol) and 4-(bromodecyl)-7,8-difluoroquine | 2(1Η)-ketone (intermediate oxime 1,12 mg, 0.045 mmol). The solid mixture was heated for 2 minutes to ~22 CTC to give a dark-melt residue, which was then cooled and evaporated to </ RTI> </ RTI> </ RTI> <RTIgt; Purification by preparative HPLC (gradient: 10%~100% ACN/water) to give 7,8-difluoro_4_((2phenyl·1H•imidazo[4,5_b] 0-pyridin-1-yl) Methyl)quinolinone (12 mg, 72% yield).丨η NMR (400 MHz, DMSO-d^; TFA salt) δ 12.11 (s, 1H) ' 8.61 (d, 1H), 8.41 (d ' 1H), 7.80 (m, 2H), 7.73 (m, 1H) ' 7.57 (m ' 3H), 7.37 (m, 1H), 5.86 (s, 2H), 5.71 (s, 1H) ° LCMS : 390.5 (M+H) + 〇 Example 35 7 ' 8-Difluoro 4- ((2-(3'3,3-Trifluoro-2-(trifluoromethyl)propyl)-imidazo[4,5-b]pyrazin-1-yl)methyl)quinoline 2 (1H )-嗣

-^-1^ : N_(3_Aminopyrazine·2·ylindole] 4,4-trifluoro-3-(trifluoromethyl)butanamine

〇 Pyrazine 2,3-diamine (314 mg, 2.85 mmol), 4,4, chlorotrifluoro(trifluoromethyl)butyric acid (5 DM) in DMF (15 ml) at RT A mixture of milligrams (238 mmol), a few (1 g, 2.85 mmol), and DIEA (0.6 mL, 3.57 mmol) for 18 hours. The solvent was removed and the residue was purified by flash chromatography (5 (M EtOAc) 3-(Trifluoromethyl)butanamine yellow solid. 1H NMR (400 MHz 'DMSO-de) $10.27 (s ' 1H) ' 7.86 (d,1H), 7.59 (d,1H), 6.18 (s, 78 200924772 2H ), 4.31 (m, 1H), 3, 01 (d, 2H). LCMS: 303 (M+H) + Step 2: 2-(3,3,3-trifluoro-2-(trifluoromethyl) )propyl)-1Η-imidazolium μ,5-7 Qin

Heating N-(3-aminopyridin-2-yl)-4,4 '4·trioxo (tris-methyl)butanamine (450 mg, 1.5 ml) in AcOH (8 mL) for 18 h to 70 ° C. The solvent was removed to give 2_(3,3,3 trifluoro-2-(trifluoromethyl)propyl)-1 Η 0 m. and [4,5-b. (400MHz 'DMSO-mountain) δ 8.36 (s ' 2H), 4·75 (m, 1H), 3, 51 (d, 2H) . Step: 7 ' 8-difluoro hopper ((2-(3) ' 3 ' 3-Trifluoro-2·(trifluoromethyl)propyl)·1Η_imidazo[4,5-7]pyrazin-1-yl)indolyl)quinoline-2(1Η)-one

φ as described in step 3 of Example 34, using 2-(3,3,3-trifluoro-2-(trifluoromethyl)propyl)-1Η imidazo[4,5-b]pyrazine as starting material Synthesis of 7,8-difluoro 1((2-(3,3,3-trifluoro-2-(trifluoromethyl)propyl)-1Η-imidazo[4,5-b]pyrazine-1 -yl)methyl)quinoline-2(1H)-one. 1HNMR (400MHz, DMSOO δ 12.05 (s ' 1H), 8.57 (d, 1H), 8.39 (d ' 1H) ' 7.81-7.77 (m,1H) ' 7.42-7.36 (m,1H), 5.94 (s, 2H ), 5.32 (s, 1H), 4.98 (m, 1H), 3.68 (d, 2H). LCMS: 478 (M+H)+ » Example 36 79 200924772 7 ' 8-V--4-((2 -(4-methylthiazole·54)_1Η_imidazo[4 5 b]pyridinyl)methyl)porphyrin-2(1H)-one

F

F : 5_(1H-isoxazolo[4,5-b]pyrazine·2-yl)

For example, as described in the first step of Example 1 (modification: 18 (TC, 9 hours), 4-methyl oxazole-5-carboxylic acid and pyridazine-2' 3-diamine were used as raw materials to synthesize 5 (1H). Imidazo[4,5-7]pyrazine_2_yl)_4-methyloxime. LCMS · 218.1. Dijon* 7 ' 8-difluoroindole-((2-(4.methylcarbazole) -5-yl)-1Η-imidazo[4,5-b]pyrazinyl)methyl)quinoline-2(1H)嗍

As described in Example 2, Step 2 (Modification: Heating for 3 minutes), use 5_(1H-imidazo[4 5-7]pyridazin-2-yl>4-methyl sin and 4_(bromomethyl) Synthesis of 7,8-difluoro 4-((2-(4-mercaptothiazole-5-yl)-iH) from 7,8•difluoroquinolin-2(1H) ketone (intermediate 1}) -Imidazo[4,5-b]pyrazin-1-yl)indolyl porphyrin-2 (1H) per 1H NMR (4 〇〇 MHz, DMSOO δ 12.12 (s, 1H), 9.19 (s, 1 Η) ) ' 8.64 (d ' 1Η) ' 8.46 (d,1Η), 7.73 (m,1Η), 7.34 (m,1Η), 5.83 (s ' 80 200924772 2H), 5.63 (s,1H), 2.63 (S, 3H); LCMS: 4110 (4) + taken. Example 37 7,8-Difluoro~4-((2-isobutyl-1H-imidazo[4' 5-b]pyridinyl)methylmethyl Quinoline-2(1H)-one

As described in Example 1, 'in the second step, 2-isobutyl-1H-imidazo[4,5-b]pyridinium and 4·(bromomethyl)-7,8-difluoro 3_A were used. Synthesis of 7,8-difluoro-4-((2-isobutyl-1H-imidazo[4,5-b]pyrazine)methyl)- by using quinolinone (intermediate 2) as a starting material 3-methylquinoline-2(1H)-one. 1HNMR (400MHz ' CD3OD) δ 8.44 (d ' 1H), 8.34 (d,1H) ' 7.60-7.55 (m, 1H) ' 7.01 (q ' 1H), 5.91 (s ' 2H), 2.78 (d, 2H) , 2.27 (s, 3H), 2.12-2.02 (m, 1H) 0.87 (d, 6H) » LCMS : 384.25 (M+H)+ « ^ Example 38 7 ' 8-Difluoro 4-((2-) Butyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-3-methylquinoline·2(1Η&gt; ketone

81 200924772 As described in Example 1, 2-isobutyl-7-methyl-3H-flavored [4,5-b] «bipyridine and 4-(bromomethyl) were used in the second step. -7,8-Difluoro 3-methylquinolin-2(1H)-one (Intermediate 2) was used as a starting material to synthesize 7,8-difluoro 4-((2-isobutyl-7-methyl-) 3H-Imidazo[4,5-b]pyridinyl) indenyl)-3-methylquinolin-2(1H)-one. 1HNMR (400MHz, DMSO-A) δ 8.20 (d ' 1H), 7.63-7,59 (m, 1H), 7.10-7.00 (m, 2H) ' 5.79 (s ' 2H), 2.56-2.50 (m, 5H) ), 2. Π (s ' 3H) 1.92-1.84 (m, 1H), 0.73 (d, 6H) &lt;» LCMS : 397.39 (M+H)+. Example 39

7,8-diqi·4-((2-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)indolyl)quinoline-2 (1H) -ketone

'Use 2-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine and 4-(bromomethyl)-7,8-difluoroquinolinone as described in Example 1. (Intermediate 1) is a raw material for the synthesis of 7,8-difluoro 4 ((2-isobutyl-7-methyl-3H-imidazo[4,5-7]pyridin-3-yl)methyl)_3 · Methyl quinolinium. 〇lHNMR (400MHz &gt; DMSO-d^) δ 8.09 (d » 1Η) » 7,80-7.70 (m ΊΗ) &gt; 7.20-7.12 (m ' 1H),7.09 (d,1H) ' 5.69 (s ' 2H) ' 5.09 (s ' 1H), 2.69 (d, 2H), 2.58 (s, 3H), 2.25-2.15 (m ' 1H), 0.92 (d, 6H). LCMS: 383.25 (M+H)+. Example 40 4-((7-Amino-2-cyclobutyl-3H-imidazo[4' 5-b]pyridyl-3-yl)methyl)·7,8-difluoroquinoline 82 200924772 -2(111)-83⁄4

Step 1: 2-cyclobutyl-N-(4-oxobenzyl)-3H-salt [4,5-b]0 is more than -7-amine OMe Φ at 10 (TC under 'stirring 7- Chloro-2-cyclobutyl-3H-imidazo[4,5-b]pyridine (445 mg, 2.14 mmol) and p-decyloxybenzylamine for 72 hours. The reaction was filtered through hydrazine gel and then HPLC. (semi-preparative 'reverse phase') further purified to obtain 2-cyclobutyl-indole-(4&gt;methoxybenzyl)-3H-m-sodium and [4,5-b]e than 唆-7-amine off-white solid LCMS: 309.6 (M+H)+ » 2 steps: 2-(2-cyclobutyl-3H-imidazo[4,5-b]pyrazine-7-yl)isoporphyrin·3 Diketone

2-Hetero-N-(4-methoxybenzyl)-311- miso [4 '5-7] «°°Q-7-amine in 'HBr/AcOH (10 ml) at 50 °C (390 mg, 1.26 mmol) overnight. The crude reaction mixture was concentrated and purified by HPLC (semi-prepared, reversed) to afford 2-cyclobutyl-3H-imidazo[4,5-pyrazine-7-amine. 2-Cyclobutyl-3H-imidazo[4'5h-7-pyridin-7-amine (66 mg, 0.351 mmol) and succinic anhydride (120 mg, 0.810 mmol) were dissolved in NMP (2 mL) And stirred in a microwave reactor at 200 ° C for 0.5 hours. The target product 83 200924772 was then purified by HPLC (semi-preparative, reversed phase) to obtain 2-(2-cyclobutyl-3H-imidazo[4,5-b]°tfce Qin-7-yl)isoindole. Arachnid-1,3-dione is an off-white solid. LCMS: 319.6 (M+H). JLUl: 2-(2-cyclobutyl_3-((7,8.difluoro-2-oxo-1,2-dihydroquinolinyl)indolyl)-3H-imidazo[4' 5 -b]pyrazine-7-yl)isoindole 4,3_dione

2-(2-Cyclobutyl-3H-imidazo[4,5-7]pyran-7-yl)iso,porphyrin-bu 3-dione (20 mg '0.063 mmol) and 4-(bromo) Generation of methyl)-7,8-difluoroquinoline-2 (1H)·copper (intermediate 20 mg, 0.073 mmol) was combined in DCM (5 mL). The mixture was then stirred in a 25 TC sand bath for 5 hours, and the mixture was precipitated. The crude mixture was then dissolved in DMSO and purified by HPLC (semi-preparative, reversed) to give 2-(2-cyclobutyl-3-( (7 ' 8-Difluoro-2-oxo-1 ' 2 -dihydroquinoanyl)methyl)_3H_imidazo[4,5_b]pyrazine_7_yl)isoindene·b 3 · Bismuth. LCMS: 512.6 (M+H)+. Cover·4 steps: 4·((7-Amino-2-cyclobutyl-3Η-imidazo[4,5-b]pyrazin-3-yl )methyl)-7,8-difluoroquinolinone

Add hydrazine hydrate (250 μl) to Et 〇H (1 ml) in 2 butyl butyl collar m2 200924772 oxo-1 ' 2 dihydroquinolin _4 · yl) methyl)-3H-imidazo[ A stirred solution of 4,5-b]pyrazine·7-yl)isoindole 1, 3-dione (7 mg, 〇.014 mmol) was stirred at RT for 45 hours. The reaction mixture was directly purified by HPLC (semi-preparative, reversed phase) to afford 4-((7-amino-2-cyclobutyl-3 oxime-imidazo[4' 5-b]pyrim-3-yl)methyl ) 7,8-Difluoroquinolin-2(1Η)-ketone oily residue. NMR (400 MHz, CD3OD) δ 7.86 (d ' 1 Η), 7.76 (ddd, 1 Η), 7.36-7.29 (m, 1H), 6.73 (d ' 1H), 5.78 (s, 2H), 5.45 (1H) ' 3.84 (pent., in), 2.60-2.50 (m, 2H) ' 2.40-2.31 (m ' 2H), 2.19-2.08 (m ' 1H) ' 2.03-1.94 (m, 1H). LCMS: 382.6 (M+H) + 〇 Example 41 4_((2-(cyclopropylmethyl)-lH-mimi[4 '5-7]° ratio &quot;Qin-1-yl)methyl)_7 , 8-difluorophthalein-2 (1H&gt; ketone

Synthesis of N-(3-aminopyrazin-2-yl)- using 2-cyclopropylacetic acid and pyrazine-2,3-amine as starting materials as described in Example 35, Step 1 (Modification: 43 hours) 2-cyclopropylacetamide. LCMS : 193.3 (M+H) + 〇 : 2-(cyclopropylmethyl)_1H_imidazo[4,5 嗓比嗓 85 200924772

As described in Example 2, Step 2 (Modification: 6 (Γ (: hour), using N-(3-aminopyridin-2-yl>2-ring·_ to synthesize 2·(tetra)methyl)

LCMS : 175.3 (M+H), J 纽'· 4·((2·(Methyl)·(tetra)na, 5.bK)methyl)_7,8-difluoroquinolin-2(1H) -ketone

A mixture of 2-(cyclopropylmethyl)-iH-imidazo[4,5-b]pyrazine (158 mg, 0.91 mmol) and propylene glycol (2 mL) was heated at 190 °C. After 1 minute, 4-(bromomethyl)-7,8-difluoroindolin-2(1Η)-one (intermediate 83 mg, 0.30 mmol) was added. After a further 90 minutes, the reaction was cooled to RT&apos; and ice (20g) was added. After the ice was dissolved, the precipitate was filtered, washed with water (5 ml of 〇 ° C) * and then purified by hydrazine gel chromatography (1:0-&gt;11:1; DCM:methanol) to obtain 4^((2- (cyclopropylmethyl)-1 Η-imidazo[4,5-b]pyrazine small)methyl)-7,8.difluoroquinoline q-2 (1H&gt; ketone. 1H NMR (400 MHz, DMSOO δ 12.05 (s ' 1H),8·51 (d,1H), 8.31 (d,1Η) ' 7.82 (m,1Η), 7.39 (m,1Η), 5.84 (s ' 2Η), 5.31 (s,1Η) , 2.90 (d, 2H) 1.19 (m, 1H), 0.48 (m, 2H) ' 0·23 (m, 2H); LCMS: 368.4 (M+H) +. Example 42 4-((2- Cyclopropylmethyl)-lH-imidazole [4,5-seven]pyrazine small)methyl)-8·fluoroquinoline m 86 200924772

As described in Example 41, step 3, using 2·(cyclopropylmethyl)-1Η-imidazo[4′ 5-b]pyrazine and 4-(bromomethyl)-8-fluoroquinoline The net (intermediate 5) was used as a starting material to synthesize 4-((2-(cyclopropylmethyl)-1 Η-imidazo[4,5-b]pyrazine)-methyl) fluoroquinoquinoline-2 ( 1H)-ketone. 1H NMR (400 MHz, DMSOO δ 11.81 (s ' 1H) ' 8.51 (d, 1H) ' 8.31 (d, 1H), 7.79 (d, 1H), 7.51 (m, 1H), 7.29 (m ' 1H), 5 ,85 (s ' 2H), 5.35 (s,IH) ' 2.91 (d,2H) 1.20

(m, 1H), 0.48 (m, 2H), 0.23 (m, 2H); LCMS: 350.4 (M+H)+. Example 43 4-((2-Cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroindole "Lin_2(1H)- ketone

As described in step 3 of Example 41, 2-cyclobutyl-1H-imidazo[4,5-pyrazinepyrazine and 4-(bromomethyl)-7,8-difluoroquinolinone (intermediate) were used. 1) Synthesis of 4-((2-cyclobutyl·1Η·imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinoline·2 (1Η) as a starting material )-ketone. 1H NMR (400 MHz, DMSO-de, HCl salt) δ 8.53 (d ' 1 Η) ' 8.33 (d ' 1 Η), 7.83 (m,, 7 4 〇 (m, 1H), 5.78 (s ' 2H), 5.36 (s ' 1H), 3.95 (m ' 1H) ' 2.5-1.8 (m, 6H). LCMS : 368 (M+H) + 〇87 200924772 Example 44 7,8-Difluoro&gt;4-((2 -Isoamyl stilbene [4,5-b]e ratio &quot;Qin-l-yl)methyl) °1: 'leaf-2(1H)-ketone

'Using 2-isopentyl-1H-imidazo[4' 5-b]&quot;biazine and 4-(bromomethyl)-7,8-difluoroquinolin-2 as described in Example 34 1Η)-ketone (intermediate 1) is used as a raw material to synthesize 7,8-difluoro winter ((2-isopentyl-1Η-β-miso-[4,5-b] 0-indol-1-yl) A Base) Yulin-2 (111)-ketone. iHNMRGOO MHz, DMSO-d6) δ 12.09 (s ' 1H) ' 8.49 (s ' 1H), 8.31 (s ' 1H) ' 7.84 (d ' 1H), 7.4-7.34 (m, 1H), 5.84 (s ' 2H ) ' 5.37 (s, 1H) ' 2.94-2.90 (m, 2H), 1.70-1.61 (m, 3H), 0.92-0.85 (m, 6H). LCMS: 384.0 (M+H). Example 45 4-((2-sec-butyl-1H-imidazo[4,5-b]pyrazine-1·yl)methyl)-7,8-difluoroquinoline-2 (1H&gt; anthrone

As described in Example 34, the use of racemic 2-sec-butyl-1-indole-[oxazolo[4,5-7]pyrazine and 4_(bromo 88 200924772

Synthesis of 4-((2-sec-butylimidazo[4,5-b]pyrazine-) by using hydrazino)-7,8·difluoroquinolin-2(1H)-indole (intermediate 1) as starting material a racemic mixture of 1-yl)methyl)-7,8-difluoroquinolin-2(1Η)-one. lH NMR (400 MHz, CD3OD) δ 7.61 (s ' 1 Η), 7.45 (s, 1 Η), 6.98 (t ' 1 Η) ' 6.17-6.39 (m, 1 Η) ' 5.03 (s, 2 Η), 4.67 (s, 1Η), 2.23-2.21 (m ' 1Η) ' 1.12-1.08 (m, 1H), 0.90-0.88 (m ' 1H), 0, 51 (d, 3H), 0, 1 (m ' 3H). LCMS: 37 (U (M+H) +.) 46. 4-((2-(cyclohexylmethyl)-1 </RTI> </RTI> </RTI> <RTI ID=0.0> 7,8-difluoroquinoline

-2(1H)-ketone

As described in Example 34 'Use (cyclohexylmethyl)-1 Η-mi sir[4 ' 5-b]&quot; than olfactory and 4-(bromomethyl)·7,8-difluoroquino Synthesis of 4-((2-(cyclohexyl)-1Η-_ sara[4' 5-b] 0-indol-1-yl)methyl)-7' 8-difluoromethane啥琳·2 (1Η)- Ming. iHNMR (400 MHz, DMSO-mountain) δ 12.05 (s, 1H), 8.53 (s ' 1H) ' 8.32 (s ' 1H) ' 7.82-7J6 (m, 1Η), 7.40-7.34 (m ' 1Η) ' 5.83 (s, 2Η) ' 5.35 (s ' 1Η) ' 3.64-3.63 (m ' 2H), 2.96-2.90 (m ' 2H) ' 1.54- 1.75 (m,3H) ' 1.31-1.36 (m ' 2H) ' 1.04 -1.11 (m, 2H), 0.79-0.95 (m ' 2H). LCMS: 411.3 (M+H) + </RTI> <RTI ID=0.0>######################################################################### Difluoroquinoline 89 200924772 -2(1H)-鲷

'Use (2-(cyclopentyl)-1Η-imidazo[4,5-b]pyrazine and 4-(bromoindolyl)-7, 8-difluoroquinoline as described in Example 34 Synthesis of 4-((2-(cyclopentyl)-1Η-imidazo[4' 5-b]pyrazine-1-yl)methyl)-(2H)-one (Intermediate 1) as a starting material 7,8-Difluoroquinolin-2(1H)-one. LCMS: 396.2 (M+H)+ « Example 48 7,8-difluoro-4-((2-(3-methylpentyl)) -1Η-imidazo[4,5-b] «pyrazine-fluorenyl-fluorenyl) quinolin-2(1H)-one

As described in Example 34, racemic 2-(3-methylpentyl)-1 Η-flavored salino[4,5-b] Qin and 4-(bromomethyl)7,8-di were used. Fluorokinin-2 (1«&gt; ketone (Intermediate 1) was used as raw material to synthesize 7,8-difluoro winter ((2-(3-methylpentyl)-1Η-imidazo[4' 5-b) a racemic mixture of pyrazin-1-yl)methyl)quinolinone. 丨11 NMR (400 MHz, CD3OD) δ 8.51 (s '1H) ' 8.37 (s,1H), 7.87-7.84 (dd,1Η) ,7J2-7.27 (m,1Η), 5.91 (s ' 2Η), 5.65 (s ' 1Η), 3.04-2.97 (m ' 200924772 2H), 1.87 (m,1H),1.67-1,64 (m ' 1H ), 1.44-1, 33 (m, 2H), 1.21-1.16 (m, 1H), 0.90-0.84 (m, 6H). LCMS: 398.1 (M+H)+. Example 49 4-((2- (2-cyclopentylethyl)-1Η-imidazo[4,5-b]pyrazine·1-yl)indolyl-7,8-difluoroquinolin-2(1H)-one

F φ as described in Example 34, using 2-(2-cyclopentylethyl)-1 Η-imidazo[4,5-b]pyrazine and 4-(bromodecyl)-7,8-difluoro Synthesis of 4-((2-(2-cyclopentylethyl)-1Η-imidazo[4,5-b]pyrazine-1-yl) from Quinolin-2(1H)-one (Intermediate 1) )methyl)-7,8-difluoroquinolin-2(1H)-indole. 4 NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.53 (s ' 1H), 7.15 (m, 1H), 6.47 (m, 1H), 5.18 (s, 2H), 4.85 (s, 1H) ' 3.35 (m, 2H), 2.52-2.46 (m, 4H), 2.22-2.18 φ (m, 3H), 1.07-1.03 (m, 4H). LCMS: 410.1 (M+H). Example 50 7,8-Difluoro 4-((2-(hexan-2-yl)-1Η-imidazo[4,5-b]pyrazin-1-yl)methyl)quinoline-2 ( 1H)-ketone 200924772

'Use racemic 2_(hexan-2-yl)-- this miso and [4,5-hour azine and 4-(bromomethyl)-7,8-difluorobenzoate as described in Example 34 The compound 11)-ketone (intermediate 1) was used as a raw material to synthesize 7,8-difluoro-4_((2_(己院·2_基&gt;1H-imipo[4 '5-7]°pyrazine-1· Methyl)quinoline-2(1H)-mesh racemic mixture. 1H NMR (4〇〇MHz, CD3〇D) δ 8.49 (d' 1H), 8.33 (d,1H), 7.88-7.85 ( m,1H), 7.28-7.25 (m ' 1H) ' 5.91 (s ' 2H), 5.59 (s, 1H), 4. 〇 9_4. 〇 7 (m, 1H), 3.18-3.14 (m, 2H) ' 2.00-1.45 (m ' 4H) 1.29-1.17 (m ' 6H). LCMS: 398,0 (M+H)+« Example 51 ((2-tert-butyl·1Η-imidazo[4' 5- b] pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one

As described in Example 34, 2-butyl-1H-isoxazolo[4,5-b]pyrazine and 4-(bromomethyl)-7,8-difluoroquinolinone were used (middle Synthesis of 4·((2-tert-butyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2 as a starting material 1Η)-鲖. LCMS: 370 (Μ+Η)+. 92 200924772 Example 52 7,8-Difluoro-4-((2-(heptan-3-yl)-1Η-imidazo[4,5-b]pyrazin-1-yl)indolyl)quinoline

As described in Example 34, using racemic 2-(heptan-3-yl)-1 Η-imidazo[4,5-b]pyrazine and 4-(bromodecyl)-7,8-di Synthesis of 7,8-difluoro 4-((2-(heptin-3-yl)-1Η-imidazo[4,5-b) from fluoroquinoline-2(1H)-one (intermediate 1) a racemic mixture of pyridin-1-yl)methyl)quinoline-2(1H)-one. 1H NMR (400MHz, DMSO 〇S 12.17 (s, 1H), 8.72 (s, 1H), 8,63 (s, 1H), 7.86-7.83 (m '1H), 7.29-7.27 (m, 1H), 6.29 ( s,1H), 6.23 (s, 2H), 1.81-1.74 (m,4H) ' 1.24-1.11 (m,5H), 0.82-0.76 (m,6H). LCMS : 412.6 (M+H)+ 〇φ Example 53 7,8-Difluorocape ((2-(pentan-2-yl)-1Η-imidazo[4,5-b]pyrazine-1-yl)methyl)quinolinone

93 200924772 'Use of racemic 2-(pentan-2-yl)-1 Η-imidazo[4,5-b]pyrazine and 4-(bromomethyl)-7' heart as described in Example 34 Secondly, 啥琳-2(1H^嗣(intermediate!) is used as raw material to synthesize 7,8-difluoro_4-((2-(pentan-2-yl)&gt;1Η·imidazo[4'5 seven嗓H NMR (4(8) MHz 'DMSO-A) δ 12.12 (s ' 1H) ' 8.50 (d,1H), 8.31 (d,1H),7.87-7.84 (m ' 1H) ' 7.41-7.37 (m ' 1H) ' 5.86 (s,2H),5.3 (s, 1H),3.22-3.15 (m,1H) ' 1.88- 1.79(m ' 1H) ' 1.62-1.54 (m ' 1H), 1.27 (d, 3H), 1.25-1.17 (m, 2H), 0.77 (m ' 3H). LCMS : 384.2 (M+H)+. Example 54 8-Fluoro ((2-(pentyl-2-yl)-1Η-imidazo[4,5-b]pyrazin-1-yl)methyl)quinoline-2(1H)-

As described in Example 34, the use of racemic 2-(pentan-2-yl)-1Η-imidazo[4,5-b] oxazine and winter (bromomethyl)-8-fluoroquinoline Synthesis of 8-fluoro•4-((2-(pentyl-2-yl)-1Η-imidazo[4,5-7]吼嗓-1- by using porphyrin-2 (1H&gt; ketone (Intermediate 2) as raw material Methyl)quinoline-2 (1H&gt; racemic mixture. 丨11 NMR (400 MHz, DMSO·^) δ 11.86 (s, 1H), 8.50 (d '1H), 8.31 (d, 1H) ' 7.83-7.80 (d,1H), 7.5 wood 7.50 (m, 1H), 7.31-7.25 (m, 1H), 5_87 (s, 2H), 5.36 (s, 1H) ' 3.20-3,14 (m, 1H), 1.86-1.80 (m, 1H), 1.62-1.48 (m ' 1H), 1.26 (d, 3H), 1.23-1.09 (m ' 2H), 0J7 (m ' 3H). LCMS: 366.7 (M+ H) +. 200924772 Example 55 7,8 a &amp; 4 乂 (2-(2-methylbutyl-1H-imidazo[4,5-b]pyrrolidyl)methyl)

-2(1H)-ketone

As described in Example 34, racemic 2_(2·methylbutyl 4Η-imidazo[4,5-pyrazine]pyrazine and 4-(molybdenum methylhydrazine, difluoropterin _ _ (middle) were used. 1) NMR (400 MHz) was synthesized as a raw material for the synthesis of 7,8·dioxan ((2 m-methyl butyl (4) butterfly 4, oxazin 4 yl) methyl) material 2 (10)-cultivation racemic mixture. ' DMSIOO δ 12,〇9 (s,! V old), 8.49 (d ' 1H), 8.30 (d ' 1H), 7.86-7.82 (m,1H), 7.40-7.37 (m,1H),s *84 (s » 2H) » 5.3 l(s &gt; 1H), 2.94^2.89 (m,1H) ' 2.79-2.73 (m ' 1H),2.09-2.〇iini ... 1H),1.27-1.18 (m,1H ), 0.94-0.90 (m, 3H), 0. 384.2 (M+H)+ 〇84·°·80 (m &gt; 3H) 〇LCMS: Example 56 8-Fluoro~4-((2-(2) ·Methylbutyl)-1Η-imidazo[4,5-b] ketone than Qinqiji)methyl) Huilin 95 200924772

'Use of racemic 2·(2_methylbutyl)-1Η-imipo[4,5-b]°tt&quot;Qin and 4-(bromomethyl)-8- as described in Example 34 Fluorinone (intermediate 2) is used as raw material to synthesize 8-1 winter ((2_(2-methylbutyl)-1H- miso and [4 '5-7] ° ° Qin) methyl)喧琳-2(1H)-ketone racemic material. LCMS: 364.2 (M+H) + </RTI> &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&& Quino 2 (1H)-ketone

'Using 2-pentyl-1H-imidazo[4,5-b]pyrazine and 4-(bromomethyl)-7,8-difluoro-inviolin-2 (1H)- as described in Example 34 Feed (Intermediate 1) was used as a starting material to synthesize 7,8-digas_4_((2-pentyl-1H-imidazo[4,5-hepta]pyrazin-1-yl)methyl)quinoline. iH nmr (4〇〇MHz, DMSOO δ 12.05 (s,1H) ' 8.50 (d,1H) ' 8.30 (d,1H),7.86-7.80 (m, 1H) ' 7.41-7.32 (m,1H) ' 5.82 (s ' 2H) ' 5.24 (s, 1H), 2.92-2.88 (m, 2H), UO-1.76 (m, 4H), 1.38-1.22 (m ' 2H), 0.80 (m, 3H). LCMS: 384.3 (M+H)+. 200924772 Example 58 4-((2-(2-Cyclohexyl)-1Η-imidazo[4,5-b]pyrazin-1-yl)indolyl-7, 8-difluoroquinoline-2(1H)-one

2-(2-cyclohexyl)-1 Η-imidazo[4,5-b]pyrazine and 4-(bromomethyl)-7,8-difluoroquinoline were used as described in Example 34. Synthesis of 4-((2-(2-cyclohexyl)-1Η-imidazo[4,5-b]pyrazine-1-yl) A by using -2(1Η)-ketone (Intermediate 1) as a starting material Base)-7,8-difluoroquinolin-2(1H)-one. 1H NMR (400 MHz, DMSO-d^) δ 12.10 (s ' 1 Η), 8.49 (d ' 1 Η), 8, 30 (d, 1 Η) ' 7.84-7.80 (m ' 1H), 7.40-7.36 (m, 1H), 5.84 (s, 2H) ' 5.35 (s ' 1H), 2.96-2.92 (m, 2H), 1.69-1.58 (m, 6H), 1.30-1.10 (m, 2H), 1.10-1.08 ( m ' 3H), 0.89-0.80 (m &gt; 2H) ° LCMS: 424.7 (M+H) + 〇 Φ Example 59 7,8-difluoro·4-((2·(4-methylpentyl)-1Η) ·Imidazo[4,5-b]pyridin-1-yl)methyl)quinoline-2(1H)-one

97 200924772 'Using 2-(4-methylpentyl)-1Η-flavored [4' 5-b]°tb嗓 and 4-(代代methyl)-7,8- as described in Example 34 Difluoroquinolinium (Intermediate 1) is used as a raw material to synthesize 7,8-difluoro-4-((2-(4-methylpentyl)-1Η-imidazo[4 '5-7]&quot; -1-yl)methyl)quinolinone. 1HNMR(4〇〇MHz, CD3OD) δ 8,49 (d ' 1H) ' 8.30 (d ' 1H),7.84-7.81 (m,1H) ' 7.42-7,34 (m,2H),5.83 (s, 2H) ' 5.38 (s ' 1H) ' 2.94-2.87 (m, 2H), 1.80-1.73 (m, 2H), 1.54-1.46 (m, 1H) ' 1.25-1.18 (m ' 2H), 〇·79 ( d, 6H). LCMS : 398.6 (M+H)+ 〇

Example 60 4-((2-(2-Cyclobutylethyl)-1Η-imidazo[4,5-7]pyridinium-yl)methyl)-7,8-difluoroquinoline**2 (1H} ·Bright

〇

As described in Example 34, 'Using 2-(2-cyclobutylethyl)·1Η- miso[4,Qin and 4-(Mo-methyl)-7' 8-difluoroquinolin-2(1H)- The ketone (intermediate hip 1) is used as a raw material to synthesize 4_((2&lt;2·cyclobutylethyl)-1Η-imidazo[4 ' 5-b]&quot; bet-1-yl)methyl)-7,8- Fluoroquinolone.屯NMR (400 MHz ' DMSOd^) δ 12,09 (s ' 1H) ' 8.49 (d ' 1U), 8.30 (d,1H),7.84-7.81 (m ' 1H) ' 7.42-7.35 (m,1H) ' 5.82 (s, 2H), 5.34 (s , 1H), 2.84-2.80 (m, 2H) ' 2.36-2.28(m ' 1H) ' 1.99-1.86 (m,4H) ' Ul,7i (m,2H) , 1.59-1.50 (m, 2H). LCMS: 396.5 (M+H)+. 98 200924772 Example 61 4-((2-Cyclobutyl-6-methyl-1H-imidazo[4' 5-b]pyrazine small)methyl)-7,8-difluoroquinolin-2 ( 1H)-ketone

'Use 2_cyclobutyl-6-methyl-1H-imidazo[4,5-b]pyrazine and 4-(molylmethyl)-7,8-difluoroquinine as described in Example 1. -2(1H)-ketone (Intermediate 1) was used as raw material to synthesize 4-((2-cyclobutyl·6-methyl-1Η-imidazo[4,5-b]咐•&quot;Qin-1- A positional isomer of methyl)-7,8-difluoroquinoline ♦ pirone. 1HNMR (4〇〇MHz 'DMSO-dfi; TFA salt) δ 8 39 (s, 1H), 7.81 (m, 1H), 7.37 (m, 1H), 5.70 (s, 2H) ' 5.26 (s ' 1H) ' 3.87 (m, 1H), 2.52 (s, 3H), 1.81-2.46 (m, 6H) » LCMS: 382.2 (M+H)+. EXAMPLES ^((2-Cyclobutyl-5-methyl-1H-imidazo[4' 5-b]ntazine·i•yl)methyl)·7,8-difluorofluorene

As described in Example 1, 2-cyclobutyl-6-methylimidazo[4,5-b]pyrazine and 4((bromomethyl)-7,8-difluoroquinolin-2 were used ( 1H)-ketone (Intermediate 1) is used as a raw material to synthesize 4_((2-cyclobutyl·5_methyl-1Η·Miso[4,minute])methyl)·7 ' &amp; (10)__ another 99 200924772 positional isomer β 〖H NMR (400 MHz 'DMSO-d6; TFA salt) δ 8.19 (s ' 1H) ' 7.81 (m, 1H), 7.37 (m ' 1H), 5.73 (s ' 2H) ' 5.28 (s, 1H) ' 3.87 (m, 1H) ' 2.58 (s, 3H), 1.81-2.46 (m, 6H). LCMS: 382.2 (M+H). Example 63 7,8·Difluoro*4-((2-(pentyl s- 3·yl)-1 Η- oxazolo[4,5-pyrazine)pyridyl)methyl)porphyrinone

As described in Example 1, 'using 2-(pentyl sylvestyl)-1 Η-isoxazole and [bucket, called ton noise and 4 _ (moin methyl Η ' 8-difluoroquinolinone (intermediate 1) is Raw materials to synthesize 7,8, digas 4 •like |pentan-3-yl &gt; 1H-imidazo[4,5-b]pyrazine small)methyl)quinoline 2 (called 鲖.1h ( Complete MHz 'DMS04; TFA salt) δ 8,50 (d,1H), 8.31 (d,1H),7 挞(m,1H), 7,37 (m,1H) ' 5.86 (s,2H),5.32 (s ' 1H), 2.99 (m, 1H), 16M (m, 4H), 0.78 (t, 6H). LCMS: 384.3 (M+H)+. Example 4-((2-(2-B) Benzyl hydrazine-imiphtho[4,5-b]pyrazine-diyl)methyl)·7,8 digas gold leaching-2(1H)-ketone 100 200924772

As described in Example 34, 2-ethylbutyl HH-imidazo[4,5-b]»tb嗓 and succinyl)-7,8-difluoroquinoline-2(1H)- The ketone (intermediate oxime) is used as a raw material to synthesize 4-((2-(2·ethylbutyl)-1 Η- oxazolo[4,5-7]pyran-1-yl)methyl K7,8- Fluoroquine 2(1H)-yl. iHnmr (400 MHz, DMSO-mountain; HC1 salt) δ 8 51 (d ' 1H) ' 8.32 (d,1H) ' 7,83 (m,1Ή), 7.38 (m ,1H), 5.85 (s ' 2H) ' 5.37 (s ' 1H), 2.87 (m, 2H), 1, 92 (m, 1H), 1.33 (m, 4H), 0.77 (t ' 6H). LCMS : 398.2 (M+H)+. Example 65 4_((2·cyclobutyl-7·ethyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-7,8- Difluoroquine

Step 1: 2-cyclobutyl-7-ethyl-3H-imidazo[4,5-b]pyridine

2-cyclobutyl-7-block-3H-imidazo[4,5-b]pyridine (600 mg, 2.01 mmol), Pd(dppf)Cl2 (reduced) in dioxane (2 mL) Cat.), a mixture with Et2Zn (5 ml, 1 M) for 18 hours. The mixture was concentrated in vacuo. The solution formed by diluting 101 200924772 with 50 ml of EtOAc and 20 ml of H 2 hydrazine. The resulting solution was extracted with 50 mL of EtOAc over EtOAc. The combined organic layers were washed with EtOAc (3 mL)EtOAc. The residue was purified by flash chromatography on a hydrazine gel eluting with 30:1 DCM/MeO solvent system to give 0.2 g (48%) of 2-cyclobutyl-7-ethyl-3H-imidazole [4 ' 5-b】pyridine butter. LCMS: 202 (M+H)+. Step 2: 4-((2-Cyclobutyl-7-ethyl-3H.imidazo[4,5-b]pyridin-3-yl)indenyl)-7,8-difluoroquinoline·2 (1Η)_嗣

o 'Use 2_cyclobutyl-7-ethyl-3-indole-imidazo[4,5-b]pyridine and 4-(bromoindolyl)-7,8-difluoroquinine as described in Example 1. The ketone (intermediate 1) is used as a starting material to synthesize 4-((2-cyclobutyl-7-ethyl-3H-imidazo[4,5-7]pyridin-3-yl)methyl)-7,8- Difluoroquinolinone 丨11 NMR (400 MHz, DMSOd^; TFA salt) δ 12.〇6 (s ' 1H), 8.15 (d, 1H), 7.86 (m ' 1H), 7.37 (m, 1 Η) ' 7.16 (d ' 1H), 5.68 (s ' 2H), 5.17 (s ' 1H) ' 3.82 (m ' 1H) ' 3.03 (m, 2H), 1.80-2.45 (m ' 6H), 1.35 (t ' 3H ). LCMS: 395J (M+H)+. Example 66 3-Chlorine Ice ((2-Indolyl-1H-imidazo[4,5-b]pyridyl-1-yl)methyl)-7,8-difluororingin-2 (1H) -ketone 102 200924772

'Use 2_cyclobutyl~1H-imidazo[4,5-b]pyrazine and 4-(bromomethyl)-3-aza-7,8-difluoroquine as described in Example 1 2(1H^·net (Intermediate 6) was used as a raw material to synthesize 3-pipe ((2-cyclobutyl-1H.imidazo[4,5-b]11-pyrazin-1-yl)indolyl)- 7 ' 8-difluoroquinoline_2(11{)_ ketone. 1η NMR (400 MHz, DMSO-mountain, TFA salt) δ Π.76 (s ' 1Η) ' 8.41 (d,1Η), 8.23 (d ' 1Η), 7.70 (m,1H), 7.26 (m ' 1H), 5.84 (s ' 2H) ' 3.89 (m,1Η),1.83-2.42 (m, 6H) 〇LCMS : 402.2 (M+H)+ ° Example 6 4-((2-Cyclobutyl-7-cyclopropyl-3H-imidazo[4' 5-b]pyridin-3-yl)methyl)-7,8-difluoroquine Porphyrin-2(1H)-one

φ 笫1 step: 7-gas-2-cyclobutyl-3-(tetrahydro-2H-pyran-2-yl)-3H-indazolo[4,5-b]pyridine

'Stirring 7-chloro-2-cyclobutyl-3H-imidazo[4,5-b]pyridine (1 g, 4.78 mmol), 3,4-dihydropyran (10 ml) and p- at 80 °C A mixture of TsOH (83 mg, 0.48 mmol) was taken for 1 hour. The progress of the reaction was monitored by TLC (EtOAc/PE = 1 : 1). The residue was purified by flash chromatography on EtOAc EtOAc (EtOAc:EtOAc:EtOAc Indole-2-yl)-3H-imidazo[4,5-b]pyridine is a colorless liquid. LCMS: 292 (M+H)+. Cover 2 t. 2-cyclobutyl-7-cyclopropyl-3-(tetrahydro-2H-0 than feeding-2-yl)-311-imi "· sit and [4,5-b]

To a sealed tube maintained and maintained under a nitrogen atmosphere, was placed in toluene (3 mL) in 7-gas-2-cyclobutyl 3-(tetrahydro-2-pyran-2-yl)-3H-imidazole [ 4,5-b]pyridine (1 mg, 0.34 mmol) solution. To this was added cyclopropylboronic acid (44 mg, 0.51 mmol), Cs2C03 (224 mg '0.68 mmol), pd2(dba)3 (14 mg, 〇.01 mmol), and C26H36NP (11 mg' 〇 .〇3 mmol). The resulting solution was stirred under 2 hours. The progress of the reaction was monitored by TLC (EtOAc / PE = 1 : 5). Filter and condense the filtrate in a vacuum using a rotary evaporator. The residue was purified by flash chromatography on silica gel eluting with 1 : 10 EtOAc/EtOAc solvent to afford &lt;RTI ID=0.0&gt; -2H-Pyr-2-yl)-3H-imidazo[4,5-seven] is a yellow solid. LCMS: 298 (M+H)+.

2-Chlorobutyl-7-cyclopropyl-3H-imidazo[4,5-b]pyridine To a flask that was purified, washed, and maintained in an HCl atmosphere was added 2-ring in Et20 (50 mL) A solution of butyl-7-cyclopropyl each (tetrahydro-2H-pyran-2-yl)-3H-imidazo[4,5-b]pyridine (300 mmol 200924772 g '1 mmol). The resulting solution was stirred at RT for 10 minutes. The progress of the reaction was monitored by XLC (EtOAc / PE = 1 : 1). The reaction mixture was then quenched by the addition of 30 mL of H20. The pH was adjusted to 8 by the addition of NaHC〇3. The resulting solution was extracted with EtOAc (3×50 mL). Filtration and evaporation of the filtrate using a rotary evaporator to give 150 mg (yield: 67%) of 2-cyclobutyl-7-cyclopropyl-3H-imidazo[4,5-b]pyridine as a white solid. LCMS: 214 (M+H)+. Step: Step: 4-((2-Cyclobutyl-7-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)·7, 〇8-difluoroquine Porphyrin-2(1Η)-one

As described in Example 1, 2-cyclobutyl-7-cyclopropyl-3 oxime-mithio[4,dine 4-(bromomethyl)-7' 8-difluoro-precipitate-2 was used. Synthesis of 4-((2-cyclobutyl-7-cyclopropyl-3H-midazino[4,yl)methyl)-7,8-dioxaquine using 1H)-Ming (Intermediate 1) as starting material Lin Ketone. 1Η NMR (400 MHz, DMSOd^; TFA salt) δ 8,13 (d ' 1Η), 7,84 (m,1Η), 7.37 (m, 1H), 6.89 (d,1H), 5.71 (s, 2H), 5.29 (s, 1H) ' 3.88 (m ' 1H), 1, 80-2.60 (m , 8H), 1.21 (m, 4H). LCMS: 407.6 (M+H)+. Example 68 4-((2-Cyclobutyl-7-isopropyl-311-miso-[4'5-7] 吼-3-_yl)methyl)-7,8-difluoroantimony醐 醐 105 200924772

Step 1 -: 2-Cyclobutyl-7-isopropyl-3H-imidazo[4,5-b]pyridine

2-Bromopropene (4 g, 32.78 mmol) was added dropwise to Mg (_mg '33.34 mmol) in THF (100 mL) and then ZnC12 (44 g, 3236 mmol) was added portionwise. Cool to 0 °C. The resulting solution was stirred at 0 ° C for 5 hours and stirred at rt for an additional 1 hour. 〇 To the mixture was added 7U-cyclobutyl-3H-imidazo[4,5-b]pyridine (500 mg, 2.42 mmol) and Pd(PPh3)4 (10 mg, cat). The resulting solution was refluxed for 18 hours. The reaction mixture was then quenched by the addition of 200 mL of saturated NH4C1. The resulting solution was extracted using Et〇Ac and the organic layer was mixed. The resulting mixture was washed with brine, dried and evaporated in vacuo. The residue was purified on a hydrazine gel by flash chromatography ( eluting with 1: 2 MeOH / DCM solvent system) to yield 2-cyclobutyl-7-isopropyl- 3 Η-imidazo[4,5- b] Pyridine gave 120 mg (46%) of white solid.笫1 step: 4-((2-cyclobutyl-7-isopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methylhydrazine ' 8-difluoroquinoline-2 (1H)-ketone

106 200924772 'Use 2-cyclobutyl-7-isopropyl-3H-flavor and [4,5-b]pyridine and 4-(molylmethyl)-7' 8-di as described in Example 1 Fluoroquine-2(1H)-indole (intermediate 1) was used as a raw material to synthesize 4·((2·cyclobutyl-7-isopropyl-3Η-flavor and [4 ' 5-b]nfc唆- 3-yl)methyl)-7,8-difluoroindole-2(1Η)-net. LCMS: 409.6 (Μ+Η)+ » Example 69 4-(〇(3 '3-difluorocyclobutyl)-1Η-flavored [4,5-b]npyrazinyl)methyl)_7 , 8_ bis-quinoline-2(1H)-one

As described in Example 34 'Use 3 ' 3- 2 gas ring butyl sulphuric acid in the first step (Synthetic communications, 2005 '35, 657-662) and 2-(3,3-difluoro) in step 2 Cyclobutyl) &gt; 1H- odor and [4,5-b] nt 嗓 to synthesize 4-((2-(3' 3-difluorocyclobutyl)) and [4,5 嗓 嗓

Q -1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one b NMR (4 〇〇 MHz , DMSOdd ; HC1 salt) δ 8,54 (d,1H), 8.35 (d ' 1H) ' 7.80 (m,1H), 7.39 (m,1H),5·81 (s, 2H) ' 5.42 (s ' 1H), 3.86 (m ' 1H) ' 2.92-3.10 (m ' 4H »LCMS: 404.4 (M+H)+ « Example 70 4-((2_(3,3-Difluorocyclobutyl)-1Η-mi s[4,5-7]pyrazine-j•yl) Methyl)·8 fluoroindole-2(1Η&gt; ketone 107 200924772

As described in Example 34, use 3,3-difluorocyclobutanecarboxylic acid in Step 1 (Synthetic communications, 2005 '35 '657-662) and 2-(3' 3-difluoro ring in Step 2) Butyl)-1Η-imidazo[4,5-b]pyrazine and 4-(bromomethyl)-8-fluoroquinoline-2(1H)-one (Intermediate 2) were synthesized 4-( (2-(3,3-Difluorocyclobutyl)-1Η-imidazo[4 ' 5-b]pyridazin-1-yl)methyl)-8-fluoroquinoline-2(1H)-one . 1H NMR (400 MHz, CD3OD; HC1 salt) δ 8.61 (s ' 1H), 8.47 (s, 1 Η), 7.82 (m ' 1 Η) ' 7.48 (m, 1 Η), 7.37 (m ' 1 Η), 5.98 (s , 2Η), 5.73 (s, 1H), 3.90 (m ' 1H) ' 2.99-3.30 (m ' 4H). LCMS: 386.5 (M+H)+. Example 71 7,8-Difluorodong ((2_(3-methylpyridyl)HH-imidazo[4,5heptazin-1-yl)methyl)quinolinone

'Using 2-(3-methylpyridin-4-yl)·1Η-isoxazo[4,5-7] ton and 4((bromomethyl)-7' 8- as described in Example 34 Difluoroquinoline intermediate 1) is synthesized as raw material 7

～二I 斗((2-(3_methylpyridyl)-ex-imidazo[4 '5-7]pyrazine-1-yl)methyl)啥琳·2(1η), NMR (400 MHz , DMSCX; TFA salt) δ 8.73 (s, iH), 8 68 (d,, )' 8,6〇108 200924772 (d ' 1H), 8.53 (d, 1H), 7.63 (d, 1H), 7.57 ( m,1H&gt;,7,25 (m,1H), 5.70 (s, 3H)« LCMS : 405.5 (M+H) + 〇 Example 72 7,8-difluoro-4-((2-(3- Indenylcyclobutyl)_1H_imidazo[,5,7-pyridinyl)indenyl)quinoline-2(1H)-one

F φ as described in Example 34 'Using 2-(3-methylcyclobutyl)-1Η-flavored salino[4,5-b]e than olfactory and 4-(indi-methyl)_7,8 -Difluoroquinoline-2 (1H> ketone (Intermediate 1) as raw material to synthesize 7,8· difluoro-ice ((2·(3-methylcyclobutyl- oxazolo[4′ 5-b]pyridyl) Pyrazin-1-yl)indolylquinolin 2(1Η)_clear/trans mixture. 4 NMR (400 MHz 'DMSO-dfi; TFA salt, main isomerization Zhao) δ 8.54 (d, 1H) , 8.32 (d,1H) ' 7.80 (m,1H),7.37 (m ' 1H), 5.78 (s,2H), 5.30 (s, 0 1H) ' 3.72 (m ' 1H), 1.80-2.60 (m ' 5H), 1.02 (d ' 3H). 丨 11 NMR (400 MHz, DMSO-Mountain; TFA salt 'isomer) δ 8.54 (d ' 1H), 8.32 (d, 1H), 7.80 (m, 1H) , 7.37 (m,1H), 5.75 (s,2H) ' 5.38 (s ' 1H), 4.02 (m ' 1H), 1.80-2.60 (m, 5H), 1.10 (d ' 3H). LCMS : 382.5 (M +H) +. Example 73 4-((2-Cyclopentyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)fluoroquinoline-2(1H)- Ketone 109 200924772

'Use 2-cyclopentylimidazo[4,5-b]pyrazine and 4-(bromomethyl)-fluoroquinoline-2(1H)-one (Intermediate 2) as described in Example 34 4-((2-Cyclopentyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-fluoroquinolinone was synthesized as a starting material.丨H NMR (400 MHz, CD3OD, TFA salt) δ 8.50 (d ' 1H) ' 8.35 (d, 1H), 7.84 (d, 1H), 7.47 (m, 1H), 7.36 (m, 1H), 5.97 ( s, 2H), 5.66 (s ' 1H) ' 3.47 (m, 1H), 1.64-2.20 (m, 8H). LCMS: 364.5 (M+H) + </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> 4-((2-(cyclobutylmethyl)]H-imidazo[4,5-b]e-but-1-yl)indolyl)-8- Fluoxin

As described in Example 34, 2-(cyclobutylmethyl MH-midazo[4'5-7]pyridazine and 4-(bromomethyl)-8-fluoroquinoline (intermediate 2) were used. The starting material was used to synthesize 4-((2-(cyclobutylmethyl)-1Η-sodium [4,5-b]0-.-1-yl)methyl)fluoroindolone. HNMR (4 〇 0 MHz, CD3OD, TFA) 5 8.51 (d, 1H) ' 8.36 (d ' 1H) ' 7.84 (d, 1H), 7.47 (m, 1H), 7.37 (m, 1H), 5.93 (s ' 2H) ' 5.61 (s ' 1H) ' 3.13 (d ' 2H) ' 2.92 (m ' 1H) ' 3.47 {m ' 1H) , 1.77-2.20 (m,6H)e LCMS : 364.5 (M+H). 200924772 Example 75 8-Fluoro 4-((2-(3,3,3-trifluoro-2-(trifluoromethyl)propyl)-1 Η-imidazo[4,5-b]pyridin-1 -yl) fluorenyl)quinoline-2(1H)-one

2-(3,3,3-trioxo-2-(trifluoromethyl)propyl)-1 Η-imidazo[4,5-b]pyrazine and 4 were used as described in the second step of Example 34. Synthesis of 8-fluoro-4-((2-(3,3,3-trifluoro)-(bromomethyl)-8-fluoroquinolin-2(1Η)-one (Intermediate 2)) 2-(Trifluoromethyl)propyl)-1 Η-imidazo[4,5-b]pyrazin-1-yl)methyl)quinolin-2(1H)-one. 1HNMR (400MHz, DMSO·^ 11.95 (s,1H) ' 8.57 (d,1H), 8.38 (d,1H), 7.75 (d,1H), 7.54-7.49 (m,1H),7.31-7.26 (m, 1H), 5.95 (s, 2H), 5.36 (s, 1H), 4.99 (m, 1H), 3.69 (d, 2H), LCMS: 460 (M+H)+.

Example 76 7,8-Difluoro 4-((2-(3,3,3-trifluoropropyl)-1Η-imidazo[4,5-b]pyrazin-1-yl)indolyl) Scared

111 200924772

H: 2-(3,3,3-trifluoropropyl)-1 Η-imidazo[4,5-seven]pyrazine p3c H as in step 1 of Example 1 (modification: 17 ° °c, 5d, 2,4 equivalents of acid) The synthesis of 2-(3'3,3-trifluoropropyl)-1Η using 4'4,4-trifluorobutyric acid and pyrazine-2'3-diamine as starting materials - Imidazo[4,5-b]pyrazine. LCMS: 217.1 (M+H). - Step ^: 7 ' 8-difluoro 4 ((2-(3,3,3-trifluoropropyl)-1Η-imipo[4 ' 5-b]n ratio. Qin-1-yl) Methyl)quinoline·2(1Η&gt; ketone

2-(3,3,3-trifluoropropyl MH-imidazo[4'5-7]pyrazine and 4 (bromomethyl) were used as described in step 2 (modification: heating for 5 minutes) in Example 34. 7,8-Difluoroquinolinone (intermediate as raw material to synthesize 7 ' 8-difluoro-4((2-(3,3,3-trifluoropropyl)-1Η· miso and [4 ') 5 b]°tb嘻-1-yl)methyl)啥琳_2(邱_纳.4 (400 MHzOMSO-d^) δ 12.08 (s, 1H) » 8.53 (d » iH), 8.35 (d &gt ; 1H) , 7.80(m » 1H)» 7.39(m &gt; 1H) &gt; 5.88(s &gt; Q 2H) ' 5 43 (S ' 1H) ' 3 24 (t ' 2H&gt;,3,04-2.90 (m, 2H). LCMS: 410.0 (M+H) + </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; ]pyrazine·i•基)曱基)喧琳-2(1H)-ketone 112

200924772 As described in Example 34 (modification: heating for 3 minutes), 2-(3,3,3-trifluoropropyl)-1Η-imidazo[4,5-b]pyrazine and 4-(indifferent) were used. Synthesis of 8-fluoro&gt;4-((2-(3,3,3-trifluoropropyl)-) by using methyl)-8-fluoroquinoline #-2(1Η)-one (intermediate 5) as a starting material 1Η·Imidazo[4,5-b]pyridin-1-yl)methyl)quinolin-2(1H)-one.丨H NMR (400 MHz, DMSOO δ 11.82 (s, 1H), 8.53 (d, 1H), 8.35 (d ' 1 Η), 7.77 (d, 1 Η), 7.51 (m, 1 Η), 7.28 (m, 1 Η) , 5.89 (s, 2Η), O 5.47 (s ' 1H&gt; ' 3.25 (t, 2H), 3.04-2.90 (m, 2H). LCMS : 392.4 (M+H)+ » Example 78 7 ' 8- Fluoride ((2-(4,4,4-trifluorobutan-2-yl)-1Η-imidazo[4,5-b]pyrazine)-methyl)quinolinone

簋_1立·· 2-(4"4,4-Trifluorobutan-2-yl)-1Η·imidazo[4,5-b]pyrazine

As described in the first step of Example 1 (modification: 19 ° C, 20 hours), using racemic 4,4, winter trifluoro-2-methylbutyric acid and pyrazine·2,3·diamine Originally, 2_(4,4, fluorene trifluorobutane·2·yl) 4H-imidazo[4,5-b]pyrazine was synthesized. LCMS : 23U (Μ+Η)+ » 113 200924772 Step 2. 7,8-Di- 4-((2-(4,4 ' 4-Trifluorobutyl)&gt;-2-yl)-111 -1mi spit and [4 ' 5-b] pyridinyl]methyl)quinoline-2(1H)-one

As in Example 34, step 2 (modification: heating for 3 minutes), the use of racemic 2-(4,4,4-trifluorobutan-2-yl)-1Η-imidazo[4,5-b Pyridinium and 4-(bromomethyl)-7' 8-difluoroquinolin-2(1H)-one (intermediate 1) are thick materials to synthesize 7,8-difluoro 4-((2- (4' 4,4-Trifluorobutan-2-yl)-1 Η-mi-[sodium][4'5-7]pyridazine+yl)methyl)porphyrin·2(ιη&gt; ketone racemic mixture. 1H NMR (400 〇MHz « DMSO-c^) δ 12.08 (s » 1Η)» 8.54 (d &gt; 1H) &gt; 8.35 (d » 1H) &gt; 7.84 (m &gt; 1H) ' 7.39 (m ' 1H ), 5 91 (s, 2H), 5.34 (s ' 1H) ' 3.62 (m ' 1H), 3.12 (m, 1H) ' 2.76 (m, 1H), 1.35 (d, 3H), LCMS : 424.0 (M +H)+ Tube Example 79 8-Fluoro ((2-(4,4,4-trifluorobutan-2-yl)-1Η-imidazo[4,5-b]pyrazine-1- Methyl) quinolin-2(1H)-one

Using racemic 2-(4,4,4-trifluorobutydin-2-yl)-1 Η-imidazo[4,5-b]pyrazine as described in Example 34 (modification: heating for 3 minutes) And 4-(bromomethyl)-8-fluoroquinoline-2(1H)-one (intermediate 5) as raw material to synthesize 8·fluoro·4~((2-(4,4,4-three) Fluorine*-2-yl)-1Η-imidazo[4,5-7] 0-pyridinyl)methyl)quinoline-2(1H)-indole racemic mixture.丨H NMR (400 MHz, DMSOO 114 200924772 δ 11.82 (s, 1H), 8.54 (d, 1H), 8.36 (d ' 1H), 7.80 (d, 1H), 7.52 (m, 1H) ' 7.28 ( m,1H), 5.91 (s,2H), 5.39 (s,1H), 3.63 (m,1H), 3.12 (m,1H) ' 2.76 (m ' 1H),1,36 (d ' 3H) ; LCMS : 406.4 (M+H), Example 80 7,8-di- l~4-((2-(4,4,4-trifluorobutyl)-1Η-imidazo[4,5-b]pyrazine -1-yl) sulfhydryl)

Quinolinone

1st electricity: 2-(4,4,4-trifluorobutyl)-1Η-imidazo[4,5-b]pyrazine

As described in the first step of Example 1 (modification: 190. (:, 20 hours), using 5,5,5-trifluoropentanoic acid and pyrazine-2,3-diamine as raw materials to synthesize 2-( 4,4,4 «trifluorobutane)-1Η-imidazo[4,5-pyrazine] LCMS : 231.1 (M+H)+. JL2 Step: 7,8-difluoro 4-((2) -(4,4 '4-trifluorobutyl)-1Η-imidazo[4,5-b]pyrazineindolyl)methyl)quinoline·2(1Η)-one

As in Example 34 (modification: heating for 3 minutes) the use of '2-(4' 4, xylofluorobutyl) 4 Η _ 115 200924772 味 峻 [4 ' 5-bK 嗓 and 4 · (bromomethyl) _7,8_Difluorophone-2 (Qi-ketone (intermediate 1} as raw material to synthesize 7,8-difluoro-4-((2-(4,4,4-trifluorobutyl))) -Imidazo[4,5-b]pyridin-1-yl)methyl)morpholine-2(1H), iH (4〇〇, dmso-also) δ 12 〇8 ,1H),8 51 ( d, 1H) ' 8·33 (d ',1H) ' 7.82 (m,1H),7,39 (m ' 1H) ' 5,82 (s,2H),5.40 (s, 1H) ' 3,04 (t ' 2H), 2.43 (m, 2H), 2.05 (m, 2H); LCMS: 424.0 (M + H) +. Example 81 7 ' 8-difluoro ice (2_(3,3,3_3) Fluorine-2-methylpropyl)-1Η-imidazo[4,5-b]pyrazine-1-indenyl)methyl)quinoxaline 2(1H)-one

Poor 1 Man: · Α ^ (3 · amino "Λ" "Qin-2-yl) ~ 4,4,. 4-trifluoro-3-methylbutanamine

As described in the first step of Example 35, the synthesis of 3_aminoguanidine was carried out using racemic 4' 4 '4-trifluoro-3-methylbutyric acid and ntpyridazine-2 ' 3-diamine as starting materials. A 2-carbo&gt; 4 ' 4 ' 4-trifluoro-3-methylbutanamine racemic mixture. LCMS: 249.4 (Μ+Η)+. Complex 2.: 2-(3,3,3-trifluoro-2-methylpropyl)-lH-imidazo[4,5-b]pyrazine

116 200924772 As described in the second step (modification: 60 〇 c, 7 hours) in Example 35, the use of racemic | (3_amino- to 嗓-2-yl) 4,4,4-trifluoro-3 Synthesis of 2-(3,3,3-trifluoro-2-methylpropyl)-1 oxime-imidazo[4' 5-b]pyrazine using methylbutylide as a starting material. LCMS : 231.3 (M+ H)+. Difference~·3 steps: 7 '^工氟·^2々' 3,3-trifluoro-2-methylpropyl)-1Η-imidazo[4,5-7]pyrazine-1- Methyl)quinoline-2(1H)-嗣

〇

F heated 2-(3 '3,3-trifluoro-2-methylpropyl)·1Η-imidazo[4,5-p]pyrazine (262 mg, in 'N at °C) in N2 1.14 mmol), a mixture of sodium bicarbonate (150 mg, 1.79 mmol), and propylene glycol (2 mL). After 15 minutes, 4-(bromomethyl)-7' 8-difluoroquinolin-2(1H)-one (Intermediate 1, 164 mg, 0.60 mmol) was added. After a further 30 minutes, the reaction was cooled to rt, poured water (50 mL) andEtOAc. The mixed organic extracts were dried, concentrated, concentrated, and purified by Dream Gel Chromatography (1:0-11:1; DCM:methanol) to obtain 7, two gas _4-((2-(3 ' 3 ' 3 ) -Trifluoro-2-methylpropyl)-1 oxime-flavored [4,5-b]°tfc嘻-1-yl)methyl) oxime network racemic mixture. ^NMR (400 MHz, DMSOd«) δ 12.08 (s, 1Η)»8.54 (d ΊΗ)1 8.35 (d &gt; 1H) &gt; 7.81 (m»1H) &gt; 7.39 (m ΊΗ) &gt; 5.89 (s &gt; 2H) » 5 38 (s ΊΗ)» 338-3.24 (m» 2H)» 3.08 (m &gt; 1H) &gt; 1.20 (d» 3H) 〇LCMS : 424.4 (M+H)+- Example 82 ,3,3-trifluoro-2-methylpropyl)-1Η-Miso-[4,yl)methyl)quinolinone 117 200924772

'Use of racemic 2-(3,3,3-trifluoro-2-methylpropyl)-1 Η-imidazo[4,5-b]pyridazine and 4 as described in step 3 of Example 81 -(Bromomethyl)-8-fluoroquinoline-2(1H)-indole (intermediate 5) as starting material for the synthesis of 8-fluoro-4-((2-(3' 3 ' 3-trifluoro-) 2-Methylpropyl)-1 Η-imidazo[4,5-b]pyrazin-1-yl)methyl)quinoline-2(1H)-one racemic mixture. 1H NMR (400 MHz, DMSO 〇 δ 11.82 (s ' 1 Η), 8.54 (d ' 1 Η), 8.35 (d, 1 Η) ' 7.77 (d, 1 Η), 7.51 (m ' 1 Η), 7.28 (m ' 1H), 5.90 (s, 2H), 5.42 (s ' 1H), 3.38-3.24 (m, 2H), 3.09 (m, 1H) ' 1.21 (d, 3H) ; LCMS : 406.4 (M+H)+ 〇 Example 83 7 'Difluoro-ice ((2·( 嗟 ~ 5 5 5 Η Η Η Η 咪 咪 咪 咪 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ketone

F

U · 5~(Ex-imidazo[4,5-b]pyrazin-2-yl)thiazole... as described in the first step of Example 1 (modification: shout, 9 hours), using the grab 5. Pyrazine 2' 3-diamine as a raw material for synthesis &amp; (Ranging 4, called Turn·204.1 (Μ+Η), 118 200924772 2nd··· 7 ' 8-Difluoro'4_((2-(thiazole) -5-yl)-1Η-imidazo[4,5-b]pyrazin-1-yl)methyl)quinoline-2(1H)-one

As described in the second step (modification: heating for 3 minutes) in Example 34, using 5·(1Η-isoxazo[4,5-pyridazin-2-yl) anthracene and 4-(bromomethyl) Synthesis of 7,8-difluoro~4-((2-(thiazole-5-yl)_1H-imidazole) by using _7,8-difluoroquinoline_2(111)·鲷(intermediate ruthenium) as raw material μ,5-7]pyrazine-4-yl)methyl)quinoline-2(1H)-one "丨H NMR (400 MHZ, 0 〇0〇δ 12·12 (s, 1H), 9.36 (s, 1H) , 8.62 (d ' 1Η), 8.44 (d, 1Η) ' 8.35 (s,1Η), 7.87 (m,1Η) ' 7·42 (m,1Η), 6.09 (s,2H) ' 5.57 (s,1H LCMS: 396.9 (M+H) +. mp.: s., s, s, s, s, s, s, s, s. Linone

As described in Example j, 2-propyl-iH-imidazo[4,5-pyridinium] &quot;Qin and 4·(bromomethyl)·7,8_dioqiquine 2 (1Η)- (Intermediate U was used as a starting material to synthesize 7,8-difluorocape ((2-propylmimidazo[4,5pyrazinyl)methyl)quinoline-2(1Η)-one. 1H NMR (400 MHz, CD3OD) δ 8.58 (s,(8) ' 8 32 (S,1H) ' 7 89 (m,1 ie 7.43 (m,1H) ' 5.89 (S ' 119 200924772 2H) ' 5.45 (s ' 1H) , 2.83-2.42 (m, 2H) ' 1.95-1.83 (m, 2H), 0.95 (d, 3H)» LCMS: 357.2 (M+H)+. Example 85 7 'Difluoro-4-((2- (thiophene each)·1Η-imidazo[4,5-b]pyrazine-1-yl)methyl)喧琳

-2(1H)-ketone

The first dragon: 2·(喽-phen-3-yl HH-imidazo[4,5-b]pyrazine

In the first step of 1 (modification: 180 ° C, 3 hours), the synthesis of -(嗟- -3-yl)-1Η- miso and [4] using porphyrin and decylamine as raw materials , 5-b]e than 嘻. LCMS : 203.0 (M+H)+〇

Cover 7 8-—gas·4«((2-())-ΐΗ-Miso and [4,5-7]pyridazine·1_yl)methyl) quinolin-2(1Η)-one Soil

In the second step of 4 (modification: heating for 3 minutes), using porphin base)_ιη_ 120 200924772 imidazo[4 ' 5-b]pyrazine and 4-(molyl methyl)-7,8 -Difluoroquinone-2(1H)-net (intermediate 1) was used as raw material to synthesize 7 ' 8-difluoro 4-((2-(喧-phen-3-yl)-1Η-imidazo[4,5 -b]pyridyl&quot;qin-1-yl)T-based)quinoline-2(1H)-one. NMR (400 MHz, DMSO-d^) δ 12.12 (s,1H),8,58 (d,1H), 8.38 (d '1H) ' 8.14 (dd,1H) ' 7.83 (m ' 1H),7.77 ( Dd, 1H), 7.66 (dd, 1 Η), 7.38 (m, 1H), 5.97 (s, 2H), 5, 56 (s, 1H). LCMS: 396.4 (M+H). Example 86 o o Fluorine 4-(〇(thiophen-3-yl)-1Η-imidazo[4,5-7]pyridin-1-yl)methyl)quinoline·2(1Η)-

As described in Example 34 (modification: heating for 3 minutes), 2·(thiophen-3-yl)-lH-imidazo[4,5-b] ntazine and 4~(bromomethyl)fluorone were used. Synthesis of 8-fluoro-4-((2-(thiophen-3-yl)-1Η-imidazo[4,5-pyrazine)pyridinyl)methyl)quinolinone by using quinolinone (Intermediate 5) as a starting material . NMR (400 MHz 'DMSOO δ 11.85 (s,1H) ' 8.58 (d,1H), 8.38 (d,1H) ' 8.16 (dd, 1H) ' 7.82-7.76 (m,2H) ' 7.66 (m ' 1H) , 7.53 (m, 1H), 7.29 (m , 1H), 5.98 (s ' 2H), 5.59 (s, 1H). LCMS : 378.3 (M+H)+ « Example 87 7 ' 8-Difluoro bucket { (2-(1-Methyl-1H-pyranosyl-5-yl)-iH-imidazo[4,5-pyridin-1-yl)methyl)quinoline·2(1Η)-鲷121 200924772

",": 2-(1-methylazol-5-yl)-1Η-imidazo[4,5-seven]pyrazine

As described in the first step (modification: 180 art '9 hours) in Example 1, the synthesis of 2_(2) was carried out using ^methyl_1H•pyrazine-5-hyaloacid and pyridazine-2'3-diamine as raw materials. 1_Methyl-pyridyl-5-yl)_mimidazo[4' 5-b]pyrazine. LCMS: 201, 2 (M+H)+. Cover &quot;7 8 - gas ~ 4-((2-(ι_methyl_ιη-° than sal-5-yl)-1Η-flavored [4 ' 5-b]eitazine-1-yl) Methyl)quinoline-2 (1H&gt;_

As described in the second step (modification: heating for 3 minutes) in Example ,, use 2·&lt;1-methyl-1Η-pyrazine-based material and [4,5 咖杯4 (thief methyl)&gt; 7,8-Difluoroquinoline-2(1Η)-one (intermediate 1) was used as raw material to synthesize 7'8~methyl_1Η_5 base) 1 Η miso and [4, 5 sec-azine succinyl) methyl ) Lin Lin has an outline. Leg ^^ (4(10) leg^ * DMS0-4) δ 12.08 (s » 1H) » 8.56 (d» 1H) &gt; 8.38 (d» ijj), 7 93 (m, ih) &gt; 7.91 (d &gt; 1H * 7.40 (m &gt; 1H) * 7.10 (d &gt; 1H) &gt; 6.24 (s » 23⁄4) , 5 34 (s , 1H) &gt; 3.72 (s &gt; 3H) ° LCMS : 394.4 (M+H + 〇122 200924772 Example 88 8-Fluoro-4-((2-(1-methyl-pyran-5-yl)-1Η- miso[4 '5-7]»比嗓-1-yl) Methyl) porphyrinone

2-(1-mercapto-1H-pyrazol-5-yl)&gt;ill·imidazo[4'5-7]pyrazine and 4-(bromine) were used as described in Example 34 (modification: heating for 3 minutes) Synthesis of 8-fluoro·4-((2·(1-methyl-1H-pyrazol-5-yl)-1Η-imidazole) by using fluorenyl)-8-fluoroquinolinone (Intermediate 5) as raw material And [4,5-b]pyrazin-1-yl)methyl)quinoline-2(1Η)-one. 1H NMR (400 MHz, DMSOO δ 11.79, (s, 1H), 8.56 (d, 1H) , 8.38 (d,1H), 7.91 (d ' 1H), 7.88 (d,1H), 7.53 (m,1H), 7.31 (m, 1H) ' 7.10 (d,1H) ' 6.26 (s,2H), 5.37 (s,1H) ' 3.72 (s,3H)»LCMS : 376.4 (M+H)+°

Example 89 3-(1-((7,S-difluorooxo-4,2-dihydroquinolin&gt;4-yl)methyl)-1Η-imidazo[4,5-b]pyridinium Qin-2-yl)azetidine-1-tert-butyl tert-butyl ester

123 200924772 · 3 your aminopyridin-2-ylaminocarbamyl) n-butyl butyl bite 1-carboxylic acid tert-butyl ester

N=\ HjN y〇^0 / hn- The synthesis of tert-butyl 3 using i_(tert-butyl ester)azetidine-3-carboxylic acid and pyrazine-amine as the starting material in the first step of Example 35 -(3-Aminopyridin-2-ylaminocarbamoyl)azetidine-4-reposted. LCMS: 294 (M+H)+. Step I: Imidazo[4,5-b]pyrazin-2-yl)azetidine-1-carboxylic acid tert-butyl ester

3-(3-Aminopyridyl&quot;qin-2-ylaminoindenyl)azetidin-1-tetrate t-butyl vinegar was used as a starting material to synthesize 3-(3) as described in the second step of Example 35. 1Η-咪唾和[4,54&gt;]&quot;比°秦-2-基)β丫丁交小叛叔酸丁基L, LCMS ·· 276 (Μ+Η)+ 〇13 steps: Hl-( (7, Heart difluoro-2-oxo-1,2-dihydroquinoline)methyl)-1Η-imidazo[4 ' 5-b]pyr-2-yl)"丫丁唆_ Ic. tartrate t-butyl vinegar

As described in step 3 (modification: 1 hour) in Example 81, 'using 3-(1Η-imidazo[4,5-b] ° ratio &quot;Qin·2·基)" Acid tert-butylcool and 4-(mute methyl)-7' 8-difluoroindene-2(1H)-net 124 200924772 (intermediate 1) were synthesized as raw materials to 3-(1-((7, 8-Difluoro: oxo-i, 2 · dihydroindolyl) methyl) -1 Η - taste saliva and μ, 5 but than 2_ base) 0 丫 bite + tartrate t-butyl vinegar. 1h face _ MHz ' DMSO, δ 12.08 (s, 1H), 8.54 (d, 1H), 835 (d, 1H), 7 78 (m, m) ' 7.37 (m ' 1H), 5.74 (s, 2H) ' 5.49 (s, 1H), 4 3 (M 〇〇 (br m, 5H), i % (s, 9H) ; LCMS : 469.5 (M+H) + « Example 90 4_((2-(吖丁Benzyl-3-yl)-1H-imidazo[4,5-7-pyridazinyl)methyl) knife

-2(1H)-one was added to trifluoroacetic acid (〇5 ml) at 34-((7,8 difluoro-2-oxo),2-dihydroporphyrin-4-yl)methyl) -1Η-Imidazo[4,5-b]pyrazin-2-yl)azetidine-1-carboxylic acid tert-butyl ester (65 mg '〇, 14 mmol) solution and two gas (3) ML). After a minute, the solution was concentrated and purified by reverse phase HPLC (9: 1-&gt; 3: 2; water: acetonitrile). The salt mash (1 ml of '2MEt20) was added to a purified product, a solution of digas (3 ml), and methanol (3 ml). The mixture was immediately concentrated to obtain 4-((2-(indolyl-3-yl)_ih-imidazo[4,5-heptazin-1-yl)methyl)-7,8-difluoroquinoline. -2(1H)-one NMR (400 MHz, DMSO-mountain) δ 12.05 (br, 1H) ' 9.57 (br ' 1H) ' 9.19 (br ' 1H), 8.59 (d, 1H) ' 8.40 (d, 1H), 7.77 (m, 1H) ' 7.38 (m, 1H), 5.78 (s, 2H), 5.52 (s, 1H), 4.48 (m ' 1H), 4.36 (m, 2H) ' 4.27 (m, 2H LCMS: 369.3 (M+H)+. 125 200924772 Example 91 4-((2-Cyclopropyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolinone

Step 1: ΛΚ3-aminopyrazin-2-yl)cyclopropanamide

HjN

HN

Synthesis of iV-(3-aminopyrazin-2-yl)cyclopropane using cyclopropanecarboxylic acid and pyrazine-2,3-diamine as starting materials as described in the first step (modification: 43 hours) in Example 35. Guanamine. LCMS: 179.3 (M+H). Step 2: 2-cyclopropyl-1H-imidazo[4,5-b]pyrazine

Synthesis of 2-cyclopropyl-1H using #-(3-aminopyrazin-2-yl)cyclopropanamide as starting material as described in Step 2 of Example 35 (Modification: 6 (TC, 22 hours)) -imidazo[4,5-b]pyrazine. LCMS : 161.3 (M+H) + ° Step 3: 4-((2-cyclopropyl-1H-imidazo[4,5-b]pyrazine -1-yl)methyl)-7,8·difluoroquinine 126 200924772

As described in Example 3, Example 3, using 2·cyclopropyl-1H♦4,5-b] read and 4-(molylmethyl)-7,8-difluoroanthracene-1 'ketone (intermediate 1) as a starting material to synthesize 4 ((2cyclopropyl-1H-imidazo[4,5-hepta]pyrazine small)methyl)·7,8-difluoroquinoline-ketone .丨HNMR (4 〇〇 MHz, DMSOO δ 12.08 (s, 1H), 8.43 (d, 1H), 8, 25 (d, 1H) ' 7.87 (m ' Φ ih), 7.39 (m, 1H) ' 5.95 ( s ' 2H), 5.44 (s, 1H) ' 2.33 (m ' 1H) ' 1.21 (m, 2H), U5 (m, 2H) ; LCMS : 354·4 (M+H)+. Example 92 4- ((2-(2·cyclopropylethyl)·1Η·imidazo[4 '5-7]pyrazine-1-yl)methyl)·7,8-difluoroquinolin-2(1Η)-明

Step 1: #-(3-Aminopyrazin-2-yl)-3-cyclopropylpropanamide

HN1, as in the first step of Example 35 (modification: DMF is solvent, 24 propyl propionic acid and pyrazine-2,3-diamine are used as raw materials to synthesize #·(3_aminoamine 〇LCMS : 207.4 (Μ +Η)+ 〇*hour), using 3-cyclo^'2-yl)·3·cyclopropylpropanoid 127 200924772 Step 2: 2-(2-cyclopropylethyl)-1Η-imidazole And [4,5-b]pyrazine

The 2-step (modification: 6 (TC, 17 hours) described in 'Used (3-aminoindole-2-yl)-3-cyclopropylpropionamide as a starting material to synthesize 2-( 2-cyclopropylethyl)·1Η·味峻[4,5-7]pyrazine.LCMS : 189.3 (Μ+Η)+. o Step 3: 4-((2-(2-cyclopropyl) Ethyl)-1Η-imidazo[4,5-b]pyrazine-1-yl)methyl)-7, fluoroquinolin-2(1H)-one

2-(2-cyclopropylethyl)·1Η-imidazo[4,5-b]pyridazine and 4-(bromomethyl)-7,8-di were used as described in the third step of Example 41. Synthesis of q 4-((2-(2-cyclopropylethyl))-iH-imidazo[4,5-b]pyrazine-1- using fluoroquinoline-2 (1H&gt; oxime (Intermediate 1) as starting material ))methyl&gt;7,8, dioxin-2(1H)-one. 丨HNMR (400 MHz, DMSOOS 12.08 (s '1H), 8.49 ((1,1H), 8.30 (d '1H), 7,84 (m ' 1H), 7.39 (m,1H), 5.85 (s ' 2H) ' 5 36 &amp;, Qiu, 3.00 (t ' 2H) ' 1.73 (m, 2H), 0.80 (m, 1H) , 0.36 (m, 2H), 〇.〇3 (m, 2H). LCMS: 382.4 (M+H) + ° Example 93 128 200924772 4-((2-(2-cyclopropylethyl)·1Η _ oxazolo[4 ' 5-b]pyrazine small)methyl)·8·fluoroquinone-2(1Η)-one

Ο 0 as described in the third step of Example 41, using 2-(2-cyclopropylethyl)_1Η-imidazo[4,5-7]»pyrazine and 4·(bromomethyl)-8- Synthesis of 4-((2-(2-cyclopropylethyl)-1Η-imidazo[,5-b]pyridin-1 by using fluoroquinoline-2(1H)-one (Intermediate 5) as starting material -yl) fluorenyl) winter fluoroquinoline ketone. Η NMR (400 MHz, DMSOO δ 11.81 (s ' 1H), 8.50 (d, 1H), 8, 32 (d, 1H), 7.81 (d, 1H), 7.52 (m, 1H), 7.29 (m, 1H) ), 5.87 (s , 2H), 5.43 (s, 1H, 3.03 (t ' 2H) ' 1.73 (m ' 2H) ' 0.80 (m ' 1H) ' 〇, 36 (m, 2H), 0.03 (m, 2H LCMS: 364.4 (M+H) + 〇 Example 9彳7-Air hopper ((2-cyclobutyl-1H-imidazo[4,5-b]pyridinium-1-yl)methyl) 8·Fluorine -2琳-2(1Η)·嗣

As described in Example 34, 2·cyclobutyl-1Η-imidazo[4,5-b]pyrazine and 4-(bromomethyl)-7-gas-8-fluoroquinoline·2 were used. (1Η)-ketone (Intermediate 7) is used as a raw material to synthesize 7-pipe ((2-cyclobutyl-1H-imidazo[4,5-b]e-pyrazinyl)methyl) fluoroquinoquine Porphyrin-2 (1Η)·_. LCMS : 384 129 200924772 (M+H)+ 实施 Example Μ

4-((2-ethyl-1Η-imiline[4,5-b]pyroxy)methyl)·7,8-fluoroquinoline-2(1Η)-one

'Using 2-ethyl-1 quinone-imidazo[4'5-7]pyrazine and 4-(bromomethyl)-7,8-difluoroquinoline-2(111)-min as described in Example 1. (Intermediate 1) is a starting material for the synthesis of 4-((2-ethyl-1Η-imidazo[4,5-b]pyrazin-1-yl)methyl)-7' 8-fluoroquinoline-2 ( 1 Η)-ketone. 1H NMR (400 MHz, DMSOO δ 12,10 (s ' 1H) ' 8.49 (d ' 1H), 8.30 (d,1H), 7.84-7.81 (m,1H), 7.41-7.37 (m ' 1H) 1 5.82 (s ' 2H) ' 5.37 (s, 1H), 2.97-2.91 (qt, 2H), 1.34-1.30 (t ' 3H). LCMS: 342.5 (M+H) + The following compounds can usually be prepared using the above methods It is expected that these compounds will have similar activities to those prepared in the above examples when prepared. The compounds herein below are represented by a simplified molecular linear input system, or SMILES. SMILES is by David Weininger and Sunlight Chemical Information Systems Co., Ltd. (Daylight Chemical Information Systems, Inc.) A modern chemical counting system built into a variety of major commercial chemical structure diagram software packages. Software does not need to be compiled into SMILES text strings ' and how to compile SMILES into structures Weininger, D., J. Chem. Inf, Comput. Sci. 1988, 28, 31-36. can find various SMILES strings used herein, as well as many IUPAC names, generated using Cambridge's software ChemDraw 10.0. 130 200924772

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0=ClN([HDC2=€gF)0^&gt;&lt;X&gt;C20(CN30(^NX(CH^=OflSK3C5000C5)=ClC

OClNPOXSOCFiC^KXX^QPGQ^OCXCH^OaSNZBOCQCXQQClC

D=ClN(Pfl)C2=q]F)〇a&gt;C20(CN3C(^KXK&gt;8SI)=〇ei&lt;3C500C5&gt;=Cl 0=ClN(PiDQ&lt;]〇F)0€0&lt;2C(CN30( ^Na&gt;0»«OC5)=〇eSK306000^=Cl 0=ClNPDC2=O^GOOC20(CN30〇SKX&gt;C®i50〇65)〇a^C3C60006i)=a OClNQHDC^qR〇a&gt;C2O(CN3O(ii&lt ;X&gt;OlOC5OC^=O0^C3C6OOO6&gt;=a 〇€ΐΝ(Ρ5)αΜχ^&gt;α&gt;α〇(€3&lt;^κχ&gt;οιαΝ(〇〇κ&gt;«^&lt;3€5σχ5)=α 0 =ClN(PiDC2=0(F)CKX&gt;C20(CN3q^OO0OQ=0a^C3C500C5)=Cl o=ciN([HDC2=qRG=a>C2〇(acq^KXK&gt;i〇cQqK&gt;®^C3C5〇oC5&gt ;=ci OClNi(pfl)C2&lt;^C&gt;€0&lt;20(CN30^W&gt;0iC5=a&gt;O&gt;C5&gt;=0e^=C306000^Cl OClN〇ifl)C2=(^)(&gt;€C&gt ; C20(CN3q^KX&gt;C4C5=W&lt;X&gt;C^=Ofl^C306〇a^K:l 0=ClN(Pfl)C2=0^〇a&gt;C20(CN3q^KX&gt;&lt;&gt;IOC5= a&gt;a&gt;C^=C«^C3〇6〇〇〇^=Cl &lt;&gt;ClN(mDC^C^)(&gt;0G=C2q:CN3C^MXK&gt;l0C5=aMX)=C5&gt;=C ^&lt;30e000^=Cl OClN(mDC2=0^CKX&gt;C20(CN30?i=CN=0W)=0ttTOC500C5&gt;=Cl OClN(im)C2=q^0&lt;XX20(CN3C^K2^&lt;VB« CC^=Ott#C306000^=Cl 0€取(5〇^2=〇5^&gt;0&gt;€2〇;0«〇5^^=00«0〇05) =0^&lt;3〇60〇〇^1 0=ClN(P[DC2=qRCKXX2〇CCN30^=a^aiOC50C?)=0»K3〇e〇00^=Cl OClNPDCMWKXXSOCaGQ^O^OICMCQqKJfi^OCSOOCSKl

OClN(KDCM3i〇CKX&gt;C20(CN3q^K^K&gt;〇qK}®i&lt;3C500C5)=Cl (&gt;ClN(im)C2=0i0C&lt;X&gt;C2q;CN30^i=CN=OI0(QqK&gt;^ &lt;3C500C5)=Cl GClN(KDC2=qRCKX&gt;C20(CN3aiWK}CS&lt;X&gt;0&gt;C5)=〇a^C3060CX^)=Cl

ociNdmja^c^ooccKsqpcci^CNK^ocsK^KXx^ottTOoeooo^ci OClM(Pfl)C2=C^CKX&gt;C20(CN3CG^IG=C4N)=Ofl^&lt;3C500C5)=Cl OClN(mDC3=qric&gt;a&gt; C20(CN3C^GOtN50C^=0®^=C3C6000d)=Cl 0=ClN(P5)C2=Of)000&lt;20(CN3C〇SHSIDOiN500C5)=〇e^C3060006)=a D=ClN(Pfl)C^0 (F) G&lt;X&gt;CaG(CN30?i=f«X)iOC50C^=O®^&lt;306000^=Cl 〇αΝΜ(3=&lt;^Χ&gt;&lt;ΧΧ20(00&lt;^Η«&gt;&lt;!40Ν(〇〇=Οβ^&lt;3〇5〇αα^α OClNPiDCM^OOOaOCCNJO^IOOOQO^KBCSOOC^Cl OClN(Pfl)C2&lt;3^C=a&gt;C2C(aSD〇pSi=MOOIC(QC) =C«'i&lt;3C5〇a^)=Cl O=ClN(P5)C2=C^C&gt;0G&lt;2C(CN305««&gt;C4C5=a&gt;a&gt;C^=〇e^=C306000^= Cl OClN(pi))C20(R(&gt;a&gt;C3C(CN3〇i^lG=C4C5=^K&gt;a&gt;C^=0»K30600C^=Cl ο=αΝρ])α2=〇ρ)〇&lt ;χχ2αρ〇φί=Μ〇οιοα5&lt;χ&gt;α&gt;€5Η&gt;β^&lt;3〇«χχ^Κΐ 0=ClN(im)C2O(R(&gt;0G=C2a(CN3q^K&gt;0K)C5= aW&gt;C5H&gt;8WC»000^=Cl 132 200924772 The activity of the compound as an iNOS inhibitor in Example 1-95 by the following test, the other compounds listed above which have not been prepared and/or tested are in these It is expected to be also active in the assay. Biological Activity Detection Sources of Enzyme Source Nitric Oxide S(NO) can induce endogenous cytokines and/or lipopolysaccharide (LPS) in several cell types, including various cell types well known in the art. The method of iN〇s is produced. Another option is that the gene encoding the enzyme can be cloned as is known in the art and the enzyme can be heterologously expressed in the cell from transient or stable with appropriate characteristics for protein expression. Expression plasmids are produced. As is well known in the art, for iNOS, enzymatic activity (nitrogen monoxide production) is not related to calcium, whereas when various cofactors are added to the cell culture medium or extract, the structural NOS isomer nNOS and eN0S becomes active. The enzymes listed in Table 1 were expressed in HEK293 cells transiently transfected with human iNOS. The main metabolic pathways for DAN to detect nitric oxide are nitrates and nitrites, which are stable metabolites in tissue culture, tissue, plasma, and urine (S Moncada, Alfiggs, N Eng J Med 329, 2002 (1993) ). Longitudinal studies in humans have shown that it is possible that 5 〇% of the whole human nitric acid/nitrite is derived from the enzyme substrate for NO synthesis, L-arginine. (PM Rhodes, AM Leone, PL Francis &gt; AD Struthers &gt; S Moncada &gt; Biomed Biophys Res. Commun. 209 &gt; 590 (1995); L. Castillo et al. 'Proc Natl Acad Sci USA 90, 193 (1993) Although nitrate and nitrite are not indicators of bioactive NO, plasma and urine samples from subjects after appropriate fasting and selective administration of a controlled diet (low nitrate/low arginine) Nitrate and tellurite are allowed as indicators of NO activity. (C Baylis, P Vallance, Out Opin 133 200924772

Nephrol Hypertens 7 » 59 (1998)) The level of nitrate and nitrite in sputum samples can be quantified by any method known in the art to provide sufficient sensitivity and reproducibility. Various drafts have also been described by ion chromatography (eg , SA Everett et al, J. Chromatogr. 706, 437 (1995); JM Monaghan et al, J. Chromatogr. 770, 143 (1997)), high performance liquid chromatography (eg, M Kelm et al. ' Cardiovasc.

Res. 41 '765 (1999)) and capillary electrophoresis (ma Friedberg et al., J. Chromatogr. 78 491 (1997)) to detect and quantify nitrite and nitrate levels in biological fluids ^, 2, 3- The diaminonaphthalene reacts spontaneously with the nitrous cation to form the fluorescent product naphthalene triazole from N0. Using 2' 3-diaminonaphthalene ('ΌΑΝ1')' researchers have developed a rapid, quantitative fluorescence assay that is capable of detecting 10 nM to 10 μM nitrite and is compatible with multi-well microplate formats. . DAN is a highly selective spectrophotometric reagent for Se and nitrite ions. DAN reacts with nitrite ions to form fluorinated naphthalene triazole (MC Carr6 et al., Analusis 27, 835-838 (1999)) Table 1 provides test results for various compounds of the invention using the DAN assay. Before the detection of nitrate or nitrite, the sample can be processed by quantitative analysis when needed, or to improve the results, or In order to facilitate the investigator. For example, the treatment can include centrifugation, passing, or evenly aligning the sample. If the sample is whole blood, the blood can be removed by centrifugation, and the acid salt or nitrite assay is performed in the plasma or fraction. If the sample is tissue, the tissue can be arbitrarily or homogenized by any method known in the art prior to detecting the acid salt or nitrite. Preferably, the cells and other debris are removed by centrifugation or other means, and preferably only the liquid portion of the sample, or the extracellular liquid portion of the sample, is used to detect the level of nitrate or nitrite. The sample may also be stored for later testing, For example by passing a cold bed urine or plasma sample. When appropriate, an additive may be introduced into the sample to protect or improve its characteristics for nitrate or nitrite detection 134 200924772. The "level" of a june, sub-hybrid or other N0-related product, refers to the concentration of the liquid or t-acid salt of the sample, or the liquid portion of the sample (mol/L, mmol/L, or other suitable unit). Other age units can also be used to express nitrate or nitrite levels. For example, absolute amounts (micrograms, milligrams, nanomolars, moles, or other suitable units) can be used, especially considering the amount Refers to the constant of the sample (for example, grams, kilograms, milliliters, liters, bites other suitable units), which can be used before the secret material. In some real money, the two regioisomers correspond to one implementation_ 'Exit, table> towel separately _ w considering the activity value gives an example

Wife 1, biological law cream application ^ J®OS EC50 ten J pain 1 μ] νί .1 + 2 + 3 + 4 + 5 6 — + 7 + 8 —— -. + 9 + 10 + 11 + 12 + 13 + one--- 135 200924772 14 + 15 + 16 + 17 - 18 + 19 + 20 + 21 - 22 + 23 + 24 + 25 + 26 + 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 35 + 36 37 + 38 - 39 + 40 + 41 + 42 +

136 200924772

φ 43 + 44 + 45 + 46 - 47 + 48 49 - 50 + 51 52 NT 53 + 54 + 55 + 56 + 57 + 58 - 59 60 + 61 - 62 + 63 + 64 + 65 + 66 + 67 + 68 + 69 + 70 + 71 + 137 200924772 72 + 73 + 74 + 75 + 76 + 77 + 78 + 79 + 80 + 81 + 82 + 83 NT 84 - 85 - 86 - 87 88 - 89 - 90 - 91 + 92 + 93 + 94 + 95 - Ο

Pharmacokinetics detection of metabolic stability of compounds after hatching of male gastric liver microsomes 138 200924772 A liver granule is a subcellular part, which includes a drug-containing cytochrome P45〇s (CYPS) Enzyme and glucosyltransferase. These enzymes are required to provide an active cake in this test system. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ : Prepare a potassium silicate buffer (solution buffer) with a ΡΗ value of 7.4 from 110 ml 1 Μ - Yuanqing 4 and 390 ml 1 Μ binary ΚΡ〇 4 (total volume φ liter), add 1 mM EDTA, 3 mMMgC' LMmMD-glucose diacid broth vinegar monohydrate before it is diluted to 100 mM with water. It can be stored for up to - month at 4tT. Add 2 mg of propanol to 2 (8) ml of hatching magnesium sputum the day before the study The bacteriocin and Q2 gram bovine serum albumin a was simultaneously sonicated for 2 minutes and scrambled for several hours. Add to the sputum in a 15 ml polypropylene nut tube containing 85 ml of deionization buffer. U5 weight compound to obtain 5 8 willow solution (test). Liver microsomes with a concentration of 20 mg / ml (from male rat liver microsomes, for example, BD Ge Fu 'Woburn ' ΜΑ; can be at -7 〇 tSave until application) Dilute to 5 mg/ml in the D-flush in the separation tube. The ΝΑ〇ρΗ production system was prepared by combining a batch of the following pre-formed raw materials: 1, 1 mM (10) ml/part of 100 mM _ acid buffer, 6Q () mM glucose·6 sate stock solution; 2. 100 mM phosphate 1 〇 ml (〇 5 ml / part) 12 mM 〇NA〇p stock solution in buffer; and 1 liter (〇 5 ml / part) in 3,100 mM phosphate buffer 12 〇 unit / ml glucose _6_$ acid Dehydrogenase stock solution, 139 200924772 100 mM phosphate buffer prepared on the same day, medium volume of 2 mM UDP-GA. Each of U3 can be stored in aliquots at -80 °C until application. Determination of abundance period In a suitable incubator, 5.88 μΜ 425 μl of incubation buffer containing the compound test and 5 μl of microliters of 5 mg/ml of dilute liver microsomes were pre-bottled in a 371 water bath for at least 5 minutes. Add 25 μl of NADPH generation system to the vial and immediately remove aliquots of 1 μl of microliter sample from each incubator and with 300 μl of cryo-quenching reagent containing internal standard (1: 2 water) : Acetonitrile) mixed. At each subsequent resolution time point (15, 30 or 60 minutes), the microliters are removed or quenched. The final concentration of the test was 5 μΜ' and the final concentration of DMSO solvent in the incubation was 〇 4% (ν/ν).代谢 Metabolic stability is determined based on the disappearance half-life. The percentage of residual sample (%) was determined at each incubation time point relative to the zero time sample. These results are naturally logarithmically transformed such that the concentration of the enzyme substrate decreases linearly with time. The line is compounded by a standard linear regression algorithm and the slope is determined. If the data points show high-order cancellation kinetics (non-linear), the earliest data points are used for slope calculations. The disappearing half-life (Τ丨/2) expressed in minutes is calculated by multiplying the slope inversion by the natural logarithm 2 (Μ2). All data analysis was performed using Microsoft Excel (2007 version). The results are reported in Table 2 below. 'S in A indicates half-life of $30 minutes' B indicates half-life> 3 minutes, but &lt;12 minutes minutes' C indicates no half-life 2 120 ηώι, where the value is typically representative of the number of subsequent averages performed by the same test. Table 2. Metabolic stability Hepatic microparticles Compound abundance period A : &lt;30 minutes Example &gt; 30 minutes, &lt;120 minutes C: 2120 minutes NT means untested 140 200924772

Embodiment 1 NT Embodiment 2 B Embodiment 3 C Embodiment 4 B Embodiment 5 NT Embodiment 6 B Embodiment 7 A Embodiment 8 B Embodiment 9 NT Embodiment 10 B Example 11 A Example 12 C Example 13 C Example 14 c Example 15 c Example 16 c Example 17 c Example 18 c Example 19 c Example 20 c Example 21 NT Example 22 c Example 23 B 141 200924772

Example 24 C Example 25 C Example 26 C Example 27 B Example 28 A Example 29 B Example 30 C Example 31 C Example 32 C Example 33 C Example 34 C Example 35 C Example 36 C Example 37 NT Example 38 NT Example 39 B Example 40 B Example 41 C Example 42 C Example 43 C Example 44 C Example 45 NT Example 46 NT 142 200924772

Example 47 B Example 48 NT Example 49 NT Example 50 B Example 51 NT Example 52 NT Example 53 C Example 54 C Example 55 C Example 56 C Example 57 C Example 58 NT Example 59 NT Embodiment 60 A Embodiment 61 NT Embodiment 62 C Embodiment 63 c Embodiment 64 B Embodiment 65 B Embodiment 66 B Example 67 C Example 68 A Example 69 C 143 200924772 Example 70 C Example 71 NT Embodiment 72 C Example 73 C Example 74 C Example 75 C Example 76 C Example 77 C Example 78 C Example 79 C Example 80 C Example 81 C Example 82 C Example 83 NT Example 84 c Example 85 NT Example 86 NT Example 87 NT Example 88 NT Example 89 NT Example 90 NT Example 91 C Example 92 c

144 200924772

Example 93 C

Example 94 NT Example 95 NT in vivo detection 畠.LPS attack The inhibition of iNOS induction can be quantified by LPS challenge. Inflammation, edema, and sepsis episodes were observed after injection of lipopolysaccharide (LPS), a substance produced by a Gram-negative bacterium. Injection of lipopolysaccharide (LPS) has been shown to induce iNOS transcription, resulting in a measurable increase in both iNOS and NO. (Iuvone T et al.'s evidence of inducible nitric oxide synthase induced by LPS-induced plasma leakage in rat skin with nuclear factor _kb, BrJPharm 1998: 123 1325-1330) » As described above, mono-oxidation in the sample The level of nitrogen can be chemiluminescent, fluorescent, spectrophotometric, or any method known in the art that provides sufficient sensitivity and reproducibility by correlation with blood plasma nitrate or nitrite salt (including those described above) ) to quantify. Male Lewis rats weighing 150-250 grams are commonly used in the study. 'Φ rats can be fasted for up to 16 hours* before administration of LPS* to maintain free drinking water. The test compound is administered alone with LPS. Dissolve the compound in 0.5% methylcellulose (methyceley 〇〇 25% Tween 2 〇 or 20 ° /. According to Kapusheng (such as Xiangru) medium for oral administration. For intravenous injection of compound dissolved in saline or 0.5 -3% DMSO / 20% incapone. The compound can also be dissolved in 1% of a stock solution of 9〇% pGE_4〇〇, 5% Tween 80, 5% PVP and 9〇% CMC. The volume of the preparation is 1-2 ml or 0.3] ml for intravenous administration. In the disinfected 0.9% saline (chlorinated sodium), the dose by intravenous or intraperitoneal injection is 〇1·1〇mg/kg 'Zhao product does not exceed Lps of ML. The needle is 26 3 sputum. After Lps injection, rat 145 200924772 usually shows symptoms similar to flu, mainly including lack of activity and diarrhea. In routine screening experiments, LPS is injected 1.5-Μ, then large Rat died 'and dying was performed under anesthesia to obtain a w ml jk-like sample, and then the animal was euthanized by CO 2 . The draft using the mouse instead of the rat was rewritten to adjust the species and weight difference according to the method disclosed above, for example, using this A well-known modification in the field. Compounds are administered at 30 mpk. The percentage of inhibition results, where ND is "no information." Table 3, inhibition of inflammation

〇146 200924772 70 95% ND 73 ND 54% 74 ND 54% 75 77% ND 78 92% ND 81 ND 92% 82 ND 95% 92 ND 88% 93 ND 67% Ο As mentioned above, those skilled in the art can It is easy to ascertain the essential characteristics of the present invention, and various changes and modifications can be made to the various applications and conditions without departing from the spirit and scope thereof.

147

Claims (1)

200924772 X. Patent application scope: 1. A compound of formula II Or a salt, ester, or prodrug thereof, wherein: ¥ is selected from the group consisting of CR4 and N; X2 is selected from the group consisting of CR5 and Ν; X3 is selected from the group consisting of CR6 and Ν; -R6 is independently selected from the group consisting of hydrogen, halogen, cyanoalkyl, low oxiranyl, low dentate alkoxy, lower alkynyl, lower cycloalkyl, lower aryl, lower a heteroaryl group, (CH2)mOR12, (CH2)mSR13 and (CH2)mN(R14)R15, any of which may optionally be selected from the group consisting of methyl, ethyl, halogen, perfluoromethyl and perfluoromethoxy Substituting one or two substituents in the group of radicals; R7 is selected from the group consisting of lower alkyl, _(CH2)n-lower cycloalkyl, -(CH2)n-low heterocycloalkane a group, -(CH2)n-loweraryl, and -(CH2)n-lowheteroaryl, any of which may optionally be selected from the group consisting of methyl, ethyl, halogen, perfluoromethyl and perfluoro One or two substituents in the group of oxy groups are substituted; R, R9, R1G and R11 are independently selected from the group consisting of hydrogen, an alkyl group and a halogen; R12 and R13 are independently selected from hydrogen, halogen, and low. Alkyl, low cycloalkyl, low a group consisting of an aryl group, a low heteroaryl group, and a low heterocyclic ketone group, any of which may optionally be composed of a methyl group, an ethyl group, a halogen, a perfluoromethyl group, and a perfluoromethoxy group selected from 200924772. Substituting one or two substituents in the group; R14 and R15 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, lower aryl, lower heteroaryl, lower heterocyclic, and lower heterocyclic A group consisting of a group of thiol groups, which are optionally substituted by one or two selected from the group consisting of methyl, ethyl, dentate, perfluoromethyl and perfluorodecyloxy. Substituent; or R 〖4 and R15 together with the atom to which they are bonded may be combined to form an optionally substituted 3-7 membered heterocycloalkyl moiety; and 〇m and η are independently 0*4. 2. The compound of claim 1 wherein R10 and R11 are hydrogen. 3. The compound of claim 2, wherein X2 is CR5; and X3 is CR6. 4. The compound of claim 3, wherein R5 and R6 are hydrogen. 5. The compound of claim 4, wherein R9 is selected from the group consisting of fluorine and hydrogen. 6. The compound of claim 5, wherein fR8 is hydrogen. 7. The compound of claim 6 wherein: R4 is selected from the group consisting of hydrazine, i-, cyano, acetonyl, low-dentate alkyl, low-dentate alkoxy, (CH2)m〇R12, (CH2) a group consisting of mSR13 and (CH2)mN(R14)R15, any of which may optionally be selected from the group consisting of methyl, ethyl, arginine, perfluoromethyl and perfluoromethoxy Substituted with one or two substituents; and R14 and R15 are independently selected from the group consisting of hydrogen and a low-form group; or the inverse 14 and the size 5, together with the nitrogen to which they are bound, may be combined to form an optional a 3-5 membered heterocycloalkyl moiety. 8* The compound of claim 7, wherein 149 200924772 R7 is selected from the group consisting of lower cycloalkyl and -(CH2)n-low cycloalkyl, any of which may optionally be selected from the group consisting of methyl, One or two substituents in the group consisting of ethyl, dentate, perfluoromethyl, and perfluorodecyloxy; and η is 0 or 1. The compound of claim 8, wherein X1 is Ν» 10. The compound of claim 8, wherein hydrazine is CH. 11. A compound selected from the group consisting of: 7,8-Difluoro-4-((2-isopropyl-1Η-imidazo[4,5-b]pyrazine-1-yl)methyl)quinoline-2(1Η)-嗣, 4~ ((2-Cyclobutyl-3Η-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8-difluoroquinolin-2(1Η)-one, 7' 8·^ -Fluoro-4-((2-(戍烧-3-yl)-3Η, ϋ米峻和[4,5-b]°lfc bit-3-yl)methyl)啥琳闲, 4-(( 2-cyclobutyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8-difluoroquinolin-2(1Η)-one, 7, 8-Difluoro~4-((7-methyl-2-(pentan-3-yl)-3Η-imidazo[4,5-b]pyridin-3-yl)methyl)Q quinolin·2 (1Η)-keto, 4-((7-chloro-2-cyclobutyl-3Η-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8-difluoroquinoline- 2(1H)-keto, 4-((2-cyclobutyl-7-(dimethylcarbyl)-3H-midazo[4,5-b]0 than -3-yl)methyl)&gt ; 7 ' 8-difluoroquinoline-2(1H)-min, 4-((2_cyclobutyl-7-(°fc)&gt;·1-yl)-3H-mimi[4 ' 5 -b]0 than -3-yl)methyl)-7' 8-difluoroquinolin-2(1H)-one, 150 200924772 4-((2-cyclobutyl-7-(ethylamino)- 3H-imidazo[4,5-b]pyridinyl)methyl)_7 '8 diazide-2(1H)·, 4-((2·cyclobutyl-7-(methylamino)) -3H -imidazo[4,5-b]pyridine each)methyl)·7,difluoroquinoline-2(1H)-one, 4-((2-cyclobutyl-7-(ethyl (a) Amino)-3H-imidazo[4,5-b]«pyridin-3-yl)methyl)-7,8-difluoroquinoxaline-2(1H)-one, 4-((2- Cyclobutyl-7-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7' 8-difluoroquinoxaline-2(1H)-indole, 4 -((2-Cyclobutyl-7-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8-difluoroquinolin-2 ( 1H)·ketone, 7,8_difluorocape ((2_isobutyl_1H_imidazo[4,5_b]pyryl 1_yl)methyl)quinoline_2(1H)- discretion, 4- ((2-Cyclopentyl-1H-imidazo[4' 5-b]pyrazin-1-yl)methyl)-7,8-difluorofluorene-2(1Η)_ 明, ^ 7,8 -Fluoro·4«((2-(3-methylbutan-2-yl)·1Η-*φ峻[4,5-1}]»«;嗓_1_yl)methyl) Quinoline-2 (1H&gt; ketone, 4-((2-(cyclobutylmethyl)) oxime- oxazolo[4,5-7]pyrazine small)methyl)·7,8 difluoroindolene-2 ( 1Η)__, 4·((2-butyl·1Η-imidazo[4,5-7]pyranyl)methyl)_7,8-difluoroquinoline·2(1Η)_ 辋, heart (6)乂3 ' 3 -Dimethylcyclobutyl)-1 Η-imidazo[4,5-b]pyrazine-1-yl) Base)_7,8-'one gas*嗟淋-2(1 H}-嗣, abundance ((2. sec-butyl-1H-imidazo[4,5-timerazine-based small group) methyl H' 8-two Fluoroquinone 2(10)_ 151 200924772 Ketone, 4-((2-cyclobutyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)·7,8-difluoromethyl淋-2(1H)-net, 4-((2-cyclobutyl-1H-imidazo[4,5-b]pyridinium)methyl)·3,7 '8' trifluorofluorene- 2(1H)-one, 4-((7-bromo-2-cyclobutyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8-difluoroquine Porphyrin-2(1H)-net, 2-cyclobutyl-3-((7,8-difluoro-2-oxo-bu 2-dihydroquinolin-4-yl)methyl)-3H-mpy And [4, bite-7-carbonitrile, 4-((7-(aminomethyl)-2_cyclobutyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)- 7,8-Difluoroquinolinone, 4-((7-chloro-2-isobutyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8-di Fluoroquinoline feeding, 4·((7-(dimethylamino)-2-isobutyl-3H- miso[4 '5-7]咐)-3-yl)methyl)-7' 8- Difluoroquinoline·2(1Η&gt; ketone, winter ((8-cyclobutyl-9Η-indolyl)methyl)-7,8-difluoroquinolin-2(1Η)-one, 4-(( 8-cyclobutyl-6-methyl-9Η-indoleyl)methylhydrazine 7,8-di Fluoroquinoline-2(1Η)-one, 8-fluoro-4-((2.isobutyl-1Η-flavored salido[4,5-b]e than 0-methyl-1-yl)methyl)indole Lin-2(1Η)-copper, 4-((2-cyclobutyl-1Η-imidazo[4,5-b]pyrazinyl)methyl)-8-fluoroquinoline-2 (1Η) -ketone, 7,8-digas*4-((2-phenyl-1indole-imidazo[4,5-b]pyrrolidyl)methyl)quinoline-2(1Η)-one, 7' 8-Difluoro winter ((2-(3,3 '3-trifluoro-trifluoromethyl)propyl) Η)-imidazo[4,5-b]pyrazine-1-yl)methyl)quinoline鲷, 200924772 7 '4-Difluoro_4·((2-(4-methylthiazole-5-yl)-1H-imidazo[4,5-b]pyridinium)methyl)quinoline- 2(1H)-one, 7' 8-difluoro-4-((2-isobutyl-1H-imidazo[4,5-b]pyridinium. Qin-1-yl)methyl)-3methylquinolinone, 7' 8-difluoro-4-((2-isobutyl-7-methyl-3H-imidazo[4,5-b] Pyridin-3-yl)methyl)-3-methylquinolin-2(1H)-one, 7' 8-difluorocape ((2-isobutyl-7-methyl-3H-imidazo[ 4,5-b]pyridin-3-yl)methyl)quinolin-2-(1H)-one, 4-((7-oxy-2-cyclobutyl-3H-imidazo[4,5 -b]pyridin-3-yl)methyl)-7'8-difluoroquinine, 4-((2-(cyclopropylmethyl)_1H•imidazo[4,5-hepta]pyrazine) Methyl)-7 ' 8-difluoroquinoline 4-((2-(cyclopropylmethyl)_1Η_imidazo[4,5-7]pyradinyl)methyl)-8-fluoroquinoline 2(1Η)~ 嗣, 4-((2-cyclobutyl-1Η-imidazo[4,5-b]pyrazine small)methyl) knife, 8-difluoroquinoline-2(1Η)- Ketone, ^ 7 ' 8-difluorocape ((2_isoamyl-1Η-imidazo[4,5-b]pyrazin-1-yl)methyl)quinoline-2(1Η)-嗣, 4 -((2-sec-butyl-1Η-flavored) sits and [4,5-b]*pyrazin-1-yl)methyl)·7' 8-difluoroindene-2(1Η)-net, 4-((2-(cyclohexylmethyl)-ιη-imidazo[4,5-b]pyrazin-1-yl)methylhydrazine ' 8-difluoroquinolin-2(1H)-min, 4 -((2-(cyclopentylmethyl)-1Η-imidazo[4,5-b]pyrazine small)methyl)·7 Heart difluoroquinoline-2 (1H&gt;-keto, 153 200924772 7,8-two-step 4((2-(3-methylpentyl)-1Η-imidazo[4,5-b]pyrazine-1 -yl)methyl) "# -2-2(1H)-嗣, 4-((2-(2•cyclopentylethyl)-1 Η-imidazo[4,5-b]pyrazin-1-yl) Methyl)-7,8-difluoroquinolin-2(1H)-one, 7,8-difluoro-4-((2-(hexane-2-yl)-1Η-imidazo[4,5 -b]Pyrazine-1-yl)methyl)quinoline-2(1H)-emergence, 4-((2-tert-butyl-m-imidazo[4,5-b]pyridin-1-yl) )methyl)-7,8-difluoroquinoline-2(1H)-one, 7,8-Difluorocape ((2-(heptan-3-yl)-1Η-imidazo[4' 5-b]pyrazin-1-yl)methyl)quinoline-2(1H)-one 7,8-Difluoro-4-((2-(pentan-2-yl)-1Η-imidazo[4' 5-b]pyrazine-1·yl)methyl)quinoline-2 (1H) )-ketone, S-fluoro&gt;4-((2-(pentyl)2-yl)-1Η·imiban[4,5_b]0-pyridinyl)methyl)linone, 7,8 -difluoro 4&lt;(2-(2-methylbutyl-1H-imidazo[4' 5-b]pyrrolidyl)methyl) -2(1Η)-ketone, 8-fluoro-ice ((2-(2-methylbutyl)-1Η-imidazo[4' 5-b]pyrazinyl)methyl)wollen-2(1H) -ketone, 7' 8-difluorocape ((2-mercapto-1H-imidazo[4'5-7]pyrazine-1.yl)methyl)唉琳2(10)· ketone, 4-((2-( 2_cyclohexylethyl)-1Η-mijun and [4 '5 sulphate small base) methyl)_7,8_difluoroanthrene-2(1H)-one, 7' 8-difluoro-ice ( (2-(4_Methylpentyl HH_material and μ, 5 比 纠 base) methyl) 喧琳154 200924772 -2(1 Η)-ketone, 4-((2-(2-cyclobutylethyl)) -1Η-imidazo[4,5-b]pyrazin-1-yl)indolyl-7,8-difluoroquinolinone, 4-((2-cyclobutyl-6-mercapto-1H- Imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one, 4-((2-cyclobutyl-5-methyl) -1H-imidazo[4,5-b]pyridyl-heptyl-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one, 7,8-Difluoro 4-((2-(pentan-3-yl)-1Η-imidazo[4,5-7]pyran-1-yl)methyl)quinoline-2(1H)-嗣4-((2-(2·ethylbutyl)-1Η-imidazo[4,5-b]pyrazine)methyl)-7,8-difluoroquinolinium, 4-(( 2-Cyclobutyl-7-ethyl-3H-imidazo[4,5-7-pyridin-3-yl)methyl)-7,8-difluoroquinolin-2(1H)-one, 3- Gas-4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one, 4-((2-Cyclobutyl-7-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7,8-difluoroketone, 4-((2 -cyclobutyl-7-isopropyl-3-indole-imidazo[4,5-b]pyridin-3-yl)indolyl-7,8-difluoroquinolin-2(1 H)-one, 4 -((2-(3,3-difluorocyclobutyl)-1Η-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoro»#4-2 (111)-keto, 4-((2-(3,3-difluorocyclobutyl)-1Η-imidazo[4,5-b]pyridin-1-yl)methyl)-8-fluoro Quinolin-2(1H)-net, 155 200924772 7'8-difluoro~4-((2-(3-methyl-T-~4-yl)-111-isoxazole[4,5-7]吼嗓-1-yl)methyl)quinoline-2 (1Η&gt; ketone, 7' 8-difluoro 4-((2-(3-methylcyclobutyl)-1Η-imidazo[4,5-7) Pyrazine-1- )methyl)quinoline-2(1H)-one, 4_((2·cyclopentyl-1H-imidazo[4,5-b]pyridin-1-yl)indolyl)-heart fluoroquineline · 2 (1Η)-Ming, 4-((2_(cyclobutylmethyl)-1Η-imidazo[4' 5_b]pyr i-yl)methyl)) each quinolin-2(1H)-indole, 8. Fluoride ice ((2-(3,3,3_trifluoro.2.(trifluoromethyl)propyl)4(tetra)) and μμ,Μ]pyridinium)))))## (1H),, ' 7 ' 8-difluorocape ((2-(3,3 ' 3 ·trifluoropropyl[4,5_ ah quinine-2(1Η)-one, fluorenyl) 8 -Fluorine 4((2-(3' 3 ' 3-trifluoropropyl)-1Η-imidazo[4,5-7]pyroxypyrene, methyl)啥琳 7 ' 8-difluoro-4-( (2-(4,4,孓Trifluorobutane-2-yl)-1Η-imidazo[4,yl)methyl)quinolin-2(1H), 〇8-fluoro 4-((2- (4 '4,4-Trifluorobutan-2-yl)-1H-imidazo[4,5-7]pyridinium (10)-Ming, Sang 'Keller 7 ' 8- 2 gas>4·(( 2-(4 '4,4-Trifluorobutyl)-1Η-imidazo[4, fluorenone, methyl) 7 ' 8-difluoro·4&lt;2«(3' 3,3-trifluoro- 2-methylpropyl)-1Η-imidazo[4,5-yl)methyl)indolene-2(1H),8-fluoro-1((2-(3,3,3-trifluoro-2-) Methylpropyl)-1Η-imi Azolo[4,5-7]yl)phosphonium-2 (1H&gt; ketone, ) A 156 200924772 5-b]pyrazine-1-yl)methyl)quinoline 7,8-difluoro-4·(( 2-(indolazole-5-yl HH, imidazo[4,5 . -2(1H)-one, ' 8-difluoro- 4 medical secret · 1 (four) butterfly 4,5 as known as tearing (10) _ ketone 5- b]°Biazin-1-yl)methyl)啥# 7 ' 8-difluoro-4-((2-(indol-3-yl)-1Η, oxazolo[4, -2(1H)) -嗣, Ketone 8 preparation ((2_(Powder 3•基)·1Η咪简 4' 5 supplement...Tear base trace imidazole and [4,5-7]pyrazine small base) 7,8-difluoro-4-(( 2-(1-methyl-1Η-pyrazole-5.methyl)quinoline-2(1H)-one, 8-gas transmission G-methyl-(tetra)jun-5-jimail·face and [4 threat比嗓小基)Methyl)quinoline-2(1H)-one, yl)methyl)-7,8-difluoroquinoline 4-((2-(indolyl-3-yl)-1Η- Imidazo[4,5-7]%嗓^-2(1H)-car, Ketone 4-((2-(2·环喊淡1H+卿,岣如^·研基)_7,&amp; Dioxaporphyrin-2 (1H&gt; ketone, 4-((2-(2-cyclopropyl)) 6 base) - melonton 4, xantazine] pin base &gt; 8 gas generation two -2 (1H>-ketone, 7-chlorocyclobutyl-1H-material and [4 '5_bK„ Qin Xiaoji) methyl) Each fluorophthalocyanine-2 (1Η&gt;·辋, and 4-((2-ethyl-m_味吐和[4,5_b(10)秦小基)methyl)-7,8- 气代哇琳-2 157 200924772 Vehicles 12. Use of the compound according to claim 1 for the use of a medicament. 13. A compound according to claim 1 as a medicament for preventing or treating a disease or improving conditions by inhibition of iNOS Use 14. A pharmaceutical composition comprising a compound as claimed in claim C and a pharmaceutically acceptable carrier 15. A method of inhibiting iNOS in vitro vz&gt; o) comprising contacting iNOS as claimed in claim 1 A pharmaceutical composition for the treatment of iNOS-induced diseases, comprising a therapeutically effective amount of the compound of claim 1, wherein the pharmaceutical composition according to claim 16, wherein the disease Choose free pain, inflammatory disease, self A group consisting of an immunological disease and a respiratory disease, wherein the pharmaceutical composition according to claim 17 wherein the disease is selected from the group consisting of neuropathy, inflammatory pain, nerve damage, peripheral nerves Lesions, diabetic neuropathy, chronic pain, refractory cancer pain, complex local pain syndrome, invasive neuropathy (carpal canal syndrome), neuropathic pain, acute banded rash (shingles), band Posthermetic neuralgia (PHN), eye pain, postoperative pain, toothache/extraction, pain caused by skin damage, low back pain, headache, migraine, tactile pain and hyperalgesia. The pharmaceutical composition, wherein the pain is inflammatory pain. 20. The pharmaceutical composition according to claim 18, wherein the pain is caused by skin damage, and the skin damage is burns. The pharmaceutical composition of the invention, wherein the disease is selected from the group consisting of neuropathic pain and postherpetic neuralgia. 22. The pharmaceutical composition according to claim 17 From the group consisting of 158 200924772 New Zealand's inflammatory diseases: sepsis, sedative, sedative, young (four) 'bone _, bone: 's disease w stimuli and ulcers = win = victory, spur 23. The pharmaceutical composition according to claim 1, wherein the disease is a respiratory disease selected from the group consisting of asthma, chronic obstructive pulmonary disease, including chronic bronchitis, acute respiratory distress syndrome, pneumonia Pulmonary hypertension and asthma persistence. 24. A pharmaceutical composition for treating iNOS-induced disease comprising: a. a therapeutically effective amount of a compound of claim 1; and b. an additional therapeutic agent. 〇 159 200924772 VII. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None. 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 5 200924772 ^ The application case also states that the department has changed the shell (there is no underlined version) (February 1998) f. Mb is smashing the invention patent specification (the format, order and rough words of this manual, please do not change it. ※Please do not fill in the mark) /^&gt;1^ go: %IPC Category:- ^ ^UO, Uj) (2〇〇6,〇1} JD 1) ※Application number: 097132342 ※Application date: August 25, 1995, inventor name: (Chinese / English) As nitric oxide synthase Heterobicyclic Substituted Quinolones for Inhibitors / HETEROBICYCLIC-SUBSTITUTED QUINOLONES USEFUL AS NITRIC OXIDE SYNTHASE INHIBITORS 0 —, Applicant: (Total 1 person) Name: (Chinese/English) Calep Systems/KALYPSYS, INC. Representative: (Chinese / English) Stewart A Nobel / NOBLE, STEWART A· Residence or Business Office Address: (Chinese / English) 1020 WaterIDGE CIRCLE, SAN DIEGO, San Diego, California, USA CA 92121, USA Nationality: (Chinese/English) US/USA 〇3, inventor: (8 in total) Name: (Chinese/English) L Nicolas D Smith / SMITH, NICHOLAS D. 2·Joseph E Pei恩/PAYNE, JOSEPHE. 3' Celine Bonifis / BONNEFOUS, CELINE 4 · Sergio G Duro / DURON, SERGIO Ci 5. Zhuang Hui / ZHUANGHUI 6 · Chen Xiaohong / CHEN, XIAOHONG 7 · Stephen P.克/GOVEK, STEVEN P.