TW200526196A - Substituted nitrogen-containing six-membered amino-heterocycles as vanilloid-1 receptor antagonists for treating pain - Google Patents

Abstract

The present invention provides a compound of formula I: Y-J-NH-Z, wherein: Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from halogen, haloC1-4alkyl, C1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, nitro and amino; J is pyridine, pyridazine, pyrazine, pyrimidine or triazine optionally substituted with one or two substituents independently chosen from halogen, haloC1-4alkyl, C1-4alkyl, C3-5cycloalkyl, C1-4alkoxy, haloC1-4alkoxy, nitro and amino; wherein J is substituted at positions meta to each other by NH and Y; and Z is phenyl or pyridyl optionally substituted with one or two substituents independently selected from halogen, haloC1-4alkyl, C1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, nitro and amino; or a pharmaceutically acceptable salt thereof; pharmaceutical compositions containing the same; the compound for use in therapy; and use of the compound for the manufacture of a medicament for treating or preventing diseases requiring administration of an antagonist of the vanilloid-1 (VR1) receptor.

Description

200526196 IX. Description of the invention: [Technical field to which the invention belongs] The present invention _ in the substituted nitrogen-containing μ amine silk ring and its analogs and organisms, is also related to its pharmaceutically acceptable salts, these substances are especially in It is suitable as a therapeutic compound for the treatment of pain and other conditions that are improved by modulating the function of "vanillin receptors" (VRi). [Previous technology] For a long time, I have recognized that the pharmacologically active ingredient of pepper is capsaiein. Applying the pepper test to mucous membranes or intradermal injections can cause severe burning pain. The use of capsaicin as an analgesic drug has been well established. However, understanding of the underlying molecular pharmacology that regulates these responses to capsaicin has recently evolved. Capsaicin receptors, known as vanilloid VR1 receptors, were cloned by ucsf's Caterina and colleagues in 1997 (Nature, 398: 816, i997). VR1 is controlled by the cation channels found on the innervation of the skin, internal organs, peripheral tissues and the spinal cord. The activation of VR1 causes action potentials in the sensory fibers, which ultimately produces painful sensations. Importantly, VR1 stylistics are activated not only by capsaicin, but also by acidic pH and harmful thermal shock. It is also a polymorphic integrant that is sensitized by a variety of inflammatory mediators and therefore appears to be a pain stimulus.

The original i VR1 t-resistance was capsazepine (Walpole et al., CA. 37: 1942, 1994) -42 nM VR1 ICw. A number of novel submicromolar antagonists have also recently been reported in 97258.doc 200526196 (Lee et al., 5z '(9 (9rg. Λ / Μ. C / zd, 9: 1713, 2001)), however these The report does not provide evidence of in vivo efficacy. A higher affinity antagonist has been derived from the "super effective" agonist resiniferatoxin. Indo-resiniferatoxin (Wahl et al., Mo / · Pharmacol., 59: 9, 2001) Although it is a nemol antagonist of VR1, it does not have properties suitable for oral medicine. This last point also applies to

A micromolecular peptoid antagonist as described by Garcia Martinez (Proc. Natl. Acad. Sci, USA, 99: 2374, 2002). The most recent International (PCT) Patent Publication No. WO 02/08221 has described a number of novel VR1 antagonists which are said to show efficacy in a variety of animal models. We describe a number of other novel VR1 modulators in this article. These modulators mainly include VR1 antagonists, but also cover VR1 partial antagonists and VR1 agonists. These compounds have been shown to be effective in animal pain models. Structurally related compounds have been disclosed in WO-A-03099284 (Amgen Inc.). However, it does not disclose the quinoline or isoquinoline moieties required for the present invention. In addition, preferred compounds of the present invention have improved pharmacokinetics, lower clearances and therefore improved half-lives. [Summary] The present invention provides a compound of formula I:

Y-J-NH-Z (I) where: Y is optionally selected from halogen, halogenated Cw alkyl, 97258.doc 200526196

Cl-4 alkyl, Ci-4 alkyloxy, halogenated Cl-4 alkyloxy, linyl and amine substituted quinoline or isoquinoline; J is selected from one or two independently selected as appropriate Halogen, haloCw alkyl, C 1-4 alkyl, C 3-5 alkyl, C 1 · 4 alkyl, _ substituted C 1-4 alkyl, sulfosyl, and amino substituents Amidin, crocodile, alpha biazine, pyrimidine or triazine; where J is replaced by NΗ and Υ at positions meta to each other; and Z is optionally selected from halogen, halogenated cN4 via one or two Alkyl group, Ci_4 alkyl group, Cw alkyl group, substituted CN4 alkyl group, phenyl group substituted by wall group and amino group. Pyridine; or a pharmaceutically acceptable salt thereof. In specific examples, Υ is optionally selected from halogen, iRCw alkyl, Cw alkyl, Ch alkoxy, _ (alkoxy, nitro, and amine groups) Substituted quinoline or isomaline; J is optionally selected from halogen, halo Cl 4 alkyl, C ^ 4 alkyl, Cw alkoxy, halo cN4 alkoxy, Nitro and amine substituted substituents, such as bipyramid, pyrimidine, or triazine; where J is substituted with Nh and γ at positions meta to each other; z is optionally substituted by one or two Independently selected from halogen, haloalkyl,

Cw alkyl, Cw alkoxy, phenyl substituted with a substituted alkoxy group, a nitro group, and an amino group or a sigma-to-stilbyl group; or a pharmaceutically acceptable salt thereof. Preferred substituents include fluorine and methyl. γ is most preferably quinoline, especially quinoline-7-yl. Υ is especially quinoline or isoquinoline. 97258.doc 200526196 Y special values include quinolin-8-yl, quinolin-7-yl, 3-methylquinolin-7-yl, quinolin-5-yl, quinolin-6-yl, 6-yl Fluoroquinolin-7-yl, 8-fluoroquinolin-7-yl, 6-trifluoromethylhalin-7-yl, 8-fluorohalin-7-yl, and isohalin-7-yl. J may be unsubstituted, mono-substituted or di-substituted by a substituent preferably selected from the group consisting of chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro and amine. To replace. J is preferably unsubstituted or mono-substituted with fluorine, methoxy, methyl, amine or nitro. J is preferably σσ, which may be substituted or unsubstituted. j 可 为。 j may be. Pyridine 'may be substituted or unsubstituted. A special embodiment of J is the mouth. Definite _2-yl, ° ratio β-Qin-2-yl, Qin-3-yl, pyrimidin-4-yl, pyrazin-4-yl, 1,3,5-triazin-2-yl, 5-methyl Oxypyrimidin-4-yl, 5-methylpyrimidin-4-yl, 5-fluoropyrimidin-4-yl, 2-methoxypyrimidin-4-yl, 2-methylpyrimidin-4-yl, 5-nitropyrimidin-4-yl and 5-aminopyrimidin-4-yl. For the avoidance of doubt, the aforementioned list indicates the location to which νη is connected. Z is preferably mono-substituted at the para position of the point where N is connected. Zeta can be replaced by F, CF3 or OCF3. The substituent is preferably CF3. Therefore, Z may be 2-trifluoromethyl. Defining a 5-base. Specific specific examples of Z include 4-trifluoromethylphenyl, trifluoromethyl ° specification 6-yl, and 2-trifluoromethyl. Defining a 5-base. Further specific examples include 4-trifluoromethoxyphenyl and 2-fluoro-4-trifluoromethylphenyl. Particularly preferred is a compound of formula I, wherein: γ is optionally selected from halogen, halogenated CN4 alkyl, 97258.doc 200526196 via one or two, as appropriate.

Ci-4 alkynyl, Cw alkoxy, halo Ci_4 alkoxy, wall and amine substituted quinoline or isoquinoline; j is optionally selected from halogen, halogen C i_4 alkyl, Ci_4 alkyl, C3-5 cycloalkyl, C! _4 alkyl, halo Cl-4 alkyl, pyrrolidine and amine substituted substituents; where J is to each other It is substituted with NH and Y at the position of meta position; and Z is a σpyridyl group substituted with CF3 or 0CF3 at least at the para position to the point connected to nh and further substituted with halogen, as appropriate; or its medicine Academically acceptable salt. As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, second butyl, and third butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy and third butoxy. "C3 · 7 cycloalkyl, examples of which are cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, and methylcyclopropyl. As used herein, the term" haloCl-6 alkyl "and, halo A C1-6 alkoxy group means a 010 alkyl group or a Cl 6 alkoxy group in which one or more (especially 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially II or chlorine atoms. Preferred is fluorine. Ci 6 alkyl and fluorinated alkoxy, especially fluorinated c1-3 alkyl and fluorinated Ci3 alkoxy 'such as CF3, CH2CH2F, CH2CHF2, CH2CF3, 0CF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most particularly Are cf3 and OCF3. As used herein, the term "halogen," or, "halo" means fluorine, chlorine, bromine 97258.doc 200526196, and iodine. The best dentin is fluorine and chlorine, especially fluorine. In the advanced aspect of the present invention, the compound of formula I can be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt. For use in medicine, the salt of the compound of formula Γ will be pharmaceutically acceptable Accepted! Raw salt. However, other salts may also be suitable for the preparation of the chemical compounds according to the invention or their pharmaceutically acceptable Non-toxic salts. Medically acceptable salts suitable for medical use of the compounds of the present invention include acid addition salts, solutions of the compounds according to the present invention and such as hydrochloric acid, butanil, etc.) , Succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, dishic acid, or sulfuric acid, a solution of a pharmaceutically acceptable acid is formed by mixing. Further: The salt is an acid addition salt formed from benzoic acid. The pharmaceutically acceptable and preferred salt of the compound of the present invention is benzoate. The hydrochloride can also be used. The salt of an amine group can also include a fourth salt, in which the amine nitrogen atom carries, for example, an alkyl group, an alkenyl group Suitable alkynyl or aryl group moieties. In addition, when the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include, for example, alkali metal salts (e.g., sodium or potassium salts) and alkaline earth A metal salt of a metal salt (such as a calcium or magnesium salt). 4th grade salts can be formed by the conventional method, for example, by dissolving a compound of formula I in free form with one or more equivalents of a suitable acid in D or " shell or in a solvent such as water ( The salt is formed by reaction in a vacuum or by freeze-drying), or by exchanging the anion of an existing salt with another anion on a suitable ion exchange resin. The Fan also includes the oxide of the above formula "dagger compound. -Generally, the N_oxides can be formed on any available nitrogen atom. These 97258.doc 200526196 allow the compound of formula I to be reacted with a solvate of persulfide and its salt, N-oxides can be formed by conventional methods, for example, potassium hydrogen acid is reacted in the presence of wet alumina. The invention includes within its scope compounds of formula j such as hydrates. The compounds according to the invention may have one or more asymmetric centers and may therefore exist as enantiomers and diastereomers. It is understood that all such isomers and mixtures thereof are encompassed by the present invention. In addition, type! The compounds may also exist in tautomeric forms and the present invention includes within its feedstock compounds and individual individual isomers. ▲ The present invention further provides a pharmaceutical composition comprising one or more compounds of formula 1 in association with a pharmaceutically acceptable carrier or excipient. The composition according to the present invention is preferably in the form of tablets, pills, capsules, W'sugar pills, I 11 parenteral solutions or suspensions, metered aerosols or fluids, sprays, ampoules, autoinjector devices, test agents , Cream or gel unit dosage forms are for oral, parenteral, intrathecal, intranasal, translingual, rectal or topical application, or by inhalation or insufflation. Oral compositions such as tablets, pills, or capsules are particularly suitable. For the preparation of solid compositions such as lozenges, the main active ingredient is combined with a peony carrier (for example, Powder, lactose, caramel, sorbose powder / shaw powder, stearic acid, magnesium stearate, dicalcium phosphate, or gelatin (injury), and its pharmaceutical diluent (such as water), To form a solid pre-withering composition comprising a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. The solid pre-formulation composition is then subdivided into unit dosage forms of the above type containing from 0.1 to about 500 mg of the active ingredient of the present invention. 97258.doc -12- 200526196 Advantageous unit dosage forms contain 1 to 500 mg (e.g., i, 5'M, 25, 100, 300, or 500 mg) of the active ingredient. The bond or pill of the Xinlai composition can be coated or otherwise compounded to provide a type that gives the advantage of prolonged action. For example, a pill or pill may contain an internal dose and an external dose component, the latter being in the form of a coating of the former. The two components can be separated by a casing, which is used to resist decomposition in the stomach and to allow the internal plants to pass through the duodenum intact or to delay release. A variety of materials can be used for such casings or coatings, and the materials include a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. : The novel compositions of the present invention can be added for oral administration or by injection. Liquid forms include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and flavored emulsions. In the treatment of painful conditions such as those listed below, a suitable dosage level is about 1.0 mg to 15 g per day, preferably about 50 mg M g per day, more preferably ^ about 5 mg to 500 mg per day 'particularly daily Call from 10 to 100. : Other compounds can be used up to 4 times a day. It should be understood that the amount of the compound of formula I required for any treatment will vary not only depending on the particular compound or composition, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, And ultimately will be treated according to the judgment of the attending physician. The invention further provides a compound of formula I as defined above or a pharmaceutically acceptable salt thereof for use in the treatment of a human or animal body. This treatment is preferably used for a condition that is sensitive to the second effect of VR1 receptor modulation (preferably antagonism). Oral therapy 97258.doc -13- 200526196 The compounds of the present invention will be suitable for the prevention or treatment of diseases and conditions in which pain and / or inflammation are present, including chronic and acute pain conditions. These conditions include: rheumatoid arthritis; osteoarthritis; postoperative pain; muscle-bone pain (especially after injury); spinal cord pain; myofascial pain Hou Jun f, headache, which includes migraine, acute Or chronic muscle tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain; ear pain; vulvomy pain; burns and especially primary hyperalgesia associated with it, ice and visceral pain, such as heart pain, muscle pain , Eye pain, oral and facial pain (such as toothache), abdominal pain, gynecological pain (such as dysmenorrhea, pain associated with cystitis and childbirth pain, chronic pelvic pain, chronic months) Pain associated with nerve and root injuries such as peripheral neurological disorders (eg, nerve compression and brachial plexus tears, resection, peripheral neuropathy, painful spasms, atypical facial pain, nerve root injuries, and spiders Omentitis) -related pain; itching disorders, including pruritus, pruritus due to blood dialysis, and contact dermatitis; For example, pain (and bronchoconstriction and inflammation) caused by ingestion, inhalation, or eye contact) of peppers and related irritants such as tear gas, hot pepper, or pepper spray; For example, diabetic neuropathy, neuropathy induced by chemotherapy, and postherpetic neuropathy, second pain 'non-painful' neuropathy; pain syndromes in complex regions; cancer-related pain 'is often called cancer pain; central nervous system pain, For example, pain in the spine or brain stem, lower back pain, sciatica and ankylosing spondylitis; gout; scar pain; large bowel irritability; inflammatory large bowel disease; urinary incontinence, which includes excessive detrusor defecation of the bladder and Bladder allergies; 97258.doc -14- 200526196 Respiratory diseases, including chronic luchi * and 驷 obstructive pulmonary disease (COPD), chronic bronchial fire, 1 ± fibrosis, asthma and including such as seasonal and perennial Island fire allergic rhinitis and non-allergic rhinitis rhinitis; autoimmune: disease, and immunodeficiency disorders. Cicada + Ping S conditions that can be treated or prevented by the compounds of the present invention include respiratory diseases such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, bloated fibrosis, asthma, and diseases such as seasonal and Perennial rhinitis excels in rhinitis and rhinitis and cough in non-allergic rhinitis. The compounds of the present invention are also suitable for treating camp depression. The pelvis can also be used to treat howls of gastroesophageal reflux disease, especially pain associated with gerd. Therefore, according to the "progressive aspect," the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of a physiological disorder that can be improved by modulating VR1 activity. The invention also provides a method for treating, treating or preventing a physiological disorder that can be improved by modulating VR1 activity, which method comprises administering to a patient in need thereof an effective amount of a compound of formula I or comprising a compound of formula Of the composition. According to a further aspect or alternative aspect 'the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of a disease or condition in which pain and / or inflammation dominates. According to a further alternative aspect, the present invention provides a formula composition for the manufacture of a medicament for the treatment or prevention of respiratory diseases such as cough. The present invention also provides a method for treating or preventing a disease or condition in which pain and / or inflammation predominates, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I or a composition comprising a compound of formula J. 97258.doc -15- 200526196 The present invention also provides a method for treating or preventing a respiratory disease such as cough, which method comprises administering to a patient in need thereof an effective amount of a compound of formula I or a composition comprising a compound of formula I . According to a further aspect of the invention, it may be desirable to treat any of the foregoing conditions in combination with a compound according to the invention and one or more other pharmacologically active agents suitable for treating that particular condition. Compounds of formula I and other (multiple) pharmacologically active agents can be administered to a patient simultaneously, sequentially or in combination. Thus, for example, to treat or prevent pain and / or inflammation, the compounds of the present invention may be used with painkillers such as acetaminophen (paracetamol), aspirin, and other NSAIDs, such painkillers include options COX-2 inhibitors as well as opioid analgesics (especially morphine bases), NR2B antagonists, bradykinin antagonists, anti-migraine agents such as oxcarbazepine and carbama Carbamazepine anticonvulsants, antidepressants (such as TCA, SSRI, SNRI, substance P antagonists, etc.), spinal block, gabapentin, pregabalin, and asthma treatment (such as epinephrine Receptor agonists or leukotriene D4 antagonists (eg, montelukast). Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, Nabumetone, ketoprofen, naproxen, piroxicam and sulindac, etodolac, meloxicam Selic (Celecoxib), etoricoxib, parecoxib, valdecoxib, and tilicoxib. Suitable for use with the compound 97258.doc -16-200526196 of the present invention in combination with opioid analgesia Medicines include morphine test, codeine, dihydrocodeine, diethyl morphine test, hydrocodone, hydromorphone, levorphanol, and Mokou oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, ginseng Meperidine, methadone, nalbuphine, propoxyphene, and pentazocine or their pharmaceutically acceptable salts. Suitable for use with the compounds of the present invention 倂Anti-migraine agents used include CGRP-antagonists, ergotamine or 5-HTi agonists, especially sumatriptan, naratriptan, levomatriptan ( zolmatriptan) or rizatriptan. Therefore, in a further aspect of the invention, the invention provides a pharmaceutical composition comprising a compound of the invention and an analgesic agent and at least one pharmaceutically acceptable carrier or excipient. In a further aspect or alternative aspect of the present invention, the present invention provides a product comprising a compound of the present invention and an analgesic, which are used as a combined preparation for simultaneous, independent or sequential use in the treatment or prevention of pain and / or Inflammation is the dominant disease or condition. Compounds of formula I can be prepared by reacting a compound of formula II with a compound of formula III:

Y-J-L1 H2N-Z (II) (III) wherein J, Y, and Z are as defined above and L1 is a leaving group such as gas. 97258.doc -17- 200526196 The reaction can be performed on bases such as tertiary sodium butoxide or sodium bicarbonate and 2- (diamidoamine) -2-biphenylpalladium (II) dinorbornylphosphine In the presence of a coupling agent of the complex, it is generally carried out by heating and refluxing in a solvent such as toluene or tetrahydrofuran for several hours to several days. Alternatively, the reaction may be in the presence of cesium carbonate, a coupling agent such as 4,5_bis (diphenylphosphino) -9,9-dimethyl (Koushan) (Kouxing), and a catalyst such as Pd / dba) 3 Generally, it can be carried out in a solvent such as anhydrous dioxane under reflux for several hours. The reaction can also be carried out in a solvent such as anhydrous dimethylformamide in the presence of a base such as diisopropylethylamine at 0 ° C to room temperature for about 2 hours. In an alternative process, a compound of formula I can be prepared by reacting a compound of formula IV with a compound of formula V: υ · β (οη) 2 lLj-nh-z (IV) (V) where J, L and z are as As defined above. This reaction can be performed under conditions suitable for a Suzuki coupling reaction (for review, see A Suzuki immediately, but 〆CAem. '1991, 63, 419_422), for example, such as tetrakis (triphenylphosphine) palladium (0), three (Dialkylene acetone) dipalladium (0), (1,1 bis (diphenylphosphino) ferrocene) digas palladium or dichloro (1,4 · bis (diphenylphosphino) butane) In the presence of a palladium catalyst, a chemical agent, in a suitable solvent such as an ether (for example: methoxyethyl or dioxane) or an aromatic hydrocarbon (for example, toluene), at high temperature and in a solution such as sodium carbonate or phosphoric acid This is done in the presence of a potassium base. The B (〇2) portion may be replaced by, for example, a 4,4,5,5-tetramethyl-l, 3,2-dioxo-2-yl moiety. II The conversion of methoxy groups to radicals is carried out by refluxing with an acid catalyst such as an aqueous hydrogenated hydrogen solution or a trimolyte fossil in a solvent such as dichloromethane (rising to reflux) for 97 days. 58258.doc -18- 200526196 And react for several hours, whereby the group can be introduced. The radical substituent is then allowed to react with trifluoromethanesulfonic anhydride in the presence of a base such as pyridine and a solvent such as monochloromethane at about room temperature, and then allowed to react with bis (pentamidine) diboron And a base such as potassium acetate is reacted at about 80 ° C for several hours in the presence of a solvent such as 1,4-dioxane and a coupling agent such as pd (dppf) cl2. When part of γ is quinoline, it can be obtained by combining aniline derivative with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum, s Acid is prepared by the reaction of female acetonitrile, followed by reaction with trimethyl orthoformate, which is generally refluxed for about three hours. The product is heated in high-boiling solvents of * D0wtherm A (g) for about one Hours to obtain quinoline_4 (1H) __. If a mixture of isomers is obtained, these isomers can be separated before or after quinoline aromatization. The reaction is achieved in about 1 hour at about 80t. The compound of formula II can be prepared by reacting a compound of formula IV with a compound of formula vnb. L ^ J-L1 (VI) where J and L1 are as defined above. The reaction It is also a coupling reaction. The compound of formula VI can be protected if necessary. For example, when J is pyrazine, the starting chlorinated qinone can be reacted with 3,4-dihydro-2H-piperan and p-toluenesulfonic acid The acid catalyst of the monohydrate is heated under reflux for about 60 hours and protected by the tetrahydropiperanyl group. After the Suzuki coupling, the protective group can be removed and phosphorous thoron can be used while heating The product was chlorinated at about 85.0 to give the resulting compound of formula 97258.doc -19-200526196 II. The compound of formula V can be used for the compounds of formula II and III above by using a compound of formula III and a compound of formula VI as described above. The compound of formula VI can be protected by reacting under the conditions of the reaction, and the further process for producing the compound of formula I involves reacting the compound of formula VII with the compound of formula VIII: yj-nh2 l2-z (VII) ( VIII) wherein J, Y and Z are as defined above and L2 is a leaving group such as bromine. These reaction conditions are those described above for the reaction of compounds of formulae II and III. Compounds of formula VII can be prepared by A compound of formula IV is prepared by reacting a compound of formula IX: l1-j-nh2 (IX) where L1 and J are as defined above for the Suzuki coupling reaction. The NH2 part of the compound of formula IX can be obtained by allowing the chlorine part In a solvent such as butanol, it is generally prepared by reacting under pressure at about 90 ° C. for about 2.5 hours. These compounds can be prepared by bringing a compound with two hydroxyl moieties and phosphorochlorine in a solution such as anhydrous toluene. Solvent (at near reflux) In the presence of test such as triethylamine for about one hour the reaction was prepared, when J is a pyrimidine, the compound may be a compound of formula X by making the compound of formula XI obtained by reacting:. 97258.doc -20- 200526196

NH

r21 \ A〇.r19 ⑻ R19 (XI) wherein R and R21 are optional substituents on j as defined above, and R is generally a C κ alkyl group. The reaction is generally carried out in a solvent such as ethanol in the presence of a strong test such as ethanol for several hours. Perone is usually introduced as the hydrochloride or acetate. Compounds of formula IX can be converted to other compounds of formula IX by standard methods. For example, a reducing agent such as 100/0 palladium charcoal is generally used in the presence of a > grains such as methanol and distillate > cereals in a hydrogen atmosphere for about two hours to convert the Schottky to amine group. In fact, these reactions can be performed with any starting material to introduce the desired substituent. For example, a methoxy group can be introduced into the J part by replacing sodium with sodium methoxide and methanol for about two hours under reflux. The chlorine portion can be removed by a reducing agent such as 10% of its charcoal in a hydrogen atmosphere in the presence of a solvent such as triethylamine and a solvent such as methanol over several hours. The end group can be converted to an amine group by reacting with diphenylphosphonium azide in the presence of a base such as triethylamine in a solvent such as toluene. The Curtius rearrangement of the resulting azide is by heating under reflux in a solvent such as toluene for about 1 hour, then reacting with 2-fluorenylpropanol in a solvent such as toluene for about five hours and then Acids such as trifluoroacetic acid are deprotected in > cereals such as digasmethane to produce the desired amine. If the synthesis of intermediates and starting materials is not described, the compounds 97258.doc -21-200526196 are commercially available or can be prepared from commercially available compounds by standard methods. During any of the above synthetic sequences, it may be necessary and / or necessary to protect sensitive or reactive groups on any of the molecules concerned. [Embodiments] The following examples are used to illustrate the preparation of compounds of the present invention. Description 1 2-Ga-4- (quinolin-8-yl) pyrimidine Add Pd (PPh3) 4 (334 mg '0.29 mmol) to 2,4-dichloropyrimidine (861 mg, 5.78 mmol), quinoline Boric acid (1.0 g, 5.78 mm) and a 2 M aqueous solution of sodium carbonate (2.89 ml, 5.78 mmol) in a mixture of toluene (50 ml) and ethanol (10 ml). The mixture was degassed three times and the separator was heated under reflux. The reaction mixture was cooled and diluted with EtoAc (50 ml), the bars were washed with water (2 x 100 ml), saturated NaCl (100 mi), dried over NajO4, filtered and evaporated. The residue was purified by silica dioxide column chromatography (eluent: 2% MeOH and 0.5% NH4OH in DCM) to give the title compound (650 mg, 46%) as a white solid. 4 NMR (500 MHz, CDC13) 7.49 (1 H, dd, J8.3 and 4.2), 7.69 (1 H, L /7.9 and 7.6) '7.98 (1 H, d, /8.1), 8.25 (1 H, dd, J8.3 and 1.5) '8.43 (1 H, d, J7.1)' 8.46 (1 H, d, J5.2), 8.69 (1 H, d /5.2), 8.97 (1 H, dd, "73.9 and 1.5). Description 2 2-Ga-6- (quinolin-8-yl) pyrazine was prepared from 2,6-dichloro ° ratio σ Qin according to the procedure of description 1 to obtain a white solid (1.2 g 86%). iH NMR (500 MHz, CDC13), 7.48 (1 h, dd, /8.3 and 4.2), 7.69 (1 H, t, /8.1 and 7.4), 7.95 (1 h, dd, J8.1 and 1.2), 8.24 (1 H, dd, J8.3 and 1.7), 8.27 (1 η, dd, ^ and 97258.doc -22- 200526196 1.5), 8.57 (1 H, s), 8.97 (1 H, dd, /4.2 and 2.0), 9.52 (1 H, s) o Description 3 4-Ga-6- (quinolin-8-yl) pyrimidine Pd (PPh3) 4 (334 mg, 0.29 mmol) Added to 4,6-diaziridine (1.72 g, 11.6 mmol), quinoline-8-boronic acid (1.0 g, 5.78 mm) and tripotassium phosphate (2.46 g, 11.6 mmol) in In a mixture of 1,4-dioxane (50 ml). The mixture was degassed three times and heated under reflux overnight. The reaction mixture was cooled and diluted with EtOAc (50 ml), washed with water (2 x 100 mi), saturated NaCl (100 ml), dried over Na 2 SO 4, transitioned and evaporated. The residue was purified by silica dioxide column chromatography (eluent: 2% MeOH + O.5% NEUOH in DCM) to give the title compound (200 mg, 14%) as a white solid). 4 NMR (500 MHz, CDC13) 7_50 (1 H, dd, /8.1 and 4 · 2), 7.71 (1 H, t, J7.8 and 7.6), 7.98 (1 H, dd, / 8 · 1 And 1.3), 8.26 (1 H, dd, J8.4 and 1.8), 8.41 (1 H, dd, /7.3 and 1.5), 8.56 (1 H, d, /1.0), 9.01 (1 H, dd , J4.2 and 2.0), 9.12 (1 H, d, several 0). Description 4 Quinoline-7-yl trifluoromethanesulfonate Trifluoromethanesulfonic anhydride (7.94 ml, 47.1 9 mmol) was added dropwise to 7-hydroxyquinoline (6.23 g, 42.9 mmol) and pyridine (4.51 ml, 55.77 mmol) in an ice-bath-cooled suspension in anhydrous digas methane (100 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was washed with water (250 ml), saturated NaCl (150 ml), dried over Na 2 SO 4, filtered and evaporated to give the title compound (11.3 g, 95%) as a beige solid. 4 NMR (400 Hz, CDC13) 7.47-7.51 (2 H, m), 7.93 (1 H, d, 97258.doc -23- 200526196 /9.0), 8.04 (1 H, d, /2.4), 8.22 (1 H, dd, "78.2 and 0.7), 9.00 (1 H, dd, J4.3 and 1.9) 〇 Description 5 7- (4,4,5,5_tetramethyl_1,3,2-dioxyboron埭 _2_yl) quinine Add Pd (dppf) Cl2 (860 mg, 0.94 mmol) to description 4 (8.7 g, 31.4 mmol), bis (pentamidine) diboron (8.8 g, 34.5 mmol) ) And potassium acetate (9.25 g, 94.2 mmol) in anhydrous 1,4-dioxane (150 ml)

in. The mixture was degassed twice and heated overnight at 80 ° C. The mixture was cooled and diluted with ethyl acetate (200 ml), washed with water (required to filter through celite), saturated NaCl, dried over NaJO4, filtered, and evaporated to give the title compound as a brown, oily product in Solidifies when standing. 1h NMR (400 MHz, CDC13) 1.39 (12 H, s), 7.42 (1 H, dd, /8.2 and 3.9), 7.79 (1 H, d, J7.8), 7.90 (1 H, d, J9.0), 8.15 (1H, dd, Jr8.6 & 1.2) '8.61 (lH, s), 8.90 (lH, dd, Jr4.3 & 2.0). Description 6 6-(Halin-7 -yl) pain bite-4 -amine prepared according to the procedure of description 1 from 4-amino-6-Qiming bite (w0-A-0245 6 5 2) and description 5 Light brown solid (600 mg, 38%). 4 NMR (400 MHz, DMSO-A) 7.01 (2 H, br s), 7.12 (1 H, d, several 0), 7.59 (1 H, dd, J8.2 and 4.2), 8.10 (1 H, d , J8.6), 8.21 (1 H, dd, /8.6 and 1.6), 8.42 (1 H, dd, J8.2 and 0.5), 8.53 (1 H, d, J0.7), 8.62 (1 H, s), 8.98 (1 H, d, 6). Description 7 4-Amino-6-gas-5-methoxypyrimidine: 4,6-dichloro-5-methoxypyrimidine (5.0 g, 27.9 mmol), 33% ammonia (30 ml), and 1-butane A mixture of alcohol (15 ml) was placed in a sealed tube. 〇 Heating for 2.5 hours. The mixture was allowed to cool and the precipitate was removed by filtration 97258.doc -24- 200526196 and dried to give the title compound (18 g, 40%) as a white solid. NMR (400 MHz, DMSO, 3.71 (3 H, s), 7.30 (2 H, br s), 7.96 (1 H, s)) Description 8 4-amino_6-gas-5_methyl Shout bite from 4,6-digas-5-methyl spray according to the procedure of description 7. Prepare a white solid (3.1 g, 70%). 4 NMR (400 MHz, DMSO-d6) 2.08 (3 H, s), 7.11 (2 H, br s), 8.06 (1 H, s). Description 9 5-methyl-6- (Halin-7-yl) mouth bite-4-amine according to the procedure of description 1 described by 8 and description 5 to obtain a beige solid (410 mg, 29%). NMR (400 MHz, CDC13) 2.22 (3 H, s), 5.09 (2 H, br s), 7.46 (1 H, dd, / 8.2 and 4 · 2), 7.79 (1 H, dd, /8.4 and 1.5), 7.94 (1 H, d, J8.4), 8.20_8 · 24 (2 H, m), 8.59 (1 H , S), 8.98 (1 H, d, /1.5). Description 10 4-Amino_6_gas-5-fluoropyrimidine According to the procedure of description 7, from 4,6-digas-5_fluoropyrimidine (DE- A-10014607) was prepared to give a white solid (5.8 g, 94%). 4 NMR (400 MHz, DMSO-d6) 7.69 (2 H, br s), 8.07 (1 H, s). Description 11 5-Fluoro- 6- (Quinolin-7 · yl) pyrimidin-4-amine was prepared from description 10 and description 5 according to the procedure of description 1 to obtain a beige solid (900 mg, 64%). 〇4 NMR (400 MHz, DMSO-d6) 7.47 (2 H, br s), 7.63 (1 H, dd, /8.2 and 4.2), 8.13 (1 H, d, /8.6), 8.19 (1 H, d, J8.6), 8.34 (1 H , D5 «72.3), 8.45 (1 H, d, /8.1), 8.59 (1 H, s), 9.00 (1 H, d, /1.4). Description 12 4-Amino-6-gas-2-methyl Oxygen, bite 97258.doc -25- 200526196 Sodium methoxide (12 nU, 25% by weight solution in methanol) was added to methanol (300 ml) and amidino-2,6-dichloropyrimidine (5.0 g, 30.5 mmol) was added to the αααααα. The resulting solution was heated under reflux for 2 hours and then burst to dryness. The residue was treated with water (250 ml) and the The formed precipitate was filtered and dried in vacuo to give the title product (3 g, 61%) as a white solid. NMR (400 MHz, CDCd 3 92 (3 h, s), 5.21 (2 H, br s), 6.14 (1Η, s). Description 13 2-Methoxy-6-quinolinyl) pyrimidine-cardiamine was prepared according to the procedure of description 1 from description 12 and description 5 to obtain an orange solid (1.15 mg, 65%). A NMR (400 MHz, DMSO-d6) 3.93 (3 H, s) '6.83 (1 H, s), 7.05 (2 H, br s), 7.59 (1 H, dd, /8.3, and 4.2), 8.09 (1 H, d, J8.6), 8.20 (1 H, dd, /8.6 and 1.7), 8.42 (1 H, d, /8.3), 8.63 (1 H, s), 8.98 (1 H, d , A few 6). Description 14 7-methoxy 3-methylquinoline adds 10% of palladium charcoal at the end of the spatula to 2-gas-7-methoxy-3-methylσ: [Organic Preparations and Procedures International (1990) '22 (5)' 579-88] (7.20 g, 34.7 mmol) and triethylamine (5 32

ml ' 38.17 mmol) in methanol was flushed the suspension with nitrogen and the resulting mixture was stirred in a hydrogen balloon overnight. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane (100 ml) and washed with water (150 ml), dried over Na2SO4, filtered and evaporated to give the title compound (6 g, 99%) as a light brown oil. iHNMROOO CDC13) 2.47 (3 H, s), 3.94 (3 H, s), 7.16 (1 H, dd, J8.9 and 2.5), 7.39 (1 H, d, J2.5), 7.61 (1 H, d, J8.9), 7.82 (1 H, t, 97258.doc -26- 200526196 J0.9), 8.68 (1 H, d, /2.2). Description 15 3-methylquinoline. Alcohol A mixture of 14 (6.0 g, 34.6 mmol) and 48% HBr in water (150 ml) will be heated under reflux for 5 days. The mixture was cooled and tested by careful addition of 33% ammonia. The obtained sink was removed by filtration, and the 'wash bar was washed with water and dried in vacuum to give the title compound (4.6 g' 84%) as a pink solid. 4 NMR (400 MHz, DMSO-d6) 2.41 (3 H, s), 7.13 (1 H, dd, / 8 · 8 and 2.4), 7.22 (1 H, d, /2.4) '' 7.71 (1 H, d, /8.8), 7.96 (1 H, t, / 0 · 7), 8.61 (1 H, d, J2.2), 10.01 (1H, s) 〇 Description 16 6 • Gas_5_nitro-N-μ- (tridecylmethyl) phenyl] Xanidine-4 • Amine Sodium bicarbonate (2.38 g, 28.38 mmol) and 4- (trifluoromethyl) aniline (3 24 ml '25.8 mmol) was added to a suspension of 4,6-dichloro-5-nitropyrimidine (5.00 g, 25.8 mmol) in anhydrous tetrahydrofuran (100 ml), and the resulting mixture was at room temperature Stir for 3 days. The mixture was filtered and the filtrate was evaporated. The residue was triturated with diethyl ether and the filtrate from the wet trituration was evaporated to give the title compound (3.2 g, 38%) as a yellow solid. NMR (400 MHz, CDC13) 7.70 (4 H, q, /9.0), 8.55 (1 H, s) '8.92 (1 H, s), 9.25 (1 H, br s). Description 17 4-Ga-6- (quinoline-5-yl) pyrimidine was prepared from 4,6-dichloropyridine and succinyl-5-mono-acid according to the procedure described in Putian 1, and a white solid was obtained. 4 NMR (400 MHz, CDC13) 7.49 (1 H, dd, /8.6 and 4 · 2), 7.69 (1 H, d, several 1), 7.76 (1 H, dd, /7.2 and h3) '7 83 (1 H, dd, /8.3 and 7.2), 8.28 (1 H, dd, /7.4 and 97258.doc -27- 200526196 1.0), 8.65 (1 H, dd, "77.2 and 0.8", 8.65 (1 H, dd, J4.2 and 1.9), 9.17 (1 H, d, "71 · 0) 〇Description 18 5 _ {[(4-fluoro-3-methoxyphenyl) amino Methylene oxide 2,2-dimethyl-1,3-dioxane-4,6-dione 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldem's acid) (22.5 g, 156 mmol) was added to a stirred solution of 4-fluoro-3-methoxyaniline (20 g, 142 mmol) in acetonitrile (200 ml), followed by the original Trimethyl formate (18.6 ml, 170 mmol). The mixture was heated to reflux for 3 hours. The cooled mixture was filtered to give the title compound (3.99 g, 74%). 4 NMR (400 MHz, CDC13) 1.76 (6 H, s), 3.94 (3 H, s), 6.76-6.83 (2 H, m), 7.14 (1 (, dd, /10.5, and 8.4), 8.56 (1 H, d, J14_4), 11.23 (1 H, d, J14.4). Description 19 6-Fluoro-7-methoxyquinolin-4 (1H) -one 4 parts of 18 (30.9 g ' 105 mmol) were added in portions to a boiling solution of Dowtherm A® (80 ml). After the addition was completed, heating was continued for 1 hour and the mixture was then cooled to room temperature. The mixture was poured into hexane (200 ml) and filtered. The filtrate was washed with more hexane to give a 2: 1 ratio mixture of the title compound and 6-fluoro-5-methoxyquinolin-4 (1 //)-one (22.6 g, 100%). Description 20 4-Gas-6-fluoro-7-methoxyquinoline will describe the suspension of the crude product of 19 (22.6 g, 117 mmol) in squall gas (110 ml, 1.1 8 mol) at 80 ° C was heated for 1 hour. The reaction mixture was allowed to cool and evaporate. The residue was neutralized with a saturated sodium bicarbonate solution, extracted with DCM (3x200 ml) and evaporated. The residue was purified by silica dioxide column chromatography (dissolution 97258.doc * 28-200526196 agent · 2% MeOH in DCM) to give the title compound (11 g, 44%). 1H NMR (400 MHz, CDC13) 4 0.05 (3 H, S), 7.40 (1 H, dd, /4.7 and 0.8), 7.53 (1 H, d, /8.2), 7. · 85 (1 H, d, / 11 · 7), 8.68 (1 H, dd, J4.7 and 0.8). Description 21 6-fluoro-7-methoxyquinoline Prepared from description 36 according to the procedure of description I4. lH Nmr (400 mhz, CDC13) 4.04 (3 H, s), 7.29-7 · 33 (1 H, m), 7.43 (1 H, d, /11.3), 7.52 (1 H, d, "78.2), 8.0 (1 H, dd, .2 and h6), 8.82 (1 H, dd, /4.3 and 1.2). Description 22 6-Fluoroquinolin-7-ol. Prepared from description 21 according to the procedure of 4th paragraph 15 to obtain a hetero-white solid (5.11 g, 60%). NMR (400 MHz, DMSO-d6) 7.37_7 · 41 (1 H, m), 7.44 (1 H, d, / 8 · 4), 7.78 (1 H, d, J11.9) , 8.29 (1 H, dd, t / 8.2 and 1.4) '8.78 (1 H, dd, J4.4 and 1.4), ΐ0.88-ΐι · 04h, br s) o Description 23 6- ( 6-fluoroquinolin-7-yl) pyrimidin-4-amine

Prepared by description 22 according to the procedures of description 4, 5, and 6, respectively. ipi NMR (400 MHz, DMSO-d6) 7.01 (1 H, s), 7.10 (2 h, s), 7.63 (1 Η, m), 7.94 (1 Η, d, J12.1), 8.40 ( 1 Η, d, J8.2), 8.53 (1 Η, d, /1.2), 8.63 (1 Η, d, J7.4), 8.96 (1 Η, dd, / 4 · 1, and 1.8 ). Description 24 2-Fluoro-3-methoxyaniline Diphenylphosphonium azide (20 · 9 ml, 96.8 mmol) was added to 2-fluoro-3-methoxyphenylbenzoic acid [Synlett (1991) , (10), 731-2] (15.0 g, 88 97258.doc -29- 200526196 mmol) and diethylamine (13.49 m, 96.8 mmol) in toluene (300 ml) and the resulting mixture was refluxed Heat for 1 hour. After this time, 2-methyl-2-propanol (12.5, e.g., 132 faces) was added and heating was continued for 5 hours. The mixture was cooled and evaporated and the residue was partitioned between water and methane. The dichloromethane layer was dried over Na2S04, filtered through a 1 inch plug of silica and evaporated. The residue was dissolved in digas methane (200 and difluoroacetic acid (25 ml) was added and the resulting mixture was stirred at room temperature. The mixture was evaporated and the residue was taken up in dichloromethane and saturated K2C 〇3, and the methane layer was dried over Na2S04, filtered, and evaporated. The residue was purified by silica column chromatography (eluent: 15% EtOAc in isohexane) to give a gray-yellow oil. The title compound (10.8 g, 87%). 4 NMR (400 MHz, CDC13) 3.72 (2 H, br s), 3.85 (3 H, s), 6.34-6.41 (2 H, m), 6.81 -6.86 (1 H, m). Description 25 8-methyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxoborofluoren-2-yl) quinoline respectively according to Describe the procedures of 18, 19, 20, 14, 15, 4, and 5, which were prepared from 3-methoxy-2 · methylaniline to obtain an orange oil. 4 NMR (400 MHz, CDC13) 1.40 (12 H, s) , 3.08 (3 H, s), 7.40 (1 H, dd, /8.2 and 3.9), 7.62 (1 H, d, /8.2), 7.85 (1 H, d, /8.2), 8 · 10 (1 H, dd, · 78 · 2 and 2.0), 8.96 (1 H, dd, J4.3 and 2.0). Description 26 5-Fluoro-6- (8-methylquinoline- 7-yl) pyrimidin-4-amine according to description 1 The procedure was prepared from descriptions 10 and 25 to give a white solid (300 mg, 26%). NMR (400 MHz, CDC13) 2.77 (3 H, d, J2.2), 5.26 (2 H, br s), 7.47 (1 H, dd, J8.2 and 4.3), 7.56 (1 H, d, J8.6), 7.77 (1 H, d, /8.6), 8.18 (1 H, dd, J8. 2 and 97258.doc -30- 200526196 2 · 〇) '8.50 (1 H, d, /2.4), 9.01 (1 H, dd, /4.3 and 2.0). Description 27 6 (8-fluoro Quinolin-7-yl) -5-methylpyrimidin-4-amine was prepared according to the procedures described in 1, 18, 19, 20, 14, 15, 15, 4, and 9 from description 24. 4 NMR (400 MHz, CDC13 ) 2.10 (3 H, d, J3.3), 5.02 (2 H, s), 7.56-7.52 (1 H, m) 8.26-8.24 (1 H, m), 8.60 (1 H, s), 9.03 (1 H, dd, J4.2 and 1.6). Description 28 5-methoxy-2-methylpyrimidine-4,6-diol will be cut into small pieces of sodium (7.00 g, 305.25 mmol ) Added to absolute ethanol (300 ml) in portions. Once all sodium has been dissolved, the mixture is cooled in an ice bath, and acetamidine hydrochloride (9.57 g, 10 · 75 mmol) is added and the mixture is stirred for 20 minutes. A solution of methoxydimethylmalonate (15.0 g, 92.5 mmol) in ethanol (50 ml) was added dropwise to the mixture, and once the addition was completed, the mixture was stirred at room temperature Overnight. The ethanol was removed by evaporation and the residue was dissolved in water. The mixture was acidified by adding concentrated hydrochloric acid, and the resulting precipitate was removed by filtration and dried in vacuo to give the title compound (8 g, 55%) as a white solid. NMR (400 MHz, DMSO. 2.19 (3 H, s), 3.59 (3 H, s), 11.70 (2 H, brs). Description 29 4,6-Digas-5-methoxy-2-methoxy Pyrimidine Add dropwise a solution of phosphatidine gas (10.5 ml, 112.6 mmol) in toluene (50 ml) to description 28 (7.99 g, 51.2 mmol) and triethylamine (7.14 ml, 51.2 mmol) in anhydrous toluene (100 ml) ) In a suspension (heated at 100 tt). After the addition is complete, the mixture is heated under reflux for one hour. The mixture is cooled in an ice bath and carefully added cold water (100 mi) to 97258.doc -31. 200526196. The organic layer was washed with saturated NaHC03, saturated NaCl and evaporated to dryness to yield the title compound (95 g, 96%). iH NMR (400 MHz, CDC13) 2.65 ( 3 H, s), 3.95 (3 H, S). Description 30 6_ (6-fluoroquinoline_7_yl) -5-methylpyrimidine · 4_amine According to the procedures described in descriptions 4, 5, and 6, respectively, described by 22 and Description 8. 4 NMR (400 MHz, DMSO 1.9.90 (3 H, d, 5), 5.75 (2 Η, s), 7.62 (1 H, dd, 8 · 4, and 4.0), 7.92 (1 H, d, / 10.4), 8.03 (1 H, d, J7.0), 8.34 (1H, s) 8.43 (1 H, d, J = 8.4 Hz), 8.94 (1 H, dd, /4.1 and 1.6). Description 31 5,6-Diazirimidine 4-amine was prepared from diethyl chloromalonate according to the procedures described in 28, 29 and 7 respectively. Preparation of esters and formazan acetate. 4 NMR (400 MHz, DMSO. 7.46 (1 H, br s), 7.91 (1 H, br s), 8.17 (1 H, s)). Description 32 5-Gas -6-quinolin-7-ylpyrimidin-4-amine was prepared according to the procedure of description 1 from description 3 1 and description 5 to obtain a hetero white solid (1.1 g, 61%). NMR (500 MHz, DMSOO 7.49 (2 H, br s), 7.62 (1 H, s), 7.90 (1 H, d, /7.4), 8.10 (1 H, d, /7.6), 8.35 (1 H, s), 8. · 45 (3 H, m), 8.98 (1 H, s). Example 1 6-quinolin-8-yl-N- [4-trifluoromethylphenyl] pyrazine-2-amine mg, 1.16 mmol), 4,5-bis (diphenylphosphino) _9,9-dimethyl (Koushan) (Kouxing) (29 mg, 0.05 mmol) and Pd2 (dba) 3 (15 mg, 0.017 mmol) was added to a mixture of description 2 (200 mg, 0.83 mmol) and 4-trifluoromethylaniline (0.14 ml, 0.83 mmol) in anhydrous i, 4-dioxane (15 ml) in. The mixture was degassed three times and heated at reflux 97258.doc -32- 200526196 overnight. The mixture was cooled, diluted with dichloromethane (10 ml), filtered through hyflo and the filtrate was directly loaded onto a silica gel chromatography column (eluent: 2% MeOH + O in DCM .5% NH40H). The product was further purified by mass-directed HPLC to give the title compound (20 mg '6.5%) as a white solid. ^ NMR (500 MHz, CDC13) 6.92 (1 H, br s) '7.49 (1 H, dd, J8.3 and 4.2), 7.56 (2 H, d, J8.6), 7.68 (2 H, d, J8.6), 7.71 (1 H, d, /7.6), 7.95 (1 H, dd, /8.3 and 1.3) '8.17 (1 H, dd, /7.4 and 1.5), 8.25-8.27 (2 H, m ), 8.95 (1 H, s), 9.00 (1 H, dd, / 4 · 2, and 1 · 7); m / z (ES +) 367 (M + H +). The following compounds were prepared by the procedure of Example 1. Example 2 6-Quilin_8-yl-N_ [4-Sfluoromethylphenyl] bite_4_amine Prepared from descriptions 3 and 4-trifluoromethylaniline to give a white solid (6 mg, 4%). NMR (500 MHz, CDC13) 7.47 (1 η, dd, 3 and 4 · 2) '7.56 (2 H, d, / 8 · 8), 7.62 (2 H, d, "78.8), 7.71 (1 H, t, J7.9 and 7.6), 7.78 (1 H, s), 7.82 (1 H, s), 7.94 (1 H, dd, J8.3 and 1.3), 8.26 (1 H, dd, /8.3 and 1.5), 8 32 (i H, dd, 4 and 1.3), 8.87 (1 H, s), 8.94 (1 H, dd, where 2 and 17); m / z (ES +) 367 (M + H +). Example 3 6-quinolin-7-yl-N- [5-trifluoromethylpyridinyl] pyrimidin-4-amine was prepared from description 6 and 2-bromo-5-trifluoromethylpyridine to give a white solid . 〇〇mg ^ 60〇 / 〇) NMR (500 MHz, CDC13) 7.48 (1 H5 dd? J8.3 and 4.2), 7.73 (1 H, d, J8.8), 7.79 (1 H, br s) , 7.90 (1 H, dd, /8.M2.2), 7.97 (1H, d, J8.6), 8 23 (iH, d, j77), 97258.doc -33- 200526196 8.31 (1 H, s), 8.36 (1 H, dd, /8.5 and 17), 8 0 · 80 (1 H, s), 9.00 (1 H, s), 9 · (Μ nus ) 'm / z, H, d, J1.7); (ES +) 368 (M + H +) 〇 Example 4 5 -Fluoro-6-sullen-7 · yl_N- [4_trifluoromethylbenzene Based on the preparation of 11 and 4-trifluoromethyl bromobenzene to give a white bite 4-amine solid (I94mg, 61%). 4 NMR (400 MHz, CDC13) 7.27 (1 η ri, α, · 1), 7 49 (1 Η, dd, J8.2 and 4 · 3), 7.66 (2 Η, d, J8.6), 7 9〇 (2 η \ 16), 7.98 (1 Η, d, /8.6), 8.23 (1 η, d, /8.2), 8 29 (1, ^ d, / 8 · 6), 8.70 (1 Η, d, Ji 6), 8.83 (1 η, s), 9.00 (ι η dd /4.3 and 1.6); m / z (ES +) 385 (M + Η +) 〇 Example 5 2- Methoxy-6-quinolin-7-yl [4-trifluoromethylphenyl] pyrimidin-4_amine was prepared from description 13 and 4-trifluoromethylbromobenzene to give a hetero-white solid (130 mg, 41%). 4 NMR (400 MHz, CDC13) 4_11 (3 H, s), 7.00 (1 H, s), 7.38 (1 H, br s), 7.45 (1 H, dd, "78.2 and 4.3), 7.64 (4 H , S), 7.90 (1 H, d, /8.6), 8.19 (1 H, d, /7.4), 8.27 (1 H, dd, /8.6 and 1.6), 8.69 (1 H, s), 8.96 (1 H, dd, J4.3 and 2.0); m / z (ES +) 397 (M + H +). Example 6 6-Quinolin-5-yl-N- [4-trifluoromethylphenyl] pyrimidin-4-amine Prepared as described in 17 and 4-trifluoromethylaniline to give a white solid. NMR (400 MHz, DMSO-A) 7.16 (1 H, d, /1.2), 7.59 (1 H, dd, J4.2 and 8.8), 7.72 (2 H, d, J8.8), 7.83 (1 H, dd, J7.1 and 1.2), 7.88-7.91 (1 H, m), 8.01 (2 H, d, /8.6), 8.17 (1 H, d, /8.3), 8.69 (1H, d /8.6), 8.90 (1 H, d, 2), 8.98 (1 H, dd, J3.9 and 1.7), 10 · 20 (1 H, s); m / z (ES +) 97258. doc -34- 200526196 367 (M + H +). Example 7 6- (6-fluoroquinolin-7-yl) -N- [4-trifluoromethylphenyl] pyrimidin-4 · amine was prepared from description 23 and 4-trifluoromethylbromobenzene to give a white solid (28 mg, 430 / ^ 4 ^ 11 (400 1 ^ 1 ^ 0 ^ 1800 7.49 (115), 7.63-7 · 67 (1 H, m), 7.72 (2 H, d, · 78.4), 8.01 (3 H, m), 8.44 (1 H, dd, J8.4 and 1.1), 8.75 (1 H, d, "77.4), 8.91 (1 H, d, Jl.l), 8.99 (1 H , Dd, /4.2 and 1.8), 10.25 (1 H, s); m / z (ES +) 385 (M + H +). Example 8 5-nitro-6-quinolin-7-yl_N- [4 · Trifluoromethylphenyl] pyrimidine_4 · amine

Add 2 M sodium carbonate (3.15 ml, 6.3 mmol) and Pd (PPh3) 4 (364 mg, 0.315 mmol) to description 16 (2.01 g, 6.3 mmol) and description 5 (2.41 g, 9.45 mmol) in toluene (50 ml) and ethanol (10 ml) in a mixture. The mixture was degassed three times and heated under reflux overnight. The cooled mixture was diluted with EtOAc (100 ml) and washed with water (200 ml), saturated NaCl (100 ml), dried over Na2SO4, filtered and evaporated. The residue was purified by silica column chromatography (eluent: 1% MeOH + 0.5% NH3 in DCM), and then by a second column (eluent · 20% EtOAc in isohexane) Perform purification. The product was triturated with diethyl ether to give the title compound (100 mg, 4%) as a gray-yellow solid. 4 NMR (500 MHz, CDC13) 7.50 (1 H, dd, "78.3 and 4.2", 7.70 (2 H, d, /8.1), 7.72 (1 H, dd, / 8 · 6 and 1.7), 7 81 (2 H, d, J8.1), 7.95 (1 H, d, J8.6), 8.24 (1 H, d, /7.6), 8.36 (1 H, s), 8.87 (1 H , S), 9.00 (1 H, dd, J4.2 and 1.7); m / z (ES +) 412 (M + H +). Examples 9-13 were prepared from the indicated compounds according to the procedure of Example 2. 97258.doc -35- 200526196 Example 9 6- (8-fluoroquinolin-7-yl) -5-methyl-N_ [5-trifluoromethylpyridin-2-yl] pyrimidine-4-amine Description 27 and 2-Bromo-5-trifluoromethylpyridine produced a solid (171 mg, 72%). NMR (400 MHz, DMSO 02 · 23 (3 H, d, /2.2), 7.68 (1 H, dd, /8.4 and 6.5), 7.73 (1 H, dd, "78.4 and 4.2), 7.97 (1 H, d, /8.5), 8.19 (1 H, dd, /9.0 and 2.4), 8.39 (1 H, d, J8.8), 8_54 (1 H, d, /8.4), 8_73 (1 H, s), 8.81 (1 H, s), 9.04 (1 H, dd, where 2 and 1.6), 9.66 (1 H, s); m / z (ES +) 400 (M + H +). Example 10 5-methyl-6-quinolin-7-yl-N- [5-trifluoromethylpyridin-2-yl] pyrimidine 4-amine description 9 and 2-> -5-Trifluoromethylamidine ratio σ gave a white solid (180 mg, 55%). Tun NMR (500 MHz, CDC13) 2.43 (3 H, s), 7.48 (1 H, dd, "78.3 and 4 · 2), 7.66 (1 H, s), 7.80 (1 H, dd, / 8, 4 and 1.5), 7.97 (2 H, d, /8.5), 8.23 (2H, m ), 8.56 (1 H, s), 8.80 (1 H, d, J8.8), 8.87 (1 H, s), 9.00 (1 H, dd, J4.2 and 1.5); m / z (ES +) 382 (M + H +). Example 11 6_ (6_fluoroquinolin-7-yl) _5-methyl-N_ [5_trifluoromethylpyridin-2_yl] pyrimidin-4_amine Description 30 and 2- The 5-trifluorofluorenyl group formed a solid (5 mg, 3%). NMR (500 MHz, DMSO 02 · 22 (3 H, s), 7 66 (1 H, dd, J8.4 and 4.2), 7.99 (1 H, d, / 10.3), 8.13 (1 H, d, J7.0), 8.19 (1 H, d , /8.9), 8.38 (1 H, d, "78.9), 8.46 (1 H, d, J8.2), 8.73 (1 H, s), 8.80 (1 H, s), 8.97 (1 H, d , J2.8), 8.97 (1 97258.doc -36- 200526196 H, d, J2.8), 9.66 (1 H, s); m / z (ES +) 400 (M + H +). Example 12 5-fluoro-6- (8-methylquinolin_7_yl) -N- [5-trifluoromethylpyridin-2-yl] pyrimidin-4-amine description 26 and 2-bromo-5-trifluoro Methylpyridine yielded a white solid (40 mg, 41%). 4 NMR (500 MHz, CDC13) 2.80 (3 H, s), 7.26 (1 H, s), 7.49 (1 H, dd, J8.3 and 4 · 2), 7.58 (1 H, /8.6), 7.80 (1 H, d, Γ8 · 6), 8_00 (1 H, /8.6), 8.07 (1 H, s), 8.19 (1 H , • / 7.6), 8.59 (1 H, s), 8.78 (2 H, t, J4.5 and 3.9), 9.02 (1 H, d, /2.7); m / z (ES +) 400 (M + H +). Example 13 5-Ga-6-quinolin-7-yl-N- [4-trifluoromethylphenyl] pyrimidin-4-amine Description 32 and 4-trifluoromethylbromobenzene gave a white solid (180 mg , 57%). 4 NMR (400 MHz, DMSO-A) 7.65 (1 H, t, / 3 · 7), 7.74 (2 Η, d, J7.9), 7.94 (1 Η, d, /8.2 ), 8.01 (2 Η, d5 J7.9), 8.13 (1 Η, d, "78 · 2), 8.41 (1 Η, s), 8.47 (1 Η, d, • 78.0), 8.72 (1 Η, s), 9.01 (1 Η, s), 9.58 (1 Η, s); m / z (ES +) 401 (M + Η +) Example 14 Phenyl acid 7_ (5-methyl-6_ {[5_Trifluoromethyl〇 比 唆 -2-yl] amino} Pyrimidin-4-yl) quinoline hydrazone Add Benzolite (1_05 equivalent, 4.3 g, 27.2 mmol) to the example at 40C 10 in DMF (40 ml). Isopropyl acetate (10 ml) was added to the solution, and then it was inoculated with the product (10 mg). The solution was aged for 30 minutes, and then more isopropyl acetate (70 ml) was added over 1 to 2 hours, keeping the internal temperature at about 40 ° C. After the addition, the batch was cooled to 20-25 ° C, aged for 2 hours, and then filtered. The obtained filter cake was washed with isopropyl acetate 97258.doc -37- 200526196 (10 ml) and then dried to give the title compound (13.4 g, 95%). NMR (400 MHz, DMSO-d6): 510.07 (1H, br s), 9.26 (1H, dd, J-4.8, 1.5 Hz) '8.94 (1H, d, J = 8.2 Hz), 8.90 (1H , S), 8.79 (1H, m), 8.38 (1H, d, J = 8.6 Hz), 8.36 (1H, m), 8.32 (1H, d, J = 8.8 Hz), 8.25 ( 1H, dd, J = 8.9, 2.4 Hz), 8.02 (1H, dd, J = 8.5, 1.6 Hz), 7.97 (ih, dd, J = 8.4, 4.8 Hz), 7.64-7.58 (2 H, om ), 7.35-7.26 (3H, om), 2.37 (3H, s); m / z (ES +) 382 (M + H +). The following compounds were prepared according to the procedure described in Example 14. Example only ~~ 15 benzenesulfonic acid 7- (2-cyclopropylfluoromethylpyridin-2-yl] amino} pyrimidin-4-yl) quinone monohydrate alley 16 Benshi Yin, acid 7- (2- ¾Propyl-5 ^^^--Methyl] amino} pyrimidin-4-yl) UU 1 mouse T 丞 ben 17 benzenesulfonic acid 7- (5-isopropyl 2 & q amino} pyrimidine -4-yl) quinoline T group than fluoren-2-yl] 18 benzenesulfonic acid 6-fluoro-7- (5-methyl-yl] amino} pyrimidin-4-yl) quinoline -2- 19 Benzenesulfonic acid 6-fluoro_7- (5-methyl} pyrimidin-4-yl) quinoline hydrazine a messy methyl group] yue female 20 benzene Si 7- (5- It -6- { [5-ΓξΓΪ ~ ^^ Ϊ 一 Γ ---- yl} pyrimidin-4-yl) -8-methylquinolylpyridin-2-yl] amine '------- 97258.doc 38-

Claims (1)

200526196 10. Scope of patent application: 1. A compound of formula I: YJ-NH-Z (I) where: Y is optionally selected from halogen, halogenated CN4 alkyl, Cu4 alkyl, CN4 alkyl via one or two, as appropriate. Quinoline or isoquinoline substituted with substituents of oxy, haloCw alkoxy, nitro and amine; j is optionally selected from one or two halogen, halo C 1-4 alkyl, Cw alkyl, C3-5 cycloalkyl, CU4 alkoxy, halo cN4 alkoxy, nitro and amine substituents. Ratio σ fixed, σ 荅 比, σ specific olfactory, sigma σ fixed or triazine; where J is replaced by NΗ and Υ at positions meta to each other; and ζ is optionally selected from halogen through one or two independently , A halogen-substituted Ci-4 alkyl group, a Cw alkyl group, a Cl · 4 alkoxy group, a halogenated Ci4 alkoxy group, a nitro group, and a phenyl group substituted with an amino group. Pyridine; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim 1, wherein γ is lindene or isoxanline optionally substituted with fluorine or methyl. 3. A compound as claimed in claim 1 or 2, in which j is pyrimidine, optionally substituted with fluorine, methoxy, methyl, amine or nitro. 4. A compound as described above, 2 or 3, wherein ζ is substituted with a trifluoromethyl group at a position para to the point of attachment. 5_ — compounds, which are: 97258.doc 200526196 4-Halin-8-yl-N- [4-difluoromethylphenyl] sigmadin-2-amine '6-waline-8-yl- N_ [4-Diaminomethylphenyl] 11 is amine-2-amine, 5-Halene-8-yl-N- [4-diaminomethylphenyl]. answer. Qin-3-amine, 6-xylene-8-yl-N- [4-difluoromethylphenyl] ° dense. Amine-4-amine '6-quinolin-7-yl-N- [4-trifluoromethylphenyl]. Biazine-2-amine, 4-quinolin-7-yl-N- [4-trifluoromethylphenyl] pyrimidin-2-amine, 6-waline-7-yl-N- [4-digas Methylphenyl] σ · σ din-4-amine '5 -Xining-7-yl-N- [4-Dimethylmethylphenyl] tower 17 Qin-3-amine' 6 -Xuanlin-7- -N- [5-Di-Mercaptomethyl ° Specific Bitumen-2-yl] Mouth-Bite-Cardioamine '6_ 喧 琳 -7-yl-N- [6_-Mercaptomethyldegree Ratio ° -3 -Yl] ° sigma-4-amine '5-methoxy-6-quinolin-7-yl-N- [4-trifluoromethylphenyl] pyrimidin-4-amine, 5-methyl- 6-quinolin-7-yl-N- [4-trifluorofluorenylbenzyl] pyrimidin-4-amine, 5-fluoro-6-quinolin-7-yl-N · [4-trifluoromethylbenzene Yl] pyrimidin-4-amine, 2-methoxy-6-khalin-7-yl-N- [4-dioxanylphenyl] amidin-4-amine '2-methyl-6-quinoline -7-yl-N- [4-trifluoromethylphenyl] pyrimidin-4-amine, 6- (3-methylquinolin-7-yl) -N- [4-trifluoromethylphenyl] Pyrimidin-4-amine, 6-quinolin-5-yl_N- [4-trifluoromethylphenyl] pyrimidin-4-amine, 6-quinolin-6-yl-N- [4-difluoromethyl Phenylphenyl] ^-4-4-amine '6- (2-fluorenylquinolin-7-yl) -N- [4-trifluoromethylphenyl] pyrimidin-4-amine, 6- (6- Fluoroquinolin-7-yl) -N- [4-trifluoromethylphenyl] pyrimidin-4-amine, 6- (8- Quinoline-7-yl) -N- [4-trifluoromethylphenyl] pyrimidin-4-amine, Ν- [4- (trifluoromethyl) phenyl] -6_ [6 · trifluoromethylquine 7-yl] pyrimidin-4-amine, 6- (8-methylquinolin-7-yl) -N- [4-trifluoromethylphenyl] pyrimidin-4-amine, 97258.doc -2 -200526196 5-Fluoro-6- (8-fluorenylquinoline-7-yl) -N- [4-trifluoromethylphenyl] pyrimidin-4-amine, 6-isopropane-7-yl-N -[4-Difluoromethylphenyl]. Dsigidine-4-amine '6-quinolin-8-yl-N- [4-trifluoromethylphenyl] pyrazine-4-amine, 4-quinolin-8-yl-N- [4- Trifluoromethylphenyl] -1,3,5-triazin-2-amine, 5-stioketyl-6-waline-7-yl-N- [4-difluoromethylphenyl]. Midolidine-4 -amine '6-amidine-7-yl-1 ^ 4- [4-diaminomethylphenyl] midylamine-4,5-diamine, and its pharmaceutically acceptable Of salt. 6. A compound, which is: 6- (8-fluoroquinolin-7-yl) -5-fluorenyltrifluoromethylarmidin-2-yl] pyrimidin-4-amine, 6- (8-fluoro Quinolin-7-yl) -5-fluorenyl-#-[4-trifluoromethylphenyl] pyrimidin-4-amine, 5-methoxy-2-methyl-6-quinolin-7-yl -"-[4-trifluoromethylphenyl] pyrimidin-4-amine, 2-methyl-6- (8-methylsulfin-7-yl) -iV- [4-digasmethylbenzene Yl] glutidine-4 amine, 7V- [2-Ga-4-digasmethylphenyl] -5 -methyllactyl-6-σ quelin-7-yl ^ dense lake-dou-amine, 5-methoxy-6-sullen-7-yl-iV- [4-difluoromethyllactylphenyl] ^. Amidinylamine, 5-methyl-6- (8-methylhalene-7-yl) -A / "-[4-Diaminofluorenylphenyl] ^ dense. Amine-4_amine, 5-methyl-6- (8-methylquinolin-7-yl) -N- [5-trifluoromethylpyridin-2-yl] pyrimine 97258.doc 200526196 pyridin-4-amine , 6-quinolin-7-yl-5-trifluoromethyltrifluoromethylphenyl] pyrimidin-4-amine, 5-ethyl-6-11 quinine-7-yl-TV- [4-di Gas methylphenyl] ^ dense. Amine-4 -amine '5-ethyl-6-quinolin-7-yl-# _ [5-trifluoromethylpyridin-2-yl] pyrimidin-4-amine, 5-methyl-6-quinoline -7-yl-, [5-trifluoromethylpyridin-2-yl] pyrimidin-4-amine, 2-bad-propyl-5 -methyl-6-sullen-7 · yl · Λ ^ _ [5 _Difluoromethyl ° ratio 定 -2 -yl] pyrimidin-4-amine, 2-propyl propyl-5-fluorenyl-6-oxolin-7 -yl-iV- [4-diaziridinyl Phenyl] ^ dense. _ 4-amine, 5-isopropyl-6-quinolin-7-yl-#-[5-trifluoromethylpyridin-2-yl] pyrimidin-4-amine, 6- (6-fluoroquinoline -7-yl) -5-methyl-#-[5-trifluoromethylpyridin-2-yl] pyrimidin-4-amine, 6- (6-fluoroquinolin-7-yl) -5-methyl -7V- [4-trifluoromethylphenyl] pyrimidin-4-amine, 5-Ga-6- (8-fluorenylsalin-7-yl) -iV- [5 -Digasmethyl 0 ratio σ Definite -2 -yl] ° Mididin-4-amine, 7V- (2-Halene-7 -yl ° than fluorene -4 -yl)-5 -difluoromethyl. Titanium-2 -Amine '2 -Anoline-7-yl_N- [4-Diaminomethylphenyl] ^ bita-cardiamine' 5 -Aka-6-Halyin-7-yl-7V -[4-Diaziridinylphenyl]. D7-7A-4-amine '5 -Ga-6-Xuanlin-7-yl-7V- [5 -Difluoromethyl 0 ratio ° -2 -yl]. Midodine-4 -amine, 97258.doc -4- 200526196 and its pharmaceutically acceptable salts. 7. A pharmaceutically acceptable salt, which is: benzathionic acid 7-5 -methyl-dioxane, LU (monomethyl) pyridin-2-yl] amino} pyrimidine_ 4- Base) waline mine, benzyl flavonic acid 7- (2-cyclopropyl · 5-methyl_6 _ {"5 zhi r 丞 〇 5- (dimuryl) pyridine_2_yl] amine group" Yt-4-yl) oxalanine; benzoic acid 7- (2-cyclopropyl-5-methyl-6- (Γ4 r -dioxanyl) phenyl] amino} pyrimidin-4-yl ) Quinolinium hydrazone; Benzoite flavonic acid 7- (5-isopropyl-6-{[* 5 彳 Dimethylformamidine,! _ U (monomuryl) ° pyridin-2-yl] amino} Pyrimidin-4-yl) quinine rust; 6-fluoro-7- (5-methyl-6-benzite flavonic acid) {[5- (dichloro ψ its, I + U 1 mono-T group) pyridine-2 -Yl] amino} pyrimidin-4-yl) quinoline rust; benzathionate 6-fluoro-7- (5-fluorenyl_6-iU f ϋ 田 #, 丞 6 {[4- (二 鼠 甲Base) stupid] amine group} bite _ 4-yl) sullen 镔. 8.-A pharmaceutical composition 'comprising as described in any one of claims! To 6: or a pharmaceutically acceptable Salt, or salt as claimed in claim 7, and: a pharmaceutically acceptable carrier. — 9 · The compound is called a compound of any one of claims 1 to 6. Or a pharmaceutically acceptable salt thereof, or a salt as claimed in claim 7, which is a method for treating a human = an animal body by therapy. / 10. -A compound such as item # in claim 或 or Its pharmacologically-acceptable salt, or the salt as claimed in claim 7, for use in the manufacture of a medicament for the treatment of pain, pulmonary obstructive pulmonary disease, depression or gastro-oesophageal reflux disease 0 97258.doc 200526196 7 1. Designated representative map (1) The designated representative map in this case is: (none) (2) The component symbols of this representative map are briefly explained: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: YJ- NH-Z (I) 97258.doc