TW200535136A - 4-oxo-1-(3-substituted) phenyl-1,4-dihydro-1,8-naphthyridine-3-carboxamide phosphodiesterase-4 inhibitors - Google Patents

Abstract

Compounds represented by Formula (I): or a pharmaceutically acceptable salt thereof, are phosphodiesterrase 4 inhibitois useful in the treatment of asthma and inflammation and useful for the enhancement of cognition.

Description

200535136 Rose, description of the invention: [Technical field to which the invention belongs] The present invention relates to 4-oxo-1- (3-substitutedphenyl) -1,4-dihydro-1,8-naphthyridine-3-fluorene Amines, which are used as inhibitors of tandem esterase-4. [Prior art] Hormones are compounds that affect cell viability in various ways. In many perspectives, 'hormones act as messengers to elicit specific cellular responses and activities. However, many hormone-produced results are not just caused by a single hormone effect. The hormone is first bound to the receptor, thereby causing the release of a second compound, which in turn affects cell viability. In this case, the hormone is known as the first courier. Cyclic adenosine monophosphate (adenosine 3,5, _cyclic monophosphate, "cAMP" or "cyclic AMP") is the second messenger of hormones, which include epinephrine, pancreatic height Glucagon, Calcitonin, Corticotrophin, Hpotropin, Lutein Hormone, Epinephrine, Parathyroid Hormone, Thyroid Stimulating Hormone and Vasopressm. Therefore, cAMp Regulates the cell's response to hormones. Cyclic AMP also regulates the cell's response to different nerve transmitters. Phosphodiesterase (" PDE ") is metabolized to 3, 5, and cyclic nucleotides become 5, nucleotide single A family of enzymes of phosphate esters, thus terminating the activity of the second messenger of cAMp. A special phosphodiesterase · phosphodiesterase-4 (,, pDE4 ", also known as "PDE-IV"), which For high affinity, specific cAMp ιν 卩 ^^ classes, interest has emerged as a potential target for the development of novel anti-asthmatic and anti-inflammatory compounds. PDE4 is known to have at least four heteroenzymes, each with a different gene Coding. Four known PDE4 gene products were phased out The letter plays a different role in anti-allergy and / or inflammation anti-92545.doc 200535136. Yin Biji believes in the inhibition of pDE4, especially the production. The specific PDE4 isoform that produces harmful reactions can beneficially affect the symptoms of allergies and inflammation It is desirable to provide novel compounds and compositions that inhibit PDE4 activity. · The main concern with the use of PDE4 inhibitors is the side effects of vomiting, which has been reported in several years:

Observed on several candidate compounds, as described by c. Bernouf et al. (, Berner J. Fu ") in Ann. Rep. In Med. Chem., Red: 91-109 (1998) Hughes et al. In Br. L Pharmac01, 118: 1 183-1 191 (1996); MJ Perry et al. In Cell Bi〇chem #

Biophym: 113-132 (1998); SB Christensen et al. In J. Med. Chem., Il: 821-835 (1998); and Bernaford describe the unwanted side effects shown by different compounds Of a wide range of types. For example, MD · Houslay et al. In Adv · Iri Pharmac01, Division: 225-342 (1998) and D · Spina et al. In Adv. In Pharmacol., Ϋ: 33-89 (1998) described a great interest in and research on therapeutic pOE4 inhibitors. The international patent publication W09422852 describes Humira as a PDE4 inhibitor. International Patent Publication W09907704 describes a 1-aryl-1,8-naphthalene sigmadine derivative as a PDE4 inhibitor. «* Α.Η. Cook et al. In J. Chem. Soc., 413-417 (1943) describe _-pyridine quinoline. Among them, quinoline compounds are described in Kei Manabe et al. In J. Org · Chem ·, 58 (24): 6692-6700 (1993); Kei Manabe et al. In J · Am. Chem. Soc., 115Π2): 5324-5325 (1993); and K. Manabe et al. In J. Am. C hem. So c., 92545 doc 200535136 114 (17): 6940-6941 (1992). Compounds of the ring-forming system have been described by various researchers as effective for a variety of treatments and uses. For example: International Patent Publication No. WO 98/25883 describes the basic ketone donkey amines as caipain inhibitors. Is the European patent publication ugly? 811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describe substituted sodium betelate tunnel blockers, and U.S. Pat. Nos. 5,7 3,627 and 7 describe ring systems for use as photosensitive compositions.

U.S. Patent Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,8 59,03_4, 5,866,593, 5,891,896 and International Patent Publication WO 95/35283 describe PDE4 inhibitors , Which is a tri-substituted aryl or heteroarylphenyl derivative. U.S. Patent No. 5,5 80,888 describes a PDE4 inhibitor, which is a styrene derivative. U.S. Patent No. 5,550.0,137 describes a PDE4 inhibitor, which is a phenylaminoweilyl derivative. U.S. Patent No. 5,34,0,827 describes an inhibitor, which is a phenylcarboxamide compound. U.S. Patent No. 5,78,0,478 describes a PDE4 inhibitor ' which is a tetra-substituted phenyl derivative. International patent publication WO 96/002 15 describes substituted derivatives as pDE4 inhibitors. U.S. Patent No. 5,633,257 describes PDE4 inhibitors, which are cyclic (alkyl and alkenyl) phenyl-alkenyl (aryl and heteroaryl) compounds. However, there remains a need for novel compounds and compositions that therapeutically inhibit pDE4 with minimal side effects. [Summary of the Invention] The present invention relates to a bisaryl substituted -1,8-naphthyridine-4 (1H) -one represented by formula ⑴: 92545 doc 200535136

⑴ or a pharmacologically acceptable salt thereof, which is a phosphodiesterase · 4 inhibitor. The present invention also provides a pharmaceutical composition, which includes a novel bisaryl-1,8-naphthyridin-4 (1H) -one and a pharmacologically acceptable carrier. The present invention also provides further treatments in mammals such as: asthma, chronic bibronchitis, chronic obstructive pulmonary disease (COPD) 'eosinophilic granuloma, psoriasis, and other benign or malignant skin Illness, endotoxic shock (and related symptoms, such as equine lamelitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, myocardial and brain recurrence Perfusion injury, inflammatory arthritis, osteoporosis, femeral glomerulonephritis, allergic dermatitis, urticaria, adult respiratory distress, infant respiratory distress, chronic obstructive pulmonary disease on animals, diabetes insipidus, Allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, arterial restenosis, arteriosclerosis, neural tissue inflammation, pain, rheumatoid arthritis, arthritis spondylitis, transplant rejection and graft-to-host Disease, hypersecretion of gastric acid, bacterial, fungal or virus-induced septic or septic shock, inflammation and chronic cytokine regulation 92545 doc 200535136 Wet degeneration, osteoarthritis, cancer, debilitating, debilitating, depressed, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson's Of Alzheimer's disease, Alzheimer's disease, spinal nerve trauma, head trauma, multiple sclerosis, tumor growth and cancer invasion of normal tissues, by administering an effective amount of a compound of formula 1 or a prodrug compound, which is formed in a living Formula! Compound 'It is a phosphodiesterase-4 inhibitor. The present invention also provides a method for improving cognitive ability on a healthy subject. [Embodiment] In a JL of the present invention, the " body only indicates the compound represented by formula (I) in the examples. 〇 〇

(I) and its pharmacologically acceptable salts, where γ is an escutcheon selected from the group consisting of: 2545 doc 200535136 vr

C〇〇H H3C

C〇〇H

R3 R4

^^^ COOH R3 R4

/ \ ^ X ^ C〇〇H

R1 is cyclopropyl or -CH2-CF3; R2 is fluorene, F, or Cl; R3 is H or CH3; and R4 is fluorene or CH3. In this embodiment, there is a class of compounds in which one of R3 and R4 is CH3. In this embodiment, there is another class of compounds in which R3 and R4 are each CH3. In this embodiment, there is another type of compound R1 is cyclopropyl, and R3 and R4 are each CH3. Among such compounds, there is a class of compounds where Y is:

^ \ < ^ pC00H In this specific embodiment, there is another class of compounds in which R1 is -CH2-CF3, and R3 and R4 are each CH3 0. In one aspect, the compounds of the present invention are used to treat psychological Cognitive impairment of disorders, neurological deficits (such as strokes), or mental disorders (such as: memory 02545 doc -11-200535136 impairment ^ 'mentioned elsewhere in this specification). In another aspect, the present invention indicates a method for enhancing cognition in healthy subjects, which comprises administering a phosphodiesterase-4 inhibiting 安全 which is a safe and cognitively-enhancing amount. In particular, the present invention indicates a method for improving cognition, learning, memory, recall and judgment in healthy subjects, comprising administering a safe and effective amount of a squamyl acetate-4 inhibitor of formula I. For the purpose of this specification, objects that are within the normal range are defined by their age or other classification. The cognition of a healthy subject and the σ mind of the healthy subject are reported in Psychobiology, 1993, 21, 101-108 by McNamara and Skelton. The compound shown in the Morris water maze is illustrated. Further details of the relevant method are described in World Patent WO 96/25948. Other assessments used to measure cognitive enhancement include, but are not limited to, Ding, Maze Test; Radial Arm Maze Test; Delayed Unpaired or Paired Test (Delayed Non-Match or Delayed Match Test), passive Avoidance Procedure; 5 Choice Test, disclosed in World Patent WO 01/87281 A2 published on November 22, 2001. For the purposes of this description, healthy subjects include teenagers, adults, and the elderly who have average cognition; teenagers, adults, and the elderly who have higher than average knowledge; and teenagers, adults, and elderly who have lower than average cognition. Defined as a human subject as young as 18 years old. For the purposes of this specification, an adult subject is defined as a human subject as 18 years old or older. In this category are adults 18 to 40 years old. As for 92545 doc 200535136 of this specification Purpose 'Elderly subjects are defined as human subjects aged 40 or older. In this category are adults 55 or older, 65 or older, and 70 or older. Understandably, from about 25 years old, the cognition of healthy people declines at a measurable rate of I and reproducibility, for example: Cambridge Neuropsychological Test Automated Battery (CANTAB, de jager) cA, Milwain E, Budge M. 'Early detection of isolated memory deficits in the elderly: the need for more sensitive neuropsychological tests), Psychol Med 2002 Apr; 32 (3): 48j-91) or ($ The Cognitive Drug Reseach Battery (CDR), Barker A, Jones R, Simpson ) P, (Wesnes KK (1995)). Cognitive-induced cognitive impairment is a predictor of cognitive decline in healthy elderly volunteers (International Journal of Geriatric Psychiatry 10: 105 9-1062). Therefore, when the patient becomes 40 years old, the decline in cognitive function will be greatly reduced, and will benefit from the memory enhancement method. As used herein, "alkyl" and other groups having the prefix "alk", such as: alkoxy, alkylfluorenyl, alkenyl, alkynyl, and the like, which may mean straight or branched or Combined carbon chain. Examples of the alkyl group include fluorenyl, ethyl, propyl, butyl, second-butyl and third-butyl, pentyl, hexyl, heptyl, and the like. "Alkenyl'f," alkynyl '' and other similar terms include carbon chains containing at least one unsaturated C-C bond. Unless specifically stated otherwise, the term, ' amine, includes primary, secondary and tertiary amines. ^ 2545 doc -13-200535136 The term "halogen" includes fluorine, gas, bromine and iodine atoms. The term "oxide" of a heteroaryl group is used in the general sense, such as N-oxides of nitrogen heteroatoms. The compounds described herein contain one or more double bonds, and thus produce cardiac trans isomers and their morphological isomers. The invention includes isomers and mixtures of such isomers. Include all such possible compounds that include one or more asymmetric centers, and therefore diastereomers and optical isomers. The invention includes all such possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmacologically acceptable salts. The above formula I shows that there is no specific stereochemistry at some positions. The present invention includes all stereoisomers of formula! And their pharmacologically acceptable salts. Again: Stereoisomers and mixtures of specifically isolated stereoisomers are also included. The products of such steps can be a mixture of stereoisomers during the synthetic steps used to prepare such compounds or when using a racemic or epiisomerization (epi) step known to those skilled in the art. . The term "pharmacologically acceptable salt" means a salt prepared from a pharmacologically acceptable non-toxic test or acid. When the compound of the present invention is acidic, the pot is relatively shoreless: the salt is conveniently from a pharmacologically acceptable non-toxic test Preparation, including inorganic and organic tests. Salts derived from such inorganic tests include m copper (copper and cuprous), iron, ferrous, bell, magnesium, magnesium (might and sub bell), potassium, sodium , Zinc and similar salts. Particularly preferred are magnesium, potassium, and sodium salts. Salts derived from organic nontoxic bases that are acceptable to Arthur include salts of primary, secondary, and tertiary amines, as well as cyclic amines and chemicals. Substituted amines, such as: naturally occurring and substituted amines formed in 200535136. Other pharmacologically acceptable organic compounds from which salts can be formed include ion exchange resins, such as methionine, betaine , Caffeine, choline, N, N'-dibenzyl vinyl diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N -Ethyl moline, N-ethylpyridine, giucamine, glucosamine, Histidine, hydrabamine, isopropylamine, lysine, glucosamine, molybdenum, zinc hydrazone, solder, polyamine resin, procaine, purine, theobramine, Triethylamine, trimethylamine, dipropylamine, tromethamine and the like. When the compound of the present invention is basic, its corresponding salt can be conveniently obtained from pharmacology Non-toxic acids can be prepared, including inorganic organic acids. The acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, Aminoglutaric acid, hydrobromic acid, hydrogen acid, ethyl acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, filling Acids, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Particularly preferred are stuporic acid, citric acid, hydrobromic acid, hydrogen acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. The pharmaceutical composition of the present invention comprises a compound represented by formula (or a pharmacologically acceptable salt thereof) As a raw material, a pharmacologically acceptable carrier, and optionally a therapeutic raw material or an adjuvant. This additional therapeutic raw material includes, for example: leukotriene receptor antagonist, 丨 丨) leukotriene biosynthesis Inhibitors, iii) steroids, iv) Hl receptor antagonists, v) β2 adrenergic receptor antagonists, vi) COX-2 selective inhibitors, vii) Shide, Ding (Gamma), vm) non ^ 2545 doc -15-200535136 Sterol anti-inflammatory drugs ("NS Kan,") and ix) M2 / M3 antagonists. The composition includes compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration. 'While in any given case, the most appropriate route depends on the active ingredient being administered. The nature and severity of the particular host and disease. The pharmaceutical composition may conveniently be presented in unit dosage form and prepared by any method well known in the pharmaceutical arts. Creams, ointments, gums, solutions or suspensions containing a compound of formula I may be used topically. For the purpose of the present invention &, from 11 i +% Θ, your mouthwash and mouthwash are included in the scope of topical use. From about 0.001 mg / kg body weight to about 14 (mg) / kg daily ❹ is used to treat the following diseases such as: 0 lung disorders such as: asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult breathing Obsessive-compulsive disorder, infant respiratory obesity; ii) gastrointestinal disorders such as: ulcerative colitis, Crohn's disease, excessive secretion of gastric acid; Hi) allergic diseases, such as bacterial or prion-induced spoilage or sepsis Shock, endotoxic shock (and related symptoms, such as: equine lamelitis and colic in horses) and septic shock; iv) neurological disorders, spinal trauma, head trauma, nerve tissue inflammation, pain and brain Reperfus-) injury; v) inflammatory disorders such as: psoriatic arthritis, rheumatoid arthritis, arthritis spondylitis, osteoarthritis, inflammatory and cytokine-regulated chronic tissues HW) Allergic disorders, such as: Allergies! Skin fire, allergic conjunctivitis and eosinophilic granuloma; mental atrophy. Depression, memory impairment and unipolar depression; viii) Neurodegeneration I. loss of life. Zhou '&. Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis; ix) skin disorders, such as: psoriasis and other benign or malignant increases 92545.doc -16-200535136 natural skin diseases, hereditary allergies Dermatitis and expectation; X) tumor diseases, such as: cancer, tumor growth and normal tissues invaded by cancer; xi) metabolic disorders such as · diabetes collapse, xii) osteoporosis, such as: osteoporosis X :): blood: maladjusted ten arterial restenosis, arteriosclerosis' myocardial reperfusion injury; and other disorders, such as: chronic glomerulonephritis, spring conjunctivitis, transplant rejection and graft-to-host disease , And debilitating · It is in response to PDE4 inhibition; or about ⑽ milligrams to about 7 grams per patient per day. For example, inflammation can be effectively treated by administering from about 0.01 mg to 50 mg of the compound per kilogram of body weight per day, or about 0.5 mg to about 2.5 g per patient per day. Furthermore, it is understood that the pDE4 inhibitory compound of the present invention can be administered in a prophylactically effective dose to prevent the above-mentioned symptoms. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example: a formulation intended for oral administration to humans may conveniently contain from about 0.5 g to about 5 g of active agent, compounded with a suitable and convenient amount of a carrier material, the carrier material may be from about 5 to about 95% of the total composition varies. Single dosage forms typically contain between about 0.01 mg to about 1000 mg of active ingredient, typically 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg , 100 mg, 200 mg, 300 mg, 4.0 mg, 500 mg, 600 mg, 800 mg, or 1000 mg. However, it is important to understand that the specific dose for any particular patient depends on a variety of factors, including age, weight, general health, gender, diet, time of administration, route of administration, rate of secretion, drug combination, and administration of 92545 doc -17- 200535136 / C7 severity of special diseases. In practice, the compound represented by formula 1 or a pharmacologically acceptable compound of the present invention can be used as an active raw material. According to the conventional pharmacological compounding technology, it can be combined with a pharmacological carrier in a carotene. The carrier can take a wide variety of form two: Depending on the form of preparation to be administered, for example: oral or parenteral (intravenous injection). Therefore, the pharmacological composition of the present invention may be suitable for oral administration, such as capsules, gelatin tablets or tablets, which contain a predetermined amount of active ingredient. Furthermore, the composition can be presented as a powder, a particulate, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion in a solution. In addition to the general dosage forms described above, the compound represented by Formula I, or a pharmacologically acceptable salt thereof, can also be administered by controlling the release mode and / or the delivery device. The composition may be prepared by any pharmacological method. Generally, such methods include the step of bringing the active material into contact with a carrier, which constitutes one or more of the necessary materials. In general, the composition can be prepared by uniformly and intimately mixing an active material and a liquid carrier, or a finely divided solid carrier, or both. The product is then conveniently shaped into the desired appearance. Therefore, the pharmacological composition of the invention may include a pharmacologically acceptable carrier and a compound of formula I or a pharmacologically acceptable salt. Compounds of the formula or their pharmacologically acceptable salts ' may also be included in a pharmacological composition in combination with one or more other therapeutically active compounds. For example: solid, liquid or gaseous pharmacological carriers can be used. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers include 02545 doc -18- 200535136 sugar polysaccharides, peanut oil, olive oil and water. Examples of the gaseous carrier include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmacological medium may be used. Water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, colorants and the like can be used to form oral liquid preparations, such as: suspensions, elixir and solutions; and such as: powder, Carriers of sugars, microcrystalline cellulose, diluents, granules, lubricants, binders, disintegrants and the like can be used to form oral solid preparations, powders, capsules and tablets. Essence of solid drug carriers, tablets and capsules are preferred oral dosage units because they are easy to administer. Full stick 匁 匁 用 Depending on the case, the tablets can be coated with aqueous or non-aqueous techniques. The tablets containing the pharmacological composition of the present invention can be made by shrinking or casting, optionally with one or more additional raw materials or adjuvants. Compressed tablets can be co-formed by compressing active ingredients in a free-flowing form such as 末 tail or granules in a suitable machine. Preparations are made 'as appropriate with binders, lubricants, inert diluents, surfaces Active August or knife blend. The cast tablets can be cast in a suitable machine, a mixture of gland, &, ^, ^ liquid diluent moistened into a powdered compound. Each wicker ancient t A, car sheet qe Nai Quan comprise from about 0.1 mg to about 500 alkylene ,,, lozenges or capsules each gum preferably comprises from about 0.1 mg to about 500 millimoles of her original Shaw. The pen is suitable for parenteral administration of the & compound in water: "" Moon pharmacological composition and can be prepared as active, kappa or suspension. Suitable surfactants may include, for example, hydroxypropyl glycol, Lukalin. Dispersions can also be prepared in a mixture of glycerin, liquid poly, and oils. Furthermore, preservatives can include -19-200535136 to prevent the harmful growth of microorganisms.-This invention is suitable for injectable use Pharmacological composition, which contains a sterilized aqueous solution or dispersion. In addition, the composition can be in the form of a ready-to-use sterilized powder for such injectable solutions or dispersions. All injectable forms must It is sterilized and must be effective for: = needles and injectables. The pharmacological composition must be stable under the conditions of manufacture and storage; therefore, it is preferably resistant to microorganisms such as bacteria and fungi. The pollution effect is antiseptic. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol: = (:! Eg, glycerin, propylene glycol, and liquid polyethylene glycol), vegetable oil, and a suitable δ mixture thereof The pharmacological composition of the present invention may be in a form suitable for topical use, for example, qi, cream, ointment, lotion, dust, or the like. Furthermore, the composition may be in a form suitable for use in a transdermal device. These formulations are prepared according to the formula of the present invention! The compounds or pharmacologically acceptable salts thereof are prepared by adding: For example, creams or ointments are prepared by mixing hydrophilic [biological shellfish and water, and about 5 From about 10% to about 10% by weight of the compound to produce a cream or ointment with the desired consistency. The pharmacological composition of the present invention may be in a form suitable for rectal administration and the body is solid. Preferably, the mixture is formed Unit dose test agent. Suitable carriers include cocoa butter and other substances commonly used in this art. Suppositories: Cocoa: First, mix the Kunhe composition with a softened or refined carrier. Cold part and formed in the mold order. Male, in addition to the above carrier raw materials, the above pharmacological preparations include the—or multiple quota carrier raw materials, such as: thinner, buffer, fragrance; 92545 doc -20 -200535136 4 ports μ, surfactants, thinners, lubricants, preservatives (including antioxidants), and the like. In addition, 'other adjuvants can be included so that the two formulations are isobaric to the blood of the intended recipient A composition comprising a chemical substance described in the formula or a pharmacologically acceptable salt thereof can also be prepared in the form of a powder or a liquid evil concentrate. The compounds and pharmacological compositions of the present invention have been found to show PDE4 inhibition Biological activity of agents. Because of & another aspect of the present invention is the treatment of mammals such as: i) lung disorders, such as: asthma, chronic bronchitis, chronic obstructive pulmonary disease (CDPD), adult Disease, infant respiratory irritation, coughing, chronic obstructive pulmonary disease in animals, adult respiratory distress, respiratory irritation in children, η) gastrointestinal disorders,%: ulcerative colitis, Crohn's disease, hyperacidity Secretion; out) infectious diseases, such as: bacterial, fungal or virus-induced septic or septic shock, endotoxic shock (and related symptoms: such as: horse equine laminitis and colic) and septic shock; iv) Neurotic Loss of alpha weeks such as: spinal trauma, head trauma, nervous tissue inflammation, pain and reperfusion injury to the brain; V) inflammatory disorders, psoriasis arthritis, rheumatoid arthritis, stiff spondylitis, bone Arthritis, inflammatory and cytokine-regulated chronic tissue degradation; vi) allergic disorders, such as: allergic dermatitis, allergic conjunctivitis, and eosinophilic granulation M; vii) mental disorders such as: and loss of memory, memory impairment And unipolar suppression; viii) neurodegenerative disorders ... Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis; no skin disorders, such as: psoriasis and other benign or malignant skin diseases, hereditary allergies Dermatitis and anesthesia; χ) tumor diseases, such as: cancer, tumor growth and normal tissues invaded by cancer; called metabolism ^ 2545 doc -21-200535136 disorders, such as: diabetes insipidus; Xii) bone disorders, Such as: osteoporosis; xiii) cardiovascular disorders, such as: arterial restenosis, atherosclerosis, myocardial reperfusion injury; and Xiv) other disorders, such as chronic glomerulonephritis, spring Conjunctivitis, graft rejection, and host disease, as well as mental malaise. Diseases that are improved in response to the inhibition of PDE4 isoenzymes and the resulting increase in the amount of cAMp. One is by administering an effective amount of a compound of the invention. . The term "mammal" includes humans and other animals, such as dogs, cats, horses, pigs and cattle. It is therefore understood that the treatment of mammals other than humans is the treatment of clinically-associated symptoms of the cited examples of those human symptoms described above. Furthermore, as described above, the compound of the present invention can be used in combination with other therapeutic compounds. In particular, the combination of the PDE4 inhibitory compounds of the present invention can be advantageously used in combination with: 丨) leukotriene receptor antagonists, 10 leukotriene biosynthesis inhibitors, iu) COX-2 selective inhibitors, iv ) Stertin, v) NSAID, vi) M2 / M3 antagonists, vii) class VII, viii) m (histamine) receptor antagonists and β) adrenergic receptor antagonists. Thus, for example: lung disorders such as: asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress, infant respiratory distress, cough, chronic obstructive pulmonary disease in animals, adult respiratory distress, Infant respiratory distress can be conveniently composed of active ingredients of the compounds of the present invention each containing i mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 4 mg or 5 mg, or its pharmacology Acceptable salts, capsules, lozenges or tablets are administered once, twice or three times daily. For example, ulcerative colitis, Crohn's disease, gastrointestinal disorders with excessive secretion of gastric acid, can be conveniently divided into 8 mg, 400 mg or 5 mg each containing i mg, 5 mg, 25 mg, 50 mg, 92545 doc -22-200535136 500 mg of active ingredient of a compound of the present invention, or a drug thereof ". ^ ^ — Capsules, gelatin tablets, or tablets that have been killed by the salt of the text" Oral therapy, administered twice, three times on mother's day Infectious money, such as: bacterial, virulent or septic shock, endotoxic shock (and related symptoms, such as horse equine laminitis and pain), and septic shock Conveniently each contains! Mg, 5 mg, '5 pen grams to 50 pen grams, 100 * (, 200 milligrams, 300 milligrams, 400 milligrams or 500 ¾ grams of active ingredient of the compound of the present invention, or its pharmacology Acceptable salt capsule, gel or tablet treatment, once, twice or three times daily 0. Neurological disorders such as spinal trauma, head trauma, nervous tissue inflammation, pain and brain reperfusion Injuries can be conveniently taken by each containing 丨 mg, 5 mg, 25¾ g, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of a compound of the present invention, or a capsule, gel, or tablet of a pharmacologically acceptable salt thereof, each Apply once, twice or three times a day. Inflammatory disorders such as: psoriasis arthritis, rheumatoid arthritis, arthritis spondylitis, osteoarthritis, inflammatory and cytokine-regulated chronic tissue degradation, which can be conveniently Capsules, tablets, each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present invention, or a pharmacologically acceptable salt thereof Or tablet treatment, once, twice or three times a day. Allergic disorders, such as: allergic dermatitis, allergic conjunctivitis, and eosinophilic granuloma, can be conveniently contained 1 mg, 5 mg, 25 mg, 50 mg each 92545 doc -23-200535136 Capsules, gels or tablets of the active ingredient of the compound of the present invention in mg, ⑽mg, 200mg, 3⑽mg, mg or other mg, or pharmacologically acceptable salts thereof Treatment is given once, twice or three times a day. Mental disorders, such as depression, memory impairment and unipolar depression, can be conveniently taken with each containing 1 mg, 5 fragrant, 95 Huigu-Shier Maoxiong 5 Pendant, 50 mg, 100 mg, 200 mg, 300 mg, 400 coupons srm; ^^ Brother gram of active ingredients of the compound of the present invention, or capsules, gelatin tablets of pharmacologically acceptable salts thereof Or tablet treatment, once, twice or three times a day. Neurodegenerative disorders such as: Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, can be conveniently Capsules, gels, or tablets of the active ingredient of the compound of the present invention, or a pharmacologically acceptable salt thereof, in the form of mg, 50 mg, 100 mg, 100 mg, 300 mg, 300 mg, 500 mg, or 500 mg, administered daily Once, twice or three times. Skin disorders, such as psoriasis, and other benign or malignant hyperplasia skin diseases, such as allergic dermatitis and ramie therapy, can be easily included in the form of i-Eg, 5 mg, 25 mg, 50 mg, 10 0 mg, 200 mg, 300 mg, 400 mg or 500 mg of the active ingredient of the compound of the present invention, or capsules, gels or tablets of pharmacologically acceptable salts thereof, administered once or twice a day Or three times. Cancerous diseases, such as cancer, tumor growth, and normal tissue invasion by cancer, can conveniently be divided into i mg, 5 mg, 25 mg, 50 mg, 100 ¾ g, 200 ¾ g, 300 mg, 40 mg or 500 mg of the active ingredient of the compound of the present invention, or a capsule, gel or tablet of a pharmacologically acceptable salt thereof, is administered once, twice or three times a day. 92545 doc -24- 200535136 Metabolic disorders such as ··········································································································· Six milligrams or 500 milligrams of chrome μ hair grams "⑻ home grams, active ingredients of 400X compounds, capsules of salt, 脒 # + # u χ_, Liang Li J, or tablets For treatment, use it once, twice or twice a day. Such as osteoporosis of bone loss # Lu Tianju, such as arterial hemorrhage, atherosclerosis, magic illusion ^, the main known harm, and other disorders, such as: chronic glomerulonephritis, Shi Tengsheng ,, , Flame, transplant rejection, and graft on the host and disease and mental debility, can be conveniently containing img, qi, 25mg, 50mg, 100mg, 200mg · mg Cheek Or 500 mg of the active ingredient of a compound of the present invention, or a capsule, gel, or tablet of a pharmacologically acceptable salt thereof, administered once, twice, or three times a day. For cognitive improvement (eg, to improve memory, learning, memory, recall, perception and judgment), daily doses from 0.0001 mg / kg body weight to about 50 mg / kg are useful, or each disease Suffering from about 0.05 mg to about 2.5 grams per day. In addition, the dosage portion is from 0.00 mg to 100 mg of the compound per kg of body weight per day, or about 0.05 mg to about 500 mg per patient per day. The amount of active ingredient 'which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. For example, formulations intended for oral administration to humans may conveniently contain from about 0.005 mg to about 2.5 grams of active agent, complexed with a suitable and convenient amount of carrier substance. A single dosage form typically contains between about 0.005 mg to about 1,000 mg of the active ingredient, typically 0.005, 0.001 mg, 0.055 2545 doc -25-200535136 mg, 0.2 5 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, administered once, twice, or three times per day. The abbreviations used herein have the meanings listed below. The following unlisted abbreviations have their general meaning unless otherwise stated.

Ac = ethenyl Bn = benzyl CAMP = cyclic adenosine 3f, 5'-cyclic monophosphate DBU = 1,8-diazobicyclo [5.4.0] undec-7-ene DIBAL = hydrogenated di Isobutylaluminum DMAP = 4- (diamidinoamino) said pyrimidine DMF = N, N-dimethylformamidine Et3N = triethylamine GST = glutathione transferase HMDS = bis (trimethyl Silane) amine LDA = lithium diisopropylammonium m-CPBA = m-peroxyperbenzoic acid MMPP = monoperoxyphthalic acid MPPM = monoperoxy magnesium phthalate 6H2〇Ms = formazan Burntite yellow base = mesyl = S〇2Me MsO = mesylate xanthate = mesylate NSAID = = non-steroidal anti-inflammatory drug o-T o 1 di-o-tolyl 92545 doc -26- 200535136 〇X〇NE® = 2KHS〇5 * KHS〇4 * K2S〇4 PCC Digassed chromic acid p ratio bite PDC = Pyridine dichromate PDE = Phosphodiesterase Ph = Phenyl Phe = Phenyldiyl PMB = p-methoxybenzyl Pye = leaf 匕 σ = diyl rt = room temperature Rac. '= Racemic SAM = amine sulfo or sulfa or S02NH2 SEM = 2- (trisyllithium) ethoxy fluorenyloxy SPA = close Scintillation proximity assay TB AF = vaporized tetra-n-butyl TEA = triethylamine Th = 2- or 3-thienyl TFA = trifluoroacetic acid TFAA = trifluoroacetic anhydride THF = tetrahydrofuran Thi = thiobenzenediyl TLC = Thin Layer Chromatography TMS-CN = Trimethylstilbene cyanide 92545 doc -27- 200535136 Abbreviation for alkyl group

Me = methyl Et = ethyl n-Pr = n-propyl i-Pr '= isopropyl n-Bu = n-butyl i-Bu = isobutyl s-Bu = second butyl tB u = third Butyl c-Pr = Cyclopropyl c-Bu = Cyclobutyl c-Pen = Cyclopentyl c-Hex = Cyclohexyl Analytical method to explain biological activity TMSI = Trimethyllithium hard Tz = 1H (or 2H)- Tetramethyl-5-yl CAN = ammonium nitrate 钸 C3H5 = allyl in human whole blood LPS and FMLP-induced TNF-α and LTB4 analysis method Whole blood provides resistance such as: PDE4-selective inhibitor Protein-rich and cellular environment for biochemical efficacy studies of inflammatory compounds. Normal non-irritating person 92545 doc -28-200535136

Additional LPS stimulation, followed by human whole blood wfMLp challenge, is required for LTB4 synthesis by activating neutrophils. Therefore, by using the same blood sample, it is possible to use the following steps when two types of blood in the whole blood do not contain a detectable portion of tnf ', the activated I 枋 white a is also set to τθ 2. Therefore, the efficacy of a compound was evaluated by surrogate markers that make PDE4 active. Fresh blood was collected from healthy volunteers by venipuncture. In formula g. These subjects showed no significant signs of inflammation and did not take any NSAIDs for at least 4 days before blood collection. 500,000 microliters of blood, 42 microliters of the test compound with 2 microliters of vehicle (DMS0) at different concentrations, were pre-incubated at 37 C for 15 minutes. This was continued with the addition of 10 microliters of vehicle (pBs) as a blank, or a serotype (luO) from E. coli, diluted at 0.1% w / v bs A (in PBS). ^ 1 (^^ lps ⑴L / ml final concentration, # L-263 0 (Sigma Chemical Co., St. Louis, MO)). Cultured at 37 ° C. twenty four

After an hour, an additional 10 μl of PB s (blank) or 10 μl of Lp s (final microliters / ml final concentration) was added to the blood, and incubated for 30 minutes at 37 ° C. Then the blood was diluted with 10 μl of PBS (blank) or 10 μl of £% 1 ^ (1 final concentration '# F-3506 (Sigma); diluted in 1% weight / volume BSA (in pBS 92545 doc -29- 200535136)), J7 C excitation for 15 minutes. The blood sample was centrifuged at 1500 xg, 4 minutes for 10 minutes to obtain plasma. A 50 microliter portion of plasma was mixed with 200 microliters of methanol to make a protein sink, and centrifuged as described above. The decantation was analyzed for LTB4 using an enzyme immunoassay tool (# 520 1 1 1 from Cayman Chemical Co., Ann Arbor, MI) according to the manufacturer's procedure. TNF-α was analyzed in diluted plasma (in pBS) using an ELISA tool (Cistron Biotechnology, Pine Brook, NJ), according to the manufacturer's procedure . The ic50 values of the examples are generally in the range from 0 075 micromolar to 2 micromolar. ^ IC50 value of selected examples (TNF-oQ: Example: IC50 (micromolar concentration) 1 0.3 3 0.075 4-(-)-isomer 0.16 6-(-)-isomer 0,5 7 0.09 Isomer 0.16 10 0.1 1.8 Antiallergic activity in vivo t The compounds of the present invention were tested on sensitized guinea pigs, and the effect of IgE induced by antigen inhalation on the regulation of allergic lung inflammation. Guinea pigs were initially induced by mild cyclophosphamide Sensitization to ovalbumin under immunosuppression is a combination of intraperitoneal injection of the antigen with a hydroxide hydroxide and pertussis vaccine by 92545 doc -30-200535136. Additional doses of the antigen are given after two and three weeks. Six weeks later The animals were challenged with aerosolized avidin, and administered under the peritoneal administration of an antihistamine (mepyramine). After an additional hour, bronchoalveolar lavage (BAL) was performed, and Count the number of eosinophils and other white blood cells in the bal fluid. The lungs were also removed for tissue inspection of the inflammatory lesions. During 48 hours after antigen challenge, the application of the example compounds (〇. 〇〇 丨 _ 丨〇mg / kg i · ρ · ρ · 〇.) Twice, leading to a large decrease in eosinophils and the accumulation of other inflammatory white blood cells. There is also less inflammatory damage in the lungs of animals treated with the example compounds. SPA-based PDE activity analysis method steps inhibit c AMP compounds are hydrolyzed into AMP compounds by type IV c AMP specific phosphodiesterases, and they are screened in a 96-well plate format as follows: Test compounds (dissolved in 2 microliters of DMSO), 188 ml of matrix buffer containing [2,8-3H] adenosine 3,5, -cyclic phosphate (cAMP, 100 nanomolar to 50 micromolar), 10 Millimolar concentration MgCl2, 1 millimolar concentration EDTA, 50 millimolar concentration

Tris, pH 7.5. The reaction was initiated by adding 10 ml of human recombinant ρOE4 (the amount was controlled so that ~ 10% of the product was in the form of 10 minutes). The reaction was stopped after 10 minutes by adding 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc., Piscataway, NJ) in Piscataway, New Jersey. The resulting product, AMP, was quantified on a Wallac Microbeta® 96-well plate counter (EG & G Wallac Co., Gaithersburg, MD) in Gatsburg, MD. The term 92545 doc -31-200535136 deficient enzyme is defined as the background. 100% activity is defined as the signal detected in the presence of enzymes and DMSO, with background subtracted. The percentage of inhibition is therefore calculated. The IC50 value was calculated using the standard 4-parameter / multi-bond position equation, and nonlinear regression was used to calculate the similarity. The IC50 value of the example disclosed below is the use of human recombinant phosphodiesterase IVb (met-248), a GST fusion protein purified from a bacuivirus / Sf-9 expression system, at 100 milliliters. Micromolar concentration. The IC50 values of the examples disclosed below range from a nanomolar concentration of 0.7 to a nanomolar concentration of 0.7. IC50 values of selected examples: Examples: Κ50 (nanomolar concentration) 1 0.3 3 0.6 4-(-)-isomer 0.7 6-(-isomer 0.4 7___ 0.1 9-(+)-isomer物 0.4 _ 0.3 JLL-— 0.4 _ The following examples are intended as illustrations of some preferred embodiments of the present invention and are not meant to limit the present invention. Except where otherwise stated, the experimental steps were performed under the following conditions. All The operation is carried out in the room's fox or the temperature. That is to say, the temperature range is 18-25. The evaporation of the solvent is under reduced pressure (600-4000 Pascals: 4 5.30 nm,) 2545. doc -32- 200535136

Hg), use at temperatures as high as 60. “,,-, ν ^ ^. ~ In a rotary evaporator. The reaction is performed by TLC, and the reaction time is just an illustration. The melting point is uncorrected, and Only the knife is known. The melting point given is the same as that obtained from the narrated preparation.-The Xibei body can cause the separation of different melting points in some preparations. The structure and purity of all the final products should be at least the following techniques. One of the guarantees is that: Behemeter, nuclear magnetic resonance spectroscopy (NMR), or microanalytical materials. # When given, the yield is for illustration. When given, NMR data is in the form of a thorium value for most characteristic protons, relative to Partial parts per million (PPm) is given as standard in tetramethylsilane (TMS), and the solvents shown are measured at megahertz, megahertz, or megahertz. It is used for the custom of signal shape Abbreviations are: singlet; d: doublet; t: triplet; m: multimodal; br: Broad Ridge, etc. In addition, "Af |" stands for aromatic signal. Chemical symbols have their usual meanings: the following abbreviations are also used : V (ancestor product), W (weight), bp, (boiling point) mp (melting point), L (liter), company (ml) g (grams), mg (t grams), ml (mol), mm (imol), eq (equivalent). Methods The compounds of the present invention can be prepared according to the following methods. The substituents are the same as in formula j, except where otherwise defined. Bromo-phenyl) -1,4-dihydro- [1,8] naphthyridine-4 The general structure VII of keto-3-carboxamidine is prepared according to the general method described in Scheme 1. First 2_ Gasoyl nicotine fluorenyl acetate (II) ethyl ester and triethyl phthalate, in the presence of acetic anhydride Condensation at room temperature to produce 2-amino nicotine fluorenyl acrylate (in). When an appropriately substituted ig aryl amine of formula IV is added, the resulting 3-arylaminopropylpropane class V 45925 doc -33 is obtained -200535136 enoate. V cyclized to 丨 -dentylaryl_M_dihydro [丨 chuannaphthyridine_4_copper-3, copperamine-3 'in the presence of excess strong test at room temperature Achieved. In addition, intermediates ... can be obtained from one-pot steps, using, for example: 2-nicotinylphosphonium chloride and N, N-dimethylaminoethyl acrylate and haloarylamine ..., in triethyl like In the presence of a base of .VI solvent acetonitrile and subsequent hydrolysis of the resulting amine acid coupling becomes (RRiNH2) using HATU and Nigel Howard (Himig's) experience, the key to produce the desired aryl bromide intermediate νπ. Scheme 1

π η

Formula I compounds are prepared using one of the following three general routes. · Catalytic Suzuki-Miyaura coupling between an aryl bromide of type VII and an appropriately substituted aryl pinacol borate of type VIII, can propose the desired compound I, or Corresponding alkyl ester IX. The IX ester can be hydrolyzed using LiOH in 92545 dooc-34-200535136 THF / MeOH to produce the desired acid I. In addition, the aryl filler VII can be converted to pinacol borate XI by palladium catalysis and coupled with pinacol dimethylborane. The aforementioned alder and Miara reaction between XI and XII type aryl bromides can provide acid I or the corresponding alkyl ester IX. Recently, a Stielie coupling between a Group VII aryl bromide and a suitably substituted Group X arylstannate has also produced the desired acid of Formula I. Process 2

From the aryl bromide pinacol VIII type borate and the type X stannate (Scheme 3), they can be used as XII intermediates and palladium-catalyzed coupling reactions, and fluorenylborane and hexaalkyltin can be used respectively. preparation. 92545 doc -35-200535136 process 3

BT

C〇〇R4 XII

\ L〇〇Jl / wj〆VIII PdCI2 (dppf) 2 KOAc R2 ~ C〇〇R 4 Pd (PPh) 4 (Alkyl) 3Sn, A ^ Y ^ COOR (Alkyl) 3Sn-Sn (Alkyl) 3 R2 4 X XII intermediates in which Y is cyclopropyl, such as compounds of formula XIV can be used

Prepared by one of the following four general steps (Scheme 4). XIII cinnamyl esters are commercially available or prepared from the corresponding acid anhydride XV by the Horner-Emmons reaction, which can be calcined with In the presence of cyclopropane. The obtained trans-cyclopropane S-XIV can be analyzed by HPLC using a Chiral-Pak column to produce two separated enantiomers. In the second path, the anhydride XV can be converted into the corresponding phenylglycol XVI by the Wittig reaction, followed by the use of bis-oxazoline pair palmate ligand / copper complex and dicouple Nitroacetate, enantioselectively cyclopropanelated (Evans et al. In J. Am. Chem. Soc. 1991, 113, 726). The obtained mixture of trans XIV and cis XVII cyclopropane can be selectively hydrolyzed and separated under basic conditions (hydrolysis rate: trans > cis). Individual enantiomers (XIV or XVII) can be obtained using R or S pair ligands. The cis-cyclopropane ester XIV can also be prepared from cis-cinnamate XVIII using the aforementioned diazomethane / Pd (Ac) 2 # step. Cis-cinnamate XVIII can be altered by Hall-Imos olefination, using bis (trifluoroethyl) phosphine ester and strong base to produce (Still et al. In Tetrahedron Lett, 1983, 24, 4405 in). Process 4 92545 doc -36- 200535136

Br, x > ^ X〇〇R4 Pd (0Ac) 2 B ", / C ^ XPPR4 reward 1_PakAD." ", '/ ≪] / (: 〇〇berry 4

CH2N2 analysis S XIII (R4 = alkyl) XIV XIV2 (R4 = H)

Chiral

(Et0) 2P (0) CH2C00Et ί-BuOK / -78 ° C

Br-Ar ^ 〇 R2 XV

CuOTf

b``, aX1-c〇〇r4 ^ + XIV palm 2 XV! 1 palm Br-Ar COOR4 R2

(CF3CH20) 2P (〇) CH2C〇〇Me Br ,, R2 COOR4 XVIII KN (TMS) 2 / -78 ° C18-C-6 (s or R) XIV and XVII cis and trans para-palladium propane intermediate The body can also be prepared by the following two methods, respectively. In the presence of CDI, cinnamic acid XIII is converted to fluorenyl-imidazole XIX, which reacts with optically pure oxazolinone XX under basic conditions to produce p-cinnamyl ester-oxazolone XXI. The cyclopropanation of XXI follows the method described previously to produce a separable (crystalline, SiO2) mixture of diastereomers XXII (> 5 to 1). The latter hydrolysis yields the desired paracyclopropenyl XIV. Similarly, a racemic mixture of XIV (XVII) cyclopropyl groups can be converted in two steps to a 1: 1 diastereomeric mixture of the aforementioned cinnamyl-oxazolinone XXI. 92545 doc -37-200535136 process 5

`` \ / ≪ ^ / C〇〇R4 CDI Βγ ^ α, Αγ-Α 「R2 R2 XIII (R4 = Η) XIX Br, Αγ

(R4 = Η) \ __ J XXV intermediates (Scheme 6) can be obtained by dehydrogenation of XXIV esters in the presence of an alkylating agent such as R5I using an excess of strong test. The relative amounts of the base and alkylating agent to the starting S are based on the substituted portions (single vs. double). For propionic acid-based XXVII analogs, tertiary-butyl ester XXVI can be dehydrogenated using a sterically hindering base. The addition of alkylating reagents results in a mixture of mono- and di-alkylating compounds. Repeating this step produces mainly XXVII esters. Cyclopropyl analogues of class XXX can be prepared in two steps from the corresponding arylacetonitrile XXVIII. In a strong aqueous base, a phase transfer reaction of XXVIII and 2-chlorobromoethane was used to produce cyclopropyl XXIX (Org. Prep. &Amp; Proc. 1995, 27, 3 5 5). Hydrolysis in refluxing ethanol using NaOH yields the desired acid XXX. (1,1-Difluorenyl) ethyl-aryl group of XXXIII can be prepared in three steps. The (2-amino-1,1-dimethyl-ethyl) -aryl group of XXXI can first be terminated by the carbon dioxide of 92545.doc -38-200535136 XXXI's Grignard salt, followed by two Azomethane esterifies the resulting acid to the corresponding XXXII esters. Electrophilic substitution on the aryl ester XXXII in the medium produces a sulfonium cation to produce the desired iodoaryl XXXIII (J. Am_Chem. Soc. 1948, 70, 370). Scheme 6 R5 R5 Br \ Α Ar C〇〇R4 NaH / R5-l B ", △ 乂. Ar R2 DMF R2 XXIV XXV R4 = Me, Et, f-Bu Li C〇〇R4

R5-I / THF

Br \ Ar ^ / C〇〇e R2 XXVI R4 = i-Bu B 「\ ^ .. COOR4

Ar X

r2 R5 R5 XXVII

Br, .Cl

Ar CN R2 XXVIII

BnEt3NCI NaOH

Br ^ CN. Na0H R2 XXIX

EtOH

B ", Ar and C〇〇H

R2 XXX

Ar R2

1. Mg / C02 2. CH2N2

Cl

Ar R2 XXXII

C〇〇Me 丨 2 / _〇2

COOMe

H2S04

R2 XXXIII naphthalene stilbone 1 N-cyclopropyl-1- (3-bromophenyl) -1,4-dihydro [1,8] naphthyridin-4-one-3-carboxamide 92545 doc -39 -200535136

Step 1: 3- (3-Bromoaniline) -2- (2-chloronicotinylfluorenyl) ethyl acrylate 2-chloronicotinylfluorenylethyl acetate (丨 eq), triethyl phthalate A mixture of esters (1.5 eq) and acid anhydride (5 eq) (prepared according to the procedure described in j. Het. Chem., 30, 855, 1993) was heated at 13 CTC for 2.5 hours. The volatile components were distilled off 'and the residue was co-evaporated twice with xylene. The oily residue was dissolved in digas methane and 3-bromoaniline (1.2 eq) was added slowly. The resulting solution was stirred at room temperature for 18 hours, and the solvent was evaporated. The obtained crude compound was used as such in the next step. Step 2: 1- (3-Bromophenyl) -1,4-dihydro [L8] naphthyridin-4-one-3-carboxylic acid ethyl ester The crude compound from step 1 was dissolved in tetrahydrofuran (0.3 Molar concentration), the solution was cooled to 0 ° C, and sodium hydride (60% dispersion in oil, 1.3 eq) was added in portions. After stirring at 0 ° C for 1 hour, the mixture was allowed to warm to room temperature. After 2 hours, water was added to the suspension, and insoluble solids were filtered and washed with a large amount of water. When dry, the solid was stirred at room temperature in ether for 24 hours and filtered to give the title compound as a cream-colored solid. 4 NMR (acetone 4) δ 1.32 (t, 3H), 4.29 (q, 2H), 7.54-7.63 (m, 2H), 7.69 (dd, 1H), 7.78 (dd, 1H), 7.93 (s, 1H), 8.66-8.71 (m, 3H) 〇 In addition, the following steps can be used for step 1 or 2: 92545 doc -40- 200535136 2-gas based on fermenting chloride (1 eq), triethylamine (4 eq ) And a mixture of 3,3-dimethylaminoethyl acrylate (1.5 eq) in acetonitrile (0.5 mole concentration), heated to reflux for 3 hours, cooled to 40-50 ° C, and added 3- Bromobenzylamine (1 eq). The reaction was heated to reflux overnight, cooled to room temperature, and diluted with water (2 volumes). The product was isolated by filtration and washed with water, ether or acetonitrile-water (1: 1). Step 3: 1- (3-Bromophenyl) -1,4-dihydro [1,8] naphthyridin-4-one-3-carboxylic acid is derived from 1- (3-bromophenyl) in step 2 -1,4-Dihydro [1,8] naphthyridin-4-one-3-carboxylic acid ethyl ester (1 eq) in tetrahydrofuran-methanol (0.15 mole concentration) and 1 equivalent sodium hydroxide (2 eq) The suspension in a mixture of aqueous solutions was heated and stirred at about 50 ° C for 20 minutes. After cooling, the mixture was diluted with water and acidified at 1 equivalent concentration HC1. After stirring for 45 minutes, the precipitate was filtered, washed, and dried to give the title acid as a cream-colored solid. 4 NMR (acetone_ (ΐ6) δ 7.65 (t, 1H), 7.76 (m, 2H), 7.84 (d, 1H), 7.99 (s, 1H), 8.87 (m, 2H), 9.01 (s, 1H). Step 4: N-Cyclopropyl-1- (3-bromophenyl) -i, 4-dihydro [i, 8] naphthyridin-3-carboxamide pair from step 1- ( 3-Bromophenyl) -l, 4-dihydro [1,8] naphthyridin-4-one-3-endoic acid (1 eq) and triethylamine eq) in tetrahydrofuran (0.08 Molar concentration ), And isobutyl chloroformate (ι · 8 eq) was added at 0 ° C. At 〇. After stirring for 2 hours at 0 °, cyclopropylamine (5 eq) was added, and the mixture was allowed to warm to room temperature 'and stirred overnight. The mixture was then distributed between ethyl acetate and water. The organic phase was dried and evaporated to a solid, which was stirred at room temperature for 3 hours and filtered to produce N-cyclopropylbromobenzyl ^ 92545. doc -41-200535136 Diaz [1,8] Cai bite, Carboxamide. 1H NMR (propyl, d6) δ 0.59 (m, 2H), 0.80 (m, 2H), 2.96 (m, 1H), 7.59-7.68 (m, 2H), 7.72 (dd, 1H ), 7.82 (dd, 1H), 7.97 (s, 1H), 8.72 · 8 · 81 (m, 2H), 8.89 (s, 1H), 9.70 (br, NH). Nalidinone 2 N-cyclopropyl-4-oxo, monotetramethyl-i, 3,2, dioxaborolan-2-yl) benzyl] _1,4, dihydro], 8-naphthalene. Diammonium

Qin ° Ding brewing I1 (1.0 eq), pinacol dimethyl Pengxuan (1.5 eq), K〇Ac (4 eq) and PdCl2 (dppf) (called 0.05) in DMF (〇 · 2 mole concentration) was stirred at 70-80 C for 3 hours. The mixture was cooled to room temperature and diluted with EtoAc and vη / ι solution. The organic extract WH20, washed with brine, dried over MgS04, filtered and concentrated. The mother liquor was crystallized from ether and flash chromatography (HAh EtOAc, 50.50) was used to produce the title compound as a white solid. lHNMR (5GG megahertz, acetone ,: S9,78 (s, lH), 8.90 (s, 1H), 8.79 (dd, lH), 8.72 (dd, lH), 7.94 (d, lH), 7.91 (s , 1H), 7.80 (d, 1H), 7.69 (t lFn 7 to 1 'H), 7.62 (dd, 1H), 2.9 (m, 1H), 1.38 (s, 12H), 0.80 (m, 2H ), 60 (m, 2H). Example 1 92545 doc -42- 200535136 2- (trans-H3 '-[3-[(cyclopropylamino) amido] _4-oxo] biphenyl-4 -Yl} cyclopropanecarboxylic acid

Step 1: Ethyl 2- (trans-H4-bromophenyl) cyclopropanecarboxylic acid ethyl ester 4-bromo cinnamic acid and Pd (0Ac) 2 (0.05eq) in digas methylbenzene (1 mole concentration) The CH2N2 solution was added dropwise until the reaction was complete by NMR analysis. The mixture was filtered through a tube of silica and concentrated 'to give the title compound as an oil. Step 2: 2- (trans)-[4- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2_yl) phenyl] cyclopropanecarboxylic acid ethyl ester from step 1 Bromide (1.0 eq), pinacol dimethylborane ester (丨. 4 eq), K〇Ac (3.5 eq) and PdCl2 (dppf) 2 (0.03 eq) in DMF (0.14 Molar concentration ) And stir at 60 ° C for 24 hours. The resulting mixture was cooled to room temperature and diluted with EtOAc: hexane (1 ·· 丨). The organic phase was dried on M g S 04 with (3χ), salt and water washing bars ν, transitioned and concentrated. Flash chromatography (hexane: EtOAc; 90:10) gave the title compound. Step 3: 2- (trans)-[4- (4,4,5,5_tetrafluorenyl-l, 3,2-dioxaborolan-2-yl) benzyl] cyclopropanecarboxylic acid 92545 doc -43 200535136 from The mixture of the ester from step 2 and NaOH (20%, 30 ml) was heated to 100 ° C for 1.5 hours, cooled to room temperature, acidified with HC1 10%, and extracted with EtOAc. The organic extract was dried over Na2SO4 and the solvent was evaporated to give the title compound. Step 4: 2- (trans)-{3 '-[3- [Cyclopropylamino] carbonyl] -4-oxo-1,8-naphthyridin-1 (4H) -yl] -1,1, Biphenyl-4-yl} cyclopropanyl naphthyridinone 1 (1.0 eq), acid from step 3 (1.5 eq), Na2C03 (3.5 eq; 2 mole concentration in H2O), Pd ( 〇Ac) 2 (0.05 eq) and PPh3 (0.15 eq) or PdCl2dppf (0.05 eq) in n-propanol-DMF (1: 1, mol concentration) was stirred at 70QC for 2 hours. The mixture was cooled to room temperature, quenched with AcOH, and diluted with EtOAc. The combined organic extracts were washed with brine, dried over NadCU, filtered and concentrated. Flash chromatography (CH2C12: EtOAc, 60:40, 2% AcOH) gave the title compound as a white solid. 4 NMR (500 megahertz, CDC13): δ 9.9 (d, 1H), 9.08 1H), 8.77 (dd, 1H), 8.69 (dd, 1H), 7.71 (d, 1H), 7.60 (m, 2H), 7.52 (d, 2H), 7.45 (m, 1H), 7.38 (d, 1H), 7.13 (d, 2H), 2.97 (m, 1H), 2.54 (m, 1H), 1.87 (m, 1H), 1.60 (m, 1H), 1.35 (m, 1H), 0.85 (m, 2H), 0.65 (m, 2H). MS (IT): 464.2. The optically active isomers of Example 1 can be separately isolated using column chromatography, chromatography analysis; for example: Chiral Pak AD, stripped with hexane: EtOH or hexane: iPrOH containing 0-2% TFA. Alternatively, 'isolation can be achieved on the intermediate (trans) -2- (4-bromophenyl) cyclopropanecarboxylic acid. 92545 doc -44-200535136 (trans) -2- (4-molylphenyl) cyclopropanecarboxylic acid: For the ester solution from step i in THF-MeOH (4: 1, 0.5 mole) , LiOH (3 eq, .2 Molar concentration) was added, and the mixture was at 50. (: Stirred for 1 hour. The organic solvent was evaporated, the aqueous phase was acidified with 1 HC1, and the acid was extracted with EtOAc (3X). The organics were washed with brine, dried, and the solvent was evaporated to give 2- (4-bromo Phenyl) cyclopropanecarboxylic acid. Optically active precursors can be obtained by stripping on a chiral Pak AD column with hexane: EtOH or hexane: iPrOH containing 0.2% TFA. Another way is Use the following palm-up assistants, Step 1 ··· (trans) -3- (4-Molyl-phenyl) -1-tauza-l-yl-propene hydrazone in toluene (0.2 mole concentration) (Trans) -3- (4-bromo-phenyl) acrylic acid (1.0 eq) solution, CDI (1.5 eq) was added. The mixture was stirred at room temperature for 3 hours. The resulting precipitate was isolated by filtration, The title compound was produced as a white solid. Step 2: (trans) -3- [3- (4-bromo-phenyl) -propenylmethyl] -4-methyl-5-phenyl- -2 · _ 3- (4-bromo-phenyl) -1-imido-1-yl-propenone (1.05 eq), (4R, 5S)-(+) — 4 from step 1 -Methyl-5-phenyl-2-oxazolinone (1.0 eq) or (-)-isomer, and Et3N (1.2 eq) in CH3CN (0.2 The mixture in Mohr concentration) was refluxed overnight. The resulting mixture was cooled to room temperature, filtered on a silica pad and finely divided. Crystallized in hexane: Et20 to give the title compound as a white solid. Step 3: ( Trans) -3- [2- (4-bromo-phenyl) cyclopropanecarbonyl] -4-methyl-5-phenyl-oxazol-2-one 92545 doc -45-200535136 from step 2 of ( Trans) -3- [3- (4-Bromo-phenyl) _propenylmethyl] methyl-5-phenyl-oxazolin-2-one and Pd (〇Ac) 2 (0.05 eq) in THF (0.2 mole concentration) solution, CH2N2 was added dropwise until the reaction was complete. The reaction was monitored by NMR of each part. The resulting mixture was concentrated and analyzed by chromatography (Hex · EtOAc; 3: 2) to produce two Respective diastereomers. Each diastereomer is passed to the next step separately to produce (+) and the enantiomers of Example 1 of hydrazone. Step 4: 2- (transH4-bromo Phenyl) cyclopropanecarboxylic acid from step 3 of a solution of amidine in THF-Et0H-H20 (4: 1 ·· 1,0 · 1 Molar concentration) was added with LiOH (2.4 eq, 2 Molar concentration) And the mixture was stirred at room temperature for 2 hours. At equivalent concentrations} HC1 was neutralized to PH 7, the organic solvent is evaporated and the resulting residue was dissolved in ether. Article organic was washed with brine to a concentration of 1 when ϊ NaOH (2X). The combined aqueous layer was acidified and extracted with ether (3X). The organic extract was washed with brine, dried and the solvent was evaporated to give (+) or (-)-(trans) -2- (4-benzylphenyl) cyclopropanecarboxylic acid as a white solid. Step 5 ·· 2- (trans)-{3 '-[3-[(Cyclopropylamino) carbonyl] -4-oxo-i, 8-naphthyridin-1 (4H) -yl] -1, lf-biphenyl-4-yl} cyclopropanyl naphthyridinone 2 (1.0 eq), 2- (trans)-(4-bromophenyl) cyclopropanecarboxylic acid (1.2eq) from step 4, A mixture of Na2C03 (3.5 eq; 2 Molar concentration in H2O), Pd (〇Ac> 2 (0.05 eq.) And PPh3 (0.15 eq) in n-propanol (0.1 Molar concentration), in Stir at 70QC for 4 hours. The mixture is cooled to room temperature and poured into water and extracted with EtO Ac (2x). The combined organic extracts are washed with brine, dried over Na2S04, filtered and concentrated. Fast color layer 92545.doc -46- 200535136 analysis (CH2C12: Et0Ac, 50: 50%, 2% AcOH) to give the title compound as a self-colored solid. Another way is enantioselective cyclopropaneation, such as the use of bis_ Oxazoline p-palladium ligand / copper complex and diazoacetate (Evans et al. In J. Am. Chem. Soc. 1991, 1 13,726), Preparation of optical activity from en-brominated styrene 2- (transbromophenyl) cyclopropanecarboxylic acid ethyl ester. A mixture of cis and trans isomers starting with Li H (1 eq, based on trans ester) selective hydrolysis to produce 2- (trans)-(4-molylphenyl) cyclopropanecarboxylic acid and (cis) _ (4_bromophenyl) cyclopropane Ethyl carboxylate, which can be used in Example 4. Example 2-2 [3 ~ [(Cyclopropylamino) Hexyl] -4-oxonaphthalene bite_1 (4 印 _ 基] -1, ί- Biben-4-yl} -2-fluorenylpropionic acid

Step 1: A solution of methyl 2- (4-bromophenyl) -2-methylpropionate in UHJVIDS (1 mole concentration, THF, 2.1 eq) in THF (0.06 mole concentration), Add 4-bromophenylmethyl acetate (1 eq). After 15 minutes, 'Me 1 (4 eq) was added and the reaction mixture was slowly warmed to room temperature' and stirred for 18 hours. Mix at HC1 10 ° /. The reaction was stopped, diluted with EtOAc 92545 doc -47-200535136, washed with 10% HCl, washed with brine, dried and evaporated the solvent. Flash chromatography (hexane: EtOAc, 95: 5) gave the title compound. Step 2: A solution of the 2- (4-bromophenyl) -2-methylpropionic acid ester from Step 1 in THF-MeOH (4: 1, 0.5 mole concentration), add LiOH (3 eq, 2 mole concentration), and the mixture was stirred at 50γ for 1 hour. The organic solvent was evaporated, the aqueous phase was acidified with 1 HC1 and the acid was extracted with EtOAc (3X). The organics were washed with brine, dried and the solvent was evaporated to produce the acid. Step 3: 2- {3 '-[3-[(Cyclopropylamino) carbonyl] -4-oxo-1,8-naphthyridin-1 (4H) -yl] -1,! /-Biphenyl -4-yl} -2-methylpropionate naphthyridinone 2 (1.0 eq), acid from step 2 (1.5 eq), Na2CO3 (3.5 eq; 2 mole concentration in HA), and pd (Ph3 ) 4 or a mixture of PdCl2 (dppf) or Pd (OAc) 2 (Ph3P) 3 (0.05 eq) in n-propanol (0.1 mole concentration), and stirred at 70-90 ° C for 3 hours. The mixture was cooled to room temperature, quenched with HC1 and diluted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and concentrated. Flash chromatography (CH2C12: EtOAc, 40: 60, 2% AcOH) gave the title compound as a white solid. 4 NMR (500 megahertz, DMS 0-d6): δ 9.75 (d, 1H), 8.81 (s, 1H), 8.77 (m, 1H), 8.71 (d, 1H), 7.92 (s , 1H), 7.86 (d, 1H), 7.70 (d, -2H), 7.70-7.55 (m, 3H), 7.45 (d, 2H), 2.88 (m, 1H), 1.50 (s, 6H), 0.77 (m, 2H), 0.55 (m, 2H). Example 3 92545.doc -48-200535136 3- {3 ·-[3-[(Cyclopropylamino) carbonyl] -4-oxo_ι, 8-naphthalene sigidine_i (4h) -mono]] Benzene 4-yl} -3 -methylbutanoic acid

Prepared according to the procedure described in Example 2, steps 2 and 3, but using 3- (4-iodo-phenyl) -3-methyl-butyrate (according to J. Am. Chem. Soc. 1948, 70 370) was prepared as the starting material. Flash chromatography (CH2C12: EtOAc, 40: 60, 2% AcOH) gave the title compound as a white solid. 4 NMR (500 megahertz, DMSO-d6): δ 9.75 (d, 1H), 8.82 (s, 1H), 8.78 (dd, 1H), 8.72 (dd, 1H), 7.94 (s, 1H), 7.86 (d, 1H), 7.68-7.60 (m, 2H), 7.66 (d, 2H), 7.57 (d, 1H), 7.49 (d, 2H), 2.88 (m, 1H), 2.60 (s , 2h), 140 (s, 6H), 0.76 (m, 2H), 0.55 (m, 2H). Example 4 2- (cis) -3- {3f- [3-[(cyclopropylamino) carbonyl group ] Oxo- 丨, 8-naphthyridine-1 (4-imido-yl) -1,1'-bibenzyl-4-yl} cyclopropanecarboxylic acid 92545 doc -49- 200535136

Step 1 · 2-(cis) -3-(4-Methenyl) propan-2-enoic acid methyl ester of p-bis (difluoroethyl) (methoxyepimethyl) linate and 18 _Coronary ether-6 (5 eq) in THF (0.05 Molar concentration), add KHMDS (1 eq, 0.5 Molar concentration, toluene), followed by 'bromobenzoic acid (1 eq) . The reaction mixture was at _78. (: Stir for 1 hour, stop the reaction with saturated ammonium hydroxide solution and dilute with ether. The combined organic extracts were washed with brine, dried over NajO4, filtered and concentrated. Flash chromatography (hexane: EtOAc; 9: 1 to 7: 3) yield the title compound. Step 2: Methyl 2- (cis)-(4-bromophenyl) cyclopropanecarboxylate versus the ester from step 1 and Pd (〇Ac) 2 (〇 .05 eq) A mixture in dichloromethane (1 mole concentration), CH2N2 solution was added dropwise at 0. (: until the reaction was complete by NMR analysis. Fast chromatography (hexane: EtOAc; 100) : 0 to 90: 10) yields the title compound. Step 3: 2- {3 '-[3-[(Cyclopropylamino) carbonyl] -4-oxo-1,8-naphthyridine-1 (4H) -Yl] biphenyl-4-yl} cyclopropanecarboxylic acid methyl ester was prepared according to the procedure described in Example 2 and Step 3, but using the ester from Example 4 and Step 2 as the starting material. The product was analyzed by rapid chromatography ( Hexane: EtOAc; 60 · 40) was purified and then vigorously stirred in hexane / ether and separated by filtration to give the title compound as a white solid. 92545 doc -50- 200535136 Step 4: 2- (Shun)- {3,-[3-[(Cyclopropylamino) carbonyl μ4, oxo β1,8-naphthyridine-U4H) -yl] -1, Guanglianben_4_yl} cyclopropanecarboxylic acid pair in THF -EtOH (1: 0.05 mole concentration) in s solution, UOH (5 eq '2 mole concentration) was added, and the mixture was stirred at 600 ° C for * hours. The mixture was cooled to room temperature and extracted with ether. The aqueous phase was acidified with an equivalent concentration of hci, and the acid was extracted with EtoAc (3x). The organics were washed with brine, dried, and the solvent was evaporated. The residue was stirred vigorously in hexane / propane and filtered and isolated 'to give the title compound as an off-white solid. Gu Fu 11 (5 00 megahertz, 1) then 0- (16): 5 11.88 (1) 1 ^, 111), 9.75 (d, 1Η), 8.80 (s, 1H), 8.79 (dd , 1H), 8.74 (dd, 1H), 7.95 (s, 1H), 7.87 (d, 1H), 7.63-7.70 (m, 4H), 7.59 (d, 1H), 7.35 (d, 2H), 2.89-2.93 (m, 1H), 2.62 (dd, 1H), 2.04-2.09 (m, 1H), 1.31-1.35 (m, 1H), 0.77-0.87 (m, 2H), 0.56-0.59 (m, 2H) ). The optically active diastereomers of Example 4 can be isolated separately using a counter column and chromatographic analysis; for example: Chiral Pak AD, hexane: EtOH or hexane. IPr containing 0.2% TFA. H lift up. In addition, 'optically active intermediates can be obtained as follows: (cis) -2- (4-bromophenyl) cyclopropanecarboxylic acid pair from Step 2, in THF-MeOH (4: 1, 0.5 Molar concentration The ester solution in) was added UOH (3 eq, 2 mole concentration), and the mixture was stirred at 50 ° C. for 1 hour. The organic solvent was evaporated, the aqueous layer was acidified with 1 HC1, and the acid was extracted with EtoAc (3X). The combined organic extracts were washed with brine, dried and evaporated to give (cis) -2- (4-bromobenzyl) -cyclopropanecarboxylic acid. Optically active intermediate on a Chiral PakAD column using hexane: 92545.doc -51-200535136

EtOH (90:10, 0.2% TFA) was isolated. Another way is to use the palm assistant as follows, Step 1: (cis) -1-{[2- (4- > Stylenylphenyl) cyclopropyl] several bases. Sit on a solution of (cis) -2- (4-bromophenyl) cyclopropanecarboxylic acid (1_0 eq) in toluene (0.2 mole concentration) and add CDI (1.5 eq). The mixture was stirred at 50 ° C for 18 hours. The solvent was evaporated, the resulting residue was vigorously stirred in hexane / CH2C12, filtered, and the filtrate was evaporated to give the title compound as a white solid. Step 2: (cis) -3-{[2- (4-Bromophenyl) cyclopropyl] jibyl 4-methyl-5-phenyl 1,3-° C. Ziran-2 -Copper comes from step 1 of (cis) -1-{[2- (cardiobromophenyl) cyclopropyl] chime imidazole (1 eq), (4R, 5SH +)-4-methyl A mixture of -5-phenyl-2_oxazolinone (i.2 eq) or hydrazone-isomer and DBU (added 1.2 eq at 0 ° C) in CH3CN (0.2 mole concentration). Stir at 0 ° C for 4 hours. The solvent was evaporated and the residue was purified by flash chromatography (hexane: EtOAc; 100: 0 to 80: 20) to give each diastereomer. Step 3 · (cis) -2-(4-Bromophenyl) cyclopropanesulfuric acid pair in THF-H20 (4: 1, 0.5 mole concentration), the amine ((+) or ㈠ isomer) solution at 0. LiOH (1.6 eq, 2 Molar concentration) and H2O2 (3 5%, 4 eq) were added at 0 °. The mixture was stirred at 0 ° C for 4 hours. The organic solvent was evaporated, the mixture was extracted with CHWh, the aqueous phase was acidified with 1 equivalent HCI, and the acid was extracted with EtoAc (3X). The combined organic extracts are washed with brine, dried, and the solvent is evaporated to produce fluorene or (0 optically active (cis) -2- (4-bromophenyl) cyclopropanecarboxylic acid. Another way is enantioselectivity Geocyclopropanation, for example using bis_.evil. Sit 92545.doc -52- 200535136

Porphyrin ligand / copper complex and diazoacetate (Evans et al. In J. Am. Chem. Soc. 1991, 1 13, 726), starting from 4-bromo The purpose of preparing styrene from optically active 2- (cis)-(4 > styrenylphenyl) cyclopropanesulfate is g. A mixture of cis and trans isomers was selectively hydrolyzed with LiOH (1 eq, based on the trans isomer) to produce 2- (transH4-bromophenyl) cyclopropanecarboxylic acid (used in Example 1) and The desired 2- (cis)-(4-> styrenylphenyl) cyclopropanethioic acid ethyl ester. Example 5 1- {3 ^ [3-[(Cyclopropylamino) amino] -4-oxo-1,8-naphthalene-1 (4H) -yl] -1,1'-biphenyl- 4-yl} cyclopropanecarboxylic acid

Step 1: 1- (4-Bromophenyl) cyclopropanecarbonitrile 4-bromophenylacetonitrile (1 eq), 1,2-bromoylaminoethane (1.5 eq), vaporized benzyltriethyl A mixture of ammonium (0.14 eq) in NaOH 50% (4 mole concentration) was heated to 50 ° C for 18 hours. The mixture was cooled to room temperature, the reaction was quenched with 5% HC1, and diluted with ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (hexane: EtOAc, 95: 5) gave the title compound. Step 2: 1-(4-Methenyl) cyclopropanesulfonic acid 92545 doc -53-200535136 Nitrile from Step 1, NaOH 25 ° / 〇 (12 eq) in EtOH (0.5 mole concentration) 'Heat to 100 ° C for 5 hours. The mixture was cooled to room temperature, quenched with AcOH and diluted with ether. The combined organic extracts were washed with brine, dried over MgS04, filtered and concentrated. Flash chromatography (hexane: EtOAc, 90:10 to 50:50) gave the title compound. Step 3: 1- {3 '-[3-[(Cyclopropylamino) carbonylcardioxo_ 丨, 8_naphthyridin-1 (4H) -yl] -1,1 · -biphenyl-4- Cyclopropanoic acid was prepared according to the procedure described in Example 2 and Step 3, but using the acid from Step 2 as the starting material. Flash chromatography (CH2C12: MeOH, 98: 2) gave the title compound as a white solid. H NMR (500 megahertz, C_36): δ 9.92 (d, 1H), 9.77 (d, lri [), 8.96 (s, 1H), 8.79 (dd, 1H), 8.74 (dd, 1H ), 8.00 (s, 1H), 7.76-7.72 (m, 3H), 7.65 (dd, 1H), 7.61 (dd, 1H), 7.52 (d, 2H), -.98 -2.94 (m, 1H), 1.60-1.58 (m, 2H), 1.25-1.22 (m, 2H), 0.82-0.88 (m, 2H), 0.62-0.59 (m, 2H). Example 6 (trans) 2- {3- [3-[(Cyclopropylamino) cyclo-oxo-naphthyll · 3 * · fluoro-1,1 \ biphenyl-4-yl} cyclopropyl Carboxylic acid 92545 doc -54- 200535136

Step 1: (trans) -2- (4-> Alkyl-2-fluorophenyl) cyclopropanecarboxylic acid, peptone, 4-bromo-2-fluorocinnamic acid and Pd (OAc) 2 ( 0.05 eq) of a mixture in dichloromethane (1 mole concentration), and a CH2N2 solution was added dropwise at 0 ° C until the reaction was complete by NMR analysis. The residue was purified by flash chromatography (hexane: EtOAc, 100: 0 to 70:30). Step 2: (trans) -2- {3 '-[3-[(Cyclopropylamino) carbonyl] -4-oxo-1,8-naphthyridin-1 (4H) -yl] -3 -fluoro -1, Γ-biphenyl-4-yl} cyclopropanethioate, naphthyridinone 2 (1.0 eq), ester from step 1 (1.3 eq), Na2C03 (3.5 eq; in H20) 2 Molar concentration), Pd (〇Ac) 2 (0.05 eq) and PPh3 (0.15 eq) or PdChdppf (0.05 eq) in n-propanol (oi Molar concentration), at 60-80. (: Stirred for 1-3 hours. The mixture was cooled to room temperature and poured into water 'and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over NhSCn, filtered and concentrated. Fast Chromatographic analysis (<: 20: 12 = EtOAc, 90: 10) yielded the title compound. Step 3: -2 Xanthen > {3 '-[3-[(Cyclopropylamino) carbonyl] -4- Oxo-1,8-naphthyridine-U4H) -yl] -3-fluoro-1,1'-bibenzyl-4-yl} cyclopropanecarboxylic acid in THF-MeOH (2: 1,2.2 Mo Ear concentration), the ester solution from step 2, LiOH (5, 2 mole concentration) was added, and the mixture was stirred at room temperature 92545.doc -55-200535136 for 6 hours. The organic solvent was evaporated, the aqueous phase was acidified with AcOH, and the acid was extracted with EtOAc (OX). The organics were washed with brine, dried, and the solvent was evaporated. The residue was triturated with CH2a2 / & | and then was filtered and filtered to give the title compound as a solid. H NMR (5GG megahertz, CDci3): § 9 85 ⑷ 叩, $ 〇8 (s, 1H), 8.80 (dd, 1H), 8.70 (dd, 1H), 7 71 (d, 1H), 7 63 (t, 1H), • 60 (s, 1H), 7.46 (dd, 1H), 7.40 (d, 1H), 7.28 (m, 2H), 7.01 (t '1H), 2.97 (m, 1H), 2.66 (m, ih), 1.93 (m, 1H), 1.62 (m, 1H), 1.40 (m, 1H), 0.84 (m, 2H), 066 (m, 2H). Optically active (+) or ㈠_ (trans) -2 · {3, _ [3 _ [(Cyclopropylamino) amino] _4_ oxo-1,8-naphthyridine] (4H) -yl] -3_ Fluoro], bisbiphenyl-4-yl} cyclopropanecarboxylic acid can use optically active (+) or (_) _ (trans) -2- (4-bromo-2-fluorobenzene) prepared according to the following procedure Methyl) cyclopropane to obtain methyl chitoate. Step A: 4-bromo-2-fluoro-1-vinylbenzene bromomethyltriphenyl bromide in tetrahydrofuran (0.13 mole concentration) The base scale (11 eq) suspension was added dropwise n-butyllithium (2.5 mol concentration in hexane, 1.1 eq) at -78 C over 20 minutes. The reaction mixture was stirred at -78 ° C for 15 knives and 4 seconds, warmed to 0 ° C, stirred for 15 minutes, and cooled back. 'A solution of bromo-2-fluoro-benzaldehyde (1 69) in 100 ml of THF was added dropwise over 30 minutes. The final mixture was allowed to warm slowly to room temperature and stirred for 1 hour. The resulting mixture was quenched with a saturated NHUa solution and diluted with 2 volumes of hexane. The organic extract was washed with brine, dried over MgSCu, filtered and concentrated. The residue was diluted with hexane / EtoAc (9: 1) and filtered on an oxidized crushed pad. The parts are combined and concentrated to produce the desired substance 92545.doc -56- 200535136. Step B: Ethyl (+)-2- (4-bromo-2-fluorophenyl) cyclopropanecarboxylate on copper (I) trifluoromethylite in aerated form (100 ml) A suspension of benzene complex (0.01 eq) was added with (R, R) -2,2, -isopropylidene-bis (4-tert-butyloxazoline) (0.01 eq) at room temperature. The mixture was stirred for 1 hour, and then poured through glass wool at 4C with a styrene solution (1.2 eq) in chloroform (0.1 mole concentration) from step 5. To this solution was added dropwise ethyl diazoacetate (0.8 eq) in aeroform (1 mole concentration) over 3 hours. The final mixture was searched overnight at 4 C. The mixture was concentrated. Flash chromatography (hexane: EtOAc; 95: 5) yielded the desired compound (84: 16, cis: trans isomer, Evans et al. In J. Am. Chem. Soc. 1991, 1 13, 726). Step C: (+)-2- (4-Bromo-2-fluorophenyl) cyclopropanecarboxylic acid (+) _ 2- (4-bromo-2- in tetrahydrofuran-methanol (2: 1) Fluorophenyl) Ethyl cyclopropanecarboxylate (mixed esters, 1 eq), and lithium hydroxide (〇84 eq) was added. The reaction was stirred at room temperature for 2 days. The resulting mixture was concentrated, diluted with water, and extracted with i (2x) to obtain a cis ester. As the aqueous phase, HC1 10 was used. / 〇Acidification 'is taken with ether (2x) to obtain (+) _ trans acid. The organic extracts containing trans acid were combined and washed with brine, dried over MgSCU, filtered, and concentrated. Step D:-(+)-2- (4-bromo-2-fluorobenzyl) cyclopropanecarboxylic acid The methyl ester pair (+) _ 2_ (4-bromofluorophenyl) cyclopropanecarboxylic acid solution in dichloromethane from step C (1 eq) was added to the diazomethane ether solution until the reaction was analyzed by TLC For completeness. The obtained was concentrated. The crude optically active ester was used as such in step 2 above 92545.doc '57-200535136. Example 7 2_ (trans)-{3-Gamo-3f- [3-[(Cyclopropylamino) carbonyl] -cardiooxoq, 讧 cai-1 (4H) -yl] -1, 1 Phenyl-4-yl} cyclopropane benzyl acid.

Step 1: Ethyl 2- (trans) -3- (4-bromo-2-chlorophenyl) prop-2-enoate 4-bromo-2-chlorobenzoic acid (1 eq) and triethyl A solution of phosphonium acetate (丨. 丨 in THF (0.3 Molar concentration)) was added dropwise at room temperature to the third potassium butoxide (1.1 eq, 1 Molar concentration, THF). The mixture was in It was stirred at room temperature for 3 hours, the reaction was stopped with HC1 10%, diluted with ether, strips were washed with NaHC03 solution, brine, dried on MgSCU, filtered and concentrated. Fast chromatography (hexane: EtOAc; 90: 1 〇 to 70 ·· 30), yielding the title compound. Step 2: 2- (trans)-{3-chloro_3 '-[3-[(cyclopropylamino) carbonyl] -4-oxo- 1,8-naphthyridine-1 (4H) -yl] -ΐ, ι'_biphenyl-4-yl} cyclopropancarboxylic acid was prepared according to the procedure outlined in Example 1, but using the ester from step 1 As starting material: lHNMR (500 megahertz, CDC13) 19.88 (S, 1H), 9.10 (s, 1H), ^ 2545.doc -58- 200535136 8.80 (d, 1Η), 8.70 ( d, 1H), 7.72 (d, 1Η), 7.65 (m, 3H), 7.45 (m, 3H), 7.05 (Mountain 1H), 2.95 (m, 1H), 2.70 (m , 1H), 1.80 (m, 1H), 1 65 (m, 1H), i · 35 (m, 1 H), 0 · 85 (m, 2H), 0 · 65 (m, 2H). Example 8 2_ (cis) _ (3,-[3-[(Cyclopropylamino) weiyl-oxo-1 , 8-naphthalene ° d-1 (41 ·!)-Yl] amino-biphenyl-4-yl} cyclopropanecarboxylic acid

〇VO〇H 制备 was prepared according to the procedure described in Example 4, but using 4-bromofluorobenzaldehyde as the starting material. NMR (500 million n **, ', paper, DMSO-d6): δ 11.91 (br s, 1H), "5 (d, 1H), 8.83 (s, lm 〇 (Ί), 8.79 (dd , 1H), 8.74 (dd, 1H), 8.02 (s, 1H), 7,93 (d, 1H), 7 7rw 1H), 7.54 (d, m) 736 (^^ 7 ^ -66 (m, 2H), 7.57 (d, iH), 2.08_2.13 (m (t, 1H), 2.88-2.94 (m, 1H), 2.55 (q, 0-77-oS! (m, 2 ^, 〇5: `` 53 ^ 1H) > ^ 36-1 · 40 ^ 1H ^ ~ · 56 · 〇.59 (Π !, 2Η). K Example 9 2- (反) _ {3,-[ 4_ oxo, 3 producing V ,, 2_digasethyl) amino] carbonylcarbonyl 1,8-naphthalene 92545 dooc -59- 200535136 pyridin-1 (4H) -yl] -1,1'-linked Phenyl-4-yl} cyclopropanecarboxylic acid

Step 1: 1- (3-Bromophenyl) > 4-oxo- > |-(2,2,2-trifluoroethyl) -1,4-dihydro-1,8-naphthyridine- 3-Carboxamide is added to naphthyridone 1 (1 eq) from step 3, and the acid solution in DMF (0.1 mole concentration) is added with HATU (4eq), diisopropylethylamine (8eq), Continue with 2,2,2-difluoroethaneamine (4 eq). The mixture was stirred at room temperature for 12 hours and then heated at 80 ° C for 2 hours' was cooled to room temperature and diluted with water. The residue was then treated with It was separated and washed with water and triturated in acetone to give the title compound. Step 2: 2- (transH3,-[4_ oxo_3 _ {[(2,2,2_trifluoroethyl) amino] carbonyl) (Earth) 1,8 naphthalene-1 (4H) -yl] ,: ^ Guangbiphenyl + yl} cyclopropanecarboxylic acid was prepared according to the procedure described in Example 1, but using amidine from the process as the starting point H NMR (500 megahertz,… m / LDC13) δ 11.3 (s, 0Η), 10.34 (s, ΝΗ), 9.1-1 (s, 1Η), 8.88 (dd ⑴, Ω, ⑽, 1Η), 8.77 (dd, 1Η), 7.78 (d, 1Η), 7.68 (t, 1H), 7.65 (s, 1H) 7… called, 7.56 (d, 2H) , 7.52 (dd, 1H), 7.44 (dd, 1H), 7.22 (d 2H) 4 ”λ 4 · 21 (br qt, 2H), 2.62 (m, 1H), 1.97 (m, 1H), 1.70 (m, ^,), i · 45 (m, 1H). MS + ESI Q1 (M + 1) 92545 doc -60- 200535136 508.1. Example 1 〇 (+ H transfluoro-3 '-[4-oxo-3 _ {[(2,2,2-trifluoroethyl) amino] Yinaphthalene σ ^ -1 (4Η) -based] bibenzyl_4_yl} cyclopropane

Step 1: 1- (3-Bromophenyl) -1,4-dihydro [1,8] naphthyridin-4-one-3-brantoate ethyl 2-chloronicotinyl ethyl acetate ( 1 eq) (purchased or prepared according to the procedures described in j. Het Chem ·, 30, 855, 1993), triethylamine (4 eq), and 3,3-dimethylaminoethyl acrylate (1.5 eq) The mixture in acetonitrile (0.5 Molar concentration) was 'heated to reflux for 3 hours' and cooled to 40-50 C, and 3-> aniline (1 eq) was added. The reaction was heated to reflux overnight, cooled to room temperature, and diluted with water (2 volumes). The product was isolated by filtration and washed with water, ether or acetonitrile-water (1: 1). NMR (acetone-d6) δ 1.32 (t, 3H), 4.29 (q, 2H), 7.54-7.63 (m, 2H), 7.69 (dd, 1H), 7.78 (dd, 1H), 7.93 (s, 1H), 8.66-8.71 (m, 3H). Step 2: 1- (3-Bromophenyl) -l, 4-dihydro [1,8] naphthyridin-4-one-3-carboxylic acid 92545 doc -61- 200535136 from step 1 of 1- (3 -Bromophenyl) -1,4-dihydro [1,8] naphthyridin-4-one-3-carboxylic acid ethyl ester (1 eq) in tetrahydrofuran-methanol (0.15 Molar concentration) and 1 The suspension in a mixture of an equivalent concentration sodium hydroxide (2 eq) aqueous solution was heated and stirred at about 50 ° C for 20 minutes. After cooling, the mixture was diluted with water and acidified with 1 HC1 aqueous HC1. After stirring for 45 minutes, the precipitate was filtered, washed well with water, and dried to give the title acid as a cream-colored solid. 4 NMR (acetone-d6) δ 7.65 (t, 1H), 7.76 (m, 2H), 7.84 (d, 1H), 7.99 (s, 1H), 8.87 (m, 2H), 9.01 (s, 1H ). Step 3: 1- (3-Bromophenyl) -N- (2,2,2-trifluoroethyl) -1,4-dihydro-1,8-naphthyridin-4-one-3-carboxyl The amidamine is from 1- (3-bromophenyl) -1,4-dihydro [1,8] naphthalene-4--4--3-carboxylic acid (1 eq) and triethylamine (3 eq) A suspension in tetrahydromethane (molar concentration of 0.08) was added at 0 ° C. with isobutyl chlorophosphonate (1.8 eq). At 〇. After stirring at 0 ° C for 2 hours, 2,2,2-trifluoroethylamine (5 eq) was added, and the mixture was allowed to warm to room temperature, and stirred overnight. The mixture was then distributed between ethyl acetate and water. The organic phase was dried and evaporated to a solid. The ether was stirred at room temperature for 3 hours and filtered to give n_ (2,2,2- as a white solid. Digas ethyl odorant base) -i, 4-diazine [1,8] Cai. Ding-4-Qi-3- Jun acid amine. In addition: 1- (3-Bromophenyl) -i, 4-dihydro [1,8] naphthalene-4 -_- carboxylic acid (1 eq) from step 2 in DMF (0.1 Molar concentration) The suspension was added with HATU (4eq), diisopropylethylamine (8eq), followed by 2,2,2-trifluoroethaneamine (4eq). The mixture was stirred at room temperature for 12 hours, then 92545.doc -62- 200535136 was added at 80 t for 2 hours, cooled to room temperature and diluted with water. The residue was then isolated by filtration, the bars were washed with ether, and triturated in acetone to give the title compound. Step 4: N- (2,2,2-trifluoroethyl) _; μ [3_ (4,4,5,5-®ψ * -l, 3,2-dioxaborolan-2-yl) phenyl] ιι, 4-dihydro- 丨, 8-naphthyridin-4-one-3-carboxamimine 1- [3- (bromophenyl) -N- (2,2,2_trifluoroethyl)- hydrazone, 4-dihydro-1,8-naphthyridin-4-one-3-carboxamide (1.0 eq), pinacol dimethylborane (15 eq), kAc (4 eq), and PdCl2 ( A mixture of dppf) (0.05 eq) in DMF (0.2 Molar concentration) was stirred at 70-80 ° C for 3 hours. The mixture was cooled to room temperature and diluted with EtOAc and NHW1 solution. The organic extract was washed with h20, brine, dried over MgSCU, filtered and concentrated. The mother liquor was crystallized from isopropyl ether-hexane (0: 1: 2) and flash chromatography (CH2Cl2: EtOAc, 50:50) yielded the title compound as a white solid. Step 5: 4-bromo-2-fluoro-vinylbenzene bromide methyl triphenyl scale (11 eq) suspension in tetrahydrofuran (0.13 Molar concentration) at -78 C, Within 20 minutes, n-butyl chloride (2.5 mol concentration in hexane, .1 eq) was added dropwise. The reaction mixture was at -78. Stir for 15 minutes, warm to 0 ° C, stir for 15 minutes, and cool back to -78 ° C. A solution of 4-bromo-2-fluoro-benzaldehyde (1 eq) in 1000 ml of thf was added dropwise over 30 minutes. The final mixture was allowed to slowly warm to room temperature, and the mixture was filtered for 1 hour to stop the reaction with a saturated NH4C1 solution, and diluted with 2 times the volume of hexane. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The residue was diluted with hexane / EtOAc (9: 1) and filtered on a pad of silica gel. The parts are combined and concentrated to produce the desired substance 92545 doc -63-200535136. Step 6: (+)-2- (4-Bromo-2-fluorophenyl) cyclopropanecarboxylic acid ethyl ester of copper trifluoromethanesulfonate benzene benzene complex in aerosol (100 ml) (0.01 eq) suspension, (R, R) _2,2, -isopropylidene-bis (cardio-tertiary-butyl-2-oxazoline) (0 · (Π eq) was added at room temperature. Mixture Stir for 1 hour, and then pour a styrene solution (1.2 eq) from aerosol (0.1 mol) in step 5 through glass wool at 4C. Add this solution dropwise over 3 hours. Ethyl diazoacetate (0.8 eq) in imitation (1 mole concentration). The final mixture was stirred overnight at 4 ° C. The mixture was concentrated. Flash chromatography (hexane: EtOAc; 95: 5) yielded The desired compound (84:16, cis: trans isomer, the method described by Evans et al. In J. Am. Chem. Soc. 1991, 113, 726). Step 7: (+)- 2- (4-Bromo-2-fluorophenyl) cyclopropanecarboxylic acid (+)-2- (4-bromo-2-fluorophenyl) ring in tetrahydrofuran-methanol (2: 1) A solution of ethyl propanecarboxylate (mixed esters, 1 eq) was added with lithium hydroxide (0.84 eq). Stir for 2 days. The resulting mixture is concentrated, diluted with water, and extracted with ether (2x) to obtain the cis ester. The aqueous phase is acidified with HC1 10%, and extracted with ether (2x) to obtain (+) _ trans Acid. Organic extracts containing trans acid are combined and washed with brine, dried over MgS04, filtered, and concentrated. Step 8 ·-(+)-2-(4-> Sulfur-2- Fluorophenyl) cyclopropanecarboxylic acid methyl ester. (+)-2- (4-Bromo-2-fluorophenyl) cyclopropanecarboxylic acid in dioxane from step 7 (1 eq) Add diazomethane in ether solution until the reaction is complete by TLC analysis. The resulting mixture is concentrated. The crude ester is used as such in the next step 92545 doc -64- 200535136. Step 9: (+ ) -2- {3-Fluoro-3 '-[4-oxo-3-{[(2,2,2-trifluoroethyl) amino] carbonyl group 1,8-naphthyridine-1 (4H ) -Yl] biphenyl-4-yl} cyclopropanecarboxylic acid methyl ester from (+)-2- (4-Molyl-2-fluorobenzyl) cyclopropanecarboxylic acid methyl acetate from step 8 (1 · 2 eq) and a borate solution (1 eq) in DMF-iPrOH (1: 1 molar ratio), and two ginseng (dibenzylideneacetone) two ( ) (〇_〇55 eq), 2- (dimethylamino) -2 '-(dicyclohexylidene) biphenyl (〇.ΐ3 eq) and sodium carbonate solution (2 mole concentration, 4 eq ). The reaction mixture was heated at 78 ° C for 2 hours. The reaction mixture was filtered over Celite and silica (1: 1) and washed with EtoAc. The filtrate was concentrated in vacuo and the remaining solvent was evaporated in vacuo. The resulting yellow solid was stirred vigorously in ether. The residue was then isolated by filtration and the bars were washed with ether. The mother liquor was purified by flash chromatography (benzene / EtOAc, 100: 0 to 70:30). Step 10: (+)-2- {3-Fluoro-3 '-[4-oxo-3-{[(2,2,2-trifluoroethyl) amino] carbonyl 1,8-naphthalene Pyridin-1 (4H) -yl] biben-4-yl} cyclopropanecarboxylic acid For the ester solution from step 9 in THF-MeOH-HaO (7: 3: 10 mol concentration), add LiOH (1.1 eq, 1 mole concentration), and the mixture was stirred at 50 C for 3 hours' and then at room temperature for 24 hours. The organic solvent was acidified by evaporation 'and the aqueous phase was acidified at 1 equivalent concentration HC1, and the acid was extracted with EtoAc (3X). The organics were washed with brine, dried, and the solvent was evaporated to give 2- (3-bromophenyl) cyclopropanecarboxylic acid. The obtained solid was vigorously stirred in hexane_ether_acetone for 1 hour, and then collected by filtration. Enantiomers 0-2- {3-Fluoro-3 '_ [4-oxo_3-{[(2,2,2-trifluoroethyl) amino] carbonylnaphthyridinyl] bibenzyl -4_yl} cyclopropanecarboxylic acid 92545 doc -65-200535136 (S, S) -2,2, -isopropylidene-bis (4-tert-butyl_2-oxo) in step 6 can be used Zolium) was obtained. !! ^ 1 ^ 11 (500 million hertz, 00 (: 13): 3 10.31 (3, that is), 9.10 (3, 1H), 8.9 (dd, 1H), 8.78 (m, 1H), 7.78 (dd, 1H), 7.7l (t, 1H), 7.64 (br s, 1H), 7.53 (m, 1H), 7.47 (dd, 1H), 7.35 (m, 2H), 7.09 (t, 1H), 4.16 (m, 2H), 3.77 (m, 1H), 2.00 (m, 1H), m (m, 1H), 1.52 (m, 1H). MS + ESI Q1 (M + l) 525.9 Example 11 1-({31- [3-[(Cyclopropylamino) carbonyl] _4-oxo-1,8-naphthyridine, 1 (4] 9 [) _ yl]

Biphenyl-4-yl} methyl) cyclobutane

Step 1: 1-(4-> Benzyl benzyl) cyclobutane

Ethyl acetate (1 eq) and the reaction mixture was warmed to -400c for 10 minutes. The reaction mixture was cooled back to -78 ° C for 1 hour and then added as a solid odor

^ 2545 doc -66- 200535136 (9 5 · 5 hexane · ethyl acetate) to produce electricity, such as J to produce 1- (4- / styrenyl) cyclobutanecarboxylic acid ethyl SI ° Step 2: 1 · ({3,-[3-[(Cyclopropylamino) amido] _4-oxo- 丨, 8-Ceadidine-1 (4Η) -yl] biphenyl-4-yl} methyl) ring Ethyl butanecarboxylate nalidone 2 (1.0 eq), ester from step 1 (1.5 eq), Na2CO3 (3.5 eq; 2 mole concentration in 0), Pd (〇Ac) 2 (0055 eq) and Ca 3 (0-15) or PdCl2dppf (0.05 eq) in n-propanol-dmfg: lo (mole concentration), and stirred at 70 ° C for 2 hours. The mixture was cooled to room temperature, the reaction was quenched with AcOH and diluted with EtoAc. The combined organic extracts were washed with brine, dried over NadO4, filtered and concentrated. Flash chromatography (CH2Cl2 / MeOH, 99: 1) gave the title compound. Step 3: 丨-({3 '-[3-[(Cyclopropylamino) carbonyl] -4_oxo- 丨, 8-naphthyridin-1 (4H) -yl] biphenyl-4-yl} Methyl) cyclobutanecarboxylic acid was added to the ester solution from step 2 above in THF-Me0H-H20 (2: 1: 0.5, 0.1 Molar concentration), and LiOH (5 eq, 2 Molar concentration) was added And the mixture was stirred at 50QC for 4 hours. The organic solvent was evaporated, the aqueous phase was acidified with AcOH, and the acid was extracted with EtOAc (3X). The organics were washed with brine, dried, and the solvent was evaporated. The residue was analyzed by flash chromatography (CH2Cl2 / MeOH, 10% NEUOH, 85:15) to give the title compound as a white solid. 4 NMR (500 megahertz, acetone-d6): δ 9.87 (s, NH), 9.1 (s, 1H), 8.84 (dd ·, 1Η), 8.72 (dd, 1Η), 7.72 (d, 1Η) ), 7.61 (m, 2Η), 7.49 (m, 3H), 7.39 (d, 1H), 7.27 (m, 1H), 3.18 (s, 2H), 3.05 (m, 1H), 2.5 (m, 2H), 2.12 (m, 2H), 1.95 (m, 2H), 0.90 (m, 2H), 0.70 (m, 2H). MS 492.0 ㈠. 92545 doc -67- 200535136 The following compounds are used according to the previous steps ... under spray or chemical ionization conditions. :: Analyze the mass spectrometer, and point out the (M-D. Value. Say " respective (M + υ + value. * Example 12 ~~ ----__ chemical name --- --- ---_______________________ (Trans) -2- {3 |-[3-[(Cyclopropylamino) amido] _4-oxo-1,8-naphthyridin-1 (4H) _yl] biphenyl_4_yl} _2 • methylcyclopropanecarboxylic acid LRMS (M + 1) + 480.2 13 3-methyl-3- {3 '-[4-oxo-3 _ {[(2,2, fluorenetrifluoroethyl) amino ] Carbonyl} -1,8-naphthyridin-i (4H) -yl] biphenyl-4-yl} butanoic acid 524.3 14 (+ H trans) -2- {3-amino-3 '-[3- [ (Cyclopropylamino) carbonyl] -4-oxo-1,8-naphthyridine-i (4H) -yl] biphenyl-4-yl} cyclopropanecarboxylic acid 500.2 15 (-)-(trans)- 2- {3 '-[4-oxo-3-{[(2,2,2-trifluoroethyl) amino] carbonylnaphthyridine-1 (4H) -yl] biphenyl-4-yl} Propanecarboxylic acid 506.2 * 16 3- {3 '-[3-[(Cyclopropylamino) carbonyl] -4-oxo-1,8-naphthalene ° denyl] biphenyl-4-yl} -2,2 -Difluorenylpropanoic acid 482.2 17 4-mono {3 '-[3-[(Cyclopropylamino) carbonyloxo-1,8-naphthyridin-1 (4H) -yl] biphenyl-4-yl } -3,3-Difluorenyl butyric acid 496.2

92545 doc * 68 * 200535136 example chemical name LRMS (M + 1) + 18 l-({3f- [4-oxo-3-{[(2,2,2-trifluoroethyl) amino] weiyl } -1,8-nai ° ^ -1 (4Η) -yl] biphenyl-4-yl} methyl) cyclobutanecarboxylic acid 534.2 * 19 2,2-dimethyl-4- {3f- [4 -Oxo-3-{[(2,2,2-trifluoroethyl) amino] carbonyl} -1,8-naphthyridin-1 (4H) -yl] biphenyl-4-yl} butanoic acid 538.2 20 2,2-dimethyl-3- {3f- [4-oxo-3 · {[((2,2,2-trimurylethyl) amino] amido}}-1,8-naphthalene -1 (411) -yl] biphenyl-4 -yl} propionic acid 524.4

92545.doc -69-200535136

02545 doc -70- 200535136

Other changes or modifications apparent to those skilled in the art are within the scope and teachings of the present invention. The invention is not limited except as indicated in the scope of the following patent applications. 92545.doc -71-

Claims (1)

200535136 Scope of patent application: 1. A compound represented by formula (I): 〇 〇 Or a pharmacologically acceptable salt thereof, wherein Y is selected from the group consisting of: R3 R4 / \ ^ X ^ C〇〇H R1 is cyclopropyl or -CH2-CF3; R2 is Η, F or C1; R3 is Η or CH3; and R4 is Η or CH3. 92545 doc 200535136 2 · The compound according to item 1 of the scope of patent application, wherein one of R3 and R4 is CH3. ,,, 3. The compound according to item 范围 of the scope of patent application, wherein r3 & r4 are each CH3. 4. The compound according to item 1 of the scope of patent application, wherein: R1 is cyclopropyl; and R3 and R4 are each CH3. 5_ > The compound according to item * in the scope of patent application, wherein γ is \ ^ Ρ〇〇〇Η 6. The compound according to item 1 in the scope of patent application, wherein R1 is -CH2_CF3; and R3 and R4 are each ch3. 7. The compound according to item 1 of the scope of patent application, which is: 3- {3f- [3-[(cyclopropylamino) carbonyl] -4_oxo-1,8-naphthyridine-1 (4 « O-yl] -1,1'-biphenyl-4-yl} _3-methylbutanoic acid; 2 (trans) cyclopropylamino) epiyl] -4-oxo-1,8-naphthalene. N-U4H) -yl] -3-fluorobiphenyl-cardiyl} cyclopropanecarboxylic acid; 2- (trans)-{3-chloro-3 '-[3 _ [(cyclopropylamino) carbonyl]- 4-oxo_ 丨, 8_ Nai.疋 -1 (4H) -yl] biphenyl-4-yl} cyclopropanecarboxylic acid; 2- (cisM3 '-[3-[(cyclopropylamino) carbonyloxo- 丨, 8_naphthyridine-U4H ) -Yl] -3-fluoroyldecylbenzyl-4-yl} cyclopropanecarboxylic acid; (+)-(trans) -2- {3-fluoroyl-3 '-[4-oxo-3- { [(2,2,2-trifluoroethyl) amino] carbyl 1,8-naphthyridin-1 (4H) -yl] biphenyl-4-yl} cyclopropanecarboxylic acid; 200535136 cyclopropylamine Group) carbonyl] -4_oxo-i, 8-naphthyridinyl] biben-4-yl} methyl) cyclobutanecarboxylic acid; (trans) -2- {3M > [(cyclopropylamino) Carbonyl] -4-oxo-1,8-naphthyridine-U4H) -yl] bibenzyl 2-methylcyclopropanecarboxylic acid; 3-fluorenyl-3- {3,-[4_oxo_ 3-{[(2,2,2-trifluoroethyl) amino] carbonyl group, 8-naphthyridine 4 (4H) -yl] biphenyl-4-yl} butanoic acid; 3_ {3H > [( Cyclopropylamino) carbonyl] -4_oxo- 丨, 8-naphthyridine-; 1 (4] 9 [) _ yl] biphenyl-4-ylbu 2,2-dimethylpropanoic acid; 4 -{3, [> [(cyclopropylamino) carbonyl] -4_oxo- 丨, ^ naphthyridin_1 (4Η) -yl] bibenzyl-4-ylb, 3,3-dimethyl Butyric acid; oxo-3-{[(2,2,2-trifluoroethyl) amino] carbonyl} -1,8-naphthalene. Ding-1 (411) -yl] biphenyl-4-yl} fluorenyl) cyclobutanecarboxylic acid; 2,2-dimethyl-4- {3 '-[4-oxo-3-{[( 2,2,2-trifluoroethyl) amino] carbonyl} -1,8-naphthyridin-1 (4Η) -yl] biphenyl-4-yl} butanoic acid; 2,2_dimethyl-3 -{3f- [4-oxo-3-{[(2,2,2-trifluoroethyl) amino] carbonyl group, 8-naphthyridin-1 (4Η) -yl] biphenyl-4-yl } Propionic acid; trans: M3 '-[4-oxod-{[(2,2,2-trifluoroethyl) amino] carbonyl group, 8-naphthyridine-fluorene (4Η)-group; μm , Ι, _biphenyl + yl> cyclopropanecarboxylic acid; and 0) '(trans) -2- {3'-[4-oxo-3-{[(2,2,2-trifluoroethyl ) Amine] carbonyl 1,8-naphthyridin-i (4H) -yl] biphenyl-4-yl} cyclopropanecarboxylic acid. 8. The compound according to item 丨 in the scope of the patent application, which is: 2, (trans)-{3 '-[3-[(cyclopropylamino) carbonylcarbonyloxo-1,8-naphthyridine • 1 (4-Hexyl) -3-fluoro-1,1, bibenz-4-yl} cyclopropanecarboxylic acid. 9 · A pharmaceutical composition comprising: 92545.doc 200535136 A therapeutically effective amount according to the scope of patent application The compound of item 1 or a pharmacologically acceptable salt thereof; and a pharmacologically acceptable carrier. 10. A pharmaceutical composition for the treatment or prevention of asthma, chronic bronchitis, K-type obstructive pulmonary disease (COPD), Eosinophilic granuloma, psoriasis, and other benign or malignant proliferative skin diseases, endotoxic shock (and related symptoms, such as horse equine lamelitis and colic), septic shock, ulcerative colitis, cloning 'S disease, myocardial and brain reperfusion injury, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, allergic skin, anesthesia, adult respiratory distress, infant respiratory distress, Bifurcated obstructive pulmonary disease, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, spring Conjunctivitis, arterial restenosis, arteriosclerosis, nerve tissue inflammation, pain, cough, rheumatoid arthritis, arthritis spondylitis, transplant rejection and graft-to-host disease, excessive gastric acid secretion, bacterial, fungal or viral causes Septic or septic shock, inflammation and cytokine-regulated chronic tissue degradation, osteoarthritis, cancer, atrophy, mental weakness, depression, memory impairment, unipolar depression, acute and chronic with inflammatory components Neurodegenerative disorders, Parkinson's disease, Alzheimer's disease, spinal nerve trauma, head trauma, multiple sclerosis tumor growth, and normal tissue invasion by cancer, which contain a therapeutically effective or preventive effective amount according to the scope of patent application Compound or a pharmacologically acceptable salt thereof. 11. A pharmaceutical composition for improving cognitive ability in a healthy subject, comprising a safety-enhancing amount of a 200535136 compound or a pharmacological salt thereof in accordance with the scope of application for patent application No. 丨12. The pharmaceutical composition according to item 10 or 11 of the scope of patent application, The amount of the compound is not enough to emisis the patient. 13. The pharmaceutical composition according to item 10 or 11 of the scope of patent application, wherein the patient is a human being 55 years of age or older. 92545 doc 200535136 Figures: (1) The designated representative of this case is: (None) (B) The representative symbols of the representative diagram are briefly explained: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 02545 doc 200535136 Patent Application No. 093110725 Chinese Application for Patent Scope Replacement (July 1984) Pick up and apply for patent scope: 1. A compound represented by formula (I): 〇〇R1 ..................... N Η Or a pharmacologically acceptable salt thereof, wherein Υ is a group selected from: \ < ^ pCOOH ^ X ^ COOH R3 R4 H3C R3 R4 Human) ^ CO〇H R3 R4 o ^^ X ^ COOH R1 is cyclopropyl or -CH2-CF3; R2 is hydrazone, F or Cl; R3SH * CH3; and R4 is H or CH3. 92545-) 407 Π.doc 200535136 2. The compound according to item 1 of the scope of patent application, wherein one of r3 & r4 is CH3. ·, '3 · The compound according to item 1 of the scope of patent application, wherein R3 and R4 are each CH3. 4. The compound according to item 1 of the scope of patent application, wherein: R1 is cyclopropyl; and R3 and R4 are each CH3. 5. According to the compound in the scope of the patent application, item 4, wherein γ is x ^ pCOOH 6. According to the compound in the scope of the patent application, item 1, wherein R1 is -CH2-CF3; and R3 and R4 are each CH3. 7. The compound according to item 1 of the scope of patent application, which is: 3- {3f- [3-[(cyclopropylamino) carbonyl] _4_oxo- 丨, 8_naphthyridine_1 (4h) _ Group] -1, Γ-biphenyl-4-yl} -3-methylbutanoic acid; 2- (trans)-{3 '-[3-[(cyclopropylamino) carbonyl] -4_oxo -丨, 8-naphthyridin-1 (4Η) -yl] -3-fluoro-,-biphenyl-4-yl} cyclopropanecarboxylic acid; 2- (transM3-chloro group 4434 (cyclopropylamino) ) Carbonyl oxo 4, ^ naphthyridin-1 (4H) -yl] -U, · biphenyl-4-yl} cyclopropanecarboxylic acid; 2- (cis)-{3 '-[3-[(cyclopropyl Amino) carbonyl] -4_oxo_ 丨, 8_naphthyridin-1 (4H) -yl> 3-fluoro-U, biphenyl-4-yl} cyclopropanecarboxylic acid; (+ H 反) _2_ {3-Fluoro-3 '-[4-oxo-3-{[(2,2,2-trifluoroethyl) amino] weiyl} -1,8-naphthyridine-1 (4H ) -Yl] bibenzyl-4-yl} cyclopropanecarboxylic acid; 92545-940711.doc 200535136 cyclopropylamino) carbonyl] -4-oxo-, 8-naphthyridin-1 (4h) _yl] Biphenyl-4-yl} methyl) cyclobutanecarboxylic acid; (trans ^-^ '^-"cyclopropylamino 丨 carbonyl ^ -oxo- 丨 naphthalene-1 (4H > yl) biphenyl _4-yl} -2-methylcyclopropanecarboxylic acid; 3-methyl | {3, _ [4_oxo_3 _ {[(2,2,2-trifluoroethyl) amino] carbonyl group 1, 8-naphthyridin-1 (4H) -yl] biphenyl-4-yl} butanoic acid; 3- {3-[3-[(cyclopropylamino) hexyl] -4-oxo-1,8 _Naphthalene lake_ 1 (4pj) _yl] biphenyl-4-yl} _2,2-dimethylpropanoic acid; 4_ {3-[3-[(cyclopropylamino) amido] -4-oxy -I, 8-naphthalene_i (4H) __ yl] biphenyl-4-ylbu 3,3-dimethylbutanoic acid; 1-({3 '-[4-oxo_3 _ {[ (2,2,2-trifluoroethyl) amino] carbonyl} -1,8-naphthalene% -1 (4Η) -yl] biphenyl-4-yl} methyl) cyclobutanecarboxylic acid; 2, 2-dimethyl-4- {3,-[4-oxo-3-{[(2,2,2-trifluoroethyl) amino] carbonyl M, 8-naphthyridin_1 (4H)- Phenyl] biphenyl-4-yl 丨 butanoic acid; 2,2-dimethyl-3- {3,-[4-oxo-3-{[(2,2,2-trifluoroethyl) amino ] Carbonylcarbonyl 1,8 · naphthyridine-U4H) -yl] biphenyl-4-yl} propanoic acid; _trans)-{3,-[4-oxo_3-{[(2,2,2 · Trifluoroethyl) amino] carbonyl], 8 · naphthyridine-U4H) -yl] -1,1, _biphenyl_4-yl} cyclopropanecarboxylic acid; and (+ (trans) -2- { 3,-[4-oxo-3-{[((2,2,2-trifluoroethyl) amino] carbonyl], 8-naphthyridinyl;] biphenyl-4-yl} cyclopropanecarboxylic acid . 8_ Compound according to item 1 of the scope of patent application, which is ... 2_ (trans)-{3, -1 > [(cyclopropylamino) carbonyl] -4-oxo-1,8-naphthyridine 1 (4Η) -yl] -3-fluoro 丄 ′ ′ -biphenyl-4-yl} cyclopropanecarboxylic acid. 9. The compound according to item 8 of the scope of application for a patent, which is: 92545-940711.doc 200535136 () (trans) -2- {3f- [3-[(cyclopropylamino) quinoyl] oxo -i, 8-naphthylpyridine (fluorenyl)]-3_fluoroyl, ι'_biphenyl_4_yl} cyclopropaneweiric acid. 11: A pharmaceutical composition comprising: a therapeutically effective amount of a compound according to item 1 of the scope of patent application or a pharmacologically acceptable salt thereof; and a pharmacologically acceptable carrier. • A pharmaceutical composition for the treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis " " benign or malignant skin disease, endotoxic shock (And related symptoms such as equine lamelitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, inflammation = key inflammation, osteoporosis, Chronic glomerulonephritis, allergic dermatitis, ramie therapy, adult respiratory distress, infant respiratory distress, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic, 'fire, spring Conjunctivitis, arterial restenosis, arteriosclerosis, neural tissue inflammation, pain, cough, rheumatoid arthritis, arthritis spondylitis, transplant rejection and graft-to-host disease, hyperacidity, drowsiness, In the main bacteria, spoilage or septic shock that is not caused by a single disease, test X and cytokine-regulated beer drop, namely k-type tissue degradation, osteoarthritis, Disease, debilitating, mentally debilitating ginseng, ^ 'and long 5 丨 thinking of deduction, soap polarity depression, acute inflammation with inflammatory composition B ^ aa / less ~, sexual and k neurodegeneration disorders, Parkinson's 'S disease, Alzheimer's disease, spinal dysfunction, k is a naive god altar, head trauma, multiple sclerosis, tumor growth and normal phase, and I know about cancer, which includes effective treatment 92545-940711. doc 200535136, or a pharmacologically acceptable salt thereof, of a compound of scope i of the patent scope, or a prophylactically effective amount. 12. 13. 14. A pharmaceutical composition for enhancing cognitive ability in a healthy subject, comprising a compound or a pharmacological salt thereof according to the scope of the patent application for a safety-enhancing amount. According to the pharmaceutical composition in the scope of claims 11 or 12, the amount of the chelating substance is not enough to vomit in the affected area. The pharmaceutical composition according to item 11 or 12 of the scope of application for a patent, wherein the human suffers from a human age of 55 years or older. '' 92545-940711.doc