TW201121941A - Adamantyl amide derivatives and uses of same - Google Patents

Abstract

The present invention provides adamantyl amide derivatives of formula (I): wherein R1, R2, and L are as defined herein; or a pharmaceutically acceptable salt thereof; and pharmaceutical compositions and methods using the same.

Description

201121941 VI. Description of the Invention: [Technical Field to Which the Invention Is Applicable] The present invention provides an adamantylamine derivative, a pharmaceutical composition using the same, and a method of treatment. [Prior Art] The present invention is directed to an adamantane derivative which acts as an ectopic modulator of the metabolic glutamate receptor 5 (mGhi5 receptor or mGluR5), and a pharmaceutical composition and a treatment method using the specific compound. The face acid is the major excitatory neurotransmitter in the mammalian central nervous system. One is the regulation of glutamate. The way of neurotransmission is regulated via a metabotropic glutamate receptor (mGluR); the other is an ionotropic receptor. Currently, eight mGluRs have been selected and are divided into three groups based on sequence homology, preferred signal transduction pathways, and pharmacology. Group I mGluR includes mGluR1 and mGluR5, while Group II contains mGluR2 and mGluR3 and the in group contains mGiu4 '6, 7 and 8 receptors. The mGlu receptor has an essential role in normal brain function as well as in neurological, neurological and neuromuscular disorders. The mGlu5 receptor is mainly localized to postsynaptic and highly expressed in the marginal zone of the brain. The mGlu5 receptor is also expressed in the thalamus, spinal cord, and vagus nerve system' and on the nerve endings and C fibers in the periphery of the skin. Ligands of the mGlu5 receptor have been shown to be useful for the treatment of peripheral and central nervous system disorders. See, for example, G. Jaeschke et al., "mGlu5 receptor antagonists and their therapeutic potential", EXpert TTier. 2008, 75, 2: 123-142. It has also been suggested that the facial acid analogs of the 201121941 Geba to the orthotopic binding site may be limited by the low brain permeability and insufficient selectivity of different mG丨uR subtypes. Synthetic agonists are likely to cause continuous receptor stimuli because they are usually designed to be metabolically stable. This continuous stimulation is undesirable because of potential receptor desensitization problems. Similarly, with regard to receptor occupancy, synthetic antagonists may result in long-term blockade of receptor function, which may be incompatible with the dynamics of the pathology of central nervous system disorders. However, a more selective and controlled "fine tuning" effect on the mGlU5 receptor has become feasible due to ectopic regulation. See, for example, p Bach et al. "Metabotropic giutamfte recept()r 5 (4) to (4) _ chemist potential therapeutic applications^ Expert Opin Ther

Pa_’ 2007, i7, 4: 371_381. Ectopic regulation refers to the binding of a modulator ligand to a site on the receptor that is different from the ortho-level acceptor or ligand binding site. This ligand binding process results in a conformation of 冉~叹' which may completely affect protein function (e.g., G-protein coupled receptor J, such as mGluR, including mGluR5). The novel mGluR5 ligand of ectopically regulated mGluS receptors can improve the treatment of traditional Chinese sacral nervous system agents 縻1 and/or treatment of central nervous system disorders. The present invention is directed to these and other important objects. SUMMARY OF THE INVENTION The present invention provides a compound of formula (I)

0) 201121941 wherein: R1 and R2 are each independently aryl, heteroaryl, decyl, cycloalkyl, _cyclocycloalkyl 'heterocyclyl, fluorenyl, alkoxy, as appropriate, independently Monosubstituted, disubstituted or trisubstituted: alkyl, functional, hydroxy, cyano, amine, alkylamino, dialkylamino 'mercapto, aryl, heteroaryl, heterocyclic, ring Alkoxy group, trifluoromethyl group; and L is -CO-N(X)_, -NH-C(〇)-N(Y)-, -(w)NC(〇)〇_, -〇 C(0)N(Z)-, 屮HS〇2_, _NH_, _heteroaryl or a bond; wherein: X is hydrogen, or is attached to R2 and forms a heterocyclic bond together with the sequence thereof; Or to form a heterocyclic ring together with a heterocyclic ring which is bonded to R and which forms a heterocyclic ring to form hydrogen, or is a bond to and connected to r2; and Z is hydrogen or is attached to R2 And a link to it; or a pharmaceutically acceptable salt thereof. The invention also provides at least one salt of the genus, and at least one medical composition. Medicament of a compound of formula (I) or a pharmaceutically acceptable pharmaceutically acceptable carrier thereof: The invention also provides a method of treating a disease or condition, wherein a mammal in need thereof is administered at least a therapeutically effective amount a substance or a pharmaceutically acceptable salt thereof, ^ central nervous system - *". The disease or condition is ... disease or condition. In some specific examples of the method, 201121941 1 * treatment of disease or Symptoms of the disease. [Embodiment] In one aspect, the present invention provides an adamantylamine derivative in a month. The amantadine has the formula (I):

HIN

(1) wherein: R and R2 are each independently aryl, heteroaryl, alkyl, cycloalkyl, ketoalkyl, heterocyclyl, decyl, alkoxy, which are optionally independently subjected to the following Substituted, monosubstituted or trisubstituted: alkyl, hydroxyl, hydroxy, cyano, kanyl, alkylamino, dialkyl, decyl, decyl, aryl, heteroaryl, oxalyl, ring Alkyl, alkoxy, trifluoromethyl; and L is -CO-N(X)-, _NH-C(0)-N(Y)-, -(W)NC(〇)〇_, -0C (0) N(Z)-, _NHS〇2_, _NH_, ·heteroaryl or a bond; wherein: X is hydrogen or is bonded to R2 and forms a bond with the N to which it is attached; Or a bond to and connected to R2; W is hydrogen, or is a bond to R2 and is attached to it; and the ring forms a heterocyclic ring to form 7 201121941 together to form a heterocyclic z Hydrogen, or a bond to r2 and to which it is attached: or a pharmaceutically acceptable salt thereof. Unless otherwise stated, a compound used alone or as part of a group is defined herein as a straight or branched chain saturated hydrocarbon having from 1 to carbon atoms. In some embodiments, the alkyl moiety contains 8, 7, 6, 5 4, 3, 2 or 1 carbon atoms. If the term "alkyl" as used herein does not have a range of carbon atoms, it means the range of Ci_Q. If the term "alkyl" as used herein has a carbon range, it is meant to have any number of alkyl groups within the identified carbon range, such as Cl_C3 alkyl means methyl, ethyl or propyl. Examples of saturated hydrocarbon alkyl moieties include, but are not limited to, such as mercaptoethyl, n-propyl, isopropyl, n-butyl, t-butyl > isobutyl, t-butyl, n-pentyl Chemical groups of n-hexyl groups, and the like. Alkyl also refers to a burnt moiety of an alkyl group substituted with a hydroxy group, a cyano group, an alkoxy group, an alkylamino group, a dialkylamino group, a alkyl decylamine, a dimercaptoamine, and the like, including But not limited to) -OCi-C^ alkyl-OH, -OCVC4 alkyl-〇CH3, -OCi-CU alkyl-NHCH3, -0CVC4 alkyl-N(CH3)2, -OCVC4 alkyl-C0NHCH3,- 0CVC4 alkyl-CON(CH3)2, -OCi-C* alkyl-NHCOCH3 and -OCVC4 alkyl-N(CH3)COCH3. Unless otherwise stated, alone or in combination with other terms, "alkoxy" is defined herein as -O-alkyl group, wherein "hospital group" is as previously defined herein. Examples of alkoxy moieties include, but are not limited to, such as decyloxy, ethoxy, isopropoxy, second butoxy, third butoxy, and homologs, isomers, and the like. The chemical group of the group. Alkoxy also refers to a burnt moiety of a 201121941 alkyl group substituted with a hydroxy group, a cyano group, a decyloxy group, an alkylamino group, a dialkylamino group, an alkyl decylamine, a dialkyl decylamine, and the like. Including, but not limited to, -OCVC4 alkyl-OH, -OCVC4 alkyl-〇CH3, -OCVC4 alkyl-NHCH3, -OCVC4 alkyl-N(CH3)2, -OCVC4 alkyl-CONHCH3, -OCVC4 alkyl -CON(CH3)2, -OCVC4 alkyl-NHCOCH3 and -OCi-C^alkyl-N(CH3)COCH3. Unless otherwise stated, the use of "hydroxyalkyl", alone or in combination with other terms, is defined herein as -alkyl_0H, wherein "alkyl" is as previously defined herein. Non-limiting examples of the preparation include methyl-0H, ethyl_0H, n-propyl-OH, and the like. As used herein, unless otherwise stated, the term "cycloalkyl", used alone or in combination with other terms, is defined herein as a cyclic alkyl group having from 3 to 8 ring carbon atoms, the form of which is referred to herein as "alkyl". definition. Examples of the cycloalkyl moiety include, but are not limited to, a chemical group such as a fluorenyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. As used herein, unless otherwise stated, the term "_cyclohexyl", used alone or in combination with other terms, is defined herein as a cycloalkyl group to which a keto group is attached, wherein "cyclic oxime, earth" is used herein. Defined. Examples include cyclopentanone or cyclohexanone. Unless otherwise stated, the bottle 々Λ U ^ Γ ^ is used alone or in combination with other terms. The term "self" or "halogen" is used herein to mean fluorine, gas, bromine or iodine. Unless otherwise stated, the "50 square base" used in the "W #早 alone or in combination with other terms" is defined herein as having a sufficiency, 1 岌 „, 丹 has a carbon atom a hydrocarbon, which is an early ring (monocyclic) or a plurality of rings that are covalently bonded or covalently bonded to 201121941 (eg, bicyclic, tricyclic, polycyclic). Any suitable ring position of the aryl moiety may be shared with the specified chemical structure. Valency linkage. Examples of aryl moieties # (but not limited to) chemical groups such as stupid, 1-naphthyl, 2-naphthyl and the like. The aryl group may be unsubstituted or as described herein Unless otherwise stated, the term "heteroaryl" used alone or in combination with other terms is defined herein as a monocyclic ring containing one or more of the same independently selected from the group consisting of nitrogen, oxygen and sulfur (_ Aromatic hydrocarbon ring. Heteroaryl contains up to 14 carbon atoms and U 6 heteroatoms. Examples of heteroaryl groups include, but are not limited to. Bipyridyl, argon-based, tri-negative, sulfhydryl, hydrazino, (1,23) and (1,2,4)-triwax...dimorphyl, pyrimidinyl, tetrazole , 0 soil 0 soil 廿 ^ 'Tufu ketone, thienyl, isoxazolyl, thiazolyl, hiring saliva, hiring two ° sit-base, 2 啥 基 、, 2-啥 啥 咐, 3- benzene Base 2_ quinolinyl and the like. The heteroaromatic heteroaryl group can be unsubstituted or substituted as described herein. - "= Γ, otherwise the text used alone or in combination with other terms is defined as a radical of 1, 2, ... removed from any ring atom of the heterocycle. In some embodiments, the 'heterocyclyl-containing group (4) is selected from the group consisting of ruthenium, § and ruthenium atoms. In some articles, the heterocyclic ring group contains 3 to 14 carbon atoms. In some specific examples, the carbonogen: contains ^5, 6, 7, 9, 11, unless otherwise stated, "mercapto" is previously described herein; it is also used in combination with 'in the alkyl group, ethyl thiol group and its 'otherwise or otherwise defined as the formula -C(O)-alkane The group of the group is a group of a ketone group, such as a similar group of the genus 10 201121941. The term "aminoalkyl", used alone or in combination with other terms, is defined herein as _alkyl-amino, unless otherwise stated, wherein the term "alkyl" is as previously defined herein and the term "amine" is _NH2. , _NH- or. Non-limiting examples include -ch3NH_, CH3CH2NH_, (Ci_c3 appearance) / (CVC3) 2N- and the like.

The term "alkylamino", alone or in combination with other terms, is defined herein as _amino-alkyl, wherein the term "alkyl" is as previously defined herein and the term "amine" is _ΝΗ2 unless otherwise stated. Examples of 艮·J include -NHCH3-NHCH2CH3, -ΝΗ((ν<:3 alkylene), -NCCi-C3 alkyl h, and the like. In some embodiments, the compound of formula (1) And R2 are all aryl; in some embodiments, R1 is heteroaryl and R2 is aryl. In a specific embodiment, R1 and R2 of the compound of formula (I) are heteroaryl, in two In some embodiments, 'R1 or R2 is a heteroaryl group; in some embodiments: a heteroaryl group and R2 is a heterocyclic group; in some embodiments, ... is a heteroaryl group and R2 is a cycloalkyl group. In some embodiments, the R of the compound of formula (I) is aryl' and the R2 of the compound of formula (I) is an alkyl group. In some specific examples, the L of the compound of formula (I) is -CO-N (X). -, where X is as defined herein; in some embodiments, L is -ΝΗ_(:(0)_Ν(Υ)_, where γ is as defined herein; in some specific examples t, L Is _(W)N_C(0)0_, where % is as defined herein; in some specific examples t, L is -0C(0)N(Z)-, where Z is as defined herein; in two specific examples , L is _NHS〇2_; in some specific examples, l is 201121941 -NH-; in some specific examples, L is heterozygous. In the case, L· is a bond. 岙, and in some specific examples in some Specific examples, 4 (in some specific examples, the formula is a reverse guanamine derivative. In some embodiments, the compound is a urea derivative. 1 compound is a urethane derivative In some embodiments, in some embodiments, in some embodiments, in some embodiments, the disclosed compounds (see, for example, the compound of formula (1) is a heteroaryl derivative. The compound of formula (1) is a sulfonamide Derivatives The compound of the formula (1) is an amine derivative. The sub (1) compound is shown in Table 1-2 below in the experimental part below. Another aspect of the present invention is an effective amount of the present invention and medicinal herbs of eight to three sides. The acceptable composition is that it is not depleted. The composition of the hydrazine or excipient. The composition of the present invention Can be adapted to any __ 7 * and mode 'such as oral (including sublingual), via implant, non-sacral (sacral (including intravenous, intraperitoneal, joint)

Internal and subcutaneous injection), transrectal, g meat R ΤΓ 邛 邛 经 'eye (through eye drops), transvaginal and transdermal. The present invention may be used in a free form or in the form of a salt derived from a pharmaceutically acceptable acid or base. The compounds of the present invention can also be used in the form of esters, urethanes and other conventional prodrugs which will generally be functional derivatives of compounds which are readily converted in vivo to the active moiety. Also included are metabolites of the compounds of the invention defined as active substances which are produced following introduction of the compound into the biological system. When a compound of the invention is used as described above, it can be combined with one or more of the pharmaceutically acceptable excipients or carriers (e.g., solvents, diluents, and analogs thereof). Such pharmaceutical preparations may, for example, lozenges, capsules (including, for example, time release and sustained release formulations), pills, buccal tablets, aerosols, dispersible powders, granules, solutions, suspensions (including, for example, suspending agents, For example, from about 0.05 to about 5% of a suspending agent), a syrup (containing, for example, a sugar or sugar substitute, such as aspartame, for example, from about 1 to about sugar or a sugar substitute), an elixir and The analog is administered orally or parenterally in a sterile injectable solution, suspension or emulsion containing, for example, from about 0.05 to about 5% of a suspension in an isotonic medium. Such formulations may contain, for example, from about 25 to about 90% of the active ingredient in admixture with the carrier, more usually about 5% and about 60% by weight of the active ingredient in combination with a carrier. The effective dose of the active ingredient (e.g., a compound or salt of the present invention and its prodrug or metabolite) can be used depending on the particular compound, salt, prodrug or metabolite used, the mode of administration, the age, weight, sex and medical condition of the patient. And the severity of the disease, condition, condition and/or system being treated. Those skilled in the art will readily appreciate the selection of appropriate dosage forms and dosage forms for use in the individual mammals. Such determinations are routine techniques for physicians, veterinarians or clinicians having the general skills in the art (see, for example, Harrison>s Principles In(10)_Stealing Mountain-e, Anthony F Zero et al. (eds.) 14th edition New Y 〇rk: McGraw Hill (1998) h In addition, the dosing regimen can be adjusted to provide an optimal therapeutic response. For example, several divided doses or doses can be administered daily, which can be scaled down as indicated by the needs of the treatment. The solid carrier (for example, starch, lactose, dicalcium phosphate, microcrystalline cellulose, cane 13 5 201121941 sugar and kaolin), liquid carrier (for example, sterile water, etc.) may be suitably used depending on the nature of the active ingredient and the particular formulation desired. Polyethylene glycol, glycerin, nonionic surfactants and edible oils, such as corn oil, peanut oil and sesame oil. It may be advantageous to include adjuvants commonly used in the preparation of pharmaceutical compositions. Non-limiting examples of adjuvants include flavoring agents. 'Colorants, preservatives, and antioxidants' such as vitamin E, ascorbic acid, beta Τ and BHA. The active compounds can also be administered parenterally or intraperitoneally. A solution or suspension of the active compound in the form of a free base, a neutral compound or a pharmacologically acceptable salt in water, suitably mixed with an active agent such as hydroxypropylcellulose. Also available in glycerol, liquid polyethylene glycol And dispersions thereof are prepared in mixtures with oils. These preparations may contain preservatives to prevent the growth of microorganisms under normal conditions of storage and use. Suitable pharmaceutical forms for injectable or infusion include sterile aqueous solutions, suspensions or dispersions Liquid, and a sterile powder for the temporary preparation of a sterile injectable or infusion solution, suspension or dispersion. In all cases, the form must be sterile and fluid to be easily injectable and infused. It must be stable under the conditions of manufacture and storage. The carrier may be a solvent or a dispersion medium containing, for example, water, ethanol, and a polyol (for example, glycerin, propylene glycol, and liquid polyethylene glycol), a suitable mixture thereof, and a vegetable oil. The active compound can be administered intranasally or via a vehicle suitable for intranasal or transdermal delivery as known to those of ordinary skill in the art. Transdermal administration includes the use of such agents as lotions, creams, foams, pastes, patches, suspensions, solutions, and sputum (rectal and vaginal) t-carrier systems through the body surface = and body passage All of the inner liners (including epithelial and mucosal tissues). Creams and ointments can be oil-in-water or water-in-oil viscous liquids or semi-solid milk 14 201121941 Liquid containing absorbent powder dispersed in active ingredients Pastes in petroleum or hydrophilic petroleum are also suitable for use in a variety of occlusion devices for the release of active ingredients such as semipermeable membranes covering the storage of active ingredients with or without carriers, or active ingredients. Substrates. Other occlusion devices are also known in the literature. When a transdermal delivery system is used, the dose administration will be continuous rather than single or divided doses per dose. The compounds of the invention may also be administered in the form of a liposome delivery system in which a plurality of phospholipids are formed from a liposome lipid bilayer. The compounds of the invention may also be delivered by the use of carriers such as monoclonal antibodies that are coupled to the compound. Other carriers which may also be coupled to the compounds of the invention are soluble polymers or biodegradable polymers suitable for achieving controlled release of the active ingredient.

According to the technique of Tang Kexin / τ X Shi Feng, some compounds of formula (I) may contain one or more asymmetric centers, and the field μ* is too 丄, and thus can produce enantiomers. And diastereomers include all stereoisomers, including individual diastereomers and resolved enantiomerically pure stereoisomers, oxime racemates, and stereoisomers. Other variants, such as the form of sputum, and mixtures thereof, and pharmaceutically acceptable salts, all have the activity of + > Pure forms and equimeric isomers can be obtained by procedures known to those skilled in the art and include, but are not limited to, chiral chromatographic separation, ., ', formation, kinetic analysis, and asymmetric synthesis. . It should also be understood that the present invention includes all possible possible isomers, internal-external-displayed constructs, and mixtures thereof, which can be indicated by the procedures known to those skilled in the art... (but not limited to) column chromatography, thin 匕^ L ^ ^ "segregation method, and high performance liquid chromatography. 细细·········································· Rotation 15 201121941 爻 而 而 , , , , , , , , , , , , 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 Further understanding, some formulas (isomers; compounds including structural isomers, including mutual and oxime also include polymorphs and hydrates of the compound of formula (1), with analogs labeled with a single element (eg 2h, 3h, 13c analogs. Another aspect of the invention A + & face is the method of use of the compounds of the invention. It is to be understood that the invention encompasses the present invention and any of the four compositions that are suitable for use in the methods described herein. Any fine, 7 or all of the same, sequential or single In some embodiments, the TD method comprises administering an effective amount of a compound of formula (I) or a salt thereof. In one embodiment, the method comprises administering a therapeutically effective amount of a compound described herein. Or a salt thereof. μ As used herein, the phrase "effective amount j when applied to a compound of the invention is intended to mean an amount sufficient to cause a predetermined biological effect. The phrase "therapeutically effective amount" when applied to the compound of the present invention is intended to mean sufficient improvement. Attenuating, stabilizing, reversing, slowing or delaying the progression of a disease or condition of a disease, or the progression of a symptom of a condition or disease. In some embodiments, the method of the invention provides for the administration of a combination of compounds. In such cases An "effective amount" is an amount sufficient to cause a combination of desired biological effects. In some embodiments, the method comprises administering an effective amount of a combination of two or more of the compounds described herein or a salt thereof. "" or a combination of two or more of the compounds described herein or a salt thereof" or "at least one compound as described herein or a pharmaceutically acceptable compound thereof Salt or Description 16 201121941 A similar language expression for a particular compound includes the administration of a compound in any ratio and combination of salts, in any combination, wherein the compounds are 卞 卞 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 亥 谷 谷Forms of J-salt form, or one or more forms of examination and one:: ::: or more in the form of examination and - or more in the form of salt, or = and more or more in the form of salt, Any ratio, ... or alkaline compound and / or salt. Burning neutral and / As used in this article, the term "treatment, string, push. 縻" thinking to improve or transcend disease or disease ^ 3 ? Or reversing one of the diseases or conditions or side effects. (4) ώ ώ 种 种 一 一 σ σ 可 可 可 可 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰"Treatment as used herein" also means inhibiting or blocking, such as preventing, arresting, arresting, obstructing, or obstructing the progression of a system, condition, or condition of a disease or condition. "Treatment" for the purposes of the present invention additionally means a method of obtaining a beneficial or desired clinical result, wherein the beneficial or desired clinical outcome includes, but is not limited to, relieving symptoms, attenuating (or reducing) the extent of the disorder or disease, and stabilizing ( That is, it does not worsen. The state of the disease or condition, delay or slow down the disease or condition, improve or alleviate the disease or condition, and alleviate the disease or condition, whether it is a part; or overall, detectable or undetectable. The term "prevention" as used herein means the occurrence or presence of a control. The term "administering" as used herein refers to the direct administration of a compound of the invention, or administration of an effective amount of a compound in a mammal. Prodrug, derivative, or analog. The present invention also provides a method for treating a disease or condition, which comprises administering to a mammal in need thereof a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof, Or the disorder is a central nervous system disease or disorder. The compound of the present invention ectopically regulates the mGlii5 receptor. An ectopic modulator that enhances or enhances the affinity of the orthosteric ligand for the mGluR5 receptor and/or enhances or enhances the efficacy of the orthosteric agonist as an ectopic enhancer (or synergist) or a positive ectopic modulator (positive allosteric modulator, ΡΑΜ). See the example 〇 May, L.T. and ev_ 7b; n’co/. 2007, 彳 7, i_51. The ectopic modulator that reduces or diminishes the efficacy of the orthosteric agonist is an ectopic antagonist (or inhibitor) or a negative all 〇 steHc modulator (NAM). Do it all. A silent aU〇steric modulator (SAM) binds to the ectopic site of the receptor but does not have the inherent efficacy of measurability. SAM can indirectly demonstrate efficacy by preventing the ectopic binding compound from exhibiting its own positive (PAM) or negative (NAM) efficacy. In some embodiments, the mammal of the method of the invention is a human. In some embodiments of the methods of the invention, the central nervous system disease or condition is a cognitive, neurodegenerative, psychiatric or neurological disease or condition. In some such specific embodiments, the cognitive, neurodegenerative, psychiatric, or neurological disease or disorder is selected from the group consisting of: an emotional disorder 'anxiety, schizophrenia (including an emotional splitting psychosis), Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease (Huntington, s chorea), muscle atrophic lateral sclerosis, gram-Asian Creutzfeld-Jakob disease, trauma-induced neurodegeneration, brain lesions induced by aids 18 201121941, brain lesions associated with another infection (ie, non-aids-induced brain lesions), fragile x syndrome, Autism sPectrum disorder and combinations thereof. As used herein, the phrase "emotional disorder" refers to any of a number of mental disorders characterized by abnormal mood states such as (but not limited to) bipolar disorder, sorrow glutinous disorder, circulatory emotional disorder, mood disorder, general Emotional disorders caused by medical conditions, emotional disorders not mentioned otherwise, and substance-induced emotional disorders; and characteristics such as Naichuan 'c α«ί/ Mawwa/ 〇/

Meraia/ D/sorders, 4th Edition (DSM-IV) (American Psychiatric

Association: Arlington, VA, 1994) Hu Jinding. As used herein, the phrase 'Autism Spectrum Disorders' (ASD) refers to a condition that causes serious and extensive injury in thinking, feeling, s s and other related abilities, which are usually diagnosed early in the child and ranged. Includes severe forms (called autism ("traditional" autism) to pervasive development disorder n〇t otherwise specified (PDD-NOS) to lighter forms (Asperger Asperger syndrome). As used herein, the phrase also includes Rett syndrome and childhood disintegration disorders, and as used herein, synonymous with the phrase "developmental disorder" (PDD). In some such specific instances, the emotional disorder is depression (i.e., depression). In some such specific instances, the depression is selected from the group consisting of atypical depression, bipolar depression #, single Polar depression, severe depression, internal depression t (ie, acute inhibition without obvious cause), decay period 19 201121941 fee (also known as middle-aged or middle-aged depression), reactive inhibition (also That is, depression caused by traumatic experience in life, postpartum depression, primary depression (ie, depression without physiological or psychological causes such as medical diseases or illnesses), mental depression, and secondary depression ( That is, depression that appears to be caused by some other hidden condition (such as another medical disease or condition). In some such specific examples, the anxiety disease or condition is selected from the group consisting of: generalized anxiety disorder, Panic (4), obsessive-compulsive disorder, social phobia, occupational anxiety, post-traumatic stress disorder, acute stress response, disorders, suspected illness, separation anxiety, phobia, specific phobia, general medicine Anxiety disorders caused by conditions, substance-induced anxiety disorders, alcohol withdrawal-induced anxiety disorders, and combinations thereof. In some embodiments, the central nervous system disease or disorder of the method of the present invention is an episode disease or disorder. In an example, the seizure disease or disorder is selected from the group consisting of convulsions, temple pain, continuous state of pain episodes, and combinations thereof. In some embodiments, the disease or disorder of the nervous system is in the method of the present invention. A painful disease or condition selected from the group consisting of: Inflammation! • Pain-pain #Shenzhen pain and migraine. In some embodiments, the neuralgia or migraine disease or disorder is selected from the following Groups of: abnormal pain, hyperalgesia, phantom pain, neuralgia associated with diabetic neuropathy, neuralgia associated with migraine, and combinations thereof. In some embodiments, the method of the present invention is a central nervous system A disease or condition is a disease or condition in which a neuron is overexcited. In some specific examples, a neuronal hyperexcitability state disease or disorder is a medicine God of withdrawal 20 201121941 , "to the yuan", field overstate, neuronal hyperexcitability state during poisoning or a combination thereof 0 In some specific examples of the method of the invention, treatment of cognitive, neurodegenerative, spiritual or At least one symptom of a neurological disease or disorder. In some embodiments, the cognitive, neurodegenerative, psychiatric, or neurological disease or condition is depression. In some such specific instances, at least one symptom of depression is depression Low mood, loss of interest or pleasure in some or all activities, loss of appetite, weight change, sleep pattern change, lack of energy, fatigue, low self I, thinking, concentration or determination, weak feeling, feeling desperate or worthless, psychomotor Excitement or dullness, self-blame, inappropriate guilt, frequent consideration of death or suicide, planned or attempted suicide, or a combination thereof. In some embodiments, cognitive, neurodegenerative, psychiatric or neurological diseases or conditions are anxiety. In some such specific examples, at least one of the symptoms of anxiety is anxiety, harming, mooring, muscle pain, insomnia, abdominal upset, dizziness, stress, persistent reversal, strong return, Palpitations, chest pain, chest treatments, sweating, numbness, feelings of resentment, fear of loss of control, resume, nightmares, intrusive thinking, intrusive memories, avoidance behavior, emotional numbness, inability to fall asleep, feelings of anxiety, excessive surprise response, Excessive alertness - outbreak of anger, syncope, blushing, sweating or a combination thereof. In some specific examples, the cognitive, neurodegenerative, psychiatric neurological disease or condition is schizophrenia. In one; at least one of the symptoms of schizophrenia is selected from the group consisting of positive syndromes, hallucinations, delusions, paranoia and their, in some of the 21 201121941 class specific examples, the symptoms of schizophrenia are Choose from the negative symptoms of the group consisting of social withdrawal, feelings of dullness, lack of pleasure, reduced motivation, and combinations. In some such specific examples, the symptoms of schizophrenia are cognitive symptoms selected from the group consisting of severe attention deficit, severe lack of object naming, severe lack of working memory, severe chronic memory storage, and executive function. Severe deficiency, slowing of information processing, slowing of neurological activity, long-term depression and their combination. In some embodiments of the methods of the invention, the cognitive, neurodegenerative, psychiatric or neurological disease or condition is Parkinson's disease. In some such specific examples, at least one of the symptoms of Parkinson's disease is levodopa-induced dyskinesia, poor balance, kinsonian gait, bradykinesia, stiffness, tremor, Voice change, loss of facial expression, writing too small, difficulty swallowing, eccentricity, pain, cancer, confusion, sleep disorders, constipation, skin problems, depression, fear, anxiety, memory difficulties, slow thinking, sexual dysfunction, urinary Problems, fatigue, pain, loss of energy, or a combination thereof. In some embodiments, the cognitive, neurodegenerative, psychiatric or neurological disease or condition is Alzheimer's disease. In some such specific examples, at least one symptom of Alzheimer's disease is memory impairment, attention disorder, judgment disorder, decision disorder, physical environment orientation disorder, speech disorder, speed-related activity disorder, abstract reasoning disorder, vision Spatial dysfunction, executive dysfunction, behavioral disorder, disrespect and passive, indifference, improper clothing, poor self-care ability, agitation, violent eruption, aggression, depression, anxiety, hallucinations, delusions, personality changes, mood changes, dementia Or a combination thereof. 22 201121941 In some specific cases, cognitive, neurodegenerative neuropathy. Ge's string As spirit ί·sheng a disease is multiple sclerosis. In some of these specific examples of pasteurism, at least one symptom is optic neuritis, visual acuity, unstable, monthly pain, loss of color vision, blindness, complex vision, nystagmus, eye movement, poor eyesight, and low At or above the rated eye movement, internuclear ophthalmoplegia 'eyeball tremor, diplopia, movement and sound illusion, diplopia, pupillary afferent disorder, numbness, single limb palsy, hindquarters palpitations, Half-length squat, arm and leg paralysis (quadraparesis plegia), paraplegia, half body not $, limb itching, quadriplegia, paralysis, difficulty in pronunciation, muscle atrophy, cramps, painful paralysis, hypotonia, clonic, myoclonus挛, multiple myoclonus, restless leg syndrome, vertical dysfunction reflex (MRS, BaMnski's, Hoffman's (secret), Chaddock's), feeling Abnormal, numbness, neuralgia (neuralgia, neur〇pathic pain) 'neurogenic pain (n read 叩 heart pain), ehmite disease (rhermitte, s), proprioceptive dysfunction, -fork neuralgia, total Aversion, intentional tremor Poor distance, vestibular ataxia, dizziness, speech ataxia, dystonia, alteratory dyskinesia, frequent urination, bladder spasm, flaccid bladder, detrusor external sphincter ataxia, erectile dysfunction, lack of sexual pleasure, retrograde Sexual ejaculation, cold sensation, constipation, urgent bowel movements, depression, cognitive dysfunction, dementia, emotional changes, emotional instability, euphoria, bipolar syndrome, anxiety, aphasia, language difficulties, fatigue, Utov syndrome (uhthoffs) Symptom), gastroesophageal reflux, sleep disorders, or a combination thereof. The invention further provides a method for treating a gastroesophageal reflux, the method 23 201121941 comprising administering to a mammal in need thereof a therapeutically effective amount of at least one compound of the formula (1) or a pharmaceutically acceptable salt thereof. A method of treating alcohol dependence, which comprises administering to a mammal in need thereof a therapeutically effective amount of at least one of the compounds of formula (1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the invention are used in the manufacture of a medicament for the treatment of a central nervous system disorder or condition. In some specific examples, the sacral neuropathy or condition is as disclosed above. Another aspect of the invention is a process for the manufacture of a compound of the invention. Preparation of the Compounds of the Invention The compounds of the invention may be prepared according to, but not limited to, the general methods described below. For example, the following Schemes 1-24 are intended to be illustrative of some specific examples of the invention and are not intended to limit the invention. – Unless otherwise stated in the specific case, the following definitions are used as abbreviations as used herein. B 〇 c = third butoxycarbonyl BOP = benzotriazole hexafluorophosphate _ 丨 _ _ oxy _ _ _ (dimethylamino) scale, CAS No. 56602-33-6 DCM = dichloromethane, CAS No. 75-09-2 DIEA = W-Diisopropylethylamine' cas No. 7087-68-5 DMA = W-Dimercaptoacetamide, CAS No. 127-19-5 DMAP = 4-Diamine Pyridine, CAS No. μ22-58-3 24 201121941, DMC = 2-Gas-1,3-dimethylammonium chloride, CAS No. 37091-73-9 DMF = W-dimethylformamide, CAS No. 68-12-2 DMPU = 1,3-dimercapto-3,4,5,6-tetrahydro-butanone, CAS No. 7226-23-5 DMSO = Disulfoxide, CAS No. 67-68 -5 DPPA = diphenyl azide, CAS No. 263 86-8 8-9 EDC = 1-ethyl-3-(3-dimethyl 1-aminopropyl)carbodiimide EDCI - A/ "-Ethyl-A^'-(3-diamidinopropyl)carbodiimide hydrochloride, CAS No. 93128-40-6 HATU = 2-(1//-7-azabenzone) Triazole_ι_基)__〗, 〗 3,3_tetradecyl hydrazine hexafluorophosphate, CAS No. 148893-10-1 HBTU = hexafluoro-acid 2-(1//-benzotriene嗤_ι·基) 四曱基名尿, CAS No. 94790-37-1 MTBE = decyl tertiary butyl ether , c AS No. 1452 88-29-5 NBS = ΑΛ·bromobutane diimine, CAS No. 128-08-5 NMP = #-曱基比罗pyridine_, CAS No. 872-50-4

PyBOP = benzotriazole hexafluorophosphate _ 丨 _ _ oxypyrrolidine scale ' Cas No. 128625-52-5 rt = room temperature RT = LC-MS retention time TEA = triethylamine, CAS No. 121.44-8 TFA = trifluoroacetic acid 'CAS No. 76-05-1 THF = tetrahydrofuran, CAS No. i〇9_99_9 The conventional amilylation procedure can be used from 25 201121941 by the method outlined in Scheme 1.

2 N Intermediate A and R2(X)NH (wherein X is hydrogen or a bond to form a heterocyclic ring together, and R1 and R2 are as previously defined) to prepare the '(I - a) compound. Process 〇

, R2

a) R2(X)NH, PyBOP (or BOP or DMC or EDCI or HBTU, etc.) DIEA or TEA, DCM 戚丁戒CH3CN. etc.); or R2(X)NH. HATU, DIVIAP, THF can also be processed The method outlined in 2 uses the conventional aromatization procedure intermediate B and I^COzH or Rioci to prepare a compound of formula (Ia). Process

a) R1C0CI, DIEA or TEA, DCM; b) R1C02H, PyBOP (or BOP or DMC or EDCI or HBTU, etc.), DEA or TEA, DCM (or THF or DMF or CH3CN, _:); or R'CC^ H, HATU, DMAP, THF Intermediate A can be prepared via the procedure outlined in Scheme 3. 26 201121941 Process 3

a) H2SC\, HN03, MeCN; b) HCI, H20; c) SOCI2, MeOH; d) R1COCI, TEA, DCM; or R1C02H, PyBOP, NEt3, DCM; e) LiOH, H20, THF Commercially available 1-King Kong The alkanoic acid (Compound 1) can be converted to the acetamide 2 via the Ritter reaction. Hydrolysis of compound 2 under acidic conditions affords the corresponding amine salt' which is then converted to the oxime ester 3. Conventional amide amination of compound 3 affords compound 4. Hydrolysis of ester 4 under conventional conditions affords intermediate A. Intermediate b can be prepared via the method outlined in Scheme 4. Process 4

a} _2〇, THF, NaOH, in water); b>_ΝΗ·pqing.DCM 丨 HF Under the normal conditions (see, eg, step a of Scheme 4), Boc protection of compound $ is obtained to obtain 166 M Using a conventional procedure (see, for example, step b of Scheme 1) 卩R2(X)NH, the acid 6 is amidated to give compound 7, which is then converted to intermediate b by removal of the BGe group under conventional conditions. Step c) of Process 4. The heterocycle can be formed from the intermediate C with the amine R2N(Y)H (Y is 氲 or is attached to R2 and is hydrazine-forming) under the usual conditions (see Example 27 201121941 as step a). The compound of formula (Ib) is prepared by the reaction of one of the bonds. Process 5

Intermediate ca) R2N(Y)H, DCM (or DMF or no solvent), microwave at room temperature or at 160 ° C can also be subjected to conventional methods under the conditions outlined in Scheme 6 (see for example steps a or b) The compound of formula (Ib) is prepared from the reaction of intermediate D with an amine helium (Y) (R2) NC(0)C1 or an isocyanate R2NCO. Process 6

Intermediate D a) (Y) (R2 > NC(0)-CI, DIEA, DCM; b) R2NCO, DCM (or DMF or no solvent), microwave at room temperature or at 160 ° C can be used in Process 7 The methods outlined are used to prepare intermediates C and D. 28 201121941 Process 7 Ο R1

C〇2H

Intermediate A Intermediate C a) TEA, DPPA, toluene, room temperature.go 〇C; b) HC|, h2〇

Nh2

Intermediate D Under standard conditions (see, for example, step a of Scheme 7), the intermediate A is subjected to standard Curtis rearrangement. (Curtius rearrangement) to obtain an isocyanate intermediate c which, after acidic hydrolysis, produces an intermediate D ^ Prepared by the reaction of the intermediate C and the alcohol R2〇H or the reaction of the ten substances d with the chloroformate R2〇C(〇)Cl under the conventional conditions (see, for example, step a or b) via the method outlined in Scheme 8. Formula (1_〇 compound. Scheme 8

The intermediate c is called a) R2〇H, DCM; b) R2〇c(〇)c| TEA. dcm rw nh2

Intermediate D can be prepared as a cyclic urethane (I-d) compound via the method outlined in Scheme 9, ^ ^ ^ „ X.- 10,000. 29 201121941 Process 9

Intermediate D 8 Formula (I# η = 1, 2 a) C!(CH2)2(CH2)n0C(0)CI, TEA, THF; b) NaH, DMF, 50 ®C Under normal conditions (see for example Step a) of Scheme 9 a) amidating the intermediate D with chloroformate Cl(CH2)2(CH2)n0C(0)Cl to obtain compound 8, which can be obtained at 50 ° C with a base such as NaH The cyclized compound of formula (Id) is treated in DMF. The compound of formula (I-e) can be prepared via the methods outlined in Scheme 10 using conventional conditions (see, for example, step a of Scheme 10). Process 10

Equation {Ι·β} a) R2S02CI, TEA, DCM

Intermediate D can be prepared by the method described in Scheme U (compound wherein Z is hydrogen or is attached to R2 and forms a bond with one of the heterocycles. 201121941 Process 11

a or b or.

Formula (1-0

Intermediate E

a) CIC02CCI3l R2(Z)NH, TEA, DCM; b) R2(Z)NC(0)CI, TEA, DCM; c) R^NCO, D〇M Intermediate E and chloroformic acid phosgene and R2 (Z NH (see, for example, step a of Scheme 11) or aminoguanidino chloride R2(Z)NC(0)C1 (see, for example, step b of Scheme 11) or isocyanate R2NCO reaction (see, for example, step c of Scheme 11) (If) a compound. Intermediate E can be prepared from compound 9 and RiC^H under conventional guanidation conditions (see, for example, step c) via the procedure outlined in Scheme 12. Process 12

a) R1C〇2H, BOP, TEA, DCM

OH Intermediate E The compound of formula (I-g) can be prepared via the procedure described in Scheme 13. 31 201121941 Process 13

Intermediate E 10 (|·9)

a) MeS02CI, TEA, DCM, 0 °C; b) R2NH2, 160 °C Intermediate E reacts with MeS〇2Cl (see, for example, step a of Scheme 13) to produce mesylate 10. Alkylation of R2NH;2 with compound 10 (see, for example, step b of Scheme 13) affords the formula (compound. Also by using the method outlined in step a of Scheme 14 by the presence of a test such as TEA or K2CO3 DMF allows the alkylation of intermediate D with r2ci or R2Br戍R2I to prepare a compound of formula (][_g). The intermediate can be obtained by using the method outlined in Scheme 14 (see, for example, step b of Scheme 14) UR2CH〇 Reductive amination preparation (compound. Scheme 14 〇Μ

0 rf' /R2 Formula (|-(1) Intermediate D a)R2CI or R2Br or R2|, base, DMF, room temperature or addition

Ri Formula (Ι·9) b) R2CH〇, Na(0Ac)3BH, THF can be passed through the compound outlined in Scheme 15. Method preparation

32 201121941 Process 15

a Ο Λ .nh2 R3〇 ^

Formula (l-i> υ is aryl or heteroaryl. Its tv and N are on two adjacent carbon atoms \/ = NH or Ο 'f 13

Formula 0-j) R30 is an alkyl group using a suspension condition (see, for example, step a of Scheme 15) to amidate the intermediate A with compound 11 to obtain compound 12 which, after intramolecular cyclization, yields a compound of formula (Ii) See, for example, step b) of Scheme 15. The intermediate A is amidated with compound 13 using conventional conditions (see, for example, step a of intermediate 15) to yield compound 14, which is at 1 Torr. The compound of the formula (Η) is produced after treatment with ammonium acetate in hoac/qing. Intermediate D diatom I-k can be made with compound 15 in DMF in the presence of, for example, kw by using the method outlined in Scheme 16, servant 33 201121941 Process 16 〇 R1 NH2

Gj Formula (|-k> u is an aryl or heteroaryl group

Intermediate D a) K2C03, DMF Two CH2Br groups can be prepared on two adjacent carbon atoms of U via the procedure outlined in Scheme 17. Process 17

ΝΗΝΗ R1

a) Ethylene chloride, TEA, DCM; b) TEA, DCM dicarboxylic acid 6 is reacted with ethylene dioxane (see, for example, step a of Scheme 17) to produce anhydride 17, which is under conventional conditions (such as in the presence of TEA) Treatment with intermediate D in DCM yields a compound of formula (1-丨). The compound of formula (I-m) can be prepared via the method outlined in Scheme 18. 34 201121941 Process 18 ^νΛ

Prepared base heteroaryl MWCO/.PyBOP.DCM; I^RK^H.EDCI, 1-hydroxy benzotriazole; C) RiCocl TEA DCM. 屮~<:03,01^, room temperature or 50- 70. (:; training 8$, 2, 2, - azo-bis-isobutyronitrile, (: (:|4; 〇1^ (or 〇), [3 (^

Intermediate D is calibrated using conventional procedures (see, for example, steps a, b, c of Scheme 18). 2!! or RiOCl amidates the intermediate E to give a compound of formula (i-m). Alkylation / oximation of the intermediate d with intermediate F or compound 19 in the presence of a base (see, for example, steps d and f of Scheme 18) also yields a compound of formula (i-m). The non-commercial intermediate ρ can be prepared by bromination of compound 18 using conventional conditions, such as step e of Scheme 18. Intermediate E can be prepared via the method outlined in Scheme 19. 35 201121941 Process 19

a}TEA, POCI3, toluene; b) Zn, AcOH, room temperature to 9 ° C; c) 1) DPPA, toluene, 9 〇 ° 〇; 2) Ηα compound 3 reacts with anhydride 17 (see eg process Step a) of 19 produces phthalimide 20 . Reduction of compound 20 (see, for example, step b of Scheme 19f) affords the indoleamine 21 which, after successively performing the Curtis reaction and acidic hydrolysis (see, for example, step d of Scheme 19), produces intermediate E. The compound of formula (I-n) can be prepared via the method outlined in Scheme 20. Process 20 R2C02Me 22 0 Intermediate

R2C(0)NHNH2 Intersite I

0 a or b or c _ ^n^r2 " Ai (|-n> Intermediate G R1

a) R1C02H, PyBOP, DCM; b> R1C02H, EDCI, 1-p-benzotriazine; C> R1COCI, TEA, DCM d) PyBOP, TEA, DCM: e) Tf20, DCM; f) hydrazine, MeOH, 70 0C 36 201121941 The intermediate G is amidoxigenic to give a compound of formula (In) using RlC〇2H or R1C〇Cl using conventional procedures (see, for example, steps a, b and c of Scheme 20). The amidation of the intermediate A by the brewing intermediate H (see, for example, the evening of the scheme 20)' followed by intramolecular cyclization (see, e.g., step e of Scheme 20) also yields a compound of formula (I-n). Non-commercial intermediates can be prepared by treating the ester 22 with hydrazine under conventional conditions (see, for example, step f of Scheme 20). Intermediate g can be prepared via the method outlined in Scheme 21. Process 21 R2y^MHNH2 Ο

"Intermediate<3 a) PyBOP, TEA, DCM; b) Tf20, DCM; c) 6 N HCI amide amidation of compound 6 with intermediates using conventional conditions' followed by intramolecular cyclization and removal of Boc (See, for example, Steps & b, and Ο of Scheme 21 for intermediate G. Formula (;[_〇) compounds can be prepared by the method of Scheme 22. 37 201121941 Process 22

R2CN

ο Intermediate A

a> R1C02H. PyBOP. TEA. DCM: called R<C02H, EDCI, 1-hydroxybenzotriene. Sc) Ric〇c| T d) TBTU, DMF, microwave, 150. 0; e) NH2〇H.HCI, KjC03, MeOH, reflux ' ' using conventional procedures (see for example steps a, b of Scheme 22 or c) amination of the intermediate I by hydrazine or R^COCI to give a compound of formula (ι). The intermolecular cyclization of the intermediate oxime and the intermediate j also produces a compound of the formula (ρο) (see, for example, step d of Scheme 22). It can be prepared from the reaction of nitrile.23 with hydroxylamine hydrochloride (see, for example, step e of Scheme 22), which is not commercially available. The intermediate oxime can be prepared by the method outlined in Scheme 23. Process 23

a> TBTU, DMF·microwave, 150 〇C; HCI/MeOH The intermolecular cyclization of compound 6 with intermediate J followed by removal of b〇c (see, for example, steps a and b of Scheme 23) yields intermediate G. 38 201121941 A compound of the formula (Ι-p ) can be prepared by the method outlined in Scheme 24. Process 24

Formula (丨-p)

a) EDAC, DMAP_TEA, DCM; b> (Tf)20, 〇bite, DCM Under normal conditions (see, for example, step a of Scheme 24), the intermediate A is amidated with compound 24, followed by intramolecular ring (See, for example, step b of Scheme 24) to produce the formula: (ip) compound. EXPERIMENTAL PART 1. GENERAL METHODS Unless otherwise specifically stated, the experimental procedure was carried out under the following conditions. All operations were carried out at room temperature (about 18. (to: about 25 ° C) under a nitrogen atmosphere. Evaporate/treat in a high-efficiency solvent evaporation system HT-4X (Genevac, Valley Cottage, NY, USA) using a rotary evaporator. The slave phase is a device from Biotage (Initiator). Layer chromatography (TLC) or liquid chromatography-mass spectrometry (lc_ms) tracking, and the reaction time given is for illustration only. CombiF/ΜΛ® system with pre-filled Shimassian filter cartridge ( 39 201121941 Silicone Chromatography on Telckyne Isc, Inc., Unc〇in, NE, USA). Ensure the structure and purity of all final products by at least one of the following analytical methods. : Nuclear Magnetic Resonance (NMR). and LC-MS. Bmker AVanceTM 300 Spectra 4 (Brook Bi〇Spin, Billerica, MA, USA) or Varian UNITY / ATOM® 4〇〇 (Varian, Palo Alto) using the specified solvent , CA, USA) NMR spectra were recorded. Chemistry

The displacement (δ) is given in parts per million (ppm) relative to tetramethyl decane (tmS) as an internal standard. The coupling constant (J) is expressed in Hertz (hz), and the conventional abbreviations for signal shapes are: s = singlet; d = doublet; t = = triplet; m = multiplet; br = broad; . Mass spectra were obtained and reported (M+H)+ using electrospray ionization (ESMS) via a Micromass® Platform II system or a Quattro microTM system (both from Waters, Milford, MA, USA) unless otherwise stated. General LC-MS method: Method A Mobile phase: A) water/acetonitrile (99/1) and 0.2% ammonium citrate; B) acetonitrile gradient: 0 to 1.7 minutes 20-85% B' 1·7 to 1.84 minutes 85 % B, 1.84 to 1.85 minutes 85-100% Β, 1.85-1.99 minutes 1:00% Β, 1.99-2 minutes 100-20% Β. Flow rate: 5.0 mL/min Column: Inertsil® ODS-3, 50 X 4.6 mm, 3 μπι Particle size ' ·. Method Β : Mobile phase: Α) water/acetonitrile (99/1) and 0.2% ammonium formate; ) Acetonitrile gradient: 0 to 1.7 minutes 30-90% B, 1_7 to 1.84 minutes 90% B, 1.84 to 1.85 40 201121941, minutes 90-100% B, 1.85-1.99 minutes 100% B, 1.99-2 minutes 100-20 % B. Flow rate: 5.0 mL/min Tube column: Inertsil® C8, 50 x 4.6 mm, 3 ptm Particle size Method C: Mobile phase: A) water/acetonitrile (99/1) and 0.2% ammonium citrate; B) acetonitrile gradient: 0 to 1.7 minutes 10-8 5% B, 1.7 to 1.84 minutes 85% B, 1.84 to 1.85 minutes 85-100% B, 1.85-1.99 minutes 100% B, 1.99-2 minutes 100-20% B. Flow rate: 5.0 mL/min Tube column: Inertsil® C8, 50 X 4.6 mm, 3 /xm Particle size Method D: Mobile phase: A) water/acetonitrile (99/1) and 0.2% ammonium citrate; B) acetonitrile gradient : 0 to 4.5 minutes 10-80% B, 4.5 to 4.54 minutes 80% B, 4.54-4.85 minutes 80-100% B, 4.85: to 4.99 minutes 100% B, and 4.99-5.00 minutes 100-20% B. Flow rate: 5.0 mL/min Tube column: Inertsil® ODS-3 _, 50 X 4.6 mm, 3 μηι Particle size method 移动 : Mobile phase: Α) water/acetonitrile (99/1) and 0.2 «% acetic acid; Β) acetonitrile Gradient: 0 to 4.5 minutes 10-80% B, 4.5 to 4.54 minutes 80% B, 4.54-4.85 41 201121941 100% B, and 4.99 to 5. 〇〇 minutes 80-100% B, 4.85 to 4.99 minutes minutes 100- 20% B. Flow rate: 5.0 mL/min / xm particle size column: Inertsil® ODS-3, 50 X 4.6 mm 2 · Preparation of intermediates of the invention All starting materials and reagents were obtained from commercial suppliers, such as Sigma, unless otherwise indicated. - Aldrich (St. Louis, M., USA) and its son: Division, and used without further purification. Intermediate 1 : 3-丨("Bistidine-2-carbonyl)_Aminopyrrolidinecarboxylic acid

Intermediate 1 was synthesized via the method of Scheme 3 above, as described below. Step 1: 3 - Ethylamino-carbolysis formic acid ^y〇h-- 0 0 Addition of 1_adamantanic acid to the 10 L reactor (5〇3 g, 2 79 and 70% nitric acid (400 mL ' 6.72 mol )' and the resulting suspension was cooled in a crucible. The temperature was kept below 丨〇. Slowly add 98% sulfuric acid (3.00 L' 55.5 mol>, after the addition is completed, so that the temperature is kept below 1 〇. Acetonitrile is added at a rate of 〇 (2.00 L, 38 5 mol. After all acetonitrile is added, the reaction is stirred for 1 hour. The crude reactant was added to 2 〇l counter 42 201121941 filled with about 1 〇L of ice and mixed with a small amount of water and the resulting mixture was stirred and allowed to warm to room temperature. The solid was then filtered and washed with water. More solids were formed from the acidic water layer, and it was also filtered and washed with water. The combined solid matter was then dried under high vacuum at 5 ° C for 2 days to obtain 432 g (73 〇 / 〇) white. The title compound 3-ethylhydrazino-adamantane-indole-formic acid as a solid. Step 2: 3-Amino-adamantane-1-formate

Add 3-ethoxyethyl-carbo- _ 1 _ decanoic acid (4 3 2 g } 8 2 mol) to water in a 3-neck 5 L flask equipped with a reflux condenser, mechanical stirrer and temperature probe. (1·00 L) and concentrated hydrochloric acid (2.44 l), and the resulting mixture was heated at 95 C for 6 days. During this time, solid matter emerged from the solution. Here. After cooling, the mixture was cooled and the mixture was washed with acetone. The solid was then dried under high vacuum at 50 ° C for about 2 hours to give 328 g (78%) of the title compound 3 -amine - ss. NMR (300 MHz, DMSO-^6) δ 12.35 (br s, 1H), 8.27 (br s, 3H), 2.12-2.22 (m, 2H), 1.85-1.92 (m, 2H), 1.71-1.83 (m , 6H), 1.48-1.69 (m, 4H). Step 3: 3-Amino-adamantane-1-carboxylic acid oxime ester hydrochloride

3-Amino-adamantane-1-formate (100 g, 432 mm 〇1) and decyl alcohol (i 〇 43 201121941 L) were added to a 3-neck 2 L flask equipped with a reflux condenser and a temperature probe. ). To this solution was slowly added 5.7 mL of sulfite gas, 216 mmol) and the reaction was heated at 60 °C for 4 hours. After cooling to room temperature, the crude reaction mixture was concentrated under reduced pressure to remove most of methanol. Then, heptane (about 2 L) was added and the mixture was concentrated again under reduced pressure, at which time the solid began to smother. This process was repeated three more times. The solid was then filtered, washed with heptane and dried in vacuo to afford 97.2 g (92%) of the title compound as a white solid. salt. NMR (300 MHz, CDC13) δ 8 40 (br s, 3H), 3.65 (s, 3H), 2.24-2.33 (m, 2H), 2.16-2.23 (m, 2H), 1.95-2.11 (m, 4H) , 1.78-1.94 (m, 4H), 1.62-1.75 (m, 2H). Step 4: 3-[("Bipyridin-2-yl)-amino]_adamantane+methyl formate

To the round bottom flask was added 3-amino-adamanium-1 _carboxylic acid methyl ester (20.0 g, 81.4 mmol) and dichloromethane (5G 〇 mL) and the solution was in hydrazine. 〇 郃 郃 郃. Then, to this solution was added 57 mL of triethylamine, 〇41 m〇i), followed by the addition of pyridinecarboxamidine hydrochloride (152 g, 85 4 mm 〇l), and the reaction was stirred at 0 c for 3 g minutes. It was then mixed for 6 hours at room temperature τ. A saturated aqueous solution of sodium hydrogencarbonate (5 mL) was added to the mixture, and the mixture was stirred vigorously for a few minutes, then transferred to a 1 2 L separatory funnel. The extract mixture was separated into layers and the aqueous layer was extracted with di-methane (2 x 2 mL). The combined organic layers were washed with brine (3 mL), dried over sodium sulfate, and then evaporated to dryness under reduced pressure to obtain 24 8 g (97 must) as a light brown solid. [(Pyridin-2-carbonyl)-amino]- carbaryl 丨 丨 carboxylate. 1h 44 201121941 NMR (400 MHz, CDC13) δ 8.49-8.54 (m, 1H), 8.16 (dt, J = 7.8, 1.0 Hz, 1H), 7.96 (br s, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.40 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 3.66 (s, 3H) , 2.30-2.34 (m5 2H), 2.25-2.29 (m, 2H), 2.13-2.17 (m, 4H), 1.80-1.97 (m, 4H), 1.62-1.78 (m, 2H). ESI-MS m/ z: 315 (M+H)+. Step 5: 3·[(pyridine-2-carbonyl)-amine-based adamantane d-formic acid

To the round bottom flask was added 3-[(pyridine-2-carbonylamino]-adamantanic acid methyl ester (24.8 g, 78.9 mmol), tetrahydrofuran (250 mL), water (250 mL), and hydr. 14·9 g, 355 mmol), and the mixture was vigorously stirred at room temperature for 2 g. The crude mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran, and the aqueous solution was diluted with water (200 mL) and added. The solid citric acid monohydrate adjusted the pH to about 3-4. A large amount of white precipitate appeared 'filtered' with water and dried under high vacuum at 50. Under a high vacuum, 22.1 g (93%) was obtained in white. The title compound 3-[(0:0-but-2-yl)-amino]]--------- NMR (400 MHz CDC13) δ 8.50-8.55 (m, 1H), 8.18 (d, J = 7.7 Hz, 1H), 7.97 (br s, 1H), 7.85 (td5 J = 7.8, 1.8 Hz, 1H), 7.42 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 2.31 ^2.35 (m, 2H), 2.25-2.31 (m5 2H), 2.09-2.25 (m, 4H), 1.86-2.00 (m, 4H), 1.64-1.80 (m, 2H). ESI-MS m/z: 301 (M + H)+. 45 201121941 Intermediate 2 : 3·[(6-Methyl-β-pyridin-2-carbonyl)-amino]-adamantane-1-carboxylic acid

In a manner similar to Intermediate 1, from 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride (product of Step 3 of Intermediate 1) and 6-mercapto-pyridine at 60.8 mmol reaction scale. Intermediate 2 was prepared as 2-decanoic acid and 12.2 g of the title compound was obtained. 1H NMR (400 MHz, CDC13) δ 8.07 (br s,lH), 7.98 (d, 7=7.7 Hz, 1H), 7.73 (t, / = 7.7 Hz, 1H), 7.24-7.29 (m, 1H), 2.5 8 (s, 3H), 1.66-2.3 7 (m, 14H). ESI-MS m/z: 315 (M + H)+. Intermediate 3: 3-[(6-Methyl-pyridin-2-carbonyl)-aminopyrrolane-1-one

Intermediate 3 was prepared from 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride and 6-methylpyrimidin-2-furic acid in a manner similar to Intermediate 1 at a reaction size of 422 mmol, and 66 g of the crude title compound were obtained. It was used in the next step without further purification. 1H NMR (400 MHz, CDC13) δ 10.2-12.3 (br s5 1H), 9.17 (s, 1H), 8.60 (s, 1H), 7.72 (br s, 1H), 2.60 (s, 3H), 2.26-2.34 (m, 4H), 2.18-2.26 (m, 2H), 2.08-2.16 (m, 2H), 1.88-1.98 (m, 4H), 1.66-1.80 (m, 2H). LC-MS (method C): RT: 0.78 min; ESI-MS m/z: 316 (M+H)+. Intermediate 4: 3-[(pyroxy-2_carbonyl)-amino]-adamantan-1·formic acid

46 201121941 In the same manner as the intermediate i, the intermediate 4' was prepared from 3-amino-adamantane-1 -carboxylic acid methyl ester hydrochloride and 2_pyridin: formic acid at a reaction scale of 32.6 mmol. 2 g of the title compound. It was used in the next step without further purification. LC-MS (method A): rt: 0.45 min; ESI-MS m/z: 302 (M + H)+. Intermediate 5: 3-[(2-Methyl-pyrimidin-4-ylcarbonyl)-amino]-adamantane_1-carboxylic acid

Intermediate 5 was prepared from 3-amino-adamanganese-1-decanoate hydrochloride and 2-methylpyrimidine-4-carboxylic acid in a manner similar to Intermediate 1 at a reaction weight of 27 6 mmol, and 8 14 g of the crude title compound were obtained. It was used in the next step without further purification. iH NMR (400 MHz, CDC13) δ 8.85 (d, J - 5.0 Hz, 1H), 7.97 (br s, 1H), 7.88 (d, J = 5.0 Hz, 1H), 2.77 (s, 2H), 1.89- 2.34 (m, 12H), 1.67-1.79 (m, 2H). LC-MS (method A). RT: 0.55 min; ESI-MS m/z: 316 (M + H)+. Intermediate 6 : 3-[(pyrimidin-4-ylcarbonyl)-amino]-adamantane-1-carboxylic acid

In one step. LC, MS (method A): RT: 〇·43 min; ESI-MS m/z: 302 47 2011 21941 (M+H)+. Dibasic oligoamine Intermediate 7 : 3 · Amino-adamantane-1-carboxylic acid pyridine

Intermediate 7 is smashed by the method of Scheme 4 above, as described below. Step 1: 3_Tertidinoxycarbonylamino-adamantane-Icarboxylic acid

Adding di-tert-butyl dicarbonate to a round flat-bottomed flask containing 3-amino-amostane-1-carboxylic acid (1 g, 5 mmol), THF (1 mL) and 2 M aqueous NaOH (3.8 mL) (1 · 1 g, 5.1 mmpl). After 16 hours at room temperature, the reaction was cooled in an ice-bath, neutralized with 2N aqueous HCI, and then partitioned from ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered 4 NMR (400 MHz, CDC13) δ 4.46 (br s, 1H), 1.80-2.23 (m, 12H), 1.61-1.67 (m, 2H), 1.43 (s, 9H) 〇ESI-MS m/z: 296 (M + H)+ 0 Step 2: 3-Amino-adamantane-1-carboxylic acid pyridine-2r decylamine

48 201121941 to contain 3-tert-butoxy:carbonylamino-adamantane-丨-carboxylic acid (47

To a vial of DMC (23.7 mg > 0.180 mmol) and DIEA (39 mg, 〇. 30 mmol) was added 2-pyrimidineamine (21 mg, 0.22 mmol). After stirring at room temperature for μ hours, the reaction mixture was partitioned between DCM and sodium bicarbonate and solution. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 5 mL THF and treated with aq. 6 M EtOAc. After stirring at room temperature for 16 hours, the reaction mixture was partitioned from EtOAc EtOAc m. ESI_MS m/z: 3 72 (M + H)+. The crude product was used in the next step without further purification. Intermediate 8: 3-Amino-adamantane-i-formic acid (3_gas_phenyl)-decylamine

Intermediate 8 was prepared in a manner similar to Intermediate 7. Coupling of 3 -3 -butoxy-amino-yl-alkanoic acid with % gas-aniline in the 〇6 mm〇1 reaction scale was carried out in a reverse phase HPLC/MS purification system (gradient: acetonitrile in water' 1 8-95% in 3.6 minutes, cycle time 5 minutes. Use a shallow gradient of 20-40% acetonitrile to separate near-dissolved impurities between 0.75-3.3 minutes. Flow rate: 1 〇〇 mL / min. Mobile phase additive : 48 mM ammonium citrate. Column: Inertsil C8, 30 x 5 〇 mm, 5 μιη granules) After purification, 155 mg (60%) 3-(3-gas-phenylamine fluorenyl)_ King Kong Alkyl-1-yl]-amino decanoic acid tert-butyl ester. 4 NMR (400 MHz, CDC13) δ 7.67-7.71 (m, 1H), 7.31-7.36 (m, 2H), 7.22 (t, J = 8.1 Hz, 49 201121941 1H)} 7.05-7.08 (m, 1H), 4.49 (br s, 1H), 1.64-2.31 (m, 14H), 1.43 (s, 9H). ESI-MS m/z: 405 (M+H)+. The title compound, 3-amino-adamantane-indole-formic acid (3-carbo-phenyl)-guanamine, was obtained using a 4M HCl solution to afford the title compound, which was used in the next step without further purification. Intermediate 9 : 6-Methyl- acridine-2-carboxylic acid (3-isocyanato-adamantane)-decylamine

Intermediate 9 was synthesized via the method of Scheme 7 above, as described below: To a solution containing 3-[(6-fluorenyl-pyridine-2-carbonylamino)-adamantane-1-carboxylic acid (Intermediate 2, 1600 mg, Addition of diphenyl azide to a flask of 5.0 mmol), toluene (50 mL, 500 mmol) and TEA (0.76 g, 7.5 mmol)

(18 g' 6.5 mmol). After stirring at room temperature for 15 minutes, the reaction was heated at 8 ° C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the obtained residue was partitioned from ethyl acetate and sodium hydrogen carbonate. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to dry. Purification of the residue by flash chromatography using EtOAc EtOAc (EtOAc) 4 NMR (400 MHz, cDC13) δ 8.07 (br s,lH), 7.99 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7*7 Hz, 1H), 7.27-7.30 (m, 1H ), 2.58 (s, 3H), 1.86-2.39 (m, 12H), 1.57-1.74 (m, 2H). ESI-MS m/z: 312 (M+H). Intermediate 10: Pyridine-2-carboxylic acid (3-carbendamine fundane _i_yl)_decylamine 50 201121941

In a manner similar to the intermediate 9, from the preparation of 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-decanoic acid (Intermediate 1) at a reaction scale of 4.2 mmol. And 0.3 g (50%) of the title compound was obtained as an oil. 1H NMR (400 MHz, CDC13) δ 8.47-8.53 (m, 1H), 8.11-8.17 (m, 1H), 7.93-8.03 (m, 1H), 7.77-7.87 (m, 1H), 7.35-7.44 (m , 1H), 1.59-2.41 (m, 14H). ESI-MS m/z: 298 (M + H)+. Intermediate 11: Pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-guanamine

Intermediate 11 was synthesized via the method of Scheme 7 above, as described below: To 3-[(.pyr.-2-yl)-amino]-m-glycolic acid (intermediate 1, 10.0 g '33.3 mmol) TEA (5.6 mL, 40 mmol) was added to a suspension in toluene (100 mL) and the mixture was stirred for a few minutes until most of the solid dissolved. Then, diphenylphosphoryl azide (7.9 mL, 37 mmol) was added to the mixture and the reaction was stirred at room temperature for a few hours. The reaction mixture was transferred to an addition funnel and was added dropwise to a 3-neck round bottom flask equipped with a reflux condenser and toluene (70 mL) at 9 Torr. After the addition, the reaction was further stirred at 90 C for 2 hours, and then allowed to cool to room temperature. The reaction mixture was then slowly added to a flask containing 6.0 N HCl aqueous solution (55 mL, 330 mm 〇1) and stirred vigorously for a few hours. The two phase mixture was transferred to a knife funnel and the toluene layer was discarded. The acid 51 201121941 aqueous layer was then slowly treated with solid sodium carbonate until a pH of 10 was reached. The water layer is transferred to! It was extracted in a 500 mL separatory funnel with dioxane (3 X 1 00 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, evaporated, evaporated Alkyl-1-yl)-guanamine. If! NMR (300 Μϊίζ, CDC13) δ 8.50-8.55 (m, 1Η), 8.16 (d, J = 7.9 Hz, 1H), 7.94 (br s} 1H), 7.84 (td, 7 7.7, 1.7 Hz, 1H ), 7.40 (ddd, J = 7.6, 4.7, 1.3 Hz, 1H), 2.21-2.31 (m, 2H), 1.97-2.13 (m, 6H), 1.51-1.71 (m, 6H). ESI-MS m/z: 272 (M+H)+. Intermediate 12: 6-Methyl-pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-guanamine

Prepare intermediate from 3-[(6-nonylpyridin-2-carbonyl)-amino]-adamantane-1-carboxylic acid (Intermediate 2) in a manner similar to Intermediate 11 at a reaction scale of 3 1.8 mmol The title compound 6-methyl-pyridin-2-furic acid (3-amino-adamantan-1-yl)-guanamine was obtained as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.81-7.89 (m, 2H), 7.42-7.46 (m, 1H), 2.59 (s, 3H), 2.06-2.44 (m, 6H), 1.67-2.09 (m, 8H ). ESI-MS m/z: 286 (M+H) + 0 1 Intermediate 13: 2-Methyl-pyrimidine-4-furic acid (3-amino-adamantan-1-yl)·decylamine

In a manner similar to the intermediate 11, at a reaction scale of 15_8 mmol 52 201121941 . From 3·[(2-methyl-pyrimidin-4-ylcarbonyl)-amine-based adamantane_ι_decanoic acid (intermediate 5) Intermediate i3 was prepared, and *6 g of the title compound was obtained. It was used in the next step without further purification. LC-MS (method A): RT: 0.32 min; ESI-MS m/z: 287 (M+H)+. Intermediate 14 : 6-Methyl-pyridin-2-decanoic acid (3-amino-adamantan-1-yl)-breasted knee

In the same manner as the intermediate 11, the intermediate was prepared from M(6-methyl than well 2_4yl)-amino]-adamantane-1-carboxylic acid (intermediate 3) at a reaction frequency of 15·8 mm〇i 14' and obtained 4. 7 g of the title compound. LC-MS (Method A): RT: 0.35 min; ESI-MS m/z: 287 (M+H) + 〇 Intermediate 15: 2-(3-Amino-adamantyl)-], 2 - 2 Hydropyrrolo[3,4_c]β ratio bit -3-ketone

Intermediate 15 is prepared via the method of Scheme 19 above, as follows: Step 1: 3-(1,3-Di-oxyl-1,3-dihydro-pyrrolo[3,4_c]^pyridine|Christine" Adamantane-1-carboxylic acid methyl ester H, 0

The 3-amino-adamantane-indole-carboxylic acid decyl ester·HC1 (product of Step 3 of 2011, 201121941, 1 step 3, 3.59 g, 14.S mmol), ° ratio was heated at 100 °C. A mixture of 3,4-dicarboxylic anhydride (2.29 g' 15.4 mm 〇i) and TEA (6.22 mL, 43.9 mmol) in toluene (100 mL) was taken overnight. After cooling to room temperature, phosphonium chloride (1.50 mL, 16.1 mmol) was slowly added. The reaction mixture was heated at 90 ° C for 3 hours and cooled to room temperature. The reaction mixture was filtered to remove a solid, and the filtrate was concentrated under reduced pressure, and then quenched with aqueous NaHCO3 (1 mL) and basified to a pH of 10 with solid Na2CO3. The aqueous layer was extracted with DCM (2×1 00 mL). The combined organic layers were washed with brine, dried with EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3,4-cp-pyridin-2-yl)-adamantane-1-carboxylate was used in the next step without further purification. 1H NMR (400 MHz, CDC13) δ 9.07 (d, J = 0.8 Hz, 1H), 9.02 (d, J = 4.8 Hz, 1H), 7.67 (dd, = 1.2, 4.8 Hz, 1H), 3.68 (s, 3H), 2.28-2.64 (m, 8H), 1.65-1.99 (m, 6H). LC-MS (method A): RT: 1.30 min; ESI-MS m/z: 341 (M+H) + 〇 Step 2: 3-(3-Alkoxy-i,3-dihydro-pyrrolo[ 3,4_c]pyridine_2_yl)_ammanone-1-carboxylic acid methyl ester

White 3_(1,3 --sideoxy-1,3 -diaza-D-pyrolo[3,4-c].ββ定_2_yl)-Adamant-1-carboxylate (3.74 g, ll. Ommol) Zinc (3.59 g, 54.9 mmol) was added to the > trough solution in acetic acid (4 〇.〇mL). The reaction mixture was mixed for 1 day at room temperature. The reaction mixture was filtered to remove the solid, and the mash was concentrated under reduced pressure 54 2011 21941. The residue was diluted with DCM (50 mL) andEtOAcEtOAc The aqueous layer was extracted with DCM (2×30 mL). The organic layer is condensed under reduced pressure/agriculture. The residue was purified by CombiF / EtOAc / EtOAc (EtOAc: EtOAc EtOAc EtOAc) [3,4_c]0-pyridinium-2, hexyl phthalate, iji NMR (400 MHz, CDC13) δ 9.04 (d, · / = 0.9 Hz, 1H), 8.73 (d, J = 5.1 Hz, 1H), 7.39 (dd, J = 0.7, 5.0

Hz, 1H), 4.53 (s, 2H), 3.67 (s, 3H), 1.57-2.46 (m, 14H). LC-MS (method A): RT: 0.92 min; ESI-MS m/z: 327 (M + H)+. Step 3: 3-(3-Phenoxy-i,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantan-1-formic acid

Stirring 3-(3-oxo-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantane decanoate with LiOH (0.658 g, 27.5) at room temperature Methyl) mixture of water (15 mL) and THF (45 mL) overnight. The THF was evaporated under reduced pressure and the aqueous layer was acidified to pH 2 with IN HCl. The precipitate was filtered, washed with water, and dried under reduced pressure at 50 ° C to give 3.17 g of the title compound 3-(3-s-oxy-1,3-dihydro-pyrrolo[3,4-c] Pyridin-2-yl)-amostane-1-decanoic acid was used in the next step without further purification. LC-MS (method A): RT: 〇·38 min; ESI-MS m/z: 313 (M + H)+. Step 4: 2-(3-Amino-adamantan-1-yl)-1,2-dihydro-pyrrolo[3,4-c]indole-3-one 55 201121941

Stir 3-(3-sidedoxy-l,3->hydrogen-°pyrolo[3,4-c]»pyridin-2-yl)-adamantane-1-carboxylic acid (3.17) at room temperature g), a mixture of diphenyl azide (2.35 g, 8.54 mmol) and TEA ( 1.66 g, 16.4 mmol) in hydrazine (32 mL) for 1 hour, followed by mixing at 90 ° C for 2 hours . After cooling to room temperature, the reaction mixture was added to a cold 6 M aqueous HCl solution (1 6 mL), stirred vigorously at room temperature for 1 hour, and diluted with water (50 mL). Separate the benzene layer. The aqueous layer was basified to a pH of 10 with solid Na.sub.3 and extracted with DCM (3.times. The combined organic layers were washed with brine, dried with EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Hydrogen-pyrrolo[3,4-c]e was pyridine-3-one which was used in the next step without further purification. 1H NMR (400 MHz, CDC13) </RTI> LC-MS (Method A): RT: 0.22 min; ESI-MS m/z; 284 (M+H)+. Intermediate 16 : 6-(3-Amino-adamantan-1-yl)-6,7-dihydro-pyrrolo[3,4-bl* than bite-5-嗣: similar to intermediate 15 By the way, an intermediate 16 was prepared from 3-amino-adamantane 丨 丨 吡啶 曱 曱 Η : : (: η and pyridine 2, 3-dicarboxylic anhydride) at a reaction concentration of 14.2 mmol, and a title of 1 · 5 g was obtained. The compound was used in the next step without further purification. LC-MS (Method A): RT: 0.26 min; ESI-MS m/z: 284 56 2011 21941 (M + H) + Intermediate 17 : 6 · (3_Amino-adamantane)-2_mercapto-6,7-dihydro-pyrrolo[3,4 - b] than bite _ 5 - steel

, 0 Ν, acid anhydride Step 1: 6 -Methyl-β ratio bite _2,3_dimethyl

Co2h

NT, C02H

A solution of 6-methyl-2, bismuth dicarboxylic acid (2〇〇g ii〇匪〇1) in acetic acid liver (1〇.4mL) was mixed at l〇〇°C for 4 hours, followed by decompression Concentrated under. The residue was diluted with EtOAc (30 mL). The organic layer was washed with a saturated aqueous solution of (10), &lt;3&gt;3, and brine, and then evaporated to dryness, and concentrated under reduced pressure to give the title compound 6-methyl, bite 2,3 dicarboxylic anhydride. 1hnmr (300 MHz, CDC13) δ 8.22 (d, 8.0 Hz, 1H), 7.65 (d, /= 8.0

Hz, 1H), 2.85 (s, 3H). Step 2: 6-(3-Amino-gold-alkano-4-yl)_2-methyl-6,7-dihydropyrrolo[3,4-b]&quot;Bite-5-one

In a manner similar to the intermediate 15, from 3-amino-adamantane-l-methyl ester·HC1 and pyridine 6-fluorenyl-pyridine·2,3-57 201121941 at a reaction scale of 3.34 mmol, and obtained 203 Mg title compound. It was not LC-MS (Method C): RT: 0.59 min; L( ESI-MS m/z: 298 (M+H)+ 〇 Intermediate 18 : ° ratio 0 formic acid (3-carbyl-adamantan-1-yl)-nitramine

Intermediate 18 was synthesized via the method of Scheme 12 above, as follows: Add η to sigmacarboxylic acid (0.68 g, 5.5 mmol), DMF (15 ml), TEA (0.90 mL, 6.4 mmol) in a white 40 ml vial and HBTU (2.3 g, 6.0 mmol). The mixture was stirred at room temperature for 5 minutes to obtain a clear solution. To the above solution was added 3-amino-adamantane-tanol (0 84 g, 5_0 mmol) and the mixture was stirred at room temperature for 2 hr. The DMF was removed in a vac. EtOAc (EtOAc) (EtOAc). The crude title compound pyridine-2-formic acid (3-hydroxyl-adamant-l-yl)-guanamine showed a colorless solid after standing at room temperature. LC/MS method A: RT: 0.79 min; purity (UV254): 1 00%; ESI-MS m/z: 273 (M+H)+. It was used in the next step without further purification. Intermediate 19: 2-bromomethyl-nicotinic acid ethyl ester

Intermediate 19 was prepared by bromination of commercially available ethyl 2-mercaptonicotinic acid as described above, as follows: 58 201121941 Stirring 2-f-nicotinic acid ethyl ester (1.00 g at 90 ° C) , 6.05 mmol), Dihydrodiphenylimine (1·4〇g, 7.87 mmol) and 2,2,-Azo-bis-isobutyronitrile (99.4 mg, 0.605 mmol) in CC14 (20 mL) The mixture was taken overnight and then cooled to room temperature. The solid was filtered and washed with CCU. The combined organic layers were washed with aq. EtOAc EtOAc. The residue was purified by CombiF / w / EtOAc (DCM) to afford 1.0 g (68%) 4 NMR (400 MHz, CDC13) δ 8.71 (dd, "/= 1.8, 4.8 Hz, 1H), 8.28 (dd, / = 1.8, 7.9 Hz, 1 H), 7.34 (dd, /= 4.8, 7.9 Hz, 1H), 5.04 (s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). LC-MS (method A): RT: 0.99 min; ESI-MS m/z: 244 (M+H)+. Intermediate 20: methyl 3-bromodecyl-pyridine-2-carboxylate

Intermediate 20 was prepared from methyl 3-methyl-pyridine-2-carboxylate at a reaction scale of 6.05 mmol, and the title compound was obtained after system (DCM). ^ NMR (400 MHz, CDC13) δ 8.66 (dd, J = 1.7, 4.6 Hz, 1H), 7.89 (dd, J = 1.6, 7.9 Hz, 1H), 7.47 (dd, J = 4.7, 7.9 Hz, 1H) , 4.94 (s, 2H), 4.03 (s, 3H). LC-MS (method C): RT: 0.89 min; ESI-MS m/z: 230 (M+H)+. s Intermediate 21 : 3-[5-(6-Methyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-adamantan-1-yl-amine 59 201121941

Intermediate 21 was prepared via the method of Scheme 21 above, as described below: Step 1: 3-Tertoxycarbonylamino-adamantanic acid

Add 3% to a solution of 3-Amino-Kingyuan-1-1-carboxylate.HCl (5.00 g, 20.3 mmol) and hydrazine (6.24 mL, 44.8 mmol) in DCM (100 mL). Di-tert-butyl carbonate. (4.88 g, 22.4 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with Ac. The organic layer was washed with water, citric acid, a saturated aqueous solution of NaHCO3 and brine, and dried over <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Used without further purification

In the next step. 1H NMR (300 MHz, CDC13) δ 4.41 (br s, 1 HL 3.65 (s, 3H), 1.79-2.22 (m, 12H), 1.63 (br s, 2H), I.43 (Sj 9H). A solution of [ion (1.46 g, 61.0 mmol) in water (60.0 mL) was added to a solution of EtOAc (60.0 mL). The mixture was stirred at room temperature overnight and concentrated under reduced pressure to remove THF. The aqueous layer was acidified with citric acid: EtOAc (EtOAc) eluted Base-adamantane-1-carboxylic acid. 4 NMR (400 MHz, CDC13:) δ 4.45 (br s, 1H)0 1.82-2.24 (m, 12H), 1.62-1.66 (m, 2H), 1.43 60 201121941 (s , 9H). · Step 2: 3-丨5-(6-methylpyridin-3-yl)-[i,3,4]oxadiazol-2-yl]-omostrum-1-ylamine

Add 3-tert-butoxycarbonylamino-adamantane-i-decanoic acid (1.00 g, 3.3 8 mmol), 6-methylnicotinium 〇 (〇 512 g, 338 mmol) and DCM to a 20 mL vial (25.0 mL) followed by pyBOP (1_85 g, 3.55 mmol) and TEA (0.94 mL, 6.77 mmol). The reaction mixture was stirred at room temperature overnight and diluted with DCM (50 mL). The organic layer was washed with a saturated aqueous solution of NaHC03 and brine (30 <RTI ID=0.0></RTI> <RTIgt; </RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Truncate]•Vajra-1-yl}-aminobutyric acid tert-butyl ester, which was used in the next step without further purification. Trifluoromethanesulfonic anhydride (1.14 mL, 6.77 mmol) was added to a solution of EtOAc (EtOAc m. The reaction mixture was stirred at room temperature overnight and was quenched with aq. The aqueous layer was extracted in dcm (2 times). The combined organic layers were washed with brine, dried over Na~~~~~ The obtained residue was suspended in acetonitrile, and the mound was collected by filtration to obtain crude 5-[5-(3-isocyanato-adamantane_ι_yl)-1,3,4-dioxa-2- ]]-2-mercapto-pyridine. iH NMR (300 MHz, CDC13) δ 9.14 (d, J = 2.0 Hz, 1H), 8.26-8.32 (m, 1H), 7.37 (d, /= 8.2 Hz, 1H), 2.71 (s, 3H), 1.74 -2.43 (m, 14H) ° LC-MS (^ 61 201121941 Method A): RT: 1.35 min; ESI-MS m/z: 33,7 (M + H)+. Add 5-[5-(3-isosanoyl-adamantan-1-yl)-l,3,4-oxadiazol-2-yl]- to 6NHC1 solution (5 mL) at 〇 °C A solution of 2-mercapto-pyridyl in a stupid (5 mL). The mixture was stirred at room temperature for 1 hour and basified to about pH 10 with solid K2CO3. The aqueous layer was extracted with z-PrOH/CHCl3 (1,3,3x). The combined organic layers were dried over EtOAc EtOAc (EtOAc:EtOAc: Diazol-2-yl]-adamantan-1-ylamine was used in the next step without further purification. 1H NMR (400 MHz, CDC13) δ 9.11 (d, / = 2.0 Hz, 1H), 8.21 (dd, /= 2.3, 8.1 Hz, 1H), 7.30 (d, 7= 8.1 Hz, 1H), 2.65 (s , 3H), 1.62-2.34 (m, 14H). LC-MS (method A): RT: 0.42 min; ESI-MS m/z: 311 (M+H)+. Intermediate 2 2 . 6 -ethyl - in the acid test

Intermediate 22 was prepared from commercially available 6-gas-nicotinic acid methyl ester by the method of Scheme 20 above, as follows: Step 1: 6-Ethyl-final acid methyl vinegar

6-gas to acid test (2.00 g, 11.6 mmol) and iron acetylacetonate (0.21 g, 0.58 mmol) in THF (36.4 mL) 62 201121941 and 沁methyl-pyrrolidine at room temperature A solution of 3 〇M ethyl magnesium bromide (4.66, mL) was added to the solution in the ketone (3.64 mL). The reaction mixture was stirred at room temperature overnight and quenched with brine. The aqueous layer was extracted with EtOAc (20 mL EtOAc). The combined organic layers were washed with brine, dried over MgSO. The residue was purified with EtOAc EtOAc (EtOAc) iH Nmr (400 MHz, CDC13)6 9.13 (d, J = 1.9 Hz, 1H), 8.20 (dd, J = 2.2 8.1 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 3.94 (s, 3H), 2.90 (q, j = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). Step 2: 6-ethyl·nicotinate

A solution of 6-ethyl-nicotinic acid decyl ester (0.9 g) and hydrazine (4.00 mL, 127 mmol) in methanol (4 mL) was stirred at 70 ° C overnight and concentrated under reduced pressure. 1 g of the title compound 6-ethyl-nicotinate, which was used in the next step without further purification. 4 NMR (400 MHz, CDC13) δ 8.86 (d, J = 1.9 Hz, 1H), 8.01 (dd, J = 2.4, 8.1 Hz, 1H), 7.43 (br s, 1H), 7.26 (d, /= 8.0 Hz, 1H), 4.10 (br s, 2H), 2.89 (q, = 7.6 Hz, 2H), 1.3 2 (t, / = 7.6 Hz, 3H). Intermediate 23: 6-mercapto-nicotinic acid bismuth

63 201121941 Using the same experimental procedure as described in the synthesis of intermediate 22 (step 2) 'Preparation of intermediate 23' from 6-methyl hydrazide vinegar at 9.3 9 mmol reaction scale and obtaining 〇.50 g of the title compound . It was used in the next step without further purification. 1H NMR (400 MHz, CDC13) δ 8.85 (d / = 2.2 Hz, 1H)5 7.99 (dd, J = 2.4, 8.1 Hz, 1H), 7.68 (br s, 1H), 7.26 (d, = 8.9 Hz, 1H), 4.13 (br s, 2H), 2.62 (s, 3H). Intermediate 24: 5-methyl-nicotinate Γ(Γ^Ι Η N^SrN, NH2 Ο using the same experimental procedure as described in the synthesis of intermediate 2 2 (Step 2) at a reaction scale of 19.8 mmol Intermediate 24 was prepared from 5-mercapto nicotinic acid and the title compound was obtained from EtOAc EtOAc (EtOAc) 1.8 Hz, 1H)S 8.58 (d, J = 1.7 Hz, 1H), 7.93 (s, 1H), 7.74 (br s. 1H), 6.86 (br s, 2H), 2.41 (s, 3H). 25: 6-trifluoromethyl-nicotinate

Intermediate 25 was prepared from 6-(trifluoromethyl)nicotinic acid methyl acetate at the 9.75 mmol reaction scale using the same experimental procedure as described in Synthesis Intermediate 22 (Step 2), and 1.7 g of the crude title compound was obtained. . It was used in the next step without further purification. 1H NMR (400 MHz, CDC13) δ 8 98 (br 64 201121941 s, 1H), 8.83 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8 2 (dd, J = 2.0, 8.2 Hz , 1H), 4.13 (br s, 2H) » LC-MS (method T* 〇, 48 min; ESI-MS m/z: 2.6 (M + H) +. Intermediate 26: 3-[3-(6 -Methyl-pyridin-3-yl)-[1,2,4] employed diterpene. S• Fundane-1-ylamine oxime

Intermediate 26 is prepared via the method of Scheme 23 above, as described for γβ, F: Step 1: {3-[3-(6-Methyl-pyridin-3-yl)-[1,2,4] Diazole, Thai]·adamantane-l-yl}-tert-butyl methacrylate

3-tert-butoxycarbonylamino-adamantane-1-carboxylic acid (0.20 g, 〇68 mmol), A/~ carbyl-6-methyl-inspection (0.51 g' 3.38 mmol), diisopropyl A mixture of ethylethylamine (1.47 mL, 8.46 mmol) and TBTU (ΐ·〇9 g, 3.3 8 mmol) in DMF (7-50 mL) was microwaved at 150 °C for 20 min. The reaction mixture was diluted with EtOAc (50 mL). The organic layer was washed with a saturated aqueous solution of NaH.sub.3 and brine, and evaporated. The residue was purified with EtOAc EtOAc (EtOAc) 2,4-Diazol-5-yl]-adamantan-1-yl}-carbamic acid tert-butyl ester. NMR (400 MHz, CDC13) δ 9.17 (

(d, = 1.7 Ηζ, 1 Η), 8.22 (dd, = 2.2, 8.1 Ηζ, 1 Η), 7.26 (d, J 65 201121941 = 8.1 Hz, 1H), 2.63 (s, 3H), 1.71-2.38 (m, 14H), 1.44 (s, 9H). LC-MS (method C): RT: 1.65 min; ESI-MS m/z: 411 (M + H)+. Step 2: 3-[3-(6-Mercapto-pyridin-3-yl)-[1,2,4]-assised diazol-5-yl]-adamantyl-1 -ylamine

To {3-[3-(6-fluorenyl-fluorenyl)--3-yl)-1,2,4---------------------------------------------------------- A solution of 2.0 M HCl in diethyl ether (0.974 mL) was added to a solution of &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred overnight at room temperature and was taken to a saturated aqueous NaH.sub.3. The aqueous layer was extracted with DCM (3 times). The combined organic layers were washed with brine and dried with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ] 〇 〇 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 It was used in the next step without further purification. !H NMR (400 MHz, CDC13) δ 9.17 (d, /= χ 9 Ηζ 1Η), 8 22 (dd, /= 2.2, 8·1 Ηζ, 1Η), 7.26 (d, 7.9 Ηζ, ιη), 2.63 (s, 3Η), 1.65-2.34 (m, 14Η). LC-MS (method C): RT: 0.76 min; ESI-MS m/z: 311 (M+H)+. Intermediate 27: iV-hydroxy-6-methyl-nicotine 脒

66 201121941 Intermediate 27 was prepared by the method of Scheme 22 above, as follows: To a 5-cyano group: methyl port specific ratio (5. 〇〇g, 42 3 axis 〇 1), methanol (17 mL) A solution of hydroxylamine hydrochloride (5.88 g, 84 6 mrrml, δ 〇mmo1) in methanol (50 mL) was added to a mixture of fine powder K2C03 ( 8.77 g, 63 s OJ·5 mmol). The reaction mixture was heated at reflux overnight under H.sub.2 to dryness at room temperature and concentrated under reduced pressure. The residue was wet-milled with a cold e- and the obtained solid was taken through a mixture of hydrazine, and y, y y y y y y y y y y y y y y y y y y y y y y y y y - in the base. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (br s 1H^ R το r V 5 1H)s 8·72 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8 1 Hz 1H,...

Hz, 1H), 5.91 (S, 2H), 2.47 (s,

3H) 〇J 3. Preparation of the Compounds of the Invention Unless otherwise indicated, all starting materials and reagents are obtained from commercial suppliers, such as si Ald 1 Cft A 3 (St. Louis, MO, USA) and its subsidiaries, and Used without further purification. Example 4: 6-Methyl-pyridine 2 -carboxylic acid τ adenylamine sulfhydryl _ _ 金 烧 ι ι ι 酿 酿 酿

The following example: Example 4 was synthesized from the intermediate 2 by the above process ^ method such as 67 201121941 to contain 3-[(6-methyl than bit_2-alkyl)-amino]_金刚烧_ι_carboxylic acid Add 0.5 ml of 2M methylamine in THF (1 mmol) to a vial of intermediate (2,60 mg, 0.2 mmol), DCM (1 mL), DIEA (39 mg, 0.30 mmol) and TBTU (96 mg, 0.30 mmol) ). After stirring at room temperature for μ hours, the reaction mixture was partitioned between dcm and saturated sodium hydrogencarbonate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. Purification system in reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: water containing acetonitrile at 3 6 minutes in the middle of 1 8 - 9 5 % 'June ring time 5 min. in 〇. 7 - Use a shallow gradient of 25-48% acetonitrile between 3.3 minutes to separate the near-dissolved impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM ammonium citrate. Column: Inertsii C1 8, 30 X The residue obtained was purified by 50 mm (5 μm) to give the title compound 6-methyl-pyridin-2-decanoic acid (3-methylaminemethanyl-yield-1). Base) - Amine. In the manner similar to Example 4, Examples 1-3, 5-6, 25, 26, 28 and 29 of Table 1 (below) were prepared from Intermediate 2 and the corresponding commercially available amines. Examples 7-21, 27 and 30-32 of Table 1 were prepared in the same manner as in Example 4 from the intermediate i and the commercially available amine. Examples 22 and 23 were prepared in a manner similar to that of Example 4 from commercially available 3-benzoic acid and Intermediates 8 and 7, respectively. Example 24: 3-(3-Gas-benzhydrylamino)-adamantane! _carboxylic acid (6-subunit-pyridin-2-yl)•guanamine

68 201121941 Example 24 was prepared via the procedures of Schemes 2 and 4 above. Step 1 : 3-Amino-amostane-1-carboxylic acid (6-fluorenyl-2-yl)-nitramine

3-Amino is prepared from 3-tert-butoxycarbonylamino-adamantane-1, formic acid and 6-mercaptopyridin-2-amine in a manner similar to Intermediate 7 at a reaction of 1 mmol. Adamantane-1-decanoic acid (6-fluorenyl-pyridin-2-yl)-guanamine. The crude product 3-amino-adamantane-1 -carboxylic acid (6-fluorenyl-.pyridin-2-yl)-decalamine was used in the next step without further purification. Step 2: 3-(3-Gas-benzylidenylamino)-adamantane-1-carboxylic acid (6-methyl-pyridin-2-yl)-decylamine

乙祖座物兴市 I reacted in a similar manner to the method of Example 4 '3-chlorobenzoic acid to obtain 22 mg (50%) of the title compound 3-(3_glybenylamino)-adamantane- 1-carboxylic acid (6-methyl-pyridyl)-decylamine. Example 37: 6-Methyl-0-pyridin-2-carboxylic acid [3 (3propyl-glycolyl dadyl)·decylamine

69 201121941 Example 3 7 was synthesized from Intermediate 9 via the procedure of Scheme 5 above, as described below: To a solution containing 6-methyl-picolinic acid (3-isocyanato-adamantanyl)-decylamine ( Add 1 -propylamine (6 〇〇 mg, i 〇 mm 〇 1) to the vial of intermediate, 9, 30 mg, 0.1 mm 〇i ) and DMF (2 mL). The mixture is at i 6 〇. The underarm was subjected to microwave treatment for 15 minutes, followed by concentration under reduced pressure. The residue was partitioned between DCM and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. In reverse phase liquid chromatography/mass spectrometry (Rp_HpLc/Ms) purification system, first (gradient 'acetonitrile-containing water, 24_95% in 36 minutes, cycle time 5 minutes. ο·". .. Separating the nearly dissolved impurities with a shallow gradient of acetonitrile between 3〇6〇%. Flow rate: 1〇〇mL/min. Mobile phase additive. 39 mM acetic acid. Column: Inertsii C8, 3〇χ 5 The obtained residue was purified by 〇mm, 5 μηι particle size to obtain 丨8 吕 ( () titled 6-methyl-bite _2•carboxylic acid [3_(3-propyl-ureido)-adamantane] Base]-bristamine. Also, Example 3 was prepared from the intermediate j 2 by the method of Scheme 6. Under the shirt, the intermediate 12 (6-methyl-pyridine-2-formic acid (3-amino-adamantane)-based amine) (60 mg '〇. 2 mmol) and propyl isocyanate (_mg, 7 calendar 〇) React in DCM! 6 hours, and after Ηριχ purification, 4 〇 式 〇 〇 。 。 。. In the same manner as in Example 37, the examples "" of the watch were prepared from the reaction of the intermediates 13, 14, and 12 with the corresponding commercially available isocyanuric acid, respectively. Examples 39-40 were prepared from the reaction of hydrazine with the corresponding commercially available isocyanate; respectively, from the reaction of the intermediate 9 with the corresponding commercially available amine, respectively. 70 201121941 Examples 36 and 38; respectively, from the middle Examples 41, 42 and 45 of Table 1 were prepared by reacting the materials with the corresponding commercially available amines. Example 43: Tofolin _4_carboxylic acid {3-[(»tb bite_2-carbonyl)-amino]-adamantane • 1-ylindole-nonylamine

Example 4 3 was synthesized from the intermediate via the method of Scheme 6 above, as follows: To a solution containing pyridin-2-indole; (3-amino-adamantan-1-yl)-decylamine (intermediate 11 ' 20 mg, 0,07 mmol) was added dropwise to the vial of the solution in DCM (2 mL) and DIEA (19 mg, 0.15 mmol) (16.5 mg, 0·11) Mm). After stirring at room temperature for 16 hours, the reaction mixture was partitioned between DCM and saturated sodium bicarbonate. The organic layer was separated, dehydrated by sodium sulfate and concentrated under reduced pressure. Purification system in reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: water containing acetonitrile, 20-95% in 3.4 minutes) The cycle time was 5 minutes. The near-dissolved impurities were separated using a shallow gradient of 'λ 22-48% acetonitrile between 0.51 and 3.2 minutes. Flow rate: 100 mL/min. Mobile phase additive: 39 mM ammonium acetate. The resulting residue was purified with EtOAc EtOAc m.

I Example 44 of Table 1 was prepared in the same manner as in Example 43 from Intermediate 11 and piperidin-1 -carbonyl chloride. Example 54: {3-[(6-Methyl-pyridine-2-carbonyl)-amino-p-amantane-yl b 71 201121941 2,2-difluoro-propyl carbamate

Example 54 was synthesized from Intermediate 9 via Scheme 8 above, as described below: To a solution containing 6-fluorenyl-pyridine-2-decanoic acid (3-isocyanato-adamantan-1-yl)- 2,2-difluoropropanol (500 mg, 5 mmol) was added to a vial of guanamine (intermediate 9 '30 mg, 0.1 mmol) and DMF (2 mL). The solution was microwaved at 165 ° C for 25 minutes. The reaction mixture was concentrated and partitioned between dCM and sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. Purification system in reverse phase liquid chromatography/mass spectrometry (rp_hplc/ms) (gradient: acetonitrile-containing water, 29-95% in 3.6 minutes, cycle time 5 minutes. Use 40_70% between 0.75_3 4 minutes) The shallow gradient separation of acetonitrile is close to the dissolved impurities. Flow rate: 1 〇〇mL/min. Mobile phase additive: 39 mM acetic acid. Column: inertsil C8, 40 X 50 mm, 5 μηη particle size) , 12 mg (3%) of the title compound {3·[(6-fluorenyl-pyridine-2-carbonylamino)-adamantane-丨-yl-amino-decanoic acid 2,2-fluoro-propanyl In a manner similar to that of Example 5, Examples 46-53 and 55 of Table 1 were prepared from Intermediate 9 and the corresponding commercial alcohol, respectively. In a manner similar to Example 54, from Intermediates 1 and 2 , 2-difluoropropanol Preparation Example 59 of Table 1. 72 201121941 :. Example 57: {3-[(6·Methyl-Bite-2-Carbo)-Amino]-Astragalus 2-methoxy-ethyl carbamic acid

Example 57 was synthesized from Intermediate 12 via the method of Scheme 8 above. ' As described below. · To contain 6-methylpyridin-2-indoleic acid (3-amino-adamantane-1-yl)-decylamine ( Add TEA (0.028) to the vial of intermediate 12) (30 mg, 〇_i mm〇i), DCM (2 mL) and 2-methoxyethyl chloroacetate (2 1 mg ' 〇. 1 5 mmol) After stirring for 6 hours at room temperature, the reaction mixture was concentrated and dried over EtOAc EtOAc m. Purification system in reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: acetonitrile-containing water, 27-95% in minutes, at 3·6 | 27-95%' cycle time 5 minutes. 75_3 3 minutes with 35-rate .10 0 m L / mi η. 64% separation of acetonitrile in shallow gradients close to the dissolved impurities 100 mL / min. Mobile phase added Qi · Inertsil C18, 35 χ 5 &lt; 1 5 mg Γ 4 Ο %, monument s Cl 8,35 χ 50 mm, 5 mm, 5 /zm

. The impurities which are close to dissolving are separated between 0.75 and 3.3 minutes. flow

Respectively from intermediates 12 and corresponding f1,3] gas nitrogen heterocycles 73 201121941 hexyl-3-yl)-diamond xyl-1-ylamine

Example 60 was prepared from intermediate 12 via the method of Scheme 9 above, as follows:

To contain 6-methyl-pyridine-2-decanoic acid (3-amino-adamantan-1-yl)-decylamine (Intermediate 12) (50 mg, 0.2 mmol), CH3CN (5 mL) and TEA ( To the vial of 26 mg, 0.26 mmol) was added 3-chloropropionate (0.06 g, 0.4 mmol). After stirring at room temperature for 1 hour, the reaction was partitioned between DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to afford 65 mg (yield of &lt;RTIgt; Amygdalin-1 -yl}-carbamic acid 3-a-propyl ester. It was used in the next step without further separation. 1H NMR (400 MHz, CDC13) δ 8.02 (br s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 4.63 (br s, 1H), 4.10-4.20 (m, 2H), 3.61 (t, /= 6.3 Hz, 2H) 2.55 (s, 3H), 1.55-2.40-1.55 (m5 14H). ESI-MS m/z: 406 (M + H)+. The above intermediate (52 mg '0·14 mmol) was dissolved in DMF (3 mL) and sodium hydride (13 mg, 0.52 mmol) was added. At 5 〇. 〇下槐 74 201121941 ♦ After 2 hours off, the reaction mixture was concentrated and partitioned between DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. Purification system in reverse phase liquid chromatography, / mass spectrometry (RP_HPLC/MS) (gradient: acetonitrile-containing water, 23_95% in 3, 6 minutes, cycle time 5 minutes. Use 27_55% between 0.75-3.3 minutes) A shallow gradient between acetonitrile is separated from the dissolved impurities. Flow rate: 1 〇〇mL/min. Mobile phase additive: 48 mM ammonium formate. Column: Inertsil C8, 30 X 50 mm, 5 / m particle size) Residue 'obtained 4 mg ( 8% ) of the title compound 6-methyl_吼 bit_2_ decanoic acid [3-(2-trioxy_[ι,3]oxazepine_3_yl)_ Adamantane 丨 基 基 醯 醯 。. ··· Example 61: pyridine 2 -carboxylic acid (3-benzenesulfonylamino-adamantyl) decylamine

Example 6 1 was prepared from intermediate u by the method of Scheme 10 above, as follows: To a solution containing pyridin-2-decanoic acid (3-amino-adamantane-i-decylamine (2〇mg' 0.07 mmol) ), DCM (b ml) and DIEA (0.018 g, 0.14 mmol) were added to the vial (1 8 mg, 0.1 〇mmol). After mixing for 3 hours at room temperature, saturated solution with sodium bicarbonate The reaction mixture was washed, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. Purified by reverse phase liquid chromatography / mass spectrometry (RP-HPLC/MS) (gradient: acetonitrile-containing water, within 3.6 minutes 24-95%, cycle time 5 minutes. Use a shallow gradient of 35-65% acetonitrile between 〇·75_3 5 minutes to separate the nearly dissolved miscellaneous 75 201121941. Flow rate: 100 mL / min. Mobile phase additive : 48 mM formic acid. Column: Inertsil C18, 30 X 50 mm, 5 / m particle size) on the purified residue 'paid 2 2 mg (80%) of the title compound bite _ 2 _ decanoic acid (3 _ benzene Anthraquinone-adamantan-1-yl)-guanamine. Example 62: ethyl-aminocarbamate 3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl

Example 62 was prepared from Intermediate 18 via the procedure of Scheme 11 above, as described below: To a solution containing pyridine-2-carboxylic acid (3-hydroxy-adamantane-i- decylamine (Intermediate 18, 20 mg, 0.07 mmol) And a mixture of DMF (2 mL, 20 mmol) in isocyanate-ethylamine (50 mg, 0.7 mmol). The reaction mixture was microwaved at 165 C for 25 min then concentrated under reduced pressure. Distribute to a saturated solution of DCM and sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated to dryness under reduced pressure. Purification system by reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: Acetonitrile-containing water, 24-95% in 3 6 minutes, cycle time 5 minutes. Use a shallow gradient of 30-60% acetonitrile to separate near-dissolved impurities between 0.75-3.3 minutes. Flow rate: 100 mL /min. Mobile phase additive: 48 mM ammonium formate. Column: inertsil C18, 3 〇 X 5 〇 mm, 5 μιη particle size) The residue was purified to give 7 mg (30%) of the title compound ethyl- carbamic acid 3 -[(pyridine-2-carbonyl)-amino]-adamantane 76 201121941 -1 - based on the scheme. Example 63: 6-methyl-pyridine-2-carboxylic acid [3-(β Bis-2-ylamino)-adamantane-1-ylbuminamide

Example 63 was prepared via the method of Scheme 13 above, as follows: Step 1: 6-Methyl-pyridine-2-carboxylic acid (3-hydroxy-adamantane);

Add 3 to a flask containing 6-mercapto ratio 0 decanoic acid (41 〇mg '3 · 〇 mmol ), DMF (10 mL), BOP (1400 mg, 3.3 mmol) and DIEA (390 mg, 3.0 mmol) - Amino-amostane-1-ol (500 mg, 3 mmol). After stirring at room temperature for 16 hours, the reaction mixture was washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was purified by CombiFMeOH / EtOAc (hexane: ethyl acetate = 1:1) to yield 600 mg (70%) of the title compound 3-hydroxy-adamantane-l-carboxylic acid (6-mercapto-pyridine-2) -yl)-guanamine. 4 NMR (.400 MHz, CDC13) δ 8.06 (br s,1H), 7.95 (d, 7 = 7.7 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 7· 7 Hz, 1H), 2.55 (s, 3H), 1.54-2.35 (m, 14H). ESI-MS m/z: 287 (M+H)+. Step 2: 6-Methyl-pyridine-2-carboxylic acid [3-(pyridin-2-ylamino)-adamantan-1·yl]-decylamine 77 201121941

Containing 6-methyl-t&gt; at a temperature of 0 °C than bite-2-carboxylic acid (3-carbyl-adamanganese-l-yl)-decylamine (700 mg, 2 mmol), DCM (5 mL, 80) Methanesulfonate (500 '6 mmol) was added dropwise to a vial of mmol and TEA (680 gL, 4_9 mmol). After stirring for 16 hours at room temperature, the reaction mixture was successively washed with water and a saturated solution of sodium hydrogencarbonate. The organic layer was separated, dried <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Amino]-adamantane-1_ vinegar was used in the next step without further purification. ESI-MS m/z: 3 65 (M+H). Add 2- to the vial containing the acid (1 〇〇 mg, 〇 _3 mmol). Bisylamine (380 mg, 4.0 mmol). After heating at 160 ° C for 1 hour, the reaction mixture was allowed to cool to room temperature and was partitioned between DCM and saturated sodium hydrogen carbonate. The organic layer was separated, dried over sodium sulfate and evaporatedEtOAc. Purification system in reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: acetonitrile-containing water, 28_95% in 36 minutes, cycle time 5 minutes. Use between 〇·75·3 4 minutes) 38 67% of the shallow gradient separation of acetonitrile is close to the dissolved impurities. Flow rate: i 〇〇 mL / min. Mobile phase additive. 48 mM ammonium formate. Column: Inertsil eg, 30 X 50 mm, 5 μιη grain size) The above purified residue 'obtained ^ (2) was obtained as the title compound 6 methyl-bite _2-decanoic acid [3 decapyridin-2-ylamino) adamantane small group]-decylamine. Example 64. ° ratio biting · 2_ formic acid ratio biting -2_yl fluorenyl) _amino group - - diamond burning • 1-based} • decylamine 78 201121941

Example 64 was prepared from the intermediate u via the method of Scheme 14 above as follows: To the contained. Add to a flask of THF (1 〇 mL) of pyridine-2-decanoic acid (3-amino-adamantane-;!-yl)-decylamine (intermediate 11, HO mg, 〇·52 mm〇1) 2-. The mixture was blunt (61 mg '〇·57 mmol) and the mixture was stirred at room temperature for 45 minutes. Sodium triethoxysulfonate (164 mg, 774 774 mmol) was then added and the reaction was stirred at room temperature overnight (&gt; 16 hr). The reaction was quenched by the addition of decyl alcohol (1.0 mL) and stirred vigorously for a few minutes. The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative thin-layer chromatography ( EtOAc) eluting with DCM (1% ammonium hydroxide) containing 10% decyl alcohol. Purification system in reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: acetonitrile-containing water' 15-95% in 3.9 minutes, cycle time 5 minutes. Flow rate: 100 mL/min. Mobile phase Additive: 78 mM ammonium acetate. Column: Inertsil C8, 30 X 50 mm, 5 μm particle size) The product was purified to give 47 mg (25%) of the title compound as a white solid. [(° ratio. deutero-2-ylindolyl)-amine Qin]-金刚院-1 - 丨 _ _ amine.

-1-Gipoxime

79 201121941 Example 66 was synthesized from Intermediate 1 via the method of Scheme 15 above, as follows: To a solution containing 3-[(° 〇 _2 _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ EDCI (230 mg, 1.2 ψπιοί) and 4-gas-benzene-1,2- were added to the flasks (intermediate 1,300 mg, 1 mmol), DCM (2 mL) and DIEA (1 mL, 6 mmol). Diamine (1 71 mg, 1.2 mmol). After stirring at room temperature for 16 hours, the reaction &gt; compound was partitioned between D C Μ and saturated sodium hydrogencarbonate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. Purification system in reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: acetonitrile-containing water, 16-95% in 3 95 minutes 'cycle time 5 minutes. Flow rate: 1 〇〇 mL/min Mobile phase additive. 96 mM citric acid. Column: Inertsil C8, 30 X 50 mm, 5 μηι particle size) The residue was purified to give the intermediate guanamine regiois

Mixture (300 mg '70%). ESI-MS m/z: 425 (Μ+Η)+. A portion of the above guanamine intermediate (20 mg, 0.05 mmol) was dissolved in 1 mL of THF and 2 mL of 6M HCl. and the solution was microwaved at i6 (TC) for one minute. After cooling to room temperature, under reduced pressure The reaction mixture was concentrated and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjj (Gradient: acetonitrile-containing water, 25-95% in 3.9 minutes, cycle time 5 minutes. Flow rate: 1 〇〇 mL/0 lin. Mobile phase additive: 48 mM formic acid. Column: Inertsil C8, 30 X 50 Mm, 5 μιη granules) The residue was purified to give 6 mg (30%) of the title compound pyridine 2 -carboxylic acid [3 (5 - gas-1 benzo s. s 2 _ yl) _ _ _ _ _ _ _ _ Brewing amine. In a manner similar to Example 66, from Intermediate 2 and commercially available 2·amine 80 201121941 Benzene Preparation Example 表67 of Table 1; Preparation from Intermediate 2 and corresponding commercially available diamines Examples 68-71. Example 72: 6-Methyl-pyridine-2-carboxylic acid [3-(3-methyl-3 ugly-imidazo[4,5-b] &quot;bipyridin-2-yl)- Adamantane -1-yl]-nonylamine

Example 72 was prepared via the method of Scheme 15 from Intermediate 2 and #2-mercaptopyridine-2,3-diamine (prepared by reduction of the corresponding nitro compound above) as described below:

To a vial containing decylamine (2,3 g, 10.0 mmol) of decylamine (25 mL) containing fluorenyl-3-stone succinyl- 2-0 was added 1%/carb (15 〇 mg). The mixture was hydrogenated at 30 psi for 16 hours, filtered through celite, and the filtrate was concentrated under reduced pressure to yield quantitative yield of #2-methylpyridine·2,3-diamine as a brown solid. It was used in the next step without purification. NMR (4〇〇 ΜΗζ, CDC13) δ 7.79 (dd, = 5.2, 1.5 Ηζ, 1 Η), 6.85 (dd, = 7.3, 1.6

Hz, 1H), 6.53 (m, 1H), 4.18 (br s, 1H), 3.17 (br s, 2H), 3.01 (s, 3H). 81 201121941 To contain 3-[(6-fluorenyl-pyridine-2-carbonyl)-amino]-adamantane decanoic acid (Intermediate 12, 1.9 g, 6.0 mmol), DCM' (50 mL), DIEA (1 Add 9-mercapto 0 to bite-2,3-diamine (0.74 g, 6 mmol) to a flask of 9 g, 15 mm 〇l) and TBTU (2·2 g '7·〇mm〇1). After aging at room temperature for an hour, the reaction mixture was concentrated and partitioned between DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated. Purification system in reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: acetonitrile-containing water, 23-95% in 3.6 minutes, cycle time 5 minutes. Use between 〇75_34 knives 4) A shallow gradient of -56% separation of acetonitrile is close to the dissolved impurities. Flow rate: 1 〇〇 mL / min. Mobile phase additive: 48 mM methicillin. Official column. Inertsil C8, 30 X 50 mm, 5 μηι particle size The residue is purified to yield a quantitative yield of the indoleamine intermediate in the form of a regioisomeric mixture. ESI-MS m/z: 420 (Μ+Η)+. To a microwave vial of 3 of the above-mentioned succinamine intermediate (80 mg, 〇. 19 mmol) was added 3 mL of acetic acid. The reaction mixture was slowly poured into ice-cold sodium hydrogencarbonate solution at 16 rc under microwave (25 min 4 min) and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. Liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (gradient: acetonitrile-containing water, 28-95% in 3.6 minutes, cycle time 5 minutes. Use 3375_3 4 minutes between 33-62 The shallow gradient separation of acetonitrile is close to the dissolved impurities. Flow rate: 1 〇〇 mL / min. Mobile phase additive: 48 mM ammonium formate. Column: Inertsil C8, 30 x 50 mm 5 / m particle size) 60 mg (78%) of the title compound 6-methyl-pyridine-2-carboxylic acid [3-(3-methylpyrano[4,5-b]pyridine-2-yl] 82 201121941 -1 -yl]-nonylamine. Example 73: 6-methyl-0-pyridin-2-carboxylic acid [3-(4-methyl-1H-imidazol-2-yl)-adamantan-1-yl] - brewing amine

Example 7 was synthesized from Intermediate 2 via the method of Scheme 15 above, as follows:

To a solution containing 3-[(6-fluorenyl "bipyridin-2-carbonyl)-amino]-adamantane-1-decanoic acid (intermediate 2, 100 mg, 0.3 mmol), DCM (15 mL, 230 mmol) BOP (210 mg, 0.48 mmol) was added to a vial of DIEA (62 mg, 0.48 mmol) and amidoacetone hydrochloride (52 mg, 0.48 mmol). After stirring at room temperature for 3 hours, concentrated under reduced pressure. The reaction mixture was partitioned between DCM and sat. sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. Purified system by reverse phase liquid chromatography/mass (rp_hpLC/ms) (gradient: Acetonitrile &amp; water, 18_95% in 3_5 minutes, cycle time 5 minutes. Use a shallow gradient between 2〇4〇% between 0.75-3.3 minutes to separate the near-dissolved impurities. Flow rate: i 〇〇mL/min. mm mobile phase additive: 3 9 mM etozone. Total ^_ τ G ^ know. Official column: Inertsil C8, 30 X 50 5 Mm particle size) on the residue, 馀, do not produce 5〇 Mg(40%) decylamine intermediate ESI-MS m/z: 370 (M+H) + 83 201121941 Adding acetic acid to dmf (200 /iL) containing the above intermediate (20 mg) (1 50 mg ) and acetic acid (1 After heating for 4 hours at rc (rc), the reaction mixture was cooled to room temperature, concentrated under reduced pressure and partitioned between DcM and saturated sodium bicarbonate. Concentrate under reduced pressure. Purification system by reverse phase liquid chromatography/mass spectrometry (rP_HPlc/MS) (gradient: acetonitrile-containing water, 12_95% in 3 · 6 minutes, cycle time 5 minutes. Between 0.6-3.25 minutes The near-dissolved impurities were separated using a shallow gradient of 2〇_42% acetonitrile. Flow rate: 1〇〇mL/min. Mobile phase additive: 48 mM ammonium formate. Column: Inertsil C8, 3〇x 5〇mm The residue was purified by 5 mg (25 g) to give the title compound 6-mercapto-pyridin-2-furic acid [3-(4-mercaptoimidazo-2-yl)-adamantyl] Example 74: 6-Methyl-pyridine-2_carboxylic acid [3_(1,3-dihydro-isoindole_2 benzobumantan-1-yl oxime)

Example 74 was prepared from Intermediate 12 via the method of Scheme 16 above, as follows: Add 6-mercaptopyridine-2-formic acid (3-amino-adamantane-I group) to the culture tube, decylamine (intermediate 12, 50.0 mg '〇_175 mmol), 1,2-bis(bromoindolyl), benzene (46 mg, 〇.l7 mm〇1), and DMF (2.0 mL), and the mixture is mmol) Potassium carbonate (60 mg, 0.43 mmol) and the mixture was stirred at room temperature for 18 h. Next, 84 201121941 Water (10 mL) and ethyl acetate (i 〇 mL) were added to the reaction mixture, and the mixture was stirred vigorously for several minutes. The organic layer was separated, and the aqueous layer was mixed with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (1 EtOAc), dried over sodium sulfate. Purification system in reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: acetonitrile-containing water, 20-95% in 3.5 minutes, cycle time 5 minutes. Use between 24 3 3 minutes) -52〇/. The shallow gradient between acetonitrile is separated from the dissolved impurities. Flow rate: 100 mL/min. Mobile phase additive: 96 mM ammonium citrate. Column: 1 read ^08, 3 (^'5〇 1^,5_particles)The residue was purified to give 1 2 mg (1 8%) of the title compound 6-methyl- 〇 咬 咬 [ [3-(1,3-dihydro-isoindole) -2-yl)-adamantane-丨-yl]-decylamine. Example 87. 6-Methyl-pyridyl-g-carboxylic acid [3-(5-sideoxy-5,7-dihydro-pyrrole) And [3,4_1&gt;]° than 唆-6-yl)-Astragalus _1_yl] _ guanamine

N

Example 87 was prepared from Intermediate 16 via the procedure of Scheme 18 above, as follows: 6-(3-Amino-adamantan-1-yl)-5,6-dihydropyrazole was added to a 20 mL vial And [3,4-b]. Bipyridin-7-one (intermediate 16, 50.0 mg » 0.18 mmol) &gt; mercaptopyridinic acid (26.6 mg, 0.19 mmol) and DCM (4.0 mL, 62.4 mmol), followed by PYBOP (110 mg, 0.21 mmol) And trihexylamine (61.5 mL, 0.44 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with DCM (30 mL). The organic layer was separated, washed with EtOAc EtOAc m. Purification system in reverse phase liquid chromatography/mass spectrometry (rP_HPLC/MS) (gradient: acetonitrile-containing water, 23-95% in 3.6 minutes, cycle time 5 minutes. Use 27_5〇% between 0.75-3.3 minutes) The shallow gradient separation of the acetonitrile is close to the dissolved impurities. Flow rate: i 〇〇 mL / min. Mobile phase additive: 78 mM ammonium acetate. Column: Inertsil C8, 30 X 50 mm, 5 (four) particle size) , yielding 41 mg (58%) of the title compound 6-methyl-pyridine-2-carboxylic acid [3-(7-o-oxy-5,7-dihydro-pyrido[3,4-b]acridine- 6-Base)_Astragalus-1 -yl]-bristamine. In a manner similar to that of Example 87, respectively, from Intermediate 15 and commercially available 6-mercaptopyridinic acid, 2-methylpyrimidine-4-enoic acid, 5-fluoropyridine-2carboxylic acid, and fluoro-pyridine-2- Formic acid Examples 75-77 and 79 of Table 1 were prepared. In a manner analogous to Example 87, Example 78 of Table 1 was prepared from Intermediate 15 and 4-mercapto-2-pyrimidine decanoic acid, and 4-mercapto-2-pyrimidinic acid was prepared by the following procedure:

Step 1 : Add sodium cyanide (286 g, 58 3 mm 〇1) to TEA to a solution of 2-ox-4-methylpyrimidine (3 〇〇g, 23 3 mm 〇1) in Acrylic (24 mL). And a solution of water (1:3, 24.0 mL). The reaction mixture was stirred overnight at room temperature. The aqueous layer was extracted with diethyl ether (3 x 2 mL). The combined organic layers were filtered through <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> lH NMR (400 MHz, D20) δ 8.64 (d, = 5 4 Hz, 1H), 7 59 (d, j = 5 5

Hz, 1H). { Step 2: Stir 4_methyl-pyrimidine_2-carbonitrile (5〇〇mg, 4 2〇86 201121941 mmol) and sodium hydroxide (504 mg' 12.6 mmol) in water (12.5 mL) at 60 °C The solution was taken for 1 hour. The mixture was cooled to room temperature, and acidified to about pH 2 with citric acid, and the combined organic layers were extracted with CHCl 3:z_-PrOH (3:1, 2 &lt; 20 mL) and dehydrated under reduced pressure. Concentration, 〇29 g of 4-decyl-2-pyrimidinecarboxylic acid was obtained, which was used in the next step without further purification. 〇1HNMR (300 MHz, D20) 3 8.50 (d, &lt;/=5.2HZ, lH) , 7.31 (d, ·/ = 5.3 Hz, 1H). Example 8 of Table 1 was prepared in the same manner as in Example 8 from Intermediate 15 and commercial nicotine chloride hydrochloride. In a manner similar to that of Example 87, respectively, from Intermediate 16 and commercially available 5-fluoropyridine-2-carboxylic acid, 2-mercaptopyrimidine-4-enoic acid and 2-mercapto-1,3-thiazole-4_carboxylic acid. The reaction was prepared in Table 1, Examples 8 1-82 and 86. In a manner similar to that of Example 87, the preparation of Table 1 was carried out separately from the reaction of the intermediate 16 with commercially available nicotine helium hydrochloride, isoxazole-5-carbonyl gas and 1,3-thiazole-2-carbonyl gas. Examples 83-8 5. In a manner analogous to Example 87, Examples 89-91 of Table 1 were prepared from the reaction of intermediate 17 with commercially available 2-mercaptopyrimidinecarboxylic acid, 6-methylpicolinic acid and 5-fluoropyridine-2-carboxylic acid, respectively. Example 87 was also prepared from intermediates 12 and 19 via the procedure of Scheme 18 above, as described below: to 6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-decylamine (〇·33 g ' 〇.82 _〇1) and 2-bromoindolyl-ethyl citrate (〇.20 g, 〇82 mm.1) in (l.oo mL, 12.9 mmol) Add carbon to potassium (0.226 g, 1 64 mm 'bl ). The reaction mixture was stirred overnight at room temperature 87 201121941 and stirred at 50 ° C for 2 days. The reaction mixture was cooled to room temperature, then cooled to room temperature with the reaction mixture, followed by

The near-dissolved impurities were separated by a shallow gradient of 26-56% between acetonitrile. Flow rate: 100 mL/min. Mobile phase additive: 46 mM ammonium formate. Tube column: Inertsil C8 '30 X 50 mm, 5 μηι particle size) 'further purified to give 3 2 mg ( 9.7% ) of the title compound 6-methylpyridine 2 decanoic acid [3_(5-side oxy-5,7- Dihydropyrrolidino[3,4-b].pyridin-6-yl)-adamantan-1-yl]•decalamine. Example 8 of Table 1 was prepared from the interstitial materials 13 and 20 in a manner similar to that of Example 87. Example 92: acridine-:2-carboxylic acid [3-(1 oxo-dihydro-isoindole-2-yl)-adamantan-1-yl]-decylamine

Example 92 was synthesized from the intermediate via the square of Scheme 18 above, as follows:

To the pyridine-2-decanoic acid (3-amino-adamantan-1-yl)-decylamine (intermediate, 20 mg, 0.07 mmol), DCM (5 ml) and DIEA (14 mg, 0.1 mm 2-bromomethyl-benzene, formazan bromide (23 mg, 0.08 mm 〇i) was added to the vial. After stirring at room temperature for 16 hours, the reaction mixture was partitioned between DCM 88 201121941 and saturated sodium bicarbonate. The layer was dehydrated with sodium sulfate and concentrated under reduced pressure. Purified by reverse phase liquid chromatography / mass spectrometry (rP_HPLC/ms) (gradient: acetonitrile-containing water, 24_95% in 3 6 minutes, cycle time 5 minutes Use a shallow gradient knife between 35-65% acetonitrile to separate the dissolved impurities between 0.75-3.5 minutes. Flow rate: 丨〇〇mL/min. Mobile phase additive · 48 mM ammonium formate. Purification of the residue on Inertsil C8, 30 X 50 mm, 5 mp.) yielded 14 mg (40%) of the title compound pyridine-2-carboxylic acid [3-(1- s-oxy- oxime, % dihydro-isoindole) _2 adamantane-yl]-bristamine. Example 93: pyridine-2-carboxylic acid [3_(5,7-di- oxy_5,7-dihydro-pyrrolo[3,4-b] Pyridine_6_yl)-adamantyl]-guanamine

Example 93 was synthesized from the amine intermediate u via the method of Scheme 17 above, as described below: To a solution containing sorghum-2,3-didecanoic acid (20 mg, 0.1 mmol), dCm (5 mL) and ethylene Addition to a vial of helium (3 〇 mg ' 〇 2 mm 〇 1 ) - DMF was added to the next 16 hours, and the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in DCM (5 mL), and then n was added to &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&& TEA (7 mg '0.07 mmol). After 16 hours at room temperature, the reaction mixture was partitioned between DCM and sat. sodium bicarbonate. Sub- 89 201121941 The organic layer was separated and concentrated under reduced pressure. Force; ^ Purification system in reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: water containing 3 acetonitrile, 23-95% in 3.6 minutes 'cycle time 5 minutes. 〇75_3 5 minutes A near-dissolved impurity was separated using a shallow gradient of 27-57% between acetonitrile. Flow rate: 100 mL/min. Mobile phase additive: 48 mM ammonium citrate. Column: C8, 30 X 50 mm, 5 grit The residue was purified to give 8 mg (3%) of the title compound pyridine-2-carboxylic acid [3-(5,7-di- oxy-5,7-dihydro-pyrrolo[3,4_1)] Biming: -6-yl)-omostrum--1-yl]-guanamine. Example 101: 6-Methyl-pyridine-2-carboxylic acid [3_(5-pyridyl-[L3,4]-doxazol-2-yl)-adamantan-1-yl]-guanamine

Example 101 was prepared from Intermediate 2 via the method of Scheme 20 above, r is as follows: Step 1 · 6-Methyl than bite _2-formic acid {3-[TV-(e ratio bite_2_ ))-indenyl group] - Donkey Kong · 1 - yl} _ amidoxime

Add 3 -[(6-fluorenyl-α to β-densyl)-amino]-ambron~1-decanoic acid (intermediate 2,157 mg, 0.50 πιηιο 1), 2 - ° ratio to the flask 0 甲甲醯肼 (8 2 90 201121941 mg, 〇, 6 〇 mmol) and DCM (5. 〇mL), followed by pyB〇p (312 mg, 0.600 mmol) and TEA (〇17 mL,) 25 咖〇 1). Search at room temperature: After 5 hours of mixing, the reaction mixture was transferred to a separatory funnel with DCM (15 mL) and a saturated aqueous solution of hydrogencarbonate (about 30 mL). After extraction, the layers were separated and the aqueous layer was extracted again with DCM (2×1 5 mL). The combined organic layers were washed with brine (25 mL) dried over sodium sulfate. Purification system in reverse phase liquid chromatography/mass spectrometry (RP-HPLC/MS) (gradient: acetonitrile-containing water, 23-95% in 3 6 minutes, cycle time 5 minutes. Use 2675_3 4 minutes between 4 minutes) • A shallow gradient of acetonitrile separated by 54% close to the dissolved impurities. Flow rate: 丨〇〇mL/min. Mobile phase additive: 65 mM ammonium acetate. Column: lnertsil C8, 30 X 50 mm, 5 μΐη particle size) The residue was purified to give the title compound: 6-methyl-pyridin-2-carboxylic acid (3-ethyl-pyridin-2-carbonyl)-fluorenylcarbonyl]-King. Alkyl hydrazine. iH NMR (300 ΜΗζ, CDC13) δ 10.28 (br d, J = 6.6 Hz, 1H), 8.56-8.61 (m, 1H), 8-46 (br d, / = 6.4 Hz, 1H), 8.07-8.17 ( m, 2H)} 7.98 (d, J = 7.7 Hz, 1H), 7.86 (td, y = 7.7, 1.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.46 (ddd, J = 7.6 , 4.7, 1.2 Hz, 1H), 7.3 0-7.24 (m, 1H), 2.58 (s, 3H), 2.14-2.42 (m, 8H), 1.93-2.07 (m, 4H), 1.67-1.86 (m, 2H). ESI-MS m/z: 434 (M+H)+. Step 2: Methyl-pyridine-2-carboxylic acid [3-(5-pyridine-2-yl-[l,3,4]-doxazol-2-yl)-adamantane_; 91 201121941

Add 6-mercaptopyridinium 2i decanoic acid {3_[jv(pyridine_2carbonyl)-fluorenylcarbonyl]-adamantane-l-yl}-decylamine (5〇.〇mg, 〇16) to the culture tube 〇姐^) mouth bite (46 mg '〇_58 mmol) and DCM (i 〇社). The solution was cooled down and treated with a solution of trifluoromethyl acid (107 mg., 381 381 mm 〇1) in DCM (1·0 mL) and the mixture was gradually warmed to room temperature. After about 25 hours, the reaction mixture was diluted with DCM (3 mL) and then stirred with a saturated aqueous sodium hydrogen carbonate (5 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue is purified by preparative thin-layer chromatography (TLC) eluting with 100% ethyl acetate to afford 24 mg (44% &gt; 88% purity) of the title compound as a colorless oil. 2-carboxylic acid [3-(5-0 than bit-2-yl-[1,3,4]indole di-indol-2-yl)-Kinggang Institute_ι_yl]-guanamine. In a similar manner, Examples 94-100 and 102-103 were prepared from Intermediate 2 and the corresponding commercially available oxime, respectively. Examples 104-106 were prepared from Intermediate 3 and corresponding commercially available oximes in a manner similar to Example 1-1; Examples 107-108 were prepared from Intermediate 1 and corresponding commercially available oxime, respectively; Preparation of Examples 4〇9 and 11〇 by reacting materials 4 and 5 with commercially available lanthanum niobate; Preparation of Example 11 and 114 from the reaction of intermediate 23 with intermediates 1, 5, 2 and 3, respectively; Reaction of the substance 24 with the intermediates 1 and 5 to prepare Examples 115-116; respectively, from the reaction of the intermediate 25 with the intermediates 1 and 5, Preparation Example 117_11 8; 92 92 201121941 from the intermediate 22 and the intermediates 2 and 5 The reaction was prepared in the manner of Example 119-1 20. Example 121: 5-Fluoro-pyridine-2-carboxylic acid p_[5-(6-methyl-pyridin-3-yl)-[1,3,4]Didis-2-yl]-金刚炫-1 _ base}-bristamine

Example 12 1 was prepared from ten substances 21 by the method of Scheme 2 above, as follows: ι Γ Add 3-[5_(6-fluorenyl-pyridin-3-yl)-1,3 to a 20 mL vial , 4-diazol-2-yl]-adamantan-1-ylamine (intermediate 21 '7〇.〇mg, 0.23 mmol), 5-fluoro 0 疋 疋-2-decanoic acid (35·0 Mg, 0.25 mmol) and DCM (2.80 mL, 43.7 mmol), followed by hydrazine ( 129 mg, 〇 248 mmol) and TEA (69.2 gL, 0.50 mmol) » The reaction mixture was stirred overnight at room temperature and DCM (30 mL) diluted. The organic layer was washed with aq. EtOAc EtOAc. Purification system in reverse phase liquid chromatography/mass spectrometry (Rp_HpLC/MS) (gradient: acetonitrile-containing water, 25-95% in 3.6 minutes, cycle time 5 minutes. Use between 35_65% between 0.75-3.3 minutes) The shallow gradient separation of acetonitrile is close to the dissolved impurities. Flow rate: 1 〇〇 mL / min. Mobile phase additive: 92 read formic acid. Column: If (4) with (10) (10), a positive granule is used to purify the residue, and obtain 7 7 Mg (丨7%) of the title compound 5_gas picolinic acid {3-[5-(6-fluorenyl-fluorene. _3_yloxadiazole_2_ kib-tricyclo[3·3·1.1( 3,7)]decane-1-carbamidamine. A 93 201121941 In a manner similar to that of Example 121, sub-existing from intermediate 21 and commercially available 2-pyridinic acid and pyrimidine-4-carboxylic acid Reactions Prepared Examples 122 and 123 of Table 1. Example 124: 2-Methyl-pyrimidine-4-carboxylic acid {3 bis[3-(3-fluoro-phenyl)-[1,2,4] -S-Kibbum - l-yl}-bristamine

Example 124 was prepared from Intermediate 5 via the method of Scheme 22 above, as follows:

Microwave treatment of 3-[(2-indolyl-sound-4-yl)-amino]-adamantane-1-carboxylic acid (intermediate 5, 50.0 mg '0.16 mmol), trans-base-cracked at 150C A mixture of hydrazine (24.4 mg, 0.16 mmol), hydrazine/hydrazine-diisopropylethylamine (69.0 / x L '0.40 mmol) and TBTU (50.9 mg, 0.16 mmol) in DMF (1.0 mL) The reaction mixture was diluted with EtOAc (5 mL). The organic layer was washed with a saturated aqueous solution of NaH.sub.3 and brine, and then evaporated. Purification of the residue by CombiF/wA® system (4 g of dialysis cartridge; gradient: hexanes with 10 to 50% ethyl acetate over 15 min) afforded 54 mg (78%) of - mouth bite_4_ formic acid {3-[3-(3-fluoro-phenyl)-l,2,4-oxadiazol-5-yl]-adamantyldiamine 0 ·« in a similar manner to the examples In the manner of 124, Example 1 25 of Table 1 was prepared from Intermediate 5 and commercially available 3-0. 94 201121941. Example 126 of Table 1 was prepared in a manner analogous to Example 124 from Intermediate 4 and commercially available 3 pyridine amide. In the same manner as in Example 124, Example 丨27 was prepared from Intermediate 2 and commercially available 3 -pyridinium amidoxime. In the same manner as in Example U4, Example 1 28_丨3 1 of Table 1 was prepared from the reaction of Intermediate 27 with Intermediates 2, 5, 1 and 6, respectively. Example m: 5_fluoropyridine_2_decanoic acid {M3 (6-methyl-indolyl-3-yl)-[1,2,4]oxadiazolyl]-adamantan-1

Example 134 was prepared from the intermediate via the method of Scheme 22 above, as follows: at 〇 ° C, to a ratio of 2 - decanoic acid (22.7 mg, 0.16 〇 1) to DCM (3.0) Add ι (3 dimethylaminopropylethylcarbamate-imide (500γπρ,Γ)7ι, υPg 〇.32 mm〇l) and 1-hydroxybenzotriazole (0.022 g) to the solution in mL) , 0.16, then add 3[3(6-methyl acridine H1,2,4] to hire diterpene _5_yl]_Astragalus small amine (intermediate %, 5 〇〇, 〇.ΐ6_υ之DCM (2). The reaction mixture was stirred overnight at room temperature and diluted with DCM. The organic layer was washed with a saturated aqueous solution of (4) (3) and brine, and concentrated under reduced pressure. _ C_b he W system (4 g stone Erasing cartridge; Gradient: Dcm containing hydrazine to 5〇% acetic acid for 10 minutes, followed by DCM containing acetoacetate for 1 hr) Purification of the residue, 95 201121941 Obtaining 48 mg (690/〇) title Compound 5-fluoro-pyridine-2-decanoic acid {3_[3-(6-methyl-β ratio. D--3-yl)-[1,2,4] hired two tons of 5-yl]-金刚炫-1-yl}-decylamine. In a manner similar to that of Example 134, respectively, from Intermediate 26 and commercially available 2-pyridinic acid Examples 6 and 133 of Table 1 were prepared for 6-methyl-2-pyrionic acid. Example 135: 6-Methyl-pyridine-2-formic acid {3-[5-(3-gas-phenyl). Azol-2-yl]-amsarone- l-yl}-bristamine

Example 135 was prepared from Intermediate 2 via the procedure of Scheme 24 above, as follows: Step 1: 6-Mercapto-pyridine-2-carboxylic acid {3-[2-(3- gas-phenyl)-2- Side oxy-ethylamine methyl sulfhydryl]-amostane-l-yl}-guanamine

To the flask was added 3-[(6-fluorenyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid (188 mg '0.60 mmol), 2-amino-1-(3-chloro- Phenyl)-ethanone hydrochloride (103 mg '0.50 mmol) and DCM (5.0 mL). The solution was successively butyl EA (240 / iL ' 1.7 mmol), 4-dimethylamino group. Treated with 0 (9 mg, 0.07 mm〇l) and EDCI (144 mg, 0.750 mmol). After stirring for 5 days at room temperature 96 201121941, the reaction mixture was diluted with DCM (5 mL) and then stirred vigorously with saturated aqueous sodium hydrogen carbonate (W mL). The organic layer was separated, dried over sodium sulfate and filtered and evaporated. The residue was then purified by preparative thin-layer chromatography (TLC) eluting with 50% ethyl acetate in hexane to afford 42 mg (1 8%) of the title compound 6-methylpyridin-2-carboxylic acid {3 -[2-(3-Gas-phenyl)-2-oxo-ethylamine formamidine hexanyl 丨 基 基 醯 醯 。 。. ESI-MS m/z: 466, (M+H)+. Step 2: 6-Methyl-pyridine-2_carboxylic acid {3-[5_(3_气_phenyl)_carbazole_2_ylb-m-butyl-1-yl}-decylamine

Add 6-mercapto-pyridine-2-hydranoic acid {3-[2-(3-gas-phenyl)2 oxo-ethylamine-mercapto]-adamantane_i-kib to the culture Indoleamine (a mg, 0.09 mmol),. Ratio D (36 mg, 〇 46 _〇ι) and ο·(] 〇 mL ). The liquid is then treated with two gas sulfonic acid sulfonate (6411^, 〇23111111〇1) in 〇〇]^(1.〇^之谷谷液. After stirring overnight at room temperature, the reaction mixture is Μ ( 3 (M) dilute 'subsequent with saturated aqueous solution of sodium bicarbonate ($) (deeply mix. Separate the organic layer, dehydrate with sodium sulfate, m under concentration and reduce the concentration of 4 藉 by preparative thin layer chromatography (π. The residue was purified by hexane/branze containing 5% by weight to obtain 30 mg (70%) of the title compound 6 methyl·° ratio bite·2_carboxylic acid {H5-(3-gas-phenyl) -H2-based]-金刚院-1 - kibamine. 97 201121941 Table 1: Adamantylamine derivatives lion J Structural chemical name Synthetic amount yield LC/MS JHNMR 1 Release 6-mercapto-. -2_ decanoic acid [3-(2-hydroxyphenylaminoindolyl)-diamond-1-yl]-guanamine 22 mg 30% Method C RT: 1.36 min m/z: 406 (if+H)+ (400 MHz, CDC13) δ 8.11 (brs, 1H), 7.95 (d, 7=7.7 Hz, 1H), 7.82 (br s, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.20-7.27 ( m, 2H), 6.99-7.09 (m, 2H), 6.83 (m, lH), 3.16 (m, lH), 2.56 (s, 3H), 2.16-2.44 (m, 14H) 2 6-methyl-0 Than 2-pyruic acid (3-isopropylamine-methyl fluorenyl-gold) Cycloalkyl-1-yl)-nonylamine 5 mg 20% Method A RT: 1.24 min m/z: 356 (M+H)+ (400 MHz, CDCI3) δ 8.01 (br s, 1H), 7.98 (d, /=7.8 Hz, 1H), 7.73 (t, J=1.S Hz, 1H), 7.27 (m, 1H), 5.44 (m,lH), 4.09 (m, 1H), 2.58 (s, 3H), 1.63-2.33 (m, 14H), 1.15 (d, 7=6.6 Hz, 6H) 3 6-Methyl-pyridine-2-decanoic acid [3-(2-Sideoxy-propylaminoindolyl)- Adamantan-1-yl]-nonylamine 50 mg 40% Method C RT: 1.10 hr m/z: 370 (M+H)+ 4 ρΛ CH]h3c 6-mercapto-D ratio bite-2· citric acid (3-mercaptoaminemethanyl-adamantane-I-yl) *nitramine 45 mg 70% Method C RT: 1.09 \ min m/z: 328 (M+H)+ (300 MHz, CDCI3) δ 8.07 (s, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.26 (d, 7 = 7.7, 1H), 2.79 (d, / = 4.8 Hz, 3H), 2.55 (s, 3H), 1.61-2.33 (m, 14H) 5 Hp~V&r 6-mercapto-pyridin-2-decanoic acid (3-aminoindenyl-adamanganese-1 -yl) - guanamine 6 mg 70% Method c RT: 1.02 min m/z: 314 (M+H) + (300 MHz, CDCI3) δ 8.07 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.71 (t, /= 7.3 Hz, 1H), 7.26 (d, /=7.3 Hz, 1H), 5.92 (s , 2H), 2.56 (s, 3H), 1.65-2.32 (m, 14H) 98 201121941 6 6 -A -pyridine-2-decanoic acid [3-j2-hydroxy-2-phenyl-ethylamine decyl)-adamantan-1-yl]-bristamine 50 mg 40% Method c RT: 1.27 min m/z : 434 (M+H)+ (400 MHz, CDC13) δ 8.05 (brs, 1H), 7.61-7.93 (d, /=7.7 Hz, 1H), 7.70 (t, J=ll Hz, 1H), 7.27- 7.20 (m, 1H), 7.36-7.23 (m, 6H), 6.21-6.15 (m, lH), 4.87-4.82 (m, lH), 3.73-3.65 3.38-3.30 (m, lH), 2.56 (s, 3H), 2.30-1.63 (m, 14H) 7 〇NH, N 6 0 than bite-2-carboxylic acid [3-(3-cyano-phenylaminemethanyl)-adamantan-1-yl]-醯Amine 12 mg 40% Method c RT: 1.39 min m/z: 401 (M+H) + 8 ° γ α Pyridine-2:-carboxylic acid [3-(3-Gas-phenylaminoindenyl)-adamantane -1-yl]-nonylamine 4 mg 10% Method C RT: 1.55 min m/z: 410 (M+H) + 9 J gas acridine-2-carboxylic acid [3-(6-methyl-pyridinium) -2-ylaminocarbamimidyl)-adamantan-1-yl]-nitramine 15 mg 40% Method c RT: 1.39 min m/z: 391 (M+H) + 10 〇W'H Pyridine-2- Formic acid [3-(2-hydroxy-ethylaminecarbamimidyl)-adamantane-1-yl]-nonylamine 9 mg 20% Method c RT: 0.88 min m/z: 344 (M+H)+ 11 οΛρ ^° Pyridine-2-carboxylic acid (3-cyclohexylamine-methyl-adamantan-1-yl)-nonylamine 25 mg 60% Method C RT: 1.41 min m/z: 382 (M+H)+ 12 a^f°H Pyridine-2: formic acid [3-(3-hydroxy-azetidin-1-carbonyl)-adamantane-1- Amino group 46 mg 40% Method C RT: 0.9 min m/z: 356 (M+H)+ 99 201121941 13 Pyridine-2-furic acid [3-(°-pyridin-2-ylaminoindolyl)- Adamantyl-1-yl]-nonylamine 13 mg 50% Method c RT: 1.28 min m/z: 377 (M+H) + 14 crS rushing P pyridine-2-decanoic acid [3-(benzothiazepine- 2-Based amine-mercapto)-adamantan-1-yl]-guanamine 12 mg 40% Method C RT: 1.50 min m/z: 433 (M+H)+ 15 Pyridine-2-furic acid [3- (4-Mercapto-thiazol-2-ylaminemethanyl)-adamantan-1-yl]-nonylamine 19 mg 80% Method c RT: 1.34 min m/z: 397 (M+H)+ f ( 400 MHz, CDC13) δ 9.90 (br s, 1H), 8.50-8.52 (m, 1H), 8.13-8.17 (m,1H)7 8.00 (s, 1H), 7.83 (t, J= 7.8 Hz, 1H) , 7.38-7.43 (m, lH), 6.48-6.49 (m, 1H), 1.92-2.40 (m, 15H), 1.68-1.82 (m, 2H). 16 0 than °-2-carboxylic acid [3-( 1//-benzimidazol-2-ylaminecarbazyl)-adamantan-1-yl]-nonylamine 15 mg 60% Method c RT: 1.30 min m/z: 416 extension + H) + 17 oi P pyridine-2-decanoic acid [3-(1-methyl-1//-benzoimidazol-2-ylamino)-adamantane- 1-yl]-indoleamine 13 mg 50% Method c RT: 1.41 min m/z: 430 (M+H)+ 18 CrW &lt;O Pyridine-2-furic acid [3-(quinolin-3-ylaminoindolyl)-adamantyl]-bristamine 12 mg 40% gas method c RT: 1.35 min m/z: 427 (M +H)+ 19 乂^'ch» Pyridine-2-furic acid P-(4,5-dimercapto-thiazol-2-ylaminoindenyl)-adamantane-I-yl]-bristamine 16 mg 60% Method c RT: 1.41 min m/z: 411 (M+H)+ 100 201121941 20 h3c H Pyridine-2-carboxylic acid [3-(2-hydroxy-2-indolyl-propylaminemethanyl)- Diamond-1-yl]-nitramine 11 mg 50% Method c RT: 1.00 min m/z: 372 (M+H) + 21 pyridine-2-carboxylic acid [3-(3,3-difluoro-cyclobutane)胺 醯 ) ) - -1- -1- -1- 23 23 23 23 23 23 23 mg 84% Method c RT: 1.27 min m/z: 390 (M+H) + 22 夂. ' 3-(3-Gas-phenylhydrazino)-adamantane-1-decanoic acid (3-a-phenyl)-guanamine 12 mg 40% Method C RT: 1.64 min m/z: 443 ( M+H)+ (400 MHz, CDC13) δ 7.67-7.70 (m, 2H), 7.58 (m, 1H), 7.20-7.48 (m, 5H), 7.05-7.09 (m, 1H), 5.88 (br s , 1H), 1.69-2.40 (m, 14H) 23 3-(3-Gas-benzhydrylamino)-amostane-1-carboxylic acid °°°-2-carbylamine 20 mg 30% Method c RT: 1.43 min m/z: 410 (M+H)+ (400 MHz, CDCI3) δ 8.20-8.27 (m, 2H), 8.12 (brs, 1H), 7.66-7.71 (m, 2H), 7.55-7.59 (m, 1H), 7.42-7.46 (m, 1H), 7.32-7.37 (m, 1H), 7.00-7.06 (m, 1H), 5.90 (s, 1H), 1.90-2.38 (m, 12H), 1.67 -1.80 (m, 2H) 24 3-(3-Gas-phenylhydrazino)-adamantane-1-decanoic acid (6-fluorenyl-σ ratio bit:-2-yl)-nonylamine 22 mg 50% Method c RT: 1.51 min m/z: 424 (M+H)+ (400 MHz, CDC13) δ 7.97-8.08 (m, 2H), 7.68-7.71 (m, 1H), 7.55-7.60 (m, 2H), 7.42-7.46 (m, 1H), 7.32-7.37 (m, 1H), 6.86-6.90 (m,1H), 5.91 (s, 1H), 1.65-2.47 (m, 17H) 25 Pir^VCHi h3c 3 6-Methyl-pyridine-2-decanoic acid (3-dimethylaminoindenyl-adamantan-1-yl)-nitramine 12 mg 40% Method C RT: 1. 24 min m/z: 342 (M+H)+ 101 201121941 26 6-Methyl-pyridine-2-carboxylic acid [3-((R)-3-fluoro-pyrrolidine-1-carbonyl)-adamantane -1-yl]-nonylamine 15 mg 60% Method c RT: 1.27 min m/z: 386 (M+H)+ 27 〇ir^^N〇..,F ° ratio bite-2-carboxylic acid [3- ((8)-gas-.pyrrol.1 -1 -yl)-adamantan-1-yl]-nonylamine 13 mg 50% Method c RT: 1.16 min m/z: 372 (M+H)+ 28 V ςΜ ch3 6-mercapto-pyridine-2-carboxylic acid [3-(4-hydroxy-piperidin-1-carbonyl)-adamantan-1-yl]-guanamine 2 mg 8% $Method A RT: 0.97 min m/z: 398 (M+H)+ 29 6-fluorenyl-0-pyridin-2-carboxylic acid [3-(TMFolin-4-carbonyl)-amostane-1 -yl]-bristamine 3 mg 10 % Method A RT: 1.12 min m/z: 384 (M+H) + 30 pyridine-2-carboxylic acid [3-(TMFolin-4-carbonyl)-adamantan-1-yl]-nitramine 13 mg 60 % Method c RT; 1.00 min m!z: 370 (M+H)+ 31 . Ratio 0-carboxylic acid [3-(piperidin-1-carbonyl)-adamantan-1-yl]-nonylamine 16 mg 70% Method c RT: 1.32 min m/z: 368 (M+H)+ (400 MHz, CDC13) δ 8.50-8.54 (m, 1H), 8.15 (d, *7 = 7.8 Hz, 1H), 8.00 (s, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.38- 7.43 (m,lH), 3.60-3.66 (m, 4H), 1.50-2.45 (m, 20H). 32 pyridine-2-carboxylic acid [3-(0 to 0 each bit-1-carbonyl)-adamantane-1 -yl]-bristamine 8 mg 30% Method c RT: 1.22 min m/z: 354 (M+H)+ 33 2-mercapto-pyrimidine-4-decanoic acid [3-(3-propyl-ureido) )-adamantan-1-yl]-nitramine 22 mg 30% Method A RT: 1.07 min m/z: 372 (M+H)+ 102 201121941 34 6-Methyl-pyridin-2-furic acid P- (3-propyl-ureido)-adamantan-1-yl]-nonylamine 25 mg 30% Method A RT: 1.10 min m/z: 372 (M+H)+ 35 CH, ° 6 &lt;3-{3|methyl-° ratio sigma-2-yl)-amino]-adamantane-l-yl}-glycosyl)-ethyl hexanoate 35 mg 40% Method A RT: 1.38 Min m/z: 471 (M+H)+ 36 ch3 6-methyl-0 ratio bite-2-indole bismuth-(3-ethyl-ureido)-adamantan-1-yl]-nonylamine 19 Mg 74% Method A RT: 1.08 min m/z: 357 (M+H)+ (400 MHz, CDC13) δ 8.05 (br s, 1H), 7.93 (d, 7.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.23 (d , J = 7.6 Hz, 1H), 4.35-4.45 (m, 2H), 3.09-3.19 (m, 2H), 2.55 (s, 3H), 1.60-2.40 (m, 14H) 1.09 (t, /=7.3 Hz, 3H) 37 Η^&amp;-ν/ i. . L, ch3 6-methylpyridine-2-decanoic acid [3-(3-propyl-ureido)-adamantan-1-yl]-guanamine 18 mg 50% Method A RT: 1.20 min m/ z: 371 (M+H)+ (400 MHz, CDCI3) δ 8.06 (br s, 1 H), 7.89 (d, /=8.0 Hz, 1H), 7.65 (t, /=8.0 Hz, 1H), 7.16 -7.21 (m, 1H), 4.30 (brs, 1H), 2.99 (t, /=7.1 Hz, 3H), 2.51 (s, 3H), 2.32 (s, 2H), 1.85-2.23 (m, 10H), 1.36-1.66 (m, 4H), 0.84 (t, J-7.3Hz, 3H) 38 CH, 6-fluorenyl-α ratio ° -2 decanoic acid [3-0-butyl-ureido)-adamantane -1-yl]-nonylamine 24 mg 60% Method A RT: 1.32 min m/z: 385 (M+H)+ 103 201121941 39 0^3⁄4 0 ratio. Benzene-2-carboxylic acid [3-(3-phenyl-ureido)-adamantan-1-yl]-nonylamine 18 mg 60% Method c RT: 1.33 rriin m/z: 391 (M+H)+ ( 400 MHz, CDC13) δ 8.50-8.54 (m,1H), 8.05-8.17 (m, 2H), 7.83 (t,/=7.8 Hz, 1H), 7.38-7.43 (m,lH), 7.13-7.31 (m , 5H), 6.93-6.99 (m,lH), 5.35 (s, 1H), 1.59-2.51 (m, 14H) 40 pyridin-2-furic acid [3-(3-propyl-glycosyl)-embroid -1 -yl]-guanamine 12 mg 50% Year A RT: 1.06 min m/z: 357 (M+H) + 41 pyridine-2-carboxylic acid [3-(3-cyclopropyl-ureido)- Adamantan-1-yl]-nitramine 3 mg 10% Method C RT: 1.12 min n^z: 355 (M+H)+ 42 H^&-NWH min!? Pyridine-2-carboxylic acid [3-( 3-butyl-ureido)-adamantan-1-yl]-nonylamine 18 mg 60% Method A RT: 1.19 min m/z: 371 (M+H)+ 43 〇Λ公Ύ 0 福福林- 4-decanoic acid {3-[(° ratio)-amino]-amostane-l-yl}-nitramine 6 mg 20% Method c RT: 1.07 min m/z: 385 (M+H) + (400 MHz, CDCI3) δ 8.49 (d, /=4.7 Hz, 1H), 8.14 (¢1, /=8.0 Hz, 1H), 8.0 (br s, 1H), 7.82 (t, J=ll Hz, 1H), 7.37-7.42 (m, 1H), 4.26 (br s, 1H), 3.65-3.69 (m, 4H), 3.26-3.30 (m, 4H), 2.42 (s, 2H), 2.27-2.30 (m , 2H) , 2.11-2.15 (m, 4H), 2.01-2.04 (m, 4H), 1.82 (s, 2H) 44 Ο^,^ν pyridine-2-decanoic acid {3-[(piperidin-1-carbonyl)- Amino]-adamantane-l-yl}-nonylamine 8 mg 30% Method c RT: 1.32 min m/z: 383 (M+H)+ 104 201121941 45 ° ratio sigma-2-carboxylic acid {3-[ (0 is 0-specific -1. carbonyl)-amino]-adamantane-lr basalin; 9 mg 40% Method c RT: 1.19 min m/z: 369 (M+H)+ (400 MHz , CDC13) δ 8.47-8.52 (m, 1H), 8.14 (d, 7.8 Hz, 1H), 8.00 (s, 1H), 7.83 (t, /=7.8 Hz, 1H), 7.38-7.41 (m, lH) , 6.5 (br s, 1H), 3.22-3.32 (m, 4H), 1.84-2.43 (m, 16H), 1.63-1.69 (m, 2H) 46 (J. . Heart ch3 {3-[(6-methyl-pyridin-2-enyl)-amino]-adamantan-1-yl}-amino phthalic acid 2-(2-trans-ethyl-lactyl) -ethyl ester 21 mg 50% Method A RT: 1.02 min m/z: 418 (M+H) + (400 MHz, CDCI3) δ 8.03 (br s, 1H), 7.94 (d, J = 7.8 Hz, 1H) , 7.68 (t, 7=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 4.79 (br s,lH), 4.12-4.24 (m, 2H), 3.58-3.77 (m, 6H) , 2.55 (s, 3H), 1.59-2.42 (m, 14H) 47 (?.. ch3 {3-[(6-indolyl-leaf. ding-2-prison)-amino]-adamantane- 1-Base}-Amino decanoic acid 3,3,3-tris-propyl ester 20 mg 50% Method A RT: 1.50 min m/z: 426 (M+H)+ (400 MHz, CDCI3) δ 8.03 ( Br s, 1H), 7.90-7.97 (m, 1H), 7.65-7.74 (m, 1H), 7.21-7.28 (m, 1H), 4.71 (brs, 1H), 4.17-4.26 (m, 2H), 2.55 (s, 3H), 1.60-2.50 (m, 16H) 48 ".. CHa.. {3-[(6-曱基-〇比 bit-2-reyl)-amino]-adamantan-1 -yl}-amino phthalic acid 3-gas-propyl vinegar 24 mg 60% Method A RT: 1.36 min m/z: 390 (M+H)+ (400 MHz, CDCI3) δ 8.03 (brs, 1H), 7.94 (d, J= 7.7 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.24 (d, 7=7.7 Hz, 1H), 4.68 (br s, 1H), 4.43-4.61 (m, 2H) ), 4.10-4.18 (m, 2H), 2.55 (s, 3H), 1.60-2.38 (m, 16H) 49 ^&&quot;V〇ch3 F {3-[(6-fluorenyl-pyridin-2-enyl)-amino]-gold Decane-1-yl}-amine i decanoic acid 4,4,4-trifluoro-butan 25 mg 60% Method A RT: 1.59 min m/z: 440 (M+H)+ (400 MHz, CDCb) δ 8.03 (br s, 1H), 7.92-7.96 (m, 1H), 7.68 (t, 7=7.7 Hz, 1H), 7.24 (d, /=7.7 Hz, 1H), 4.64 (brs, 1H), 4.00 -4.11 (m, 2H), 2.55 (s, 3H), 1.60-2.40 (m, 18H) 105 201121941 50 Vf {3-[(6-fluorenyl-pyridin-2-yl)-amino] - 金刚炫ι-1-基}-Amino phthalic acid 2,2,2-trifluoro-ethyl ester 18 mg 40% Method A RT: 1.53 min m/z: 412 (M+H)+ (400 MHz, CDC13) δ 8.00 (br s, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.69 (t, /=7.7 Hz, 1H), 7.24 (d, J=7.6 Hz, 1 H), 4.86 ( Br s, 1H), 4.30-4.45 (m, 2H), 2.55 (s, 3H), 1.59-2.41 (m, 14H) 51 \ CH, {3-[(6-methylpyridin-2-carbonyl) -amino]-adamantan-1-yl}-carbamic acid 2-(2-methoxy-ethoxy)-ethyl ester 25 mg . 60% square, method A RT: 1.23 min m/z: 432 (M+H)+ (400 MHz, CDCI3) δ 8.03 (brs, 1H), 7.94 (d, J=ll Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.24 (d, J= 7.7 Hz, 1H), 4.75 (br s, 1H), 4 .13-4.20 (m, 2H), 3.53-3.70 (m, 6H), 3.38 (s, 3H), 2.55 (s, 3H), 1.60-2.38 (m, 14H) 52 '〇{3-[(6 - mercapto-pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amino decanoic acid 3-fyfolin-4-yl-propyl ester 28 mg 60% Method A RT: 1.08 min m /z: 457 (M+H)+ (400 MHz, CDCI3) δ 8.03 (br s, 1H), 7.94 (d, /=7.7 Hz, 1H), 7.68 (t, J=ll Hz, 1H), 7.24 (d, J=ll Hz, 1H), 4.80 (br s, 1H), 4.00-4.16 (m, 2H), 3.80-3.84 (m, 4H), 2.65-2.83 (s, 6H), 2.55 (s, 3H), 1.60-2.40 (m, 16H) 53 &lt;?. . 1 ch3 {3-[(6-Mercapto-pyridin-2-carbonyl)-amino]-adamantan-1-yl}-carbamic acid Cyclopropyl decyl ester 12 mg 43% Method A RT: 1. 51 min m/z: 384 (M+H)+ (400 MHz, CDC13) δ 8. 03 (br s, 1H), 7. 94 (d, J=l. l Hz, 1H), 7. 69 (t, J=7. 7 Hz, 1H), 7. 24 (d, J=7. 7 Hz, 1H), 4. 65 (br s, 1H), 3. 82 (d, J-7. 3 Hz, 2H), 2. 55 (s, 3H), 1. 60-2. 40 (m, 14H).  1. 06-1. 14 (m, 1H), 0. 51-0. 581 (m, 2H), 0. 23-0. 29 (m, 2H) 106 201121941 54 CH, {3-[(6-fluorenyl-pyridin-2-yl)-amino]-amstrane-1-yl}-carbamic acid 2,2- Difluoro-propyl ester (, 12 mg 30% Method A RT: 1. 48 min m/z: 408 (M+H)+ (400 MHz, CDClj) δ 8. 10 (br s,,lH),7. 97 (d, 7=7. 7 Hz, 1H), 7. 72 (t, J=7. 7 Hz, 1H), 7. 27 (d, 7=7. 7 Hz, 1 H), 4. 82 (br s, 1H), 4. 18 (t, 7=12. 2 Hz, 2H), 2. 58 (s, 3H), 1. 90-2. 43 (m, 12H), 1. 58-1. 74 (m, 5H) 55 (J. L ch3 {3-[(6-fluorenyl-«比°定_2·square)-amino]-adamantan-1-yl}-carbamic acid 2 -hydroxy-ethyl ester 14 mg 50% Method A RT: 0. 99 min m/z: 374 (M X H)+ (400 MHz, CDC13) δ 8. 05 (brs, 1H), 7. 95 (d, 7=7. 7 Hz, 1H), 7. 70 (t, J=l. l Hz, 1H), 7. 24 (d, /=7. 7 Hz, 1H), 4. 76 (br s, 1H), 4. 11-4. 20 (m, 2H), 3. 76- 3. 85 (m, 2H), 2. 55 (s, 3H), 1. 60-2. 42 (m, 14H) 56 93⁄43⁄4 h3c 0 {3-[(6- f-pyridin-2-yl)-amino]-adamantan-1-yl}-amino phthalic acid 3-chloro- C 6 is 65 mg 80% Method A RT: 1. 50 min m/z: 406 (M+H)+ (400 MHz, CDCb) δ 8. 02 (br s, 1H), 7. 95 (d, /=7. 6 Hz, 1H), 7. 69 (t, 7=7. 7 Hz, 1H), 7. 24 (d, J=7. 7 Hz, 1 H), 4. 63 (br s, 1H), 4. 10-4. 20 (m, 2H), 3. 61 (t, J-6. 3Hz, 2H), 2. 55 (s, 3H), 1. 55-2. 40 (m, 16H) 57 HfQN. HQ^0 °\ H3C °'CH3 {3-[(6-fluorenyl-.pyr.din-2-yl)-amino]-adamantan-1-yl}-amino phthalic acid 2-methoxy Ethyl ethyl ester 15 mg 40% Method A RT: 1. 23 min m/z: 388 (M+H)+ (400 MHz, CDCI3) δ 8. 02 (br s.  1 H), 7. 94 (d, • 7=7. 5 Hz, 1H), 7. 69 (t, J=7. 6 Hz, 1H), 7. 24 (d, J=7. 5 Hz, 1H), 4. 75 (br s, 1H), 4. 12-4. 19 (m, 2H), 3. 54-3. 59 (m, 2H), 3. 39 (s, 3H), 2. 55 (s, 3H), 1. 56-2. 38 (m, 14H) 58 Y〇N- pr4. . \H,C V ,h3 {3-[(6-decylpyridin-2-carbonyl)-amino]-adamantan-1-yl}-carbamic acid hexyl ester 12 mg 30% Method D RT: 4. 12 min m/z: 414 (M+H)+ 107 201121941 59 Η f {3-[(mouth ratio σ-defined 2-enyl)-amino]-amstrane-l-yl}-aminocarboxylic acid 2 , 2,2-Trifluoro-B, 18 mg 33% Method A RT: 1. 40 min rri/z: 398 (M+H)+ 60 ςή御h3c 0 6-mercaptopyridine-2-carboxylic acid [3-(2-o-oxy-[U]oxazepine-3- Base)-adamantan-1-yl]-nonylamine 4 mg 8% Method c ΚΓ: 1. 20 min m/z: 370 (M+H)+ (400 MHz, CDC13) δ 8. 02 (brs, lH), 7. 88(d, /=7. 8 Hz, 1H), 7. 64 (t, 7=7. 8 Hz, 1H), 7. 16-7. 20 (m, 1 H), 4. 05 (t, /= 5. 2 Hz, 2H), 3. 32 (t, /=5. 2 Hz, 2H), 2. 55 (brs, 2H), 2. 50 (s, 3H), 2. 00-2. 30 (m, 10H), 1. 86-1. 94 (m, 2H), 1. 57-1. 62 (m, 2H) 61 pyridine-2-carboxylic acid (3-Benzic acid amine fund just burned-1 -yl)-bristamine 22 mg 80% i Method c RT: 1. 30 min m/z: 412 (M+H)+ (300 MHz, CDCI3) δ 8. 50- 8. 52 (m, 1H), 8. 11-8. 15 (m, 1H), 7. 89-7. 93 (m, 3H), 7. 83 (t, 7=7. 6 Hz, 1H), 7. 46-7. 56 (m, 3H), 7. 38-7. 42 (m, 1H), 4. 72 (s, 1H), 2. 26 (br s, 2H), 2. 18-2. 23 (m, 2H), 1. 50- 2. 08 (m, 10H) 62 O Ethyl-aminocarbamate 3-[(pyridine-2-carbonyl)-amino]-diamond **-1-yloxime 7 mg 30% Method A RT: 1. 20 min m/z: 344 (M+H)+ (400 MHz, CDCI3) δ 8. 48-8. 52 (m, 1H), 8. 15 (d, /=8. 2 Hz, 1H), 7. 99 (s, 1H), 7. 82 (dt, J=1. 7, 7. 6 Hz, 1H), 7. 35-7. 43 (m, 1H), 4. 50 (s, 1H), 3.  08-3. 20 (m, 2H), 2. 50 (s, 2H), 2. 03-2. 37 (m, 10H), 1. 59-1. 68 (m, 2H), 1. 11 (t, 7=7. 3 Hz, 3H) 108 201121941 63 Η 6-Methyl-pyridine-2-decanoic acid [3-( ° pyridine-2-ylamino)-adamantan-1-yl]-nonylamine 15 mg 20% Method c RT: 1. 53 min m/z; 363 (M+H)+ (400 MHz, CDC13) δ 8. 06 (br s, 1H), 7. 89-7. 97 (m, 2H), 7. 70 (t, &gt;7. 8 Hz, 1H), 7. 44-7. 50 (m, 1H), 7. 23-7. 25 (m, 1H), 6. 69 (d, 7=8. 7 Hz, 1H), 6. 55 (t, J=6. 0 Hz, 1H), 1. 93-2. 56 (m, 15H), 1. 73-1. 66 (m, 2H) 64 C^° 0 ratio °-2-carboxylic acid {3-[(-pyridin-2-ylindenyl)-amino]-adamantane-l-yl}-nonylamine 47 mg 25% Method c RT: 0. 81 min m/z: 363 (M+H)+ (400 MHz, CDCh) δ 8. 51-8. 56 (m, 2H), 8. 16 (dt, J= 1. 0, 7. 8 Hz, 1H), 7. 99 (br s, 1H), 7. 84 (td, J= 1. 8, 7. 7 Hz, 1H), 7. 65 (td, J = 1. 8,7. 7 Hz, 1H), 7. 41 (ddd, J= 1. twenty four. 7, 7. 6 Hz, 1H), 7. 32-7. 36 (m, 1H), 7. 15-7. 20 (m, 1H), 4. 06 (s, 2H), 3. 92 (br s, 1H), 1. 60-2. 37 (m, 14H) 65 cf° Pyridine-2-carboxylic acid (3-phenylhydrazinoamino-adamantan-1-yl)-indoleamine 51 mg 27% Method C RT: 0. 91 min m/z: 362 (M+H)+ (400 MHz, CDCI3) δ 8. 53 (dq, /=0. 9, 4. 8 Hz, lH), 8. 17(dt, 1. 0, 7. 8 Hz, 1H), 8. 00 (br s, 1H), 7. 85 (td, J= 1. 6, 7. 7 Hz, 1H), 7. 36-7. 45 (m, 3H), 7. 29-7. 36 (m, 2H), 7. 23-7. 29 (m, 1H), 5. 95 (brs, 1H), 3. 87 (s, 2H), 1. 60-2. 36 (m, 14H) 66 0^NH 6 ° ratio bit -2-decanoic acid [3-(5-chloro-1//-benzimidazol-2-yl)-adamantan-1-yl]-guanamine , 6 mg 30% Method C RT: 1. 39 min m/z: 407 (M+H)+ (400 MHz, CDCb) δ 9. 24 (br s, 1H), 8. 51-8. 54 (m, 1H), 8. 14 (d, y=7. 8Hz, 1H), 8. 09 (s, 1H), 7. 84 (t, 7=7. 7 Hz, 1H), 7. 63 (brs, 1H), 7. 40-7. 44 (m; 1H), 7. 18 (d, J=8. 6Hz, 1H), 2. 59 (s, 2H), 2. 29-2. 41 (m, 4H), 2. 08-2. 19 (s, 4H), 1. 82 (s, 4H) 109 201121941 67 HjC 6-Methyl-pyridine-2-decanoic acid (3-benzoxazol-2-yl-adamantan-1-yl)-guanamine 16 mg 20% Method E RT : 3. 74 min m/z: 388 (M+H)+ (400 MHz, CDC13) δ 8. 11(s, 1H), 7. 94-7. 98 (m, lH), 7. 67-7. 74 (m, 2H), 7. 46-7. 51 (m, lH), 7. 23-7. 33 (m, 3H), 2. 54-2. 58 (m, 5H), 1. 65-2. 41(m, 12H) 68 ςή^° h3c 6-methyl-α ratio bite-2·capric acid [3-(1//-benzimidazol-2-yl)-adamantan-1-yl]- 醯Amine 50 mg 50% Method c RT: 1. 30 min m/z: 387 (M+H) + 69 H, C 6-methyl-0 ratio bite-2-carboxylic acid [3-(6-fluoro-1//-benzimidazol-2-yl)- Adamantan-1-yl]-bristamine 35 mg 30% Method c RT: 1. 37 min m/z: 405 (M+H)+ (400 MHz, CDC13) δ 10. 14-10. 40 (m, 1H), 8. 17 (s, 1H), 7. 92 (d, J = 8. 11 Hz, 1H), 6. 80-7. 67 (m, 5H), 2. 55-2. 60 (m, 5H), 2. 11-2. 36 (m, 10H), 1. 69-1. 80 (m, 2H) 70 6-methyl-° ratio ° -2 - decanoic acid [3-(1//-imidazo[4,5-bp ratio α-but-2-yl)-diamond-1 -Based]-Tain Amine 200 mg 20% 4 Method c RT: 1. 16 min m/z: 388 (M+H)+ (400 MHz, CDCI3) δ 13. 70 (brs„lH), 8. 50 (d, J=5. 4 Hz, 1H), 8. 18(s, 1H), 8. 08( d, J=8. 8 Hz, 1H), 7. 97 (d, 7=7. 7 Hz, 1H), 7. 70 (t, 7=7. 7 Ηζ,ΙΗ), 7. 19-7.  28 (m, 2H), 2. 66 (br s, 2H), 2. 56 (s, 3H), 2. 42-2. 48 (m, 4H), 2. 22-2. 30 (m, 6H), 1. 83-1. 95 (m, 2H) 71 H,C 6-methyl-° ratio ° -2 - formic acid [3-(37/-m-[sodium][4,5-c] 0-pyridin-2-yl)- King Kong Alkan-1-yl]-nonylamine 20 mg 20% Method c RT: 1. 08 min m/z: 388 (M+H)+ 1 (400 MHz, CDCI3) δ 10. 66 (br s,1H), 8. 98-9. 35 (m, 1H), 8. 21-8. 44 (m, 1H), 8. 17 (s, 1H), 7. 92 (d, /=7. 8 Ηζ, ΙΗ), 7. 72-7. 83 (m, 1H), 7. 69 (t, J = 7. 8 Ηζ, ΙΗ), 7. 25 (d, 7=7. 5 Hz, 1H), 2. 64 (s, 2H), 2. 56 (s, 3H), 2.  10-2. 41 (m, 10H), 1. 75-1. 87 (m, 2H) 110 201121941 72 O H3C.  N=\ H, C 6-methyl·α ratio 0-but-2-decanoic acid [3-(3-methyl-3//-imidazo[4,5-b]pyridin-2-yl)-King Kong Alkan-1-yl]-nonylamine 60 mg 78% Method c RT: 1. 21 min m/z: 402. 0 (M+H)+ (400 MHz, CDC13) 5 8. 34 (dd, /=1. 5, 4. 8 Hz, 1H), 8. 14 (br s, 1H), 8. 01 (dd, /=1. 5,7. 9 Hz, 1H), 7. 97 (d, J=7. 8 hz, 1H), 7. 71 (t, 7=7. 8 Hz, 1H), 7. 26 (d, y=7. 6Hz, 1H), 7. 17-7. 21 (m, 1H), 4. 12 (s, 3H), 2. 69 (s, 2H), 2. 57 (s, 3H), 2. 22-2. 48 (m, 10H), 1. 77-1. 90 (m, 2H) 73 h3c 6-methyl-pyridine-2-decanoic acid [3-(4-methyl-1//-imidazol-2-yl)-adamantan-1-yl]-nonylamine 5 Mg 26% Method c RT: 1. 00 min m/z: 351 (M+H)+ (400 MHz, CDCI3) δ 8. 07 (br s, 1H), 7. 5 (d, /=8. 0 Hz, 1H), 7. 0 (t, J= 7. 9 Hz, 1H), 7. 27-7. 23 (m, 2H), 2. 56 (s, 3H), 2. 34-1. 65 (m, 17H).   74 Α&gt;λ 6-Methyl-1⁄4 pyridine-2-decanoic acid [3-(1,3-diazepine-iso-purine 丨 朵-2-yl)-adamantan-1-yl]-nonylamine 12 mg 18% Method c RT: 1. 19 min m/z: 388 (M+H)+ (400 MHz, CDC13) δ 8. 07 (brs, 1H), 7. 97 (d, / = 7. 7 Hz, 1H), 7. 71 (t, J = 1. 1 Hz, 1H), 7. 14-7. 32 (m, 5H), 4. 17(s, 4H), 2. 57 (s, 3H), 2. 06-2. 44 (m, 8H), 1. 58-1. 96 (m, 6H) 75 6-fluorenyl-° than 唆-2-decanoic acid [3-(3-sideoxy-1,3 -di-rho-D is more than [3,4-c] 0 Ratio σ - 2 - yl) - acetonide - 1 - yl] - tyrosine 12 mg 16% Method A RT: 1. 08 min m/z: 403 (M+H)+ (400 MHz, CDCI3) δ 9. 07 (s, 1H), 8. 77 (d, /=5. 2 Hz, 1H), 8. 16 (s, 1H), 7. 98 (d, 7=7. 7 Hz, 1H), 7. 74 (t, J=7. 0 Hz, 1H), 7. 52 (¢1, /=5. 4 Hz, 1H), 7. 29 (d, 7=6. 9 Hz, 1H), 4. 64 (s, 2H), 2. 76 (s, 2H), 2. 60 (s, 3H), 2. 13-2. 46 (m, 10H), 1. 78 (s, 2H) 111 201121941 76 2-methyl-pyrimidine-4-decanoic acid [3-(3-sideoxy-1,3-diaza-°Biloze[3,4-c] ° ratio Pyridin-2-yl)-adamantan-1-yl]-nonylamine 23 mg 31% i 0 Method A RT: 0. 86 min m/z: 404 (M+H)+ (400 MHz, CDC13) δ 9. 07 (s, 1H), 8. 87 (d, /=5. 0 Hz, 1H), 8. 78 (d, /=4. 8 Hz, 1H), 8. 00 (s, 1H), 7. 88 (d, /=5. 0 Hz, 1H), 7. 52 (d, /=5. 0 Hz, 1H), 4. 63 (s, 2H), 2. 80 (s, 3H), 2. 76 (s, 2H), 2. 15-2. 48 (m, 10H), 1. 78 (br s, 2H) 77 5-Fluorine bite-2-decanoic acid [3-(3-sideoxy-1,3-dihydrogen ratio σ[3,4-c] ° ratio. 2-Base)-adamantan-1-yl]-nitramine 17 mg 23% Method A RT: 1. 06 min Wz: 407 (M+H)+ (400 MHz, CDC13): δ 9. 07 (s, 1H), 8. 85 (d, /=5. 6 Hz, 1H), 8. 36 (d, /=2. 7 Hz, 1H), 8. 17(dd, /=4. 6, 8. 7 Hz, 1H), 7. 83-7. 89 (m, 2H), 7. 53 (dt, /=2. 8, 8. 2 Hz, 1H), 4. 78 (s, 2H), 2. 76 (s, 3H), 2. 00-2. 46 (m, 10H), 1. 76 (brs, 2H) 78 Xi^^rP 4-mercapto-pyrimidine-2-carboxylic acid [3-(3-sideoxy-1,3-two-mouse-0-slightly [3,4-c] ° Bipyridin-2-yl)-amostane-1-yl]-S&amine 18 mg 27% Method A RT: 0. 76 min m/z: 404 (M+H)+ l (400 MHz, CD3OD): δ 9. 22 (s, 1H), 9. 01 (d, J=6. 0 Hz, 1H), 8. 88 (s, 1H), 8. 35 (d, J=6. 0 Hz, 1H), 7. 73 (d, 7=5. 2 Hz, 1H), 5. 10 (s, 2H), 2. 85 (s, 2H), 2. 73 (s, 3H), 2. 12-2. 50 (m, 10H), 1. 83 (s, 2H) 79 0 γ ^ ° ^ 4-fluoro-0 ratio.曱-2-decanoic acid [3-(3-sideoxy-1,3-dihydrol ratio 17-[3,4-c]»pyridin-2-yl)-adamantan-1-yl]- Amine amine 25 mg 23% Method A RT: 1. 06 min m/z: 407 (M+H)+ (400 MHz, CDCI3) δ 9. 01 (s, 1H), 8. 71 (d, J=5. 2 Hz, 1H), 8. 47 (dd, J=5. 6f 7. 9 Hz, 1H), 7. 96 (s, 1H), 7. 83 (dd, 7=2. 5, 9. 3 Hz, 1H), 7. 43 (d, J=5. 0 Hz, 1H), 7. 09-7. 14 (m, 1H), 4. 56 (s, 2H), 2. 71 (s, 2H), 1. 68-2. 41 (m, 12H) 112 201121941 80 ···&gt; N-[3-(3-sideoxy-1,3-dihydro-° ratio 0 each [3,4-c] ° than pyridine-2 -基)-金刚院-1-基]-Autumn amine: 20 mg 30% Method A RT: 0. 69 min m/z: 389 (M+H)+ (400 MHz, CDC13) δ 8. 91-9. 08 (m, 2H), 8. 66- 8. 76 (m, 2H), 8. . 02-8. 09 (m, 1H), 7. 33-7. 45 (m, 2H), 4. 55 (s, 2H), 2. 76 (s, 2H), 1. 67- 2. 49 (m, 12H) 81 5-fluoro-pyridine-2-carboxylic acid [3-(5-sideoxy-5,7-dihydrogen ratio) each [3,4-cyanopyridine-6-yl)-gold Firing -1-yl]-guanamine 40 mg 60% Method A RT: 1. 09 min m/z: 407 (M+H)+ (400 MHz, CDCI3) δ 8. 73 (dd, /=1. 6, 5. 0 Hz, 1H), 8. 36 (d, 7=2. 8 Hz, 1H), 8. 20 (dd, J=4. 5, 8. 6 Hz, 1H), 8. 07 (d,&gt;1. 6, 7. 7 Hz, 1H), 7. 87 (brs, 1H), 7. 53 (dt, /=2. 8, 8. 2 Hz, 1H), 7. 40 (dd, /=5. 0, 7. 7 Hz, 1H), 4. 58 (s, 2H), 2. 77 (s, 2H), 2. 15-2. 47 (m, 10H), 1. 77 (s, 2H) 82 2-mercapto-pyrimidine-4-decanoic acid [3-(5-sideoxy-5,7-dihydro-0- 0 each and [3,4-7]0 bite- 6-yl,)-adamantan-1-yl]guanamine 43 mg 60% Method A RT: 0. 92 min m/z: 404 (M+H)+ (400 MHz, CDCI3) δ 8. 84 (d, 7=5. 0 Hz, 1H), 8. 69-8. 73 (m, 1H), 8. 06 (dd, 1. 5,7_7 Hz, 1H), 7. 97 (s, 1H), 7. 86 (d, /=5. 0 Hz, 1H), 7. 38 (dd, /=4. 9, 7. 6 Hz, 1H), 4. 56 (s, 2H), 2. 77 (s, 3H), 2. 75 (s, 2H), 2. 16-2. 46 (m, 10H), 1. 76 (s, 2H) 83 A43-(5-sideoxy-5,7-dihydro-° ratio 0 and [3,4-b].pyridin-6-yl)-金刚院-1 -based ]- must-test amine 46 mg 67% Method A RT: 0. 73 min m/z: 389 (M+H)+ (400 MHz, CDCI3) δ 8. 95 (d, J=1. 8Hz, 1H), 8. 73 (dd, 7=1. 6,4. 9 Hz, 1H), 8. 05-8. 11 (m, 2H), 7. 37-7. 43 (m, 2H), 5. 97 (s, 1H), 4. 58 (s, 2H), 2. 80 (s, 2H), 2. 15-2. 45 (m, 10H), 1. 78 (s, 2H) 113 201121941 84 Isoazol-5-decanoic acid [3-(5-sideoxy-5,7-dihydro-β is 0 and each [3,4-b]&quot; -6-yl)-adamantan-1-yl]-nitramine 8 mg 20% • l Method A RT: 0. 80 min m/z: 379 (M+H)+ (400 MHz, CDC13) δ 8. 64 (d, /=3. 5 Hz, 1H), 8. 24 (d, J=1. 8 Hz, 1H), 7. 98 (dd, 7=1. 4,7. 7 Hz, 1H), 7. 31 (dd, 7-5. 0, 7. 6 Hz, 1H), 6. 78 (d, y=1. 8 Hz, 1H), 6. 31 (s, 1H), 4. 48 (s, 2H), 2. 67 (s, 2H), 2. 01-2. 37 (m, 10H), 1. 62-1. 74 (m, 2H) 85 . Sesin-2-decanoic acid [3-(5-sideoxy-5,7-di-argon-. ratio 0 each [3,4-b].pyridin-6-yl)-adamantane-1- Base]-bristamine 18 mg 43% Method A RT: 0. 97 min m/z: 395 (M+H)+ (400 MHz, CDCI3) δ 8. 73 (dd, J=1. 6,4. 9 Hz, 1H), 8. 08 (dd, 7=1. 6, 7. 7 Hz, 1H), 7. 84 (d, J=3. 1 Hz, 1H), 7. 56 (d, /=3. 1 Hz, 1H), 7. 40 (dd, J=5. 0, 7. 7 Hz, 1H), 7. 19(brs, 1H), 4. 58 (s, 2H), 2. 77 (s, 2H), 2. 12-2. 46 (m, 10H), 1. 71-1. 83 (m, 2H) 86 乂Υ0〇(5) 2-methyl-thiazole-4-decanoic acid [3-(5-sideoxy-5,7-diaza-° ratios each [3,4-b ] 比 啶 -6-6-yl)- acetonide-1-yl]-nonylamine 43 mg 30% Gofa A RT: 0. 98 min m/z: 409 (M+H)+ (400 MHz, CDCI3) δ 8. 73 (dd, J=1. 5, 5. 0 Hz, 1H), 8. 07 (dd, /=1. 5, 7. 7 Hz, 1H), 7. 88 (s, 1H), 7. 40 (dd, J=5. 0, 7. 6 Hz, 1H), 4. 58 (s, 2H), 2. 74 (s, 2H), 2. 71 (s, 3H), 2. 18-2. 45 (m, 10H), 1. 76 (s, 2H) 87 6-fluorenyl-° ratio 定-2-decanoic acid [3-(5-side oxy-5,7-diaza ratio and [3,4-b] 0 ratio定定-6-yl)-amyrosin-1-yl]-S-panamine method 1 41 mg 58% Method 2 32 mg 10% Method A RT; 12 min m/z: 403 (M+H)+ (400 MHz, CDCI3) δ 8. 73 (dd, 7=1. 5,4. 9 Hz, 1H), 8. 13 (brs, 1H), 8. 07 (dd, J=1. 5, 7. 6 Hz, 1H), 7. 98 (d, /=7. 6 Hz, 1H), 7. 73 (t, J=7. 7 Hz, 1H), 7. 39 (dd, J=5. 0, 7. 7 Hz, 1H), 7. 27 (d, 7=8. 2 Hz, 1H), 4. 58 (s, 2H), 2. 77 (s, 2H), 2. 58 (s, 3H), 2. 21-2. 46 (m, 10H), 1. 77 (s, 2H) 114 201121941 88 2-Mercapto-pyrimidine-4-decanoic acid [3-(7-sideoxy-5,7-dihydro-D ratio arden[3,4-b]. °定-6-基)-金刚炫"-1-yl]-nitramine 30 mg 20% Method C RT: 1. 01 min m/z: 404 (M+H)+ (400 MHz, CDC13) δ 8. 86 (d, y-5. 0Hz, 1H), 8. 80 (dd, J=1. 3, 4. 8 Hz, 1H), 8. 00 (brs, 1H), 7. 88 (dd, 7=0. 4, 5. 0 Hz, 1H), 7. 78-7. 83 (m, 1H), 7. 43 (dd, 7=4. 8,7. 7 Hz, 1H), 4. 54 (s, 2H), 2. 79 (s, 3H), 2. 78 (s, 2H), 2. 17-2. 47 (m, 10H), 1. 78 (t, /= 14. 8 Hz, 2H) 89 2-methyl-pyrimidine-4-carboxylic acid [3-(2-methyl-5-oxo-5,7-dihydro-pyrolo[3,4-b]0 ratio Oral-6-yl)-adamantan-1-yl]-醯_ 32 mg 41% Method A RT: 1. 01 min m/z: 418 (M+H)+ (400 MHz, CDCb) 5 8. 83 (d, 7=5. 0 Hz, 1H), 7. 99-7. 93 (m, 2H), 7. 86 (d, 7=5. 0 Hz, 1H), 4. 52 (s, 2H), 2. 78-2. 73 (m, 5H), 2. 67 (s, 3H), 2. 46-2. 38 (m, 4H), 2. 29-2. 18 (m, 3H), 1. 75 (s, 2H), 1. 25 (s, 3H).   90 χ/Ρ^ 6-mercapto-pyridine-2-carboxylic acid [3-(2-methyl-5-sideoxy-5,7-dihydro-°pyrho[3,4-b]0 ratio 0--6-yl)-adamantan-1-yl]-nonylamine 30 mg 40% Method c RT: 1. 31min m/z: 417 (M+H)+ (400 MHz, CDCI3) 5 8. 09 (s, 1H), 7. 97-7. 92 (m, 2H), 7. 70 (t, J=l. l Hz, 1H), 7. 24-7. 20 (m, 1H), 4. 51 (s, 2H), 2. 73 (s, 2H), 2. 66 (s, 3H), 2. 55 (s, 3H), 2. 44-2. 36 (m, 4H), 2. 30-2. 17 (m, 6H), 1. 74 (s, 2H).   91 5-gas ratio biting-2-carboxylic acid [3-(2-methyl-5-sideoxy-5,7-dihydro-° ratio D and [3,4-b]0 ratio -6 -yl)-adamantan-1-yl]-S&amp;amine: 39 mg 55% Method C RT: 1. 26 min m/z: 421 (M+H)+ 'H NMR (400 MHz, CDCb) δ 8. 34 (d, J=2. 8 Hz, 1H), 8. 17 (q, 7=4. 5 Hz, 1H), 7. 93 (d, J=7. 9 Hz, 1H), 7. 84 (s, 1H), 7. 54-7. 47 (m, 1H), 7. 22 (d, 7=7. 9 Hz, 1H), 4. 50 (s, 2H), 2. 74 (s, 2H), 2. 65 (s, 3H), 2. 44-2. 36 (m, 4H), 2. 25-2. 16 (m, 6H), 1. 74 (s, 2H) 115 201121941 92 mouth pyridine-2-carboxylic acid [3-(1-sideoxy-1,3-diaza-iso-p-but-2-yl)-ambron-1-yl ]-Stemmed amine 14 mg 40% Method c RT: 1. 37 min m/z: 388 (M+H)+ (300 MHz, CDC13) δ 8. 50-8. 54 (m, 1H), 8. 14-8. 20 (m, 1H), 7. 79-8. 01 (m, 3H), 7. 30-7. 52 (m, 4H), 5. 35 (s, 2H), 2. 0-2. 5 (m, 12H), 1. 66-1. 75 (m, 2H) 93 0 is determined by the concentration of 2-carboxylic acid [3-(5,7-di- oxo-5,7-di-rho-e-ff匕-[3,4-b] 6-based)-Kinggang Xuan rl-based]-Taolin amine 8 mg 30% Method c RT: 1. 23 min m/z: 404 (M+H)+ (400 MHz, CDC13) δ 8. 90 (s, 2H), 8. 52 (d, /=4. 5 Hz, lH), 8. 16(d, J=7. 9 Hz, 1H), 8. 04 (s, 1H), 7. 83 (td, J=1. 7, 7. 80 Hz, 1H), 7. 38-7. 44 (m, 1H), 2. 97 (br s, 2H), 1. 71-2. 69 (m, 12H) 94 CH, 6-mercapto-° ratio.曱-2-decanoic acid [3-(5-phenyl [1,3,4]oxadiazol-2-yl)-amostane-1-yl]-bristamine 43 mg 90% Method c RT: 1. 57 min m/z: 415 •1 (M+H)+ (300 MHz, CDCI3) δ 8. 12 (br s, 1H), 8. 02-8. 09 (m, 2H), 7. 97 (d, J=7. 7 Hz, 1H), 7. 72 (t, J=7. 7Hz, 1H), 7. 45-7. 57 (m, 3H), 7. 23-7. 29 (m, 1H), 2. 63-2. 52 (m, 5H), 2. 34-2. 43 (m, 2H), 2. 08-2. 34 (m, 8H), 1. 74-1. 91 (m, 2H) 95 6-fluorenyl-pyridine-2-carboxylic acid {3-[5-(4-methoxy-phenyl)-[1,3,4]-doxazol-2-yl]- Amanta-l-based}-bristamine 120 mg 54% Method A RT: 1. 62 min m/z: 445 (M+H)+ (400 MHz, CDCI3) δ 8. 11 (s, 1H), 8. 00 (d, J=9. 0 Hz, 2H), 7. 76 (t, /=7. 8 Hz, 1H), 7. 30 (d, 7=7. 4 Hz, 1H), 7. 01 (d, 7=9. 0 Hz, 2H), 3. 90 (s, 3H), 2. 61 (s, 3H), 2. 57 (s, 2H), 2. 40 (br s, 2H), 2. 29 (br t, /=11. 6 Hz, 4H), 2. 17 (q, 7=12. 6 Hz, 4H), 1. 77-1. 91 (m, 2H) 116 201121941 96 (f° ? 6-methyl-α ratio bite-2-decanoic acid {3-[5-(3-decyloxy-methane)-[1,3,4] _ oxadiazol-2-yl]-adamantan-1-yl}-nitramine 96 mg 43% Method A RT: 1. 65 min m/z: 445 (M+H)+ (400 MHz, CDC13) 5 8. 11 (s, 1H), 8. 00 (d, J=7. 7Hz, 1H), 7. 76 (t, /=7. 7 Hz, 1H), 7. 58-7. 66 (m, 2H), 7. 42(t, J=8. 1 Hz, 1H), 7. 30 (d, 7=9. 6 Hz, 1H), 7. 06-7. 11 (m, 1H), 3. 91 (s, 3H), 2. 60 (s, 3H), 2. 58 (s, 2H), 2. 10-2. 44 (m, 10H), 1. 78-1. 91 (m, 2H) 97 pregnancy. c, 6-methyl ratio 0-but-2-carboxylic acid {3-[5-(3-a-phenyl)-[1,3,4]oxadiazol-2-yl]-adamantane: 1-yl }-Indoleamine:: 80 mg 36% Method A RT: 1. 77 min m/z: 449 (M+H)+ (400 MHz, CDCI3) δ 8. 11 (s, 1H), 8. 03 (t, 7=1. 6 Hz, 1H), 7. 94-7. 99 (m, 2H), 7. 71 (t, J=7. 7 Hz, 1H), 7. 47-7. 51 (m, 1H), 7. 44 (t, J=7. 8Hz, 1H), 7. 26 (d, /=7. 3 Hz, 1H), 2. 57 (s, 5H), 2. 09-2. 43 (m, 10H), 1. 76-1. 89 (m, 2H) 98 (f° 6-fluorenyl-0 to 0-but-2-carboxylic acid {3-[5-(4-gas-phenyl)-[1,3,4] oxadiazole-2 -yl]-adamantan-1-yl}-nonylamine 53 mg 24% Method A RT: 1. 76 min m/z; 449 (M+H)+ (400 MHz, CDC13) δ 8. 10 (s, 1H), 7. 95-8. 01 (m, 3H), 7. 71 (t, J=7. 7 Hz, 1H), 7. 45-7. 50 (m, 2H), 7. 26 (d, /=7. 4 Hz, 1H), 2. 57 (s, 5H), 2. 08-2. 42 (m, 10H), 1. 76-1. 88 (m, 2H) 99 pregnancy. 6-Methylpyridin-2-carboxylic acid {3-[5-(4-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-adamantan-1-yl}-oxime Amine 134 mg 62% Method A RT: 1. 64 min m/z: 433 (M+H)+ (400 MHz, CDCI3) δ 8. 10 (s, 1H), 8. 03-8. 08 (m, 2H), 7. 96 (d, J=7. 7 Hz, 1H), 7. 71 (t, 7=7. 7 Hz, 1H), 7. 26 (d, J=7. 6 Hz, 1H), 7. 15-7. 22 (m, 2H), 2. 57 (s, 5H), 2. 09-2. 41 (m, 10H), 1. 76-1. 88 (m, 2H) 117 201121941 100 -PrtQ F 6-mercapto-0 to 0-but-2-indole {3-[5-(3-fluoro-phenyl)-[1,3,4] 腭Zin-2-yl]-adamantan-1-yl}-nonylamine 40 mg 19% Method A RT: 1. 68 min m/z: 433 (M+H)+ (400 MHz, CDC13) δ 8. 11 (s, 1H), 7. 97 (d, /=7. 6 Hz, 1H), 7. 83-7. 87 (m, 1H), 7. 74-7. 77 (m, 1H), 7. 71 (t, J=7. 8Hz, 1H), 7. 48 (dt, J=5. 6, 8. 2 Hz, 1H), 7. 26 (d, /=7. 4 Hz, 1H), 7. 19-7. 25 (m, 1H), 2. 57 (s, 5H), 2. 10-2. 42 (m, 10H), 1. 77-1. 88 (m, 2H) 101 HpYK&gt; (^° ch3 6-fluorenyl-pyridine-2-carboxylic acid [3-(5-° ratio. de-2-yl-[1,3,4]-administered diazole-2 -yl)-adamantan-1-yl]-nonylamine 24 mg 44% Method C RT: 1. 31 min m/z: 416 (M+H)+ (400 MHz, CDCI3) δ 8. 76-8. 80 (m, 1H), 8. 21-8. 25 (m, 1H), 8. 10 (brs, 1H), 7. 95 (d, J=7. 8 Hz, 1H), 7. 86 (td, J=1. 8, 7. 7 Hz, 1H), 7. 70 (t, J=l. l Hz, 1H), 7. 44 (ddd, 7=1. twenty four. 9, 7. 6 Hz, 1H), 7. 25 (d, *7=7. 8 Hz, 1H), 2. 54-2. 60 (m, 5H), 2. 15-2. 40 (m, 10 H), 1. 75-1. 88 (m, 2H) 102 hAik^: (^° ch3 6-mercapto-pyridin-2-furoic acid P-(5-. than biti-4-yl-[1,3,4]oxadiazole-2 -yl)-adamantan-1-yl]-guanamine 35 mg 66% Method c RT: 1. 31 min m/z: 416 (M+H)+ (400 MHz, CDC13) δ 8. 77-8. 82 (m, 2H), 8. 11 (brs, 1H), 7. 96 (d, J=7J Hz, 1H), 7. 89-7. 93 (m, 2H), 7. 71 (t, 7=7. 7 Hz, 1H), 7. 24-7. 28 (m, 1H), 2. 53-2. 62 (m, 5H), 2. 28-2. 44 (m, 4H), 2. 09-2. 25 (m, 6H), 1. 76-1. 89 (m, 2H) 118 201121941 103 ^xK) ς^° ch3 6-methyl-pyrene than bite-2-carboxylic acid [3-(5-° ratio -3⁄4 -3-yl-[1,3,4] Oxazol-2-yl)-adamantan-1-yl]-nonylamine 99 mg 48% Method C RT: 1. 31 min m/z: 416 (M+H)+ (400 MHz, CDC13) δ 9. 26-9. 30 (m, 1H), 8. 77 (dd, J=1. 6, 4. 9 Hz, 1H), 8. 37 (dt, /=1. 9, 8. 0 Hz, lH), 8. 15(brs, 1H), 7. 98 (d, J=7. 7 Hz, 1H), 7. 73 (t, J=7. 7 Hz, 1H), 7. 47 (ddd, J=0. 7,4. 9, 8. 0 Hz, 1H), 7. 25-7. 30 (m, 1H), 2. 62-2. 55 (m, 5H), 2. 10-2. 44 (m, 10 H), 1. 77-1. 90 (m, 2H) 104 6·methyl-indoleamine^2·carboxylic acid [3-(5-pyridin-3-yl-[1,3,4]-doxazol-2-yl)-adamantane- 1-yl]-nonylamine 90 mg 45% Method A RT: 1. 05 min m/z: 417 (M+H)+ (400 MHz, CDC13): δ 9. 17 (s, 1H), 8. 81 (dd, J=l. 6, 4. 5 Hz, 2H), 8. 60 (s, 1H), 7. 91 (dd, /=1. 7, 4. 5 Hz, 2H), 7. 78 (br s, 1H), 2. 61 (s, 3H), 2. 58 (s, 2H), 2. 11-2. 45 (m, 10H), 1. 78-1. 89 (m, 2H) 105 6-methyl-indolepyryl-2-ylic acid [3-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-adamantane- 1-yl]-guanamine 143 mg 72% Method A RT: 1. 07 min m/z: 417 (M+H)+ (400 MHz, CDC13) δ 9. 27 (d, 7=1. 5 Hz, 1H), 9. 17 (s, 1H), 8. 77 (dd, J=1. 7,4. 9 Hz, 1H), 8. 60 (s, 1H), 8. 33-8. 38 (m, 1H), 7. 78 (s, 1H), 7. 43-7. 48 (m, 1H), 2. 61 (s, 3H), 2. 58 (s, 2H), 2. 11-2. 44 (m, 10H), 1. 77-1. 89 (m, 2H) 106 6-mercapto-pyridin-2-carboxylic acid [3-(5-indole bite-2-yl-[1,3,4]oxadiazol-2-yl)-adamantane -1-yl]-nonylamine.  107 mg 54% Method A RT: 1. 04 min m/z: 417 (M+H)+ (400 MHz, CDC13) δ 9. 17 (s, 1H), 8. 79 (d, J=4. 6 Hz, 1H), 8. 60 (s, 1H), 8. 24 (d, J=7. 9 Hz, 1H), 7. 88 (dt, 7=1. 6,7. 8 Hz, 1H), 7. 78 (s, 1H), 7. 46 (dd, /=5. 3, 7. 4 Hz, 1H), 2. 60 (s, 3H), 2. 57 (s, 2H), 2. 14-2. 43 (m, 10H), 1. 77-1. 88 (m, 2H) 119 201121941 107 (^0 ° than pyridine-2-carboxylic acid [3-(5-acridin-3-yl-[1,3,4]-doxazol-2-yl)-adamantane -1-yl]-nitramine 113 mg 56% Method A RT: 1. 10 min m/z: 402 (M+H)+ (400 MHz, CDC13) δ 9. 29 (¢1, /=1. 8 Hz, 1H), 8. 79 (dd, 7=1. 6, 4. 9 Hz, 1H), 8. 55 (d, 7=4. 2 Hz, 1H), 8. 37-8. 43 (m, 1H), 8. 18 (d, 7=7. 8 Hz, 1H), 8. 07 (br s, 1H), 7. 87 (dt, /=1. 7, 7. 7 Hz, 1H), 7. 42-7. 52 (m, 2H), 2. 80 (s, 3H), 2. 62 (s, 2H), 2. 12-2. 46 (m, 10H), 1. 79-1. 91 (m, 2H) 108 H-Pl-VO Pyridine-2-decanoic acid [3-(5-.pyridin-2-yl-[1,3,4]oxadiazol-2-yl)-adamantane -1-yl]-bristamine 14 mg 7% Method A RT: 1. 15 A mm m/z: 402 (M+H)+ (400 MHz, CDCI3) δ 8. 79-8. 83 (m, 1H), 8. 53-8. 56 (m, 1H), 8. 26 (d, J=7. 9 Hz, 1H), 8. 19 (d, J=7. 8Hz, 1H), 8. 11 (s, 1H), 7. 86-7. 92 (m, 2H), 7. 43-7. 49 (m, 2H), 2. 62 (s, 2H), 2. 17-2. 44 (m, 10H), 1. 79-1. 89 (m, 2H) 109 H. ^Sir〇C^°pyridin-2-decanoic acid [3-(5-acridin-3-yl-[1,3,4]oxadiazol-2-yl)-adamantan-1-yl]- Amine amine 194 mg 48% Method A RT; 95 min m/z: 403 (M+H)+ (400 MHz, CDCI3) δ 9. 40 (d, J-7. 9 Hz, 1H), 9. 29 (s, 1H), 8. 79 (s, lH), 8. 77(d, J=2. 5Hz, 1H), 8. 50-8. 54 (m, 1H), 8. 38 (dt, /=1. 8, 8. 0 Hz, 1H), 7. 77 (s, 1H), 7. 48 (dd, /=4. 8, 7. 8 Hz, 1H), 2. 60 (s, 2H), 2. 13-2. 46 (m, 10H), 1. 80-1. 91 (m, 2H) 110 2-methyl-pyrimidine-4-carboxylic acid [3-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-adamantane-1- Base]-guanamine 137 mg 50% Method A RT: 1. 03 min m/z: 417 (M+H)+ (400 MHz, CDCI3) δ 9,20 (s, 1H), 8. 78 (d, • 7:5. 0 Hz, 1H), 8. 71 (s, 1H), 8. 29 (dt, /=1. 9, 8. 0 Hz, 1H), 7. 91 (s, 1H), 7. 81 (d, J=5. 0 Hz, 1H), 7. 40 (dd, J=5. 0, 7. 8 Hz, 1H), 2. 71 (s, 3H), 2. 50 (s, 2H), 2. 05-2. 37 (m, 10H), 1. 71-1. 81 (m, 2H) 120 201121941 111 . Ακ&gt;- c^° ° ratio 0 to-2-carboxylic acid {3-[5-(6-methyl-0 ratio °-3-yl)_[1,3,4]oxadiazol-2-yl ]-adamantan-I-based}-guanamine method 1 23 mg 9% Method 2 80 mg 40% Method A RT; 23 min m/z: 416 (M+H)+ (400 MHz, CDC13) δ 9. 13 (d, /=1. 9 Hz, 1H), 8. 51-8. 54 (m, 1H), 8. 22 (dd, /=2. 3,8. 2 Hz, 1H), 8. 14-8. 18 (m, 1H), 8. 04 (s, 1H), 7. 84 (dt, J=1. 7, 7. 7 Hz, 1H), 7. 39-7. 44 (m, 1H), 7. 30 (d, 7=8. 2 Hz, 1H), 2. 65 (s, 3H), 2. 58 (s, 2H), 2. 10-2. 43 (m, 10H), 1. 77-1. 88 (m, 2H) 112 2-methyl-pyrimidine-4-carboxylic acid {3-[5-(6-methyl-° ratio, α--3-yl MUH]oxadiazol-2-yl]-King Kong院-1-基}-@&amp;amine 43 mg 17% Method A RT: 1. 11 min m/z: 431 (M+H)+ (400 MHz, CDCI3) δ 9. 15 (d, y=1. 9Hz, 1H), 8. 87 (d, J=5. 0 Hz, 1H), 8. 29 (d, 7=7. 4 Hz, 1H), 8. 00 (s, 1H), 7. 89 (d, 7=5. 0 Hz, 1H), 7. 36 (d, J=8. 1 Hz, 1H), 2. 80 (s, 3H), 2. 70 (s, 3H), 2. 58 (s, 2H), 2. 43 (br s, 2H), 2. 28 (dd, J=13. 0, 19. 3 Hz, 4H), 2. 19 (dd, /=13. 8, 19. 3 Hz, 4H), 1. 85 (dd, 7=14. 4, 16. 3 Hz, 2H) 113 孑. 6-Methyl-pyridine-2-decanoic acid {3-[5-(6-fluorenyl-Btb -3-yl)-[1,3,4] oxadiazole•2_yl]-reopenane Small base}-; guanamine 80 mg 31% Method A RT: 1. 35 min m/z: 430 (M+H)+ (400 MHz, CDClj) δ 9. 15 (d, 7=1. 8 Hz, 1H), 8. 26 (d, 7=7. 1 Hz, 1H), 8. 13 (s, 1H), 7. 98 (d, /=7. 6 Hz, 1H), 7. 33 (d, 7=8. 1 Hz, 1H), 7. 28 (d, J=6. 1 Hz, 1H), 2. 68 (s, 3H), 2. 59 (s, 5H), 2. 12-2. 45 (m, 10H), 1. 79-1. 90 (m, 2H) 121 201121941 114 6-mercapto-»bi-pyridyl-2-carboxylic acid {3-[5-(6-methyl-. σσ-3-yl)_ [1,3,4] Znoxazol-2-yl]-adamantan-1-yl}-8&amine 73 mg 28% Method A RT: 1. 13 min m/z: 431 (M+H)+ (400 MHz, CDC13) δ 9. 19 (s, 1H), 9. 16 (d, J=2. 0 Hz, 1H), 8. 62 (s, 1H), 8. 27 (d, J=6. 9 Hz, 1H), 7. 80 (s, 1H), 7. 34 (d, J-8. 3 Hz, 1H), 2. 69 (s, 3H), 2. 62 (s, 3H), 2. 58 (s, 2H), 2. 13-2. 46 (m, 10H), 1. 80-1. 91 (m, 2H) 115 C^° Pyridine-2-carboxylic acid {3-[5-(5-fluorenyl-mouth-p--3-yl)-[1,3,4]-doxazol-2-yl ]-adamantan-1-yl}-3 leucine 21 mg 10% &gt; Method A RT: 1. 24 min m/z: 416 (M+H)+ (400 MHz, CDCb) δ 9. 09 (s, 1H), 8. 61 (s, 1H), 8. 53-8. 57 (m, 1H), 8. 22 (s, 1H), 8. 16-8. 20 (m, 1H), 8. 07 (s, 1H), 7. 87 (dt, J=1. 7, 7. 7 Hz, 1H), 7. 41-7. 47 (m, 1H), 2. 61 (s, 2H), 2. 48 (s, 3H), 2. 12-2. 45 (m, 10H), 1. 80-1. 91 (m, 2H) 116 WMN 丫2-methyl-pyrimidine-4-decanoic acid {3-[5-(5-fluorenyl-11-bite-3-yl)-[1,3,4] hired two Zin-2-yl]-adamantan-1-yl}-nitramine 27 mg 20% Square: Method A RT; 14 min m/z: 431 (M+H)+ (400 MHz, CDCI3) δ 9. 09 (br s, 1H), 8. 87 (d, /=5. 0 Hz, 1H), 8. 62 (br s, 1H), 8. 23 (s, 1H), 8. 00 (s, 1H), 7. 90 (d, y=5. 0 Hz, 1H), 2. 80 (s, 3H), 2. 59 (s, 2H), 2. 48 (s, 3H), 2. 13-2. 46 (m, 10H), 1. 81-1. 91 (m, 2H) 117 π-Λν〇^ρ (ί0 0 than bite-2-decanoic acid {3-[5-(6-trifluoromethyl-° ratio α--3-yl)-[1, 3,4]oxadiazol-2-yl]-adamantane-l-yl}-nitramine 9 mg 4% Method A RT: 1. 47 min m/z: 470 ,1 (M+H)+ (400 MHz, CDCb) δ 9. 04 (s, 1H), 8. 54 (d, /=4. 4 Hz, 1H), 8. 39 (d, J=8. 3 Hz, 1H), 8. 18 (d, J=. 8Hz, 1H), 8. 13(dd, J=\. 9, 8. 3 Hz, 1H), 8. 06 (s, 1H), 7. 86 (dt, J=1. 5, 7. 7 Hz, 1H), 7. 43 (dd, /=4. 9, 6. 6 Hz, 1H), 2. 64 (s, 2H), 2. 16-2. 46 (m, 10H), 1. 79-1. 91 (m, 2H) 122 201121941 118 H-^Si-VC!HF ς^° 2-Methyl-^^-4-carboxylic acid {3-[5-(6-trifluoromethyl-° ratio α- 3-yl)-[1,3,4]oxadiazol-2-yl]-adamantan-1-ylbuconamide 15 mg 10% Method A RT: 1. 37 min m/z: 485 (M+H)+ (400 MHz, CDC13) δ 8. 96 (s, 1H), 8. 78 (d, /=5. 0 Hz, 1H), 8. 32 (d, /=8. 3 Hz, 1H), 8. 05 (dd, /=1. 8,8. 3 Hz, 1H), 7. 90 (s, 1H), 7. 81 (d, y=5. 0 Hz, 1H), 2. 71 (s, 3H), 2. 52 (s, 2H), 2. 11-2. 37 (m, 10H), 1. 71-1. 82 (m, 2H) 119 V 6-fluorenyl-_α ratio σ定-2-carboxylic acid {3-[5-(6-ethyl-π ratio σ--3-yl)-[1,3,4] Oxazol-2-yl]-amostrum-1 -yl} -S&amine 75 mg 26% Method A RT: 1. 48 min m/z: 444 (M+H)+ (400 MHz, CDCI3) δ 9. 18 (s, 1H), 8. 28 (d, J=5. 5Hz, 1H), 8. 12 (s, 1H), 7. 98 (d, J=5. 7Hz, 1H), 7. 70-7. 77 (m, 1H), 7. 34 (d, J=7. 0 Hz, 1H), 2. 91-3. 00 (m, 2H), 2. 59 (s, 5H), 2. 11-2. 46 (m, 10H), 1. 78-1. 91 (m, 2H), 1. 34-1. 42 (m, 3H) 120 ς^° i 2-mercapto-anthracene-4-carboxylic acid {3-[5-(6-ethyl-α ratio σ--3-yl)-[1,3,4 ]Diazol-2-yl]-adamantan-1-yl}-§&amp;amine 58 mg 41% Method A RT: 1. 27 min m/z; 445 (M+H)+ (400 MHz, CDCh) δ 9. 18 (s, 1H), 8. 87 (s, 1H), 8. 29 (brs, 1H), 7. 99 (s, 1H), 7. 89 (s, 1H), 7. 35 (br s, 1H), 2. 91-3. 01 (m, 2H), 2. 80 (s, 3H), 2. 58 (s, 2H), 2. 11-2. 47 (m, 10H), 1. 79-1. 91 (m, 2H), 1. 34-1. 42 (m, 3H) 121 5-octyl-pyridin-2-decanoic acid {3-[5 as-fluorenyl-° ratio °-3-yl)-[1,3,4]oxadiazole-2- Base]-adamantan-1-yl}-nitramine 17 mg 17% Method C RT: 1. 36 min m/z: 434 (M+H)+ (400 MHz, CDCI3) δ 9. 15 (d, 7-2. 0 Hz, 1H), 8. 37 (d, 7=2. 8 Hz, 1H), 8. 19-8. 26 (m, 2H), 7. 86 (s, 1H), 7. 54 (dt, /=2. 8, 8. 3 Hz, 1H), 7. 32 (d, J=8. 1 Hz, 1H), 2. 67 (s, 3H), 2. 58 (s, 2H), 2. 11-2. 44 (m, 10H), 1. 79-1. 90 (m, 2H) 123 201121941 122 ° than morphine-2-decanoic acid {3-[5-(6-methyl-0 ratio. -3-yl)-[1,3,4] conjugated diazole- 2-yl]-adamantan-1-yl}-guanamine 35 mg 52% Method C RT: 1. 13 min m/z: 417 (M+H)+ 1 (400 MHz, CDC13) δ 9. 40 (s, 1H), 9. 15(s, 1H), 8. 76 (s, 1H), 8. 52 (s, 1H), 8. 26 (dd, /=1. 8, 8. 1 Hz, 1H), 7. 76 (s, 1H), 7. 33 (s, 1H), 2. 67 (s, 3H), 2. 59 (s, 2H), 2. 13-2. 46 (m, 10H), 1. 80-1. 90 (m, 2H) 123 03⁄4 u定-4-曱 acid {3-[5-(6-methyl-^ is more than -3-yl)-[1,3,4]oxadiazol-2-yl ]-adamantane-l-yl}-nitramine 26 mg 39% Method C RT: 1. 13 min m/z: 417 (M+H)+ (400 MHz, CDC13) δ 9. 23 (d, J=1. 3 Hz, 1H), 9. 15 (d, 7=1. 9 Hz, 1H), 8. 98 (d, J=5. 0 Hz, 1H), 8. 24 (dd, 7=2. 2, 8. 1 Hz, 1H), 8. 11 (dd, J=1. 4, 5. 0 Hz, 1H), 7. 96 (br s, 1H), 7. 32 (d, /= 8. 1 Hz, 1H), 2. 67 (s, 3H), 2. 58 (s, 2H), 2. 12-2. 46 (m, 10H), 1. 80-1. 90 (m, 2H) 124 ς^° 2-methyl-pyrimidine-4-decanoic acid {3-[3-(3-fluoro-phenyl)-[1,2,4]oxadiazole-5-yl ]-金刚炫(-1-yl}-nonylamine 54 mg 78% Method B RT: 1. 39 min m/z: 434 (M+H)+ (400 MHz, CDCb) δ 8. 85 (d, J=6. 7 Hz, 1H), 7. 96 (br s, 1H), 7. 85-7. 91 (m, 2H), 7. 75-7. 82 (m, 1H), 7. 44 (dt, 7=7. 6, 10. 8 Hz, 1H), 7. 15-7. 23 (m, 1H), 2. 78 (s, 3H), 2. 57 (s, 2H), 2. 11-2. 44 (m, 10H), 1. 80-1. 86 (m, 2H) 125 Ayo r^° 2-methyl-pyrimidine-4-曱8man|; 3-(3-» ratio -3-yl-[1,2,4] hired two° sitting -5-yl)-adamantan-1-yl]-nonylamine 43 mg 65% Method A RT: 1. 32 min m/z: 417 (M+H)+ (400 MHz, CDC13) δ 9. 33 (s, 1H), 8. 87 (d, •7=5. 0 Hz, 1H), 8. 76 (d, 7=3. 5 Hz, 1H), 8. 37 (dt, /=1. 9, 8. 0 Hz, 1H), 7. 98 (s, 1H), 7. 94 (dd, /=0. 3, 5. 0 Hz, 1H), 7. 44 (dd, «7=4. 9, 7. 8 Hz, 1H), 2. 80 (s, 3H), 2. 61 (s, 2H), 2. 14-2. 35 (m, 10H), 1. 80-1. 91 (m, 2H) 124 201121941 126 . PrtQ C^° pyridin-2-furoic acid [3-(3-° ratio -3-yl-[1,2,4]oxadiazol-5-yl)-adamantan-1-yl]-acoustic Amine 43 mg 64% Method C RT: 1. 31 min m/z: 403 (M+H)+ (400 MHz, CDC13) δ 9. 41 (s, 1H), 9. 34 (s, 1H), 8. 76 (s, 2H), 8. 52 (s, 1H), 8. 40 (br s, 1H), 7. 75 (s, 1H), 7. 47 (br s, 1H), 2. 62 (s, 2H), 2. 14-2. 48 (m, 10H), 1. 80-1. 92 (m, 2H) 127 6-methyl-D ratio 0-but-2-carboxylic acid [3-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)-adamantane -V-based]-guanamine 37 mg 56% Method c RT: 1. 56 min m/z: 416 (M+H)+ (400 MHz, CDC13) δ 9. 33 (s, 1H), 8. 75 (s, 1H), 8. 35-8. 42 (m, 1H), 8. 12 (s, 1H), 7. 96-8. 03 (m, 1H), 7. 70-7. 78 (m, 1H), 7. 40-7. 49 (m, 1H), 2. 62 (s, 2H), 2. 59 (s, 3H), 2. 12-2. 46 (m, 10H), 1. 79-1. 91 (m, 2H) 128 H-pxKh (f° 6-methyldipyridin-2-carboxylic acid {3-[3-(6-methyl-σ ratio 0--3-yl)-[1,2 , 4] oxadiazol-5-yl]adamantan-1 -yl}-nitramine 63 mg 46% Method c RT: 1. 63 min m/z: 430 (M+H)+ (400 MHz, CDCh) δ 9. 20 (s, 1H), 8. 26 (d, J=1J Hz, 1H), 8. 11 (br s, 1H), 7. 99 (d, y=7. 8 Hz, 1H), 7. 73 (t, J=7. 5 Hz, 1H), 7. 25-7. 33 (m, 2H), 2. 66 (s, 3H), 2. 61 (s, 2H), 2. 59 (s, 3H), 2. 12-2. 45 (m, 10H), 1. 79-1. 90 (m, 2H) 129 ς^° 2-methyl-pyrimidine-4-decanoic acid {3-[3-(6-methyl-° ratio °-3 -yl)-[1,2,4] 〇| oxazol-5-yl]-adamantan-1 -yl}-nitramine 31 mg 23% Method c RT: 1. 45 min m/z: 431 (M+H)+ (400 MHz, CDCb) δ 9. 21 (s, 1H), 8. 87 (d, 7=2. 4 Hz, 1H), 8. 32 (br s, 1H), 7. 98 (s, 1H), 7. 90 (d, 7=2. 7 Hz, 1H), 7. 34 (d, J=6. 3 Hz, 1H), 2. 80 (s, 3H), 2. 70 (s, 3H), 2. 60 (s, 2H), 2. 13-2. 47 (m, 10H), 1. 80-1. 90 (m, 2H) 125 201121941 130 c^° . Bipyridine-2-decanoic acid {3-[3-(6-methyl-0 ratio. -3-yl) [1,2,4]oxadiazol-5-yl]-adamantane-l-yl }-Indoleamine 70 mg 50% Method C RT: 1. 53 min m/z: 416 (M+H)+ (400 MHz, CDC13) δ 9. 20 (s, 1H), 8. 54 (d, J=4. 4 Hz, 1H), 8. 27 (d, /=7. 7 Hz, 1H), 8. 19 (d, 7=7. 9 Hz, 1H), 8. 05 (br s, 1H), 7. 86 (t, J=7. 8Hz, 1H), 7. 43 (t, J=6. 7Hz, 1H), 7. 30 (d, /=9. 1 Hz, 1H), 2. 67 (s, 3H), 2. 62 (s, 2H), 2. 12-2. 45 (m, 10H), 1. 79-1. 90 (m, 2H) 131 r^° pyrimidine-4-decanoic acid {3-[3-(6-methyl-0 ratio °-3-yl)·[1,2,4]oxadiazole-5 -yl]-adamantane-l-yl}-bristamine 62 mg 45% Method C Rt: 1. 37 min m/z: 417 (M+H)+ (400 MHz, CDCI3) δ 9. 18-9. 27 (m, 2H), 8. 99 (d, /=4. 5 Hz, 1H), 8. 30 (d, 7=5. 2 Hz, 1H), 8. 12 (d, 7=3. 5 Hz, 1H), 7. 96 (brs, 1H), 7. 33 (d, /=8. 2 Hz, 1H), 2. 69 (s, 3H), 2. 61 (s, 2H), 2. 15-2. 47 (m, 10H), 1. 80-1. 91 (m, 2H) 132 H,P&gt;nyCf °VN pyridin-2-carboxylic acid {3-[3-(6-fluorenyl-° ratio -3-yl)-[1,2,4]腭二Zyrid-5-yl]-adamantane-l-yl}-nitramine 38 mg 51% Method c RT: 1. 34 min m/z: 417 (M+H)+ (400 MHz, CDCI3) δ 9. 39(d, J=1. 4 Hz, 1H), 9. 17-9. 20 (m, 1H), 8. 74 (d, /=2. 4 Hz, 1H), 8.  48-8. 50 (m, 1H), 7. 71-7. 74 (m, 1H), 7. 30-7. 32 (m, 1H), 2. 63-2. 68 (m, 3H), 2. 59 (s, 3H), 2. 38-2. 44 (m, 3H), 2. 26-2. 33 (m, 2H), 2. 20-2. 24 (m, 2H), 1. 80-1. 85 (m, 2H), 1. 49-1. 50 (m, 3H) 126 201121941 133 . 1--6-Methyl-° than well·2-carboxylic acid {3-[3-(6-fluorenyl-»pyridin-3-yl)-I,2,4-trans. Sodium-5-yl]adamantane _1-yl}-guanamine 44 mg 58% Method C RT: 1. 45 min m/z: 431 (M+H)+ (400 MHz, CDC13) δ 9. 17-9. 20 (m, 2H), 8. 60 (s, 1H), 8. 21-8. 29 (m, 1H), 7. 73-7. 78 (m, 1H), 2. 62-2. 69 (m, 3H), 2. 60 (s, 3H), 2. 58 (s, 2H), 2. 39-2. 43 (m, 2H), 2. 27-2. 29 (m, 1H), 2. 23-2. 26 (m, 1H), 2. 15-2. 18 (m, 4H), 1. 81-1. 85 (m, 1H), 1. 49-1. 51 (m, 1H) 134 5-Fluoro-pyridine-2-decanoic acid {3-[3-(6-methyl-indole-Butyl-3-yl)·[1,2,4]oxadiazole-5 -yl]adamantane-l-yl}-bristamine 48 mg 69% Method C RT: 1. 58 min m/z: 434 (M+H)+ (400 MHz, CDCI3) δ 9. 18 (s, 1H), 8. 35 (d, J=2,8 Hz, 1H), 8. 20 (q, J=4. 2 Hz, 2H), 7. 84 (s, 1H), 7. 52 (dt, /=3. 0, 8. 4 Hz, 1H), 7. 28-7. 33 (m, 1H), 2. 63-2. 67 (m, 3H), 2. 58 (s, 2H), 2. 37-2. 42 (m, 2H), 2. 26-2. 33 (m, 2H), 2. 14-2. 23 (m, 4H), 1. 80-1. 85 (m, 2H), 1. 48-1. 51 (m, 2H) 135 ς^° ch3 6-Methyl-pyridine-2-carboxylic acid {3-[5-(3-Gas-phenyl)-Azole-2·yl]-adamantan-1_ Indoleamine 30 mg 70% Method C RT: 1. 82 min m/z: 448 (M+H)+ (400 MHz, CDCb) δ 8. 12 (brs, 1H), 7. 99 (d, J=l. l Hz, 1H), 7. 72 (t, /=7. 7 Hz, 1H), 7. 62 (t, J=1. 8Hz, 1H), 7. 52 (dt, 7=1. 4, 7. 7 Hz, 1H), 7. 35 (t, /=7. 8 Hz, 1H), 7. 25-7. 31 (m, 3H), 2. 58 (s, 3H), 2. 51-2. 55 (m, 2H), 2. 43-2. 06 (m, 10H), 1. 76-1. 89 (m, 2H) Example 1 3 6 - 14 9 of Table 2 was prepared in a manner similar to that of Example 61, from the reaction of the amine intermediates 12, 14 and 11 with the corresponding commercially available helium. In a manner similar to that of Example 62, the process can be carried out by the method of Process 127 from 201121941, with the phosgene of chloroantimonic acid and the city of f-amine (see, for example, step a of the process u). Step (VIII) of Process u or isocyanate (see, for example, the reaction of Step 11 of Scheme 11 to prepare Examples 150-156 of Table 2. In a manner similar to Example 64, the separation was prepared from the reaction of Intermediate 12 with the corresponding commercially available aldehyde. Examples 157_163 and i65_167 of Table 2. In a manner similar to that of Example 63, commercially available 2-aminothiazide can be used separately. Sit and 4-aminotetrahydropyran to prepare Examples 1 64 and 1 68 of Table 2. Table 2 - Hypothetical Compound Example Structural Chemical Name 136 ^iN^o;s^ 6-Methyl-pyridine-2-carboxylic acid (3·Benzenesulfonylamino-Golden Ranthyl)-Sfe Amine 137 6- Methyl-.pyrimidin-2-carboxylic acid (3-benzenesulfonylamino-amstrand-1-yl)-guanamine 138 pyridine-2-carboxylic acid P-(2-fluoro-benzenesulfonylamino)-King Kong Hyun-1-yl]-nonylamine 139 pyridine-2-carboxylic acid [3-(3-fluoro-benzenesulfonylamino)-adamantan-1-yl]-nonylamine 140 pyridine-2-carboxylic acid [3-( 4-fluoro-benzenesulfonylamino)-金刚炫-1-秦]-bristamine 141 —— iN^〇X° Pyridine-2-carboxylic acid (3-methanesulfonylamino-adamantane-1-yl aryl amine 142 Ο^Ν cut, pyridin-2-furoic acid (3-ethanesulfonylamino group-金刚烧小基)-醯骑128 201121941 143 Pyridine-2-decanoic acid (3-cyclopropyl sulfonylamino- acetonide-1-yl)-bristamine 144 pyridine-2-carboxylic acid (3-cyclobutyl) Sulfonamide-adamantan-1-yl)-bristamine 145 ^-0 pyridine-2-carboxylic acid [3-(tetrahydro-pyran-4-sulfonylamino)-adamantan-1-yl]- Indoleamine 146 iN^o;S^pyridine-2-decanoic acid (pyridine-2-sulfonylamino)-adamantan-1-yl]-bristamine 147 pyridine-2-carboxylic acid [3-(pyridine-3- Sulfonylamino)-ammanicone-1-yl]-bristamine 148 pyridine-2-carboxylic acid [3-(pyridin-4sulfonylamino)-adamantan-1-yl]-bristamine 149 ίΝ^〇Αγ Pyridine-2-decanoic acid [3-(thiazole-2-sulfonylamino)-adamantan-1-yl]-bristamine 150 νΑ.  C(H °ν ethyl-amino decanoic acid 3-[(6-fluorenyl-pyridine-2-carbonyl)-amino]-osmantine _ 1 -yl S 151 νΑ 〇ethyl-amino decanoic acid 3-[(6-Mercapto-pyridin-2-carbonyl)-amino]_金刚烧-1-基酉 152 (Ν 〇^&quot;Ν-Η Λ Λ Cyclopropyl-aminocarboxylic acid 3- [(6-Methyl-pyridine-2-carbonyl)-amino]-amostrum-1-yl vinegar 153 V^o 0 乂Να Azetidine-1-decanoic acid 3-[(6-fluorenyl) -pyridine-2-carbonyl)-amino]-adamantan-1-yl ester 129 201121941 154 Piperidine-1-decanoic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]- King Kong炫τΐ-基 s purpose•' 155 福福林-4- decanoic acid 3-[(6-methyl"pyridin-2-carbonyl)-gum base]_金刚烧_ 1_基s s 156 yA Q. Human On, 4-methyl-piperidin-1-carboxylic acid 3-[(6-fluorenyl-.pyridin-2-ylcarboyl)-amino]-diamond-1-yl s 157 H 6- -Pyridine-2-carboxylic acid [3-(cyclohexylmethyl-amino)-adamantan-1-yl]-nonylamine 158 H 6-fluorenyl-»tb pyridine-2-decanoic acid 1&gt; (n-(cyclobutylmethyl-amino)-adamantane- 1-yl]-nonylamine 160 H 6-fluorene-pyridine-2-carboxylic acid (3·benzylamine) -adamantan-1-yl)-nonylamine 161 Mei AH 6-mercapto-pyridine-2-carboxylic acid [3-(2-fluoro-phenylhydrazino)-adamantan-1 -yl]-bristamine 162 H 6-mercapto-acridine-2-carboxylic acid [3-(3-fluoro-benzylamino)-adamantan-1-yl]-nonylamine 163 H 6-mercapto-pyridin-2-indole [3-(4-Benzylamino)-adamantan-1-yl]-bristamine 164 ^Ίν2〇-Ρ H 6-methyl-pyridine-2-decanoic acid [3-(thiazol-2-yl) Amino)-adamantan-1-yl]-nonylamine 130 201121941 165 6-Methyl-pyridine-2-carboxylic acid (3-isobutylamino-adamantan-1-yl)-nonylamine 166 6-A Kebitan-2-decanoic acid (3-propylamino-adamantan-1-yl)-guanamine 167 6-methyl-pyridine-2-carboxylic acid {3-[(tetrahydro-pyranyl-4-)曱 ))-amino]-adamantane-l-yl}-nonylamine 168 Η 6-mercapto-0-pyridin-2-indole [3-(tetrahydro-indole-4-ylamino) )-adamantan-1-yl]-nonylamine 4. Pharmacological Evaluation of Compounds of the Invention The compounds of the invention have been tested in vitro and can be tested in vitro and in vivo in the assays described below. In vitro assay radioligand binding assay using [J.  A.  O’Bri+en et al., Mo/2003, The human metabotropic glutamate receptor 5 (hmGluR5) protein described in &lt;54, 731-740] was subjected to a binding assay. Briefly, after thawing, the membrane homogenate was resuspended in 50 mM Tris-HCl, 0.9% NaCl binding buffer (pH 7.4) until a final assay concentration of 40 gg protein per well was used for [3h] 2-mercapto -6-Phenylethynyl-pyridine ([3H] MPEP) (American Radiolabeled Chemicals, St. Louis, MO) filter binding. Breeding includes 5 nM [3H] MPEP, membranes and buffers or compounds at various concentrations. The samples were incubated for 60 minutes at room temperature with shaking. Non-specific binding was determined with 1 〇 MPEP. After incubation, the sample is filtered through a GF/C filter (pre-soaked in 0.25% poly-B-131 201121941 imine (PEI)); followed by Tomtec®

The Harvester 96® Mach III cell harvester (iomtec, Hamden, CT) was washed 4 times with 0.5 mL ice-cold 5 mM Tris-HCl (pH 7.4). The IC50 value is obtained from the self-suppression curve and is based on [γ· Cheng and W.H.

Cheng and prusoff equations as described in Prusoff 5zoc/zem. PAarmaco/· 1973, 22, 23: 3099-3108; = IC5() / (1 + [L] / foot d) Calculate the undervalue, where [ L] is the radioligand concentration and the rule d is its dissociation constant at the acceptor's self-saturated isotherm. The representative values of the representative examples 丨丨3, 75, 82, 68 and 85 are 8.2 nM, 35 η Μ M nM, 130 nM and 380 nM, respectively. The cDNA of the metabotropic glutamate receptor 5 ( rmGluR5 ) and the cDNA of the human metabotropic form of alanine receptor 5 ( hmGluR5 ) were tested by negative or positive ectopic activity. Nakanishi) (Kyoto University, Kyoto, Japan) generously presented. rmGluR5 or hmGluR5 is stably expressed in the HEK 293 cell line and has a supplement at 37C, 5% C〇2 (10% fetal bovine serum, 4 mM acetophenine, 100 units/mL penicillin, 100 jug) /mL streptomycin and 0.75 mM G1418) were grown in Dulbecco's Modified Eagle Medium &gt; DMEM (Invitrogen, Carlsbad, CA). 24 hours prior to assay, cells were seeded in a 384-well black wall microtiter plate coated with poly-D-lysine. Before the test, the medium was aspirated and assayed with 3 μΜ Fluo-4/0.01% oxidized pluronic acid at 5% C.02, 37 °C. 132.201121941 (Hanke's) Balanced Saline Solution (HBSS): 1 50 mM NaCl &gt; 5 mM KC1 M mM CaCl2 &gt; 1 mM MgCl2, plus 20 mM N-2-hydroxyethylpipenetin_N,_2_B Sulfonic acid (HEPES) (pH 7.4), 〇·1〇/0 bovine serum albumin (BSA) and 2 5 probenecid loading of dyes on sputum cells (25 μM per well for 1 hour. Discard excess After the dye, the cells are washed in assay buffer and layered at a final volume equal to 30 per well. In the fluorescence imaging plate reader (FLIPR) (Molecular Devices, Sunnyvale, CA) ta 488 nm excitation wavelength and 500 to The 560 nm emission range monitors the base fluorescence. Adjust the laser excitation energy so that the base fluorescence reading is about 1 〇, one relative fluorescence unit. In the presence of the compound to be tested, the concentration of £(:2 or EC8q) The glutamine-stimulated cells (both diluted in the dancing buffer) and allowed to stand at room temperature for 3 minutes. The relative time interval (exposure = 0.6 sec) was measured relative to the fluorescence.. The base reading obtained from the negative control group was subtracted from all samples. The maximum fluorescence change for each well was calculated. By nonlinear regression (Hill The equation (Η(1) equation)) analyzes the concentration response curve obtained from the maximum fluorescence change. If the compound produces a concentration-dependent inhibition of the ECS() glutamic acid reaction, a negative regulator can be identified from the concentration response curves. Negative ectopic regulation of exemplary compounds 1-5, 7 24, ^, 4, 43-45, 61, 63_83, μ"12 and 135 was tested using rmGluR5 in the above assay: FLIPR maximal inhibition at 43 To the range of 99%, and FLIpRic5 is in the range of 〇% nM to 4700 nM. Illustrative compounds were tested using hmGiuR5 in the above assay Examples 6, 25, 33-38, 40, 42, 46-60, 62, 84 -91, 112-134: FLIPR maximal inhibition is in the range of 77% to 96%, while 133 201121941 FLIPR. ic5 is in the range of 〇44 nM to 770 nM. If the compound causes EC2Q glutamate to react in a concentration-dependent manner Enhanced, from this concentration response curve can identify positive regulators PAM). A resting ectopic modifier (SAM) can be identified based on the results from the radioligand assay and the calcium shift assay. If the Keling radioligand assay compound actively binds to the ectopic site of the receptor, but there is no inherent efficacy in the #5 mobile assay, the compound is SAM. In vivo assays The in vivo effects of the compounds of the invention can also be assessed by non-limiting examples using the following in vivo behavioral animal models. The following behavioral models are not intended to be useful for determining the efficacy of a compound of formula (I) in treating a corresponding condition or disease. Only models. * Similar to the mouse described in [K·Njung'e, K. and SL Handley, odem (4) 5daw〇r, 1991, 35, 03- 07]. The marble marble burying (mMB) test can be used for living organisms. The anti-anxiety effect of the compound was evaluated. Example 丨12 is effective after administration of 3 mpk sc. More specifically, for the mMB test, adult male CD1 mice (Charles River Laboratories (Kingston, NY)) weighing 25 to 3 g were used. All animals were housed in a standard breeding room on the i2:12 light/dark cycle (lights on at 6:00 am) for at least one week prior to testing. Provide any food and water. Animals were weighed and performed prior to testing; tail markers were randomly assigned to the treatment group. 134 .201121941 ^ K 'The main agent or test compound 60 minutes later, or injection positive to qg Ding γ γ soil, human, ',. After 3 minutes, the mice were individually tested; 3 had a 1.5 吋 whitewood sawdust bottom (pwi logo) and two columns of 1 〇 stone (a total of 2 茏 〇 total 2 〇 block marble) in the test cage . Cover each test cage with a filter tops. After 3 minutes, the mice were removed from the test and returned to the home cage.胄 The number of fully visible marbles (with less than 2/3 of wood chip coverage) is counted and subtracted from 2() to obtain the number of buried marbles. For example, 2 mice were tested per group. The test included multiple tests&apos; each test was performed to evaluate, for example, buspirone hydrochloride (BUS; Sigma Aldrich) (positive control) and/or compound of formula (1). Prior to testing, each compound was dissolved in 20% cyclodextrin (compound of formula (I)) or distilled water (.BUS) and at a specified pretreatment time (ie 30, 60 or 120 minutes pretreatment) Or multiple doses (such as 3, 10 and/or 30 mg/kg) are administered via subcutaneous (SC) or intraperitoneal (ip) injection. The dose is measured in milligrams of the drug (salt form) used per kilogram of body weight. Data were analyzed using single factor AN0VA and post-hoc Dunnett's test. It can also be done by [N.A. Moore et al., 56 〇^0«, &lt;2/ corpse/^7^&lt;3. A modified version of the Geller-Seifter conflict test described in 〇/&lt;? 少少· 1994, 5, 196-202] to test the anxiolytic effect in vivo. For example, more specifically, use the rodent operating room (ENV-007CT' Med Associates (Georgia, VT)) and the muffler chamber (ENV-018MD 'Med Associates), and each room is equipped with field lights, instructions #, Passing a stylized electric shock (ENV-414 'Med Associates) to transmit the foot-shaped electric floor and food leak 135 201121941 bucket. Two levers are positioned on each side of the food funnel. The rats were trained to respond only to the left lever. Use food to strengthen (such as dust-free precision food group (Dustless

Precision Pellets) ' 45 mg ' BioServ ( Frenchtown, NJ)). The MED-PCIV software (Med Associates) was used to perform the experimental period and collect data. Before the conflict procedure begins, the animal is initially trained to press the lever according to a fixed ratio time course (FR 1 2 5 and 1 〇). After the animal received 25 remunerations in the fr 1 〇 time course for two consecutive days, the animals were trained to compete according to the gas component conflict schedule. The three components are as follows: (1) food fortified! No penalty, variable interval 3 〇 (VI30) time course to enhance the lever press with a variable time duration of 3 〇 on average, this period lasts 9 minutes, and Signaling only by back-field illumination; (2) followed by a 3-minute pause period (τ〇) recorded by the overall darkness, but without compensation or punishment; (3) enhanced penalty, fixed ratio 1 〇 (FR10) time course, providing food and foot shock (0.3 mA, 500 ms) for each lever stroke in 3 minutes; this component is illuminated by the backlight and the indicator above each lever The signal is repeated twice in the same order during the 3 minute period of each day. The test is started when a steady reaction rate (no significant upward or downward trend) is observed for 5 days. For example, used on Wednesdays and Fridays. Latin-squares design test animals The animals themselves were used as controls and all treatments were performed. In order to maintain basic performance, animals were also trained for the remaining three days of the week. 12 adult adults weighing 426-567 g were used ( Male history Bogdori rats (SpragUe_Dawley m) (charles are tested in Lab〇rat〇ries 136 201121941 • (Kingston, NY)). Animals are at controlled temperature (68·72卞) and 12 hours light/dark cycle (in 〇 6: Open the lamp in the breeding room in pairs. Animals are free to use water, and food is limited to 15 g Bacon L〇ver's Treats (Bi〇Serv) after training/test from Monday to Thursday. Friday to Sunday, Animal Free Access Laboratory Diet 5〇12 Rat Diet (PMI Nutrition International, LLC, Brentwood, MO) 'Change the cage until Sunday and remove food. Test includes multiple tests' Each test is to evaluate a reference compound or a compound of formula (I), and the reference anti-anxiety agent may include chlordiazepoxide, diazepam, and buspirone, which are dissolved in physiological saline or water and Subcutaneous, intraperitoneal and/or oral administration. The test compound is dissolved in 20% /3-cyclodextrin and the pH is adjusted to 7 with NaHC〇3. For each test, in one or more doses (such as i 〇, 20, Oral administration at 30 and/or 50 mg/kg, 6 hours later, using a 2 mL/kg injection volume compared to the vehicle control group to test the compound to be evaluated. Dosage for each kilogram of body weight (Salt form) milligrams. Analytical data were analyzed using repeated measures ANOVA and post-mortem Dunnett's test. The "Vogel Conflict Test" described by J. R. Vogel et al., 1971, 27 1.1-7] can be used to detect the anxiolytic activity of compounds of formula (I) because anxiolytics increase penalties for drinking water. In the test, the rats were deprived of drinking water for about 48 hours, and then individually placed in a transparent Plexiglas® fence (15 X 32 X 34 cm) consisting of a 1 cm stainless steel strip (〇.4 cm). The wall behind the fence is made of 137 201121941 opaque Plexlglas®, which hides the observer from the experimental animals. In the middle of the opposite wall, at 5 cm above the floor, the metal outlet pipe extends into the cage and is connected to one pole of the shock generator (Apelex: Model 011346). The other pole of the shock generator is connected to the metal grid floor. The rats were probed until they found a water tube.纟 Next, each time the rat is drinking water, it receives a slight electric shock (1 7 mA, 1 s) two seconds after the start of 舔舐2. Count the number of drinking waters during the 3 minute test period. Blind tests were performed on each group of rats. Testing can include the use of reference compounds and multiple tests of the formula (n compounds of formula I can be prepared and administered as described in the LES test below. As described therein, male Rj: Wistar (Hans) rats can reach the environment Use after adapting to conditions. Unpaired Student St test can be used to analyze data by comparing treatment groups with appropriate control groups. For example, [Walker and Davis.拗〇/. 吟, 1997 can also be used. The light-enhanced startle (LES) reflex method described in 仏6:461_471] is used to evaluate the anxiolytic effect of the compounds of the present invention in vivo. The startle response is a synergistic contraction of skeletal muscle groups in response to high-intensity unexpected stimulation. Most sensory modalities can be used, but sound is most commonly used because it is easy to control. Therefore, when a short pulse of sufficient intensity (for example, 115 dB) occurs, an involuntary startle response occurs. High luminosity makes nocturnal species (such as large The rat's startle response is enhanced' and this action does not require any pretreatment. Anti-anxiety agents (anxiolytic agents) reduce photo-enhanced startle jumps. For LES tests, Equipment consisting of a city's soundproofing room (eg SR-LABTM Shocking Reaction System, San Diego Instruments, San Diego, 138 201121941 CA). All supervisors &amp; ancient, inspection events and data records can be programmed by computer ( For example, the sr-labTM control unit controls the rats in a small Perspex® cylinder slightly larger than the rat, and the cylinder is attached to the bottom plate containing the strain gauge. The first 4th army and movement (such as during the startle reaction) caused the deformation of the bottom plate. This is the same as the scale of the movement (that is, the start-up reaction rule). , i; , θ * J heart motor. The speaker is placed directly above the rat to provide background sound and stimulation. Set the light source (2500 - 3500 Lux) in the Jiu Shi Shi·% jump room. LES test by Two 2 〇 minutes (first turn off the lights, then turn on the lights), and Λ Λ 刖 5 minutes for adaptation, during which the background noise of the intensity is provided indoors. At the end of each adaptation period, 1 〇 u〇dB is provided. The stimulation makes the animal get used to it. After that, 'three trials Types are provided in pseudo-random order for each 8-person. The interval between each type of test is 15-25 seconds. The test type is 1〇〇, 1〇5 or i 1〇dB startle' provides 1〇〇, 1〇5 Or 11 〇 4 〇 (4) White ^ sang sound burst, resulting in a shocking reaction. There is no light or noise between the two periods of 5 minutes. Appropriate + rat species including male Rj: Wister (Hans) Rats (body weight 丨80_280 g at the start of the test, maximum weight range of 50 g per test) (Elevage janvier, Le Genest_Saint Isle, ~(10)). Rats should be allowed to acclimate to laboratory conditions for free access to food and water for at least 5 days after e. The environment. Adaptation conditions should be comparable to those described in the scientific literature and/or known to those skilled in the art. Spontaneous startle stimuli began recording the output of the startle platform for 4 〇 ms. Three variables were recorded for each test: average response over the entire recording period, calyx response, and peak reaction time. The mean jump of each rat was calculated by averaging 8 139 201121941 tests of each type under dark or light conditions. Strongness, and calculate the percentage increase in the amplitude (average and peak) of the startle caused by light (LES). The peak response time is a measure of reaction time. Unblinded tests were performed using, for example, 2 rats per group. The test includes multiple benefit 4 ' where each test is performed to evaluate a reference compound (e.g., sevoflurane), a comparative compound (e.g., pregabalin), and/or a compound of the present invention. For example, 'In test 1, a known anti-anxiety agent (marine and pribin) was used, followed by 丨 iiGluR5 antagonist 2-mercapto-6-(phenylethynyl)-pyridine (MpEp) Test 2 was carried out, and then the compound of the present invention was used to measure the formula 3. For each of the test words or some combinations, the tests are performed sequentially or simultaneously. For each test, one or more doses (such as 3, 10, 3, and / or 1 〇〇 mg / kg) were administered orally, and after 6 minutes, the test was compared with the vehicle control group to evaluate the compound. Scholarship test. The solubility of the test compound can be tested by cold stirring the highest predetermined dose in distilled water for 10 minutes prior to testing. If it is tolerant, ^ steam water W material. If not, the heart test compound can be suspended in steamed water containing 0.2% propylmethylcellulose (HpMC). The dose can be prepared as a weight-to-volume (W/V) stock solution and then weighed against the solution (combined: continuous dilution (V/V) or separately for the compound in the suspension for each test, using a non-paired history The Duodeng test was analyzed by comparison: each: the analysis data of the control group was analyzed by using the paired Studden's t-test to compare the darkness of the group and the intensity of the shock under the money. 140 201121941 It can be used to estimate the antidepressant effect of the compound of formula (1) in vivo.

Like the test of forced swimming test described in [J.F. Cryan Reviews 2005, 29 2005, 29, 547-569.]

MD)), adapting the mice to the environment and captivity as described above for the mice used in the mMB test. For the mouse forced swim test (mFST), 60 minutes after the injection of the vehicle or test compound, or the injection of the positive control imipramine hydrochloride (IMI; Sigma Aldrich, St. Louis, MO) 30 Thereafter, the mice were individually placed in a clean Pyrex® cylinder (11 丨 em diameter, 16 5 cm height) containing 11 cm deep tap water (2 3 - 25 ° C). C. Rice was prepared using isotonic saline and test compounds were prepared as previously described for the mMB J: test. The dose used can be as previously described for the mMB test. Measure the percentage of time spent floating, swimming and struggling ("climbing") during the minute. The swimming period is monitored by video and can be analyzed immediately using Biobserve Automated FST equipment and software (Biobserve GmbH, Bonn, Germany). The group size can range from 12 to 13 mice. The dose is measured in milligrams of drug (salt form) per kilogram of body weight. Data were analyzed using single factor ANOVA and post-hoc Dunnett's test. Anti-depressive effects can also be assessed in FST and social interaction tests using Flinders Sensitive Line 'FSL rats, eg [d.η. Overstreet and G. Griebel PAarmflco/ 厶eAav., 2005, 52 1: 223-227]. More specifically, the invention was tested at multiple doses (Example 1 such as 1 mg/kg, 3 Torr, etc.) by preparation in 20% HP-/3-cyclodextrin 141 201121941 and against vehicle control. Compound. In addition to the FSL vehicle control group, the Flinders resistant strain (FhiiderS (10)) was tested for the vehicle vehicle control group. The test compound was administered daily by intraperitoneal injection (2 mg/kg injection volume) for a day. On the 15th day, at 24 hours after the 14th day of the injection, the animals were tested in social interaction and forced swimming tests, such as

As described in Overstreet and Griebel 2005. Six to eight animals per group were tested. Anti-awareness and antidepressant effects can also be assessed using the standard for the reduction of the axis feedback (David et al., 2007, SFN meeting in San Diego). This model is based on the long-term delivery of corticosterone in drinking water, causing anxiety and depression-like behavior in mice. The model consisted of continuous administration of high dose 1 (35 pg/mL) instead of low dose (7 /ig/mL) corticosterone for 4 or 7 weeks. For example, during the 30-minute open field test (〇peil fieid test, OF), the time and frequency of entering the center of the site decreased and the total walking did not change. 'This treatment induces anxiety and depression in the C57B16/NTac mouse line. behavior. Similarly, the waiting time for eating in the corticosterone-treated mice subjected to the novelty suppression feeding (NSF) paradigm increased. Because corticosterone treatment does not alter the feeding in the living cage (familiar with the environment), the change in eating waiting is not caused by an altered appetite or an implicit metabolic abnormality. Importantly, the response of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) to acute stressors (6-minute forced swimming test (FST)) was reduced in C57BL/6NTac mice, as measured by blood loss. These results were confirmed in CD 1 strain mice. Treatment with anti-inhibitor mimethion (40 mg/kg per day, intraperitoneal) and fluoxetine (18 mg/kg per day, 142 201121941 'intraperitoneal) for 3 weeks reversal: of, nsf and FST Anxiety and depression-like effects caused by 7-week corticosteroid treatment. In this test, for example, 8 x 10 weeks old adult male mice using 240 c57B1/6 Ntac strains (Taconic Farms (Denmark)) were acclimated to the facility for at least i weeks prior to testing (eg at 22 °c) i 2 hours (06:00-18:00) 5 per cage under light and dark circulation), free access to food and water. The compounds of the invention (30 or 60 mg/kg administered daily in food) and fluoxetine (1 8 mg/kg) were administered to mice treated with vehicle or corticosterone (35 Mg/mL) via drinking water. , administered daily in drinking water) or vehicle (0.45% jS-cyclodextrin, 0CD in drinking water). After 7 weeks of treatment as described below, mice were tested in the following behavioral tests: OF, NSF, FST and sucrose splash carding tests. The treatment was continued with 3 weeks of administration of j3CD or corticosterone (35 pg/mL) via drinking water: n (n=200 mice per group). Thereafter, 0CD or corticosterone was continued, and the mice were divided into 8 groups of 30 mice each as described below for another 4 weeks.笫1-8调__ Vehicle (jSCD) Vehicle (|3CD) Vehicle (|8CD) Vehicle ()3CD) 35pg/mL corticosterone daily 35pg/mL corticosterone daily 35pg/mL corticosterone 35pg per day /mL corticosterone 篦 3-7 weeks fluoxetine, 18 mg/kg test compound, 30 mg/kg test compound '60 mg/kg vehicle fluoxetine' 1 8 mg/kg test compound, 30 mg/kg Test compound, 60 mg/kg 143 201121941 Test small in this order in the behavioral paradigm: OF, NSF, Yan sugar splash test, followed by mouse FST (15 animals per group). Open field testing at the Plexiglas® open space box 43 X 43 cm2 (MED associates,

Georgia, VT) quantified motor activity over a 10-minute period. Two sets of 16 pulse-adjusted infrared beams were placed on opposite walls at an interval of 2.5 cm to record x-y ambulatory motion. Place a 40 W white light bulb (W|iite bulb) in the middle of the room to provide approximately 200-lx illumination at the floor level. The activity room is docked to the computer for data sampling at 100 ms resolution. The computer defines grid lines that divide each open field into the middle and surrounding areas, each of the four lines being 11 cm from each wall. The accompanying measurement measures the total time spent in the middle, the number of times entering the middle and the distance moved in the middle divided by the total moving distance. The total exercise activity is quantified as the total moving distance (cm). Novel inhibition of meals? Novel Inhibition Feeding (NSF) is a conflict test that triggers competitive motivation: the power of eating and the risk of entering the middle of the illuminated field. Waiting for the start of eating is used as an indicator of anxiety-like behavior^ because traditional anxiolytics reduce this index. This was done during the 5 minute period as described in (Santare (1) et al., 2, 3, Chuan B 5 634.805-9). In short, the test was prepared by a plastic box 5〇&gt;&lt;5〇&gt;&lt;2〇(:111. The floor was covered with about 2: wood chips. 24 hours before the behavior test, removed from the cage All foods. During the test, a single bolus (ordinary feed) was placed on the white 144 201121941 paper platform in the middle of the box. The animals were placed in the corner of the labyrinth and the mouse hips were immediately seated and the chewing horse was fed by means of the front paws. When the leaves are in the mouth. Immediately after this test, the mice were transferred to ^ and the amount of food consumed in 5 minutes was measured (food consumption in the living cage = test mice in the segment. Because the antidepressant is known to have a different effect), In order to assess the dietary motility by immediately returning the animal to its living cage (familiar with the environment) after testing, the amount of food consumed during the 5 minute period is measured. The splash test is at the end of the corticosterone regimen (end of 7 weeks). Or no 3 weeks of gas; the carding waiting time is evaluated. The test consists in spraying 2 (9) μ 1 10 % of the recommended sugar solution onto the mouth of the mouse. Then the combing frequency is recorded. The mouse is forced to swim test using [Dulawa] Et al., (3)/, 2〇〇4, 2ρ, 7:1321-1330; Holick et al., "Token" test by (4) "讣, 2〇〇8, 2: 406-41 7] Modified version of the procedure. The mice were placed in a glass cylinder (height: 25 cm 'diameter: i〇cm) containing 18 cm of water maintained at 23-25 t, and a tripod directly on the side of the cylinder was used. The camera is installed for 6 minutes. Swimming and climbing are increased in rats [see for example J. F· Cryan and I. Lucki PAarwaco/. ά 77^广叩·, 2000, 2Ρ5, 3·1120-1126] and mice [see for example Dulawa et al. (2004); Holick et al., (2〇〇8 )] is related to the activation of serotonin and the activation of the accessory adrenal gland system. Therefore, the main behavior (swim, still or climbing) is scored during the last 4 145 201121941 minutes of the 6-minute test period. Use other tests to assess anti-anxiety-like properties: () [s E File and P. Seth J(10)rna/ return 2〇〇3 M3, 1-3:3 5-53] social interactions, and (2) [ s m. Korte and sF De

The elevated cross maze described in Boer European Journal of Pharm.acology, 2003, 463, 1-3: 163-175]. By measuring the sputum in the rat as described in [Ε·H. Lee et al., C7n«. «/. 尸/^ίο/., 1992, 35, 4: 3 17-3 6] Neurotoxicity is assessed for Parkinson's disease (PD). In addition, the experimentally induced striatum da consumption in animals is an effective Parkinson's disease model such as [W. Schultz iVc»g· A^wroWo/·, 1982, 7&lt;5, 2-3: 12 1-66] Said in the middle. The ability of these substances to destroy catecholamine-stimulating neurons has been widely used to produce DA deficiency in animals, such as [L. E.

Annett et al., 1994, /25, 2: 228-46]. Also, as [N. Breysse et al., J. iVeMrosc/., 2002, 22, 13: 5669-5678; D. Rylander et al., /. P/iar/Ttaco/. heart/?. Γ/ier·, 2009, 330, 1: 227-235; and L. Chen et al., "Chronic, systemic treatment with a metabotropic glutamate receptor 5 antagonist in 6-hydroxy dopamine partially lesioned rats reverses abnormal firing of dopaminergic neurons," Brain 2009,1286, PD was assessed by measuring 6-hydroxydopamine (6-OHD A ) induced neurotoxicity as described in 192-200]. A mouse model as described in [QJ Yan et al., 2005, 49, 7: 105 3-1066] can be used as in [G. D6len et al., iVewrow, 2007, 5ί5, 6: 955-962]. The mGluR5 expression was selected as 146 201121941 Selectively reduced cadaveric knockout mice to assess vulnerable X chromosome syndrome. Blocking/attenuation of symptoms associated with schizophrenia in animals can also be assessed prior to clinical use. The change in the overall activity level of dopamine (DA) can be measured in parallel with the motility activity as described in [R. DeP〇〇rtere et al., 2003, %, 11: 1889-902], such as [W · J. Freed et al, Neuropharmacology, 1984, 23, 2A: 175-81; F. Sams-Dodd Neuropsychopharmacology, 1998 19, 1: 18-25] by D-amphetamine (AMPH) And phencyclidine (PCP) evaluates positive symptoms in an animal model of schizophrenia by inducing a model of psychosis or hyperkinesia. For example, Depoortere et al., 2003, have described tests for assessing motor activity, rigidity, climbing, and repetitive motion involving positive symptoms and side effects, by describing compounds with typical and atypical antipsychotic effects. For example, [γ. K. Fung ^ A, Pharmacol. Biochem. Behav., 1986, 24, 1: 139-41 and YK Fung et al., 5/eroz.i^, 1987, 岑P, 4-5: 287 -94] evaluated apomorphine (apomoi^hine) induced climbing, repeated exercise, and attenuation of rigidity (AIC). In addition, as described in j?. Sams-Dodd, 1998, the negative symptoms of schizophrenia can be assessed by measuring social interactions under the influence of NMDA antagonists (such as PCP). This can be done, for example, in [TJ Gpuld et al., P/iarmaco/., 2002, 13, 4: 287-94 » ^ A. 〇. Hamm f A, Brain, 2003, 126, Pt 2: 267-75] The Racjiai Arm Test described in the Feai Conditioning Paradigm and [j. P Agg! eton ^ A, Behav. Brain Res., 1986, iP' 2. 1 33-46] Model 147 201121941 assesses cognitive symptoms of memory (including symptoms from Alzheimer's disease), as in [RGM Morris·Zearw. MWv., 1981, /2, 239-260; b Bontempi et al. V/· ATewr〇iSCZ· ι996, 5, ι1: 2348-60] The spatial reference memory and learning were evaluated in the Morris water maze test described. More specifically, in the Morris water maze test, fill the annular sink (150 cm diameter and 45 cm height) with about 30 cm of water and keep it at 26-28C, fleeing the platform (15 cm diameter) and perimeter. 18 cm apart and always at the same position 15 cm below the water surface. The water is opaque by the addition of non-toxic colorants such as milk powder, making the platform invisible. The animals were given a training period one day. The training period consisted of 4 consecutive water maze tests with 6 sec intervals. For each experiment, the animal was placed in a water maze at one of two starting points equidistant from the escape platform and allowed to find an escape platform. The animals stayed on the platform for 6 seconds before starting a new test. If the animal did not find the platform within 120 seconds, the animals were removed from the water and placed on the platform for 60 seconds. During the four trials, the animals were started at the water maze test at each starting point in the order in which each animal was randomly determined. Suitable animals tested under environmental adaptation conditions are, for example, males as previously described for the LES test...:

Wistar (Hans) rat. Video recordings were performed on 4 tests, and animal behavior was analyzed using a video tracking system (smart, Panlab, S.L., CornelU (Barcel〇na), Spain). The primary measure used in each trial was to find the distance the platform was moving. The secondary measures used are swimming speed and escape waiting time. A blind test was performed using, for example, 12 rats per test group. The test involves the use of a 148 201121941 multiple test S formula using the reference compound prepared and administered as described above for the LES test and the winter invention compound. For each test, the single factor AN VA and Dunnett test were used to analyze the data by comparing the treatment group to the vehicle control. In order to increase the comparability of the above-mentioned Vogel conflict test, the rats were deprived of drinking water for about 24 hours (day i) before the test; however, the test was performed in rats that were not deprived of water (2nd) day). In addition, fine by such as [M. Day

Cognition, memory, and hippocampal hypofunction were assessed by measuring the recovery of synaptic plasticity in ovariectomized (〇νχ) female rats as described in Afew·' 2005', 53, 1: 13-21. In addition, it can be obtained by [j. L. Muir et al., W. 1995, &quot;&lt;?, 1:82_92 and τ w R〇bbins et al, j(10)y Jed. Sd·' 1998, 222-37] The five items described were selected for continuous reaction time/shell. (Five (5) Choice Serial Reaction Time Test, 5CSRT) tests for changes in attention function caused by schizophrenia. &quot;T Evaluate cognitive diseases or conditions in human patients by any test within the skill of the skilled artisan. Analgesia can be assessed by a neuralgia model ("Chung model") as described in [S, H. Kim and JM Chung, pai/2, 1992, π, 3: 3 55-363] Agent activity. The tight spinal purple in the rat spinal cord is associated with hyperalgesia, allodynia, and spontaneous pain, and thus constitutes a model of peripheral neuralgia in humans. Anti-hyperalgesics reduce these chronic signs of painful allergies. Therefore, in the spinal nerve tight ligation model, anesthetized (sodium pentobarbital 50 mg/kg, intraperitoneal) rats and incision at the L4_S2 level after chlorhexidine cleaning of the flank Expose the left L5 nerve. A pure alcohol-sterilized cotton thread (standard, non-149 201121941 surgical quality) was placed around the L5 nerve and tightly tied around the .L5 nerve for simple ligation. The wound was then sutured and sprayed with c〇thiVet® (hydrocotyle tincture spray) (Ne〇gen®, Lexingt〇n, κγ). Rats received subcutaneous injection of Ciam〇xyi (〇 67 mL/kg) and allowed to recover. At least 2 weeks after surgery, when the chronic pain state was completely established, the two hind paws of the rat were continuously subjected to tactile and thermal stimulation. For tactile stimuli, place the animal in an inverted acrylic plastic box (18xll.5xl3cm) on the grid floor. Then, with the added pressure, the Von Frey probe (161〇, BI〇SEB, 〇11 to Cedex,

The tip of France) is first applied to the undamaged hind paw, then to the hind paw of the lesion, and the pressure required to induce paw retraction is automatically recorded. This procedure is performed on 3 _ people, followed by the average pressure of the heterozygous paws. For thermal stimulation, the equipment (No. 737, Ug0 BasUe, comeri〇 VA, Italy) consists of individual acrylic plastic boxes (Ηχ Η X = cm) placed on the glass floor of the raft. The rats were placed in a box and allowed to freely lick for 〇 minutes. The movable infrared radiation source (96 ± 丨〇 mW/cm2) is then first focused on the undamaged hind paws and then focused on the hind paws 纟 纟 automatically recording the paw retracting wait time. To prevent tissue damage, the heat source is automatically turned off after 45 seconds. All animals were subjected to hind paw tactile stimulation before receiving &amp; object treatment and assigned to the treatment group based on the pain response matching of the paws after injury. A blind test was performed using, for example, rats in each group that only deprived drinking water at 1 G. Suitable animals for testing are, for example, male Rj Wistar (Hans) rats as previously described for the LES test. Testing involves multiple tests using reference compounds and compounds of the invention. In addition to the Puriba 150 201121941 * Lin and MPEP as described above for the LES test, duloxetine can be used as a reference compound because it is related to neuralgia associated with diabetes and muscle fiber pain. Anti-hyperalgesic drugs. Compounds were prepared and administered as described in the LES test described above. The same batch of surgical rats can be re-tested with minimal rest between treatments for 1 week. Similarly, in order to improve the comparability of the above-mentioned Vogel conflict test, in all tests, the rats were deprived of drinking water for about 48 hours before each test. For each spinal nerve tight ligation model test, data were analyzed by comparing the treatment groups with appropriate controls using an unpaired Studden's t test. In addition, the analgesic/anti-inflammatory activity can be assessed in vivo using a Formalin Paw Test in mice, such as described in [H Wheeler_Acet〇 et al., Psychopharmacoiogy (BeH), 1991, J. 4, U35-44]. . For testing, 5% fumarin (25 μΐ) was injected into the left hind paw of the mouse. This treatment induced paws in control animals. The f-claw was counted immediately after the injection of formalin for 5 minutes (early), and it took time to count the paws 15 minutes after the injection of formalin for 5 minutes (late). Blind testing was performed using, for example, 10 rats per group. Suitable animals for testing are, for example, male Rj: NMRI mice (Elevage Janvier), weighing 20 - 30 g at the start of the test (maximum range = 5 g per experiment). Animals were adapted to the environment as described for the animals used in the LES test. Tests include multiple tests using a reference compound (e.g., morphine), a comparative compound (e.g., gabapentin and duloxetine), a compound of the invention. The compounds of the invention may be evaluated as described above in the various doses described in the LES test and are administered subcutaneously 6 weeks prior to formalin compared to the vehicle control group, while morphine (64 mg/kg, oral) Gabapentin (3〇〇151 201121941 mg/kg, oral) and duloxetine (10 mg/kg, orally) were orally administered 60 minutes before the formalin. Data were analyzed by comparing the treatment group with the vehicle control group using the unpaired Mann-Whitney U test. Multiple sclerosis can be assessed using the experimental autoimmune encephalomyelitis (ΕΑΕ) model described in [Η·Y. Liu et al. /. 夂 and., 2002, 70, 2. 238-48J. Those skilled in the art will recognize that various changes and/or modifications may be made to the various aspects and embodiments of the invention, and that such changes and/or modifications may be made without departing from the spirit of the invention. . m .7 ^ Therefore, it is expected that the accompanying patent application scope will cover all such equivalent changes, such as in the month. The spirit and scope of the present invention, the patents and patent applications in the present application (including the literature reference, the book is cited in full text and in this article. [Simplified illustration] No [main Component symbol description] No 152

Claims (1)

201121941 ' VII. Patent application scope: 1. A compound of formula (I), Wherein: R1 and R2 are each independently an aryl group, a heteroaryl group, an alkyl group, a cycloalkyl group, a ketocycloalkyl group, a heterocyclic group, a fluorenyl group, or an alkoxy group, which are optionally independently subjected to the following Substituted, disubstituted or trisubstituted: alkyl, halo, hydroxy, cyano, amine, alkylamino, diasteryl amine, aryl, aryl, heteroaryl, heterocyclyl, cycloalkyl, Alkoxy; and L is -CO-N(X)_, -NH-C(0)-N(Y)-, -(W)NC(〇)〇_, -〇C(0)N(Z ---NHS〇2_, _NH_, _heteroaryl or a bond; wherein: X is hydrogen' or is attached to R2 and is attached to form a heterocyclic bond; or is attached to R and attached thereto Y which forms a heterocyclic ring or which is bonded to R2 and forms a heterocyclic ring with N to which it is attached is hydrogen, a bond; W is hydrogen, a bond; and = hydrogen or a bond ... is formed by the connection thereof 4 of the pharmaceutically acceptable salts of the heterocyclic ring. 2. The compound of claim 1, wherein R, R2 153 201121941 aryl. 3. A compound according to claim 1 wherein R1 is heteroaryl and R2 is aryl. 4. A compound as claimed in claim 1 wherein R1 and R2 are each X heteroaryl. 5. A compound as claimed in claim 1, wherein R1 or R2 is a heteroaryl group. 6. The compound of claim 1, wherein R1 is heteroaryl and R2 is heterocyclyl. 7. The compound of claim 1, wherein R1 is aryl and R2 is alkyl. 8. The compound of claim 1, wherein R1 is heteroaryl and R2 is cycloalkyl. 9. A compound as claimed in claim 1 wherein L is -CO-N(X)-. 10. The compound of claim 1, wherein L is -NH-C(0)-N(Y)-. 11. A compound as claimed in claim 1 wherein L is -(W)N-C(0)0-. 12. A compound as claimed in claim 1 wherein L is -0C(0)N(Z)-. 13. A compound as claimed in claim 1 wherein L is -nhso2-. 14. A compound as claimed in claim 1 wherein L is -NH-. 154 201121941 15. The compound of claim 3, wherein L is a heteroaryl group. 16. The compound of claim 3, wherein L is a bond. 17. The compound of claim 3, wherein the compound is ··· 6-methyl·•pyridine_2_carboxylic acid [3-(2-hydroxyphenylaminemethanyl)-adamantane b-based]- Indoleamine; 6-methyl-n-pyridin-2-carboxylic acid (3-isopropylamine-methyl-adamantane-indole-yl) decylamine; 6-methyl-pyridine-2-decanoic acid [3- (2-Sideoxy-propylaminoindenyl)-adamantyl]-bristamine, y •i 6-methyl-pyridine-2-carboxylic acid (3-methylaminoindenyl-adamantane_i -yl)-nonylamine; 6-methyl-pyridine-2-decanoic acid (3. Aminyl-adamantan-1-yl)-guanamine; 6-methyl-pyridine-2-decanoic acid [3_ (2-hydroxy-2-phenyl-ethylamine decyl)-adamantan-1-yl]-nonylamine; pyridine-2rcarboxylic acid [3-(3-nitro-phenylaminecarbamyl)_ Astragalus-1·yl]-bristamine; outer sputum -2-decanoic acid [3-(3-chloro-phenylaminoindenyl)-adamantan-1-yl]-nonylamine; pyridin-2- Formic acid [3_(6_曱 比 咬 咬 胺 ) ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -1-yl]-nonylamine; mouth ratio % -ζ - Ί &gt; σcarboxylic acid (3-cyclohexylamine oxime-adamantan-1-yl)-guanamine ; t&gt;tb a/t~z' 1 &lt;7&lt;7&gt;[3-(3-carbyl-cyclohexane-1-carbonyl)-adamantane-buki l·U ratio bite-Z - T 醯Amine; 匕-匕甲匕 bite-2-carboxylic acid [3-(pyridin-2-aminoamine)-adamantan-1-yl]-guanamine; acid [3-(benzo-pyrene) Salin-2-aminoguanidino)-adamantan-1-yl]-guanamine; 155 201121941 Pyridine-2-carboxylic acid [3_(4-mercapto-thiazol-2-ylamine_醯-fundane_丨_ ] - ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; And imidazolium 2_ylamine-methyl fluorenyl) ruthenium _ 1 -yl]-decylamine; pyridine-2-carboxylic acid [3_(quinolin-3-ylaminoindolyl)-adamantyl]-guanamine ; ratio. 疋-2-carboxylic acid [3-(4,5-dimercapto-thiazolaminecarboxylidene)-adamantane"-yl]-nonylamine; bis--2-decanoic acid [3-(2- Hydroxy-2-mercapto-propylamine-mercapto)-adamantane-buyl]-guanamine; bismuth citrate [3·(3,3-difluoro-cyclobutylaminocarbamyl)-King Kong Alkyl-1-yl]-decylamine; (3-gas-acidylmethylamino)-amkron _ 1 -decanoic acid (3 _ phenyl-phenyl) amide; Amino group)_ Diamond _ 1 - bismuth citrate. _2 _ acid amide; 3 '(3- gas - benzhydrylamino) _ adamantane-1- decanoic acid (6 曱 比 比 _2 _ _ _ )-decylamine; 'methyl-pyridine-2-formic acid (3-didecylaminecarboxamyl-adamantane-i-yl)-decylamine; 6-methyl-pyridine-2-carboxylic acid [3-( (R)-3-fluoropyrrolidine-1-carbonyl)-adamantan-1-yl]-bristamine; % bite '2_carboxylic acid [3-((R)-fluoro-pyrrolidine-1-carbonyl) -adamantan-1-yl]-nonylamine; 6-methyl-pyridine-2-hydric acid [3-(4-hydroxy-piperidin-ί-carbonyl)-adamantan-1-yl]-guanamine; 156 201121941 Zun, 6-mercapto"pyridin-2-decanoic acid [3-(norfosin-4-carbonyl)-recamantyl-1-yl]-nonylamine; pyridin-2-furoic acid [3- (ofofolin-4-carbonyl)-adamantan-1-yl]-guanamine; pyridine-2-decanoic acid [3-(piperidin-1-carbonyl)-adamantan-1-yl]-guanamine; Pyridine-2-furic acid [3-(pyrrolidin-1-carbonyl)-adamantan-1-yl]-guanamine; 2-mercapto-pyrimidine-4-decanoic acid [3-(3-propyl-urea) (n-)-adamantan-1-yl]-nonanamine; 6-mercapto-indol-2-carboxylic acid [3-(3-propyl-ureido)-adamantan-1-yl]-nonanamine; -(3-{3-[(6 - fluorenyl-. Ratio of -2 - terminal group - amino group - - 金刚院 - 1 - base} - glandyl) ethyl hexanoate; 6-fluorenyl-pyridine-2-carboxylic acid [3-(3-ethyl- Ureido)-adamantan-1-yl]-guanamine; 6-mercapto-pyridine-2-carboxylic acid [3-(3-propyl-ureido)-adamantan-1-yl]-nonanamine; - mercapto-acridine-2-carboxylic acid [3-(3-butyl-ureido)-adamantan-1-yl]-guanamine; ° ratio °-2-carboxylic acid [3-(3-phenyl) - 脉基)-Astragalo-1 -yl]-bristamine, ° ratio σ -2丨; decanoic acid [3 - (3-propyl-glycosyl)-amostane-1 -yl]-bristamine, Pyridine-2-furic acid [3-(3-cyclopropyl-ureido)-adamantan-1-yl]-guanamine; Bis-pyridine-2-carboxylic acid [3-(3-butyl-ureido)-adamantan-1-yl]-nonanamine; phenylephrine-4 -decanoic acid {3 - [(sigma-precipitate-2 - carbon) ))-amino]-amostane-1 -yl}-acid amine; pyridin-2-furoic acid {3-[(piperidin-1-carbonyl)-amino]-adamantane-l-yl}-醯Amine; ° ratio σ--2 - decanoic acid {3 - [( ° 洛洛定定-1 - prison)-amino]-amostane-1 -yl}•------- -曱基- σΛ°^-2-enyl)-amino]-金刚院- l-yl}-amino phthalic acid 2-(2-light-ethoxy)-ethylidene; {3- [(6-曱基-°比定定-2- prison)-Amino]-Astracia-l-yl}-Aminoformic acid 157 201121941 3.3.3-Trifluoro-propyl ester; {3-[( 6 - fluorenyl-° ratio. -2 -numberyl)-amino]-adamantan-1-yl}•-amino phthalic acid 3-fluoro-propyl ester; {3-[(6-fluorenyl- Pyridine-2-carbonyl)-amino]-adamantane-buki}-aminocarboxylic acid 4.4.4-trifluoro-butyl ester; {3-[(6-fluorenyl-fluorenyl-and-number)- Amino]--amostane-1-yl}-aminocarboxylic acid 2.2.2-trifluoro-ethyl ester; ': {3-[(6-methyl-π ratio ° -1 -yl)-amino group ]--Adamant-1-yl}-carbamic acid 2-(2-methoxy-ethoxy)-ethyl ester; {3-[(6-decylpyridin-2-carbonyl) )-Amino]-adamantane-l-yl}-amino phthalic acid 3-*, phenylephrine-4-yl-propion S, {3-[(6-methyl-acridin-2-carbonyl) -amino]-adamantane-l-yl}-aminocarbamic acid cyclopropyl decyl ester; {3-[(6-fluorenyl-[rho]-but-2-yl)-amino]-embroidal- L-yl}-aminocarboxylic acid 2.2-difluoro-propyl ester; {3·[(6-fluorenyl-° ratio ̄-2-phenyl)-amino]-amostane-l-yl}-amine 2-carboxylic acid 2-hydroxy-ethyl ester; {3-[(6-fluorenyl-acridin-2-carbonyl)-amino]-adamantan-1-yl}-amino decanoic acid 3-a-propyl- , {3-[(6-methyl-. ̄ ̄ ̄-2-yl)-amino]-amostane-l-yl}-aminocarboxylic acid 2_ methoxy-ethyl ester; {3-[( 6-methyl ratio σ determinin-2-rebase)-amino group]-amkron- l-yl}-amino decanoic acid hexamene; [3-[(σΛσ定-2-mineyl)-amino group] -amostane-l-yl}-carbamic acid 2,2,2-di 158 201121941 / - fluoro-ethyl ester; 6-methyl-pyridine-2_carboxylic acid [3-(2-sideoxy-[1 , 3] oxazacyclohexane 3 konjam _ 1 -yl]-bristamine; a) ° ratio ° -2 - formic acid (3-benzenesulfonamide adamant-1-yl)-guanamine; Ethyl-aminocarbamic acid 3-[(pyridin-2-carbonyl)-amino]-adamantyl; 6 -methyl-pyridin-2-carboxylic acid [3-(pyridin-2-ylamino)-adamantane-yl]-bristamine; 吼唆-2-carboxylic acid {3_[(pyridin-2-ylmethyl) _Amino]-adamantane-fluorenyl}_bristamine; V pyridine-2-decanoic acid (3-benzylamino-adamantan-1-yl)-guanamine; pyridine-2-decanoic acid [3_ (5-Chloro-1 ugly-benzimidazol-2-yl)-adamantan-1-ylguanamine; 6-fluorenyl-° ratio. Benzene-2-carboxylic acid (3-benzoindole-2-yl-diamond-1-yl)-guanamine; 6-fluorenyl-pyridine-2-decanoic acid 0 (1//-benzimidazole-2 -yl)-adamantane-^glycidylamine; 6-mercapto-D ratio bite-2-carboxylic acid [3-(6-11-1//-benzo-°°° sitting-2-yl)-King Kong烧基]-nonylamine; 6-mercapto ratio bite_2_formic acid Ρ-Οβ-mi- 0 sitting and [4,5_b] ° bite -2_ base)-amostane-1 -yl]-guanamine; 6-fluorenyl-acridine_2_decanoic acid [3-(3//-imidazo[4,5-c]pyridine-2-yl)-adamantan-1 -yl]-nonylamine; 6-oxime Base-pyridyl. _2·carboxylic acid [3-(3-mercapto-3//-imidazo[4,5-b]pyridine-2-yl)-adamantan-1-yl]-nonanamine; 6-fluorenyl-pyridyl Bite_2_carboxylic acid [3T(4-mercapto-1//-imidazol-2-yl)-adamantane 159 201121941 base]-nonylamine; 6-methyl-0 to 0-but-2-decanoic acid [3 -(1,3-di-rho-iso- 0-indol-2-yl)-adamantine-1 _yl]-nonylamine; 6-mercaptopyridin-2-carboxylic acid [3-(3-sideoxy) -1,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantel-1 -yl]-bristamine, 2-mercapto-pyrimidine-4-decanoic acid [3 -(3-Sideoxy-1,3-dihydro-.pyrolo[3,4-c]pyridin-2-yl)-amostane-1 -yl]-bristamine, 5-fluororho Pyridin-2-decanoic acid [3-(3-o-oxy-1,3-dihydro-pyrrolo[3,4-c]acridin-2-yl)-adamantan-1-yl]-guanamine ; 4-mercapto-pyrimidine-2-carboxylic acid [3-(3-sideoxy-1,3-dihydro-.pyrolo[3,4-c].pyr.-2-yl)-King Kong -1 -yl]-bristamine, 4-fluoropyridin-2-carboxylic acid [3-(3-o-oxy-1,3-dihydro-pyrrolo[3,4-c]. -yl)-adamantan-1-yl]-guanamine; W-[3-(3-o-oxy-1,3-dihydropyrolo[3,4-c].pyridin-2-yl )-adamantan-1 -yl]-in the amine, 5-fluoropyridin-2-carboxylic acid [3-(5-side) 5-,7-di-ar-ar-pyrrolo[3,4-b]pyridin-6-yl)-adamantan-1-yl]-guanamine; 2-mercapto-pyrimidine-4-carboxylic acid [3-( 5-sided oxy-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-adamantan-1-yl]-decylamine; N-[3-(5-side oxygen) -5,7-di-ar-pyrrolo[3,4-b]pyridin-6-yl)-adamantan-1 -yl]-in the amine, Isoazole-5-carboxylic acid [3-(5 -Sideoxy-5,7-dihydropyrrolo[3,4-b]acridin-6-yl)-amylone-1 -yl]-S leucine, thiazole-2-decanoic acid [3-( 5-sided oxy-5,7-dihydro-&gt;1 pyrrolo[3,4-13]° pyridine-6-160 201121941 j 'yl)-adamantan-1-yl]-guanamine; 2-methyl-thiazole-4-carboxylic acid [3-(5-sided oxy-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-adamond-1 - Alkylamine, 6-mercapto-pyridine-2-carboxylic acid [3-(5-o-oxy-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl) -amostrum-1 -yl]-bristamine, 2-mercapto-pyrimidine_4_decanoic acid [3-(7-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridinium定-6-yl)-amostane-1 -yl]-acid amine, 2-mercapto-pyrimidine-4-carboxylic acid [3-(2-mercapto-5-sideoxy-5,7-di-argon) - 吼 并 [3,4-b]0 than sigma-6-yl)-diamond--1-yl]-bristamine 6-mercapto-acrididine-2-decanoic acid [3-(2-mercapto-5-sideoxy-5,7-diaza-pyrrolo[3,4 - b] ° ratio -6 - Base)·Astragalus-1 -yl]-bristamine, 5-disorder-吼°定-2 -capric acid [3 - (2-indolyl-5-sideoxy-5,7-dual-to-mouse ratio) Slightly [3,4-b]pyridin-6-yl)-adamantan-1-yl]-nonanamine; σ 定 曱 曱 曱 曱 [3-(1-side oxy-1,3 -di-rho-iso-l-yl)-diamond-1 _ yl]-decylamine; pyridine-2-decanoic acid [3-(5,7-di-oxy-5,7-dihydro-indolo[3,4-1)]pyrazine-6-yl)-adamantan-1-yl]-guanamine; 6-mercapto-acridine-2-carboxylic acid [3-(5-phenyl-[1,3,4]oxadiazol-2-yl)-adamantan-1 -yl]-bristamine, 6-oxime Base-pyridine-2-carboxylic acid {3-[5-(4-decyloxy-phenyl)-[1,3,4]-doxazol-2-yl]-adamangan-1-yl}-acid&gt Amine, 6-fluorenyl-pyridine-2-carboxylic acid {3-[5-(3-indolyloxy-phenyl)-[1,3,4]-doxazol-2-yl]-adamond-1 - 丨--bristamine, 6-mercapto-acridine-2-decanoic acid {3-[5-(3-a-phenyl)-[1,3,4]oxadiazol-2-yl]- 161 201121941 Astragalus-1 -yl} - s basket amine, 6-methyl-pyridine-2-carboxylic acid {3-[5-(4-carbo-phenyl)-[1,3,4]-diazole- 2-Based]-Golden Cyclosyl-1 -1 -yl}-Arylamine, 6-mercaptopyridin-2-indole {3-[5-(4-fluoro-phenyl)-[1,3,4] Oxazol-2-yl]-adamantan-1 -yl}-acid amine, 6-fluorenyl-. Bipyridine-2-decanoic acid {3-[5-(3-fluoro-phenyl)-[1,3,4]diazol-2-yl]-adamantane-l-yl}-decylamine; 6 - mercapto-pyridine-2-decanoic acid [3-(5-pyridin-2-yl-[1,3,4]oxadiazol-2-yl)-adamantan-1-yl]-bristamine, 6 - mercaptopyridin-2-carboxylic acid [3-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-adamantan-1-yl]-bristamine, 6- Methyl-pyridine-2-decanoic acid [3-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-Gyenbranches &gt; -1 -yl]-bristamine, 6-mercapto-pyridin-2-decanoic acid [3-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-adamantan-1 -yl]-bristamine , 6-mercapto-pyridin-2-decanoic acid [3-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-amostane _ 1_yl]- Amine, 6-mercapto-pyridin-2-yl phthalate [3-(5.pyridine_2-yl-[I,3,4]oxadiazole-2-yl)-adamantan-1-yl]- Amine, pyridine-2-decanoic acid [3-(5-pyridin-3-yl-[1,3,4]-doxazol-2-yl)-adamantan-1-yl]-nonanamine; pyridine- 2-carboxylic acid [3-(5-pyridin-2-yl-[1,3,4]oxadiazol-2-yl)-adamantan-1-yl]-nonylamine; pyridin-2-decanoic acid [ 3-(5-pyridine-3-yl-[I,3,4]-diazol-2-yl)-adamantane-1- 162 201121941 Λ '·: yl]-nonylamine; 2_mercapto -pyrimidine_4_decanoic acid [3-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-adamonda-1 -1 -yl]-acid amine, pyridine-2 - citric acid {3-[5-(6-fluorenyl-pyridin-3-yl Hl,3,4]oxadiazol-2-yl]-adamantane-l-yl}-nonylamine; 2-indenyl -pyrimidine-4-decanoic acid {3-[5-(6-methyl-pyridin-3-yl)-[1,3,4] employed dioxo-2-yl]-amostane-1 -yl}- Indoleamine; 6-mercapto-acridin-2-indole {3-[5-(6-fluorenyl-acridin-3-ylindole 1,3,4]indenyl-2-yl]-gold -1 -yl}-decylamine; hydrazine; 6-mercapto-pyrazine-2-decanoic acid {3:[5-(6-fluorenyl-acridin-3-yl)-[1,3,4腭二.. Base-2 -yl]-Adamant-1 -yl}-bristamine, pyridine_2_decanoic acid {3-[5-(5-fluorenyl-pyridin-3-yl)-[1, 3,4]oxadiazole-2-yl]-adamantan-1-yl}-decylamine; 2-methyl, -pyrimidine-4-decanoic acid {3-[5-(5-methyl-pyridine- 3-yl)-[1,3,4]diazol-2-yl]-adamantane-l-yl}-decylamine; pyridin-2-furoic acid {3-[5-(6-trifluoromethyl) base-. Bispin-3-yl)-[1,3,4]diazol-2-yl]-adamantan-1-yl}-oxime; amine; 2-methyl-pyrimidine-4-decanoic acid {3- [5-(6-Trifluoromethylpyridin-3-yl)-[1,3,4] oxadiazol-2-yl]-adamantane-l-yl}-decylamine; 6-fluorenyl- Pyridine-2-furoic acid {3-[5-(6-ethyl-pyridin-3-yl)-[1,3,4]-doxazol-2-yl]-adamantane-l-yl}-醯Amine; 2-mercapto-pyrimidine-4-decanoic acid {3-[5-(6-ethyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-adamantane -1- cis decylamine; 5-fluoro-pyridin-2-decanoic acid {3-[5-(6-methyl-acridin-3-yl)-[1,3,4] octazolium 163 201121941 -2 -yl]-amostane-l-yl}-decylamine; pyridin-2-decanoic acid {3-[5-(6-fluorenyl-acridin-3-yl)-[1,3,4 Diazol-2·yl]-adamantane-l-yl}-decylamine; : pyrimidine-4-carboxylic acid {3-[5-(6-fluorenyl-acridin-3-yl)-[1, 3,4]oxadiazol-2-yl]-adamantane-l-yl}-decylamine; 2-mercapto-pyrimidine-4-decanoic acid {3-[3-(3-fluoro-phenyl)- [1,2,4]oxadiazol-5-yl]-adamantan-1-yl}-decylamine; &gt; 2-methyl-pyrimidine-4-decanoic acid [3-(3-pyridine-3- -[1,2,4]oxadiazol-5-yl)-amostane-1 -yl]-bristamine, pyridin-2_decanoic acid [3_(3_pyridine·3_yl-[1, 2,4]oxadiazole-5_ (6-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl) )--Astragalo-1 -yl]-bristamine, 6-mercapto-pyridine-2-carboxylic acid {3-[3-(6-methylpyridin-3-yl)-[1,2,4] Diazol-5-yl]adamantane-l-yl}-decylamine; 2-mercapto-pyrimidine-4-carboxylic acid {3-[3-(6-methylpyridin-3-yl)-[1, 2,4]Diazol-5-yl]-adamantane-l-yl}-decylamine; pyridin-2-furoic acid {3-[3-(6-fluorenyl-pyridin-3-yl:j- [l,2,4]oxadiazol-5-yl]-adamantane-l-yl}-decylamine; pyrimidine-4-carboxylic acid {3-[3-(6-fluorenyl-acridin-3-yl) )-[1,2,4]Diazol-5-yl]-adamantan-1-yl}-nonylamine; pyridinium-2-decanoic acid {3-[3-(6·曱 比 比 _) 3_Base H1,2,4]Diazol-5-yl]-adamantane-l-yl}-guanamine; 6-methyl-pyridine-2-decanoic acid {3-[3-(6- Mercapto-pyridin-3-yl)-1,2,4-oxadiazole 164 201121941 丨' '-5-yl]-Kinggang Xuan-1 -yl}-bristamine; 5-fluoro-pyridine-2-carboxylic acid {3-[3-(6-Mercapto-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-amostane-1_yl}-bristamine; 6-methyl -pyridine-2-carboxylic acid {3-[5-(3-chloro-phenyl) oxazol-2-yl]-adamantan-1 -yl}-bristamine, 6-mercapto-purine -2-decanoic acid (3-benzenesulfonylamino-adamantan-1-yl)-guanamine; 6-mercapto-indole-2-decanoic acid (3-benzenesulfonylamino-adamantan-1 -yl)-guanamine; Ding-2-carboxylic acid [3_(2-failed-phenylindoleamine)-Golden &lt;-1-yl]-nonylamine; Specific bite _2_carboxylic acid [3-(3-fluoro-benzene continudyl)-adamantan-1-yl]-bristamine; π ratio bite_2_carboxylic acid [3-(4- gas-benzene) Amino)-amostane-1-yl]-bristamine; ° than bite-2 - formic acid (3_ vermiculite amino- _ _ _ _ _ _ base) _ guanamine; 0 ratio. -2 - formic acid (3 - ethyl hydrazide - konjam * - 1 - yl) - guanamine; ° ratio of α - 2 - formic acid (3 - cyclopropyl f 醢 醢 - - - _ base) _ guanamine; 11 than bite-2.-formic acid (3_cyclobutylsulfonylamino- _ _ _ 1_ base) _ guanamine; 〇 than bite-2-carboxylic acid [3_ (four 氲 _ α Desulfuryl amidino) _ acetonide-1-yl]-acid amine; Specific bite _ 2 - formic acid [3 _ (° ratio ° _ 2 - continued hydrazine group) _ diamond just _ 1 _ base] - guanamine; 0 than bite-2-carboxylic acid [3_ (° ratio bite -3- Renewed amine base)_金刚炫*_1_基]-decylamine; Than bite-2 - formic acid [3- (° ratio α _ 4 醯 醯 amino) _ _ _ 1 - yl] - tyrosine; 0 than α -2 - - 曱 [ [3_ (° 塞 ° sitting _ 2--, continued indoleamine)_金刚院_1-yl]-decylamine; ethyl-amino phthalic acid 3-[(6-fluorenyl-α-bit-2-yl)-amino]- Adamyryl-1-yl ester; ethyl-amino phthalic acid 3-[(6-fluorenyl tillyl-2-carbonyl)-amino]-adamantan-1-yl 165 201121941 cyclopropyl-aminocarboxylic acid 3-[(6-fluorenyl-pyridine-2-carbonyl)-amino]-adamantan-1-yl ester; azetidine-1-carboxylic acid 3-[(6-fluorenyl-pyridine J-carbonyl) )-amino]-adamantane Λ-l-yl ester; piperidine-1-carboxylic acid 3-[(6-fluorenyl-.pyridin-2-carbonyl)-amino]-adamantan-1-yl ester ; TMFolin-4-decanoic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-1-yl ester; 4-mercapto-piperidin-1-carboxylic acid 3- [(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-1 -yl S, !( 6-fluorenyl-pyridine-2-carboxylic acid [3-(cyclohexylfluorenyl-knee) --adamantan-1-yl]-nonylamine; 6-fluorenyl-acridine-2-carboxylic acid [3-(cyclopentyldecyl-amino)-adamantan-1-yl]-nonanamine; -methyl-pyridine-2-decanoic acid [3-(cyclobutylindenyl-amino)- Cycloalkyl-1-yl]-nonylamine; 6-methyl-pyridine-2-carboxylic acid (3-benzylmethylamino-adamantan-1-yl)-guanamine; 6-methyl-pyridine-2- [3-(2-Fluoro-phenylhydrazino)-adamantan-1-yl]-nonanyl phthalate; 6-fluorenyl ratio 曱-2-decanoic acid [3-(3- gas-benzoquinone) Amino group]-amostane-1 -yl]-bristamine; 6-methyl-° ratio biting-2-decanoic acid [3-(4- s-phenylhydrazino)-adamanium-1 -yl ]-acid amine; 6-mercapto-acridin-2-decanoic acid [3-(thiazol-2-ylamino)-adamantan-1-yl]-醯166 201121941 丨' Λ amine; 6-methyl -pyridine-2-carboxylic acid (3-isobutylamine adamantane-yl)-decylamine; 6-methyl-pyridine-2-carboxylic acid (3-propylamine, adamantane-yl)·醯Amine; 6_mercaptopyralic acid {3_[(tetrahydro-l-amyl-4-ylmethyl)-amine-based gold-l-yl}-bristamine; or 6-fluorenyl-pyridine-2- Formic acid [3_(tetrahydro-pyran-4-ylamino)-adamantane; or a pharmaceutically acceptable salt thereof. 8 - a certain composition comprising at least one patent application scope A compound of item 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 19. A method of treating a disease or condition, comprising administering to a mammal in need thereof a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein The disease or condition is a central nervous system disease or condition. And 20. The method of claim 19, wherein the mammal is a human. 21. The method of claim 19, wherein the central nervous system disease or condition is a cognitive, neurodegenerative, psychiatric or neurological disease or condition. 22. The method of claim 21, wherein the cognitive or neurodegenerative disease or disorder is selected from the group consisting of: an emotional disorder, anxiety, schizophrenia, Alzheimer's disease ( Alzheimer, s disease), Parkinsen's disease, multiple sclerosis 167 201121941, Huntington's chorea, amyotrophic lateral sclerosis, gram-Asian disease (Creutzfeld-Jakob disease), trauma-induced neurodegeneration, AIDS-induced brain lesions, non-AIDS-induced brain lesions, Fragile X syndr〇me, autism spectrum disorder, And their combinations. 23. A method of treating a lunar esophageal reflux, the method comprising administering to a mammal in need thereof a treatment of at least one of the right sacred county + E, a political one, such as a compound of claim 1 or a pharmaceutically acceptable compound thereof Tooth. 24. A treatment of alcohol dependence: Hu ^ Wan Wan, the method comprises administering to the right mammal a therapeutically effective amount, a compound of the desired substance or a medicinal aunt thereof, as claimed in the patent application. Accept the salt. Eight, schema · None 168