TW201113280A - Aminoalkamides for use in the treatment of inflammatory, degenerative or demyelinating diseases of the CNS - Google Patents

Abstract

An aminoalkamide of the formula I for use as a medicament to treat inflammatory, degenerative or demyelinating diseases of the CNS in a subject in need thereof.

Description

201113280 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to amine-based guanamines for the treatment of diseases of the middle nervous system (CNS), such as inflammatory diseases of the CNS, demyelination Disease or degenerative disease. [Prior Art] Skull sclerosis (MS) is an autoimmune disease of the central nervous system. The pathology of MS is characterized by white matter lesions of inflammation, demyelination of the lesion, scar formation, and axonal damage in the brain and ridge ride. Initially, most patients experience a relapsing-remitting disease process, which then typically shifts to an ongoing process, i.e., secondary progressive MS. In some patients, there is no recurrence phase and the disease is progressive from the onset (primary progressive Ms). The cause of MS remains to be resolved, but = is responsible for the interaction of genetic factors with unidentified environmental factors. Due to the lack of measurable triggers, the most important diagnostic criteria are the magnetic resonance imaging to illustrate the dissemination of demyelinated CNS lesions in time and space. The pathological hallmark of Ms is myelin destruction and axonal degeneration driven by both T lymphocytes and antibodies. Because the etiology of Ms is unknown and lacks the identified factors that cause disease invasion, current therapies are only partially effective in reducing disease activity and MS is therefore still a disease with a large number of unmet medical needs. The pathogenesis of MS has been considered as an immune-mediated disorder for many years, with intermittent disease symptoms and inflammatory damage in the CNS white matter and subsequent demyelination. However, recent research has expanded the understanding of the pathogenesis of MS and especially neuropathology, which has led to the weakness of the progress that can be observed in MS patients despite the use of novel anti-inflammatory or immune-free treatments. The new 5 endurance. Therefore, it is now recognized that the MS disease process is more related to the diffuse changes in white matter and gray matter. Therefore, MS is currently considered not only as an immune disorder, but also as a neurodegenerative disease with progressive neuronal damage and CNS tissue atrophy. In addition, the progressive neurological damage observed in (iv) is considered to be the result of the neurodegenerative process and consequent cumulative axonal loss and neuronal damage (for a review of MS neurobiology, see HaUSer SL and 0ksenberg JR ( 2〇〇6) 52(1): 61-76). Tian's disease-modifying drugs for the treatment of MS include interferon cold, glatiramer acetate 'natalizumab (sperm (four) 讣) and mitoxantrone (mit〇xantrone). These therapies reduce the frequency and number of clinical relapses' to reduce disease activity as measured by the number of new lesions present on brain MRI, and may have the potential to slow long-term progression. However, these disease palliative therapies have only partial therapeutic effects and are also associated with a number of undesirable side effects (Gonsette RE (2〇〇7) Εχρ 〇pin

Pharmac0ther 8(8): 1103_16; Leary SM and Th〇mps〇n AJ (2005) CNS Drugs 19(5): 369-76; Wiendl H f Λ, (2008) J Neurol 255(10): 1449-63 ) . In summary, recent research has highlighted the existence of a neurodegenerative process in Ms that is unresponsive to immunosuppressive therapy and is ineffective for progressive nerve damage. There is therefore evidence that the development of novel neuroprotective drugs designed to interfere with ongoing neurodegeneration, or regenerative therapies aimed at repairing myelin or nerve function, can provide MS patients with a reduction in symptoms and a profound effect on the disease 201113280

The benefits of the latent process of the load. In addition, these treatment strategies can also be demonstrated to manage other neurodegenerative diseases such as ischemia or stroke, Parkins〇nis disease, Alzheimer's disease, CNS injury, etc. It has great value. It has previously been reported that aminoalkamide Esaprazol has anti-ulcer activity and inhibits gastric acid secretion (Scuri et al., (1984) Boll Chim Farm 123(9): 425-38; Biandizzi C et al. (1992). Digestion 51(4): 226-32: Luzzani F et al. (1989)

Drugs Exp Clin Res 15(9): 417-20). However, up to now, esarelatone or related aminoalkanamides have not been shown to have the neurotrophic and neuroprotective properties stated herein. U.S. Patent No. 4,123,530 and German Patent No. 27 02 537 disclose the anti-secretion and anti-cancer activity of I cyclohexyl-pelphantylamine and propiamine. A compound called cyclosporin-l-beta-dextrinylacetamide, also known as acesulfazol and Hexaprazol, is included in the mouth. U.S. Patent 4,278,796 discloses that a piperidine derivative or homologue has anti-cance and anti-cancer activity. U.S. Patent 4,495,186 and German Patent No. 33 10 584 disclose organometallic complexes of cyclohexyl-pipetosylamine or propylamine and their use as a buffer for anti-secretion. WO 9405648 discloses diaryl piperazine compounds as anti-drug agents for the treatment of a variety of indications (such as Parkinson's syndrome, motion sickness) and for inhibition of gastric acid secretion. WO 98/57643 discloses iV-substituted piperidylamine compounds as a nuclear* 201113280 transport inhibitor for the treatment of warm-blooded animals suffering from chronic pain conditions such as neuralgia, inflammatory pain and cancer pain. WO 02/066446 discloses heterocyclic substituted carbonyl derivatives and their use as dopamine D3 receptor ligands for the treatment of CNS disorders such as psychosis, substance dependence, substance overdose, cancer, anxiety, sleep disorders 'circadian rhythm , affective disorder and dyskinesias such as Parkins〇n, s disease, Parkinsonism, neuroleptic-induced delayed movement, Gilles de la Tourette syndrome and Huntington's disease (Huntington's disease). EP 0 5 82 1 64 discloses diphenyl groups. evil. sit,. Stopping and vomiting. Meter. One of the series 1-° bottom basal-7V-phenylacetamide derivatives is a novel adenosine transport inhibitor, which is a CNS tissue, specifically a neuron, providing effective protection against ischemic protection. There is still an unmet medical need for a safe and effective treatment modality for the treatment of inflammatory, degenerative or demyelinating diseases of the CNS, such as multiple sclerosis. In addition, there is a large unmet need for intervention in neurodegenerative components dedicated to these types of CNS diseases. OBJECT OF THE INVENTION One object of a specific embodiment of the present invention is to provide a compound for use as a medical treatment for an inflammatory disease, a degenerative disease or a demyelinating disease of a CNS having a therapeutic need. Another object of a particular embodiment of the invention is to provide novel compounds suitable for the treatment of inflammatory, degenerative or demyelinating diseases of the CNS. Another object of a specific embodiment of the present invention is to provide a pharmaceutical composition comprising the compound of the present invention as an active ingredient. 6 201113280 Another object of a specific embodiment of the present invention is to provide a compound of the present invention for use in therapy. Another object of the present invention is to provide a pharmaceutical composition comprising a <! compound as an active ingredient and at least another active ingredient. Further, another object of the present invention is to provide an inflammatory disease, a degenerative disease or a demyelinating disease for treating a H CNS having a therapeutic need. The present inventors have found certain aminoalkylguanamines. It can reduce the clinical symptoms associated with chronic inflammation in chronic relapsing experimental autoimmune brain radiance (EAE, a well-known animal model of MS). It has been surprisingly found that the amine guanamines of the present invention can reduce the severity of the disease and delay the onset of chronic diseases when administered to mice after induction of EAE. In addition, the treatment of (iv) iso-amino (tetra)amines can also reduce the number of neurons that degenerate after CNS nerve damage in rats induced by total forebrain ischemia (a well-known animal model of stroke/ischemia). In addition, it has been observed that these aminoalkanamides have neuroprotective f in the cultured cortical nerve it undergoes cytotoxic damage, and can even be induced by inducing the growth of new neurites in the cortical nerve 7〇. Neurotrophic factor +. Due to the observed cytoprotective and regenerative potential, it is considered that these amine (tetra)amines will actually be able to be in other animal models of demyelin, neuroinflammation, neurodegeneration, CNS nerve damage, typhoid or ischemia. Show efficacy. Furthermore, as assessed by, for example, histology and immunohistochemistry, it is contemplated that the therapeutic effects of such amine (tetra)amines on MS clinical symptoms in animal models may be associated with beneficial effects of brain and spinal cord tissue t. The findings of the 201113280 E model and the full forebrain ischemia model and the effects of the above-described in vitro test indicate that treatment with an amine (tetra)amine not only has the potential to reduce CNS human disease but may also interfere with the neurodegenerative process in the CNS. Or even contribute to the nervous system repair mechanism. Therefore, it has also been demonstrated that the treatment with these amine-based guanamines has value in other inflammatory diseases, demyelinating diseases or degenerative diseases or injuries such as cns: (4) Hermite, traumatic brain Injury, spinal cord injury, Parkinson's disease, amyotrophic lateral sclerosis, ischemia, stroke, epilepsy, acute disseminated encephalomyelitis (ADEM), Devic, s disease, optic neuritis , Hantington's disease, AIDS (acquired immunodeficiency syndrome) dementia complex. In a first aspect, the invention relates to a compound of formula (j):

Wherein Ri is hydrogen or Cw alkyl; the rule 2 is selected from the group consisting of alkyl, C3 μ cycloalkyl, C4-l2 bicycloalkyl, C5·!2 spiroalkyl, Cno bridged cycloalkyl, Alkyl-C3.1 0 cycloalkyl or C3 · 1 G cycloalkyl-C]-, anthracenyl, each optionally substituted by one or more identical or different substituents r7; R3 is ci·6 An alkyl group may be optionally substituted with one or more of the same or different substituents of 201113280, and R, or 4, on the 1 atom may be present in the same or different from the C: may be attached thereto The atom-bonded to form 5::J?, C4-12 heterobicyclic or R4. You are selected from the following composition: CHO, C(=〇)_Ci 6 Burning A &amp; " Burning base, C3.8 ring burning Base, · 6 bauxite ( = 〇) _C3-8 cycloalkyl and - cpcoo-Cu = which may be: substituted by one or more of the same or different substituents R7; Erlian 4: thiol or C ( = 0) - Cl-6, the UR4 can be joined together with the atoms of the jin to form a heterogeneous soil with 12 ring members of the heart, 6 independently selected from hydrogen, CK6 alkyl and c3 under each Qing/Brother 6 ring-burning bases can be viewed as appropriate - or multiple identical or different Substituted by a substituent 1, R7 is selected from the group consisting of hydrogen, dentate, hydrazine H, c alkyl and &lt;3,_6 alkoxy; um is 1, 2 or 3; η is 〇, 1 or 2 Ρ is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use as an inflammatory disease, a inflammatory disease or a detoxification of CNS in an individual in need of treatment Pharmaceutical products of myelin diseases. In the second aspect, the present invention relates to a compound selected from the group consisting of: <br><br>2-(4-ethinyl-i,4-diazepane ·卜基)_# face, hexyl acetonitrile 9 201113280 hexyl-2-(4-methyl), 4 diazepane small group) acetamidine, isopropyl isopropyl 1-yl) Acetamide, #: hexyl 3-(4-(cyclopropanyl)pyrrolidyl) propylamine, fluorenylcyclohexyl-4. (1,4-diazepane.1·yl) Butylamine, indole cyclohexyl-2-(4.cyclopentyl(tetra)yl)butanamine, #衣己基_2_(dihydro-pyridyl(1)^α]pyridine 2(6Η,ΊΗ,%Η , 9Η, 9αΗ)·1) oxime, cyclopentyl-2-(4•ethyl_3.methylbenzolyl), methyl ethylamine, #-(4-tert-butyl ring Heji )·二十底啡小基)Acetamine '#methyl#pentyl·2_(ι,4_diazaspiro[5 5]undaze_4_yl)acetamidoxime (2-methyl) Butyl)-2_(4_propionylpiperidine-1-yl)acetamide, 2-(1,4-diazepan-1-yl)-indole (pentane-3-yl) Indoleamine, butyl-2-(reverse_2,5-dimethylpipenyl-hydrazinylpropylamine, 2-(1,4-azacycloheptan-1-yl)-# -(2-mercaptobutyl)acetamide, 2-(1'4-azacycloheptane_丨_yl)_#·decylpentylacetamide, anthracenecyclohexyl-2-(piperidin Phenyl-1-yl)hexylamine, #-(2·decylbutyl)_2_(piperidinyl)acetamide, hydrazine (3,3-didecylbutyl)·2·(piperidin-b Ethylamine, (i?)-W-(3,3-dimethylbutane-2-yl)_2-(piperidin-mercapto)acetamide, hydrazinebutyl-2-(piper trap)丨 基 基 沁 沁 沁 基 基 基 沁 沁 沁 沁 沁 沁 沁 沁 沁 沁 沁 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Butyl 2-(ι,4-diazepan-2-yl)acetamide, 201113280 = pentyl-2-(M-diazepine), propylamine, pentyl 2 (1,4-azacycloheptane-j-yl)_, methyl acetamide, hydrazine Butyl-2·(piped-1'-yl)acetamide, amyl-3-yl)-2_(4-propyl aryl-based basement) acetamidine, cyclohexyl-2-(4- Propyl hydrazide · t-based) acetamidine, 2 (4-ethyl cyanoside), cyclopentyl mercaptoacetamide, W4'4-difluorocyclohexyl) Small base) acetamidine, 2-(°-endo-l-yl), 2w, 5e)_2,6,6-trimethylbicyclo[m]heptan-3-yl)acetamide, hydrazine (4 -ethylcyclohexyl)_2_(piperidinylhydrazinyl)acetamide, (Λ) #-(1-cyclohexylethyl)_2_(piperidinyl-1)ylacetamide, and 2" small group Good (2,5,5'tridecylcyclohexyl)acetamide or a pharmaceutically acceptable salt, hydrate or solvate thereof. In a third aspect, the present invention relates to a compound comprising a compound as defined above in relation to the second aspect, or a pharmaceutically acceptable salt, hydrate or solvent thereof, as an active ingredient, and a pharmaceutically acceptable compound. Pharmaceutical composition of the agent and additive. In a fourth aspect, the invention relates to a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined above in relation to the first aspect, for use in therapy. In a fifth aspect, the present invention relates to a compound selected from the group consisting of: ((U,25&quot;,4々-rel-bicyclo[2.21]heptane Iyl)_2_(4_propionoid0-endorphine- 1-yl) acetamidine, check 201113280 iV-cyclohexyl-2·(4_carbamidyl-1-yl)butanamine, 3-((1,,4,2,2,5-diaza) Bicyclo[2.2.1]heptan-2-yl)-#-cyclohexylpropionamide, cyclohexyl-2·(4·cyclopentylpiperidinyl)-ethylamine, #-(2-ring Octylethyl)_2_(piperidin-1-yl)propanamide, #-((1bicyclo[2.2.1]heptan-2-yl)-2-(pipedino-1-yl)acetamide Cyclohexyl-2·(hexahydropyrrolo[i,2_ap than tillage_2(ι//))) acetamidine, (7)-#-cyclohexyl-2-(hexahydro-" ,2-α]〇比耕-2(1//)-yl)acetamide, 2-(4-cyclohexyldecyl-1-yl)-#-isopropyl-2-methylpropionamidine Amine, 2_(4·(cyclohexanyl)-l-morphyl-1-yl)-_/V-(3,3-dimethylbutyl)acetamidamine 2-(4·cyclohexylpiped- 1-ylbicyclo[3.1.1]heptan-3-yl)acetamide, cyclopentyl-2-(4-propionyl-l-phenyl-1-yl)propanamine, AK (M, M, 4i〇) -bicyclo[2_2.1]heptane_2·yl)_2·(4_propyl fluorenyl) Piperidin-1-yl)acetamide, (/?)-]^-(3,3-methylbutan-2-yl)-2-(4-isopropyl-1,4-dinitrogen Heterocyclic heptane-1-yl)acetamide, W-(3-cyclopentylpropyl)-2-(4-methyl-1,4-diazepine-bupropion) , 2-((15,4 phantom-2,5-diazabicyclo[2_2.1]heptane-2-yl)- fluorenylcyclohexyl 12 201113280 decyl 3-(4-ethyl fluorenyl-1,4 -diazepine-indole-yl^cycloheptylpropionamine cyclohexyl-2-(4-cyclopentylphenidamine-1-yl)-2-methylpropanamide, #-(( /?)-Bucyclohexylethyl)-; 2-((Λ)-hexahydropyrrolopyridin-2(1ϋ〇-yl)acetamide, #-((reverse_2-ylcyclohexyl) Mercapto)-3-(piperidinyl)propanamide, trans-2-(4-butylphenidamine:-1-yl)-AM2-ethoxycyclohexyl)acetamide, cis_2_(4_丁Base (B), good (2_Ethylcyclohexyl) acetamidine, iV-cyclobutane* guanamine, anti-wolf ethoxycyclohexyl)-2-(4_methyl-10-4 diazepine Ethylamine, cis-indole-(2-acetamidinecyclohexyl)_2_(4_曱;己院| 炭 基 ) 1 1 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿Ethyl 2-(1,4-diazepane 1 I, λ, amine amines, small base) good (1·(methyl)cyclopentyl) acetamidine (3-cyclopentyl) Propyl)_2 9 MP ^ 1 , methylpiped-1-yl) acetamidine, 2-(4-(%hexane)-based J ^(2-3⁄4 octylethyl)propan-2- 4-cyclohexylpiperin 1-yl)U 戊 戊 Λ 甲 甲 i iV-ethyl-2-(piperazine) pottery 醯 醯 、, 肷 -1- 基 基 | | | | | | | | | | | | Trifluoromethyl, hexyl) hexylamine, 13 201113280 (*^)_ΛΛ·(4,4-difluorocyclohexyl)-2-(2-isopropyl-4-methylpiped -1-yl) acetamidine, 2_(4·acetamidiperamine: small group) 沁 沁 ethyl good (4_(trifluoromethyl)cyclohexyl) acetamidine, cyclohexyl-3-(4- Cyclopentylpiperidin-1-yl)_2-methylpropanamide, (cis-4-t-butylcyclohexylpipen-1-yl)acetamide, #-(trans-4-third Cyclohexyl)_2_(piperidinyl)acetamide, cyclohexyl-2_(4·(2,2,2·trifluoroethyl)pipedyl-p-ethyl) acetamidine, cycloheptyl-3-( 4-cyclohexylpipenino-indole-propanylamine, 2-(旅耕-l-yl)-#•(anti-3,3,5-tridecylcyclohexyl)acetamide' 2-( Piper-1-base)_#_(shun_3,3,5_three Cyclohexyl) acetamidine, 2-(4-ethyl aryl 耕 丨 基 基 _ _ _ 顺 顺 顺 顺 顺 顺 顺 顺 、 、 、 、 、 、 、 、 、 、 、 、 Good (trans-4 hydroxycyclohexyl) B or a pharmaceutically acceptable salt, hydrate or solvate thereof, in a sixth aspect, the invention relates to a compound as defined above in relation to the fifth state: a pharmaceutically acceptable salt, hydrate or solvent

The second is an active ingredient, and a pharmaceutically acceptable shaped pharmaceutical composition. The above-mentioned acceptable salt, Wenguan hydrate in the treatment of the seventh aspect, the present invention relates to a compound or a pharmaceutically acceptable substance or solvate thereof for use in the fifth aspect. In an eighth aspect, the present invention relates to a composition comprising Λ^^m.., a compound as an active wound, further comprising a group of the following 14 201113280: an immunomodulator, An immunosuppressive agent, an anti-proliferative agent, an antimetabolite agent, or an agent that acts on a surface ligand. In a ninth aspect, the invention relates to a method of treating an inflammatory disease, a degenerative disease or a demyelinating disease of a CNS in an individual in need of treatment comprising administering an effective amount of a compound of the formula. In a tenth aspect, the present invention relates to a compound of the formula τ in the manufacture of a medicament for the treatment of a CNS inflammatory inflammatory tract, a heart-heart fire disease, a degenerative disease or a degenerative sheath disease in an individual in need of treatment. use. [Embodiment] The term "burning" in the present case means a linear or branched hydrocarbon group having (10), for example, 1 to 8 carbon atoms. Representative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, oxime-ethylpropyl, 2-methylbutyl, pentyl 2, 3 Methyl butyl storm, hexyl, heptyl, octyl and the like. The term "cycloalkyD" has 3 to 10 in the current situation, such as 3 to 8 carbon atoms, Tfi2, and 乂 乂 。. Propyl, cyclobutyl, cyclopentyl, cyclohexylcyclooctyl. 'hexyl, cycloheptyl and the term "bicycloalkyl" are used to represent two needles in the form of a needle. % % by %, of which 2 adjacent carbon atoms are used to condense 2 in a ring structure such as heptatriene. Wind coat, heptadienyl, T 虱 基, octahydrocyclopentadienyl, etc. "Spiroalkyl", in the present context, denotes two 15 201113280 cyclic hydrocarbon rings in which a single carbon atom is used to join two ring structures together. Representative examples include spiro[2.4]heptane, Spirulin [2.6] decyl, spiro[45]decyl, spiro[5.5]undecyl, etc., the term "bridged cycloalkyl" in the present case means 2 cyclic hydrocarbons a ring in which two non-adjacent carbon atoms are used to join two ring structures together. Representative examples include bicyclo [2.2.1] g- 丨 基 yl, bicyclo [2.2.1] g _2 _ base, bicyclo[2·2丨]heptyl-7,ylbicyclo[3 1 1]heptyl,bicyclo[2.2.2]octyl i-yl'bicyclo[2·2.2]octyl-2-yl, bicyclic [3 3 〇] octyl, bicyclo [4.4.0] fluorenyl, etc. The term "heterobicycle" in the present case means 2 cyclic rings ' + 2 adjacent atoms for 2 ring structures The fused form is fused. Typical examples include diazabicyclo[4.3 〇]decane, octahydrocyclopenta[external oxime, M.diazabicyclo[4 4〇] brothel, decahydroquinone. Decahydrocyclopenta(4)[1,4]diazepine, decahydro_1H-benzo(4)[M]diazepine, etc. The term "heterospirocycle" means two cyclic rings in the present case. , wherein a single carbon atom is used to join two ring structures at I. Representative examples include 5,8-diazaspiro[3 6]nonane, 6,9-diaza-spiro[4 5]hexacyclohexane, 1,4-diaza-spiro[5 5]undecane, 8"j•diazepine[5 6]dodecane, etc. The term "heterobridged" means 2 % in the current situation. Hydroquinone, in which two non-adjacent carbon atoms are used to combine the two. The representative examples include 2,5.diazabicyclo[22ι]heptane diazepidine [3] .2.1] Octane '2,6-diazabicyclo[3.2 2]nonane, 2 $•-'bicyclo[4.3.1]decane, etc. — the term "alkoxy" is used in the present case 16 13 之 16 201113280 % Group, wherein R is an alkyl group as defined above. The term "halogen" in the present case means fluorine, gas, bromine and angstrom. A pharmaceutically acceptable salt in the case of a pharmaceutically acceptable salt, which in the case of a compound of the formula, does not cause significant irritation to the organism to which it is administered and does not eliminate the biological activity of the compound ) raw and | · raw materials. The pharmaceutical salt can be obtained by reacting a compound of the present invention with a mineral acid (including salt hydrazine, hydrobromic acid, sulfuric acid, and phosphoric acid) and an acid metal salt (such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate) which form a suitable salt. Illustrative organic acids which form suitable salts include monocarboxylic acids, dicarboxylic acids and tricarboxylic acids. Illustrative of such acids are, for example, acetic acid, trifluoroacetic acid, glycolic acid, lactic acid, pyruvic acid, propionic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, Maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, stupid acetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid and sulfonic acid, such as decanesulfonic acid and 2-hydroxyl Ethanesulfonic acid. These salts may be present in hydrated or substantially anhydrous form. The term "prodrug" in the present case refers to an agent that is converted into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, it may be bioavailable via oral administration and the parent drug is not bioavailable. Prodrugs may also have improved solubility in the pharmaceutical composition over the parent drug. A non-limiting example of a prodrug would be that the compound of the present invention is administered in the form of vinegar ("prodrug") to promote transport across the cell 纟 'where water solubility is detrimental to fluidity, but once it enters water soluble cells are beneficial Internally, it is then metabolically hydrolyzed to a carboxylic acid (another example of a prodrug of a living entity may be a short peptide (polyamino acid) bonded to an acid group, wherein the peptide is metabolized to show the active moiety. "Solvate" means, in the present case, a compound of the invention in combination with - or a plurality of solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be capable of isolation, for example, when - or a plurality of solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate"; both the solution solution phase and the separable solvate "suitable Non-limiting examples of the solvate include an ethanolate, a methanolate, and the like. "Hydrate" is a solvate in which the solvent molecule is H2?. Treatment at present situation It is intended to cover the healing of a disease or to restore health, to inhibit the progression of a disease state, to improve the disease state'; to prevent or reduce the risk of disease, to restore function or to improve the secondary effects of the disease and/or to inhibit the progression of the secondary effects of the disease. "Inflammatization of CNS disease" In the case of Tian Yue, J, it indicates that CNS tissue damage or destruction caused by inflammation is special (biochemical disease, that is, the complex biological defense and repair process of the body is targeted. / number 'such as sense $, irritants, damaged cells, etc. However, inflammation can also be attributed to the autoimmune process. The inflammatory response involves the local vascular system, the immune system, and various cells within the damaged tissue. Deg 〇 CN CN CN deg deg v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v Symptoms of the neurodegenerative disorder often associated with the affected CNS structure

1S 201113280 Shrink related. The term "demyelinating CNS disease"

In the current situation, the main __ 6 J * no, 'being the loss of the myelin around the neuron or dysfunction characterization, r- medium; sagittal disease. Myelin damage can debilitate the damage of the affected nerve in the affected nerve, causing sensation, movement, cognition, or other functions dependent on the nerve involved. Specific Specific Examples of the Invention Specific Examples are compounds of formula (I) compounds of formula I

〇

R2 RS ^

(I) wherein t is hydrogen or Ci-6 alkyl; Han 2 is selected from the group consisting of Γ.砰丨c丨-丨〇alkyl, c3-丨0 cycloalkyl, bicycloalkyl, (: 5_|2 spiroalkyl, c &amp; ^5·10 衢bicycloalkyl, C丨-丨0 alkyl 3-1 〇 cycloalkyl or (: 3-1 〇 cycloalkyl-Ci 桉 u u —, L丨-丨〇alkyl, each of which may be substituted by the same or a plurality of the same or different substituents r7; h is a Cl.6 leuco group which may optionally be substituted by one or more identical or different substituents R7 Substituted, and if ? is 2, 3 or 4, the R3 groups which may be present on the same or different 201113280 atom may form a c5_丨2 hetero-spiro, together with the atom to which they are attached, form a shape 4_丨2 heterozygous or C5·丨0 hybrid bridging ring system; 4 series ^ free of the following group of components: hydrogen CH 〇, C (J 虱 C - pit base, C 3-8 cycloalkyl ' Μ Μ alkyl, C(=0)-C3.8 cycloalkyl and _c(= alkyl, which may optionally be substituted by one or more 1-6, the same or different substituents R7. Field 4...C|·6 alkyl Or C(=0)-C丨-6 alkyl, R, : the attached atom - one forms a ring member:: Hyun group I::: widely in each case independently selected from hydrogen, Cl·6 The base and the ring. White as the case - or a plurality of identical or different substituents I taken from the group R7 is selected from the group consisting of: hydrogen, a hydroxyl, OH, CN'c 炫, and &lt;^·6氧基; ^ m is 1, 2 or 3; η is 〇, 1 or 2; Ρ is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt, hydrate or solvate thereof. A specific example is a compound of formula j wherein R] is hydrogen. A specific example of the invention is a compound of formula I wherein r2 is selected from the group consisting of: C丨_8 alkyl, 匸3-8 Each of the cycloalkyl or C3.8 cycloalkyl-Cw alkyl groups may be optionally substituted with one or more identical or different substituents R7. One specific embodiment of the invention is a compound of formula I wherein r2 is cyclohexyl. A specific example of the invention is a compound of formula I, wherein R3 is c, _6 alkane 20 201113280 base 'which may optionally be substituted by one or more of the same or different substituents R -, &quot;, and if P is 2' The 3 groups present on the same or different atoms may be joined together with the atoms to which they are attached to form a C5_丨〇 hybrid bridged ring system. One specific example of the invention is Formula I A compound wherein p is 〇2. 1, or a specific example of the present invention is a hydrazine compound wherein p is hydrazine or one of the present invention is a compound of formula I wherein p is hydrazine. Is a compound of formula j, wherein b is selected from the group consisting of hydrogen, C, -6 alkyl, C3 8 cycloalkyl, CH〇, = alkyl and C(=〇)-C3.8 cycloalkyl, It may optionally be substituted by one or more identical or different substituents R7; and when 1 is Ci 6 alkyl or c(=〇)Ci όalkyl, R3 and R4 may be joined together with the atoms to which they are attached to form A heterobicyclic ring having 4·10 ring members. One specific embodiment of the invention is a hydrazone compound wherein R4 is hydrogen. A specific example of the invention is a compound of formula 1, wherein I and R4 may be joined together with &gt;, attached atoms to form a hetero-double % having 4-10 ring members, which may optionally be substituted by one or more identical or different Substrate 7 is substituted. A particular embodiment of the invention is a compound of formula i wherein the center and Re are independently selected from the group consisting of hydrogen and alkyl, each of which may be optionally substituted with one or more of the same or different substituents r7. One specific embodiment of the invention is a compound of formula 1, wherein the sum is hydrogen. A specific example of the invention is a formula compound wherein the compound is selected from the group consisting of ruthenium, 〇h, c, -6 alkyl and. 6 group of alkoxy groups. A specific example of the present invention is a hydrazine compound wherein 1 is selected from the group consisting of 21 201113280 halogen, c, .6 alkyl and one of the present invention having a halogen and a C 1 -6 alkyl group. One of the inventions has one of the inventions

A group consisting of Ci-6 alkoxy groups. An example of a compound of formula I wherein r7 is selected from the group consisting of. An example of a compound of formula I wherein m is 1 or 2. A exemplified is a compound of formula I wherein m is 1. A exemplified is a compound of formula I wherein n is 1 or 2. An example of a compound is a compound of formula I wherein n is 1. In one aspect, an example of a compound of formula I is hydrazine ((1 coffee, 4/〇-rel_bicyclo[2 2 Gengyuan_2yl) 2_(派哄小基) acetamidine, then (1 coffee, 4/?) Heart 1-bicyclo[2 21]heptan-2-yl)_2_(4-propionipipipide=-1-yl)acetamide, 7V-(3,3-dimethylbutyl) · 2_(piperidinyl)acetamide, 2-(4-(cyclohexanecarbonyl)piperidine: _丨_yl)_#_(3,3 dimethylbutyl)acetamide, 2-( 4·Ethyl pepido-1-yl)cyclohexylacetamide, cyclohexyl-2_(4-carbamimidino-indolyl)acetamide 'TV-cyclopentyl_2-(4_ Propylamine, iV-cyclobutyl-2-(l,4-diazepane-indoleyl)acetamide, cyclopentyl-2-(1) , 4-diazepane-indole-yl)propanamine, 2-(4-acetamido-1,4-diazepane-bu), cyclohexylacetamide, succinyl -2-(4-methyl-1,4.diazepan-2-yl)acetamide, iV-cyclohexyl-3-(4-(cyclopropanecarbonyl)piperidinyl) Amine, 22 201113280, cyclohexyl-2-(4-cyclopentylpiperidin-1-yl)butanamine, cyclohexyl-2-(dihydro-li/-pyrido[1,2_α]. -2(6//,7//,8//,9β/ -yl)acetamide, cyclopentyl-2-(4-ethyl-3-methylpiperidin-1-yl)mercaptoacetamide, decylpentyl-2-(1,4-dinitrogen) Spiro[5.5]undec-4-yl)acetamide, ΑΚ2-mercaptobutylpropanylpiphthyl hydrazinyl) acetamidine, 2-(1,4-diazepane pentane Alkyl-3_yl)acetamide, -butyl-2-(trans_2,5-didecylpiperidin-buyl)I.propylacetamide, #_(2-methylbutyl) _2-(°-Phenyl-1-yl)acetamide,

Base)·2-(4-propionylpiperidin-1-yl)acetamide, -•(4-propionylpiperidin-indoleyl)acetamide, 7V-(pentyl- 3-indole) Cyclohexyl-2. 2-((15,45)-2,5--~(4-mercaptopemide: _:!-yl)butanamine, diazabicyclo[2.2.1]heptane- 2-based) cyclohexyl

Long anakan-1-yl)mercapto-pentyl acetamide, fenamine)-indole _cyclopentyl decyl acetamide, decylamine, 2-(14-diindole 2- (4-ethyl)醯基呢 3- ((U,4i?).2 'decalamine, ',5' diazabicyclo[2.2.1]heptan-2-yl)cyclohexylpropane iV-cyclohexyl_ 2. 2-( 4-Cyclohexyl-cyclopentylpiperidin-1·yl)acetamide, ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ %hexyl_2-(hexahydro-c ratio 咯[12_十比耕_2(ι外基) acetamidine, 3-(4-ethylindolyl_M_diazepane +yl)j Cycloheptylpropionamide 'isopropyl-1-pyridylacetamide, Μ 底 + + base) good ((10) from from 5 outside 2, M_trimethylbicyclo[3丄1] gargin-3 -yl)acetamide, 2-(4-cyclohexyl0-endo-1-yl)I (U-external 2,M-trimethylbicyclo[3'1.1]heptan-3-yl)acetamide, W-AKi-cyclohexylethyl)-2 decandyl small group) acetamamine, W-iV-(3,3-dimethylbutan-2-yl)_2_(pigmented small base) acetamide , four (by hi (3,3-dimethyl-bromo-2-yl)_2_(4-isopropyl-M-diazepan-1-yl)acetamide, #-(3- Cyclopentylpropyl)-2-(4-methyl-indole, 4-diazacyclocycle Heptane-mercapto) acetamidine, #-(trans-4-hydroxycyclohexyl)_2_(piped-indole-yl)acetamide, #-(2-cyclooctylethyl)_2_(parecene_丨·) propylamine, % hexyl-2-phenylephthyl-1-yl-ethinamine, cyclobutyl·2-(piperidin-1-yl)acetamide, indole cyclohexyl-2-(4) -cyclopentylpiperidin-1-yl)_2-mercaptopropionamide, indole cyclohexyl-3·(4-cyclopentylpiperidin-1-yl)·2-methylpropionamide' cyclohexyl_ 2·(Phime:-ΐ-yl) hexylamine, cyclohexyl-2-(pemidine:-fluorenyl)butanamine, #-(cis-4-t-butylcyclohexyl)_2_(piperidin啩μ•基)acetamide, 24 201113280 #-(trans-4-t-butylcyclohexyl)·2-(piped-i-yl)acetamide, cyclohexyl_2-(4_(2, 2,2-trifluoroethyl)pipep-indolyl)acetamide, cycloheptyl 3-(4·cyclohexylpiperidin-1-yl)propanamine, 2-(parecene-1- Base)_#_(trans-3,3,5-tridecylcyclohexyl)acetamide, 2-(bred 1-yl)_w_(cis-3,3,5-trimethylcyclohexyl) Acetamide, 'cyclohexyl-2-(4-isopropylpiperidin-1-yl)acetamide, #-(4-t-butylcyclohexyl)-2-(piperidin-indole) Acetamide, cyclohexyl-2_(hexahydropyrrolo[1,2-fl ]pyridin-2(1//)-yl)acetamide, Y-(4,4-difluorocyclohexyl)·2_(pemidine:-fluorenyl)acetamide, (7)-7V-(4 ,4-difluorocyclohexyl)-2-(2-isopropyl-4-methylpipelin-1-yl)acetamide, #((Λ)-1-cyclohexylethyl)_2_((and ) _ hexahydroindole 〇 〇 -2 -2 -2 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( -2-( 1,4-diazepane)-yl)-mercaptoacetamide, #-(3-cyclopentylpropyl)-2-(trans-2,5-dimethyl Piperidin-1-yl)acetamide, 2-(4-carbamimidoxime: _ι_yl)·&quot;_(trans-4_hydroxycyclohexyl)acetamidamine 2- 2-(cyclo) Hexanecarbonyl, piperidine, hydrazine, hydrazine, hydrazine, hydrazine, hydrazine, hydrazine, hydrazine, hydrazine, hydrazine, hydrazine, hydrazine, hydrazine 2-(4-Ethyl hydrazine hydrazine _ 丨 yl)_&quot;_(cis.4-hydroxycyclohexyl)acetamide, hydrazine (cis-4-hydroxycyclohexyl)-2_(piperidin-i• group Ethylamine, ring-butylbutyl-2-(piperidin-1-yl)propanamide, 25 201113280 decylamine TV-cyclobutyl-2-(W-hexahydroindole[2] (called base) C &gt; 2-(1,4-azacycloheptane ·! ·) 沁 (1_(hydroxymethyl)cyclopentyl)acetamide 2-(4-(cyclohexanecarbonyl)piperidinyl)-indole (1_(hydroxymethyl)cyclopentyl) Acetamine, hydrazine (4_ethylcyclohexyl)-2_(piped-indole-yl)acetamide, 2-(4-ethylindoleyl)-ethylidene (4_(trifluoromethyl) (cyclohexyl) acetamidine, iV-ethyl-2 decanoside small base) also (4_(Sandunmethyl)cyclohexyl)acetamide, anti-2* butyl piperene) 沁(2_ ethoxycyclohexyl) acetamidine, cis- 2-(4-butyl. morphine small group) spring (2-ethoxycyclohexyl) ethylamine, anti # (ethoxy hexyl) 2_(4_methyl·丨,4_diazacycloheptyl)acetamide, ethoxy(J-hexyl)-2-(4-methyl-indole, 4·diazepane Ethylamine, (also: [2.2.1] gargin-2-denyl-pyridinyl) acetamide 'amine (also [2.2.1] heptane_2_yl)_2, _醯 哌 哌 ) ) ) ) ) ~ ~ ~ ~ ~ ~ 4 4 4 4 ~ ~ 4 4 4 4 4 4 4 4 4 4 4 4 4 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ) _(3,3,5_three w its base % hexyl) acetamidine, butyl-2-(2,5-didecylpiperidinium oxime & listening group) propyl acetamide 2-(2,5--Azabicyclo[2 2丨]heptyl)-nonylcyclohexylacetamide 3-(2,5-azabicyclo[2 2yl)cyclohexylpropionamide 26 201113280 iV- Cyclohexyl-2-(hexahydropyrrolo(1)octapirinyl)acetamidamine, 2_(parphin-1-yl)good (2,6,6-trif-bicyclo[3丄(10)烧_3· Base) Ethylamine, 2-(4-cyclohexyl) phenoxy-1-yl) _(2,6,6-trimethylbicyclo[3"heptan-3-yl)ethonamide, '( 4,4-Difluorocyclohexyl)-2-(2·isopropyl-4-methylphenamine: 丨丨-yl)acetamide, #-(1-cyclohexylethyl)_2-(piper trap)丨 基 基 基 # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # -(3,3-mercaptobutylbutan-2-yl)·2_(〇底哄基) acetamidine, dimethyl-bromo-2-yl)_2·(4-isopropyl) , heart diazepane-1-yl)acetamidine, #·(4-cyclohexyl)-2-(pine 丨 丨 基) acetamide, #-((2-hydroxy ring)基 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) (1 ugly)·yl)propionylcyclohexyl)acetamide or-1,4·diazide Heterocyclic heptane-1_yl) 2_(4-butylphenidin-1-yl)-W-(2-ethyl W-(2-ethoxycyclohexyl)-2-(4-methylacetic acidamine or &quot;J pharmaceutically acceptable salt, water eight private;, σ or &gt; cereal composition. In the other way - 'style! An example of a compound is: #-((15,23,411)_^1-bicyclo[2.2.11忠&amp;14^]heptan-2-yl)_2-(&lt;j 哄小基) 27 201113280 Amine, AK(lS,2S,4R)-rel-bicyclo[2.2"]heptane-2-yl)_2_(4_propionylpipen-1-yl)acetamide, iV-(3,3-dioxin Butyl) 2 - (piperidin 4 - yl) acetamide, 2-(4-(cyclohexanecarbonyl) piperazine 丨 基 基 曱 butyl butyl acetamide, 2-(4-ethyl hydrazine Hydropamine:-1-yl)-cyclohexyl acetamide, 7V-cyclohexyl-2-(4-carbamoylpiperinyl)acetamide, hydrazine-cyclopentyl-2-( 4_丙醯基培耕_丨_基) propylamine, #-1⁄4 butyl-2-(l,4-diazepane)-acetamide, #-1⁄4pentyl-2 -(1,4-Diazepane-buyl)propanamine, 2-(4-ethylindenyl-M-diazepane)-)cyclohexylacetamide, #- 3⁄4-hexyl-2-(4-mercapto-1,4-diazepane-indole-yl)acetamide 'hexyl-3-(4-(cyclopropanecarbonyl)piperidinyl-yl)propyl Indoleamine, #-1⁄4 己基_2-(4_cyclopentylpipedylhydrazinyl)butanamine, cyclohexyl·2·(dihydro-1//-pyrido[l,2-fl]pyridinium Listen _2(6//,7//,811,9//,9«//)-based Acetamide, A^-% amyl-2-(4-ethyl-3-ylmercaptamine:-i-yl)mercaptoacetamide, ^methylpentyl-2-(1,4- Diazospiro[5.5]undec-4-yl)acetamidamine, #_(2_mercaptobutyl)_2_(4-propionylpiperidin-1-yl)acetamide, 2_(1, 4·-azacycloheptane·1-yl)-7V-(pentan-3-yl)acetamide, hydrazine butyl-2_(reverse_2,5-dimethylpipen-1-yl) Propyl acetamide, 28 201113280

V #-(2-methylbutyl)_2·(Pan-small base) acetamidine, butyl-2-decorphinyl), propyl propyl acetamide, 'cyclohexyl·2·(4· Imidylpiperidin-1-yl)butanamine, iV-(pentan-3-yl)_2-(4-propenylpiperidinyl)acetamide, hexyl·2_(4-propyl Indomethacin-indole-yl)acetamide, 2_((1*?,4*5)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-indolecyclohexylacetamidine Amine, 2-(1,4-diazepane-indole-yl)_#_(2-mercaptobutyl)acetamide, //- pentylmethyl-2-(parphine) Small base) acetamidine, 2-(1,4-diazepane-buyl)^曱-yl-p-amylacetamide, 2_(4_乙乙基耕耕-基)-/ /-Cyclopentyl-V-methylacetamide, 3-((17?,4))2,5-diazabicyclo[2.2.1]heptan-2-yl)-#-cyclohexylpropane Indoleamine, decylyl 2-(4-cyclopentylphenamine: _ _yl) acetamidine, 2-(4-cyclohexylphenamine:-1_yl)_//·isopropyl 2_Methylpropanamide, (/?)-#-cyclohexyl-2-(hexahydroindolo[ι,2-α]morphine-2(1//)-yl)ethinamide, 3 - (4-Ethyl-1,4-diazepan-1-yl)-7V-cycloheptylpropionamide, isopropyl-1 Acetamide, 2-(pemamine:-1-yl)-indole_((υ,2&amp;3Α5/?)_2,6,6-trimercaptobicyclo[3.1.1]heptan-3-yl)B Indoleamine, 2-(4-cyclohexylpiperidin-1-yl)-#-((11^,2&gt;5(,3义5幻-2,6,6-tridecylbicyclo[3.1.1] Heptan-3-yl)acetamidamine, 29 201113280 cyclohexylethyl)-2-(pipedino-1-yl)acetamidine, (magic-#-(3,3-dimethylbutane-2) _ base)-2-(piped-1-yl)acetamide, (Λ)-#-(3,3-dimethylbutan-2-yl)-2-(4-isopropyl-14 -diazepan-1-yl)acetamide, (3-cyclopentylpropyl)-2-(4-indolyl-1,4-diazepan-indoleyl) Acetamide, (trans-4 hydroxycyclohexyl)-2-(pipedino-1-yl)acetamide, #-(2-cyclooctylethyl)-2-(piperidin-1-yl) Propanamine or cyclohexyl-2·bran-1-yl-acetamide or a pharmaceutically acceptable salt, hydrate or solvate thereof. In another aspect, an example of a compound of formula I is: # -((15,219,4)-161-bicyclo[2.2.1]heptan-2-yl)-2-(piperidin-1-yl) ethanoamine, bicyclo[2.2.1]heptane-2- 2-(4-propionylphenidamine-1-yl)acetamide, #-(3,3·dimethylbutyl)·2· (piperidin-mercapto) acetamidine, 2-(4-(cyclohexanecarbonyl)pememide: 丨 基 yl) 沁 (3,3 dimethyl butyl) acetamidine, fluorenylcyclopentyl -2-(4-propionylpiperidine hydrazinyl)propanamide 'butyl-2-(1,4-diazepane-indoleyl)acetamide, 2-(4- Ethyl-1,4-diazepane small group)-cyclohexylacetamide, hexyl-2-(4-indolyl_ι,4-diazepanyl)acetamide Cyclohexyl 3-(4-(cyclopropanecarbonyl) decyl brown) propylamine, 30 201113280 ΑΑ-cyclohexyl-2 -(4-cyclopentyl B morphin-1 -yl)butanamine, iV-cyclohexyl-2-(dihydro-if ruthenium ratio. And [ΐ, 2-α].比明1 -2{6Η,Ί H, up to H,9H,9aH)-l) Ethylamine, cyclopentyl-2-(4-ethyl-3-methylpipen-1-yl)methyl Acetamide, 'methyl-iV-pentyl-2-(1,4-diazaspiro[5.5]undec-4-yl)acetamide, #-(2_methylbutyl)_2_( 4_ propyl hydrazide-1 yl) acetamidine, bis-^' heart diazepane-^ kib pentane-Hongji ^ acetamidine, butyl · 2- (reverse _ 2,5-didecylpiperidinyl) propylacetamide, #—(2-decylbutyl)-2-(piperidin-1-yl)acetamide, ^butyl·2-( &lt;Ι底啩-1-yl) propyl acetamide, cyclohexyl 2-(4·decylpiperin-1-yl)butanamine, #(戊院_3'基)~2- (4_propionylpiperidin-1-yl)acetamide, -j,2-(4·propionylpiperidin-bu)acetamide, 2-((1,5,45)- 2 二 diazabicyclo[2·2·1]heptan-2-yl)-#-cyclohexylacetamide, 2 - (1,4 - *4 八, although cycloheptan-1-yl)-# -(2-mercaptobutyl)acetamide, I, although heptane-1-yl)-iV-mercapto-oxime-amylacetamide, 2-(4-ethyl-branched w), speak _ 1_yl)_cyclopentyl-TV·mercaptoamine, &lt;r 4,5'diazabicyclo[2.2.1]heptan-2-yl)-iV-cyclohexane Propionamide, N-cyclohexane 1, 2 Λ (4'-cyclopentylpiperazin-1-yl) acetamidine, 2-(4-cyclohexyl nr&gt; '氏耶-1-yl)-A /·Isopropyl-2-mercaptopropionamide, (•/?)-·Λ/~cyclohexyl 丞'2-(hexahydropyrrolo[1,2-α]pyridin:-2(1 //)-Base) B 31 201113280 Hydrazine 3-(4-ethylindolyl_ι,4·azepane-1-yl)-indolecycloheptylpropanoid 2-(parphinyl) r, , 1llfe ^ U ώ, ", 3 to /?) -2,6,6-trimethylbicyclo[3.1.1] heptane _3-yl) ethanoamine ' 2_(4-cyclohexylpiped Xiaomei, 雒 ring "3 1 1! 庵rq technique, soil - ((, 2 to & 5 magic-2,6,6-trimethyl and bad [3丄1]heptan-3-yl) Acetamide, (R)-N-(l-cyclohexylethyl, ...^ hexyl)·2·(Nangsui small base) acetamidine, (R) N-(3,3-methyl butyl Γ Γ 'base) '2 decylamine) acetamamine, (and) j-(3,3-dimethylbutyrrole A ^ , «. λ soil)-2-(4-isopropyl_1, 4-diazahypoindole-1 -yl)acetamidamine ##-(3·cyclopentylpropylacetamide or -methyl-μ-diazepane small group) #•(2 ·% octylethyl), benzoic acid small base) acrylamide or a pharmaceutically acceptable salt thereof Hydrate or solvate thereof. In another aspect, the compound of formula I is indole cyclohexyl-2-pipedyl-1-yl-acetamide or a pharmaceutically acceptable compound, hydrate or solvate thereof. Individual stereoisomers containing one or more compounds of formula I, which are referred to as centers, can be resolved by methods known to those skilled in the art using |t|_ 4+ 1 -,. For example, a repelling knife can be carried out by (1) forming a diastereomeric salt, a complex or a ', a derivative thereof, (2), for example, via enzymatic oxidation or reduction, and a stereoisomer-specific reagent. Performing a selective reaction; (3) performing a gas phase in a chiral environment (eg, on a chiral support incorporating a chiral ligand (such as cerium oxide) or in the presence of a hand-carrying 'valley') - Liquid or liquid chromatography. Those skilled in the art will understand how to convert a desired stereoisomer to another chemical entity via one of the above separation procedures, requiring an additional step to release the formula. Alternatively, the t-isomer can be synthesized by asymmetric synthesis using an optically active reagent, substrate, catalyst or solvent, or by converting the enantiomer to the other by asymmetric transformation. The compound may also contain any asymmetric centers. If a cycloalkyl group is present, some of the substituent patterns may result in an axial configuration or an equatorial configuration. Unless otherwise specified, both forms are included. Structure is also included in the formula ^, regardless of The tautomeric system is present in an equilibrium state or predominantly in one form. Pharmaceutical Compositions In treating a patient suffering from the above conditions or conditions, the formula compound can be administered in a biological mode at a therapeutically effective amount. Including oral, sublingual, serotype, or veins, internal, transdermal, intranasal, transrectal preparation techniques may be based on the treatment of the condition or condition and other relevant conditions. :

Determine the appropriate form of administration and 』(四)U

Pharmaceutical Sciences, pp. 18: 2: see Remingt〇n, S (called it in the form of a scorpion). The compound of formula I can be administered as a separate drug composition... The practicability and chemical nature,/proportion and nature of the acceptable carrier are determined by the solubility criteria of the selected compound. The route of administration, standard pharmaceutical practice and other phase 1 compounds can be administered, for example, in the form of: Key, sugar coating 33 201113280 ingots, capsules, elixirs, suspensions, solutions 'syrups, powders, chewing tablets and the like and may contain one or more of the following adjuvants · binders, such as microcellulose, Astragalus gum or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, sodium carboxyacetate, corn starch and the like; lubricants such as magnesium stearate or hydrogenated vegetable oils (Sterotex); a slip agent such as colloidal cerium oxide; and a sweetener (such as sucrose or saccharin added) or a flavoring agent such as peppermint, methyl salicylate or orange flavour (orange flav〇ring) When the unit agent In the case of a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as polyethylene glycol or a fatty oil. Other unit dosage forms may contain other materials which modify the dosage unit form (for example, in the form of a coating). Therefore, the tablet or the pellet may be coated with sugar, shellac or other enteric coating agent. The syrup may contain Wei as a sweetener and some preservatives, dyes and coloring agents in addition to the compound. Administration: solution, ointment or gel base. Base stone butterfly, lanolin, polyethylene glycol, such as water and alcohol), and emulsifiers and stable solutions or suspensions may also include a dose such as water for injection, saline solution Glycerol, propylene glycol or other synthetic solvent p-hydroxybenzoate; anti-oxidant nano; chelating agent 'such as ethylene diamine tetra, citrate or phosphate; and tension tempering and when so do the carrier should contain For example, one or more of the following may be included: beeswax, mineral oil, diluent (additives or various adjuvants: sterile dilution, fixed oil, polyethylene glycol, antibacterial agent, such as Sterols or such as ascorbic acid or hydrogensulfite L acid; buffers such as acetates, sorbents such as sodium or dextrose. 34 201113280 Non-left bowel preparations can be packaged in human ampoules, disposable syringes or multi-dose vials The dosage range of the compound of formula II which exhibits its therapeutic effect may be in accordance with the particular disease or condition and its severity being treated, the patient, the formulation, other latent disease states suffering from f 1 w, and others may be concurrent In general, the compound of formula 1 will exhibit its therapeutic activity at the following doses: about 〇ι call per kilogram of patient weight per day to about 1000 mcr/w per kilogram of patient weight per day 4 _ - g /kg 'For example, a mother-in-law kg patient weighs about 1.0 mg to a mother-in-law kg patient body weight of about mg, such as about 1 mg per kg of patient weight per day to about 300 mg per kg of patient weight per day. In particular, (4) is a pharmaceutical composition comprising the compound of the formula I as an active ingredient, which further comprises a compound selected from the group consisting of an immunomodulator or an immunosuppressive d. Such therapies include immunomodulators (such as no interferon and glatiramer acetate) and immunosuppressive agents, such as antiproliferative agents (such as mitox or cyclophosphamide), antimetabolites (such as cladribine). (cladnbme), teriflUnomide or lanqUmim〇d or an agent acting on a surface ligand (such as rituximab (ntUXimab) 'alumuzumab, Daclizumab, natalizumab (fingolimod or fingolimod). One specific embodiment of the present invention is for use as a treatment for a human disease selected from the group consisting of CNS Or medicinal products of demyelinating diseases or degenerative diseases, such as sclerosis, Alzheimer's disease, traumatic brain injury, Parkinson's disease, amyotrophic lateral sclerosis, ischemia, Stroke m ADEM, Devic's disease, optic neuritis, Huntington's disease, Na dementia 35 201113280 complex syndrome, etc. Selected from: specific examples for the treatment of individuals with therapeutic needs =: group of lower CNS's method of inflammatory disease, Guanle disease or disease retreat. Sclerosis, Alzheimer brain injury, Parkinson's disease, R ^ muscle ginger fine lateral sclerosis, ischemia, stroke, tumor epilepsy, ADEM, Devic's disease, suitcase sleeve

^ A Lu brother &amp; disease optic neuritis, Huntington's disease 'AIDS dementia complex alpha disease, etc., the method comprises administering an effective amount of the formula "匕. One specific example of the invention is the preparation of the compound of formula 1 Use of a medicament for treating an inflammatory disease, a demyelinating disease or a degenerative disease of a CNS selected from the group consisting of: multiple hard: disease, Alzheimer's disease, traumatic brain injury , Parkinson's disease, muscle: systolic lateral sclerosis, ischemia, stroke, scratch, adem 'Devic's C, optic neuritis, Huntington's disease, AIDS dementia complex, etc. A specific example is a formula for use as a medicament for treating sclerotherapy in an individual in need of treatment. A specific embodiment of the invention is a method for treating a multiple dynaplasia in a subject in need of treatment comprising An effective amount of a compound of the formula. A specific example of the invention is the use of a compound of formula J for the manufacture of a medicament for the treatment of multiple sclerosis in an individual in need of b' therapy. Examples are used to treat individuals with therapeutic needs A compound of formula I. A specific embodiment of the invention is a method of treating a stroke in an individual in need of treatment comprising administering an effective amount of a compound of formula I. One specific embodiment of the invention is a compound of formula I for use in the preparation. The use in the treatment of an individual having a need for treatment of 36 201113280 is a compound of the formula for the treatment of medicinal products requiring treatment of I. A specific example of the present invention is a method for treating an individual having a therapeutic need, which comprises administering a compound of the formula I in an effective form. A specific example is the use of a compound of formula 1 in the preparation of a discus for the treatment of ischemia in an individual in need of treatment. A specific example of the invention is, .A. ·" It is used as a compound of formula 786 which is a pharmaceutical for Parkinson's disease in an individual in need of treatment. A specific example of the present invention, Λ森氏 o n ^ ^ is a method of treating Parkinson's disease in an individual in need of treatment, which comprises administering an effective amount! Compound. A specific example of the invention is the use of &amp; ι compound in the preparation of a medicament for the treatment of Parkinson's and Kingson's disease in an individual in need of oral/oral treatment. A specific example of the present invention is that h^ is used as an /alpha therapeutic individual in need of treatment. A compound of formula j for a drug of Herzegovina. A specific embodiment of the invention is a method of treating Alzheimer's disease in a subject in need of treatment, comprising 〃G 3 匕 administering an effective amount of a compound of formula I. DETAILED DESCRIPTION OF THE INVENTION One example of the present invention is the use of a compound of the formula in the manufacture of a medicament for the treatment of Az沲&apos;, J. Hyehmorrhosis in an individual in need of treatment. As in the following examples, the *4 &amp; π _ hall is more detailed, and the individual used in the treatment of the CNS is the same as the South China, X disease, degenerative disease or demyelinating disease. The efficacy of the compound of formula I can be demonstrated in the actual and ambiguous travels (four) μ. Therefore, the effect can be demonstrated in the recurrence of recurrence, ^, afflicted with myelitis (ΕΑΕ, a kind of animal model of MS) &lt; full forebrain deficiency '', Dingfeng / cochlear blood A well-known animal model 37 in 201113280 type). Neuroprotection can be demonstrated by preventing glutamate-induced toxicity. The pathogenic process caused by the over-activation of excitatory neurotransmitter receptors by the protagonist and the maternal sex is impaired and killed by the pathological process. Because the face-to-face virgin is the major excitatory neurotransmitter in the mammalian CNS, excitatory sputum usually refers to prolonged or increased exposure to glutamate. High levels of face acid allow a pathologically high amount of about ions to enter the neuron by binding to excitatory receptors. Calcium influx at this order of magnitude activates a large number of knives, including phospholipases, endonucleases and proteases. These enzymes destroy cellular structures such as the cytoskeleton, membrane and DNa. Free radicals are produced that disrupt mitochondria and induce progressive cell death or necrosis. △ (4) Neurodegenerative diseases with unique causes share the excitotoxicity of common pathogens. Therefore, glutamine-induced excitotoxicity is involved in a large number of neurodegenerative diseases of the CNS, such as MS, ischemia/stroke, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington. Disease. A review of the effects of excitotoxicity on neurodegenerative diseases 'see D0ng XX et al., (2〇〇9) VIII as pharmac〇l sin 30(4): 379-87; Gonsette RE (2008) J Neurol Sci 274 (1 2).48-53, Vucic S and Kiernan MC (2009) Curr Mol Med 9(3): 255-72; Hyiid MR et al., (2004) Neurochem Int 45(5): 583-95; or Guy 〇t et al., (2〇〇1) valence (10) with Leu 299(1 -2): 37-40. Furthermore, neuroprotection can be explained by preventing oxidative damage. During physiological conditions, reactive nitrogen species (RNS) and reactive oxygen species (r〇s) 38 201113280 are produced in the aerobic life of all organisms. In mitochondria, free radicals are produced by incomplete reduction of 〇2 and during the "oxidative burst", inflammatory cells use RNS and R〇s to kill bacteria and viruses. The production of ROS and RNS is countered by an antioxidant defense system consisting of enzymatic and non-enzymatic antioxidants. Under pathological conditions (such as mitochondrial respiratory chain dysfunction or inflammation), excessive production of free radicals occurs, antioxidant defenses are overwhelmed and 〇xidative stress occurs. This abnormal regulation between RNS or ROS formation and antioxidant defenses is followed by an increase in the production of highly toxic nitrifying and oxidizing compounds that have the potential to alter the structure and function of mitochondria, proteins and nucleic acids. The peroxidation of polyunsaturated fatty acids that cause extensive structural damage to the membrane is extremely important due to its self-propagating response, which will not be terminated until the defense takes action or the text is exhausted. Mitochondria are primarily susceptible to oxidative stress-mediated damage due to their fatty membranes&apos; and because mitochondrial DNA lacks a protective group of proteins, it has fewer non-coding regions than nuclear DNA and has only limited repair. Oxidative stress is a recognized part of the pathogenesis of a large number of neurodegenerative diseases such as multiple sclerosis, stroke/ischemia, Parkinson's disease and Alzheimer's disease (Kaur C and Ling EA (2008) Curr Med Chem 15(29): 3068-80). In MS, R〇S and RNS are adhered by monocytes to the brain's endothelium. 'This adhesion introduces a morphological change in the blood-brain barrier (BBB) and thus makes it easier for white blood cells to enter the brain (van der G〇es a et al., (2〇〇1) FASEB J 1 5(1 0): 1 85 2-4). Once the activated white blood cells enter the brain, their production of ROS/RNS', which is enriched in 39 201113280, causes oligodendrocyte damage (van Meeteren ME et al. (2004) Biochem Pharmacol 67(5): 967-75), Myelin destruction and phagocytosis (van der Goes A et al. (1998) J Neuroimmunol 92(1-2): 67-75) and axonal and neuronal damage (Gilgun-Sherki Y et al., (2004) J Neurol 251(3): 261-8). Oxidative stress is induced by the depletion of the antioxidant system during MS, which has been shown in the serum of MS patients and in MS plagues (Gilgun-Sherki Y et al., (2004) J Neurol 251(3): 261-8: van Meeteren ME et al. (2005) Eur J Clin Nutr 59(12): 1347-61). Limited blood flow into the brain can cause ischemic stroke, which can be induced, for example, by cardiac arrest or cerebral arterial occlusion. Insufficient supply of oxygen and glucose leads to activation of multiple processes, such as oxidative and nitrification pressures and excessive glutamate release as described above, but will also cause blood-brain barrier dysfunction, acid toxicity, ion imbalance, mitochondrial damage, inflammation, and Apoptosis. Each of these mechanisms can cause cell death together or separately (Doyle et al. (2008) Neur〇pharmac〇 1 55(3): 310-318). The timing of each of these events is different, and necrosis-mediated cell death is often observed in permanent occlusion, and cell death most likely caused by apoptosis is mediated by mild injury (Br〇uns and De Deyn (2〇) 〇9)

Clin Neurol Neurosurg 1 1 1(6): 483_495 ). When the cells in the cerebral ischemia model are prevented from dying, the compound has significant neuroprotective effects and the neuroprotective effect can be produced by inhibiting one or more of the deleterious pathophysiological processes described above. 40 201113280 Neurotrophic properties or nerve regeneration potential can be explained. The differentiation and growth of neurons is a process mainly occurring in the developing nervous system and the formation of new neurons is extremely limited in the adult brain. Due to the lack of spontaneous neurite outgrowth and axonal regeneration in the adult central nervous system, even though many affected neurons can survive the initial injury, nerve damage in the brain and spinal cord often leads to destructive and persistent loss of function. . Under certain conditions, neurotrophic agents are able to induce neurite outgrowth, thus promoting regeneration that would be beneficial to conditions in which nerve cells are damaged or lost (Cm (2006) Mol Neur〇bi〇l 33(2): 155-179 These conditions are, for example, multiple sclerosis, stroke/ischemia, traumatic brain injury, spinal cord injury, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and the like. Neurotrophic properties can be accounted for in primary cell cultures of immature rodent brains, as these cell cultures still have the ability to form neurite outgrowth, which is further enhanced by treating cells with neurotrophic compounds (Radio) And Mundy (2008) Neurotoxicol 29(3): 361-379). Progressive loss of neurons is a hallmark of neurodegenerative diseases. In addition, it is recognized that when a patient first experiences neurological symptoms such as amyotrophic lateral sclerosis and Parkinson's disease, substantial neurodegeneration has occurred. In multiple sclerosis, most patients develop progressive irreversible damage 8–15 years after the onset of the disease. This appears to occur when axonal losses reach a threshold and cns compensatory resources are exhausted. Axonal degeneration is considered to be the main cause of irreversible nerve damage during the malignant phase of multiple sclerosis (9), et al. (2003) J Neurol Sci 206(2): 165-171, Trapp et al., (1999) Curr Opin Neurol 12(3): 295-302) 〇41 201113280 Example High Pressure Liquid Chromatography (hplc) HPLC was performed on a Waters Alliance e2695 separation module.

The Waters 2998 Photodiode Array Detector detects at wavelengths set to 22 〇 nm. The column used was a Waters XBridge C18 (100 X 4.6 mm, 3.5 /zm, 135A) which was held in a heating unit at 3 °c. Rt is the residence time of the compound. Conditions using phosphate buffer: Buffer A was 1 mM potassium dihydrogen phosphate in 95% water, 5% acetonitrile. Buffer B was 丨〇 mM potassium dihydrogen phosphate in 25% water, 75% acetonitrile. The flow rate is 丨〇 mL/min. After maintaining 1. 〇 min initially at 1% buffer B, the compound was eluted using a gradient of 1〇_9〇% buffer B for 10.0 min, followed by 2.0 min at 9〇% buffer B. Conditions using TFA buffer: Buffer a is 〇 1 〇 % trifluoroacetic acid in 95% water, 5% acetonitrile. Buffer B was 〇 8% 8% trifluoroacetic acid in 1% water, 90% acetonitrile. The flow rate is 1 _ 〇 mL/min. After 1_0 min of initial incubation in 〇% buffer B, the compound was eluted using a gradient of 0. 90% buffer b for 1 〇 min, followed by 2.0 min at 90% buffer β. High pressure liquid chromatography mass spectrometry (LCMS)

LCMS was performed on a Waters 27 95 separation module and detected via uv (TAC 215-350 nm), MS (TIC 100-1000 mz, ESI+ or ESI-). The column used was Waters XBridge C18 (2 x 30mm, 2 x 30mm, 5 // m) and was kept at 25 °C. Eluent A: aqueous phase (water, 10 mM acid-depleted hydrogenation &apos; pH 1 〇). Eluent b: acetonitrile. The flow rate is 丄〇 42 201113280

After mL/min and the injection was held for 0.1 min, the solution B was kept for 8 minutes for 4 minutes. Prepare HPLC product 5 # L. The following elution was carried out under the initial 1%% eluent a: increased to 95 over 3 minutes. / wash for a few minutes and return to i 〇〇% Eluent A. For total operation, perform preparative HPLC on the WaterS 3100 Separation Module and use the Waters 2998 Photodiode Array Detector set to PDA for detection. . The column used was Waters XBridge C18 (150 χ 3〇 mm) and was kept at room temperature. Eluent A was o.i% w/w ΝΗ4〇Η/Η20, and eluent B was MeOH. The flow rate was 50 mL/min. Develop methods for each goal. Mass Directed Automatic Purification (MDAP) MDAP was performed on a Waters 3 100 Separation Module and detected using a Waters 2998 Photodiode Array Detector set to PDA. The column used was Waters XBridge C18 (100 χ 19 mm) and was kept at room temperature. Eluent A was 0.1% w/w ΝΗ40Η/Η20, and eluent B was MeOH. The flow rate was 20 mL/min. After an initial hold of 1 minute, the compound was eluted using a gradient as defined in the following Table 历 for 1 * min*. Table 1 Method No. Initial Eluent B% Final Eluent B% Target LCMSRt (min) 1 2 20 0-1 2 5 40 0.5-1.5 3 10 50 1.0-2.0 4 20 70 1.5-2.5 5 30 _ 80 2.0 -3.0 6 50 95* (6 min gradient, hold for 4 min) 2.5+ 43 201113280 Nuclear magnetic resonance (NMR) using CDC13 or cd3〇d as solvent in Varian Mercury 3〇〇MHz or JEOL ECX300 ( MHz ) or ECX400 ( MHz The 1H NMR spectrum was operated on a spectrometer. The residual solvent signal (CDCl3 7.26 and CD3OD 5 3.31) was used as a reference. Gas liquid chromatography (GC)

The gc was performed on an Agilent 6890N instrument and the FID prediction was performed at 250 ° C with a flow rate of 25 ml/min ’ air flow rate of wo ml/min. The official column used is Varian VF5 (30 m X 0.32 mm X 0.25 // m). The initial temperature was set at 40 C (for 2 minutes) and the temperature was ramped to 250 ° C at 1 5 /min, where it was held for 4 minutes and the total operating time was 22 minutes. Example A. 1 · 1 : General procedure 1 ( 1 ) The amine (2_1 里) &gt; gluten is added dropwise to acetonitrile (1 mL per mm 酸i acid halide) and added dropwise at about 15 C. The solution was stirred at room temperature for _2 hours, then diluted with ethyl acetate (methanol, 2 mL). The reaction was then diluted with ethyl acetate (1 〇 ) 醢 。). The organic layer was washed with aq. hydrochloric acid (1.sub.2, 1 mL per mm of hydrazide, followed by 1 </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> and the aqueous layer was extracted with ethyl acetate (1 mL per mM hydrazide). The combined organic layers were washed with aq. EtOAc (1 mL EtOAc) Example A. 1 _ 2 · 2 -gas·jV-cyclohexylacetamide (〇〇2NK13) According to GP1, cyclohexylamine (21 mmobu 2.08 g) and ethyl chloroform (10 mmol, 1.12 g) were used. 2_Gacyclohexyl 44 201113280 acetamide (1.631 g, 93%) was obtained as a fluffy white crystal. NMR (CDC13) (5 6.44 (1H, broad s (Broad s), CO-NH-CH), 4.02 (2H, s, Cl-CIL), 3.89 (1H, m, CO-NH-CH), 1.92 (2H, m, cyclohexyl), 1 · 74 (2H, m, cyclohexyl), 1.63 (1H, m, cyclohexyl), 1.38 (2H, m, cyclohexyl), 1.25 (2H, m, cyclohexyl) , 1.16 (1H, m, cyclohexyl). HPLC phosphate buffer · · Rt 8.47 min (purity 98.5%). Example A.1.3: 3- gas-iV-cyclohexylpropionamide (002NK16) used according to GP1 Cyclohexylamine (210 mmol, 20.88 g) and 3-acetonide (100 mmol, 12.69 g) gave 3-cyclohexylideneamine (18.29 g, 96%) as fluffy white crystals. NMR (CDC13) (5 6.39 ( 1 H, broad unimodal, CO-NJi-CH), 3.72 (2H, t, J = 6.6 Hz, CI-CH2), 3.68 (1H, m, CO-NH-CH) , 2.56 (2H, t, J = 6.6 Hz, CI-CH2-CH2), 1.84 (2H, m, cyclohexyl), 1·64 (2H, m, cyclohexyl), 1.56 (1H, m, cyclohexyl) , 1.25 (2H, m, cyclohexyl), 1.13 (3H, m, cyclohexyl). HPLC phosphate buffer: Rt 8.67 min (purity: 94.5%). Example A.1.4: 4-V-AT-cyclohexyl Butylamine (002NK17) using cyclohexylamine according to GP1 210 mmol ' 20.83 g) and 4-gas butyl hydrazine (100 mmol, 14·10 g ) 'produces a light-colored solid. This crude material is vortexed in acetonitrile 1 (about 1 L) and filtered. , 4-chlorocyclohexylbutyramine (17.45 g, 86%) was obtained as a white powder. 'H NMR (CDCI3) δ 5.50 (1 Η, broad unimodal, CO-NH-CH), 3.77 (1H, m, CO-NH-CH), 3.61 , (2H, t, 3 = 6.1 Hz, 01-0Η2), 45 201113280 2.34 (2H,t, J = 7.1 Hz, C1-CH2-CH2-CH2), 2.11 ( 2H, m, Cl-CH2-Cii2), 1.91 (2H, m, cyclohexyl), 1.69 (3H, m, cyclohexyl), 1.35 (2H, m, cyclohexyl), 1.14 (3H, m, cyclohexyl) . HPLC phosphate buffer: Rt 9.56 min (purity 95.1%). EXAMPLES 1.1·5 : 2-bromo-AT-cyclohexylpropionamide (002NK18) Cyclohexylamine (210 mmol, 20.82 g) and 2-bromopropionium bromide (100 mmol, 21.63 g) were used according to GP1. 2-Bromo-TV-cyclohexylpropionamide (22.12 g, 94%) was obtained as a fluffy white crystal. ]H NMR (CDC13) δ 6.25 (1 Η, broad unimodal, CO-Nii-CH), 4.39 (1H, q, J = 7.0 Hz, Br-CH), 3.74 (1H, m, CO-NH-CH) , 1.90 (2H, m, cyclohexyl), 1.88 (3H, d, J = 7.0 Hz, Br-CH-CH3), 1_71 (2H, m, cyclohexyl), 1·64 (1H, m, cyclohexyl) , 1.37 (2H, m, cyclohexyl), 1_22 (3H, m, cyclohexyl). HPLC phosphate buffer: Rt 9.73 min (purity 99.4%). Example A. 1.6: 2-Bromo-A/··cyclohexylbutyridamine (〇〇2NK19) Cyclohexylamine (105 mmol, 10-40 g) and 2-bromobutane bromide (50 mmol, 11.49 g) were used according to GP1. ), producing a white solid. Recrystallization of the solid from methylene chloride / heptane gave 2-bromo-TV-cyclohexylbutylamine (10-32 g, 83%) as a white crystal. 'H NMR (CDC13) δ 6.30 (1 Η, broad unimodal, CO-Nii-CH), 4.29 (1H, dd, J = 7.4, 5.0 Hz, Br-CH), 3.75 (1H, m, CO-NH- CH), 2.15 (1H, m, Br-CH-CHH'), 2.12 (1H, m, Br-CH-CHU:, 1.92 (2H, m, cyclohexyl), 1.70 (2H, m, cyclohexyl), 1.62 (1H, m, cyclohexyl), 1.38 (2H, m, cyclohexyl), 1.22 (3H, m, 46, 201113280 cyclohexyl), 1.05 (3H, t, J = 7.2 Hz, Cii3-CH2-CHBr). HPLC phosphate buffer: Rt 10.83 min (purity 99.5%). Example A.1.7 ·· 2-Bromo-indole-cyclohexylhexylamine (〇〇2NK20) Cyclohexylamine according to GP1 (21 mmol, 2.09 g) And 2 - dimethyl bromide (10 mmol, 2.57 g) gave 2-bromocyclohexylhexylamine (2.65 g, 96%) as a white powder. 'H NMR (CDC13) δ 6.27 (1 Η, Width Single peak, CO-NH-CH), 4.29 (1H, dd, J=8.0, 5.1 Hz, Br-CH), 3.75 (1H, m, CO-NH-CH), 2.12 (1H, m, Br-CH -CHH'), 2.01 (1H, m, Br-CH-CHiL), 1.92 (2H, m, cyclohexyl), 1.70 (2H, m, cyclohexyl), l. 62 (1H, m, cyclohexyl), 1.5-1.3 (2H, m, cyclohexyl), 1.5-1.3 (4H, m, CH3-CH2-CH2), 1.22 (3H, m, cyclohexyl) Base), 0.92 (3H, t, J = 7.1 Hz, CH3-CH2-) 0 HPLC structuring buffer: Rt 1 3 · 〇 3 min (purity 98.9%). Example A.1.8: 2-ring Amylmethylacetamide (〇〇2NK31) was used as a light yellow oil based on GP1 using iV-decylcyclopentylamine (21 mmol, 2.09 g) and ethyl chloroform (10 mmol, 1·13 g). 2-Chlorocyclopentyl-mercaptoacetamide (1.56 g, 89%). 'H NMR (CDC13, mixture of two rotamers in a ratio of 5:4) δ 4.90 (4/9 Η, m, CO -NMe-CH), 4.19 (5/9H, m, CO-NMe-CH), 4.12 (10/9H, s, CI-CH2-), 4.07 (8/9H, s, CI-CH2-), 3.75 (1H, m, CO-NH-CH), 2.93 (12/9H, s, CH3-N), 2·83 (15/9H, s, Cii3-N), 2.0-1.8 (2H, m, cyclopentyl) Base), 1.8-1.4 (6H, m, cyclopentyl). 47 201113280 HPLC phosphate buffer: Rt 8.60 min (purity 95.3%). EXAMPLES 1·1·9 : ΛΚ4-tert-butylcyclohexyl)_2-chloroacetamidamine (002ΝΚ32) 4-tert-butylcyclohexylamine (42 mmol, 6.52 g) and acetamidine were used according to GP1 ( 20 mmol, 2.30 g), giving a crude material as a beige solid. The solid was extracted with diethyl ether (300 mL) and the mixture was filtered. Concentrate the solute to give cis-#-(4-t-butylcyclohexyl)_2_ephthylamine and trans-W-(4-t-butylcyclohexyl)-2-air B as a light beige solid A mixture of guanamine (3.52 g, 76%). 4 NMR (CDCh, a mixture of cis isomer and trans isomer in a ratio of about 2:3) &lt;5 6.80 (2/5H, broad unimodal, CO-NH-CH), 6.34 (3/5H , wide single peak, CO-NH-CS), 4.14 (2/5H, m, CO-NH-CJL), 4.07 (4/5H, s, CI-CH2-), 4.04 (6/5H, s, Cl -CHa-), 3.70 (3/5H, m,CO-NH-Cii), 2.04 (lH, m, cyclohexyl), i.95-1.8 (2H, m, cyclohexyl), 1.70 (1H, m, Cyclohexyl), 1.56 (1H, m, cyclohexyl), 1.3-1.0 (4H, m, cyclohexyl), 0.89 (18/5H, s, (Cii3) 3-C-), 0.87 (27/5H, s , (CH3)3-C-)- HPLC phosphate buffer: Rt 13.06 and 13.28 min (59.1% and 37.4%, respectively). Example AllO: 2-chloro-iV-methyl-iV-amylacetamide (002NK33) 7V-methylpentane-1 -amine (ι〇·5 mmol, 1 ·0 g) was used according to GP1 and Ethyl chloride (10 mmol, 564 mg) gave 2- gas-iV-mercapto-7/-mercaptoamine (766 mg, 8 6%) as a colorless oil. iH NMR (CDC13, a mixture of 2 rotamers in a ratio of approximately 1:1 48 201113280) (5 4.09 (1H, s, C1-CH2-), 4.07 (1H, s, CI-CH2-), 3.35 (2H, m, CO-NMe-CiL), 3.07 (3/2H, s, CiL-N), 2.96 (3/2H, s, CH3-N), 1.60 (2H, m, CH3-CH2-CH2- CH2), 1.32 (4H, m, CH3-CH2-CH2), 0.93 (3/2H, t, J=7.2 Hz, CH3-CH2-), 0.90 (3/2H, t, J = 7.2 Hz, C| i3-CH2-) HPLC phosphate buffer: Rt 9.97 min (purity 98.4%). Example VIII.1.11: 2-gas-#-(2-mercaptobutyl)-acetamide (002 &gt;^34 Using 2-methylbutan-1-amine (21 mmol, 1.82 g) and acetonitrile chloride (10 mmol, 1.13 g) according to GP1 to give 2- gas-#-(2-fluorenyl) as a colorless oil Butyl)-acetamide (1.47 g, 90%). 'H NMR (CDC13) δ 6.60 (1 Η, broad unimodal, CO-Nii-CH), 4.07 (2H, s, CI-CH2-), 3.27 (1H, m, CO-NH-CHH'), 3.14 (1H, m, CO-NH-CHH:), 1.64 (1H, m, NH-CHH'-CHMe), 1.43 (1H, m, CH3-CHH '-)5 1.22 (1H, m, CH3-CHH:)5 0.94 (3H, d, J = 6.7 Hz, CH3-CH-)5 0.94 (3H, m, CHj-CH2-) ° HPLC phosphate buffer : Rt: 8.34 min (purity 98.8%). Example A.1.12: 2-chloro(pentan-3-yl)- Indoleamine (002NK35) 2-Pentyl-3-yl (pentan-3-yl) was obtained as a pale yellow solid, using pentane-3-amine (42 mmol, 2.26 g) and acetonitrile (20 mmol ' 2.25 g) -Ethylamine (2.44 g, 75%). 'H NMR (CDC13) δ 6.26 (1 Η, broad unimodal, CO-Nii-CH), 4.08 (1H, s, Cl-CHs-), 3.83 (1H , m, CO-NH-CH), 1.61 (2H, m, CH3-CH2), 1.47 (2H, m, CH3-CH2), 0.93 (6H, t5 J = 7.4 Hz, CH-(CH2-CH3)2 ). 49 201113280 HPLC salt buffer: Rt 7·67 min (purity 9?·3%). Example A.l_13: TV-butyl-2-gas-TV-propylacetamide (002ΝΚ3 6) propylbutane-1-amine (4 mmol, 1.00 g) and ethyl hydrazine chloride (8.4) according to GP1 Methyl bromoacetamide (650 mg, 85%). ]H NMR (CDC13) (5 4.07 (2H, s, Cl-CH2-)5 3.31 (4H, m, CH2-N-CH2), 1-61 (4H, m, CH2-CH2-N-CH2-CH2 ), 1.34 (2H, m, N-CH2-CH2-CH2), 0.93 (3H, t, J = 7.4 Hz, CH3-CH2-)5 0.92 (3H, t, J = 7.4 Hz, C-CH2-) HPLC phosphate buffer: Rt 11.03 min (purity 97.0%). Example A.1.14: 2-bromo-iV-cyclohexyl-2-mercaptopropanamide (002NK67) Cyclohexylamine (210 mmol) according to GP1 20.8 g) and 2-bromo-2-mercaptopropyl bromide (100 mmol, 23.0 g) gave 2-bromo-TV-cyclohexyl-2-methylpropanamide (23.6 g, white powder). 95%). 'H NMR (300 MHz, cd3od) δ 3.77 - 3.52 (1 H, m, NH-Cii), 1.97 - 1.89 (6 Η, m, C(0)-C(CiL)2), 1.89 - 1.73 (4H, m, cyclohexyl), 1.73 -1.58 (1H, m, cyclohexyl), 1.54 -1.10 (5H, m, cyclohexyl) HPLC TFA buffer: Rt 15.28 min (purity 99.5%) Example A.1.15: 3U-cycloheptylpropionamide (002NK92) Cycloheptylamine (52_5 mmol, 5.94 g) was dissolved in DCM (5 ml) and added dropwise to about 1 (TC stirring) 3_Bromopropionium chloride (25 mmol, 4.28 g) in DCM (25 mL). Stirring at room temperature i Then, 50 201113280 Then add concentrated HC1 (2.5 mL), water (7.5 mL) and DCM (10 mL). Separate the layers with hydrochloric acid (丨·2 M, 丨〇mL), saturated aqueous sodium bicarbonate (1 0 (mL) The organic phase was washed, dried over magnesium sulfate, filtered and concentrated in vacuo. A column containing 40 g of cerium oxide (buffer a: 4 〇 _6 〇 petroleum ether, buffer B: 3:1 40) -60 petroleum ether: EtOAc) crude material was purified using 0% buffer B (1 min), then 〇 〇〇 〇〇 缓冲 缓冲 缓冲 ( ( ( ( ( ( 14 14 14 14 Elution was carried out to give 3-bromocycloheptylpropionamide (4.65 g, 75 〇/) as a white powder. HPLC TFA buffer: Rt 14 14 min (purity 78 2%). NMR (300 MHz, CDC13) 5.84 - 5.35 (1 H, m, ΝΗ), 3.98 (1 Η, ddq, J 13.2, 8.9, 4.4, NH-CH), 3.65 (2 H, t, J 6.6, CHj- Br), 2.71 (2 H, t, J 6.6, 01^-0(0)), 2.03 - 1.84 (2H, m, cyclopentyl, 1.78 - 1.35 (10 H, m, cyclopentyl). Example A·2 · 1 : General Procedure 2 ( GP2 ) The amine (1.0 eq.) was dissolved in acetonitrile (5 ml per g of amine) and the acid sulphate was added dropwise at 5 ° C (1 · 〇 equivalent And cesium carbonate (丨.〇 equivalent) in acetonitrile (15 mL per gram of acid halide). Stir the mixture at 5 °C for 15 minutes' then stir at room temperature for 1 hour. 15 mL) The mixture was diluted and extracted three times with Et 2 〇 or dioxane (DCM) (20 mL per gram of acid halide). The combined organic layers were passed through a phase separation cartridge, dried over magnesium sulfate, filtered and concentrated. The product was produced. Example A.2.2: #-((15,23,4 and)-substituted 1-bicyclo[2_2.1]heptan-2-yl)-2-ethaneacetamide (LJM 465-1) Use of exo-2-aminonorbornane (18 mmol, 1.43 51 201113280 mL) according to GP2 'chloroeththene (18 mmol, 5.9 g) and cesium carbonate (1 8 mmol, 5·9 § ) Extraction with Et20 gave #-((1 215,4 and)-l-biscyclo[2.2.1]heptan-2-yl)-2-chloroacetamide (2.7 g) as a yellow/white solid. 5 80%) LCMS: 95% Rt 2.16 min [M+H] + 188.1. Example A.2.3: 2-V-cyclopentylpropionamide (LJM 465-2) Cyclopentylamine (59 mmol) based on GP2 , 5_8 mL), 2-Acetone (59 mmol, 5.7 ml) and a carbonated hammer (59 mmol, 19_1 g), extracted with EtzO to give a 2-y-cyclopentyl propylamine as a yellow/white solid. (6.17 g, 60%) LCMS: 82% Rt 1.95 min [M + H] + 176.0. Example Α_2·4: 2- gas-iV-cyclobutyl acetamide (LJM 465-6) used according to GP2 Cyclobutylamine (42.2 mmol, 3 g), gas oxime (42.2 mmol, 3_4 ml) and carbonic acid (42.2 mmol, 13.7 g) were extracted with DCM to give a 2-yel-TV- Cyclobutyl acetamide (4.45 g ♦ 71%). LCMS: 99% Rt 1_39 min [M+H] + 148.0. Example A.2.5: 2-Gas-#-(3,3-Dimercaptobutyl)acetamide (LJM 465-7) 3,3-Dimethylbutylamine (29.6 mmol, 3) according to GP2 g), gas oxime (29.6 mmol, 2.4 ml) and bismuth sulphate (29 _ 6 mmol, 9.7 g), extracted with DCM to give 2- gas-W- (3,3- Dimercaptobutyl)acetamide (4.11 g, 78%). LCMS: 97% Rt 2.33 min [M + H] + 178.11 « 52 201113280 Example A_2.6: 2-chloro 1-((1^25,31570-2,6,6-trimethylbicyclo[3.1.1 Heptan-3-yl)acetamide (LJM 465-26) used according to GP2 (151,2 &lt;S,3&lt;S,5 and)(+)-isopinocamphoylamine (19.6 mmol » 3 g), chlorohydrazine chloride (19.6 mmol, 1.6 ml) and carbonic acid (1 9.6 mmol, 6.4 g), extracted with DCM to give 2-chloro 4- (1,125,315/0- 2,6,6-Trimethylbicyclo[3.1.1]heptan-3-yl)acetamide (4.56 g, &gt;99%), solidified upon standing. LCMS: 97% Rt 2.89 min [M+ H] + 230.1. Example A.2.7: 2-Chloro-indole-(4,4-difluorocyclohexyl)acetamide (LJM 465-29) 4,4-difluorocyclohexylamine hydrochloride was used according to GP2 ( 1 1.65 mmol, 2 g), methylene chloride (11.65 mmol, 0.878 ml) and carbazide (25.63 mmol, 8.4 g), eluted with DCM to yield 2- gas-/-- (4, 4-difluorocyclohexyl)acetamide (1.68 g, 68%). LCMS: 100% Rt 1.79 min [M + H] + 212.04. Example A. 2.8: (i?)-2-chlorocyclohexyl Acetylamine (LJM 465-30) used according to GP2 (Λ) ( -)-cyclohexylethyl-2-amine (23.58 mmol, 3 g), gas with gas (23.58 mmol, 2.66 g) and carbonic acid (23.58 mmol, 7.7 g), extracted with DCM (only) 2-(cyclohexylethyl)acetamide (3 g, 62%) as an orange solid. LCMS: 95% Rt 2.63 min [M + H] + 204.07.

Example A.2.9: 2-Chloro-#-(4-ethylcyclohexyl)acetamide (LJM 53 201113280 465-44) 4-ethylcyclohexylamine (23.57 mmol, 3 g), gas according to GP2 Chlorine (23.57 mmol, 2_2 ml) and cesium carbonate (23.57 mmol, 7.7 g) were extracted with DCM to give 2- gas-iV-(4-ethylcyclohexyl)acetamide as a pale yellow oil. 4.36, 91%). LCMS: 89% Rt 2.72 min [M + H] + 204.09. Example A.2.10: 2-Chlorohydroxyindole)cyclopentyl)acetamide (LJM 456-43) 1-Amino-1-cyclopentanol (17.37 mmol, 2 g), gas according to GP2 Ethyl chloride (17.37 mmol, 1.4 mL) and carbonic acid (17.37 mmol, 5.7 g) were obtained eluted with DCM to yield 2- hydroxy hydrazyl) cyclopentyl) acetamide (3.2 1 g, 96%), crystallized upon standing. LCMS: 7 8% Rt 1.63 min [M + H] + 192.0. Example A.2.1 1 : 3-Gas ((trans-2-hydroxycyclohexyl)decyl)propanamide (LJM 465-35) Using trans-2-(aminomethyl)-cyclohexanol according to GP2 (19.35 Methyl acetate (2.5 g), 3-air-propionyl chloride (19.35 mmol, 1·9 mL) and carbonic acid (19.35 mmol, 6.3 g) were extracted with DCM to give 3------ Trans-2-hydroxycyclohexyl)indolyl propylamine (4.1 g, 96%). LCMS: 70% R, 1.77 min [M+H] + 184.08 (-HC1) &gt; 27% Rt 1.94 min [M+H] + 220.1 (product). Example A.2.12: 2-Gas-1(2-ethoxycyclohexyl)acetamide (LJM 465-84) 2-Ethoxycyclohexanone (10 mmol, 1.42 g), ammonium acetate (100 54 201113280) Methyl ' 7.71 g) and NaCNBH3 (7 mmol '447 mg) were placed in an vented, argon-filled flask. The sterol (3 () in L) was added and the reaction was stirred at room temperature for 5 minutes, after which some 3 molecular sieves were added. The reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo, then EtOAc (EtOAc)EtOAc. An aqueous solution of k〇h (2 Μ ) was added until pH &gt;9, followed by the addition of brine (3 〇 ml). The product was extracted with EtOAc (3 mL EtOAc)EtOAc. Crude 2-ethoxycyclohexylamine (4.89 mmol, 700 mg), methylene chloride (4.89 mmol, 0, 39 ml) and hexane (4.89 mmol, 1.6 g) Oily solid 2_ gas_^(2-ethoxycyclohexyl)acetamide (894 mg, 83%). LCMS: 38% Rt 0.62 min [M+H] + 220. Example A.2.13: 2-Chloro-7V-(3-cyclopentylpropyl)acetamide (LJM 465-11) 3-(cyclopentylpropyl)amine (23.6 mmol, 3 g) according to GP2 , gas oxime (23.6 mmol, 1.9 mL) and carbonic acid planing (23.6 mmol, 7.7 g) 'extracted with DCM to give 2-y-[3-cyclopentylpropyl) acetamidine Amine (4.32 g, 90%). LCMS: 94% Rt 2.77 min [M + H] + 204.21. Example A.2.14. 2-Gas-indole/'-(2-cyclooctylethyl)propanamide (LJM 465-17) 2-Cyclooctylethylamine (12.88 mmol, 2 g) according to GP2 , 55 201113280 2-Acetone chloride (12.88 mmol, 1 ·25 mL) and cesium carbonate (1 2.88 mmol, 4.2 g), extracted with DCM to give a 2-yel--7V- (2-ring) as a yellow oil Octylethyl) propylamine (2.98 g, 94%). LCMS: 96% Rt 3.18 min [M + H] + 246.2. Example A.2.15: 2-Chloro(cis-4-hydroxycyclohexyl)acetamide (LJM 465-16) cis-4-aminocyclohexanol hydrochloride (16.5 mmol, 2.5 g) was used according to GP2. Ethyl acesulfide (16.5 mmol, 1.3 mL) and cesium carbonate (36.3 mmol, 11.8 g) were purified eluting with DCM to yield 2-chloro-TV-(cis-4-hydroxycyclohexyl)acetamide as an orange solid ( 1.05 g, 33%). LCMS: 84% Rt 1.18 min [M + H] + 192.0. Example A.2.16: 2-Chloro-TV-(trans-4-hydroxycyclohexyl)acetamide (LJM 465-15) Using trans-4-aminocyclohexanol (26.0 mmol, 3 g) according to GP2, gas B. Chlorine (26_〇111111〇1, 2.11111) and carbonic acid (26_〇1]1111〇1,8.5§), extracted with DCM to give 2-chloro-iV- (trans-4) as a yellow oil -Hydroxycyclohexyl) acetamidine (3.34 g, 60%). LCMS: 100% Rt 1_18 min [M + H] + 1921. Example A.2.17: (i?)-2-Gas-#-(3,3-Dimercaptobutan-2-yl)acetamide (LJM 465-25) Use (i?)- according to GP2 -)-3,3-dimercapto-2-butylamine (29.65 mmo b 3g), chloroacetamidine (29.65 mmol, 2.4 mL) and carbonic acid planer (29.65 mmol, 9.7 g), extracted with DCM to give (and) 2-V-N-(3,3-didecylbutan-2-yl)acetamide (4.3 g, 82%). 56 201113280 LCMS : 84% Rt 2_24 min [M + H] + 178.1. Example A. 2.18: 2-Chlorocyclobutylpropionamide (LJM 465-10) According to GP2, cyclobutylamine (28.12 mmol, 2 g), 2-acetone chloride (28.1 2 mmol ' 2.73 ml) and Barium carbonate (28.1 2 mmo, 9.1 6 g), extracted with DCM to give a white solid, 2 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; +H]+ 162.04. EXAMPLES 2·2·19 : 2-Vethylethyl 4-(4-(trifluoromethyl)cyclohexyl)acetamide (LJM 456-78) 4-(Di-indenyl)cyclohexanone (6 Methyl acetate (1.0 mL) was dissolved in EtOAc (35 mL). And acetic acid (6 mmol, 0.34 mL). The reaction was stirred under an argon atmosphere for 4 hours, followed by addition of KOH (about 1 M) to pH &gt; Add brine (20 mL) and EtOAc (3 mL (EtOAc) Amine (1.4 g, 89%). According to GP2, crude oxime-ethyl_4_(trifluoromethyl)cyclohexylamine (5.12 mmol '1 g), gas oxime (5.12 mmol, 0.41 mL) and carbonic acid planer (5.12 mmol, 1.7 g) were used. DCM extraction gave 2-chloroethyl-τν_(4-(trifluoromethyl)cyclohexyl)acetamide (982 mg, 71%) as an orange oil. LCMS: 94% Rt 0.79 min [M + H] + 272.08.

Example A.2.20: 2-Ga-7-(4,4-difluorocyclohexyl)acetamide (LJM 57 201113280 465-28) 4,4·difluorocyclohexylamine hydrochloride (11.65) according to GP2 Methyl 2-chloro-, (4,4-difluoro) was obtained as a yellow solid, eluting with EtOAc (EtOAc: EtOAc (EtOAc) Cyclohexyl) acetamidine (1.68 g, 68%). LCMS: 100% Rt 1.79 min [M + H]. 212.04. EXAMPLES 3·3 · 1 : General procedure 3 ( GP3 ) Adding an amine (1·0 equivalent) of ethanol (1 mL per mmol of amine) to ethanol containing strontium (1.1 equivalents) and sodium carbonate (3 equivalents) (2 mL per mm〇i amine). The reaction was heated to reflux for 2 to 3 hours, followed by water (5 mL per mmol of amine) and aqueous sodium carbonate (iM, 5 mL per mmol of amine). The product was extracted with ethyl acetate (3 times, 2 mL mL per mm.) and organic layers were combined. Wash Dowex® 50WX2 hydrogen type 1 00-200 mesh (4 g per mm〇i amine) with methanol (10 mL of mother resin). The reaction mixture was loaded onto an ion exchange resin using gravity filtration and the resin was washed with methanol (Raspberry Resin 丨〇 mL). The product was eluted with about 1 ΝΑ of a decyl alcohol solution (1 〇 mL per gram of resin) and the solution was concentrated to give the product. Example A_3·2 : 2-(4-Ethyl-i,4-diazepane-yl)-τν_cyclohexylacetamide (002NK24) Addition of 1-(1,4-dinitrogen) Heterocyclic heptyl-acetophenone (1 mmol '127 mg) in ethanol (0.5 mL) to 2-gas-AT-cyclohexylacetamide (1 1 mmol, 193 mg) and sodium carbonate (i_i mm 〇1, n7 mg) in ethanol (2 mL) and the reaction was heated to reflux for 75 min. Add sodium carbonate (i.9 58 201113280 min. Use well (4 g) 〇 exchange resin mmol ' 2〇5 mg ) and heat the reaction to reflux, then continue to 45 sterol (40 mL) to wash Dowex® 50WX2 hydrogen type The reaction mixture was filtered through a sieve of iOQ.zoQ and then loaded onto the ions using gravity filtration. The reaction flask was washed with methanol (2 mL) and the washing was transferred and loaded onto the resin, and the resin was washed with methanol (40 mL). The product was eluted with a solution of about 1 in methanol (20 mL·) and the solution was concentrated to give 2-(4-ethyiyl-1,4-diazepane-indole) as a pale yellow oil. ) 沁 Cyclohexyl acetamide (247 mg, 88%). NMR (CDsOD, a mixture of 2 rotamers in a ratio of about 1:1) 5 3.6 〇 (1H, m, CO-NH-Cii), 3.61 (4H, m, diazane: alkane), 3.16 ( 1H, s, CO-CiL-N), 3.14 (1H, s, C0_CH2_N), 2 83 (lH, m, diazepane), 2.73 (3H, m, diazepane), 213 (3/2H, s, CH3-CO), 2.11 (3/2H, s, CH3-CO)5 1.95-1.7 (2H, m diheptane), 1.95-1.7 (4H, m, cyclohexyl) ), 164 (1H, m, cyclohexyl), 1.5-l-2 (5H, m, cyclohexyl). HPLC phosphate buffer: Rt 6.19 min (purity 94 5%). Example A.3.3. ΑΓ-cyclohexyl-2-(4-mercapto-1,4-dicycloheptane-1·yl)acetamide (002NK25) 1-methyl_ι according to GP3 , 4-diazepane 〇mm〇1,115 mg ), 2-dis-AA-cyclohexylacetamide (1 · 1 mm〇i, 193 mg) and sodium carbonate (3 mmol ' 312 mg) '############################################################################ H NMR (CD3OD) δ 3.69 (1Η, m, CO-NH-CH), 3.12 (2H, s, CO-CH2-N), 2.39 (3H, s, CH3-N), 2.85-2.6 (8H, m , 59 201113280 diazepane), 1.9-1.6 (2H, m, diazepane), 1.9-1.6 (5H, m, cyclohexyl), 1.5-1.2 (5H, m, cyclohexyl) . HPLC pH buffer: Rt 4.86 min (purity 94.3%). Example A.3.4: Indole cyclohexyl-2-(dihydro-indene/f-pyrido[1,2-α]pyridin-2[6Η,7Η,名Η,9Η,9αΗ)·基)乙醢Amine (002: 30) According to GP3, octahydro-l/ί-pyrido[1,2-α]pyrazine (1 mm〇l, 141 mg), 2-cyclohexylacetamide (1.1 mmol, 194) Mg) and sodium carbonate (3 mmol '32 1 mg), yielding cyclohexyl-2-(dihydro-I//.0-pyridyl[1,2-α]pyrazine-2 (67) /, 7//, 8//, 9//, %//)-based) Acetamine (274 mg, 98%). 'H NMR (CD3OD) δ 3.68 (1Η, m, CO-NH-CH), 2.98 (2H, s, CO-CiL-N), 2.82 (2H, m, pyrido[1,2-α]pyrazine ), 2.71 (2H, m, pyrido[1,2-α]pyridine), 2_39 (2H,m,pyrido[1,2-α]pyridinyl), 2.11 (2H,m,pyridin[1] , 2-α]pyrazine, 2.00 (lH, m, pyrido[1,2-α]. specific tillage), 1.84 (2H, m, cyclohexyl), 1_75 (2H, m, cyclohexyl), 1.75 (lH,m,pyrido[1,2-ίζ]pyridin), 1.65-1.5 (3H,m,pyrido[1,2-α]pyrazine), 1.66 (lH,m,cyclohexyl), 1.45 -1.2 (5H, m, cyclohexyl), 1.25 (2H, m, pyrido[1,2·α]pyrazine). HPLC pH buffer: Rt 5.9 1 min (purity 95.9%). Example A.3.5: Cyclopentyl-2·(4·ethyl·3_mercaptopipen-bu)-#-mercaptoacetamide (002ΝΚ37) 1-ethyl-methyl 0 according to GP3 Dessin (1 mmo 1,12 8 mg), 2-cyclopentylmethylethylamine (1.1 mmol, 193 mg) and sodium carbonate (3 mmol, 317 mg) gave a yellow oil. Amyl 2-(4-201113280 ethyl-3-mercaptopiperidin-1-yl)-iv-mercaptoacetamide (265 mg, 99%). H NMR (CDsOD, a mixture of 2 rotamers in a ratio of about 2:3) &lt;5 4.85 (2/5 H, m, CO-NMe-CH), 4.50 (3/5 H, m, CO -NMe-CH), 3.24 (6/5H, s, CO-CHa-N), 3.19 (4/5H, s, CO-Ciia-N), 2.94 (6/5H,s, CO-NCE3-), 2.85 (4H, m, piperidine), 2.80 (9/5H, s, CO-NCE3-), 2.51 (1H, m, piperene), 2.37 (1H, m, piperidine), 2·37 (2H, m,CH2-CH3)' 2.04 (1H, m, piperidine), 1.90 (lH, m, cyclopentyl), 1.76 (3H, m, cyclopentyl), 1.62 (4H, m, cyclopentyl), 1·07 (3H, t, J = 7.2 Hz, Cijb-CH), 1·07 (3H, d, J = 6.3 Hz, CiL_CH2) ° HPLC phosphate buffer: Rt 5.22 min (purity 96.0%). Example A.3.6: #-(2-Mercaptobutyl)-2-(4-propionylpiperidin-1-yl)acetamide (002NK40) 1 -(η辰明:-1) according to GP3 -yl)propan-1-one (1 mmol, 144 mg), 2-chloro-indole/(2-nonylbutyl)ethinamide (1.1 mmol, 182 mg) and sodium carbonate (3 mmol '3) 1 6 mg ), iV-(2-mercaptobutyl)-2-(4-propenyloxymethyl-2-yl)acetamide (258 mg, 96%) was obtained as a colorless oil. H NMR (CD3OD) δ 3·69 (m, 4 Η, piperene), 3.17 (1Η, dd, J=13.1, 6.2 Hz, CO-NH-CHH'), 3.06 (1H, dd, J=13.1, 7.4 Hz, CO-NH-CHH:), 3.05 (2H, s, CO-CH2-N), 2.52 (4H, m, piped), 2.41 (2H, q, J = 7.4 Hz, CO-CH2-CH3 ), 1_60 (1H, m, CH2-CHMe-CH2-), 1.43 (1H, m, CH3-CHH'-CHMe-), 1.19 (1H, m, CH3-CHH:-CHMe-), 1.12 (3H, t, J = 7.4 Hz, CH3-CH2-CO), 0.94 (3H, t, J = 7.3 Hz, CH3-CH2-CHMe-), 61 201113280 0.91 (3H,d,J=6.7 Hz,CH3-CH- ). HPLC phosphate buffer: Rt 7.74 min (purity 91.7%). Example A.4.1: General Procedure 4 (GP4) An amine (2.0 eq.) was added to aqueous hydrochloric acid (2.0 eq, 1.2 Μ) and stirred for about 5 minutes. Add ethanol (1.o. equivalent) of ethanol (2 mL per mmol of amine) and heat the reaction to reflux for 2-3 hours. The reaction was cooled to room temperature and an aqueous solution of sodium carbonate (1 Μ, 10 mL per m. The product was extracted with ethyl acetate (3 times, 20 mL per mmol) and the organic layers were combined. Dowex® 50WX2 hydrogen type 100-200 mesh (4 g per mmol of halocarbon) was washed with methanol (1 〇 mL per gram of resin). The reaction mixture was loaded onto an ion exchange resin using gravity filtration and the resin was washed with decyl alcohol (per gram of resin). The product was eluted with a solution of about 1 Μ NH 3 in methanol (1 〇 mL per gram of resin) and the solution was concentrated to give the product. Example A.4.2: #-(4-Tert-butylcyclohexyl)-2-(andnidinyl)acetamide (002NK38) was used according to GP4.啡 ( (2 mmo 卜 170 mg ) 'hydrochloric acid (2 mmo Bu 1 · 67 mL) and a mixture of cis and trans-#-(4-t-butylcyclohexyl)-2· chloroacetamide (1 ·0 Ment, 23 1 mg ), which produces a mixture of cis- and trans-iV-(4-di-dibutyl-thenyl)-2-(parphin-1-yl)ethene in the form of a yellow molten solid (209 Mg &gt; 74%). 4 NMR (CDsOD, a mixture of cis and trans isomers in a ratio of about 1:1) &lt;5 4.02 (1/2H, m, CO-NH-CH), 3.59 (i/2H m CO-NH- CH), 3.00 (1HS m5 CO-CH2-N), 2.96 (iH m 62 201113280 CO-CH2-N), 2.87 (4H, m, piperidine), (3H, m, cyclohexyl ring 2.50 (4H, m , Parylene), 1.87 hexyl), 1_57 (1H, m, cyclohexyl), 1.3-1.0 (4H, m, cyclohexyl), 0·89 (9/2H, s, (Cii3) 3-C). °·91 (9/2Η, s, (CH3)3-C), HPLC phosphate buffer: Rt 8.32 and 40·2%). 8.73 min (purity: 38.5% Example Α·4.3: 2-(1,4-diyl)acetamidine (002ΝΚ41) azepan-1-yl)-7V-(pentane-3- According to GP4, 1'4-diazacycloheptane (2 ca. 1199), hydrochloric acid (2 mm〇1 'i.67 mL) and 2_gas|(戍烧冬基) acetamide (i 〇) Mmoh 169 mg) yielded 2_(1,4_di-heterocycloheptan-1-yl)-7V-(pentan-3-yl)acetamide (184 mg, 81%) as a colorless oil. NMR (CD3OD) δ 3.69 (1Η, m5 CO-NH-CH), 3.18 (2H, s, CO-Ci^-N), 2.91 (4H, m, diazepane), 2.75 (4H, m , diazepane), 1.81 (2H, m, diazepane), 16 〇 (2h, m, CH3.CH2), 1.48 (2H, m, CH3-CH2), 0.91 (6H, t, J = 7.4 Hz, CH-(CH2-CiL)2) 〇HPLC wall acid buffer: Rt 2.61 min (purity: 91.7%). Example A.4.4: Λ/'-butyl-2-( Anti-2,5-dimercapto-l-yl-l-yl)-τ^_propyl acetamide (002NK42) According to GP4, anti-2,5-diinyl ryphine (2 mmol, 229 mg), Hydrochloric acid (2 mmo, 1.67 mL) and TV-butyl-2-gas-AT-propylacetamide (〇mmol '192 mg) 'produced as a yellow solid -2-(trans-2,5-monodecylamine^1-yl)-iV-propylacetamide (135 mg, 50%). 63 201113280 'H NMR (CD3OD) δ 3.75 (1Η, m , CO-N(CH_H,-)-CHH 丨), 3.48 (1H, m, CO-N(CHH:-)-CHH'), 3.38 (1H, m, CO-N(CHH'-)-CHH' ), 3.35 (2H, s, CO-CH2-N), 3.23 (1H, m, CO-N(CHH'-)-CHii:), 2.82 (2H, m, piperene), 2.67 (2H, m, Piper), 2.51 (1H, dd, J = 12.3, 10.5 Hz, piped), 2.35 (1H, dd, J = 12.2, 10.6 Hz, piped), 1.59 (4H, m, N-(CH2-CH2) -CH3)2), 1.34 (2H, m, CH2-CH2-CH2-CH3)} 1.05 (3H, d, J=6.2 Hz, CH3-CH), 1.02 (3H, d, J = 6.4 Hz, CH3- CH), 0.95 (CH3-CH2), 0.90 (Ciis-CHz). HPLC phosphate buffer: Rt 7.5 7 min (purity 83.3%). Example A_5.1: General Procedure 5 (GP5) Adding an amine (2.0 eq.) to aqueous hydrochloric acid (2.0 eq., 1.2 Μ), followed by the addition of a halogenated alkane (1_0 equivalent) of ethanol (2 mL per mmol of amine) and The reaction was heated to reflux. The reaction was cooled to room temperature and aqueous sodium carbonate solution (1 Μ, 10 mL per mmol) was added. The product was extracted with EtOAc (3 EtOAc EtOAc) The crude material was purified using Combiflash (buffer A: Et.sub.2, buffer b: &lt;RTI ID=0.0&gt;&gt; EXAMPLES 5·5·Π(2-methylbutyl)_2·(Peptin-Buji) acetamamine (002ΝΚ46) According to GPS, the use of travel (6_〇卜6〇1 mg), hydrochloric acid (6匪) 〇1, 5mL) and 2·gas (2_methylbutyl) acetamidine (3〇 〇丨, 49丨64 201113280 and the reaction is heated to reflux for 6 hours. Use contains 2 g of cerium oxide The crude material was purified by column column and eluted with 0% buffer B (1 min) followed by 〇1〇〇% buffer B (for u minutes) and 1% buffer B (3 minutes). Colorless oily bismuth (2-methylbutyl)_2_(peptidin-yl-yl)acetamide (358 mg, 56%). HPLC TFA buffer: Rt 6 78 min. 'H NMR (300 MHz, cd3 〇(l) 3.17 (1 H, dd, J 13.2, 6.2, C(O)-NH-CHH'), 3.05 (1 H, dd, J 13.2, 7.2, C(0)-NH-CHH3, 3.00 ( 2 H,s,C(0)-CE2-N), 2.97 - 2.84 (4 H,m,piped), 2.58 -2.46 (4 H,m,piped), 1.59 (1 H,m, NH- CH2-Cii-(Me)Et), 1_41 (1 H, m, NH-CH2-CHMe-CHH'), 1.16 (1 H, m, 丽-CH2-CHMe-CHE〇, 0.93 (2 h, t, ;; 7 4, CH2_CK3), 〇.91 (3 H, d, / 6.7, CH-Cii3). Example A.5.3: Butyl 2 · (Peptonol-bu) propyl acetamide (002NK50) According to GP5, piperidine (4.5 mmol, 388 mg), hydrochloric acid (4.5 mmol ' 3.75 mL) and A/&quot;-butyl-2-gas- TV&quot;-propylacetamide (2_25 mmol, 43 1 mg) and heat the reaction to reflux for 5 hours. Purify the crude material using a column containing 12 g of cerium oxide, using 〇% buffer B (1 In the next minute), followed by 0-100% buffer B (for n minutes) and 1% buffer B (5 minutes) for elution, resulting in a pale yellow oil of butyl-2_(pipeline_j _ group -1 propyl acetamide (480 mg, 88%). HPLC TFA buffer: Rt 8.48 min. 'Η NMR (300 MHz, cd3od) 3.40-3.20 (4 H, m, 65 201113280 C(0)- NH-(Cii2)2), 2_97 (4H, m, phloem:), 2.58 (4H, m, piperene), 1.59 (4 H, m, C(0)-NH-(CH2-CH2) 2), 1.35 (2 H, m, C(0)-NH-CH2-CH2-CiL·), 0.99 (3 H, t, J 7.3, CH2-CH3), 0.95 (5 H, t, J 7.2, CH2-CH3) 〇 Example A.5.4: 2-(1,4-diazepanemethylbutyl)acetamide (002NK59) High piperazine (5.1 mmo b 5 16 mg) according to GP5 , hydrochloric acid (5.1 mmol, 4.25 mL) and 2-gas-#-(2-A Butyl) acetyl amine (1.7 mmol, 278 mg) and the reaction was heated to reflux for i 8 hours. The crude material was purified using a column containing 2 g of cerium oxide in summer, using 〇% buffer B (1 minute), followed by 0-100% buffer B (for 11 minutes) and 1% buffer b (9: 3⁄41⁄2) elution to give 2-(1,4-diazepan-1-yl)-#-(2-mercaptobutyl)acetamide as a yellow oil (331 mg, 86%) . HPLC TFA buffer: Rt 6.84 min. 'Η NMR (300 MHz, cd3od) 3.18 (2 H, s, C(〇)-CH2-N), 3.18 (1 H, dd, J 13.9, 5.6, C(0)-NH-CHH')5 3.06 (1H} dd, J 13.2, 7·1' 〇(〇)·ΝΗΤΗί〇, 2.95 (4 H,m,diazepane), 2.77(4H,m,diazepane乂^纟(1) is called diazepane), 161 (1 H,m,NH-CH2-CH-(Me)Et), 1.43 (i H,m,NH-CHrCHMe-CilH'), 1.17 (1 H , m, NH-CH2-CHMe-CHiD, 0.94 (2H, t, J 7.4, CH2-CH3)5 0.91 (3H, d5J 6.7, CH-CH3) 〇 Example A.5.5: Icyclopentyl Methyl-2_(pipestatin-yl)acetamide (002NK60) According to GP5, piperidine (12 mm〇l, 1.04 g), hydrochloric acid (12 mm 66b 66 201113280 10 mL) and 2-chloro-ΛΑ -cyclopentyl-indole/'-mercaptoacetamide (4 mmol, 70 1 mg) and the reaction was heated to reflux for 18 h. The crude material was purified using a column containing 12 g of cerium oxide. 0% buffer B (1 minute), followed by 〇_1 〇〇% buffer B (for 11 minutes) and 100% buffer B (7 minutes) for elution, yielding a light yellow oil-like cyclopentyl group - mercapto-2-(pemamine: -1 -yl) acetamidine (601 mg, 67%). HPL C TFA buffer: Rt 5·92 min. 4 NMR (CD3〇D, a mixture of 2 rotamers at a ratio of about ι:ι) δ 4.83 (1/2 H, m, CO-NMe-CH), 4.50 (1/2 H, m5 CO-NMe-CH), 3.28 (1 H, s, CO-CH2-N), 3.23 (1 H, s, CO-CiL-N), 2.94 (3/2 H, s, CO-NCD, 2_92 (4H, m, piperidine), 2.79 (3/2 H, s, CO-Nd), 2, 55 (4H, m, piperphine), i.91 (1H, m, Cyclopentyl), 1.77 (3H, m, cyclopentyl), i.63 (4H, m, cyclopentyl). Example A.5.6: 2-(l,4-diazepane-丨·Base)methyl_#· amyl acetamide (002NK64) According to GP5, use high piperage (12 claws 1 19 g), hydrochloric acid (12, H) mL) and 2-gas 4 methyl province. Ethylamine (4 m;; 〇i, 7〇9) and the reaction was heated to reflux for 3.5 hours. The crude material was purified using a column containing 12 g of sulphur dioxide, with 〇% slow for #m minutes), followed by 0-1 00% buffer B (duration I] eight pulls, 乪吋 11 minutes) and 1〇〇 % Buffer B (7 minutes) was eluted to give 2-(1,4-diazepine + base) good methyl I amyl decylamine (367 mg) , 38%). HPLCTFA buffer: Rt7 53 min. H NMR (CD3OD, a mixture of 2 rotamers in &amp; ι:ι ratio 67 201113280) 3.41 (1 h, s, CO-Cii2-N), 3.39 (1 H, s, CO-Cii2-N ), 3.36 (2 H, m, C〇-NMe-CH2), 3.08 (3/2 H, s, CO-NCH3-)5 2.91 (4 H, m, _ azepane), 2·9 〇(3/2 h, s,CO-NCiis-), 2.76 (4 H, m, azepane), i 82 (2 H,m,diazepane),i 6〇( 2 H, m, CO-NMe-CH2-CH2)5 1.34 (4 H, m, -CH2-CH2-CH3), 0.95 (3/2 H, t, J 7.1, -CH2-CH2-CH3)5 0.92 (3/2 H, t, J 7.1, -CH2-CH2-Ca3). Example A.5.7: #-Cyclohexyl-2-(piperidin-yl-yl)hexylamine (002ΝΚ1 1〇) Using piperidine (12 mmo Bu 1.04 g), hydrochloric acid (12 mmo Bu 1 mL) And 2-bromo-TV-cyclohexylhexylamine (4 mmol, 1 · 1 〇g). The reaction was heated to reflux under GP5 for 2 days, u-bottom (6 mmol, 500 mg) was added and the reaction was heated to reflux for a further 1 day. The crude material was purified using a column containing g2 g of cerium oxide using 0% buffer B (1 min) followed by 〇·1 〇〇% buffer B (for 1 1 min) and 1 〇〇% buffer B (7 minutes) elution was carried out to give a white powder of A/·J 己 基 - 2- (Ltyphin-1-yl) hexylamine (5 50 mg j 49%). HPLC TFA buffer: Rt 10.42 min. H NMR (300 MHz, cd3od) 3.67 (1 H, m, CO-NH-Cii), 2.86 (4 H, m, piperphine), 2.82 (1 H, m, CO-Cii-N), 2.59 ( 4 H,m,piperidin), 1.97 · 1.50 (5 H, m, cyclohexyl), 1.97 -1.50 (2 H, m, CO-CH-CH2), 1.50 - 1.08 (5 H, m, cyclohexyl) , 1.50 - 1.08 (4 H, m, -Cii2-CiL-CH3), 0.92 (3H, t, J 7.1, -CH2-CH2-Cii3). Example A.5·8: Cyclohexyl-2_(piperidin-1-yl)butanamine 68 201113280 (002NK1 1 1 ) Using morphine (1 2 mmol ' 1.02 g), hydrochloric acid (12 mmol, 1 〇) mL) and 2-Mo-TV-cyclohexylbutylidene (4 mmol, 998 mg). The reaction was heated to reflux according to GP5 for 2 days, then broth (6 mmol, 506 mg) was added and the reaction was heated to reflux for one more day. The crude material was purified using a column containing 12 g of cerium oxide using 0% buffer B (1 min) followed by 〇 1 〇〇% buffer B (for 11 minutes) and 1 〇〇% buffer b ( 7 (Minute) elution was carried out to give cyclohexyl-2-(pipedino-1-yl)butanamine (771 mg &gt; 76%) as a white powder. HPLC TFA buffer. Rt 8.23 min. 'Η NMR (300 MHz, cd3〇d) 3.69 (1 H, m, CO-NH-CH), 2.93 (4 H, m, piped), 2.82 (1 H, dd, / 8.5, 5.7, CO- Cii-N), 2.65 (4 H, m, piperidine), 1.96 - 1.72 (5 H, m, cyclohexyl), 1.72-1.56 (2 H, m, CO-CH-Cj^), ι·5〇 - i.ii (5 h, m, cyclohexyl), 0-90 (3H, t, J 7.4, -CH2-CH2-CH3) ° Example A.5.9: (cis-4-tert-butyl ring Hexyl)-2-(piped-i-yl) acetamidine and #-(trans-4-t-butylcyclohexyl)_2·(piperidinyl)ethylamine (002NK118) used according to GP5 Piperphine (9 mmol, 774 mg), hydrochloric acid (9 mmo b 5 mL), and τν_(4-t-butylcyclohexyl)_2_qiethyleneamine (3 mmol, 698 mg) and the reaction was heated to reflux. Lasts for n hours. Purify the crude material using a column containing i 2 g of oxidized stone, using 0% buffer B (1 min), followed by 〇_1〇0% buffer B (for 11 minutes) and 100% buffer B (7 / knife face) elution, thereby partially separating the cis and trans isomers, resulting in 69 201113280 colorless oil (cis-4-t-butylcyclohexyl) 2 - (anthracene-i-based Acetamine (154 mg, 18%), γ_(trans-4-t-butylcyclohexyl-2-(piperidin-1-yl)acetamide (129 mg, 15%) as a white solid And a cis:trans product (339 mg, 40%) containing a ratio of 1:2. (cis-4-t-butylcyclohexyl)-2-(piperidin-i-yl)acetamide HPLC TFA buffer · Rt 11·63 min 4 NMR (300 MHz, cd3od) 4.02 (1 H, m, CO-; NH-Cii), 3.01 (2 H, s, CO-Cii2-N), 2.89 ( 4 H, m, piperidine), 2.56 (4 H, m, P.:), 1.86 (2 H, m, cyclohexyl), l, 7i (2 h, m, cyclohexyl), 1.57 (2 H, m, cyclohexyl), 1·16 (3 H, m, cyclohexyl), 〇_9! (9 H, s, -C-(C£L) 3) (trans-4-tert-butyl ring) Hexyl-2-(piperidin-1-yl)acetamide e HPLC TFA buffer · Rt 1 1·79 min 'H NMR (300 MHz, cd3od) 3.59 (1 H, CO-NH-CH), 2.96 (2 H, s, CO-Cg^-N), 2.86 (4 H, m, 旅啡) , 2.48 (4 H, m, cultivating), I.94 (2 H, m, cyclohexyl), I.85 (2 h, m, cyclohexyl), 1.36 -0.96 (5 H, m, cyclohexyl) , 0.89 (9 H, s, -C-(CH3)3). Example A.5_l〇: 2-(Peptin-1-yl)_#_(anti-3,3,5•trimethylcyclo Hexyl) acetamidine and 2_(Brigade-1-yl)(cis-3,3,5-trimethylcyclohexyl)acetamide (002NK127) Step 1: 2-Gas-iV-(3,3, 5-tridecylcyclohexyl)acetamide Dissolve 3,3,5-trimethylcyclohexylamine (42 111111〇5.92 §) in 1) 〇1^ (20 ml) and stir at 5-HTC Add dropwise to a solution of 2_gas ethane (2 〇mmol ' 2.25 g) in DCM (20 mL). Mix at room temperature for 11 hrs for 1 hour, then add concentrated HCl (25 mL), Water (7.5 mL) and DCM (10 mL). The layers were separated and washed with EtOAc (EtOAc m. Purification using a column containing 80 g of cerium oxide (buffer A: heptane, buffer B: diethyl ether)

The crude material was eluted with 0% Buffer B (2 min), then 0-100% Buffer B (min. min) and 100% Buffer B (3 min) to give a 2-chloro residue as a white solid. -(3,3,5-tridecylcyclohexyl)acetamide (3.69 g » 85%). HPLC TFA buffer: Rt 15.49 and 15.65 min (mixture of isomers (4:1)) Step 2: 2-(piperidin-1-yl)-, (trans-3,3,5-tridecyl ring) Hexyl) acetamidine and 2-(parothin-1-yl (cis-3,3,5-tridecylcyclohexyl)acetamide are used according to GP5: (9 mmo 775 mg), hydrochloric acid (9) Mmo b • 5 mL ), 2 - chaos-Λ/·-(3,3,5-trimethylcyclohexyl)ethinamide (3 mmol, 652 mg) and the reaction was heated to reflux for 16 h. The crude material was purified by column containing 12 g of cerium oxide, using 〇% buffer B (1 minute), followed by 0-1 00% buffer B (for 11 minutes) and 1 〇〇% buffer b (7 knives) The elution is carried out to partially separate the cis and trans isomers to give 2-(piperidin-1-yl)(trans-3,3,5-trimethylcyclohexyl)B as a colorless oil. Indoleamine (178 mg, 22%) in the form of a white solid 2_(piperidin _*)_#·(cis-3,3,5-tridecylcyclohexyl)acetamidamine (57 mg, 5%) And the cis:6:丨 ratio: 583 mg, 73% of the library. 2-(&quot; 哄-1-yl (trans-3,3,5-trimethylcyclohexyl) Ethylamine 71 201113280 HPLCTFA Flush: Rt 10.52 min 〇'H NMR (300 MHz, cd3〇d) 4.11 (1 H} m, CO-NH-CH), 2.97 (2 H, s} CO-CHj-N), 2.85 (4 H, m, piperidine), 2.53 (4H, m, piperidine), 1.74 (2H, m, cyclohexyl), 1.53 (2H, m, cyclohexyl), 1.40 (1H, m, cyclohexyl), 1.17 (1 H, m, cyclohexyl), 1.07 (3 H, s, C-(CH3)CH3), 0.95 (3H, d, J 6.4, CH-CH3), 0.94 (4 H, S, C- (CE3)CH3) 2-(Peptin-1-yl)-iV-(cis-3,3,5-trimethylcyclohexyl)acetamide HPLC TFA buffer: Rt 10.84 min 'H NMR (300 MHz, cd3〇d) 3.93 (1 H, m, CO-NH-CH), 2_96 (2 H, s, CO-CiL-N), 2.86 (4 H, m, piperidine), 2.49 (4 H, m, piperene), 1.85 (1 H, m, cyclohexyl), 1.72 (1 H, m, cyclohexyl), 1.54 (lH, m, cyclohexyl), i.4〇 (i H, m, cyclohexyl) ), 1.07 (1 H, m, cyclohexyl), 0.98 (3 H, s, C(Cii3)CH3), 〇·96 (3 H, s, C(CH3)C£L), 0.92 (3 H, d, 6.5, CH-CiL), 0.78 (2H, m, cyclohexyl). Example A.6.1: General procedure (GP6) Adding amine (1. 0 equivalents) of ethanol (1 mL per mmol of amine) to a halogenated alkane (1.1 equivalents) and sodium carbonate (3 equivalents) of ethanol (per mmol Amine in 2 mL). The reaction was heated to reflux followed by water (5 mL per mmol of amine) and aqueous sodium carbonate (1 s, 5 mL per mmol of amine). The product was extracted with ethyl acetate (3×1 mL EtOAc) and EtOAc. The crude material was purified using Combiflash (buffer A: Et20, buffer B: 0·1 M NH3 in Me OH: EtaO (1:1)), and the corresponding fractions were combined and concentrated to yield the product. Example A.6.2: TV-(pentane-3-yl)_2_(4-propionylphenidyl)acetamide (002NK52) 1-(piperidin_;!-yl)propanone was used according to GP6 (4 mm 〇 1,566 mg), 2-chloro(pentan-3-yl)acetamide (4 4 mmol, 726 mg) and sodium carbonate (12 mmol, 1.27 g) and the reaction was heated to reflux. 18 hours. The crude material was purified using a column containing 12 g of ruthenium dioxide using 〇% buffer B (1 min) followed by 〇_丨00% buffer B (duration 丨丨 min) and 100% buffer B (3 min) The elution was carried out to give #-(pentane-3-yl)-2-(4-propenylpiperidinyl)acetamide (i 〇 4 g, 100%) as a colorless oil. HPLC TFA buffer: Rt 7 49 min. 'H NMR (300 MHz, cd3od) 3.70 (1 H, m5 CO-NH-CH), 3.61 (4 H, m, piperidine), 3.07 (2 H, s, CO-CH2-N), 2.53 (4 H, m piperidine), 2.41 (2 H, q, "/ 7.5, NC(〇)_c out_CH3), 159 (2H, % CH3-CH2), 1.43 (2H, m5CH3-CH2), 1.12 (3 H, t, J 7.5, NC(0)-CH2-CE3), 0.91 (6H, t, J = 7.4 Hz, CH_(CH2-Cii3)2). Example A.6.3: iV-cyclohexyl_2_(4_propionylpiperidinylhydrazinyl)acetamide (002NK53) used according to GP6 (dimorphine small base), propyl acetonide (4 _〇ι , 569 mg), 2-gas-good cyclohexylacetamide (4 4 caffeine 777) and sodium carbonate (12 mmol, 1.29 g) and the reaction was heated to reflux for 18 hours. The crude material was purified using a column containing 12 g of cerium oxide, using 〇% buffer b U minutes), followed by 0-100% buffer B (for n minutes) and 1%% 73 201113280 buffer B (3 minutes) The elution was carried out to give AT-cyclohexyl-2-(4-propenylbenzylidin-1-yl)acetamide (1. 〇 8 g, 96%) as a colorless oil. HPLC TFA buffer: Rt 8.00 min. ]H NMR (300 MHz, cd3〇d) 3.70 (1 H, m, CO-NH-CH), 3.61 (4 H, m, piperene), 3.03 (2 H, s, CO-Ci^-N) , 2·51 (4 H, m, piperene), 2.41 (2 H, q, *7 7.5, NC^CO-Ciia-CHs), 1.81 (4 H, m, cyclohexyl), 1.65 (1 H, m, cyclohexyl), 1.31 (5 H, m, cyclohexyl), 1.12 (3H, t, 7.5, NC(0)-CH2-Cii3). Example A.6.4: 2-((1乂4 phantom-2,5-diazabicyclo[2.2.1]heptan-2-yl)cyclohexylacetamide (002NK57) 2,5-di according to GP6 Nitrobicyclo[2.2.1]heptane-2-capric acid (15,45)-t-butyl ester (4 mmol '792 mg), 2-chloro-iV-cyclohexylacetamide (4.4 mmol, 776 mg) And sodium carbonate (12 mmol, 1.27 g) and the reaction was heated to reflux for 4 h. The crude material was purified using a column containing 12 g of sulphur dioxide, with 0% buffer B (1 min), followed by 〇 1 〇〇% buffer B (during 11 minutes) and 100% buffer B (3 minutes) were eluted to give 5-(2-(cyclohexylamino)-2-oxoethoxy B as a colorless oil. Base)·2,5· Diazabicyclo[2.2.1]heptane-2-carboxylic acid (1&amp;45&gt;T-butyl ester (1〇4 g, 77%). HPLC TFA buffer: Rt 1 1·52 Min. lK NMR (300 MHz, cd3od) 4.29 (1H, broad unimodal, diazabicyclo[2.2.1]heptyl), 3.68 (1 H, m, CO-NH-CIL), 3.52 (1 H, Wide unimodal, diazabicyclo[2.2.1]heptyl), 3.45 (1 H,m,diazabicyclo[2 2 heptyl), 3.26 (1 H,d,J 16.0,CO-CUH'-N) , 3.18 (1 h,d,/ 74 201113280 16.〇, CO-C HN), 2.93 (1 h, d (W9 6, 2 ι, diazabicyclo[2·2·1]heptyl), 2.63 (1 H, m, diazabicyclo[22 a]heptyl), column (2 H,m,diazabicyclo%)]heptyl....(^called cyclohexyl),... Ο H,m,cyclohexyl),i.47 (9 H,s,(CiL""c),i 32 (5 H,m cyclohexyl). 5-(2-(cyclohexylamino)-2-yloxyethyl)_2,5-diazabicyclo[2.2.U heptane-2-carboxylic acid (10) The third vinegar (1〇4§) was dissolved in ethanol (9 (4), followed by Hci (4 6 ml of 2 〇m solution) in diethyl ether. The reaction was stirred at room temperature for 8 days, then at 6 〇t Stir for 8 hours. Add Na2C03 aqueous solution (1 M, 20 mL), extract with Et EtOAc (3×3 〇^, and organic phase. The crude material was purified by column column and eluted with 〇% buffer B (丨 min), followed by 0-100% buffer B (for U minutes) and 1% buffer B (6 minutes) to produce a white precipitate. 2 ((15,4 phantom, 2,5-diazabicyclo[2.2_1]heptan-2-yl)-indole-cyclohexylacetamide (17 mg, 2%). HPLC TFA buffer: Rt 6.62 min 〇'η NMR (300 MHz, cd3od) 3.69 (1 H, m, CO-NH-CH), 3.62 (1 s. s. s., diazabicyclo[2]heptyl), 3 43 (1 ^[, broad unimodal, diazabicyclo[2·2·1]heptyl)ff, 3.24 (1 H, d, J 16.0, CO-CHH'-N), 3.17 (1 h, d , J 16.0, COCHH:-N), 3.09 (1 H, dd, / 10.5, 1.1, diazabicyclo[2 2 qheptyl), 2 9 〇 (1 h, dd, 10.0, 2.5, diazabicyclo[ 2.2.1] heptyl), 2.82 (lP^dd^lOJ, 2.3, diazepam [2.2.1] heptyl), 2.58 (1 H, dd, · / 10.0, 1.0, diazabicyclo[2.2.1 ] heptyl), 1.81 (4 H, m, cyclohexyl), 1.81 (1 H, m, dinitrobis 75 201113280 ring [2.2_1] heptyl), 1.63 (1 heart 111, diazabicyclo[2.2.1] ]heptyl), 1.63 (lH, m, cyclohexyl), 1.30 (5 H, m, cyclohexyl). Example A.6.5: 3-((15,4^-2,5-diazabicyclo[2.2.1]heptan-2-yl)-·/ν-cyclohexylpropionamide (002NK66) used according to GP6 2,5-diazabicyclo[2_2·1]heptane-2-capric acid (15,45)-t-butyl ester (4 mmol, 794 mg), 3- gas-7V-cyclohexylpropionamide (4.4 Methanol, 837 mg) and sodium carbonate (12 mmol ' 1.27 g) and the reaction was heated to reflux for 4 hours. The crude material was purified using a column containing 12 g of cerium oxide, with 0% buffer B (1 min) Then, eluted with 0-1 〇〇% buffer B (for 8 minutes) and 100% buffer B (3 minutes) to give 5-(3-(cyclohexylamino)-3 as a colorless oil. _Sideoxypropyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (H4 phantom-t-butyl ester (463 mg, 33%). HPLC TFA buffer: Rt 1 1.84 NMR (300 MHz, cd3〇d) 4.28 (1 H, broad unimodal, diazabicyclo[2.2.1]heptyl), 3·64 (lH,tt,J9·5,3·2,CO- NH-CiD, 3·55 (1H, broad unimodal, diazabicyclo[2.2.1]heptyl 4.2, diazabicyclo[2.2.1]heptyl), 3.18 (1 H, dd (W 10.1, 8.1, 1.9, diazabicyclo[2.2.1]heptyl), 2.83 (1 H,m Diazabicyclo[2.2.1]heptyl), 2.83 (2H,m, C(0)-CH2-Cii2), 2.66 (1 H,t,9_3,diazabicyclo[2.2.1]heptyl), 2.31 (2H,t,6.9, C(0)-Cii2-CH2), 1.84 (2H, m, diazabicyclo[2.2.1]heptyl), 1.84 (lH, m, cyclohexyl), 1.74 ( 2 H, m, diazabicyclo[2.2.1]heptyl), 1.74 (1 H, rn, cyclohexyl), 1.65 (1 H, m, cyclohexyl), 1.47 (9H, s, (Cii3)3 -C), 1.28 (5 H, m, cyclohexan 76 201113280 base). 5-(3-(cyclohexylamino)_3_sideoxypropyl)·2,5-diazabicyclo[2.2.U Gengbu-2-f acid (10) is called third vinegar (463) dissolved in ethanol ^ mL) 'then added concentrated HC1 (5 drops). The reaction was heated to 6 generations for 18 hours. Add Na2C〇3 aqueous solution. (1 M, 2 〇 mL), extract the product with (10)~ Ο X 30... and dry with organic (4) 〇4, transition and concentrate. Purify the crude material using a column containing 4 g of sulphur dioxide, using 〇% buffer B (1 minute), followed by buffer b (for η minutes) and chamber buffer B (8 minutes) for elution, resulting in 3-((1(tetra))-2,5-diazabicyclo[ 2.21] Geng Xuan_2_base) Yihuan Propan-yl brewing amine (35 mg, 1 1%). HPLC TFA buffer: Rt 7 〇6 _. 'HNMR (300 MH2, cd3od) 3.63 (1 H, m, CO-NH-CH), 3·52 (1 Η, broad unimodal, diazabicyclo[22i]heptyl" oxime, broad unimodal, diazobicyclo [(1)]heptyl), 3.09 (1H, ddJl〇6, i3^i bicyclo[(1)]heptyl, :azabicyclo[22i]heptyl), 28i ring [(1)]heptyl H,m,% hexyl), 1.78 (1 H, m, diazabicyclo[2 2 heptyl), i 62 UH, m, diazabicyclo[2.2"heptyl), 162 (1 H, m, cyclohexyl), 1.32 (5 H, m, cyclohexyl). Example A.6.6: iV-ring p, 〇^-hexyl-2-(4-propionylpiperidin-1-yl)acetamide (002NK69) b-cyclopentylpyramine (4 inm〇) according to GP6 i, 622 mg), 2_ 77 201113280 Gas-A/·cyclohexylacetamide (4.4 mmol, 771 mg) and sodium carbonate (12 mmol, 1 _26 g) and the reaction was heated to reflux for 4 h. The crude material was purified using a column containing 12 g of cerium oxide and washed with 〇% buffer b (1 minute) followed by 0-100% buffer B (for 11 minutes) and 100% buffer B (3 minutes). This gave a cyclohexyl-2-(4-cyclopentylpiperidinyl)acetamide (1 g, 86%) as a white solid. HPLC TFA buffer: Rt 8.84 min. 'Η NMR (300 MHz, cd3od) 3.68 (1 H, m, CO-NH-CH), 2.99 (2 H, s, CO-Cii2-N), 2.57 (8 H, m, piperidine), 2.51 ( 1 H,m, (CH2)2-N-Cii),1·91 (2 H,m,cyclohexyl), 1_91 (2 H,m,cyclopentyl),1.66 (3 H,m,cyclohexyl) , 1.66 (4 H, m, cyclopentyl), 1.31 (5 H, m, cyclohexyl), 1.3 1 (2 H, m, cyclopentyl). Example: 6.7 : TV-cyclohexyl-2-(4-cyclopentylpiperidin-1-yl)butanamine (002NK29) 1-cyclopentyl n-parothin according to GP6 (4 mmol, 619 mg) , 2-bromo-AT-cyclohexylbutyridamine (4.4 mmol, 1.10 g) and sodium carbonate (12 mmo, 1.33 g) and the reaction was heated to reflux for 18 hours. Purify the crude material using a column containing 12 g of sulphur dioxide, using 〇% buffer B (1 min), followed by 0-100% buffer B (for 11 minutes) and 100% buffer B (3 min) Elution was carried out to give 7V-cyclohexyl-2-(4-cyclopentylpiperidin-1-yl)butanamine (95 3 mg, 74%) as a white powder. HPLC TFA buffer: Rt 9.63 min. δ η (300 MHz, cd3od) 3.68 (1 H,tt,/ 1〇·5,3.9, CO-NH-CH), 2.76 (1 H, dd, J 8.2, 6.0, CO-CH-N), 2.53 (8 H, 78 201113280 m, piperidine), 2.53 (1 H, m, (CH2)2-N-Cii), 1.87 (2 H, m, cyclohexyl), 1.87 (2 H, m, cyclopentyl) ), ΐ·7〇(2 H,m,CH3-Cii2), 1.68 (3H,m,cyclohexyl), 1.68 (4 H,m,cyclopentyl), 1.30 (5 H,m,cyclohexyl), 1·30 (2 H, m, %·pentyl), 0.89 (3 H, t, Τ' 7.4, Cii3-CH2). EXAMPLES 6.8·6.8: 2-(4-Cyclohexylpipenyl-i-yl)_#-isopropyl-2-methylpropanamide (002NK85) Step 1: 2-Bromoisopropyl-2-methyl Propyl-2-amine (210 mmol, 18 ml) was dissolved in DCM (21 mL) and was added dropwise to 2-bromo-2-methylpropanium bromide with stirring at about 10 °C. 1 〇〇mmol, 23.0 g) in DCM (1 mL) solution. The reaction was stirred at room temperature for 30 minutes, followed by addition of concentrated HCl (10 mL) and water (40 mL). The layers were separated and EtOAc (EtOAc m. Propylamine (20.2 g, 97%). HPLC TFA buffer: Rt 12.06 min. 'Η NMR (300 MHz, CDC13) 6.50 (1 H, s, NH), 4.01 (l H, dhept, J 7.8, 6.6, CO-NH-CH), 1.95 (6 H, s, C(0)- C(CE_i)2),1_20 (6 H,d,J 6.5,(:0-ΝΗ-(:Η-((^)2)) Step 2: 2-(4-cyclohexylphenamine:-i- Base)-iv-isopropyl-2-indolopropanamide 1-cyclohexylpiperidine according to GP6: (20 mmol, 3.37 g), 2-bromo-AT-isopropyl-2-mercaptopropylidene Amine (48 mmo, 9.92 g) and sodium carbonate (60 mmol, 6.35 g) and heat the reaction to reflux for 16 hours. Use 79 201113280 to purify the crude liquid B with 80 g of sulphur dioxide. The elution was carried out in minutes. The fraction containing the product was re-purified using a sputum-cylinder column, using 〇% buffer B. Minutes; the eve was washed with 0-50% buffer B (for 21 minutes). ^ 2-(4_Cyclohexyl(tetra)-yl)-ytyl-isopropylamine = 1.31 g, 22 〇/.). Off-line HPLC TFA buffer: Rt 8.53 min NMR (300 MHz, Cd3od) 3.94 (1 H, hept, y 6 7 CO-NH-CiD, 2.66 (4H, s, piperidine), 2.55 (4H, m, piperidine) a (1 H' m, (CH2)2-N -Cii), (2 H, m, cyclohexyl), i 83 (2 &amp; m, cyclohexyl), 1.66 (lH, m, cyclohexyl.. H, m, cyclohexyl): 1.17 (6 H, s, C(0)-C(CH3)2), 1.15 ( 6 H, d, J 6 6 CO-NH-CH-(C|i3)2). ' ' Example A.6.9: (i?)-沁cyclohexyl_2-(hexahydrogen. , 2_α] morphine-2 (li/)-yl) ethylamine (002ΝΚ86) according to GP6 (/?)-octahydropyrrolo[υ-α]pyridin (2〇mm〇2.52 g), 2 - gas-iV-cyclohexylamine (22 mmol, 3.86 g) and sodium carbonate (60 mmol ' 6.35 g) and the reaction was heated to reflux for one hour. Purification of crude using a column containing 80 g of cerium oxide Substance, eluted with 〇% buffer B (2 minutes), followed by 0-1 〇〇% buffer B (for 21 minutes) and 100% buffer B (4 minutes) to give a white waxy appearance (and ), Cyclohexyl-2-(hexahydropyrano[1,2-β]pyrazine-2(l/〇-yl)acetamide (3.81 g, 72%) 〇80 201113280 HPLC TFA Buffer :Rt 7.82 min. 'H NMR (300 MHz, cd3od) 3.68 (1 H, m, CO-NH-CH), 3.08 (2 H, m, piroxi[l,2-a]pyridin), 3.06 (2 H, s,CO-dN), 2.97 (1 H,m,pyrrolopyrrole),2·81 (1 H, m,pyrrolo[l,2-fl]pyridin), 2_43 (2 H, m, pyrrole And [ι,2-α]pyridin), 2.29 (2 η is called pyrrole [1,2-foreign tillage), 2.11 (111,111, pyrrole [1,2_ external ratio tillage), U3 (4 H, m, cyclohexyl), U3 (3 η, m, pyrrole #[1,2 α]〇pyramine), 1- 64 (lH,m, cyclohexyl^.^(^)pyrrolopyrene ), 1.32 (5 H, m, cyclohexyl). Example A.6.10: (p-cyclohexyl-2·(hexahydropyrrolo[^...pyridin-2(1//)-yl)acetamide) Q02NK87) According to GP6, (*S)-octahydropyrrolo[nypyrrole (2〇mm〇1, 2-53g), 2 good cyclohexylacetamide (22mm〇1, 3 93 g) and sodium carbonate ( 60 mmol, 6.41 g) and the reaction was heated to reflux for 16 h.

The crude material was purified using a column containing 80 g of sulphur dioxide, using 〇% buffer B (2 minutes), followed by 0-100% buffer B (for 21 minutes) and 〇〇% buffer B (4 minutes). Elution was carried out to give (7) ginger cyclohexyl-2-(hexahydropyrrolo π,2_β]pyrazine-2(m)D-acetamide 82 g, 72%). HPLC TFA buffer: Rt 7.82 min. NMR NMR (300 MHz, cd3〇d) 3.69 (1 H, C〇-NH-CH), 3.05 (2 H, s' C0_CiL_N), 3 〇1 (3 H, m, d is more than [...] pyridyl啩), 2.79 (1 H,m,pyrrolo[u-exo-pyrrolidone), 2 37 (2 h, shamepyrrolo[1,2-external oxime), 2·22 (2 H,m,^ each And with a small ratio of brown), 2 〇 5 〇 ^ 81 201113280 m,. Compared with [1,2-α]pyrazine, U7 (4 H,m,cyclohexyl),1·87 (3 H, m,&quot;t匕和和[ι,2-α]η比啡), 164 (1 H, m, cyclohexyl), 1.33 (1 η, «1, pyrrole [1, 2-4 pyridinium), 1.33 (5 11,111, cyclohexyl). Example A.6.11: AT-cyclohexyl-2-(4-methyl.1,4-diazepan-1-yl)acetamide (002ΝΚ88) 1-mercapto-l according to GP6, 4-diazepane (30 mmol, 3.43 g), 2-chlorocyclohexylacetamide (33 mmol, 5.81 g) and sodium carbonate (90 mmol, 9.60 g). (:, for 15 hours. Purify the crude material using a column containing 80 g of cerium oxide, using 〇% buffer b (2 minutes), then 0-100% buffer B (for 21 minutes) and 100% buffer B (4 minutes) elution to give cyclohexyl-2-(4-methyl-i,4-diazepan-1-yl)acetamide as a colorless oil (159 g, 21 〇 /〇) HPLC TFA buffer: Rt 6.68 min. 'Η NMR (300 MHz, cd3od) 3.69 (1 H, m, CO-NH-CH), 312 (2 H, s, CO-Cii2-N), 2.73 (8 H, m, diazep), 2.39 (3 H, s, N-Ciij), 1.81 (2 H, m, diazep), i.8i (4 h, m, cyclohexyl), 166 (11111, cyclohexyl), 1.33 (5,11^cyclohexyl). Example Α·6· 12 : 3-(4-ethylindolyl_i,4-diazepane small group) ring Heptylpropionamide (002NK96) using diazepane small) ethyl ketone according to GP6 (3 mmol '426 mg), 3-bromo-U-heptylpropionamide (4 5 mm〇1,112, carbonic acid) Nano (6 mmo 636 mg) and potassium iodide (3 3 549 549 mg) and the reaction was heated to reflux for 17 hours. The crude material was purified using a column containing 12 g of cerium oxide. Buffer 玖 1 min), followed by 〇 丨〇〇〇 〇 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 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 -Ethyl-1,4-diazepine-bu-ki)-A/&quot;-cycloheptylpropionamide (661 mg, 71%). HPLC TFA buffer: Rt 9.18 min. NMR NMR (3 0 0 Μ H z, cd 3 〇d) 3.8 3 (1 Η,m,C 〇- N Η - C Η) 3.59 (4 Η, m, diazep), 2.8 1 (2 Η, m,CO-CHyC^-N), 2.77

(1 Η, m, dinitrogen), 2.69 (3 Η, m, dinitrogen), 2.33 (2 Η, td, J 6.9, 1.8, CO-CH2-CH2-N), 2.11 (3 H, s , N-CO-CH3)5 1 86 (2H, m, diazet), 1.86 (2H, m, cycloheptyl), 1.56 (1 〇Hm, cycloheptyl). EXAMPLES Α_6·13 : AT-cyclohexyl-2-(4-cyclopentylpiperidin-buyl)_2-mercaptopropionamide and indole cyclohexyl-3_(4-cyclopentylphenamine: _丨_ Base)_2_Methylpropionamide (002NK100) 1-cyclopentylpiped according to GP6 (4〇 bribe 1,6 17 $), Cyclohexyl-2-mercaptopropylamine (4 〇 〇 〇1,9% g), sodium carbonate (_ _ 7.3 g) and a broken clock (44 mm 〇 1,8 48 §) and the reaction was heated to reflux for 2 days. Purify the crude material using a column containing 8 〇g of sulphur dioxide, using buffer B (2 minutes), followed by 〇_1〇〇% buffer B (days ^ minutes) and buffer B (9 minutes) ) elution, yielding the form of cyclohexyl 2_2 (4_cyclopentylmura small base) _2 • methyl propylamine (1.78 g, 14%) 〇 using 12 g of dioxide dioxide Xi Xidian , (4) 官 官 矽 矽 ( 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲iV-cyclohexyl-3-(4-cyclopentylpiperidin-1-yl)-2-mercaptopropanamide (343 mg, 30/〇) as a white solid. Cyclohexyl-3-(4-cyclo) Pentyl piperidin-1-yl)-2-mercaptopropionamide HPLC TFA buffer: Rt 10.50 min. *H NMR (300 MHz, cd3od) 3.64 (1 H, m, CO-NH-CH), 2.96 - 2.17 (8 H, m, piperene), 2.96 - 2.17 (1H, m, (CH2)2-N-Cii), 1.91 (2 H, m, cyclohexyl), 1.86 - 1.51 (3 H, m, Cyclohexyl), 1_86 - 1.51 (6 H, m, cyclopentyl), 1.50 - 1.21 (2H, m, cyclopentyl), 1.50 - 1.21 (5 H, m, cyclohexyl), 1.18 (6 H, s, CO-C-(CH3)2) Cyclohexyl-3-(4-cyclopentylpiperazin-1-yl)-2-mercaptopropionamide HPLC TFA buffer: Rt 8.79 min !H NMR (300 MHz, cd3 〇d) 3.64 (1 H, m, CO-NH-CH), 2.91 - 2.30 (8 H, m, piperene), 2.91 - 2.30 (1 H, m, CO-CH(Me)-CHHl), 2.91 - 2.30 (1 H, m, COCH(Me)), 2.91 -2.30 (1 H, m, (CH2)2-N-CH), 2.25 (1 H, dd, J 11.6, 4.1, CO-CH(Me)-CHH'), 1.99 - 1.50 (5 H,m,cyclohexyl), 1.99 -l.50 (6 H, m, cyclopentyl), 1.50 - 1.12 (2H, m, cyclopentyl), 1,50-1.12 (5 H, m, cyclohexyl), ι·〇6 (3 H,d,·/ 6.6, CO-0-KCE3)). Example A.6.14: #-cyclohexyl-2-(4-(2,2,2) -Trifluoroethyl)piped-1-yl)acetamidamine (002NK119) 1-(2,2,2-trifluoroethyl)piperidine dihydrochloride (3 mmol, 722 mg) according to GP6, 2- Chlorocyclohexylacetamide (3.3 mmol, 586 mg) 84 201113280 and aqueous sodium carbonate (15 mmol '2 Μ, 7.5 mL) and the reaction was heated to reflux for 17 hr. Use a column containing 12 g of cerium oxide, use 〇% buffer B (1 minute), then 〇_1〇〇% buffer B (over n minutes) and 100% buffer B (3 minutes) Stripping; then using a column containing 12 g of oxidized stone, using 〇% buffer b (1 minute), followed by 〇3〇〇/〇 buffer B (for 11 minutes) and 3% buffer B (3 minutes) was eluted to purify the crude material to give the indane cyclohexyl-2·(4-(2,2,2-trifluoroethyl)piperidinyl)acetamide as a white solid. 62〇mg, 67%). HPLC TFA buffer: Rt 10.33 min. H NMR (300 MHz, cd3〇d) 3.68 (1H, m, C(O)-NH-CH), 3.07 (2H, q, J 9.8, -CH2-CF3), 2.99 (2 H, s, C(Q)-CH?-NH), 2.73 (4 H, m, piperene), 2.55 (4 H, m, piperene), 1.84 (2 H, m, cyclohexyl), 1.75 (2 H, m , cyclohexyl), 1.64 (ih, m, cyclohexyl), 1.33 (5 H, m, cyclohexyl). %% of the examples A. 6.1 5 . TV-% hexyl _ 3 _(4_ (cyclopropanyl)啡 ···················································································· 3.3 mm (n, 638 mg) and sodium carbonate (12 mmol, 1.27 g) and heat the reaction to reflux for 18 hours. Purify the crude material using a 12 g two-rolled fossil column, using 〇% buffer B (1 minute), followed by 〇-50% buffer b (for 11 minutes) and 50% buffer B (10 minutes) for elution to give iV-cyclohexyl-3-(4-( Cyclopropane carbonyl) piperidine- oxime-propanylamine (132 mg, 14%) 85 201113280 HPLC TFA buffer: Rt 8.63 min. 4 NMR (300 MHz, cd3od) 3.77 (2 H, m, piperphene ),3·68 (1 H, m, C(O)-NH-CH), 3_62 (2H, m, piperidine), 2.69 (2H, t, 7.1, C(0)-CH2-Cii2-N), 2.55 (2 H , m, tourism), 2.47 (2 H, m, piperidine), 2.38 (2 H, t, J 7.0, (^(CO-Cii^CHrN), 1.96 (1 H, m, cyclopropyl), 1.85 (2 H, m, cyclohexyl), ι·76 (2 H, m, cyclohexyl), 1.64 (1 H, m, cyclohexyl), 1.30 (5 H, m, cyclohexyl), 0.85 (4 H , m cyclopropyl). Example A _ 6 · 1 6 : TV-cycloheptyl-3 -(4-cyclohexyl linphin-1 yl)propanamide (002NK122) 1-cyclohexyl η according to GP6 Desorphin (3 mmo 1,508 mg), 3_bromocycloheptylpropionamide (3.3 mmo 819 mg) and sodium carbonate (9 mmol, 95 7 mg) and the reaction was heated to reflux for one hour. The crude material was purified by 12 g of ruthenium dioxide column and washed with 〇% buffer B (1 minute), then 0-50% buffer B (for 1 minute) and 5 〇% buffer b (3 minutes). This gave a cyclopeptyl-3-(4-cyclohexyl0 morphin-1-yl)propanamide (187 mg, 19%) as a white solid. HPLC TFA buffer: Rt 9.68 min. 'Η NMR (300 MHz, cd3od) 3.85 (1 H, m, C(O)-NH-CH), 2.65 (2 H, t, J 7.1, C(0)-CH2-CH2-N), 2.55 ( 8 H, m, 2.35 (2 H, t, J 7.1, C(0)-CH2-CH2-N), 2.26 (1 H, m, (CH2)2-N-Cii), 1.88 (6 H, m , cycloheptyl), 1.54 (6 H, m, cycloheptyl), l_54 (5H, m, cyclohexyl), 1.24 (5H, m, cyclohexyl). General procedure 7 ( GP7) 86 201113280 (10 equivalents), amine (0.9-10 equivalents) and optionally base (2.7 fields) and halogenating agent (0.5 equivalents) are mixed together in industrial methanol (15 mL per g - compound) at 15 G ° Microwave heating for 1 hour under C. 仃4 complex. After completion of the reaction, the mixture was passed through a phase separation cartridge, concentrated and purified. Example A·7.1 · W'cyclopentyl-2-(4-propanthene) Propylamine-1-yl)propanamide (LJM 465-3-3) According to GP? 2' gas cyclopentylpropionamide (LJM 465-2, 5.7 mm〇1 '1 g), Base 0 botins (5.2 mmo 736 mg), Na2C03 (15 mmol ' 1.63 g) and (2 84 〇 1,43 〇), purified by bl〇_SP4 (2 cycles), resulting in shallow #-3⁄4pentyl-2-(4-propenyl) Phenylhydrazine (794 mg, 54%) H NMR 300 MHz (CDC13): 6.99 (1H broad doublet, CO-NH-CH), 4.10-4.30 (1H, m, NH-CH -(CH2)2), 3.40-3.70 (4H, m, piperidinyl), 3.02 (m, 1H, CO-CiL-CH3), 2.4-2.6 (m, 4H, cyanoyl), 2.32 (q, 2H, CO-C to 2-CH3), 2.0 (m, 2H, cyclopentyl), 1.63 (m, 4H, cyclopentyl), 1.2-1.4 (m, 2H, cyclopentyl), 1.22 (d, 3H, CH-CH3), 1.16 (t, 3H, CH2-CH3). LCMS: 90% Rt 0·56 min [M + H] + 282.2. GC: 96.6% Rt 15.2 min. Example A.7.2: V -cyclopentyl-2-(1,4-diazepane-butyl)propanamide (LJM 465-4-4) 2-Glycyclopentylpropanamide (LJM 465-2) according to GP7 , 5.7 mmo 1 g) and high piperidine (57 mmo 5.7 g) were purified by bi〇Uge δΡ4 87 201113280 (2 cycles) to give a yellow oily 沁 ring 2 diazepine Alkan-1-yl)propanamide (668 mg, 49%). ' _ *H NMR 300 MHz (CDC13): 7.26 (1H 官-本, '见-重蜂_CO-NH-CH), 4.16 (1H, m, NH-CH-(CH2)2), ·3.24 ( lH q CO-CE-CH3), 2_90 (4H, m, high piperage), 2.65 (4H, m, high piperidinyl), 1.92 (2H, m, high berberine), 1.5-1.8 (6H , m, cyclopentyl), 1.35 (2H, m, cyclopentyl), 1.21 (3H, d, CH-CJi3). LCMS: 94% Rt 1.96 min, [M + H] + 240.2. GC: 96% Rt 12.93 min. EXAMPLES 7.3·7.3: Bicyclo[2.2.1]heptan-2-yl)-2-(piperidin-1-yl)acetamide (LJM 465-12-2) Using #-((15,215, according to GP7) 4/?)-^1-bicyclo[2.2.1]heptan-2-yl)-2- oxetamine (LJM 465-b 5.35 mmo b 1 g) and piperene (53.5 mmol, 4.6 g), Purification via Biotage SP4 gave #-((1&amp;2乂4/〇-"1-bicyclo[2.2.1]heptan-2-yl)-2-(piped-bry) Acetamide (991 mg, 78%), solidified upon standing. 'H NMR 300 MHz (CDC13): 7.01 (1H, broad doublet, CO-NH-CH), 3.74 (1H, m, NH-CH -(CH2)2), 2.88 (6H, m, piperidinyl), 2·48 (4H, m, piperidinyl/norbornyl), 2.26 (1H, m, CO-CEz.N), 2.18 ( 1H, m, CO-CH2-N), 1.78 (1H, m, norbornyl), 1.5 (2H, m, norbornyl), 1.1-1.35 (6H, m, norbornyl) LCMS: 94% Rt 0.54 min [M + H] + 238.16 0 GC: 99.7% Rt 13.20 min. Example A.7.4: Bicyclo[2_2·1]heptane-2- 88 201113280 yl)-2-(4-propenyl) Phenyl-1-yl)acetamide (LJM 465-13-2) used according to GP7 #-((15,25&gt;,47?)-"1-bicyclo[2.2.1]heptan-2-yl)- 2-gas Indoleamine (LJM 465-1, 5.35 mmol, 1 g), Α/&quot;-propionyl piperidine (4.87 mmo b 0.69 g) and Na2C03 (14.45 mmol, 1.53 g) were purified by Biotage SP4 to yield Yellow oily Α^((15,25,4;?)-π1-bicyclo[2_2.1]heptan-2-yl)-2-(4-propionylpiperidin-1-yl)acetamidine Amine (1·35 g, 95%). NMR (CDC13): 6.90 (1H, broad doublet, CO-Nii-CH), 3·70 (1H, m, NH-CH_-(CH2)2), 3.61 (2H, m, norbornyl), 3.47 (4H, m, piperene), 2·98 (2H, s, COCi^-N), 2·48 (4H, m, piperidinyl), 2.31 (2H, q, CO-CH2-CH3) , 2.15 (1H, m, norbornene), 1.8 (lH, m, norbornene), 1.5 (2H, m, norbornene), l.23 (2H, m norborne), 1.09 (3H, t, CH2-Cii3). LCMS: 96% Rt 0.56 min, [M + H] + 294.2. GC: 95.1% Rt 16.4 min. Example A. 7.5 · vV-cyclobutyl-2 -(xylphthyl-1.-yl)acetamide (ljm 465-21-2) 2-Chloro-A/·cyclobutyl B according to GP 7 Amine (LJM 465-6, 6 78 mmol '1 g) and piperidine (67.8 mmo 5.8 g) were purified via Bi〇tage sp4 to give a yellow solid, cyclobutyl-2-(piperidin)丨 基 基 醯 acetamide (989 mg, 74%). 'H NMR 300 MHz (CDC13): 7.24 (1H, wide double front, CO-NH-CH), 4.38 (1H, in, NH-CH-(CH2)2), 2.90 (6Hj 4 χ piperene + CO-C£LN), 2.50 (3H, m, piperidinyl and cyclobutyl), 233 89 201113280

(3H, m, cyanoyl and cyclobutyl), 1.86 (2H, m, cyclobutyl) 丨7〇 (2H m, cyclobutyl). LCMS: 99% R, 0.44 min [M + H] + 198.1 GC: 99% Rt 11.02 min. EXAMPLES 7.6·7.6: iV-cyclobutyl-2-(l,4-diazepane-indoleyl)acetamide (LJM 465-22-3) 2-gascyclobutyl used according to GP7 Acetamine (Ljm 465_6, 6 78 mmo b 1 g) and high bridging (67.8 mmo b 6.79 g) were purified by Bi〇tage SP4 to give a yellow oily λγ 环 cyclobutyl 2_(1, 4_Diazepane-1 -yl)acetamide (1.05 g, 73%). 4 NMR 300 MHz (CDC13): 7.48 (1H, broad doublet, CO-NH-CH), 4.42 ( 1H, m, NH-CH-(CH2)2)9 3.1〇(2H, s, (:0-^!2-&gt;〇, 2.93 (411,111, high piperage), 2.71 (offence, 111 , high piperidinyl), 2_2-2·5 (4H, m, nallutyl and cyclobutyl), (5h m cyclobutyl) LCMS : 77% R, 0.46 min [M+H]+ 212.1 GC : 97% Rt 11·97 min. Example A·7·7 . //-(3,3-Dimethylbutyl)~2_(.endothinyl-1-yl)acetamide (LJM 465 -19-2) 2-Chloro-iV-(3,3-dimethylbutyl)acetamide (LJM 465-7, 5.63 mmo Bu 1 g) and piperculosis (56.3 mm. Bu 4 85) according to GP7 g), Purification via Biotage SP4 to give the product as a pale yellow solid, 3- dimethylbutyl)-2-(piperidine-i-yl) Indoleamine (1 〇 9 g, 94%). iH NMR 300 MHz (CDC13): 7.05 (1H, wide double hua, 90 201113280 CO-NH-CH), 3.25 (2H, m, CO-CH2-N) , 2.85-3.00 (6H, m, piperene), 2·45_2·6〇 (5H, m, piperage and 3,3-dimethylbutyl), 1.39 (2H, dt, CH2-Cii2- (CH3)3), 0.89 (9H, s, CH2-(Cii3)3) LCMS: 99%, Rt 0.58 min, [M + H] + 228.1. GC: 99.8% Rt 11.69 min. Example Α·7.8 : 2·(4_(cyclohexanecarbonyl)piped-1-yl)-W-(3,3-dimethylbutyl)acetamide (LJM 465-20-2) 2-Chloro-based according to GP7 7V-(3,3-dimercaptobutyl)acetamidamine (LJM 465-7' 5.63 mmol' 1 g), 1-(cyclohexyl)-propanol: (5.12 mmol, 1 g) and Na2C Purification by Biotage SP4 afforded 2-(4-(cyclohexanecarbonyl)piperidin-1-yl)-#- (3,3) - Dimercaptobutyl) acetamidine (1.56 g, 88%). NMR 300 MHz (CDC13): 6.96 (1H, wide double bee, CO-NJi-CH), 3.4-3.7 (4H, m, cyanoyl), 3.28 (2H, m, (:0-(:112-) &gt;〇, 3.01 (211, broad unimodal, piperene), 2.47 (411, 111, piperidinyl and CE2-CH2(CH3)3), 1.2-1.8 (12H, m, cyclohexyl and CH2-CE2 -(CH3)3), 0.94 (9H, s, CH2-(Cii3)3) LCMS: 99% Rt 0.7s min [M+H]+ 338.3 GC . 95.9% Rt 18.14 min 0 Example Α·7.9: 2-(Peptin-1-yl)trimethylbicyclo[3.1.1]heptane-3-yl)acetamide (LJM 465-32-2) 2-Chloro-2,6,6 according to GP7 -Trimethylbicyclo[3.1.1]heptan-3-yl)acetamide (LJM 465-26, 4.3 5 mmol, i and piperidine (43.5 mmol, 3.75 g), purified via Biotage SP4, 91 201113280 Produces 2-(pipeline-1-yl)-&quot;-((1乂251,315,5 and)-2,6,6-tridecylbicyclo[3.1.1]g in a viscous yellow oil Alkyl-3-yl)acetamide (1.04 g, 86%). 'H NMR 300 MHz (CDC13): 7.00 (1H, broad doublet, CO-NH-CH), 4.25 (1H, m, NH- CH-(CH2)2)5 2.97 (2H, s, COCH2-N), 2.91 (4H, m, piperidinyl), 2.50 (6H, m, 4H piperene and 2H isospinyl), 2.04 (1H, m, isosyl), 1.95 (1 H, m, isosyl), 1.83 (1H, m, isosyl), 1.75 (1H, m, isosyl), 1.50 ( lH, m, isosyl), 1.22 (3H, s, isosyl), 1.11 (3H, d, isosyl), 1.04 (3H, s, isosyl), 0.84 (lH, d, Isopurinyl) LCMS: 93% Rt 0.69 min [M+H] + 280.2. GC: 96.2% Rt 14.28 min. Example A.7.10: 2-(4-cyclohexylpiperidin-1-yl )-7^-((112135,5/0-2,6,6-tridecylbicyclo[3.1.1]heptan-3-yl)acetamide (LJM 465-33-2) is used according to GP7 2 -gas-#-((1&amp;25,3)5,5/?)-2,6,6-trimercaptobicyclo[3.1.1]heptan-3-yl)ethanoamine (LJM 465-26 , 4.35 mmol, 1 g), cyclohexyl piperidine (3.96 mmol, 666 mg) and Na2C03 (1 1.74 mmol, 1.25 g), purified by Biotage SP4 to give 2-(4-cyclohexyl) as an orange oil. Ororphan-1-yl)-tV-((125,35^5^)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)acetamidamine (1.15 g, 87%). H NMR 300 MHz (CDC13): 6.98 (1H, broad doublet, CO-NH-CH), 4.25 (1H, m, NH-CH-(CH2)2), 2.99 (2H, s, 92 201113280 CO -CiL-N), 2.6 (8H, m, piperidinyl), 2.41 (2H, m, isospininyl), 2.27 (2H, m, isospininyl), 1.7-2.0 (7H, m, ring Hexyl and isosyl), 1.65 (2H, m, isosyl), 1.5 (2H, m, isosyl), 1.22 (7H, m, cyclohexyl and isosyl), 1.11 (3) Only, (1, isosyl), 1〇4 (311,8, isosyl), 0.85 (111, (1, isosyl). LCMS: 99%, Rt 1.05 min, [m+ H]+ 362.3 0 GC: 92.68% Rt 18.4 min. Example A.7.11: iV-(4,4-difluorocyclohexyl)_2·(piperidin·ι_yl)acetamide (LJM 465-45- 1 )

According to GP7, 2-gas-#-(4,4-difluorocyclohexyl)acetamide (LJM 465-29' 3.97 mmo 840 mg) and piperene (39 7 mmol, 3.42 g) were used via MDAP (method) 3) Purification afforded /(-(4,4-difluorocyclohexyl)-2-(piperidin-1-yl)acetamide (36 mg, 35%) as a white solid. 4 NMR 400 MHz (CDC13): 7.07 (1H, broad doublet, CO-NH-CH), 3.89 (1H, m, NH-CH-(CH2)2), 2.96 (2H, s, CO-Cg_2- N), 2·89 (4H, m, piperidinyl), 2.48 (4h, m, piperidinyl), 2.05 (2H, m, cyclohexyl), 1.75-2.0 (4H, m, cyclohexyl), 1.55 (2H, m, cyclohexyl). LCMS: 98%, Rt 1.75 min, [M+H] + 262.3. GC: 99.19% Rt 12.23 min. Example A.7.12: (Magic-#-(1-cyclohexylethyl)-2-(pipedino-1-yl)acetamide (LJM 465-47-2) used according to GP7 (Λ)-2- Chloro-//-(1-cyclohexylethyl)acetamidine (LJM 465-30, 4_91 mmob 1 g) and piperene (49"mmob 4 23 g), 93 201113280 Purified by Biotage SP4, produced 'Yu _#_(1_cyclohexylethyl)-2 decendamine: -丨·yl)acetamide (12 g, 96%), solidified upon standing. 'H NMR 3〇 〇MHz (CDC13): 7.03 (1H, wide doublet, C0-NH-CH), 3.85 (iH, m, NH-CH-CH3), 2.96 (2H, s, CO-Ci^-N), 2.90 (4H, m, piperidinyl), 2.50 (5H, m, 4H piperylene and 1H cyclohexyl), 丨.7〇 (5H, m, cyclohexyl), 0.8-1.4 (9H, m, cyclohexyl) CH-CiL) 〇LCMS: 97% Rt 〇·62 min [Μ + Η]+ 254.3. GC. 99.5% Rt 13.41 min. Example Α·7· 13 : 1-cyclohexylethyl)-2-(( /〇-hexahydropyrrolo[1,2-α].Peptide-2(1 孖)·yl)acetamide (465-48-2)

Use according to GP7 (Phantom-2-gas-ΑΚ1-cyclohexylethyl)acetamidamine (LJM 465-30, 4.35 mmol, 886 mg), diazabicyclo[4.3.0] oxime (3.96 mmol '〇·5 g) and Na2C 〇3 (11.75 mmol, 1.24 g), purified by Biotage SP4 to give cyclohexylethyl)-2-((/?)-hexahydropyrrolo[ΐ,2- α]pyrone-2(l/f)·yl)acetamide (1.7 g, &gt; 99%). 4 NMR 300 MHz (CDC13): 7·02 (1H, broad doublet, CO-NH-CH), 3.86 (1Η, m, NH-CH-CH3), 3.0-3.2 (4H, (:〇-( : over 2_&gt;^ and diazabicyclo[4.3.0]nonane), 2.92 (111, 〇1, di-cyclobicyclo[4.3.0]nonane), 2.7 (111,111, diazabicyclo[4.3.0 ] decane), 2.45 (111, m, diazabicyclo[4.3_0]nonane), 2.0-2.4 (5H, diazabicyclo[43〇]decane and cyclohexyl), 1.5-2.0 (8H, dinitrogen) Bicyclo[4.3.0]nonane and cyclohexyl), 94 201113280 0.8-1.5 (9H, one mouse bicyclo[4_3.0] terpine, cyclohexyl and CH-CHO 〇LCMS : 93% Rt 2.97 min [M+H ] + 294.45. GC: 91% Rt 14.59 min 施 Example A. 7.14: (4-ethylcyclohexyl)-2-(piperidinyl)acetamide (LJM 465-70-1) Use according to GP7 2 - gas-iV-(4-ethylcyclohexyl)acetamide (Ljm 465-44, 9.8 mmo b 2 g) and piper (98 mmo 8.5 g) via

Biotage SP4, followed by purification by preparative HPLC to give #-(4-ethylcyclohexyl)-2-(piamine: - hydrazino) acetamide (8 〇 0 mg » 32%) . NMR 400 MHz (CDC13): 6.95 (1H, broad doublet, CO-NH-CH), 3.70 (1H, m, NH-CH-(CH2)2), 2.93 (2H, s, CO-C^- N), 2.88 (4H, m, cyanoyl), 2.5 (4H, m, cyanoyl), 1.95 (2H, m, cyclohexyl), 1.78 (2H, m, cyclohexyl), u (2H, m ,

Cg_2-CH3), 0.9-1.15 (6H, m, cyclohexyl), 0.84 (3H, t, CH2-CiL). LCMS: 93% Rt 2.64 min [M + H] + 254. GC: 95.49% 13.72 min. Example A.7.15: 2-(4-(Cyclohexanecarbonyl)piperidine-1-yl)-(1-hydroxyindole)cyclopentyl)acetamide (LJM 465-69-1)

2-Chloro-7V-(l-(hydroxyindenyl)cyclopentyl)acetamide (LJM 465-43, 5.2 mmo 1 g), 1-(cyclohexylcarbonyl)pipenine (4.7 mmo) according to GP7 Purification of <RTIgt; ν*(1-methyl) sulfhydryl) ethanoamine (670 mg, 36%). NMR 400 MHz (CDC13): 7.30 (1H, broad doublet, (:0屮--::1), 4.78 (1^1, broad single peak, 〇11), 3.6 (611,111, piperazine) Base and C out OH), 2.98 (2H, s, CO-C out _N), 2.5 (5H, m, ° thiophene and N-CO-CE), 1.6-1.9 (14H, m, cyclohexyl and Cyclopentyl), i 5 (2H, m, cycloaliphatic), 1.24 (3H, m, cycloaliphatic) LCMS: 73% Rt 2.56 min [M + H] + 352.23. GC: 94% Rt 16.99 min EXAMPLES Α7.16: 2-(1,4-diazepane(hydroxyindole)cyclopentyl)acetamide (LJM 465-68-1 1 )

According to GP7, 2-hydroxyhydroxyl)cyclopentyl)acetamide (LJM 465-43, 5·2 mmob 1 g) and high piperage (52 mmo 5.2 g) were used via MDAP (Method 3). Purification 'produced 2_(丨,4_diazepan-1-yl)-7V-(l-(sulfenyl)cyclopentyl)acetamide (322 mg, 24%). 4 NMR 400 MHz (CDC13): 7_59 (1H, broad doublet, CO-NH-CH), 3.63 (2H, s, CH2OH), 3.11 (2H, s, CO-CEb-N), 2'9 ( 4H, m, homopiperidinyl), 2.73 (4H, m, high piperidinyl), 1.77 (2H, m, high phlephthyl), 1.60-1.70 (8H, m, cyclopentyl). LCMS: 93% Rt 1.75 min [M + H] + 256.19. GC : 98% Rt 14.04 min 0 Example A_7.17 : TV-((trans-2-hydroxycyclohexyl)methyl)·3_(piperidin-bu)profenamide (LJM 465-59-1) according to GP7 was prepared using 3-gas ((trans-2-hydroxycyclohexyl)methyl)propanamide 96 201113280 (LJM 465-3 5, 4.5 5 mmo 1 g) and piperidine (45.5 mmo b 3.92 g ) Purification by HPLC (Method 3) gave #-((trans-2-hydroxycyclohexyl)decyl)-3-(piperidinyl)-propanamine (7 〇〇 mg) as a color oil. 5 7%). 'H NMR 400 MHz (CDC13): 8.44 (1H, broad doublet, CO-NH-CH), 3.90 (1H, m, CH-OH), 3.1 (m, 2H, NH-COCH2), 2.9 (3H , m, NH-Ci^-CH and CH2-CIL-CHOH), 2.8 (1H, m, cyclohexyl), 2.62 (2H, m, CH2-CE2-N), 2.51 (4H, m, piperidinyl) , 2_41 (4H, m, piperidinyl), 1.94 (1H, m, cyclohexyl), i, 70 (1H, m, cyclohexyl), l_63 (2H, m, cyclohexyl), 0.9-1.4 (5H, m, cyclohexyl). LCMS: 93% Rt 1.7 1 min [M + H] + 270.38. GC: 95% Rt 15.25 min. EXAMPLES 7.1·7.18: Reverse_2·(4_butyl0-endo-i_yl)_#_(2_ethoxycyclohexyl)ethinamide (465-98-1) and cis-2-(4) - Butyl π □ 啡 _ _ _ _ _ _ _, (2 _ ethoxycyclohexyl) acetamide (465-98-2) according to GP7 using 2-gas-//-(2-ethoxycyclohexyl) Indoleamine (Ljm 465-84, 2.04 mmol, 447 mg), 1-butyl piperene (186 mm〇1,

264 mg) and Na2C 〇3 (5.58 mmol, 591 n^g), purified by preparative HPLC (MeOH 65-95% over 10 min) Phenyl-1-yl)-AM2·ethoxycyclohexyl)acetamide (2^ mg ' 35% ) and cis-2-(4-butylsuccin-1-yl)ethoxycyclohexyl)acetamide (160 mg, 26%). Trans-2·(4_butylpiperidin-1-yl)-#-(2_acetamidinecyclohexyl)acetamide 'H NMR 300 MHz (CDC13): ά 7.20 (width doublet, / = - 97 201113280 7.5 Hz, 1H, CO-NH-CH), 3.68 (m, 1H, CH2-0-CH), 3.63 (ddd, J = 14.0, 9.2, 7.0 Hz, 1H, 0-CHH'-CH3), 3.37 (dq, J = 9.1, 7.0 Hz, 1H, O-CHHl-CHa), 3.14 (tt, 7 = 8.4, 4.0 Hz, 1H, NH-CH), 2.98 (d, J = 16.2 Hz, 1H, NHC (O)-CHH'-N), 2.93 (d, J = 16.2 Hz, 1H, NHC(0)-CHH:-N) 2.56 (8H, m, piperene), 2.34 (2H, t, N- CH2-CH2), 2.15 (1H, m, cyclohexyl), 2.0 (1H, m, cyclohexyl), 1.75 (1H, m, cyclohexyl), 1.6 (1H, m, cyclohexyl), 1.2-1.5 (8H , m, cyclohexyl and aliphatic), 1.2 (3H, t, CH2-CH3), 0.91 (3H, t, CH2-CH3). LCMS: 87% Rt 2.92 min [M + H] + 327.24. GC: 94.43% Rt 15.06 min. Cis-2-(4-butylpiped-1-yl)-7V-(2-ethoxycyclohexyl)acetamide 4 NMR 400 MHz (CDC13): 7.59 (1H, broad doublet, CO-NH -CH), 3.91 (1H, m, O-CH2-CH3), 3.63 (1H, m, 〇-CH2-CH3), 3.45 (0-CH(CH-CH2)) 3.33 (m, 1H, NH-CH -(CH2)2), 3.0 (2H, dd, CO-CH2-N), 2.50 (8H, m, piperene), 2.33 (2H, t, #-CH2-CH2), 1.89 (2H, m, Cyclohexyl), 1.6 (2H, m, cyclohexyl), 1.25-1.55 (8H, m, cyclohexyl and aliphatic), 1.21 (3H, t, CH2-CH3), 0.91 (3H, t, CH2-CH3) . LCMS: 76 〇 / 〇 Rt 3.18 min [M + H] + 327.26. GC : 95.54% Rt 14.89 min o

Example A.7.19: trans-W-(2-ethoxycyclohexyl)-2-(4-indolyl-1,4-diazepan-1-yl)acetamide (LJM 465-99 -1) and cis-iV-(2-ethoxycyclohexyl)-2-(4-mercapto-1,4-diazepan-1-yl)acetamide (LJM 98 201113280 465-99 -2) According to GP7, use 2_gas-#-(2-ethoxycyclohexyl)acetamide (LJM 465_84 ' 2.〇4 mm〇i ' 447 mg), 卜 methyl high (four) (i % 〇1,

0.23 ml) and Na2C03 ( 5.88 mmol, 591 mg) were purified via MDAP (Method 5) to give the _#_(2_ethoxycyclohexyl)-2-(4-indolyl-i) as an orange oil. , 4-diazepane-i-yl)acetamide (47 claws, 8%) and shun (2-ethoxycyclohexyl)_2_(4_ψdiazepine"-based) Indoleamine (92 mg, 17%). Anti-#-(2-ethoxycyclohexyl)_2·(4_fluorenyl), 4-diazepane small group) acetamide iH NMR 400 MHz ( CDC13): 7.3 (1Η, broad doublet CO-Nii-CH), 3.7 (1H, m, 〇-CK2-CH3), 3.62 (1H m 0-CH2-CH3)5 3.37 (0-CH(CH- CH2)) 3.15 (m ^ NH-CH-(CH2)2), 3.11 (2H, s, CO-CH2-N), 2.76 (du ' \^·ιΐ5 ΓΤ1, high piperage base), 2.6 (4Η, m, high piperage base), 2.36 (3Η, s, w rtr, 1^3), 2·15 (lH, m, cyclohexyl), 2.0 (lH, m, cyclohexyl), 1.75-19 m, 2H : high piperage base, 2«[〇-(:112-(^3), 1.75 (111,111, cyclohexyl, 1 blanket), 1.6 (1H, m, cyclohexyl), 1.2-1.4 (2H, m , cyclohexyl), i], ·13 (3H, t, CH2-CH3) ° LCMS : 96% Rt 2.39 min [M + H] + 298.13. GC : 94.29% Rt 14.05 min. TV·(2-ethoxycyclohexyl)-2_(4_mercapto-1,4-diaza)-heptan-1-yl)acetamide Η NMR 400 MHz (CDC13): 7.65 (1H, Zhiwei Double Peak 3 99 201113280 CO-NH-CH), 3.9 (1H, m, 0-C£L-CH3), 3.57 (1H, m, 0-CH2-CH3), 3.45 (m, 1H, NH -CH-(CH2)2) 3.34 (0-CH(CH-CH2)), 3.10 (2H, s, CO-CH2-N), 2.75 (4H, ms high piperage), 2.6 (4H, m, Homopylin 1 base), 2.35 (3H, s, N-Cii3), 1.95 (2H, m, high piperage), 1.82 (2H, m, cyclohexyl), 1.59 (3H, m, cyclohexyl), 1.45 ( 1H, m, cyclohexyl), 1.35 (3H, m, cyclohexyl), 1.18 (3H, t, CH2-CiL)). LCMS: 97% Rt 2.68 min [M+H] + 298. GC: 92.17% Rt 14.19 min » Example A.7.20: #-(3-cyclopentylpropyl)-2-(4-methyl-1,4-diazepan-1-yl) Guanamine (LJM 465-53-2)

According to GP2, 2-gas-iV-(3-cyclopentylpropyl)acetamide (LJM 465-1 1 '4.9 mmo bl), 1-methylhomopelphine (4.47 mmobu 0.5 6 ml) and Na2C03 (13.23 mmol3, 1.4 g), purified by Biotage SP4 to yield #-(3-cyclopentylpropyl)-2-(4-methyl-1 fluorene-diazepane as an orange oil. -1-yl) acetamidine (727 mg, 58%). NMR 300 MHz (CDCI3): 7.45 (1H, wide double front, CO-NH-CH), 3.25 (2H, q, NH-CI^-CHa), 3.15 (2H, s, C〇-CH2-N) , 2.8 (8H, m, high piperage), 2.50 (3H, s, N-CHj), 195 (2H, m, aliphatic), 1.75 (3H, m, high piperage and cyclopentyl ch) , 1-55 (611, 111, cyclopentyl), 1.3 (211, 111, aliphatic), 1. 〇 (211, 111, aliphatic). LCMS: 98%, Rt 0.76 min, [M + H] + 282.221. GC: 93·62〇/〇Rt 14·71 min 〇100 201113280 Example A.7.21 . _/V-(3-cyclopentylpropyl)-2-(trans-2,5-dimethyl. Acetylamine (LJM 465-54-1) 2-Chloro(3-cyclopentylpropyl)acetamide (Ljm 465-1 1,4.3 mmol, 890 mg) and anti-2 according to GP7 , 5-Dimethyl berberine (21.8 mmol » 2.5 g), purified by MDAP (Method 6) to give A/·(3-cyclopentylpropyl)-2-(anti- 2,5-Dimethyl. Desphingo-1-yl) Ethylamine (470 mg, 3 9%). 'H NMR 400 MHz (CDC13): 7·3 (1H, broad doublet, CO-NH-CH), 3.29 (1H, d, CO-CH2-N), 3.25 (2H, m, NH-CH2- CH2), 2.92 (1H, d, CO-CH2-N), 2.8 (1H, m, N-CH_-CH3), 2.72 (2H, m, piperene), 2.53 (1H, m, piperene) , 2.27 (1H, m, piperidinyl), 1.96 (1H, m, piperidinyl), 1.73 (3H, m, aliphatic and cyclopentyl), 1.5 (7H, m, aliphatic and cyclopentyl) , i 3 (2H, m, cyclopentyl), 1·〇5 (2H, m, cyclopentyl), l.oo (3H, d, CH-CH3), 〇·96 (3H,d, CH_CH3) . LCMS: 96% Rt 2.84 min [M + H] + 280.19. GC: 97.09 Rt 14.35 min. Example A.7.22: 2-(4-(Cyclohexanecarbonyl)piperidinyl)-^(2_cyclooctylethyl)propanamide (LJM 465-58-1)

According to GP7, 2-chloro-iV-(2-cyclooctylethyl)propanamide (LJM 465-17, 4.07 mmo 1 g), 1-cyclohexylcarbonylphenamine: 〇70 mmo 727 mg), Na2C03 (10. 99 mmol ' 1.16 g) and Nal (4.07 mmol ' 610 mg Base ethyl) acrylamide 101 201113280 (1.58 g, 96%). 'H NMR 400 MHz (CDC13): 7.03 (1H, broad doublet, CO-NH.-CH), 3.6 (2H, m, ^°^*), 3_5(2Η,Γη,^^*), 3.25 (2H,m,NH-Cii2-CH2), 3.05 (1H,q,CO-CH-CH3), 2.44 (5H,m,piped and CO-C|i-(CH2)2), 1.35- 1.85 (2 1 H, m, cyclooctyl and cyclohexyl), 1.15 - 1.35 (9H, m, CH-CiL and cyclooctyl and cyclohexyl). LCMS: 96% rt 3.36 min [M + H] + 406.17. Example A.7·23: #-(2-cyclooctylethyl)-2-(pipedino-1-yl)propanamide (LJM 465-57-2) 2-gas-iV~ according to GP7 (2-cyclooctylethyl) propylamine (ljm 465-17 '4.07 mmo 1 g), piperidine (40.7 mmol, 3.5 g) and

Nal (4.07 mmol &gt; 610 mg), purified by Biotage SP4 to give #-(2-cyclooctylethyl)-2-(piperidin-1·yl)propanamine (1.13) as a pale yellow oil. g, 94%). NMR 300 MHz (CDC13): 7·16 (1H, broad doublet, CO-NH-CH), 3.15-3.30 (2H, m, NH-CH2-CH2), 2.8-3.05 (4H, m, piperidine Base), 2.30-2.60 (5H, m, piperidinyl and CO-Cii-(CH2)2), 1.10-1.70 (21H, m, cyclooctyl and aliphatic). LCMS: 95% Rt 0.76 min [M + H] + 296.3. GC: 97.06% Rt 15.95 min. Example A.7.24: 2-(4-Ethyl peptidyl-hydrazinyl)-#-(cis_4.hydroxycyclohexyl)acetamide (LJM 465-63-1)

According to GP7, 2-gas-TV-(cis-4.hydroxycyclohexyl)acetamide (LJM 102 201113280 465-16, 2.6 mmol, 0-5 g), 1-ethylhydrazine-based (2.36 mmol,

3 03 mg ) and Na 2 C 〇 3 (7.02 mmo 744 mg) were purified by preparative HPLC (MeOH 10-15% over 10 min) to give 2-(4-ethylhydrazino) as a pale yellow oil. Phenyl-1-yl)-#-(cis-4-ylcyclohexyl)acetamide (90 mg &gt; 13%). NMR 400 MHz (CDC13): 7.07 (1H, broad doublet, CO-NH-CH), 3.9 (2H, m, OU_A NH-CH), 3.61 (2H, m, piperidinyl), 3.47 (2H, m, piperidinyl), 3.00 (2H, s, CO-CH2-N), 2.51 (4H, m, piperidinyl), 2.08 (3H, s, CO-C£L), 1.67 (9H, cyclohexyl) ). LCMS: 99.5% Rt 1.38 min [M + H] + 284.22. GC: 95.53% Rt 16.59 min. Example A.7.25: 2-(4_decylpiperidine-1-yl)-#-(trans-4-hydroxycyclohexyl)acetamide (LJM 465-56-1) 2-gas according to GP7 - ΛΓ-(trans-4-hydroxycyclohexyl)acetamide (LJM 465-15, 5.21 mmol, 1 g), 1-decanoic acid 0 bottom: 4.75 mmol, 0.6 1 mL) and Na2C03 (14.07 mmol, Purification by MDAP (Method 2) yielded 2-(4-carbamoylpiperidin-1 -yl)-AK-trans-4-hydroxycyclohexyl)acetamide as a yellow oil (400 mg) , 31%). 'H NMR 400 MHz (CDC13): 8.00 (1H, s, CHO), 6.80 (1H, broad doublet, CO-Nii-CH), 3.85 (1H, m, CE〇H), 3.6 (1H, m , CENH), 3.55 (2H, m, piperidinyl), 3.37 (2H, m, piperene), 2.99 (2H, s, CO-Ci^-N), 2.46 (4H, m, hydrazine) , 2·1 (1H, broad unimodal, 〇H), 1.95 (4H, m, cyclohexyl), 1.38 (2H, m, cyclohexyl), 1.22 (2H, m, cyclohexyl). 103 201113280 LCMS : 89% Rt 1.24 [M + H] + 270.17. GC: 96.18% Rt 16.51 min. EXAMPLES 7.2·7.26 : #-(trans-4-hydroxycyclohexyl)-2-(pipedino-1-yl)acetamide (LJM 465-55-6) 2-gas-iV- (reverse) according to GP7 -4-hydroxycyclohexyl)acetamide (LJM 465-15, 5.21 mmol, 1 g), morphine (52.17 mmol, 4.5 g), via preparative HPLC (MeOH 3%-20% over 1 min) Purification, yielding 2 batches (1: 345 mg, 27%; 2: 146 mg, 12%) in the form of a yellow oil (consistent with the analytical data) (trans-4-hydroxycyclohexyl)-2·(piperazine) _1_ base) acetamide. *H NMR 300 MHz (MeOD): 3.65 (1H, m, CHOH), 3.5 (1H, m, C_), 2·94 (2H, s, CO-CiL-N), 2.83 (4H, m, piperine Base), 2.45 (4H, m, piperidinyl), 1.9 (4H, m, cyclohexyl), 1.33 (4H, m, cyclohexyl). LCMS: 99.5% Rt 0.37 min [M + H] + 242.16. GC: 95.45% Rt 14.12 min. Example A.7.27 . (i?(3,3-Dimercaptobutyl-2-yl)-2-decapine-1-yl)acetamide (LJM 465-51-2) Used according to GP7 ( /?)-2-Gas-#-(3,3-Dimercaptobutan-2-yl)acetamide (LJM 465-25, 5.63 mmo 1 g) and piperphine (56.3 mmol, 4.8 g) 'Purification via Biotage SP4 to give (and) · τν-(3,3-dimethylbutan-2-yl)-2-(piperidin-1-yl)acetamide (894 mg, 70%) . 'H NMR 300 MHz (CDC13): 7.16 (1H, broad doublet, CO-NH-CH), 3.83 (1H, m, NH-CH-CH3), 2.97 (2H, s, 104 201113280

C〇-Cii2-N), 2·89 (4H, m, piperene), 2·5 (4H, m, piperene), 2.43 (1H, s, NH), I.05 (3H, d , CH-CH3), 0.88 (9H, s, 3X ca3). , LCMS: 77% Rt 0.46 min [M + H] + 2121. GC: 96.5 ° /. Rt 1 1.97 min. Example A.7.28: (Λ)-ν-(3,3-Dimercaptobutan-2-yl)_2-(4-isopropyl-1,4-diazepan-1-yl) Acetamide (ljm 465-5 2-2 ) was used according to GP7 (Heart-2-gas-#-(3,3-didecylbutan-2-yl)acetamide (LJM 465-25, 5.63 mmol) ' 1 g), #-isopropyl (ι, 4)·diazepane (5_12 mmo, 0.73 g) and Na2C03 (1. 2 mmol, 1.61 g), purified by Biotage SP4 to give a yellow oil (R)-N-{3,3-._曱基丁炫&gt;·2-yl)-2-(4-isopropyl-1,4-diazepan-1-yl) Acetamide (794 mg, 5 5%). !H NMR 300 MHz (CDC13): 7.34 (1H, broad doublet, CO-NH-CH), 3.83 (1H, m, NH-CH-CH3), 3.10 (2H, s, CO-CiL-N) , 2·89 (1H, m, N-Cii-(CH3)2, 2.7 (8H, m, diazepanyl), 1.77 (2H, m, diazepanyl), 1.05 ( 3h, d, CH-CiL), 1.00 (6H, d, CH-(Cii3)2), 0.89 (9H, s, 3xCii3) LCMS: 96% Rt 0.77 min [M + H] + 284.23. GC : 98.14 Rt 12.74 min. Example 7.7·29: A/&quot;-cyclobutyl-:2-(piperonyl-l-yl)propanamide (LJM 465-65-1) 2-gas ring according to GP7 Butylpropanamide (LJM 465-10, 6.19 mmol, 1 g), piperazine (61.9 mmo 5.4 g) and Nal ( 6.19 mmol, 105 201113280 928 mg ) were purified via MDAP (Method 3). Two batches (1: 570 mg '44%, 2: 240 mg '18%) of cyclobutyl-2-(piperidin-1-yl)propanamide were obtained as a yellow solid (consistent with analytical data). 4 NMR 400 MHz (CDC13): 7.25 (1H, broad doublet, CO-NH-CH), 4.36 (m, 1H, NH-CH-(CH2)2), 2.95 (6H, m, (:0- (: 112-&gt;1 and piperene), 2.5 (411, 〇1, piperidinyl), 2.3 (211, paw, cyclobutyl), 1.8 (2H , m, cyclobutyl), l_69 (2H, m, cyclobutyl), 1.18 (3H, d, CH-CIL). LCMS: 95% Rt 1.53 min [M + H] + 210.11. GC : 92.25% Rt 11.20 min 〇Example Α_7·30 : 7/-cyclobutyl-2-((/?)-hexahydropyrrolo[ΐ,2-α]吼耕-2(1//)-yl)propanamide (LJM 465-66-1) 2-Gy-indole-cyclobutylpropanamide (LJM 465-10, 4.36 mmo 704 mg), (Λ)-1,4-diazabicyclo [4- 3-0] tritium (3.96 mmo, 0.5 g), Na2C03 (1 1.74 mmo, 1.24 g), and Nal (4.35 mmo, 652 mg), purified by Biotage SP4 to give a cyclobutyl-yt. 2-((R)-hexahydropyrrolo[丨,2_β]pyridin:_2(1//)-yl)propanamide (710 mg, 65%). 'H NMR 400 MHz (CDC13): 7.30 (1H, broad doublet, CO-NH-CH), 4.38 (m, 1H, NH-CH-(CH2)2), 3.06 (5H, m, CO-Cil -CH3-N and pyrrolo[i,2_a]pyrazine), 2.8 (2H,m,pyrrolo[1,2-α].pyramine),1.65 (2H,m,pyrrolopyrrole),2.0- 2.5 (6H, m, piroxi[1,2-β]pyridine and cyclobutyl), 16_2 () (6H,m,pyrrolo[1,2-α].pyryl and cyclobutyl) , 1_45 (1H, m, cyclobutyl), 1.19 (3H, &lt; 106 201113280 CH-CMj). LCMS: 99% Rt 2.18 min [M + H] + 252.23. GC: 98% Rt 12.58 min. Example A.7.31: Cyclopentyl-2-(l,4-diazepan-1-yl)-iV-methylacetamide (LJM 465-50-1)

According to GP7, 2-gas-AT-cyclodecyl-ΑΓ-mercaptoacetamide (LJM 465-8, 5.69 mmob 1 g) and homopiperone (56 9 mmol, 5.70 g) were used via MDAP (Method 4 Purification to give 沁cyclopentyl-2-(1,4-diazepan-1 ι^) Α 曱 曱 醯 醯 ( (8 〇〇 mg, 59%) 〇' as a yellow oil H NMR 400 MHz (CDC13): 4.92 (1H, m, N-CH-(CH2)2), 4.45 (1H, CH2-N-CH2)5 3.32 (2H, d, CO-CH2-N), 2.93 ( 4H, claw, high piperage base), 2.76 (411, 111, high piperage), 2.07 (3, 8, (: 3), 1.6-1.9 (6H, m, high piperidinyl and cyclopentyl) m) (2H, m, cyclopentyl), 1.4 (1H, m, cyclopentyl). LCMS: 97% Rt 1.98 min [M + H] + 241.14 ° GC: 96% Rt 13.01 min. Example A.7.3 2 : 2-(4-cyclohexylpiperidin-i-yl)-#-cyclopentyl_A^-mercaptoacetamide (LJM 465-49-1)

According to GP7, 2-gas-AT-cyclopentylmethylacetamide (LJM 465-8 ' 5.69 mmo Bu 1 g), cyclohexylpiped (5 18 mm〇l ' 872 mg) and Na2C03 ( 15.4 mmo Purification by MDAP (Method 6) gave 2-(4-cyclohexylpiperidin-1-yl)-y-cyclodecyl-iV-mercaptoacetamide (458) as a pale yellow oil. Mg, 29%). a 107 201113280 'H NMR 400 MHz (CDC13): 4.92 (1H, m, N-CH-(CH2)2), 4.42 (1H, CH2-iV-CH2)5 3.18 (2H, d, CO-CH2-N ) 2.86 (2H, s, 0-endyl), 2.76 (2H, s, piperidinyl), 2.5 (8H, m, piperidinyl and cycloalkyl), 2·19 (3H, s, W- Ciia), 1.4-1.9 (11H, m, cycloalkyl), m.3 (6H, m, cycloalkyl). LCMS: 86% Rt 3.00 min [M + H] + 308.22. GC: 97.55% Rt 15.94 min. EXAMPLES ····································································································· -1 ) 2-Gethylethyl-#-(4.(trifluoromethyl)cyclohexyl)acetamide (LJM 465-78, 1.807 mmol, 49 1 mg), 1-ethylidene-based Phenyl (1.64 mmol ' 2 1 1 mg) and Na2C03 (4.9 mmol, 520 mg) were purified by MDAP (Method 6) to give 2-(4-ethylhydrazinyl-1-yl) as an orange oil. -#-Ethyl-iV-(4-(trifluoromethyl)cyclohexyl)acetamide (124 mg &gt; 2 6%). NMR 400 MHz (CDC13): 3.62 (2H, m, EtOAc), 3.45 (2H, m, EtOAc), 3.25 (m, N-Cii2-CH3), 3·17 (2H, s, CO- Cii2-N), 2.50 (4H, m, brimone), 2.29 (1H, m, cyclohexyl), 2.15 (2H, m, cyclohexyl), 2.06 (3H, s, CO-C to 3), 97 (1H, m, cyclohexyl), 1.8 (1H, m, cyclohexyl), 1.6I (4H, m, cyclohexyl), 1.4 (1H, m, cyclohexyl), 1.8-1.21 (3H, m, W -CH2-C£i3). LCMS: Rotamers were present in total 97% Rt 2.6 min [M + H] + 364.42 ° GC: 33.61% Rt 15.68 min, 63.43% Rt 15.77 min. 108 201113280 « Example A. 7.3 4. A/&quot;-Ethyl-2 -(parphin-1-yl)-V-(4_(trifluoromethyl)cyclohexyl)acetamide (LJM 465-97 -1 ) 2-Ga-iV-ethyl-#-(4-(trifluoromethyl)-yl acetamide (LJM 465-78, 1.807 mmol, 491 mg) and lemma (18 根据) according to GP7 7 mmol - 1.56 g), purified by MDAP (Method 5, 2 cycles) to give A7·ethyl-2-(β morphin-1-yltrifluoromethyl)cyclohexyl) as a dark yellow oil. Acetamide (212 mg, 37%). 'H NMR 400 MHz (CDC13): 3.27 (1H, q, piperidinyl), 3.18 (1H, q, piperidinyl), 3.1 (2H, m, CO-Ci^-N), 2.86 (4H, m , piperidinyl), 2.62 (1H, s, 7V-Cii), 2.45 (4H, m, cyclohexyl and Cii2-CH3), 2·25 (1H, m, cyclohexyl), 1.9-2.15 (2H, m , cyclohexyl), 1.5-1.85 (5H, m, cyclohexyl), 1.36 (1H, m, cyclohexyl), 1.0-1.8 (3H, m, CH2Ca3). LCMS: Rotamer is present in total, 80% Rt 2.6 min [M + H] + 322.38 〇 GC : 40.35% Rt 12.93 min, 56.54% Rt 13.05 min. Example A.7.3 5 : (*S)-#-(4,4-Difluorocyclohexyl)-2-(2-isopropyl-4-methylphenidin-1-yl)acetamide (465 -46-1) 2-Glycol-, (4,4-difluorocyclohexyl)acetamide (LJM 465-28, 3.85 mmol, 815 mg), (3*S)-3-isopropyl group according to GP7 1-nonylpyrazine (3.5 mmol, 0.5 g) and Na2C03 (10.5 mmol, 1-11 g) were purified by MDAP (Method 5) to give (5)-ΑΚ4,4-difluoro as a pale yellow solid. Cyclohexyl)-2-(2-isopropyl-4-mercaptopefene-1-yl)acetamide (105 mg, 1 〇〇/0). 109 201113280 4 NMR 400 MHz (CDC13): 7·28 (1H, broad doublet, CO-NH-CH), 3.88 (1H, m, CH2-A^-CH), 3.37 (1H, d, CO- CH.2-N), 2.8 (1H, m, piperene), 2·75 (1H, d, CO-CiL-N), 2·57 (2H, m, piperage), 2.46 (1H, m, cyclohexyl), 2.26 (1H, m, cyclohexyl), 2_24 (3H, s, W-CiL), 1.75-2.13 (9H, m, cyclohexyl), 1.52 (2H, m, cyclohexyl), 〇 , 92 (3H, d, CH-CiL), 0.83 (3H, d, CH-CiL). LCMS: 75% Rt 2.69 min, [M + H] + 318.42. GC: 93.47% 13.40 min. Example A.7.36: 2-(4-Ethylpiperidine-1-yl)-#-cyclohexylacetamide (LJM 465-23-2) Also as Ventura P et al. (1984) Farmaco 39 ( 6): Preparation was carried out as described in 190-198. According to GP2, 2-gas-7V-cyclohexylacetamide (LJM 465-5, 5.7 111111〇1'1 layer), 1_ethylthiol morphine (5.18 1]1111〇1,663 111苢) and ^2€;03 (15.36 mmol &gt; 1.63 g), purified by Biotage SP4 to give 2-(4-ethyipiperamine:-1-yl)-, cyclohexylacetamide as a yellow oil. 1.56 g, 88%) 〇

Ih NMR 300MHZ (CDC13): ό.94 (1H, broad doublet, CO-Nii-CH), 3·77 (1H, m, NH-CE-(CH2)2), 3.62 (2H, m, Phenyl), 3.47 (2H, m, piperidinyl), 3.01 (2H, s, CO-dN), 2.51 (4H, m, arable), 2·08 (2H, s, c〇_C£ L_N), i 85 (2H, m, cyclohexyl), 1.66 (3H, m, cyclohexyl), 1.40 (2H, m, cyclohexyl), hl5 (3H, m, cyclohexyl). 110 201113280 LCMS : 97% Rt 0.78 min [M + H] + 338.3 = GC . 96% Rt 18·14 mill. Example A.7.37: 1 cyclohexyl-2-(4-mercaptopiperidin-1yl)acetamide (LJM 465-24-2) Also as Ventura P et al. (1984) Farmaco 39 (6) The preparation was carried out as described in :190-198. 2-Ga-indole-cyclohexylacetamide (LJM 465-5, 5.7 mmo 1 g), i-mercaptipipamine: (5.18 mmol, 0.58 ml) and Na2C03 (15.36 mmol &gt; according to GP2 Purification by Biotage SP4 gave iV-cyclohexyl-2-(4-carbamimidino-1 -yl)acetamide (1.15 g, 87%). 'H-NMR 300 MHz (CDC13): 8.01 (1H, s, CHO), 6.90 (1H, broad doublet, cO-NH-CH), 3·80 (1H, m, NH-CK-(CH2) 2), 3·57 (2H, m, piperene), 3.40 (2H, m, piperene), 3.01 (2H, s, CO-Cl-N), 2.51 (4H, m, piperidinyl) , 1.86 (2H, m, cyclohexyl), U6 (3H, m, cyclohexyl), 1.36 (2H, m, cyclohexyl), 1.17 (3H, m, cyclohexyl). LCMS: 93% Rt 0.54 min [M + H] + 254.1 〇 GC: 95% Rt 15.06 min. Example A.7.38: W-(trans-4-hydroxycyclohexyl)-2-(pipenphin-i-yl)etheneamine (LJM 465-55-6) can also be used as Ventura P et al. (1984) Farmaco The preparation was carried out as described in 39(6): 190-198.

2-Chloro(trans-4-hydroxycyclohexyl)acetamide (LJM 111 201113280 465_15 '5.21 mmol, 1 g), piperidine (52.17 mmol, 4·5 g) according to GP2, via preparative HPLC (MeOH Purification by 3%-20% over a period of minutes, yielding 2 batches (1. 345 mg '27%, 2: 146 mg, 12%) in yellow oil (consistent with analytical data) #-(反-4 -Hydroxycyclohexyl)acetamide. 'H NMR 300 MHz (MeOD): 3.65 (1H, m, CHOH), 3.5 (1H, m, CH.N), 2.94 (2H, s, CO-C 1^2 N), 2.83 (4H, m, Oral phenyl), 2.45 (4H, m, phenylidene), 1.9 (4H, m, cyclohexyl), 1.33 (4H, m, cyclohexyl). LCMS: 99.5% ’ Rt 0.37 min [M + H] + 242.16. GC: 95.45% Rt 14.12 min. Example A.7.39: iV-(cis-4-hydroxycyclohexyl)-2-(pipedino-1-yl)acetamide (LJM 465-64-1) can also be as Ventura P et al. (1984) Farmaco The preparation was carried out as described in 39(6): 190-198. According to GP2, 2-gas (cis-4-ylcyclohexyl)acetamide (LJM 465-16, 2.6 mmo dip·5 g), piperidine (26 mm〇1, 2 24 g), via MDAP ( Method 2) Purification afforded (cis-4-hydroxycyclohexyl)-2-(piperidin-yl)acetamide (39 mg, 62%) as a yellow solid. 4 NMR 400 MHz (CDC13): 7.22 (1H, broad doublet, CO-NH-CH), 3.88 (2H, m, 〇H and NH-CH), 2.93 (2H, s, CO-Ciia-N) , 2·8δ (4H m, piperage), 2.46 (4h m, piperage), 1·64 (10H m, cyclohexyl). LCMS: 85% Rt 1.25 [m + H] + 242.19. 112 201113280 GC : 97.38 Rt 13.96 min. Example A.8.1: y-mercapto-iV-pentyl-2-(1,4-diazaspiro[55]_^___-4-yl)acetamide (002NK39) is added with dihydrochloride 1, 4 -Diazane[5.5] eleven-burn (1 mmol, 229 mg) in ethanol (1 mL) to 2-chloro-N-indenyl-N-pentylacetamide (1"mm〇1, 197 (mg) and sodium carbonate (5 mmol, 530 mg) in ethanol (2 mL), and the reaction was heated to reflux for 3 h. The reaction was cooled to room temperature then water (5 mL) and aqueous Na.sub.2CO. The product was extracted with EtOAc (3 X 20 mL). Dowex® 5 0WX2 hydrogen type 100-200 sieve 孑L (4 g) was washed with methanol (40 mL). The reaction mixture was filtered and then loaded onto an ion exchange resin using gravity filtration. The resin was washed with decyl alcohol (40 mL). The product was eluted with a solution of about 1 Μ NH 3 in methanol (20 mL) and the solution was concentrated. The crude material was purified via Combiflash (buffer A: Et20, buffer B: 0_1 ΜNH3 in MeOH: Et20 (1:1) using a 4 g silica gel column, using 〇% buffer B ( 1 minute), followed by 0-100% buffer B (during minutes) and 100% buffer Β (2 minutes) elution to give V-mercapto-indolyl-2-(1) as a yellow oil 4-Diazirospiro[5.5]undec-4-yl)acetamidamine (1〇2 mg, 35%). HPLC TFA buffer: Rt 10.26 min H NMR (3 00 MHz, cd3od, mixture of 2 rotamers at a ratio of about 1:1) 3·47 (1 H, m, CO-NMe-CiL·), 3.36 (1 H, m, CO-NMe-CH2), 3.13 (2 H, s, CO-CH2-N), 3.12 (3/2 H, s, CO-NCHj-), 2.90 (3/2 H, s , CO-NCH3-), 2.87 (2 H, m, morphine), 2.37 (4 H, m, pyrene), 1.84 -1.25 (10 H, m, cyclohexyl), 113 201113280 1.84 - 1.25 (6 H, m, -CH2-CH2-CH2-CH3), 0.95 (3/2 H, t, J 7.1, -CH2-CH2-CH3), 0.94 (3/2 H, t, J 7.1, -CH2-CH2-CH3 0 Example A.8.2: W cyclohexyl-2-(4-mercapto-peptazin-yl)butanamine (002NK51) will contain piperage (40 mmol '3·45 g), carbonic acid planing ( 4 mm 丨 丨 3 〇 g) and 2-bromocyclohexyl decylamine (4 mmol, 990 mg) of dimethyl guanamine (20 mL) were heated to reflux for 1 hour, then stirred at room temperature 18 hours. Water (40 mL) was added and the product was extracted with EtOAc (3 &lt The organic layer was washed with aqueous MgS04 (4%, 2 X 40 mL) dried over EtOAc EtOAc The crude material was purified via Combiflash (buffer a: Et20, buffer B: 〇j Μ NH3 in MeOH: Et 2 〇 (1:1) using a column containing 12 g of cerium oxide, buffered with 〇0/〇 Liquid 8 (1 minute), followed by 0-100% buffer solution (11 minutes) and 1% buffer B (3 minutes) were eluted to produce A^cyclohexyl-2-(4) in the form of a solid cream. - formazan. thiophene: -1-yl) butylamine (41 mg, 4%). HPLC TFA buffer · Rt 8.69 min 4 NMR (300 MHz, cd3od) 7.97 (1 H, S, C(O).), 3 67 (1 H, m, C(O)-NH-CIL), 3.51 (2 H, m, piperphine), 3.44 (2 H m piperidine), 2.87 (1 H, dd, 8.5, 5.8, C(0)-Cii_NH), 2.61 (2 hm piperidine), 2.5 2 (2 H, m, piperidine), 1.90 - 16 〇 (5 H, m, cyclohexyl) 1_90 -1_60 (2 H, m, CCOpCH-CiL-), 1.31 (5 H, m, cyclohexyl) 0.91 (4 H , t, 7.4, CH2-Cii3). Example A.8.3: 2-(4-Ethylpipenyl-indenyl)cyclopentyl-methylammoniumamine (002NK65) 114 201113280 · Addition of acetic anhydride (2 mmol, 206 mg) DCM (1 mL) was added to hydrazine cyclopentyl fluorenyl-2-(piperidinyl)acetamide (2 mL in DCM (4 mL) and stirred at room temperature for 3 hr. Ν &amp; (1 Μ, 10 mL) and the product was extracted with Et0Ac (3 χ 2 〇 mL). The organic layer was dried over MgSO 4 , filtered and concentrated. Using a column containing 4 g of cerium oxide, via Combiflash (buffer A: Et20, buffer B. 0.1 Μ NH3 in MeOH: Et20 (1:1)) Purified crude material with 〇〇/〇 buffer B (1 min) followed by 〇_1〇〇% buffer b (duration n Stripped with 100% buffer B (2 minutes) to give 2-(4·ethylmerinopiperidin-1-yl)-;V-cyclopentylmethylacetamide as a yellow oil ( 359 mg, 67%) ° HPLC TFA buffer: Rt 6.57 min 4 NMR (300 MHz, cd3od, mixture of 2 rotamers at about 1:1 ratio) 4.83 (1/2 H, m, CO- NMe-CSL), 4.49 (1/2 H, m, CO-NMe-Cii), 3.57 (4 H, m, parrot), 2.95 (3/2 H, s,

CO-NCH3-), 2.80 (3/2 H, s, CO-NCH3-), 2.51 (4 H, ddd5 J 16.0, 11.5, 5.1, piperidine), 2.09 (3 H, s, C(O)- CiL), 1.90 (1 H, m, cyclopentyl), 1_76 (3H, m, cyclopentyl), 1.62 (4 h, m, cyclodecyl). Example A. 8 3 : V-Isopropyl-1 - borneioacetamide (1} 9 _ i ) from Acros Organics (a member of the Thermo Fisher Scientific Group). CAS number 39890-42-1, catalog number 205610250. EXAMPLES 1 1 - Efficacy in chronic EAE (r experimental autoimmune encephalomyelitis)) as described by Baker D 4 (1990) J Neuroimmunoi 115 201113280 28(3).261-70, EAE induced in Bi〇zzi aBH mice (7-8 weeks old, Harlan). Briefly, autoimmune CNS inflammation was induced by immunization of experimental animals with homologous spinal cord homogenate with complete Freund's a (jjuvant) emulsification. After immunization of the third day, the mother-day test animals Weight loss and neurological symptoms. After the initial symptomatic remission is relieved, the test item is administered orally every day (ie, 29th to 6th day) (2〇〇mg in η2〇 vehicle) /kg bismuthrazine dihydrochloride. The clinical disease was assessed and scored as follows: 〇 = asymptomatic, 1 = tail numbness, 2 = anterior reflex injury, 3 = partial hind limb paralysis, 4 = complete hind limb paralysis, and 5 = Sudden death or death due to EAE. As shown in Table 1, the treatment with esalazol resulted in a severe and significant reduction in EAE in the chronic phase of the disease. The therapeutic effects of Ai Sara include a significant reduction in disease burden (ie, (10) EAE score). And the onset of delayed relapse. In addition, 5 of the 12 animals in the acesulfazol-treated group did not develop any recurrence during the 61-day study period.

* Ixaazole treatment significantly reduced the cumulative EAE score compared to vehicle-treated animals (P = 0.04). &quot;There were 9 of the 10 animals in the drug-treated group who developed chronic EAE with a confirmed recurrence episode, while only 7 of the 12 Ai'erjuan treatment groups had a recurrence. Example B.2 - Efficacy in total forebrain ischemia Sprague Dawley rats were orally treated with escarazole per day starting five days prior to induction of ischemia. Transient ischemia was induced in anesthetized male rats on the third day of the study as described by others (Smith 荨 (1984) Acta Neurol Scand 69(6): 3 85-401). Briefly, the mean arterial blood pressure was reduced to 30-35 mm Hg, as seen by blood draw through the jugular vein. At the same time, the two common carotid arteries were clamped with an anti-injury surgical clip for 8 minutes, after which the clip was removed and blood was transfused. Sham-operated animals undergo vascular exposure under unpumped or unclamped carotid arteries. High doses (4 〇〇 _8 〇〇 mg/kg) of acesulfazol were given before occlusion and the concentration was generally low (200-800 mg/kg) after occlusion. Fifteen days after ischemia, the animals were sacrificed and the hipp〇campal brain block was fixed in 4% polymethyst for 24 hours. After cryoprotection in 30% sucrose, cryosections of 20 microns thickness were prepared and stained with indole staining to label neurons that survived the C a 1 pyramidal cell layer on the dorsal hippocampal level. It is recognized that total ischemia can degenerate neurons, and in particular, vulnerable neurons are particularly hippocampal CA A 1 neurons that have been observed to have delayed cell death after total ischemia. Table 2: Treatment control, pseudoischemic + vehicle ischemia + Aesa beta number of living neurons (mean ± 5 £ ^ 1) 127, 2 ± 5, 5 28, 0 ± 6, 7 60, 5 ± 11,5 N 15 11 19 in 201113280 . Phase lx In vehicle-treated animals, treatment with acesulfazol increased the number of viable neurons in the hippocampal cA1 region, see Table 2 (i). In addition, an improvement in the behavioral study of the M〇rris Wkr Maze behavior was also observed, indicating that the cognition in the eraxazole-treated animals was improved compared to the vehicle-treated group (results not shown). EXAMPLES -3 - Neuroprotection by Preventing Excitatory Toxicity of Glutain In vitro studies were conducted to investigate whether escarazole protects cortical neurons & toxicities induced by k-classin. The following experimental procedures were used to identify neuronal survival. Mixed cortical cultures were prepared from rat embryos. The cortex was cut and finely collected; 3 blood β medium was applied to a plate coated with poly- 1 lysine. In-vitro experiments were performed on day ίο. Cell death was induced using 2 〇 glutamic acid for 5 min. Wells treated with media alone served as unstimulated controls. Azarazol was weighed into the cells 30 min before the addition of glutamic acid. After 24 hours of incubation in vitro, the number of viable neurons was identified. The culture is fixed and the cells are permeabilized and block non-specific binding. An anti-neuronal nucleus (anti-NeuN) was used as a primary antibody followed by a biotin-labeled secondary antibody and an avidin-biotin-peroxidase complex (ABC reagent). Chuan-enhanced diaminobenzidine (DAB) was used as a substrate-positive positive cell. NeuN immunopositive neurons were counted using light microscopy. The results are shown in Table 3 as a percentage of viable neurons compared to unstimulated controls. The number of culture wells for each compound concentration used was $6. Three concentrations of esalazol (0.1, 1 and 10 /zM) were studied. The values were analyzed using a single factor AN〇VA followed by Deng 118's 201113280 Dunnet's test. Table 3 Unstimulated control (η = 6) Toxicity induced by alanine (η = 6) glutamic acid + esaza η sitting 0,1 μΜ (η=6) glutamic acid + esala. Sit 1 μΜ (η=6) glutamic acid + aitaxazole ΙΟμΜ (η=6) Percentage of living neurons (average soil SD) 100±9 28±7 85±7 77±17 87±12 Ρ value Ρ ;0,001 Ρ&lt;0,001 Ρ&lt;0,001 Aesa is extremely effective and extremely significantly reduces glutamate-induced toxicity. All test concentrations were equally effective. Example B. 4 - Neuroprotection by preventing oxidative damage In vitro studies were conducted to investigate whether escarazole protects cortical neurons from oxidative damage induced by ΙΟ2. The following experimental procedure was used to identify cortical cell death. Mixed cortical cultures were prepared from rat embryos. The cortex was cut and finely collected in 3 serum medium and applied to a plate coated with poly-L-lysine for the third day of the test, and undesirable colloidal cell division was inhibited. ^ On-line experiment was carried out on the 10th day. Let 〇# Μ Η202 1 h induce cell death. Wells treated only with media served as unstimulated controls. 3 〇〇 甲基 methyl aspartate (NMDA) was used as the total neuron death for 24 h, and azarazol was dosed to the cells 30 min before the addition of H 2 〇 2 . In addition: after further incubation in a test tube for 24 h in the presence of latazole, the cells were measured and the medium was removed and the cell debris was removed. An aliquot was placed in a drip tray and an equal amount of lactate dehydrogenase (LDH) test 119 201113280 was dosed into the wells. The absorbance at 340 nm was measured immediately using an ELISA reader. The change in absorbance per minute is measured, which is proportional to the released LDH. Results are shown in Table 4 as a percentage increase in cell death compared to unstimulated controls. The number of culture wells for each compound used was 6. Studied Ai Sarah. Three concentrations of sitting (〇·1, 1 and 10 #Μ). Values were analyzed using a one-way ANOVA' I5 followed by a Dunnett's multiple comparison with a Η2〇2 poisoning well as a control. Table 4 Unstimulated vs. (n = 6) H2O2-induced toxicity (η = 6) Η2Ο2 + Ai salad-sitting 0,1 μΜ (η=6) Η2〇2 + esalaladrol 1 μΜ (η=6) Η2ο2 + 艾沙拉嗤 10 μΜ (η=6) Total cell death according to NMDA (η = 6) Percentage of cell death (mean ± SD) 0 ± 7 37 ± 4 26 ± 7 20 ± 6 15 ± 1 〇 100 ±13 P value Ρ &lt;0,05 Ρ&lt;0,001 Islacazole is extremely effective and extremely significantly reduces the toxicity induced by Η2〇2. The effect is significantly dose dependent. Example 5.5 » Neurotrophic properties. In the experiment, the experiment was conducted to evaluate the nerves of Ai Sara's saliva. The nutrient effect measurement, θ 八, ^ 刀神 is the induction of the growth of each cell in this neuron culture. m rat embryo month. A mixed cortical culture is prepared. The cortex is cut and the cells are harvested. Will be in the serum containing the Lagos collection. The cells in the nutrient are coated on a culture plate coated with poly-L-lysine. After four hours of coating, azsalazine or a positive control (5 ng/mi 120 201113280 brain-derived neurotrophic factor, (BDNF)) was dosed onto the wells. After 48 h of re-cultivation, cells were fixed and incubated with a single ΜΑρ·2 antibody followed by AleXaFlU0r568 goat anti-rabbit secondary antibody. Use a fluorescent microscope to acquire a digital image. The number of neurites was analyzed using ImagePr(R) enhanced software and the results are shown in Table 5 for the number of wells per compound^6. The values were analyzed using a one-way ANOVA followed by a Dunnett's test. Table 5 ~~— - Unstimulated control (n = 6) Parent salad spit 0,01 μΜ (η=6) Isardazole 0,1 μΜ. (η=6) Ai salad spit 1 μΜ (n=6) Positive control (n = 6) Total number of neurites per cell (mean ± SD) 3, 〇 3 ± 〇, 32 4, 17 ± 0, 37 4, 50 ± 0, 55 4, 75 ± 0, 64 5 , 67 ± 0, 82 P value Ρ &lt; 0, 01 ρ &lt; ο, οοι P &lt; 0, 001 P &lt; 0,00 The factory analyzed the number of primary neurites plus the number of branches derived from their primary neurites. Also, safflower significantly increased the average number of neurites and branches of each cell at all concentrations tested. Example C. 1 - Neuroprotection by preventing agonistic toxicity of glutamate _ 2 In-vitro studies to investigate whether amine-based guanamine protects cortical nerves. Neuronal survival was identified by measuring LDH according to the same experimental procedure as described in the Examples and 以上 above. As a result, the percentage of cell death after glutamate-induced toxicity (Ping Xi value SI) was not shown in Table 6. Three concentrations (1, =_heart) were studied for each compound and the number of wells for each compound used was 6 10 . All test compounds were reduced by cell death t (results indicated; 121 201113280 statistical significance) Reduced the toxicity of the face acid. Table 6: Compound number control mean SD glutamine control mean SD glutamate +1 μ Μ compound mean SD glutamic acid + 10 μ Μ compound mean SD glutamic acid + 100 μ Μ compound mean SD 119-1 0 ,0 5,4 78,1 5,3 67,4 8,4 Ρ&lt;0,05 61,7 6,3 P&lt;0,001 53,0 4,3 P&lt;0,001 002NK24 0,0 1,8 73,3 2,8 69,7 3,4 61,6 5,4 P&lt;0,01 50,5 7,0 P&lt;0,001 002NK25 0,0 3,1 51,3 4,7 43,4 6,2 Ρ&lt; 0,05 39,1 6,1 P&lt;0,01 31,8 2,1 P&lt;0,001 002NK29 0,0 2,2 64,1 3,5 36,0 6,8 Ρ&lt;0,001 25,1 5, 5 P&lt;0,001 25,3 2,0 P&lt;0,001 002NK30 0,0 0,8 73,4 5,6 72,6 5,8 70,0 5,6 57,6 6,2 P&lt;0,001 002NK37 0, 0 U 63,8 2,7 56,8 2,5 Ρ&lt;0,001 51,3 2,9 P&lt;0,001 nd 002NK40 0,0 4,3 70,5 12,7 56,8 9,7 61,1 6 ,0 49,5 10,7 P&lt;0,01 002NK41 0,0 7,3 67,7 13,1 56,3 8,5 52,8 8,9 46,9 10,1 P&lt;0,01 002NK42 0,0 3,4 55,1 3,9 44,4 4,1 Ρ&lt;0,001 40,1 3,5 P&lt;0,001 34,0 1,8 P&lt;0,001 002NK27 0,0 9,6 65,9 8 ,4 63,5 9,2 57,6 7,4 45,3 6,9 P&lt;0,001 002NK39 0,0 2,0 41,9 3,0 38,1 7,5 35,6 11,5 nd 002NK46 0,0 3,1 55,6 3,4 58,6 5,4 54,6 7,6 37,9 6,9 P&lt;0,001 002NK50 0,0 3,5 62,5 3,8 64,8 5,8 59 ,4 8,1 42,4 11,2 P&lt;0,001 002NK51 0,0 4,8 65,9 8,9 62,1 6,8 58,8 13,1 49,4 9,2 P&lt;0,05 002NK52 0,0 10,3 56,7 12,3 54,7 11,8 49,2 6,3 31,8 5,3 P&lt;0,001 002NK53 0,0 2,1 48,3 2,1 43,5 4,9 39,6 3,6 P&lt;0,01 34,0 4,4 P&lt;0,001 002NK60 0,0 2,9 64,6 10,8 65,6 10,5 58,0 11,8 35, 3 14,7 P&lt;0,001 002NK66 0,0 3,8 46,4 7,9 41,4 5,2 40,2 1,9 36,9 5,0 P&lt;0,05 002NK69 0,0 2,5 39,9 7,9 36,5 7,0 35,5 6,7 31,0 6,3 465-57-2 0,0 3,2 42,5 9,9 36,8 4,5 38,4 4,4 nd 122 201113280 465-4-4 0,0 2,7 40,1 6,0 41,4 3,7 39,4 2,3 30,7 2,2 ρ&lt;〇〇ι 465-19- 2 0,0 3,0 63,6 5,8 60,6 4,2 59,2 7,5 55,5 7,3 465-22-3 0,0 2,4 43,6 4,0 39, 2 1,4 39,9 3,8 36,5 3,8 p&lt;0 〇1 465-12-2 0,0 1,6 48,1 2,8 46,0 5,5 45,7 3,2 45,6 6,0 465-32-2 0,0 2,6 56,0 5,9 54,1 10,1 56,0 11,8 64,8 10,7 002NK85 0,0 1,4 40, 8 3,8 39,2 3,6 34,0 3,7 31,4 4,8 P&lt;0 01 465-20-2 0,0 2,5 61,2 6,7 57,2 5,4 56 ,0 5,0 48,2 6,0 P&lt;0 01 465 -33-2 0,0 3,7 44,4 5,2 36,2 8,0 47,0 9,2 nd 465-47-2 0,0 4,5 55,2 6,0 56,8 4 , 4 51,0 3,7 44,5 7,4 p&lt;0 01 465-3-3 0,0 4,7 41,0 U 37,9 1,5 37,2 4,3 32,7 4, 5 P&lt;0 001 465-52-2 0,0 8,6 53,2 5,0 53,3 8,8 52,3 8,7 48,0 5,3 • — 0,0 3,6 — 465 -53-2 40,5 2,5 38,2 1,5 38,2 2,3 40,4 4,4 002NK57 0,0 4,1 53,0 7,3 51,2 8,4 51,4 3,2 44,2 5,2 002NK59 0,0 2,4 47,1 6,8 41,9 7,1 41,5 8,9 38,2 7,6 0,0 | 002NK96 4,3 55, 8 8,1 55,6 5,9 49,3 1,4 44,0 4,6 P&lt;0,01 Example C.2 _Starting in-vitro studies by studying neuroprotection against oxidative damage to study amine-based burning Does the brewing amine protect the cortical neurons from oxidative damage induced by 〇2? Cortical cell death was identified by the same experimental procedure as described in Example B4 above. Results The percentage of cell death (mean ± SD) after H202 induced toxicity is shown in Table 7. Three concentrations of the compound (1, 1 〇 and 1 〇〇 #M) were investigated and the number of wells for each compound used was 6. Almost all test compounds were reduced by reducing cell death (results showed statistical significance) 仏〇2 ^ 123 201113280 Table 7: Compound number control mean SD H202 control mean SD H2〇2 + 1 μΜ Compound mean Value SD H2〇2 + l〇μΜ Compound mean SD H202 + ΙΟΟμΜ Compound mean SD 119-1 0,0 3,0 41,9 3,3 27,9 6,0 P&lt;0,001 24,6 6,9 P&lt;0,001 19,0 P&lt;0,001 4,8 002NK24 0,0 1,5 50,1 8,1 45,7 11,1 43,4 6,1 24,7 P&lt;0,001 7,5 002NK25 0,0 3,4 48,2 4,1 45,6 8,8 35,2 9,8 P&lt;0,05 27,1 P&lt;0,001 9,8 002NK29 0,0 2,4 49,2 1,5 45, 7 7,5 37,4 10,1 P&lt;0,05 29,0 P&lt;0,001 8,5 002NK30 0,0 3,2 52,5 6,2 44,7 7,2 42,4 8,1 25 ,7 P&lt;0,001 6,9 002NK37 0,0 2,0 51,5 10,1 37,9 12,5 P&lt;0,05 31,5 10,5 P&lt;0,01 nd 002NK40 0,0 2, 9 59,5 11,2 57,2 10,4 48,6 12,9 31,1 P&lt;0,01 11,5 002NK41 0,0 1,7 49,9 7,6 49,6 9,2 37 ,5 11,5 17,1 P&lt;0,001 10,9 002NK42 0,0 2,1 78,5 7,6 70,5 10,3 67,6 9,0 37,9 P&lt;0,001 7,4 002NK27 0 ,0 3,6 50,8 6,9 47,0 3,5 38,8 5,3 P&lt ;0,05 24,0 P&lt;0,001 8,0 002NK39 0,0 7,5 61,3 10,2 58,5 10,5 62,5 10,5 nd 002NK46 0,0 8,1 52,8 10 ,5 49,2 11,6 44,6 10,1 30,1 P&lt;0,01 11,3 002NK50 0,0 8,3 71,2 7,6 69,6 9,7 61,7 10,1 46,0 P&lt;0,001 9,6 002NK51 0,0 4,9 44,1 5,1 42,2 2,2 38,2 3,0 P&lt;0,05 35,6 P&lt;0,01 3,9 002NK52 0,0 2,3 66,3 10,5 66,4 12,4 61,9 10,2 49,0 P&lt;0,05 10,3 002NK53 0,0 1,6 71,8 3,3 68 ,5 9,1 69,2 5,3 48,0 P&lt;0,001 11,4 002NK60 0,0 5,4 72,0 7,7 75,1 8,9 72,6 11,0 56,2 P&lt; 0,01 9,4 002NK66 0,0 4,0 69,6 11,9 63,9 6,0 56,7 11,5 24,5 P&lt;0,001 9,7 002NK69 0,0 3,2 69,1 9,5 60,6 9,1 57,9 10,9 58,9 10,0 465-57-2 0,0 6,2 50,3 6,7 41,8 6,7 36,6 7,5 P&lt;0,01 nd 465-4-4 0,0 4,0 62,2 10,6 57,7 10,7 55,4 11,6 50,0 12,5 124 201113280 465-21-2 0, 0 7,3 53,8 8,7 51,3 9,1 42,7 9,6 41,1 1〇,〇002ΝΚ85 0,0 3,1 60,4 13,3 54,6 13,9 50, 9 11,8 42,7 1〇,8 465-20-2 0,0 5,8 64,6 10,7 59,9 12,6 59,8 8,9 62,6 10J 465-23-2 0 ,0 3,4 58,3 9,5 48,4 13,3 38,9 12,9 Ρ&lt;0,05 34,5 7,0 ρ&lt;0,01 _ 465-24-2 -- -— 0,0 4,4 45,6 10,1 38,3 5,9 29,8 7,3 Ρ&lt;0,01 28,7 7,3 Ρ&lt;0,01 —_ 465-47-2 0 , 0 2,1 76,3 4,2 79,4 7,9 72,5 9,8 62,4 11,5 Ρ&lt;0.05 465-51-2 0,0 3,1 86,9 7,8 80 ,8 10,4 86,5 4,8 67,2 6,5 Ρ&lt;0,001 —_ 465-3-3 0,0 4,〇73,3 8,6 71,9 4,6 70,6 8, 5 61,1 10,8 465-13-2 0,0 3,5 73,4 7,8 64,1 10,3 57,6 4,1 Ρ&lt;0,01 59,2 8,3 Ρ&lt;0.05 465-55-6 0,0 3,1 42,1 10,9 37,5 10,8 34,9 12,3 35,7 11,〇002ΝΚ57 0,0 5,7 37,0 7,6 30, 2 1〇,〇23,8 8,6 Ρ&lt;0,05 7,2 10,4 Ρ&lt;0.001 ... 002ΝΚ64 0,0 4,4 47,0 1〇,2 45,6 11,8 41, 8 12,4 31,4 7,8 002ΝΚ65 0,0 2,0 62,5 7,1 54,8 10,5 48,4 10,6 Ρ&lt;0,05 44,0 6,6 Ρ&lt;〇01 002ΝΚ96 0,0 5,3 61,6 7,5 58,9 4,1 45,8 7,8 Ρ&lt;0,01 Bu! · 1 27,0 8,8 Ρ&lt;0,001 Example I ·J Sighting f meal properties An in vitro test was conducted to evaluate the neurotrophic potential of the aminoalkylamine. As in the above example B 5, stand up for your life. 1 XL arsenic is measured by the nutritional effect as two kinds of concentrated production of 々田+, 丄& Induction of large growth. The number of pores with a compound degree of 6 . , #Μ) and the number of branches of each compound used in the thickening of the menstrual or the number of arsenic arsenic was added to the nerves derived from each of the primary gods. 8 in. Compounds increase the significance of the test). Average number of branches (Results indicate that the system reached 125 201113280 Table 8: Compound number control mean SD compound 0,001 μΜ average SD compound 〇, 1 mm average SD compound 10 μΜ Compound mean SD 119-1 3,11 0,23 3,14 0,19 3,25 0,17 3,83 0,33 P&lt;0,01 002NK25 3,11 0,23 3,19 0,19 3,81 0,34 P&lt;0,01 3,69 0,39 P&lt;0,05 002NK37 3,08 0,17 3,03 0,19 3,25 0,17 3,33 0,28 002NK39 3,08 0,17 3,14 0,29 3,44 0 ,40 3,44 0,14 002NK51 3,06 0,17 3,19 0,36 3,33 0,18 3,28 0,17 002NK52 3,14 0,13 3,06 0,14 3,50 0 ,38 3,64 0,25 P&lt;0,01 002NK60 3,19 0,16 3,33 0,15 3,89 0,27 P&lt;0,001 3,97 0,22 P&lt;0,001 002NK69 3,19 0, 16 3,36 0,07 3,92 0,66 P&lt;0,01 3,75 0,23 P&lt;0,05 465-57-2 3,14 0,13 3,25 0,09 3,78 0 ,17 P&lt;0,001 3,69 0,16 P&lt;0,01 465-22-3 3,17 0,18 3,33 0,18 3,83 0,30 P&lt;0,001 3,61 0,23 P&lt; 0,05 465-12-2 3,17 0,24 3,17 0,21 3,83 0,26 P&lt;0,01 4,06 0,51 P&lt;0,001 465-32-2 3,17 0, 24 3,28 0,23 3,67 0,30 P&lt;0,05 3,89 0,49 P&lt;0,01 002NK86 3,17 0,18 3,36 0,25 3,67 0,2 6 P&lt;0,05 3,56 0,20 002NK85 2,97 0,13 3,06 0,25 3,39 0,27 P&lt;0,05 3,61 0,34 P&lt;0,001 List of references:

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Claims (1)

201113280 VII. Patent application scope: 1. - Compound of formula (I) 4Ην 〇r4, (^3)ρ Re r5 where R 1 is wind or C 1 -6 alkyl; R2 is selected from the following group: Group · r M a &lt; group .Cl, alkyl, C3-1G cycloalkyl, C 4 - 1 2 and ε, C 5 -丨 2 spiro, r CS-1G bridged cycloalkyl , q ι () alkyl-c3.1Q cycloalkyl or c3.1G cycloalkyl-c soil '-丨-10 pit base, each of which may be substituted by one or more identical or different substituents R7; R3 is c!.6 alkyl group' which may be substituted by a substituent R7, and if P is 2, 3 or 4, or a plurality of the same or different, the 1 group may be present on the same or different atoms. Joining together with the atoms to which they are attached to form a Gu heterospiro, Cm heterobicyclic or ruthenium (9) heterobridged ring system; b is selected from the group consisting of hydrogen, Cie alkyl, Ch cycloalkyl, CHO, C ( = 0)_Cl.6 alkyl, cycloalkyl and _c(=〇)〇c^ alkyl, which may optionally be substituted by one or more identical or different substituents R?; and § R4 is CBu6 When an alkyl group or a C(=〇)-Ci 6 alkyl group, and R 4 may be bonded together with the atom to which they are attached to form There are 4_12 ring members of the heterogeneous is. %, Rs and R0 are in each case independently selected from nitrogen C] -6 alkyl and C3_6 ring 129 201113280 &amp; base 'each can be seen by the case - or multiple Or substituted with a different substituent base 7; R7 is selected from the group consisting of hydrogen, halogen, 〇h, CN, C|_6 alkyl and Ch6 alkoxy; m is 1, 2 or 3; η is 〇, 1 Or 2; Ρ is 0, 1'2, 3 or 4; $4 a pharmaceutically acceptable salt, hydrate or solvate for use as an inflammatory or degenerative disease in an individual treated for treatment (10) Or a drug for demyelinating diseases. 2. For example, the compound of the patent scope 帛j of June, wherein I is hydrogen. 3. The compound according to any one of the claims, wherein the towel r2 is selected from the group consisting of: Cl-8 alkyl, (: 3-8 cycloalkyl or C3.8 cycloalkyl) In the case where one or more of the same or different substituents R7 are substituted for "3', as described in any one of the scope of the patent application, 纟 环 cyclohexyl. 匸 匸 4. A compound according to any one of the claims Where &amp; is a surrogate = it may be taken by one or more of the same or different substituents r7 and the right is 2, then the RA group which may be present on the same or different atoms may be accompanied by 斛$ π 3 &amp; jin, the atoms connected together are joined together to form (: 5·10 hetero-bridged ring system. The compound of any one of the patent applications, such as 0, 1 or 2. P von 130 201113280 or 1 6. A compound according to any one of the claims, wherein P is 0. 7. A compound according to any one of the claims, wherein ρ is 0. 8 as described in the scope of the patent application - A compound of the formula wherein R4 is selected from the group consisting of hydrogen, Ci6, c3.8 cyclos, ch〇 C( 〇)-C卜6@基和c(=〇)_c3_8 裒 裒 院 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , When Cl-6 is calcined, 'R3 and R4 may be bonded together with the atom to which they are attached to form a heterobicyclic ring having 4 to 10 ring members. Hydrogen. 9. A compound of the formula I is Π). A compound according to any one of the preceding claims may be joined to the atom to which it is attached to form: a heterocyclic ring of 1 in the middle of the ring, and 1% of the ring is substituted by 1%. See the case - or a plurality of identical or different substituents &amp; R in 1 丄: a compound of any of the patent applications, wherein R and 6 are each independently selected from the group consisting of hydrogen and C&quot; In the case of ~ or by - or a plurality of the same or different substituents - ... see case R: · a compound according to any one of the preceding claims, wherein the rule 5 and the ^ are as claimed in the aforementioned patent scope a compound, wherein μ is the compound of any of the preceding claims, wherein ^ is 131 C 201113280 15. as before A compound of any of the preceding claims, wherein n is 1 or 2. 1 6. A compound according to any one of the claims, wherein n is 1 ° 17. a compound selected from the group consisting of 2-(4-ethylidene-l54-diazepane-butylindole cyclohexylacetamide, #%-hexyl-2-(4-methyl) -L4-diazepane-indole-yl)acetamide, #%-hexyl-2-(4-isopropylpipephinyl)acetamide, hexyl-3-(4-(cyclopropanecarbonyl)per丨 丨 基 基 醯 醯 醯 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ((577,7/7 recommended me 9 dip)_yl) acetamidine, fluorenylcyclopentyl 2-(4·ethyl-3-hydrazinopiperidin-1-yl)-#_曱基乙醯Amine, #-(4-t-butylcyclohexyl) 2 (piperidinyl) acetamide, hydrazine methylpentyl-2-(1,4-diazaspiro[5.5]undecane- 4-yl)acetamide, methylbutyl)~2-(4·propionylpiperidin-1-yl)acetamide, 2-(1,4·diazepan-1-yl) -Ν-(pentane-3-yl)acetamide, iV-butyl-2-(reverse_2,5_dioxin Zipipin small base) propyl acetamide, 2_(1,4-diazepan-1-yl)-iV-(2-mercaptobutyl)acetamide, 2-(M_ Diazaheptane-1·yl)-#-methylpentylacetamide, succinyl·2·(piperidin-1-yl)hexylamine, 132 201113280 #-(3,3-Dimethylbutyl)·2 iR)-Ν-(2&gt; .3 - Ertian a — -1-yl) acetamidine, .)-2-(piperidinyl) acetamide, —fly-2-yl)-2-(pipedino-1-yl)acetamide, base) Propyl acetamide, -1 -yl)butanamine, -1 -ylpropionamide, fluorenylcyclopentyl-2-(1,4-dioxazacycloheptan-1-yl) Acetamide, diazepane-1-yl)propanamine, iV-cyclopentyl-2-(1,4-diazepane-indoleyl)_#_methylacetamidine Amine, iV-cyclobutyl 2 - (piperidin-1-yl)acetamide, AK pentam-3-yl) 2 - (4 - propionylpiperazinyl) decylamine, cyclohexyl _2-(4-propionylpipen- 丨-yl)acetamide, 2-(4.Acetylpiperidin-1-ylcyclopentylmethylacetamide, W-(4,4-di) Fluorocyclohexyl)-2-decalin-indolyl)acetamide, 2-(piperidin-1-yl-5Λ)-2,6,6-trimercaptobicyclo[3.1.1]heptane_3 -yl)acetamide, #-(4.ethylcyclohexyl)-2-(piperidin-1-yl)acetamide, &lt;%)-#-(1-cyclohexylethyl)-2- (pepirin: - oxime) acetamidine, #-((15,2&amp;4;?)-substituted 1-bicyclo[2.2.1]heptan-2-yl)-2-(4-propanthene Alkyl phenanthrene-1-yl)acetic acid amine, cyclohexyl-2_(4-carbamimidin-1-yl)butanamine , V-cyclopentyl fluorenyl 2 - (pepirin) - acetamide, 3- ((1/?, 4/〇-2,5-diazabicyclo[2.2.1]heptane-2 -yl)-:^-cyclohexylpropionamide' 133 201113280 沁cyclohexyl-2-(4-cyclopentylpiperidin-1-yl)acetamide, AK2-cyclooctylethyl)-2_(piper ^^1-yl)propanamide, &quot;-((lSJS/iO-rel-bicyclo[2.2.1]heptane-2yl)-2-(piperidin-1-yl)acetamide, ring Hexyl-2-(hexahydropyrrolo[i,2-ap-pyridyl-2(1//)-yl)acetamide, (7)-fluorenylcyclohexyl-2-(hexahydropyrrole[ _2 (1 milk base) acetamidine, 2_(4·cyclohexylpiperidin-1-yl)isopropyl-2-methylpropanamide, 2_(4·(cyclohexanecarbonyl) trace tillage-1 ·Based good (3,3-dimethylbenzyl)acetamidine, 2-(4-cyclohexylpiperidin-1-yl)6-trimethylbicyclo[3.1.1]heptan-3-yl Ethylamine, fluorenylcyclopentyl-2-(4·propanylpiperidine hydrazinyl)propanamide, hydrazine ((10)2L bicyclo[2.U] pentane. 2 yl)_2·(4) propyl hydrazine娘娘耕-1 -yl) acetamidine, (%) good (3,3-dimethylbutan-2-yl).2_(4_isopropyl-M dihepane-heptyl Ethylamine, Α/·-(3-cyclopentylpropane )-2-(4-fluorenyl_ι 4_ -doped mi,4-oxazepine-heptan-1-yl) acetamidine, 2-((15,45)-2,5-diazabicyclo[ 2.2 11 庵, p 2 thereof, λγ a dioxane 2_yl)_#_cyclohexylacetamide, amine 3-(4-ethinyl-1,4-diazepine-1 ))-iV-cycloheptylpropanoid 134 201113280 iV-cyclohexyl- 2-(4-cyclopentyl benzyl-1-yl)-2-methylpropionamide, cyclohexylethylhexahydropyrrole[ Hey, 2-^. Specificin-2(1//)-yl)acetamide, iV-((A-2-cyclohexylidene)indolyl)-3-(parnor, 1_yl)propanamide, and -2 -(4-butylpiped-1-ylethoxycyclohexyl)acetamide, guang-2-(4-butylpiped-indole-yl)-(2-ethoxycyclohexyl)acetamidine Amine, ΑΓ-cyclobutylhexahydropyrrolo π,2_α]pyrazine_2(1 ugly)·propanylamine, and ethoxycyclohexyl)_2_(4_mercapto-indole, 4-diaza Cycloheptane small group) acetamidine, bis-indolyl 2-ethoxycyclohexyl)-2-(4-indolyl-indole, 4-diazacycloheptane) _yl) acetamidine, 2-(4 -(cyclohexanecarbonyl)piped_丨_yl)-沁(1_(hydroxymethyl)cyclopentyl)acetamide, 2-(1,4-azacycloheptane small group) good (1 Mercapto)cyclopentyl)acetamide, ΑΚ3-cyclopentylpropyl)_2_(and-2,5-dimethyl-phenyl-phenyl)acetamide, 2-(4-(cyclohexanecarbonyl) Piperidinyl)^_(2-cyclooctylethyl)propanamide, 2-(4-cyclohexylpiperidin-1 yl) 4_cyclopentyl _#·methyl acetamide, 'ethyl -2"小基)善(4·(三气methyl)cyclohexyl)acetamide, "幻#(4'4 fluorocyclohexyl)_2_(2_isopropyl_4_曱) Iptylamine, etidamine, 2-(4-ethylindenyl(tetra)q.yl)_'ethyl·#_(4•(trifluoromethyl)cyclohexyl) 135 201113280 Acetamide, cyclohexyl -3-(4-cyclopentylpipenyl-1-yl)-2-methylpropanamide, #-(Guang-4-t-butylcyclohexyl)_2-(piped-丨-yl)B Indoleamine, AK and -4-t-butylcyclohexyl)-2-(piperidinyl-yl)acetamide, A/·cyclohexyl·2_(4_(2,2,2-trifluoroethyl) 0 啡 丨 丨 丨 基 ) 醯 醯 醯 醯 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 3,3,5-trimethylcyclohexyl)acetamidamine, 20 decimum-1·yl)_#-(Guang_3,3,5·trimethylcyclohexyl)acetamide, 2-( 4-Ethylpipenyl 丨 基 基 ) 广 广 广 广 广 广 广 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 4- 4- 4- 4- 4- 4- 4- 4- 4- An acetamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 18. A compound selected from the group consisting of 2-(4-ethylindenyl-i,4-diaza Cycloheptane 丨 基 基 υ υ 己 己 己 己 、 、 # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # Acetamide, A/&quot;-cyclohexyl_2-(4-isopropylisophthalide)-acetamide, indole cyclohexyl-3-(4-(cyclopropanecarbonyl)piped·丨_ Propylamine, #-1⁄4 己基_2_(4-cyclodecyl phenyl phenyl)-butanamine, cyclohexyl 2-(dihydro-177-pyrido[丨,^]pyrazine -2(6//, yl) acetamidine, cyclopentyl-2-(4-ethyl-3-indolylpipenyl-1-yl)_#_mercaptoacetamide, #-(4- Tert-butylcyclohexyl)_2_(piperidin-indolyl)acetamide, 7/-mercapto-//-pentyl-2-(1,4-dioxaspiro[5.5]undecane_4 _基)乙醯136 201113280 9 Amine, #-(2-methylbutyzan)·2-(4·propionylpipen-1-yl)acetamide, 2-(1,4-dinitrogen卢卢', hexyl heptane-1-yl)_//_(pentane_3_yl)acetamide, Ν-~Γyl-2-(and) ζ dimercapto-p-propyl Acetamide, 2_(1,4-oxazepin-1-yl)-indole 2-methylbutyl)acetamide, 2-(1,4-azacycloheptan-1-yl )-#-decylpentylacetamide, Cyclohexyl-2-decaquinole small base) hexamethyleneamine, #_(2_methylbutyl)-2•(硬讲-1-基)乙醯Amine, #-(3,3-dimethylbutylhydrazine•(派耕小Ethylamine, (--3,3-didecylbutan-2-yl)-2-(piperidin-1-yl)acetamide, butyl-2-phenylphenanthyl Ethyl amide, AA-cyclohexyl-2-(pemamine: 丨 丨) butylamine, hydrazine butyl-2-(piperidin-1-yl) propyl hydrazine, anthracene butyl-2- (1,4-diazacycloheptyl)acetamide, fluorenylcyclopentyl-2-(1,4-dihydroheptanyl)propanamine, 'cyclopentyl-2-(1) , 4-diazepane-1 -yl)_#_mercaptoacetamide, anthracycline-2-(piperidin-1_yl)acetamide, AKpentan-3-yl) -2-(4-propionylpiperidine·〗 _yl) acetamidine, cyclohexyl 2 - (4-propenylpiperidine hydrazinyl) acetamidine, 2-(4-ethyl fluorenyl) Pemide = 1-yl)cyclopentylmethylacetamide, AK4,4·difluorocyclohexyl)-2-(piperidinyl)acetamide, 2-(parphin-1-yl) (/iS, from 3乂)_2,6,6 trimethylbicyclo[3.1.1]heptan-3-yl)acetamide, iV-(4-ethylcyclohexyl)·2-(piperidine丨 基 基 ) 醯 、 、 137 137 137 137 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 2011 2011 2011 Ji Ji Ji Ji Ji Ji (4-propionylpiperidine-1-yl)B Amine, cyclohexyl·2·(4-mercapto-phenanthyl)-butylamine, cyclopentyl-nonyl-2-(ethinyl)acetamide, 3-((/Λ^ Λ)-2,5-diazabicyclo[2.21]heptane-2-yl)-cyclohexyl propyl decylamine, cyclohexyl·2·(4_cyclopentyl linyl-1 yl) acetamide, W-(2-cyclooctylethyl)·2·(pemamine:_1_yl)propanamide, #-((/乂MJ/O-rel-bicyclo[2.2.1]heptan-2-yl )-2-(piperidin-1-yl)acetamide, cyclohexyl-2-(hexahydro).咯 并 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Amine, 2-(4-cyclohexylpiperidin-1-yl)isopropyl-2-mercaptopropanamide, 2-(4-(cyclohexanecarbonyl)-ptanyl-1-yl)-ΑΓ-(3 ,3-dimethylbutyl)acetamide, 2-(4-cyclohexylpiperidin-1-yl)-#-((7 and 2^&amp;5/?)-2,6,6-three曱基双, [3.1.1] heptano-3-yl) hexamidine, decyl-2-(4-propylglycine-1-yl)propionate, bicyclo [2.2.1] Heptan-2-yl)-2-(4-propionylpiperazin-1-yl)acetamide, -TV*(3,3-dimercaptoin-2-yl)-2-(4 -isopropyl-1,4-diazepine 138 201113280 «cycloheptan-1-yl)acetamide, iV·(3-cyclopentylpropyl)-2-(4-indolyl_ι 4 B Indoleamine, 2-((7Κ^-2,5-diazabicyclo[2 2 ”heptazepan-1-yl)indan-2-yl)-indole-cyclohexylethylamine 3-( 4-ethenyl-1,4-diazaheptylcycloheptylpropanylcyclohexyl-2_(4·cyclopentylpiperidinium 丨_美π | )_2-mercaptopropionamide iV- ((8)-1 -cyclohexylethyl)_ 2 _ (<幻六-2(1//)-yl)acetamide, #-(( And -2-ylcyclohexyl)methyl, 1 ^ τ violent -3·(piperidin-1-yl)propanamide and 2-(4-butylpiperidin-indole-based) Cyclohexyl) acetamidine broad _2_(4_butylpiperidin-1-yl)-indole (2 ΛΓ-cyclobutyl-2-(W_hexahydroindoleamine, and -#-(2-ethoxylated) Cyclohexyl bromide 2_yl) acetamidine, waste-#-(2-ethoxycyclohexyl)_2-yl)acetamide, oxygen-pyrolo[1,2_α]pyroxyethoxycyclohexyl)acetamide, [1,2·α]pyramine)propanyl (4.methyldiazepan-1-(4~methyl-1,4-diazepane-delamamine 2-(1) ,4·diazepane_丨_yl)·ι#-(3-cyclopentylpropyl)_2_(and _2,5_di-U-(hydroxymethyl)cyclopentyl)acetamidine Benzyl-1-yl) acetamamine, 139 201113280 2-(4-(cyclohexanyl) π-endophthyl 丨-yl) also (2_cyclooctylethyl)propanamide, 2- (4·cyclohexylpiperidin-1-yl)·#cyclopentyl hydrazinylacetate, ethyl-2-(Nangneng-1·yl (trimethylsulfonyl)cyclohexyl)acetamide, (7) Good (4,4-difluorocyclohexyl)_2_(2_isopropyl_4•methylpipedinyl) acetamidine, 2-(4-ethylhydrazine) [•, Ethyl (trifluoromethyl)cyclohexyl) acetamidine, cyclohexyl-3-(4-cyclopentylpipen-yl)-2-methylpropionamide, #·(waste-heart tributyl) Cyclohexyl)_2_(pipeline_丨_yl)acetamide, #-(and-4-t-butylcyclohexyl)_2_(piped-indole-yl)acetamide, hexyl-2-(4·4· (2,2,2-trifluoroethyl)pipepone·ι_yl)acetamide, cycloheptyl-3-(4·cyclohexylpipenyl)-propanylamine, 2-(piped- 1-yl)·λγ·(and _3,3,5_tridecylcyclohexyl)acetamide, 2·(Peptin-1-yl)-fluorene (Guang_3,3,5_tridecyl) Cyclohexyl)acetamide, 2-(4-ethylhydrazinopiperidinyl)-γ·(Guang 4·hydroxycyclohexyl)acetamide, and 2-(4-mercaptopiperine_丨_ base) • (trans-hydroxycyclohexyl) acetamamine, or a pharmaceutically acceptable salt, hydrate or solvate thereof. A pharmaceutical composition comprising, as an active ingredient, a pharmaceutically acceptable salt, hydrate or solvate of the compound of claim 8 or a pharmaceutically acceptable excipient and an additive. 20. A compound for use in therapy as claimed in claim 8 or a pharmaceutically acceptable salt, hydrate or solvate thereof. 140 201113280 The heart grading composition </ RTI> further comprises a compound selected from the group consisting of an immunomodulator, an immunosuppressive agent, an anti-proliferative agent, an antimetabolite agent, or an agent that acts on a surface 2-position. 22. A method of treating an inflammatory disease, a degenerative disease or a demyelinating disease in (10) an individual in need of treatment comprising administering an effective amount of a compound. The formula is used for the preparation of a medicament for treating a degenerative disease or a demyelinating disease. 23. Use of a compound of the formula I. An inflammatory disease of a CNS in an individual in need thereof. Eight, the pattern: (none) 141