TW201103914A - Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors - Google Patents

Abstract

Disclosed are compounds, compositions and methods for treating diseases, syndromes, conditions and disorders that are affected by the inhibition of MGL, including pain. Such compounds are represented by Formula I as follows: wherein R1, W and (A) are defined herein.

Description

201103914 VI. INSTRUCTIONS: This application claims the benefit of US Provisional Application No. 61/171,661 (filed on Apr. 22, 1989), the entire disclosure of which is incorporated herein by reference. This application is related to U.S. Provisional Application No. 61/171,66 (filed on April 22, 2009). The invention is entitled "Hybrid and aromatics used as mono-mercaptoglycerol lipase inhibitors". Provisional application for hexahydrogen to chlorinated azetidinyl amide. The research and development of the following inventions is not federally sponsored. TECHNICAL FIELD OF THE INVENTION The present invention is directed to the use of a compound of formula (1) as defined herein for the treatment, amelioration and/or prevention of MGL disorders in a subject, including mammals and/or humans, wherein the disease, syndrome Or the symptoms are affected by MGL. [Prior Art] Cannabis decoction has been used to treat pain for many years. Hydrogen cannabinol (△^tetrahydrocannabinol) is a major active ingredient from cannabis and is an agonist of cannabinoid receptor (Pertwee, 10,000 corpse). /zarmaco/, 2008, 153, 199-215). Two cannabinoid prion-coupling receptors have been selected, namely type 1 cannabis receptors (CBi, Matsuda ei a/., iVflfiwre, 1990, 346, 561-4) and type 2 cannabinoid receptors (CB2, Munro ei α/., iWziMre, 1993, 365, 61-5). CB1 is mainly expressed in the brain region, such as the hypothalamus and nucleus accumbens, and the periphery of the liver, digestive tract, septic, adipose tissue and bone muscle (Di Marzo ei a/, Cwrr 2007, 18, 129-140). CB2 is mainly expressed in immune cells, such as mononuclear spheres (Pachereh/., dwer 2008, 294, H1133-H1134) and, in some cases, also in the brain (Benito W 〇/., J /Tzarmaco/, 2008) ,153, 4 201103914 277-285) and bone muscles (Cavuoto ei fl/., and

Commww, 2007, 364, 105-110) and myocardium (Hajrasouliha ei fl/., five wr J P/zarmaci?/, 2008, 579, 246-252). Under the use of synthetic agonists, a large number of pharmacological, anatomical, and electrophysiological data indicate that cannabinoid signals enhanced by CBVCB2 promote analgesia in acute pain tests and inhibit hyperalgesia in chronic neurological and inflammatory pain patterns. / or allodynia (Cravatt ei al, J Neurobiol, 2004, 61, 149-60; Guindon et al., Brit J / Tzarmaei? /, 2008, 153, 319-334). The efficacy of the synthetic cannabinoid receptor stimulating agent has been well established. In addition, studies using cannabinoid receptor agonists and knockout mice have also shown that endogenous cannabis systems are important regulators of nociception. Anandamide (AEA) (Devane et al., Science, 1992, 258, 1946-9) and arachidonic acid (2 provinces & 1 ^ 11 〇丫 guns. 61 * 〇 1; 2 Into 0) () ^ 〇 11 〇 111 & 111 〇 /., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., Biochem price and a Comm (10), 1995, 215, 89-97) Primary endogenous cannabis, AEA is hydrolyzed via fatty acid indoleamine hydrolase (FAAH) and 2-AG is hydrolyzed via monomercaptoglycerol lipase (MGL) (Piomelli, and ev 2003, 4, 873-884). FAAH gene shedding increases endogenous AEA, leading to CB!-dependent analgesia in acute and inflammatory pain patterns (Lichtman d W., corpse (1)·, 2004, 109, 319-27), suggesting endogenous The cannabis system acts naturally to suppress nociception (Cravatteifl/., JiVewr MzW, 2004, 61, 149-60). Unlike the use of FAAH knockout mice to increase endogenous cannabinoid concentrations, the use of specific FAAH inhibitors transiently increases AEA concentrations and causes antinociceptive effects in vivo (Kathuria ei α/·, Mec/, 2003, 9, 76 -81). Additional evidence for the state of antinociceptive regulation by cannabinoids 201103914 is the formation of AEA in the periqUeductai gray (a known pain center) after adverse stimulation around the area, 3/3⁄4 1999, 96, 12198-203), conversely, confirmed by hyperalgesia induced by administration of CB] antisense RNA to the spinal cord (Dogrul as α/, corpse (1)·„, 2〇〇2, 100, 203-9) 'About 2-AG' flicks at the tail (Mechoulam ei α/., 1995, 50, 83-90) and hot plates (Lichtman d α/·, corpse / ^ sinking / heart /? 77^, 2002 , 302, 73-9) In the analysis, intravenous delivery produced analgesia. In contrast, 'confirmed that 2-AG alone did not stop pain in hot plate analysis' but when combined with other 2-monodecyl glycerol (ie 2- When flax decyl glyceride and 2-palmitino glyceride are used, significant pain relief can be obtained, which is a known

The phenomenon of "entourage effect" (Ben-Shabat buckle α/•, five J corp. krmacO/, 1998, 353, 23-31). These "accompanied" 2-monothiol glycerol is an endogenous lipid that is co-released with 2-AG and, to some extent, enhances endogenous cannabinoid signaling by inhibiting 2-AG decomposition, possibly via competitive mGL Active position on the top. This suggests that synthetic MGL inhibitors will have similar effects. Indeed, URB602 is a rather weak synthetic MGL inhibitor that exhibits antinociceptive effects in a murine model of acute inflammation 2007, 152, 787-794). Although the use of synthetic cannabinoid agonists has clearly demonstrated that increased cannabinoid signaling produces analgesic and anti-inflammatory effects, it is difficult to isolate the advantages and undesirable side effects of these compounds. Another pathway is to enhance the signal of the endogenous 6 201103914 cannabis system by increasing the concentration of 2-AG (the endogenous cannabis in the central nervous system (CNS) and the gastrointestinal tract), which can be achieved by inhibiting MGL. Therefore, MGL inhibitors are potentially useful for the treatment of pain, inflammation and CNS diseases (Di Marzo playing alpha/., Curr Pharm Des, 2000, 6, 1361-80; Jhaveri et al, Brit J Pharmacol, 2007, 152, 624 -632; McCarberg Bill et al., Amer J 77zer, 2007, 14, 475-83), and glaucoma and disease caused by elevated intraocular pressure, % (Njie, Ya Fatou; He, Fang; Qiao, Xhuanhong Song, Zhoa-Hui, Exp. Eye Res., 2008, 57(2): 106-14) ° SUMMARY OF THE INVENTION The present invention is directed to treating, ameliorating or preventing an affected by inhibiting MGL A method of disease, syndrome, symptom, or disorder, such as pain, a disease that causes the pain, inflammation, and a CNS disorder, which is included, constitutes, and/or substantially

^Formed as a therapeutically effective amount of the compound of the desired subject (1) Compound R

It is selected from the group consisting of: where W is Ν, ν is h, Θ

A compound of -, Χ-Υ-Ζ, and R3 is 2,2-dimercaptopropyl; wherein W is N,! ^为H, Θ

z, X-Y-Z is

X 201103914 0-C(R2)=N-, and R2 is a cyclohexyl compound;

Wherein W is a compound wherein N'R1 is Η, ν^ is , χ_γ_Ζ is -0-C(R2)=N-, and R2 is a 3-fluorophenyl group;

, where W is N'R1 is H, V^ is V, χ_γ·Ζ is -CH-C(R2)-N(R3)- 'R2 is 4-mercaptophenyl, and R3 is isobutyl Compound

Wherein W is N, W is H, ® is v 乂 , Χ-γ_Ζ is •CH-C(R )-N(R3)-, R 2 is phenylmethyl, and R 3 is an isobutyl compound;

X Z wherein W is Ν, ν is H, 0> is -0-C(R2)=N·, and R2 is a 4-fluorophenyl compound; X-Y-Z is

X A compound wherein w is N, R1 is H, © is v Y , χ_γ_ζ is -0_C(R2)=N-, and R2 is a 4-methoxyphenyl group;

XYZ 4 wherein W is N, W is η,® 8 201103914 -CH-C(R2)-N(R3)-, R2 is isobutyl, and R3 is an isobutyl compound; Θ where W is N' R1 is Η

X Χ-Υ-Ζ is -CH-C(R2)-N(R3)-, R2 is a phenoxymethyl group, and R3 is an isobutyl compound;

Wherein W is N'R1 is H, ® is -CH-C(R2)-N(R3)·, R2 is phenyl' and R3 is 2,2_; z, Χ-Υ-Ζ is decylpropyl Combination

Wherein W is N'R1 is Η, a von~1, XYZ is -CH-C(R)-N(R)-'R is a phenoxymethyl group, and R3 is a cyclohexylmethyl group ;

Wherein W is N, Ri is h, @CH_C(R2) is a compound in which V R2 is a cyclopentyl fluorenyl group, and R 3 is a methyl group: wherein W is 1 SMR1 is H, and ® is XYZ is Χ-Υ-Ζ is CH_C(R2)-N(R3)_, R2 is a stupid group, and R3 is an isobutyl compound; wherein W is N'R1 is H,®

X-Y, Z is 9 201103914

_CH-C(R2)-N(R3)- 'R2 is a cyclohexylfluorenyl group, and R3 is a hydrogen compound; -X ,®

Wherein W is N, R is H, 乂-^ is r, XYZ is -0-C(R2)=N-, and R2 is a 2-nonoxyphenylindenyl compound; wherein W is N'R1 H, is a compound in which XYZ is -CH-C(R2)-N(R3)-'R2 is a propyl group, and R3 is a fluorenyl group;

Θ

Wherein W is CH, R1 is 2-decyloxy, ^ is, χ-γ-ζ is -CH-C(R2)-N(R3)-, R2 is phenoxyfluorenyl, and R3 is isobutyl Compound;

Wherein W is Ν, Ν is H, V·^ is , X-Y-Z is -CH-C(R2)-N(R3)-, R2 is phenylmethyl, and R3 is a cyclohexylfluorenyl compound;

, XYZ is a compound in which W is N, ; ^ is H, Vフ is -0-C(R2)=N- ' and R2 is a third butyl group; nx> where W is N'R1 is Η,® Is a compound wherein XYZ is 201103914 -0-C(R2)=N-, and R2 is a 3-decyloxyphenyl group; wherein W is CH, R1 is 2-decyloxy, 4 is Z, and XYZ is a compound of -CH-C(R2)-N(R3)-, wherein R2 is phenylfluorenyl, and R3 is isobutyl;

XYZ wherein W is CH, R1 is 2-decyloxy, is -CH-C(R2)-N(R3)-, R2 is phenoxymethyl, and R3 is 2,2-dimethylpropyl Compound

a compound wherein W is CH, R1 is 2-decyloxy, is -CH-C(R2)-N(R3)-, R2 is phenylmethyl, and R3 is cyclohexylfluorenyl;

XYZ a compound wherein W is CH, R1 is 2-decyloxy, is _CH-C(R2)-N(R3)-'R2 is phenyl, and R3 is 2,2-dimercaptopropyl; Θ wherein W is CH, R1 is 4-fluoro, "^ is -CH-C(R2)-N(R3)-, R2 is phenyl, and R3 is 2,2-;

z, XYZ is a combination of methyl propyl 201103914 wherein W is N'R1 is h, ® is, χ_γ_ζ is -CH_C(R2)-N(R3)-, R2 is a third butyl group, and R3 is 2,2 a compound of dimethylpropyl; wherein w is N'R1 is Η, Θ is, χ_γ_ζ is -NH-C(R2)-C(R3)-, R2 is 4·methylphenyl, and R3 is methoxy a compound of the group - fluorenyl group - carbonyl; wherein W is N'R1 is η, ® is kAz', Χ_Υ_Ζ is -CH-C(R2)-N(R3)'R2 is n-propyl' and R3 is cyclohexyl a compound of a thiol group; and a mirror image isomer, a non-image isomer, a solvate, and a pharmaceutically acceptable salt. The invention further relates to the use of a compound of formula (1) as defined herein for the preparation of a medicament or a pharmaceutical composition for use in inhibiting MGL for treating, ameliorating or preventing a disease or syndrome affected by a patient in need thereof , symptoms or disorders. DETAILED DESCRIPTION OF THE INVENTION In general, the standard nomenclature is used throughout the text, and the end portions of the side chains indicated are described first towards the point of attachment followed by adjacent functionalities, thus, for example, "Ci-C; 6 alkyl groups. "Substituent represents a radical of the formula: 12 201103914 Unless otherwise indicated, it is contemplated that the definition of a number at a particular position in a molecule is independent of its substituent at another position in the molecule, on a compound of formula (1), a substituent And replace the pattern ^ j to understand the common knowledge of the human body, to provide a chemically stable compound ^ which has been readily prepared by the techniques known in the art, and these methods are listed in the "Technology" used in this article. - Class, best for humans, ^!: ί" - έ 5 Ί — - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - "Therapeutic effective amount" means that the active compound or agent, veterinarian, doctor or other clinical probing, can cause biological or pharmaceutical reactions in planting, animal or human, including relief or partial = treatment Disease signs, syndromes, r, use, "composition" 22 contains a therapeutically effective amount of a product of a special knife' and any product is produced directly or indirectly by combining specific components. Terms such as "treatment", "treatment", "improvement" as used herein, unless otherwise indicated, shall include treating and caring for a subject or patient for the purpose of combating a disease, symptom or disorder (preferably It is a mammal, more preferably a human), and includes administration of a compound of the invention to avoid the onset of symptoms or complications, to alleviate symptoms or complications, or to rule out diseases, symptoms or disorders. "Prevention" as used herein, unless otherwise indicated, shall include (4) reduce the frequency of one or more symptoms; (1) reduce the severity of one or more symptoms; (c) delay or avoid additional symptoms. Development; and/or (d) delay or avoid the development of disorders or symptoms 13 201103914. Those skilled in the art will be able to confirm that the subject to be judged (ie, the subject to be prevented) should include at least one symptom of the desired prevention, disease, or symptom. , better for humans). Furthermore, the required person or patient (preferably any disorder that is to be prevented from being mistreated, is not presented as a human being), but it has been treated by a doctor or a clinical person. Good for breastfeeding, genetic testing of the medical staff in the wind, the disease or the progression of symptoms, etc. 'but not limited to this, the subject is dysfunctional or symptomatic, or symptomatic (and therefore need to be prevented or prevented) The term "disorders, disease MGL inhibitors" is intended to exclude compounds whose catalytic activity is due to "substantially lowering the scoop 2." - the term is used to mean that it is affected by the regulation of MGL enzymes. ^%~)(^ ^sj # tastes to reduce one or more symptoms, or the disease ": signs of syndrome: performance of symptoms or disorders of the syndrome or disease, residual, = compound for treatment, improvement and / Or a method of preventing a disease, a symptom, a symptom, or a disorder caused by sputum. This method includes; 201103914 and/or substantially constitutes a self-administered subject (including animals, mammals) in need of such treatment, improvement, and/or prevention. And human) a therapeutically effective amount of a compound of formula (1), or a mirror image isomer thereof, a non-image-isomer, solvate or pharmaceutically acceptable salt. In particular, the compound of formula (I) is useful for treating, ameliorating and/or preventing pain; the disease, syndrome, symptom, or disorder caused by the disease; Inflammation and/or CNS disorders. More specifically, the compounds of formula (I) as defined herein are useful for treating, ameliorating and/or preventing inflammatory pain, inflammatory allergy symptoms and/or neuropathic pain, including administration The subject is a therapeutically effective amount of a compound of formula (1) as defined herein. Examples of inflammatory pain include pain due to disease, symptoms, syndrome, disorder or pain state, including inflammatory bowel disease, visceral pain, migraine, surgery Post-pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor pain, musculoskeletal diseases, skin diseases, toothache, fever, burns, sunburn, snake bites, snake bites, Spider bites, insect bites, neurogenic bladder dysfunction, interstitial cystitis, urinary tract infections, rhinitis, contact dermatitis / allergies, itching, eczema, pharyngitis, mucosa Inflammation, enteritis, irritable bowel syndrome, cholecystitis, tendinitis, post-mammary pain syndrome, menstrual pain, endometriosis, pain due to trauma, headache, sinus headache, nervousness Sexual headache or lack of I. A type of inflammatory pain associated with inflammatory hyperalgesia/allergy. Examples of inflammatory hyperalgesia include diseases, syndromes, symptoms, disorders or painful conditions, including inflammation, osteoarthritis, Rheumatoid arthritis 'back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, postoperative pain, headache, toothache, burns, sunburn, insect bites, neurogenic bladder dysfunction, urinary incontinence, interstitial cystitis , urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis 201103914 / allergies, itching, eczema, pharyngitis, enteritis, stimulating intestinal syndrome, inflammatory bowel disease, including Crohn's disease (Crohn's disease), ulcerative colitis, urinary incontinence, benign prostatic hypertrophy, cough, asthma, rhinitis, nasal allergies, itching, contact dermatitis and/or Skin allergies and chronic obstructive pulmonary disease. In a specific embodiment, the present invention is directed to a method of treating, ameliorating, and/or preventing visceral stress inflammatory visceral hyperalgesia, comprising, constituting, and/or substantially constituting a self-administered treatment. The subject is a therapeutically effective amount of a compound, salt or solvate of formula (1). In another embodiment, the invention is directed to a method for treating inflammatory sore hyperalgesia in which there is an allergy to heat, mechanical and/or chemical stimuli, comprising administering a therapeutically effective amount of a compound of formula (1) to a mammal in need of such treatment. Or its mirror image isomer, non-image isomer, solvate or pharmaceutically acceptable. Another embodiment of the invention is directed to a method of treating, ameliorating and/or preventing neuropathic pain. Examples of neuropathic pain include pain due to disease, syndrome, symptoms, disorders, or pain states, including cancer, neurological disorders, spinal and peripheral nerve surgery, brain tumors, traumatic brain injury (TBI), spinal nerve injury, chronic pain Symptoms, fibromyalgia, chronic fatigue syndrome, lupus, sarcoma, peripheral neuropathy, bilateral neuropathy, diabetic neuropathy neuropathy, mid-frame pain, spinal nerve injury-related neuropathy, stroke, muscular atrophic spinal cord Lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatica, ankle neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, fracture, oral cavity Neuropathic pain, Charcot's pain, complex regional pain syndrome I and n (complex

Regional Pain Syndrome I and II) (CRPS I/II), radiculopathy, 201103814 Guillain-Barre syndrome, sensory paresthetica, burning sign, ocular neuritis , post-thermal neuritis, migratory neuritis, segmental neuritis, Gombault neuritis, neuronitis, cervical neuralgia, cranial neuralgia, knee neuralgia, glossopharyngeal neuralgia, partial Headache neuralgia, primary neuralgia, intercostal neuralgia, breast pain, Morton neuralgia, nasal ciliary neuralgia, occipital neuralgia, neuralgia after running pain, burning pain, erythema Pain, Sluder neuralgia, butterfly bronchial neuralgia, orbital neuralgia, trigeminal neuralgia, vulvar pain, and pterygoid pain. One type of neuropathic pain is neuropathic cold tenderness (c〇ld allodynia), which is characterized by the presence of a neuropathy-related tender state and is sensitive to the presence of cold stimuli. Examples of neuropathic cold tenderness include tenderness due to disease, symptoms, syndrome, disorder, or pain state, including neuropathic pain (neuralgia), vertebrae and peripheral nerve surgery or pain caused by trauma, traumatic brain injury , ^BI), bipolar neuralgia, postherpetic neuralgia, burning pain, peripheral neuropathy = 'diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II) and nerve root lesions. In a specific embodiment, the present invention is directed to a method of treating, ameliorating, and/or pre-curing cold tenderness that is sensitive to the presence of cold touches, including, mf/ or substantially self-injecting A subject in need of such treatment is a therapeutically effective amount of a drug, a sputum, or a spheroidal isomer, a non-image isomer, a solvate or a genomic salt. In a specific embodiment, the present invention is directed to a method of treating, ameliorating, and/or pre-disordering. Examples of CNS disorders include domain disorders, such as social 17 201103914 syndrome, phobia, social phobia, special phobia, IS Anxiety disorder, and pan-anxiety disorder, depression, depression, bipolar disorder, seasonality, the invention is directed to a method for suppressing the improvement of the temperament and/or preventing the disorder of the line, bribery, and recording, including And a compound of formula (1) consisting of: (1-(2,2-dimethyl-propyl)· 2_phenoxyindenyl_1H吲哚·5-base]_[3 (4_ mouth ratio biti-2-yl-hexahydroazepine + base) 丫 咬 bite 4 base]_甲嗣; (compound #1 (2-3⁄4 hexyl-benzoxazole-6-yl)_[3_(4pyridine_2_yl_hexahydropyrazine_)_yl)-furanol-1-yl]-fluorenone; (Compound #2) [2-(3-Fluoro-phenyl)-benzopyrazole _7_yl]_[3_(4_D-pyridin-2-yl-hexahydro-β-plough-1-yl)-吖丁°-1-yl]-fluorenone; (Compound #3) (Bu isobutyl-2-indole-p-phenyl-l-indole-5_yl)_[3_(4_pyridine-2 -yl-hexahydrogen. Plung-1-yl)-azetidin-1·yl]-anthone; (Compound #4) [1-Isobutyl-2-(4-indolyl-phenylhydrazyl)_1Η_吲哚-5- Base]-[3-(4-«pyridin-2-yl-hexahydroindole-1-yl)-azetidine-fluorenyl]-fluorenone; (Compound #5) [2-(4- Fluoro-phenyl)-benzoxazole _7•yl]_[3_(4_„bipyridin-2-yl-hexahydroindole-1-yl)-azetidin-1-yl]-fluorenone; (Compound #6) 201103914 [2-(4-Methoxy-phenyl)_benzoxazole _7_yl]_[3_(4_0 pyridine-2-based _ hexahydro ° ratio till -1- Base)-azetidine small group]-methanone; (compound #7) G,2-diisobutyl-1Η·吲哚-5-yl)-[3-(4-acridin-2-yl- Hexahydro- to -1-yl)-azetidin-1-yl]-fluorenone; (Compound #8) (1-isobutyl-2-phenoxymethyl-1Η-吲哚_5_ Phenidyl-2-yl-hexahydro"1 cultivating small base)-azetidin-1-yl] fluorenone; (Compound #9) [1-(2,2__Dimercapto-propyl) _2_phenyl_1Η,哚_5_yl]-[3-(4-°-pyridin-2-yl-hexahydro-ratio-1-yl)-azetidine-based]-anthone; Compound #1〇) (1-cyclohexylmethyl-2-phenoxymethyl-1H-indol-5-yl) 43-(4-0pyridin-2-yl-hexahydropyrazine_1_ Base) _ azetidine small group] _ fluorenone; (compound #11) (2 -cyclopentyl fluorenyl_1_indolyl-out-.inducing 哚_5_yl)-[3-(4-. Bipyridin-2-yl-hexahydrogen ratio tillin-1-yl)-butyrate _1_yl]-fluorenone; (compound #12) (1-isobutyl-2-phenyl-1H-indole哚-5-yl)-[3-(4-°Bite-2-yl-hexahydro-ratio-1)-azetidin-1-yl]-fluorenone; (Compound #13) ( 2-cyclohexyldecyl-1H-0-bambo-5-yl)-[3-(4-° ratio bit-2-yl-hexahydrogen ratio] well-1-yl)-azetidine-1 -yl ketone; (compound #14) [2-(2-decyloxy-phenylhydrazino)-benzoxanthazole _5_yl]-[3_(4_π比pyridine_2_yl_six Hydrogen pyridin-1-yl)-azetidin-1_yl]-methanone; (Compound #15) (2-ethyl-1-indolyl-1Η-吲哚-5-yl)-[3- (4-pyridin-2-yl-hexahydropyrrol-1-yl)-azetidin-1-yl]-fluorenone; (Compound #16) (1-isobutyl-2-propoxycarbonyl) -1 Η·π3 π-to-5-yl)-{3-[4-(2-methoxy-phenyl)-hexahydro-ratio-1-yl]-azetidin-1-yldipyridinium Ketone; (Compound #17) (2-Benzenyl-1-cyclohexylfluorenyl-fluorene-α-bendo _5_yl)_[3-(4-. 比〇定_2_基_六氢Pyridin-1-yl)-azetidin-1-yl]-fluorenone; (Compound #18) 201103914 (2-Terbutyl-benzoxazole-6-pyridin-2-yl-hexa Hydrogen η ratio tillage base)-azetidin-1-yl]-fluorenone; Compound # 19) 2_ (3_ Yue group [- phenyl) - benzo < 7. Sodium-5-yl]_[3-(4-indole-2-yl-2-hexahydropyrrol-1-yl)-azetidin-1-yl]-fluorenone; (Compound #20) (2 -benzyl-1-isobutyl·1Η-吲哚-5-yl)-{3-[4-(2-oximeoxyphenyl)-hexahydropyridin-1-yl]-rutin (1-(2,2-dimercapto-propyl)_2-phenoxymethyl-1Η-吲哚_5_yl]-{3- [4-(2-decyloxy-phenyl)-hexahydro. Specific cultivating base]_吖丁丁_丨_基布甲酮; (compound #22) (2-phenylhydrazin-1-cyclohexyldecyl_1Η•吲哚_5 base)_3_[4(2曱oxy_phenyl)-hexahydropyrazole-1-yl]-azetidin-1_yl}-methanone; (Compound #23) [1-(2,2-Dimercaptopropyl) _2_phenyl_ιη "bamboo-5-yl]-{3-[4-(2-decyloxy-phenyl)-hexahydropyridin-1-yl]-azetidine-丨-yl }_曱酮; (compound #24) [1-(2,2-dimethyl-propyl)_2_phenyl_1Η吲哚^fluoro-phenyl)-hexahydroindol-1-yl]-吖丁啶_丨_基布甲_; (Compound #25) [2-Ternyl-l_(2,2-dimethyl-propyl)_1Η_吲哚·5 base]_[3_(4 _Pyridine-2-yl-hexahydroindole and · kibidine bite]-yl] A class; (Compound #26) 2-曱oxyl small {5-[3-(4-吼唆_2·六 吼 吼 井 ) ) ) ) ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] 1- 1- 1- 1- -propyl]Η_σ引口朵_5d_[3 (4k2_yl-hexahydronyl-butyr-1-yl)_竹唆]_yl], ketone; (Compound #28) and its mirror image isomer, Non-image isomers, solvates, and pharmaceutically acceptable salts. Preferably, by inhibiting MGL The affected disease, syndrome, symptom or disorder is selected from the specific examples of pain, inflammatory money, inflammatory 20 201103914 allergic symptoms and neuropathic pain as defined herein, this group: improvement or prevention Affected disease:::: For a subject to be treated by inhibiting MGL, a therapeutically effective amount of a form or disorder

0-〇 or its mirror image isomer, non-mirror w (in the case of R1, W and a, structure, solvate or pharmaceutically acceptable examples, the present invention is directed to the disadvantage Z as defined herein In another specific affecting disease, syndrome, MGL, treating, ameliorating or preventing a therapeutically effective amount (lb) compounding, which comprises administering a subject to the subject R1.

Or a mirror image isomer thereof, a non-(ib) salt thereof, wherein R1, w and the oxime isomer, solvate or pharmaceutically acceptable embodiment, the present invention is directed to _z as defined herein. Treating, ameliorating or preventing a therapeutically effective amount of a compound of formula (10) or a disorder, in addition to specifically affecting the disease, syndrome, syndrome, or gamma, comprising administering a subject to be treated 201103914

"f1', mirror image isomer, non-image isomer, solvate or pharmaceutically acceptable two, R, w and -XYZ - as defined herein. In another embodiment, the invention is directed to inhibition MGL· is to treat, ameliorate or prevent an affected disease, syndrome, symptom or disorder, and comprises a compound selected from the group consisting of: (1, (2, 2-) Mercapto-propyl)-2-phenoxymethyl-1H-indole-5-yl]-[3-(4-Bit-2-yl-hexahydro. Ratio 0 well]_base)_〇 Kenting bite ketone; (compound work) (2-% hexyl-benzoxazole·6_yl)_[3_(4_ π-pyridin-2-yl-hexahydroindole _ bas) Azetidin-1-yl]-methyl _; (compound #2) |; 2-(3-fluoro-phenyl)-benzoxazole _7_yl]_[3 (4_π pyridine-2-yl) - hexahydropyrene than cultivating • 1-yl)-azetidin-1-yl]-fluorenone; (Compound #3) (1-isobutyl-2-indole-tolyl-1Η-吲哚-5- Base]-[3-(4-pyridin-2-yl-hexahydro-ratio-1-yl)-azetidin-1yl]-methanone; (Compound #4) [1-Isobutyl- 2-(4-indolyl-phenylhydrazinyl)_ιη-吲哚-5-yl]-[3-(4-«pyridin-2-yl-hexahydro-ratio-1-yl)-吖丁咬(anthracene ketone; (compound #5) [2-(4-fluoro-phenyl)-benzoindole sal. 7-7-yl]-[3-(4-α ratio -2-yl-hexahydro) Smaller than the basic), 丫 咬 小 ] ] ] ] ( ( 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物4_πBipyridine_2_yl-hexahydropyrrol-1-yl)-azetidin-1-yl]-fluorenone; (Compound #7) 22 201103914 (1,2-Diisobutyl-ih-吲哚_5_yl)_[3-(4-Pyridin-2-yl-hexahydropyrylene-1-yl)-azetidin-1-yl]-methanone; (Compound #8) (1-iso Butyl-2-phenoxymercapto_1H-indole-5-yl)-[3_(4_pyridine·2•yl_hexahydropyrylene-1-yl)-azetidinyl]-methanone; Compound #9) [1-(2,2-Dimercapto-propyl)_2·phenyl phenylindole-5-yl]_[3-(4-0 than bit-2-yl-hexahydropyrene -1-yl)_azetidine-fluorenyl-yl)-methanone; (Compound #1〇) (1-cyclohexylnonyl-2-phenoxyindolyl-1Η-吲哚_5_*)_[ 3_(4_πBipyridin-2-yl-hexahydropyrryl-μ-yl)-azetidine-丨-yl]-methanone; (Compound #11) (2-cyclopentylmethyl-1-indenyl) ΗΗ_吲哚_5_基)_[3_(4_η比丁_2_yl-hexahydropyrrol-1-yl)-azetidin-1-yl]-methanone; (Compound #12) (1 -isobutyl-2-phenyl-1Η-吲哚- 5-yl)_[3-(4-pyridin-2-yl-hexahydropyridin-1-yl)-azetidin-1-yl]-fluorenone; (Compound #13) (2-cyclohexyl) Mercapto-1Η-吲哚-5-yl)-[3-(4-pyridin-2-yl•hexahydropyrazole-1-yl)-azetidin-1_yl]-fluorenone; 14) [2·(2_曱-oxybenzoyl)-benzopyrene _5_yl]_[3_(4_η比唆_2_yl_hexahydroindole cultivating base)-azetidine- 1-yl]-methanone; (Compound #15) (2-Ethyl-1-methyl-ΐΗ_η弓布朵-5-yl)-[3-(4-° ratio bit-2-yl-hexahydro) . 〇井-1-yl)-azetidin-1-yl]-fluorenone; (Compound #16) (1-Isobutyl-2-phenoxymercapto-1HH5-yl)_{3-[ 4-(2-methoxy-phenyl)-hexahydro-ratio-1-yl]-azetidine-;1_yl}-anthone; (Compound #17) (2-Benzyl-1 -cyclohexyl fluorenyl-1 Η-oral 引.朵-5-yl)-[3-(4-° ratio. 1,4--2-yl hexahydro. 1,4- -1-) 吖 吖 啶 _1 _1 (meth) ketone; (Compound #18) and its mirror image isomers, non-image isomers, solvates and pharmaceutically acceptable salts. 23 201103914 In another embodiment, the invention is directed to the use of a compound selected from the group consisting of: [1-(2,2-dimercapto-propyl)_2-phenoxyindolyl-1H吲哚_5基]_[3_(4) pyridin-2-yl-hexahydropyrrol-1-yl)-azetidinone; (Compound #1) [2-(3-Fluoro-phenyl)-benzo Carbazole _7_yl]_[3_(4^pyridin-2-yl_hexahydroσ-pyridin-1-yl)-butyrate-1-yl]-fluorenone; (Compound #3) (1- Isobutyl-2-ρ-methylphenyl-1Η-吲哚-5-yl)-[3-(4-pyridin-2-yl-hexahydro"-rough-1-yl)-吖丁 bit-1 -yl]-fluorenone; (Compound #4) [1-Isobutyl-2-(4-indolyl-phenylhydrazinyl-5-yl]-[3_(411-pyridin-2-yl-hexahydro) 0 than tillage-1_base)-butine bite-ΐ_yl]-fluorenone; (compound #5) [2-(4-11-phenyl)-benzopyrazazolyl]-[3-( 4-n-bipyridyl-2-yl-hexahydro-•• 1,4-butyl-1-azetidin-1-yl]-fluorenone; (Compound #6) [2-(4-methoxy-ben ))-benzoquinone u-β sit _7_yl]-[3-(4-β-Bist-2-yl-hexahydropyrylene-1-yl)-azetidin-1-yl]-fluorenone (Compound #7) (1-Isobutyl-2-phenoxyindolyl-1Η-吲哚-5-yl)-[3-(4-Acridine-2-yl-hexahydropyrazine-1 -yl)-azetidin-1-yl]-fluorenone ; (Compound #9) [1-(2,2-Amidino-propyl)-2-phenyl 1 Η-α 丨 D D-5-yl]-[3-(4-0 than bite-2 -ylhexahydropyrrol-1-yl)-azetidin-1-yl]-methanone; (Compound #1〇) (1-cyclohexyldecyl-2-phenoxyindenyl-1H-indole -5-yl)-[3-(4-»pyridin-2-yl-hexahydropyrrol-1-yl)-azetidin-1-yl]-methanone; (Compound #11) Butyl-2-phenyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-hexahydroindol-1-yl)-azetidin-1-yl]-oxime Ketone; (Compound #13) (2-Benzyl-1-cyclohexyldecyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-hexahydropyrazole-1- ())-butyridin-1-yl]-methanone; (compound #18) 24 201103914 ^ (1_cyclohexylmethyl-2-propyl fluorenyl)_[3_(4_pyridine_2_yl _六氲比井-1-yl)-σ丫丁咬_1_基]_methanone; (Compound #28) and its mirror image isomers, non-image isomers, solvates and pharmaceutical salts In another embodiment, the present invention is directed to treating, ameliorating or preventing an affected disease, syndrome, symptom or disorder by inhibiting MG:L, the inclusion thereof being treated with a desired subject The effective amount is selected from the following Group consisting of compounds: (2-cyclohexyl-benzoxazole _6·yl)_[3-(4_pyrodo_2_yl-hexahydroindole-1-yl)-azetidine-1 -yl]-methanone; (Compound #2) [2-(3-Fluoro-phenyl)-benzoxanthene_7_yl]-[3_(4_n-bipyridyl-2-yl-hexahydro-• 〇井-1-yl)-azetidin-1-yl]-fluorenone; (Compound #3) [1-Isobutyl-2-(4-indolyl-benzoyl)_ΐΗ-σ _5_基]-[3-(4-°Bite-2-yl·hexahydro"Comparative -1-yl)_吖丁丁-卜基]·曱 ketone; (Compound #5) [2- (4-曱-oxy-phenyl)benzo-α 嗤_7_yl]-[3-(4-° ratio °-2-yl-hexahydrogen ratio 0 well small base)·0丫丁咬Small base]-methanone; (compound #7) [1-(2,2-monomethyl-propyl)-2-phenyl-111-° ππ-5-yl]-[3-(4 -0 π-but-2-yl-hexahydro-ratio to -1-yl)-azetidin-1-yl]-fluorenone; (Compound #1〇) (1-cyclohexyldecyl-2-benzene oxymethyl-1Η-indol-5-yl)-[3-(4-acridin-2-yl-hexahydropyrrolidin-1-yl)-azetidin-1-yl]•anthrone; (Compound #ιι) (2-cyclopentylmethyl-1-methyl-1Η-indol-5-yl)-[3-(4-pyridin-2-ylhexahydropyrylene-1-yl)- Azetidin-1-yl]-fluorenone; (Compound #12) (1-Isodine -2-phenyl-1Η·吲哚-5-yl)-[3-(4-pyridin-2-yl-hexahydropyrrol-1-yl)-azetidin-1-yl l-fluorenone; (Compound #13) 25 201103914 (2-Benzenyl-1-cyclohexyldecyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-hexahydro). Pentidin-1-yl) azetidine small group]-anthrone; (compound #18) [2-(3-methoxy-phenyl)-benzoindazole _5_yl]_[3_(4_ „Bistidine_2_yl_hexahydrogen 0 to cultivate-1-yl)-azetidine small group]_anthrone; (Compound #20) (2-Benzenyl 4·cyclohexylmethyl-1H-吲哚-5-yl)-{3-[4-(2-decyloxy-phenyl)-hexahydro-ratio-1-yl]-azetidine ketone; (Compound #23) 2-曱oxy-1-{5-[3-(4-° than 唆-2-yl-hexahydroindole_1_yl)_. 丫丁唆e-Ι-carbonyl]-2·ρ-曱 stupid ··1H_. 哚 哚 哚 } } _ _ ketone; (Compound #27) (1-cyclohexylmethyl-2-propyl-1H-indol-5-yl)-[3-(4-pyridine-2 -yl-hexahydroindole-1-yl)-azetidine_;!_*]_fluorenone; (Compound #28) and its mirror image isomers, non-image isomers, solvates and pharmaceutically acceptable In another embodiment, the invention is directed to treating, ameliorating or preventing an affected disease, syndrome, symptom or disorder by inhibiting MGL comprising administering a therapeutically effective amount to a subject in need thereof The compound selected from the group consisting of: (2-cyclohexyl-benzoxazol-6-yl)-[3-(4-pyridyl-hexahydropyrazine q) _ base)-azetidin-1-yl]-methanone; (Compound #2) [2-(3-Fluoro-phenyl)-benzoxazol-7-yl]-[3-(4-吼啶_2_yl-hexahydro. Tr.-1-yl)-azetidin-1-yl]-methanone; (Compound #3) [2-(4-Ga-phenyl)-Benzene _7_基]-[3_(4_〇 啶 啶 _2 _ _ _ 六 六 -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1-) 2-tert-butyl-benzo-xylindole_6jH3_(4_n2des hexanitroindoles than wells)-σ丫丁°-1-yl]•甲酿 I ;(化合物#19) 26 201103914 Mirroring isomers, non-image isomers, solvates, and pharmaceutically acceptable salts. In another specific embodiment, the invention is directed to any single compound or a compound selected from Tables 1-3, or Use of a subset of mirror image isomers, non-image isomers, solvates or pharmaceutically acceptable salts; for treating, ameliorating or preventing affected diseases, syndromes by inhibiting MGL in a subject in need thereof , symptom or disorder. The compound of the formula (I) of the present invention is as shown in the following Tables 1-3. Table 1: Compound of the formula (la) Compound No. W R1 Χ-Υ-Ζ R2 3 Ν Η -oc(r2)=n- 3- Fluorophenyl 6 Ν -o-c (r2) = n- 4- fluorophenyl 7 Ν Η -o-c (r2) = n- 4- Yue-phenyl Table 2: Formula (LB) Compound

27 201103914 Compound No. W R1 Χ-Υ-Ζ R2 R3 1 N Η -CH-C(R2)-N(R3)- phenoxyfluorenyl 2,2-dimethylpropyl 2 N Η -0-C (R2)=N-cyclohexyl 4 N Η -ch-c(r2)-n(r3)-4-nonylphenylisobutyl 5 N Η -CH-C(R2)-N(R3)-benzene Base oxime isobutyl 8 N Η -CH-C(R2)-N(R3)-isobutyl isobutyl 9 N Η -CH-C(R2)-N(R3)- phenoxy fluorenyl Butyl 10 N Η _ch-c(r2)-n(r3)-phenyl 2,2-dimercaptopropyl 11 N Η -CH-C(R2)-N(R3)-phenoxyindenyl ring Hexyl-fluorenyl 12 N Η -CH-C(R2)-N(R3)-cyclopentyl-methylindenyl 13 N Η -CH-C(R2)-N(R3)-phenylisobutyl 14 N Η -CH-C(R2)-N(R3)- hexylhexyl-fluorenylhydrogen 16 N Η -CH-C(R2)-N(R3)-propylmercapto 17 CH 2-decyloxy-CH -C(R2)-N(R3)-phenoxymercaptoisobutyl 18 N Η -CH-C(R2)-N(R3)-phenylindenylcyclohexyl-methyl19 N Η -0- C(R2)=N- tert-butyl 21 CH 2-decyloxy-CH-C(R2)-N(R3)-phenylmercaptoisobutyl 28 201103914 22 CH 2-decyloxy-CH- C(R2)-N(R3)-phenoxyindenyl 2,2-dimercapto-propyl 23 CH 2-methoxy-CH-C(R2)-N(R3)-phenylmethyl ring Hexyl-mercapto 24 C H 2 —methoxy-CH-C(R 2 )-N(R 3 )-phenyl 2,2-dimercapto-propyl 25 CH 4-fluoro-CH-C(R 2 )-N(R 3 )-benzene 2,2-dimercapto-propyl 26 N Η -CH-C(R2)-N(R3)-t-butyl 2,2-dimercaptopropyl 28 N Η -ch_c(r2)-n (r3)-Π-propyl-d-hexyl-indenyl group Table 3: Compound of formula (Ic) Compound No. W R1 Χ-Υ-Ζ R2 R3 15 N Η -0-C(R2)=N- 2-decyloxy -Phenylmethyl 20 N Η -oc(r2)=n-3-methoxy-phenyl27 N Η -NH-C(R2)-C(R3)-4-nonylphenyl fluorenyloxy- In the specific embodiment, the present invention improves or prevents the affected disease, the disease 1, the disease, the group, the symptom or the disorder which is affected by the inhibition of MGL and the inhibition of MGL. Sexual Pain and Neuropathic Pain Group 1 矣 group, symptom or disorder is selected from the group consisting of inflammatory (including mammals and / or humans) treatment group; including the compound of formula (1)

(I) which is selected from the group consisting of Ba, solvates and pharmaceutically acceptable salts as defined herein, like isomers, non-image isomers. In the specific examples, the invention is directed to the treatment, amelioration or prevention. Inflammatory pain; comprises administering a therapeutically effective amount of a compound of formula (I) to a subject (including mammals and/or humans)

R •0

(I) It is selected from the group defined herein; and its mirror image isomers, non-image isomers, solvates, and pharmaceutically acceptable salts. In another embodiment of the invention, the inflammatory pain is selected from the group consisting of visceral pain and inflammatory hyperalgesia, preferably visceral pain. In a specific embodiment A, the present invention is directed to treating, ameliorating or preventing inflammatory hyperalgesia, comprising administering a therapeutically effective amount of a compound of formula (I) to a subject in need thereof (including mammals and/or humans) 201103914

It is selected from the group defined herein; and its mirror image isomers, non-image isomers, solvates, and pharmaceutically acceptable salts. In another embodiment of the invention, the inflammatory hyperalgesia is ulcerative colitis. In a particular embodiment, the invention is directed to treating, ameliorating or preventing neuropathic pain comprising administering to a subject in need thereof (including mammals and/or humans) a therapeutically effective amount of a compound of formula (I).

It is selected from the group defined herein; and its mirror image isomers, non-image isomers, solvates, and pharmaceutically acceptable salts. In another embodiment of the invention, the neuropathic pain is neuropathic cold tenderness. Regarding the use of the agent, the salt of the compound of the formula (I) represents a non-toxic "pharmaceutically acceptable salt". However, other salts can be used to prepare the compound of formula (1) or a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts which may, for example, be by mixing compound solutions with, for example, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, Formed from a pharmaceutically acceptable acid solution of benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compound of formula (I) carries an acidic moiety, suitable pharmaceutically acceptable salts may include metal salts such as sodium or potassium salts; soil metal salts such as J. Bow or Town 31 201103914 Salts And salts formed with suitable organic ligands, such as quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetate, besylate, benzoate, bicarbonate 'heavy sulfate, hydrogen tartrate, borate bromide, calcium edetate, right Cyclonic acid sulfonate, carbonate, vapor, clavulanate, citrate, dihydrochloride, ethylenediaminetetraacetate, ethanedifuate, propyl sulphate Salt (est〇late), esylate, cis-butyrate, glucoheptonate (e), gluconate, glutamate, α-ethylamine Benzate (giyC〇iiyiarsaniiate), hexyl benzene diphenol, hydrabamine, bromine oxygen, hydrogen chloride, hydroxynaphthoate, filler, isothionate, lactate, Lactinate, laurate, malate, maleate, mandelate, sulfonate, methyl bromide, methyl nitrate, sulfonate, mucilage, naphthalene sulfonate, nitric acid Salt, N-methyl reduced glucosamine ammonium salt, oleate, pamoate (pamoate; embonate), palmitate Pantothenate, g-dibasic/discalate, galacturonate, salicylate, stearate, sulfate, basic acetate, succinate, citrate, tartrate, Tea chlorate, toluene sulfonic acid, triethyl iodine and shikimic acid. Representative acids and bases useful in the preparation of pharmaceutically acceptable salts include acids such as acetic acid, 2,2-diacetoacetic acid, deuterated amino acid, adipic acid, alginic acid, ascorbic Jk acid, L- Aspartic acid, benzoic acid, benzoic acid, 4-ethylguanidinium benzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+M1S)_camphor-10-sulfonic acid, citric acid, caproic acid, Octanoic acid, cinnamic acid, lemon acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, hydrazine Acid, fumaric acid, mucic acid, gentisic acid, gluconic acid, D-glucose 32 201103914 Acid, D-glucuronic acid, L-glutamic acid, α-ketoglutaric acid, glycolic acid, horse Uric acid, hydrobromic acid, hydrochloric acid, (+)-L_lactic acid, (4)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (y-DL·almond Acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid , pamoic acid, phosphoric acid, L-pyro face acid, salicylic acid, 4-amino-salicylic acid , azelaic acid, stearic acid, succinic acid, sulfuric acid, citric acid, (+)-L-tartaric acid, thiocyanic acid, P-toluene acid and undecylenic acid; and test class 'including ammonia, L-fine Amine acid, phenylethylbenzylamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, B Diamine, N-mercapto-reducing glucosamine, hambamamine, p-m-sodium, L-isoamine, oxyhydrin, 4-(2-transethylethyl)-morphine, hexahydro well, Potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, triterpene aminodecane and zinc hydroxide. Specific examples of the invention include prodrugs of the compound of formula (I) In general, a prodrug is a functional derivative of a compound that is readily converted into a desired compound in vivo. Thus, in the method of treatment or prevention of a particular embodiment of the invention, the term "administering" encompasses _ revealing a compound 'or a compound that is not specifically disclosed' but which is converted into a specific compound in vivo after administration to a patient to treat or prevent various diseases and symptoms described , syndromes and disorders. The conventional procedures for selecting and preparing appropriate prodrugs and organisms are described, for example, in "Design 〇f pr〇drugs,,, h Bundgaard, Elsevier, 1985 ,, the compounds of the examples have at least a pair of palms. Center 〆,, beans can be the same day: the second brother is like an isomer. When the compound has two or more pairs of palms in the palm of the pentagon is not a mirror image isomer. It should be understood that all such isomeric 33 201103914 and its Mixtures are all included within the scope of the invention. In addition, crystalline forms of some of the compounds may be present in the form of polymorphs, and as such, are intended to be included in the present invention. In addition, some of the compounds may form solvates (i.e., hydrates) or general organic solvents with water. This solvate is also intended to be encompassed within the scope of the invention. Those skilled in the art will appreciate that a compound term as used herein refers to a solvate comprising a compound of formula (1) as defined herein. The process for preparing the compounds of certain embodiments of the present invention results in a mixture of stereoisomers which can be separated by conventional techniques, such as preparative chromatography. The compounds can be prepared in racemic form, or the individual mirror image isomers can be prepared by mirror image specific synthesis or by resolution. The compound can be decomposed, for example, by standard techniques, into its constituent mirror image isomers, for example, by formation of a non-mironomer, which forms a salt with an optically active acid, for example, tolyl-d-/pyric acid and/or Or (+) _ _ 卩 曱 曱 曱醯 曱醯 小 tartaric acid, then partially crystallized and formed a free base. The compound can also be resolved via formation of a non-image material isomer or guanamine, followed by chromatographic separation and removal of the palm auxiliaries. Alternatively, the compound can be decomposed using a palm HPLC column. A particular embodiment of the invention is directed to a composition comprising a pharmaceutical composition comprising, consisting of, and/or consisting essentially of a (+)-mirromer of a compound of formula (1), wherein the composition is substantially free of Isomer of the compound. As used herein, substantially free means less than about 25% 'preferably less than about 1 〇〇 / 0, more preferably less than about 5% 'excellently less than about 2%, and preferably less than less than about 2% About 1% (+ isomer, which is calculated by the following formula: %(+)-mirror isomer ==-image of the opposite substance)__ ((+)-赛伟异称物租§· + ((-)·Competition: the amount of the compound (1) (_)_ mirror image isomer, wherein the composition is substantially free of the (+)-isomer of the compound. As used herein, substantially does not mean less than about 25%, preferably less than about 10%, more preferably less than about 5% 'excellently less than about 2%, and most preferably less than about 1%. (+)-isomer, which is calculated by the following formula: ----- ---1)-competition variants rent f)_xl〇〇((+)-余谭异楫物量量)+( (-) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ This can be achieved by a conventional method of protecting the base, for example, in Grow/??? Organic Chemistry^ Second Edition, JFW McOmie, Plenum Press, 1973, TW Greene & PGM Wuts, Protective Groups in Ogamc, plus /ze·^ , John Wiley & Sons, 1991; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis ^ Third, described in John Wiley & Sons, 1999. The protecting group can be removed at a later stage of convenience using methods known in the art. Although the compounds of the specific embodiments of the invention, including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates, can be administered separately, they are usually selected by mixing medical or veterinary habits related to the intended route and criteria for administration. It is administered as a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent. Accordingly, specific embodiments of the invention are directed to pharmaceutical and veterinary compositions comprising a compound of formula (I) as defined herein and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or medicinal Acceptable diluent. 35 201103914 By way of example, in a pharmaceutical composition of a particular embodiment of the invention, the compound of formula (i) can be combined with any suitable binder, lubricant, suspending agent, coating, solubilizing agent, and combinations thereof. A solid oral dosage form containing a compound of the present invention, such as a troche or a capsule, may be administered as appropriate in at least one dosage form at a time. It is also possible to administer the compound as a sustained release formulation. Additional oral forms which may be administered to the compounds of the invention include elixirs, solutions, syrups and suspensions; each optionally containing a flavoring agent and a pigment. Alternatively, the compound of formula (I) is administered by inhalation (intratracheal or intranasal), or in the form of a suppository or pessary, or it may be administered topically in the form of a detergent, solution, cream, ointment or spray, for example It may be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycol or liquid paraffin. Creams having a concentration of from 1% by weight to about 10% by weight may also be incorporated into the ointment comprising, consisting of, and/or consisting essentially of a white wax or a white soft paraffin base, and may require a stabilizer and a preservative. Another mode of administration involves skin penetration through the use of skin or skin penetration patches. The pharmaceutical composition of the present invention (and the compound of the present invention alone) can also be administered parenterally, for example, in the body, intravenously, intramuscularly, subcutaneously, intradermally or intrauterinely. In this case, the composition also includes at least one suitable carrier, a suitable excipient, and a suitable diluent. Regarding parenteral administration, the pharmaceutical composition of the present invention is preferably used in the form of a sterile aqueous solution which may contain other substances such as a sufficient amount of salts and monosaccharides to produce a solution of osmotic pressure with blood. 36 201103914 With regard to buccal or sublingual administration, the pharmaceutical composition of the present invention can be administered in the form of a spiking or vine-shaped ingot, which can be formulated by a conventional method. By way of further embodiments, pharmaceutical compositions containing at least one compound of formula (I) may be administered according to conventional pharmaceutical compounding techniques, by pharmaceutically acceptable carrier, pharmaceutically acceptable diluent, and/or pharmaceutical acceptability. Prepared by mixing the excipients. The carrier, excipient, and diluent can take a wide variety of forms depending on the route of administration (eg, oral, parenteral, etc.). Therefore, for liquid oral preparations, such as suspensions, syrups, elixirs and solutions, suitable carriers, excipients and diluents, including water, glycols, oils, alcohols, flavoring agents, preservatives, stability Agents, pigments, etc.; for solid oral preparations, such as powders, capsules and lozenges, suitable carriers, excipients and diluents include starches, saccharides, diluents, granulating agents, lubricants, binders, disintegrating agents Wait. The solid oral preparation can also be optionally coated or enteric coated with a substance such as an anthraquinone to adjust the main site of absorption and disintegration. For parenteral administration, the carriers, excipients and diluents usually comprise sterile water, and additional ingredients are added to increase the solubility and preservation of the composition. Injectable suspensions or solutions can also be prepared using aqueous, suitable additives, diligent and preservatives. A therapeutically effective amount of a compound of formula (1) or a pharmaceutical composition thereof, includes a dosage range of from about 0" to about 3 mg of the compound of formula (I) as defined herein, or any amount or range herein, In particular, about ** 々丄, soil, 疋1 home gram to about 1000 mg' or any number or range in this article, more particularly nose * h, ~ horse about 10 gram to about 500 mg ' or this article Any number or range, 芈 > / , β 乂 ten mothers (70 kg) per 曰 about 1 to about 4 times of the method of birth; however, for 孰 umbrella " Formula (1) Compound 37 201103914 The therapeutically effective amount of the substance will vary depending on the disease, syndrome, symptoms and disorders to be treated. For oral administration, the pharmaceutical composition is preferably provided as a lozenge containing a compound of formula (1) of about (iv), about (7), :10 zaoli (10), about 150, about 200, about 250, and about fine milligrams. Advantageously, the compound of formula (I) can be administered in a single daily dose. It can be administered in divided doses of two, three and four times a day. (4) The desired dosage of the compound of formula (I) can be easily determined. : The compound, the mode of administration, the efficacy of the preparation, and the disease, the symptoms of the disease, and the progress of the spoon. In addition, factors relating to the particular subject to be treated, including the age, weight, diet, and time of administration of the inventor, will result in the need for conditioning agents to achieve the appropriate level of treatment and the desired therapeutic effect. The above dosages are therefore exemplary of the "birth", and, of course, there may be individual instances that are subject to higher or lower dosage ranges' and are included within the scope of the invention. It will be appreciated by those skilled in the art that in vivo and in vitro assays using appropriate, known and generally acceptable cell or animal models are predictive of the ability to treat or prevent test compounds. Those skilled in the art will be more able to test 'human clinical trials including the first human trial, range of measurement and efficacy test' in healthy patients and/or those with specific disorders, which can be done according to clinical and medical techniques. f. Each time the subject needs to use a compound of formula (I), the compound of formula (I) can be administered as a composition of the month and by dose regimen, or administered in a dose established by the technique established in the art. [Comprehensive Mode] 38 201103914 Representative compounds of the present invention can be synthesized according to the general synthetic methods described below and in the following flow chart diagrams, as the flowchart is illustrative, and the present invention should not be construed as being described in the flowcharts and examples. Specific chemical reactions and specific conditions are limited. The different starting materials used in the schemes are commercially available or can be prepared by methods well known to those skilled in the art. The variables are as defined herein and by those skilled in the art. The following abbreviations used in the specification, in particular in the schemes and examples: DCC = N,N-dicyclohexylcarbodiimide DCM = dichlorodecane DIPEA or DIEA = diisopropylethylamine DMF = N,N-dimercaptoamine DMSO = diterpenoid EDTA = ethylenediaminetetraacetic acid

EtOAc = Ethyl acetate for HATU = 0-(7-azobenzotriazol-1-yl)-oxime, hydrazine, Ν'Ν''-tetramethylurea hexafluorophosphate HBTU = 0-benzotriazole -1-yl-N,N,N',N'-tetradecylurea hexafluorophosphate HEPES = 4-(2-hydroxyethyl)-1-hexahydropyrrylethanesulfonic acid TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran 39 201103914 The compound of the formula (1) of the present invention can be produced according to the method outlined in Scheme 1 below.

Scheme 1 Thus, 'appropriately substituted compounds of formula (V) (known compounds or compounds prepared by known methods) are reacted with a suitably substituted compound of formula (VI) wherein p is a suitably selected nitrogen protecting group, for example -CH(phenyl) 2, phenyl fluorenyl, tert-butyl, fluorenyl 4 is preferably -CH(phenyl) 2, a known compound or a compound prepared by a known method; in the presence of an organic base, for example DIPEA, pyridine, etc. (preferably not TEA) 'in an organic solvent such as acetonitrile, THF, DCM, etc.; preferably in a temperature range of from about 5 ° C to about 9 ° C; produces a corresponding formula (VII) Compound. The compound of formula (VII) is deprotected according to known methods to give the corresponding compound of formula (VIII). For example, wherein p is ^((phenyl), the compound of formula (VII) 201103914 is deprotected by reaction with 1-oxyethyl chlorodecanoate in an organic solvent such as di-methane, and then in, for example, methanol Recirculation in an organic solvent to produce a corresponding compound of formula (VIII). In the presence of a suitable selected coupling agent, such as HATU, HBTU, DCC, etc., a compound of formula (VIII) is reacted with a suitably substituted (Ιχ) compound, wherein LG1 Selecting a group consisting of -C(0)C1 and _C(0)0H, and wherein LGi is benzo-fused with a compound of formula (IX) (a known compound or a compound prepared by a known method) The position of the part of the benzene ring to be combined; in the presence of an appropriate organic test, such as DIPEA, TEA, specific biting, etc.; in organic solvents, such as acetonitrile, DMF, DCM, etc.; corresponding formula (I) The following examples are given to aid in the understanding of the invention, and are not intended to be and should not be construed as limiting the invention as set forth in the scope of the appended claims in any way. In the following examples, some are listed to be separated. Residue product It will be understood by those of ordinary skill in the art that the term "residual" is not intended to limit the physical state in which the product is separated, and may include, for example, solids, oils, saponins, gums, syrups, etc. Example 1: (2 Cyclohexyl-benzoxazol-6-yl)-[3-(4-pyridin-2-yl-hexahydropyrylene-1-yl)-azetidin-1-yl]-fluorenone oxime

41 201103914 Step A: 2-cyclohexyl-benzo σ-fl-sodium-6-decanoic acid in 4-amino-3-yl-benzoic acid-methyl hydrazine (5 g, 29 91 mM CH3 〇H ( In a solution of 150 ml), add cyclohexanone (3 6 ml, 29.91 house moles) at room temperature. The resulting mixture was evaporated at room temperature for 2 hours to remove the solvent' and add cation (3) ((10) ml) to Residue. Add acetic acid (4) 13_26 A ' 29.91 mmol) in one portion at K and reflux the resulting mixture for H) min. After cooling, the solid produced was filtered and washed with cH3CN. Then, 3N NaOH (40 ml) was added to the mash, and the resulting mixture was stirred at 5 ° C for 1 M. The solvent was removed by evaporation, and the resulting residue was purified by flash chromatography on silica gel to yield """"""""" Step B: (2-cyclohexyl-benzo-x-seat _6 boat (3 times base _. 丫丁咬小基)_A class in the presence of 2_cyclohexyl benzobenzene carboxylic acid (〇, ^ ^ ^ ^ ^ ^ ^ 克 '2.5 mM KDMFa / ml ^ Mo: eight a U ml ' 7.6 mmol). The resulting mixture is stirred at room temperature for 10 knives 'then add η 丫 bite _3_ alcohol Hydrochloride (〇 452 g, 4 7 mmol). = = mixture of product at room temperature (four) i hours 'and then reverse phase liquid chromatography pure =. Cold beam drying of the product containing the fraction, resulting in such as hexyl benzene And azole _6_ soil H3-& base "丫丁唆小基)_甲嗣. Heart (10) +% of the Bu: C. 2, hexyl _6_{[3_(4 〇 bite · 2 · base six Hydrogen. 哎 ) ) ) + + 基 基 基 基 基 基 基 基 基 于 于 于 于 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 ^ Add dropwise to (2-cyclohexyl-benzoxac-6-yl)-(3-carbyl- succinyl-1-bita-1-(0.48 g, 1.6 mmol) and mpEA ( 〇 558 ml, 3 2 mM 42 201103914 ear) in DCM (20 ml) solution, immediately remove the cooling bath after the addition, and slowly warm the mixture to room temperature. The mixture was washed with water, dried with sulphuric acid, dried, and evaporated, and solvent was evaporated. The residue obtained was dissolved in acetonitrile (1 ml). DIPEA (0.41 ml, 2.4 mM) and N- (2-Pyridine) hexahydropyrazine (1.6 mmol). The resulting mixture was then microwaved for 4 hours at 160 ° C. DMF (3 mL) was added to the resulting mixture, which was then inverted Purification by liquid chromatography. The product-containing mash was diluted with IN HC1 (5 ml) and then lyophilized to give 2-cyclohexyl-6-{[3-(4_pyridine-2-ylhexahydro 11 The corresponding hydrochloride salt of -1-yl)azetidin-1·yl]carbonyl}_1,3_benzopyrene. 1h NMR (400MHz, DMSO-d6) δ= 9.21 (s,1 H),8· 15 (d, "/ = 5.1 Hz, 1 Η), 7.96 (d, J = 8.3 Hz, 1 H), 7.81 (br. s., 1 H), 7.16 - 7.22 (m, 1 H), 7.06 ( d, J = 8.3 Hz, 1 H), 6.88 (s, 1 H), 4.54 (br. s" 2 H), 4.38 (d, c/= 6.6 Hz, 2 H), 4.13 (br. s., 1 H), 3.73 (br. s·, 8 H), 3.31 - 3.60 (m, 1 H), 1.77 (d, "/= 13.7 Hz, 4 H), 1.65 (br. s" 1 H), 1.32 _ 1.44 (m, 2 H), 1.15 _ 1.32 (m 2 H), I.06 (t, 7.0 Hz, 1 H). MS m/z (M+H+) 446. Compounds #2 to 28 can be similarly prepared and replaced according to the procedure described in Example 1 above. Suitable reagents, starting materials and purification methods are known in the art selected and/or substituted. Example 2 (In vitro analysis): MGL enzyme activity assay All ratios were performed on a black 384-well polypropylene PCR microplate (Abgene) in a total volume of 30 microliters. Diluting the substrate 4-methylumbelliferyl sulphate (4MU-B; Sigma) and the purified mutant MGL enzyme (mut-MGLL 11-313 L179S L186S) into 20 mM PIPES buffer 43 201103914 ( pH = 7) with 150 mM NaCl and 0.001% Tween 20. The compound of formula (I) was pre-dispensed (50 nL) into the assay dish using Cartesian Hummingbird (Genomic Solutions, Ann Arbor, MI) prior to the addition of 4MU-B (25 microliters of 1.2 Χ solution, final concentration ΙΟμΜ). The reaction was then started by adding the enzyme (5 microliters of 6X solution to a final concentration of 5 nM). The final compound concentration ranged from 17 to 0.0003 μΜ, with individual excitation and emission of luminescence changes due to 4MU-B splitting. The 335 and 440 nm wavelengths were monitored at 37 ° C for 5 minutes with a bandwidth of 10 nm (Safire 2, Tecan). The IC5G value of the compound of formula (I) is determined by Excel using the concentration-response pattern of the partial activity of the equation, which is a function of the inhibitor concentration. Example 3 (In vitro analysis): MGLThermoFluor® analysis

ThermoFluor (TF) analysis is a 384-well disc binding assay that measures the thermal stability of proteins (Pantolian O, MW, Petrella, EC, Kwasnoski, JD, Lobanov, VS, Myslik, J., Graf, E., Carver , T., Asel, E., Springer, BA, Lane, P., and Salemme, FR, JBiomol Screen 2001, 6, 429-40; Matulis, D., Kranz, JK, Salemme, FR, and Todd, MJ , party zoc/zewzWr less 2005, 44, 5258-66). Experiments were performed using an instrument obtained from Johnson & Johnson Pharmaceutical Research & Development, LLC, and the TF dye used in all experiments was 1,8-ANS (Invitrogen: A-47). The final TF assay conditions used in the MGL study were 0.07 mg/ml purified mutant MGL (mut-MGLL 11-313 L179S L186S), 100 μΜ ANS, 200 mM NaCl, and 0.001% Tween-20 at 50 mM PIPES (pH = 7.0). )in. 44 201103914 Screening compound disks containing a single concentration of 100% DMSO compound solution, for subsequent concentration-reaction studies, the compounds were arranged into pre-distribution plates (Greiner Bio-one: 781280) 'where the compounds were continuous in l〇〇〇/0 DMSO Dilute in 11 consecutive rows, 12 and 24 rows as DMSO reference values and no compounds. For concentration-reaction experiments of single and complex compounds, use Cartesian

Hummingbird Liquid Body Processor (Genomic Solutions, Ann Arbor, MI) 'Automatically pre-dispensed compound aliquots (50 liters) to black 384-well polypropylene PCR microplates (Abgene : TF-0384/k) . The compound was then dispensed and protein and dye solutions were added to achieve a final assay volume of 3 microliters. One microliter of polyoxygenated oil (Fluka, type DC 200: 85411) was overlaid on the analytical solution to avoid evaporation. For all experiments, the barcode analysis disk was automatically loaded on a thermostatically controlled PCR type hot plate and then heated 40 to 90 at a slope of 1 °C/min. Fluorescence is measured by continuous irradiation of UV light (Hamamatsu LC6) supplied by an optical fiber and color filtering via a band pass filter (380-400 nm; > 6 OD cut). The luminescence intensity of all 384-well plates was detected by measuring the light intensity using a CCD camera (Sensys, Roper Scientific) with a filter scale of 500 ± 25 nm, producing simultaneous and independent readings of all 384 wells. A single image with a 20 second exposure time is collected at each temperature, and the sum of the pixel intensities relative to temperature is recorded in a particular region of the analysis disk, and in conjunction with a standard equation, yields: Tw (Pantolian O, M. W^Petrell^ EC, Kwasnoski, JD, Lobanov, V. S,, Myslik, J., Graf, E.,

Carver, T., Asel, E., Springer, B. A., Lane, P., and Salemme, F. R., J price omo/ «Screew 2001, 6, 429-40) o Example 4: 2-AG cumulative analysis 45 201103914

HeLa cells were homogenized with (10) (10) in 1 mL (about 400 million cells) of HEpES buffer (HEPES 20 mM, pH 7.4, NaCl 125 mM, EDTA 1 mM, KC1 5 mM, glucose 20 mM). Homogeneous fluid (0.5 ml) of 20 million cells was incubated with the MGL inhibitor for 15 minutes to block MG]L activity, and then the HEPES buffer solution was incubated with calcium (1 mM) for 20 minutes. The total reaction volume is 5 ml. The reaction was terminated by extraction with 6 ml of an organic solvent (2:1 gas/methanol). A decyloxyrachidonic acid fluorophosphonic acid (MAFP) was used as a positive control group. In the absence of MAFP, the 2-AG value is approximately 3.4 picomoles per sample. In the presence of lOOnMMAFP, the '2-AG value increased to 174 picomoles/sample. The 2-AG accumulated in the organic phase was measured by the HPLC/MS method according to the following equation: %MAFP = (Compound 2-AG/MAFP 2-AG) X 1〇〇 According to the above Examples 2, 3 and 4 The representative compounds of formula (I) were tested and the results are shown in Table 4. Table 4 Compound numbering Example 2 IC5〇(μΜ) Example 3 Kd (μΜ) Example 4% MAFP @ ΙμΜ Example 4 % MAFP @ ΙΟμΜ 1 0.031 0.001 2 0.050 0.130 39.7 87.6 3 0.055 0.091 45.7 82.9 46 201103914 Compound number Example 2 IC5 〇 (μΜ) Example 3 Kd (μΜ) Example 4 % MAFP @ ΙμΜ Example 4 % MAFP @ ΙΟμΜ 4 0.060 0.002 5 0.077 0.008 82.9 6 0.100 0.048 30.6 68.8 7 0.186 0.083 79.5 8 0.220 0.330 72.9 9 0.230 0.040 67.8 10 0.330 0.020 160.1 11 0.350 0.010 160.1 12 0.360 5.000 142.0 13 0.430 0.030 93.5 14 0.440 5.000 53.7 15 0.470 1.850 57.6 16 0.810 4.550 61.1 17 0.880 4.000 25.9 18 0.920 0.050 134.6 19 1.073 0.172 19.9 47.3 47 201103914 Compound numbering example 2 IC5〇(μΜ) Example 3 Kd (μΜ) Example 4 % MAFP @ ΙμΜ Example 4 % MAFP @ ΙΟμΜ 20 1.340 5.560 86.9 21 1.420 6.670 29.2 22 1.670 5.560 50.1 23 1.890 2.500 84.5 24 1.980 5.000 58.8 25 3.810 6.670 65.8 26 5.460 11.110 37.0 27 9.441 28.569 76.3 28 0.090 77 .0 Example 5: Solid, Oral Formulation - Predictive Example A specific embodiment of an oral composition, such as 100 mg of Compound #12 prepared in accordance with Example 1, is formulated with a sufficient amount of dispersed lactose to provide a total Amounts of 580 to 590 mg were filled to fill hard gelatin capsules. While the invention has been described by the foregoing embodiments of the invention, the invention, 48 201103914 [Simple description of the diagram] None [Key component symbol description] None

Claims (1)

201103914 VII. Scope of Application: 1. A method for treating, ameliorating or preventing an affected disease, syndrome, symptom or disorder by inhibiting MGL, comprising administering an effective amount of the desired subject (I Compound Hard® (I) which is selected from the group consisting of: wherein W is N'R1 is H, is, χ_γ_ζ -ch-c(r2)-n(r3)-, re is phenoxy a compound wherein r3 is a 2 2 dimethyl propyl group; -0-C(R2)=N-, and R2 is a cyclohexyl compound; 'X-Y-Z is a compound of -0-C(R2)=N-' and R2 is a 3-phenyl group; Wherein W is a compound wherein N'R1 is H' is vi, XYZ is -CH-C(R2)-N(R3)-, R2 is 4-mercaptophenyl, and R3 is isobutyl 201103914; N'R1 is η,® is, χ_γ_ζ is -CH-C(R2)-N(R3)-' R2 is a phenylfluorenyl group, and R3 is an isobutyl compound; X-Y-Z is a compound wherein -0-C(R2)=N-' and R2 is a 4-fluorophenyl group; A compound in which XYZ -0-C(R2)=N-, and R2 is a 4-decyloxyphenyl group, wherein W is N'R1 is H, and Χ-Υ-Ζ is -CH-C(R2)- N(R3)-'R2 is an isobutyl group, and r3 is an isobutyl compound; ^Vv\ where W is N'R1 is Η, β is, χ_γ_ζ is -CH-C(R)-N(R) - 'R2 is phenoxy fluorenyl' and r3 is an isobutyl 4-merate; 51 201103914 , where W is N'R1 is H, UA ΛΛ ^ Υ Ζ , χ·γ_ζ is -CH-C(RYN(R3)-, V is phenyl, and r3 is 2,2_dimercaptopropyl^ Compound Χ-γ-ζ is where Ν is Ν, ΙΙ1 is Η, ® is, 八_1 ^ sentence -CH-C(R )-N(R )_ ' R is phenoxy fluorenyl, and R3 is cyclohexyl a compound of 曱^; where W is Ν, ί^ is Η Χ-Υ-Ζ is a compound of CH-C(R)-N(R)-, R is a cyclopentyl fluorenyl group, and R3 is a methyl group; Wherein W is a compound wherein N'R1 is Η, Θ is , χ_γ_ζ is -CH-C(R2)_N(R3)-, R2 is a stupid group, and R3 is an isobutyl group; Wherein W is N'R1 is Η, ® is v, Ζ, χ_γ_ζ is -CH-C(R2)-N(R3)- 'R2 is a cyclohexyl fluorenyl group, and R3 is a hydrogen compound; Ζ Χ-Υ- Ζ is a compound wherein W is N'R1 is Η, 52 201103914 -0-c(r2)=n-, and ft 2 is 2-methoxyphenyl fluorenyl; wherein W is N'R1 is h, ¢ And XYZ is a compound of <Η-(:(Ι12)·Ν(Κ3)- ' R2 is a propyl group, and R3 is a methyl group; Θ Wherein W is CH'R1 is 2-methoxy, χ_γ·ζ is ·〇Η-(:(Ι12)-Ν(ί13)-, r2 is phenoxyfluorenyl, and R3 is isobutyl Compound , wherein W is N, R is η, is Χ5ί^^"''ζ, Χ-Υ-Ζ is , R2 is a phenylmethyl group, and R3 is a cyclohexylfluorenyl compound; Wherein W is N'R1 is η, ® is v ', XYZ is -〇_c(r2)=n-' and R2 is a compound of a third butyl group; ΓΎχ, γ where w is N, W is Η,® a compound in which Χ_γ_ζ is 〇-C(R2)=N- ' and R2 is a 3-methoxyphenyl group; z »X-Y-2 wherein w is a compound wherein cm1 is 2-methoxy, <53 201103914 is -CH-C(R2)-N(R3)-, R2 is phenylfluorenyl, and R3 is isobutyl; X wherein W is CH曱R1 is 2-decyloxy, © is v 'XYZ is -CH-C(R2)_N(R3)· 'R2 is phenoxymethyl, and R3 is 2,2-dimercaptopropyl Base compound; X wherein...is 匸(1) 尺1 is 2_曱oxy, ν, Ζ, χ_γ_ζ is -CH-C(R2)-N(R3)- ' R2 is phenyl fluorenyl, and r3 is cyclohexyl Base compound; X wherein W is CH'R1 is 2_methoxy, ® is W, χ_γ_ζ is -CH-C(R2)-N(R3)- 'R2 is phenyl, and R3 is 2 2 -didecylpropyl Compound; X wherein W is CH, R1 is 4_fluoro, ® is ν, τ m is -CH-C(R2)-N(R3)-, R2 is phenyl, and R3 is 2,2-dimercaptopropyl a compound; wherein W is N11 is H, © is X z , X-Y-Z is 54 201103914 -CH_C(R2)-N(R3)-, R2 is a third butyl group, and R3 is a compound of 2,2-dimethylpropyl; Wherein W is N'R1 is H, ¢) is, v", XYZ is -NH-C(R2)-C(R3)-, R2 is 4-mercaptophenyl, and R3 is decyl- a compound of a carbonyl group; a compound wherein W is N'R1, χ_γ_ζ is -CH-C(R2)-N(R3), R2 is η_propyl, and R3 is a cyclohexylfluorenyl group; 2. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of: 2, XYZ is where W is N, R1 is η, ® is 1-CH-C(R2)-N(R3)-, R2 is phenoxyfluorenyl, and R3 is 2,2-dimercaptopropyl Compound XYZ ^ wherein W is N'R1 is Η, ® is ~ζ/, -〇-C(R2)=N- ' and R2 is a cyclohexyl compound; 55 201103914 -0-C(R2)=N- 'and R2 is a compound of 3-1 phenyl; , XYZ is where W is Ν, Ρ^ is Η-CH-C(R2)-N(R3)-, and R2 is Compound 'X-Y-Z is 4-mercaptophenylene' and R3 is isobutyl wherein W is Ν and ί^ is H, , X-Y-Z is a compound of -CH-C(R2)-N(R3)-, R2 is a phenylfluorenyl group, and R3 is an isobutyl group; Wherein W is a compound wherein N'R1 is H, © -0-C(R2)=N-' and R2 is a 4-fluorophenyl group; Z is X, and X-Y-Z is X is a compound wherein W is N, Ri is Η is X-Y-Z 4 _0-C(R2)=N-, and R2 is 4-methoxyphenyl; wherein W is N'R1 is Η X Ζ , X-Y-Z is 201103914 _ch-c(r2)-n(r3)-, R2 is isobutyl, and R3 is an isobutyl compound; Wherein W is a compound wherein N'R1 is η, Θ is v, χ_γ_ζ is -CH-C(R2)-N(R3)-, R2 is phenoxyfluorenyl, and R3 is an isobutyl group; Wherein W is N, Ri is Η, _乂 is 八-~巧-CH-CXRYNd^)- ′ Μ is phenyl, and r3 is 2,2_dioxadipropene compound; Χ-Υ-Ζ is And a compound wherein W is N, R1 is η, ^ is V, t -CH-C(R2)-N(R3)-, R2 is phenoxyfluorenyl, and r3 is cyclohexylmethyl; Wherein W is n'rUh, ® is v, χγζ is -CH-C(R2)_ quasi V R2 is a cyclopentyl f group, and r3 is a compound of the f group; wherein W is N'R1 is H, 0 ) -CH 2) Na V R2 is a stupid group, and r3 is an iso-t- group compound ^ XYZ is 57 201103914, Θ a compound wherein W is lShR1 is Η, U is, χ_γ_ζ is -CH-C(R2)- N(R3)- 'R2 is a cyclohexylfluorenyl group, and R3 is hydrogen; and Ri is Η, Θ where W is Ν, κ·H is, 1 is 1 - *, and Χ-Υ-Ζ is -0- C(R2)=N- 'and R2 is a compound of 2-nonyloxyphenylmethyl; wherein W is IsnR1 is η Χ-Υ-Ζ is -CH-C(R)-N(R3)-, R2 is a propyl group, and R3 is a fluorenyl group; , wherein W is a compound wherein CH'R1 is a 2-decyloxy group, and m is a compound wherein 'R2 is a phenoxyfluorenyl group, and R3 is an isobutyl group; Wherein W is a compound wherein N'R1 is h, is z, XYZ is _CH-C(R)-N(R)- 'R2 is phenylfluorenyl, and R3 is cyclohexylmethyl; Structures, non-image isomers, and pharmaceutically acceptable salts. 3. For the method of the Ministry of Education, the formula (1) is selected from the following group: 58 201103914 , where W is N'R1 is Η, Ζ, Χ-Υ-Ζ is -CH-C(R2)-N(R3)- 'R2 is phenoxy fluorenyl, and R3 is 2,2- a compound of methyl propyl; W wherein W is a compound wherein N'R1 is 1^, ^_/ is -0-C(R2)=N-, and R2 is a 3-fluorophenyl group; Χ-Υ-Ζ is Ζ , Χ-Υ-Ζ is a compound wherein W is N, I^ is Η-CH-C(R2)-N(R3)-'R2 is 4-fluorenylphenyl, and R3 is isobutyl; , wherein n is n, r is h, ^^ is t, m horse -CH-C(R2)-N(R3). 'R2 is phenyl fluorenyl' and the ruler 3 is an isobutyl compound; Where W is N'R1 is Η, Θ is X Ζ -0-C(R2)=N- ' and R2 is a 4-fluorophenyl compound; and X-Y-Z is 59 X 201103914 , wherein W is a compound wherein N'R1 is H, U is ',,, χ_γ_ζ is -0-C(R2)=N-, and R2 is a 4-methoxyphenyl group; Wherein W is N, W is Η, Θ is t m 'face -CH-C(R2)-N(R3)-, R2 is phenoxyfluorenyl, and R3 is an isobutyl compound; Wherein W is N, R1 is Η, ® is, χ_γ_Ζ is -CH-C(R2)-N(R3)-, R2 is phenyl, and R3 is a compound of 2,2-dimercaptopropyl; Wherein w is η11 is η, 〇 is ^, -CH-C(R2)-N(R3)- 'R2 is a phenoxyfluorenyl group, and R3 is a cyclohexylfluorenyl compound; z, XYZ is W Is a compound wherein N'R1 is Η, ® is _-CH-C(R2)-N(R3)-, R2 is phenyl, and R3 is isobutyl; wherein W is N'R1 is Η, Θ is, Χ_γ_ζ is 201103914 -CH, C(R2)-N(R3)-, R2 is a stupyl fluorenyl group, and the ruler 3 is a cyclohexyl fluorenyl compound; wherein W is N'R1 is H and ® is -CH- C(R2)-N(R3)' 1^2 is a compound of n-propyl and R3 is cyclohexylfluorenyl; 4. and its mirror image isomer, non-image isomer and pharmaceutically acceptable salt. The method of claim 1, wherein the compound of the formula (1) is selected from the group consisting of: X-Y-Z is a compound wherein -0-C(R2)=N-' and R2 is a cyclohexyl group; -0-C(R2)=N- ' and R2 is a 3-phenylphenyl compound; X-Y-Z is wherein W is N,! ^为Η , Χ-Υ-Ζ is a compound of -CH-C(R2)-N(R3)-'R2 is a phenylfluorenyl group, and R3 is an isobutyl group; 201103914 Wherein W is a compound wherein N'R1 is η, ® is ^^z/Y, χ_γ_ζ is -0-C(R2)=N-, and R2 is a 4-methoxyphenyl group; wherein W is N'R1 H,® is, χ_γ_ζ is -CH-C(R2)-N(R3)- 'R2 is a phenyl group, and R3 is a compound of 2,2-dimercaptopropyl; , X-Y-Z is a compound wherein W is N, l·^ is H, -CH-C(R2)-N(R3)-'R2 is phenoxyfluorenyl, and R3 is cyclohexylfluorenyl; Wherein W is N, RI is H, ® is V, ζ, χ_γ_ζ is -CH-C(R2)-N(R3)-' R2 is a cyclopentylmethyl group, and R3 is a methyl compound; Wherein w is n, rUh, © is v m -CH-C(R2) · although 3) _, R 2 is a stupid group, and ^ is an isobutyl compound; X-Y-Z % 62 201103914 -CH-C(R2)-N(R3)-, R2 is a phenylmethyl group, and R3 is a cyclohexylmethyl group; Where W is N,! ^ is a compound of H, -0-C(R2)=N-' and R2 is a 3-methoxyphenyl group; X-Y-Z is Wherein W is CH, R1 is 2-methoxy, hydrazine is, Χ_γ_Ζ is -CH-C(R2)-N(R3)-'R2 is a phenylmethyl group, and R3 is a cyclohexylfluorenyl compound; W is N'R1 is Η, ® is Λ; ΧΖΧΖ/Υ, χ_γζ is -NH-C(R )_C(R )·, R2 is 4曱-phenylphenyl and r3 is decyloxy_methyl-carbonyl Compound; Η-propyl and R3 are a cyclohexylfluorenyl group wherein W is N, R1 is -CH-C(R2)-N(R3), R2 is a substance; (iv) a quinone structure and a therapeutic accepting salt. The method of paragraph 1: wherein the compound of the formula (1) is selected from the group consisting of: 63 5. 201103914 Wherein W is a compound wherein 1R1 is H, (J) is -〇-C(R2)=N_, and r2 is a cyclohexyl group: wherein N'R1 is H, and 0) is 〇C(R)-N-, and R2 is a compound of 3-fluorophenyl; XYZ ^ X-Y-Z 4 Wherein w is n, r^h, @ is -〇-C(R2)=N, and R2 is a compound of 4-fluorophenyl; XYZ is XYZ 6. Heart = drug acceptable salt, treatment, improvement Or prevent the affected ^:/, (d) by suppressing the group consisting of a group consisting of pain, * a disease, symptom group, symptom or disorder. Pain, sputum riding symptoms and neuropathic pain The method of item 1, _ by suppressing the genus of the genus, the transfer, money or loss of t 8. • XZ, such as the application for a patent, the method of t, which should treat, improve or prevent inflammatory pain by inhibiting 201103914. (4), syndrome, symptom or disorder 9. If the patent application scope ljf treatment, improvement Or prevent visceral pain by inhibiting MGjL. The disease, syndrome, symptom or disorder that is ringing is 10. If you apply for a patent, you can treat, improve, or prevent greed, or inhibit MGL. ^The disease, syndrome, money or disorder is U. If the method of applying for a patent scope, the method of basing or prevention is affected - the method 'in which the disease, syndrome, symptoms are suppressed by nerves Or the disorder is 13. ^ Please use the method of β, which includes 14. The group of sexual pain and neuropathic pain, the medical treatment of the group V:: compound in the preparation of pharmacy _^^ by 抑Face to the middle, used for tune. Lw's money, group, symptom or smuggling application of the patent scope of the third item of the compound ♦ the use of the drug 'the agent or pharmaceutical composition in the place;: or the medical group for the treatment of inflammatory pain or neuropathic pain. And the caller, for 65 15. 201103914 IV. Designation of the representative figure: (1) The representative representative of the case is: No (2) The symbol of the symbol of the representative figure is simple: No. 5. If there is a chemical formula in this case, please Reveal the chemical formula that best shows the characteristics of the invention: 3