HK1170413A

HK1170413A - Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors

Info

Publication number: HK1170413A
Application number: HK12111062.6A
Authority: HK
Inventors: Christopher M. Flores; Marina I. Nelen; Erica L. Nulton; Stephen Prouty; Matthew Todd; Sui-Po Zhang
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2009-04-22
Filing date: 2010-04-22
Publication date: 2013-03-01

Description

Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors

Cross reference to related patent applications

This patent application claims the benefit of U.S. provisional application No.61/171,661 filed on 4/22/2009, which is incorporated herein by reference in its entirety.

This patent application is related to U.S. provisional patent application serial No.61/171,660, entitled Heteroaromatic and aromatic Piperazinyl Azetidinyl Amides useful as Monoacylglycerol Lipase Inhibitors, filed 22/4/2009.

Statement regarding federally sponsored research or development

The development project of the present invention described below was not federally sponsored.

Technical Field

The present invention relates to the use of a compound of formula (I) as defined herein for the treatment, alleviation and/or prevention of MGL disease in a subject, including a mammal and/or a human being, suffering from a disease, syndrome or condition affected by MGL.

Background

Cannabis sativa (Cannabis sativa) has been used for many years to treat pain. Delta⁹Tetrahydrocannabinol is the major active ingredient derived from cannabis and is a cannabinoid receptor agonist (Pertwee, Brit J Pharmacol, 2008, 153, 199-) 215(Pertwee, British journal of pharmacology, 2008, Vol 153, page 199-) 215). Two cannabinoid G protein-coupled receptors, the cannabinoid type 1 receptor (CB)₁Matsuda et al, Nature, 1990, 346, 561-4(Matsuda et al, Nature, 1990, 346, p. 561-564)) and cannabinoid type 2 receptors (CB)₂Munro et al, Nature, 1993, 365, 61-5(Munro et al, Nature 1993, vol. 365, p. 61-65)). CB (CB)₁Centrally in brain regions such as the hypothalamus and nucleus accumbens, and peripherally in the liver, gastrointestinal tract, pancreas, adipose tissue and skeletal muscle (Di Marzo et al, Curr Opin Lipidol, 2007, 18, 129-. CB (CB)₂Are expressed predominantly in immune cells, such as monocytes (Pacher et al, Amer J Physiol, 2008, 294, H1133-H1134(Pacher et al, journal of U.S. physiology, 2008, 294, pp.H 1133-H1134)), and in some cases in immune cellsAlso expressed in the brain (Benito et al, Brit J Pharmacol, 2008, 153, 277-. A large body of pharmacological, anatomical and electrophysiological data using synthetic agonists suggests that CB is₁/CB₂The involved enhanced cannabinoid signaling promotes analgesia in acute nociceptive response studies and inhibits hyperalgesia and/or allodynia in models of chronic neuropathic and inflammatory pain (Cravatt et al, J Neurobiol, 2004, 61, 149-60(Cravatt et al, J. Neurobiology, 2004, Vol. 61, p. 149-160); Guindon et al, Brit J Pharmacol, 2008, 153, 319-334(Guindon et al, J. Pharmacol, 2008, Vol. 153, p. 319-334)).

The efficacy of synthetic cannabinoid receptor agonists is well documented. In addition, studies with cannabinoid receptor agonists and knockout mice have shown that the endocannabinoid system is an important regulator of nociceptive responses. Arachidonic Acid Ethanolamine (AEA) (Dekane et al, Science, 1992, 258, 1946-9 (Dekane et al, Science, 1992, vol. 258, p. 1946-1949)) and 2-arachidonic acid glycerol (2-AG) (Mechoulam et al, Biochem Pharmacol, 1995, 50, 83-90(Mechoulam et al, Biopharmacology, 1995, vol. 50, p. 83-90); Sugiura et al, Biochem Biophys Res Commun, 1995, 215, 89-97(Sugiura et al, Communication of biochemistry and biophysical research, 1995, vol. 215, p. 89-97) are the two major endocannabinoids. AEA is hydrolyzed by Fatty Acid Amide Hydrolase (FAAH), 2-AG by monoacylglycerol lipase (MGL) (Piomelli, Nat RevNeurosci, 2003, 4, 873-Comments), 2003, volume 4, pages 873 and 884). Deletion of the FAAH gene increased endogenous AEA levels and played a role of CB in an acute inflammatory pain model₁Dependent analgesia (Lichtman et al, Pain, 2004, volume 109, page 319-327)), which suggests that the endocannabinoid system itself has a function of inhibiting nociceptive responses (Cravatt et al, J Neurobiol, 2004, volume 61, 149-60(Cravatt et al, journal of neurobiology, 2004, volume 61, page 149-160)). Unlike the constitutive increase in endogenous cannabinoid levels that occurs when FAAH knockout mice are used, the use of specific FAAH inhibitors only transiently increases AEA levels and produces in vivo antinociceptive responses (Kathuria et al, Nat Med, 2003, 9, 76-81(Kathuria et al, nature-medicine, 2003, volume 9, pages 76-81)). This is further confirmed by the theory of endocannabinoid-mediated antinociception that regulates menstruation: AEA (Walker et al, Proc Natl Acad Sci USA, 1999, 96, 12198-₁Hyperalgesia is induced following antisense RNA (Dogrul et al, Pain, 2002, 100, 203-9(Dogrul et al, Pain 2002, Vol. 100, p. 203-209)).

For 2-AG, intravenous delivery of the substance was demonstrated to produce analgesia in tail flick experiments (Mechoulam et al, Biochem Pharmacol, 1995, 50, 83-90(Mechoulam et al, Biochemical Pharmacol, 1995, volume 50, pages 83-90)) and in hotplate experiments (Lichtman et al, J Pharmacol Exp Ther, 2002, 302, 73-9(Lichtman et al, J Pharmacol J. Pharmacol. therapeutics and Experimental, 2002, volume 302, pages 73-79)). In contrast, 2-AG alone proved not to have analgesic effect in the hot plate experiment, but when co-administered with other 2-monoacylglycerols (i.e., 2-linoleate and 2-palmitate glyceride), significant analgesic effect was achieved, a phenomenon known as "synergistic effect" (Ben-Shabat et al, Eur J Pharmacol, 1998, 353, 23-31(Ben-Shabat et al, J. Eur. Pharmacol., 1998, 353, pp. 23-31)). These "synergistic" 2-monoacylglycerols are endogenous lipids that are released in concert with 2-AG, enhancing endocannabinoid signaling, in part by inhibiting 2-AG breakdown, most likely by competitive binding to the active site on MGL. This suggests that synthetic MGL inhibitors will have similar effects. The relatively weak synthetic MGL inhibitor URB602 did show an antinociceptive effect in an acute inflammatory murine model (Comelli et al, Brit J Pharmacol, 2007, 152, 787-.

Although the use of synthetic cannabinoid agonists has definitively demonstrated that enhanced cannabinoid signaling produces analgesic and anti-inflammatory effects, it is difficult to decouple the beneficial effects of these compounds from the deleterious side effects. An alternative approach is to enhance the signaling of the endocannabinoid system by increasing the level of 2-AG, which is the most abundant endocannabinoid in the Central Nervous System (CNS) and gastrointestinal tract, by inhibiting MGL. MGL inhibitors are therefore useful in the treatment of pain, inflammation and disorders of the central nervous system (Di Marzo et al, Curr Pharm Des, 2000, 6, 1361-80(Di Marzo et al, Current drug design, 2000, vol. 6, p. 1361-1380), Jhaveri et al, Brit J Pharmacol, 2007, 152, 624 (Jhaveri et al, J. British Pharmacol, 2007, vol. 152, p. 624-632), McCarberg Bill et al, Amer J Ther, 2007, 14, 475-83(McCarberg Bill et al, J. USA. therapeutics, 2007, vol. 14, p. 483), as well as glaucoma and disease states resulting from elevated intraocular pressure (Njie, Ya Fatou; He, Fang; Qiao, Xhong, Huang, Hu-475, He, J. 2008, 106, He, J. 2008, J. Col, 106, He, J. 2008. 12, J. Col, J. 35, J. Col, J. 11, J. Col, J. 35, J. Col, J. 11, J. Col, J. E. Xhuanhong, Song, zhoha-Hui, research in experimental ophthalmology, 2008, vol 87, 2 nd page 106-.

Disclosure of Invention

The present invention relates to a method of treating, ameliorating or preventing a disease, syndrome, condition or disorder (such as pain, diseases leading to such pain, inflammation and central nervous system disorders) affected by inhibition of MGL, said method comprising, consisting of and/or consisting essentially of the steps of: administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I)

It is selected from:

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenoxymethyl, and R³A compound that is 2, 2-dimethylpropyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) N-, and R²A compound that is cyclohexyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) N-, and R²A compound which is a 3-fluorophenyl group;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is 4-methylphenyl, and R³A compound that is isobutyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenylmethyl, and R³A compound that is isobutyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) N-, and R²A compound that is 4-fluorophenyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) N-, and R²A compound that is 4-methoxyphenyl;

whereinW is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is isobutyl, and R³A compound that is isobutyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenoxymethyl, and R³A compound that is isobutyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenyl, and R³A compound that is 2, 2-dimethylpropyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenoxymethyl, and R³A compound that is a cyclohexylmethyl group;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is cyclopentylmethyl, and R³A compound that is methyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenyl, and R³A compound that is isobutyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is cyclohexylmethyl, and R³A compound which is hydrogen;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) N-, and R²A compound that is 2-methoxyphenylmethyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is n-propyl, and R³A compound that is methyl;

wherein W is CH, R¹Is a compound of 2-methoxyl group,is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenoxymethyl, and R³A compound that is isobutyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenylmethyl, and R³A compound that is a cyclohexylmethyl group;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) N-, and R²A compound that is a tert-butyl group;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) N-, and R²A compound that is 3-methoxyphenyl;

wherein W is CH, R¹Is a compound of 2-methoxyl group,is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenylmethyl, and R³A compound that is isobutyl;

wherein W is CH, R¹Is a compound of 2-methoxyl group,is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenoxymethyl, and R³A compound that is 2, 2-dimethylpropyl;

wherein W is CH, R¹Is a compound of 2-methoxyl group,is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenylmethyl, and R³A compound that is a cyclohexylmethyl group;

wherein W is CH, R¹Is a compound of 2-methoxyl group,is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenyl, and R³A compound that is 2, 2-dimethylpropyl;

wherein W isCH，R¹Is a compound of 4-fluoro group,is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenyl, and R³A compound that is 2, 2-dimethylpropyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is tert-butyl, and R³A compound that is 2, 2-dimethylpropyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-NH-C (R)²)-C(R³)-，R²Is 4-methylphenyl, and R³A compound that is methoxy-methyl-carbonyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is n-propyl, and R³A compound that is a cyclohexylmethyl group;

and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof.

The invention also relates to the use of a compound of formula (I) as defined herein for the preparation of a medicament or pharmaceutical composition for the treatment, alleviation or prevention of a disease, syndrome, condition or disorder affected by the inhibition of MGL in a subject in need thereof.

Detailed Description

In general, the terminal portion of a given side chain is described first, followed by a description of the adjacent functional group toward the point of attachment, according to standard nomenclature used throughout this disclosure. Thus, for example, "C₁-C₆An alkylcarbonyl "substituent refers to a group represented by the formula:

unless otherwise specified, the definition of any substituent or variable at a particular position in a molecule is intended to be independent of its definitions elsewhere in that molecule. It will be appreciated that substituents and substitution patterns on the compounds of formula (I) can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art and those methods set forth herein.

The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the target of treatment, observation or experiment.

As used herein, the term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in therapeutically effective amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

As used herein, unless otherwise specified, the terms "treat", "treating", "treatment", "alleviation" and the like shall include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the invention to prevent the onset of, alleviate a symptom of, or complication, or to eliminate the disease, condition, or disorder.

As used herein, unless otherwise specified, the terms "prophylaxis" and "prevention" shall include (a) reducing the frequency of one or more symptoms; (b) reducing the severity of one or more symptoms; (c) delay or avoid the development of additional symptoms; and/or (d) delaying or avoiding the development of the disorder or condition.

One skilled in the art will recognize that, in the context of a method of prevention wherein the present invention is directed to a subject in need thereof (i.e., a subject in need of prevention), shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Furthermore, a subject in need thereof can also be a subject (preferably a mammal, more preferably a human) who does not exhibit any symptoms of the disorder, disease or condition to be prevented, but who is deemed by a physician, clinician or other medical professional to be at risk of developing the disorder, disease or condition. For example, the subject may be considered at risk of developing a disorder, disease, or condition (and thus in need of prophylactic or preventative treatment) due to the subject's medical history, including but not limited to family history, predisposition to the disease, co-existing disorder or condition (with concurrent morbidity), genetic testing, and the like.

The term "MGL inhibitor" is intended to encompass compounds that interact with MGL to reduce or eliminate MGL catalytic activity, thereby increasing MGL substrate concentration. The term "MGL-modulated" is used to indicate conditions affected by MGL enzyme modulation, including conditions affected by MGL enzyme inhibition, such as pain and diseases causing such pain, as well as inflammation and central nervous system disorders.

As used herein, unless otherwise specified, the term "affect" or "affected" (when referring to a disease, syndrome, condition, or disorder affected by inhibition of MGL) shall mean that one or more symptoms or clinical manifestations of the disease, syndrome, condition, or disorder are reduced in frequency and/or severity; and/or means that the development of one or more symptoms or clinical manifestations of the disease, syndrome, condition or disorder is prevented or that the development of the disease, syndrome, condition or disorder is prevented.

The compounds of formula (I) are useful in methods for treating, ameliorating and/or preventing a disease, syndrome, condition or disorder affected by inhibition of MGL. Such methods comprise, consist of, and/or consist essentially of the steps of: administering a therapeutically effective amount of a compound of formula (I) or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof to a subject, including animals, mammals and humans in need of such treatment, alleviation and/or prevention. In particular, the compounds of formula (I) are useful for treating, alleviating and/or preventing pain; the disease, syndrome, condition or disorder that causes such pain; inflammation and/or central nervous system disorders. More specifically, the compounds of formula (I) are useful for treating, alleviating and/or preventing inflammatory pain, inflammatory hypersensitivity disorders and/or neuropathic pain comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined herein.

Examples of inflammatory pain include pain due to a disease, condition, syndrome, disorder or pain state, including: inflammatory bowel disease, visceral pain, migraine, post-operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, dental pain, fever, burn, sunburn, snake bite, venomous snake bite, spider bite, insect bite, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/allergy, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, pain syndrome after mastectomy, dysmenorrhea, endometriosis, pain due to physical trauma, headache, frontal sinus headache, tension headache, or arachnoiditis.

One type of inflammatory pain is inflammatory hyperalgesia/hypersensitivity. Examples of inflammatory hyperalgesia include a disease, syndrome, condition, disorder, or pain state including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, post operative pain, headache, toothache, burn, sunburn, insect bites, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel diseases including crohn's disease, ulcerative colitis, urinary incontinence, prostatic hyperplasia, cough, asthma, rhinitis, nasal hypersensitivity, scabies, contact dermatitis and/or skin allergy, and chronic obstructive pulmonary disease.

In one embodiment, the present invention relates to a method for treating, alleviating and/or preventing inflammatory visceral hyperalgesia in which increased visceral hyperalgesia is present, the method comprising, consisting of and/or consisting essentially of the steps of: administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of formula (I). In another embodiment, the present invention relates to a method for treating inflammatory somatic hyperalgesia in which hypersensitivity to thermal, mechanical and/or chemical stimuli is present, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to a method for treating, alleviating and/or preventing neuropathic pain. Examples of neuropathic pain include pain due to a disease, syndrome, disorder or pain state including cancer, neurological disorders, spinal and peripheral nerve surgery, brain tumors, Traumatic Brain Injury (TBI), spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathy associated with spinal cord injury, stroke, Amyotrophic Lateral Sclerosis (ALS), parkinson's disease, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, residual limb pain, phantom limb pain, fracture, oral neuropathic pain, charcot's pain, complex regional pain syndrome type I and type II (psi cr/II), Radiculopathy, guillain-barre syndrome, paresthesia, causalgia syndrome, optic neuritis, postfebrile neuritis, wandering neuritis, segmental neuritis, Gong Bos neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate ganglionic neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, rhinociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, erythromelalgia, Studis neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or winged canal neuralgia.

One type of neuropathic pain is neuropathic allodynia, which is characterized by the presence of a neuropathic-related allodynic state (in which there is a hypersensitivity reaction to cold stimuli). Examples of neuropathic allodynia include allodynia due to a disease, condition, syndrome, disorder or pain state including neuropathic pain (neuralgia), pain resulting from spinal and peripheral nerve surgery or trauma, Traumatic Brain Injury (TBI), trigeminal neuralgia, post-herpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome types I and II (CRPS I/II), or radiculopathy.

In another embodiment, the present invention relates to a method for treating, alleviating and/or preventing neuropathic abnormal cold pain in which hypersensitivity to cold stimulus is present, the method comprising, consisting of and/or consisting essentially of the steps of: administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) as defined herein or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a method of treating, ameliorating and/or preventing a central nervous system disorder. Examples of central nervous system disorders include anxiety disorders such as social anxiety disorder, post-traumatic stress disorder, phobias, social phobia, phobias of particular subjects, painful conditions, obsessive compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder, and depression disorders such as major depressive disorder, bipolar disorder, seasonal affective disorder, post-partum depressive disorder, manic depressive disorder, and bipolar disorder.

The present invention relates to a method of treating, ameliorating and/or preventing a disorder, syndrome, condition or disease affected by inhibition of MGL, said method comprising, consisting or consisting essentially of the steps of: administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I)

It is selected from:

[1- (2, 2-dimethyl-propyl) -2-phenoxymethyl-1H-indol-5-yl ] - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #1)

(2-cyclohexyl-benzoAzol-6-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl]-a ketone; (Compound #2)

[2- (3-fluorophenyl) -benzoAzol-7-yl]- [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl]-a ketone; (Compound #3)

(1-isobutyl-2-p-tolyl-1H-indol-5-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #4)

[ 1-isobutyl-2- (4-methylbenzyl) -1H-indol-5-yl ] - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #5)

[2- (4-fluorophenyl) -benzoAzol-7-yl]- [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl]-a ketone; (Compound #6)

[2- (4-methoxy-phenyl) -benzoAzol-7-yl]- [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl]-a ketone; (Compound #7)

(1, 2-diisobutyl-1H-indol-5-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #8)

(1-isobutyl-2-phenoxymethyl-1H-indol-5-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #9)

[1- (2, 2-dimethyl-propyl) -2-phenyl-1H-indol-5-yl ] - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #10)

(1-cyclohexylmethyl-2-phenoxymethyl-1H-indol-5-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #11)

(2-cyclopentylmethyl-1-methyl-1H-indol-5-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #12)

(1-isobutyl-2-phenyl-1H-indol-5-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #13)

(2-cyclohexylmethyl-1H-indol-5-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #14)

[2- (2-methoxy-benzyl) -benzoAzol-5-yl]- [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl]-a ketone; (Compound #15)

(2-ethyl-1-methyl-1H-indol-5-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #16)

(1-isobutyl-2-phenoxymethyl-1H-indol-5-yl) - {3- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -azetidin-1-yl } -methanone; (Compound #17)

(2-benzyl-1-cyclohexylmethyl-1H-indol-5-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #18)

(2-tert-butyl-benzoAzol-6-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl]-a ketone; (Compound #19)

[2- (3-methoxy-phenyl) -benzoAzol-5-yl]- [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl]-a ketone; (Compound #20)

(2-benzyl-1-isobutyl-1H-indol-5-yl) - {3- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -azetidin-1-yl } -methanone; (Compound #21)

[1- (2, 2-dimethyl-propyl) -2-phenoxymethyl-1H-indol-5-yl ] - {3- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -azetidin-1-yl } -methanone; (Compound #22)

(2-benzyl-1-cyclohexylmethyl-1H-indol-5-yl) - {3- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -azetidin-1-yl } -methanone; (Compound #23)

[1- (2, 2-dimethyl-propyl) -2-phenyl-1H-indol-5-yl ] - {3- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -azetidin-1-yl } -methanone; (Compound #24)

[1- (2, 2-dimethyl-propyl) -2-phenyl-1H-indol-5-yl ] - {3- [4- (4-fluoro-phenyl) -piperazin-1-yl ] -azetidin-1-yl } -methanone; (Compound #25)

[ 2-tert-butyl-1- (2, 2-dimethyl-propyl) -1H-indol-5-yl ] - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #26)

2-methoxy-1- {5- [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidine-1-carbonyl ] -2-p-tolyl-1H-indol-3-yl } -ethanone; (Compound #27)

(1-cyclohexylmethyl-2-propyl-1H-indol-5-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl ] -methanone; (Compound #28)

And enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof. Preferably, the disease, syndrome, condition or disorder affected by inhibition of MGL is selected from pain, inflammatory allergic conditions and neuropathic pain as defined herein.

In one embodiment, the invention relates to treating, ameliorating or preventing a disease, syndrome, condition or disorder affected by inhibition of MGL comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (Ia)

Or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, wherein R¹W and-X-Y-Z-are as defined herein. In another embodiment, the invention relates to treating, ameliorating or preventing a disease, syndrome, condition or disorder affected by inhibition of MGL comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (Ib)

Or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, wherein R¹W and-X-Y-Z-are as defined herein. In another embodiment, the invention relates to treating, ameliorating or preventing a disease, syndrome, condition or disorder affected by inhibition of MGL comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (Ic)

Or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, wherein R¹W and-X-Y-Z-are as defined herein.

In another embodiment, the invention relates to a method of treating, ameliorating or preventing a disease, syndrome, condition or disorder affected by inhibition of MGL comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:

(2-cyclohexyl group)-benzo (b)Azol-6-yl) - [3- (4-pyridin-2-yl-piperazin-1-yl) -azetidin-1-yl]-a ketone; (Compound #2)

In another embodiment, the present invention relates to the use of a compound selected from the group consisting of:

In another embodiment, the present invention relates to the use of any single compound or collection of compounds selected from the compounds listed in tables 1 to 3 below, or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof; treating, ameliorating or preventing a disease, syndrome, condition or disorder affected by inhibition of MGL in a subject in need thereof. The compounds of formula (I) of the present invention are listed in tables 1 to 3 below.

Table 1: a compound of formula (Ia)

Table 2: a compound of formula (Ib)

Table 3: a compound of formula (Ic)

In one embodiment, the invention relates to the treatment, alleviation or prevention of a disease, syndrome, condition or disorder that is affected by inhibition of MGL, wherein the disease, syndrome, condition or disorder that is affected by inhibition of MGL is selected from inflammatory pain and neuropathic pain; comprising administering to a subject (including mammals and/or humans) in need thereof a therapeutically effective amount of a compound of formula (I)

Selected from compounds as defined herein; and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof.

In one embodiment, the invention relates to the treatment, alleviation or prevention of inflammatory pain; comprising administering to a subject (including mammals and/or humans) in need thereof a therapeutically effective amount of a compound of formula (I)

Selected from compounds as defined herein; and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof. In another embodiment of the invention, the inflammatory pain is selected from visceral pain and inflammatory hyperalgesia, preferably visceral pain.

In one embodiment, the invention relates to the treatment, alleviation or prevention of inflammatory hyperalgesia, comprising administering to a subject (including mammals and/or humans) in need thereof a therapeutically effective amount of a compound of formula (I)

Selected from compounds as defined herein; and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof. In another embodiment of the invention, the inflammatory hyperalgesia is ulcerative colitis.

In one embodiment, the present invention relates to the treatment, alleviation or prevention of neuropathic pain comprising administering to a subject (including mammals and/or humans) in need thereof a therapeutically effective amount of a compound of formula (I)

Selected from compounds as defined herein; and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof. In another embodiment of the invention, the neuropathic pain is neuropathic allodynia.

For use in medicine, a salt of a compound of formula (I) refers to a non-toxic "pharmaceutically acceptable salt". However, other salts may be useful in the preparation of compounds of formula (I) or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts which may be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric, sulphuric, fumaric, maleic, succinic, acetic, benzoic, citric, tartaric, carbonic or phosphoric acid. Furthermore, if the compound of formula (I) carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts with suitable organic ligands, such as quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, dexcamphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, dedecyl propionate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, para- α -hydroxyacetaminophenylarsonate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthalenesulfonate, nitrate, potassium, sodium, potassium, Ammonium salts of N-methylglucamine, oleates, pamoates, palmitates, pantothenate, phosphates/diphosphates, polygalacturonates, salicylates, stearates, sulfates, subacetates, succinates, tannates, tartrates, theachlorates, tosylates, triethyliodides and valerates.

Representative acids and bases that can be used to prepare pharmaceutically acceptable salts include the following: such as acetic acid, 2-dichloroacetic acid, acetylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) -camphoric acid, camphorsulfonic acid, (+) - (1S) -camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, alpha-ketoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+) -L-lactic acid, (+ -) -DL-lactic acid, citric acid, tartaric acid, citric acid, cyclamic acid, lauric acid, Lactobionic acid, maleic acid, (-) -L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid; and the following bases: including ammonia, L-arginine, benzphetamine, benzathine, calcium hydroxide, choline, dimethylethanolamine, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) morpholine, piperazine, potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

Embodiments of the invention include prodrugs of the compounds of formula (I). Typically, such prodrugs will be functionalized derivatives of the compounds which can be readily converted in vivo to the desired compounds. Thus, in the methods of the treatment or prevention embodiments of the present invention, the term "administering" encompasses treating or preventing the various diseases, conditions, syndromes and disorders described with specifically described compounds or compounds not specifically described, but which convert in vivo to the specified compounds upon administration to a patient. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of produgs", ed.h. bundgaard, Elsevier, 1985 (prodrug Design, editions h.bundgaard, Elsevier, 1985).

Where compounds according to embodiments of the invention have at least one chiral center, they may accordingly exist as enantiomers. If the compounds have two or more chiral centers, they may also exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, certain crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, certain compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvate compounds are also intended to be encompassed within the scope of the present invention. The skilled person will understand that the term compound as used herein is intended to include solvated compounds of formula (I).

If the processes used to prepare compounds according to certain embodiments of the present invention produce a mixture of stereoisomers, these isomers may be separated by conventional techniques, such as preparative chromatography. The compounds may be prepared in racemic form, or the individual enantiomers may be prepared by enantiospecific synthesis or by resolution. For example, the compounds may be resolved into their component enantiomers by standard techniques, such as formation of diastereomeric pairs by salt formation with an optically active acid (e.g., (-) -di-p-methylbenzoyl-d-tartaric acid and/or (+) -di-p-methylbenzoyl-l-tartaric acid), followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column.

One embodiment of the present invention is directed to a composition, including a pharmaceutical composition, comprising, consisting of, and/or consisting essentially of the (+) -enantiomer of a compound of formula (I), wherein the composition is substantially free of the (-) -isomer of the compound. Substantially free, as used herein, means less than about 25%, preferably less than about 10%, more preferably less than about 5%, more preferably less than about 2%, and more preferably less than about 1% of the (-) -isomer, which can be calculated as follows:

another embodiment of the present invention is a composition, including pharmaceutical compositions, comprising, consisting of, and consisting essentially of the (-) -enantiomer of a compound of formula (I), wherein the composition is substantially free of the (+) -isomer of the compound. Substantially free in this context means less than about 25%, preferably less than about 10%, more preferably less than about 5%, more preferably less than about 2%, and more preferably less than about 1% of the (+) -isomer, which can be calculated as follows:

during any of the processes used to prepare the compounds of the various embodiments of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved using conventional protecting groups, such as those described in the following documents: protective Groups in organic Chemistry, Second Edition, J.F.W.McOmie, Plenum Press, 1973 (Protective Groups in organic Chemistry, Second Edition, J.F.W.McOmie, Plenum Press, 1973); T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991(T.W.Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis, John Wiley & Sons, 1991); and t.w.greene & p.g.m.wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999(t.w.greene and p.g.m.wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999). The protecting group may be removed at a convenient subsequent stage using methods known in the art.

While the compounds of the present embodiments (including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof) may be administered alone, they are generally administered in admixture with a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable diluent selected with regard to the route of administration and standard pharmaceutical or veterinary practice. Accordingly, a particular embodiment of the present invention relates to pharmaceutical and veterinary compositions comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent.

For example, in the pharmaceutical compositions of the present embodiments, the compound of formula (I) may be mixed with any suitable binder, lubricant, suspending agent, coating agent, solubilizing agent, and combinations thereof.

Optionally, a solid oral dosage form (e.g., a tablet or capsule) containing a compound of the invention may be administered in at least one dosage form at a time. The compounds may also be administered in sustained release formulations.

Other oral dosage forms in which the compounds of the invention may be administered include elixirs, solutions, syrups and suspensions; each dosage form optionally contains flavoring and coloring agents.

Alternatively, the compounds of formula (I) may be administered by inhalation (intratracheal or intranasal) or in the form of suppositories or pessaries, or they may be administered topically in the form of lotions, solutions, creams, ointments or dusting powders. For example, they may be incorporated into a cream comprising, consisting of and/or consisting essentially of an aqueous emulsion of polyethylene glycol or liquid paraffin. They may also be incorporated in ointments comprising, consisting of and/or consisting essentially of white wax or white soft paraffin base, and any stabilizers and preservatives, as may be desired, at a concentration of from about 1% to about 10% by weight of the cream. Alternative means of administration include transdermal administration by use of a skin patch or transdermal patch.

The pharmaceutical compositions of the invention (as well as the compounds of the invention alone) may also be injected parenterally, for example intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally. In such a case, the composition will also comprise at least one of a suitable carrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of the invention are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositions of the invention may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.

As another example, a pharmaceutical composition containing at least one compound of formula (I) may be prepared by mixing the compound with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical mixing techniques. The carriers, excipients, and diluents can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral, etc.). Thus, for liquid oral preparations such as suspensions, syrups, elixirs and solutions, suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations such as powders, capsules and tablets, suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. The solid oral preparation may also be optionally coated with sugar or the like, or enteric-coated, in order to regulate the main site of absorption and disintegration. For parenteral administration, carriers, excipients, and diluents typically include sterile water, and other ingredients may be added to increase the solubility and preservability of the composition. Injectable suspensions or solutions may also be prepared in aqueous vehicles with appropriate additives such as solubilizers and preservatives.

A therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof comprises: a compound of formula (I) in a dosage range of about 0.1mg to about 3000mg, or any amount or range therein, particularly about 1mg to about 1000mg or any amount or range therein, more particularly about 10mg to about 500mg or any amount or range therein, for a typical (70kg) human, in about 1 to 4 times daily administrations; it will be apparent to those skilled in the art that the therapeutically effective amount of the compound of formula (I) will vary with the disease, syndrome, condition and disorder being treated.

For oral administration, the pharmaceutical composition is preferably provided in the form of a tablet containing about 0.01, about 10, about 50, about 100, about 150, about 200, about 250 and about 500 milligrams of the compound of formula (I).

Advantageously, the compound of formula (I) may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three and four times daily.

The optimal dosage of a compound of formula (I) to be administered can be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the course of the disease, syndrome, condition or disorder. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dosage to achieve the appropriate level of treatment and the desired therapeutic effect. The above doses are thus exemplary of the general case. Of course, there may be individual instances where a higher or lower dosage range is beneficial, and such instances are within the scope of this invention.

One skilled in the art will recognize that both in vivo and in vitro assays can predict the ability of a test compound to treat or prevent a given condition using appropriate, known and generally accepted cellular and/or animal models. Those skilled in the art will also recognize that human clinical trials (including human first use trials, dose exploration trials, and pharmacodynamic trials) conducted in healthy patients and/or patients suffering from a given disease can be accomplished according to methods well known in the clinical and medical arts.

The compound of formula (I) may be administered in any of the compositions and dosage regimens described above, or with the aid of those compositions and dosage regimens established in the art, so long as the use of the compound of formula (I) is required by the subject in need thereof.

General synthetic methods

Representative compounds of the invention can be synthesized according to the general synthetic methods described below and illustrated in the schemes that follow. Since the schemes are illustrative, the invention should not be construed as being limited to the specific chemical reactions and specific conditions described in the schemes and examples. The various starting materials used in the schemes are either commercially available or can be prepared by methods well known to those skilled in the art. The variables are as defined herein and are within the skill of one of ordinary skill in the art.

Abbreviations used in this specification, particularly in "schemes" and "examples", are as follows:

the compounds of formula (I) of the present invention may be prepared according to the methods described in scheme 1 below.

Scheme 1

Thus, an appropriately substituted compound of formula (V) (a known compound or compound prepared by known methods) and an appropriately substituted compound of formula (VI) (a known compound or compound prepared by known methods) wherein PG is present in the presence of an organic base such as DIPEA, pyridine, etc. (preferably not TEA), etc¹For a suitably selected nitrogen protecting group, e.g. -CH (phenyl)₂Benzyl, t-butyl, methyl, etc., preferably-CH (phenyl)₂) Reaction in an organic solvent (e.g., acetonitrile, THF, DCM, etc.), preferably at a temperature in the range of about 50 ℃ to about 90 ℃, affords the corresponding compound of formula (VII).

The compound of formula (VII) is deprotected according to known methods to give the corresponding compound of formula (VIII). For example, wherein PG¹is-CH (phenyl)₂The compound of formula (VII) is deprotected by reaction with 1-chloroethyl chloroformate in an organic solvent (e.g. dichloromethane) and then refluxed in an organic solvent (e.g. methanol) to obtain the corresponding compound of formula (VIII).

A compound of formula (VIII) is reacted with an appropriately substituted compound of formula (IX) (known compound or by known methods) in the presence of an appropriately selected coupling agent (e.g. HATU, HBTU, DCC, etc.), an appropriately selected organic base (e.g. DIPEA, TEA, pyridine, etc.)Compounds of the preparation, wherein LG¹Selected from-C (O) Cl and C (O) OH, and wherein LG¹The desired bonding position attached to the phenyl ring of the benzo fusion moiety of the compound of formula (IX) in an organic solvent (e.g., acetonitrile, DMF, DCM, etc.) to afford the corresponding compound of formula (I).

The following examples are given to aid in the understanding of the present invention and are not intended to, and should not be construed to, limit in any way the invention set forth in the claims that follow thereafter.

In the examples that follow, some of the synthesis products that have been isolated as residues are listed. It will be understood by those skilled in the art that "residue" does not limit the physical state of the product as it is isolated and may include, for example, solids, oils, foams, gums, slurries, and the like.

To methyl 4-amino-3-hydroxy-benzoate (5g, 29.91mmol)/CH at room temperature₃A solution of OH (150mL) was added to cyclohexylformaldehyde (3.6mL, 29.91 mmol). The resulting mixture was stirred at room temperature for 2 h. Removing the solvent by evaporation to remove CH₃CN (150mL) was added to the residue. In N₂Adding a portion of acetic acid under an atmosphereLead (IV) (13.26g, 29.91mmol) and the resulting mixture was refluxed for 10 min. After cooling, the resulting solid was filtered and used with CH₃And (5) CN washing. Then 3N NaOH (40mL) was added to the filtrate. The resulting mixture was stirred at 50 ℃ for 18 hours. The solvent was removed by evaporation and the resulting residue was purified by flash column chromatography on silica gel to give 2-cyclohexyl-benzoOxazole-6-carboxylic acid. MS M/z (M + H)⁺)246.2。

To 2-cyclohexyl-benzoA solution of oxazole-6-carboxylic acid (0.47g, 1.9mmol) and HBTU (0.94g, 2.5mmol) in DMF (10mL) was added DIPEA (1.4mL, 7.6 mmol). The resulting mixture was stirred at room temperature for 10 minutes, then the hydrochloride salt of azetidin-3-ol (0.452g, 4.7mmol) was added. The resulting mixture was stirred at room temperature for 1 hour and then purified by reverse phase liquid chromatography. Lyophilizing the product-containing fraction to obtain (2-cyclohexyl-benzo)Oxazol-6-yl) - (3-hydroxy-azetidin-1-yl) -methanone. MS M/z (M + H)⁺)301。

And C: 2-cyclohexyl-6- { [3- (4-pyridin-2-ylpiperazin-1-yl) azetidin-1-yl]Carbonyl-

Methylsulfonyl chloride (0.152mL, 1.9mmol) was added dropwise to (2-cyclohexyl-Benzo (b) isOxazol-6-yl) - (3-hydroxy-azetidin-1-yl) -methanone (0.48g, 1.6mmol) and DIPEA (0.558mL, 3.2mmol) in DCM (20 mL). Immediately after the addition, the cooling bath was removed and the mixture was allowed to slowly warm to room temperature. The resulting mixture was then washed with water, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was dissolved in acetonitrile (1 mL). DIPEA (0.41mL, 2.4mmol) and N- (2-pyridyl) piperazine (1.6mmol) were added. The resulting mixture was then microwaved at 160 ℃ for 4 hours. DMF (3mL) was added to the resulting mixture, followed by purification by reverse phase liquid chromatography. The product-containing fraction was diluted with 1N HCl (5mL) and then lyophilized to obtain 2-cyclohexyl-6- { [3- (4-pyridin-2-ylpiperazin-1-yl) azetidin-1-yl as its corresponding hydrochloride salt]Carbonyl } -1, 3-benzoAnd (3) azole.

¹H NMR(400MHz，DMSO-d₆)δ＝9.21(s，1H)，8.15(d，J＝5.1Hz，1H)，7.96(d，J＝8.3Hz，1H)，7.81(br.s.，1H)，7.16-7.22(m，1H)，7.06(d，J＝8.3Hz，1H)，6.88(s，1H)，4.54(br.s.，2H)，4.38(d，J＝6.6Hz，2H)，4.13(br.s.，1H)，3.73(br.s.，8H)，3.31-3.60(m，1H)，1.77(d，J＝13.7Hz，4H)，1.65(br.s.，1H)，1.32-1.44(m，2H)，1.15-1.32(m，2H)，1.06(t，J＝7.0Hz，1H)。MSm/z(M+H⁺)446。

Compounds #2 through 28 can be similarly prepared according to the procedure described in example 1 above by substituting appropriately selected and/or substituted reagents, starting materials, and purification methods known to those skilled in the art.

Example 2: (in vitro assay): MGL enzyme activity assay

All rat-based detection assays were performed in black 384-well polypropylene PCR microplates (Abgene) in a total volume of 30. mu.L.The substrate 4-methylumbelliferone butyrate (4MU-B, Sigma) and purified mutant MGL enzyme (mut-MGLL 11-313L 179S L186S) were diluted into 20mM PIPES buffer (pH 7) containing 150mM NaCl and 0.001% Tween 20, respectively. The compound of formula (I) was pre-dispersed (50nL) into the assay plate using a Cartisian Hummingbird pipette (Genomic Solutions (Ann Arbor, MI)), followed by the addition of 4MU-B (25. mu.L of 1.2X solution at a final concentration of 10. mu.M) followed by the addition of enzyme (5. mu.L of 6X solution at a final concentration of 5nM) to initiate the reaction. The final compound concentration was in the range of 17 to 0.0003 μ M. Excitation and emission wavelengths of 335nm and 440nm, respectively, at 37 deg.C, and a bandwidth of 10nm (Safire)²Tecan) was monitored for 5 minutes for the change in fluorescence due to 4MU-B cleavage.

Determination of the IC of the Compounds of formula (I) Using Excel from a concentration-response plot fitting equation to partial Activity as a function of inhibitor concentration₅₀The value is obtained.

The ThermoFluor (TF) assay is a 384-well plate-based binding assay that can measure the thermal stability of proteins (Pantoliano, M.W., Petrella, E.C., Kwasnsoski, J.D., Lobanov, V.S., Myslik, J.F., E.C., Carver, T.S., Asel, E.E., Springer, B.A., Lane, P.and Salemme, F.R.J. Biomol Screen 2001, 6, 429-40(Pantoliano, M.W., Petrella, E.C., Kwasnsoski, J.D., Lobanov, V.S. S. Puik, J.Myf, Carf, E.E., T.Asel, E.E., Spgerin, B.A., Labanov, S. Skik, J.S., My, T.S. Asel, E.E.E.Spgerin, B.A., Labazoo.P.S. S. Sslik, J. My, J. S. My, J. Myf, J. S. J. S. J. S. Myf, J. No. 58, J. 58, M.S. No. 58, J. Toemk, J. 58, J. Toemy, No. Toemr.58, No. 58, No. Toeml, No. 58, No. Toemf, No. 58, No. S. The experiments were performed using instruments from Johnson & Johnson pharmaceutical research & Development, LLC. The TF dye used in all experiments was 1, 8-ANS (Invitrogen: A-47). The final TF assay conditions for MGL studies were 0.07mg/ml purified mutant MGL (mut-MGLL 11-313L 179S L186S), 100 μ M ANS, 200mM NaCl, 0.001% tween-20 in 50mM PIPES (pH 7.0).

The screening compound plate contained a single concentration of 100% DMSO compound solution. For subsequent concentration-response studies, compounds were arrayed in pre-dispersed plates (Greiner Bio-one: 781280) with compounds in successive 11 rows serially diluted in 100% DMSO. Lines 12 and 24 were used as DMSO references and contained no compound. For both single and multiple compound concentration-response experiments, aliquots of compounds (50nL) were automatically pre-dispersed directly onto black 384-well polypropylene PCR microplates (Abgene: TF-0384/k) using a Cartesian Hummingbird pipette (Genomic Solutions (AnnArbor, MI)). After the compound was dispersed, protein and dye solutions were added to obtain a final assay volume of 3 μ L. A thin layer of 1. mu.L silicone oil (Fluka, model DC 200: 85411) was spread over the assay solution to prevent evaporation.

The barcoded assay plates were loaded onto a thermostatically controlled PCR-type thermal block using an automatic machine and then all experiments were heated from 40 to 90 ℃ at a ramp rate of 1 ℃/min. Fluorescence was measured using continuous irradiation with ultraviolet light (Hamamatsu LC6) supplied by an optical fiber and filtered through a bandpass filter (380-. Fluorescence emission from the entire 384-well plate was detected by measuring light intensity using a CCD camera (Sensys, Roper Scientific) with filter detection at 500 + -25 nm, producing simultaneous and independent readings of all 384 wells. A single image of 20 seconds exposure time was collected at each temperature and the sum of pixel intensity versus temperature in the designated area of the panel was recorded and fitted to a standard formula to obtain T_m。(Pantoliano，M.W.，Petrella，E.C.，Kwasnoski，J.D.，Lobanov，V S.，Myslik，J.，Graf，E.，Carver，T.，Asel，E.，Springer，B.A.，Lane，P.，and Salemme，F.R.，J Biomol Screen 2001，6，429-40(Pantoliano，M.W.、Petrella，E.C.、Kwasnoski，J.D.、Lobanov，V S.、Myslik, j., Graf, e., Carver, t., Asel, e., Springer, b.a., Lane, p., and saleme, f.r., "journal of biomolecular screening", 2001, 6, 429 and 440)).

Example 4: 2-AG accumulation assay

Heila cells were homogenized with Polytron in 10ml (about 4 hundred million cells) HEPES buffer (HEPES 20mM, pH 7.4, NaCl 125mM, EDTA 1mM, KCl 5mM, glucose 20 mM). Homogenate from 0.2 million cells (0.5ml) was incubated with MGL inhibitor for 15 minutes to block MGL activity, and then HEPES buffer was incubated with calcium (10mM) for 20 minutes. The total reaction volume was 5 ml. The reaction was stopped by extraction with 6mL of organic solvent (2: 1 chloroform/methanol). Methyl Arachidonyl Fluorophosphonate (MAFP) was used as a positive control. In the absence of MAFP, the level of 2-AG was about 3.4 picomoles/sample. In the presence of 100nM MAFP, the level of 2-AG increased to 174 picomoles/sample. The accumulated 2-AG in the organic phase was measured by HPLC/MS method according to the following formula: % MAFP ═ 100 (compound 2-AG/MAFP 2-AG).

Representative compounds of formula (I) were tested according to the procedures described in examples 2, 3 and 4 above and the results are listed in table 4.

TABLE 4

Example 5: oral formulations-hypothetical example

As a specific example of an oral composition, 100mg of Compound #1 prepared in example 1 was formulated with lactose sufficiently comminuted to provide a total amount of 580-590mg to fill an O-sized hard capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the appended claims and their equivalents.

Claims

1. Use of a compound of formula (I) in the manufacture of a medicament for treating or ameliorating a disease, syndrome, condition or disorder affected by inhibition of MGL, wherein the disease, syndrome, condition or disorder is selected from pain and inflammatory allergic conditions,

(I)

wherein the compound is selected from:

whereinW is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenoxymethyl, and R³A compound that is 2, 2-dimethylpropyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) = N-, and R²A compound that is cyclohexyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) = N-, and R²A compound which is a 3-fluorophenyl group;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) = N-, and R²A compound that is 4-fluorophenyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) = N-, and R²A compound that is 4-methoxyphenyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is isobutyl, and R³A compound that is isobutyl;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) = N-, and R²A compound that is 2-methoxyphenylmethyl;

wherein WIs N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenylmethyl, and R³A compound that is a cyclohexylmethyl group;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) = N-, and R²A compound that is a tert-butyl group;

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) = N-, and R²A compound that is 3-methoxyphenyl;

wherein W is CH, R¹Is a compound of 4-fluoro group,is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is phenyl, and R³A compound that is 2, 2-dimethylpropyl;

wherein W is N，R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-CH-C (R)²)-N(R³)-，R²Is tert-butyl, and R³A compound that is 2, 2-dimethylpropyl;

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.

2. The use according to claim 1, wherein the compound of formula (I) is selected from:

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.

3. The use according to claim 1, wherein the compound of formula (I) is selected from:

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.

4. The use according to claim 1, wherein the compound of formula (I) is selected from:

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed of，X-Y-Z is-O-C (R)²) = N-, and R²A compound that is 4-methoxyphenyl;

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.

5. The use according to claim 1, wherein the compound of formula (I) is selected from:

wherein W is N, R¹Is a compound of formula (I) in the formula (H),is composed ofX-Y-Z is-O-C (R)²) = N-, and R²Is cyclohexylA compound of (1);

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.

6. The use of claim 1, wherein the disease, syndrome, condition or disorder affected by inhibition of MGL is pain.

7. The use of claim 1, wherein the disease, syndrome, condition or disorder affected by inhibition of MGL is inflammatory pain.

8. The use of claim 1, wherein the disease, syndrome, condition or disorder affected by inhibition of MGL is visceral pain.

9. The use of claim 1, wherein the disease, syndrome, condition or disorder affected by inhibition of MGL is ulcerative colitis.

10. The use of claim 1, wherein the disease, syndrome, condition or disorder affected by inhibition of MGL is neuropathic pain.

11. The use of claim 1, wherein the disease, syndrome, condition or disorder affected by inhibition of MGL is neuropathic allodynia.

12. The use of claim 1, wherein the disease, syndrome, condition or disorder affected by inhibition of MGL is selected from inflammatory pain and neuropathic pain.