TW201313702A - Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors - Google Patents

Abstract

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds, and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, are represented by Formula (Ia) and Formula (Ib) as follows: wherein Y, Z, and n are defined herein; and wherein Yb and Zb are as defined herein.

Description

As a monothioglyceryl lipase inhibitor, oxypiperidin-tetrahydrofurfurylamine and oxadiazepine-tetrahydrofurfurylamine

The present invention relates to compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders (including pain)

Cannabis sativa has been used for many years to treat pain. Δ ⁹ -tetrahydrocannabinol is the main active ingredient in cannabis and is an agonist of cannabinoid receptors (Pertwee, Brit J Pharmacol, 2008, 153, 199-215). Two cannabinoidal G protein-coupled receptors have been artificially selected, namely cannabinoid receptor type ₁ (CB ₁ Matsuda et al., Nature, 1990, 346, 561-4) and cannabinoid receptor type ₂ (CB ₂ Munro et al). ., Nature, 1993, 365, 61-5). CB _{1 is} expressed in central brain regions such as the hypothalamus and nucleus accumbens, as well as the surrounding liver, gastrointestinal tract, pancreas, adipose tissue and skeletal muscle (Di Marzo et al., Curr Opin Lipidol, 2007, 18, 129-140). CB _{2 is} mainly expressed in immune cells such as mononuclear leukocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134) and, under certain conditions, also in the brain (Benito et al., Brit). J Pharmacol, 2008, 153, 277-285) and skeletal muscle (Cavuoto et al., Biochem Biophys Res Commun, 2007, 364, 105-110) and myocardium (Hajrasouliha et al., Eur J Pharmacol, 2008, 579, 246-252). Numerous pharmacological, anatomical, and electrophysiological data using synthetic agonists indicate that increased cannabin signaling through CB ₁ /CB ₂ promotes analgesic effects in acute pain nociception trials and is modeled in chronic neurological and inflamed pain models. It can inhibit hyperalgesia (Cavatt et al., J Neurobiol, 2004, 61, 149-60; Guindon et al., Brit J Pharmacol, 2008, 153, 319-334).

The efficacy of synthetic cannabinoid receptor agonists has been supported by the literature. Furthermore, studies using cannabinoid receptor antagonists and knockout mice have also shown that the endocannabinoid system is an important regulator of pain perception. Anandamide (AEA) (Devane et al., Science, 1992, 258, 1946-9) and 2-arachidinoylglycerol (2-AG) (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., Biochem Biophys Res Commun, 1995, 215, 89-97) are two major endogenous cannabis. AEA is hydrolyzed by fatty indoleamine hydrolase (FAAH) and 2-AG is hydrolyzed by monoterpene glycerol lipase (MGL) (Piomelli, Nat Rev Neurosci, 2003, 4, 873-884). Genetic ablation of FAAH increases endogenous AEA and causes analgesic effects associated with CB ₁ in acute and inflammatory pain patterns (Lichtman et al., Pain, 2004, 109, 319-27), meaning endogenous The cannabis system is inherently capable of inhibiting pain (Cravatt et al., J Neurobiol, 2004, 61, 149-60). Unlike the constitutive increase in the amount of endogenous cannabinoid compounds when FAAH knockout mice are used, the use of specific FAAH inhibitors will increase the amount of AEA in a short period of time and lead to anti-noise perception in vivo (Kathuria et al.) , Nat Med, 2003, 9, 76-81). Further evidence of anti-pain perception by endogenous cannabis is shown to form AEA in the gray matter surrounding the cerebral aqueduct after peripheral noxious stimulation (Walker et al., Proc Natl Acad Sci USA, 1999, 96, 12198- 203), and conversely in the spinal cord exhibit antisense RNA-mediated hyperalgesia initiator of CB (Dogrul et al inhibition after _1., pain, 2002,100,203-9).

Regarding 2-AG, intravenous delivery of 2-AG produces analgesic effects in the flash tail test (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90) and produces analgesic effects in hot plate assays (Lichtman et al) ., J Pharmacol Exp Ther, 2002, 302, 73-9). In contrast, 2-AG alone has been shown to have no analgesic effect in hot plate assays, but when administered in combination with other 2-monosaccharides (eg, 2-linolenic acid glyceride and 2-palmitic acid glyceride), A significant analgesic effect is obtained, a phenomenon known as the "entourage effect" (Ben-Shabet et al., Eur J Pharmacol, 1998, 353, 23-31). These "follow-up" 2-monomercaptoglycerols are endogenous lipids that are co-released with 2-AG, and partially enhance endogenous cannabis signaling by inhibiting 2-AG decomposition, which is most likely derived from inhibition of 2-AG decomposition. Competing for active sites on MGL. This means that synthetic MGL inhibitors will have similar effects. In fact, URB602, a relatively weak synthetic MGL inhibitor, has been shown to have anti-pain perception effects in acutely inflamed murine patterns (Comelli et al., Brit J Pharmacol, 2007, 152, 787-794).

Although the results of the use of synthetic cannabis agonists have shown that increased cannabis signaling produces analgesic and anti-inflammatory effects, it is not easy to separate these benefits from the deleterious side effects of these compounds. An alternative method is to enhance the signal transmission of the endogenous cannabis system by increasing the amount of 2-AG, which is the endogenous cannabis most abundant in the central nervous system (CNS) and the gastrointestinal tract. This is achieved by suppressing MGL. Therefore, MGL inhibitors may be effective in treating pain, inflammation, and CNS disorders (Di Marzo et al., Curr Pharm Des, 2000, 6, 1361-80, Jhaveri et al., Brit J Pharmacol, 2007, 152, 624-632; Mc Carberg Bill et al., Amer J Ther, 2007, 14, 475-83), and may also be effective for glaucoma and disease states caused by elevated intraocular pressure (Njie, Ya Fatou; He, Fang; Qiao, Zhuanhong; Song, Zhao-Hui, Exp. Eye Res., 2008, 87(2): 106-14).

The present invention relates to a compound of the formula (Ia),

among them

Y is

i) a C _6-10 aryl or

Ii) one selected from thiazolyl, a heteroaryl group of the group consisting of oxazolyl, pyridyl and pyrimidinyl,

Wherein Y is unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of fluorine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, cyano and trifluoromethyl Group of members;

Z is

i) a C _6-10 aryl group,

Ii) one selected from benzo a heteroaryl group of the group consisting of benzoxazolyl, benzothiazolyl, benzothienyl, oxazolyl and fluorenyl, or

Iii) benzyl-phenyl; wherein the phenyl group of the benzyl group is unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of bromine, chlorine, fluorine, iodine, C _1-4 a group consisting of an alkyl group, a C _1-4 alkoxy group, and a trifluoromethyl group,

Wherein the C _6-10 aryl group of Z and the heteroaryl group are unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of bromine, chlorine, fluorine, iodine, C _1-4 alkyl a group consisting of C _1-4 alkoxy, trifluoromethyl and phenyl; the limitation is that no more than one substituent of Z is a phenyl group, and the phenyl group is unsubstituted or one or two Substituted, each substituent is independently selected from the group consisting of trifluoromethyl, chloro, cyano and fluorine; n is 1 or 2; and its mirror image isomer, non-image isomer, solvent And pharmaceutically acceptable salts.

The invention further relates to a compound of formula (Ib),

among them: Y _b is

i) a C _6-10 aryl or

Ii) one selected from thiazolyl, a heteroaryl group of the group consisting of azolyl, pyridyl and pyrimidinyl,

Wherein Y _b is unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of fluorine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, cyano and trifluoromethyl Group of groups;

Z _b is

i) a C _6-10 aryl group,

Ii) one selected from benzo a heteroaryl group of the group consisting of azolyl, benzothiazolyl, benzothienyl and fluorenyl, or

Iii) benzyl-phenyl; wherein the phenyl group of the benzyl group is unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of bromine, chlorine, fluorine, iodine, C _1-4 a group consisting of an alkyl group, a C _1-4 alkoxy group, and a trifluoromethyl group,

Wherein the C _6-10 aryl group of Z _b and the heteroaryl group are unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of bromine, chlorine, fluorine, iodine, C _1-4 alkane a group consisting of a C _1-4 alkoxy group, a trifluoromethyl group and a phenyl group; the limitation is that no more than one Z _b substituent is a phenyl group, and the phenyl group is unsubstituted or Or two substituents, each substituent being independently selected from the group consisting of trifluoromethyl, chloro, cyano and fluorine; and mirror image isomers, non-image isomers, solvates and pharmaceuticals Salt is acceptable.

The invention also provides, in particular, a pharmaceutical composition comprising, consisting of, and/or consisting essentially of: a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable A diluent, and a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt form thereof.

Also provided is a method for making a pharmaceutical composition comprising, consisting of, and/or consisting essentially of: blending a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof And a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent.

The invention further provides, in particular, a method for treating or ameliorating an MGL-mediated disorder in a subject using a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, the subject comprising a human or other mammal The disease, syndrome or condition is affected by modulation of the MGL enzyme, such as pain and diseases that cause the pain, inflammation, and CNS disorders.

The invention also provides, in particular, methods for producing the ready-to-use compounds and pharmaceutical compositions and medicaments therefor.

When referring to a substituent, the term "independent" refers to the case where, when there may be more than one substituent, the substituents may be the same or different from each other.

The term "alkyl", whether used alone or as part of a substituent group, refers to both straight and branched carbon chains having from 1 to 8 carbon atoms. Thus, the specified number of carbon atoms (e.g., _C1-8 ) refers independently to the number of carbon atoms in an alkyl moiety or the number of carbon atoms in an alkyl moiety on a larger alkyl-containing substituent. In the substituent group having a complex alkyl group such as (C _1-6 alkyl) ₂ amine group, the C _1-6 alkyl group of the dialkylamino group may be the same or different.

The term "alkoxy" refers to a mono-O-alkyl group, wherein the term "alkyl" is as defined above.

The terms "alkenyl" and "alkynyl" refer to both straight and branched carbon chains having 2 or more carbon atoms, wherein one alkenyl chain contains at least one double bond and the alkynyl chain contains at least one triple bond. .

The term "cycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic hydrocarbon ring having from 3 to 14 carbon atoms. Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.

The phrase "benzo-fused cycloalkyl" means a 5- to 8-membered monocyclic cycloalkyl ring fused to a benzene ring. The carbon atom ring member forming the cycloalkyl ring may be fully saturated or partially saturated.

The term "heterocyclyl" refers to a non-aromatic monocyclic or bicyclic ring system having from 3 to 10 ring members, the ring member comprising at least one carbon atom and from 1 to 4 independently selected from the group consisting of N, O and S. Hetero atom. The term "heterocyclic group" is a 5- to 7-membered non-aromatic ring (wherein 1 to 2 ring members are N), or a 5- to 7-membered non-aromatic ring (where 0, 1 or 2 rings) Is N and at most 2 ring members are O or S and at least one ring member must be N, O or S); wherein optionally, the ring contains 0 to 1 unsaturated bond, and optionally, when When the ring is 6 or 7 members, it contains up to 2 unsaturated bonds. The ring of carbon atoms forming a heterocyclic ring can be fully saturated or partially saturated. The term "heterocyclyl" also includes two 5-membered monocyclic heterocycloalkyl groups which are bridged to form a bicyclic ring. Such groups are not considered to be fully aromatic and are not referred to as heteroaryl groups. When a heterocyclic ring is bicyclic, the two rings of the heterocyclic ring are non-aromatic and at least one of the two rings contains a heteroatom ring member. Examples of heterocyclic groups include, but are not limited to, pyrrolinyl groups (including 2H-pyrrole, 2-pyrroline or 3-pyrroline), pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyridyl Zyridinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperidine Piperazinyl. Unless otherwise indicated, the heterocyclic ring attaches its pendant group to any heteroatom or carbon atom which results in a stable structure.

The term "benzo-fused heterocyclic group" means a 5- to 7-membered monocyclic heterocyclic ring fused to a benzene ring. The heterocyclic ring contains a carbon atom and 1 to 4 hetero atoms independently selected from N, O and S. The carbon atom ring forming the heterocyclic ring may be fully saturated or partially saturated. Unless otherwise indicated, a benzo-fused heterocyclic ring has pendant groups attached to one of the carbon atoms of the phenyl ring.

The term "aryl" refers to an unsaturated, aromatic monocyclic or bicyclic ring of 6 to 10 carbon members. Examples of the aromatic ring include a phenyl group and a naphthyl group.

The term "heteroaryl" refers to an aromatic monocyclic or bicyclic ring system having from 5 to 10 ring members and which contains a carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S. The term "included in heteroaryl" is a 5 or 6 membered aromatic ring wherein the ring system consists of carbon atoms and has at least one heteroatom. Suitable heteroatoms include N, O and S. In the case of a 5-membered ring, the heteroaryl ring preferably contains a member of N, O or S, in addition to containing up to 3 additional N atoms. In the case of a 6-membered ring, the heteroaryl ring preferably contains from 1 to 3 nitrogen atoms. For the case where the 6-membered ring has 3 N, at most 2 nitrogen atoms are adjacent. When a heteroaryl group is a bicyclic ring, at least one hetero atom is present in each ring. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, Oxazolyl, thiazolyl, imidazolyl, pyrazolyl, iso Isozolyl, isothiazolyl, Oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, anthracene Pyridazinyl, pyrimidinyl and pyridyl Pyrazinyl. Unless otherwise indicated, the heteroaryl group attaches its pendant groups to any heteroatom or carbon atom which results in a stable structure.

Unless otherwise indicated, the term "benzo-fused heteroaryl" refers to a 5- to 6-membered monocyclic heteroaryl ring fused to a phenyl ring. The heteroaryl ring contains a carbon atom and 1 to 4 hetero atoms independently selected from N, O and S. Examples of heteroaryl groups having a selectively fused benzene ring include anthracenyl, isodecyl, benzofuranyl, benzothienyl, oxazolyl, benzimidazolyl, benzothiazolyl, benzene and Benzozolyl, benzopyrene Benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolyl, isoquinolinyl and quinazolinyl. Unless otherwise indicated, the benzo-fused heteroaryl group attaches its pendant groups to any heteroatom or carbon atom which results in a stable structure.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine atoms.

The term "methyl thiol" refers to the group -C(=O)H.

The term "sideoxy" refers to a group (=O).

Whenever one of the terms "alkyl" or "aryl" or its prefix root appears in the nomenclature of a substituent (eg, aralkyl, alkylamino), the nomenclature is interpreted to include the above for "alkanes" These limits are given by "base" and "aryl". The number of carbon atoms (e.g., C ₁ -C ₆₎ alkyl-based part of a separate means, a number of carbon atoms in the aryl moiety, or (wherein the alkyl group present in the alkyl portion of a larger substituent groups as The number of carbon atoms in the prefix root). For alkyl and alkoxy substituents, the specified number of carbon atoms includes all independent members that are included in a given range. For example, a C _1-6 alkyl group may specifically include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group, and a second combination thereof (for example, C _1-2 , C _1-3 , C _1-4 , C _{1-5 ,} C _2-6 , C _3-6 , C _4-6 , C _5-6 , C _{2-5 ,} etc.).

In general, under the standard nomenclature used throughout the disclosure of the present invention, the description begins with the end portion of the designated side chain, and then the adjacent functional groups are described sequentially toward the point of attachment. Thus, for example, a "C ₁ -C ₆ alkylcarbonyl" substituent refers to a group of the formula:

The term "R" in a stereocenter means that the stereocenter is purely the R-configuration as defined in the technique; likewise, the term "S" means that the stereocenter is purely S-configured. . As used herein, the term "*R" or "*S" in a stereocenter is used to mean that the stereocenter is a pure but unknown structure. As used herein, the term "RS" refers to a stereocenter that exists as a mixture of R and S configurations. Similarly, the term "*RS" or "*SR" refers to a stereocenter that exists as a mixture of R and S configurations and that is unknown relative to another stereocenter in the molecule.

A compound containing a stereocenter and not showing a stereo bond is a mixture of two mirror image isomers. A compound containing two stereocenters and neither of which depicts a stereo bond is a mixture of four non-image isomers. A compound having two stereocenters identified as "RS" and having a three-dimensional bond signature is a two component mixture having the relative stereochemistry as depicted. A compound having two stereocenters identified as "*RS" and having a stereobonding signature is a two component mixture having an unknown relative stereochemistry. The stereocenter that is not identified and does not have a stereo bond symbol is a mixture of R and S configurations. For a stereoscopic center that is not identified and has a three-dimensional bond signature, the absolute stereochemistry is as depicted.

Unless otherwise stated, the definition of any substituent or variable at a particular position in a molecule is intended to be independent of its definition at other positions in the molecule. It will be understood that the substituents and substitutions on the compounds of formula (Ia) and (Ib) may be selected by those of ordinary skill in the art to provide chemically stable compounds, and such compounds may be used in the art. The techniques or methods presented herein are easily synthesized.

The term "subject" refers to an animal that has become a subject of treatment, observation or experiment, preferably a mammal, more preferably a human.

The term "therapeutically effective amount" means an amount of an active compound or agent (including a compound of the invention) capable of inducing a biological or medical response in a tissue system, animal or human, the organism or medical response being a researcher, beast Attended by a physician, physician, or other clinician, including alleviating or partially alleviating the symptoms of the disease, syndrome, condition, or disorder to be treated.

The term "composition" means a product comprising a therapeutically effective amount of a particular component, and any product which results, directly or indirectly, from the combination of the particular component of that particular amount.

The term "MGL inhibitor" is intended to encompass a compound that interacts with MGL to substantially reduce or eliminate its catalytic activity, thereby increasing its concentration. The term "regulated by MGL" is used to refer to conditions that are affected by MGL enzyme regulation, including conditions that are affected by MGL enzyme inhibition, such as pain, and diseases that cause such pain, inflammation, and CNS disorders.

As used herein, unless otherwise stated, the terms "affected" or "affected" (when referring to a disease, syndrome, condition, or disorder affected by MGL inhibition) should include a reduction in the disease, syndrome, condition, or disorder. The frequency and/or severity of one or more symptoms or manifestations; and/or the prevention of the development of one or more symptoms or manifestations of the disease, syndrome, condition or disorder or the development of the disease, syndrome, condition or disorder.

The compounds of formula (Ia) and (Ib) are useful for methods of treating, ameliorating and/or preventing a disease, syndrome, condition or disorder affected by MGL inhibition. Such methods comprise, consist of, and consist essentially of: administering to a subject in need of such treatment, alleviation and/or prevention (including an animal, a mammal, and a human) a therapeutically effective amount of one (Ia) Or (Ib) a compound or a mirror image isomer, a non-image isomer, a solvate or a pharmaceutically acceptable salt thereof. In particular, the compounds of the formulae (Ia) and (Ib) or a mirror image isomer, a non-image isomer, a solvate or a pharmaceutically acceptable salt thereof are useful for the treatment, amelioration and/or prevention of: Pain; the disease, syndrome, condition, or disorder that causes such pain; inflammation and/or CNS disorders. More particularly, the compounds of formula (Ia) and (Ib) or a mirror image isomer, non-mirogram, solvate or pharmaceutically acceptable salt thereof for the treatment, amelioration and/or prevention of inflammatory pain, inflammation Allergic conditions and/or neuropathic pain are useful, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (Ia) or (Ib), or a mirror image thereof as defined herein. A conformation, a non-image isomer, a solvate or a pharmaceutically acceptable salt.

Examples of inflammatory pain include a disease, condition, symptom, disordered pain, or a state of pain, including inflammatory bowel disease, visceral pain, migraine, postoperative pain. Post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain , chest pain, labor, musculoskeletal disease, skin disease, toothache, pyresis, burn, sunburn, snake bites (snake bite), venomous snakebite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection Ttract infection), rhinitis, contact dermatitis/hypersensitivity, itching, eczema, pharyngitis, mucositis Cositis), enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, intrauterine Endometriosis, due to physical due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.

One type of inflammatory pain is inflammatory hyperalgesia/allergy. Examples of inflammatory hyperalgesia include a disease, condition, symptom, abnormal or pain state, including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal disorders, 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/allergy, hair Itching, eczema, pharyngitis, enteritis, colonic irritability, inflammatory bowel disease including 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 one embodiment, the invention relates to a method for treating, ameliorating and/or preventing visceral inflammatory hyperalgesia in which visceral irritability is present, comprising, consisting of, Or consisting essentially of the following steps: administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of formula (Ia) or (Ib). In a further embodiment, the invention relates to a method for treating somatic inflammatory hyperalgesia in which there is thermal, mechanical and/or chemical irritancy, which comprises, consists of, and/or consists essentially of Step composition: administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a mirror image isomer, a non-image isomer, a solvate or pharmaceutically acceptable salt.

A further embodiment of the invention relates to a method for the treatment, amelioration and/or prevention of neuropathic pain. Examples of neuropathic pain include pain resulting from a disease, condition, symptom, abnormal or pain state, including cancer, neurological disorder, spine and peripheral nerve surgery, brain Brain tumor, 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, related to Neuropathy: spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, Sciatic neuritis, mandibular joint neuralgia ), peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fracture, oral neuropathic pain , Charcot's pain, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-barre syndrome, sensation Meralgia paresthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis , Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, cephalic nerve Migrainous neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neu Ralgia), nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, red neuralgia, Slude's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia or vidian neuralgia .

One type of neuropathic pain is a neuropathic cold allodynia characterized by the presence of a neuropathy-related allodynic state in which cold irritation is present. Examples of allodynia of the neuropathic cold allergy include pain hypersensitivity caused by a disease, condition, symptom, disorder, or pain state, including neuropathic pain (neuralgia), surgery or trauma to the spine or peripheral nerves. Pain, brain trauma (TBI), trigeminal neuralgia, post-herpetic neuralgia, burning neuralgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex Regional pain syndromes I and II (CRPS I/II) and radiculopathy.

In a further embodiment, the invention relates to a method for treating, ameliorating and/or preventing neuropathic cold hyperalgesia in which cold irritation is present, comprising, consisting of, and/or Composed of the following steps: administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a mirror image isomer, a non-image isomer, a solvate or a pharmaceutical Salt is acceptable.

In a further embodiment, the invention relates to a method for treating, ameliorating and/or preventing a CNS disorder. Examples of CNS disorders include anxiety disorders such as social anxiety, post-traumatic stress disorder, phobias, social phobia, special phobias, Panic disorder, obsessive-compulsive disorder, acute stress disorder, separation anxiety disorder and generalized anxiety disorder, and depression such as severe depression Major depression, bipolar disorder, seasonal affective disorder, post natal depression, manic depression, and bipolar depression.

Embodiments of the invention include a compound of formula (Ia),

among them:

a) Y is

i) phenyl or

Ii) a heteroaryl group which is a thiazolyl or pyrimidinyl group;

b) Y is a thiazolyl or pyrimidinyl group; c) Z is

i) a C _6-10 aryl or

Ii) one selected from benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl,

Wherein the C _6-10 aryl and heteroaryl groups of Z are independently independently substituted by one or two groups selected from the group consisting of chlorine, fluorine, C _1-4 alkyl, trifluoromethyl and phenyl Substituting, the limitation is that no more than one substituent is a phenyl group, and the phenyl group is unsubstituted or substituted with one or two substituents, each of which is a trifluoromethyl group or a fluorine;

d) Z is one selected from benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl,

Wherein the heteroaryl group of Z is unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of chlorine, trifluoromethyl and phenyl, with no more than one restriction. a substituent of Z is a phenyl group, and the phenyl group is unsubstituted or substituted with one or two substituents, each substituent being a trifluoromethyl group or fluorine; n is 1; n is 2; and any of the above examples a combination of a) to f), the limitation being that it is understood that a combination in which different embodiments of the same substituent are combined will be excluded; and a mirror image isomer, a non-image isomer, a solvate thereof and a pharmaceutically acceptable salt .

An embodiment of the invention comprises a compound of formula (Ia),

among them: Y is

i) phenyl, or

Ii) a heteroaryl group which is a thiazolyl or pyrimidinyl group;

Z is

i) C _6-10 aryl, or

Ii) one selected from benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl,

Wherein the C _6-10 aryl group of Z and the heteroaryl group are unsubstituted or substituted with one or two substituents, each substituent being selected from the group consisting of chlorine, fluorine, C _1-4 alkyl, trifluoromethyl a group consisting of a phenyl group; the limitation is that no more than one substituent of Z is a phenyl group, and the phenyl group is unsubstituted or substituted with one or two substituents, each of which is a trifluoromethyl group Or fluorine; n is 1 or 2; and its mirror image isomer, non-image isomer, solvate and pharmaceutically acceptable salt.

A further embodiment of the invention comprises a compound of formula (Ia),

among them: Y is

i) phenyl or

Ii) a heteroaryl group which is a thiazolyl or pyrimidinyl group;

Z is

i) a C _6-10 aryl or

Ii) one selected from benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl,

Wherein the C _6-10 aryl group of Z and the heteroaryl group are unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of chlorine, fluorine, C _1-4 alkyl, trifluoromethyl a group consisting of a phenyl group and a phenyl group, the limitation is that no more than one substituent of Z is a phenyl group, and the phenyl group is unsubstituted or substituted with one or two substituents, each of which is trifluoromethyl Or a fluorine; n is 1; and a mirror image isomer, a non-image isomer, a solvate thereof and a pharmaceutically acceptable salt.

An embodiment of the invention comprises a compound of formula (Ia),

Wherein: Y is a thiazolyl or pyrimidinyl group; Z is one selected from the group consisting of benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl, wherein the heteroaryl of Z is unsubstituted or substituted with one or two substituents, each substituent Is independently selected from the group consisting of chlorine, trifluoromethyl and phenyl, with the proviso that no more than one substituent of Z is phenyl, and the phenyl is unsubstituted or substituted with one or two substituents. Substituted, each substituent is trifluoromethyl or fluoro; n is 1 or 2; and its mirror image isomer, non-image isomer, solvate and pharmaceutically acceptable salt.

An embodiment of the invention comprises a compound of formula (Ia),

Wherein: Y is a thiazolyl or pyrimidinyl group; Z is one selected from the group consisting of benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl, wherein the heteroaryl of Z is unsubstituted or substituted with one or two substituents, each substituent Is independently selected from the group consisting of chlorine, trifluoromethyl and phenyl, with the proviso that no more than one substituent of Z is phenyl, and the phenyl is unsubstituted or substituted with one or two substituents. Substituted, each substituent is trifluoromethyl or fluoro; n is 1; and its mirror image isomer, non-image isomer, solvate and pharmaceutically acceptable salt.

A further embodiment of the invention comprises a compound of formula (Ia),

among them: Y is

i) phenyl or

Ii) a heteroaryl group which is a thiazolyl or pyrimidinyl group;

Z is

i) a C _6-10 aryl or

Ii) one selected from benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl,

Wherein the C _6-10 aryl group of Z and the heteroaryl group are unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of chlorine, fluorine, C _1-4 alkyl, trifluoromethyl a group consisting of a phenyl group and a phenyl group, the limitation is that no more than one substituent of Z is a phenyl group, and the phenyl group is unsubstituted or substituted with one or two substituents, each of which is trifluoromethyl Or a fluorine; n is 2; and its mirror image isomer, non-image isomer, solvate and pharmaceutically acceptable salt.

The invention further relates to a compound of formula (Ia),

It is selected from the group consisting of Y: phenyl, Z is 4-(benzyl)-phenyl, and n is a compound of 1; wherein Y is phenyl and Z is 4-phenyl-benzene a compound wherein n is 1; wherein Y is pyrimidin-2-yl, Z is 1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl, and n is a compound of 1; Wherein Y is pyrimidin-2-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is a compound of 1; wherein Y is thiazol-2-yl, Z is 1 a compound of -(4-fluoro-phenyl)-1H-indol-5-yl and n is 1 wherein Y is thiazol-4-yl and Z is 1-(4-fluoro-phenyl)-1H- a compound of 吲哚-5-yl and n is 1; a compound wherein Y is thiazol-4-yl, Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl, and n is 1. a compound wherein Y is pyrimidin-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl, and n is 1; wherein Y is pyrimidin-2-yl and Z is 4 a phenyl-phenyl group, wherein n is a compound of 1; wherein Y is pyrimidin-2-yl, Z is 2-phenyl-benzothiazole-6-yl, and n is a compound of 1; wherein Y is thiazole- 2-based, Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl, and n is a compound of 1; wherein Y is thiazol-2-yl and Z is 2-phenyl a benzothiazole-6-yl group, wherein n is a compound of 1; wherein Y is phenyl, Z is 1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl, and n is a compound of 1 wherein Y is phenyl, Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl, and n is 1; wherein Y is phenyl and Z is 1-(3) , 4-difluoro-phenyl)-1H-indol-5-yl, and n is a compound of 1; wherein Y is thiazol-2-yl and Z is 2-phenyl-benzo a compound having an oxazol-6-yl group and wherein n is 1; wherein Y is pyrimidin-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl, and n is a compound of 2; Wherein Y is thiazol-2-yl, Z is 4-phenyl-phenyl, and n is a compound of 1; wherein Y is thiazol-2-yl and Z is 3-chloro-6-trifluoromethyl-benzo a compound wherein thiophen-2-yl and n is 2; a compound wherein Y is pyrimidin-2-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is 2 a compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is 2; wherein Y is thiazol-2-yl, Z is 2-phenyl-benzo a compound having an oxazol-6-yl group and wherein n is 2; and a pharmaceutically acceptable salt form thereof.

Embodiments of the invention relate to a compound of formula (Ib),

among them: a) Y _b is thiazolyl or pyrimidinyl; b) Z _b is one selected from benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl,

Wherein the heteroaryl group of Z _b is unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl and phenyl; Provided that the substituent of not more than one Z _b is a phenyl group, and the phenyl group is unsubstituted or substituted with one or two substituents, each of which is a trifluoromethyl group or a fluorine;

c) Z _b is a benzothienyl or anthracenyl group,

Wherein Z _b is unsubstituted or substituted with one or two substituents, each substituent being a trifluoromethyl or phenyl group, with the proviso that no more than one substituent of Z _b is a phenyl group, and the phenyl group is substituted The base is unsubstituted or substituted with a trifluoromethyl or fluoro substituent; and any combination of the above examples a) to c), with the proviso that it is understood that combinations of different embodiments in which the same substituents are combined are excluded And its mirror image isomers, non-image isomers, solvates and pharmaceutically acceptable salts.

Embodiments of the invention relate to a compound of formula (Ib),

Wherein: Y _b is thiazolyl or pyrimidinyl; Z _b is one selected from benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl, wherein the heteroaryl of Z _b is unsubstituted or substituted with one or two substituents, each substitution The substrate is independently selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl and phenyl; the limitation is that no more than one substituent of Z _b is phenyl, and the phenyl is unsubstituted or Substituted by one or two substituents, each substituent is trifluoromethyl or fluoro; and mirror image isomers, non-image isomers, solvates and pharmaceutically acceptable salts thereof.

Embodiments of the invention relate to a compound of formula (Ib),

Wherein: Y _b is a thiazolyl or pyrimidinyl group; Z _b is a heteroaryl group selected from the group consisting of a benzothienyl group and a fluorenyl group, wherein the heteroaryl group of Z _b is unsubstituted or Or two substituents, each substituent being a trifluoromethyl group or a phenyl group, with the proviso that no more than one Z _b substituent is a phenyl group, and the phenyl group is unsubstituted or via a trifluoromethyl group Or a fluorine substituent; and a mirror image isomer, a non-image isomer, a solvate thereof, and a pharmaceutically acceptable salt.

Embodiments of the invention relate to a compound of formula (Ib),

Is a compound wherein Y _b is pyrimidin-2-yl and Z _b is 6-trifluoromethyl-benzothiophen-2-yl; or wherein Y _b is pyrimidin-2-yl and Z _b is 1- a compound of (4-trifluoromethyl-phenyl)-1H-indol-5-yl; or a pharmaceutically acceptable salt thereof.

Regarding the use in medicine, the salts of the compounds of the formulae (Ia) and (Ib) refer to "pharmaceutically acceptable salts" which are non-toxic. However, other salts can be used in the preparation of the compounds of formula (Ia) and (Ib) or pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the compounds of formula (Ia) and (Ib) include acid addition salts, for example, which may be formed by mixing a solution of one of the compounds with a pharmaceutically acceptable acid solution, The acid is such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Further, if the compound of the formula (Ia) and (Ib) has an acidic moiety, suitable pharmaceutically acceptable salts thereof may include an alkali metal salt such as a sodium or potassium salt; an alkaline earth metal salt such as a calcium or magnesium salt. And a salt formed with a suitable organic ligand, such as a quaternary ammonium salt. Thus, representative pharmaceutically acceptable salts include acetate, besylate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, calcium ethylenediaminetetraacetate ( Calcium edetate), campsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, ethanedisulfonate (edisylate), propionate dodecane sulfate, esylate, fumarate, gluceptate, gluconate, glutamate , hydroxyacetamid phenyl arsenate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate Iodide, 2-hydroxyethanesulfonic acid (isothionate), lactate, lactobionate, laurate, malate, maleate, mandelic acid, mesylate, methyl bromide, methyl Nitrate, methyl sulfate, pyrophosphate, napsylate, nitrate, N-methyl reduced N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturate, salicylate, Stearates, sulfates, acetates, succinates, tannins, tartrates, teoclates, tosylates, triethiodides and valerates.

Representative acids and bases useful in the preparation of pharmaceutically acceptable salts include acids including acetic acid, 2,2-dichloroacetic acid, acetamino acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, Benzenesulfonic acid, benzoic acid, 4-ethylguanidinobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, citric acid, hexyl Acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, Formic acid, fumaric acid, galactose diacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L- Gluten, a-side oxygen-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactanoic 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-amino-salic acid, azelaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, hydrogen Calcium oxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-reduced glucosamine, sea Hydrabamine, 1H-imidazole, L-isoamine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholin, piperazine (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 (Ia) and (Ib). Generally, such prodrugs are functional derivatives of the compound that are rapidly converted to the desired compound in vivo. Therefore, in the method of treating or preventing the embodiment of the present invention, the phrase "administering" encompasses the compound disclosed by the specific disclosure, or may be not specifically disclosed, but may be converted into a body after administration to a patient. Compounds of this particular compound for the treatment or prevention of various such diseases, conditions, syndromes and disorders. Conventional procedures for the selection and preparation of suitable precursor drug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

If the compounds according to embodiments of the invention have at least one palm center, they may therefore be present as mirror image isomers. If the compound has two or more palmitic centers, they may additionally be present as non-image isomers. It is understood that all such isomers, as well as mixtures thereof, are within the scope of the invention. Furthermore, certain crystalline forms of the compound may exist as polymorphs, and such forms are intended to be included in the present invention. In addition, certain compounds may form solvates (with water as hydrates) with water or a common organic solvent, and such solvates are also intended to be encompassed within the scope of the invention. Those skilled in the art will understand that the terms of the compounds used herein are meant to include solvate compounds of formula (Ia) and (Ib).

If the process for the preparation of the compounds according to certain embodiments of the invention provides a mixture of stereoisomers, these isomers can be separated by prior art techniques such as preparative chromatography. The compound can be prepared in racemic form, or individual mirror image isomers can be prepared by enantiospecific synthesis or resolution. The compound can be resolved, for example, by its standard techniques as a component mirror image isomer, such as by reacting with an optically active acid such as (-)-di-p-tolylmethyl-d-tartaric acid and/or (+) -Di-p-tolylmethylidene-1-tartaric acid forms a salt to form a diastereomer pair, followed by fractional crystallization and free base regeneration. The compound can also be resolved by formation of an ester or guanamine of a non-image isomer, followed by separation and removal of the chiral auxiliary by chromatography. Alternatively, the compound can be resolved using a palm HPLC column.

An embodiment of the invention relates to a composition comprising a pharmaceutical composition comprising, consisting of, and/or consisting essentially of: (+)-mirror of a compound of formula (Ia) or (Ib) A construct wherein the composition is substantially free of the (-)-isomer of the compound. In the context of the present invention, it is not meant to mean substantially less than 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2%, and even more preferably less than about 1%. (-)-isomer, which is calculated as follows.

Another embodiment of the present invention is a composition comprising a pharmaceutical composition comprising, consisting of, and/or consisting essentially of: (-)-mirror of a compound of formula (Ia) or (Ib) A construct wherein the composition is substantially free of the (+)-isomer of the compound. In the context of the present invention, it is not meant to mean substantially less than 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2%, and even more preferably less than about 1%. (+)-isomer, which is calculated as follows.

In any process for preparing the various embodiments of the present invention, it may be necessary and/or advantageous to protect sensitive or reactive groups of any associated molecule. This can be achieved by existing protecting groups, such as those described in Protective Groups in Organic Chemistry, Second Edition, JFW McOmie, Plenum Press, 1973; TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. And TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. The protecting group can be removed in a convenient subsequent stage using methods known in the art.

Even though the compounds of the present invention (including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof) can be administered alone, they will generally be administered in accordance with the desired route of administration and standard pharmaceutical or animal medical practice. A pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent is incorporated. Accordingly, a particular embodiment of the invention relates to a pharmaceutical and animal pharmaceutical composition comprising a compound of formula (Ia) or (Ib) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and/or medicinal Acceptable diluent.

By way of example, in the pharmaceutical compositions of the present invention, the compounds of formula (Ia) and (Ib) may be admixed with any suitable binder, lubricant, suspending agent, coating agent, dissolving agent and combinations thereof. Hehe.

Solid oral dosage forms, such as tablets or capsules, containing a compound of the invention may be administered to at least one dosage form at a time, as appropriate. The compound can also be administered in a sustained release formulation.

Other oral dosage forms that may be used to administer the compounds of the invention include elixir, solutions, syrups and suspensions; each optionally containing a flavoring and coloring agent.

Alternatively, the compounds of formula (Ia) and (Ib) may be administered by inhalation (tracheal or nasal) or in the form of a suppository or pessary, or in the form of an emulsion, solution, cream, ointment or dusting powder. Topical administration. 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 an ointment at a concentration of from about 1% to about 10% (by weight of the cream), which comprises, consists of, and/or consists essentially of: a wax or soft paraffin matrix, together with any possibility Stabilizers and preservatives are required. An alternative means of administration involves transdermal administration using a skin or transdermal patch.

The pharmaceutical compositions of the invention (as well as the compounds of the invention alone) may also be administered parenterally, such as intracavernous, intravenous, intramuscular, subcutaneous, intradermal or intrathecal. In this case, the composition will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.

For parenteral injection, the pharmaceutical compositions of the present invention are preferably employed in the form of a sterile aqueous solution which may contain other materials such as sufficient salts and monosaccharides to render the solution isotonic with the blood.

For oral or sublingual administration, the pharmaceutical compositions of the present invention can be administered in the form of tablets or lozenges which can be made in a conventional manner.

By way of further example, a pharmaceutical composition comprising at least one compound of the formula (Ia) or (Ib) as an active ingredient can be obtained according to the existing pharmaceutical synthesis technique by using the compound with a pharmaceutically acceptable carrier, a pharmaceutical It can be prepared by mixing a diluent with a pharmaceutically acceptable excipient. The carrier, excipient and diluent can take a wide variety of different forms depending on the desired route of administration (eg, 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, flavors, 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 Similar. Solid oral preparations may also be optionally coated with a substance such as a sugar or coated with an enteric coating to adjust the primary location of absorption and disintegration. For parenteral administration, the carriers, excipients and diluents will usually include sterile water; and other ingredients may be added to increase the solubility and preservability of the composition. Injectable suspensions or solutions can also be prepared using aqueous carriers and suitable additives such as dissolving agents and preservatives.

In a mean (70 kg) human daily from about 1 to about 4 treatments, a therapeutically effective amount of one of the compounds of formula (Ia) or (Ib) or a pharmaceutical composition thereof, including the active ingredient, is as follows: about 0.1 mg to Approximately 3000 mg, or any particular amount or range thereof, especially from about 1 mg to about 1000 mg, or any particular amount or range thereof, more particularly from about 10 mg to about 500 mg, or any particular amount thereof or Scope; although it will be apparent to those skilled in the art that the therapeutically effective amount of a compound of formula (Ia) or (Ib) will vary with the disease, condition, condition, and disorder being treated.

With regard to oral administration, a pharmaceutical composition is preferably provided in the form of a tablet containing about 1.0, about 10, about 50, about 100, about 150, about 200, about 250 and about 500 mg. Compound Ia) or (Ib).

Advantageously, the compound of formula (Ia) or (Ib) can be administered in a single daily dose, or the total daily dose can be divided into two, three or four daily doses.

The optimal dosage of the compound of formula (Ia) or (Ib) administered can be readily determined and will vary depending upon the particular compound employed, the mode of administration, the strength of the formulation, and the progression of the disease, condition, condition or disorder. In addition, factors associated with the particular subject being treated include the subject's gender, age, weight, diet, and time of administration, which will require the dosage to be adjusted to achieve the appropriate level of treatment and desired therapeutic effect. Therefore, the above dosages are illustrative examples on average. Of course, it is feasible to require higher or lower doses in individual cases, and this is also included in the scope of the present invention.

Whenever a compound of formula (Ia) or (Ib) is required to be treated, any of the above compositions and dosage regimens may be used, or by the compositions and dosing regimens established in the art. Compound Ia) or (Ib).

As an MGL inhibitor, the compounds of the formula (Ia) and (Ib) can be used for the treatment and prevention of a disease, a syndrome, a condition or a disorder in a subject, the subject comprising an animal, a breastfeeding An animal and a human, wherein the disease, syndrome, condition, or disorder is affected by modulation (including inhibition) of the MGL enzyme. Such methods comprise, consist of, and consist essentially of administering a therapeutically effective amount of a compound of formula (Ia) or (Ib) to a subject in need of such treatment or prevention, including an animal, a mammal and a human. , salt or solvate.

General synthetic method

Representative compounds of the present invention can be synthesized in accordance with the general synthetic schemes described below, and are illustrated by subsequent procedures and examples. Since the process is an illustrative example, the invention should not be construed as being limited by the chemical reactions and conditions described in the process. The various starting materials used in the schemes and examples are either commercially available or can be prepared by methods well known to those skilled in the art. The variables are as defined herein.

The abbreviations used in this manual, especially those used in the process and examples, are as follows:

AcCl acetonitrile

AcOH glacial acetic acid

Aq.

Bn or Bzl benzyl

Boc tertiary butoxycarbonyl

Conc.

DCC N,N'-dicyclohexyl-carbodiimide

DCE 1,2-dichloroethane

DCM dichloromethane

DIPEA diisopropyl-ethylamine

DMAP 4-dimethylamine pyridine

DMF N,N-dimethylformamide

DMSO dimethyl hydrazine

DPPA diphenylphosphoryl azide

EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

ESI electrospray ionization

EtOAc ethyl acetate

EtOH ethanol

h hours

HATU O-(1H-7-Nitrobenzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate

HBTU O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate

HEK human fetal kidney (embryonic kidney)

HEPES (4-(2-hydroxyethyl)-1-piperidyl Ethane

Sulfonic acid

HPLC high performance liquid chromatography

mCPBA m-chloroperoxybenzoic acid

MeCN acetonitrile

MeOH methanol

MeOTf methyl triflate

MHz megahertz

Min minute

MS mass spectrometry

NMR nuclear magnetic resonance

PIPES piperazine -N,N'-bis(2-ethanesulfonic acid)

PyBrOP bromo-gin-pyrrolidinium

Hexafluorophosphate

RP reverse phase

R _t residence time

TEA or Et ₃ N triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMS tetramethyl decane

Scheme A illustrates a synthetic route to a compound of formula (Ia) wherein the Y and Z systems are as defined herein.

Compounds of formula A1 are commercially available or can be prepared by conventional methods described in the scientific literature. A compound of formula A1 can be reductively aminated with a compound of formula A2 wherein P is an existing amine protecting group such as Boc, Fmoc, Cbz and the like in the presence of a hydride source such as sodium triethoxysulfonate. A compound of formula A3 is given. The Y group of the present invention can be iodinated by a compound of the formula A4 (i.e., YX, wherein X is a suitable leaving group such as bromine or iodine, and under certain reaction conditions may be chlorine or triflate) Copper, 1,10-morpholine is introduced in the presence of potassium phosphate to produce a compound of formula A5. The protecting group (P) is removed in a conventional manner to yield a compound of formula A6. A compound of formula A6 may be prepared by the use of an A7 carboxylic acid (wherein Q is a hydroxy group) in the presence of a suitable coupling reagent such as HATU, DCC, EDC, HBTU, PyBrOP and the like; and optionally in the presence of a base such as DIPEA to yield a formula (Ia) compound. Similarly, a formula A7 chloroquinone (wherein Q is chloro) can be used to cause deuteration of a compound of formula A6. In such cases, a non-nucleophilic base such as pyridine can be added to yield a compound of formula (Ia).

Scheme B illustrates a synthetic route to a compound of formula (Ib) wherein Y _b and Z _b are as defined herein.

Process B

Compounds of formula A2 are commercially available and can be deprotected using existing chemical methods to yield the corresponding amine of formula B1. Treatment of a compound of formula B1 with a compound of formula B2 (in a manner analogous to that described for Scheme A for Scheme A7) yields a compound of formula B3. Reductive amination with a diamine of formula B4 wherein P is an existing amine protecting group in the presence of a hydride source such as sodium triethoxysulfonate produces a compound of formula B5. Deuteration with a formula of B6 ruthenium chloride followed by removal of the protecting group (P) by an existing method will provide a cyclized product of formula B7. A compound of formula B7 may be a compound of the formula B8 (wherein X _b is fluoro, bromo, chloro, iodo or triflate) compound to yield a treated formula (Ib) to react under suitable conditions. For example, when Y _b is 2-pyrimidinyl, 4-pyrimidinyl, 2-pyridyl, 2-thiazolyl or 2- In the case of 2-oxazolyl, a compound of formula B8 is added in the presence of a base such as potassium carbonate or sodium hydrogencarbonate to provide the desired compound of formula (Ib). Alternatively, other Y _b groups of the invention may be combined by the addition of Y _b -X _b (B8) in the presence of a palladium catalyst, optionally with a phosphine ligand, and in the presence of an inorganic base such as potassium carbonate.

Scheme C illustrates one of the compounds of formula (Ib) in place of the synthetic route, wherein Y _b and Z _b are as defined herein.

Compounds of formula B8 (which may be commercially available or prepared by conventional methods found in the scientific literature) may be treated with a compound of formula B4 to yield a compound of formula C1. More specifically, when Y _b of formula B8 is 2-pyrimidinyl, 4-pyrimidinyl, 2-pyridyl, 2-thiazolyl or 2- In the case of oxazolyl, a compound of formula B8 is added in the presence of a base such as potassium carbonate or sodium hydrogencarbonate to provide the desired compound of formula C1. Alternatively, other Y _b groups of the invention may be combined by the addition of B8 in the presence of a palladium catalyst, optionally with a phosphine ligand, and in the presence of an inorganic base such as potassium carbonate. Removal of the amine protecting group (P) by prior methods followed by reductive alkylation with a compound of formula A2 yields a compound of formula C2. Deuteration with a compound of formula B6 followed by treatment with a strong base such as sodium hydride affords the cyclized product of formula C3. Amine-based deprotection will provide the corresponding free amine of formula C4 which will yield a compound of formula (Ib) upon deuteration with a compound of formula B2 as previously described.

Scheme D illustrates the preparation of certain compounds of formula A7 and B2 (Q is hydroxy) the available intermediates, wherein Z / Z _b is a substituted selectively by one of the phenyl group (Ar _D) substituted heteroaryl. For illustrative purposes only, the heteroaryl ring is represented by one oxime.

Compounds of formula D1 are commercially available or can be prepared by conventional methods described in the scientific literature. The compound D1 can be treated with a solution of iodinated benzene of the formula D2 in the presence of copper iodide, trans-N,N'-dimethylcyclohexane-1,2-diamine and potassium phosphate to give a compound of the formula D3. Subsequent saponification yields a useful intermediate of the formula D4 carboxylic acid.

Scheme E illustrates the preparation of certain useful intermediates of formula A7 and B2 (Q is a hydroxy group) wherein Z/Z _b is a phenyl group substituted with a selectively substituted phenyl group. Benzoxazolyl (Ar _E ).

Compounds of formula E1 are commercially available or can be prepared by conventional methods described in the scientific literature. The compound of the formula E1 can be optionally substituted by the formula E2 benzoic acid chloride in an organic solvent such as two Treatment in a dioxane at elevated temperature to produce a substituted benzoate of formula E3 Benzoxazole. Subsequent saponification yields a useful intermediate of the formula E4 carboxylic acid.

Scheme F illustrates the preparation of certain useful intermediates of formula A7 and B2 (Q is a hydroxy group) wherein Z/Z _b is a selectively substituted benzothienyl group and R _F represents as in formula (Ia) Suitable substituents as defined in formula (Ib).

Process F

Formula F1 compounds are either commercially available or can be prepared by conventional methods described in the scientific literature. The compound of formula F1 can be treated with sulfoxide in an aprotic organic solvent followed by methanol to yield a compound of formula F2. Subsequent saponification yields a useful intermediate of formula F3 carboxylic acid. Those skilled in the art will appreciate that asymmetrically substituted compounds of formula F1 can result in a mixture of positional isomers when cyclized with sulfinium chloride. The isomers can then be separated and separated using existing chromatographic methods known to those skilled in the art.

Scheme G illustrates the preparation of certain compounds of formula A7 and B2 (Q is hydroxy) the available intermediates, wherein Z / Z _b is a substituted selectively by one of benzyl (Ar _T - methyl) substituted phenyl.

Compounds of formula G1 are commercially available or can be prepared by conventional methods described in the scientific literature. The compound of formula G1 can be treated with a suitably substituted formula G2 boronic acid or ester in the presence of a palladium catalyst and a suitable base such as potassium carbonate to yield a compound of formula G3. Subsequent saponification will provide a useful G4 carboxylic acid intermediate.

Scheme H illustrates the preparation of certain useful intermediates of formula A7 and B2 (Q is a hydroxy group) wherein Z/Z _b is a benzene substituted with a fluoro substituent and a selectively substituted phenyl group (Ar _H ) And a thienyl group.

Compounds of formula H1 are commercially available or can be prepared by conventional methods described in the scientific literature. The compound of formula H1 can be cross-coupled with boric acid or ester (H2) in the presence of a palladium catalyst; and in the presence of a suitable base such as potassium carbonate to yield a compound of formula H3. Saponification yields the corresponding carboxylic acid H4 which can be treated with N-fluorobenzenesulfonimide in the presence of an organometallic base such as n-butyllithium to yield a fluorinated compound of formula H5.

Scheme I illustrates the preparation of certain compounds of formula A7 and B2 (Q is hydroxy) the available intermediates, wherein Z / Z _b is a substituted selectively by one of the phenyl group (Ar _I) substituted benzothiazolyl group.

Compounds of formula I1 are commercially available or can be prepared by conventional methods described in the scientific literature. The compound of formula I1 can be cross-coupled with boric acid or ester (I2) in the presence of a palladium catalyst; and in the presence of a suitable base such as potassium carbonate to yield a compound of formula I3. Saponification yields the corresponding carboxylic acid of formula I4.

Example 1 4-pyrimidin-2-yl-1-(1-{[6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}tetrahydroindol-3-yl)piperidinyl -2-ketone, Cpd 23

Step A. 1-(6-Trifluoromethyl-benzo[b]thiophene-2-carbonyl)-tetrahydroindol-3-one 1e. The N-Boc- 3-one-tetrahydroacridine Well 1a (171 mg, 1.0 mmol) and TFA (1 mL) was stirred for 2 hours at room temperature in a solution of _{CH 2 Cl 2 (4 mL)} . The solution was concentrated to provide intermediate 1b which was used in the next step without further purification. Add oxalic acid chloride (0.105 mL, 1.2) to a suspension of 6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid 1c (246 mg, 1.0 mmol) in CH ₂ Cl ₂ (10 mL) Methyl) followed by DMF (2 drops). The reaction mixture was stirred at room temperature for 4 h and concentrated to give EtOAc (EtOAc). To 1b (1.0 mmol) and _{Et 3 N (0.835 mL, 6.0} mmol) was added 1d at 0 ℃ in the solution of CH ₂ Cl ₂ (7 mL) of (1.0 mmol) in CH ₂ Cl ₂ (5 mL) in Solution. The reaction mixture was slowly warmed to room temperature over 2 hours, and is quenched aqueous NaHCO _3. The resulting mixture was extracted with CH ₂ Cl ₂ . The organic solution was dried over Na ₂ SO ₄ and concentrated. Purification by column chromatography (EtOAc, 40%EtOAcEtOAcEtOAc)

Step B. {2-[1-(6-Trifluoromethyl-benzo[b]thiophene-2-carbonyl)-tetrahydroindol-3-ylamino]-ethyl}-carbamic acid tert-butyl 1 g of ester.

Add Na to a mixture of 1e (62 mg, 0.207 mmol), N-Boc-ethylenediamine 1f (100 mg, 0.62 mmol) and acetic acid (0.3 mL) in 1,2-dichloroethane (3 mL) (OAc) ₃ BH (53 mg, 0.25 mmol). The reaction mixture was stirred overnight at room temperature and then quenched in aqueous NaHCO _3. The resulting mixture was extracted with CH ₂ Cl ₂ . The organic solution was dried over Na ₂ SO ₄ and concentrated. By column chromatography (silica _{gel, 4% MeOH / CH 2 Cl} 2) provides the purified form of a colorless oil of intermediate 1g (30 mg).

Step C. Cpd 23

To 1g (30 mg, 0.068 mmol) and _{Et 3 N (0.04 mL, 0.28} mmol) was added chloro-acetyl chloride (11.5 mg, 0.10 mmol) at 0 ℃ in a solution of CH ₂ Cl ₂ (3 mL) in. The reaction mixture was stirred at 0 ℃ 1.5 hours and then quenched in aqueous NaHCO _3. The resulting mixture was extracted with CH ₂ Cl ₂ . The organic solution was dried over Na ₂ SO ₄ and concentrated. The resulting residue was stirred with CH ₂ Cl _{2 (2} mL) of the TFA (0.5 mL) 1.5 hours. The solution was concentrated, and the residue was stirred for 24 hours (3 mL) in THF with aqueous NaHCO ₃ (2 mL). To the obtained intermediate 1 h (in this mixture of aqueous NaHCO ₃ and THF) was added K ₂ CO ₃ (28 mg, 0.20 mmol) and 2-bromopyrimidine (32 mg, 0.20 mmol). The reaction mixture was heated to reflux for 16 hours, then extracted in CH ₂ Cl _2. The organic solution was dried over Na ₂ SO ₄ and concentrated. By column chromatography (silica _{gel, 3% MeOH / CH 2 Cl} 2) to afford Cpd as a white solid of 23 (7 mg). MS 462 (M+H ⁺ ).

Example 2 4-pyrimidin-2-yl-1-[1-({1-[4-(trifluoromethyl)phenyl]-1H-indol-5-yl}carbonyl)tetrahydroindol-3-yl] Piper -2-ketone, Cpd 24

Step A. [2-(Pyrimidin-2-ylamino)-ethyl]-carbamic acid tert-butyl butyl ester 2a.

2-Bromopyrimidine 1i (600 mg, 3.77 mmol), N-Boc-ethylenediamine 1f (1000 mg, 6.24 mmol) and K ₂ CO ₃ (781 mg, 5.66 mmol) Dioxane (20 mL) and H mixture (10 mL) of the ₂ O was heated to reflux for 9 hours. Concentrate the mixture to remove most of the two The alkane was taken and the mixture was extracted with EtOAc. The organic solution was washed with aqueous NaCl, dried in Na ₂ SO ₄ and concentrated. Purification by column chromatography (EtOAc, 50%EtOAcEtOAcEtOAc)

Step B. 3-[2-(Pyrimidin-2-ylamino)-ethylamino]-tetrahydroindole-1-carboxylic acid tert-butyl ester 2b.

A mixture of intermediate 2a (610 mg, 2.56 mmol) and the solution in CH ₂ Cl ₂ (8 mL) was stirred for 2 hours at room temperature in TFA (2 mL). The solution was concentrated. The residue obtained was combined with N-Boc-tetrahydroindol-3-one 1a (526 mg, 3.07 mmol) and Na(OAc) ₃ BH (651, 3.07 mmol) in 1,2-dichloroethane (8 mL) Stir at room temperature overnight with HOAc (0.8 mL). Additional 1a (175 mg, 1.02 mmol) and _{Na (OAc) 3 BH (217} mg, 1.02 mmol) was added. The reaction was stirred for an additional 5 hours, then quenched in aqueous NaHCO _3. The resulting mixture was extracted with CH ₂ Cl ₂ . The organic solution was dried over Na ₂ SO ₄ and concentrated. By column chromatography (silica _{gel, 6% MeOH / CH 2 Cl} 2) to afford a pale yellow solid of Intermediate 2b (268 mg).

Step C. 3-(2-Sideoxy-4-pyrimidin-2-yl-piperidin 1-yl)-tetrahydroindole-1-carboxylic acid tertiary butyl ester 2c.

To Intermediate 2b (210 mg, 0.72 mmol) and _{Et 3 N (0.50 mL, 3.58} mmol) was added chloro-acetyl chloride (0.086 mL at 0 ℃ in a solution of CH ₂ Cl ₂ (8 mL) in, 1.07 mmol ). The reaction was slowly warmed to room temperature over 3 hours. And it is extracted with CH ₂ Cl ₂ aqueous NaHCO ₃ to quench. The organic solution was dried over Na ₂ SO ₄ and concentrated. NaH (60% in oil, 24 mg, 0.60 mmol) was added at 0<0>C in a solution of the crude material (150 mg, 0.41 mmol). The reaction was slowly warmed to room temperature over 3 hours. Which was extracted with EtOAc and H ₂ O to quench. The organic solution was washed with aqueous NaCl, dried in Na ₂ SO ₄ and concentrated. By column chromatography (silica _{gel, 3% MeOH / CH 2 Cl} 2) to afford a white solid of Intermediate 2c (47 mg).

Step D. Cpd 24

Intermediate 2c (47 mg, 0.14 mmol) in the solution was stirred for 1.5 hours at room temperature in CH ₂ Cl _{2 (2} mL) and TFA (0.5 mL). The reaction mixture was concentrated and the resulting residue was dissolved in _{CH 2 Cl 2 (5 mL)} , and diethyl ether was added (0.42 mL, 0.42 mmol) in of 1N HCl. The mixture was concentrated to provide intermediate 2d which was used in the next step without further purification. Intermediate 2d (0.14 mmol), 1-(4-trifluoromethyl-phenyl)-1H-indole-5-carboxylic acid 2e (56 mg, 0.18 mmol), HATU (70 mg, 0.18 mmol) A mixture of Et ₃ N (0.11 mL, 0.85 mmol) in CH ₂ Cl ₂ (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ether and washed with NaHCO ₃ and aqueous NaCl. The organic solution was dried over Na ₂ SO ₄ and concentrated. By (silica _{gel, 3% MeOH / CH 2 Cl} 2) was purified by column chromatography to provide Cpd 24 (46 mg). MS 521 (M+H ⁺ ).

Example 3 1-pyrimidin-2-yl-4-[1-({1-[4-(trifluoromethyl)phenyl]-1H-indol-5-yl}carbonyl)tetrahydroindol-3-yl] Piper -2-ketone, Cpd 3

Step A. 3-Phenoxy-4-pyrimidin-2-yl-piperidin 1-carboxylic acid tertiary butyl ester 3b.

1-Boc-3-oxopiperine in DMF (5 mL) (1-Boc-3-oxopiperazine) 3a (390 mg, 1.95 mmol) was added NaH (60% in oil, 97 mg, 2.44 mmol). The reaction was stirred at 0 <0>C for 25 min then 2-bromopyrimidine 1i (465 mg, 2.92 mmol) in DMF (2 mL). The reaction was slowly warmed to room temperature overnight. H ₂ O was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic solution was washed with aqueous NaCl, dried in Na ₂ SO ₄ and concentrated. By column chromatography (silica _{gel, 3% MeOH / CH 2 Cl} 2) to afford 3b as a yellow-oil (120 mg).

Step B. 3-(3-Oxy-4-pyrimidin-2-yl-piperidin 1-yl)-tetrahydroindole-1-carboxylic acid tertiary butyl ester 3c.

Intermediate 3b (120 mg, 0.43 mmol) in the solution was stirred for 1.5 hours at room temperature in TFA (0.75 mL) and _{CH 2 Cl 2 (3 mL)} . The solution was concentrated. The residue obtained was combined with N-Boc-tetrahydroindol-3-one 1a (81 mg, 0.47 mmol) and Na(OAc) ₃ BH (100, 0.47 mmol) in 1,2-dichloroethane (4 mL) Stir at room temperature overnight with HOAc (0.2 mL). The reaction was quenched aqueous NaHCO _3. The resulting mixture was extracted with CH ₂ Cl ₂ . The organic solution was dried over Na ₂ SO ₄ and concentrated. By column chromatography (silica _{gel, 3% MeOH / CH 2 Cl} 2) to afford a pale yellow solid of intermediate 3c (15 mg).

Step C. Cpd 3

Cpd 3 was prepared according to the procedure described in Example 2, Step D, using intermediates 3c and 2e as starting materials. MS 521 (M+H ⁺ ).

The following compounds were prepared using the procedure described in Example 3, except that commercially available 1-phenyl-piperone was used. 2-ketone was used as the starting material.

Example 3a

A. Methyl 1-(4-fluorophenyl)-indole-5-carboxylate, 3 g.吲哚-5-carboxylic acid methyl ester 3e (0.5 g, 2.85 mmol), 1-bromo-4-fluoro-benzene 3f (2 mL, 18.21 mmol), CuI (0.544 g, 2.85 mmol) and K ₂ CO ₃ A mixture of (0.591 g, 4.28 mmol) was heated in a microwave at 220 °C for 2.5 hours. The reaction mixture was diluted with CH _{2 2} Cl and filtered. The solution was concentrated and the residue was purified by flash chromatography eluting eluting eluting

I. 1-(4-Fluorophenyl)-indole-5-carboxylic acid, 3 h. Methyl 1-(4-fluorophenyl)-indole-5-carboxylate 3 g (0.58 g, 2.15 mmol) and LiOH‧H ₂ O (0.36 g, 8.6 mmol) in THF (15 mL) with H ₂ The mixture in O (10 mL) was stirred at room temperature for 5 days. A 10% aqueous HCl solution was added to the reaction mixture to adjust the pH = 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aqueous NaCl, dried over Na ₂ SO ₄ and concentrated to afford 3h (0.5 g).

The following intermediates were prepared according to the procedure described in Example 3a above and substituting the appropriate reagents, starting materials and purification methods familiar to those skilled in the art:

Example 4 4-(1-{[1-(4-fluorophenyl)-1H-indol-5-yl]carbonyl}tetrahydroindol-3-yl)-1-pyrimidin-2-ylpiperidyl -2-ketone, Cpd 4

Step A. 3-(3-Side Oxygen-Peptide 1-yl)-tetrahydroindole-1-carboxylic acid tertiary butyl ester 4b.

3-oxopiperine 4a (490 mg, 4.89 mmol) and N-Boc-tetrahydroindol-3-one 1a (922 mg, 5.38 mmol) in 1,2-dichloroethane (10 mL) and HOAc (0.5 mL) was added _{Na (OAc) 3 BH (1141,5.38} mmol). The reaction was stirred at room temperature overnight. Additional 1a (335 mg, 1.96 mmol) and _{Na (OAc) 3 BH (415} mg, 1.96 mmol) was added. The reaction was stirred for a further 24 hours, then quenched in aqueous NaHCO _3. The resulting mixture was extracted with CH ₂ Cl ₂ . The organic solution was dried over Na ₂ SO ₄ and concentrated. By column chromatography (silica _{gel, 4% MeOH / CH 2 Cl} 2) to afford as a white solid of intermediate 4b (860 mg).

Step B. 3-(3-Oxy-4-pyrimidin-2-yl-piperidin 1-yl)-tetrahydroindole-1-carboxylic acid tertiary butyl ester 3c.

Intermediate 4b (52 mg, 0.204 mmol), 2-bromopyrimidine 1i (65 mg, 0.41 mmol), CuI (8 mg, 0.04 mmol), 1,10-morpholine (18 mg, 0.10 mmol) and K _{3 PO 4 (95 mg, 0.45 mmol} ) in toluene (1 mL) was heated in the N ₂ at 110 ℃ 9 hours. The reaction mixture was diluted with CH _{2 2} Cl and filtered. The solution was concentrated and (silica _{gel, 3% MeOH / CH 2 Cl} 2) was purified by column chromatography to provide a pale yellow solid of intermediate 3c (25 mg).

Step C. Cpd 4

Cpd 4 was prepared according to the procedure described in Example 2, Step D, using intermediate 3c and 1-(4-fluoro-phenyl)-1H-indole-5-carboxylic acid 3h as starting material. MS 471 (M+H ⁺ ).

The following compounds were prepared according to the procedure described in Example 4.

Example 5 4-(1-{[3-chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}tetrahydroindol-3-yl)-1-pyrimidin-2-ylperidine -2-ketone, Cpd 8

The intermediate 3c (the preparation procedures of Example 4 by) in the solution was stirred for 1 hour at room temperature in CH ₂ Cl _{2 (2} mL) and TFA (0.5 mL). The solution was concentrated, and the residue was dissolved in _{CH 2 Cl 2 (2.5 mL)} . Et ₃ N (0.11 mL, 0.79 mmol) was added to the resulting solution at 0 ° C, followed by 3-chloro-6-trifluoromethyl-benzo[b]thiophene-2-carbonylcarbonyl 5a (prepared from 3 - chloro-6-trifluoromethyl - benzo [b] thiophene-2-carboxylic acid, prepared according to this procedure based step 1 of example A) (0.14 mmol) in CH ₂ Cl ₂ (1.5 mL) in the Solution. The reaction was slowly warmed to room temperature over 2 hours, and is quenched aqueous NaHCO _3. The mixture was extracted with CH ₂ Cl ₂ . The organic solution was dried over Na ₂ SO ₄ and concentrated. By column chromatography (silica _{gel, 3% MeOH / CH 2 Cl} 2) to afford as a yellow solid of Cpd 8 (28 mg). MS 496 (M+H ⁺ ).

The following compounds were prepared according to the procedure described in Example 5.

Example 6 4-(1-{[3-chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}tetrahydroindol-3-yl)-1-phenylperidine -2-ketone, Cpd 14

Cpd 14 was prepared as intermediates 6a and 5a according to the procedure described in Example 5. Intermediate 6a was prepared according to the procedure described in Example 3, Step B, using commercially available 1-phenyl-peri 2-ketone was used as the starting material. MS 494 (M+H ⁺ ).

Examples 7-26 provide synthetic routes for the preparation of useful intermediates for compounds of formula (I).

Example 7

A. 1-(3-Trifluoromethyl-phenyl)-1H-indazole-5-carboxylic acid ethyl ester (7c) with 2-(3-trifluoromethyl-phenyl)-2H-carbazole- 5-carboxylic acid ethyl ester (7d). 1H-indazole-5-carboxylic acid ethyl ester 7a (150 mg, 0.79 mmol), 1-bromo-3-trifluorotoluene 7b (0.13 mL, 0.95 mmol), CuI (22.5 mg, 0.12 mmol), N, N'- dimethyl cyclohexane-1,2-diamine (0.056 mL, 0.36 mmol) in toluene (1.5 mL) and heated in the K (, 1.74 mmol 0.37 g) 3 PO 4 at 110 ℃ 16 hours. The reaction mixture was diluted with CH _{2 2} Cl and filtered. The solution was concentrated and the residue was purified by flash column chromatography eluting eluting eluting

B. 1-(3-Trifluoromethyl-phenyl)-1H-indazole-5-carboxylic acid (7e) with 2-(3-trifluoromethyl-phenyl)-2H-indazole-5- Carboxylic acid (7f). 7c and 7d of the mixture and H ₂ O (60 mL) of LiOH in a stirred for 5 days at room temperature in THP (120 mL). A 10% aqueous HCl solution was added to the reaction mixture to adjust the pH = 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl solution, dried over Na ₂ SO ₄ and concentrated to afford 7e and 7f.

Example 8

A. 2-(4-Fluoro-benzylaminoamido)-3-hydroxy-benzoic acid methyl ester, 8c. 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate 8a, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 8b, 10 mL of DMF and 2.9 mL (20.6 mmol) of TEA The flask was placed and stirred for 10 minutes. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give <RTI ID=0.0>>>>> MS m/z (M+H ⁺ ) 290.1.

B. 2-(4-Fluorophenyl)benzo[d] Methyl azole-4-carboxylate, 8d. 2-(4-Fluoro-benzylaminoamido)-3-hydroxy-benzoic acid methyl ester 8c (7.4 mmol, 1.2 g crude product) and 1.3 g (7.5 mmol) of p-toluenesulfonic acid in 10 mL of Reflow in toluene overnight. After cooling, saturated NaHCO ₃ was added and the resulting mixture was extracted with EtOAc. The organic solvent was evaporated to provide 1.1 g (55%) of 2-(4-fluorophenyl)benzo[d] Methyl azole-4-carboxylate, 8d. MS m/z (M+H ⁺ ) 272.0.

C. 2-(4-Fluorophenyl)-benzo[d] Oxazole-4-carboxylic acid, 8e. 1.1 g (4.0 mmol) of 2-(4-fluorophenyl)benzo[d] A mixture of methyl ester of azole-4-carboxylate 8d and 3.7 mL of aqueous 3N NaOH in 10 mL of THF was refluxed overnight. After cooling, the reaction mixture was poured into water and acidified with concentrated HCl. The resulting solid was filtered and dried to give 830 mg (79%) of 2-(4-fluorophenyl)-benzo[d] Oxazole-4-carboxylic acid, 8e. MS m/z (M+H ⁺ ) 258.1.

The following intermediate compounds were prepared according to the procedure described in Example 8 above and substituting the appropriate reagents, starting materials and purification methods familiar to those skilled in the art:

Example 9

A. Methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 9b. Argon was bubbled through methyl 4-bromobenzoate 9a (9.3 mmol, 2.0 g), 2 mL THF and 4-trifluoromethylbenzyl zinc chloride (0.5 M in THF, 46.5 mmol, 93 mL) The mixture was allowed to stand for 5 minutes. Pd(dffp)Cl ₂ ‧CH ₂ Cl ₂ (0.5 mol, 409 mg) was added and the reaction tube was capped and heated at 70 ° C for 16 hours. The mixture was cooled and filtered through celite. Water was added to the filtrate and the resulting solid was filtered. The organic solution was dried over MgSO ₄ and concentrated. The crude product was purified by flash chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc , 9b.

B. 4-(4-(Trifluoromethyl)benzyl)benzoic acid, 9c. Methyl 4-(4-(trifluoromethyl)benzyl)benzoate 9b (1.5 g, 5.1 mmol) was refluxed with aq. After cooling, the mixture was poured into ice water and acidified with concentrated HCl. The resulting solid was filtered and dried to give 1.31 g (92%) of 4-(4-(trifluoromethyl)benzyl)benzoic acid, 9c. MS m/z (M+H ⁺ ) 279.1.

Intermediate compounds are optionally prepared by the following alternative procedures:

Methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 9b. 4-bromomethyl-benzoic acid methyl ester 9d (1.0 g, 4.37 mmol), 4-trifluorophenylboronic acid 9e (0.995 g, 5.24 mmol) and Pd(PPh ₃ ) ₄ (50 mg, 0.044 mmol) two The mixture in alkane (15 mL) was stirred at room temperature for 1 min. Next, 4 mL of an aqueous 2 M Na ₂ CO ₃ solution was added. The resulting solution was heated at 90 ° C for 5 hours and then cooled to room temperature. EtOAc and water were added to the reaction mixture. The organics were concentrated and purified by flash chromatography (EtOAc EtOAc EtOAc

Example 10

A. Methyl 5-phenyl-benzo[b]thiophene-2-carboxylate, 10c. Compound 10a (542.3 mg, 2 mmol), phenylboronic acid 10b (268.2 mg, 2.2 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (98 mg, 0.12 mmol) and K ₂ CO ₃ (414.6 mg, a mixture of 3 mmol) (in two The alkane (4 mL) / water (1 mL) mixture was placed in a capped vial and heated at 80 ° C overnight. The reaction mixture was then diluted with EtOAc and water. The organic layer was concentrated under reduced pressure and purified by flash column chromatography eluting eluting MS m/z (M+H ⁺ ) 269.1.

B. 5-Phenyl-benzo[b]thiophene-2-carboxylic acid, 10d. Compound 10c (510 mg, 1.9 mmol) and _{LiOH.H 2 O (319 mg, 7.6} mmol) in THF / H (10/10 mL) ₂ O in the solution was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The aqueous layer was acidified with aqueous 1N HCl to pH ~ 4 and extracted in CH ₂ Cl _2. The organic solution was dried over Na ₂ SO ₄ and concentrated to afford 10d (479 mg), which is used without further purification in the next reaction. MS m/z (M+H ⁺ ) 255.0.

C. 3-Fluoro-5-phenyl-benzo[b]thiophene-2-carboxylic acid, 10e. To a solution of compound 10d (507 mg, 1.99 mmol) in THF (8 mL) EtOAc (EtOAc) The mixture was stirred at -70 °C for 1 hour; then a solution of N-fluorobenzenesulfonimide (817.3 mg, 2.59 mmol) in THF (2 mL) was slowly added. The reaction mixture was allowed to warm to rt and stirred overnight. The resulting mixture was partitioned between dilute aqueous HCl and EtOAc. The organic solution was washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was tritiated CH ₂ Cl _2, filtered and the solid was dried to provide Compound 10e (391.9 mg). MS m/z (M+H ⁺ ) 273.0.

D. 3-Fluoro-5-phenyl-benzo[b]thiophene-2-carbonyl chloride, 10f. The compound 10e (136.2 mg, 0.5 mmol) was added in a solution of CH ₂ Cl ₂ (5 mL) at room temperature _{(COCl) 2 (0.064 mL,} 0.75 mmol), followed by DMF (0.01 mL, 0.125 mmol) . The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated to provide compound 10f (light pink powder).

Example 11

A. 6-Methyl 3-(4-fluorophenyl)-1H-indole-1,6-dicarboxylic acid 1-tertiary butyl ester, 11c. Compound 11a (1.00 g, 2.49 mmol), 4-fluorophenylboronic acid 11b (523 mg, 3.74 mmol), Pd(OAc) ₂ (44.8 mg, 0.2 mmol), 2-dicyclohexylphosphino-2', A mixture of 6'-dimethoxybiphenyl (SPhos, 204.7 mg, 0.5 mmol) and K ₃ PO ₄ (1.06 g, 4.99 mmol) in toluene (5 mL) was placed in a capped vial and at 90 ° C Heat in N ₂ for 3 hours. The reaction mixture was then diluted with EtOAc and water. The organic layer was washed with EtOAc (EtOAc EtOAc (EtOAc) Further recrystallization gave a white solid (707 mg). MS m/z (M+H ⁺ ) 370.2.

B. 3-(4-Fluorophenyl)-1H-indole-6-carboxylic acid methyl ester, 11d. The compound 11c (705 mg, 1.91 mmol) was added trifluoroacetic acid (1.5 mL) at room temperature in a solution of CH ₂ Cl ₂ (4 mL) in. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to give compound 11d (603.3 mg) as a white solid. MS m/z (M+H ⁺ ) 270.1.

C. 3-(4-Fluoro-phenyl)-1H-indole-6-carboxylic acid, 11e. Compound 11d (303 mg, 0.79 mmol) and _{LiOH.H 2 O (132.7 mg, 3.16} mmol) (10 mL / 10 mL) the solution was stirred for 5 hours at 45 ℃ in THF / H ₂ O. The resulting mixture was concentrated and diluted with water. The aqueous layer was acidified with aqueous 1N HCl to pH ~ 4 and extracted in CH ₂ Cl _2. The organic solution was dried over Na ₂ SO ₄ and concentrated to afford 11e (249 mg). MS m/z (M+H ⁺ ) 256.0.

The following intermediate compounds were prepared according to the procedure described in Example 11 above and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art:

Example 12

A. 3-(4-Fluoro-phenyl)-1-methyl-1H-indole-6-carboxylic acid methyl ester, 12a. NaH (60% in mineral oil, 68.9 mg, 1.72 mmol) was added to a solution of compound 11d (300 mg, 0.78 mmol) in DMF (3 mL). The mixture was stirred for 30 min at 0 ℃, after the _{CH 3 I (0.053 mL, 0.86} mmol) was added and stirring was continued for another 1 hour at 0 ℃. The resulting mixture was diluted with EtOAc and water. The organic layer was washed with brine and concentrated. The residue was recrystallized from heptane, filtered and dried to afford compound 12a (265 mg). MS m/z (M+H ⁺ ) 284.1.

B. 3-(4-Fluoro-phenyl)-1-methyl-1H-indole-6-carboxylic acid, 12b. Compound 12a (264 mg, 0.93 mmol) and _{LiOH.H 2 O (156.4 mg, 3.73} mmol) (10 mL / 10 mL) the solution was stirred for 5 hours at 45 ℃ in THF / H ₂ O. The resulting mixture was concentrated and diluted with water. The aqueous layer was acidified with aqueous 1N HCl to pH ~ 4 and extracted in CH ₂ Cl _2. The organic solution was dried over Na ₂ SO ₄ and concentrated to provide compound 12b (252 mg). MS m/z (M+H ⁺ ) 270.1.

The following intermediate compounds were prepared according to the procedure described in Example 12 above and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art:

Example 13

A. 1-Methyl-3-phenyl-1H-indazole-5-carboxylic acid ethyl ester, 13b. Compound 13a (300 mg, 0.91 mmol), phenylboronic acid 10b (133 mg, 1.09 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (40 mg, 0.055 mmol) and K ₂ CO ₃ (251.2 mg, A mixture of 1.82 mmol) in a mixture of toluene (2 mL) / water (0.4 mL) was placed in a capped vial and heated at 90 ° C overnight. The reaction mixture was then diluted with EtOAc and water. The organic layer was concentrated under reduced pressure and purified by flash column chromatography eluting eluting MS m/z (M+H ⁺ ) 281.1.

B. 1-Methyl-3-phenyl-1H-indazole-5-carboxylic acid, 13c. Compound 13b (230 mg, 0.58 mmol) and _{LiOH.H 2 O (98 mg, 2.33} mmol) was stirred for 8 hours at 45 ℃ in THF / H (10/10 mL) solution of the ₂ O. The resulting mixture was concentrated and diluted with water. The aqueous layer was acidified with aqueous 1N HCl to pH ~ 4 and extracted in CH ₂ Cl _2. The organic solution was dried over Na ₂ SO ₄ and concentrated to afford 13c (206 mg). MS m/z (M+H ⁺ ) 253.1.

The following intermediate compounds were prepared according to the procedure described in Example 13 above and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art:

Example 14

A. 3-Methyl-[1,1'-biphenyl]-4-carboxylic acid, 14b. Compound 14a (0.025 g, 0.115 mmol), compound 10b (0.0139 g, 0.14 mmol) and Cs ₂ CO ₃ (0.094 g, 0.288 mmol) Pd(dppf)Cl ₂ (0.0084 g, 0.0115 mmol) was added to a suspension of the alkane (3 mL) and EtOH (1 mL). The reaction mixture was stirred at 80 ° C for 3 hours. After cooling, the solid was removed by filtration and is washed with CH ₃ OH. The filtrate was concentrated. The crude product 14b was purified by reverse phase chromatography. MS m/z (M+H ⁺ ) 213.1.

The following intermediate compounds were prepared according to the procedure described in Example 14 above and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art:

Example 15

A. 3-Fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 15b. A solution of 6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid 15a (2.031 mmol, 0.50 g) in THF (8 mL) at -70 ° C with n-BuLi in hexane (4.26 Treatment with 1.6 M solution in mmol, 2.66 mL). After 1 hour at -70 °C, N-fluorobenzenesulfonimide (2.64 mmol, 0.833 g) in THF (2 mL) was slowly added and the reaction warmed to room temperature. After 1 hour the mixture was partitioned between dilute aqueous HCl and EtOAc. The organic layer was washed with water and brine and then concentrated. The residue was deuterated with CH ₂ Cl ₂ . The off-white precipitate was filtered and collected to provide 15b.

B. 3-Fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 15c. (COCl) ₂ (0.051 mL, 0.58 mmol) was added at room temperature to compound 15b (0.14 g, 0.53 mmol) in CH ₂ Cl ₂ (5 mL), followed by 2 drops of DMF. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture is then concentrated to provide compound 15c.

Example 16

A. 6-Methyl 3-phenyl-1H-indole-1,6-dicarboxylic acid 1-tertiary butyl ester, 16a. 6-Methyl 3-iodo-1H-indole-1,6-dicarboxylic acid 1-tertiary butyl ester 11a (5.02 mmol, 2.016 g), phenylboronic acid 10b (7.53 mmol, 0.92 g), Pd (OAc) ₂ (0.402 mmol, 90 mg), Sphos 0.904 mmol, (0.37 g) and a mixture of K ₃ PO ₄ (10.1 mmol, 2.13 g) in toluene (10 mL) in a sealed reaction vial stirred at room temperature for 2 min Then, it was heated in N ₂ at 90 ° C for 4 hours. The reaction mixture was quenched with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (EtOAc EtOAc The product was obtained as a pale yellow solid and washed with a small portion of hexane to afford 16a as a white solid.

B. 3-Phenyl-1H-indole-6-carboxylic acid methyl ester TFA salt, 16b. Add to a solution of 6-methyl 3-phenyl-1H-indole-1,6-dicarboxylic acid 1-tert-butyl butyl ester 16a (4.04 mmol, 1.42 g) in CH ₂ Cl ₂ (8 mL) 6 mL of TFA. The resulting solution was stirred for 3 hours. The mixture was then concentrated and washed with hexane to yield 16b.

C. Methyl 1-methyl-3-phenyl-1H-indole-6-carboxylate, 16c. NaH (60% dispersion in mineral oil, 4.52 mmol, 186 mg) was added in portions at 0 ° C to methyl 3-phenyl-1H-indole-6-carboxylate TFA (2.07 mmol, 757 mg) in a solution in DMF and the mixture was stirred for 20 minutes. Methyl iodide (2.28 mmol, 0.14 mL) was added and the reaction mixture was maintained at 0 ° C for one hour. Water was then added and the reaction was extracted with EtOAc. The organics were concentrated and purified by flash chromatography (EtOAc EtOAc)

D. 1-Methyl-3-phenyl-1H-indole-6-carboxylic acid, 16d. Compound 16c (517 mg, 1.95 mmol) and LiOH (187 mg, 7.80 mmol) was stirred in THF / MeOH / H mixture (4/4/4 mL) of the ₂ O 4 hours. A 15% citric acid solution (20 mL) was added and the mixture was extracted with EtOAc (3×). The combined extracts were dried Na ₂ SO ₄ was washed with brine, filtered and concentrated under reduced pressure. The residue (Compound 16d) was dried under reduced pressure for 18 hr.

The following intermediate compounds were prepared according to the procedure described in Example 16 above and substituting the appropriate reagents, starting materials and purification methods familiar to those skilled in the art:

Example 17

A. 6-Methyl 3-(3-(trifluoromethyl)phenyl)-1H-indole-1,6-dicarboxylic acid 1-tertiary butyl ester, 17b. The title compound 17b was prepared by the method described in Example 16 except that in step A, 10b was replaced by 17a.

B. 3-(3-(Trifluoromethyl)phenyl)-1H-indole-6-carboxylic acid methyl ester TFA salt, 17c. The title compound 17c was prepared by the method described in Example 16 except that in step B, 16a was replaced with 17b.

C. 3-(3-(Trifluoromethyl)phenyl)-1H-indole-6-carboxylic acid, 17d. The title compound was prepared using the method described in Example 16 but substituting 16c in step D.

The following intermediate compounds were prepared according to the procedure described in Example 17 above and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art:

Example 18

A. 1-(5-Chloro-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone, 18c. Add 1-fluoro-4-chloro-benzene 18a (23.0 mmol, 2.45 mL) slowly at -78 °C in a solution of LDA (2.0 M in THF / heptane / ethylbenzene, 25.3 mmol, 12.6 mL) in dry THF. ). The mixture was stirred at -78 °C for 1 hour and ethyl trifluoroacetate 18b (25.3 mmol, 3.02 mL). The reaction mixture was allowed to warm to room temperature overnight and washed with saturated NH ₄ Cl aqueous quench. The mixture was extracted with EtOAc. The organic extract was concentrated and purified by flash column chromatography (EtOAc, 15% EtOAc/hexanes) to afford compound 18c and regio-isomeric by-product (1-(5-fluoro-) A mixture of 2-chloro-phenyl)-2,2,2-trifluoro-ethanone in a ratio of 5:1 (18c is the major product).

B. Methyl 5-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 18e. Compound 18c (6.62 mmol, 1.5 g) , 2- methyl thioglycolate 18d (6.62 mmol, 0.6 mL) and _{Et 3 N (8.6 mmol, 1.2} mL) (12 mL) solution of acetonitrile was heated at 75 deg.] C 4 hours. The reaction was diluted with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (EtOAc:EtOAc

C. 5-Chloro-3-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 18f. Compound 18e (574 mg, 1.95 mmol) and LiOH (187 mg, 7.80 mmol) in THF / MeOH / H ₂ O mixture (4/4/4 mL) was stirred for 4 hours in the. A 15% citric acid solution (20 mL) was added and the mixture was extracted with EtOAc (3×). The combined extracts were dried Na ₂ SO ₄ was washed with brine, filtered and concentrated under reduced pressure. The residue (Compound 18f) was dried under reduced pressure for 18 hr and used without purification.

D. 5-Chloro-3-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 18 g. (COCl) ₂ was added to compound 18f in CH ₂ Cl ₂ (5 mL) at room temperature followed by 2 drops of DMF. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated to afford compound 18 g.

Example 19

A. 1-(4-Chloro-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone, 19b. 4-Chloro-2-fluoro-1-iodo-benzene 19a was slowly added to N ₂ at -78 ° C in a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL) in dry THF. (3.9 mmol, 1.0 g). The mixture was stirred at -78.degree. C. for 1 h and ethyl trifluoroacetate 18b (0.51 mL, 4.29 mmol). The reaction was allowed to warm to room temperature overnight and washed with saturated NH ₄ Cl aqueous quench. The mixture was extracted with EtOAc. The organic extract was concentrated and purified by flash column chromatography (EtOAc:EtOAc:EtOAc

B. 6-Chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid methyl ester, 19c. The title compound 19c was prepared using a procedure analogous to that described in Example 18, but in step B, 18c was replaced by 19b.

Example 20

A. 3-Fluoro-1H-indole-6-carboxylic acid methyl ester, 20b. 1H-indole-6-carboxylic acid methyl ester 20a (11.4 mmol, 2.0 g) with N-fluoro-2,4,6-trimethylpyridine triflate (14.8 mmol, 4.3 g) in MeOH The solution in (100 mL) was heated under reflux for 18 hours. The reaction mixture was concentrated and purified by flash column chromatography eluting elut elut elut

B. Methyl 3-fluoro-1-(4-fluorophenyl)-1H-indole-6-carboxylate, 20d. Compound 20b (0.264 mmol, 51 mg) , CuI (0.0264 mmol, 5 mg) and _{K 3 PO 4 (0.66 mmol,} 40 mg) were combined in a sealed tube and the reaction vial was inverted to N ₂ flushed (back-flushed) . 4-Fluoro-iodobenzene 20c (0.264 mmol, 0.0394 mL) was added via syringe with N,N'-dimethylcyclohexane-1,2-diamine (0.0792 mmol, 0.0125 mL) followed by toluene. The reaction mixture was heated at 95 ° C for 6 hours. The reaction was diluted with EtOAc and water. The reaction mixture was concentrated and purified by flash column chromatography (EtOAc EtOAc

C. 3-Fluoro-1-(4-fluorophenyl)-1H-indole-6-carboxylic acid, 20e. The title compound 20e was prepared using the method described in Example 18 Step C.

Example 21

A. 7-Fluoro-1H-indole-5-carboxylic acid, 21b. To a solution of 5-bromo-7-fluoroindole 21a (1.71 mmol, 365 mg) in THF was added n-BuLi (1.6 M solution in hexanes, 5.2 mmol, 3.2 mL). The solution was kept at -60 °C for 4 hours and then poured into an excess of freshly ground anhydrous dry ice. Water was added and the mixture was acidified to pH 4. The organic phase was concentrated and the residue was purified mpjjjjjjj

Example 22

A. 7-Methyl-1H-indole-5-carboxylic acid methyl ester, 22c. Compound 22a (0.613 mmol, 156 mg), methylboronic acid 22b (0.92 mmol, 79 mg), Pd(OAc) ₂ (0.09 mmol, 20 mg), SPhos (0.215 mmol, 88 mg) and K ₃ PO ₄ ( 1.23 mmol, 0.26 g) of the mixture in toluene (2 mL) was heated to 100 ° C in a sealed reaction vessel for 3 hours. The reaction was diluted with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (EtOAc EtOAc)

B. Methyl 1-(4-fluorophenyl)-7-methyl-1H-indole-5-carboxylate, 22d. The title compound was prepared using the method described in Example 20, but in step B, 20b was replaced by 22c.

C. 1-(4-Fluorophenyl)-7-methyl-1H-indole-5-carboxylate, 22e. The title compound was prepared using the method described in Example 18 Step C.

The following intermediate compounds were prepared according to the procedure described in Example 22 above and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art:

Example 23

A. 4-Amino-2-chloro-benzoic acid methyl ester, 23b. Acetyl chloride (35.2 mmol, 2.5 mL) was added dropwise to a stirred solution of 4-amino-2-chloro-benzoic acid 23a (12.9 mmol, 2.22 g) in methanol (50 mL). The mixture was heated under reflux for 18 h, cooled and concentrated in vacuo. The residue was added to EtOAc, washed with saturated aqueous NaHCO ₃ and brine, dried and concentrated in vacuo. The crude product was purified by flash column chromatography (EtOAc EtOAc EtOAc

B. 4-Amino-2-chloro-5-iodo-benzoic acid methyl ester, 23c. The compound 23b (1.18 g, 6.38 mmol) and _{CaCO 3 (12.8 mmol, 1.28 g} ) in MeOH (13 mL) in the suspension in a dropwise manner added iodine monochloride (6.70 mmol at room temperature, 1.09 g A solution in CH ₂ Cl ₂ (6 mL). The resulting reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (EtOAc, 20-25%EtOAc /hexane) to afford 4-amino-2-chloro-5-iodo-benzoic acid methyl ester 23c as the main product And 4-amino-2-chloro-3-iodo-benzoic acid methyl ester 23d (as a minor product).

C. 4-Amino-2-chloro-5-((trimethylamido)ethynyl)benzoic acid methyl ester, 23e. Add ethynyl trimethyl to a mixture of compound 23c (0.642 mmol, 200 mg), CuI (0.064 mmol, 12.2 mg) and Pd(PPh ₃ ) ₂ Cl ₂ (0.064 mmol, 45 mg) in THF (2 mL) Silane groups (0.963 mmol, 95 mg), followed by _{Et 3 N (7.19 mmol, 1} mL) in N _2. The reaction mixture was stirred at room temperature for 1.5 h then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (EtOAc:EtOAc

D. 6-Chloro-1H-indole-5-carboxylic acid methyl ester, 23f. A mixture of compound 23e (0.532 mmol, 150 mg) and EtOAc (0.32 mmol, 60 mg) The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (EtOAc:EtOAc

Example 24

A. Methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate, 24c.吲哚-5-carboxylic acid methyl ester 24a (2 g, 11.4 mmol), 1-iodo-3,4-difluoro-benzene 24b (1.5 mL, 12.5 mmol), CuI (0.22 g, 1.14 mmol), reverse -N, N'- dimethyl cyclohexane-1,2-diamine (0.54 mL, 3.43 mmol) and _{K 3 PO 4 (6.06 g,} 28.5 mmol) in toluene (12 mL) at 110 deg.] C in the Heat for 7 hours. The reaction mixture was diluted with CH _{2 2} Cl and filtered. The solution was concentrated and the residue was purified mpjjjjjjjj

B. 1-(3,4-Difluorophenyl)-indole-5-carboxylic acid, 24d. 1- (3,4-difluorophenyl) - indole-5-carboxylic acid methyl ester 24c (3.0 g, 10.4 mmol) and LiOH (1.0 g, 41.8 mmol) in THF (120 mL) and H ₂ O The mixture in (60 mL) was stirred at room temperature for 5 days. A 10% aqueous HCl solution was added to the reaction mixture to adjust the pH = 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aqueous NaCl, dried over Na ₂ SO ₄ and concentrated to provide 24d (2.85 g).

Example 25

A. 2-Phenyl-benzo Methyl oxazole-6-carboxylate, 25c. 4-Amino-3-hydroxy-benzoic acid methyl ester 25a (0.3 g, 1.8 mmol) and benzamidine chloride 25b (0.23 mL, 2.0 mmol) The mixture in alkane (2.5 mL) was heated in a microwave at 210 ° C for 15 min. The reaction mixture was diluted and washed with aqueous NaHCO ₃ in CH ₂ Cl _2. The organic solution was dried over Na ₂ SO _4, and concentrated by (silica gel, 20% EtOAc / heptane) was purified by flash column chromatography to provide 25c (0.39 g).

B. 2-Phenyl-benzo Oxazole-6-carboxylic acid, 25d. 2-phenyl-benzo -6-carboxylic acid methyl ester 25c (0.37 g, 1.46 mmol) and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH ( 4 mL) and a mixture (4 mL) in H ₂ O in the chamber Stir for 6 hours at room temperature. A 1 N aqueous HCl solution was added to the mixture to adjust the pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aqueous NaCl, dried over Na ₂ SO ₄ and concentrated to provide 25d (0.34 g).

Example 26

A. Ethyl 2-phenyl-benzothiazole-6-carboxylate, 26b. 2-bromo-benzothiazole-6-carboxylic acid ethyl ester 26a (300 mg, 1.05 mmol), phenylboronic acid 10b (192 mg, 1.57 mmol), K ₂ CO ₃ (188 mg, 1.36 mmol) and Pd (dppf) )Cl ₂ .CH ₂ Cl ₂ (43 mg, 0.05 mmol) in two Dioxane (2 mL) was heated in a microwave for 25 min at 120 deg.] C and H mixture (0.4 ml) in the ₂ O. The reaction mixture was diluted with CH _{2 2} Cl, washed with H ₂ O, dried over Na ₂ SO ₄ and concentrated. Purification by flash column chromatography (silica gel, 15% EtOAc / heptane) afforded 26b (220 mg).

B. 2-Phenyl-benzothiazole-6-carboxylic acid, 26c. 2-phenyl - benzothiazole-6-carboxylate 26b (220 mg, 0.78 mmol) and LiOH (74 mg, 3.1 mmol) was stirred 16 (4 mL) in THF (4 mL) and H ₂ O hour. A 1 N aqueous HCl solution was added to the mixture to adjust the pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aqueous NaCl, dried over Na ₂ SO ₄ and concentrated to afford 26c (200 mg).

Biological instance In vitro method Example 1 MGL enzyme activity assay

All rating-based assays were performed in black 384-well polypropylene PCR microwells (Abgene) for a total of 30 mL. The substrate 4-methylumbelliferyl butyrate (4MU-B; Sigma) and purified mutant MGL (mut-MGLL 11-313 L179S L186S) or purified wild-type MGL (wt- One of MGLL 6H-11-313) was diluted to 20 mM PIPES buffer (pH = 7.0) containing 150 mM NaCl and 0.001% Tween 20, respectively. The compounds of formula (Ia) and (Ib) were pre-dispensed (50 nL) to the assay disk using a Cartesian Hummingbird machine, followed by the addition of 4MU-B (25 mL of 1.2X solution to a final concentration of 10 mM). The enzyme was then added (5 mL of 6X solution to a final concentration of 5 nM) to initiate the reaction. The final compound concentration ranged from 17 to 0.0003 mM. Fluorescence changes due to 4MU-B fragmentation were monitored at excitation and emission wavelengths of 335 and 440 nm, respectively, and monitored for 5 minutes at 37 °C with a 10 nm (Safire ² , Tecan) bandwidth.

IC The compound of formula (Ia) or (Ib) ₅₀ is determined by the adaptation value based equation using Excel, the adaptation equation system adapted to the concentration of active inhibitor concentration as a function of the fractional (fractional activity) - the response curve.

Example 2 2-AG cumulative test

To measure 2-AG accumulation due to MGL inhibition, one gram of rat brain was homogenized in 10 mL of 20 mM HEPES buffer (pH = 7.4) using a Polytron homogenizer (Brinkmann, PT300) containing 125 mM NaCl, 1 mM EDTA, 5 mM KCl and 20 mM glucose. The compound of formula (Ia) or (Ib) (10 mM) was preincubated with rat brain homogenate (50 mg). After incubation at 37 ° C for 15 minutes, CaCl ₂ (final concentration = 10 mM) was added and then incubated at 37 ° C for 15 minutes in a total volume of 5 mL. The reaction was quenched with 6 mL of an organic solvent extraction solution (2:1 chloroform/methanol). The cumulative 2-AG in the organic phase was measured by HPLC/MS according to the following equation:

Percent vehicle = (2-AG accumulation in the presence of compound / 2-AG accumulation in vehicle) × 100

Example 3 MGL Verification-mutation

The ThermoFluor (TF) assay is a 384-well plate based binding assay that measures the thermal stability of protein ^1,2 . 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 0.07 mg/ml mutant MGL, 100 μM ANS, 200 mM NaCl, 0.001% Tween-20 in 50 mM PIPES (pH=7.0).

The screening compound well plates contained a single concentration of 100% DMSO compound solution. For subsequent concentration-response studies, the compounds were placed in pre-dispensed well plates (Greiner Bio-one: 781280) in which the compounds were serially diluted in 100% DMSO and placed in successive 11 column wells. Columns 12 and 24 are used as a DMSO reference and do not contain compounds. For single or multiple compound concentration-reaction experiments, compound aliquots (46 nL) were pre-dispensed directly into a 384-well black assay plate (Abgene: TF-0384/k) using an Hummingbird liquid handler using an automaton. After the compound was dispensed, the protein and dye solution were added to achieve a final assay volume of 3 mL. The assay solution was covered with 1 mL of polyoxygenated oil (Fluka, type DC 200: 85411) to avoid evaporation.

In all experiments, a barcode-equipped assay disk was loaded on a thermostatically controlled PCR type thermal block by an automaton, and then heated from 40 to 90 ° C at a heating rate of 1 ° C/min. Fluorescence was measured by continuous illumination with UV light (Hamamatsu LC6), which was filtered through an optical fiber and through a bandpass filter (380-400 nm; >6 OD cutoff). Fluorescence emission of the entire 384-well disk was detected by measuring the light intensity using a CCD camera (Sensys, Roper Scientific), which was filtered to detect 500 ± 25 nm, and all 384-well simultaneous and independent readings were obtained. . An exposure system having a single image collected at time of 20 seconds at various temperatures, and the assay plate to the sum of the pixel intensity in a given area to be recorded and adapted to change the temperature to produce a standard equation T _m ^1.

1. Pantoliano, MW, Petrella, EC, Kwasnoski, JD, Lobanov, VS, Myslik, J., Graf, E., Carver, T., Asel, E., Springer, BA, Lane, P., and Salemme, FR (2001) J Biomol Screen 6, 429-40.

2. Matulis, D., Kranz, J. K., Salemme, F. R., and Todd, M. J. (2005) Biochemistry 44, 5258-66.

Of formula (Ia) or the K _d values for compounds (Ib) is determined by fitting the equation system, the adaptation equation system as adapted to the fractional concentration of the active function of T _m - response curve. About some experiments, quantitative NMR spectroscopy (qNMR) system for measuring the concentration of the initial solution of the compound of 100% DMSO, and the same method is adapted to determine the value qK _d.

In vivo method Example 4 CFA-induced paw radiant heat hypersensitivity

Each rat was placed in a test chamber and placed on a warm glass surface and allowed to acclimate for approximately 10 minutes. A radiant heat stimulus (beam) is sequentially focused through the glass onto the sole surface of each hind paw. When the paw moves or the critical time arrives (for 20 seconds of radiant heat at 5 amps), the thermal stimulus can be automatically turned off by the photointerrupter. The initial (baseline) response latency of each animal for thermal stimulation can be recorded prior to the injection of complete Freund's adjuvant (CFA). Twenty-four hours after CFA injection in the plantar, the response latency of the animals to thermal stimulation was reassessed and compared to the baseline reaction time of the animals. Only rats exhibiting at least a 25% reduction in response latency (ie hyperalgesia) were included in further analysis. Immediately after the completion of the post-CFA (post-CFA) latency assessment, the indicated test compound or vehicle can be administered orally. The post-compound treatment retraction latency can be assessed at fixed time intervals, typically 30, 60, 120, 180 and 300 minutes.

The percentage of allergic recovery (percent reversal, %R) can be calculated in one of two different ways: 1) using a group mean or 2) using individual animal values. More specific is:

Method 1. For all compounds, the allergic %R can be calculated using the average of the animal groups at each time point and based on the following formula:

Replies%=[(group therapy response-group CFA response)/(group baseline response-group CFA response)]×100

The results are provided as the maximum % recovery of each compound observed at any test point.

Method 2. For some compounds, the allergic %R of each animal is calculated separately according to the following formula:

Recovery % = [(individual treatment response - individual CFA response) / (individual baseline response - individual CFA response)] x 100.

The results are provided as an average of the maximum % of recovery calculated for each individual animal.

Example 5 CFA-induced paw hypersensitivity

Rats were allowed to acclimate to the procedure twice a day for two days prior to testing. The test consisted of placing the left hind paw on a Teflon platform and applying a linearly increasing machine with a dome (radius 0.7 mm) between the third and fourth turns on the back of the rat's hind paw. Force (constant rate of 12.5 mmHg/s) and analgesy-meter (Stoelting, Chicago, IL), also known as Randall-Selitto instrument. The end point is automatically reached at the hindpaw withdrawal and the terminal strength (in grams) is recorded. The initial (baseline) response threshold for each mechanical stimulus was recorded for each animal prior to injection of the complete Freund's adjuvant (CFA). Forty hours after CFA injection in the plantar, the animal's response threshold for mechanical stimulation was reassessed and compared to the baseline response threshold for the animal. The reaction can be defined as the retraction of the hind paws, the struggle to move the hind paws, or the screaming. Only rats exhibiting a reduction in response threshold of at least 25% (ie hyperalgesia) were included in further analysis. Immediately after completion of the post-CFA (post-CFA) threshold assessment, rats were orally administered the indicated test compound or vehicle. The post-treatment retraction threshold was assessed at 1 hour. The Paw withdrawal threshold can be converted to an allergic recovery percentage according to the following formula:

% recovery [(post-treatment reaction - pre-administration reaction) / (baseline reaction - pre-dose reaction)] x 100.

Example 6 Chronic constriction injury (CCI)-induced neuropathic pain pattern - cold acetone allergy test

Male Sprague-Dawley rats (225-450 g) were used to assess the ability of selected compounds to restore CCI-induced cold allergy. Four loose ligatures of 4-0 amniotic suture were surgically placed around the left sciatic nerve under inhalation anesthesia, such as Bennett et al. (Bennett GJ, Xie YK. Pain 1988, 33(1): 87-107). 14 to 35 days after CCI surgery, the subject was placed in an elevated observation room equipped with a metal mesh floor, and five parts of acetone (0.05 mL/part, about 5 minutes apart) was sprayed onto the sole of the foot with a multi-dose syringe. On the surface. A sudden retraction or lifting of the paw is recognized as a positive reaction. Five trials were repeated and the number of positive responses per rat was recorded. After determining the number of baseline retractions, the compounds are administered by the indicated route in the indicated vehicle (see Table 6). The number of retractions was measured again 1 to 4 hours after administration of the compound. The results are presented as percent inhibition of shaking, which is calculated for each subject as follows: [1 - (test compound retraction times / pre-test retraction times)] x 100, and then processed average.

Example 7 Spinal nerve ligation (SNL) mode of neuropathic pain - tactile hyperalgesia test

For the lumbar 5 (L ₅ ) spinal nerve ligation (SNL) study, anesthesia was induced and maintained with isoflurane inhalation. The fur on the back pelvic region was removed and a 2-cm skin incision was made slightly to the left of the midline of the L ₄ -S ₂ ridge, followed by separation of the spinous process from the paraspinal muscle. Carefully remove the L ₆ transverse process and identify the L ₅ spinal nerve. The left L ₅ spinal nerve tightly ligated 6-0 silk thread, the muscle to 4-0 vicryl sutures, and wound clips to the skin (wound clip) adhesion. After the surgery, sc saline (5 mL) was administered.

Conduct behavioral tests four weeks after ligation. Performing baseline von Frey assay to confirm the presence of mechanical allodynia, L ₅ SNL rats orally administered vehicle or designated agent. Tactile hyperalgesia was quantified by recording the force exerted on the retracted paw (on the same side as the nerve ligation), which was performed 30, 60, 100, 180 and 300 minutes after administration, from the application of a series The von Frey filaments were corrected (0.4, 0.6, 1.0, 2.0, 4, 6, 8, and 15 g; Stoelting; Wood Dale, IL). Starting from medium hardness (2.0 g), the filament is applied to the middle of the hind paw for about 5 seconds to determine the reaction threshold. If the paw is quickly retracted, the next time the light is stimulated, and if there is no retraction, then Strong use of the second time. A total of four reactions were collected after the first threshold detection. The 50% paw withdrawal threshold is interpolated by the Dixon method modified by Chaplan et. al., and when the reaction threshold is above or below the detection range, the values are each specified as 15.0 or 0.25 g. Threshold data from the von Frey filament test is reported as the paw withdrawal threshold in grams. Regularize the data and calculate the results as % MPE (maximum possible effect) according to the following formula:

% MPE=x g/strength-baseline g/strength × 100

15 g / strength - baseline g / strength

While the present invention has been described in connection with the embodiments of the present invention, it is understood that the invention is intended to cover all such modifications, changes and/ or modifications The scope of the patent application and its equivalents.

Claims (30)

a compound of formula (Ia), Wherein Y is i) a C _6-10 aryl or ii) one selected from the group consisting of thiazolyl, a heteroaryl group of the group consisting of azolyl, pyridyl and pyrimidinyl, wherein Y is unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of fluorine, chlorine, C _1-4 alkane a group consisting of C _1-4 alkoxy, cyano and trifluoromethyl; Z is selected from the group consisting of i) a C _6-10 aryl group, ii) one selected from the group consisting of benzene and a heteroaryl group of the group consisting of azolyl, benzothiazolyl, benzothienyl, oxazolyl and fluorenyl, or iii) benzyl-phenyl; wherein the phenyl group of the benzyl group is not Substituted or substituted with one or two substituents, each substituent is independently selected from the group consisting of bromo, chloro, fluoro, iodo, C _1-4 alkyl, C _1-4 alkoxy and trifluoromethyl a group; wherein the C _6-10 aryl group of Z and the heteroaryl group are unsubstituted or substituted with one or two substituents, each substituent being independently selected from the group consisting of bromine, chlorine, fluorine, iodine, C _1-4 a group consisting of an alkyl group, a C _1-4 alkoxy group, a trifluoromethyl group and a phenyl group, with the proviso that no more than one substituent of Z is a phenyl group, and the phenyl group is unsubstituted or Or two substituents, each substituent being independently selected from the group consisting of trifluoromethyl, chloro, cyano and fluorine; n is 1 or 2; and its mirror image isomer, non-image isomer and Pharmaceutically acceptable salts. A compound of claim 1, wherein Y is phenyl, thiazolyl or pyrimidinyl. A compound of claim 3, wherein Y is thiazolyl or pyrimidinyl. A compound of claim 1, wherein Z is i) a C _6-10 aryl or ii) one selected from the group consisting of benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl, wherein the C _6-10 aryl group of Z and the heteroaryl group are unsubstituted or one or two Substituted by a substituent, each substituent being independently selected from the group consisting of chloro, fluoro, C _1-4 alkyl, trifluoromethyl and phenyl, with the proviso that no more than one substituent of Z is phenyl And the phenyl group is unsubstituted or substituted with one or two substituents, each of which is a trifluoromethyl group or a fluorine. The compound of claim 4, wherein Z is one selected from the group consisting of benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl, wherein the heteroaryl of Z is unsubstituted or substituted with one or two substituents, each substituent Is independently selected from the group consisting of chlorine, trifluoromethyl and phenyl, with the proviso that no more than one substituent of Z is phenyl, and the phenyl is unsubstituted or substituted with one or two substituents. Substituted, each substituent is trifluoromethyl or fluoro. A compound of claim 1, wherein n is 1. A compound of claim 1, wherein n is 2. a compound of formula (Ia), Wherein: Y is i) phenyl or ii) a heteroaryl group of thiazolyl or pyrimidinyl; Z is i) a C _6-10 aryl or ii) one selected from benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl, wherein the C _6-10 aryl group of Z and the heteroaryl group are unsubstituted or one or two Substituted by a substituent, each substituent being independently selected from the group consisting of chloro, fluoro, C _1-4 alkyl, trifluoromethyl and phenyl, with the proviso that no more than one substituent of Z is phenyl And the phenyl group is unsubstituted or substituted with one or two substituents, each of which is trifluoromethyl or fluoro; n is 1 or 2; and its mirror image isomer, non-image isomer and pharmaceutical Acceptable salt. A compound of claim 8 wherein n is 1. A compound of claim 8 wherein n is 2. a compound of formula (Ia), Formula (Ia) wherein: Y is thiazolyl or pyrimidinyl; Z is one selected from benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl, wherein the heteroaryl of Z is unsubstituted or substituted with one or two substituents, each substituent Is independently selected from the group consisting of chlorine, trifluoromethyl and phenyl, with the proviso that no more than one substituent of Z is phenyl, and the phenyl is unsubstituted or substituted with one or two substituents. Substituted, each substituent is trifluoromethyl or fluoro; n is 1 or 2; and its mirror image isomer, non-image isomer and pharmaceutically acceptable salt. A compound of claim 11, wherein n is 1. a compound of formula (Ia), It is selected from the group consisting of Y: phenyl, Z is 4-(benzyl)-phenyl, and n is a compound of 1; wherein Y is phenyl and Z is 4-phenyl-benzene a compound wherein n is 1; wherein Y is pyrimidin-2-yl, Z is 1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl, and n is a compound of 1; Wherein Y is pyrimidin-2-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is a compound of 1; wherein Y is thiazol-2-yl, Z is 1 a compound of -(4-fluoro-phenyl)-1H-indol-5-yl and n is 1 wherein Y is thiazol-4-yl and Z is 1-(4-fluoro-phenyl)-1H- a compound of 吲哚-5-yl and n is 1; a compound wherein Y is thiazol-4-yl, Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl, and n is 1. a compound wherein Y is pyrimidin-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl, and n is 1; wherein Y is pyrimidin-2-yl and Z is 4 a phenyl-phenyl group, wherein n is a compound of 1; wherein Y is pyrimidin-2-yl, Z is 2-phenyl-benzothiazole-6-yl, and n is a compound of 1; wherein Y is thiazole- 2-based, Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl, and n is a compound of 1; wherein Y is thiazol-2-yl and Z is 2-phenyl a benzothiazole-6-yl group, wherein n is a compound of 1; wherein Y is phenyl, Z is 1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl, and n is a compound of 1 wherein Y is phenyl, Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl, and n is 1; wherein Y is phenyl and Z is 1-(3) , 4-difluoro-phenyl)-1H-indol-5-yl, and n is a compound of 1; wherein Y is thiazol-2-yl and Z is 2-phenyl-benzo a compound having an oxazol-6-yl group and wherein n is 1; wherein Y is pyrimidin-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothiophen-2-yl, and n is a compound of 2; Wherein Y is thiazol-2-yl, Z is 4-phenyl-phenyl, and n is a compound of 1; wherein Y is thiazol-2-yl and Z is 3-chloro-6-trifluoromethyl-benzo a compound wherein thiophen-2-yl and n is 2; a compound wherein Y is pyrimidin-2-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is 2 a compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoro-phenyl)-1H-indol-5-yl, and n is 2; wherein Y is thiazol-2-yl, Z is 2-phenyl-benzo a compound having an oxazol-6-yl group and wherein n is 2; and a pharmaceutically acceptable salt form thereof. a compound of formula (Ib), Formula (Ib) wherein: Y _b is i) a C _6-10 aryl or ii) one selected from thiazolyl, a heteroaryl group of the group consisting of oxazolyl, pyridyl and pyrimidinyl, wherein Y _b is unsubstituted or substituted with one or two substituents, each substituent being selected from the group consisting of fluorine, chlorine, C _1-4 alkane a group consisting of a C _1-4 alkoxy group, a cyano group and a trifluoromethyl group; Z _b is i) a C _6-10 aryl group, ii) one selected from the group consisting of benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl, or iii) benzyl-phenyl; wherein the phenyl group of the benzyl group is unsubstituted or Substituted with one or two substituents, each substituent being selected from the group consisting of bromo, chloro, fluoro, iodo, C _1-4 alkyl, C _1-4 alkoxy and trifluoromethyl, wherein Z _b The C _6-10 aryl group and the heteroaryl group are unsubstituted or substituted by one or two substituents, each substituent being selected from the group consisting of bromine, chlorine, fluorine, iodine, C _1-4 alkyl, C _{1 a} group consisting of _-4 alkoxy, trifluoromethyl and phenyl; the limitation is that no more than one substituent of Z _b is a phenyl group, and the phenyl group is unsubstituted or substituted by one or two Substituent, each substituent is selected from the group consisting of trifluoromethyl, chloro, cyano and fluorine; and mirror image isomers, non-image isomers and pharmaceutically acceptable salts thereof. A compound according to claim 14 wherein Y _b is thiazolyl or pyrimidinyl. A compound according to claim 14 wherein Z _b is one selected from the group consisting of benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl, wherein the heteroaryl of Z _b is unsubstituted or substituted with one or two substituents, each substitution The substrate is independently selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl and phenyl; the limitation is that no more than one substituent of Z _b is phenyl, and the phenyl is unsubstituted or Substituted by one or two substituents, each substituent being a trifluoromethyl group or a fluorine. The compound of claim 16, wherein Z _b is benzothienyl or fluorenyl, wherein Z _b is unsubstituted or substituted with one or two substituents, each of which is trifluoromethyl or benzene The substituent is such that the substituent of not more than one Z _b is a phenyl group, and the phenyl group is unsubstituted or substituted with a trifluoromethyl group or a fluorine substituent. a compound of formula (Ib), Wherein: Y _b is thiazolyl or pyrimidinyl; Z _b is one selected from benzo a heteroaryl group of the group consisting of oxazolyl, benzothiazolyl, benzothienyl and fluorenyl, wherein the heteroaryl of Z _b is unsubstituted or substituted with one or two substituents, each substitution The group is selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl and phenyl; the limitation is that no more than one substituent is phenyl, and the phenyl is unsubstituted or one or two Substituted by a substituent, each substituent is a trifluoromethyl group or a fluorine; and a mirror image isomer, a non-image isomer thereof, and a pharmaceutically acceptable salt. a compound of formula (Ib), Wherein: Y _b is thiazolyl or pyrimidinyl; Z _b is benzothienyl or fluorenyl, wherein Z _b is unsubstituted or substituted with one or two substituents, each of which is trifluoromethyl or benzene a substituent which is not more than one Z _b substituent is a phenyl group, and the phenyl group is unsubstituted or substituted with a trifluoromethyl or fluorine substituent; and its mirror image isomer, non-image isomerism And pharmaceutically acceptable salts. a compound of formula (Ib), It is selected from the group consisting of a compound wherein Y _b is pyrimidin-2-yl and Z _b is 6-trifluoromethyl-benzothiophen-2-yl; wherein Y _b is pyrimidin-2-yl and pharmaceutically acceptable salts thereof; lH-indol-5-yl compounds of -, and Z _b 1- (4-trifluoromethyl-phenyl) was. A pharmaceutical composition comprising a compound as claimed in claim 1 or 13 and a member selected from the group consisting of: a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutical Acceptable diluent. The pharmaceutical composition of claim 21, wherein the composition is a solid oral dosage form. The pharmaceutical composition of claim 21, wherein the composition is selected from the group consisting of a syrup, a sputum, and a suspension. A method for treating inflammatory pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described in claim 1 or claim 13. The method of claim 24, wherein the inflammatory pain is caused by inflammatory bowel disease, visceral pain, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint Pain, abdominal pain, chest pain, childbirth, 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/allergy, itching, eczema, pharyngitis, mucositis, enteritis, colonic urgency, cholecystitis, pancreatitis, pain syndrome after mastectomy, menstrual pain, endometriosis, Pain, pain caused by physical trauma, headache, sinus headache, tension headache or arachnoiditis. A pharmaceutical composition comprising a compound as claimed in claim 14 or 20 and a member selected from the group consisting of: a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutical Acceptable diluent. The pharmaceutical composition of claim 26, wherein the composition is a solid oral dosage form. The pharmaceutical composition of claim 26, wherein the composition is selected from the group consisting of a syrup, a sputum, and a suspension. A method for treating inflammatory pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as claimed in claim 14 or 20. The method of claim 29, wherein the inflammatory pain is caused by inflammatory bowel disease, visceral pain, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint Pain, abdominal pain, chest pain, childbirth, 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/allergy, itching, eczema, pharyngitis, mucositis, enteritis, colonic urgency, cholecystitis, pancreatitis, pain syndrome after mastectomy, menstrual pain, endometriosis, Pain, pain caused by physical trauma, headache, sinus headache, tension headache or arachnoiditis.