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Definitions

• the present invention relates to compounds that have TRPM8 antagonist properties and are useful in preparing medicaments and compositions and in treating diseases and conditions such as those mediated by TRPM8.
• the compounds and compositions may be used to treat various diseases or conditions modulated by TRPM8 such as, but not limited to, migraines and neuropathic pain.
• Cold sensation is derived from activation of the somatosensory system by a cold stimulus.
• Calcium imaging and patch clamp experiments in dissociated trigeminal and dorsal root ganglia neurons have revealed cold stimuli induced calcium influx, suggesting the direct opening of a calcium-permeable ion channels by cold (Thut et al, 2003; Reid, 2005).
• TRPM8 transient receptor potential melastatin 8
• trp-p8 trp-p8
• TRPM8 is highly expressed in sensory neurons of the trigeminal and dorsal root ganglia (McKemy et al, 2002; Peier et al, 2002; Thut et al, 2003). TRPM8 is also expressed in nerve fibers innervating urinary bladder in guinea pigs (Tsukimi et al., 2005) and humans (Mukerji et al., 2006) and believed to contribute to the bladder hypersensitivity. Activation mechanism of TRPM8 by menthol and icilin appears to differ. Icilin requires calcium for robust activation of TRPM8, whereas menthol and cold do not (Chuang et al., 2004).
• TRPM8 is shown to mediate the analgesia by agonists such as menthol and icilin (by desensitization of the receptor) during experimental neuropathic pain in rodents (Proudfoot et al., 2006). Further, attenuation of cold sensation and cold allodynia after chronic constriction injury model of neuropathic pain in TRPM8 knockout mice (Colburn et al., 2007; Dhaka et al, 2007) suggests that antagonists of TRPM8 may be considered as pain therapeutics for chemotherapy-induced pain, neuropathic pain and bladder disorders.
• Mint oil that contains menthol an agonist of TRPM8 has been reported to alleviate pain in post-herpetic neuralgia (Davies et al., 2002), a neuropathic pain condition. Furthermore, oral or intracerebro ventricular injection of menthol decreased nociceptive responses to hot-plate test and acetic acid-induced writhing in mice (Galeotti et al., 2002). These responses are believed to be mediated by the activation and desensitization of the TRPM8. These observations and the knockout mice studies indicate that TRPM8 modulation by antagonists might be beneficial for patients experiencing neuropathic pain.
• TRPM8 antagonist compounds that can be used to treat diseases and conditions mediated by TRPM8 such as, but not limited to, migraines and neuropathic pain and those other conditions described herein.
• the present invention comprises a new class of compounds useful in the treatment of diseases, such as TRPM8-mediated diseases and other maladies, such as inflammatory or neuropathic pain and diseases involving sensory nerve function such as asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis.
• the compounds of the invention are useful for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non- vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, anxiety, depression, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions
• the invention also comprises pharmaceutical compositions comprising the compounds, methods for the treatment of TRPM8-receptor- mediated diseases, such as inflammatory or neuropathic pain, asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis diseases, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
• TRPM8-receptor- mediated diseases such as inflammatory or neuropathic pain, asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis diseases
• the compounds of the invention are represented by the following general structure:
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , m and n are defined below.
• the invention provides compounds of Formula I having the structure:
• n 0, 1, 2 or 3;
• n 0 or 1 ;
• X 1 is C(R 4 ) or N;
• X 2 is CH, CF, or N;
• R 2 is Ci_ 6 alk substituted by 0, 1, 2 or 3 halo substituents and additionally substituted by 0 or 1 substituents selected from R c ;
• R 4 is independently, at each instance, H, Ci_ 6 alk, -Ci_ 3 haloalk, -OCi_ 6 alk,
• R 3 and R 4 together form a four- atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R 5 substituents;
• R 5 is independently, in each instance, halo, OR a , CH 3 or CF 3 ;
• R a is independently, at each instance, H or R b ;
• R b is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, the phenyl, benzyl and Ci_ 6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -OH, -NH 2 , -OCi_ 4 alk, -OCi_ 4 haloalk, -NHCi_ 4 alk, and -N(Ci_ 4 alk)Ci_ 4 alk; and
• R c is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the Ci_ 6 alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or 3 substituents selected from Ci_ 8 alk, Ci_ 4 haloalk, halo and cyano.
• the compound of Formula I has the Formula
• X 2 is selected from CH or N;
• R 1 is selected from Ci_ 6 alk or a direct-bonded, Ci_ 2 alk-linked, Ci_ 2 alkO- linked, saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 1 1-membered bicyclic ring containing 0, 1 , 2, 3 or 4 heteroatoms selected from N, O and S, but containing no more than one O or S atom, the Ci_ 6 alk and ring being substituted by 0, 1 , 2 or 3 substituents
• R 3 and R 4 together form a four-atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R 5 substituents;
• R 5 is independently, in each instance, F, CH 3 or CF 3 ;
• R 6 is F.
• the invention provides pharmaceutical compositions that include the compound of any of the embodiments or the
• the invention provies methods of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, depression, anxiety, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced
• Such methods typically include administering the compound according to any of the embodiments or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof to the subject.
• the subject is suffering from neuropathic paid whereas in other embodiments the subject is suffering from migraines or migraine pain.
• the compounds of the invention may also be used to prepare
• the invention provides the use of the compound according to any of the embodiments or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof in the preparation of a medicament.
• the invention provides the use of the compound according to any of the embodiments or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof for treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, depression, anxiety, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds,
• the compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.
• Ci_ 6 alkyl means an alkyl group comprising a minimum of a and a maximum of ⁇ carbon atoms in a branched, cyclical or linear relationship or any combination of the three, wherein a and ⁇ represent integers.
• the alkyl groups described in this section may also contain one or two double or triple bonds.
• a designation of Coalk indicates a direct bond. Examples of Ci_ 6 alkyl include, but are not limited to the following:
• C a ⁇ alkyl and “C a ⁇ cycloalkyl” relate to acyclic saturated alkyls and cyclic saturated alkyls, respectively.
• cyano refers to a nitrile group which may be written as -C ⁇ N.
• Halo or "halogen” means a halogen atoms selected from F, CI, Br and I.
• Cv-whaloalk means an alk group, as described above, wherein any number, but at least one, of the hydrogen atoms attached to the alk chain are replaced by F, CI, Br or I.
• the group N(R A )R A and the like include substituents where the two R A groups together form a ring, optionally including a N, O or S atom, and include roups such as:
• N(C a -palk)C a -palk wherein a and ⁇ are as defined above, include substituents where the two C a -palk groups together form a ring, optionally including a N, O or S atom, and include groups such as:
• Heterocycle means a ring comprising at least one carbon atom and at least one other atom selected from N, O and S. Examples of heterocycles that may be found in the claims include, but are not limited to the followin :
• “Pharmaceutically-acceptable salt” means a salt prepared by conventional means, and are well known by those skilled in the art.
• the “pharmacologically acceptable salts” include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
• suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like.
• pharmaceutically acceptable salts see infra and Berge et al., J. Pharm. Sci. 66: 1 (1977).
• “Saturated, partially-saturated or unsaturated” includes substituents saturated with hydrogens, substituents completely unsaturated with hydrogens and substituents partially saturated with hydrogens.
• leaving group generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
• Protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.
• aralkyl examples include, but are not limited to, benzyl, ortho- methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts.
• aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like.
• cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like.
• Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl, phthaloyl and the like.
• a mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group.
• Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example,
• heterocyclic groups can further include adjoining aryl and cycloalkyl rings.
• heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.
• Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
• an addition salt such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
• Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups.
• Alkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
• Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert- butyldimethylsilyl, dimethylphenylsilyl, 1 ,2-bis(dimethylsilyl)benzene,
• silylation of an amino groups provide mono- or di-silylamino groups.
• Silylation of aminoalcohol compounds can lead to a ⁇ , ⁇ , ⁇ -trisilyl derivative.
• Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group.
• Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride,
• phenyldimethylsilyl chloride diphenylmethyl silyl chloride or their combination products with imidazole or DMF.
• Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art.
• Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
• Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like.
• a preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
• a t- butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HC1 or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride.
• the resulting amino salt can readily be neutralized to yield the free amine.
• Carboxy protecting group such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.
• Prodrugs of the compounds of this invention are also contemplated by this invention.
• a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
• the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
• For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985).
• Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
• esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
• Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989
• drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).
• One aspect of the current invention relates to compounds having the general structure:
• n 0, 1, 2 or 3;
• X 1 is C(R 4 ) or N;
• X 2 is C or N
• Y is NH or O
• R 2 is C 1 6 alk substituted by 0, 1, 2 or 3 halo substituents and additionally substituted by 0 or 1 substituents selected from R c ;
• R 3 and R 4 together form a four- atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R 5 substituents;
• R 5 is independently, in each instance, F, CH 3 or CF 3 ;
• R 6 is F
• R a is independently, at each instance, H or R b ;
• R b is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, the phenyl, benzyl and Ci_ 6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -OH, -NH 2 , -OCi_ 4 alk, -OCi_ 4 haloalk, -NHCi_ 4 alk, and -N(Ci_ 4 alk)Ci_ 4 alk; and
• R c is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the Ci_ 6 alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or 3 substituents selected from Ci_galk,
• Ci_ 4 haloalk, halo and cyano Another aspect of the current invention relates to compounds having the general structure:
• n 0, 1, 2 or 3:
• n 0 or 1 ;
• X 1 is C(R 4 ) or N;
• R 2 is C 1 6 alk substituted by 0, 1 , 2 or 3 halo substituents and additionally substituted by 0 or 1 substituents selected from R c ;
• R 3 and R 4 together form a four- atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R 5 substituents;
• R 5 is independently, in each instance, F, CH 3 or CF 3 ;
• R 6 is F
• R a is independently, at each instance, H or R b ;
• R is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, the phenyl, benzyl and Ci_ 6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -OH, -NH 2 , -OCi_ 4 alk, -OCi_ 4 haloalk, -NHCi_ 4 alk, and -N(Ci_ 4 alk)Ci_ 4 alk; and
• R c is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the Ci_ 6 alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or 3 substituents selected from Ci_ 8 alk,
• Ci_ 4 haloalk, halo and cyano.
• Another aspect of the current invention relates to compounds having the general structure:
• n 0, 1, 2 or 3;
• n 0 or 1 ;
• X 2 is C or N
• R 2 is C 1 6 alk substituted by 0, 1 , 2 or 3 halo substituents and additionally substituted by 0 or 1 substituents selected from R c ;
• R 5 is F, CH 3 or CF 3 ;
• R 6 is F
• R a is independently, at each instance, H or R b ;
• R b is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, the phenyl, benzyl and Ci_ 6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -OH, -NH 2 , -OCi_ 4 alk, -OCi_ 4 haloalk, -NHCi_ 4 alk, and -N(Ci_ 4 alk)Ci_ 4 alk; and
• R c is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the Ci_ 6 alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or 3 substituents selected from Ci_galk,
• Ci_ 4 haloalk, halo and cyano.
• Another aspect of the current invention relates to compounds having the general structure:
• n 0, 1, 2 or 3;
• R 1 is a direct-bonded, partially-saturated or unsaturated 5- or 6-membered monocyclic ring containing 1 or 2 atoms selected from N, O and S, but containing no more than one O or S atom, the Ci_ 6 alk and ring being substituted by 0, 1, 2 or 3 substituents independently selected from halo, oxo, Ci_ 6 alk, Ci_ 4 haloalk and cyano;
• R 2 is selected from F and CF 3 ;
• R 3 is CH 3 , CF 3 , F or CI
• R 4 is H or F
• R 6 is F
• R a is independently, at each instance, H or R b ;
• R b is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, the phenyl, benzyl and Ci_ 6 alk being substituted by 0, 1 , 2 or 3 substituents selected from halo, oxo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -OH, -NH 2 , -OCi_ 4 alk, -OCi_ 4 haloalk,
• R c is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the Ci_ 6 alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or 3 substituents selected from Ci_ 8 alk,
• Ci_ 4 haloalk, halo and cyano.
• Another aspect of the current invention relates to compounds having the general structure:
• n 0, 1, 2 or 3
• R is a direct-bonded, partially-saturated or unsaturated 5- or 6-membered monocyclic ring containing 1 or 2 atoms selected from N, O and S, but containing no more than one O or S atom, the Ci_ 6 alk and ring being substituted by 0, 1, 2 or 3 substituents independently selected from halo, oxo, Ci_ 6 alk, Ci_ 4 haloalk and cyano; and
• R 2 is selected from F and CF 3 .
• Another aspect of the current invention relates to compounds having the general structure:
• n 0, 1, 2 or 3;
• n 0 or 1 ;
• X 1 is C(R 4 ) or N;
• X 2 is C or N
• Y is NH or O
• R 2 is C 1 6 alk substituted by 0, 1 , 2 or 3 halo substituents and additionally substituted by 0 or 1 substituents selected from R c ;
• R 5 is F, CH 3 or CF 3 ;
• R 6 is F
• R a is independently, at each instance, H or R b ;
• R b is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, the phenyl, benzyl and Ci_ 6 alk being substituted by 0, 1 , 2 or 3 substituents selected from halo, oxo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -OH, -NH 2 , -OCi_ 4 alk, -OCi_ 4 haloalk, -NHCi_ 4 alk, and -N(Ci_ 4 alk)Ci_ 4 alk; and
• R c is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1 , 2, 3 or 4 atoms selected from N, O and S, wherein the Ci_ 6 alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1 , 2 or 3 substituents selected from Ci_galk,
• Ci_ 4 haloalk, halo and cyano.
• R 1 is a direct-bonded saturated, partially-saturated or unsaturated 3- , 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 1 1-membered bicyclic ring containing 0, 1 , 2, 3 or 4 atoms selected from N, O and S, but containing no more than one O or S atom, the ring being substituted by 0, 1 , 2 or 3 substituents independently selected from halo, oxo, Ci_ 6 alk, Ci_ 4 haloalk, cyano, nitro,
• R 1 is a direct-bonded partially-saturated or unsaturated 5- or
• R 1 is a direct-bonded partially-saturated or unsaturated 6-membered monocyclic ring containing 1 or 2 N atoms, substituted by 0, 1, 2 or 3 substituents independently selected from halo, oxo, Ci_ 6 alk, Ci_ 4 haloalk, cyano and -OR a .
• R 1 is a direct-bonded unsaturated 10-membered bicyclic ring containing 1 or 2 N atoms, substituted by 0, 1, 2 or 3 substituents independently selected from halo, oxo, Ci_ 6 alk, Ci_ 4 haloalk, cyano and -OR a .
• Another aspect of the invention relates to a method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, depression, anxiety, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions
• Another aspect of the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically-acceptable diluent or carrier.
• Another aspect of the invention relates to the use of a compound according to any of the above embodiments as a medicament.
• Another aspect of the invention relates to the use of a compound according to any of the above embodiments in the manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, anxiety, depression, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders
• the invention procides a compound of Formula I having the structure:
• n 0, 1, 2 or 3;
• n 0 or 1 ;
• X 1 is C(R 4 ) or N;
• X 2 is CH, CF, or N
• R 2 is Ci_ 6 alk substituted by 0, 1, 2 or 3 halo substituents and additionally substituted by 0 or 1 substituents selected from R c ;
• R 3 and R 4 together form a four- atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R 5 substituents;
• R is independently, in each instance, halo, OR a , CH 3 or CF 3 ;
• R a is independently, at each instance, H or R b ;
• R b is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, the phenyl, benzyl and Ci_ 6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -OH, -NH 2 , -OCi_ 4 alk, -OCi_ 4 haloalk, -NHCi_ 4 alk, and -N(Ci_ 4 alk)Ci_ 4 alk; and
• R c is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the Ci_ 6 alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or 3 substituents selected from Ci_galk, Ci_ 4 haloalk, halo and cyano.
• X 2 is selected from CH or N;
• R 1 is selected from Ci_ 6 alk or a direct-bonded, Ci_ 2 alk-linked, Ci_ 2 alkO- linked, saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but containing no more than one O or S atom, the Ci_ 6 alk and ring being substituted by 0, 1, 2 or 3 substituents
• R 3 and R 4 together form a four-atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R 5 substituents;
• R 5 is independently, in each instance, F, CH 3 or CF 3 ;
• R 6 is F. 4.
• R 1 is the saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring and the monocyclic or bicyclic ring is substituted by 0, 1, 2, or 3 substituents, wherein the substituents are selected from F, CI, Br, I, oxo, cyano, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
• R 1 is a phenyl, pyridyl, pyridinonyl, piperidinonyl, pyridazinonyl, pyrazinonyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetradyrofuranyl, tetrahydropyranyl, thiazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, triazolyl, oxazolyl, imidazolyl, pyrrolidinonyl, piperidinyl, cyclohexyl, cyclohexanonyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, benzothiophenyl, pyrazolopyrimidin
• R 2 is -H, halo, cyano, -0-Ci-C 6 alk, or Ci_ 6 alk substituted by 0, 1, 2 or 3 halo substituents.
• R 3 is H, Ci_ 8 alk, Ci_ 8 alkOH, Ci_ 4 haloalk, halo, or -OR a .
• R 4 is F, CI, Ci_ 6 alk, -OCi- 6 alk, or -Ci_ 3 haloalk.
• X 1 is N.
• a pharmaceutical composition comprising the compound according to any one of embodiments 1-3 or 5-77 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, and a pharmaceutically-acceptable diluent or carrier.
• NMP - N-Methyl-2-pyrrolidinone also known as
• 2-Formylpyridines of the Formula (1) were treated with 2-methylpropane-2-sulfinamide and copper sulfate in DCM to give 2-methyl-N-(pyridin-2-ylmethylene)propane-2-sulfinamides of the Formula (2a).
• the compounds of Formula (2a) were treated with aryl or heteroaryl metal halides of Formula (3) at low temperature to give sulfinamides of the Formula (4).
• Hydrolysis of sulfinamides (4) with hydrochloric acid in MeOH gives diaryl amines of Formula (5a).
• diaryl amines of Formula (5 a) An alternative approach to diaryl amines of Formula (5 a) is shown in Scheme 2.
• Aryl or heteroaryl aldehydes of the Formula (6) were treated with 2- methylpropane-2-sulfinamide and copper sulfate in DCM to give sulfinimines of the Formula (7).
• the compounds of Formula (7) were treated with aryl or heteroaryl metal halides of Formula (8) at low temperature to give sulfinamides of the Formula (4).
• Hydrolysis of sulfinamides (4) with hydrochloric acid in MeOH gives diaryl amines of Formula (5 a).
• the coupling reaction of diarylamines of Formula (5a-c) with the various carboxylic acids of Formula (9) can be performed as shown in Scheme 4.
• the coupling reaction can be mediated by a suitable coupling agent such as HATU in the presence of a base in a suitable solvent to afford compounds of the present invention (Formula (I)).
• Step 1 3-Fluoropicolinaldehyde To a stirred solution of DABCO (262.4 g, 2342 mmol) in anhydrous Et 2 0 (2.1 L) at -25 °C in a 10 L 3-neck round bottom flask was added n-BuLi (2.5 M in hexane, 938 mL, 2342 mmol). The mixture was stirred between -25 °C to -10 °C for 45 min. and then cooled to -70 °C.
• reaction mixture was quenched with saturated aqueous NH 4 C1 (2.5 L), and the solution was extracted with Et 2 0 (5 x 500 mL). The organic layers were combined, dried over Na 2 S0 4 , concentrated, and purified by column chromatography using silica (100-200 mesh) with 25-30% EtOAc in petroleum ether as eluent to give the title compound as a brown oil.
• ⁇ hese amines were prepared employing (i?)-2-methylpropane-2-sulfinamide in the first step (Scheme 5).
• Scheme 5 For reversal of stereochemistry observed in the Ellman sulfonylimine chemistry observed with 2-pyridyl substrates, see Kuduk, S.D.; DiPardo, R. M.; Chang, R. K.; Ng, C; Bock, M. G. Tetrahedron Lett. 2004, 45 s 6641-6643.
• Step 1 N-Methoxy-N-methyl-4-(trifluoromethyl)nicotinamide
• Step 2 (R)-2-Methyl-N-((4-(trifluor omethyl)pyridin-3-yl)methylene)propane- 2-sulfinamide
• N-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide (1.50 g, 6.41 mmol) in THF (20 mL) at 0 °C was added diisopropylaluminum hydride (7.69 mL, 7.69 mmol) (1.0 M in hexanes). After addition, the reaction was immersed in an ice/water bath and stirred for 1 h. Additional
• Step 3 (S)-(4-(Trifluoromethyl)phenyl)(4-(trifluoromethyl)pyridin-3-yl)- methanamine hydrochloride

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