MX2008010365A - Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same - Google Patents

Abstract

Compounds are disclosed that have a formula represented by the following:Formula (I). The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.

Description

DERIVATIVES OF AMIDAS AS LIGANDS OF IONIC CHANNELS AND PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USING THEM This application claims the benefit of the US provisional applications. 60 / 776,106, filed on February 23, 2006, 60 / 775,949, filed on February 23, 2006, 60 / 776,058, filed on February 23, 2006, 60 / 776,057, filed on February 23, 2006, 60 / 775,930, filed on February 23, 2006, 60 / 776,033, filed on February 23, 2006, 60 / 775,945, filed on February 23, 2006, 60 / 776,056, filed on February 23, 2006, 60 / 776,105, filed on February 23, 2006, 60 / 776,064, filed on February 23, 2006, 60 / 839,903, filed on August 24, 2006 and 60 / 839,994, filed on August 24, 2006, the contents of which are they are hereby incorporated by reference in their totalities.

FIELD OF THE INVENTION This invention relates to novel compounds and pharmaceutical compositions containing such compounds. This invention also relates to methods for preventing and / or treating pain and conditions related to inflammation in mammals, such as (but not limited to) arthritis, Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, the treatment and prophylaxis of pain syndromes (acute and chronic or neuropathic), traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease, urinary incontinence, chronic obstructive pulmonary disease, irritable bowel, osteoarthritis and autoimmune disorders, using the compounds and pharmaceutical compositions of the invention.

BACKGROUND OF THE INVENTION Studies of signaling pathways in the body have revealed the existence of ion channels and have sought to explain their role. Ionic channels are integral membrane proteins with two distinctive characteristics: they are activated (open and close) by specific signals such as membrane voltage or the direct binding of chemical ligands and, once opened, they conduct ions from one side of the membrane to the other cellular at very high rates. There are many types of ion channels. Based on their selectivity for ions, they can be divided into calcium channel, potassium channel, sodium channel, etc. The calcium channel is more permeable to calcium ions than to other types of ions, the potassium channel selects potassium ions over other ions, etc. Ionic channels can also be classified according to their activation mechanisms. In a voltage-activated ion channel, the opening probability depends on the membrane voltage, whereas in an ion channel activated by ligands, the opening probability is regulated by the binding of small molecules (the ligands). Since ion channels activated by ligands receive signals from the ligand, they can also be considered as "receptors" for ligands. Examples of ion channels activated by ligands include the nAChR (nicotinic acetylcholine receptor) channel, GluR (glutamate receptor) channel, ATP sensitive potassium channel, G protein activated channel, cyclic nucleotide activated channel, etc. Channel proteins with transient receptor potential (TRP) constitute a large and diverse family of proteins that are expressed in many tissues and cell types. This family of channels mediates responses to nerve growth factors, pheromones, olfaction, blood vessel tone, and metabolic stress et al., And the channels are found in a variety of organisms, tissues, and cell types including smooth muscle and neuronal cells. excitable. Additionally, TRP-related channel proteins are implicated in various diseases, such as various tumors and neurodegenerative disorders and the like. See, for example, inke, et al., APStracts 9: 0006P (2002). Nociceptors are specialized primary afferent neurons and the first cells in a series of neurons that lead to the sensation of pain. The receptors in these cells can be activated by different harmful chemical or physical stimuli. The essential functions of nociceptors include the transduction of noxious stimuli into depolarizations that activate action potentials, the conduction of action potentials of the primary sensory sites to synapses in the central nervous system and the conversion of the action potentials into neurotransmitter release in the presynaptic terminals, which all depend on ion channels. A TRP channel protein of particular interest is the vanilloid receptor. Also known as VR1, the vanilloid receptor is a non-selective cationic channel which is activated or sensitized by a series of different stimuli including capsaicin, heat and acid stimulation and metabolism products of the lipid bilayer (anandamide) and lipoxygenase metabolites. See, for example, Smith, et al., Nature, 418: 186-190 (2002). VR1 does not discriminate between monovalent cations, however, it exhibits a remarkable preference for divalent cations with a permeability sequence of Ca2 + >; Mg2 + > Na + = K + = Cs +. Ca2 + is especially important for VR1 function, since extracellular Ca2 + mediates desensitization, a process that enables a neuron to adapt to specific stimuli by decreasing its overall response to a particular chemical or physical signal. VR1 is highly expressed in primary sensory neurons in rats, mice and humans, and innervates many visceral organs including the dermis, bones, bladder, gastrointestinal tract and lungs. It is also expressed in other neuronal and non-neuronal tissues including the CNS, nuclei, kidney, stomach and T cells. The VR1 channel is a member of the superfamily of ion channels with six membrane-spanning domains, with the highest homology with the TRP family of ion channels. It has been shown that inactivated mice in the VR1 gene have reduced sensory sensitivity to thermal and acid stimuli. See, for example, Caterina, et al. Science, 14: 306-313 (2000). This supports the concept that VRl contributes not only to the generation of pain responses but also to the maintenance of a basal activity of the sensory nerves. VR1 agonists and antagonists have been used as analgesics for the treatment of pain of various origins or etiology, for example acute, inflammatory and neuropathic pain, dental pain and headache (such as migraine, cluster headache and tension headache). They are also useful as anti-inflammatory agents for the treatment of arthritis, Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, treatment and prophylaxis of pain syndromes (acute and chronic [neuropathic]), injury traumatic brain injury, spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease, irritable bowel disease and autoimmune disorders, kidney disorders, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleep disorders, cognition, depression, anxiety, blood pressure, lipid disorders, osteoarthritis and atherosclerosis. Compounds, such as those of the present invention, which interact with the vanilloid receptor can thus play a role in treating or preventing or ameliorating these conditions. A wide variety of Vanilloid Compounds of different structures are known in the art, for example those described in European Patent Applications Nos. EP 0 347 000 and EP 0 401 903, British Patent Application GB No. 2226313 and International Patent Application, Publication WO 92/09285 Particularly notable examples of vanilloid compounds or modulators of vanilloid receptors are capsaicin or trans 8-methyl-N-vanillyl-6-nonenamide which is isolated from the pepper plant, capsazepine (Tetrahedron, 53, 1997, 4791) and olvanila or N - (4-hydroxy-3-methoxybenzyl) oleamide (J. Med.

Chem., 36, 1993, 2595). International Patent Application, Publication Number WO 02/08221 discloses diarylpiperazine and related compounds which bind with high selectivity and high affinity to vanilloid receptors, especially vanilloid type I receptors, also known as capsaicin or VR1 receptors. The compounds are said to be useful in the treatment of conditions of chronic and acute pain, stinging and urinary incontinence. International Patent Applications, Publications Numbers WO 02/16317; WO 02/16318 and WO 02/16319 suggest that compounds having a high affinity for the vanilloid receptor are useful for treating stomach-duodenal ulcers. The International Patent Application, Publication No. WO 2005/046683, published May 26, 2005, commonly owned, describes a series of compounds that have demonstrated activity as VR-1 antagonists, and which are suggested to be useful for the treatment of conditions associated with VR-1 activity. U.S. Patent Nos. 3,424,760 and 3,424,761 describe a series of 3-Ureidopyrrolidines which are said to exhibit analgesic, central nervous system and psychopharmacological activities. These patents specifically describe the compounds 1- (1-phenyl-3-pyrrolidinyl) -3-phenylurea and 1- (1-phenyl-3-pyrrolidinyl) -3- (4-methoxyphenyl) urea respectively. The International Patent Applications, Publications Numbers WO 01/62737 and O 00/69849 describe a series of pyrazole derivatives which are stipulated to be useful in the treatment of disorders and diseases associated with the NPY receptor subtype Y5, such as obesity. WO 01/62737 specifically describes the compound 5-amino-N-isoquinolin-5-yl-l- [3- (trifluoromethyl) phenyl] -lH-pyrazole-3-carboxamide. WO 00/69849 specifically describes the compounds 5-methyl-N-quinolin-8-yl-l- [3 - (trifluoromethyl) phenyl] -lH-pyrazole-3-carboxamide, 5-methyl-N-quinolin-7-yl -l- [3-trifluoromethyl) phenyl] -lH-pyrazole-3-carboxamide, 5-methyl-N-quinolin-3-yl-1- [3- (trifluoromethyl) phenyl] -lH-pyrazole-3-carboxamide, N-Isoquinolin-5-yl-5-methyl-l- [3- (trifluoromethyl) phenyl] -1H-pyrazole-3-carboxamide, 5-methyl-N-quinolin-5-yl-l- [3- (trifluoromethyl) ) phenyl] -lH-pyrazole-3-carboxamide, 1- (3-chlorophenyl) -N-isoquinolin-5-yl-5-methyl-lH-pyrazole-3-carboxamide, N-isoquinolin-5-yl-1- (3-methoxyphenyl) -5-methyl-lH-pyrazol-3-carboxamide, 1- (3-fluorophenyl) -N-isoquinolin-5-yl-5-methyl-lH-pyrazole-3-carboxamide, 1- (2 -chloro-5-trifluoromethylphenyl) -N-isoquinolin-5-yl-5-methyl-lN-pyrazole-3-carboxamide, 5-methyl-N- (3-methylisoquinolin-5-yl) -1- [3- ( trifluoromethyl) phenyl] -lN-pyrazole-3-carboxamide, 5-methyl-N- (1,2,3,4-tetrahydroisoquinolin-5-yl) -1- [3- (trifluoromethyl) phenyl] -lH-pyrazole- 3 -carboxamide. German Patent Application Number 2502588 describes a series of piperazine derivatives. This application specifically describes the compound N- [3- [2- (diethylamino) ethyl] -1,2-dihydro-4-methyl-2-oxo-7-quinolinyl] -4-phenyl-1-piperazinecarboxamide. It has now been discovered that certain compounds have surprising potency and selectivity as VR-1 antagonists. The compounds of the present invention are considered particularly beneficial as VR-1 antagonists since certain compounds exhibit adequate aqueous solubility and metabolic stability.

SUMMARY OF THE INVENTION It has now been found that the compounds set forth herein are capable of modifying mammalian ion channels, such as the VR1 cation channel. Accordingly, the compounds provided herein are potent VR1 antagonists with analgesic activity by systemic administration. The compounds of the present invention can show low toxicity, good absorption, good half-life, good solubility, low affinity of protein binding, low drug-drug interaction, low inhibitory activity in the HERG channel, low QT prolongation and good metabolic stability . This finding leads to novel compounds that have therapeutic value. It also leads to pharmaceutical compositions having the compounds of the present invention as active ingredients and to their use for treating, preventing or alleviating a variety of conditions in mammals such as but not limited to pain of various origins or etiology, for example acute, chronic, inflammatory and neuropathic pain, dental pain and headache (such as migraine, cluster headache and tension headache) ). Accordingly, in a first aspect of the invention, compounds having a formula are provided wherein: each of W, Z and X is independently N or CR4; and Y is CR4"; L is - (CR5 = CR6) - or - (C = C) -; R1 is substituted or unsubstituted bicycloaryl or bicycloheteroaryl, R3 is CR6'R7R8, each R4 is independently hydrogen, alkyl of 1 to 6 carbon atoms, hydroxyl-alkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, amino-alkoxy of 1 to 6 carbon atoms, substituted amino-alkoxy 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, cycloalkyl-alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylarylamino of 1 to 6 carbon atoms, aryl-alkyloxy of 1 to 6 carbon atoms, amino, aryl, aryl-alkyl of 1 to 6 carbon atoms, sulfoxide, sulfone, sulphanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfuric acid ester, azido, carboxy, carbamoyl, cyano, cycloheteroalkyl, dialkylamino of 1 to 6 carbon atoms, halo, heteroaryloxy, heteroaryl, hetero alkyl, hydroxyl, nitro or thio; R4"is alkyl, trihaloalkyl, alkoxy, sulfone or halo, each of R5 and R6 is independently H or alkyl of 1 to 6 carbon atoms, and R6 'is hydrogen, halo or alkyl of 1 to 6 carbon atoms; one of R7 and R8 is independently halo or alkyl of 1 to 6 carbon atoms, or R7 and R8 together form a cycloalkyl ring of 3 to 8 carbon atoms, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers and tautomers thereof Compounds according to formula I are capable of modifying ion channels in vivo In a further embodiment of the invention, there are provided compounds of formula IA wherein R3-L represents-is CR3R6 = CR5. Such compounds are referred to below as compounds of the formula IA ': (?? ') wherein R3 is as defined for the compounds of the formula I and R5 and R6 are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms. In the compounds of the formula IA ', R5 and R6, for example, can independently represent hydrogen or Me. Preferably R5 and R6 represent hydrogen. In another embodiment, compounds of the formula IA are provided wherein R3-L is R3C = C-. Next, such compounds are referred to as compounds of the formula IA ": wherein R3 is as defined for the compounds of the formula I Generally in the compounds of the formula I, L is preferably - (C = C) - or -C = C-. In this way, in certain modalities, L is - (C = C) -. In certain modalities, L is -C = C- In the compounds of formula I, IA 'and IA ", R3 for example can represent CR6'R7R8 wherein R6' represents hydrogen, halo, alkyl of 1 to 6 carbon atoms or hydroxyl-alkyl of 1 to 6 carbon atoms. carbon; each of R7 and R8 is independently halo, alkyl of 1 to 6 carbon atoms or hydroxyl-alkyl of 1 to 6 carbon atoms; or R7 and R8 together form a cycloalkyl ring of 3 to 8 carbon atoms substituted or unsubstituted. For example, R7 can represent lower alkyl (for example methyl). For example R8 can represent lower alkyl (for example methyl). In particular examples, R6 'may represent hydrogen and R7 and R8 may represent methyl. Alternatively, each of R6 ', R7 and R8 may represent methyl. Alternatively, each of R6 ', R7 and R8 may represent fluorine. Alternatively, R6 'may represent hydrogen and R7 and R8 together form a cyclopropyl ring. In a first alternative embodiment of the compounds of formula I, R3 is CF3, i-propyl, t-Bu or cycloalkyl. In another embodiment R3 is CF3, t-Bu, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Still in another embodiment R3 is CF3, t-Bu or cyclopropyl. Still in another particular embodiment, with respect to the compounds of the formula I, R3 can be substituted or unsubstituted cyclopropyl. Still in a particular additional mode, with respect to the compounds of the formula I, R3 can be CF3. Still in a further particular embodiment, with respect to the compounds of the formula I, R3 can be t-Bu. With respect to the compounds of the formula I, R 1 can be substituted or unsubstituted naphthyl or, alternatively, substituted or unsubstituted tetrahydronaphthyl. In addition, R1 may also be substituted or unsubstituted bicycloheteroaryl and, in a particular embodiment, the bicycloheteroaryl may be selected from the group consisting of tetrahydroquinoline, tetrahydroisoquinoline, benzodioxane, benzopyran, indole and benzimidazole. More particularly, the bicycloheteroaryl can be quinoline, isoquinoline, benzodioxane and benzoxazine. In a particular embodiment, the substitution on the bicycloheteroaryl is selected from the group consisting of hydrogen, alkyl, trifluoromethyl, halo, methoxy, trifluoromethoxy, amino and carboxy. In a still further particular embodiment, the substitution on the bicycloheteroaryl is selected from the group consisting of tert-butyl, cyano, trifluoroalkyl, halo, nitro, methoxy, amino and carboxy. Still in another particular embodiment, with respect to the compounds of the formula I, R 1 can be isoquinolin-5-yl, quinolin-3-yl, benzodioxan-6-yl or unsubstituted or substituted benzoxazin-6-yl. Still in another particular embodiment, with respect to the compounds of the formula I, R1 can be substituted or unsubstituted, wherein each of A1, A2, A3, A4, B1 and B2 is independently CR4 'and N; and each of R 4 'is independently H, alkyl of 1 to 6 carbon atoms, halo or hydroxyalkyl of 1 to 6 carbon atoms. Still in another particular embodiment, with respect to the compounds of the formula I, R1 can be substituted or unsubstituted, wherein each of A5 and A8 is independently CR R4 ', NR4', O, S, SO or S02; each of A6 and A7 is independently CR4 ', NR4', CR4'R4 'or CO; each of B3 and B4 is independently CR4 'and N; when R4 is attached to C, each of R is independently H, alkyl of 1 to 6 carbon atoms, halo or hydroxyalkyl of 1 to 6 carbon atoms, and when R4 'is attached to N, each of R4' is independently H or alkyl of 1 to 6 carbon atoms; and the dotted link represents a single link or a double link. Still in another particular embodiment, with respect to the compounds of the formula I, R1 can be substituted or unsubstituted, wherein each of A9, A10 and A11 is independently CR4 ', CR4'R4', CO, CS, N, NR4 ', 0, S, SO or S02; each of B5 and B6 is independently CR4 'and by liquefying R4' is bound to C, each of R4 'is independently H, alkyl of 1 to 6 carbon atoms, halo or hydroxyalkyl of 1 to 6 carbon atoms, and when R4 'is attached to N, each of R4' is independently H or alkyl of 1 to 6 carbon atoms; and each of the dotted links independently represents a single or a double link. Still in another particular embodiment, with respect to the compounds of the formula I, R 1 can be: -c.-Co. -OO.HOO. -c. -o. -00. -or -CO "-OR substituted or unsubstituted VV, wherein the ring can be further substituted with R '4' 4 'YR' is as described above, and where feasible, the N ring can be further substituted with H or alkyl of 1 to 6 carbon atoms Still in another particular embodiment, with respect to the compounds of formula I, R 1 can be: and substituted or unsubstituted, wherein the ring can be further substituted with R4 ', and R' is as described above; and when feasible, the ring N can be further substituted with H or alkyl of 1 to 6 carbon atoms. Still in another particular embodiment, with respect to the compounds of the formula I, R1 can be: wherein each of A1, A2, A3, A4, B1 and B2 is independently CH and N; and R4 'is alkyl of 1 to 6 carbon atoms or hydroxyalkyl of 1 to 6 carbon atoms. Still in another particular embodiment, with respect to the compounds of the formula I, R1 can be: substituted or unsubstituted, wherein each of A5 and A8 is independently CH2, CHMe, NH, Me, 0, S, SO or S02; and R4 'is alkyl of 1 to 6 carbon atoms or hydroxyalkyl of 1 to 6 carbon atoms. Still in another particular embodiment, with respect to the compounds of the formula I, R1 can be: substituted or unsubstituted, wherein each of A9, A10 and A11 is independently CH, CH2, N, NH, 0 or S; each of B5 and B6 is independently CH and N; each of R4 'is independently H, alkyl of 1 to 6 carbon atoms or hydroxyalkyl of 1 to 6 carbon atoms; and each of the dotted links independently represents a single or a double link. Still in another particular embodiment, with respect to the compounds of the formula I, R1 can be and where R4 'is as described in the preceding paragraphs. In a particular embodiment, with respect to the compounds of the formula I, R1 is as described in the preceding paragraphs and R4 'is alkyl or substituted alkyl. Still in another embodiment, R4 'is substituted alkyl. Still in another particular embodiment, R4 'is hydroxyalkyl. In yet another particular embodiment, R4 'is hydroxymethyl, hydroxyethyl or hydroxypropyl. In still another particular embodiment, R4 'is hydroxymethyl.

In a particular embodiment, with respect to the compounds of the formula I, R1 is wherein, when feasible, the ring N can be further substituted with H or alkyl of 1 to 6 carbon atoms. In one embodiment, with respect to the compounds of formula I, R1 is where each of A1, A2, A3, A4, B1? B2 is independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl or halo; R4d is alkyl, hydroxyl, alkoxy, or a group -NR4eRf; R4e and Rf are independently H, alkyl, substituted alkyl; or R4c and Rf together form a substituted or unsubstituted cycloheteroalkyl ring of 4-8 atoms. In a particular modality the ring -c. -co. -CD.-CO. or. o.-co 0 or Still in another particular embodiment, Rd for example may represent -NMe 2, methoxy, hydroxyl, methyl or ethyl. Still in another particular embodiment, R4d for example can represent -NReRe and where Re is H or Me, -CH2-CH2-OH; and Rf is H, Me, -CH2-CH2-OH, -CH2-CH2-OMe, -CH2-CH2-Me2, -CH2-C (OH) H-CH2OH, -CH2-CH-Cyx, - or CH- C (OH) H-CH2-Cy1; and Cy1 is - -? - 0 - / ~? ° or - - ° h Still in another particular modality, R4d for example can represent Cyl and Cy1 is -. - -O -O-. or ~ ° "In one embodiment, with respect to the compounds of formula I, R1 is wherein each of A1, A2 and A3 is independently CR4 ', S, 0, N, NR4'; B1 and B2 are independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl or halo; Rd is alkyl, hydroxyl, alkoxy, or a group -NReRf; Re and Rf are independently H, alkyl, substituted alkyl; or Re and Rf together form a substituted or unsubstituted cycloheteroalkyl ring of 4-8 atoms. In a particular modality the ring Still in another particular embodiment, R 'for example can represent -N e2, methoxy, hydroxyl, methyl or ethyl. Still in another particular embodiment, Ra for example can represent -NR4eR4e and where Re is H or Me, -CH2-CH2-OH; and Rf is H, Me, -CH2-CH2-OH, -CH2-CH2-OMe, -CH2-CH2-NMe2, -CH2-C (OH) H-CH2OH, -Ci ^ -CH ^ Cy1, or -CH2 -C (OH) HC ^ -Cy1; and Cy1 is Still in another particular mode, R '4d for example can represent Cyl and Cy1 is In one embodiment, with respect to the compounds formula I, R1 is wherein each of A1, A3 and A4 is independently CR 'R4', 0, NR4 ', S, SO or S02; B1 and B2 are independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl or halo; Rd is alkyl, hydroxyl, alkoxy, or a group -NReRf; R4e and R4f are independently H, alkyl, substituted alkyl; or R4e and R4f together form a substituted or unsubstituted cycloheteroalkyl ring of 4-8 atoms. In a particular modality the ring is Still in another particular embodiment, R for example may represent -Me2, methoxy, hydroxyl, methyl or ethyl. Still in another particular embodiment, R4d for example can represent -NR4eRe and where Re is H or Me, -CH2-CH2-OH; and R4f is H, Me, -CH2-CH2-OH, -CH2-CH2-OMe, -CH2-CH2-Me2, -CH2-C (OH) H-CH2OH, -CHs-CHs-Cy1, or -CH2- C (OH) H-CH2-Cy1; and Cy1 is -O - (- -O "-1 *. • - ~~ °? Still in another particular mode, R4d for example can represent Cyl and Cy1 is - - - - ~ Me In one embodiment, with respect to the compounds of wherein each of A1, A2, A3, A4, B1 and B2 is independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl or halo; Rk is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; R49 and Rh are independently H, alkyl, substituted alkyl; or R 9 and R together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; and n is 0-4. In a particular modality the ring -oo. -oo. -co.-oo. In one modality, n is 0-4. In another modality, n is 0-3. Still in another modality, n is 0-2. In a particular embodiment n is 0 or 2. In one embodiment, each of Rg and R4h is H. In another embodiment one of R4g and Rh is Me. Still in another embodiment, each of R4s and R4h is Me. In one embodiment, R4k for example may represent H, Me or Et. In another embodiment, Rk is i-Pr, -CH2-CH2-OH, -CH2-CH2-OMe, -CH2-CH2-Me2, COMe, COCH2 Me2, COCH2OH, COC (Me2) OH, COCH2OMe, CONHMe, CO Me2 , CONHCH2CH2OH, CON (CH2CH2OH) 2, COCy1 or COCi ^ Cy1; and Cy1 is -O - - or - > MO, In one embodiment, with respect to the compounds of formula I, R1 is wherein each of A1, A2 and A3 is independently CR4 ', CR' R4 ', S, SO, S02, O, N, NR4'; B1 and B2 are independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl or halo; R K is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; R4G and RH are independently H, alkyl, substituted alkyl; or R49 and RH together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; and n is 0-4. In a particular modality the ring In one modality, n is 0-4. In another modality, n is 0-3. Still in another modality, n is 0-2. In a particular embodiment n is 0 or 2. In one embodiment, each of R49 and Rh is H. In another embodiment one of R4g and Rh is Me. Still in another modality, each of Rg and Rh is Me. In one embodiment, Rk for example may represent H, Me or Et. In another embodiment, Rk is i-Pr, -CH2-CH2-OH, -CH2-CH2-OMe, -CH2-CH2-Me2, COMe, COCH2NMe2, COCH2OH, COC (Me2) OH, COCH2OMe, CONHMe, CO Me2, CONHCH2CH2OH, CON (CH2CH2OH) 2, COCy1 or COCi ^ Cy1; and Cy1 is -o -o- -o- In one embodiment, with respect to the compounds of formula I, R1 is where each of A1 and A4 is independently CR 'R4', 0, NR4 'OR; B1 and B2 are independently CR4 'or N; each of R '4' is independently H, substituted or unsubstituted lower alkyl or halo; R '4k hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; R4g and R4h are independently H, alkyl, substituted alkyl; or R49 and Rh together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; and n is 0-4. In a particular modality the ring is selected from In one modality, n is 0-4. In another modality, n is 0-3. Still in another modality, n is 0-2. In a particular embodiment n is 0 or 2. In one embodiment, each of R4g and R4h is H. In another embodiment one of R49 and Rh is Me. Still in another modality, each of R 9 and R is Me. In one embodiment, Rk for example may represent H, Me or Et. In another embodiment, Rk is i-Pr, -CH2-CH2-OH, -CH2-CH2-OMe, -CH2-CH2-Me2, COMe, COCH2 Me2, COCH2OH, COC (Me2) OH, COCH2OMe, CONHMe, CO Me2 , CONHCH2CH2OH, CON (CH2CH2OH) 2, COCy1 or COCHaCy1; and Cy1 is or - O-0"In one embodiment, with respect to the compounds of the formula I, R1 is independently CR 'R4' or CO; B1 and B2 are independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl or halo; Rk is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; Rg and R4h are independently H, alkyl, substituted alkyl; or R49 and R4h together form "a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms, and n is 0-4, in a particular embodiment the ring is selected from In one modality, n is 0-4. In another modality, n is 0-3. Still in another modality, n is 0-2. In a particular embodiment n is 0 or 2. In one embodiment, each of Rg and R4h is H. In another embodiment one of R4a and R4h is Me. Still in another modality, each of Rg and Rh is Me. In one embodiment, Rk for example may represent H, Me or Et. In another embodiment, Rk is i-Pr, -CH2-CH2-OH, -CH2-CH2-OMe, -CH2-CH2-Me2, COMe, COCH2NMe2, C0CH20H, COC (Me2) OH, COCH2OMe, CONHMe, CO Me2, CONHCH2CH2OH, CON (CH2CH2OH) 2, COCy1 or COCHaCy1; and Cy1 is In one embodiment, with respect to the compounds of formula I, R1 is wherein A1 is CR 'R4'; each of A2 and A4 is independently CR R4 'or CO; A3 is S, SO or S02; and B1 and B2 are independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl or halo; R K is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; R4G and R4H are independently H, alkyl, substituted alkyl; or RG and R4H together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; and n is 0-4. In a particular modality the ring - o. -ca0"oor.

In one modality, n is 0-4. In another modality, n is 0-3. Still in another modality, n is 0-2. In a particular embodiment n is 0 or 2. In one embodiment, each of R49 and Rh is H. In another embodiment one of Rg and Rh is Me. Still in another embodiment, each of R49 and R4h is Me. In one embodiment, Rk for example may represent H, Me or Et. In another embodiment, Rk is i-Pr, -CH2-CH2-OH, -CH2-CH2-OMe, -CH2-CH2-Me2, COMe, COCH2 Me2, COCH2OH, COC (Me2) OH, COCH2OMe, CONHMe, CO Me2 , CONHCH2CH2OH, CON (CH2CH2OH) 2, COCy1 or COCHzCy1; and Cy1 is one embodiment, with respect to the compounds formula I, R1 is wherein each of A1, A2, A4, B1 and B2 is independently CR4 'or N; each R '4' is independently H, substituted or unsubstituted lower alkyl or halo; R '4m is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted arainocarbonyl; R n is independently H or substituted or unsubstituted lower alkyl; R4g and Rh are independently H, alkyl, substituted alkyl; or R4g and Rh together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; and n is 0 or 1. In a particular embodiment the ring In one modality, n is 0-4. In another modality, n is 0-3. Still in another modality, n is 0-2. In a particular embodiment n is 0 or 2. In one embodiment, each of R4g and Rh is H. In another embodiment one of R49 and R4h is Me. Still in another modality, each of R4g and Rh is Me. In one embodiment, Rm is H, Me or -CH2-CH2-OH. In another embodiment R4n is H, Me, -CH2-CH2-OH, -CH2-CH2-OMe or -CH2-CH2-Me2. In still another embodiment the group -NRmRn is -O -. - O - MB. -O In a particular embodiment with respect to formula (I), the compound is or a pharmaceutically acceptable salt, solvate or prodrug thereof, or stereoisomers, isotopic variants and tautomers thereof and wherein R4p is independently H, alkyl of 1 to 6 carbon atoms, halo, hydroxyl, carbalkoxy [C (O) (alkoxy from 1 to 6 carbon atoms)], acyl [C (0) (alkyl of 1 to 6 carbon atoms)] or hydroxyalkyl of 1 to 6 carbon atoms. In an Rp mode it is H or Me. In a particular embodiment R is H. In a particular embodiment with respect to formula (I), the compound is or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, isotopic variants and tautomers thereof, wherein: Ra is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, sulfon [S (O) 2 (alkyl of 1 to 6 carbon atoms)] or halo; R4p is independently H, alkyl of 1 to 6 carbon atoms, halo, hydroxyl, carbalkoxy [C (0) (alkoxy of 1 to 6 carbon atoms)], acyl [C (0) (alkyl of 1 to 6 carbon atoms) carbon)] or hydroxyalkyl of 1 to 6 carbon atoms; and each of R5 and R6 is independently H or alkyl of 1 to 6 carbon atoms. In one embodiment each of R5 and R6 is H. In another embodiment one of R5 and R6 is Me. In an R4a mode it is Me. In another embodiment R4p is H, Me or CH20H. In a particular embodiment R is H. Still in another particular embodiment, R4a is Me, Rp is CH20H and each of R5 and R6 is H. In a particular embodiment with respect to formula (I), the compound is or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, isotopic variants and tautomers thereof, wherein: R 4a is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, sulfon [S (0) 2 (alkyl of 1 to 6 carbon atoms)] or halo; Rp is independently H, alkyl of 1 to 6 carbon atoms, halo, hydroxyl, carbalkoxy [C (O) (alkoxy of 1 to 6 carbon atoms)], acyl [C (0) (alkyl of 1 to 6 carbon atoms) carbon)] or hydroxyalkyl of 1 to 6 carbon atoms; and each of R5 and R6 is independently H or alkyl of 1 to 6 carbon atoms. In one embodiment each of R5 and R6 is H. In another embodiment one of R5 and R6 is Me. In a Ra mode, it is Me. In another modality Rp is H or Me. In a particular embodiment Rp is H. Still in another particular embodiment, R4 is Me, Rp is H and each of R5 and R6 is H. In the compounds of formula I, IA 'and IA' ', W, Z and X for example may each represent CR4, especially CH. Alternatively X may represent N, and W and Z may each represent CR. In another exemplary set of compounds, each of X and Z represents CR4, especially CH. In another example set of compounds, W is N. Still in another exemplary set of compounds, Y is N. In the compounds of formula I, IA 'and IA' ', each of W, X and Z is CR4 and R 4 is selected from H, halo, alkoxy, sulfo, alkyl, haloalkyl or hydroxyalkyl. In the compounds of formula I, IA 'and IA ", each of W, X and Z is CR4 and R4 is selected from H, halo or alkyl. In the compounds of formula I, IA 'and IA' ', each of W, X and Z is CR4 and R4 is selected from H, F, Cl or Me.

In the compounds of formula I, IA 'and IA ", Y is CR 4" and wherein R 4"is independently selected from alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms and halo. In the compounds of formula I, IA 'and IA' ', Y is CR4 'and wherein R4"is independently selected from CH3 CF3, Cl or F. In the compounds of formula I, IA' and IA", each of W and X is CH, and each of Y and Z is independently C-CH3, C-Cl or CF. In the compounds of formula I, IA 'and IA' ', each of W and X is CH, and each of Y and Z is independently C-CH3 or CF. In still further particular embodiments, the compounds of the invention are established and may be selected from a comprehensive list of such compounds, set forth hereinbelow in Table 1. The Table contains more than 100 compounds that have been or may be synthesized and, as a group, have demonstrated activity in their ability to modify ion channels, in vivo, and consequently function in the therapeutic applications set forth herein in relation to capsaicin and the vanilloid receptor.The compounds of the present invention are useful for the treatment of inflammatory pain and hyperalgesia and ald associated inia. They are also useful for the treatment of neuropathic pain and associated hyperalgesia and allodynia (for example trigeminal or herpetic neuralgia, diabetic neuropathy, causalgia, sympathetically maintained pain and deadening syndromes such as brachial plexus avulsion). The compounds of the present invention are also useful as anti-inflammatory agents for the treatment of arthritis and as agents to treat Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, traumatic brain injury, spinal cord injury. , neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease and autoimmune disorders, kidney disorders, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleep disorders, cognition, depression, anxiety, blood pressure, lipid disorders and atherosclerosis. In one aspect, this invention provides compounds which are capable of modifying ion channels, in vivo. Representative modified ion channels thus include voltage-activated channels and ligand-activated channels, including cationic channels such as vanilloid channels. In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutical carrier, excipient or diluent. In this aspect of the invention, the pharmaceutical composition may comprise one or more of the compounds described herein. In a further aspect of the invention, there is disclosed a method for treating mammals, including humans, as well as lower mammalian species, susceptible to or afflicted by a condition among those listed herein, and, particularly, such a condition as may be associated, for example. with arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, alopecia (hair loss), inflammatory bowel disease and autoimmune disorders, which method comprises administering an effective amount of one or more of the pharmaceutical compositions now described. In still another method of the treatment aspect, this invention provides a method for treating a mammal susceptible to or afflicted by a condition that gives rise to pain responses or that is related to imbalances in the maintenance of basal activity of the sensory nerves. The compounds have use as analgesics for the treatment of pain of various origins or etiology, for example acute inflammatory pain (such as pain associated with osteoarthritis and rheumatoid arthritis); various syndromes of neuropathic pain (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb pain, post-mastectomy pain, peripheral neuropathy, HIV neuropathy and neuropathies induced by chemotherapy and other iatrogenic); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis and various gynecological and urological disorders), dental pain and headache (such as migraine, cluster headache and tension headache). In a further method of the treatment aspects, this invention provides methods for treating a mammal susceptible to or afflicted by neurodegenerative diseases and disorders - such as, for example, Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example, traumatic brain injury, stroke and encephalitis; centrally mediated neuropsychiatric disorders and disorders such as, for example, mania for depression, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example, urinary incontinence, initial dysuria, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; irritable bowel syndrome, overactive bladder, respiratory and respiratory disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example, rheumatoid arthritis and osteoarthritis, myocardial infarction, various diseases and autoimmune disorders, uveitis and atherosclerosis; stinging / pruritus such as, for example, psoriasis; alopecia (hair loss); obesity; lipid disorders; Cancer; blood pressure; spinal cord injury; and renal disorders, the method comprises administering an effective amount, to treat the condition or prevent the condition, of one or more of the pharmaceutical compositions now described. In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic routes and protocols described hereinafter. Other objects and advantages will become apparent to those skilled in the art from a consideration of the subsequent detailed description, in conjunction with the following illustrative drawings.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: The graph represents the significant inhibition of the intracellular calcium response induced by Capsaicin, under the experimental conditions described, by 3 nM of the Compound having Id No. 225. Figure 2: The graph represents the inhibition of the intracellular calcium response induced by Capsaicin, under the experimental conditions described, by 3 nM of the Compound having Id No. 187. Figure 3: The graph represents the significant inhibition of the intracellular calcium response induced by Capsaicin, under the experimental conditions described, by 3 nM of the Compound having Id No. 96. Figure 4: The graph represents the significant inhibition of the intracellular calcium response induced by Capsaicin, under the experimental conditions described, by 3 nM of the Compound having Id No 45. Figure 5: The graph represents the significant inhibition of the calcium response intrace Capsaicin-induced cell, under the experimental conditions described, by 3 nM of the Compound having Id No. 233. Figure 6: The graph represents the significant inhibition of the intracellular calcium response induced by Capsaicin, under the experimental conditions described, by nM of the Compound that has Id No. 167.

DETAILED DESCRIPTION OF THE INVENTION Definitions When describing compounds, pharmaceutical compositions containing such compounds and methods for using such compounds and compositions, the following terms have the following meanings unless otherwise indicated. It should also be understood that any of the portions defined below in the following may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted portions within their scope. By way of non-limiting example, such substituents may include, for example, halo (such as fluorine, chlorine, bromine), -CN, -CF3, -OH, -OCF3, alkenyl of 2 to 6 carbon atoms, alkynyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, aryl and di-alkylamino of 1 to 6 carbon atoms. "Acyl" refers to a radical -C (0) R, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like. "Acylamino" refers to a radical -NR'C (0) R, where R 'is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl and R is hydrogen, alkyl, alkoxy, cycloalkyl, cycloheteroalkyl , aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl, as defined herein. Representative examples include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino, and the like. "Acyloxy" refers to the group -OC (0) R where R is hydrogen, alkyl, aryl or cycloalkyl. "Substituted alkenyl" includes those groups listed in the definition of "substituted" herein, and particularly refers to an alkenyl group having 1 or more substituents, for example from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl , keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O) 2- and aryl-S (0) 2-. "Alkoxy" refers to the group -0R where R is alkyl. Particular alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy and the like. "Substituted alkoxy" includes those groups listed in the definition of "substituted" herein, and particularly refers to an alkoxy group having 1 or more substituents, for example 1 to 5 substituents, and particularly 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl , hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl- S (0) 2- and aryl-S (0) 2 -. "Alkoxycarbonylamino" refers to the group -NRC (0) OR 'where R is hydrogen, alkyl, aryl or cycloalkyl and R' is alkyl or cycloalkyl. "Aliphatic" refers to organic hydrocarbyl compounds or groups, characterized by a linear, branched or cyclic arrangement of the constituent carbon atoms and an absence of aromatic unsaturation. Aliphatics include, without limitation, alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene. The aliphatic groups typically have from 1 or 2 to about 12 carbon atoms. "Alkyl" refers to saturated monovalent aliphatic hydrocarbyl groups having in particular up to about 11 carbon atoms, more particularly as a lower alkyl, from 1 to 8 carbon atoms and even more particularly, from 1 to 6 carbon atoms. The hydrocarbon chain can be either straight or branched chain. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like. The term "lower alkyl" refers to alkyl groups having 1 to 6 carbon atoms. The term "alkyl" also includes "cycloalkyls" as defined in the following. "Substituted alkyl" includes those groups listed in the definition of "substituted" herein, and particularly refers to an alkyl group having 1 or more substituents, for example from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl , heteroaryl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl-S (0) -, aryl-S (O) -, alkyl-S (0) 2- and aryl-S (0) 2 -. "Alkylene" refers to divalent saturated aliphatic hydrocarbyl groups having in particular up to about 11 carbon atoms and more particularly 1 to 6 carbon atoms which may be straight chain or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (for example, -CH2CH2CH2- and CH (CH3) CH2-) and the like. "Substituted alkylene" includes those groups listed in the definition of "substituted" herein, and particularly refers to an alkylene group having 1 or more substituents, for example from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl-S (O) -, aryl-S (0) -, alkyl-S (0) 2- and aryl-S (0) 2-. "Alkenyl" refers to monovalent olefinically unsaturated hydrocarbyl groups preferably having up to about 11 carbon atoms, in particular, 2 to 8 carbon atoms and, more particularly, 2 to 6 carbon atoms, which may be straight or branched chain and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH = CH2), n-propenyl (-CH2CH = CH2), isopropenyl (-C (CH3) = CH2), vinyl and substituted vinyl and the like. "Alkenylene" refers to divalent olefinically unsaturated hydrocarbyl groups having in particular up to about 11 carbon atoms and, more particularly, 2 to 6 carbon atoms, which may be straight chain or branched and having at least 1 carbon atoms. and particularly from 1 to 2 sites of olefinic unsaturation. This term is exemplified by groups such as ethenylene (-CH = CH-), the isomers of propenylene (e.g., CH = CHCH2- and -C (CH3) = CH- and -CH = C (CH3) -) and the like. "Alkynyl" refers to acetylenically unsaturated hydrocarbyl groups, having in particular up to about 11 carbon atoms and, more particularly, 2 to 6 carbon atoms, which may be straight chain or branched and having at least 1 and , particularly, from 1 to 2 sites of alkynyl unsaturation. Particular non-limiting examples of alkynyl groups include ethynyl (-C = CH), propargyl (-CH2C = CH) acetylenics and the like. "Substituted alkynyl" includes those groups listed in the definition of "substituted" herein, and particularly refers to an alkynyl group having 1 or more substituents, for example from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl , keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O) 2- and aryl-S (0) 2-. "Alkanoyl" or "acyl" as used herein refers to the group R-C (O) -, where R is hydrogen or alkyl as defined above. "Aryl" refers to a monovalent aromatic hydrocarbon group derived by the removal of a hydrogen atom from a single carbon atom of a progenitor system of aromatic rings. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexane, hexalene, as-indacene, s-indacene, indane. , indene, naphthalene, octazene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picenum, pleiadene, pyrene, pyrenethrene, rubynene, triphenylene, trinaphthalene and the like. Particularly, an aryl group comprises from 6 to 14 carbon atoms. "Substituted aryl" includes those groups listed in the definition of "substituted" herein, and particularly refers to an aryl group which may be optionally substituted with 1 or more substituents, for example from 1 to 5 substituents, particularly 1 to 3 substituents , selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol, alkyl-S (0) -, aryl-S (O) -, alkyl-S (0) 2- and aril-S (0) 2-. "Fused Aryl" refers to an aryl having two of its ring carbons in common with a second aryl ring or with an aliphatic ring. "Alkaryl" refers to an aryl group, as defined above, substituted with one or more alkyl groups, as defined above. "Aralkyl" or "arylalkyl" refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. "Aryloxy" refers to -O-aryl groups wherein "aryl" is as defined above. "Alkylamino" refers to the group alkyl-NR'R ", wherein each of R 'and R" are independently selected from hydrogen and alkyl. "Arylamino" refers to the group aryl-NR'R ", wherein each of R 'and R" is independently selected from hydrogen, aryl and heteroaryl. "Alkoxyamino" refers to a radical -N (H) OR where R represents an alkyl or cycloalkyl group as defined herein. "Alkoxycarbonyl" refers to a -C (0) -alkoxy radical where alkoxy is as defined herein. "Alkylarylamino" refers to a radical -NRR 'wherein R represents an alkyl or cycloalkyl group and R' is an aryl as defined herein. "Alkylsulfonyl" refers to a radical -S (0) 2R where R is an alkyl or cycloalkyl group as defined herein. Representative examples include, but not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like. "Alkylsulfinyl" refers to a radical -S (0) R where R is an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like. "Alkylthio" refers to a radical -SR where R is an alkyl or cycloalkyl group as defined herein that may be optionally substituted as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio and the like. "Amino" refers to the radical -NH2. "Substituted amino" includes those groups listed in the definition of "substituted" herein, and particularly refers to the group -N (R) 2 wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl , substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl and wherein both R groups associate to form an alkylene group. When both R groups are hydrogen, -N (R) 2 is an amino group. "Aminocarbonyl" refers to the group -C (0) NRR where each R is independently hydrogen, alkyl, aryl and cycloalkyl, or where the R groups associate to form an alkylene group. "Aminocarbonylamino" refers to the group -NRC (0) NRR where each R is independently hydrogen, alkyl, aryl or cycloalkyl, or where two R groups associate to form an alkylene group. "Aminocarbonyloxy" refers to the group -OC (0) NRR where each R is independently hydrogen, alkyl, aryl or cycloalkyl, or where the R groups associate to form an alkylene group. "Arylalkyloxy" refers to a -0-arylalkyl radical wherein arylalkyl is as defined herein. "Arylamino" means a radical -NHR where R represents an aryl group as defined herein. "Aryloxycarbonyl" refers to a -C (0) -0-aryl radical where aryl is as defined herein. "Arylsulfonyl" refers to a radical -S (0) 2R where R is an aryl or heteroaryl group as defined herein. "Azido" refers to the -N3 radical. "Carbamoyl" refers to the radical -C (0) N (R) 2 wherein each R group is independently hydrogen, alkyl, cycloalkyl or aryl, as defined herein, which may be optionally substituted as defined herein. "Carboxy" refers to the radical -C (0) OH. "Carboxyamino" refers to the radical -N (H) C (0) OH. "Cycloalkyl" refers to cyclic hydrocarbyl groups having from 3 to about 10 carbon atoms and having a single cyclic ring or multiple fused rings, including fused and connected ring systems, which may be optionally substituted with 1 to 3 alkyl groups . Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl and the like, and multiple ring structures such as adamantanyl, and the like. "Substituted cycloalkyl" includes those groups listed in the definition of "substituted" herein, and particularly refers to a cycloalkyl group having the most substituents, for example from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected of the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl-S (0) -, aryl-S (O) -, alkyl-S (0) 2- and aryl-S (0) 2-. "Cycloalkoxy" refers to the group -0R where R is cycloalkyl. Such cycloalkoxy groups include, by way of example, cyclopentoxy, cyclohexoxy and the like. "Cycloalkenyl" refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple fused rings, including fused and connected ring systems, and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl and the like. "Substituted cycloalkenyl" includes those groups listed in the definition of "substituted" herein, and particularly refers to a cycloalkenyl group having 1 or more substituents, for example from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl , keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (0) -, aryl-S (0) -, alkyl-S (0) 2- and aryl-S (0) 2-- "Fused cycloalkenyl" refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation positioned to impart aromaticity to the cycloalkenyl ring. "Cianato" refers to the radical -OCN. "Ciano" refers to the radical -CN. "Dialkylamino" means a radical -NRR 'wherein R and R' independently represent an alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl or substituted heteroaryl group as defined herein. "Ethenyl" refers to - (C = C) - substituted or unsubstituted. "Ethylene" refers to - (C-C) - substituted or unsubstituted. "Ethinyl" refers to - (C = C) -. "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. Preferred halo groups are either fluorine or chlorine. "Hydroxy" refers to the -OH radical.

"Nitro" refers to the radical -NO2. "Substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituents. Typical substituents include, but are not limited to, -X, -R1, -0", = 0, -0R14, -SR14, -S", = S, -NR1R15, = NR14, -CX3, -CF3, - CN, -OCN, -SCN, -NO, -N02, = N2, -N3, -S (0) 20", -S (0) 20H, -S (0) 2R14, -0S (02) CT, - OS (0) 2R14, -P (0) (CT) 2, -P (0) (OR14) (O-), -0P (0) (OR14) (OR15), -C (0) R14, -C (S) R14, -C (0) 0R14, -C (0) NR14R15, -C (0) 0 ~, -C (S) 0R14, -NR16C (0) NR14R15, - NR16C (S) NR14R15, NR17C (NR16) NR14R15 and -C (NR16) NR14R15, wherein each X is independently a halogen; each R14, R15, R16 and R17 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted alkyl, aryl, substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted, -NR18R19, C (0) R18 or -S (0) 2R18 or optionally R18 and R19 together with the atom to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and R18 and R19 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted alkyl, aryl, substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. Examples of representative substituted aryls include the following In these formulas, one of R6 and R7 'may be hydrogen and at least one of R6' and R7 'are each independently selected from alkyl, alkenyl, alkynyl, cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR10CORn, NR10SOR # NR10SO2R14, COOalkyl, COOarilo, CONR R11, CONR10OR11, NR10RU, SO2NR10Rn, S-alkyl, S-alkyl, SO-alkyl, S02-alkyl, S-aryl, SO-aryl, S02-aryl; or R6 'and R7' may be associated to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S. R10, R11 and R12 are independently hydrogen, alkyl , alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl, substituted or heteroaryl alkyl or the like. "Hetero", when used to describe a compound or group present in a compound, means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen or sulfur heteroatom. Hetero can be applied to any of the hydrocarbyl groups described above such as alkyl, for example heteroalkyl, cycloalkyl, for example cycloheteroalkyl, aryl, for example heteroaryl, cycloalkenyl, cycloheteroalkenyl and the like having from 1 to 5 and, especially, from 1 to 3 heteroatoms. "Heteroaryl" refers to a monovalent heteroaromatic group derived by the removal of a hydrogen atom from a single atom of a progenitor system of heteroaromatic rings. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, beta-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline , isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline , tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene and the like. Preferably, the heteroaryl group is heteroaryl between 5-20 members, with 5-10 membered heteroaryl being particularly preferred. Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine. Examples of representative heteroaryls include the following: CO or > or > where each Y is selected from carbonyl, N, NR4, O and S. Examples of representative cycloheteroalkyls include the following each Y is selected from NR4, O and S, and where R6 'is R2. Examples of representative cycloheteroalkenyls include the following: wherein each X is selected from CR 4, NR 4, 0 and S; and each Y is selected from carbonyl, N, NR, 0 and S. Examples of representative aryl having heteroatoms containing substitution include the following: wherein each X is selected from C-R4, CR 2, NR 4, O and S; and each Y is selected from carbonyl, NR4, O and S. "Heterosubstituent" refers to a functionality containing halo, O, S or N atoms, which may be presented as an R4 in a R4C group, present as substituents directly in A , B, W, X, Y or Z of the compounds of this invention or can be presented as a substituent on the "substituted" aryl and aliphatic groups present in the compounds. Examples of heterosubstituents include: -halo, -N02, -NH2, -NHR, -N (R) 2, -NRCOR, -NRSOR, -NRS02R, OH, CN, -C02H, -R-OH, -OR, -COOR , -CON (R) 2, -CONROR, -S03H, -RS, -S02N (R) 2, -S (0) R, -S (0) 2R, wherein each R is independently an aryl or aliphatic, optionally with replacement. Among the heterosubstituents containing R groups, preference is given to those materials having R aryl and alkyl groups as defined herein. Preferred heterosubstituents are those listed in the foregoing. As used herein, the term "cycloheteroalkyl" refers to a stable heterocyclic non-aromatic ring and fused rings containing one or more heteroatoms independently selected from N, 0 and S. A system of fused heterocyclic rings may include carbocyclic rings , and may only need to include a heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl, and are shown in the following illustrative examples: optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl , substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl-S (0) -, aryl-S (0) -, alkyl-S (0) 2- and aryl- S (0) 2-- Substituent groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives. In the examples, M is CR7, NR2, 0 or S; Q is 0, NR2 or S. R7 and R8 are independently selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido , carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl-S (0) -, aryl-S (O) -, alkyl-S (0) 2- and aryl-S (0) 2-. "Dihydroxyphosphoryl" refers to the radical -P0 (0H) 2. "Substituted dihydroxyphosphoryl" includes those groups recited in the definition of "substituted" herein, and particularly refers to a dihydroxyphosphoryl radical wherein one or both hydroxyl groups are substituted. Suitable substituents are described in detail in the following. "Aminohydroxyphosphoryl" refers to the radical -P0 (0H) NH2. "Substituted aminohydroxyphosphoryl" includes those groups recited in the definition of "substituted" herein, and particularly refers to an aminohydroxyphosphoryl wherein the amino group is substituted with one or two substituents. Suitable substituents are described in detail in the following. In certain embodiments, the hydroxyl group may also be substituted. "Thioalkoxy" refers to the group -SR where R is alkyl. "Substituted thioalkoxy" includes those groups listed in the definition of "substituted" in this, and particularly refers to a thioalkoxy group having 1 or more substituents, for example 1 to 5 substituents, and particularly 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl- S (0) -, aryl-S (O) -, alkyl-S (O) 2- and aryl-S (0) 2-. "Sulfañilo" refers to the radical HS-. "Substituted sulfanyl" refers to a radical such as RS- where R is any substituent described herein. "Sulfonyl" refers to the divalent radical -S (02) -. "Substituted sulfonyl" refers to a radical such as R- (02) S- wherein R is any substituent described herein. "Aminosulfonyl" or "Sulfonamide" refers to the radical H2N (02) S-, and "substituted aminosulfonyl", "substituted sulfonamide" refers to a radical such as R2N (02) S- wherein each R is independently any substituent described at the moment. "Sulfone" refers to the group -S02R. In particular embodiments, R is selected from H, lower alkyl, alkyl, aryl and heteroaryl. "Thioaryloxy" refers to the group -SR where R is aryl.

"Tioceto" refers to the group = S. "Tiol" refers to the group -SH. One who has ordinary experience in the technique of organic synthesis will recognize that the maximum number of heteroatoms in a chemically feasible, stable heterocyclic ring, whether aromatic or non-aromatic, is determined by ring size, degree of unsaturation and valence. of the heteroatoms. In general, a heterocyclic ring can have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable. "Pharmaceutically acceptable" means approved by a regulatory agency of the Federal government or a state agency, or listed in the US Pharmacopoeia. or another pharmacopoeia generally recognized for use in animals and, more particularly, in humans. "Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, acid benzoic, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid , 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-en-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, acid glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, for example, an alkali metal ion, an alkaline earth ion or an aluminum ion; or is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. The salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetralkylammonium and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable, non-toxic, cationic counterion of an acid functional group. Such cations are exemplified by cations of sodium, potassium, calcium, magnesium, ammonium, tetralkylammonium and the like. "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. "Prevent" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject who may be exposed or predisposed to the disease but still does not experience or show symptoms of the disease). "Prodrugs" refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo. Similar examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. "Solvate" refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. "Subject" includes humans. The terms "human," "patient" and "subject" are used interchangeably herein. "Therapeutically effective amount" means the amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. "Treating" or "treating" any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . In another embodiment, "treat" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In still another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder. Other derivatives of the compounds of this invention have both acid and acid derivative activity, but in the acid sensitive form they often offer solubility, tissue compatibility or delayed release benefits in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by the reaction of the parent acid with a suitable alcohol, or amides prepared by the reaction of the parent acid compound with a substituted or unsubstituted amine. , or acid anhydrides, or mixed anhydrides. The simple aliphatic or aromatic esters, amides and anhydrides, derived from acidic groups pendent in the compounds of this invention, are preferred prodrugs. In some cases it is desirable to prepare double ester prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. Preferred are alkyl esters of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, aryl, substituted aryl of 7 to 12 carbon atoms and arylalkyl of 7 to 12 carbon atoms of the compounds of the invention. It should also be understood that compounds that have the same molecular formula, but differ in the nature or binding sequence of their atoms or in the arrangement of their atoms in space, are termed "isomers". The isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are termed "diastereomers" and those that are mirror images that can not overlap each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is linked to four different groups and a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center, and is described by the R and S sequencing rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light, and is designated dextrographic or levogyratory (that is, as isomers (+) or (-), respectively). A chiral compound can exist either as a single enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture." "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen and electron atoms. In this way, two structures can be in equilibrium through the movement of electrons n and an atom (usually H). For example, enols and ketones are tautomers since they are rapidly interconverted by treatment with either an acid or a base. Another example of tautomerism is the aci and nitro forms of phenylnitromethane, which are also formed by treatment with an acid or base. Representative enolketo structures and equilibrium are illustrated in the following: The tautomeric forms may be relevant for attaining the optimum chemical reactivity and biological activity of a compound of interest. The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims, is intended to include both individual enantiomers and mixtures, racemic or in some other way, thereof. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art.

Compounds The compounds provided herein are useful for preventing and / or treating a wide variety of conditions, including arthritis, Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, treatment and prophylaxis of syndromes. of pain (acute and chronic or neuropathic), traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease and autoimmune disorders or conditions in mammals. In order that the invention described herein may be more fully understood, the following structures representing typical compounds of the invention are established. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting this invention in any way. Accordingly, additional groups of particular compounds are provided. Thus, and as discussed hereinabove, suitable compounds, capable of modifying ion channels in vivo, can be selected from those listed in Tables 1-1 and 1-2, in the following, and can be prepared either as shown or in the form of a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers and tautomers thereof. All similar variants are contemplated herein and are within the scope of the present invention. In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulas in the foregoing. The prodrugs are derivatives of the compounds of the invention, which have cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention, which are pharmaceutically active, in vivo. Similar examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds of this invention have both acid and acid derivative activity, but the acid sensitive form often offers solubility, tissue compatibility or delayed release benefits in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by the reaction of the parent acid with a suitable alcohol, or amides prepared by the reaction of the parent acid compound with a substituted or unsubstituted amine. , or acid anhydrides, or mixed anhydrides. The simple aliphatic or aromatic esters, amides and anhydrides, derived from acidic groups pendent in the compounds of this invention, are preferred prodrugs. In some cases it is desirable to prepare double ester prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) allylesters. Preferred are alkyl esters of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, aryl, substituted aryl of 7 to 12 carbon atoms and arylalkyl of 7 to 12 carbon atoms of the compounds of the invention.

TEST METHODS Chronic Constriction Injury Model (Model CCI): Male Sprague-Dawley rats (270-300 g, B) are used.

W., Charles River, Tsukuba, Japan). The operation of chronic constriction injury (CCI) is performed according to the method described by Bennett and Xie (Bennett, G.J. and Xie, Y.K. Pain, 33: 87-107, 1988). Briefly, the animals are anesthetized with sodium pentobarbital (64.8 mg / kg, i.p.) and the left common sciatic nerve is exposed at the level of the mid-thigh by direct dissection through the biceps femoris. A portion of the sciatic nerve close to its trifurcation is released from the adherent tissue and 4 ligatures (4-0 silk) are tied loosely around it with approximately 1 mm of space. A simulated operation is performed in a similar way to ICC surgery, except for the ligation of the sciatic nerve. Two weeks after surgery, mechanical allodynia is evaluated by the application of von Frey hairs (VFHs) to the plantar surface of the hind paw. The lowest amount of force of the VFH, required to elicit a response, is recorded as the leg retraction threshold (PWT). The VFH test is performed at 0.5, 1 and 2 h after dosing. The experimental data are analyzed using the Kruskal-Wallis test followed by the Dunn test for multiple comparisons or the Mann-Whitney U test for paired comparison.

Permeability in Caco-2 cells Permeability in Caco-2 cells is measured according to the method described in Shiyin Yee, Pharmaceutical Research, 763 (1997) Caco-2 cells are grown on filter holders (insertion system Multi-well Falcon HTS) for 14 days.The culture medium is removed from the apical and basolateral compartments and the monolayers are pre-incubated with 0.3 ml of pre-heated apical buffer and 1.0 ml of basolateral buffer for 0.75 hour at 37 ° C in a water agitator bath at 50 cycles / min.The apical buffer consists of Hanks Balanced Salts Solution, 25 mM D-glucose monohydrate, 20 mM MES Biological Buffer, 1.25 mM CaCl2 and 0.5 mM MgCl (pH 6.5). The basolateral buffer consists of Hanks Balanced Salts Solution, 25 mM D-glucose monohydrate, 20 mM HEPES Biological Buffer, 1.25 mM CaCl2 and 0.5 mM MgC12 (pH 7.4) At the end of the preincubation, the media is removed and the compound solution Test (10 μ?) in buffer is added to the apical compartment. The inserts are moved to wells containing freshly prepared basolateral buffer and incubated for 1 h. The concentration of drug in the buffer is measured by LC / MS analysis. The flow rate (F, mass / time) is calculated from the slope of the cumulative appearance of the substrate on the receiver side and the apparent permeability coefficient (Papp) is calculated from the following equation: Papp (cm) / sec) = (F * VD) / (SA * MD) where SA is the surface area for transport (0.3 cm2), VD is the donor volume (0.3 ml), MD is the total amount of drug on the side donor at = 0. All data represent the average of 2 inserts. The integrity of the monolayer is determined by transport of Yellow Lucifer.

Binding to human dofetilide A cell paste of HEK-293 cells expressing the HERG product can be suspended in a 10-fold volume of 50 mM Tris buffer adjusted to pH 7.5 at 25 ° C with 2 M HCl containing 1 mM MgCl 2, 10 mM KCl. . The cells are homogenized using a Polytron homogenizer (at maximum power for 20 seconds) and centrifuged at 48,000 g for 20 minutes at 4 ° C. The granule is resuspended, homogenized and centrifuged once more in the same way. The resulting supernatant is discarded and the final granule is resuspended (volume 10 times of 50 mM Tris buffer) and homogenized at the maximum power for 20 seconds. The membrane homogenate is placed in aliquots and stored at -80 ° C until use. An aliquot is used for determination of protein concentration using a Protein Assay Rapid Kit and ARVO SX plate reader (Wallac). All the manipulation, reservation solution and equipment are kept on ice at all times. For saturation tests, the experiments are conducted in a total volume of 200 μ? . Saturation is determined by incubating 20 μ? of [3 H] -dofetilide and 160 μ? of membrane homogenates (20-30 μg of protein per well) for 60 minutes at room temperature in the absence or presence of 10 μm dofetilide? in final concentrations (20 μ?) for total or non-specific binding, respectively. All incubations are terminated by rapid vacuum filtration on glass fiber filter papers soaked in polyetherimide (PEI) using a Skatron cell harvester, followed by two washes with 50 mM Tris buffer (pH 7.5 at 25 ° C). The radioactivity bound to receptor is quantified by liquid scintillation counting using a Packard LS counter. For the competition assay, the compounds are diluted in 96-well polypropylene plates as 4-point dilutions in a semi-logarithmic format. All dilutions are made in DMSO first and then transferred to 50 mM Tris buffer (pH 7.5 at 25 ° C) containing 1 mM MgCl2, 10 mM KC1 so that the final concentration of DMSO becomes equal to 1%. The compounds are distributed in triplicate in test plates (4 μ?). The total binding and non-specific binding wells are prepared in 6 wells as a vehicle and dofetilide 10 μ? in final concentration, respectively. The radioligand is prepared at a final concentration of 5.6x and this solution is added to each well (36 μ?). The assay is initiated by the addition of YSi poly-L-lysine beads for Scintillation Proximity Assay (SPA) (50 μl, 1 mg / well) and membranes (110 μl, 20 g / well). Incubation is continued for 60 min at room temperature. The plates are incubated for an additional 3 hours at room temperature for the beads to settle. The radioactivity bound to the receptor is quantified by counting in a Wallac MicroBeta plate counter.

HERG assay Cells HEK 293, which stably express the HERG potassium channel are used for the electrophysiological study. The methodology for stable transfection of this channel in HEK cells can be found elsewhere (Z.Zhou et al., 1998, Biophysical Journal, 74, pp230-241). Before the day of experimentation, the cells are harvested from culture flasks and plated on glass coverslips in a standard medium Minimum Essential Medium (MEM) with 10% Fetal Bovine Serum (FCS). The cells in plates are stored in an incubator at 37 ° C maintained in an atmosphere of 95% 02/5% C02. The cells are studied between 15-28 hours after being harvested. HERG currents are studied using standard techniques of zonal membrane clamping of the whole cell mode. In the course of the experiment, the cells are superfused with a standard external solution of the following composition (mM); NaCl, 130; KC1, 4; CaCl2, 2; MgCl2, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole cell logs are made using a zonal membrane clamp amplifier and pipettes for membrane patches which have a resistance of 1-3 MOhm when filled with the standard internal solution of the following composition (mM); KC1, 130; MgATP, 5; MgCl2, 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only those cells with access resistances below 15? O and sealing resistances > 1 GQ are accepted for further experimentation. The series resistance compensation is applied up to a maximum of 80%. There was no escape subtraction. However, an acceptable access resistance depended on the size of the recorded currents and the level of resistance of series resistance that can be safely used. After achieving full cell configuration and sufficient time for cell dialysis with pipette solution (> 5 min), a standard voltage protocol was applied to the cell to evoke membrane currents. The voltage protocol is as follows. The membrane was depolarized from a holding potential of -80 mV to +40 mV for 1000 ms. This is followed by a descending voltage ramp (rate 0.5 mV msec "1) back to the maintenance potential.The voltage protocol is applied to a cell continuously throughout the experiment every 4 seconds (0.25 Hz). amplitude of the peak current produced in response to around -40 mV in the course of the ramp Once stable responses of evoked current are obtained in the external solution, the vehicle (0.5% D SO in the standard external solution) applied for 10-20 min by a peristaltic pump Minimal changes were provided in the amplitude of the current response evoked in the vehicle control condition, the test compound of each 0.3, 1, 3, 10 mM is applied during a period of 10 min The 10 min period included the time in which the supply solution is passing through the reservoir tube of the solution to the recording chamber by the pump. The solution of the compound is more than 5 min after the concentration of drug in the well of the chamber reaches the intended concentration. There is a subsequent washout period of 10-20 min to assess the reversibility. Finally, the cells are exposed to a high dose of dofetilide (5 mM), a specific blocker of IKr, to evaluate the insensitive endogenous current. All experiments are carried out at room temperature (23 ± 1 ° C). The evoked membrane currents are recorded online in a computer, filtered at 500-1 KHz (Bessel -3dB) and sampled at 1-2 KHz using the zonal membrane clamp amplifier and a specific data analyzer software. The peak current amplitude, which usually occurs at around -40 mV, is measured off line in the computer. The arithmetic mean of the ten amplitude values is calculated under vehicle control conditions and in the presence of the drug. The percentage decrease of IN in each experiment is obtained by the normalized value of the current using the following formula: IN = (1 - ID / IC) x 100, where ID is the average value of current in the presence of the drug and IC is the average value of current under control conditions. Separate experiments are performed for each concentration of drug or control coincident in time, and the arithmetic mean in each experiment is defined as the result of the study.

Model ?? of induction by Mono-Yodoacetate (MIA) Male Sprague-Dawley rats (SD, Japan SLC or Charles River Japan) of 6 weeks of age are anesthetized with pentobarbital. The injection site (knee) of MIA is shaved and cleaned with 70% ethanol. Twenty-five ml of MIA solution or saline solution is injected into the right knee joint using a 29 G needle. The effect of joint damage on the distribution of weight across the right (damaged) and left (untreated) knee ) is assessed using a disability tester (Linton Instrumentation, Norfolk, UK). The force exerted by each hind foot is measured in grams. The weight bearing deficit (WB) is determined by a difference in the step loaded on each leg. Rats are trained to measure WB once a week up to 20 days after injection of MIA. The analgesic effects of the compounds are measured at 21 days after the injection of MIA. Before the administration of the compound, the "pre-value" of the WB deficit is measured. After the administration of the compounds, the attenuation of WB deficits is determined as analgesic effects.

Thermal and mechanical hyperalgesia induced by Freund's complete adjuvant (CFA) in rats Thermal hyperalgesia Six-week-old male SD rats are used. Freund's complete adjuvant (CFA, 300 mg of Mycobacterium Tuberculosis H37RA (Difco, MI) was injected into liquid paraffin (Wako, Osaka, Japan)) on the plantar surface of a hind paw of the rats. Two days after the injection of CFA, thermal hyperalgesia is determined by the method previously described (Hargreaves et al., 1988) using the plantar test apparatus (Ugo-Basil, Varera, Italy). The rats adapt to the test environment for at least 15 minutes before any stimulation. Radiant heat is applied to the plantar surface of a hind paw and latencies of retraction of the paw are determined (P L, seconds). The radiant heat intensity is adjusted to produce the stable PWL from 10 to 15 seconds. The test compound is administered in a volume of 0.5 mL per 100 g of body weight. PWL is measured after 1, 3 or 5 hours after drug administration.

Mechanical hyperalgesia Male SD rats of 4 weeks of age are used. CFA (300 mg of Mycobacterium Tuberculosis H37RA (Difco, MI) in 100 μL of liquid paraffin (Wako, Osaka, Japan)) is injected into the plantar surface of a hind paw of the rats. Two days after the CFA injection, mechanical hyperalgesia is tested by measuring the leg retraction threshold (PWT, grams) at the pressure using the Analgesia Meter (Ugo-Basile, Varese, Italy). The animals are slightly restricted and a growing pressure is applied to the dorsal surface of a hind paw by a plastic tip. The pressure required to elicit the retraction of the leg is determined. The test compound is administered in a volume of 0.5 mL per 100 g of body weight. PWT is measured after 1, 3 or 5 hours after drug administration.

Pharmaceutical Compositions When used as pharmaceuticals, the amide compounds of this invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art, and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the current compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms and the like. The pharmaceutical compositions of this invention can be administered by a variety of routes including, by way of non-limiting example, oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Depending on the intended route of delivery, the compounds of this invention are preferably formulated as either injectable or oral compositions or as ointments, as lotions or as patches, all for transdermal administration. Compositions for oral administration may take the form of liquid solutions or suspensions in bulk, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units, suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material, calculated to produce the desired therapeutic effect, in association with a pharmaceutical excipient. suitable. Typical unit dosage forms include pre-filled, pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various carriers or carriers and useful processing aids. to form the desired dosage form. Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and distributing agents, colorants, flavors and the like. The solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. Injectable compositions are typically based on saline or buffered saline solution of sterile injectable phosphates or other injectable carriers known in the art. As before, the active compound in such compositions typically is a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like. The transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient (s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with an ointment base either paraffinic or water miscible. Alternatively, the active ingredients may be formulated in a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or formulation. All similar known transdermal formulations and ingredients are included within the scope of this invention. The compounds of this invention can also be administered by a transdermal device. Accordingly, transdermal administration can be achieved using a patch of either the reservoir or porous membrane type, or a variety of solid matrices. The components described in the foregoing, for orally administrable, injectable or topically administrable compositions, are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative continuous release materials can be found in Remington's Pharmaceutical Sciences. The following formulation examples illustrate the representative pharmaceutical compositions of this invention. The present invention, however, is not limited to the following pharmaceutical compositions.

Formulation 1 - Tablets A compound of the formula I is mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1: 2. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 240-270 mg (80-90 mg of active compound per tablet) in a tablet press. Formulation 2 - Capsules A compound of the formula I is mixed as a dry powder with a starch diluent in an approximate weight ratio of 1: 1. The mixture is poured into 250 mg capsules (125 mg of active compound per capsule). Formulation 3 - Liquid A compound of the formula I (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) are combined, passed through a No. 10 mesh screen of E.U. and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor and color are diluted with water and added with agitation. Sufficient water is then added to produce a total volume of 5 mL. Formulation 4 - Tablets The compound of the formula I is mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1: 2. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 450-900 mg (150-300 mg of active compound) in a tablet press. Formulation 5 - Injection The compound of the formula I is dissolved or suspended in an injectable aqueous medium of sterile buffered saline at a concentration of about 5 mg / ml. Formulation 6 - Topical Stearyl alcohol (250 g) and a filata vaseline (250 g) are melted at about 75 ° C and then a mixture of a compound of the formula I (50 g), methylparaben (0.25 g), propylparaben is added (0.15 g), sodium lauryl sulfate (10 g) and propylene glycol (120 g), dissolved in water (approximately 370 g), and the resulting mixture is stirred until frozen.

Methods of Treatment The present compounds are used as therapeutic agents for the treatment of conditions in mammals. Accordingly, the compounds and pharmaceutical compositions of this invention find use as therapeutic substances to prevent and / or treat neurodegenerative, autoimmune and inflammatory conditions in mammals including humans. In a method of the treatment aspect, this invention provides a method for treating a mammal susceptible to or afflicted with a condition associated with arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, alopecia (loss of hair), inflammatory bowel disease and autoimmune disorders, which method comprises administering an effective amount of one or more of the pharmaceutical compositions now described. In still another method of the treatment aspect, this invention provides a method for treating a mammal susceptible to or afflicted by a condition that gives rise to pain responses or that is related to imbalances in the maintenance of basal activity of the sensory nerves. The compounds have use as analgesics for the treatment of pain of various origins or etiology, for example acute inflammatory pain (such as pain associated with osteoarthritis and rheumatoid arthritis); various syndromes of neuropathic pain (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb pain, post-mastectomy pain, peripheral neuropathy, HIV neuropathy and neuropathies induced by chemotherapy and other iatrogenic); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis and various gynecological and urological disorders), dental pain and headache (such as migraine, cluster headache and tension headache). In a further method of the treatment aspects, this invention provides methods for treating a mammal susceptible to or afflicted by neurodegenerative diseases and disorders such as, for example, Parkinson's disease, Alzheimer's disease and multiple sclerosis.; diseases and disorders which are mediated by or result in neuroinflammation such as, for example, traumatic brain injury, stroke and encephalitis; centrally mediated neuropsychiatric disorders and disorders such as, for example, mania for depression, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example, urinary incontinence, initial dysuria, rectal hypersensitivity, fecal incontinence, benign prosthetic hypertrophy and inflammatory bowel disease; respiratory and respiratory tract diseases and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example, rheumatoid arthritis and osteoarthritis, myocardial infarction, various diseases and autoimmune disorders, uveitis and atherosclerosis; stinging / pruritus such as, for example, psoriasis; alopecia (hair loss); obesity; lipid disorders; Cancer; blood pressure; spinal cord injury; and renal disorders, the method comprises administering an effective amount, to treat the condition or prevent the condition, of one or more of the pharmaceutical compositions now described. Injection dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all of from about 1 to about 120 hours and especially 24 to 96 hours. A rapid intravenous injection of preload of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate levels of steady state. It is expected that the maximum total dose does not exceed approximately 2 g / day for a human patient of 40 to 80 kg. For the prevention and / or treatment of long-term conditions, such as neurodegenerative and autoimmune disorders, the regimen for treatment usually lengthens for many months or years, so that oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosage standards, each dose provides from about 0.01 to about 20 mg / kg of the compound or its derivative, with the preferred doses each providing from about 0.1 to about 10 mg / kg and especially about 1 to about 5 mg /. kg. Transdermal doses are generally selected to provide blood levels similar or lower than those achieved using injection doses. When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory condition, the compounds or their derivatives of this invention will be administered to a patient at risk of developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described in the above. Patients at risk of developing a particular condition generally include those who have a family history of the condition, or those who have been identified, by genetic testing or screening, as being particularly susceptible to developing the condition. The compounds of this invention can be administered as the sole active agent, or they can be administered in combination with other agents, including other active derivatives. A VR1 antagonist can be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain. For example, a VR1 antagonist, particularly a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above, can be administered simultaneously, in sequence or separately, in combination with one or more agents selected from: an opioid analgesic, for example morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine , butorphanol, nalbuphine or pentazocine; • a non-steroidal anti-inflammatory drug (NSAID), for example aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; • a barbiturate sedative, for example amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, teamilal or thiopental; · A benzodiazepine having a sedative action, for example chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam; • an Hl antagonist having a sedative action, for example diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone; • a skeletal muscle relaxant, for example baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orfrenadine; • an MDA receptor antagonist, for example dextromethorphan ((+) - 3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+) - 3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline, cis-acid 4- (phosphonomethyl) -2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, for example ifenprodil, traxoprodil or (-) - (R) -6-. { 2 - [4- (3-fluorophenyl) -4-hydroxy-l-piperidinyl] -l-hydroxyethyl-3,4-dihydro-2 (1H) -quinolinone; • an alpha-adrenergic, for example doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2- (5-methansulfonamido-1,2,3,4-tetrahydroisoquinol- 2-yl) -5- (2-pyridyl) quinazoline; · A tricyclic antidepressant, for example desipramine, imipramine, amitriptyline or nortriptyline; • an anticonvulsant, for example carbamazepine, lamotrigine, topiratmate or valproate; • a tachykinin (NK) antagonist, particularly an antagonist of NK-3, NK-2 or NK-1, for example (aR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9 , 10,11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino [2, 1-g] [1,7] naftridin-6-13-dione (TAK-637 ), 5- [[(2R, 3S) -2- [(IR) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] methyl] -1 , 2-dihydro-3H-l, 2,4-triazol-3 -one (MK-869), aprepitant, lanepitanto, dapitanto or 3- [[2-methoxy-5- (rifluoromethoxy) phenyl] -methylamino] -2 phenylpiperidine (2S, 3S); • a muscarinic antagonist, for example oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverin and ipratropium; • a selective COX-2 inhibitor, for example celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib or lumiracoxib; · An analgesic of coal pitch, in particular paracetamol; • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine , lurasidone, amisulpride, balaperidone, palindora, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan; • a beta-adrenergic agent such as propranolol; • a local anesthetic such as mexiletine; • a corticosteroid such as dexamethasone; • a 5-HT receptor agonist or antagonist, particularly a 5-HT1B / 1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan; • a 5-HT2A receptor antagonist such as R (+) - alpha- (2,3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl)] -4-piperidinemethanol (DL-100907); • a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E) -N-methyl-4- (3-pyridinyl) -3-buten-1-amine (RJR-2403), (R) - 5- (2-azetidinylmethoxy) -2-chloropyridine (ABT-594) or nicotine; · Tramado1®; • a PDEV inhibitor, such as 5- [2-ethoxy-5- (4-methyl-l-piperazinyl-sulfonyl) phenyl] -l-methyl-3-n-propyl-l, 6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one (sildenafil), (6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) - pyrazino [2 ', 1': 6, 1] -pyrido [3,4-b] indol-1,4-dione (IC-351 or tadalafil), 2- [2-ethoxy-5- (4-ethyl- piperazin-l-yl-l-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-fI [1, 2, 4] triazin-4-one (vardenafil), 5- ( 5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (l-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (l-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidine -7-one, 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H- pyrazolo [4, 3-d] pyrimidin-7-one, 4- [(3-chloro-4-methoxybenzyl) amino] -2- [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- (pyrimidin-2-ylmethyl) pyrimidi n-5-carboxamide, 3 - (l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo [4, 3-d] pyrimidin-5-yl) -N- [2- ( 1-methylpyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide; · An alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, acid (la, 3a, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic, acid ( 3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-octanoic acid, (2S, 4S) -4- (3-chlorophenoxy) proline, (2S, 4S) -4- (3-fluorobenzyl) -proline, [(IR, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid, 3- ( 1-aminomethyl-cyclohexylmethyl) -4H- [1,2, 4] oxadiazol-5-one, C- [1- (lH-tetrazol- -methylmethyl) -cycloheptyl] -methylamine, (3S, 4S) - (l -aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic, (3S, 5R) -3_aminomethyl-5-methyl-octanoic acid, (3S, 5R) -3-amino-5-methyl-nonanoic acid, (3S, 5R) -3-amino-5-methyl -octanoic, (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid; · A cannabinoid; • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (demethylated fluoxetine metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite, desmethylcitalopram, escitalopram, d, 1-fenfluramine, femoxetine, ifoxetine, cyanodotiepin, lithoxetine, dapoxetine, nefazodone, cericlamine and trazodone; • a norepinephrine reuptake inhibitor (norepinephrine), such as maprotiline, lofepramine, mirtazepine, oxaprotiline, phezolamine, tomoxetine, mianserin, buproprione, metabolite of buproprione hydroxybuproprione, nomifensin and viloxazine (Vivalan®), especially a selective norepinephrine reuptake inhibitor such as reboxetine, in particular (S, S) -reboxetine; • a double inhibitor of serotonin-norepinephrine reuptake, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite, desmethylclomipramine, duloxetine, milnacipran, and imipramine; • an inducible inhibitor of nitric oxide synthase (iNOS) such as S- [2- [(1-iminoethyl) amino] ethyl] -L-homocysteine, S- [2- [(1-iminoethyl) -amino] ethyl] -4,4-dioxo-L-cysteine, S- [2- [(1-iminoethyl) amino] ethyl] -2-methyl-L-cysteine, (2S, 5Z) -2-amino-2-methyl-1 acid 7- [(1-iminoethyl) amino] -5-heptenoic, 2- [[(IR, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -5-chloro- 3-pyridinecarbonitrile; 2- [[(IR, 3S) -3-amino-4-hydroxy-l- (5-thiazolyl) butyl] thio] -4-chlorobenzonitrile, (2S, 4R) -2-amino-4- [[2- chloro-5- (trifluoromethyl) phenyl] thio] -5-thiazolebutanol, 2- [[(IR, 3S) -3-amino-4-hydroxy-l- (5-thiazolyl) butyl] thio] -6- (trifluoromethyl) ) -3-pyridinecarbonitrile, 2- [[(IR, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] -io] -5-chlorobenzonitrile, N- [4- [2- (3 -chlorobenzylamino) ethyl] phenyl] thiophene-2-carboxamidine or guanidinoethyldisulfide; • an acetylcholinesterase inhibitor such as donepezil; · An antagonist of prostaglandin E2 subtype 4 (EP4) such as N- [(. {2 - [4- (2-ethyl-4,6-dimethyl-lH-imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl}. amino) -carbonyl] -4-methylbenzenesulfonamide or 4- [(1S) -1- ( { [5-chloro-2- (3-fluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic; · A leukotriene B4 antagonist; such as acid 1- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), 5-12- (2-carboxyethyl) -3- [6- (4-methoxyphenyl)) -5E-hexenyl] oxyphenoxy] -valeric (ONO-4057) or DPC-11870, · a 5-lipoxygenase inhibitor, such as zileuton, 6- [(3-fluoro-5- [4-methoxy-3, 4, 5,6-tetrahydro-2H-pyran-4-yl]) phenoxy-methyl] -l-methyl-2-quinolone (ZD-2138) or 2,3,5-trimethyl-6- (3-pyridylmethyl), 1 , 4-benzoquinone (CV-6504); • a sodium channel blocker, such as lidocaine; • a 5-HT3 antagonist, such as ondansetron; and the pharmaceutically acceptable salts and solvates thereof. Whereas it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, can conveniently be combined in the form of a suitable equipment for the co-administration of the compositions.

Preparation of the Compounds The compounds of this invention can be prepared from readily available starting materials, using the following methods and general procedures. It will be appreciated that, where the typical or preferred conditions of the process (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless stipulated. otherwise. Optimal reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art, conventional protection groups may be necessary to prevent certain functional groups from being subjected to unwanted reactions. The choice of an appropriate protection group for a particular functional group, as well as the appropriate conditions for protection and deprotection, are well known in the art. For example, numerous protection groups, and their introduction and removal, are described in T. W. Greene and P. G. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1999, and references cited therein. The objective compounds are synthesized by known reactions detailed in the following schemes. The products are isolated and purified by standard known procedures. Such procedures include (but are not limited to) recrystallization, column chromatography or HPLC. In this specification, especially in "General Synthesis" and "Examples", the following abbreviations may be used: DCM dichloromethane DME 1, 2-dimethoxyethane, dimethoxyethane DMF N, -dimethylformamide DMSO dimethyl sulfoxide EDC l-ethyl-3-acid chloride (3'-dimethylaminopropyl) carbodiim EtOAc ethyl acetate EtOH ethanol HOBt 1-hydroxybenzotriazole MeOH methanol THF tetrahydrofuran TFA trifluoroacetic acid Preparation of acid building blocks Preparation of Replaced Benzoic Acid Intermediary 1 Preparation of 2-chloro-6- (3, 3-dimethylbut-1-ynyl) nicotinic acid 2, 6-Dichloropyridine-3-carboxylic acid (2.0 g, 10.42 mmol), 3,3-dimethylbut-l-ina (1.4 mL, 11.46 mmol), copper iodide (I) (0.198 g, 1.04 mmol) and chloride of bis (triphenylphosphine) palladium (II) (1.46 g, 2.08 mmol) were stirred in 40 mL of triethylamine at room temperature for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 10-50% MeOH / EtOAc to give 125 mg (5%) of the title compound as an orange solid, m / z = 236 (M-1).

Intermediary 2 Preparation of (e) -2-methyl-4- (3,3,3-trifluoroprop-l-enyl) benzoic acid A mixture of 4-bromo-2-methylbenzoic acid (25 g, 0.12 mol), tri-o-tolylphosphine (7.1 g, 0.023 mol), tetra-N-butylammonium chloride (9.7 g, 0.035 mol), potassium acetate (22.8 g, 0.232 mol), 3, 3 , 3-trifluoroprop-l-ene (89 g, 0.93 mol), palladium acetate (1.3 g, 0.0058 mol) and N, N-dimethylacetamide (150 mL, 1.6 mol) was sealed in a Parr instrument and stirred at 180 ° C for 120 h. After cooling, the reaction mixture was filtered through celite and the filtrate was partitioned between EtOAc and 1N HC1 (pH 2-3). The organic layer was separated and washed with brine, dried (Na 2 SO) and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give an unpurified product (which contains a small amount of the corresponding (Z) -isomer). The (2) -isomer and other impurities can be removed by column after transforming the acid into the corresponding methyl ester. Saponification of the methyl ester gave the pure acid as a white solid (16.5 g, 62%).

Intermediary 3 Preparation of the acid 4- (cyclopentiletinil) -2- 4- (Cyclopentylethynyl) -2-fluorobenzoate methyl. 4-Bromo-2-fluorobenzoic acid methyl ester (1.Og, 4.0 mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (38mg, 5 mol%), followed by PdCl2 (PPh3) 2 (140mg, 5mol%) and ethynylcyclopentane (0.85mL, 6.3mmol). The mixture was heated in a sealed tube under pressure at 80 ° C for 3 hours. After completion of the reaction, the triethylamine was removed under vacuum and the residue was dissolved in EtOAc and filtered through celite. The organic layer was washed with water, brine, and dried (Na 2 SO 4) filtered and the mixture was concentrated under vacuum. The residue was purified using column chromatography on silica using EtOAc-hexane (0-100% gradient) as eluent to give the product (0.92g). 4- (Cyclopentiletinyl) -2-fluorobenzoic acid. Methyl 4- (cyclopentylethynyl) -2-fluorobenzoate was dissolved in lOmL of MeOH and lOmL of 2N LiOH and the mixture was refluxed overnight. The MeOH was removed under vacuum and the basic layer was washed with EtOAC, acidified, and extracted again with EtOAC. The organic layer was washed with brine, dried (Na2SO, j) filtered and concentrated under vacuum to give the desired product (645 mg) as a beige solid. m / z = 233 (M + 1).

Intermediary 4 Preparation of 2-chloro-6- (cyclopropylethyl) nicotinic acid Ethyl 2,6-dichloropyridine-3-carboxylate. 2,6-Dichloropyridine-3-carboxylic acid (2.0 g, 10.42 mmol) was added to 100 mL of EtOH, 2 mL of concentrated H2SO4 and the mixture was refluxed for 18 h. The reaction mixture was cooled and the pH was adjusted to 5 with saturated aqueous NaHCO 3 and then extracted with EtOAc. The organic layer was separated and dried (Na2SO4). The solvent was removed in vacuo to give 2.1 g of the ethyl ester which was used in the next step without further purification, m / z = 220.6 (M + 1).

Ethyl 2-chloro-6- (2-cyclopropylethynyl) pyridine-3-carboxylate. Ethyl 2,6-dichloropyridine-3-carboxylate (2.0 g, 9.1 mmol), ethynylcyclopropane (1.6 mL of a 70% w / v solution in toluene, 13.63 mmol), copper (I) iodide (173 mg, 0.9 mmol), bis (triphenylphosphine) palladium (II) chloride (1.28 g, 1.82 mmol) were stirred in 40 mL of triethylamine at room temperature for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 10-50% EtOAc / hexane to give the product (0.7g, 31%) as a brown oil, m / z = 250 (M + l) . 2-Chloro-6- (cyclopropylethynyl) nicotinic acid. The aster was hydrolyzed as follows: ethyl 2-chloro-6- (2-cyclopropylethynyl) pyridine-3-carboxylate (0.7 g, 2.8 mmol) and lithium hydroxide (0.4 g, 16.86 mmol) were refluxed in a mix 30 mL of cOH and 10 mL of water. The mixture was cooled and the methanol was removed in vacuo. The remaining solution was acidified to pH 2 with 1M HC1 at 0 ° C. The precipitate was filtered and dried to give 0.4 g (57%) of the title compound, m / z = 222.4 (M + 1).

Intermediate 5 Preparation of (Z) -2-methoxy-4- (3 # 3, 3-trifluoroprop-1-enyl) benzoic acid and preparation of (E) -2-methoxy-4- (3 # 3, 3) acid -trifluoromethylprop-l-enyl) benzoic acid Methyl 4-formyl-2-methoxybenzoate. A slow stream of CO was passed into a suspension of methyl 4-bromo-2-methoxybenzoate (2.4g, 0.010 mol), bis (triphenylphosphine) aladdin (II) chloride (140 mg, 0.00020 mol), sodium format (1.02 g, 0.0150 mol), and dry DMF (10 mL). The mixture was stirred vigorously at 110 ° C for 2 h. After cooling, the mixture was treated with aqueous Na 2 CO 3 solution and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel with AcOEt-hexane as eluent (0 to 50%) to give a colorless oil.

(E) -4- (3,3, 3-trifluoroprop-l-enyl) -2-methoxybenzoate methyl and (Z) -4- (3,3,3-trifluoroprop-1-enyl) -2-methoxybenzoate. MS 4A (powder, 16 g) was added to a solution of 1M TBAF in THF (20 mL, 20 mmol), and the mixture was stirred at room temperature overnight under an argon atmosphere. To the mixture was added a solution of methyl 4-formyl-2-methoxybenzoate (420 mg, 0.0022 mol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (1.23 g, 0.00432 mol) in THF (20 mL). After the mixture was stirred for 2 h, MS was removed 4Á by filtration. The filtrate was concentrated and water (120 mL) was added. The mixture was extracted with AcOEt. The extract was washed with brine, dried (Na2SC > 4), and concentrated. The residue was purified by column chromatography on silica gel using AcOEt-hexane (0-15%) as eluent to give 4- (3,3,3-trifluoroprop-1-enyl) -2-methoxybenzoate of (E) - methyl as a white solid, followed by (3, 3, 3-trifluoroprop-1-enyl) -2-methoxybenzoate of (Z) -methyl as a colorless oil.

(E) -4- (3, 3, 3-Trifluoroprop-l-enyl) -2-methoxybenzoic acid. A mixture of (E) -methyl 4- (3, 3, 3-trifluoroprop-l-enyl) -2-methoxybenzoate (340 mg, 0.0013 mol), MeOH (20 mL), and 2N aqueous NaOH solution (1.5 mL) ) was stirred at 65 ° C overnight. The solvents were removed under reduced pressure and the residue was treated with water, acidified with 1N HC1 to pH 2-3, and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried (Na 2 SO 4) filtered and concentrated in vacuo to give the product as a white solid. LC-MS: 2.59 min, 244.8 (M-l).

(Z) -4- (3, 3, 3-trifluoroprop-l-enyl) -2-methoxybenzoic acid. A mixture of 4- (3, 3, 3-trifluoroprop-l-enyl) -2-methoxybenzoate (Z) -methyl (60.0 mg, 0.000230 mol), MeOH (10 mL), and 2N aqueous NaOH solution (0.5 mL) ) was stirred at 65 ° C for 5 h. After cooling the mixture, the solvent was removed under reduced pressure. The residue was treated with water, acidified with 1N HC1 to pH 2-3, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried (Na 2 SO 4) filtered and concentrated in vacuo to give the product as a syrup which became a creamy white solid while remaining at room temperature for a long time. LC-MS: 2.49 min, 244.8 (M-l).

Intermediary 6 Preparation of 4- (cyclopropylethynyl) methylbenzoic acid Meti1-4-bromo-2-methylbenzoate. 4-Bromo-2-methylbenzoic acid (5.0g, 23 mmol) was suspended in methanol (30mL). To the mixture was added a solution of HCl in diethyl ether (1.0M, 30mL). The mixture was refluxed for 24 hours and concentrated to dryness. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate. The organic layer was washed with brine, dried (Na 2 SO 4) filtered and concentrated under vacuum to give the desired compound (5.5 g) as a brown oil. 4- (Cyclopropylethynyl) -2-methylbenzoic acid. Methyl 4-Bromo-2-methylbenzoate (1.Og, 4.4 mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (43mg, 5mol%), followed by PdCl2 (PPh3) 2 (157mg, 5mol%) and ethynylcyclopropane (1.43ml, 12mmol). The mixture was heated in a sealed tube under pressure at 80 ° C for 3 hours. After completion of the reaction, the triethylamine was evaporated and the residue was dissolved in EtOAc and filtered through celite. The organic layer was washed with water, brine, and dried (Na2SO4), then filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel using EtOAc-hexane (0-100% gradient) as eluent to give the desired product (630 mg). The product was dissolved in 10 mL of MeOH and 10 mL of 2N LiOH and the mixture was refluxed overnight. The MeOH was evaporated and the basic layer was washed with EtOAC, acidified, and extracted again with EtOAC. The organic layer was washed with brine, dried (Na2SC > 4) filtered and concentrated under vacuum to give the desired product as a beige solid (461 mg). m / z 201 (M + l).

Intermediary 7 Preparation of 4- (cyclopropylethynyl) -2-fluorobenzoic acid This compound was prepared using the same method as for 4- (3, 3-dimethylbut-1-ynyl) -2-methylbenzoic acid, with the exception that cyclopopylacetylene was used as the alkyne coupling association.

Intermediary 8 Preparation of 4- (3, 3-dimethylbut-l-ynyl) -2-methoxybenzoic acid Methyl 2-methoxy-4- (3, 3-dimethylbut-l-ynyl) benzoate. A mixture of methyl 4-bromo-2-methoxybenzoate (? .2 g, 0.0049 mol), copper iodide (I) (0.093 g, 0.00049 mol), 3,3-dimethyl-l-butine (0.70 mL, 0.0059 mol) and bis (triphenylphosphine) palladium (II) chloride (0.34 g, 0.00049 mol) in Et3N (10 mL) was heated at 100 ° C in a sealed reaction vessel of 50 mL for 16 hours. After cooling, the mixture was filtered through celite and the filter cake was washed repeatedly with ethyl acetate. The filtrate was concentrated under vacuum and the residue was purified by column chromatography on silica gel to give a viscous oil (1.10g, 91%). 2-Methoxy-4- (3, 3-dimethylbut-1-ynyl) benzoic acid. A mixture of methyl 2-methoxy-4- (3, 3-dimethylbut-l-ynyl) benzoate (1.10 g, 0.00447 mol), MeOH (20 mL), and 2N aqueous NaOH solution (5 mL) was stirred at 65 ° C during the night. After it was allowed to cool, the mixture was concentrated under vacuum. The residue was treated with water, and extracted with hexane. The aqueous layer was acidified with 1N HCl to pH 2-3, and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried (Na204) filtered and concentrated under vacuum to give the product (870 mg, 84%) as a white solid. LC-MS: 3.22 min, 233.4 (M + 1).

Intermediary 9 Preparation of 4- (Cylopropylethynyl) -2,6-difluorobenzoic acid Methyl ester of 4-Bromo-2,6-difluoro-benz (200mg, 0.8mmol) was dissolved in triethylamine (5mL) and dichloropalladium (bis) triphenylphosphine (29mg, 5mol%) was added followed by copper iodide (8mg, 5mol%) and cyclopropylacetylene (0.09mL, 0.96mmol). The mixture was heated to reflux in a sealed tube for 1 hour. The mixture was cooled to room temperature and filtered through celite and evaporated. The residue was dissolved in dichloromethane and purified using 0-100% gradient EtOAc / Hexane to give 178 mg (94%) of the ester compound. m / z = 237 (M + l). The ester was subjected to hydrolysis using the detailed methodology for 4- (cyclopentylethynyl) -2-fluorobenzoic acid to give the desired acid product.

Intermediate 10 Preparation of methyl (cyclopentylethynyl) methylbenzoic acid 4- (cyclopentylethynyl) -2-methylbenzoate. Methyl 4-bromo-2-methylbenzoate (1.Og, 4.4 mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (43mg, 5mol%), followed by PdCl2 (PPh3) 2 (157mg, 5mol%) and ethynylcyclopentane (0.75mL, 5.3mmol). The mixture was heated in a sealed tube under pressure at 80 ° C for 3 hours. After completion of the reaction, the triethylamine was evaporated and the residue was dissolved in EtOAc and filtered through celite. The organic layer was washed with water, brine, and dried (Na2SO4), then filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel using EtOAc-hexane (0-100% gradient) as an eluent to give the desired product. 4- (Cyclopentylethynyl) -2-methylbenzoic acid. The product of step 1 was dissolved in lOmL of MeOH and lOmL of 2N LiOH and the mixture was refluxed overnight. The MeOH was evaporated and the basic layer was washed with EtOAC, acidified, and extracted again with EtOAC. The organic layer was washed with brine, dried (Na 2 SO) filtered and concentrated under vacuum to give the desired product (461 mg) as a beige solid. m / z = 243 (M + l).

Intermediary 11 Preparation of 4- (3, 3-dimethylbut-l-ynyl) -2-methylbenzoic acid Methyl 4-bromo-2-methylbenzoate. 4-Bromo-2-methylbenzoic acid (10 g, 46.5 mmol) was dissolved in 200 mL of EtOH, 5 nL of conc. H2SO4 was added and the mixture was refluxed for 18 h. The reaction volume was reduced to 50 mL in vacuo, and neutralized to pH 7 with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SC > 4) filtered and the filtrate was concentrated to give the product (6.5g) as an oil.

Ethyl 2-methyl-4- (3, 3-dimethylbut-l-ynyl) benzoate. Ethyl 4-bromo-2-methylbenzoate (6 g, 0.02 mol), 1-butyne, 3, 3-dimethyl- (4.56 mL, 0.0382 mol) copper (I) iodide (0.47 g, 0.0025 mol) and bis ( triphenylphosphine) aladium (II) chloride (3.46 g, 0.00493 mol) were placed in 40 mL of triethylamine and stirred at room temperature overnight in a sealed tube. The reaction mixture was diluted with MeOH and filtered through celite. The filtrate was concentrated in a brown residue. The residue was purified by column chromatography on silica gel using hexanes as eluent to give the product (4.8g, 42%) as a brown oil. 4- (3, 3-Dimethylbut-l-ynyl) -2-methylbenzoic acid. Ethyl 2-methyl-4- (3, 3-dimethylbut-l-ynyl) benzoate (4.8 g, 0.020 mol) and lithium hydroxide (2.8 g, 0.058 mol) were placed in 3: 1 methanol: water mixture (80 mL) and heated at 60 ° C for 3.5 h. TLC and LCMS indicated product formation. The reaction was cooled and concentrated in vacuo to a volume of 20 mL. The mixture was placed in an ice water bath and acidified to pH 5 with concentrated HC1. A pulverized white solid which was filtered and washed thoroughly with water. The solid was dried in a vacuum oven to give the product (4.1 g, 97%) as a solid, m / z = 215.1 (M-1).

Intermediary 12 Preparation of (E) -2-fluoro-4- (3,3,3-trifluoroprop-1-enyl) benzoic acid Methyl-2-fluoro-4-bromobenzoate. 4-Bromo-2-fluorobenzoyl chloride (45.0 g, 0.190 mol) was added slowly to a solution of methanol (31 mL, 0.76 mol) and triethylamine (53 mL, 0.38 mol) at 0 ° C and the mixture was stirred at Room temperature during the night. The mixture was washed with water, dried (Na2SC > 4), and concentrated to give a white solid.

(E) -2-Fluoro-4- (3,3,3-trifluoroprop-1-enyl) benzoic acid. A mixture of methyl-2-fluoro-4-bromobenzoate (5.0 g, 0.021 mol), tri-o-tolylphosphine (1.31 g, 0.00429 mol), tetra-N-butylammonium bromide (2.08 g, 0.00644 mol), potassium acetate (4.2 g, 0.043 mol), 3, 3 , 3-trifluoroprop-1-ene (20 g, 0.2 mol), palladium acetate (0.24 g, 0.0011 mol) was sealed on a Parr instrument and stirred at 180 ° C for 96 h. After cooling, the reaction mixture was filtered through Celite and the filtrate was partitioned between EtOAc and aqueous 1N HC1. The organic layer was separated and washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed with hexane-EtOAc (5% AcOH) (0 to 60%) to give the product as a white solid. LC-MS: t = 2.98 min, m / z = 233.2 (M-l).

Intermediate 13 Preparation of (Z) -2-fluoro-4- (3, 3f 3-trifluoroprop-1-eny1) benzoic acid 4-bromo-2-fluorobenzoate of tert-butyl acid. To a stirred solution of 4-bromo-2-fluorobenzoic acid (3.0 g, 0.014 mol) in THF (50 mL) at 0 ° C was added DMF (0.1 mL) and oxalyl chloride (1.5 mL, 0.018 mol). The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature the solvent was removed under reduced pressure. The acid chloride obtained was added to a mixture of tert-butyl alcohol (5.0 g, 0.067 mol), pyridine (10 mL), and CH2C12 (50 mL) at 0 ° C. The mixture was stirred at room temperature for 3 h, and then at 50 ° C overnight. The mixture was washed with water, 2N NaOH, and brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by column to give a colorless oil (1.5 g, 45%). 2-Fluoro-4-formylbenzoate of tert-butyl. To a stirred solution of tert-butyl 4-bromo-2-fluorobenzoate (1.5 g, 5.45 mmol) in THF (70 mL) at -100 ° C under argon was carefully added BuLi (2.5 M in hexane, 2.3 mL, 5.75 mmol). The mixture was kept at -100 ° C to -80 ° C for 1 h and then DMF (1.0 mL) in THF (5 mL) was added. After lh, the mixture was warmed to 0 ° C and quenched by the addition of saturated aqueous NH 4 Cl, and extracted with EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc / hexane (0-10%) as eluent to give the product (750 mg, 61%) as a white solid. 2-Fluoro-4- (3, 3, 3-trifluoroprop-l-enyl) benzoate of (E) -tez * -butyl and 2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoate of (Z) - er-butyl. A 4A molecular sieve (powder, 24 g) was added to a solution of 1M TBAF in THF (30 mL, 30 mmol), and the mixture was stirred at room temperature overnight under an argon atmosphere. To the mixture was added a solution of tert-butyl 2-fluoro-4-formylbenzoate (750 mg, 0.0033 mol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (1.9 g, 0.0067 mol) in THF (30 mL). The mixture was then stirred for 2 h and filtered. The filtrate was concentrated under vacuum and water (120 mL) was added. The mixture was extracted with AcOEt and the organic extract was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel using AcOEt-hexane (0-15%) as eluent to give 2-fluoro-4- (3,3,3-trifluoroprop-1-enyl) benzoate of (E) -tert-butyl as a colorless oil (620 mg, 64%), followed by (Z) -tert-butyl 2-fluoro-4- (3, 3, 3-trifluoroprop-l-enyl) benzoate as a colorless oil (80 mg, 8%).

(E) -2-Fluoro-4- (3,3,3-trifluoroprop-1-enyl) benzoic acid. A solution of (E) -tert-butyl 2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoate (500 mg, 0.002 mol) in CH2C12 (10 mL) and TFA (1.0 mL) it was stirred at room temperature for 2 h, the solvent was removed under reduced pressure to give a white solid. LC-MS: 2.99 min, 233.2 (M-l).

(Z) -2-Fluoro-4- (3,3,3-trifluoroprop-1-enyl) benzoic acid. (2) A solution of 2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoate of (Z) -tert-butyl (35 mg, 0.12 mmol) in CH2C12 (5 mL) and TFA (0.5 mL) it was stirred at room temperature for 2 h. , the solvent was removed under reduced pressure to give a white solid. LC-MS: 2.86 min, 233.2 (M-l).

Intermediary 14 Preparation of 4- (3, 3-dimethylbut-l-ynyl) -2-fluorobenzoic acid 4-Bromo-2-fluoro-benzoic acid methyl ester. 4-Bromo-2-fluorobenzoic acid (10 g, 0.04 mol) was suspended in 1,2-dichloroethane (60 mL, 0.8 mol) to which was added thionyl chloride (10 mL, 0.1 mol) followed by a drop of D F. The mixture was refluxed for 1 hour. Excess thionyl chloride and 1,2-dichloroethane were removed and the crude product was treated with methanol (50 mL, 1 mol) and heated to reflux for one hour. The mixture was concentrated to dryness, dissolved in dichloromethane, treated with a cold saturated sodium bicarbonate solution. The organic layer was dried, then concentrated under vacuum to obtain the title compound as a white solid. 4- (3 # 3-Dimethyl-but-l-ynyl) -2-fluoro-benzoic acid methyl ester. In a sealed reaction vessel was added bis (triphenylphosphine) palladium (II) chloride (1.03 g, 0.00145 mol) N, N-diisopropylethylamine (9.0 mL, 0.050 mol), copper iodide (I) (0.353 g, 0.00186 mol) , and 1,4-dioxane (70 mL, 0.8 mol) in that order. 1-Butyne, 3,3-dimethyl- (6.1 mL, 0.050 mol) was added and the vessel was allowed to stir at room temperature for 24 hrs. The mixture was filtered through celite and concentrated in vacuo. The mixture was subjected to chromatography using a gradient of 0-20% ethyl acetate: hexanes. The combined pure fractions were reduced in vacuo and dried under high vacuum to produce a light brown solid. 4- (3 # 3-Dimethyl-but-l-ynyl) -2-fluoro-benzoic acid. Methyl 2-fluoro-4- (3, 3-dimethylbut-l-ynyl) benzoate (8.2 g, 0.035 mol) was suspended in a 3: 1 mixture of H20 and methanol to which everything was added all at once lithium hydroxide (2.5 g, 0.10 mol) and the mixture was stirred overnight at room temperature. The mixture was then concentrated to 3/4 of the volume and acidified with 1N HC1 until the pH reading was barely acidic. The white precipitate was filtered, washed with water and dried under vacuum at 80 ° C for several hours, m / z = 218.9 (M-1).

Intermediary 15 Preparation of 2-chloro-4- (3, 3-dimethylbut-l-ynyl) benzoic acid Methyl 2-chloro-4- (3, 3-dimethylbut-l-ynyl) benzoate. A mixture of methyl 4-bromo-2-chlorobenzoate (400 mg, 0.0016 mol), copper (I) iodide (30 mg, 0.00016 mol), 3,3-dimethyl-l-butyne (0.29 mL, 0.0024 mol) bis (triphenylphosphine) palladium (II) chloride (110 mg, 0.00016 mol) in Et3N (5 mL) and DMF (2 mL) was heated at 100 ° C in a sealed reaction vessel of 50 ml for 32 hours. After cooling, the mixture was filtered through celite and the filter cake was washed repeatedly with ethyl acetate. The organic phase was washed with brine, dried (Na2SC > 4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the product (330 mg, 82%) as a light yellow oil. 2-Chloro-4- (3, 3-dimethylbut-1-yny1) benzoic acid. A mixture of methyl 2-chloro-4- (3, 3-dimethylbut-l-iniD-benzoate (330 mg, 0.0013 mol), aqueous 2N NaOH (3.0 mL), THF (5 mL), and MeOH (5 mL) were added. The mixture was concentrated under vacuum and the residue was treated with water and acidified with 1N HCl to pH 2-3, and extracted with EtOAc The organic layer was washed with brine, dried ( Na2SO4), and concentrated in vacuo to give the product (305 mg, 98%) as a white solid LC-MS: 3.56 min, 234.9 &236.9 (Ml).

Intermediary 16 Preparation of 2-chloro-4- (cyclopropylethynyl) benzoic acid methyl 2-chloro-4- (2-cyclopropylethynyl) benzoate. A mixture of methyl 4-bromo-2-chlorobenzoate (450 mg, 0.0018 mol), copper (I) iodide (34 mg, 0.00018 mol), 70% cyclopropylacetylene solution (0.26 g, 0.0027 mol) in toluene and bis (triphenylphosphine) palladium (II) chloride (130 mg, 0.00018 mol) in Et3N (5 mL) and DMF (3 mL) was heated at 100 ° C in a sealed reaction vessel of 50 mL for 36 hours. After cooling, the mixture was filtered through celite and the filter cake was washed repeatedly with ethyl acetate. The organic phase was washed with brine, dried (Na 2 SO 4) filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the product (320 mg, 76%) as a brown oil. 2-Chloro-4- (2-cyclopropylethynyl) benzoic acid. A mixture of methyl 2-chloro-4- (2-cyclopropylethynyl) benzoate (310 mg, 0.0013 mol), aqueous 2N NaOH (3.0 mL), THF (5 mL), and MeOH (5 mL) was stirred at room temperature for 5 h. The mixture was concentrated under vacuum and the residue was treated with water and acidified with 1N HC1 to pH 2-3, and extracted with EtOAc. The organic layer was washed with brine, dried (Na 2 SO) filtered and concentrated under vacuum to give the product (270 mg, 93%) as a yellow solid. LC-MS: 3.18 min, 218.9 & 220.9 (M-l).

Intermediary 17 Preparation of (E) -2-chloro-4- (3,3,3-trifluoroprop-l-enyl) benzoic acid Methyl 2-chloro-4-formylbenzoate. A slow stream of CO was passed into a suspension of methyl 4-bromo-2-chlorobenzoate (1.50 g, 0.00601 mol), bis (triphenylphosphine) palladium (II) chloride (80 mg, 0.0001 mol), sodium format (613 mg, 0.00902 mol), and dry DMF (10 mL). The mixture was stirred vigorously at 110 ° C for 2 h. After cooling, the mixture was treated with Na2CC solution > 3 aqueous and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with AcOEt-hexane to give the product as a colorless oil. (becoming a white solid when stored in a refrigerator). 2-Chloro-4- ((E) -3,3,3-trifluoroprop-1-enyl) enzoic acid. A molecular sieve of 4A (powder, 16 g) was added to a solution of TBAF of 1M in THF (20 mL, 20 mmol), and the mixture was stirred at room temperature overnight under an argon atmosphere. To the mixture was added a solution of methyl 2-chloro-4-formylbenzoate (210 mg, 0.0010 mol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (600 mg, 0.0021 mol) in THF (15 mL). After the mixture was stirred for 2 h, the molecular sieve was removed by filtration. The filtrate was concentrated and water was added (120 mL). The mixture was extracted with AcOEt. The organic extract was washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with AcOEt [1% HOAc] -hexane to give the product as a white solid. LC-MS: t = 3.12 min, m / z = 248.9 & 250.9 (M-l).

Intermediary 18 Preparation of 4- (cyclopropylethynyl) -2- (methy1sulfoni1) benzoic acid 4-Bromo-2-methanesulfonyl acid methyl ester (250 mg, 0.85 mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (9.0mg, 5mol%), followed by PdCl2 (PPh3) 2 (32mg, 5mol%) and ethynylcyclopentane (0.135ml, l.Ommol). The mixture was heated in a sealed tube under pressure at 80 ° C for 3 hours. After completion of the reaction, the triethylamine was removed under vacuum and the residue was dissolved in EtOAc and filtered through celite. The organic layer was washed with water, brine, and dried (Na2SO4). After filtration and concentration under vacuum, the residue was purified by column chromatography on silica gel using EtOAc-hexane (0-100% gradient) as eluent to give methyl 4- (cyclopropylethynyl) -2- (methylsulfonyl) enzoate (240mg). The product was dissolved in lOmL of MeOH and lOmL of 2N LiOH and the mixture was refluxed overnight. The MeOH was evaporated and the basic layer was washed with EtOAC, acidified, and extracted again with EtOAc. The organic layer was washed with brine, dried (Na 2 SO 4) filtered and concentrated under vacuum to give the product (165 mg) as a beige solid. m / z = 293 (M + l).

Intermediary 19 Preparation of 4- (3 # 3-dimethylbut-l-ynyl) difluorobenzoic acid Methyl 4-bromo-2,6-difluorobenzoate. 4-Bromo-2,6-difluorobenzoic acid (7 g, 0.03 mol) methyl iodide (2.8 mL, 0.045 mol) and potassium carbonate (12.22 g, 0.08842 mol) were placed in 100 mL of acetone in a sealed tube and they were heated at 50 ° C overnight. The reaction was cooled, partitioned between EtOAc and water. The organic layer was dried (Na2SO4) filtered and the filtrate was concentrated in an oil. Purification by column chromatography on silica gel gave the product, (1.3g, 17%) together with 5g of starting material.

Methyl 2,6-difluoro-4- (3, 3-dimethylbut-l-ynyl) benzoate. Methyl 2,6-difluoro-4- (3, 3-dimethylbut-l-ynyl) benzoate. Methyl 4-bromo-2,6-difluorobenzoate (1.3 g, 0.0052 mol), 1-butyne, 3,3-dimethyl- (0.96 mL, 0.0080 mol), copper (I) iodide (200 mg, 0.001 mol) and bis (triphenylphosphine) palladium (II) chloride (0.73 g, 0.0010 mol) were placed in 5.0 triethylamine and stirred in a sealed tube at room temperature for 20 h. The reaction was diluted with MeOH and filtered through celite. The filtrate was concentrated in an oil and purified by column chromatography on silica gel using hexane as eluent to give the product (1.Og, 80%) as a yellow oil. 4- (3, 3-dimethylbut-l-ynyl) -2,6-difluorobenzoic acid. Methyl 6,6-difluoro-4- (3, 3-dimethylbut-l-ynyl) benzoate (1.0 g, 0.004 mol) and lithium hydroxide (0.57 g, 0.012 mol) were placed in a 3: 1 mixture of methanol ragua (60 mL) and heated at 60 ° C for 3.5 h. TLC and LCMS indicated product formation. The reaction was cooled and concentrated in vacuo in a volume of 20 mL. The mixture was placed in an ice water bath and acidified to pH 5 with concentrated HC1. A pulverized white solid which was filtered and washed thoroughly with water. The solid was dried in the vacuum oven to give the product (0.79g, 84%) as a solid, m / z = 237.1 (M-1)..

Intermediary 20 Preparation of 4- (3, 3-dimethyl-l-ynyl) -2-fluoro-3-methoxybenzoic acid Methyl 2-fluoro-3-methoxy-4- (3, 3-dimethylbut-l-ynyl) benzoate. Methyl 4-bromo-2-fluoro-3-methoxybenzoate (960 mg, 3.5 mmol), copper (I) iodide (70 mg, 0.4 mmol), and bis (triphenylphosphine) palladium (II) chloride (300 mg, 0.4 mmol) were suspended in Et3N (10 mL) and DMF (4 mL). 1-Butyne, 3,3-dimethyl- (440 mg, 5.2 mmol) was added and the mixture was heated at room temperature to 100 ° C in a sealed tube for 60 h. The solvent was removed, and the residue was dissolved in EtOAc, washed with water, brine and dried over Na2SO4. It was purified by column chromatography on silica gel to give the product as a light yellow oil (760 mg, 79%). 2-Fluoro-3-methoxy-4- (3-dimethylbut-1-ynyl) benzoic acid. Methyl 2-fluoro-3-methoxy-4- (3, 3-dimethylbut-l-yl) benzoate (760 mg, 2.7 mmol) was dissolved in MeOH (10 mL), NaOH (in 10 mL of water) was added and stirred at 50 ° C for 1 h. The solvent was removed, more water added, neutralized by HC1 to pH ~ 2, the white solid thus formed was filtered, dried in a vacuum oven (at 65 ° C). The product was obtained as a white solid (760 mg, 93%).

Intermediary 21 Preparation of 2-chloro-4- (3, 3-dimethylbut-l-ynyl) -5-fluorobenzoic acid Methyl 2-chloro-5-fluoro-4- (3, 3-dimethylbut-1-yny1) benzoate. Methyl 4-bromo-2-chloro-5-fluorobenzoate (9.1 g, 32 mmol), copper iodide (I) (0.62 g, 3.2 mmol) bis (triphenylphosphine) palladium (II) chloride (23 g, 3.2 mmol) s suspended in Et3N (100 mL) and DMF (40 mL). mL), 1-butyne, 3, 3-dimethyl- (4.1 g, 48 mmol) was added and then the mixture was stirred at 100 ° C in a sealed tube for 40 h. The solvent was removed, the residue was dissolved in EtOAc, washed with water and brine, purified by column, the product was obtained as a light yellow oil (6.1 g, 69%). 2-Chloro-5-fluoro-4- (3, 3-dixnetylbut-1-ynyl) benzoic acid. Methyl 2-chloro-5-fluoro-4- (3, 3-dimethylbut-1-yl) benzoate (6.1 g, 22 mmol) was dissolved in MeOH (30 mL), sodium hydroxide (1.3 g, 33 mmol) (in mL, water) was added and stirred at 60 ° C overnight. The solvent was removed, the residue was dissolved in water, neutralized by HCl until pH < 2, extracted with EtOAc, washed with water, brine and dried over Na2SO4. The product was obtained as a beige solid (3.1 g, 52%).

Intermediary 22 Preparation of (E) -4- (3, 3-dimethylbut-l-enyl) -2-methylbenzoic acid 4-Bromo-2-methyl-benzoic acid methyl ester.

To a suspension of 4-bromo-2-methylbenzoic acid (10.0 g, 0.0465 mol) in 1,2-dichloroethane (60 mL, 0.8 mol) thionyl chloride (28 g, 0.23 mol) was added and the mixture was heated to reflux for 1 hour. The mixture was concentrated to dryness and dried in vacuo. Unpurified acid chloride was dissolved in methanol (100 mL, 2 mol) and the solution was treated with triethylamine (4.7 g, 0.046 mol). The mixture was heated to reflux for one hour and then concentrated to dryness. The unpurified ester was dissolved in EtOAc, washed consecutively with saturated sodium bicarbonate solution and water. The organic phase was dried and concentrated to obtain the title ester.

(E) -4- (3 # 3-dimethylbut-l-enyl) -2-methylbenzoic acid methylester. A mixture of methyl 4-bromo-2-methylbenzoate (10.0 g, 0.0436 mol), tri-o-tolylphosphine (1.31 g, 0.00429 mol), cesium carbonate (6.99 g, 0.0214 mol), tetra-N- chloride Butylammonium (1.79 g, 0.00644 mol), 1-butene, 3,3-dimethyl- (20 g, 0.2 mol), palladium acetate (0.24 g, 0.0011 mol) was sealed in a glass vessel and stirred at 150 ° C. C for 96 h. After cooling, the reaction mixture was filtered through Celite and the filtrate was partitioned between EtOAc and water. The organic layer was separated and washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed with hexane-EtOAc to give the title compound as a white solid.

Acid (E) -4- (3, 3-dimethyl-but-l-enyl) -2-xnethylbenzoic acid. A solution of (E) -4- (3,3-dimethylbut-l-enyl) -2-methylbenzoic acid methyl ester (6.5 g, 0.028 mol) and lithium hydroxide (3.4 g, 0.14 mol) in a methanol mixture (50 mL, 1 mol) and water (150 mL, 8.3 mol) was heated to reflux for 3 hours: Most of the methanol was removed from, and the aqueous solution was carefully acidified with concentrated HC1. The white precipitate was filtered, washed with water and dried under vacuum, m / z = 217.1 (M-1).

Intermediary 23 Preparation of 3-methyl-4- (3,3,3-trifluoroprop-1-ini1) benzoic acid The method was based on a detailed procedure by Yoneda et al in Bulletin Chemical Society Japan 1990, 63, 2124-2126. A solution of n-butyl lithium (2.5M in hexanes, 1 eq) was added carefully to a solution of 3,3,3-trifluoroprop-1-ane (1 eq) in THF at -78 ° C under nitrogen. The mixture was stirred at -78 ° C for 30 min, then a solution of ZnCl2 (3 eq) in THF was slowly added. The mixture was allowed to warm to room temperature, stirred for 30 min then Pd (Ph3P) 4 (5 mol%) was added, followed by 4-iodo-3-methylbenzoic acid (0.5 eq). The mixture was heated to 50 ° C and stirred for 15 h, then further heated at 80 ° C for 5 h, and finally at 100 ° C overnight. After it was allowed to cool to room temperature the mixture was concentrated under vacuum in an unpurified residue. The residue was purified by column chromatography on silica gel to give the product as a solid, m / z = 227 (M-1).

Preparation of amine building blocks Intermediate 24 Preparation of 2- ((cyclopropylmethoxy) methyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-amine 2- ((cyclopropylmethoxy) methyl) -2,3-dihydro-6-nitrobenzo [b] [1,4] dioxin. (2,3-dihydro-6-nitrobenzo [b] [1,4] dioxin-2-yl) methanol (500 mg, 0.002 mol) and sodium hydride (0.28 g, 0.0070 mol) were placed in a flask under nitrogen . The flask was placed in an ice bath and 25 mL DMF was added. The reaction was stirred at 0 ° C for 10 minutes and then (chloromethyl) cyclopropane (440 ^ L, 0.0048 mol) was added. The mixture was warmed to room temperature for 20 min then tetra-N-butylammonium bromide (1.53 g, 0.00475 mol) was added to the mixture and the reaction was stirred at room temperature overnight. The reaction was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SC > 4) filtered and the filtrate was concentrated under vacuum in an oil. The oil was purified by column chromatography on silica gel using EtOAc / hexanes (10%) as eluent to give a yellow solid (0.33 g, 50%) as a solid, m / z = 266 (M + 1). 2- ((cyclopropylmethoxy) methyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-amine. 2- ((cyclopropylmethoxy) methyl) -2,3-dihydro-6-nitrobenzo [b] [1,4] dioxin (0.33 g, 0.0012 mol) was dissolved in 20 mL of dioxane. The sodium dithionite 2.2 g, 0.013 mol was suspended in water (4 mL) and H40H (2 mL) and then added to the dioxane solution. The reaction was stirred at room temperature for 6 hrs. The mixture was filtered through a paper filter and the filtrate was concentrated under vacuum on a white solid. The solid was suspended in 10% EtOAc / hexanes and filtered. The filtrate was concentrated to a white solid and used for the next reaction without further purification. The yield of the title compound is 0.29 g (98%). m / z = 235.8 (M + l).

Intermediary 25 Preparation of l-methyl-l, 2,3 # 4-tetrahydroquinolin-7-ylamine 7-Nitro-1, 2, 3, -tetrahydroquinoline. To a solution of 1, 2, 3, 4-tetrahydroquinoline (6.5g, 0. 049 mol) in a concentrated sulfuric acid (118 mL) at 0 ° C was added a concentrated nitric acid solution (4.9 mL) in a concentrated sulfuric acid (12 mL) by dripping for 3 hours to maintain the temperature < 5 ° C. The reaction mixture was then poured into crushed ice and neutralized with solid potassium carbonate. The mixture was extracted with EtOAc (2 x 500 mL), the combined organic extracts were washed with water, dried and concentrated to give the crude product which was purified by column chromatography on silica gel using EtOAc / hexane as eluent to obtain the title compound as an orange solid. l-ethyl-7-nitro-l, 2, 3, 4-tetrahydroquinoline. To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (4.5g, 25.25 mmol) in DMF (50 mL) - potassium carbonate (15 g) was added followed by iodomethane (5.54 g, 39.0 mmol). ) and the mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with ether (3 x 200 mL). The combined ether extracts were washed with brine, dried and concentrated to give the crude product which was purified by column chromatography on silica gel to obtain the title compound as an orange liquid. 1-Meti1-1, 2, 3 4-tetrahydroquinolin-7-ylamine. A mixture of l-methyl-7-nitro-1,2,3,4-tetrahydroquinoline (4.0 g, 20.81 mmol), Pd / C (2 g) in methanol (100 mL) was hydrogenated at 10 PSI for 2 hours. The catalyst was filtered, and the filtrate was concentrated under vacuum to give the crude product which was used as such without further purification.

Intermediate 26 Preparation of 3,4-dihydro-2H-benzo [b] [1,4] oxazin-6-amine 6-Nitro-2H-benzo [b] [1,4] oxazin-3 (4H) -one. Bromoacetyl bromide (4.84 g, 24 mmol, in 10 mL of CHCl3) was added dropwise to the suspension of 2-amino-4-nitrophenyl (3.08 g, 20 mmol), benzyltriethylammonium chloride (TEBA, 4.56 g, 20 mmol ) and NaHCO 3 (6.72 g, 80 mmol) in 30 mL CHCl 3 with ice-bath cooling. The mixture was stirred with ice-bath cooling for 1.5 h then at 60 ° C overnight. The solvent was removed under vacuum and water was added to the residue. A solid precipitate which was filtered and dried under vacuum to give the product (3.45 g, 89%) as a beige solid. 6-Amino-2ff-benzo [b] [1,4] oxazin-3 (4H) -one. Pd / C (10%) was added to a suspension of 6-nitro-2H-benzo [b] [1,4] oxazin-3 (4H) -one (1.5 g) in MeOH (20 mL) and the mixture of The reaction was stirred under a mixture of hydrogen overnight. The mixture was filtered through celite and the filtrate was concentrated under vacuum to give the product (0.705 g, 56%) as a beige solid. 3, 4-Dihydro-2H-benzo [b] [1,4] oxazin-6-amine. 6-Amino-2H-benzo [b] [1,4] oxazin-3 (4H) -one (590 mg, 3.6 mmol) was added to a THF solution of tetrahydrofuranborane complex (9 mL, 1M solution) and the The reaction mixture was refluxed for 2.5 h. EtOH (2 mL) was added and stirred at 70 ° C for 1 h before 1 mL of HC1 (concentrate) was added. The mixture was stirred at 80 ° C overnight then the volatiles were removed under vacuum to leave an unpurified residue. The residue was dissolved in water, NaOH was added until pH ~ 10, and the mixture was extracted with CH2C12. The organic phase was washed with water and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel to give the product (274 mg, 51%) as a colorless oil.

Intermediary 27 Preparation of 3,4-dihydo-2H-benzo [b] [1,4] oxazin-7-amine The above was prepared using the same procedure as for 3,4-dihydro-2H-benzo [b] [1,4] oxazin-6-amine, except 2-amino-5-nitrophenol was used as starting material.

Intermediary 28 Preparation of 4-methyl-3, 4-dihydro-2H-benzo.b] [1,4] oxazin-7-amine Potassium carbonate (800 mg, 6 mmol) and methyl iodide (1.3 g, 9 mmol) were added to a solution of 3,4-dihydro-7-nitro-2H-benzo [b] [1,4] oxazine ( 540 mg, 3 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight. Sodium hydride (100 mg, 95%) and methyl iodide (1.0 g) were added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was suspended in water. A solid precipitate which was filtered and washed with water. The light yellow solid was then suspended in MeOH (20 mL) and Pd / C (10%) was added. The suspension was stirred under a mixture of hydrogen overnight, then filtered through celite and the filtrate was concentrated under vacuum to give the product (470 mg) as a purple oil.

Intermediary 29 Preparation of 6-amino-2, 2-dimethyl-2H benzo.b] [1,4] oxazin-3 (4H) -one and 2,2-dimethyl-3,4-dihydro-2H benzo.b] [1,4] oxazin-6-amine 2, 2-Dimethyl-6-nitro-2H-benzo [b] [1,4] oxazin-3 (41?) -one. 2-Bromoisobutyryl bromide (10.3 g, 45 mmol, in 20 mL of chloroform) was added dropwise to a suspension of 2-amino-4-nitrophenol (4.62 g, 30 mmol) and sodium bicarbonate (10.1 g, 120 mmol ) in chloroform (250 mL) under nitrogen with cooling bath with ice. The reaction mixture was stirred from 0 ° C to room temperature overnight, then the solvent was removed under vacuum. The residue was suspended in DMF (150 mL) and potassium carbonate (5.98 g) was added., 45 mmol), then the reaction mixture was stirred at 80 ° C overnight. The solvent was removed under vacuum and water was added to the residue. The precipitate that emerged was filtered and dried under vacuum to give the product (4.5 g, 68%) as a light brown solid. The rest of the synthesis (hydrogenation of the nitro group and then borane reduction of the lactam) was carried out using the general procedure described by 3,4-dihydro-2H-benzo [b] [1,4] oxazin-6-amine.

Intermediary 30 Preparation of 7-amino-2, 2-dimethyl-2H benzo.b] [1,4] oxazin-3 (4H) -one and 2,2-dimethyl-3,4-dihydro-2ff benzo.b] [1,4] oxazin-7-amine The above was prepared using the same procedure for 6-amino-2, 2-dimethyl-2H-benzo [b] [1,4] oxazin-3 (4H) -one and 2,2-dimethyl-3,4-dihydro -2H-benzo [b] [1,4] oxazin-6-amine except 2-amino-5-nitrophenol was used as the starting material.

Intermediary 31 Preparation of 6-chloro-3,4-dihydro-2H-benzo.b] [1,4] oxazin-7-amine 6-Chloro-7-nitro-2H-benz [Jt] [1,4] oxazin-3 (4H) -one. This compound was prepared using the general procedure described by 2,2-dimethyl-6-nitro-2-phenyl-benzo [b] [1,4] oxazin-3 (4H) -one above except 2-amino-4-chloro -5-nitrophenol was used as starting material. 7-Amino-6-chloro-2H-benzo [b] [1,4] oxazin-3 (4ff) -one. Stannous chloride dihydrate (30 g, 0.13 mol) was added in portion to a solution of 6-chloro-7-nitro-2H-benzo [b] [1,4] oxazin-3 (4H) -one (6.7 g, 0.026 mol) in DMF (100 mL) with cooling bath with ice. The mixture was allowed to warm to room temperature and then stirred overnight. EtOAc (300 mL) and MeOH (300 mL) were added to the reaction mixture, Et3N was added until pH > 8 and the resulting suspension was filtered through celite. The solvent was removed under vacuum and the residue was suspended in water, extracted with EtOAc, dried (a2SO4), filtered and concentrated in vacuo. The residue was triturated with ether to give the product (2.5 g, 45%) as a yellow solid. 6-chloro-3,4-dihydro-2H-benzo [Jb] [1,4] oxazin-7-amine. The borane reduction was performed using the general procedure described above by 3,4-dihydro-2H-benzo [b] [1,4] oxazin-6-amine except 7-Amino-6-chloro-2J-benzo [ £ > ] [1,4] oxazin-3 (4H) -one was used as the starting material.

Intermediary 32 Preparation of the acid (6-Amino-3H-imidazo [4, 5-b] pyridin-2-yl) -methanol (Solid 6-Nitro-3H-imidazo [4, 5-b] pyridin-2-yl) -methanol 2, 3-diamino-5-nitropyridine (prepared according to J. "Med. Chem. 1997, 40, 3679 -3686; 610 mg, 0.0040 mol) and solid glycolic acid (750 mg, 0.0099 mol) were combined in a sealed tube (left open) and heated to 145 ° C and stirred for approximately 30-45 min (molten solids simultaneously , liquified then solidified again.) After it was allowed to cool to room temperature the solid was extracted with 1N HC1 The aqueous mixture was concentrated under vacuum to leave an unpurified solid which was basified using concentrated NH3 solution. concentrated under vacuum to leave an unpurified solid that was dry-loaded onto silica and purified by column chromatography (using the ISCO system) to give a solid (450 mg) which was used directly in the next step. (6-Amino-3H-imidazo [4, 5-b] pyridin-2-yl) -methanol Stannous chloride dihydrate (1.6 g, 0.0070 mol) was added in one portion to a stirred solution of (6-Nitro-3H Imidazo [4, 5-b] pyridin-2-yl) -methanol (450 mg, 0.0023 mol) in 10% aqueous hydrochloric acid (20 mL) at 50 ° C. The mixture was stirred at 50 ° C for about 2 hours then allowed to cool to room temperature. The mixture was further cooled to 0 ° C and then basified to approximately pH 8 using concentrated H3 solution. The aqueous layer was then filtered through Celite® to remove the tin salts and the filtrate was concentrated under vacuum to leave an unpurified solid (380 mg, quantitative yield assumption) which was used directly in the next step (formation of amide) Intermediary 33 Preparation of the acid (3-aminojuinolin-7-yl) methanol (prepared using the general procedure of J. Am. Chem. Soc. 1997, 119, 5591) 3- (3- (hydroxymethyl) phenylamino) -2-nitroacrylaldehyde. 3-aminobenzyl alcohol (4.97 g, 0.0404 mol) was dissolved in 4 mL concentrated HC1. Sodium nitromyalonaldehyde monohydrate (prepared from mucobromic acid according to the procedure in Organic Syntheses Vol IV, pp 844, 1963) (4.25 g, 0.0269 mol) was dissolved in 35 mL of water and added to the amine solution ( a yellow precipitate formed immediately) - an additional 80 mL of water was added to help it shake. After 10 min, the precipitate was filtered, washed with water and dried in the air overnight to give the product (4.3 g) as a yellow solid. (3-nitroquinolin-7-yl) methanol. 3- (3- (hydroxymethyl) phenylamino) -2-nitroacrylaldehyde (4.3 g, 19.4 mmol) was placed in 20 mL of HOAc. 4.8 g of 3-aminobenzyl alcohol (4.8 g, 38.7 mmol) was dissolved in 5 mL of concentrated HC1, then 20 mL of HOAC was added to the HC1 solution. This mixture was added to the reaction flask containing 3- (3- (hydroxymethyl) phenylamino) -2-nitroacrylaldehyde in HOAc. The mixture was heated to reflux under nitrogen and after 20 min, benzene thiol (0.19 mL, 0.19 mmol) was added. The mixture was refluxed for 28 h (m / z = 208.1). After it was allowed to cool, the acid was removed under vacuum. The residue was dissolved in EtOAc / MeOH and loaded onto a silica gel cartridge. Purification by column chromatography on silica gel using hexane / EtOAc (0-50%) then 10% McOH / EtOAc as eluent gave the product (500 mg, 9%) as a brown solid. (3-aminoquinolin-7-yl) methanol. (3-nitroquinolin-7-yl) methanol (1.2 g, 0.0059 mol) and 400 mg of Pd / C (10% by weight) were placed in 60 mL of dry THF. The mixture was stirred under a hydrogen atmosphere (balloon) overnight. The reaction was filtered through celite and the filtrate was concentrated in an oil. Purification by column chromatography on silica gel using MeOH / CH2Cl2 (0-10%) as eluent to give 0.9 g of an oily product, m / z = 216.9 (+ acetic acid). The product was suspended in MeOH and K2CO3 (200 mg) was added. This mixture was stirred at room temperature for 4 h. m / z = 175.1. The mixture was filtered and the filtrate was concentrated under vacuum to give the product (172 mg, 19%) as a wet solid. 1H NMR (d4-MeOD) d 8.32 (1H, d), 7.69 (1H, s), 7.55 (1H, d), 7.34 (1H, dd), 7.23 (1H, d), 5.40 (211, s).

Intermediary 34 Preparation of the acid (6-amino-lff-indazol-3-yl) methanol 6-Nitro-lH-indazol-3-carbaldehyde (500 mg, 0.003 mol) was dissolved in 50 mL of THF. Lithium tetrahydroaluminate (400 mg, 0.01 mol) was added in 3 portions and the reaction mixture was stirred at room temperature overnight. Water (400 μg), 15% NaOH solution (400 μL), then water (1.2 mL) was added, and then the crystalline brown yellow precipitate was filtered. The filtrate was concentrated in an oil which was used directly in the next step without further purification. M / z = 164.0. "" "H NMR (d4-MeOH) d 7.2 (1H, d), 7.05 (1H, d), 6.85 (1H, dd), 4.74 (2H, s).

Intermediate 35 Preparation of the acid (7-aminoquinolin-3-yl) methanol 2-Dimethylaminomethylene-l, 3-bis (dimethylammonium) -propane bis (tetrafluoroborate). Bromoacetic acetic acid (25 g, 0.18 mol) and phosphoryl chloride (50 mL, 0.54 mol) were added to a neck flask equipped with a reflux condenser. The solution was cooled to 0 ° C and N, N-dimethylformamide (84 mL, 1.1 mol) was added dropwise for 30 min. The resulting solution was heated at 110 ° C for 3 h. As the mixture heated up, it began to become exothermic and C02 was released. The mixture was then cooled to 0 ° C and a solution of 50% aqueous tetrafluoroboric acid (63 g, 0.36 mol) in MeOH (100 mL) was slowly added over the course of 1 h by means of an addition funnel. Isopropanol (100 mL) was added to the dark viscous solution. The solid precipitate and the aqueous suspension was stirred at 0 ° C for 2 h. The solids were collected by filtration to provide the product (64g, 72%) as a pale yellow solid.

Benzyl 3-aminophenylcarbamate. To a stirred solution of m-phenylenediamine (5.0 g, 0.046 mol) and N, N-diisopropylethylamine (8.0 mL, 0.046 mol) in CH2C12 (150 mL) at 0 ° C was slowly added benzyl chloroformate (6.6 mL, 0.046 mol ). The mixture was stirred at 0 ° C for 2 h and then warmed to room temperature for 2 h. The aqueous NaHCC solution was added and the organic phase was separated, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel to give the desired product (8.0g, 71%) as a syrup. LC-MS: 2.11 min, 243.0 (M + l). 3-formylquinolin-7-ylcarbamate benzyl. An aqueous suspension of benzyl 3-aminophenylcarbamate (8.0 g, 0.033 mol) and 2-dimethylaminomethylene-l, 3-bis (dimethylimmonium) propane bis (tetrafluoroborate) (31 g, 0.087 mol) in ethanol (400 mL) was heated to reflux for 24h. The solution was concentrated under vacuum and the residue was dissolved in THF (200 mL) and 1N HC1 (200 mL). The reaction mixture was stirred at room temperature overnight, then poured into a saturated sodium bicarbonate solution (200 mL), and extracted with EtOAc (2 x). The combined organic layers were washed with brine, dried (a2SO4), and concentrated in vacuo to give the desired product (10.0 g, 99%) as a yellow solid. LC-MS: 2.84 min, 307.1 (M + l). 3- (hydroxymethyl) uinolin-7-ylcarbamate. To a stirred mixture of benzyl 3-formylquinolin-7-ylcarbamate (2.0 g, 0.0065 mol), THF (50 mL), MeOH (50 mL), and water (50 mL) sodium tetrahydroborate (0.25 g, 0.0065) was added. mol). The mixture was stirred at room temperature until LC-MS indicated without SM. The mixture was acidified with 1N HC1 and concentrated in vacuo, and then treated with aqueous NaHCO3 solution and EtOAc. The organic layer was separated and washed with brine, dried (Na2SO4), and evaporated. The residue was purified by column chromatography on silica gel using MeOH-EtOAc (0-10%) as eluent to give the product (1.3 g, 64%) as a light yellow solid. LC-MS: 1.83 min, 309, 2 (M + 1). (7-Aminoquinolin-3-yl) methanol. A mixture of benzyl 3- (hydroxymethyl) quinolin-7-ylcarbamate (480 mg, 0.0016 mol), 10% Pd-C (50 mg), and MeOH (50 mL) was stirred under H2 (1 atm) for 1 hr. . The catalyst was filtered and the filtrate was concentrated to give the product as a yellow solid. LC-MS: 0.34 min, 175.1 (M + 1).

Intermediary 36 Preparation of quinolin-7-amine A mixture of 7-nitroquinoline (0.30 g, 0.0017 mol, Specs, Inc.), 10% Pd-C (50 mg), and MeOH (20 mL) was stirred under H2 (1 atm) for 2 h. The mixture was filtered and the filtrate was concentrated to give a yellow solid (235 mg, 95%). LC-MS: 0.33 min, 145.1 (M + 1). ^ NMR (DMSO-d6): 8.58 (1H, dd, J = 4.4, 1.6 Hz), 8.00 (1H, dd, J = 8.0, 1.2 Hz), 7.60 (1H, d, J = 8.8 Hz), 7.07 ( 1H, dd, J = 8.0, 4.4 Hz), 6.98 (1H, dd, J = 8.8, 2.0 Hz), 6.93 (1H, d, J = 2.0 Hz), 5.75 (s, 2H).

Intermediary 37 Preparation of 5-amino-3-methylisoquinoline -amino-3-methylisoquinoline. A mixture of 3-methyl-5-nitroisoquinoline (1.3 g, 0.0069 mol - prepared according to the procedure in WO 2004/024710), 10% of Pd-C (100 mg) and MeOH (100 mL) was stirred under a mixture of hydrogen (1 atm) at room temperature 2h. The mixture was filtered and the filtrate was concentrated under vacuum to give as a light yellow solid (1.1 g, 100%). LC-MS: 0.64 min, 15 .1 (M + l).

Intermediary 38 Preparation of l-chloroisoquinolin-5-amine l-chloro-5-nitroisoquinoline.

A mixture of 1-chloroisoquinoline (6.0 g, 0.037 mol) in concentrated H2SO4 (35 mL) was treated with a solution of fuming HNO3 (10 mL) and potassium nitrate (4.0 g, 0.040 mol) in concentrated H2SO4 (35 mL). at 0-5 ° C. The mixture was stirred at 0 ° C for an additional 90 min, and then poured into ice. The precipitate was collected, washed and dried to give the product as a yellow solid. LC-MS: 3.68 min, 209.2 & 211.1 (M + l). l-chloroisoquinolin-5-axnin. A mixture of l-chloro-5-nitroisoquinoline (450 mg, 0.0022 mol), stannous chloride dihydrate (2.4 g, 0.011 mol), and EtOAc (50 mL) was stirred under reflux under a nitrogen atmosphere for 3 h. After cooling, the mixture was poured into ice water and basified to pH 10.0 with Na2CC > 3 aqueous. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (a2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the product as a light yellow solid. LC-MS: 3.17 min, 179.2 & 181.2 (M + l).

Intermediate 39 Preparation of 7-amino-3,4-dihydro-2ff-benzo [b] [1,4] oxazin-3-yl) methanol and 8-amino-2, 3,4,5-tetrahydrobenzo [b] [ 1,4] oxazepin-3-ol 3,4-dihydro-7-nitro-2H-benzo [b] [1,4] oxazin-3-yl) methanol and 8-amino-2,3,4,5-tetrahydrobenzo [b] [1,4] -oxazepin-3-ol. A mixture of 2-amino-5-nitrophenol (10.0 g, 0.0649 mol), potassium carbonate (13.4 g, 0.0973 mol), cesium fluoride (2.0 g, 0.013 mol) and l-bromo-2, 3-epoxypropane ( 5.37 mL, 0.0649 mol) in DMF (120 mL) was stirred under N2 at room temperature overnight and then heated at 100 ° C for 10 hours. After . After cooling, the solvent was removed under vacuum and the residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried (Na2SO4> and concentrated The residue was purified by column with CH2Cl2-EtOAc (containing 5% Et3N) (0 to 40%) to give an orange solid. MS: 2.30 min, 211.1 (M + l). 7-amino-3,4-dihydro-2H-benzo [b] [1,4] oxazin-3-yl) methanol and 8-amino-2, 3, 4, 5-tetrahydrobenzo [b] [1, 4] oxazepin-3-ol (3, 4-dihydro-7-nitro-2H-benzo [b] [1,4] oxazin-3-yl) methanol (3.8 g, 0.018 mol) was hydrogenated at 40 PSi for 2 hours on 10% Pd / C. The mixture was filtered through celite and the filtrate was concentrated under vacuum to give the product without purification. Purification by column chromatography on silica gel (EtOAc) gave the product as a dark brown oil. LC-MS: 0.36 min, 181.1 (M + 1). H MR (DMSO-d6): 6.32 (1H, d, J = 9.2 Hz), 6.01-5.97 (2H, m), 4.82-4.76 (2H, m), 4.29 (2H, s), 4.08 (1H, dd , J = 10.4, 1.6 Hz), 3.79 (1H, dd, J = 10.4, 6.8 Hz), 3.35 (2H, m), 3.17 (1H, m), 8-Amino-2, 3, 4, 5-tetrahydrobenzo [b] [1,4] oxazepin-3-ol was also isolated from the above procedure as a minor by-product.

Intermediary 40 Preparation of (S) - (3,4-Dihydro-7-nitro-2H-benzo.b] [1,] oxazin-3-yl) methanol acid (S) - (3,4-dihydro-7-nitro-2ff-benzo [b] [1,4] oxazin-3-yl) methanol Sodium hydride (0.810 g, 0.0202 mol) was slowly added to a mixture of 2-amino-5-nitrophenol (3.0 g, 0.019 mol) in dmf (50 ml) at 0 ° C. The mixture was stirred at room temperature for 1 h and then (r) - (oxiran-2-yl) methyl 3-nitrobenzenesulfonate (5.0 g, 0.019 mol) was added. The mixture was stirred at room temperature overnight and then DMF was removed under vacuum. The residue was partitioned between water and EtOAc.

The organic layer was washed with aqueous Na 2 CO 3 solution, brine, dried (Na 2 SC > 4) and concentrated in vacuo to give a brown solid (5.2 g). A mixture of the light brown solid, K2C03 (2.0 g) and DMF (200 ml) was stirred at 120 ° C under N2 overnight. After cooling, the solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by column chromatography on silica gel with CH2Cl2-EtOAc (containing 5% et3n-0 to 60%) to give the product as a light brown solid. LC-MS: 2.30 211.1 (M + l).

(S) - (7-Amino-3,4-dihydro-2ff-benzo [b] [1,4] oxazin-3-yl) methanol A mixture of (s) - (3,4-dihydro-7-nitro) -2h-benzo [b] [1,4] oxazin-3-yl) methanol (340 mg, 0.0016 mol), 10% Pd / C (50 mg) and MeOH (50 ml) were stirred under a mixture of hydrogen (1 atm) for 3h. The LC-MS indicated the completion of the reaction. The mixture was filtered and the filtrate was concentrated under vacuum to give the product as a brown syrup. LC-MS: 0.36 min, 181.1 (M + 1). (R) - (7-amino-3,4-dihydro-2h-benzo [b] [1,4] oxazin-3-yl) methanol was prepared using the same procedure as for (s) - (3, 4- dihydro-7-nitro-2h-benzo [b] [1,4] oxazin-3-yl) methanol, except (s) - (oxiran-2-yl) methyl 3-nitrobenzenesulfonate was used as starting material.

Intermediate 41 Preparation of the acid (7-amino-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methanol (see 43P - Intermediary 19) (7-Nitro-2, 3-dihydro-benzo- [1,4] dioxin-2-yl) -methanol. 3. Og of sodium hydrogen carbonate was suspended in 90 mL DMF. At 0 ° C a solution of 5.15 g of 4-nitrocatechol was added dropwise for 15 min. Subsequently, 3.9 g of epichlorohydrin were added in 10 mL of DMF for 15 min. Stirring was continued at room temperature, then at 80 ° C overnight. The mixture was diluted with water and extracted three times with ethyl acetate, dried (anhydrous Na2SQ4), filtered and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel using EtOAc-hexanes (0-100% gradient) to give the product (2.8g) as a yellow solid. (7-amino-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methanol. (7-nitro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methanol (l.Og, 4.7 mmol) was dissolved in methanol (30 ml) and palladium on activated carbon (0.10 g) was added. , 5% by weight). The mixture was shaken in a shaker under low H2 (g) atmosphere (60 psi) for 24 hours. The mixture was filtered through celite and evaporated to give 722 mg of the material as a white solid (86%), which was used as such for the next step. M / z = 182 (m + 1). Le: 0.82 minutes.

Intermediary 42 Preparation of the acid (6-Amino-2 # 3-dihydro-benzo [1,4] dioxin-2-yl) -methanol (6-Nitro-2, 3-dihydro-benzo [1,4] dioxin-2-yl) -methanol. 1.93g of 60% sodium hydride in 90 mL of DMF was suspended. At 0 ° C a solution of 5.15 g of 4-nitrocatechol was added dropwise for 15 min. Subsequently, 3.9 g of epichlorohydrin in 10 mL of DMF was added for 15 min. Stirring was continued at room temperature, then at 80 ° C overnight. The mixture was diluted with water and extracted three times with ethyl acetate, dried (Na2SO4), filtered and concentrated under vacuum to give a yellow oil. The oil was purified by column chromatography on silica gel using an EtOAc-hexanes (0-100% gradient) to give the product (2.3g) as a yellow solid. (6-Amino-2, 3-dihydro-benzo [1,4] dioxin-2-yl) -methanol. (6-Nitro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methanol (1.0g, 4.7 mmol) was dissolved in methanol (30 mL) and palladium in activated charcoal (0.10g) was added. , 5% by weight). The mixture was shaken in a Parr Shaker under an atmosphere of H2 (g) (60 PSI) for 24 hours. The mixture was filtered through Celite® and evaporated to give 646 mg of material as a white solid (77%), which was used as such for the next step. m / z = 182 (M + l). LC: 0.82 minutes.

Intermediary 43 Preparation of the acid (7-amino-3 # 4-dihydro-2H-pyrido [3,2- b] [1,4] oxazin-3-yl) methanol 2-amino-3-methoxy-5-nitropyridine. A sealed tube of 250 mL of 2-chloro-3-methoxy-5-nitropyridine (0.50 g, 0.00265 mol) was combined, concentrated ammonium hydroxide (5 mL, 0.1 mol) and ethanol (20 mL). The mixture was heated to 80 ° C and stirred overnight. After it was allowed to cool to room temperature, the mixture was reduced in vacuo and the residue was taken up in ethyl acetate (50 mL), then washed with equal amounts of brine and water (1 x 50 mL each). The organic layer was dried (Na 2 SO 4) filtered and concentrated under vacuum to leave a solid (0.312 g, 69%) which was used directly in the next step without further purification. LC-MS 1.94 min. M / Z = 171.0 (M + l). 2-amino-3-hydroxy-5-nitropyridine. They were combined into a 500 mL round bottom flask of 2-amino-3-methoxy-5-nitropyridine (0.300 g, 0.00177 mol) and solid pyridine hydrochloride (8.8 g, 0.076 mol). The solid mixture was heated to 150 ° C over which the solids melted (evolution of a gas was also apparent). The mixture was maintained at 150 ° C for three hours in which the reaction was considered complete by LC-MS. After it was allowed to cool to 80 ° C, the mixture was poured into ice and the aqueous layer was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with water (2 x 100 mL), dried (Na2SC> 4) filtered and concentrated in vacuo to leave an unpurified residue. The residue was purified by column chromatography on silica gel using a gradient of methanol: methylene chloride (0-10%) as eluent to give the product as a solid (0.138 g, 49%) which was used directly in the next stage. LC-MS 1.28 min. m / z = 155.9 (M + l). (7-Nitro-3,4-dihydro-2H-pyrido [3,2- b] [1,4] oxazin-3-yl) methano1. They were combined into a sealed tube of 75 mL of 2-amino-3-hydroxy-5-nitropyridine (0.138 g, 0.000890 mol), N / N-dimethylformamide (4.1 mL) and potassium carbonate (0.39 g, 0.0028 mol) . The mixture was allowed to stir at room temperature for 10 minutes then l-bromo-2 was added, 3-epoxypropane (0.12 g, 0.00089 mol) in one portion. The flask was sealed, then heated to 110 ° C and stirred overnight. After it was allowed to cool, the mixture was concentrated under vacuum to give an unpurified solid which was dissolved in EtOAc (75 mL), washed with water and brine, then dried (Na2SO4), filtered and concentrated under vacuum leave a residue without purifying. The residue was purified by column chromatography on silica gel using MeOH / CH2Cl2 (0-10% gradient) as eluent to give a solid (0.092 g, 46%). LC-MS L92 min. M / Z = 212.0 (M + l). XH MR (d6-DMS0) 6 8.8 (d, 1H), 7.8 (d, 1H), 5.1 (t, 1H), 4.2 (m, 1H), 4.0 (m, 1H), 3.62 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H). (7-amino-3,4-dihydro-2H-pyrido [3,2- b] [1,4] oxazin-3-yl) methanol. Combine within a 500 mL round bottom flask of (7-nitro-3,4-dihydro-2H-pyrido [3,2- b] [1,4] oxazin-3-yl) methanol (0.320 g, 0.00152 mol), 10% -palladium on carbon (0.06 g, 0.0005 mol) and methanol (50 mL). The apparatus was evacuated, then hydrogen was introduced and the mixture was allowed to stir overnight (at 1 atmospheric pressure). The mixture was then filtered through celite and the filtrate was concentrated under vacuum to yield an oil (0.252 g, 89%) which was used directly in the next step without further purification. (0.252 g, 89%) LC-MS 0.29 min. M / Z = 181.9 (M + l).

Intermediary 44 Preparation of the acid (5-amino-lüf-indol-2-yl) methanol 2-Ethoxycarbonyl-5-nitroindole (500 mg, 0.002 mol) was dissolved in 50 mL of THF, lithium tetrahydroaluminate (341 mg, 0.00898 mol) was added in 3 portions and stirred at room temperature overnight. Water (341 L), 15% NaOH solution (341 ML), and water (1.1 mL) were added carefully and the mixture was filtered. The filtrate was concentrated under vacuum to give the product (300 mg, 98%) as an oil, m / z = 162.9.

Intermediate 45 Preparation of the acid (5-amino-lH-indazol-3-yl) methanol 5-Nitro-lH-indazole-3-carboxylic acid (500 mg, 0.002 mol) was dissolved in 50 mL of THF, lithium tetrahydroaluminate was added (366 mg, 0.00964 mol) in 3 portions and stirred at room temperature overnight, 65 mg (15%). Water (366 μg.), 15% NaOH solution (366 μL), and water (1.1 mL) were added carefully and the mixture was filtered. The filtrate was concentrated under vacuum to give the product (65 mg, 15%) as an oil. M / z = 160.0.

Intermediary 46 Preparation of 2-methylthiazole [5, -b] pyridin-6-amine to. 2-Methyl-6-nitrothiazole [5, 4-b] pyridine 2-Chloro-3,5-dinitropyridine (2.5 g, 1.2 mmol) and thioacetamide (3.75 g, 5.0 mmol) were combined in sulfolane (13 mL) and They were heated at 100 ° C for 2 hours. After cooling, water (25 mL) was added and the mixture was filtered. The filter cake was triturated with boiling EtOH (60 mL) and filtered. The filtrate was allowed to cool overnight, then filtered to give the nitro-thiazolopyridine derivative (1.05 g, 43%). 1 H NMR (400 MHz; d 6 -DMSO) d 9.38 (1H, d), 9.25 (1H, d), 2.91 (3H, s). b. 2-Methylthiazole [5,4-b] pyridin-6-amine 2-Methyl-6-nitrothiazole [5, 4-b] pyridine (400 mg, 2.0 mmol) was suspended in concentrated HC1 (10 mL) and the mixture was heated to 50 ° C. Stannous chloride, dihydrate (1.62 g, 7.2 mmol) was added to the reaction mixture in two portions. The sides of the flask were washed with EtOAc (25 mL) and the biphasic mixture was stirred at 50 ° C for 2 h (monitored by LCMS). After it was allowed to cool to room temperature, 5N NaOH (1 mL) was added followed by water (10 mL). The mixture was cooled to 4 ° C and the pH adjusted to 9 by the addition of more 5N NaOH. The mixture was partitioned between EtOAc and water and the organic layer was washed with water, brine, dried, filtered and concentrated under vacuum. Purification by column chromatography on silica gel using EtOAc / hexane as eluent (0-75%) gave the product (134 mg, 40%) as a solid, m / z-165.9 (M + 1). 1 H NMR (400 MHz, d 6 -DMSO) 5 7.97 (1H, d), 7.35 (1H, d), 5.52 (2H, bs), 2.75 (3H, s).

Intermediate 47 Preparation of (6-aminothiazol [5, 4-J] pyridin-2-yl) methyl pivalate to. (6-Nitrothiazole [5,4-Jb] pyridin-2-yl) methyl pivalate A mixture of 2-chloro-3,5-dinitropyridine (5.1 g, 25 mmol) and 2-amino-2-thioxoethylpivalate (8.8 g) , 50 mmol) in sulfolane (50 mL) was heated to 100-110 ° C under a nitrogen atmosphere and stirred for about 2 hours. After it was allowed to cool to room temperature, the mixture was poured into EtOAc (150 mL) and the organic layer was washed with H20 (3 x 200 mL) and brine (1 x 100 mL). The organic layer was dried (MgSO4) filtered and the solvent was removed under vacuum to leave the oil unpurified. The oil was purified by filtration through a plug of silica eluted with EtOAc / hexane (10% EtOAc to 20% EtOAc) to give a solid (approximately 6-7g). The solid was then triturated with MeOH (approximately 20 mL) and filtered to give the desired product (2.17g). In addition, the product was obtained by concentrating the filtrate under vacuum and purified by column chromatography on silica gel using 0 to 20% EtOAc / hexane as eluent to give a solid (1.1 g). The solid was triturated with MeOH to give an additional product (0.5g). Total pivalate yield of (6-nitrothiazole [5, 4-b] pyridin-2-iDmethyl = 2.67g. (36%). m / z = 296.5 (M + l). ¾ MR (400 MHz; CDC13) d 9.46 (1H, d), 9.00 (1H, d), 5.54 (2H, s), 1.32 (9H, s). b. (6-aminothiazol [5, 4-b] pyridin-2-yl) methyl Pivalate of (6-Nitrothiazol [5, 4-b] pyridin-2-yl) methyl (650 mg, 2.2 mmol) was suspended in Concentrate HC1 (20 mL) and heat to 50 ° C. Stannous chloride, dihydrate (1.8 g, 7.7 mmol) was added, followed by ethyl acetate (45 mL). The reaction was heated to 50 ° C for about 10-15 minutes, then cooled in an ice bath (TLC indicated complete reaction in this step). H20 (30 mL) and EtOAc (30 mL) were added, then 5N NaOH was added carefully until the pH was adjusted to approximately 7 (the entire time record of the flask in the ice bath was vigorously stirred. a <10 ° C during neutralization). Water (50 mL) was added, then the product was extracted into EtOAc (2 x 30 mL). The combined organics were washed with brine (1 x 25 mL), dried (MgSO4) filtered and concentrated under vacuum to leave an unpurified residue. The residue was purified by column chromatography on silica gel using 50-75% EtOAc / hexane as eluent to give the desired product (330 mg, 55%) as a solid. ¾ NMR (400 MHz; CDC13) d 8.14 (1H, d), 7.51 (1H, d), 5.44 (2H, s), 1.29 (91-1, s).

Intermediate 48 Preparation of 6-aminothiazole [5, 4-b] pyridine to. 6-Nitrothiazole [5, 4-b] pyridine The reported procedure for 3-nitro-l, 3-benzothiazole was used in W02005028445. A mixture of 2-chloro-3,5-dinitropyridine (8g, 39 mmol) and N, N-dimethylthioformamide (14.5 mL, 178 mmol) was heated at 60 ° C for 3 h. A yellow precipitate formed. Xylene (20 mL) was added to the reaction mixture and the mixture was heated to reflux for 4 h, and then stirred at room temperature for 18 h. The mixture was diluted with EtOH (12 mL) filtered and the brown solid was recrystallized from EtOH to give the product (800 mg) as a solid. H MR (400 MHz, acetone-d6) d 9.6 (1H, s), 9.44 (1H, s), 9.05 (1H, s). b. 6-Amino thiazole [S, 4-b] pyridine 6-Nitrothiazole [5, 4-b] pyridine (800 mg, 4.4 mmol) was dissolved in concentrated HCl (10 mL) and heated to 50 ° C. Stannous chloride, dihydrate (3.49 g, 15.5 mmol) was added in two portions, at 50 ° C, and the sides of the flask were then 'washed with water' with EtOAc (50 mL). The mixture was stirred at 50 ° C for 60 min. The mixture was cooled in an ice bath, then 5N NaOH (1 mL) was added, followed by water (5 mL), then further 5N NaOH until the pH was adjusted to approximately 9. The mixture was filtered and the filtrate was divided. between EtOAc and water. The organic layer was separated and dried, filtered and concentrated under vacuum in an oil (300 mg, 45%). The oil was used directly in the next step without further purification - it appeared to be approximately 90% pure per nmr. ""? NMR (400 MHz, d6-DMSO) d 9.32 (1H, s), 8.15 (1H, d), 7.5 (1H, d), 4.55 (2H, bs).

Intermediary 49 Preparation of ethyl 6-aminothiazole (5, -b) pyridine-2-carboxylate to. 6-Nitrothiazol [5 4-b] pyridine-2-carboxylic acid ethyl 2-chloro-3, -dinitropyridine (200 mg, 1.0 mmol) and ethyl thioamidooxalate (133 mg, 1.0 mmol) were combined under nitrogen and sulfolane was added (3 mL). The mixture was heated to 100 ° C and stirred for 3 hours. TLC indicated a certain form of the product - another equivalent of ethyl thioamidooxalate (133 mg) was added. The mixture was stirred overnight at 100 ° C. TLC indicated complete reaction in this way, then allowed to cool to room temperature, the mixture was poured into H20 (50 mL) and EtOAc (30 mL). The organic and aqueous layers were partitioned and the aqueous layer was extracted with EtOAc (2 x 20 mL).

The combined organic extracts were washed with brine (1 x 30 mL), dried (MgSO4) filtered and the solvent removed under vacuum to leave an oil without purification. The oil was purified by column chromatography on silica gel using 5-20% EtOAc / hexane as eluent to give the desired product (60 mg, 20%) as a solid. 1H MR (400 MHz, CDC13) d 9.59 (1H, d), 9.23 (1H, d), 4.62 (2H, q), 1.53 (3H, t). to. 6-aminothiazole [5,4-b] pyridine-2-carboxylic acid ethyl 6-nitrothiazole [5, 4-b] pyridine-2-carboxylic acid ethyl ester (400 mg, 1.6 mmol) was placed in 10 mL of concentrated HCl ( 10 mL) and warmed to 50 ° C. Stannous chloride, dihydrate (1.25 g, 5.53 mmol) was added in two portions, at 50 ° C, and the sides of the flask were 'washed with water' with EtOAc (50 mL). The mixture was stirred at 50 ° C for 60 min. The mixture was cooled in an ice bath, then 5N NaOH (1 mL) was added, followed by water (15 mL), then more 5N NaOH until the pH was adjusted to approximately 9. The mixture was divided and the organic layer was washed with H2O, brine, then dried (MgSO4) and concentrated in vacuo in an unpurified oil. The oil was purified by column chromatography on silica gel to give the desired compound (100 mg,%) as a solid. 1 H NMR (400 MHz, d 6 -DMSO) d 8.25 (1H, d), 7.59 (IH, d), 5.85 (2H, s), 4.45 (2H, q), 1.35 (3H, t). to. 2- (2-Hydroxyethyl) -5-nitroisoindoline-1,3-dione K2CO3 (5 g, 40 mmol), 4-nitrophthalimide (1.5 g, 7.8 mmol) and 2-bromoethanol (1 mL, 20 mmol) in acetone ( 20 mL) was heated at 120 ° C under microwave irradiation and stirred for 90 minutes. After it was allowed to cool, the mixture was partitioned between H20 and EtOAc and the aqueous layer was extracted with EtOAc (x2). The combined organic extracts were dried (MgSC) filtered and the solvent was removed under vacuum to leave an unpurified residue. The residue was purified by column chromatography on silica gel using 1-10% MeOH / CH 2 Cl 2 as eluent to give the product (1.02 g, 58%) as a solid, m / z = 237.1 (M + 1). 1 H NMR (400 MHz; CDC13) d 8.72-8.63 (2H, m), 8.11-8.05 (1H, m), 3.00-3.87 (4H, m). b. 5-Amino-2- (2-hydroxyethyl) isoindoline-1,3-dione 2- (2-Hydroxyethyl) -5-nitroisoindoline-1,3-dione (0.62 g, 2.6 mmol) and palladium (10% by weight Calcium carbonate 0.4 g, 1.9 mmol) in MeOH was hydrogenated (1 atm) overnight. The mixture was then filtered through celite and the filtrate was concentrated under vacuum to leave the product (0.5 g, 94%) as a solid, m / z = 207.2 (M + 1). 1 H NMR (400 MHz; de-DMSO) d 7.46 (1H, d), 6.90 (1H, d), 6.77 (1H, dd), 6.43 (2H, s), 4.81 (1H, t), 3.55-3.49 (4H, m).

Intermediary 51 to. (5-Nitrobenzo [d] oxazol-2-yl) methanol NaOH (0.2 g, 6 mmol) in H20 (5 mL) was added to a solution of 2- (chloromethyl) 5-nitrobenzo [d] oxazole (0.6 g, 2.8 mmol) in THF (20 mL) and the mixture was stirred overnight. The organics were removed under vacuum and the residue was diluted with H20 then acidified using 1N HC1. The mixture was extracted with EtOAc and the organic layer was dried (Na2SO4) filtered and concentrated under vacuum to leave an unpurified product. The crude product was dissolved in CH2C12, filtered and then concentrated under vacuum to leave the product (0.43 g, 80%) as a solid. ?? MR (400 MHz; CDC13) d 8.15 (1H, s), 7.93 (1H, dd), 7.33 (1H, d), 7.26 (1H, s), 7.08 (1H, d), 4.70 (2H, s). b. (5-Aminobenzo [d] oxazol-2-yl) methano1 (5-Nitrobenzo [d] oxazol-2-yl) methanol (0.43 g, 2.2 mmol) and palladium (10% by weight on calcium carbonate, 0.43 g, 2.1 mmol) in MeOH was hydrogenated (1 atm) overnight. The mixture was then filtered through celite and the filtrate was concentrated under vacuum to leave the product (0.27 g, 75%) as a solid, m / z = 165.0 (M + 1). *? NMR (400 MHz, CDC13) 7.55 (1H, s), 6.78 (1H, d), 6.33 (1H, dd), 6.14 (1H, d), 4.58 (2H, s), 3.41-3.58 (2H, m) .

Intermediary 52 Preparation of 6-aminooxazol [4, 5-J] pyridin-2 (3ff) -one to. 6-Nitro oxazole [4,5-b] pyridin-2 (3H) -one 2,3-Dihydropyrid [2,3-d] [1,3] oxazol-2-one (1.20 g, 8.8 mmol) was introduced to sulfuric acid (3.55 mL) at about -3 ° C. The mixture was stirred for about 1 hr (the temperature is kept below 5 ° C). The mixture was re-cooled to 0 ° C and fuming nitric acid was added dropwise. The mixture was stirred overnight then heated to 40-45 ° C and stirred for an additional 18 hr. The mixture was quenched by pouring it into ice and the emergent precipitate was filtered and washed with H20 to give the product (0.69 g, 43%) as a solid, m / z = 181.9 (M + l). ½ NMR (400 MHz; d5-MeOH) d 8.24 (d, 1H), 7.54 (d, 1H). b. 6-Aminooxazolo [4, 5-J] pyridin-2 (3H) -one 6-Nitro-oxazol [4, 5-h] pyridin-2 (3) -one (0.69 g, 3.8 mmol) and palladium (10%) in weight on calcium carbonate, 0.40 g, 1.9 mmol) were combined in MeOH and hydrogenated (1 atm) overnight. The mixture was filtered through celite and the filtrate was concentrated under vacuum to leave the product (0.15 g, 30%). m / z = 152.0 (M + l). ½ NMR (400 MHz; d6-DMSO) d 11.79 (br s, 1H), 7.40 (d, 1H), 6.89 (d, 1H), 5.11 (s, 2H).

Intermediary 53 Preparation of 7-amino-quinoline-3-carboxylic acid ethyl ester to. 7- (Benzyloxycarbonylamino) quinoline-3-carboxylic acid To a stirred solution of benzyl 3-formylquinolin-7-ylcarbamate (see US 2006194801; 2.7 g, 8.8 mmol) in acetonitrile (50 mL) was added an aqueous solution of diacid phosphate of potassium (1.25 M; 35.2 mL, 44 mmol), followed by sodium chloride (2.4 g, 26 mmol). The suspension was stirred at room temperature overnight. An aqueous solution of sodium sulfite acid (1 M, 50 mL) was added and the mixture was stirred at room temperature for 1 h. HC1 1N was added until the pH was adjusted to 3-4. The emergent precipitate was collected by filtration and washed with water and dried to give the product without purification as a solid. The filtrate was extracted with EtOAc (100 mL) and the organic layer was washed with brine, dried (Na2SO4), and evaporated to give the product without further purification. The combined unpurified product (2.6 g, 92%) was used by the next reaction step without further purification, m / z = 321.2 (M-1); room temperature = 2.37 minutes. b. 7- (Benzyloxycarbonylamino) quinoline-3-carboxylic acid methyl ester To a stirred mixture of 7- (benzyloxycarbonylamino) quinoline-3-carboxylic acid (1.20 g, 3.7 mmol), THF (100 mL), and DMF (0.1 mL) at 0 ° C oxalyl chloride (0.63 mL, 7.4 mmol) was added. The mixture was stirred at room temperature for 3 h, and then MeOH (1.51 mL, 37.2 mmol) was added followed by Et 3 N (2.6 mL, 19 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and then treated with aqueous NaHCO3 (20 mL) and EtOAc (100 mL). The organic and aqueous layers were partitioned, and the organic layer was washed with brine, dried (Na2SO4), and evaporated under vacuum. The residue was purified by column chromatography on silica gel to give the product (1.02 g, 81%) as a solid, m / z = 337.4 (M + 1); room temperature = 3.02 minutes. ¾ MR (400 MHz; d6-DMSO) d 10.41 (s, 1H), 9.24 (d, 1H, J = 2.4 Hz), 8.88 (d, 1H, J = 2.4 Hz), 8.31 (d, 1H, 1.6 Hz ), 8.12 (d, 1H, J = 9.2 Hz), 7.75 (dd, 1H, J = 9.2, 2.0 Hz), 7.50-7.34 (m, 5H), 5.23 (s, 2H), 3.93 (s, 3H) . c. 7-amino-quinoline-3-carboxylic acid ethyl ester A mixture of methyl 7- (benzyloxycarbonylamino) quinoline-3-carboxylate (420 mg, 1.2 mmol), 10% Pd-C (100 mg), and MeOH (100 mg) mL) was stirred under H2 (1 atm) for 2 h. The mixture was filtered through celite and the filtrate was concentrated to give the product (240 mg, 95%) as a solid, m / z-203.3 (M + 1); room temperature = 1.43 minutes.

Intermediary 54 Preparation of 2 -. (7-Aminoquinolin-3-yl) propan-2-ol to. Benzyl 3- (2-hydroxypropan-2-yl) quinoline-7-ylcarbamate. To a stirred solution of methyl 7- (benzyloxycarbonylamino) quinoline-3-carboxylate (170 mg, 0.50 mmol) in THF (15 mL) at -78 ° C under nitrogen was added a solution of MeLi in Et20 (1.6 M; mL, 1.6 mmol). The reaction mixture was slowly warmed to room temperature and then quenched by the addition of saturated aqueous NH 4 Cl solution (10 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc / hexane (0-100% EtOAc) as eluent to give the product (95 mg, 56%) as a solid m / z = 337.1 (M + l); room temperature = 1.89 minutes. b. 2- (7-Aminoquinolin-3-yl) propan-2-ol. A mixture of benzyl 3- (2-hydroxypropan-2-yl) quinoline-7-ylcarbamate (95 mg, 0.28 mmol), 10% Pd-C (10 mg) and MeOH (10 mL) was stirred under H2 ( 1 atm) during lh. The mixture was filtered through celite and the filtrate was concentrated under vacuum to give the product (56 mg, 98%) as a solid, m / z = 203.3 (M + 1); room temperature = 1.32 minutes.

Intermediary 55 Preparation of 1- (7-aminoquinolin-3-yl) ethanol to. Benzyl 3- (1-hydroxyethyl) uinolin-7-ylcarbamate To a stirred solution of benzyl 3-formylquinolin-7-ylcarbamate (0.50 g, 1.6 mmol) in THF (40 mL) at -78 ° C under nitrogen was added a solution of MeLi in Et20 (1.6 M; 2.1 mL, 3.36 mmol). The reaction mixture was slowly warmed to room temperature, and then quenched by adding a saturated aqueous NH 4 Cl solution (10 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried (Na2SC > 4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel using EtOAc as eluent to give the product (350 mg, 66%) as a foam. m / z = 323.0 (M + 1); room temperature = 1.86 min. H NMR (400 MHz; de-D SO) d 10.15 (s, 1H), 8.82 (d, 1H, J = 2.0 Hz), 8.20 (s, 1H), 8.13 (d, 1H, J = 2.0 Hz), 7.88 (d, 1H, J = 9.2 Hz), 7.64 (dd, 1H, J = 9.2, 2.0 Hz), 7.49-7.33 (m, 5H), 5.41 (d, 1H, J = 4.4 Hz), 5.21 (s) , 2H), 4.93 (m, 1H), 1.44 (d, 3H, J = 6.4 Hz). b. 1- (7-Aminoquinolin-3-yl) ethanol A mixture of benzyl 3- (1-hydroxyethyl) quinolin-7-ylcarbamate (180 mg, 0.56 mmol), 10% Pd-C (20 mg), and MeOH (20 mL) was stirred under H2 (1 atm) for lh. The mixture was filtered through celite and the filtrate was concentrated to give the product (97 mg, 92%) as a solid, m / z = 189.0 (M + 1); room temperature = 1.08 minutes.

Intermediate 56 Preparation of 3- ((2- (tert-Butyldimethylsilyloxy) ethoxy) methyl) quinoline-7-amine a. 3- (2- (fcer-butyldimethylsilyloxy) ethoxy) methyl) -quinolin-7-ylcarbamate benzyl. To a stirred mixture of benzyl 3- (hydroxymethyl) quinolin-7-ylcarbamate (500 mg, 1.6 mmol) in DMF (10 mL) was added sodium hydride (60% dispersion in oil, 260 mg, 6.5 mmol). The mixture was stirred at room temperature for 2 h and then (2-bromoethoxy) -tert-butyldimethylsilane (580 mg, 2.4 mmol) was added. After stirring at room temperature overnight, the reaction mixture was quenched by adding aqueous NH 4 Cl solution and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 0-50% EtOAc / hexane as eluent to give the product (95 mg, 12%) as a solid, m / z = 467.4 (M + 1); room temperature = 3.46 minutes. b. 3- ((2- (tert-Butyldimethylsilyloxy) ethoxy ±) yl) quinoline-7-amine A mixture of benzyl 3- ((2- (tert-butyldimethylsilyloxy) ethoxy) methyl) quinoline-7-ylcarbamate (95 mg, 0.20 mmol), 10% Pd-C (10 mg), and MeOH (15 mL) was stirred under H2 (1 atm) for 1 h. The mixture was filtered through celite and the filtrate was concentrated under vacuum to give the product, m / z = 333.1 (M + 1); room temperature = 2.14 minutes.

Intermediary 57 to. Benzyl 3-vinylquinolin-7-ylcarbamate. A suspension of methyltriphenylphosphonium bromide (4.33 g, 12.1 Mmol) in anhydrous THF (50 mL) at -50 ° C was treated in a solution of n-butyllithium in hexane (1.6M, 7.6 mL, 12.1 mmol) for 20 minutes, and the resulting solution was heated at -10 ° C. After lh, the mixture was cooled to -70 ° C and a solution of benzyl 3-formylquinolin-7-ylcarbamate (1.06 g, 3.5 mmol) in THF (20 mL) was added over 15 minutes. The reaction mixture was warmed to room temperature, stirred overnight, then quenched by the addition of water (100 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried (Na2SO / i) and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 30-100% EtOAc / hexane as eluent to give the product (1.Og, 94%) as a solid, m / z = 305.8 (M + 1); room temperature = 2.46 minutes. X H NMR (400 MHz, d 6 -DMSO) d 10.21 (s, 1 H), 9.01 (d, 1 H, J = 2.4 Hz), 8.27 (d, 1 H, J = 1.6 Hz), 8.21 (s, 1 H), 7.87 (d, 1H, J = 8.8 Hz), 7.65 (dd, 1H, J = 8.8, 2.4 Hz), 7.49-7.33 (m, 5H), 6.90 (dd, 1H, J = 17.6, 11.6 Hz), 6.09 ( d, 1H, J = 17.6 Hz), 5.43 (d, 1H, J = 11.6 Hz), 5.22 (s, 2H). b. Benzyl 3- (1,2-dihydroxyethyl) quinolin-7-ylcarbamate To a suspension of benzyl 3-vinylquinolin-7-ylcarbamate (850 mg, 2.8 mmol) in tert-butyl alcohol (15 mL) W-oxide was added of N-methylmorpholine (360 mg, 3.1 mmol) and water (15 mL). To this suspension at room temperature was then added 4% w / w of osmium tetraoxide (440 mg, 0.07 mmol) solution in water. After 5 h, the reaction was completed and homogenized. The mixture was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with water, brine, dried (Na2SC > 4), and concentrated under vacuum. The residue was purified by column chromatography using 0-15% MeOH / EtOAc as eluent to give the product (580 mg, 61%) as a foam, m / z = 339.0 (M + 1); room temperature = 1.78 minutes. c. 1- (7-Aminoquinolin-3-yl) ethane-1,2-diol A mixture of benzyl 3- (1,2-dihydroxyethyl) quinoline-7-ylcarbamate (570 mg, 1.7 mmol), 10% Pd- C (100 mg) and MeOH (50 mL) was stirred under H2 (1 atm) for 2 h. The mixture was filtered through celite and the filtrate was concentrated under vacuum to give the product (320 mg, 93%) as a solid. m / z = 205.1 (M + l); room temperature = 0.53 minutes.

Intermediary 58 Preparation of 8-amino-1, 2, 3, -tetrahydronaf alen-2-ol The compound was prepared using the procedure described in O 2005/040119: 'Tetrahydronaphthalene and urea derivatives'. Preparation of (3-Amino-7,8-dihydro-5H-pyran [, 3- jbJpyridin-7-yl] anol to . 2-Benzyloxymethyl-2,3-dihydropyran-4-one A solution of benzyloxyacetaldehyde (8.9 g, 58 mmol) and l-methoxy-3- (trimethylsiloxy) -1, 3-butadiene (10 g, 58 mmol) in toluene ( 80 mL) was stirred for 30 minutes, then cooled to 0 ° C. Zinc chloride in tetrahydrofuran (0.5 M, 58.0 mL, 30 mmol) was added for 30 minutes. The reaction was allowed to warm slowly to room temperature and then heated to 50 ° C for 2 hours. After cooling, the mixture was evaporated to dryness, then dissolved in EtOAc (100 mL). The solution was washed with 2N HC1 (50 mL) NaHCO3 (3 x 50 mL) and brine (3 x 50 mL), dried (MgSO-j) filtered and concentrated under vacuum. Purification by column chromatography on silica gel using 0 to 20% EtOAc / hexane as eluent gave the title compound (8.24 g, 65%) as an oil, m / z = 219 m / z (M + l); room temperature 2.65 minutes. 1 H NMR (400 MHz; CDC13) d 7.39-7.26 (m, 6H), 5.42 (dd, 1H), 4.63 (m, 3H), 3.71 (m, 2H), 2.75 (dd, 1H), 2.41 (dd, 1 HOUR) . b. 2-Benzyloxymethyltetrahydropyran-4-one To a solution of 2-benzyloxymethyl-2,3-dihydropyran-4-one (8.24 g, 37 mmol) in ethanol (100 mL) was added 10% palladium on carbon (40 mg, 0.38 g). mmol). The flask was evacuated and purged with hydrogen six times and then stirred for 72 hours under a nitrogen atmosphere. The reaction mixture was filtered through celite, washed with EtOH (100 mL), and evaporated to dryness. Purification by column chromatography on silica gel using 0 to 30% EtOAc / hexane as eluent gave the title compound (6.2 g, 75%) as an oil, m / z = no mass ion was observed; room temperature = 2.59 minutes. 1H NMR (400MHz; CDC13) d 7.37-7.28 (m, 5H), 4.61 (s, 2H), 4.35 (ddd, 1H), 3.87-3.82 (m, 1H), 3.62 (dt, 1H), 3.58-3.52 (m, 2H), 2.67-2.58 (m, 1H), 2.53-2.47 (m, 1H), 2.37-2.31 (m, 2H). c. 7-benzyloxymethyl-3-nitro-7,8-dihydro-5H-pyran [4, 3-b] pyridine A stirred suspension of l-methyl-3,5-dinitro-l-pyridin-2-one (1.48 g) , 7.4 mmol) and 2-benzyloxymethyltetrahydropyran-4-one (1.64 g, 7.4 mmol) in 1M ammonia in methanol (70 mL) was stirred at 55 ° C for 5 hours. After cooling, the reaction mixture was poured into water (100 mL) and the product was extracted into EtOAc (4 x 50 mL). The combined organic extracts were dried (MgSOí) filtered and concentrated under vacuum to leave an unpurified residue. Purification by column chromatography on silica gel using 0 to 20% EtOAc / hexane as eluent, followed by trituration with Et20 / hexane gave the title compound (840 mg, 37%) as a solid, m / z = 301 (M + l); room temperature = 3.12 minutes. XH NMR (400 MHz; CDC13) d 9.27 (d, 1H), 8.15 (d, 1H), 7.37-7.29 (m, 5H), 5.04 (d, 1H), 4.88 (d, 1H), 4.65 (d, 2H), 4.09-4.03 (m, 1H), 3.70 (d, 2H), 3.13-3.00 (m, 2H). d. 7-benzyloxymethyl-7,8-dihydro-5H-pyran [4,3-J] pyridin-3-ylamine A flask containing 7-benzyloxymethyl-3-nitro-7,8-dihydro-5H-pyran [4, 3-b ] pyridine (840 mg, 2.8 mmol) and 10% palladium on carbon (30 mg, 0.3 mmol) was evacuated and purged with hydrogen four times, then stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered through celite, washed with EtOH (100 mL), then evaporated to dryness to give the title compound (650 mg, 84%) as a solid, m / z = 270 (M + 1 ); room temperature = 1.63 minutes. XH NMR (400 MHz, d6-DMSO) d 7.76 (d, 1H), 7.41-7.26 (m, 5H), 6.57 (d, 1H), 5.12 (s, 2H), 4.61 (q, 2H), 4.54 ( s, 2H), 3.93-3.86 (m, 1H), 3.60-3.52 (m, 2H), 2.58-2.54 (m, 2H). and. (3-Amino-7,8-dihydro-5H-pyran [4, 3-b] pyridin-7-yl) methanol To a stirred solution of 7-benzyloxymethyl-7,8-dihydro-5H-pyran [4, 3 -b] pyridin-3-ylamine (100 mg, 0.4 mmol) in CH 2 Cl 2 (25 mL) at -78 ° C was added boron tribromide (175 μm, 18.5 mmol). The reaction was allowed to slowly warm to room temperature and was stirred for 2 hours. Water (10 mL) was added, then the reaction mixture was evaporated on silica gel. Purification by column chromatography on silica gel using 0 to 15% MeOH / CH2Cl2 as eluent gave the title compound (35 mg, 50%) as a solid, m / z = 181 (M + 1); room temperature = 0.26 minutes.

Intermediary 59 Preparation of 3-amino-5, 6, 7, 8-tetrahydroquinolin-6-ol to. Ethylene ketal of 3-Nitro-7,8-dihydro-5H-quinolin-6-one A stirred suspension of l-methyl-3,5-dinitro-lH-pyridin-2-one (1.0 g, 5 mmol) and 1 , -dioxaspiro [4.5] decan-8-one (941 mg, 6 mmol) in 1M ammonia in methanol (50 mL) was stirred at 55 ° C for 16 hours. After cooling, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (4 x 50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum. Purification by column chromatography on silica gel using 30-40% EtOAc / hexane as eluent gave the title compound (650 mg, 50%) as a solid, m / z = 237 (M + 1); room temperature = 2.36 minutes. 1 H NMR (400 MHz, CDC13) d 9.21 (d, 1 H), 8.15 (d, 1 H), 4.06 (s, 4 H), 3.23 (t, 2 H), 3.10 (s, 2 H), 2.12 (t, 2 H) . b. 3-Nitro-7, 8-dihydro-5H-quinolin-6-one To a solution of ethylene ketal 3-nitro-7,8-dihydro-5 # -quinolin-6-one (500 mg, 2 mmol) in CH 2 Cl 2 (50 mL) was added trifluoroacetic acid (10 mL). The reaction was heated to reflux and stirred for 5 days. After cooling, the mixture was poured into saturated NaHCO3 solution (100 mL) and extracted with CH2C12 (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4) filtered and concentrated in vacuo. Purification by column chromatography on silica gel using 0 to 5% MeOH in CH2C12 as eluent gave the title compound (260 mg, 60%) as a solid. XH NMR (400 MHz, CDC13) d 9.29 (d, 1H), 8.25 (d, 1H), 3.74 (s, 2H), 3.41 (t, 2H), 2.75 (t, 2H) m / z = not observed mass ion; room temperature = 2.36 minutes. c. 3-Nitro-5,6,7,8-tetrahydroquinolin-6-ol To a stirred solution of 3-nitro-7,8-dihydro-5Ji-quinolin-6-one (270 mg, 1.4 mmol) in MeOH (40 mg). mL) was added sodium borohydride (79 mg, 2.1 mmol). The reaction was stirred at room temperature for 1 hour, then the reaction mixture was poured into saturated NaHCO 3 solution (100 mL) and extracted into EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO 4) filtered and concentrated under vacuum to give the title compound (200 mg, 70%) as a solid, m / z = 195 (M + l); room temperature = 1.85 minutes. H NMR (400 MHz, d6-DMSO) d 9.13 (d, 1H), 8.33 (d, 1H), 4.99 (d, 1H), 4.10-4.04 (m, 1H), 3.09-3.02 (m, 2H), 2.97-2.89 (m, 1H), 2.80 (dd, 1H), 2.00-1.93 (m, 1H), 1.91-1.84 (m, 1H). d. 3-Amino-5, 6, 7, 8-tetrahydroquinolin-6-ol To a solution of 3-nitro-5, 6, 7, 8-tetrahydroquinolin-6-ol (200 mg, 1 mmol) in EtOH (25 mL ) 10% palladium on carbon (20 mg, 0.1 mmol) was added. The reaction mixture was evacuated and purged with hydrogen six times, then stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered through celite, washed with EtOH (100 mL) and the filtrate was evaporated to dryness, giving the title compound (160 mg, 90%) as a solid. m / z = 165 (M + 1); room temperature = 0.29 minutes. 1 H NMR (400 MHz, d 6 -DMSO) d 7.70 (d, 1 H), 6.58 (d, 1 H), 4.95 (s, 2 H), 4.76 (d, 1 H), 3.88-3.84 (m, 1 H), 2.80- 2.70 (m, 2H), 2.65-2.57 (m, 1H), 2.52-2.46 (m, 1H), 1.90-1.86 (m, 1H), 1.71-1.62 (m, 1H).

Intermediary 60 Preparation of (7-Amino-l, 5-naphthyridin-3-yl) methanol to. 5-Aminopyridin-3-ylcarbamate benzyl To a stirred solution of pyridine-3,5-diamine hydrochloride (240 mg, 1.6 mmol) in DMF (10 mL) and CH2C12 (10 mL) at -40 ° C was added pyridine (1 drop), triethylamine (0.46 mL, 3.3 mmol) and benzyl chloroformate (0.24 mL, 1.6 mmol). The mixture was slowly warmed to room temperature and stirred at room temperature over the weekend. Aqueous NaHCO3 solution (20 mL) and EtOAc (150 mL) were added. The organic phase was separated and washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 50-100% EtOAc / hexane as eluent to give the product (170 mg, 42%) as a solid, m / z = 243.8 (M + l); room temperature = 1.62 minutes. 1 H NMR (400 MHz, d 6 -DMSO) d 9.68 (s, 1 H), 7.78 (d, 1 H, J = 2.4 Hz), 7.57 (d, 1 H, J = 2.4 Hz), 7.45-7.32 (m, 5 H) , 7.17 (s, 1H), 5.33 (s, 2H), 5.14 (s, 2H). b. Benzyl 7-formyl-1, 5-naphthyridin-3-ylcarbamate A suspension of benzyl 5-aminopyridin-3-ylcarbamate (150 mg, 0.62 mmol) and bis (tetrafluoroborate) of 2-dimethylaminomethylene-1,3-bis ( dimethylimon) propane (660 mg, 1.8 mmol) in n-butanol (10 mL) was heated at reflux for 24 h. The solution was concentrated under vacuum and the residue was dissolved in THF (20 mL) and 1N HC1 (20 mL). The reaction mixture was stirred at room temperature overnight, then poured into a saturated solution of sodium bicarbonate (20 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried (Na2SO), and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 0-100% EtOAc / hexane as eluent to give the product (45 mg, 24%) as a solid, m / z = 308.3 (M + 1); room temperature = 2.72 minutes. 1 H NMR (400 MHz, d 6 -DMSO) d 10.76 (s, 1 H), 10.27 (s, 1 H), 9.31 (d, 1 H, J = 2.0 Hz), 9.10 (d, 1 H, J = 2.0 Hz), 8.85 (d, 1H, J = 2.0 Hz), 8.63 (d, 1H, J = 2.0 Hz), 7.51-7.35 (m, 5H), 5.27 (s, 2H). c. 7- (Hydroxymethyl) -1,5-naphyridin-3-ylcarbamate benzyl To a stirred mixture of benzyl 7-formyl-l, 5-naphthyridin-3-ylcarbamate (110 mg, 0.36 mmol), eOH (55 mL ), and H20 (1 mL) was added sodium tetrahydroborate (27 mg, 0.72 mmol). The mixture was stirred at room temperature until LC-MS indicated without remaining starting material. The mixture was acidified with 1N HCl and concentrated in vacuo, and then treated with aqueous Na 2 CO 3 solution and EtOAc (100 mL). The organic layer was separated and washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 0-5% MeOH / EtOAc as eluent to give the product (85 mg, 77%) as a solid, m / z = 310.1 (M + 1). room temperature = 2.22 minutes. d. (7-Amino-l, 5-naphthyridin-3-yl) methanol A mixture of benzyl 7- (hydroxymethyl) -1,5-naphthyridin-3-ylcarbamate (55 mg, 0.18 mmol), 10% Pd-C (5 mg), MeOH (5 mL) was stirred under H2 (1 atm) for 1 h. The mixture was filtered through celite and the filtrate was concentrated under vacuum to give the product (30 mg, 54%) as a solid.

Intermediary 61 Preparation of 1,5-naphthyridin-3-amine to. Pyridine-3,5-diamine hydrochloride A mixture of 2-chloro-3,5-dinitropyridine (4.6 g, 22 mmol), EtOAc (100 mL), chloroform (30 mL), and 10% Pd-C (500 mg) was hydrogenated at 60 psi for 24 h. The mixture was filtered through celite and the filtrate was concentrated under vacuum to give the product (3.4 g, 98%) as a solid, m / z = 110.0 (M + 1); room temperature = 0.26 minutes. 1H NMR (400 Hz; d6-DMS0) d 15.02 (bs, 1H), 7.23 (d, 2H, J = 2.4 Hz), 6.68 (t, 1H, J = 2.4 Hz), 6.17 (bs, 4H). b. 1, 5-Naphthyridin-3-amine 1,2,3-Propanetriol (15 mL) was mixed thoroughly with pyridine-3,5-diamine hydrochloride (3.3 g, 23 mmol), sodium 3-nitrobenzenesulfonate (18 g, 81 mmol) and H20 (20.5 mL, 1.14 mol). Concentrated H2SO4 (22 mL) was then added carefully with stirring. The reaction mixture was heated by a hot air gun and the temperature was raised; the reaction was initialized at approximately 136 ° C and the hot air gun was removed. After the initial violent boiling had ceased, the temperature remained there for lh. After cooling, the mixture was poured into H20 (300 mL), neutralized with K2CO3 and extracted with EtOAc (x3). The organic extracts were combined, washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by basic aluminum oxide column using EtOAc as eluent to give the product (0.95 g, 29%) as a solid. m / z = 146.0 (M + 1); room temperature = 0.46 minutes. 1 H NMR (400 MHz; d 6 - DMSO) d 8.70 (dd, 1 H, J = 4.4, 1.6 Hz), 8.51 (d, 1 H, J = 2.4 Hz), 8.12 (ddd, 1 H, J = 8.4, 1.6, 0.8 Hz), 7.33 (dd, 1H, J = 8.4, 4.4 Hz), 7.20 (dd, 1H, J = 2.4, 0.8 Hz), 6.07 (s, 2H).

Intermediary 62 Preparation of 1- (7-Amino-1, 5-naphidin-3-yl) ethanol to . Benzyl 7- (1-hydroxyethyl) -1,5-naphthyridin-3-ylcarbamate To a stirred solution of benzyl 7-formyl-1, 5-naphthyridin-3-ylcarbamate (310 mg, 1.0 mmol) in THF (20 mg). mL) at -78 ° C under N2 was added a solution of eLi in Et20 (1.6 M; 1. 5 mL, 2.4 mmol). The reaction mixture was slowly warmed to room temperature, and then quenched by the addition of saturated aqueous NH 4 Cl solution (10 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography using EtOAc as eluent to give the product (185 mg, 57%) as a solid, m / z = 323.8 (M + 1). room temperature = 2.32 minutes. b. 1- (7-Amino-l, 5-naphthyridin-3-yl) ethanol A mixture of benzyl 7- (1-hydroxyethyl) -1,5-naphthyridin-3-ylcarbamate (185 mg, 0.57 mmol), 10% of Pd-C (20 mg) and MeOH (20 mL) was stirred under H2 (1 atm) for lh. The mixture was filtered through celite and the filtrate was concentrated under vacuum to give the product (155 mg) as a solid, m / z 189.9 (M + 1). room temperature = 0.60 minutes.

Intermediary 79 Preparation of (3-aminoquinolin-7-yl) methanol This compound was prepared using the procedure described in US 2006194801.

Intermediary 63 Preparation of 1- (7-Amino-3,4-dihydroquinolin-l (2H) -yl) ethanone to . 7-Nitro-1, 2,3,4-tetrahydroquinoline 1, 2, 3, 4-tetrahydroquinoline (8.0 g, 60 mmol) was slowly added to concentrated H2SO4 (160 mL) while cooling with an ice bath. To the stirred solution was slowly added a solution of concentrated HNO3 (6.0 mL) in sulfuric acid (20 mL) at 0-5 ° C for 30 minutes. Upon completion of the addition, the reaction mixture was poured into crushed ice and then neutralized with solid K2CO3. EtOAc (600 mL) was added and the mixture was filtered to remove undissolved solids. The aqueous phase was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water, dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel and recrystallized from hexane-EtOAc to give the product (7.2 g, 67%) as a solid, m / z = 179.2 (M + 1); room temperature = 3.09 minutes. XH NMR (400 MHz; CDC13) d 7.40 (dd, 1H, J = 8.0, 2.0 Hz), 7.28 (d, 1H, J = 2.0 Hz), 7.02 (d, 1H, J = 8.0 Hz), 4.30 (br s, 1H), 3.36 (t, 2H, J = 5.6 Hz), 2.81 (t, 2H, J = 6.0 Hz), 1.99-1.92 (m, 2H). b. 1- (7-Nitro-3, -dihydroquinolin-1 (2H) -yl) ethanone A solution of 7-nitro-l, 2-, 3, 4-tetrahydroquinoline (350 mg, 2.0 mmol) and acetic anhydride (600 mg , 6.0 mmol) in pyridine (5 mL) was stirred at 70 ° C overnight. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to give the product (350 mg, 81%) as a solid, m / z = 221.1 (M + 1); room temperature = 2.55 minutes. c. 1- (7-Amino-3, 4-dihydroquinolin-l (2H) -yl) ethanone A mixture of 1- (7-nitro-3,4-dihydroquinolin-1. {2 H) -yl) ethanone (350 mg , 1.6 mmol), 10% Pd-C (30 mg) and MeOH (10 mL) was stirred under a hydrogen atmosphere (1 atm) for 3 h. The mixture was filtered through celite and the filtrate was concentrated under vacuum to give the product (300 mg, 100%) as a? syrup. m / z 191.0 (M + 1); room temperature = 0.98 minutes.

Intermediary 64 Preparation of (E) -2-methyl-4- (3,3,3-trifluoro-2-methylprop-1-enyl) benzoic acid to. Ethyl 4-bromo-2-methylbenzoate Oxalyl chloride (10.6 g, 83.7 mmol) was added slowly to a mixture of 4-bromo-2-methylbenzoic acid (12.0 g, 55.8 mmol) in CH2C12 (200 mL) and DMF ( 0.2 mL) at 0 ° C. The mixture was stirred at 0 ° C for 1 h, and then warmed to room temperature and stirred overnight. The mixture was concentrated under vacuum to give the acid chloride as a solid. The obtained acid chloride was redissolved in CH2Cl2 (200 mL) and dry ethanol (20 g, 0.4 mol) was added. The mixture was stirred at room temperature for 5 h, and then concentrated under vacuum to give the product (13.5 g, 100%) as an oil. b. 2-Methyl-4- (3,3,3-trifluoro-2-methylprop-l-enyl) benzoate of (E) -Ethyl 3, 3, 3-trifluoro-2-methylprop-l-ene (7.2 g, 66 mmol) was introduced into a dry ice cooled mixture of ethyl 4-bromo-2-methylbenzoate (4.0 g, 16 mmol), tri-o-tolylphosphine (1.00 g, 3.3 mmol), cesium carbonate (5.36 g, 16.4 g). mol), tetra-N-butylammonium chloride (1.37 g, 4.9 mmol), palladium acetate (180 mg, 0.82 mol), and N, N-dimethylacetamide (30 mL). The reaction mixture was rinsed with N2 and sealed on a steel Parr instrument and stirred at 160 ° C for 48 h. After cooling, the reaction mixture was filtered through celite and the filtrate was partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was separated and washed with brine, dried (Na 2 SO) and concentrated under vacuum. The residue was purified by chromatography on silica gel using EtOAc / hexane as eluent to give the product as an oil. c. (E) -2-Methyl-4- (3,3,3-trifluoro-2-methylprop-1-enyl) benzoic acid A mixture of 2-methyl-4- (3,3,3-trifluoro-2-methylpropyl) -l-enyl) -benzoate (£) -ethyl (3.0 g, 7.7 mmol), 2N aqueous NaOH (25 mL), and MeOH (50 mL) was stirred at 40 ° C overnight. The mixture was concentrated under vacuum and the residue was treated with H20 and acidified with 1N HC1 to pH 2-3. The mixture was extracted with EtOAc (100 mL x 2) and the combined organic layers were washed with brine, dried (Na 2 SO), and concentrated in vacuo to give the product as a solid. m / z = 242.7 (M-1); room temperature = 3.29 minutes. 1ti NMR (400 MHz, d6-DMSO) d 12.96 (s, 1H), 7.87 (d, 1H, J = 8.0 Hz), 7.39 (s, 1H), 7.37 (d, 1H, J = 8.0 Hz), 7.17 (s, 1H), 2.55 (s, 3H), 2.02 (s, 3H).

Preparation of Amido Compounds Amide Formation Method A: A Representative Synthesis of Benzamides Using an Automated Parallel Synthesis Method The appropriate benzoic acid (2 mmol) was dissolved or suspended in 15 ml of chloroform and treated with 20 mmol of thionyl chloride. The reaction mixture was refluxed for fifteen minutes and the solvents were removed under vacuum. The residue was dissolved in 4 ml of anhydrous chloroform and 60 μ? (30 μ ????) of this solution was added to each well of the 96-well glass plates. The appropriate amine is then added to the corresponding well (60 μp ??), followed by n, n-diisopropylethylamine (120 μ ???). The plate is then heated at 65 ° C for 15 minutes. The solvents were removed using a centrifugal evacuator ht-12 genevac and 100 μ? of dmso was added to each well and the compounds transferred to a 96-well polypropylene reaction plate. The plates are then sealed using an abgene plate sealer and subjected to lc-ms purification.

Method B: A Representative Synthesis of Benzamides Using an Automated Parallel Synthesis Method In a well of a 96 well polypropylene reaction plate was added the appropriate benzoic acid (6.03 mg, 30 μ ????) in 15 μ? of anhydrous pyridine. To the reaction was added TFFH (TFFH is fluoro-W, N, W,? '- tetramethylformamidinium, 12mg, 45μ?), Followed by diisopropylethylamine (6.0mg, 45μp ???), followed by the appropriate amine (60 μ ????). The reaction plate was heated at 50 ° C for 15 minutes and the solvent was evaporated. The residue was dissolved in DMSO and purified using purification based on LC-MS (50mmXl Omm Phenomenex Gemini Column using a 10-100% acetonitrile-water gradient).

Method C: To a mixture of the acid (0.4 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (0.8 mmol), 1-hydroxybenzotriazole hydrate (0.24 mmol) and CH2C12 (5 mL) was added. appropriate amine (0.5 mmol) and DIPEA (0.2 mL). The mixture was stirred at room temperature overnight, diluted with EtOAc, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel to give the product.

Method D: To a mixture of acid (1.0 mmol), N- (3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (385 mg, 2.0 mmol), 1-hydroxybenzotriazole hydrate (0.5-1.0 mmol), DMF (2) mL) and CH2C12 (5 mL) were added amine (1.2 mmol) and diisopropylethylamine (0.5 mL). The mixture was stirred at room temperature overnight, diluted with EtOAc, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column to give the amide.

Method E: To a stirred solution of acid (1.0 mmol) in dry CH2C12 (10 mL) and DMF (2 drops) at 0 ° C was added oxalyl chloride (1.5 mmol). The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature for 3 h. The solvent was removed in vacuo. A solution of the acid chloride obtained in CH2C12 (2 mL) was added to a solution of amine (1.0 mmol) in CH2Cl2 (3 mL) and pyridine (2 mL) at 0 ° C. The reaction mixture was stirred at room temperature overnight, and then diluted with EtOAc. The organic phase was washed with NaHCC solution > 3 aqueous and brine, dried (Na2SO), and concentrated. The residue was purified by chromatography to give the amide.

Method F: To a stirred solution of acid (0.25 mmol) in dry THF or CH 2 Cl 2 (5 mL) and DMF (1 drop) at 0 ° C was added oxalyl chloride (0.40 mmol). The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature. The solvent was removed in vacuo. A solution of the acid chloride obtained in CH2Cl2 (2 mL) was added to a solution of amine (0.25 mmol) in CH2C12 (10 mL), Et3N (0.2 mL), DMAP (5 mg) at 0 ° C. The reaction mixture was stirred at room temperature overnight, and then diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO3 solution and brine, dried, and concentrated. The residue was purified by chromatography to give the amide.

Method G: To a cooled (0 ° C) and well-stirred suspension of the appropriate acid (1 equivalent) in CH2C12 (approximately 3 mL per mmol) and DF (catalytic amount) oxalyl chloride (1.5 equivalent) was added slowly by dropping and the mixture was stirred for one hour. The mixture was concentrated under vacuum and the residue re-suspended in CH2Cl2. The appropriate amine (0.5-1.0 equivalent) was then added and the mixture was stirred for 1-48 hours before developing and purifying.

Method H:? /, -Diisopropylethylamine (1 equivalent) was added in one portion to a stirred mixture of 2-methyl-4- (3, 3-dimethylbut-1-ynyl) benzoic acid (1 equivalent) and γ hexafluorophosphate, ?, N ',?' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium (1.05 equivalent) in N, N-dimethylformamide (approximately 3 mL per 0.5 mmol of the starting acid) at room temperature. The mixture was stirred at room temperature for about 2 hours then a solution of the appropriate amine (1 equivalent) in DMF (1 mL) was added in one portion. The mixture was stirred overnight then developed by pouring it into H20 (30 mL) and EtOAc (30 mL). The aqueous and organic layers were partitioned and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (1 x 30 mL), dried (Na2SO4) were filtered and the solvent was removed under vacuum to leave an unpurified residue. Appropriate purification was employed to provide the desired final compound.

Method I: A mixture of the acid (1 mmol), JV- (3-dimethylaminopropyl) -IV'ethylcarbodiimide hydrochloride (3 mmol), hydroxybenzotriazole-1-hydrate (1.5 mmol) and the amine (2 mmol) was stirred in DMF at room temperature overnight. The mixture was partitioned between EtOAc and water. The organic layer was separated and washed with NaHCC > Aqueous saturated, water, brine, dried (a2SO4) was filtered and the filtrate was concentrated in vacuo to a residue which was purified by flash column chromatography.

Method J: DIPEA (0.92 mmol) was added to the solution of appropriate acid (0.46 mmol), appropriate amine (0.69 mmol) and TFFH (0.69 mmol) in anhydrous pyridine (3 mL) and the reaction mixture was stirred at 60 °. C during the night. The volatiles were removed and the residue was suspended in water, extracted by EtOAc and the organic phase was washed with water, brine and dried over a2SO4, the solvent was removed and the residue chromatographed to give the product.

Method K: DIPEA (0.92 mmol) was added to the solution of appropriate acid (4.0 mmol), appropriate amine (3.2 mmol) and TFFH (6.0 mmol) in anhydrous pyridine (10 mL) and the reaction mixture was stirred at 70 °. C during the night. The volatiles were removed and the residue was dissolved in EtOAc and the organic phase was washed with water, Na2CC > Aqueous solution, brine and dried over Na 2 SO 4, the solvent was removed and the residue was subjected to chromatography to produce the product.

Method L: To a solution of acid (0.5 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (1.0 mmol), 1-hydroxybenzotriazole hydrate (1.0 mmol) in DMF (5 mL) and CH2C12 ( 5 mL) were added amine (0.75 mmol) and diisopropylethylamine (1.0 mmol). The mixture was stirred at 40 ° C overnight before it was diluted with EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by column to give the amide.

Method M: The amine (1 equivalent) was added in one portion to a stirred solution of the acid (1 equivalent), N- (3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (1 equivalent), 4-W / W- dimethylaminopyridine (1 equivalent) and Et3N (2 equivalents) in CH2C12 (about 3mL per 0.125 mmol) and the mixture was stirred until the reaction was complete (typically left overnight). The mixture was diluted with more CH2C12 (30 mL) and washed with H20 (1 x 20 mL), then dried (Na2SO4) filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel or preparative thin layer chromatography.

Compound 187 2-Methyl-N-quinolin-3-yl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide To a stirred solution of 4- ((E) -3,3 acid) 3-trifluoroprop-l-enyl) -2-methylbenzoic acid (4.0 g, 0.017 mol) in CH2C12 (50 mL) and DMF (2 drops) at 0 ° C was added oxalyl chloride (2.20 mL, 0.0261 mol). The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature during 2h the solvent was removed in vacuo. The above acid chloride was reacted with 3-quinolinamine (2.50 g, 0.0174 mol) in CH2C12 (20 mL) and pyridine (10 mL) at room temperature overnight. The mixture was concentrated in vacuo, and the residue was treated with EtOAc and aqueous NaHCO 3. The organic layer was separated, washed with brine, dried (Na2SC > 4), and evaporated. The residue was purified by column (EtOAc / CH2Cl2: 0-30%) to give a white solid (4.9 g, 81%). (d6-DMSO) d 10.86 (s, 1H), 9.04 (d, 1H, J = 2.4 Hz), 8.88 (d, 1H, J = 2.4 Hz), 7.98 (d, 2H, J = 8.8 Hz), 7.72 -7.58 (m, 5H), 7.43-7.35 (m, 1H), 6.90 (dq, 1H, J = 16.4, 7.2 Hz), 2.46 (s, 3H). MS (ESI): m / z 357 (M + H) + Compound 187 (Alternate method) A well-stirred mixture of methyl 4-bromo-2-methylbenzoate (50 g, 0.22 mol), Palladium acetate (4.9 g, 0.02 mol), tri-o-tolylphosphine (10 g, 0.04 mol) ), Tetra-N-butylammonium chloride (20 g, 0.06 mol) and Cesium carbonate (71 g, 0.22 mol) in N, N-Dimethylacetamide (200 mL, 2 mol) was cooled to -78 ° C in a reactor of pressure pair of 500 mL equipped with pressure gauze. 3, 3, 3-Trifluoroprop-l-ene was then pumped until the desired amount (84 g, 0.87 mol) was condensed in the reactor. The valve was closed firmly and the flask was heated in an oil bath at 135 ° C for 3 days. After completing the reaction, the reactor was again cooled to -78 ° C before carefully opening the valve to air. The reactor was allowed to slowly warm to room temperature. The solids were filtered through Celite®, concentrated under reduced pressure at half volume, dissolved in EtOAc (400 mL), washed successively with water (2 x 400 mL) and brine, dried (gSC and concentrated to give a dark oil The analysis with LC / MS indicated the presence of saponified product (-25%) in addition to other non-polar impurities which were not identified.The dark oil was then dissolved in anhydrous THF (200 mL), cooled at 0 ° C and treated with oxalyl chloride (30 mL, with large excess) A few drops of DF were added to start the reaction.After stirring for 1 hour at the same temperature, the mixture was concentrated to dryness, it was re-dissolved in MeOH (100 mL) and carefully treated with triethylamine (30 mL, with large excess) After stirring for a few hours, the mixture was concentrated to dryness, redissolved in hot EtOAc (500 mL) and washed twice with hot water.The organic layer was dried and concentrated to obtain the unpurified ester as a dark oil which was passed through a short column of silica gel using 30% EtOAc in Hexane. The LC / S analysis of the above product indicated ~ 80% purity. The unpurified ester was saponified as follows. The ester was treated with LiOH (10.45 g, 0.44 mol) in a mixture of 3: 1 (200 mL) of THF and water and the mixture was heated to reflux for 4 hours. The mixture was concentrated in the middle of the volume, diluted with water (1.5 L) and cooled to 0 ° C before acidifying to pH 2.0 with concentrated HC1. The white precipitate was filtered, washed with water and dried in vacuo at constant weight. The crude product was recrystallized repeatedly from EtOAc / hexane at ~ 99% purity.

To a stirred solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (30 g, 0.13 mol) in CH 2 Cl 12 (200 mL) and DMF (2 drops) at 0 ° C oxalyl chloride (19.85 g, 0.16 mol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for an additional 2 h. The mixture was concentrated to dryness and dried in vacuo to constant weight to produce the acid chloride. The above acid chloride was reacted with 3-quinolinamine (22.55 g, 0.16 mol) in THF (200 mL) and triethylamine (15.83 g, 0.16 mol) at room temperature overnight. The mixture was concentrated in vacuo, and the crude product was treated with EtOAc and aqueous NaHCO 3. The organic layer was separated, washed with brine, dried (Na2SO4), and evaporated. The crude product was purified by repetitive crystallizations to obtain the title compound as a white solid.

Compound 197 A mixture of 2-methyl-N- (2-methylbenzo [d] thiazol-5-yl) -4- (3, 3-dimethylbut-1-ynyl) benzamide (50 mg, 0.14 mmol), dioxide of selenium (46 mg, 0.41 mmol), and 1,4-dioxane (10 mL) was stirred under a nitrogen atmosphere at 80 ° C overnight or. After cooling, the mixture was filtered through celite and the filtrate was treated with aqueous NaHCO 3 and extracted with EtOAc. The organic layer was washed with brine, dried (Na 2 SO), and concentrated under vacuum. The residue was dissolved in THF-H20 (2: 1) (10 mL) and NaBH4 (50 mg) was added slowly. The mixture was stirred at room temperature for 2 h and then acidified with 1N HC1. After it was treated with aqueous NaHC03, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by preparative thin layer chromatography to give N- (benzo [d] thiazol-5-yl) -2-methyl-4- (3, 3-dimethylbut-l-ynyl) benzamide (compound 198-11 mg ) as a light yellow solid and N- (2- (hydroxymethyl) benzo [d] thiazol-5-yl) -2-methyl-4- (3, 3-dimethylbut-l-ynyl) benzamide (Compound 197-27 mg ) as a light yellow solid.

Compound 225 (£) -4- (3, 3, 3-trifluoroprop-1-enyl) -2-methyl-W- (2-methyl-benzo [d] thiazol-5-yl) -benzamide (200 mg, 0.0005 mol) and Selenium dioxide (177 mg, 0.00160 mol) was placed in 20 mL of dioxane and the reaction was heated at 80 ° C overnight under nitrogen. The reaction was cooled and filtered through celite. The filtrate was partitioned between EtOAc and NaHCO3. The organic layer was separated, washed with water, brine, dried (a2SO4) and concentrated under vacuum. The residue was dissolved in THF / H 2 O (2: 1, 20 mL) and NaBH 4 (200 mg, 5.3 mmol) was added in three batches. The mixture was stirred at room temperature for 2 h, then quenched by the addition of 1N HCl. The mixture was made alkaline by addition of saturated NaHCO 3 and extracted with EtOAc. The organic layer was washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc / hexane (0-100%) as eluent and then again using MeOH / CH2Cl2 (0-3%) as eluent to give the product (40 mg) as a solid. , m / z = 392.6 Additional purification by preparative HPLC (water / acetonitrile) gives the product (35 mg) as a white solid, m / z = 392.6.

Compound 228 To a stirred solution of (E) -4- (3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (0.20 g, 0.87 mmol) in CH 2 Cl 12 (50 mL) and DMF (2 drops) at 0 ° C oxalyl chloride (0.11 mL, 1.3 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature for 2 h. the solvent was removed in vacuo. The above acid chloride was added to a solution of (7-aminoquinolin-3-yl) methanol (76 mg, O. 43 mmol) in CH2Cl2 (5 mL) and pyridine (10 mL). The reaction mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was treated with EtOAc and aqueous NaHCO 3 solution. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel using EtOAc / hexane (0-50%) as eluent to give the ester [95 mg, m / z: 599.2 (M + 1)]. The ester was dissolved in MeOH (5 mL) and K2CO3 (200 mg) was added. The mixture was stirred at room temperature for 3 h, and then methanol was removed under vacuum. The residue was treated with water and EtOAc. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative thin layer chromatography with acetone-CH2Cl2 (1: 1) to give a white solid (43 mg, 24%). LC- S: 2.29 minutes, 387.7 (M + l).

Compound 229 To a stirred solution of 7,8-Dihydro-5J-pyran [4, 3-b] pyridin-3-ylamine (50 mg, 0.3 mmol) in anhydrous DMF (2 mL) was added a stirred solution of acid ( E) -A- (3, 3, 3-trifluoroprop-1-enyl) -2-methylbenzoic acid (91.96 mg, 0.4 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (76.59 mg, 0.4 mmol ), HOBt (62.98 mg, 0.46 mmol), 4-N, N-dimethylaminopyridine (2 mg, 0.02 mmol) and DIPEA (139 pL, 0.8 mmol) in anhydrous DMF (3 mL). The reaction was stirred overnight at room temperature. The reaction mixture was poured into saturated NaHCO3 solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (3 x 50 mL), dried (MgSO4) filtered and concentrated in vacuo. Purification by column chromatography on silica gel (0 to 5% MeOH in DCM for 60 minutes) gave the desired product (39mg, 30%) as a creamy white solid.

Compound 301 Preparation of (E) -7- (2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamido) quinoline-3-carboxylic acid to . 7- (2-Methyl-4- (3,3,3-trifluoroprop-l-enyl) benzamido) -quinolin-3-carboxylate of (E) -methyl To a stirred solution of the acid 4- ((E) -3 , 3, 3-trifluoroprop-l-enyl) -2-methylbenzoic acid (260 mg, 1.1 mmol) in CH2C12 (10 mL) and DMF (1 drop) at 0 ° C was added oxalyl chloride (140 μL, 1.7 mmol) . The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the chloride of the acid obtained was reacted with 7-amino-quinoline-3-carboxylic acid methyl ester (230 mg, 1.1 mmol) in CH2C12 (3 mL) and pyridine (2 mL) at room temperature overnight. The mixture was diluted with EtOAc (100 mL), washed with aqueous NaHCO3 and brine, dried (Na2SC > 4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 0-40% EtOAc / hexane as eluent to give the product (280 mg, 59%) as a solid, m / z = 415.2 (M + 1); room temperature = 3.45 min. 1R NMR (400 Hz, d6-DMSO) d 10.90 (s, 1H), 9.28 (d, 1H, J = 2.4 Hz), 8.93 (d, 1H, J = 2.4 Hz), 8.67 (s, 1H), 8.19 (d, 1H, J = 8.8 Hz), 7.96 (dd, 1H, J = 8.8, 2.0 Hz), 7.71 (s, 1H), 7.68 (d, 1H, J = 8.4 Hz), 7.62 (d, 1H, J = 8.0 Hz), 7.42-7.35 (m, 1H), 6.88 (dq, 1H, J = 16.4, 7.2 Hz), 3.95 (s, 3H), 2.45 (s, 3H). b. (E) -7- (2-Methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamido) quinoline-3-carboxylic acid A mixture of 7- (2-methyl-4- (3, 3) , (3-trifluoroprop-1-enyl) benzamido) quinoline-3-carboxylate of (E) -methyl (110 mg, 0.26 mmol), lithium hydroxide (65 mg, 2.7 mmol), MeOH (10 mL), THF (10 mL), and water (5 mL) was stirred at 50 ° C overnight. The mixture was concentrated under vacuum and the residue was acidified with aqueous 1N HCl to pH 4-5 and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was washed with CH2C12 to give the product as a solid, m / z = 399.2 (M-1); room temperature = 2.95 min. NMR (400 MHz; d6-DMSO) d 13.39 (br s, 1H), 10.89 (s, 1H), 9.27 (d, 1H, J = 2.4 Hz), 8.88 (d, 1H, J = 2.0 Hz), 8.66 (s, 1H), 8.16 (d, 1H, J = 8.8 Hz), 7.95 (dd, 1H, J = 8.8, 2.0 Hz), 7.71 (s, 1H), 7.68 (d, 1H, J = 8.0 Hz ), 7.62 (d, 1 H, J = 8.0 Hz), 7.42-7.35 (m, 1H), 6.89 (dq, 1H, J = 16.4, 7.2 Hz), 2.45 (s, 3H).

Compound 32 Preparation of (E) -N- (7-hydroxynaphthalen-1-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide To a stirred solution of 8-aminonaphthalen-2-ol (130 mg, 0.82 mmol) in anhydrous toluene (7 mL) was added a solution of trimethylaluminum in hexanes (1M, 0.82 mL, 0.82 mmol), dropwise for 5 minutes. The reaction was stirred at room temperature for 16 hours, then a solution of 2-methyl-4- ((E) -3,3,3-trifluoropropenyl) benzoic acid methyl ester (100 mg, 0.4 mmol) in anhydrous toluene was added. (3mL), and the reaction was heated to reflux for 3 hours. After cooling, the reaction mixture was poured into saturated NaHCO3 solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried (MgSO 4) filtered and concentrated under vacuum. Purification by column chromatography on silica gel using 0 to 30% EtOAc / hexane as eluent gave the title compound (44 mg, 30%) as a solid. M / z = 372 (M + l); room temperature = 3.32 min. H NMR (400MHz; d6-DMSO) d 10.21 (s, 1H), 9.84 (s, 1H), 7.82 (d, 1H), 7.73-7.68 (m, 4H), 7.51 (d, 1H), 7.39 (d , 1H), 7.32 -7.29 (m, 2H), 7.11 (dd, 1H), 6.93-6.84 (m, 1H), 2.51 (s, 3H).

Compound 303 Preparation of (?) -N- (3- (2-Hydroxypropan-2-yl) quinolin-7-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide acid To a stirred solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (62 mg, 0.27 mmol) in CH2C12 (5 mL) and DMF (1 drop) at 0 ° C oxalyl chloride (34 pL, 0.41 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the acid chloride obtained was reacted with 2- (7-aminoquinolin-3-yl) propan-2-ol (55 mg, 0.27 mol) in CH 2 Cl 2 (3 mL) and pyridine (2 mL). ) at room temperature overnight. The mixture was diluted with EtOAc (100 mL), washed with NaHCC > 3 aqueous and brine, dried (Na2SC > 4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 30-100% EtOAc / hexane as eluent to give the product (95 mg, 82%) as a solid. M / z = 415.2 (M + 1); room temperature = 2.33 min. * HNR (400 MHz; d6-D SO) d 10.69 (s, 1H), 9.02 (d, 1H, J = 2.4 Hz), 8.55 (s, 1H), 8.26 (d, 1H, J = 2.4 Hz) , 7.94 (d, 1H, J = 8.8 Hz), 7.84 (dd, 1H, J = 8.8, 1.6 Hz), 7.70 (s, IH), 7.66 (d, 1H, J = 8.0 Hz), 7.60 (d, 1H, J = 8.0 Hz), 7.42-7.35 (m, 1H), 6.89 (dq, 1H, J = 16.4, 7.2 Hz), 5.34 (s, 1H), 2.45 (s, 3H), 1.56 (s, 6H) ).

Compound 304 Preparation of (E) -N- (3- (l-hydroxyethyl) quinolin-7-yl) -2-methyl-4- (3,3,3-trifluoroprop-l-enyl) benzamide acid To a stirred solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (115 mg, 0.5 mmol) in CH2C12 (10 mL) and DMF (1 drop) at 0 ° C oxalyl chloride (63 L, 0.75 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the chloride of the acid obtained was reacted with 1- (7-aminoquinolin-3-yl) ethanol (94.0 mg, 0.5 mmol) in CH2C12 (3 mL) and pyridine (2 mL) at room temperature overnight. The mixture was diluted with EtOAc (100 mL), washed with aqueous NaHCO3 and brine, dried (Na2SC > 4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc as eluent to give the product (170 mg, 85%) as a solid, m / z = 401.3 (M + 1); room temperature = 2.32 min. H NMR (400 MHz; d6-DMSO) d 10.69 (s, 1H), 8.87 (d, 1H, J = 2.0 Hz), 8.55 (s, 1H), 8.17 (d, 1H, J = 2.0 Hz), 7.94 (d, 1H, J = 8.8 Hz), 7.85 (dd, 1H, J = 8.8, 2.0 Hz), 7.70 (s, 1H), 7.66 (d, 1H, J = 8.0 Hz), 7.60 (d, 1H, J = 8.0 Hz), 7.42-7.35 (m, 1H), 6.89 (dq, 1H, J = 16.4, 7.2 Hz), 5.45 (d, 1H, J = 4.4 Hz), 4.95 (m, 1H), 2.45 ( s, 3H), 1.46 (d, 3H, J = 6.4 Hz).

Compound 305 Preparation of (E) -N- (3- ((2-hydroxyethoxy) methyl) quinolin-7-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide To a stirred solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (46 mg, 0.20 mmol) in CH 2 Cl 12 (5 mL) and DMF (1 drop) at 0 ° C oxalyl chloride (25 pL, 0.30 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the acid chloride obtained was reacted with 3 - ((2- (tert-butyldimethylsilyloxy) ethoxy) methyl) quinolin-7-amine (66 mg, 0.20 mmol) in CH2Cl2 (3 mL) and pyridine (3 mL) at room temperature overnight. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel to give the intermediate as a white solid (100 mg, m / z = 545.0 (M + 1), room temperature = 3.88 min). The intermediate was dissolved in MeOH (10 mL) and concentrated HC1 (1 mL) was added. The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was treated with aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried (Na2SC > 4), and concentrated. The residue was purified by column chromatography on silica gel using 0-2% MeOH / EtOAc as eluent to give the product (67 mg, 75%) as a solid, m / z = 431.1 (M + l); room temperature = 2.33 min. XH NMR (400 MHz, d6-DMSO) d 10.73 (s, 1H), 8.84 (d, 1H, J = 2.4 Hz), 8.57 (s, 1H), 8.23 (d, 1H, J = 1.2 Hz), 7.96 (d, 1H, J = 8.8 Hz), 7.87 (dd, 1H, J = 8.8, 1.6 Hz), 7.70 (s, 1H), 7.67 (d, 1H, J = 8.0 Hz), 7.60 (d, 1H, J = 8.0 Hz), 7.42-7.35 (m, 1H), 6.89 (dq, 1H, J = 16.4, 7.2 Hz), 4.70 (s, 3H), 3.61-3.52 (m, 4H), 2.45 (s, 3H) ).

Compound 306 Preparation of (E) -2-methyl-N- (8-oxo-5, 6-7,8-tetrahydronaphthalen-2-yl) -4 (3, 3, 3-trifluoroprop-1-enyl) benzamide acid To a stirred solution of 7-Amino-3,4-dihydro-2H-naphthalen-1-one (52 mg, 0.32 mmol) in anhydrous DMF (2 mL) was added a stirred solution of 4- ((E) - 3, 3, 3-trifluoroprop-1-enyl) -2-methylbenzoic acid (75 mg, 0.32 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol), 0.5M l- hydroxy-7-azabenzotriazole in DMF (0.8 mL, 0.4 mmol) and N, N-diisopropylethylamine (0.23 mL, 1.3 mmol) in DMF (2 mL). The mixture was stirred for 16 hours at room temperature then poured into saturated NaHCO 3 solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried (MgSO4) filtered and concentrated under vacuum. Purification by column chromatography on silica gel using 0-30% EtOAc / hexane gave the product (43 mg, 35%) as a solid, m / z = 374 (M + 1); room temperature = 1.75 min. 1H NMR (400MHz; CDC13) d 8.19 (d, 1H), 7.85 (d, 1H), 7.57 (s, 1H), 7.52 (d, 1H), 7.37-7.35 (m, 2H), 7.32 (d, 1H) ), 7.14 (dd, 1H), 6.31-6.22 (m, 1H), 2.96 (t, 2H), 2.67 (t, 2H), 2.53 (s, 3H), 2.18-2.12 (m, 2H).

Compound 307 Preparation of (E) -N- (8-hydroxy-5,6,7,8-tetrahydronaphthylene-2-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) acid benzamide To a stirred solution of (E) -2-Methyl-N- (8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) -4- (3, 3, 3-trifluoroprop-1-enyl) Benzamide (35 mg, 0.09 mmol) in EtOH (2 mL) was added sodium borohydride (10.6 mg, 0.28 mmol). The mixture was stirred for 16 hours at room temperature then poured into saturated NaHCO 3 solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried (MgSO 4) filtered and concentrated under vacuum to give the product (8.5 mg, 24%) as a solid, m / z = 376 (M +. l); room temperature = 3.33 min. 1H NMR (400MHz; d6-DMS0) d 10.17 (s, 1H), 7.81 (d, 1H), 7.63 (d, 1H), 7.61 (d, 1H), 7.49-7.46 (m, 2H), 7.38-7.33 (dd, 1H), 7.01 (d, 1H), 6.93-6.84 (m, 1H), 5.13 (d, 1H), 4.56 -4.51 (m, 1H), 2.71 - 2.59 (m, 2H), 2.39 (s) , 3H), 1.91 - 1.85 (m, 2H), 1.69 - 1.63 (m, 2H).

Compound 308 Preparation of (E) -N- (3- (1, 2-dihydroxyethyl) quinolin-7-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide acid To a stirred solution of 4- ((£) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (170 mg, 0.73 mmol) in CH2C12 (10 mL) and DF (1 drop) at 0 ° C oxalyl chloride (93 μL, 1.1 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the acid chloride obtained was dissolved in CH2C12 (5 mL) and added to a solution of 1- (7-aminoquinolin-3-yl) ethane-1,2-diol (150 mg, 0.73. mol) in CH2C12 (5 mL) and pyridine (10 mL) at -30 ° C. The mixture was warmed to room temperature, stirred overnight, then diluted with EtOAc (150 mL). The organic layer was washed with NaHCC > 3 aqueous and brine, dried (Na2SC > 4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 0-15% MeOH / EtOAc as eluent for the product (210 mg, 69%) as a solid, m / z = 417.4 (M + 1); room temperature = 2.12 min. XH NMR (400 MHz; d6-DMSO) d 10.69 (s, 1H), 8.84 (d, 1H, J = 2.0 Hz), 8.55 (s, 1H), 8.18 (d, 1H, J = 1.6 Hz), 7.94 (d, 1H, J = 8.8 Hz), 7.85 (dd, 1H, J = 8.8, 1.6 Hz), 7.70 (s, 1H), 7.66 (d, 1H, J = 8.4 Hz), 7.60 (d, 1H, J = 7.6 Hz), 7.42-7.35 (m, 1H), 6.88 (dq, 1H, J = 16.4, 7.2 Hz), 5.54 (d, 1H, J = 4.4 Hz), 4.86 (t, 1H, J = 5.6 Hz), 4.75 (dd, 1H, J = 10.0, 5.6 Hz), 3.65-3.52 (m, 2H), 2.45 (s, 3H).

Compound 309 Preparation of (E) -N- (7-hydroxy-5,6,7,8-tetrahydronaphol-l-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) acid benzamide To a stirred solution of 8-Amino-1,2,4,4-tetrahydronaphthalen-2-ol (116 mg, 0.71 mmol) in anhydrous DMF (6 mL) was added a solution containing 4- ((E) - acid) 3, 3, 3-trifluoroprop-l-enyl) -2-methylbenzoic acid (196 mg, 0. 85 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (164 mg, 0.85 mmol), 0.5M l-hydroxy-7-azabenzotriazole in DMF (1.7 mL, 0.85 min), 4-N, N-dimethylaminopyridine (4 mg, 0.04 mmol) and N, N-diisopropylethylamine (0.30 mL, 1.7 branch) in anhydrous DMF (4 mL). The reaction was stirred for 16 hours at room temperature then poured into a saturated NaHCO 3 solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried (MgSC), filtered and concentrated under vacuum. Purification by column chromatography on silica gel using 0-4% MeOH / CH2C12 as eluent gave the title compound (88 mg, 33%) as a solid, m / z = 376 (M + 1); room temperature = 3.13 min. XH NR (400MHz; d6-DMSO) d 9.72 (s, 1H), 7.65-7.53 (m, 2H), 7.54 (d, 1H), 7.36 (d, 1H), 7.20 (d, 1H), 7.12 (t , 1H), 7.00 (d, 1H), 6.89-6.81 (m, 1H), 4.83 (d, 1H), 3.90 (br.s, 1H), 2.98-2.92 (m, 2H), 2.91-2.87 (m , 1H), 2.45 (s, 3H), 1.90-1.88 (m, 1H), 1.62-1.59 (m, 1H).

Compound 310, Preparation of (E) -N- (7-hydroxymethyl-7,8-dihydro-5H-pyran (4, 3-b) pyridin-3-yl) -2-methyl-4- (3,3 , 3-trifluoroprop-l-enyl) benzamide To a stirred solution of (3-amino-7,8-dihydro-5-yl-pyrano [4, 3-α] pyridin-7-yl) methanol (35 mg, 0.19 mmo]) in anhydrous DMF (2 mL) was added a solution containing 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (54 mg, 0.23 mmo]), N- (3-dimethylaminopropyl) -N 'hydrochloride -ethylcarbodiimide (45 mg, 0.23 mmol), 0.5M l-hydroxy-7-azabenzotriazole in DMF (0.5 mL, 0.23 mmol), 4-N, N-dimethylaminopyridine (1 mg, 0.008 mmol) and?,? - diisopropylethylamine ( 0.14 mL, 0.78 mmol) in anhydrous DMF (2 mL). The mixture was stirred for 16 hours at room temperature then poured into a saturated NaHCO 3 solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried (MgSO4) filtered and concentrated under vacuum. Purification by column chromatography on silica gel using 0-5% MeOH / CH 2 Cl 2 as eluent gave the product (19 mg, 23%) as a solid, m / z = 393 (M + 1); room temperature = 2.29 min. XH NMR (400MHz; CDC13) d 8.37 (s, 1H), 8.18 (s, 1H), 7.60 (br. S, 1H), 7.54 (d, 1H), 7.37 (m, 2H), 7.14 (d, 1H) ), 6.31 - 6.23 (m, 1H), 4.91 (q, 2H), 3.96 - 3.91 (m, 1H), 3.85 (dd, 1H), 3.77 - 3.72 (m, 1H), 2.94 - 2.80 (m, 2H) ), 2.52 (s, 3H).

Compound 311 Preparation of (E) -N- (7-hydroxy-l, 8-naphthyridin-2-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide acid To a stirred solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (90 mg, 0.4 mmol) in CH 2 Cl 12 (5 mL) and DMF (1 drop) at 0 ° C oxalyl chloride (50 pL, 0.6 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the acid chloride obtained was reacted with 7-amino-l, 8-naphthyridin-2-ol (63 mg, 0.4 mmol) (prepared according to Stuk, TL et al, Org. Re. Dev. 2003, 7, 851) in pyridine (5 mL) at 110 ° C overnight. The mixture was concentrated under vacuum and the residue treated with aqueous NaHCO3 solution and filtered. The solid was washed with water, EtOAc, eOH and dried under vacuum to give the product (65 mg) as a solid, m / z = 374.0 (M + 1); room temperature = 3.03 min. XH NMR (400 MHz, d6-DMSO) d 11.92 (s, 1H), 11.04 (s, 1H), 8.14 (d, 1H, J = 8.4 Hz), 8.03 (d, 1H, J = 8.4Hz), 7.89 (d, 1H, J = 9.6 Hz), 7.64 (s, 1H), 7.60 (d, 1H, J = 8.0 Hz), 7.53 (d, 1H, J = 8.0 Hz), 7.40-7.32 (m, 1H) , 6.86 (dq, 1H, J = 16.4, 7.2 Hz), 6.46 (dd, 1H, J = 9.6, 1.6 Hz), 2.40 (s, 3H).

Compound 312 Preparation of (E) -2-methyl-N- (5,6,7,8-tetrahydroquinolin-3-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide acid stirred solution of 4- ((£) -3,3,3-trifluoroprop-l-enyl) -2-methylbenzoic acid (230 mg, 1.0 mmol) in CH2C12 (10 mL) and D F (1 drop) at 0 ° C was added oxalyl chloride (130 μl, 1.5 mmol). The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the acid chloride obtained was dissolved in CH2C12 (2 mL) and added to a solution of 5, 6, 7, 8-tetrahydroquinolin-3-amine (150 mg, 1.0 mmol) (prepared from according to Skupinska, KA et al, J. Org Chem. 2002, 67, 7890) in CH2C12 (5 mL) and pyridine (5 mL). The mixture was stirred at room temperature overnight, and then diluted with EtOAc (100 mL). The organic layer was washed with aqueous NaHC03 and brine, dried (Na2SC >4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product (240 mg, 65%) as a solid, m / z = 361.8 (M + 1); room temperature = 2.24 min. XH NR (400 MHz; d6-D SO) d 10.41 (s, 1H), 8.55 (d, 1H, J = 2.0 Hz), 7.88 (d, 1H, J = 2.0 Hz), 7.67 (s, 1H), 7.63 (d, 1H, J = 7.6 Hz), 7.53 (d, 1H, J = 7.6 Hz), 7.39-7.32 (m, 1H), 6.87 (dq, 1H, J = 16.4, 7.2 Hz), 2.80-2.72 (m, 4H), 2.40 (s, 3H), 1.86-1.70 (m, 4H).

Preparation of (E) -N- ((S) -7-hydroxy-5, 6, 7, 8-tetrahydronaff ilen-1-yl) -2-methyl-4- (3,3, 3-trifluoroprop-1- enyl) benzamide A sample of racemic (E) -N- (7-hydroxy-5, 6, 7, 8-tetrahydronaphthylene-l-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide (520mg) was purified using chiral HPLC, giving the product (250 mg) which was arbitrarily assigned stereochemistry (S) (ie the stereochemistry has not been clearly assigned). m / z = 376 (M + 1); room temperature = 3.13 min. 1H NMR (400MHz; CDC13) d 7.76 (d, 1H), 7.55 (d, 1H), 7.37-7.35 (m, 2H), 7.24-7.20 (m, 2H), 7.15 (dd, 1H), 7.02 (d , 1H), 6.31-6.22 (m, 1H), 4.24-4.18 (m, 1H), 3.10-2.97 (m, 2H), 2.93-2.86 (m, 1H), 2.62-2.54 (m, 1H), 2.56 (s, 3H), 2.10-2.04 (m, 1H), 1.87-1.79 (m, 1H).

Compound 314 Preparation of (E) -N- ((R) -7-hydroxy-5,6,7,8-tetrahydronaphthylene-1-yl) -2-methyl-4- (3,3,3-trifluoroprop-1) -enil) benzamide A sample of racemic (E) -N- (7-hydroxy-5, 6, 7, tetrahydronaphthylene-l-yl) -2-methyl-4- (3,3, 3-trifluoroprop-1-enyl) benzamide (520mg ) was purified using chiral HPLC, yielding the product (250 mg) which was arbitrarily assigned stereochemistry (R) (ie the stereochemistry has not been clearly assigned). m / z = 376 (M + 1); room temperature. = 3.13 min. XH NMR (400MHz; CDC13) d 7.76 (d, 1H), 7.55 (d, 1H), 7.37-7.35 (m, 2H), 7.24-7.21 (m, 2H), 7.15 (dd, 1H), 7.02 (d , 1H), 6.31-6.23 (m, 1H), 4.24-4.18 (m, 1H), 3.11-2.98 (m, 2H), 2.92-2.84 (m, 1H), 2.62-2.58 (m, 1H), 2.55 (s, 3H), 2.11-2.04 (m, 1H), 1.83-1.78 (m, 1H).

Compound 315 Preparation of (E) -N- (6-hydroxy-5,6,7,8-tetrahydroquinolol-3-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide To a stirred solution of 3-amino-5,6,7,8-tetrahydroquinolin-6-ol (160 mg, 0.97 mmol) in anhydrous acetonitrile (2 mL) was added a solution containing 4- ((E) - acid. 3, 3, 3-trifluoroprop-l-enyl) -2-methylbenzoic acid (236 mg, 1.0 mmol), N- (3-dimethylaminopropyl) -? ethylcarbodiimide (224 mg, 1.17 mmol), 0.5M l-hydroxy-7-azabenzotriazole in DMF (2.34 mL, 1.17 mmol), 4-N, N-dimethylaminopyridine (6 mg, 0.05 mmol) and N, N-diisopropylethylamine ( 0.41 mL, 2.3 mmol) in anhydrous acetonitrile (2 mL). The mixture was stirred for 16 hours at room temperature then poured into a saturated NaHCO 3 solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried (MgSO 4) filtered and concentrated under vacuum. Purification by column chromatography on silica gel using 0-5% MeOH / CH2C12 as eluent gave the product (55 mg, 14%) as a solid, m / z = 377 (M + 1); room temperature = 1.97 min. XH NMR (400MHz; d6-DMSO) d 10.41 (s, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.67 (s, 1H), 7.63 (d, 1H), 7.53 (d, 1H) ), 7.36 (dd, 1H), 6.92-6.82 (m, 1H), 4.86 (d, 1H), 4.01-3.98 (m, 1H), 2.97-2.86 (m, 2H), 2.80-2.72 (m, 1H) ), 2.68-2.62 (m, 1H), 2.40 (s, 3H), 1.96-1.92 (m, 1H), 1.82-1.76 (m, 1H).

Compound 316, Preparation of (E) -2-methyl-N- (quinolin-3-yl) -4- (3,3, 3-trifluoro-2-methylprop-1-enyl) benzamide To a stirred solution of (E) -2-methyl-4- (3,3,3-trifluoro-2-methylprop-1-enyl) benzoic acid (90 mg, 0.4 mmol) in CH 2 Cl 12 (10 mL) and DMF ( 1 drop) at 0 ° C oxalyl chloride (47 μl, 0.6 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the acid chloride obtained in CH 2 Cl 2 (1 mL) was added to a solution of 3-quinolinamine (53 mg, 0.4 mmol) in CH 2 Cl 2 (2 mL) and pyridine (2 mL). The mixture was stirred at room temperature overnight, and then diluted with EtOAc (100 mL). The organic layer was washed with aqueous NaHCO 3 and brine, dried (Na 2 SO 4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product (125 mg, 90%) as a solid, m / z = 371.1 (M + 1); room temperature = 3.49 min. 1 H NMR (400 MHz, d 6 -DMSO) d 10.86 (s, 1 H), 9.04 (d, 1 H, J = 2.4 Hz), 8.89 (d, 1 H, J = 2.4 Hz), 7.98 (d, 2 H, J = 8.4 Hz), 7.70-7.57 (m, 3H), 7.45 (s, 1H), 7.44 (d, 1H, J = 6.4 Hz), 7.22 (s, 1H), 2.47 (s, 3H), 2.05 (s, 3H).

Compound 317 Preparation of (E) -N- (7- (Hydroxymethyl) -1,5-naphthyridin-3-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-) To a stirred solution of 4- ((£) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (98 mg, 0.43 mmol) in CH2C12 (5 mL) and DMF (1 drop) at 0 ° C oxalyl chloride (87 mg, 0.7 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 2 h. The solvent was removed under vacuum and the resulting acid chloride was reacted with (7-amino-1, 5-naphthyridin-3-yl) methanol (30 mg, 0.17 mmol) in CH2C12 (2 mL) and pyridine (2 mL). ) at 50 ° C overnight. The mixture was concentrated under vacuum and the residue was dissolved in MeOH (10 mL) and potassium carbonate (250 mg, 1.8 mmol) was added. The mixture was stirred at room temperature for 4 h then concentrated under vacuum. The residue was treated with water (10 mL) and EtOAc (100 mL). The aqueous and organic layers were partitioned and the organic layer was washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography to give the product (32 mg) as a solid. m / z = 388.1 (M + l); room temperature = 2.69 min. XH NR (400 MHz, d6-DMSO) d 10.99 (s, 1H), 9.17 (d, 1H, J = 2.4 Hz), 8.94 (d, 1H, J = 1.6 Hz), 8.91 (d, 1H, J = 2.4 Hz), 8.24 (s, 1H), 7.71 (s, 1H), 7.70-7.65 (m, 2H), 7.43-7.36 (m, 1H), 6.89 (dq, 1H, J = 16.4, 6.8 Hz), 5.55 (t, 1H, J = 5.6 Hz), 4.77 (d, 2H, J = 5.6 Hz), 2.46 (s, 3H).

Compound 318 Preparation of (E) -2-metii-N- (1, 5-naphidin-3-yl) -4- (3, 3, 3-trifluoroprop-1-enyl) benzamide To a stirred solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (120 mg, 0.52 mmol) in CH 2 Cl 12 (10 mL) and DMF (1 drop) at 0 ° C oxalyl chloride (66 iL, 0.77 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the resulting acid chloride in CH 2 Cl 2 (1 mL) was added to a solution of 1,5-naphthyridin-3-amine (75 mg, 0.52 mmol) in CH 2 Cl 2 (2 mL) and pyridine (2 mL). mL). The mixture was stirred at room temperature overnight, and then diluted with EtOAc (150 mL). The organic layer was washed with aqueous NaHC03 and brine, dried (Na2SC >), and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product (110 mg, 58%) as a solid, m / z = 358.0 (M + 1); room temperature = 2.96 min. XH NMR (400 MHz, d6-DMSO) d 11.02 (s, 1H), 9.19 (d, 1H, J = 2.4 Hz), 8.98 (dd, 1H, J = 4.4, 1.6 Hz), 8.92 (d, 1H, J = 2.0 Hz), 8.39 (dq, 1H, J = 8.0, 0.8 Hz), 7.72-7.65 (m, 4H), 7.43-7.36 (m, 1H), 6.90 (dq, 1H, J = 16.0, 6.8 Hz ), 2.47 (s, 3H).

Compues or 319 Preparation of (E) -2-methyl-N- (1, 8-naphthyridin-2-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide acid To a stirred solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (160 mg, 0.7 mmol) in CH 2 Cl 12 (10 mL) and DMF (1 drop) at 0 ° C oxalyl chloride (87 μL, 1.0 mol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the resulting acid chloride in CH2Cl2 (1 mL) was added to a solution of 1,8-naphthyridin-2-amine (100 mg, 0.7 mmol) in CH2C12 (5 mL) and pyridine (5 mL). ). The mixture was stirred at room temperature overnight, and then diluted with EtOAc (150 mL). The organic layer was washed with aqueous NaHCO 3 and brine, dried (Na 2 SO 4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product (55 mg, 22%) as a solid, m / z = 358.0 (M + 1); room temperature = 2.90 minutes. 1ti NMR (400 Hz, d6-DMSO) d 11.50 (s, 1H), 9.02 (dd, 1H, J = 4.4, 2.0 Hz), 8.51 (s, 2H), 8.44 (dd, 1H, J = 8.0, 2.0 Hz), 7.66 (s, 1H), 7.62 (s, 2H), 7.56 (dd, 1H, J = 8.0, 4.4 Hz), 7.41-7.34 (m, 1H), 6.89 (dq, 1H, J = 16.4, 6.8 Hz), 2.46 (s, 3H).

Compound 320 Preparation of (E) -N- (7- (1-hydroxyethyl) -1,5-naphthyridin-3-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) acid benzamide To a stirred solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (130 mg, 0.58 mmol) in CH2C12 (5 mL) and DMF (1 drop) at 0 ° C oxalyl chloride (74 μL, 0.87 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the resulting acid chloride in CH2Cl2 (1 mL) was added to a solution of 1- (7-amino-1, 5-naphthyridin-3-yl) ethanol (110 mg, 0.58 mmol) in CH2C12. (2 mL) and pyridine (2 mL). The mixture was stirred at room temperature overnight, and then diluted with EtOAc (150 mL). The organic layer was washed with aqueous NaHCO 3 and brine, dried (Na 2 SO 4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product (120 mg, 51%) as a solid, m / z = 401.8 (M + 1); room temperature = 2.77 minutes. 1 H NMR (400 MHz; d 6 -DMSO) d 10.99 (s, 1 H), 9.17 (d, 1 H, J = 2.4 Hz), 8.99 (d, 1 H, J = 2.0 Hz), 8.90 (d, 1 H, J = 1.2 Hz), 8.24 1H, J = 1.2 Hz), 7.72 (s, 1H), 7.70-7.64 (m, 2H), 7.43-7.35 (m, 11-1), 6.89 (dq, 1H, J = 16.0, 4.8 Hz), 5.56 (d, 1H, J = 4.4 Hz), 5.02 (m, 1H), 2.46 (s, 311), 1.49 (d, 3H, J = 6.4 Hz).

Compound 321 Preparation of (E) -2-methyl-N- (1, 8-naphthyridin-3-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide acid To a stirred solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (160 mg, 0.69 mmol) in CH 2 Cl 2 (5 mL) and DMF (1 drop) at 0 ° C oxalyl chloride (87 L, 1.0 mmol) was added. The mixture was stirred at 0 ° C for 1 h and then warmed to room temperature and stirred for 3 h. The solvent was removed under vacuum and the resulting acid chloride in CH2C12 (1 mL) was added to a solution of 1,8-naphthyridin-3-amine (100 mg, 0.69 mmol) in CH2C12 (2 mL) and pyridine (2 mL). ). The mixture was stirred at room temperature overnight, and then diluted with EtOAc (150 mL). The organic layer was washed with aqueous NaHCO 3 and brine, dried (Na 2 SO), and concentrated under vacuum. The residue was purified by column chromatography to give the product (15 mg) as a solid, m / z = 358.0 (M + 1); room temperature = 2.88 min. 1H NR (400 MHz; d <SO) d 11.00 (s, 1H), 9.18 (d, 1 H, J = 2.8 Hz), 9.01 (d, 1H, J = 2.8 Hz), 8.99 (dd, 1H , J = 4.0, 1.6 Hz), 8.52 (dd, 1H, J = 8.0, 1.6 Hz), 7.72 (s, 1H), 7.69 (AB, 1H, J = 8.0 Hz), 7.66 (AB, 1H, J = 8.0 Hz), 7.63 (dd, 1H, J = 8.0, 4.4 Hz), 7.42-7.35 (m, 1H), 6.90 (dq, 1H, J = 16.4, 7.2 Hz), 2.46 (s, 3H).

Compound 322 Preparation of (E) -N- (1-acetyl-l, 2,3,4-tetrahydroquinolin-7-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) acid benzamide A mixture of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (150 mg, 0.65 mol), 1-hydroxybenzotriazole hydrate (100 mg, 0.65 mol), hydrochloride N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (250 mg, 1.3 mmol), 1- (7-amino-3,4-dihydroquinolin-1 (2H) -yl) ethanone (120 mg, 0.65 mmol), N , N-diisopropylethylamine (230 μg, 1.3 mol) in CH2C12 (5 mL) was stirred at room temperature over the weekend. The mixture was diluted with EtOAc (100 mL), washed with brine, dried (Na 2 SO), and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the product (160 mg, 60%) as a solid, m / z = 403.1 (M + 1); room temperature = 3.03 min. XH NMR (400 MHz; d6-DMSO) d 10.33 (s, 1?), 7.79 (brs, lH), 7.66 (s, 1H), 7.62 (d, 1H, J = 8. 0 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.48 (dd, 1H, J = 8.4, 2.0 Hz), 7.39-7.32 (m, 1H), 7.14 (d, 1H, J = 8.4 Hz), 6.86 (dq, 1H, J = 16.4, 6.8 Hz), 3.67 (t, 2H, J = 6.4 Hz), 2.67 (t, 2H, J = 6.4 Hz), 2.39 (s, 3H), 2.18 (s, 3H), 1.86 ( m, 2H).

Compound 324 Preparation of (E) N- (7-Acetyl-1, 5-naphidin-3-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide acid A mixture of (E) -N- (7- (1-hydroxyethyl) -1,5-naphthyridin-3-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide ( 45 mg, 0.11 mmol), 15% by weight of Dess-Martin periodinane (950 mg, 0.34 mol) solution in CH2C12, and CH2C12 (5 mL) was stirred at room temperature for 3 h. the solvent was removed under vacuum and the residue was treated with aqueous NaHC03 solution and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 0-50% THF / CH2C12 as eluent to give the product (40 mg) as a solid, m / z = 400.0 (+ l); room temperature = 3.14 min. XH NMR (400 MHz; de-D SO) d 11.18 (s, 1H), 9.39 (d, 1H, J = 2.4 Hz), 9.29 (d, 1H, J = 2.4 Hz), 8.99 (d, 1H, J = 2.0 Hz), 8.91 (d, 1H, J = 2.0 Hz), 7.73 (s, 1H), 7.69 (s, 2H), 7.43-7.36 (m, 1H), 6.91 (dq, 1H, J = 16.4, 6.8 Hz), 2.78 (s, 3H), 2.47 (s, 3H).

Compound 325 Preparation of (E) -2-methyl-N- (quinoxalin-6-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide acid Oxalyl chloride (60 μ ?, 0.7 mmol) was added to a stirred solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (80 mg, 0.3 mmol) and DMF (1 drop) in THF (3 mL) at room temperature. The mixture was stirred at room temperature for 90 min then the solvent was removed under vacuum. The residue (acid chloride) was dissolved in CH2Cl2 and quinoxaline-6-amine (66 mg, 0.45 mmol) was added, followed by Et3N (100 μl, 1.0 mmol) and 4-N, N-dimethylaminopyridine (cat. ). The mixture was stirred at room temperature over the weekend then the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel using 1-5% MeOH / CH2Cl2 as eluent to give a solid (62 mg). The solid was triturated with hexane to give the product, m / z = 358.3 (M + 1). XH NR (400 MHz, d6-DMSO) d 10.89 (s, 11-1), 8.91 (d, 1H), 8.85 (d, 1H), 8.67 (s, 1H), 8.08 (s, 2H), 7.61- 7.71 (m, 3H), 7.38 (dd, 1H), 6.86-6.92 (m, 1H), 2.48 (s, 3H).

Compound 326 Preparation of (E) -N- (7- (2-hydroxypropan-2-yl) -1,5-naphidin-3-yl) -2-methyl-4- (3,3,3-trifluoroprop) acid -1-enyl) benzamide To a stirred solution of (E) -N- (7-acetyl-l, 5-naphthyridin-3-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide (30 mg ) in THF (15 mL) at -78 ° C under N2 a solution of eLi in THF (1.6, 0.3 mL) was added. The mixture was stirred at -78 ° C for 30 min and then quenched by the addition of sat. NH 4 Cl solution. watery The mixture was extracted with EtOAc (50 mL x 2) and the combined organic layers were washed with brine, dried (Na 2 SO 4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product (14 mg) as a solid, m / z = 416.1 (+ 1); room temperature = 2.79 min. * H NMR (400 MHz; d6-DMSO) d 10.98 (s, 1H), 9.17 (d, 1H, J = 2.4 Hz), 9.13 (d, 1H, J = 2.0 Hz), 8.89 (d, 1H, J = 2.0 Hz), 832 (d, 1H, J = 2.4 Hz), 7.72 (s, 1H), 7.70-7.65 (m, 2H), 7.42-7.35 (m, 1H), 6.91 (dq, 1H, J = 16.4, 6.8 Hz), 5.46 (s, 1H), 2.46 (s, 3H), 1.58 (s, 6H).

Compound 327 Preparation of (E) -2-methyl-N- (1, 7-naphthyridin-8-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide acid Oxalyl chloride (93 μl, 1.1 mmol) was added to a stirred suspension of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (230 mg, 1.0 mmol) in CH2Cl2 (5 mL) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes, then allowed to warm to room temperature and stirred for 2 h, after which oxalyl chloride (50 pL, approximately 0.5 mmol) was added and the mixture was stirred. for 30 min. Further, the solvent was removed under vacuum and the residue was re-dissolved in CH2C12 (5 mL) and cooled to 0 ° C. Et 3 N (280 L, 2.0 mmol) was added followed by 4-N, N-dimethylaminopyridine (cat. Amount) and 1,7-naphthyridin-8-amine (160 mg, 1.1 mmol). The mixture was stirred at 0 ° C for 1 h then allowed to warm to room temperature and stirred overnight. CH2Cl2 (30 mL) was added and the mixture was washed with H20 (1 x 20 mL). The aqueous layer was extracted with CH2C12 (1 x 20 mL) and the combined organic extracts were dried (MgSO4) filtered and concentrated under vacuum to leave an unpurified solid. The solid was purified by column chromatography on silica gel using 20-50% EtOAc / hexane as eluent to give a solid (2nd column product) which was further purified by recrystallization from a mixture of MeOH / H20 to give the product (100 mg, 30%) as a solid. m / z = 359.1 (M + 2); room temperature = 2.79 min. XH NMR (400 MHz, CDC13) 8 10.40 (1H, br s), 8.85-8.88 (1H, m), 8.49 (1H, d), 8.17 (1H, d), 7.72 (1H, d), 7.67 ( 1H, m), 7.39-7.44 (3H, m), 7.16 (1H, d), 6.25-6.34 (1H, m), 2.65 (3H, s).

Compound 401 Preparation of (E) -N- (1-methanesulfonyl-2,3-dihydro-lH-indol-6-yl] -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) acid benzamide 4- ((E) -3,3,3-Trifluoroprop-1-enyl) -2-methylbenzoic acid (104 mg, 0.45 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (260 mg, 1.4 mmol), 1-hydroxybenzotriazole hydrate (104 mg, 0.68 mmol) and 1-methanesulfonyl-2,3-dihydro-lH-indol-6-ylamine (190 mg, 0.90 mmol) were combined in DMF (40 mL) and it was stirred at room temperature overnight. The mixture was then partitioned between EtOAc and saturated NaHCO 3 and the organic layer was washed with H 2 O and brine, then dried (Na 2 SO 4) filtered and the solvent removed under vacuum to leave an oil without purification. The oil was purified by column chromatography on silica gel using 0-50% EtOAc / hexane as eluent to give the product (48 mg, 24%) as a solid, m / z = 425.2 (M + 1). lti NMR (400 MHz; d6-D SO) d 10.45 (1H, s), 7.78 (1H, d), 7.67-7.6 (2H, m), 7.5 (1H, d), 7.44 (1H, dd), 7.35 (1H, dd), 7.25 (1H, d), 6.85 (1H, m), 3.95 (2H, m), 3.15 (2H, m), 3.0 (3H, s), 2.4 (3H, s).

Compound 402 Preparation of the acid (E) N = (1-cyclopropanecarbonyl-2,3-dihydro-lH-indol-6-yl) -2-methyl-4- (3,3,3-trifluoro-prop-1-enyl) benzamide to . 4- ((E) -3,3,3-Trifluoroprop-l-enyl) -N- (indolin-6-yl) -2-methylbenzamide (E) -N- (l-Acetylindolin-6-yl) -2 methyl-4- (3, 3, 3-trifluoroprop-1-enyl) benzamide (see O, 200 mg, mmol) was placed in MeOH (40 mL) and 1 N HCl (10 mL). The mixture was heated to reflux and stirred for 4 days (note: Decytilation indicated LC / MS analysis was not complete). The mixture was neutralized, then extracted with EtOAC. Concentration of the organic layer gave a solid (200 mg). The solid was dissolved in a NaOMe solution in McOH (25% w / v, 20 mL) and refluxed for 14 h. After it was allowed to cool to room temperature, the volume of the mixture was reduced to about half by the concentration under vacuum. H20 was added and the mixture was extracted with EtOAc. The organic extract was washed with brine, dried and concentrated under vacuum to give the product as a solid. The material was used without further purification in the next step, m / z = 347.1 (M + l). b. (E) -N- (l-Cyclopropancarbonyl-2,3-dihydro-lH-indol-6-yl) -2-methyl-4- (3,3,3-trifluoroprop-l-enyl) benzamide 4- (( E) -3,3,3-trifluoroprop-l-enyl) -N- (indolin-6-yl) -2-methylbenzamide without purification (200 mg, 0.58 mmol) was placed in CH2C12 (50 mL). N, N-Di-iso-propylethylamine (202 L, 1.16 mmol) was added, followed by the addition of cyclopropanecarbonyl chloride (64 iL, 0.69 mmol). The mixture was stirred overnight at room temperature, then divided between H20 and CH2C12. The organic layer was dried and concentrated under vacuum to leave an unpurified residue. The residue was purified by column chromatography on silica gel to give a solid (100 mg, that is about 20% diacetylated material and about 80% of the title compound by LC / S). Further purification by preparative high performance liquid chromatography gave the product (75 mg, 37%) as a solid, m / z = 415.2 (M + 1). 1 H NMR (400 MHz; d 6 -DMSO) d 10.3 (1H, s), 8.45 (1H, s), 7.7-7.55 (2H, m), 7.49 (1H, d), 7.42-7.32 (2H, m), 7.27 (1H, d), 6.85 (1H, m ), 4.3 (2H, m), 3.15 (2H, m), 2.4 (3H, s), 1.9 (1H, m), 0.95-0.83 (4H, m).

Compound 403 Preparation of 4- ((E) - (3,3,3-trifluoroprop-1-enyl) -N- (2- (1-hydroxyethyl) benzo [d] thiazol-5-yl) -2-methylbenzamide 4- ((E) -3,3,3-Trifluoroprop-1-enyl) -N- (2-formylbenzo [d] thiazol-5-yl) -2-methylbenzamide (300 mg, 0.8 mmol) was placed in THF (30 mL) and cooled to -78 ° C under a nitrogen atmosphere. A solution of MeLi in Et20 (1.6 M, 1.6 mL, 2.6 mmol) was added and the mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of aqueous NH 4 Cl and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried and concentrated under vacuum to leave an oil without purification. Purification by column chromatography on silica gel using 0-50% EtOAc / hexane as eluent gave a solid (70 mg), which was further purified by preparative high performance liquid chromatography to give the product (32 mg, %) as a solid (approximately 90% pure), m / z = 407.1 (M + l). 1ti NMR (400 MHz; d6-DMSO) d 10.5 (1H, s), 8.5 (1H, s), 8.0 (1H, d), 7.73-7.55 (4H, m), 7.35 (1H, dd), 6.85 (1H, m), 6.33 (1H, d), 5.05 (1H, m), 2.4 (3H, s), 1.9 (3H, d).

Compound 404 Preparation of (E) -N- (2- (2-hydroxyethyl) -1,3-dioxoisoindolin-5-yl) -2-yl- (3,3,3-trifluoroprop-1-enyl) benzamide acid Compound 405 A mixture of 4- ((E) -3,3,3, trifluoroprop-1-enyl) -2-methylbenzoic acid (40 mg, 0.17 mol), 5-amino-2- (2-hydroxyethyl) isoindoline 1,3-dione (43 mg, 0.21 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol), 4-N, N, -dimethylaminopyridine (21 mg, 0.17 mmol) and Et 3 N (48 μ?, 0.35 mmol) were combined in CH 2 Cl 2 and stirred overnight. H20 was added and the aqueous and organic layers were divided. The aqueous layer was extracted with CH2Cl2 (x3) and the combined organic extracts were washed with brine (x1), dried (Na2SO4) filtered and the solvent removed under vacuum to leave an unpurified residue. The residue was purified by column chromatography on silica gel using 0-30% EtOAc / hexanes as eluent to give a solid (17 mg). The solid was triturated with hexanes and filtered to give the product (17 mg, 23%) as a solid, m / z = 419.5 (M + 1). XH NMR. (400 MHz, CDC13) d 7.90 (1H, d), 7.61 (1H, d), 7.26-7.31 (2H, m), 7.12 (1H, dd), 7.03 (1H, d), 6.82 (1H, dd) , 6.21-6.29 (1H, m), 4.51 (2H, t), 4.32 (1H, br. S), 4.05 (2H, t), 2.57 (3H, s).

Preparation of (E) -N- [1- (2, 2-dimethyl-propionyl-2,3-dihydro-lH-indol-6-yl] -2-methyl-4- (3,3,3-trifluoro) acid -prop-l-enyl) benzamide 4- ((E) -3,3,3-trifluoroprop-1-enyl) -N- (indolin-6-yl) -2-methylbenzamide without purification (115 mg, 0.33 mmol, prepared by NaOMe / MeOH deacetylation of ( E) -N- (1-acetylindolin-6-yl) -2-methyl-4- (3, 3, 3-trifluoroprop-1-enyl) benzamide as above) was placed in CH 2 C 12 (50 mL). N, N-Di-iso-propylethylamine (116 μ?, 0.66 mmol) was added, followed by the addition of trimethylacetyl chloride (41 μ?, 0.33 mmol). The mixture was stirred overnight at room temperature, then divided between H20 and CH2C12. The organic layer was dried and concentrated under vacuum to leave an unpurified residue. The residue was purified by column chromatography on silica gel to give a solid (35 mg, containing approximately 20% diacetylated material). Further purification by preparative high performance liquid chromatography gave the product (17 mg, 13%) as a solid, m / z = 431.2 (M + 1). 1 H NMR (400 MHz, d 6 -DMSO) d 9.5 (1H, s), 8.25 (1H, s), 7.5-7.45 (411, m), 7.42-7.22 (2H, m), 6.5 (1H, m), 4.25 (211, m), 3.05 (211, m), 2.4 (3H, s), 1.8 (911, s).

Compound 406 Preparation of (E) -2-methyl-N- (1-propionylindolin-6-yl) -4- (3,3,3-trifluoro-prop-1-enyl) benzamide acid 4- ((E) -3,3,3-Trifluoroprop-l-enyl) -N- (indolin-6-yl) -2-methylbenzamide (113 mg, 0.32 mmol) was dissolved in CH2C12 (25 mL). ?,? - Di-iso-propylethylamine (114 μL, 0.64 mmol) was added, followed by the addition of propanoyl chloride, 0.39 mmol). The mixture was stirred overnight at room temperature, then divided between H20 and CH2Cl2. The organic layer was dried (MgSO 4) and concentrated under vacuum to leave an unpurified residue. The residue was purified by column chromatography on silica gel to give a solid (62 mg). Further purification by preparative high performance liquid chromatography gave the product (31 mg, 24%) as a solid, m / z = 403.6 (M + 1). 1ti NMR (400 MHz; d6-DMSO) d 10.25 (1H, s), 8.5 (1H, s), 7.68-7.48 (2H, m), 7.5 (1H, d), 7.45-7.32 (2H, m), 7.25 (1H, d), 6.85 (1H, m), 4.15 (2H, m), 3.15 (2H, m), 2.47 (2H, q), 2.4 (3H, s), 1.1 (3H, t).

Compound 407 Preparation of (E) -N- (1- (2-hydroxyacetyl) -indolin-6-yl) -2-methyl-4- (3,3,3-trifluoro-prop-1-enyl) benzamide acid to. (E) -N- (1- (2- (Benzyloxy) acetyl) indolin-6-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide (E) -N- (indolin-6-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide (100 mg, 0.3 mmol) was dissolved CH 2 Cl 2 (25 mL). N, A / -Di-isopropylethylamine (114 μL, 0.64 mmol) was added, followed by the addition of benzyloxy acetyl chloride (49 μL, 0.31 mmol). The mixture was stirred overnight at room temperature, then divided between H20 and CH2C12. The organic layer was dried (MgSC) and concentrated in vacuo to leave an unpurified residue. The residue was purified by column chromatography on silica gel to give a solid (85 mg). m / z = 495.4 (M + l). b. (E) N (1- (2-hydroxyacetyl) -indolin-6-yl) -2-methyl-4- (3,3,3-trifluoro-prop-lenyl) -benzamide (E) -N- (1- ( 2- (Benzyloxy) acetyl) indolin-6-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide (85 mg, 0.17 mmol) was dissolved in CH2C12 (20 mL) and it was cooled to -78 ° C under a nitrogen atmosphere. Boron tribromide (49 μm, 0.52 mmol) was added, and the mixture was heated at room temperature for 6 h. The mixture was then partitioned between CH2C12 and NaHCO3 and the organic extract was dried and concentrated under vacuum to leave an oil without purification. Purification by column chromatography on silica gel gave a product (32 mg), which was further purified by preparative high performance liquid chromatography to give the title compound (8 mg, 10%) as a solid, m / z = 405.0 (M + l). XH NMR (400 MHz, d6-DMSO) d 10.25 (1H, s), 8.5 (1H, s), 7.68-7.6 (2H, m), 7.55-7.48 (2H, m), 7.35 (1H, dd), 7.2 (1H, d), 6.85 (1H, m), 4.35 (1H, t), 4.25 (2H, d), 4.15 (211, m), 3.15 (2H, m), 2.4 (3H, s).

Compound 408 Preparation of the acid (E) -N- (1-acetyl-lH- [pyrrole] 2, 3-b] pyridin-5-yl] -2-methyl-4- (3, 3, 3-trifluoroprop-1) - to . (E) -2-methyl-N- (lH-pyrrol [2, 3-b] pyridin-5-yl] -4- (3,3,3-trifluoroprop-1-enyl) benzamide Acid 4- ((E ) -3, 3, 3, trifluoroprop-1-enyl) -2-methylbenzoic acid (740 mg, 3.2 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (1.8 g, 9.4 mmol), hydrate 1-hydroxybenzotriazole (740 mg, 4.8 mmol) and 1H-pyrrole [2, 3-b] pyridin-5-amine (0.85 g, 6.4 mmol) were combined in DMF (40 mL) and stirred at room temperature overnight The mixture was then partitioned between EtOAc and NaHCC> 3 saturated and the organic layer was washed with H20 and brine, then dried (Na2SO4) filtered and the solvent removed under vacuum to leave an oil without purification. purified by column chromatography on silica gel using 0-10% MeOH / CH2Cl2 as eluent gave an oil.Additional purification by column chromatography on silica gel using 0-50% EtOAc / hexane as eluent gave a solid, which was further purified by liquid chromatography of high preparative yield to give the product (130 mg, 12%) as a solid, m / z = 345.6 (M + l). XH NMR (400 MHz; MeOH-d4) d 8.48 (21-1, d), 7.65-7.6 (3H, m), 7.48 (1H, d), 7.35 (1H, dd), 6.65 (1H, m), 6.5 (1H, d), 2.52 (3H, s) b. (E) -N (l-acetyl-lH-pyrrol [2,3-b] pyridin-5-yl] -2-methyl-4- (3,3,3-trifluoroprop-lenyl) benzamide Acetyl chloride (12) L, 0.17 mmol) was added to a stirred solution of N, N-di-iso-propylethylamine (61 L, 0.35 mmol) and (E) -2-methyl-N- (lH-pyrrole [2, 3-Jb] pyridin-5-yl] -4- (3, 3, 3-trifluoroprop-1-enyl) benzamide (60 mg, 0.17 mmol) in CH 2 Cl 2 (15 mL) at room temperature under a nitrogen atmosphere.The mixture was stirred for overnight at room temperature, then it was partitioned between H20 and CH2Cl2, the organic layer was dried (MgSO, j) and concentrated in vacuo to leave an unpurified residue Purification by column chromatography on silica gel gave a product, which was further purified by preparative high performance liquid chromatography to give the title compound (5 mg, 7%) as a solid, m / z = 388.2 (M + 1). XH NMR (400 MHz; d6-DMSO) d 10.5 (11-1, s), 8.5 (2H, d), 7.75-7.68 (4H, m), 7.4 (1H, d), 6.9 (1H, m), 6.65 (1H, d), 2.43 (3H, s ), 2.3 5 (3H, s).

Compound 409 Preparation of (E) -N- (2- (2-hydroxypropan-2-yl) benzo [d] thiazol-5-yl) -2-methyl-4- (3,3-trifluoropropyl) benzamide solution of (E) -N- (2-acetylbenzo [d] thiazol-5-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide (65 mg, 0.16 mmol) in THF ( 25 mL) was cooled to -78 ° C. To the solution of eLi in Et20 (1.6 M, 200 xL, 0.32 mmol) was added, and the mixture was slowly heated to room temperature. The mixture was then partitioned between a solution of NH 4 Cl and EtOAc. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under vacuum to leave an unpurified residue. The residue was purified by column chromatography on silica gel to give the product (23 mg). m / z = 420.8 (M + l). XH NMR (400 MHz, acetone-d6) 8 9.6 (1H, s), 8.5 (1H, s), 7.9 (1H, d), 7.72 (1H, dd), 7.6-7.5 (3H, m), 7.38 ( 1H, dd), 6.65 (1H, m), 2.45 (3H, s), 1.62 (611, s).

Compound 410 Preparation of (E) -N- (2-acetylbenzo [d] thiazol-5-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide DMSO (142 pL, 2.0 mmol) was added to a solution of oxalyl chloride (86 μl, 1.0 mmol) in CH 2 Cl 2 (10 mL) at -78 ° C under nitrogen. The mixture was stirred for 10 minutes, then a solution of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -N- (2- (1-hydroxyethyl) benzo [d] thiazole-5- il) -2-methylbenzamide (370 mg, 0.91 mmol) in CH2Cl2 (5 mL) was added. The mixture was stirred for 15 min at -78 ° C then Et 3 N (634 μL, 4.55 mmol) was added. The mixture was stirred for 30 min at -78 ° C then allowed to warm to room temperature. The mixture was partitioned between CH2C12 and water and the organic layer was dried (MgSO4) filtered and concentrated under vacuum to leave an oil without purification. The oil was purified by preparative high performance liquid chromatography to give the product (90 mg, 24%) as a solid (approximately 90% pure), m / z = 404.8 (+ l). XH NMR (400 MHz, d6-DMSO) d 10.75 (1H, s), 8.75 (1H, s), 8.2 (1H, d), 7.9 (1H, dd), 7.73-7.55 (3H, m), 7.45 ( 1H, dd), 6.9 (1H, m), 2.75 (3H, s), 2.45 (3H, s).

Compound 411 Preparation of (E) -N- (2- (hydroxymethyl) benzo [d] oxazol-5-yl) -2-yl- (3, 3, 3-trifluoroprop-l-enyl) benzamide? Di-iso-propylethylamine (80 pL, 0.6 mmol) was added to a mixture of 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (50 mg, 0.2 mmol ), 1-hydroxybenzotriazole (35 mg, 0.26 mmol) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol) in CH2C12 at room temperature. After stirring the mixture for 15 min (5- aminobenzo [dj oxazol-2-yl) methanol (43 mg, 0.26 mmol) was added and the mixture was stirred for 48 hr. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel using 0-40% EtOAc / hexane then 80% EtOAc / hexane as eluent to give the product (24 mg, 30%) as a solid, m / z 376.5 (M + 1). 1H NMR (400 Hz; CDC13) d 7.61 (2H, s), 7.49 (1H, d), 7.36 (311, t), 7.14 (1H, dd), 6.96 (1H, d), 6.83 (1H, dd) , 6.30-6.34 (1H, m), 4.60 (2H, s), 2.52 (3H, Compound 411 Preparation of (E) -2-methyl-N- (2-methylthiazole [5,4-blpyridin-6-yl] -4- (3,3,3-trifluoroprop-1-enyl) benzamide acid, n 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (700 mg, 3.0 mmol) was suspended in 0 ° 2012 (25 mL). Oxalyl chloride (520 L, 6.1 mmol) was added, followed by the addition of 1 drop of DMF. The mixture was stirred at room temperature for 2 h, then the volatiles were removed under vacuum. The residue was re-suspended in CH2C12 and triethylamine (1.26 mL, 9.0 mmol) was added, followed by the addition of a solution of 2-methylthiazole [5, 4-b] pyridin-6-amine (502 mg, 3.0 mmol) in CH2C12 (5 mL). The mixture was stirred at room temperature overnight and then partitioned between EtOAc and water. The organic layer was separated and dried, filtered and then concentrated under vacuum to an oil. Purification of the oil by column chromatography on silica gel using EtOAc / hexane as eluent (0-50%) gave a solid. Trituration with ether gave (E) -2-methyl-N- (2-methylthiazol [5, -b] pyridin-6-yl) -4- (3, 3, 3-trifluoroprop-1-enyl) benzamide (140 mg, 12%) as a solid, m / z = 377.8 (? +1). ?? NMR (400 Hz; de-DMSO) d 11.5 (1H, s), 8.85 (1H, d), 8.71 (1H, d), 7.72-7.58 (3H, m), 7.47 (1H, dd), 6.90 (1H , m), 2.85 (3H, s), 2.45 (3H, s).

Compound 13 Preparation of (E) -N- (2- (hydroxymethyl) tlazole [5, 4-b] pyridin-6-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide (E) -2-Mmethyl-N- (2-methylthiazol [5, 4-b] pyridin-6-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide (60 mg, 0.2 mmol ) was placed in dioxane (20 mL). Selenium dioxide (200 mg, 2.0 mmol) was added and the mixture was heated at 105 ° C for 28 h. After it was left to cool to room temperature, the mixture was filtered and the filtrate was partitioned between EtOAc and aqueous NaHCO3. The organic layer was washed with water then brine, dried, filtered and concentrated under vacuum to leave an oil without purification. The oil was dissolved in THF (20 mL) and water (10 mL) then sodium tetrahydroborate (60 mg, 2.0 mmol) was added in two portions. The mixture was stirred at room temperature for 2 h (monitoring by LCMS), then cooled to 0 ° C and adjusted to pH 1 with 1N HCl. The pH was then adjusted to pH 8 with saturated aqueous NaHCO 3. The mixture was extracted with EtOAc and the organic layer was dried, filtered and concentrated under vacuum to leave an oil without purification. Purification of the oil by preparative high performance liquid chromatography gave (E) -N- (2- (hydroxymethyl) thiazolo [5, 4-j] pyridin-6-yl) -2-methyl-4- (3, 3, 3-trifluoroprop-1-enyl) benzamide (13 mg, 20%) as a solid, m / z = 394.0 (M + 1). 1H NMR (400 MHz; d6- DMSO) 5 11.5 (1H, s), 8.85 (1H, d), 8.71 (1H, d), 7.72-7.58 (3H, m), 7.38 (1H, dd), 6.90 (1H, m), 6.4 (1H, bs), 4.88 (2H, s), 2.45 (3H, s).

Alternative preparation of (E) -N- (2- (hydroxymethyl) thiazolo [5, 4-J] pyridin-6-yl) -2-methyl-4- (3,3,3-trifluoroprop-l-envyl) benzamide (Compound 413) to. Pivalate of (E) - (6- (2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamido) thiazole [5, 4-b] pyridin-2-yl) methyl Oxalyl Chloride ( 236 μl, 2.8 mmol) was added in one portion to a stirred solution of (E) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzoic acid (321 mg, 1.39 mmol) in methylene chloride (10 mL) and DMF (5 drops) at 0 ° C under nitrogen. The mixture was stirred at 0 ° C for 15 min then allowed to warm to room temperature and stirred for about 45 minutes. TLC indicated a small amount of acid left so that additional oxalyl chloride (120 μ ?,) was added at room temperature and stirred for an additional 20 minutes. The mixture was then concentrated under vacuum to leave an unpurified residue which was dissolved in THF (5 mL) and cooled to 0 ° C under a nitrogen atmosphere. Triethylamine (243 pL, 1.74 mmol) was added, followed by a solution of pivalate (6-aminothiazol [5, 4-b] pyridin-2-yl) methyl (370 mg, 1.4 mmol) in THF (10 mL). The mixture was stirred at 0 ° C for 15 minutes, then allowed to warm to room temperature and stirred overnight. The solvent was removed under vacuum to leave an unpurified residue which was partitioned between EtOAc (100 mL) and H20 (50 mL). The organic layer was washed with H20 (1 x 50 mL), saturated NaHCO3 (2 x 50 mL). ), brine (1 x 50 mL), then dried (MgSO4) was filtered and the solvent was removed under vacuum to leave an unpurified solid (630 mg, 85%). The solid was used without further purification (NMR indicated that it was approximately 90% pure). b. (E) -N- (2- (hydroxymethyl) thiazole [5, 4-2>] pyridin-6-yl) -2-methyl-4- (3,3, 3-trifluoroprop-1-enyl) benzamide Sodium (200 mg, 8.7 mmol) was added in one portion to stirred methanol (25 mL) at room temperature under nitrogen. After the dissolution of sodium is completed (the reaction is exothermic), (E) - (6- (2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamido) thiazole pivalate [5] Ab] pyridin-2-yl) methyl (550 mg, 1.2 mmol) was added in one portion as a suspension in MeOH (20 mL) (an additional rinse of 10 mL of MeOH was used to secure all the materials deposited in the mixture of reaction). The mixture was stirred at room temperature for approximately 15 minutes then the mixture was concentrated under vacuum. The residue was partitioned between 1 M NH 4 Cl (100 mL) and EtOAc (150 mL). The organic layer was dried (MgSO4) filtered and the solvent removed under vacuum to leave a solid. The solid was purified by trituration with MeOH (approximately 5-10 mL) to give the desired product (140 mg) as a solid. The filtrate was concentrated under vacuum and the residue was purified by column chromatography on silica gel using 50-80% EtOAc / hexane to give a solid. This solid was triturated with MeOH to give the additional desired product (50 mg) as a solid. The filtrate was again concentrated under vacuum and the residue was purified by preparative thin layer chromatography using 75% EtOAc / hexane to give the desired compound (120 mg) as a solid. The total yield of (E) -? 7- (2- (hydroxymethyl) thiazole [5, 4- £ >] pyridin-6-yl) -2-methyl-4- (3, 3, 3-trifluoroprop-1) -enyl) benzamide of this reaction was 310 mg (67%). The analytical data were identical to those described in the above.

Compound 41 Preparation of (2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamido) thiazole [5, 4-b] pyridine-2-carboxylate of (E) -ethyl 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (103 mg, 0.45 mmol) was suspended in CH 2 Cl 2. Oxalyl chloride (77) i, 0.91 mmol) was added, followed by the addition of 1 drop of DMF. The mixture was stirred at room temperature for 1 h, then the volatiles were removed under vacuum. The residue was re-suspended in CH2Cl2 and triethylamine (187 μL, 1.35 mmol) was added, followed by the addition of a solution of ethyl-6-aminothiazole [5, 4-b] pyridine-2-carboxylate (100 mg, 0.4 mmol). The mixture was stirred at room temperature for 1 h then it was partitioned between EtOAC and water. The organic layer was separated and dried, filtered and then concentrated under vacuum to an oil. Purification of the oil by column chromatography on silica gel using 05% EtOAc / hexane as eluent gave a solid, which was further purified by trituration with Et20 to give the product (15 mg, 7%) as a solid, m / z = 436.1 (M + l). ?? NMR (400 MHz; d6-DMSO) d 11.0, (1H, s), 9.05 (2H, dd), 7.8-7.6 (3H, m), 7.4 (1H, dd), 6.95 (1H, m), 4.45 (2H, q), 2.45 (3H, s), 1.45 (2H, t).

Compound 415 Preparation of (E) -2-methyl-_V- (tlazole [5, 4-2?] Pyridin-6-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide 4- ((E) -3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (456 mg, 1.98 mmol) was suspended in CH2C12. Oxalyl chloride (340 [mu], 4.0 mmol) was added, followed by the addition of 1 drop of DMF. The mixture was stirred at room temperature for 1 h, then the volatiles were removed under vacuum. The residue was re-suspended in CH2Cl2 and triethylamine (830 pL, 6.0 mmol) was added, followed by the addition of a solution of thiazole [5, 4-jb] pyridin-6-amine (300 mg, 1.98 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 h then it was partitioned between EtOAC and water. The organic layer was separated and dried, filtered and then concentrated under vacuum to an oil. Purification of the oil by column chromatography on silica gel yielded a solid (90 mg) which was further purified by preparative high performance liquid chromatography to give the product (35 mg, 5%) as a solid, m / z = 364.3 (M +1). 1H NMR (400 MHz, acetone-d6) d 9.75, (1H, bs), 9.3 (1H, s), 8.85 (2H, dd), 7.55 (3H, m), 7.2 (1H, dd), 6.62 (1H , m), 2.4 (3H, s).

General Method for Automated LC-MS Automated Library Purification Libraries were purified using a Perkin Elmer API100 mass spectrometer coupled to Shimadzu LC pumps. The chromatographic method used was 10-100% gradient of acetonitrile to water for 8 minutes at a flow rate of 6 ml per minute. The column used was a 10X50mm YC C18 and the compounds were collected using a Gilson 204 fraction collector. Following the methods described above and the appropriate reagents, starting materials and purification methods known to those skilled in the art, the Amide compounds of this invention are or can be prepared. The synthetic and biological examples presented herein are presented to illustrate this invention and are not construed in any way as to limit the scope of this invention. In the following examples, all temperatures are in degrees Celsius (unless otherwise indicated). The compounds that have been prepared according to the invention are presented in Table 1, below. The syntheses of these preparative compounds were carried out according to the methods set forth above, and the activity of the compounds was measured by percent inhibition in a calcium uptake assay, the details of which are described in the following.

Calcium Capture Test. The functional activity of the compounds against the VR1 receptor was determined by measuring changes in intracellular calcium in HEK 293 cells expressing hVR1. The compounds are examined for their ability to inhibit the influx of calcium induced by agonists. The double wavelength proportion measurement dye, Fura2, was used as an indicator of relative levels of [Ca2 +] in a 96-well format using Flex Station®, a molecular device.

Cell line and culture conditions: hVR1 was cloned into a pcDNA5 / TO vector from Invitrogen and stably transformed into the T-REx cell line HEK 293 from Invitrogen. HEK 293 cells expressing hVRl were grown to confluence (24 hours of culture) in 96-well black-walled plastic plates, coated with PDL, in the presence of DMEM medium containing 5% PenStrep, 5% Glutamax , 200 μg / mL Hygromycin, 5pg / mL Blasticidin and 10% FBS inactivated by heat. Twenty-four hours before the assay, the cells are transferred to DMEM medium containing 1 pg / mL of doxycycline. Before the assay, the cells were loaded with 5 pg / mL Fura-2 (Molecular Probes) in saline (130 mM NaCl, 3 mM KC1, 1 mM CaCl2, 0.6 mM MgCl2, 10 mM HEPES, 10 mM glucose and 50 sucrose mM, pH 7.) at 37 ° C for 40 minutes. The dye was then aspirated and replaced with 100 pL of saline before the start of the Flex Station® test.

Agonist concentration and compound dilutions: The EC50 of the agonist was determined at the start of the assay and the IC50 experiments of the compound were run using an agonist concentration equal to its EC50 as a stimulus. The agonists used were capsaicin (EC50 2.5 nM) and protons (saline plus 10 mM citric acid buffered to pH 5.7 with HC1). The compounds were tested at concentrations ranging from 10 nM to 3.3 p.M. The test consists of two phases: a pre-treatment phase followed by a treatment phase. 50μl of a solution of compound were added to the cells (Pre-treatment). In some cases, after pre-treatment, 50μl of the test compound was added in a saline solution at pH 5.1 (Treatment). The compounds were tested as follows: For the pre-treatment phase, 50 pL of 3x concentration of the test compound in saline are added to the cells containing 100 pL of saline to achieve a final concentration of x. For the treatment phase, at a determined time after pre-treatment, 50 pL of the test compound plus agonist solution are added to the cells at the relevant concentrations. The logs were made at 4 second intervals at 340 n and 380 nM wavelengths and the fluorescence ratio was analyzed. The responses were measured as the peak fluorescence ratio after the addition of compound-agonist minus the baseline fluorescence ratio before treatment and were calculated using Soft axPro software from Molecular Devices. Percent inhibition was calculated as follows and is shown in Table 1: (Compound Response - Control Response) Percent inhibition = 1 x 100 (Response of Agonist-Control Response) TABLE 1: AMIDA COMPRESTES TABLE 2: AMIDA COMPOUNDS 10 15 Acid stimulation assay Acid changes in intracellular calcium concentration were monitored using FDSS 6000 (Hamamtsu Photonics, Japan), a fluorometric imaging system. The cell suspension in the resting buffer (HBSS supplemented with lOmM HEPES, pH 7.) was pre-incubated with varying concentrations of the test compounds or resting buffer (buffer control) for 15 minutes at room temperature under dark conditions. . Cells were automatically added to the stimulation solution (HBSS supplemented with MES, final assay buffer pH 5.8) by the FGSS 6000. The IC50 values of VR1 antagonists were determined from half the increase shown by the buffer control samples after of the acidic stimulation, and the results obtained with the selected compounds of the invention were established in Table 4, below.

TABLE 4: IC50 Data for the Selected Amido Compounds Half life in human liver microsomes (HLM) Test compounds (1 μ?) Are incubated with 3.3 mM MgCl2 and 0.78 mg / mL HLM (HL101) in 100 mM potassium phosphate buffer (pH 7.4) at 37 ° C in the plate of 96 deep wells. The reaction mixture is divided into two groups, a non-P450 group and a P450 group. NADPH is added only to the reaction mixture of the P450 group. An aliquot of samples of the P450 group is collected at the point at time 0, 10, 30 and 60 min, where the point in time of 0 min indicates the time when the NADPH is added to the P450 group reaction mixture. An aliquot of samples from the non-P450 group is collected at the point in time of -10 and 65 minutes. The collected aliquots are extracted with acetonitrile solution containing an internal standard. The precipitated protein is pelleted in the centrifuge (2000 rpm, 15 min). The concentration of compound in the supernatant is measured by the LC / MS / MS system. The value of the half-life is obtained by plotting the natural logarithm of the proportion of the peak area of the compounds / internal standard versus time. The slope of the line of best fit through the points produces the rate of metabolism (k). This is converted to a half-life value using the following equations: Average life = ln 2 / k The results of the tests and the corresponding Ti / 2 values are established in Table 3, in the following.

TABLE 5: Average Life T In Hours For Exemplary Compounds Pharmacokinetic evaluation of the compounds after intravenous and oral administration in rats. Male Sprague-Dawley rats are acclimated for at least 24 hours before the start of the experiment. During the acclimation period, all animals receive food and water ad libitum. However, the food, but not the water, is removed from the animal cages at least 12 hours before the start of the experiment. During the first 3 hours of experimentation, animals receive only water ad libitum. At least three animals are each tested for intravenous and oral dosing. For the intravenous formulation, the compounds were dissolved (0.25 to 1 mg / mL) in a mixture of 3% dimethyl sulfoxide, 40% PEG 400 and the remaining percentage of 40% Captisol in water (w / v). For the oral formulation, the compounds of this invention are dissolved (2 mg / mL) in a mixture of 5% of 10% Tween 80 in water (v / v) and 95% of 0.5% methylcellulose in water (p / v). The animals are weighed before dosing. The determined body weight is used to calculate the dose volume for each animal. Volume of dose (mL / kg) = 1 mg / kg / concentration of the formulation (mg / mL) In cases where the concentrations of the formulation were less than 0.5 mg / mL, the dosage volume is approximately 2 mL / kg. PO rats are typically dosed through oral gavage at 2.5 mL / kg to achieve a dose level of 5 mg / kg. For IV dosing, blood samples are collected (using a pre-heparinized syringe) by the jugular vein catheter at 2, 5, 15, 30, 60, 120, 180, 300, 480 and 1440 minutes after dosing . For PO dosing, blood samples are collected (using a pre-heparinized syringe) by the jugular vein catheter before dosing and at 5, 15, 30, 60, 120, 180, 300, 480 and 1440 minutes after dosing. dosage. Approximately 250 uL of blood are obtained at each point in the animal's time. Equal volumes of 0.9% normal saline are replaced to prevent dehydration. The whole blood samples are kept on ice until centrifugation. The blood samples are then centrifuged at 14,000 rpm for 10 minutes at 4 ° C and the upper plasma layer is transferred to a clean vial and stored at -80 ° C. The resulting plasma samples are then analyzed by liquid chromatography-tandem mass spectrometry. After measurement of the plasma samples and dosing solutions, the plasma concentration-time curve is plotted. The plasma exposure is calculated as the area under the concentration-time curve extrapolated to the infinite time (AUCinf). The AUCinf is averaged and the oral bioavailability (% F) for the individual animal is calculated as: AUCinf (PO) / AUCinf (IV), normalized to their respective dose levels. % F is reported as the average% F of all animals dosed orally with the compound of the invention at the specified level (Table 6). In vivo clearance in the rat was calculated by conducting a non-compartmental analysis of the pharmacokinetic profile using WinNonlin software.

TABLE 6: Oral Bioavailability of the Exemplary Compounds In vivo clearance in the rat was calculated by conducting a non-compartmental analysis of the pharmacokinetic profile using the inNonlin software.

TABLE 7: In vivo Debugging of the Compounds and Empires Parallel artificial membrane permeability test (PAMPA) The experiments were carried out on 96-well donor and acceptor plates. Such a 96-well system was described in Journal of Medicinal Chemistry, 1998, vol.41, No.7, 1001-1010. 4% phosphatidylcholine and 1% stearic acid in dodecane were used as the artificial membrane material. The acceptor plate (96-well hydrophobic filter plate (MAIP N45, Millipore)) was prepared by adding 5 μL of artificial membrane material to the top of the filter and the plate was filled with 250 μL of Hank's balanced solution of salts ( HBSS) buffered with 2- (N-morpholino) ethanesulfonic acid (MES) (pH 6.5). The donor plate (Transport Receiver plate (MATRNPS50, Millipore)) was filled with 300 μL of HBSS buffered with MES (pH 6.5) containing 10 μM of the test compounds. The acceptor plate was placed on the donor plate to form a "sandwich" and incubated at 30 ° C for 2.5 hours. After the incubation period, the acceptor, donor and initial donor solution (reference) were analyzed by LC-MS / MS. The data were reported as the effective permeability value in cm X 10"6 / sec and the membrane retention value.

Intrinsic Clearance The test compounds (1 and M) were incubated with 1 mM MgCl 2, 1 mM NADP +, 5 mM isocitic acid, lU / mL isocitric dehydrogenase and 0.8 mg / mL HLM (human liver microsomes) in phosphate buffer 100 mM potassium (pH 7.4) at 37 ° C in a series of 384-well plates. At several points in time, a plate was removed from the incubator and the reaction was terminated with two incubation volumes of acetonitrile. The concentration of compound in the supernatant was measured by the LC / MS / MS system. The intrinsic depuration value (Clj.nt) was calculated using the following equations: Clint (μ? / Min / mg protein) = (kx incubation volume) / Protein concentration k (min-1) = - slope of ln (concentration vs. time) EXAMPLE 1 Calcium Imaging Assay The VR1 protein is a heat-activated cationic channel that exchanges approximately ten calcium ions for each sodium ion, resulting in neuronal membrane depolarization and elevated intracellular calcium levels. Therefore, the functional activity of the compounds at the VR1 receptor can be determined by measuring changes in intracellular calcium levels in neurons, such as the dorsal root ganglion. DRG neurons were grown in black-walled 96-well plates coated with PDL, in the presence of DMEM medium containing 5% Penstrep, 5% Glutamax, 200 g / ml hygromycin, 5 g / ml blasticida and 10% FBS inactivated by heat. Before the assay, the cells were loaded with 5 pg / ml of Fura2 in normal saline at 37 ° C for 40 minutes. The cells were then washed with normal saline to remove the dye before the beginning of the experiment. The plaque neurons were transferred to a chamber on the stage of a Nikon eclipse TE300 microscope after which the neurons were allowed to reach a stable fluorescence for approximately 10 minutes before beginning the experiment. The test consists of two stages, a pretreatment phase followed by a treatment phase. First, a solution of the test compound was added from a multi-valve perfusion system to the cells for 1 minute (pretreatment). Immediately after, capsaicin (250 nM) was added in the presence of the test compound (treatment) for a specific period between 20 and 60 seconds. Fura2 was excited at 340 and 380 nM to indicate the relative concentration of calcium ions. Changes in wavelength measurements were made throughout the course of the experiment. The fluorescence ratio was calculated by dividing the fluorescence measured at 340 nM between that at 380 nM. Data was collected using Slidebook software from Intelligent Imaging. All the compounds that inhibited the calcium influx induced by capsaicin in more than 75% were considered positive. Table 8 provides the data obtained. Figure 1 demonstrates the results obtained when compound 225 is administered with capsaicin. The fluorescence that reflects the influx of calcium ions is reduced.

Table 8: Example 2 High performance analysis of VR1 antagonists for the determination of in vitro efficacy using a calcium imaging assay Inhibition of the response to capsacin in the presence and absence of the test compound was measured and assessed, using the method for the calcium acceptance test, described above with respect to the data presented in Table 1. Such data are also plotted in Figures 2-6, where a significant reduction of the response to capsaicin is observed in the presence of the compound of representative test. No such reduction in the response is observed in the absence of the test compound.

Example 3 Electrophysiology of total cell membrane clamping Neurons of the dorsal root ganglion (DRG) were recovered from neonatal or adult rats and placed in plates on glass coverslips coated with poly-D-lysine. The plaque neurons were transferred to a chamber to allow drug solutions to be added to the cells using a perfusion system based on a computer controlled solenoid valve. Images of the cells were acquired using standard DIC optics. The cells underwent zonal membrane clamping using finely attracted glass electrodes. Electrophysiology experiments of clamping with voltage were carried out using an amplified Axon Instruments Multiclamp, controlled by the pCLAMP8 software. The cells were placed in a clamp with full cell voltage and maintained at a voltage of -80 mV while monitoring the membrane current in register mode without gaps. Capsaicin 500 nM was added for 30 seconds as control. Test compounds at various concentrations were added to the cells for 1 minute before a 30-second capsaicin application. The differences between the control experiments and the drug-positive capsaicin experiments were used to determine the efficacy of each test compound. All compounds that inhibited the current induced by capsaicin by more than 50% were considered positive. The data obtained for compound 240 are set forth in Table 9.

Table 9: All publications, patents and patent applications cited in this specification are incorporated herein by reference as if each individual patent application or publication is specifically and individually indicated to be incorporated for reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications can be made to the same without departing from the spirit or scope of the appended claims. All similar modifications that come within the scope of the appended claims are intended to be included therein.

Claims (6)

1. CLAIMS 1. A compound according to the formula (I) (i) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers and tautomers thereof, wherein: each of W, Z and X is independently N or CR4; and Y is CR4"; L is- (CR5 = CR6) - or - (C = C) -; R1 is bicycloaryl or substituted bicycloheteroaryl 0 unsubstituted; R3 is CR6'R7R8; each R4 is independently hydrogen, alkyl of 1 to 6 carbon atoms, hydroxyl-alkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, amino-alkoxy of 1 to 6 carbon atoms, substituted amino- alkoxy of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, cycloalkyl-alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylarylamino of 1 to 6 carbon atoms, aryl-alkyloxy of 1 to 6 carbon atoms, amino, aryl, aryl-alkyl of 1 to 6 carbon atoms, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfuric acid ester, azido, carboxy, carbamoyl, cyano, cycloheteroalkyl, dialkylamino of 1 to 6 carbon atoms, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or tio; R4"is alkyl, trihaloalkyl, alkoxy, sulfone or hale-each of R5 and R6 is independently H or alkyl of 1 to 6 carbon atoms, and R6 'is hydrogen, halo or alkyl of 1 to 6 carbon atoms; one of R7 and R8 is independently halo or alkyl of 1 to 6 carbon atoms, or R7 and R8 together form a cycloalkyl ring of 3 to 8 carbon atoms 2. The compound according to Claim 1, wherein each of R5 and R6 is independently H or methyl 3. The compound according to Claim 1, wherein R1 is: wherein each of A1, A2, A3, A4, B1 and B2 is independently CR4 'and N; and each of R4 'is independently H, alkyl of 1 to 6 carbon atoms, halo or hydroxyalkyl of 1 to 6 carbon atoms. 4. The compound according to Claim 1, wherein R1 is: wherein each of A5 and A8 is independently CR4'R4 ', NR4', 0, S, SO or S02; each of A6 and A7 is independently CR4 ', NR4', CR'R4 'or CO; each of B3 and B4 is independently CR4 'and N; when R4 'is attached to C, each of R4' is independently H, alkyl of 1 to 6 carbon atoms, halo or hydroxyalkyl of 1 to 6 carbon atoms, and when R4 'is attached to N, each of R4 'is independently H or alkyl of 1 to 6 carbon atoms; and the dotted link represents a single or double link. 5. The compound according to Claim 1, wherein R1 is: A9, A10 and A11 is independently CR4 ', CR' R4 ', CO, CS, N, NR4', O, S, SO or S02; each of B5 and B6 is independently CR4 'and N; when R binds to C, each of R4 'is independently H, alkyl of 1 to 6 carbon atoms, halo or hydroxyalkyl of 1 to 6 carbon atoms, and when R4' is attached to N, each of R4 ' is independently H or alkyl of 1 to 6 carbon atoms; and each of the dotted links independently represents a single or a double link. 6. The compound according to Claim 1, wherein R1 is HCO.-CO. -eo.-oo. OO ø. -OO. -??1. -CO". wherein the ring can be further substituted with R4 ', and R4' is as described in Claim 4; and when feasible, the ring N can be further substituted with H or alkyl of 1 to 6 carbon atoms. 7. The compound according to Claim 1, wherein R1 is 30. XXi \ X¡¾ wherein the ring can be further substituted with R4 ', and R4' is as described in Claim 4; and when feasible, the ring N can be further substituted with H or alkyl of 1 to 6 carbon atoms. 8. The compound according to Claim 1, wherein R1 is: wherein each of A1, A2, A3, A4, B1 and B2 is independently CH and N; and R4 'is alkyl of 1 to 6 carbon atoms hydroxyalkyl of 1 to 6 carbon atoms. 9. The compound according to claim wherein R1 is: wherein each of A5 and A8 is independently CH2, CHMe, NH, N e, O, S, SO or S02; and R4 'is alkyl of 1 to 6 carbon atoms or hydroxyalkyl of 1 to 6 carbon atoms. 10. The compound according to Claim 1, wherein R1 is: wherein each of A9, A10 and A11 is independently CH, CH2, N, NH, O or S; each of B5 and B6 is independently CH and N; and each of R4 'is independently H, alkyl of 1 to 6 carbon atoms, halo or hydroxyalkyl of 1 to 6 carbon atoms; and each of the dotted links independently represents a single or a double link. 11. The compound according to Claim 1, wherein R1 is and where R4 'is as described in Claim 4. The compound according to any of Claims 9-11, wherein R4 is hydroxyalkyl of 1 to 6 carbon atoms. 13. The compound according to the claim 12, wherein R4 'is - (CH2) n-OH; and where n is selected from 1-3. 14. The compound according to the claim 13, wherein R4 'is CH2OH 15. The compound according to the claim 1, where R1 is wherein, when feasible, the ring N can be further substituted with H or alkyl of 1 to 6 carbon atoms. 16. The compound according to Claim 1, wherein each of W, X and Z is CR4 and R4 is selected from H, halo, alkoxy, alkyl, haloalkyl or hydroxyalkyl. 17. The compound according to Claim 1, wherein each of W, X and Z is CR4 and R4 is selected from H, halo or alkyl. 18. The compound according to Claim 1, wherein each of W, X and Z is CR4 and R4 is selected from H, F, Cl or Me. 19. The compound according to the claim I, wherein Y is CR 4"and wherein R 4" is independently selected from alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms and halo. 20. The compound according to Claim 19, "wherein R4" is independently CH3, CF3, Cl or F. 21. The compound according to Claim 1, wherein each of W and X is CH; and each of Y and Z is independently C-CH3, C-Cl or C-F. 22. The compound according to Claim 1, wherein each of W and X is CH; and each of Y and Z is independently C-CH3 or C-F. 23. The compound according to Claim 1, wherein L is - (CR5 = CR6) -; and wherein each of R5 and R6 is independently H or methyl. 24. The compound according to Claim 1, wherein L is -CH = CH-. 25. The compound according to Claim 1, wherein L is -C = C-. 26. The compound according to Claim 1, wherein R3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. 27. The compound according to Claim 1, wherein R3 is cyclopropyl or CF3 28. The compound according to Claim 1, wherein R3 is t-Bu. 29. The compound according to claim 1, wherein R1 is substituted or unsubstituted, wherein each of A1, A2, A3, A4, B1 and B2 is independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl or halo; R4d is alkyl, hydroxyl, alkoxy, or a group -NR4eRf; R4e and R4f are independently H, alkyl, substituted alkyl; or R4e and R4f together form a substituted or unsubstituted cycloheteroalkyl ring of 4-8 atoms. 30. The compound according to Claim 1, wherein R1 is substituted or unsubstituted, wherein each of A1, A2 and A3 is independently CR4 ', S, O, N, NR4'; B1 and B2 are independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl; Rd is alkyl, hydroxyl, alkoxy, or a group -NReR4f; R4e and R4f are independently H, alkyl, substituted alkyl; or Re and Rf together form a substituted or unsubstituted cycloheteroalkyl ring of 4-8 atoms. 31. The compound according to Claim 1, wherein R1 is wherein each of A1, A3 and A4 is independently CR4 < R4 ', O, NR4', S, SO or S02; B1 and B2 are independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl; R4d is alkyl, hydroxyl, alkoxy, or a group -NR4eR4f; R4e and R4f are independently H, alkyl, substituted alkyl; or Re and Rf together form a substituted or unsubstituted cycloheteroalkyl ring of 4-8 atoms. 32. The compound according to any of claims 29-31, wherein R4d is -NR4eRe and wherein R4e is H, Me or -CH2-CH2-OH; and Rf is H, Me, -CH2-CH2-OH, -CH2-CH2-OMe, -CH2-CH2-NMe2, -CH2-C (OH) H-CH2OH, -CHz-CHz-Cy1, or -CH2- CÍOHJH-CHs-Cy1; and Cy1 is - .- - -. 33. The compound according to any of claims 29-31, wherein Rd is Cy1 and Cy1 is as described in the preceding claim. 34. The compound according to any of claims 29-31, wherein Rd is NMe2 • 35. The compound according to any of claims 29-31, wherein R4d is alkyl. 36. The compound according to any of claims 29-31, wherein R4d is Me. 37. The compound according to any of claims 29-31, wherein R4d is alkoxy. 38. The compound according to any of claims 29-31, wherein R4d is OMe or OH. 39. The compound according to the claim 1, wherein R1 is substituted or unsubstituted, wherein each of A1, A2, A3, A4, B1 and B2 is independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl or halo; R 4k is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; R4g and R4h are independently H, alkyl, substituted alkyl; or R4g and R4h together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; and n is 0-. 40. The compound according to claim 1, wherein R1 is wherein each of A1, A2 and A3 is independently CR4 ', CR4'R4', S, SO, S02, O, N, NR4 '; B1 and B2 are independently CR4 'or N; each R 4 'is independently H, substituted or unsubstituted lower alkyl; R k is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; Rg and R4h are independently H, alkyl, substituted alkyl; or Rg and Rh together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; n is 0-4. 41. The compound according to claim 1, wherein R1 is wherein each of A1 and A4 is independently CR 'R4', O, NR4 'OR S; B1 and B2 are independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl; R 4k is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; R4g and Rh are independently H, alkyl, substituted alkyl; or R 9 and R together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; n is 0-4. 42. The compound according to claim 1, wherein substituted or unsubstituted, wherein A1 is CR'R4 '; each of A2 and A4 is independently CR 'R4' or CO; B1 and B2 are independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl; R 4k is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; R49 and R4h are independently H, alkyl, substituted alkyl; or R4g and Rh together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; n is 0-4. 43. The compound according to claim 1, wherein substituted or unsubstituted where A is CR R; each of A and A4 is independently CR4'R4 'or CO; A3 is S, SO or S02; and B1 and B2 are independently CR4 'or N; each of R4 'is independently H, substituted or unsubstituted lower alkyl; R41c is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; R4g and R4h are independently H, alkyl, substituted alkyl; or R4g and R4h together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; n is 0-4. 44. The compound according to any of claims 39-43, wherein n is 0 or 2. 45. The compound according to any of claims 39-43, wherein n is 1, 3 or 4. 46. The compound according to any of claims 39-43, wherein each of R4g and R4h is H. 47. The compound according to any of claims 39-43, wherein each of R4g and Rh is Me. 48. The compound according to any of claims 39-43, wherein one of Rg and Rh is H and the other is Me. 49. The compound according to any of claims 39-43, wherein Rg and R4h together form a cyclopropyl ring. 50. The compound according to any of claims 39-43, wherein R4k is H, Me, i-Pr, -CH2-CH2-OH, -CH2-CH2-OMe, -CH2-CH2-NMe2, COMe, COCH2NMe2, COCH2OH, COC (Me2) OH, COCH2OMe, CONHMe, CONMe2, CONHCH2CH2OH, CON (CH2CH2OH) 2, COCy1 or COCHzCy1; and Cy1 is 51. The compound according to any of claims 39-43, wherein R4k is H or Me. 52. The compound according to any of claims 39-43, wherein R4k is -CH2-CH2-NMe2. compound according to the claim 1, wherein substituted or unsubstituted, wherein each of A1, A2, A3, A4, B1 and B2 is independently CR4 'or N; each R4 'is independently H, substituted or unsubstituted lower alkyl or halo; R4m is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aminocarbonyl or substituted aminocarbonyl; R 4n is independently H, or substituted or unsubstituted lower alkyl; R4g and R4h are independently H, alkyl, substituted alkyl; or R4g and R4h together form a substituted or unsubstituted cycloalkyl or cycloheteroalkyl ring of 3-6 atoms; and n is 0-. 54. The compound according to Claim 53, wherein n is 0 or 2 55. The compound according to Claim 53, wherein n is 1, 3 or 4 56. The compound according to claim 53, in where each of R4g and R4h is H. 57. The compound according to the claim 53, where each of Rg and R4h is Me. 58. The compound according to claim 53, wherein one of R4g and R4h is H and the other is Me. 59. The compound according to claim 53, wherein R4g and Rh together form a cyclopropyl ring. 60. The compound according to claim 53, wherein R4m is H, Me or -CH2-CH2-OH; and R4n is H, Me, -CH2-CH2-OH, -CH2-CH2-OMe or -CH2-CH2-NMe2. 61. The compound according to claim 53, wherein -NR4mR4n is: - - - - ~ Me, 62. The compound according to any of claims 29-61, wherein each of X and Z is CR4 and R4 is selected from H, halo, alkoxy, alkyl, haloalkyl or hydroxyalkyl. 63. The compound according to any of claims 29-61, wherein each of W, X and Z is CR4 and R4 is selected from H, halo or alkyl. 6 The compound according to any of claims 29-61, wherein each of, X and Z is CR4 and R4 is selected from H, F, Cl or Me. 65. The compound according to any of claims 29-61, wherein Y is CR4"and R4" is independently selected from alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms and halo. 66. The compound according to any of Claims 29-61, wherein R4"is independently CH3, CF3, Cl or F. 67. The compound according to any of claims 29-61, wherein each of W and X is CH, and each of Y and Z is independently C-CH3, C-Cl or CF. The compound according to any of claims 29-67, wherein R4 is H. 69. The compound of according to any one of claims 29-68, wherein L is substituted or unsubstituted - (CR5 = CR6) - .70. The compound according to any of claims 29-68, wherein each of R5 and R6 is independently H or methyl 71. The compound according to any of claims 29-68, wherein L is -CH = CH-. 72. The compound according to any of claims 29-68, wherein L is -C = C- 73. The compound according to any of claims 29-72, wherein R 3 is substituted or unsubstituted cycloalkyl. placed according to any of claims 29-72, wherein R3 is cyclopropyl, cyclo-butyl, cyclopentyl, substituted or unsubstituted cyclohexyl or cycloheptyl. 75. The compound according to any of claims 29-72, wherein R3 is cyclopropyl or substituted or unsubstituted cyclopentyl. 76. The compound according to any of claims 29-72, wherein R3 is cyclopropyl. 77. The compound according to any of claims 29-72, wherein R3 is t-Bu. 78. The compound according to any of claims 29-72, wherein R3 is CF3. 79. The compound according to any of claims 29, 39 and 53, wherein the ring 80. The compound according to any of claims 30 or 40, wherein the ring composed of claim 41, wherein the ring is selected from 82. The compound of claim 42, wherein ring is selected from 83. The compound of claim 31, wherein ring 84. The compound of claim 43, wherein ring 85. A compound of the formula (I) (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, or stereoisomers, isotopic variants and tautomers thereof and wherein R p is independently H, alkyl of 1 to 6 carbon atoms, halo, hydroxyl, carbalkoxy [C (O ) (alkoxy of 1 to 6 carbon atoms)], acyl [C (O) (alkyl of 1 to 6 carbon atoms)] or hydroxyalkyl of 1 to 6 carbon atoms. 86. The compound according to claim 85, wherein Rp is H. 87. A compound according to the formula: or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, isotopic variants and tautomers thereof, wherein: R 4a is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, sulfon [S (0) 2 (alkyl of 1 to 6 carbon atoms)] or halo; R4p is independently H, alkyl of 1 to 6 carbon atoms, halo, hydroxyl, carbalkoxy [C (0) (alkoxy of 1 to 6 carbon atoms)], acyl [C (0) (alkyl of 1 to 6 carbon atoms) carbon)] or hydroxyalkyl of 1 to 6 carbon atoms; and each of R5 and R6 is independently H or alkyl of 1 to 6 carbon atoms. 88. A compound according to the formula: or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, isotopic variants and tautomers thereof, wherein: R 4a is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, sulfon [S (O) 2 (alkyl of 1 to 6 carbon atoms)] or halo; Rp is independently H, alkyl of 1 to 6 carbon atoms, halo, hydroxyl, carbalkoxy [C (O) (alkoxy of 1 to 6 carbon atoms)], acyl [C (0) (alkyl of 1 to 6 carbon atoms) carbon)] or hydroxyalkyl of 1 to 6 carbon atoms; and each of R5 and R6 is independently H or alkyl of 1 to 6 carbon atoms. 89. The compound according to any of claims 87 or 88, wherein Ra is Me and each of R5 and R6 is H. 90. The compound according to any of claims 87-89, wherein R4p is H 91. The compound according to any of claims 87-90, wherein R p is CH2OH 92. The compound according to Claim 1, wherein the compound is selected from: N- (5-isoquinolyl) -2- methyl-4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (2-oxa-5-azabicyclo [4.4.0] deca-7, 9,11-trien-9-yl) -4- [(E) -3,3,3-trifluoroprop-1 -enyl] benzamide; 2-methoxy-N- (2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl) -4- [(Z) -3,3,3-trifluoroprop-l -enyl] benzamide; N- (2, 5-dioxabicyclo [4.4.0] deca-7, 9, ll-trien-9-yl) -2-methoxy-4- [(Z) -3,3,3-trifluoroprop-1-enyl ] benzamide; N- (2, 5-dioxabicyclo [4.4.0] deca-7, 9, ll-trien-9-yl) -2-methoxy-4- [(E) -3,3,3-trifluoroprop-1-enyl ] benzamide; 4- (2-cyclopropylethynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6,8,10-trien-9-yl] -2-methyl-1-benzamide; 4- (2-cyclopentylethynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6, 8, 10-trien-9-yl] -2-methyl-benzamide; 4- (2-Cyclopentylethynyl) -2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6, 8, 10-trien-9-yl] benzamide; 4- (2-cyclopropylethynyl) -2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6, 8, 10-trien-9-yl] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-methoxy-N- (2-oxa-5-azabicyclo [.4.0] deca-7, 9, l-trien-9-yl) benzamide; 4- (2-Cyclopropylethynyl) -2,6-difluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] benzamide; 4- (2-Cyclopropylethynyl) -2,6-difluoro-N- (2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] benzamide; N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7, 9, ll-trien-9-yl] -2-methyl-4- [(E) -3, 3 , 3-trifluoroprop-1-enyl] benzamide; 4- (2-Cyclopentylethynyl) -N- [4- (cyclopropylmethoxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9,13-trien-9-yl] -2-methyl-benzamide; N- [4- (cyclopropylmethoxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] -4- (3, 3-dimethylbut-1-ynyl) -2- methyl-benzamide; 2-fluoro-N- (2-oxa-5-azabicyclo [4. .0] deca-6,8,10-trien-9-yl) -4- [(E) -3,3,3-trifluoroprop- l-enyl] benzamide; 2-fluoro-N- (2-oxa-5-azabicyclo [4.4.0] deca-7, 9,11-trien-9-yl) -4- [(Z) -3,3,3-trifluoropropyl-enyl ] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-fluoro-N- (2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7, 9-ll-trien-9 -yl] benzamide; 4- (2-cyclopentylethynyl) -2-methyl-N- (2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl) benzamide; 4- (2-cyclopentylethynyl) -N- [2, 5-dioxabicyclo [.4.0] deca-7, 9, 1-trien-9-yl] -2-methyl-benzamide; 4- (2-cyclopentylethynyl) -N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] -2-methyl-benzamide; N- (2,5-dioxabicyclo [. .0] deca-6,8,1-trien-9-yl) -2-fluoro-4- [(E) -3,3,3-trifluoroprop-1-enyl) ] benzamide; 4- (2-cyclopropylethynyl) -2-fluoro-N- (2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl) benzamide; 2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7, 9, ll-trien-9-yl] -4- [(E) -3, 3 , 3-trifluoroprop-l-enyl] benzamide; 4- (2-cyclopropylethynyl) -N- [2,5-dioxabicyclo [4. .0] deca-7, 9, 11-trien-9-yl] -2-fluoro-benzamide; 2-chloro-4- (3, 3-dimethylbut-l-ynyl) -N- (2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl) benzamide; 2-chloro-4- (2-cyclopropylethynyl) -N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9, 1, 1-trien-9-yl) benzamide; 2-chloro-N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9, ll-trien-9-yl) -4 - [(E) -3,3,3-trifluoroprop-l -enyl] benzamide; 2-fluoro-N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] -4- [(E) -3, 3, 3 -trifluoroprop-l-enyl] benzamide; 4- (2-cyclopropylethynyl) -2-fluoro-N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9, 11-trien-9-yl] benzamide; 4- (2-cyclopropylethynyl) -N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] -2-methyl-benzamide; 4- (2-cyclopropylethynyl) -N- [2,5-dioxabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] -2-methyl-benzamide; 4- (2-cyclopropylethynyl) -2-methyl-N- (2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-fluoro-N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl ] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- [2,5-dioxabicyclo [4. .0] deca-7, 9, 11-trien-9-yl] -2-fluoro-benzamide; 2-Chloro-4- (2-cyclopropylethynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] benzamide; 2-chloro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4. .0] deca-7, 9, 11-trien-9-yl] -4- [(E) -3,3-trifluoroprop-1-enyl] benzamide; 2-chloro-4- (3, 3-dimethylbut-l-ynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7,9, ll-trien-9 -yl] benzamide; 4- (2-Cyclopentylethynyl) -N- [2,5-dioxabicyclo [4.4.0] deca-7,9, Ll-trien-9-yl] -2-methylsulfonyl-benzamide; 2-fluoro-N- (5-isoquinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-chloro-4- (3, 3-dimethylbut-l-ynyl) -N- (5-isoquinolyl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-methyl-N- (2-methylbenzothiazol-5-yl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- (5-isoquinolyl) -2-methyl-1-benzamide; 2-chloro-4- (3, 3-dimethylbut-l-ynyl) -N- (3-quinolyl) benzamide; 2-Chloro-4- (3, 3-dimethylbut-1-ynyl) -N- (2-methylbenzothiazol-5-yl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2,6-difluoro-N- (5-isoquinolyl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] - 2-methyl-benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2,6-difluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7, 9-ll-trien -9-yl] benzamide; 4- (2-Cyclopropylethynyl) -2-fluoro-N- [(4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6, 8, 10-trien-9-yl ] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-fluoro-N- [(4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [. .0] deca-6, 8, 10-trien-9-yl] benzamide; 4- (2-Cyclopropylethynyl) -2-fluoro-N- [(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6, 8, 10-trien-9-yl ] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-fluoro-N- [(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4. .0] deca-6, 8, 10-trien-9-yl] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-fluoro-N- (2-methylbenzothiazol-5-yl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-fluoro-N- (3-quinolyl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-fluoro-N- (5-isoquinolyl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-fluoro-N- (5-isoquinolyl) -3-methoxy-benzamide; 2-fluoro-N- (2-methylbenzothiazol-5-yl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-fluoro-N- (3-quinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2,6-difluoro-N- (3-quinolyl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2,6-difluoro-N- (2-methylbenzothiazol-5-yl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-methyl-N- (3-quinolyl) benzamide; 2-Chloro-4- (3, 3-dimethylbut-l-ynyl) -N- [(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6, 8, 10 -trien-9-yl] benzamide; 2-chloro-4- (3, 3-dimethylbut-l-ynyl) -N- [(4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6, 8, 10 -trien-9-yl] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- [(4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6, 8, ll-trien-9 -yl] -2-methyl-benzamide; N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9, ll-trien-9-yl] -2-methyl-4- [(E) -3,3, 3 -trifluoroprop-l-enyl] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9, ll-trien-9-yl] -2- methyl-benzamide; 2-methyl-N- (3-quinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (2-methylbenzothiazol-5-yl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- (4-hydroxy-2-oxa-6-azabicyclo [5.4.0] undeca-8, 10, 12-trien-10-yl) -2-methyl-4- [(E) -3, 3, 3 -trifluoroprop-l-enyl] benzamide; N- (2,5-dioxabicyclo [.0] deca-7, 9, ll-trien-9-yl) -2-methyl-4- [(E) -3,3,3-trifluoroprop-1-enyl) ] benzamide; 2-Chloro-4- (3, 3-dimethylbut-l-ynyl) -5-fluoro-N- [4 - (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7, 9, ll-trien -9-yl] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- (lH-indol-7-yl) -2-methyl-benzamide; 2-fluoro-N- [(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7, 9, ll-trien-9-yl] -4- [(E) 3, 3, 3-trifluoroprop-1-enyl] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- [(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6, 8, 10-trien-9 -yl] -2-methyl-benzamide; N- [(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] -2-methyl-4- [(E) -3,3, 3-trifluoroprop-l-enyl] benzamide; 2-methyl-N- (3-methyl-5-isoquinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- [2- (hydroxymethyl) benzothiazol-5-yl] -2-methyl-benzamide; N-benzothiazol-5-yl-4- (3, 3-dimethylbut-l-ynyl) -2-methyl-benzamide; N- (1-chloro-5-isoquinolyl) -4- (3, 3-dimethylbut-1-ynyl) -2-methyl-benzamide; N- (1-chloro-5-isoquinolyl) -2-methyl-4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- (1-acetylindolin-6-yl) -4- (3, 3-dimethylbut-1-ynyl) -2-methyl-benzamide; 4- [(E) -3,3-dimethylbut-l-enyl] -2-methyl-N- (3-quinolyl) benzamide; N- (2, 9-diazabicyclo [4.3.0] nona-1, 3,5,7-tetraen-4-yl) -4- (3,3-dimethylbut-l-ynyl) -2-methyl-benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- (1,3-dioxoindolin-5-yl) -2-methyl-benzamide; N- (lH-benzoimidazol-5-yl) -4- (3, 3-dimethylbut-l-ynyl) -2-methyl-benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-methyl-N- (2-methyl-lH-benzoimidazol-5-yl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- [7- (hydroxymethyl) -3-quinolyl] -2-methyl-benzamide; 4- (3, 3-dimethylbut-l-ynyl) -2-methyl-N- (2-oxo-3H-benzooxazol-6-yl) benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- [8- (hydroxymethyl) -2,7,9-triazabicyclo [4.3.0] nona-2, 4,7, 10-tetraen-4-yl ] -2-methyl-benzamide; 2-methyl-N- (8-quinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (6-quinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (5-quinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (7-quinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- [2- (hydroxymethyl) benzothiazol-5-yl] -2-methyl-4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 3- [[2-methyl-4- [(E) -3,3,3-trifluoroprop-l-enyl] benzoyl] amino] -7,8-dihydro-5H-l, 6-naphthyridine-6-carboxylate tert-butyl; N- [3- (hydroxymethyl) -7-quinolyl] -2-methyl-4- [(E) -3,3,3-trifluoroprop-1-enyl] -benzamide; 2-methyl-N- (5,6,7,8-tetrahydro-l, 6-naphthyridin-3-yl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- (5,7-diazabicyclo [4.3.0] nona-1, 3,5, 8-tetraen-3-yl) -2-methyl-4- [(E) -3,3,3-trifluoroprop-1) -enyl] benzamide; N- [3- (hydroxymethyl) -lH-indazol-6-yl] -2-methyl-4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- (lH-indol-6-yl) -2-methyl-4- [(E) -3,3,3-trifluoroprop-l-enyl] benzamide; N- [3- (hydroxymethyl) -5-oxa-2, 10-diazabicyclo [4.4.0] deca-7, 9, ll-trien-8-yl] -2-methyl-4 - [(E) -3 , 3, 3-trifluoroprop-l-enyl] benzamide; N- [3- (hydroxymethyl) -lH-indazol-5-yl] -2-methyl-4- [(E) -3,3,3-trifluoroprop-l-enyl] benzamide; N- [2- (hydroxymethyl) -lH-indol-5-yl] -2-methyl-4- [(E) -3,3, 3-trifluoroprop-1-enyl] benzamide; N-indan-4-yl-2-methyl-4- [(E) -3,3,3-trifluoroprop-l-enyl] benzamide; 2-methyl-N-tetralin-l-yl-4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; and 2-methyl-N- (2-methyl-6-quinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 93. The compound according to Claim 1, wherein the compound is selected from: 4- (2-cyclopentylethynyl) -N- [4- (cyclopropylmethoxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] -2-methyl-benzamide; N- [4- (cyclopropylmethoxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] -4- (3, 3-dimethylbut-1-ynyl) -2- methyl-benzamide; 4- (2-cyclopentylethynyl) -N- [2,5-dioxabicyclo [4.4.0] deca-7, 9, 11-trien-9-yl] -2-methylsulfonyl-benzamide; 2-fluoro-N- (3-quinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- (lH-indol-7-yl) -2-methyl-benzamide; 4- (3, 3-dimethylbut-l-ynyl) -N- [8- (hydroxymethyl) -2,7,9-triazabicyclo [4.3.0] nona-2, 4, 7, 10-tetraen-4-yl ] -2-methyl-benzamide; 2-methyl-N- (8-quinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (5-quinolyl) -4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 3- [[2-methyl-4- [(E) -3,3,3-trifluoroprop-1-enyl] benzoyl] amino] -7,8-dihydro-5H-l, 6-naphthyridine-6-carboxylate tert-butyl; N- [3- (hydroxymethyl) -lH-indazol-6-yl] -2-methyl-4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide. 94. The compound according to the claim 1, wherein the compound is selected from: 7- [2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) -benzoylamino] -quinolin-3-carboxylic acid; N- [7- (Hydroxy-naphthalen-1-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide; N- [3- (1-Hydroxy-1-methyl-ethyl) -quinolin-7-yl] -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide; N- [3- (1-Hydroxy-ethyl) -quinolin-7-yl] -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide; N- [3- (2-Hydroxy-ethoxymethyl) -quinolin-7-yl] -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide; 2-Methyl-N- (8-??? - 5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- (8-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- [3- (1, 2-Dihydroxy-ethyl) -quinolin-7-yl] -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide; N- (7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- (7-Hydroxymethyl-7,8-dihydro-5H-pyrano [4, 3-b] pyridin-3-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- (7-Hydroxy- [1,8] naphthyridin-2-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; 2-Methyl-N- (5, 6, 7, 8-tetrahydro-quinolin-3-yl) -4- ((E) -3,3,3-trifluoro-propenyl] benzamide; N- ((S) - 7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- ((R) -7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- (6-) Hydroxy-5,6,7,8-tetrahydro-quinolin-3-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; 2-Methyl-N-quinoline- 3-yl-4- ((E) -3,3,3-trifluoro-2-methyl-propenyl) -benzamide; N- (7-Hydroxymethyl- [1, 5] naphthyridin-3-yl) -2-methyl -4- ((E) -3,3,3-trifluoro-propenyl) benzamide; 2-Methyl-N- [1, 5] naphthyridin-3-yl-4- ((E) -3,3, 3- trifluoro-propenyl) -benzamide; 2-Methyl-N- [1,8] naphthyridin-2-yl- ((E) -3,3,3-trifluoro-propenyl) -benzamide; N- [7- (1 -Hydroxy-ethyl) - [1,5] naphthyridin-3-yl] -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; 2-Methyl-N- [1, 8] naphthyridin-3-yl-4- ((E) -3,3,3-trifluoro-propenyl) -ben zamide; N- (1-Acetyl-1,2,3,4-tetrahydro-quinolin-7-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- (7-Hydroxymethyl-quinolin-3-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- (7-Acetyl- [1, 5] naphthyridin-3-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-properyl) benzamide; 2-Methyl-N-quinoxalin-6-yl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide; N- [7- (1-Hydroxy-1-methyl-ethyl) - [1, 5] naphthyridin-3-yl] -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; 2-Methyl-N- [1, 7] naphthyridin-8-yl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide; N- (1-Methanesulfonyl-2,3-dihydro-lH-indol-6-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- (l-Cyclopropancarbonyl-2,3-dihydro-lH-indol-6-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- [2- (1-Hydroxy-ethyl) -benzothiazol-5-yl] -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide; N- [2- (2-Hydroxy-ethyl) -1,3-dioxo-2,3-dihydro-lH-isoindol-5-yl] -2-methyl-4- ((E) -3,3,3 -trifluoro-propenyl) benzamide; N- [1- (2, 2-Dimethyl-propionyl) -2, 3-dihydro-lH-indol-6-yl] -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl ) -benzamide; 2-Formyl-5,6-dihydro-4H-pyran-3-yl ester of diethylcarbamic acid; N- [1- (2-Hydroxy-acetyl) -2, 3-dihydro-lH-indol-6-yl] -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- (1-Acetyl-lH-pyrrolo [2, 3-b] pyridin-5-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- [2- (1-Hydroxy-1-methyl-ethyl) -benzothiazol-5-yl] -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide; N- (2-Acetyl-benzothiazol-5-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; N- (2-Hydroxymethyl-benzooxazol-5-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; 2-Methyl-N- (2-methyl-thiazolo [5, 4-b] pyridin-6-yl) -4- ((E) -3,3,3-trifluoro-propenyl) -benzamide; N- (2-Hydroxymethyl-thiazolo [5, 4-b] pyridin-6-yl) -2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) benzamide; Ethyl 6- (2-methyl-4- ((E) -3,3,3-trifluoro-propenyl) -benzoylamino] -thiazolo [5,4- b] pyridine-2-carboxylic acid ethyl ester; and 2-Methyl-N-thiazolo [5, 4-b] pyridin-6-yl-4- ((E) -3,3,3-trifluoro-propenyl) -benzamide. 95. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent and a pharmaceutically effective amount of a compound of any of Claims 1-94. 96. The pharmaceutical composition of Claim 95, wherein the carrier is a parenteral carrier, oral or topical carrier. 97. A method for preventing, treating, ameliorating or managing a disease or condition, which comprises administering to a patient in need of such prevention, treatment, improvement or management, a prophylactically or therapeutically effective amount of a compound of any one of Claims 1- 94, or the pharmaceutical composition of any of Claims 95-96. 98. A method for preparing a compound of any one of Claims 1-94, which comprises contacting a compound of the formula R3-L-Cy-COCl with a compound of the formula R1R2NH under conditions sufficient to form a compound of according to any of Claims 1-94; and wherein Cy is aryl or heteroaryl. 99. A compound of any of Claims 1-94, or a pharmaceutically acceptable salt or solvate thereof for use as a pharmaceutical agent or a medicament. 100. A use of a compound as defined in any one of Claims 1-94, or a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for treating a disease for which a VR1 antagonist is indicated. . 101. The use according to Claim 94, wherein the disease is selected from acute cerebral ischemia, pain, chronic pain, acute pain, nociceptive pain, neuropathic pain, inflammatory pain, postherpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, related neuropathy. with HIV, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, visceral pain, pain from cancer, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, menstrual pain, bladder disease, such as incontinence, urination disorder, renal colic and cystitis, inflammation, such as burns, rheumatoid arthritis and osteoarthritis, neurodegenerative disease, such as stroke, post-apoplexy pain and multiple sclerosis, lung disease, such such as asthma, cough, chronic obstructive pulmonary disease (COPD) and bronchoconstriction, tra gastrointestinal conditions, such as gastroesophageal reflux disease (GERD), dysphagia, ulcer, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis and Crohn's disease, ischemia, such as cerebrovascular ischemia, emesis, such as emesis induced by cancer chemotherapy and obesity. 102. A method of treating a mammal, including a human, to treat a disease for which a VR1 antagonist is indicated, including treating the mammal with an effective amount of a compound or with a pharmaceutically salt, solvate or composition. acceptable thereof, as defined in any one of Claims 1 to 96. 103. A combination of a compound as defined in any of Claims 1 to 94, and another pharmacologically active agent.