HK1116701A

HK1116701A - Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

Info

Publication number: HK1116701A
Application number: HK08111386.1A
Authority: HK
Inventors: 迈克尔‧凯利; 约翰‧琴凯德; 马太‧达克顿; 基兰‧萨哈斯亚布赫; 萨特纳亚哈娜‧加纳格尼; 瑞温德拉‧B‧尤帕萨尼; 吴国贤; 方云峰; 魏志良; 卡尔‧考伯
Original assignee: 雷诺维斯有限公司
Priority date: 2005-02-28
Filing date: 2006-02-24
Publication date: 2009-01-02

Abstract

Compounds are disclosed that have a formula represented by the following: 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

Amide derivatives as ion channel ligands, pharmaceutical compositions and methods of use thereof

Technical Field

The present invention relates to novel compounds and pharmaceutical compositions containing such compounds. The invention also relates to methods of preventing and/or treating pain and inflammation-associated conditions such as, but not limited to, arthritis, parkinson's disease, alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, pain syndromes (acute and chronic or neuropathic), traumatic brain injury, acute spinal cord injury, neurodegenerative diseases, hair loss (alopecia), inflammatory bowel disease, urinary incontinence, chronic obstructive pulmonary disease, inflammatory bowel disease, osteoarthritis, and autoimmune diseases in a mammal using the compounds and pharmaceutical compositions of the invention.

Background

Studies of in vivo signaling pathways have shown the existence of ion channels and attempted to explain their role. Ion channels are integral membrane proteins with two distinct characteristics: they are gated (turned on or off) by a specific signal, such as membrane potential or direct binding of chemical ligands, and once turned on they direct ions across the cell membrane at a very high rate.

Ion channels are of many types. They can be classified into calcium channels, potassium channels, sodium channels, etc. according to their selectivity for ions. Calcium channels are more permeable to calcium ions than other types of ions, potassium channels are more selective for potassium ions than others, and so on. They can also be classified according to the gating mechanism of the ion channel. In voltage-gated ion channels, the opening probability depends on the membrane potential, while in ligand-gated ion channels, the opening probability is modulated by the binding of small molecules (ligands). Since ligand-gated ion channels accept signals from ligands, they can also be considered "receptors" for ligands.

Ions of ligand-gated ion channels include nAChR (nicotinic acetylcholine receptor) channels, GluR (glutamate receptor) channels, ATP-sensitive potassium channels, G protein-activated channels, cyclic nucleotide-gated channels, and the like.

Transient Receptor Potential (TRP) channel proteins constitute a large diverse family of proteins expressed in many tissues and cell types. This family of channels mediates responses to nerve growth factors, pheromones, olfaction, vascular tone, metabolic stress, and the like, and is found in a variety of organisms, tissues, and cell types, including non-excitable cells, smooth muscle cells, and neuronal cells. In addition, TRP-related channel proteins are involved in various diseases such as some tumor and neurodegenerative diseases, etc. See, e.g., Minke et al, APStracts 9: 0006P (2002).

Nociceptors are specialized primary afferent neurons and are the first cells in a series of neurons that cause the perception of pain. Receptors in these cells can be activated by various noxious chemical or physical stimuli. The essential functions of nociceptors include converting noxious stimuli into depolarizations that initiate action potentials, conducting action potentials from a first sensory site to synapses in the central nervous system, and converting action potentials into neurotransmitter release at the presynaptic terminal, all of which depend on ion channels.

One TRP channel protein of particular interest is the vanilloid receptor. Also known as VR1, the vanilloid receptor is a nonselective cation channel that is activated or sensitized by a range of different stimuli, including capsaicin, thermal and acid stimuli, lipid bilayer metabolites (arachidonoyl ethanolamide), and lipoxygenase metabolites. See, e.g., Smith et al, Nature, 418: 186-190(2002). VR1 does not distinguish between monovalent cations, but it is clearly preferred to select divalent cations whose permeability order is: ca²⁺＞Mg²⁺＞Na⁺＝K⁺＝Cs⁺。Ca²⁺Of particular importance for the function of VR1, extracellular Ca²⁺Mediate desensitization that enables neurons to adapt to a particular stimulus by reducing their 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 internal organs including the dermis, bone, bladder, gastrointestinal tract, and lungs. It is also expressed in other neural and non-neural tissues including CNS, nuclear, renal, gastric and T cells. The VR1 channel is a member of the ion channel superfamily with 6 transmembrane domains, with the highest homology to the TRP ion channel family.

VR1 knockout mice have shown reduced sensitivity to heat and acid stimuli. See, e.g., Caterina et al, Science, 14: 306-313(2000). This supports the concept that VR1 is not only capable of producing a painful response, but also of sustaining the basal activity of the sensory nerve. VR1 agonists and antagonists have been used as analgesics to treat pain of various causes or etiology, such as acute, inflammatory and neuropathic pain, dental pain, and headaches (e.g., 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, the treatment and prevention of pain syndromes (acute and chronic or neurological), traumatic brain injury, spinal cord injury, neurodegenerative diseases, hair loss (alopecia), inflammatory bowel disease and autoimmune diseases, kidney disease, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleep disorders, cognitive disorders, depression, anxiety, blood pressure, lipid disorders, osteoarthritis and atherosclerosis.

Compounds such as the compounds of the present invention may interact with vanilloid receptors and are therefore useful for treating or preventing or ameliorating these conditions.

Many vanilloid compounds of different structures are known in the art, such as those described in european patent application nos. EP 0347000 and EP 0401903, british patent application No. GB 2226313, and international patent application publication No. WO 92/09285. Particularly notable examples of vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N-vanillyl-6-nonenamide isolated from pepper plants, capsazepine (Tetrahedron, 53, 1997, 4791) and also ovanile or N- (4-hydroxy-3-methoxybenzyl) oleamide (j. med. chem., 36, 1993, 2595).

International patent application publication No. WO 02/08221 discloses diarylpiperazines and related compounds that bind vanilloid receptors, especially vanilloid type I receptors, also known as capsaicin or VR1 receptors, with high selectivity and high affinity. These compounds are said to be useful in the treatment of chronic and acute pain symptoms, itching and urinary incontinence.

International patent application publication nos. WO 02/16317, WO 02/16318 and WO 02/16319 suggest that compounds having high affinity for vanilloid receptor may be used for the treatment of gastro-duodenal ulcers.

International patent application publication No. WO 2005/046683, published 26/5/2005, discloses a series of compounds having demonstrated VR-1 antagonist activity which are believed to be useful in treating conditions associated with VR-1 activity.

U.S. Pat. Nos. US 3,424,760 and US 3,424,761 both describe a series of 3-ureidopyrrolidines which are said to have analgesic, central nervous system and physiopharmacological (pyschopharmacologic) activity. These patents specifically disclose the compounds 1- (1-phenyl-3-pyrrolidinyl) -3-phenylurea and 1- (1-phenyl-3-pyrrolidinyl) -3- (4-methoxyphenyl) urea, respectively. International patent application publication nos. WO 01/62737 and WO00/69849 disclose a series of pyrazole derivatives which are said to be useful in the treatment of disorders and diseases associated with NPY receptor subtype Y5 such as obesity. WO 01/62737 discloses in particular the compound 5-amino-N-isoquinolin-5-yl-1- [ 3-trifluoromethyl) phenyl ] -1H-pyrazole-3-carboxamide. WO00/69849 discloses inter alia the compounds 5-methyl-N-quinolin-8-yl-1- [3- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carboxamide, 5-methyl-N-quinolin-7-yl-1- [ 3-trifluoromethyl) phenyl ] -1H-pyrazole-3-carboxamide, 5-methyl-N-quinolin-3-yl-1- [3- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carboxamide, N-isoquinolin-5-yl-5-methyl-1- [3- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carboxamide, and their use as fungicides, 5-methyl-N-quinolin-5-yl-1- [3- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carboxamide, 1- (3-chlorophenyl) -N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide, N-isoquinolin-5-yl-1- (3-methoxyphenyl) -5-methyl-1H-pyrazole-3-carboxamide, 1- (3-fluorophenyl) -N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide, 1- (2-chloro-5-trifluoromethylphenyl) -N-isoquinoline-5-carboxylic acid -yl-5-methyl-1H-pyrazole-3-carboxamide, 5-methyl-N- (3-methylisoquinolin-5-yl-1- [3- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carboxamide, 5-methyl-N- (1, 2, 3, 4-tetrahydroisoquinolin-5-yl) -1- [3- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carboxamide.

German patent application No. 2502588 describes a series of piperazine derivatives. This application discloses inter alia the compound N- [3- [2- (diethylamino) ethyl ] -1, 2-dihydro-4-methyl-2-oxo-7-quinolinyl ] -4-phenyl-1-piperazinecarboxamide.

We have now found that certain compounds have surprising potency and selectivity as VR-1 antagonists. Certain compounds of the present invention are believed to be particularly beneficial as VR-1 antagonists due to their improved aqueous solubility and metabolic stability.

Summary of The Invention

It has now been found that certain compounds, such as those listed herein, are capable of altering ion channels, such as the VR1 cation channel, in mammals. Thus, the compounds of the present invention are potent antagonists of VR1, having analgesic activity by systemic administration. The compounds of the invention may exhibit lower toxicity, good absorption, good half-life, good solubility, low protein binding affinity, fewer drug-drug interactions, low inhibitory activity on HERG channels, reduced QT prolongation and good metabolic stability. These findings have led to new compounds of therapeutic value. Also described are pharmaceutical compositions comprising the compounds of the invention as active ingredients and their use in the treatment, prevention or amelioration of a number of conditions in a mammal, such as but not limited to pain of various genesis or etiology, e.g., acute, chronic, inflammatory and neuropathic pain, dental pain and headache (e.g., migraine, cluster headache and tension headache).

Thus, in a first aspect of the present invention, compounds having formula I, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, as well as stereoisomers and tautomers thereof, are disclosed that are capable of modulating ion channels in vivo:

wherein:

w, Z, Y and X are each independently N or CR⁴；

L is- (CR)⁵＝CR⁶) -or- (C ≡ C) -;

R¹is a substituted or unsubstituted bicyclic aryl or bicyclic heteroaryl;

R³is C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, halo C₁-C₆Alkyl, heteroalkyl, aryl, cycloalkyl, cycloheteroalkyl, heteroaryl, aralkyl or heteroaralkyl;

each R⁴Independently of one another is hydrogen, C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl radical, C₂-C₆Acyl radical, C₂-C₆Acylamino group, C₁-C₆Alkylamino radical, C₁-C₆Alkylthio radical, C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkyl aryl amino, aryl C₁-C₆Alkoxy, amino, aryl C₁-C₆Alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxyl, carbamoyl, carboxyl, cyano, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio; and

R⁵and R⁶Each independently is H, halo, C ₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, hetero C₁-C₆Alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.

A further embodiment of the compounds of formula IA of the present invention are the compounds hereinafter referred to as formula IA', wherein R is³-L represents CR³R⁶＝CR⁵In part

Wherein R is³Such as inDefinition in Compounds of the formula I, R⁵And R⁶Independently selected from hydrogen, halo, C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, hetero C₁-C₆Alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl groups.

In certain specific compounds, R³Is selected from C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl; each R⁵And R⁶Independently selected from hydrogen, halo and substituted and unsubstituted C₁-C₆An alkyl group; and 0-3 groups selected from W, Z, X and Y represent N.

In the compounds of formula IA', R⁵And R⁶May be, for example, independently represent hydrogen, halo, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group. Preferably, R⁵And R⁶Represents hydrogen.

Another particular embodiment of a compound of formula IA is a compound hereinafter referred to as formula IA ", wherein R is³-L represents R³The C.ident.C-moiety.

In the compounds of formulae I, IA 'and IA', W, Z, X and Y may, for example, each represent CR⁴Especially CH. Alternatively, X may represent N, and W, Z and Y may each represent CR ⁴. In another group of compounds, X, Y and Z each represent CR⁴Especially CH. In another group of compounds, W is N. In yet another set of examples of compounds, Y is N.

Typically, in compounds of formula I, L is preferably- (C ═ C) -or-C ≡ C-. Thus, in one example of a compound, L represents- (C ═ C) -. In another group of examples of compounds, L represents-C.ident.C-.

In the compounds of formulae I, IA' and IA ″, R¹For example, may represent a substituted or unsubstituted bicyclic aryl or bicyclic heteroaryl group, such as a substituted naphthyl, quinoline, isoquinoline or tetrahydroquinoline. Examples of the substituent include alkyl, alkyl (OH), -COOH, C (Me)₃、CH(Me)₂Halo, CF₃Cyano and methoxy. Or, R¹May represent a substituted or unsubstituted tetrahydroisoquinoline or benzodioxan.

In the compounds of formulae I, IA' and IA ″, R³For example may represent CR⁶’R⁷R⁸Wherein R is⁶' represents hydrogen, halogeno, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group; r⁷And R⁸Each independently is halo, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group; or R⁷And R⁸Together form a substituted or unsubstituted C₃-C₈A cycloalkyl ring. For example R⁷May represent lower alkyl (e.g. methyl). For example R⁸May represent lower alkyl (e.g. methyl). In a specific example, R ⁶' may represent hydrogen, R⁷And R⁸May represent a methyl group. Or, R⁶’、R⁷And R⁸Each may represent a methyl group. Or, R⁶’、R⁷And R⁸Each may represent fluorine. Or, R⁶' may represent hydrogen and R⁷And R⁸Together form a cyclopropyl ring.

In further embodiments of the compounds of formulas I, IA' and IA ″, R³For example, may represent a substituted or unsubstituted aryl or heteroaryl group.

In a first alternative embodiment of compounds of formula IA, R³Is CF₃N-propyl or a group of the formula

Wherein R is²' is hydrogen or alkyl; and wherein two R are²' may be joined together to form a cycloalkyl or cycloheteroalkyl ring having from 3 to 8 atoms; provided that at least two R²' is an alkyl group.

For compounds of formula I, R¹May be a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted tetrahydronaphthyl group. Furthermore, R¹And may also be a substituted or unsubstituted bicyclic heteroaryl, and in one embodiment, the bicyclic heteroaryl may be selected from: tetrahydroquinolines, tetrahydroisoquinolines, benzodioxans, benzopyrans, indoles, and benzimidazoles. More specifically, the bicyclic heteroaryl group may be quinoline, isoquinoline, benzodioxane, and benzoxazine. In one embodiment, the substituents on the bicyclic heteroaryl group are selected from the group consisting of hydrogen, alkyl, trifluoromethyl, halo, methoxy, trifluoromethoxy, amino, and carboxyl. In yet a further embodiment, the substituents on the bicyclic heteroaryl group are selected from the group consisting of tert-butyl, cyano, trifluoroalkyl, halo, nitro, methoxy, amino, and carboxyl.

In yet another embodiment, with respect to compounds of formula I, R¹May be a substituted or unsubstituted isoquinolin-5-yl, quinolin-3-yl, benzodioxan-6-yl or benzoxazin-6-yl group.

In yet another embodiment, with respect to compounds of formula I, R¹May be substituted or unsubstituted:

wherein, when possible, ring N may be further substituted with H or alkyl.

In yet another embodiment, the compounds of formula (I) areFor compounds of formula I, R¹May be substituted or unsubstituted:

wherein, when possible, ring N may be further substituted with H or alkyl.

In yet another embodiment, with respect to compounds of formula I, R³And may be a substituted or unsubstituted cyclopropyl.

In still further embodiments, with respect to compounds of formula I, R³May be CF₃。

In yet a further embodiment, the compounds of the present invention are listed and they may be selected from a list of such compounds listed in table 1 below. The table contains over 200 compounds that have been or can be synthesized and have groups that have been shown to modify ion channels in vivo and thus have functions related to capsaicin and vanilloid receptors in the therapeutic applications listed herein.

In a further aspect of the invention, compounds capable of modifying ion channels in vivo and having the formula I-I, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, and stereoisomers and tautomers thereof are disclosed:

wherein:

w, Z, Y and X are each independently N or CR⁴；

L is substituted or unsubstituted- (CR)⁵＝CR⁶) -or- (C ≡ C) -;

R¹is a substituted bicyclic aryl or bicyclic heteroaryl;

each R⁴Independently of one another is hydrogen, C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, acylamino, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkoxy, amino, aryl, arylalkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxyl, carbamoyl, cyano, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxy, nitro or thio; r⁵And R⁶Each independently is H, halo, C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.

A further embodiment of the compounds of formulae I-IA of the present invention are those hereinafter referred to as formula IA', wherein R is³-L represents CR³R⁶＝CR⁵In part

Wherein R is³As defined in the compounds of the formula I, R⁵And R⁶Independently selected from hydrogen, halo, C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl groups.

In certain specific compounds, R³Is selected from C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl; each R⁵And R⁶Independently selected from hydrogen, halo and substituted and unsubstituted C₁-C₆An alkyl group; and W, Z, X and 0-3 of Y represent N.

Another specific embodiment of the compounds of formulae I-IA is the compound hereinafter referred to as formula IA ", wherein R is³-L represents R³The C.ident.C-moiety.

In the compounds of the formulae I-I, IA 'and IA', W, Z, X and Y may, for example, each represent CR⁴Especially CH. Alternatively, X may represent N, and W, Z and Y may each represent CR⁴. In another group of compounds, X, Y and Z each represent CR ⁴Especially CH. In another group of compounds, W is N. In yet another set of examples of compounds, Y is N.

In another group of examples of compounds of formulae I-I, IA 'and IA', W, X and Z each represent CR⁴In particular CH, Y represents CR⁴". In this set of examples, R⁴"for example may represent substituted alkyl, halo, sulfone, alkoxy or amino. Specifically, R⁴"may represent substituted alkyl or halo. More specifically, R⁴"may be methyl, chloro, trifluoromethyl or fluoro.

In another group of examples of compounds of formula I-I, IA 'and IA', W and X each represent CR⁴In particular CH, Y and Z each represent CR⁴". In this set of examples, each R⁴"for example may represent substituted alkyl, halo, alkoxy or amino. Specifically, R⁴"may represent substituted alkyl or halo. More specifically, R⁴"may be methyl, trifluoromethyl, chloro or fluoro.

Typically, in compounds of formula I-I, L is preferably- (C ═ C) -or-C ≡ C-. Thus, in one example of a compound, L represents- (C ═ C) -. In another group of examples of compounds, L represents-C.ident.C-.

In the compounds of formulae I-I, IA' and IA ″, R¹For example, may represent a substituted bicyclic aryl or bicyclic heteroaryl group such as a substituted benzopyranyl, benzoxazine, benzothiazine, indolyl, indazolyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, carbazolyl, naphthalene, tetrahydronaphthalene, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinyl, or dihydroisoquinolinyl group. Examples of the substituent include alkyl, alkyl (OH), -COOH, C (Me) ₃、CH(Me)₂Halo, CF₃Cyano and methoxy. Or, R¹May represent substituted or unsubstituted benzoxazines, dihydrobenzoxazines, benzodioxines or benzodioxans.

In the compounds of formulae I-I, IA' and IA ″, R³For example may represent CR⁶’R⁷R⁸Wherein R is⁶' represents hydrogen, halogeno, C₁-C₆Alkyl orHydroxy radical C₁-C₆An alkyl group; r⁷And R⁸Each independently is halo, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group; or R⁷And R⁸Together form a substituted or unsubstituted C₃-C_aA cycloalkyl ring. For example R⁷May represent lower alkyl (e.g. methyl). For example R⁸May represent lower alkyl (e.g. methyl). In a specific example, R⁶' may represent hydrogen, R⁷And R⁸May represent a methyl group. Or, R⁶’、R⁷And R⁸Each may represent a methyl group. Or, R⁶’、R⁷And R⁸Each may represent fluorine. Or, R⁶' may represent hydrogen and R⁷And R⁸Together form a cyclopropyl ring.

In a further embodiment of the compounds of formulae I-I, IA' and IA ″, R³For example, may represent a substituted or unsubstituted aryl or heteroaryl group.

Wherein R is²' is hydrogen or alkyl; and wherein two R are²' may be joined together to form a cycloalkyl or cycloheteroalkyl ring having from 3 to 8 atoms; provided that at least two R ²' is an alkyl group.

For compounds of formulae I-I, IA 'and IA', R¹May be a substituted naphthyl group or a substituted tetrahydronaphthyl group. Furthermore, R¹Substituted bicyclic heteroaryl groups are also possible, and in one embodiment, the bicyclic heteroaryl group may be selected from: tetrahydroquinoline, tetrahydroisoquinoline, benzoxazine, dihydrobenzoxazine, benzodioxine, dihydrobenzodioxine, benzopyran, indoleIndole and benzimidazole. More specifically, the bicyclic heteroaryl group may be quinoline, isoquinoline, benzodioxane, and benzoxazine. In one embodiment, the substituents on the bicyclic heteroaryl group are selected from the group consisting of hydrogen, alkyl, trifluoromethyl, halo, methoxy, trifluoromethoxy, amino, and carboxyl. In yet a further embodiment, the substituents on the bicyclic heteroaryl group are selected from the group consisting of substituted alkyl, cyano, trifluoroalkyl, halo, nitro, methoxy, amino, and carboxyl. More specifically, the substituents on the bicyclic heteroaryl group are selected from alkyl groups substituted with hydroxy or amino. Most particularly, the substituent on the bicyclic heteroaryl is hydroxyalkyl, such as hydroxymethyl, hydroxyethyl or hydroxypropyl.

In yet another embodiment, for compounds of formulas I-I, IA 'and IA', R ¹May be substituted or unsubstituted:

wherein A is¹、A²、A³、A⁴、B¹And B²Each independently is CR⁴' and N;

and each R⁴' is independently H, substituted or unsubstituted lower alkyl, halo, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, or hydroxyalkyl. More specifically, R¹May be substituted or unsubstituted:

in yet another embodiment, for compounds of formulas I-I, IA 'and IA', R¹May be substituted:

wherein A is⁵And A⁸Each independently is CR⁴’R⁴’、NR⁴', O, S, SO or SO₂；

A⁶And A⁷Each independently is CR⁴’、NR⁴’、CR⁴’R⁴' or CO; b is³And B⁴Each independently is CR⁴' and N; when R is⁴' when C is attached, each R⁴Independently H, C₁-C₆Alkyl, halo or hydroxy C₁-C₆Alkyl, and when R⁴' when N is attached, each R⁴' independently is H or C₁-C₆An alkyl group; the dotted bond represents a single bond or a double bond. More specifically, R¹May be substituted or unsubstituted:

in yet another embodiment, for compounds of formulas I-I, IA 'and IA', R¹May be substituted or unsubstituted:

wherein A is⁹、A¹⁰And A¹¹Each independently is CR ⁴’、CR⁴’R⁴’、CO、CS、N、NR⁴', O, S, SO or SO₂；B⁵And B⁶Each independently is CR⁴' and N;

when R is⁴' when C is attached, each R⁴' independently is H, C₁-C₆Alkyl, halo or hydroxy C₁-C₆Alkyl, and when R⁴' when N is attached, each R⁴' independently is H or C₁-C₆An alkyl group; and

each dotted bond independently represents a single or double bond. More specifically, R¹May be substituted or unsubstituted:

wherein A is¹、A²、A³、A⁴、B¹And B²Each independently is CH and N; r⁴' is a substituted or unsubstituted lower alkyl group. More specifically, R⁴Is' a C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group.

In yet another embodiment, for compounds of formulas I-I, IA 'and IA', R¹May be substituted

Wherein A is⁵And A⁸Each independently is CH₂CHMe, NH, NMe, O, S, SO or SO₂；R⁴Is' a C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group.

Wherein R is⁴' is a substituted alkyl group. More specifically, R⁴Is' a C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group.

In yet another embodiment, for compounds of formulas I-I, IA 'and IA', R ¹May be substituted

Wherein A is⁹、A¹⁰And A¹¹Each independently is CH, CH₂N, NH, O or S; b is⁵And B⁶Each independently is CH and N; each R⁴' independently is H, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group; each dotted bond independently represents a single or double bond.

And wherein R⁴' independently is H, C₁-C₆Alkyl, halo or hydroxy C₁-C₆An alkyl group.

In yet another embodiment, for compounds of formulas I-I, IA 'and IA', R ¹May be a substituted dihydrobenzodioxine-6-yl or dihydrobenzoxazin-6-yl group.

wherein, when applicable, ring N can be replaced by H or C₁-C₆Alkyl is further substituted.

wherein, when possible, ring N may be further substituted with H or alkyl.

In yet another embodiment, for compounds of formulas I-I, IA 'and IA', R⁴' may be a hydroxyl group C₁-C₆An alkyl group. In more specific embodiments thereof, R⁴' may be- (CH)₂)_n-OH; n may be selected from 1-3. In further embodiments thereof, R⁴' may be-CH₂OH。

In yet another embodiment, for compounds of formulas I-I, IA 'and IA', R¹Can be as follows:

in yet another embodiment, for compounds of formulas I-I, IA 'and IA', R ¹Can be as follows:

in yet another embodiment, with respect to the compounds of formulas I-I, IA 'and IA', R³May be a substituted or unsubstituted cycloalkyl. More specifically, R³Can be substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

And then another concrete bodyIn embodiments, for compounds of formulas I-I, IA 'and IA', R³May be a cyclopropyl group.

In yet a further embodiment, with respect to the compounds of formulas I-I, IA 'and IA', R³May be CF₃Or CHF₂. More specifically, R⁵May be CF₃。

In yet another embodiment, for compounds of formulas I-I, IA 'and IA', R³It may be tert-butyl or isopropyl. More specifically, R³May be a tert-butyl group.

In yet another embodiment, the present invention provides an amide compound of formula II:

wherein R is⁵Is tert-butyl, CF₃Or cyclopropyl; z and Y are independently C-H, C-F, C-Cl, C-Me, C-SO₂Me or C-OMe; b is³And B⁴Independently is CR⁴' or N; and wherein A⁵And A⁸Each independently is CR⁴’R⁴’、NR⁴', O, S, SO or SO₂；A⁶And A⁷Each independently is CR ⁴’、NR⁴’、CR⁴’R⁴' or CO; each R⁴' is independently H, substituted or unsubstituted alkyl or aryl; the dotted bond represents a single bond or a double bond. In a specific embodiment, each R is⁴' is independently H, substituted or unsubstituted alkyl.

In yet another embodiment, the present invention provides an amide compound of formula III:

wherein R is³Is tert-butyl, CF³Or cyclopropyl; z and Y are independently C-H, C-F, C-Cl, C-Me, C-SO₂Me or C-OMe; b is³And B⁴Independently is CR⁴' or N; and wherein A⁵And A⁸Each independently is CR⁴’R⁴’、NR⁴', O, S, SO or SO₂；A⁶And A⁷Each independently is CR⁴’、NR⁴’、CR⁴’R⁴' or CO; each R⁴' is independently H, substituted or unsubstituted alkyl or aryl; the dotted bond represents a single bond or a double bond. In a specific embodiment, each R is⁴' is independently H, substituted or unsubstituted alkyl.

In yet another embodiment, the present invention provides an amide compound of formula IV:

wherein R is³Is tert-butyl, CF₃Or cyclopropyl; z and Y are independently C-H, C-F, C-Cl, C-Me, C-SO₂Me or C-OMe; b is³And B⁴Independently is CR⁴' or N; a. the⁵And A⁸Independently is O or NH.

In a particular embodiment, with respect to compounds of formula IV, R³May be a tert-butyl group. In another specific embodiment, with respect to compounds of formula IV, R ³May be CF₃. In another specific embodiment, with respect to compounds of formula IV, R³May be a cyclopropyl group.

In a particular embodiment, for compounds of formula IV, both Y and Z may be C-H. In another specific embodiment, with respect to the compound of formula IV, Y is C-H and Z is C-F or C-Cl. In another specific embodiment, with respect to the compounds of formula IV, Y is C-H and Z is C-F. In another specific embodiment, with respect to the compound of formula IV, Y is C-H and Z is C-Cl. In a further specific embodiment, with respect to the compound of formula IV, Y is C-H and Z is C-Me or C-OMe. In a particular embodiment, for compounds of formula IV, both Y and Z may be C-F. In a particular embodiment, for compounds of formula IV, both Y and Z may be C-Cl. In yet another embodiment, for compounds of formula IV, both Y and Z may be C-Me.

In a particular embodiment, for compounds of formula IV, a⁵And A⁸May be O. In a particular embodiment, for compounds of formula IV, a⁵And A⁸May be NH. In a particular embodiment, for compounds of formula IV, a ⁵Can be O, A⁸May be NH. In a particular embodiment, for compounds of formula IV, a⁵May be NH, A⁸May be O.

In yet another embodiment, the present invention provides an amide compound of formula V:

In a particular embodiment, with respect to compounds of formula V, R³May be a tert-butyl group. In another specific embodiment, with respect to compounds of formula V, R³May be CF₃. In another specific embodiment, the compounds of formula VIn the sense that R³May be a cyclopropyl group.

In a particular embodiment, for compounds of formula V, both Y and Z may be C-H. In another specific embodiment, with respect to the compounds of formula V, Y is C-H and Z is C-F or C-Cl. In another specific embodiment, with respect to the compounds of formula V, Y is C-H and Z is C-F. In a further embodiment, with respect to the compound of formula V, Y is C-H and Z is C-Cl. In another specific embodiment, for compounds of formula V, Y is C-H and Z is C-Me or C-OMe.

In a particular embodiment, for compounds of formula V, Y and Z may both be C-F. In a particular embodiment, for compounds of formula V, both Y and Z may be C-Cl. In yet another embodiment, for compounds of formula IV, both Y and Z may be C-Me.

In a particular embodiment, for compounds of formula V, A⁵And A⁸May be O. In a particular embodiment, for compounds of formula V, A⁵And A⁸May be NH. In a particular embodiment, for compounds of formula V, A⁵Can be O, A⁸May be NH. In a particular embodiment, for compounds of formula V, A⁵May be NH, A⁸May be O.

In a further aspect, the present invention provides a compound of formula (VI) or a pharmaceutically acceptable salt, solvate or prodrug thereof; stereoisomers and tautomers thereof:

wherein: w, Z, Y and X are each independently N or CR⁴；B⁷、B⁸And B⁹Each independently is N or CR⁴(ii) a L is- (CR)⁵＝CR⁶) -or- (C ≡ C) -; r³Is C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, halo C₁-C₆Alkyl, heteroalkyl, aryl, cycloalkyl, cycloheteroalkyl, heteroaryl, aralkyl or heteroaralkyl; each R ⁴Independently of one another is hydrogen, C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl radical, C₂-C₆Acyl radical, C₂-C₆Acylamino group, C₁-C₆Alkylamino radical, C₁-C₆Alkylthio radical, C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkyl aryl amino, aryl C₁-C₆Alkoxy, amino, aryl C₁-C₆Alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxyl, carbamoyl, cyano, cycloheteroalkyl, di-C₁-C₆Alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxy, nitro or thio; r⁵And R⁶Each independently is H, halo, C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; r⁴Is C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group.

In certain embodiments of formula (VI), R³Is CR⁶’R⁷R⁸Wherein R is⁶' is hydrogen, halo, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group; r⁷And R⁸Each independently being halo or substituted or unsubstituted C₁-C₆An alkyl group; or R⁷And R⁸Together form a substituted or unsubstituted C₃-C₈A cycloalkyl ring. For example, R⁷May represent lower alkyl (e.g. methyl). For example R⁶' may also represent lower alkyl (e.g. methyl). In a specific example, R ⁶' may represent hydrogen and R⁷And R⁸May represent a methyl group. Or, R⁶’、R⁷And R⁸Each may represent a methyl group. Or, R⁶’、R⁷And R⁸Each may represent fluorine. Or, R⁶' may represent hydrogen, and R⁷And R⁸May together form a cyclopropyl ring. In certain embodiments, R³Selected from CF₃T-butyl and cycloalkyl. In a specific embodiment, R³Is CF₃. In a specific embodiment, R³Is a tert-butyl group. In a specific embodiment, R³Selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a specific embodiment, R³Is cyclopropyl.

In the compounds of the formula (VI), R⁵And R⁶May, for example, independently represent hydrogen, halo, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group. Preferably, R⁵And R⁶Represents hydrogen. Typically, in compounds of formula (VI), L is preferably- (C ═ C) -or-C ≡ C-. Thus, in one example of a compound, L represents- (C ═ C) -. In another group of examples of compounds, L represents-C.ident.C-.

In certain embodiments of formula (VI), B⁷、B⁸And B⁹Each is N or CR⁴Wherein R is⁴Selected from substituted alkyl, halo, alkoxy or amino. In certain embodiments, B⁷、B⁸And B⁹Each is CR⁴. In certain embodiments, R⁴Independently H, CH₃、CF₃Cl or F. In certain embodiments, each R is ⁴Is H.

In the compounds of the formula (VI), W, Z, X and Y may for example each represent CR⁴Especially CH. Alternatively, X may represent N, and W, Z and Y may each represent CR⁴. In another group of compounds, X, Y and Z each represent CR⁴Especially CH. In another group of compounds, W is N. In yet another set of examples of compounds, Y is N.

In another group of examples of compounds of formula (VI), W, X and Z each represent CR⁴In particular CH, and Y represents CR⁴". In this set of examples, R⁴"for example may represent substituted alkyl, halo, alkoxy or amino. Specifically, R⁴"may represent substituted alkyl or halo. More specifically, R⁴"may be methyl, chloro or fluoro.

In another group of examples of compounds of formula (VI), W and X each represent CR⁴In particular CH, and Y and Z each represent CR⁴". In this set of examples, each R⁴"for example may represent substituted alkyl, halo, alkoxy or amino. Specifically, R⁴"may represent substituted alkyl or halo, more particularly methyl, chloro or fluoro.

In certain embodiments of formula (VI), W and X are each N or CR⁴Y and Z are each N or CR⁴", and each R⁴"is independently selected from the group consisting of hydrogen, alkyl, trihaloalkyl and halo. In certain embodiments, each R is ⁴"independently is H, CH₃、CF₃Cl or F. In certain embodiments, each R is⁴Is H.

In certain embodiments of formula (VI), W, X and Z are each N or CH, and Y is C-CH₃C-Cl or C-F.

In certain embodiments of formula (VI), R⁴' is a hydroxy-substituted alkyl group. In certain embodiments of formula (VI), R⁴' is- (CH)₂)_n-OH, wherein n is selected from 1-6. In certain embodiments of formula (VI), R⁴' is CH₂OH。

In certain embodiments of formula (VI), L is- (C ═ C) -or-C ≡ C-; w, X and Y are each CH; z is CR⁴", and wherein, R⁴"is lower alkyl; r³Selected from CF₃Tert-butyl and cyclopropyl; r⁴' is a hydroxy-substituted alkyl group. In certain embodiments of formula (VI), L is- (C ═ C) -or-C ≡ C-; w, W,X and Y are each CH; z is CR⁴", and wherein R⁴"is methyl; r³Selected from CF₃Tert-butyl and cyclopropyl; r⁴' is a hydroxy-substituted alkyl group.

In certain embodiments of formula (VI), L is- (C ═ C) -or-C ≡ C-; w, X and Y are each CH; z is CR⁴", and wherein R⁴"is methyl; r³Selected from CF₃Tert-butyl and cyclopropyl; r⁴' is- (CH)₂)_n-OH, wherein n is an integer from 1 to 6. In certain embodiments of formula (VI), L is- (C ═ C) -or-C ≡ C-; w, X and Y are each CH; z is CR ⁴", and wherein R⁴"is methyl; r³Selected from CF₃Tert-butyl and cyclopropyl; r⁴' is CH₂OH。

In certain embodiments of formula (VI), L is- (C ═ C) -or-C ≡ C-; w, X and Y are each CH; z is CR⁴", and wherein R⁴"is methyl; r³Is CF₃；R⁴' is CH₂And (5) OH. In certain embodiments of formula (VI), L is- (C ═ C) -or-C ≡ C-; w, X and Y are each CH; z is CR⁴", and wherein R⁴"is methyl; r³Is a tert-butyl group; r⁴' is CH₂And (5) OH. In certain embodiments of formula (VI), L is- (C ═ C) -or-C ≡ C-; w, X and Y are each CH; z is CR⁴", and wherein R⁴"is methyl; r³Is cyclopropyl; r⁴' is CH₂OH。

The compounds of the invention are useful in the treatment of inflammatory pain and associated hyperalgesia and allodynia. They may also be used to treat neuropathic pain and associated hyperalgesia and allodynia (e.g. trigeminal or herpetic neuralgia, diabetic neuropathy, causalgia, sympathetically maintained pain and afferent syndromes such as brachial plexus avulsion). The compounds of the invention are also useful as anti-inflammatory agents for the treatment of arthritis and as agents for the treatment of parkinson's disease, alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, traumatic brain injury, spinal cord injury, neurodegenerative diseases, hair loss (alopecia), inflammatory bowel disease, autoimmune diseases, renal diseases, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleep disorders, cognitive disorders, depression, anxiety, blood pressure, lipid disorders, and atherosclerosis.

In one aspect, the invention provides compounds capable of modifying ion channels in vivo. Representative ion channels that can be so modified include voltage-gated channels and ligand-gated channels, including cation channels such as vanilloid channels.

In a further aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutical carrier, excipient or diluent. In this aspect of the invention, the pharmaceutical composition may contain one or more compounds described herein.

In a further aspect of the invention, the method is for the treatment of mammals, including humans and lower mammals, which are susceptible to or affected by those conditions listed herein, in particular such conditions may be associated with, for example, arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, hair loss (alopecia), inflammatory bowel disease and autoimmune diseases, comprising administering an effective amount of one or more of the above pharmaceutical compositions.

In another aspect of the method of treatment, the invention provides a method of treating a mammal susceptible to or affected by a condition that causes a pain response or is associated with maintaining a dysregulation of sensory nerve basal activity. The compounds are useful as analgesics to treat pain of various genesis or etiology, for example, acute pain, inflammatory pain (e.g., pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, sympathetic reflex dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia syndrome, phantom limb pain, post-mastectomy pain (post-mastectomy pain), peripheral neuropathy, HIV neuropathy, and chemotherapy-induced neuropathy and other iatrogenic neuropathies); visceral pain (e.g., visceral pain associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and urological conditions), dental pain, and headache (e.g., migraine, cluster headache, and tension headache).

In other aspects of the method of treatment, the invention provides a method of treating a mammal susceptible to or affected by: neurodegenerative diseases and disorders such as parkinson's disease, alzheimer's disease and multiple sclerosis; diseases and disorders mediated by or resulting in neuritis, such as traumatic brain injury, stroke, and encephalitis; centrally mediated neuropsychiatric diseases and disorders such as depression, mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders, and cognitive disorders; epilepsy and seizures; prostate, bladder and intestinal dysfunction, such as urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; irritable bowel syndrome, overactive bladder, respiratory and airway diseases and disorders such as allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders mediated by or resulting in inflammation, such as rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis and atherosclerosis; itch/pruritus, such as psoriasis; alopecia (alopecia); obesity; lipid disorders; cancer; blood pressure; spinal cord injury; renal disease, comprising administering an amount of one or more of the above pharmaceutical compositions effective to treat symptoms or prevent symptoms.

In other aspects, the invention provides methods of synthesizing the compounds of the invention, representative synthetic methods and routes being described below.

Other objects and advantages of the present invention will become apparent to those skilled in the art from the following detailed description, taken in conjunction with the accompanying drawings.

Brief Description of Drawings

FIG. 1: under the assay conditions, 3nM compound 225 significantly inhibited capsaicin-induced intracellular calcium responses.

FIG. 2: under the assay conditions, 3nM compound 187 significantly inhibited capsaicin-induced intracellular calcium responses.

FIG. 3: under the assay conditions, 3nM compound 96 significantly inhibited capsaicin-induced intracellular calcium responses.

FIG. 4: under the assay conditions, compound 45 at 3nM significantly inhibited capsaicin-induced intracellular calcium responses.

FIG. 5: under the assay conditions, 3nM compound 233 significantly inhibited capsaicin-induced intracellular calcium responses.

FIG. 6: under the assay conditions, 3nM compound 167 significantly inhibited capsaicin-induced intracellular calcium responses.

Detailed Description

Definition of

Unless otherwise indicated, when describing compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions, the following terms have the following meanings. It is to be understood that any moiety defined above or below may be substituted with a variety of substituents and each definition includes within its scope such substituted moieties. Such substituents include, by way of non-limiting example, halo (e.g., fluoro, chloro, bromo), -CN, -CF ₃、-OH、-OCF₃、C₂-C₆Alkenyl radical, C₃-C₆Alkynyl, C₁-C₆Alkoxy, aryl and di-C₁-C₆An alkylamino group.

"acyl" refers to the group-C (O) R, where R is herein hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

"acylamino" refers to the group-NR 'C (O) R, where R' is herein hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, and R is hydrogen, alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl. Representative examples include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino, and the like.

"acyloxy" refers to the group-OC (O) R, where R is hydrogen, alkyl, aryl, or cycloalkyl.

"substituted alkenyl" includes those groups recited herein in the definition of "substituted," and particularly refers to alkenyl having 1 or more substituents (e.g., 1-5 substituents, particularly 1-3 substituents) selected from acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxy, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxy, ketone, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketone, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O) ₂And aryl-S (O)₂-。

"alkoxy" refers to the group-OR, where R is alkyl. Specific alkoxy groups include, for 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 recited herein in the definition of "substituted", specifically referring to alkoxy having 1 or more substituents, such as 1 to 5 substituents, especially 1 to 3 substituents, selected from acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxy, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, hydroxy, ketone, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketone, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O)₂And aryl-S (O)₂-。

"Alkoxycarbonylamino" refers to the group-NRC (O) OR 'where R is hydrogen, alkyl, aryl, OR cycloalkyl and R' is alkyl OR cycloalkyl.

"aliphatic" refers to a hydrocarbon-based organic compound or group in which the constituent carbon atoms are arranged in a linear, branched, or cyclic arrangement and are free of aromatic unsaturation. Aliphatic groups include, but are not limited to, alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene (alkylylene). The aliphatic group typically has about 1-12 or 2-12 carbon atoms.

"alkyl" refers to monovalent saturated aliphatic hydrocarbon groups having specifically up to about 11 carbon atoms, more specifically 1 to 8 carbon atoms, and even more specifically 1 to 6 carbon atoms. The hydrocarbon chain may be straight or branched. Examples of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like. The term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Hereinafter, the term "alkyl" also includes "cycloalkyl".

"substituted alkyl" includes those groups recited herein in the definition of "substituted", specifically referring to alkyl having 1 or more substituents, such as 1-5 substituents, especially 1-3 substituents, selected from acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxy, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxy, heteroaryl, ketone, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketone, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O) ₂And aryl-S (O)₂-。

"alkylene" means a divalent saturated aliphatic hydrocarbon radical having specifically up to about 11 carbon atoms, more specifically 1 to 6 carbon atoms, which may be straight or branched. The term is exemplified by, for example, methylene (-CH)₂-) ethylene (-CH₂CH₂-), propylene isomers (e.g., -CH₂CH₂CH₂-and-CH (CH)₃)CH₂-) and the like.

"substituted alkylene" includes those groups recited herein in the definition of "substituted", specifically referring to alkylene having 1 or more substituents, e.g., 1 to 5 substituents, especially 1 to 3 substituents, selected from acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxy, cyano, halogen, hydroxy, ketone, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketone, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O)')₂And aryl-S (O)₂-。

"alkenyl" means a monovalent olefinic bond having up to about 11 carbon atoms, specifically 2 to 8 carbon atoms, more specifically 2 to 6 carbon atoms The unsaturated hydrocarbon group of formula (I) which may be linear or branched and has at least 1, specifically 1 to 2 sites of ethylenic unsaturation. Specific alkenyl groups include vinyl (-CH ═ CH)₂) N-propenyl (-CH)₂CH＝CH₂) Isopropenyl (-C (CH)₃)＝CH₂) Vinyl and substituted vinyl, and the like.

"alkenylene" refers to a divalent ethylenically unsaturated hydrocarbon radical having up to about 11 carbon atoms, specifically 2 to 6 carbon atoms, which may be straight or branched chain, and having at least 1, specifically 1 to 2 sites of ethylenic unsaturation. The term is exemplified by, for example, ethenylene (-CH-), propenylene isomers (e.g., -CH- ═ CHCH)₂-and-C (CH)₃) CH-and-CH-C (CH)₃) -) and the like.

"alkynyl" means an acetylenically unsaturated hydrocarbon group having up to about 11 carbon atoms, specifically 2 to 6 carbon atoms, which may be straight or branched chain, and having at least 1, specifically 1 to 2 sites of alkynyl unsaturation. Specific non-limiting examples of alkynyl groups include acetylenic (acetylenic), ethynyl (-C ≡ CH), propynyl (-CH)₂C.ident.CH) and the like.

"substituted alkynyl" includes those groups recited herein in the definition of "substituted", specifically refers to alkynyl groups having 1 or more substituents, such as 1-5 substituents, more specifically 1-3 substituents, selected from acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxy, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxy, ketone, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketone, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O) ₂And aryl-S (O)₂-。

As used herein, "alkanoyl" or "acyl" refers to the group R-C (O) -, wherein R is hydrogen or alkyl, as described above.

"aryl" refers to a monovalent aromatic hydrocarbon radical derived by the removal of 1 hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from acenaphthylene (acenaphthylene), acephenanthrylene (acenaphthylene), anthracene, azulene, benzene, chrysene (chrysene), coronene, fluoranthene, fluorene, acene, naphthotetracene, acene (hexalene), asymmetric indacene (as-indacene), symmetric indacene (s-indacene), indane, indene, naphthalene, octacene (octacene), octacene (octaphene), aldrin (octalene), bianthrene (meta-tetraacene), penta-2, 4-diene, pentacene, pentalene, pentaphene (pentaphene), perylene, phenalene (phenalene), phenanthrene, dinaphthylene, plene (perylene), pyrene (pyrene), pyranthrene (pyranthrene), chrysene (chrysene), triphenylene (triphenylene, etc. Specifically, the aryl group contains 6 to 14 carbon atoms.

"substituted aryl" includes those groups recited herein in the definition of "substituted," specifically meaning that the aryl group may be optionally substituted with 1 or more substituents, for example, aryl substituted with 1 to 5 substituents, specifically 1 to 3 substituents selected from 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, hydroxy, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O) -. ₂And aryl-S (O)₂-。

"fused aryl" refers to an aryl group having 2 of its ring carbons shared with another aromatic or aliphatic ring.

"alkylaryl" refers to an aryl group as described above substituted with 1 or more alkyl groups as described above.

"aralkyl" or "arylalkyl" refers to an alkyl group as described above substituted with 1 or more aryl groups as described above.

"aryloxy" refers to-O-aryl, wherein "aryl" is as described above.

"alkylamino" refers to alkyl-NR 'R "where R' and R" are each independently selected from hydrogen and alkyl.

"arylamino" refers to aryl-NR 'R "where R' and R" are each independently selected from hydrogen, aryl, and heteroaryl.

"Alkoxyamino" refers to the group-N (H) OR, where R represents an alkyl OR cycloalkyl group as described herein.

"alkoxycarbonyl" refers to the group-C (O) -alkoxy, wherein alkoxy is as described herein.

"Alkylarylamino" refers to the group-NRR ', where R represents an alkyl or cycloalkyl group and R' is an aryl group as described herein.

"alkylsulfonyl" means a radical-S (O)₂R, wherein R is alkyl or cycloalkyl, as described herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

"Alkylsulfinyl" refers to the group-S (O) R, where R is alkyl or cycloalkyl, as described herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like.

"Alkylthio" refers to the group-SR, where R is alkyl or cycloalkyl, as described herein, and may be optionally substituted as described herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

"amino" refers to the group-NH₂。

"substituted amino" includes references herein in the definition of "substitutedIn particular the group-N (R)₂Wherein each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, wherein two R groups are joined together to form an alkylene group. When both R are hydrogen, -N (R)₂Is an amino group.

"aminocarbonyl" refers to the group-C (O) NRR where each R is independently hydrogen, alkyl, aryl, and cycloalkyl, or where the R groups are joined together to form an alkylene group.

"Aminocarbonylamino" refers to the group-NRC (O) NRR where each R is independently hydrogen, alkyl, aryl, or cycloalkyl, or where two R groups are joined together to form an alkylene group.

"aminocarbonyloxy" refers to the group-OC (O) NRR where each R is independently hydrogen, alkyl, aryl, or cycloalkyl, or where the R groups are joined together to form an alkylene group.

"arylalkoxy" refers to an-O-arylalkyl group, wherein arylalkyl is as described herein.

"arylamino" refers to the group-NHR, where R represents an aryl group as described herein.

"Aryloxycarbonyl" refers to the group-C (O) -O-aryl, where aryl is as described herein.

"arylsulfonyl" means a radical-S (O)₂R, wherein R is aryl or heteroaryl, as described herein.

"azido" refers to the group-N₃。

"bicyclic aryl" refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent bicyclic aromatic ring system. Typical bicyclic groups include, but are not limited to, groups derived from indanes, indenes, naphthalenes, tetrahydronaphthalenes, and the like. Specifically, the aryl group contains 8 to 11 carbon atoms.

"bicyclic heteroaryl" refers to a monovalent bicyclic heteroaryl hydrocarbon group obtained by removing one hydrogen atom from a single atom of a parent bicyclic heteroaryl ring system. Typical bicyclic heteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzodioxane (benzdioxane), benzopyran, chroman, cinnoline, phthalazine, indole, indoline, indolizine (indolizine), isobenzofuran, isobenzopyran (isochromene), isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzopyrazine, pyridopyrimidine (pyridopyrimidine), quinazoline, quinoline, quinolizine, quinoxaline, benzomorphane, tetrahydroisoquinoline, tetrahydroquinoline, and the like. Preferably, the bicyclic heteroaryl is 9-11 membered bicyclic heteroaryl, with 5-10 membered heteroaryl being especially preferred. Specific bicyclic heteroaryls are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole, benzodioxan.

"carbamoyl" refers to the group-C (O) N (R)₂Wherein each R group is independently hydrogen, alkyl, cycloalkyl or aryl, as described herein, which may be optionally substituted, as described herein.

"carboxy" refers to the group-C (O) OH.

"carboxyamino" refers to the group-N (H) C (O) OH.

"cycloalkyl" refers to a cyclic hydrocarbon group having about 3 to 10 carbon atoms and having a single ring or multiple condensed rings (including fused and bridged ring systems), which is optionally substituted with 1 to 3 alkyl groups. This cycloalkyl group includes, for example, a monocyclic structure such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl and the like, and a polycyclic structure such as adamantyl and the like.

"substituted cycloalkyl" includes those groups recited herein in the definition of "substituted", especially cycloalkyl having 1 or more substituents, e.g., 1 to 5 substituents, specifically 1 to 3 substituentsA group selected from acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxy, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxy, ketone, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thione, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O) ₂And aryl-S (O)₂-。

"Cycloalkoxy" refers to the group-OR, where R is cycloalkyl. Such cycloalkoxy groups include, for example, cyclopentyloxy, cyclohexyloxy, and the like.

"cycloalkenyl" refers to cyclic hydrocarbon groups having about 3 to 10 carbon atoms, having a single ring or multiple fused rings (including fused and bridged ring systems), and having at least 1, specifically 1 to 2 sites of ethylenic unsaturation. Such cycloalkenyl groups include, for example, monocyclic structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

"substituted cycloalkenyl" includes those groups recited herein in the definition of "substituted", especially cycloalkenyl having 1 or more substituents, e.g., 1-5 substituents, specifically 1-3 substituents, selected from acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxy, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxy, ketone, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketone, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O)') ₂And aryl-S (O)₂-。

"fused cycloalkenyl" refers to cycloalkenyl groups wherein 2 of the ring carbons are shared with another aliphatic or aromatic ring and have ethylenic unsaturation that imparts aromaticity to the cycloalkenyl ring.

"Cyanoxy" refers to the group-OCN.

"cyano" refers to the group-CN.

"dialkylamino" refers to the group-NRR ', where R and R' independently represent alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or substituted heteroaryl, as described herein.

"vinyl" refers to substituted or unsubstituted- (C ═ C) -.

"ethylene" means substituted or unsubstituted- (C-C) -.

"ethynyl" means- (C.ident.C) -.

"halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. Preferred halogen groups are fluorine or chlorine.

"hydroxy" refers to the group-OH.

"Nitro" means the radical-NO₂。

"substituted" refers to groups in which one or more hydrogen atoms are each replaced by the same or different substituents. Typical substituents include, but are not limited to, -X, -R¹⁴、-O-、＝O、-OR¹⁴、-SR¹⁴、-S-、＝S、-NR¹⁴R¹⁵、＝NR¹⁴、-CX₃、-CF₃、-CN、-OCN、-SCN、-NO、-NO₂、＝N₂、-N₃、-S(O)₂O-、-S(O)₂OH、-S(O)₂R¹⁴、-OS(O₂)O-、-OS(O)₂R¹⁴、-P(O)(OO₂、-P(O)(OR¹⁴)(O^-)、-OP(O)(OR¹⁴)(OR¹⁵)、-C(O)R¹⁴、-C(S)R¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁵、-C(O)O^-、-C(S)OR¹⁴、-NR¹⁶C(O)NR¹⁴R¹⁵、-NR¹⁶C(S)NR¹⁴R¹⁵、-NR¹⁷C(NR¹⁶)NR¹⁴R¹⁵and-C (NR)¹⁶)NR¹⁴R¹⁵Wherein each X is independently halogen; each R¹⁴、R¹⁵、R¹⁶And R¹⁷Independently hydrogen, alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, -NR ¹⁸R¹⁹、-C(O)R¹⁸or-S (O)₂R¹⁸Or optionally R¹⁸And R¹⁹And together with the atoms to which they are both attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and R¹⁸And R¹⁹Independently hydrogen, alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

Representative examples of substituted aryl groups include the following:

in these formulae, R⁶' and R⁷One of' may be hydrogen, R⁶' and R⁷' at least one of which is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR¹⁰COR¹¹、NR¹⁰SOR¹¹、NR¹⁰SO₂R¹⁴COOalkyl, COOaryl, CONR¹⁰R¹¹、CONR¹⁰OR¹¹、NR¹⁰R¹¹、SO₂NR¹⁰R¹¹S-alkyl, SO₂Alkyl, S arylRadicals, SO aryl radicals, SO₂An aryl group; or R⁶' and R⁷' may be linked to form a ring of 5 to 8 atoms (saturated or unsaturated), optionally containing one or more heteroatoms selected from N, O or S. R¹⁰、R¹¹And R¹²Independently hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted alkyl or heteroalkyl, and the like.

When used in describing a compound or group on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced with a nitrogen, oxygen, or sulfur heteroatom. "hetero" can apply to any of the above hydrocarbyl groups, e.g., alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocycloalkyl), aryl (e.g., heteroaryl), cycloalkenyl (e.g., heterocycloalkenyl), and the like, having from 1 to 5, especially from 1 to 3 heteroatoms.

"heteroaryl" refers to a monovalent heteroaryl group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, indole (arsindole), carbazole, β -carboline, chroman, 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, pyrroline (pyrrolizine), quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. Preferably, the heteroaryl group is a 5-20 membered heteroaryl group, particularly preferably a 5-10 membered heteroaryl group. Specific heteroaryl groups are groups derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

Examples of representative heteroaryl groups include the following:

wherein each Y is selected from carbonyl N, NR⁴O and S.

Representative examples of cycloheteroalkyl groups include the following:

wherein each X is selected from CR₂NR, O and S; and Y is selected from NR⁴O and S, wherein R⁶' is R²。

Representative examples of heterocycloalkenyl groups include the following:

wherein each X is selected from CR⁴、NR⁴O and S; and each Y is selected from carbonyl, N, NR⁴O and S. Representative examples of the aryl group having a hetero atom and containing a substituent include the following:

wherein each X is selected from C-R⁴、CR⁴ ₂、NR⁴O and S; and each Y is selected from carbonyl, NR⁴O and S.

"hetero substituent" means a functional group containing a halogen, O, S or N atom, which may serve as R⁴R in the C radical⁴Exist, said R⁴The C group is present as a substituent directly on A, B, W, X, Y or Z of the compounds of the invention, or may beAs substituents in the "substituted" aryl and aliphatic groups present in the compounds.

Examples of hetero substituents include:

-a halogen, in the form of a halogen,

-NO₂、-NH₂、-NHR、-N(R)₂，

-NRCOR、-NRSOR、-NRSO₂R、OH、CN，

-CO₂H，

-R-OH、-O-R、-COOR，

-CON(R)₂、-CONROR，

-SO₃H、-R-S、-SO₂N(R)₂，

-S(O)R、-S(O)₂r, wherein each R is independently aryl or aliphatic, optionally having substituents. Among the hetero substituents comprising the R group, those having aryl and alkyl groups described herein are preferred. Preferred hetero substituents are as listed above.

As used herein, the term "cycloheteroalkyl" refers to stable heterocyclic non-aromatic and fused rings having one or more heteroatoms independently selected from N, O and S. Fused heterocyclic ring systems may include carbocyclic rings and must contain only one heterocyclic ring. Examples of heterocycles include, but are not limited to, piperazinyl, homopiperazinyl (homopiperazinyl), piperidinyl, and morpholinyl, and are shown as the following illustrative examples:

optionally substituted with a group selected from acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,Azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, ketone, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thione, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O)₂And aryl-S (O)₂-is substituted with one or more groups. Substituents include carbonyl or thiocarbonyl groups which provide, for example, lactam and urea derivatives. In this embodiment, M is CR⁷、NR²O or S; q is O, NR²Or S. R⁷And R⁸Independently selected from acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxy, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxy, ketone, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thione, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O) ₂And aryl-S (O)₂-。

"dihydroxyphosphoryl" refers to the group-PO (OH)₂。

"substituted dihydroxyphosphoryl" includes those groups referred to herein in the definition of "substituted", specifically referring to dihydroxyphosphoryl, wherein one or both hydroxyl groups are substituted. Suitable substituents are described below.

"Aminohydroxyphosphoryl" refers to the group-PO (OH) NH₂。

"substituted aminohydroxyphosphoryl" includes those groups recited in the definition of "substituted" herein, and specifically refers to aminohydroxyphosphoryl, wherein an amino group is substituted with one or two substituents. Suitable substituents are described below. In certain embodiments, the hydroxyl group is also substituted.

"Thioalkoxy" refers to the group-SR, where R is alkyl.

"substituted thioalkoxy" includes "substituted as used hereinThose groups cited in the definition of "refer in particular to thioalkoxy groups having 1 or more substituents, for example 1 to 5 substituents, in particular 1 to 3 substituents, selected from acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, ketone, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketone, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O) ₂And aryl-S (O)₂-。

"thioalkyl" refers to the group HS-. "substituted thioalkyl" refers to a group, such as RS-, wherein R is any of the substituents described herein.

"Sulfonyl" refers to the divalent group-S (O)₂) -. "substituted sulfonyl" refers to a group, such as R- (O)₂) S-wherein R is any substituent described herein. "aminosulfonyl" or "sulfonamide" refers to the group H₂N(CO₂) S-, substituted sulphonamide means a radical, such as R₂N(O₂) S-, wherein each R is independently any substituent described herein.

"sulfone" means the group-SO₂And R is shown in the specification. In a particular embodiment, R is selected from H, lower alkyl, aryl and heteroaryl.

"Thioaryloxy" refers to the group-SR, where R is aryl.

"thione" means the group S.

"thiol" refers to the group-SH.

One of ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heteroatom, whether aromatic or non-aromatic, depends on the size of the ring, the degree of unsaturation, and the valence state of the heteroatom. Generally, the heterocyclic ring may have 1-4 heteroatoms, as long as the heteroaromatic ring is chemically feasible and stable.

"pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or generally recognized in the U.S. pharmacopeia or other pharmacopeia for use in animals, and more particularly in humans.

By "pharmaceutically acceptable salt" is meant a pharmaceutically acceptable salt of a compound of the present invention which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or 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, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxy, glucoheptonic acid (glucoheptonic acid), 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, succinic acid, malic acid, maleic acid, succinic, Muconic acid, and the like; or (2) salts formed when an acidic proton is present in the parent compound, by substitution with a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or coordination with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.). Salts also include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; when the compound contains a basic functional group, it is a salt of a non-toxic organic or inorganic acid, such as a hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. The term "pharmaceutically acceptable cation" refers to a non-toxic, acceptable cationic counterion to the acidic functionality. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient, or carrier with which the compounds of the invention are administered.

"preventing" refers to reducing the risk of acquiring a disease (i.e., causing at least one clinical symptom of a disease not to develop in a subject that is in contact with or susceptible to the disease, but does not yet experience or display symptoms of the disease).

"prodrug" refers to a compound, including derivatives of the compounds of the present invention, which have a cleavable group that, upon solvolysis or under physiological conditions, becomes a compound of the present invention that is pharmacologically active in vivo. Examples include, but are not limited to, choline ester derivatives and the like, N-alkyl morpholinyl esters and the like.

"solvate" refers to a form of the compound that is bound to a solvent, typically by a solvolysis reaction. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the invention may be prepared, for example, in crystalline form, and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also includes stoichiometric and non-stoichiometric amounts of solvates.

An "object" includes a person. The terms "human", "patient" and "subject" are used interchangeably herein.

"therapeutically effective amount" refers to an amount of a compound that, when administered to a subject in need of treatment for a disease, is sufficient to produce a therapeutic effect for the disease. The "therapeutically effective amount" may vary with the compound, the disease and its severity, the age, weight, etc. of the subject to be treated.

In one embodiment, "treating" any disease or condition refers to ameliorating the disease or condition (i.e., arresting or slowing the progression of the disease, or at least one clinical sign thereof). In another embodiment, "treating" refers to improving at least one physical parameter, which may not be discernible by the subject. In another embodiment, "treating" or "treatment" refers to controlling the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

The acid and acid derivative forms of other derivatives of the compounds of the invention are active, but their acid-sensitive forms generally provide solubility, tissue compatibility or sustained release benefits in mammalian organisms (see Bundgard, h., Design of produgs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known in the art, for example, esters prepared by reacting the parent acid with an appropriate alcohol, or amides, or anhydrides, or mixed anhydrides, of the parent acid compound reacted with a substituted or unsubstituted amine. Preferred prodrugs are simple aliphatic or aromatic esters, amides, and anhydrides of the pendant acidic groups on the compounds of the present invention. In some cases, it is desirable to prepare diester-type prodrugs, such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. Preference is given to C of the compounds of the invention ₁-C₈Alkyl radical, C₂-C₈Alkenyl, aryl, C₇-C₁₂Substituted aryl, and C₇-C₁₂An arylalkyl ester.

It is also understood that compounds having the same molecular formula but differing in their nature or in the order of incorporation of their atoms or in the arrangement of their atoms in space are referred to as "isomers". Isomers in which the atoms are arranged differently in space are referred to as "stereoisomers".

Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are non-superimposable mirror images of each other are called "enantiomers". When the compound has an asymmetric center, for example, it is bound to four different groups, it may be a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and described by the R-and S-ordering rules of cahnhprelo, or by planes of polarized light of molecular rotation and labeled as either dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). The chiral compounds may exist as individual enantiomers or as mixtures thereof. A mixture containing equal parts of an enantiomer is referred to as a "racemic mixture".

"tautomer" refers to a compound that is in a form in which the structures of the particular compound can change from one another, and the displacement of hydrogen atoms and electrons can change. Thus, the two structures are balanced by the movement of pi electrons and atoms (usually H). For example, enols and ketones are tautomers, since they can be rapidly interconverted by treatment with acid or base. Another example of tautomers are the acid (aci-) and nitro forms of phenylnitromethane, which are similarly formed by treatment with an acid or a base. Representative enol-ketone structures and equilibrium relationships are as follows:

The tautomeric form may be related to the optimal chemical reactivity and biological activity of the compound of interest.

The compounds of the present invention may have one or more asymmetric centers and, therefore, such compounds may be prepared as (R) -or (S) -stereoisomers, or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound as described in the specification and claims includes individual enantiomers and mixtures, racemates and the like. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

Compound (I)

As noted above, the compounds of the present invention are useful in the prevention and/or treatment of a number of conditions in mammals, including arthritis, parkinson's disease, alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, the treatment and prevention of pain syndromes (acute and chronic or neuropathic), traumatic brain injury, acute spinal cord injury, neurodegenerative diseases, hair loss (hair loss), inflammatory bowel disease, and autoimmune diseases or conditions.

To more fully understand the invention described herein, the following structures are listed which represent exemplary compounds of the invention. It should be understood that these examples are for illustration only and are not intended to limit the invention in any way.

Thus, another specific group of compounds is provided. Thus, as described above, suitable compounds capable of modulating ion channels in vivo may be selected from tables 1-1 and 1-2 below, and may be prepared in the forms shown or as pharmaceutically acceptable salts, solvates or prodrugs thereof; stereoisomers and tautomeric forms thereof. All such variations are contemplated herein and are included within the scope of the present invention.

In certain aspects, the present invention provides prodrugs and derivatives of the compounds represented by the above structural formulae. Prodrugs are derivatives of the compounds of the present invention which have a cleavable group and are solvolytically cleavable, or, under physiological conditions, are pharmaceutically active in vivo. Suitable examples include, but are not limited to, choline ester derivatives and the like, N-alkyl morpholinyl esters, and the like.

Other derivatives of the invention are active in both their acid and acid derivative forms, but acid-sensitive forms generally provide the benefits of solubility, histocompatibility, or delayed release in the mammalian body (see Bundgard, h., "drug Design (Drugs of Drugs), pages 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acidic derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acidic compound with a substituted or unsubstituted amine or anhydride or mixed anhydride. Simple aliphatic or aromatic esters, amides and anhydrides extending from the acidic group of the compounds of the present invention are preferred prodrugs. In some cases it is desirable to prepare a diester type prodrug, such as an (acyloxy) alkyl ester or an ((alkoxycarbonyl) oxy) alkyl ester. Preference is given to C of the compounds of the invention ₁-C₈Alkyl radical, C₂-C₈Alkenyl, aryl, C₇-C₁₂Substituted aryl and C₇-C₁₂Aryl alkyl radicalAnd (3) an ester.

Test method

Chronic constriction injury model (CCI model)

Male Sprague-Dawley rats (270-300 g; B.W., Charles River, Tsukuba, Japan) were used. Chronic Constriction Injury (CCI) procedures were performed as described by Bennett and Xie (Bennett, G. J. and Xie, Y. K.pain, 33: 87-107, 1988). Briefly, animals were anesthetized with sodium pentobarbital (64.8mg/kg, i.p.) and then the biceps femoris muscle was blunt dissected to expose the common sciatic nerve on the left to mid-femoral levels. The adherent tissue on the part of the sciatic nerve near the three branches of the sciatic nerve was dissected and loosely tied around it with 4 bandages (4-0 silk) spaced about 1mm apart. The sham procedure was the same as CCI surgery, but sciatic nerve ligation was not performed. Von Frey Hairs (VFH) were applied to the plantar aspect of the hind paw 2 weeks after surgery to assess mechanical allodynia. The minimum amount of VFH force required to induce the reaction was recorded as the Paw Withdrawal Threshold (PWT). VFH testing was performed 0.5, 1 and 2 hours after dosing. The assay data was analyzed by the Kruskal-Wallis test, followed by multiple comparisons by the Dunn test or pairwise comparisons by the Mann-Whitney U test.

Permeability of Caco-2

Caco-2 permeability was measured as described by Shiyin Yee, Pharmaceutical Research, 763 (1997).

Caco-2 cells were grown on a filter support (falcon HTS porous insert system) for 14 days. The apical and basolateral regions of the medium were removed and the single layer was preincubated with pre-warmed 0.3ml of apical buffer and 1.0ml of basolateral buffer in a 50 rpm shaker water bath at 37 ℃ for 0.75 hours. The apical buffer was composed of Hanks balanced salt solution, 25mM D-glucose monohydrate, 20mM MES biological buffer, 1.25mM CaCl₂And 0.5mM MgCl₂(pH 6.5). The buffer solution on the outer side of the substrate comprises Hanks balanced salt solution, 25mM D-glucose monohydrate, 20mM HEPES biological buffer solution and 1.25mM CaCl₂And 0.5mM_MgCl2(pH 7.4). At the end of the preincubationThe medium was removed and a buffered test compound solution (10 μ M) was added to the apical area. Inserts were placed in wells containing fresh basolateral buffer and incubated for 1 hour. The drug concentration in the buffer was measured by LC/MS analysis.

Flux rates (F, mass/time) were calculated from the cumulative apparent slope and apparent permeability coefficient (Papp) of the substrate on the receiving side, calculated as follows:

Papp(cm/sec)＝(F*VD)/(SA*MD)

Wherein SA is the surface area of the conveyor (0.3 cm)²) VD is the donor volume (0.3ml) and MD is the total amount of drug on the donor side at t-0. All data represent the mean of 2 insertions. Monolayer integrity was determined by the luciferylyellow conveyor.

Human dofetilide binding

HEK-293 cell plasma expressing HERG products can be suspended at 25 ℃ in a solution containing 1mM MgCl adjusted to pH7.5 with 2M HCl₂10 volumes of 10mM KCl in 50mM Tris buffer. Cells were homogenized with a Polytron homogenizer (maximum power maintained for 20 seconds) and centrifuged at 48,000g for 20 minutes at 4 ℃. The cell pellet was resuspended, homogenized and centrifuged again in the same manner. The resulting supernatant was discarded and the final pellet was resuspended (10 volumes of 50mM Tris buffer) and homogenized at maximum power for 20 seconds. The membrane homogenate was stored at-80 ℃ until use. An aliquot was used to determine Protein concentration using the Protein Assay Rapid Kit and ARVO SX plate reader (Wallac). All operations, stock solutions and equipment were kept on ice at all times. The test was carried out in a total volume of 200. mu.l for saturation determination. Mu.l of [3H ] in the absence or presence of dofetilide (20. mu.l) at a final concentration of 10. mu.M]Dolfitt was incubated with 160. mu.l of membrane homogenate (20-30. mu.g protein per well) for 60 minutes at room temperature to determine the saturation of total and nonspecific binding, respectively. To stop all incubations, Polyetherimide (PEI) -impregnated glass fiber filters were rapidly suction filtered using Skatron cell harvester and then washed twice with 50mM Tris buffer (pH7.5, 25 ℃). Radioactivity bound to receptor using Packard LS counter Quantification was by liquid scintillation counting.

For the competitive assay, compounds were diluted in 96-well polypropylene plates in a semi-logarithmic mode 4-point dilution. All dilutions were first performed in DMSO and then transferred into a solution containing 1mM MgCl₂10mM KCl in 50mM Tris buffer (pH7.5, 25 ℃) so that the final concentration of DMSO is equal to 1%. Compounds were added to assay plates (4 μ l) in triplicate. Total bound and non-specifically bound 6-fold wells were established containing vehicle and dofetilide at a final concentration of 10. mu.M, respectively. Radioligand was prepared at a final concentration of 5.6x and the solution was added to each well (36 μ l). YSi poly-1-lysine Scintillation Proximity Assay (SPA) beads (50. mu.l, 1 mg/well) and membrane (110. mu.l, 20. mu.g/well) were added to start the assay. Incubation was continued at room temperature for 60 minutes. The plate was incubated at room temperature for an additional 3 hours to allow the beads to set. The radioactivity of bound receptors was quantified by counting a wallacicrobeta plate counter.

HERG test

Electrophysiological studies were performed using HEK 293 cells stably expressing the HERG potassium channel. Suitable methods for stabilizing such channels in transfected HEK cells can be found elsewhere (Z. Zhou et al, 1998, Biophysical Journal, 74, 230-241). Prior to the experimental date, cells were harvested from culture flasks and placed on glass coverslips in standard Minimal Essential Medium (MEM) containing 10% Fetal Calf Serum (FCS). Plated cells were stored in a chamber maintained at 95% O ₂/5％CO₂An incubator at 37 ℃ under the atmosphere. Cells were studied within 15-28 hours after harvest.

HERG current was studied using standard patch clamp technique in whole cell mode. During the experiment, cells were cast with an external solution (superfuse) containing the following components: NaCl, 130 mM; KCl, 4 mM; CaCl₂，2mM；MaCl₂1 mM; glucose, 10 mM; HEPES, 5 mM; adjusted to pH 7.4 with NaOH. Whole cell recordings were performed with a patch clamp amplifier and a patch pipette (patch pipette) with a resistance of 1-3Mohm when the cells were filled with a standard internal solution containing the following components: KCl, 130 mM; MgATP, 5 mM; MgCl₂，1.0mM；HEPES, 10 mM; EGTA 5mM, adjusted to pH7.2 with KOH. Further experiments were performed only on those cells with a contact resistance (access resistance) below 15 M.OMEGA.and a sealing resistance (sealing resistance) above 1 G.OMEGA.. A maximum of 80% series resistance compensation is applied. No leakage subtraction (leak subtraction) was performed. However, the acceptable contact resistance depends on the size of the recording circuit and the level of series resistance compensation that can be safely used. The whole cell configuration was obtained and after fully dialyzing the cells with pipette solution (> 5min), standard voltage rules were applied to the cells to excite membrane currents. The voltage rule is as follows. The membrane was depolarized with a maintenance potential of-80 mV to +40mV for 1000 ms. The voltage ramp slope (rate 0.5 millivolts/millisecond) is then decreased back to the holding potential. The voltage regime (0.25Hz) was applied to the cells every 4 seconds continuously during the experiment. The amplitude of the peak current induced around-40 mV during the voltage increase was measured. Once the appropriate excitation current was obtained in the external solution, the vehicle (0.5% DMSO made with standard external solution) was added by peristaltic pump for 10-20 minutes. Once there was minimal change in the amplitude of the excitation current response under the vehicle control conditions, 0.3, 1, 3, 10mM test compound was applied for 10 minutes. These 10 minutes include the time for the added solution to pass from the solution reservoir through the tubing to the recording chamber via the pump. The cells are exposed to the compound solution for more than 5 minutes after the drug concentration in the recording chamber has sufficiently reached the predetermined concentration. Followed by washing for 10-20 minutes to assess reversibility. Cells were finally exposed to high doses of dofetilide (5mM), a specific Ikr blocker, to assess insensitive internal currents.

All experiments were performed at room temperature (23. + -. 1 ℃). The excited membrane current was recorded on-line with a computer, filtered at 500-1K Hz (Bessel-3dB) and sampled at 1-2K Hz using a diaphragm clamp amplifier and specialized data analysis software. The peak current amplitude (typically occurring around-40 mV) was measured off-line with a computer.

The arithmetic mean of the 10 amplitude values under the vehicle control and in the presence of drug was calculated. The current values were normalized to obtain the percentage reduction IN each experiment using the following equation: IN ═ 1-ID/IC) × 100, where ID is the average current value IN the presence of drug and IC is the average current value under control conditions. Individual experiments were performed for each drug concentration or time-matched control and the arithmetic mean of each experiment was calculated and defined as the study result.

Half-life in Human Liver Microsomes (HLM)

Test Compound (1. mu.M) and 3.3mM MgCl prepared with 100mM potassium phosphate buffer (pH7.4)₂And 0.78mg/mL HLM (HLl01) in 96-well deep-well plates at 37 ℃. The reaction mixture was divided into two groups: non-P450 group and P450 group. NADPH was added to the reaction mixture of the P450 group only. Aliquots of the P450 group were collected at time points 0, 10, 30 and 60 minutes, with the 0 minute time point indicating the time to add NADPH to the reaction mixture of the P450 group. Aliquots of samples from the non-P450 group were collected at-10 and 65 minute time points. The collected aliquots were extracted with acetonitrile solution containing an internal standard. The precipitated protein was spun off by centrifugation (2000rpm, 15 minutes). The concentration of the compound in the supernatant was measured by an LC/MS system.

The natural logarithm of peak area ratio of compound/internal standard was plotted against time to obtain half-life values. The slope of the line best fitted through each point is the metabolic rate (k). This is converted to a half-life value using the following equation:

half-life ═ ln 2/k

Mono-iodo acetate (Mono-Iodoacetate) (MIA) -induced OA model

Male Sprague-Dawley (SD, Japan SLC or Charles river Japan) rats of 6 weeks of age were anesthetized with pentobarbital. The hair at the MIA injection site (knee) was scraped off and cleaned with 70% alcohol. 25ml of MIA solution or saline was injected into the right knee joint with a 29G needle. The effect of joint injury on right (injured) and left (untreated) knee body weight distribution was evaluated with a disability tester (LintonInstrumentation, Norfolk, UK). The force of each hind limb was measured in grams. The Weight Bearing (WB) difference was determined as the difference in weight bearing for each paw. Rats were trained once a week to measure WB until 20 days after MIA injection. The analgesic effect of the compounds was measured 21 days after MIA injection. The "predictor" of WB differences was measured prior to compound administration. The reduction in the WB difference after compound administration was determined to be analgesic effect.

Complete Freund's Adjuvant (CFA) induces thermal and mechanical hyperalgesia in rats

Thermal hyperalgesia

Male SD rats of 6 weeks of age were used. Complete Freund's adjuvant (CFA, 300mg of Mycobacterium Tuberculosis (Mycobacterium Tuberculosis) H37RA (Difco, MI) (Wako, Osaka, Japan)) was injected into the plantar surface of the rat hind paw in 100. mu.l of liquid paraffin. Thermal hyperalgesia was measured two days after CFA injection by the previously described method (Hargreaves et al, 1988) using a plantar tester (Ugo-Basil, Varese, Italy). The rats were acclimatized to the test environment for at least 15 minutes before any additional stimulation. Radiant heat was applied to the plantar surface of the hind paw and paw withdrawal delay (PWL, sec) was measured. The intensity of the radiant heat is adjusted to obtain a suitable PWL for 10-15 seconds. Test compounds were administered at 0.5mL per 100g body weight. PWL was measured 1, 3 or 5 hours after drug administration.

Mechanical hyperalgesia

Male SD rats of 4 weeks of age were used. CFA (300 mg of Mycobacterium tuberculosis H37RA (Difco, MI) (Wako, Osaka, Japan)) in 100. mu.l of liquid paraffin was injected into the plantar surface of the rat hind paw. Mechanical hyperalgesia was tested two days after injection of CFA by measuring paw withdrawal threshold (PWT, grams) versus pressure with an analgesia meter (Ugo-base, Varese, Italy). Gently restrict animal movement and steadily increase the pressure applied to the back of the hind paw by the plastic prongs. The pressure required to cause the jaws to retract is measured. Test compounds were administered at 0.5mL per 100g body weight. PWT was measured 1, 3 or 5 hours after drug administration.

Pharmaceutical composition

When used as a medicament, the amide compounds of the present invention are generally administered in the form of a pharmaceutical composition. Such compositions may be prepared by methods well known in the pharmaceutical art and contain at least one active compound.

Typically, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will generally be determined by a physician, in the light of the relevant circumstances, including: the condition to be treated, the chosen route of administration, the actual 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 the present invention may be administered by a variety of routes, non-limiting examples of which include oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the desired route of delivery, the compounds of the invention are preferably formulated as injectable or oral compositions, or as ointments, lotions or patches for transdermal administration.

Compositions for oral administration may be in the form of a bolus liquid solution or suspension or a bolus powder. However, such compositions are more typically in unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions or, in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the furan sulfonic acid compound is generally the smallest component (about 0.1 to 50% by weight, or preferably about 1 to 40% by weight), with the remainder being various excipients or carriers and processing aids that aid in forming the desired dosage form.

Liquid forms suitable for oral administration may contain suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. The solid dosage form may comprise, for example, any of the following or a compound of similar nature: a binder, such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch or lactose; disintegrating agents, such as alginic acid, Primogel or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As noted above, the active compound in such compositions is generally the smallest component, usually about 0.05 to 10% by weight, with the remainder being an injectable carrier or the like.

Transdermal compositions are generally formulated as topical ointments or creams containing the active ingredient in an amount generally ranging from about 0.01 to 20% by weight, preferably from about 0.1 to 10% by weight, more preferably from about 0.5 to 15% by weight. When formulated as an ointment, the active ingredient is typically mixed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and typically contain other ingredients to enhance the ability or stability of the active ingredient or formulation to penetrate the skin. All such known transdermal formulations and formulations are included within the scope of the present invention.

The compounds of the present invention may also be administered via a transdermal device. Thus, transdermal administration can be accomplished with drug depot or porous membrane type patches or solid-based patches.

The components of the orally-administrable, injectable, or topically-administrable compositions described above are merely representative. Other materials and processing techniques are listed in Remington pharmaceutical sciences (1985, Mack publishing company, Easton, Pennsylvania) 17 th edition, section 8, the contents of which are incorporated herein by reference.

The compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system. A description of representative sustained release materials can be found in Remington's pharmaceutical sciences.

The following formulation examples illustrate representative pharmaceutical compositions of the invention. However, the present invention is not limited to the following pharmaceutical compositions.

Formulation 1-tablet

The compound of formula I in dry powder form is mixed with a dry gelatin binder in a weight ratio of about 1: 2. A small amount of magnesium stearate was added as a lubricant. The mixture was tabletted with a tabletting machine to 240-270mg tablets (each containing 80-90mg of active compound).

Preparation 2-capsule

The compound of formula I in dry powder form is mixed with a starch diluent in a weight ratio of about 1: 1. The mixture is filled into 250mg capsules (each containing 125mg of active compound).

Formulation 3-liquid formulation

Compound of formula I (125mg), sucrose (1.75g) and tragacanth (4mg) were mixed, passed through a No. 10 US sieve and then mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11: 89, 50mg) prepared previously. Sodium benzoate (10mg), flavouring and colouring agents were diluted with water and added with stirring. Sufficient water was then added to bring the total volume to 5 mL.

Formulation 4-tablet

The compound of formula I in dry powder form is mixed with a dry gelatin binder in a weight ratio of about 1: 2. A small amount of magnesium stearate was added as a lubricant. The mixture was formed into tablets of 450-900mg (each tablet containing 150-300mg of the active compound) using a tablet press.

Preparation 5-injection

The compound of formula I is dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/ml.

Formulation 6-topical formulation

Stearyl alcohol (250g) and white petrolatum (250g) were melted at about 75 ℃, then a mixture of the compound of formula I (50g), methyl paraben (0.25g), propyl paraben (0.15g), sodium lauryl sulfate (10g) and propylene glycol (120g) dissolved in water (about 370g) was added and the resulting mixture was stirred until it coagulated.

Method of treatment

The compounds of the present invention are useful as therapeutic agents to treat diseases in mammals. Accordingly, the compounds and pharmaceutical compositions of the present invention are useful as therapeutic methods for the prevention and/or treatment of neurodegenerative, autoimmune and inflammatory diseases in mammals, including humans.

In a method of treatment, the invention provides a method of treating a mammal susceptible to or affected by conditions associated with arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, hair loss (alopecia), inflammatory bowel disease, and autoimmune diseases, comprising administering an effective amount of one or more of the above pharmaceutical compositions.

In other aspects of the method of treatment, the invention provides a method of treating a mammal susceptible to or affected by: neurodegenerative diseases and disorders such as parkinson's disease, alzheimer's disease and multiple sclerosis; diseases and disorders mediated by or resulting in neuritis, such as traumatic brain injury, stroke, and encephalitis; centrally mediated neuropsychiatric diseases and disorders such as depression, mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders, and cognitive disorders; epilepsy and seizures; prostate, bladder and intestinal dysfunction, such as urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway diseases and disorders such as allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders mediated by or resulting in inflammation, such as rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis and atherosclerosis; itch/pruritus, such as psoriasis; alopecia (alopecia); obesity; lipid disorders; cancer; blood pressure; spinal cord injury; renal disease, comprising administering an amount of one or more of the above pharmaceutical compositions effective to treat symptoms or prevent symptoms.

The injection dosage level is from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all within about 1-120 hours, especially 24-96 hours. Pre-loaded injectables can also be administered in amounts of about 0.1-10mg/kg or higher to achieve a sufficiently stable state level. A maximum total dose of 40-80 kg human patients is not expected to exceed about 2 g/day.

For the prevention and/or treatment of long-term diseases such as neurodegenerative diseases and autoimmune diseases, the treatment regimen will usually be extended to months or years, and oral administration is therefore preferred in view of patient convenience and tolerability. When administered orally, a typical regimen is 1 to 5 times, especially 2 to 4 times, usually 3 times per day. Using these modes of administration, about 0.01 to 20mg/kg of compound or derivative thereof per dose is provided, with a preferred dose being about 0.1 to 10mg/kg, especially about 1 to 5mg/kg, per dose.

Transdermal agents are typically selected to provide blood levels similar to or lower than those of injectable agents.

When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory disease, the compounds of the present invention or derivatives thereof are generally administered to a patient at risk of developing such a disease under the direction or supervision of a physician in a dosage regimen as described above. Patients at risk of developing a particular disease typically include those with a family history of the disease or those identified by genetic testing or screening as particularly susceptible to developing the disease.

The compounds of the present invention may be administered as the sole active agent or they may be administered in combination with other agents, including other active derivatives. The VR1 antagonist may be used in combination with another pharmaceutically active compound or with two or more other pharmaceutically active compounds, especially active compounds for the treatment of pain. For example, a VR1 antagonist, particularly a compound of formula (I) above, or a pharmaceutically acceptable salt or solvate thereof, may be administered simultaneously, sequentially or separately with one or more agents selected from:

narcotic analgesics such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, dextropropoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

Barbituric acid sedatives, such as amobarbital, alprenbital, sec-butyl barbital, butabital, mebendal, methamphetal, methohexital, pentobarbital, ifenprodic acid, secobarbital, talbarbital, theamylal, or thiopental sodium;

benzodiazepines * with sedative action, such as for example chlorazol *, chlorazol * potassium, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazoline;

h1 antagonists with sedative action, such as diphenhydramine, mepyramine, promethazine, chlorpheniramine or clocycline;

sedatives such as glutethimide, meprobamate, methaqualone or dichlofenoxate;

skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphradine;

NMDA receptor antagonists, such as dextromethorphan ((+) -3-hydroxy-N-methyl morphinan) or its metabolite dextrorphan ((+) -3-hydroxy-N-methyl morphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, budipine, EN-3231(MorphiDex ®, combined preparations of morphine and dextromethorphan), topiramate, neramexane or perzinfotel, including NR2B antagonists, for example ifenprodil, traxoprodil or (-) - (R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl ] -1-hydroxyethyl-3, 4-dihydro-2 (1H) -quinolinone;

α -adrenergic agents, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil or 4-amino-6, 7-dimethoxy-2- (5-methane-sulfonamido-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -5- (2-pyridyl) quinazoline;

tricyclic antidepressants, such as desipramine, imipramine, amitriptyline or nortriptyline;

anticonvulsants such as carbamazepine, lamotrigine, topiramate or valproate;

tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as (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] -naphthyridine-6-13-dione (TAK-637), 5- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy-3- (4-fluorophenyl) -4-morpholinyl ] -methyl ] -1, 2-dihydro-3H-1, 2, 4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitan, or 3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ] -methylamino ] -2-phenylpiperidine (2S, 3S);

muscarinic antagonists such as oxybutynin, tolterodine, propiverine, tropium chloride, darifenacin, solifenacin, tilmicorin and ipratropium;

COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

coal tar analgesics, especially acetaminophen;

neuroleptic agents, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, quetiapine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepprazole, blonanserin, iloperidone, peropiropirone, raclopride, zotepine, bifeprunox, oxychloropeline, lurasidone, amisulpride, balaperide, palindore, elinserin, osanetant, rimonabant, mecliniertint, miraximon ® or salizoptan;

β -adrenergic agents, such as propranolol;

local anesthetics, such as mexiletine;

corticosteroids, such as dexamethasone;

5-HT receptor agonists or antagonists, especially 5-HT1B/1D agonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

5-HT2A receptor antagonists, such as R (+) - α - (2, 3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl) ] -4-piperidinemethanol (MDL-100907);

Cholinergic (nicotinic) analgesics such as isproniline (TC-1734), (E) -N-methyl-4- (3-pyridyl) -3-buten-1-amine (RJR-2403), (R) -5- (2-azetidinylmethoxy) -2-chloropyridine (ABT-594) or nicotine;

·Tramadol®；

PDEV inhibitors, such as 5- [ 2-ethoxy-5- (4-methyl-1-piperazinyl-sulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (sildenafil), (6R, 12aR) -2, 3, 6, 7, 12, 12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6, 1] -pyrido [3, 4-b ] indole-1, 4-dione (IC-351 or tadalafil), 2- [ 2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl ] -5-methyl-7-propyl-3H-imidazo [5, 1-f ] [1, 2, 4] triazin-4-one (vardenafil), 5- (5-acetyl-2-butoxy-3-pyridyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one, and pharmaceutically acceptable salts thereof, 5- (5-acetyl-2-propoxy-3-pyridyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-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) pyrrolidine- 1-yl ] -N- (pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide, 3- (1-methyl-7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo [4, 3-d ] pyrimidin-5-yl) -N- [2- (1-methylpyrrolidin-2-yl) ethyl ] -4-propoxybenzenesulfonamide;

Alpha-2-delta ligands, e.g. gabapentin, pregabalin, 3-methylcarbapentin, (1a, 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-octanoic acid, (2S, 4S) -4- (3-chlorophenoxy) proline, (2S, 4S) -4- (3-fluorobenzyl) -proline, [ (1R, 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- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine, (3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid, (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid, (3S, 5R) -3-amino-5-methyl-nonanoic acid, (3S, 5R) -3-amino-5-methyl-octanoic acid, (3R, 4R, 5R) -3-amino-4, 5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3-amino-4, 5-dimethyl-octanoic acid;

a cannabinoid;

serotonin reuptake inhibitors such as sertraline, the sertraline metabolite nortetracycline, fluoxetine, norfluoxetine (fluoxetine demethyl metabolite), fluvoxamine, paroxetine, citalopram, the citalopram metabolite norazepam, escitalopram, d, l-fenfluramine, femoxetine, efoxetine, cyanoduloxetine, ritoxetine, dapoxetine, nefazodone, citalopram, and trazodone;

Norepinephrine reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproron metabolite hydroxybuproron, nomifensine, and viloxazine (Vivalan ®), especially selective norepinephrine reuptake inhibitors, such as reboxetine, especially (S, S) -reboxetine;

serotonin-norepinephrine reuptake dual inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite norclomipramine, duloxetine, milnacipran, and imipramine;

inducible Nitric Oxide Synthase (iNOS) inhibitors, 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-7- [ (1-iminoethyl) amino ] -5-heptanoic acid, 2- [ [ (1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) -butyl ] thio ] -5-chloro-3-pir-zine Pyridine nitrile; 2- [ [ (1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl ] thio ] -4-chlorobenzonitrile, (2S, 4R) -2-amino-4- [ [ 2-chloro-5- (trifluoromethyl) phenyl ] thio ] -5-thiazolobutanol,

2- [ [ (1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl ] thio ] -6- (trifluoromethyl) -3-pyridinecarbonitrile, 2- [ [ (1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl ] thio ] -5-chlorobenzonitrile, N- [4- [2- (3-chlorobenzylamino) ethyl ] phenyl ] thiophene-2-carboxamidine, or guanidinoethyl disulfide;

acetylcholinesterase inhibitors, such as donepezil;

prostaglandin E2 subtype 4(EP4) antagonists, such as N- [ ({2- [4- (2-ethyl-4, 6-dimethyl-1H-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 acid;

leukotriene B4 antagonist; such as 1- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), 5- [2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) -5E-hexenyl ] oxyphenoxy ] -pentanoic acid (ONO-4057) or DPC-11870;

5-lipoxygenase inhibitors, such as zileuton, 6- [ (3-fluoro-5- [ 4-methoxy-3, 4, 5, 6-tetrahydro-2H-pyran-4-yl ]) phenoxy-methyl ] -1-methyl-2-quinolone (ZD-2138) or 2, 3, 5-trimethyl-6- (3-pyridylmethyl), 1, 4-benzoquinone (CV-6504);

sodium channel blockers, such as lidocaine;

5-HT3 antagonists, such as ondansetron; pharmaceutically acceptable salts and solvates thereof.

In most cases where it is desired to administer a combination of active compounds, for example to treat a particular disease or condition, the present invention encompasses that two or more pharmaceutical compositions, at least one of which contains a compound of the invention, may conveniently be combined in a kit suitable for co-administration of the compositions.

Preparation of the Compounds

The compounds of the present invention can be prepared from readily available starting materials using the following conventional methods and procedures. It will be appreciated that where typical or preferred processing conditions are given (i.e., reaction temperature, time, molar ratios of reactants, solvents, pressures, etc.), other processing conditions may be employed unless otherwise indicated. The optimal reaction conditions may vary depending on the particular reactants or solvents used, but can be determined by one skilled in the art by routine optimization procedures.

Furthermore, it will be apparent to those skilled in the art that conventional protecting groups may be required to prevent unwanted reactions of certain functional groups. The selection of suitable protecting groups for particular functional groups and suitable protection and deprotection conditions are well known in the art. For example, a number of Protecting Groups and their conditions for introduction and removal are described in "Organic synthetic Protecting Groups" (Protecting Groups in Organic Synthesis), second edition, Wiley, new york, 1991, by t.w. greene and p.g. m.wuts, and references cited therein.

The target compound was synthesized using known reactions as outlined in the following schemes. The product is isolated and purified by standard methods known per se. Such methods include, but are not limited to, recrystallization, column chromatography, or HPLC.

In the present description, in particular in the "general synthesis" and "examples", the following abbreviations are used:

DCM Dichloromethane EtOAc ethyl acetate

DME 1, 2-dimethoxyethane, dimethoxyethane EtOH ethanol

DMF N, N-dimethylformamide MeOH methanol

DMSO dimethylsulfoxide THF tetrahydrofuran

EDC 1-ethyl-3- (3' -dimethylaminopropyl) TFA trifluoroacetic acid

Carbodiimide Hydrogen chloride)

HOBt 1-hydroxybenzotriazole

Preparation of acid building blocks

Preparation of substituted benzoic acids

Intermediate 1

Preparation of (E) -4- (3, 3-dimethylbut-1-enyl) benzoic acid

To a cooled (0 ℃) suspension of 4-carboxybenzaldehyde (2.0g, 13.32mmol) in dry THF (90mL) was added over 20 minutes with stirring well a solution of 33.3mmol neopentyl magnesium chloride in hexane and the mixture was stirred at the same temperature for a further 2 hours before the reaction was stopped with saturated (satylated) ammonium chloride solution. Most of the THF was evaporated, the aqueous mixture was treated with concentrated HCl (50mL) and the mixture was heated at reflux for 2 h. The mixture was then cooled to ambient temperature and extracted with dichloromethane (2 × 100mL), and the organic layer was dried over sodium sulfate and concentrated to give the desired compound.

Intermediate 2

Preparation of (E) -4- (3-methylbut-1-enyl) benzoic acid

4-carboxybenzaldehyde (1.0g, 6.66mmol) was dissolved in anhydrous tetrahydrofuran (50mL) and cooled to 0 ℃. To the mixture was added isobutylmagnesium chloride (16mL, 32mmol, 2.0M in THF). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was acidified with 50% aqueous sulfuric acid and THF was removed under vacuum. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine and dried (MgSO)₄) Filtered and evaporated to give the desired compound (950mg) as a grey powder.

m/z＝192(M+1)

Intermediate 3

Preparation of (Z) -4- (4, 4-dimethylpent-2-en-2-yl) benzoic acid

4-carboxybenzaldehyde (1.0g, 6.66mmol) was dissolved in anhydrous tetrahydrofuran (50mL) and cooled to 0 ℃. To the mixture was added 2, 2-dimethylpropane magnesium chloride (10.7mL, 32mmol, 3.0M in diethyl ether). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was acidified with 2n hcl and the solvent was removed under vacuum. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo to give a grey powder. The gray powder was dissolved in acetone (10mL) and Jone's reagent (10mL) was added. The solvent was evaporated, the residue dissolved in diethyl ether and washed with brine and water, dried (MgSO) ₄) Filtered and concentrated in vacuo to give a white solid. The white solid (730mg) was resuspended in anhydrous THF. To the solution was added methyl magnesium bromide (3.3mL, 10mmol, 3.0M in diethyl ether). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was acidified with 50% aqueous sulfuric acid and THF was removed under vacuum. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with brine and dried (MgSO)₄) Filtered and evaporated under vacuum to give the product as a grey powder(600mg)，m/z＝219(M+1)。

Intermediate 4

Preparation of 6- (3, 3-dimethylbut-1-ynyl) nicotinic acid

Methyl 6-chloronicotinate (500 mg; 2.93mmol) was suspended in 1, 4-dioxane (3ml) in a 5ml reaction flask. To a bottle were added dichlorobis (triphenylphosphine) palladium (ii) (70 mg; 3 mol%), copper iodide (12mg), n-diisopropylethylamine (0.63 ml; 3.5mmol) and 3, 3-dimethylbut-1-yne (0.44 ml; 3.5 mmol). The bottle was sealed and the mixture was heated at 80 ℃ for 24 hours. The solvent was evaporated to dryness and 20ml tetrahydrofuran and 20ml 10n naoh were added. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layer was washed with brine, washed with Na₂SO₄Dried, filtered and evaporated to give the desired product as a brown powder (590 mg; 99%).

Intermediate 5

Preparation of 4- (3, 3-dimethylbut-1-ynyl) benzoic acid

Methyl 4-iodobenzoate (500 mg; 1.9mmol) was suspended in 1, 4-dioxane (3mL) in a 5mL reaction flask. To a bottle were added dichlorobis (triphenylphosphine) palladium (II) (44 mg; 3 mol%), copper iodide (7.5mg), N-diisopropylethylamine (0.39 mL; 3.5mmol) and 3, 3-dimethylbut-1-yne (0.275 mL; 3.5 mmol). The bottle was sealed and the mixture was heated at 80 ℃ for 24 hours. The solvent was evaporated to dryness and 20ml of tetrahydrofuran and 20ml of 10N NaOH were added. The mixture was stirred at room temperature for 30 minutes and evaporatedAnd (4) removing the solvent. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layer was washed with brine, washed with Na₂SO₄Dried, filtered and evaporated to give the desired product as a brown powder (210 mg; 28%). And M/z is 203(M + 1).

Intermediate 6

Preparation of 4- (cyclopentylethynyl) benzoic acid

4- (3, 3-dimethylbut-1-ynyl) benzoic acid was prepared by the same procedure except that ethynylcyclopentane was used instead of 3, 3-dimethylbut-1-yne.

Intermediate 7

Preparation of 4- (3, 3, 3-trifluoropropenyl) benzoic acid

A mixture of ethyl diphenylphosphinite (1.98 g; 5.8mmol) and 2, 2, 2-trifluoroethyl iodide (6.1 g; 29mmol) was stirred at room temperature under nitrogen for 24 hours. Excess reagent was removed under vacuum. The residue was purified by silica gel eluting with a gradient of 0-100% hexane-ethyl acetate to give the title compound as a white powder (800 mg; 49%). 286(M +1) M/z.

Molecular sieve 4 Å (7 g; active powder) was suspended in 8.8ml of a 1.0m tbaf solution in thf and stirred at room temperature under nitrogen. The solution was added to 10ml of anhydrous THFMethyl 4-formylbenzoate (160 mg; 0.97mmol) and 2, 2, 2-trifluoroethyldiphenylphosphine oxide (415 mg; 1.46 mmol). After stirring overnight the solvent was evaporated to dryness. The residue was dissolved in EtOAc and washed with water and brine. Na for organic layer₂SO₄Dried, filtered and evaporated. The residue was dissolved in 10mlthf and 10ml of 1N NaOH and refluxed for 30 min. The mixture was acidified with concentrated HCl and extracted three times with EtOAc. The organic layer was washed with brine, washed with Na₂SO₄Dried, filtered and evaporated to give the desired product as a brown powder (125 mg; 60%). M/z is 217(M + 1).

Intermediate 8

Preparation of 4- (3, 3, 3-trifluoroprop-1-ynyl) benzoic acid

(3, 3, 3-trifluoroprop-1-ynyl) triphenylstannane

Improved Brisdon method (chem. Commun.2002, 2420-2421) was used to prepare triphenylstannane derivatives. According to this method, 1, 1, 1, 3, 3-pentafluoropropane (2.0g, 14.9mmol) is condensed into a 500mL three-necked round bottom flask containing diethyl ether (20mL) cooled to-15 ℃. The temperature of the mixture was maintained below-10 ℃ while n-BuLi (2.5M in hexane, 16.08mL, 40.2mmol) was added. The reaction was stirred at-10 ℃ for 10 minutes, then a solution of triphenyltin chloride (5g, 13.4mmol) in ether was added and maintained at-10 ℃. The mixture was allowed to slowly warm to room temperature and stirred for an additional 4 hours. Excess hexane (300mL) was added and the mixture after standing was filtered through Celite ®. The filtrate was concentrated under vacuum to give a pale yellow solid which was purified by column chromatography (SiO) ₂Diethyl ether/hexane, 1: 10) to give 5.2 g (78%) of the triphenylstannane derivative as a milky solid.

4- (3, 3, 3-trifluoroprop-1-ynyl) benzoic acid methyl ester

A20 mL microwave reaction flask was charged with methyl 4-iodobenzoate (1g, 3.8mmol), toluene (5mL), tetrakis (triphenylphosphine) Pd (0) (0.44g, 0.38mmol), and (3, 3, 3-trifluoroprop-1-ynyl) triphenylstannane (2.52g, 5.7 mmol). The mixture was heated at 120 ℃ for 30 minutes, cooled and concentrated under vacuum. The remaining residue was added to ethyl acetate (20mL), washed with water (2X 50mL) and brine (2X 50mL), and purified by column chromatography (SiO)₂Ethyl acetate/hexane, 1: 10) to give 0.680 g (78%) of benzoate as a yellow oil.

4- (3, 3, 3-trifluoroprop-1-ynyl) benzoic acid

A100 mL round bottom flask was charged with 4- (3, 3, 3-trifluoroprop-1-ynyl) benzoate (0.68g, 2.9mmol), lithium hydroxide (0.71g, 29mmol) and methanol (30mL) to water (10 mL). The mixture was stirred at room temperature for 30 minutes, heated to reflux for 1 hour, and concentrated in vacuo. Water (100mL) was added and the mixture was cooled to 0 ℃. HCl (10N) was added slowly to the solution with stirring until the pH of the solution reached 5. A yellow precipitate formed which was filtered, washed with cold water (3 × 100mL), and dried in vacuo to give 0.540 g (86%) of 4- (3, 3, 3-trifluoroprop-1-ynyl) benzoic acid as a pale yellow solid.

Intermediate 9

Preparation of 4- (cyclopropylethynyl) benzoic acid

The above compound was prepared using the same procedure as 4- (cyclopropylethynyl) -2-methylbenzoic acid, but using methyl 4-iodobenzoate as the starting material.

Intermediate 10

Preparation of 4- (3, 3-dimethylbut-1-ynyl) -3- (2-morpholinoethoxy) benzoic acid

3- (2-Morpholinoethoxy) -4-bromobenzoic acid ethyl ester

Ethyl 4-bromo-3-hydroxybenzoate (1.5g, 6.12mmol), potassium carbonate (2.5g, 18.37mmol) and 4- (2-chloroethyl) morpholine hydrochloride (1.4g, 7.35mmol) were added to 50ml DMF and the reaction was heated at 80 ℃ for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried (Na)₂SO₄) Filtered and the filtrate concentrated to an oil. Purification by column chromatography on silica gel with 0-50% EtOAc in hexanes as eluent gave the product as a colorless oil (1.0g, 47%).

3- (2-Morpholinoethoxy) -4- (3, 3-dimethylbut-1-ynyl) benzoic acid ethyl ester

Ethyl 3- (2-morpholinoethoxy) -4-bromobenzoate (0.5g, 1.4mmol), 3-dimethyl-1-butyne (3.43mL, 2.8mmol), copper (I) iodide (27mg, 0.14mmol) and bis (triphenylphosphine) palladium (II) chloride (0.19g, 0.28mmol) were added to 50mL triethylamine and stirred in a stopcock at room temperature for 20 h. The reaction was diluted with MeOH and filtered through Celite ®, then the filtrate was concentrated to an oil. Purification by column chromatography on silica gel using 75% EtOAc in hexanes as eluent gave the product as a brown solid (0.34g, 67%), M/z 360(M + 1).

4- (3, 3-Dimethylbut-1-ynyl) -3- (2-morpholinoethoxy) benzoic acid

Ethyl 3- (2-morpholinoethoxy) -4- (3, 3-dimethylbut-1-ynyl) benzoate (0.34g, 0.95mmol) and LiOH (68mg, 2.84mmol) were added to a 3: 1 mixture of methanol: water (30mL) and heated at 60 ℃ for 3.5 hours. 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 pH5 with concentrated HCl. The precipitated white solid was filtered off and washed thoroughly with water. The solid was dried in a vacuum oven to give the product as a solid (0.24g, 70%) with M/z 330.1 (M-1).

Intermediate 11

Preparation of 4- (3, 3-dimethylbut-1-ynyl) -3-ethoxybenzoic acid

4-bromo-3-ethoxybenzoic acid ethyl ester

Ethyl 4-bromo-3-hydroxybenzoate (prepared according to M.I. Dawson et al, WO 2003048101; 0.5 g, 2.04 mmol), potassium carbonate (0.84g, 6.12mmol) and iodoethane (0.2mL, 2.45mmol) were added to 50mL of DMF and the reaction was heated at 80 ℃ for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried (Na)₂SO₄) Filtered and the filtrate concentrated in vacuo to an oil. The oil was purified by column chromatography using EtOAc/hexanes (0-50%) as eluent to give the product as a clear oil (0.35g, 62%).

3-ethoxy-4- (3, 3-dimethylbut-1-ynyl) benzoic acid ethyl ester

This compound was prepared using the same procedure as ethyl 3- (2-morpholinoethoxy) -4- (3, 3-dimethylbut-1-ynyl) benzoate.

4- (3, 3-dimethylbut-1-ynyl) -3-ethoxybenzoic acid

This compound was prepared using the same procedure as 4- (3, 3-dimethylbut-1-ynyl) -3- (2-morpholinoethoxy) benzoic acid, with M/z 244 (M-1).

Intermediate 12

Preparation of 4- (3, 3-dimethylbut-1-ynyl) -3- (2-hydroxy-2-methylpropoxy) benzoic acid

3- (2-hydroxy-2-methylpropoxy) -4-bromobenzoic acid ethyl ester

Ethyl 4-bromo-3-hydroxybenzoate (1.5g, 6.12mmol), potassium carbonate (5.07g, 36.72mmol) and 1-chloro-2-methylpropan-2-ol (0.75mL, 7.34mmol) were added to 50mL of DMF and the reaction was heated at 80 ℃ for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried (Na)₂SO₄) Filtered and the filtrate concentrated in vacuo to an oil. Purification by column chromatography on silica eluting with EtOAc/hexanes (0-50%) afforded the product as a yellow oil (0.5g, 26%).

3- (2-hydroxy-2-methylpropoxy) -4- (2-cyclopropylethynyl) benzoic acid ethyl ester

This compound was prepared using the same procedure as ethyl 3- (2-morpholinoethoxy) -4- (3, 3-dimethylbut-1-ynyl) benzoate to give the product as an oil (0.18g, 38%).

4- (3, 3-dimethylbut-1-ynyl) -3- (2-hydroxy-2-methylpropoxy) benzoic acid

This compound was prepared using the same procedure as 4- (3, 3-dimethylbut-1-ynyl) -3- (2-morpholinoethoxy) benzoic acid to give the product as a solid (0.15g, 95%) with M/z of 272.8 (M-1).

Intermediate 13

Preparation of 2-chloro-6- (3, 3-dimethylbut-1-ynyl) nicotinic acid

2, 6-dichloropyridine-3-carboxylic acid (2.0g, 10.42mmol), 3, 3-dimethylbut-1-yne (1.4mL, 11.46mmol), copper (I) iodide (0.198g, 1.04mmol) and bis (triphenylphosphine) palladium (II) chloride (1.46g, 2.08mmol) were stirred in 40mL triethylamine at room temperature for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography, eluting with 10-50% MeOH/EtOAc to give 125mg (5%) of the title compound as an orange solid, M/z 236 (M-1).

Intermediate 14

Preparation of (E) -4- (4, 4, 4-trifluorobut-2-en-2-yl) benzoic acid

(E) -4- (4, 4, 4-trifluorobut-2-en-2-yl) benzoic acid methyl ester. Methyl 4-iodobenzoate (2.62g, 10mmol), Et₃N (5ml), acetonitrile (6ml), Pd (OAc)₂(100mg, 0.4mmol) of the mixture 1, 1, 1-trifluoro-2-butene (2.20g, 20mmol) was added, sealed and heated at 125 ℃ for 20 h. After cooling, saturated Na is used₂CO₃The mixture was treated with aqueous solution and extracted with EtOAc. The combined organic phases were washed with brine and dried (MgSO) ₄) And evaporated. The residue was purified by silica gel column chromatography to give methyl (e) -methyl 4- (4, 4, 4-trifluorobut-2-en-2-yl) benzoate and methyl 4- (4, 4, 4-trifluorobut-1-en-2-yl) benzoate.

(E) -4- (4, 4, 4-trifluorobut-2-en-2-yl) benzoic acid. Preparation of (e) -4- (4, 4, 4-trifluorobut-2-en-2-yl) benzoic acid [ lc-ms: tr 3.03 min, M/z 229(M-1) ] and 4- (4, 4, 4-trifluorobut-1-en-2-yl) benzoic acid [ lc-ms: tr 2.82 min, M/z 229(M-1) ].

Intermediate 15

Preparation of (e) -2-methyl-4- (3, 3, 3-trifluoroprop-1-enyl) benzoic acid

A mixture of 4-bromo-2-methylbenzoic acid (25g, 0.12mol), tri-o-tolylphosphine (7.1g, 0.023mol), tetra-N-butylammonium chloride (9.7g, 0.035mol), potassium acetate (22.8g, 0.232mol), 3, 3, 3-trifluoroprop-1-ene (89g, 0.93mol), palladium acetate (1.3g, 0.0058mol) and N, N-dimethylacetamide (150mL, 1.6mol) was sealed in a Parr apparatus and stirred at 180 ℃ for 120 hours. After cooling, the reaction mixture was filtered through Celite ® and the filtrate was partitioned between EtOAc and 1N HCl (pH 2-3). The organic layer was separated and washed with brine and dried (Na) ₂SO₄) And concentrated in vacuo. The residue was purified by silica gel column chromatography to give a crude product (containing a small amount of the corresponding (Z) -isomer).

After conversion of the acid to the corresponding methyl ester, the (Z) -isomer and other impurities can be removed by column chromatography. Saponification of the methyl ester gave pure acid as a white solid (16.5g, 62%).

Intermediate 16

Preparation of (e) -4- (3, 3, 3-trifluoro-2-methylprop-1-enyl) benzoic acid

(E) -4- (3, 3, 3-trifluoro-2-methylprop-1-enyl) benzoic acid methyl ester

In 4-iodobenzoic acid methyl ester (2.62g, 10mmol), Et₃N (5mL), acetonitrile (6mL), Pd (OAc)₂(100mg, 0.4mmol) to the mixture was added 2-trifluoromethylpropene (2.20g, 20 mmol). The mixture was sealed and heated at 125 ℃ for 20 hours. After cooling, the mixture was saturated with Na₂CO₃Aqueous workup and extraction with EtOAc. The combined organic phases were washed with brine and dried (MgSO)₄) And evaporated.The residue was purified by silica gel column chromatography to give (E) methyl 4- (3, 3, 3-trifluoro-2-methylprop-1-enyl) benzoate.

(E) -4- (3, 3, 3-trifluoro-2-methylprop-1-enyl) benzoic acid

To a mixture of methyl (E) -4- (3, 3, 3-trifluoro-2-methylprop-1-enyl) benzoate (60mg, 0.25mmol) in THF (5mL) and MeOH (5mL) was added a solution of 2NNaOH (1mL) with stirring. The mixture was stirred at room temperature for 10 hours. The organic solvent was removed under vacuum, after which the mixture was treated with water and acidified to pH 2-3 with 1n hcl. The mixture was extracted with EtOAc (20 mL. times.3). The combined extracts were washed with brine and dried (Na) ₂SO₄) And evaporated. The residue was purified by column chromatography to give (E) -4- (3, 3, 3-trifluoro-2-methylprop-1-enyl) benzoic acid as a white solid. LC-MS: t is t_R3.04 min, 229 (M-1).

Intermediate 17

Preparation of 5- (3, 3-dimethylbut-1-ynyl) picolinic acid

5- (3, 3-dimethylbut-1-ynyl) picolinic acid methyl ester

To a 250mL closed reaction vessel were added methyl 5-bromopyridine-2-carboxylate (5g, 23mmol), copper (I) iodide (0.43g, 2.3mmol), bis (triphenylphosphine) palladium (II) chloride (3.23g, 4.6mmol), and triethylamine (80 mL). The mixture was stirred for about 10 minutes, then 3, 3-dimethylbut-1-yne (2.83g, 34.5mmol) was added. The tube was sealed, stirred overnight at room temperature, and heated at 60 ℃ for 1 hour. The mixture was allowed to cool and then concentrated in vacuo to a residue. The residue was purified by column chromatography on silica using EtOAc/hexanes (1: 10) as eluent to give the product as a tan solid (4.62g, 92%) which was used directly in the next step.

5- (3, 3-dimethylbut-1-ynyl) picolinic acid.

A500 mL round bottom flask was charged with methyl 5- (3, 3-dimethylbut-1-ynyl) picolinate (4.5g, 21mmol), lithium hydroxide (5.02g, 210mmol), methanol (80mL) and water (30 mL). The mixture was stirred at room temperature for 30 minutes, heated to reflux for 1 hour, and then concentrated in vacuo. Water (100mL) was added and the mixture was cooled to 0 ℃. Concentrated HCl was slowly added to the solution with stirring until the pH of the solution reached 6. An off-white precipitate formed which was filtered off, washed with cold water (3 × 100mL) and dried in vacuo to give the product as an off-white solid (3.97g, 95%). LC-MS 2.76 min, 202.9 (M-1).

Intermediate 18

Preparation of 4- (cyclopropylethynyl) -3- (cyclopropylmethoxy) benzoic acid

4-bromo-3- (cyclopropylmethoxy) benzoic acid ethyl ester

Ethyl 4-bromo-3-hydroxybenzoate (2.0g, 8.2mmol), potassium carbonate (3.4g, 24.48mmol) and (chloromethyl) cyclopropane (1.13mL, 12.24mmol) were added to 50mL of DMF and the reaction was heated at 80 ℃ for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried (Na)₂SO₄) Filtered and the filtrate concentrated to an oil. Purification by column chromatography on silica eluting with 0-50% EtOAc in hexanes afforded the product as a clear oil (0.77g, 31%).

4- (2-Cyclopropylethynyl) -3- (cyclopropylmethoxy) benzoic acid ethyl ester

Ethyl 4-bromo-3- (cyclopropylmethoxy) benzoate (0.77g, 2.57mmol), ethynylcyclopropane (0.45mL, 70% w/v in toluene, 3.86mmol), copper (I) iodide (49mg, 0.26mmol) and bis (triphenylphosphine) palladium (II) chloride (0.36g, 0.51mmol) were added to 50mL triethylamine and stirred in a stopcock at room temperature for 20 h. The reaction was diluted with MeOH and filtered through Celite ®, then the filtrate was concentrated to an oil. Purification by column chromatography on silica eluting with 25% EtOAc in hexanes afforded the product as a brown oil (0.47g, 61%).

4- (cyclopropylethynyl) -3- (cyclopropylmethoxy) benzoic acid

Ethyl 4- (2-cyclopropylethynyl) -3- (cyclopropylmethoxy) benzoate (0.47g, 1.65mmol) and LiOH (120mg, 4.96mmol) were added to a 3: 1 mixture of methanol: water (50mL) and heated at 60 ℃ for 3.5 h. The reaction was cooled and concentrated in vacuo to a volume of 20mL, then the mixture was placed in an ice-water bath and acidified to pH5 with concentrated HCl. The precipitated white solid was filtered off and washed thoroughly with water. The solid was dried in a vacuum oven to give the product (0.44g, 98%). M/z 257.1(M + 1).

Intermediate 19

Preparation of 2- (3, 3-dimethylbut-1-ynyl) pyrimidine-5-carboxylic acid

5-bromo-2-iodo-pyrimidines

The title compound was prepared according to The method given in The Journal of Organic Chemistry, 2002, 67, 6550-6552. Solid 5-bromo-2-chloro-pyrimidine (3.36g, 0.0174mol) was added to 57% hydroiodic acid (aq) pre-cooled to 0 ℃ in a 100ml round bottom flask. The mixture was stirred vigorously at 0 ℃ for 4 hours, allowed to warm to room temperature and stirred overnight. The mixture was then poured onto ice and carefully neutralized by the addition of solid sodium bicarbonate. Solid sodium bisulfite was added until the mixture became colorless, and the mixture was then extracted with EtOAc (2X 200 mL). The combined organic extracts were washed with brine and dried (MgSO) ₄) Filtered and concentrated in vacuo to give a white solid (4.2g) which was taken without further treatmentPurifying for use.

5-bromo-2- (3, 3-dimethylbut-1-ynyl) pyrimidine

A mixture of 5-bromo-2-iodo-pyrimidine (2.53g, 0.00888mol), copper (I) iodide (0.169g, 0.000888mol), 3-dimethyl-1-butyne (1.17mL, 0.00977mol), and bis (triphenylphosphine) palladium (II) chloride (0.623g, 0.000888mol) in triethylamine (25mL, 0.18mol) was heated at 50 ℃ in a 150mL closed reaction vessel. After 16 hours the mixture was cooled to room temperature and filtered through Celite ®, and the filter cake was washed repeatedly with ethyl acetate. The filtrate was concentrated in vacuo to give a dark solid. Purification by silica gel column chromatography, eluting with ethyl acetate: hexane (0-100% gradient) was used as eluent to give the solid product (1.9 g).

2- (3, 3-dimethylbut-1-ynyl) pyrimidine-5-carbonitrile

A mixture of 5-bromo-2- (3, 3-dimethylbut-1-ynyl) pyrimidine (2.5g, 0.010mol) and copper cyanide (1.4g, 0.016mol) in N-methylpyrrolidine was heated in a stopcock at 200 ℃ for 24 hours. The mixture was cooled to room temperature, filtered through Celite ® and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate: hexane (gradient 0-50%) to give the product (1.25 g).

2- (3, 3-dimethylbut-1-ynyl) pyrimidine-5-carboxylic acid

A mixture of isopropanol (40mL) and 2- (3, 3-dimethylbut-1-ynyl) pyrimidine-5-carbonitrile (1.0g, 0.005mol) and potassium hydroxide (2.8g, 0.05mol) in water (10mL) was heated to reflux for 3 hours. The mixture was cooled to room temperature and concentrated under vacuum. Water (200mL) was added and the mixture was cooled to 0 ℃, then concentrated HCl was added until pH 6 was reached. The resulting milky white precipitate was collected by filtration and washed with water to give the solid product, M/z 205(M + 1).

Intermediate 20

Preparation of 4- (cyclopentylethynyl) -2-fluorobenzoic acid

4- (Cyclopentylethynyl) -2-fluorobenzoic acid methyl ester

Methyl 4-bromo-2-fluorobenzoate (1.0g, 4.0mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (38mg, 5 mol%), followed by PdCl₂(PPh₃)₂(140mg, 5 mol%) and ethynylcyclopentane (0.85mL, 6.3 mmol). The mixture was heated in a sealed pressure tube at 80 ℃ for 3 hours. After completion of the reaction triethylamine was removed in vacuo, the residue was dissolved in EtOAc and filtered through Celite ®. The organic layer was washed with water and brine and dried (Na)₂SO₄) The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc-hexanes (0-100% gradient) as eluent to give the product (0.92 g).

4- (Cyclopentylethynyl) -2-fluorobenzoic acid

Methyl 4- (cyclopentylethynyl) -2-fluorobenzoate was dissolved in 10ml MeOH and 10ml 2N LiOH, and the mixture was refluxed overnight. MeOH was removed in vacuo, the basic layer was washed with EtOAC, acidified, and re-extracted with EtOAC. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated in vacuo to afford the desired product as a beige solid (645mg), M/z 233(M + 1).

Intermediate 21

Preparation of 2-chloro-6- (cyclopropylethynyl) nicotinic acid

2, 6-dichloropyridine-3-carboxylic acid ethyl ester

2, 6-dichloropyridine-3-carboxylic acid (2.0g, 10.42mmol) was placed in 100mL EtOH, 2mL of concentrated H was added₂SO₄And the mixture was refluxed for 18 hours. The reaction mixture was cooled and diluted with NaHCO₃The saturated solution was adjusted to pH 5 and then extracted with EtOAc. The organic layer was separated and dried (Na)₂SO₄). Removal of the solvent under vacuum gave 2.1 g of ethyl ester, which was used in the next step without further purification, M/z 220.6(M + 1).

2-chloro-6- (2-cyclopropylethynyl) pyridine-3-carboxylic acid ethyl ester

Ethyl 2, 6-dichloropyridine-3-carboxylate (2.0g, 9.1mmol), ethynylcyclopropane (1.6mL, 70% w/v in toluene, 13.63mmol), copper (I) iodide (173mg, 0.9mmol), bis (triphenylphosphine) palladium (II) chloride (1.28g, 1.82mmol) were stirred in 40mL triethylamine at room temperature for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography with 10-50% EtOAc/hexanes to give the product as a brown oil (0.7g, 31%). And M/z is 250(M + 1).

2-chloro-6- (cyclopropylethynyl) nicotinic acid

The ester was hydrolyzed as follows: ethyl 2-chloro-6- (2-cyclopropylethynyl) pyridine-3-carboxylate (0.7g, 2.8mmol) and lithium hydroxide (0.4g, 16.86mmol) were refluxed in a mixture of 30mL MeOH and 10mL water. The mixture was cooled and methanol was removed under vacuum. The remaining solution was acidified to pH2 with 1M HCl at 0 ℃. The precipitate was filtered and dried to give 0.4g (57%) of the title compound, M/z 222.4(M + 1).

Intermediate 22

Preparation of (Z) -2-methoxy-4- (3, 3, 3-trifluoroprop-1-enyl) benzoic acid and preparation of (E) -2-methoxy-4- (3, 3, 3-trifluoromethylprop-1-enyl) benzoic acid

4-formyl-2-methoxybenzoic acid methyl ester

A stream of CO was slowly passed over a suspension of methyl 4-bromo-2-methoxybenzoate (2.4g, 0.010mol), bis (triphenylphosphine) palladium (II) chloride (140mg, 0.00020mol), sodium formate (1.02g, 0.0150mol) in anhydrous DMF (10 mL). The mixture was stirred vigorously at 110 ℃ for 2 hours. After cooling, the mixture was washed with Na₂CO₃Aqueous workup and extraction with EtOAc. The extract was washed with brine and dried (Na)₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel using AcOEt-hexane as eluent (0-50%) to give a colorless oil.

(E) -methyl 4- (3, 3, 3-trifluoroprop-1-enyl) -2-methoxybenzoate and (Z) -methyl 4- (3, 3, 3-trifluoroprop-1-enyl) -2-methoxybenzoate

To a 1M solution of TBAF in THF (20mL, 20mmol) was added MS4 Å (powder, 16g), and the mixture was stirred under argon at room temperature overnight. To the mixture was added methyl 4-formyl-2-methoxybenzoate (420mg, 0.0022mol) and a solution of 2, 2, 2-trifluoroethyldiphenylphosphine oxide (1.23g, 0.00432mol) in THF (20 mL). The mixture was stirred for 2 hours, after which the MS4 Å was removed by filtration. The filtrate was concentrated and water (120mL) was added. The mixture was extracted with AcOEt. The extract was washed with brine and dried (Na)₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel using AcOEt-hexane (0-15%) as eluent to give methyl (E) -4- (3, 3, 3-trifluoroprop-1-enyl) -2-methoxybenzoate as a white solid, followed by methyl (Z) -4- (3, 3, 3-trifluoroprop-1-enyl) -2-methoxybenzoate as a colorless oil.

(E) -4- (3, 3, 3-trifluoroprop-1-enyl) -2-methoxybenzoic acid

A mixture of methyl (E) -4- (3, 3, 3-trifluoroprop-1-enyl) -2-methoxybenzoate (340mg, 0.0013mol), MeOH (20mL), and aqueous 2 NnaOH (1.5mL) was stirred at 65 ℃ overnight. The solvent was removed under reduced pressure and the residue was treated with water, acidified to pH2-3 with 1N HCl and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine and dried (Na) ₂SO₄) Filtered and concentrated in vacuo toThe product was obtained as a white solid. LC-MS: 2.59 min, 244.8 (M-1).

(Z) -4- (3, 3, 3-trifluoroprop-1-enyl) -2-methoxybenzoic acid

A mixture of methyl (Z) -4- (3, 3, 3-trifluoroprop-1-enyl) -2-methoxybenzoate (60.0mg, 0.000230mol), MeOH (10mL), and 2N aqueous NaOH (0.5mL) was stirred at 65 ℃ for 5 hours. The mixture was cooled and the solvent was removed under reduced pressure. The residue was treated with water, acidified to pH2-3 with 1N HCl, and extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered and concentrated in vacuo to give a slurry which turned into a milky white solid after standing at room temperature for a prolonged period of time. LC-MS: 2.49 min, 244.8 (M-1).

Intermediate 23

Preparation of 4- (cyclopropylethynyl) -2-methylbenzoic acid

4-bromo-2-methylbenzoic acid methyl ester

4-bromo-2-methylbenzoic acid (5.0g, 23mmol) was suspended in methanol (30 mL). To the mixture was added HCl in ether (1.0M, 30 mL). 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 and dried (Na)₂SO₄) Filtered and concentrated in vacuo to give the desired compound (5.5g) as a brown oil.

4- (Cyclopropylethynyl) -2-methylbenzoic acid

Methyl 4-bromo-2-methylbenzoate (1.0g, 4.4mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (43mg, 5 mol%), followed by PdCl₂(PPh₃)₂(157mg, 5 mol%) and ethynylcyclopropane (1.43 ml)12 mmol). The mixture was heated in a sealed pressure tube at 80 ℃ for 3 hours. After completion of the reaction triethylamine was evaporated, the residue was dissolved in EtOAc and filtered through Celite ®. The organic layer was washed with water and brine and dried (Na)₂SO₄) Then filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc-hexanes (0-100% gradient) as eluent to give the desired product (630 mg). The product was dissolved in 10ml MeOH and 10ml 2N LiOH and the mixture was refluxed overnight. MeOH was evaporated, the basic layer was washed with EtOAc, acidified, and re-extracted with EtOAc. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated in vacuo to afford the desired product as a beige solid (461 mg). M/z 201(M + 1).

Intermediate 24

Preparation of 4- (cyclopropylethynyl) -2-fluorobenzoic acid

This compound was prepared in the same manner as 4- (3, 3-dimethylbut-1-ynyl) -2-methylbenzoic acid, except that cyclopropylacetylene was used as the alkyne coupling partner (coupling partner).

Intermediate 25

Preparation of 4- (3, 3-dimethylbut-1-ynyl) -2-methoxybenzoic acid

2-methoxy-4- (3, 3-dimethylbut-1-ynyl) benzoic acid methyl ester

Adding Et₃Methyl 4-bromo-2-methoxybenzoate (1.2g, 0.0049mol) in N (10mL), copper (I) iodide (0.093g, 0.00049mol),A mixture of 3, 3-dimethyl-1-butyne (0.70mL, 0.0059mol) and bis (triphenylphosphine) palladium (II) chloride (0.34g, 0.00049mol) was heated at 100 ℃ for 16 hours in a 50mL closed reaction vessel. After cooling, the mixture was filtered through Celite ® and the filter cake was washed repeatedly with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography 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-1-ynyl) benzoate (1.10g, 0.00447mol), MeOH (20mL), and 2N aqueous NaOH (5mL) was stirred at 65 ℃ overnight. After cooling, the mixture was concentrated in vacuo. The residue was treated with water and extracted with hexane. The aqueous layer was acidified to pH2-3 with 1N HCl and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine and dried (Na)₂O₄) Filtered and concentrated in vacuo to give the product as a white solid (870mg, 84%). LC-MS: 3.22 min, 233.4(M + 1).

Intermediate 26

Preparation of 4- (cyclopentylethynyl) -2, 6-difluorobenzoic acid

Methyl 4-bromo-2, 6-difluoro-benzoate (200mg, 0.8mmol) was dissolved in triethylamine (5mL) and palladium dichloride (bis) triphenylphosphine (29mg, 5 mol%) was added followed by copper iodide (8mg, 5 mol%) and cyclopropylacetylene (0.09mL, 0.96 mmol). The mixture was heated to reflux in a sealed tube for 1 hour. The mixture was cooled to room temperature, filtered through Celite ® and evaporated. The residue was dissolved in dichloromethane and purified with a gradient of 0-100% EtOAc/hexanes to give 178mg (94%) of the ester compound, M/z 237(M + 1). The ester was hydrolyzed using the procedure employed for 4- (cyclopentylethynyl) -2-fluorobenzoic acid to give the desired acidic product.

Intermediate 27

Preparation of 4- (cyclopentylethynyl) -2-methylbenzoic acid

4- (Cyclopentylethynyl) -2-methylbenzoic acid methyl ester

Methyl 4-bromo-2-methylbenzoate (1.0g, 4.4mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (43mg, 5 mol%), followed by PdCl₂(PPh₃)₂(157mg, 5 mol%) and ethynylcyclopentane (0.75mL, 5.3 mmol). The mixture was heated in a sealed pressure tube at 80 ℃ for 3 hours. After completion of the reaction triethylamine was evaporated, the residue was dissolved in EtOAc and filtered through Celite ®. The organic layer was washed with water and brine and dried (Na) ₂SO₄) Then filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with EtOAc-hexanes (0-100% gradient) to afford the desired product.

4- (Cyclopentylethynyl) -2-methylbenzoic acid

The product of step 1 was dissolved in 10ml MeOH and 10ml 2N LiOH and the mixture was refluxed overnight. MeOH was evaporated, the basic layer was washed with EtOAc, acidified, and re-extracted with EtOAc. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated in vacuo to afford the desired product as a beige solid (461 mg). M/z 243(M + 1).

Intermediate 28

Preparation of 4- (3, 3-dimethylbut-1-ynyl) -2-methylbenzoic acid

4-bromo-2-methylbenzoic acid ethyl ester

4-bromo-2-methylbenzoic acid (10g, 46.5mmol) was dissolved in 200mL EtOH and 5mL concentrated H was added₂SO₄And the mixture was refluxed for 18 hours. The volume of the reaction was concentrated to 50mL under vacuum and NaHCO was used₃The saturated solution was neutralized to pH7 and extracted with EtOAc. The organic layer was dried (Na)₂SO₄) The filtrate was filtered and concentrated to give an oily product (6.5 g).

2-methyl-4- (3, 3-dimethylbut-1-ynyl) benzoic acid ethyl ester

Ethyl 4-bromo-2-methylbenzoate (6g, 0.02mol), 3-dimethyl-1-butyne (4.56mL, 0.0382mol), copper (I) iodide (0.47g, 0.0025mol) and bis (triphenylphosphine) palladium (II) chloride (3.46g, 0.00493mol) were added to 40mL triethylamine and stirred overnight at room temperature in a stopcock. The reaction mixture was diluted with MeOH and filtered through Celite ®. The filtrate was concentrated to a brown residue. The residue was purified by column chromatography on silica gel using hexane as eluent to give the product as a brown oil (4.8g, 42%).

4- (3, 3-dimethylbut-1-ynyl) -2-methylbenzoic acid

Ethyl 2-methyl-4- (3, 3-dimethylbut-1-ynyl) benzoate (4.8g, 0.020mol) and lithium hydroxide (2.8g, 0.058mol) were added to a 3: 1 mixture of methanol: water (80mL) and heated at 60 ℃ for 3.5 hours. 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 pH5 with concentrated HCl. The white solid that separated out was filtered off and washed thoroughly with water. The solid was dried in a vacuum oven to give the product (4.1g, 97%) as a solid. M/z 215.1 (M-1).

Intermediate 29

Preparation of (E) -2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoic acid

2-fluoro-4-bromobenzoic acid methyl ester

4-bromo-2-fluorobenzoyl chloride (45.0g, 0.190mol) was slowly added to a solution of methanol (31mL, 0.76mol) and triethylamine (53mL, 0.38mol) at 0 deg.C and the mixture was stirred at room temperature overnight. MeOH was removed under vacuum and the residue was dissolved in CH₂Cl₂(500 mL). The organic layer was washed with water and dried (Na)₂SO₄) 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 (5.0g, 0.021mol), tri-o-tolylphosphine (1.31g, 0.00429mol), tetra-N-butylammonium bromide (2.08g, 0.00644mol), potassium acetate (4.2g, 0.043mol), 3, 3, 3-trifluoroprop-1-ene (20g, 0.2mol), palladium acetate (0.24g, 0.0011mol) was sealed in a Parr apparatus and stirred at 180 ℃ for 96 hours. After cooling, the reaction mixture was filtered through Celite ® and the filtrate was partitioned between EtOAc and 1N aq. The organic layer was separated and washed with brine and dried (Na) ₂SO₄) And concentrated. The residue was chromatographed with hexanes-EtOAc (5% AcOH) (0-60%) to give the product as a white solid. LC-MS: t 2.98 min, M/z 233.2 (M-1).

Intermediate 30

Preparation of (E) -2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoic acid and (Z) -2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoic acid

4-bromo-2-fluorobenzoic acid tert-butyl ester

4-bromo-2-fluorobenzoic acid (3.0g,0.014mol) in THF (50mL) was added DMF (0.1mL) and oxalyl chloride (1.5mL, 0.018 mol). The mixture was stirred at 0 ℃ for 1 hour and then returned to room temperature. The solvent was removed under reduced pressure. The resulting acid chloride was added to t-butanol (5.0g, 0.067mol), pyridine (10mL) and CH at 0 deg.C₂Cl₂(50 mL). The mixture was stirred at room temperature for 3 hours and then at 50 ℃ overnight. The mixture was washed with water, 2N NaOH and brine, dried (MgSO)₄) And concentrated in vacuo. The residue was purified by column chromatography to give the product as a colorless oil (1.5g, 45%).

2-fluoro-4-formylbenzoic acid tert-butyl ester

BuLi (2.5M in hexane, 2.3mL, 5.75mmol) was added carefully to a solution of tert-butyl 4-bromo-2-fluorobenzoate (1.5g, 5.45mmol) in THF (70mL) under argon at-100 ℃ with stirring. The mixture was held at-100 ℃ to-80 ℃ for 1 hour, then a solution of DMF (1.0mL) in THF (5mL) was added. After 1 hour the mixture was raised to 0 ℃ with saturated NH ₄The reaction was quenched with aqueous Cl and extracted with EtOAc. The organic layer was separated, washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/hexanes (0-10%) as eluent to give the product as a white solid (750mg, 61%).

(E) Tert-butyl (2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoate and tert-butyl (Z) -2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoate

Molecular sieve 4 Å (powder, 24g) was added to a 1M solution of TBAF in THF (30mL, 30mmol) and the mixture was stirred under argon at room temperature overnight. To the mixture was added tert-butyl 2-fluoro-4-formylbenzoate (750mg, 0.0033mol) and a solution of 2, 2, 2-trifluoroethyldiphenylphosphine oxide (1.9g, 0.0067mol) in THF (30 mL). The mixture was stirred for 2 hours and then filtered. The filtrate was concentrated in vacuo and water (120mL) was added. The mixture was extracted with AcOEt and the organic extracts were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography on silica gel using AcOEt-hexane (0-15%) as eluent to give (E) -2-fluoro-4- (3,tert-butyl 3, 3-trifluoroprop-1-enyl) benzoate (620mg, 64%) followed by tert-butyl (Z) -2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoate (80mg, 8%) as a colorless oil.

(E) -2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoic acid

Tert-butyl (E) -2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoate (500mg, 0.002mol) in CH₂Cl₂A solution of (10mL) and TFA (1.0mL) 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-1).

(Z) -2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoic acid

Tert-butyl (Z) -2-fluoro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoate (35mg, 0.12mmol) in CH₂Cl₂A solution of (5mL) and TFA (0.5mL) 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-1).

Intermediate 31

Preparation of 4- (3, 3-dimethylbut-1-ynyl) -2-fluorobenzoic acid

4-bromo-2-fluoro-benzoic acid methyl ester

4-bromo-2-fluorobenzoic acid (10g, 0.04mol) was suspended in 1, 2-dichloroethane (60mL, 0.8mol), to which was added thionyl chloride (10mL, 0.1mol), followed by 1 drop of DMF. The mixture was heated to reflux for 1 hour. Excess thionyl chloride and 1, 2-dichloroethane were stripped off, and the crude product was treated with methanol (50mL) and heated at reflux for 1 hour. The mixture was concentrated to dryness, dissolved in dichloromethane and treated with a saturated solution of cold sodium bicarbonate. The organic layer was dried and then concentrated in vacuo to give the title compound as a white solid.

4- (3, 3-dimethyl-but-1-ynyl) -2-fluoro-benzoic acid methyl ester

Bis (triphenylphosphine) palladium (II) chloride (1.03g, 0.00145mol), N-diisopropylethylamine (9.0mL, 0.050mol), copper (I) iodide (0.353g, 0.00186mol) and 1, 4-dioxane (70mL) were added to the closed reaction vessel in this order. 3, 3-dimethyl-1-butyne (6.1mL, 0.050mol) was added, and the vessel was stirred at room temperature for 24 hours. The mixture was filtered through Celite ® and concentrated in vacuo. With 0-20% ethyl acetate: the mixture was chromatographed with a hexane gradient. The combined pure fractions were concentrated under vacuum and dried under high vacuum to give a light brown solid.

4- (3, 3-dimethyl-but-1-ynyl) -2-fluoro-benzoic acid

Methyl 2-fluoro-4- (3, 3-dimethylbut-1-ynyl) benzoate (8.2g, 0.035mol) was suspended in H₂A3: 1 mixture of O and methanol to which was immediately added lithium hydroxide (2.5g, 0.10mol) in one portion and the mixture was stirred at ambient temperature overnight. The mixture was then concentrated to 3/4 volumes and acidified with 1N HCl until the pH was again adjusted to acidic. The white precipitate was filtered off, washed with water and dried under vacuum at 80 ℃ for several hours, M/z 218.9 (M-1).

Intermediate 32

Preparation of 2-chloro-4- (3, 3-dimethylbut-1-ynyl) benzoic acid

2-chloro-4- (3, 3-dimethylbut-1-ynyl) benzoic acid methyl ester

Adding Et₃A mixture of methyl 4-bromo-2-chlorobenzoate (400mg, 0.0016mol), copper (I) iodide (30mg, 0.00016mol), 3-dimethyl-1-butyne (0.29mL, 0.0024mol), and bis (triphenylphosphine) palladium (II) chloride (110mg, 0.00016mol) in N (5mL) and DMF (2mL) in a 50mL closed reaction vesselHeating at 100 deg.C for 32 hr. 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 and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the product as a pale yellow oil (330mg, 82%).

2-chloro-4- (3, 3-dimethylbut-1-ynyl) benzoic acid

A mixture of methyl 2-chloro-4- (3, 3-dimethylbut-1-ynyl) benzoate (330mg, 0.0013mol), 2N aq. NaOH (3.0mL), THF (5mL) and MeOH (5mL) was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo and the residue was treated with water and acidified to pH2-3 with 1N HCl and extracted with EtOAc. The organic layer was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo to give the product as a white solid (305mg, 98%). t is t_R3.56 min, 234.9& 236.9(M-1)。

Intermediate 33

Preparation of 2-chloro-4- (cyclopropylethynyl) benzoic acid

2-chloro-4- (2-cyclopropylethynyl) benzoic acid methyl ester

Adding Et₃A mixture of methyl 4-bromo-2-chlorobenzoate (450mg, 0.0018mol), copper (I) iodide (34mg, 0.00018mol), 70% cyclopropylacetylene (0.26g, 0.0027mol) in toluene and bis (triphenylphosphine) palladium (II) chloride (130mg, 0.00018mol) in N (5mL) and DMF (3mL) was heated at 100 ℃ for 36 hours in a 50mL closed reaction vessel. 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 and dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give a brown oily product (320mg, 76%).

2-chloro-4- (2-cyclopropylethynyl) benzoic acid

A mixture of methyl 2-chloro-4- (2-cyclopropylethynyl) benzoate (310mg, 0.0013mol), 2N aq. NaOH (3.0mL), THF (5mL) and MeOH (5mL) was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo and the residue was treated with water and acidified to pH2-3 with 1N HCl and extracted with EtOAc. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated in vacuo to give the product as a yellow solid (270mg, 93%). LC-MS: 3.18 min, 218.9& 220.9(M-1)。

Intermediate 34

Preparation of (E) -2-chloro-4- (3, 3, 3-trifluoroprop-1-enyl) benzoic acid

2-chloro-4-formylbenzoic acid methyl ester

A stream of CO was slowly passed over a suspension of methyl 4-bromo-2-chlorobenzoate (1.50g, 0.00601mol), bis (triphenylphosphine) palladium (II) chloride (80mg, 0.0001mol), sodium formate (613mg, 0.00902mol) and anhydrous DMF (10 mL). The mixture was stirred vigorously at 110 ℃ for 2 hours. After cooling, the mixture was washed with Na₂CO₃Aqueous workup and extraction with EtOAc. The extract was washed with brine and dried (Na)₂SO₄) And concentrated. The residue was chromatographed on silica gel with AcOEt-hexanes to give the product as a colorless oil (turning to a white solid upon storage in the refrigerator).

2-chloro-4- ((E) -3, 3, 3-trifluoroprop-1-enyl) benzoic acid

Molecular sieve 4 Å (powder, 16g) was added to a 1M solution of TBAF in THF (20mL, 20mmol), and the mixture was stirred under argon at room temperature overnight. To the mixture were added methyl 2-chloro-4-formylbenzoate (210mg, 0.0010mol) and 2, 2, 2-trifluoroethyldiphenylphosphine oxide (600mg, 0.0021mol)THF (15 mL). The mixture was stirred for 2 hours, then the molecular sieve was removed by filtration. The filtrate was concentrated and water (120mL) was added. The mixture was extracted with AcOEt. The organic extracts were washed with brine and dried (Na)₂SO₄) And concentrated. With AcOEt [ 1% HOAc ] ]Hexane the residue was chromatographed on silica gel to give the product as a white solid. LC-MS: t is 3.12 min, m/z is 248.9& 250.9(M-1)。

Intermediate 35

Preparation of 4- (cyclopropylethynyl) -2- (methylsulfonyl) benzoic acid

Methyl 4-bromo-2-methanesulfonate (250mg, 0.85mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (9.0mg, 5 mol%), followed by PdCl₂(PPh₃)₂(32mg, 5 mol%) and ethynylcyclopentane (0.135ml, 1.0 mmol). The mixture was heated in a sealed pressure tube at 80 ℃ for 3 hours. After completion of the reaction, triethylamine was removed in vacuo, and the residue was dissolved in EtOAc and filtered through Celite ®. The organic layer was washed with water and brine and dried (Na)₂SO₄). After filtration and concentration in vacuo, the residue was purified by silica gel column chromatography with EtOAc-hexane (0-100% gradient) as eluent to give methyl 4- (cyclopropylethynyl) -2- (methylsulfonyl) benzoate (240 mg). The product was dissolved in 10ml MeOH and 10ml2N LiOH and the mixture was refluxed overnight. MeOH was evaporated, the basic layer was washed with EtOAc, acidified, and re-extracted with EtOAc. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated in vacuo to give the product as a beige solid (165mg), M/z 293(M + 1).

Intermediate 36

Preparation of 4- (3, 3-dimethylbut-1-ynyl) -2, 6-difluorobenzoic acid

4-bromo-2, 6-difluorobenzoic acid methyl ester

4-bromo-2, 6-difluorobenzoic acid (7g, 0.03mol), methyl iodide (2.8mL, 0.045mol), and potassium carbonate (12.22g, 0.08842mol) were added to 100mL of acetone in a sealed tube and heated at 50 ℃ overnight. The reaction was cooled and partitioned between EtOAc and water. The organic layer was dried (Na)₂SO₄) Filtered and the filtrate concentrated to an oil. Purification by column chromatography on silica gel gave the product (1.3g, 17%) and 5 g of starting material.

2, 6-difluoro-4- (3, 3-dimethylbut-1-ynyl) benzoic acid methyl ester

Methyl 4-bromo-2, 6-difluorobenzoate (1.3g, 0.0052mol), 3-dimethyl-1-butyne (0.96mL, 0.0080mol), copper (I) iodide (200mg, 0.001mol), and bis (triphenylphosphine) palladium (II) chloride (0.73g, 0.0010mol) were added to 50mL triethylamine and stirred in a stopcock at room temperature for 20 hours. The reaction was diluted with MeOH and filtered through Celite ®. The filtrate was concentrated to an oil and purified by silica gel column chromatography using hexane as eluent to give the product as a yellow oil (1.0g, 80%).

4- (3, 3-dimethylbut-1-ynyl) -2, 6-difluorobenzoic acid

Methyl 2, 6-difluoro-4- (3, 3-dimethylbut-1-ynyl) benzoate (1.0g, 0.004mol) and lithium hydroxide (0.57g, 0.012mol) were added to a 3: 1 mixture of methanol: water (60mL) and heated at 60 ℃ for 3.5 hours. 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 pH5 with concentrated HCl. The white solid that separated out was filtered off and washed thoroughly with water. The solid was dried in a vacuum oven to give the product (0.79g, 84%) as a solid, with M/z 237.1 (M-1).

Intermediate 37

Preparation of 4- (3, 3-dimethyl-1-alkynyl) -2-fluoro-3-methoxybenzoic acid

2-fluoro-3-methoxy-4- (3, 3-dimethylbut-1-ynyl) benzoic acid methyl ester

Methyl 4-bromo-2-fluoro-3-methoxybenzoate (960mg, 3.5mmol), copper (I) iodide (70mg, 0.4mmol) and bis (triphenylphosphine) palladium (II) chloride (300mg, 0.4mmol) were suspended in Et₃N (10mL) and DMF (4 mL). 3, 3-dimethyl-1-butyne (440mg, 5.2mmol) was added and the mixture was heated in a sealed tube for 60 hours from room temperature to 100 ℃. The solvent was removed and the residue was dissolved in EtOAc, washed with water and brine, washed with Na₂SO₄And (5) drying. Column chromatography on silica gel afforded the product as a pale yellow oil (760mg, 79%).

2-fluoro-3-methoxy-4- (3, 3-dimethylbut-1-ynyl) benzoic acid

Methyl 2-fluoro-3-methoxy-4- (3, 3-dimethylbut-1-ynyl) benzoate (760mg, 2.7mmol) was dissolved in MeOH (10mL), NaOH (dissolved in 10mL water) was added and stirred at 50 ℃ for 1 h. The solvent was removed, more water was added, neutralized with HCl until pH was about 2, and the white solid formed was filtered off and dried in a vacuum oven (65 ℃). The product was obtained as a white solid (760mg, 93%).

Intermediate body 38

Preparation of 2-chloro-4- (3, 3-dimethylbut-1-ynyl) -5-fluorobenzoic acid

2-chloro-5-fluoro-4- (3, 3-dimethylbut-1-ynyl) benzoic acid methyl ester

Methyl 4-bromo-2-chloro-5-fluorobenzoate (9.1g, 32mmol), copper (I) iodide (0.62g, 3.2mmol) and bis (triphenylphosphine) palladium (II) chloride (2.3g, 3.2mmol) were suspended in Et₃N (100mL) and DMF (40mL), 3-dimethyl-1-butyne (4.1g, 48mmol) was added and the mixture was stirred in a sealed tube at 100 ℃ for 40 h. The solvent was removed and the residue was dissolved in EtOAc, washed with water and brine and purified by column chromatography to give the product as a pale yellow oil (6.1g, 69%).

2-chloro-5-fluoro-4- (3, 3-dimethylbut-1-ynyl) benzoic acid

Methyl 2-chloro-5-fluoro-4- (3, 3-dimethylbut-1-ynyl) benzoate (6.1g, 22mmol) was dissolved in MeOH (30mL), sodium hydroxide (1.3g, 33mmol) (dissolved in 20mL of water) was added and stirred at 60 deg.C overnight. The solvent was removed, the residue was dissolved in water, neutralized with HCl until pH < 2, extracted with EtOAc, washed with water and brine, washed with Na₂SO₄And (5) drying. The product was obtained as a beige solid (3.1g, 52%).

Intermediate 39

Preparation of (E) -4- (3, 3-dimethylbut-1-enyl) -2-methylbenzoic acid

4-bromo-2-methyl-benzoic acid methyl ester

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

(E) -4- (3, 3-dimethylbut-1-enyl) -2-methylbenzoic acid methyl ester

A mixture of methyl 4-bromo-2-methylbenzoate (10.0g, 0.0436mol), tri-o-tolylphosphine (1.31g, 0.00429mol), cesium carbonate (6.99g, 0.0214mol), tetra-N-butylammonium chloride (1.79g, 0.00644mol), 3-dimethyl-1-butene (20g, 0.2mol), palladium acetate (0.24g, 0.0011mol) was sealed in a glass container and stirred at 150 ℃ for 96 hours. 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 and dried (Na)₂SO₄) And concentrated. The residue was chromatographed with hexanes-EtOAc to give the title compound as a white solid.

(E) -4- (3, 3-dimethyl-but-1-enyl) -2-methylbenzoic acid

A solution of methyl (E) -4- (3, 3-dimethylbut-1-enyl) -2-methylbenzoate (6.5g, 0.028mol) and lithium hydroxide (3.4g, 0.14mol) in a mixture of methanol (50mL, 1mol) and water (150mL) was heated at reflux for 3 hours. Most of the methanol was stripped off and the aqueous solution was carefully acidified with concentrated HCl. The white precipitate was filtered off, washed with water and dried in vacuo, M/z 217.1 (M-1).

Intermediate 40

Preparation of 3-methyl-4- (3, 3, 3-trifluoroprop-1-ynyl) benzoic acid

The preparation is based on the procedure described in detail in Yoneda et al, Bulletin Chemical Society Japan 1990, 63, 2124-2126. An n-butyllithium solution (2.5M in hexane; 1 eq.) is carefully added to a solution of 3, 3, 3-trifluoroprop-1-yne (1 eq.) in THF at-78 ℃ under nitrogen. The mixture was stirred at-78 ℃ for 30 minutes and then ZnCl was slowly added₂(3 equivalents) ofTHF solution. The mixture was allowed to warm to room temperature, stirred for 30 minutes, and Pd (Ph) was added₃P)₄(5 mol%) 4-iodo-3-methylbenzoic acid (0.5 eq) was then added. The mixture was heated to 50 ℃ and stirred for 15 minutes, then heated at 80 ℃ for 5 hours and finally at 100 ℃ overnight. After cooling to room temperature the mixture was concentrated in vacuo to a crude residue. The residue was purified by silica gel column chromatography to give a solid product, M/z 227 (M-1).

Amine preparation building blocks

Intermediate 41

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] dioxine

Reacting (2, 3-dihydro-6-nitrobenzo [ b ] under nitrogen][1，4]Dioxine-2-yl) methanol (500mg, 0.002mol) and sodium hydride (0.28g, 0.0070mol) were added to the flask. The flask was placed on an ice bath and 25ml of dmdff was added. The reaction was stirred at 0 ℃ for 10 min, then (chloromethyl) cyclopropane (440. mu.L, 0.0048mol) was added. The mixture was allowed to warm to room temperature over 20 minutes, then tetra-N-butylammonium bromide (1.53g, 0.00475mol) was added to the mixture and the reaction was stirred overnight at room temperature. The reaction was partitioned between EtOAc and water. The organic layer was separated, washed with brine and dried (Na) ₂SO₄) Filtered and the filtrate concentrated in vacuo to an oil. The oil was purified by column chromatography on silica gel using EtOAc/hexanes (10%) as eluent to give a yellow solid (0.33g, 50%). 266(M +1) M/z.

2- ((cyclopropylmethoxy) methyl) -2, 3-dihydrobenzo [ b ] [1, 4] dioxin-6-amine

2- ((cyclopropyl)Methoxymethoxy) methyl) -2, 3-dihydro-6-nitrobenzo [ b][1，4]Dioxins (0.33g, 0.0012mol) were dissolved in 20mL dioxane. Sodium dithionite (2.2g, 0.013mol) was suspended in water (4mL) and NH₄OH (2mL), which was then added to the dioxane solution. The reaction was stirred at room temperature for 6 hours. The mixture was filtered through filter paper and the filtrate was concentrated in vacuo to a white solid. The solid was suspended in 10% EtOAc/hexanes and filtered. The filtrate was concentrated to a white solid, which was used in the next reaction without further purification. Yield of the title compound was 0.29 g (98%). M/z 235.8(M + 1).

Intermediate body 42

Preparation of 1-methyl-1, 2, 3, 4-tetrahydroquinolin-7-ylamine

7-nitro-1, 2, 3, 4-tetrahydroquinoline

A solution of concentrated nitric acid (4.9mL) in concentrated sulfuric acid (12mL) was added dropwise to a solution of 1, 2, 3, 4-tetrahydroquinoline (6.5g, 0.049mol) in concentrated sulfuric acid (118mL) at 0 ℃ over 3 hours to maintain a temperature < 5 ℃. The reaction mixture was then poured onto crushed ice and neutralized with solid potassium carbonate. The mixture was extracted with EtOAc (2 × 500mL), the combined organic extracts were washed with water, dried and concentrated to give the crude product, which was purified by silica gel column chromatography using EtOAc/hexanes as the eluent to give the title compound as an orange solid.

1-methyl-7-nitro-1, 2, 3, 4-tetrahydroquinoline

To a solution of 7-nitro-1, 2, 3, 4-tetrahydroquinoline (4.5g, 25.25mMol) in DMF (50mL) was added potassium carbonate (15g) and methyl iodide (5.54g, 39.0mMol) and the mixture was stirred at ambient temperature overnight. The mixture was poured into water and extracted with ether (3X 200 mL). The combined ether extracts were washed with brine, dried and concentrated to give the crude product, which was purified by silica gel column chromatography to give the title compound as an orange liquid.

1-methyl-1, 2, 3, 4-tetrahydroquinolin-7-ylamine

A mixture of 1-methyl-7-nitro-1, 2, 3, 4-tetrahydroquinoline (4.0g, 20.81mmol) and Pd/C (10% w/w; 2g) in methanol (100mL) was hydrogenated at 10 PSI for 2 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the crude material, which was used without further purification.

Intermediate 43

Preparation of 3, 4-dihydro-2H-benzo [ b ] [1, 4] oxazin-6-amine

6-nitro-2H-benzo [ b ] [1, 4] oxazin-3 (4H) -one

In 30mL CHCl₃2-amino-4-nitrophenyl (3,08g, 20mmol), benzyltriethylammonium chloride (TEBA, 4.56g, 20mmol) and NaHCO₃(6.72g, 80mmol) to the suspension Bromoacetyl bromide (4.84g, 24mmol, dissolved in 10mL of CHCl) was added dropwise ₃) While cooling with an ice bath. The mixture was stirred for 1.5 hours under ice bath cooling and then at 60 ℃ overnight. The solvent was removed under vacuum and water was added to the residue. The precipitated solid was filtered and dried in vacuo to give the product as a beige solid (3.45g, 89%).

6-amino-2H-benzo [ b ] [1, 4] oxazin-3 (4H) -one

Pd/C (10%) was added to a suspension of 6-nitro-2F-benzo [ b ] [1, 4] oxazin-3 (4H) -one (1.5g) in MeOH (20mL) and the reaction mixture was stirred under hydrogen overnight. The mixture was filtered through Celite ® and the filtrate was concentrated in vacuo to give the product as a beige solid (0.705g, 56%).

3, 4-dihydro-2H-benzo [ b ] [1, 4] oxazin-6-amine

Reacting 6-amino-2H-benzo [ b ]][1，4]Oxazin-3 (4H) -one (590mg, 3.6mmol) was added to a solution of borane tetrahydrofuran complex (9mL, 1M solution) in THF and the reaction mixture was refluxed for 2.5 hours. EtOH (2mL) was added and stirred at 70 ℃ for 1 hour, then 1mLHCl (concentrated) was added. The mixture was stirred at 80 ℃ overnight and then volatiles were removed under vacuum to leave a crude residue. The residue was dissolved in water, NaOH was added until the pH was about 10, and CH was used₂Cl₂The mixture is extracted. 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 a colorless oily product (274mg, 51%).

Intermediate 44

Preparation of 3, 4-dihydro-2H-benzo [ b ] [1, 4] oxazin-7-amine

The above-described material was prepared in the same manner as 3, 4-dihydro-2H-benzo [ b ] [1, 4] oxazin-6-amine, but using 2-amino-5-nitrophenol as the starting material.

Intermediate 45

Preparation of 4-methyl-3, 4-dihydro-2H-benzo [ B ] [1, 4] oxazin-7-amine

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

Intermediate 46

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 (4H) -one

2-Bromoisobutyryl bromide (10.3g, 45mmol, in 20mL chloroform) was added dropwise to a suspension of 2-amino-4-nitrophenol (4.62g, 30mmol) and sodium bicarbonate (10.1g, 120mmol) in chloroform (250mL) under nitrogen while cooling with an ice bath. The reaction mixture was stirred overnight to bring it from 0 ℃ to room temperature and then the solvent was removed under vacuum. The residue was suspended in DMF (150mL) and potassium carbonate (5.98g, 45mmol) was added, then the reaction mixture was stirred at 80 ℃ overnight. The solvent was removed under vacuum and water was added to the residue. The precipitate formed was filtered off and dried in vacuo to give the product as a light brown solid (4.5g, 68%).

The remaining synthetic steps (hydrogenation of nitro group followed by borane reduction of lactam) were performed using the general procedure described for 3, 4-dihydro-2H-benzo [ b ] [1, 4] oxazin-6-amine.

Intermediate 47

Preparation of 7-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-7-amine

The above-mentioned materials were prepared in the same manner as 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, but using 2-amino-5-nitrophenol as the starting material

Intermediate 48

Preparation of 6-chloro-3, 4-dihydro-2H-benzo [ b ] [1, 4] oxazin-7-amine

6-chloro-7-nitro-2H-benzo [ b ] [1, 4] oxazin-3 (4H) -one

This compound was prepared using the general procedure described for 2, 2-dimethyl-6-nitro-2H-benzo [ b ] [1, 4] oxazin-3 (4H) -one but starting with 2-amino-4-chloro-5-nitrophenol.

7-amino-6-chloro-2H-benzo [ b ] [1, 4] oxazin-3 (4H) -one

Tin chloride dihydrate (30g, 0.13mol) was added in one portion to 6-chloro-7-nitro-2H-benzo [ b ]][1，4]A solution of oxazin-3 (4H) -one (6.7g, 0.026mol) in DMF (100mL) was cooled with an ice bath. The mixture was allowed to warm to room temperature and then stirred overnight. To the reaction mixture were added EtOAc (300mL) and MeOH (300mL), Et₃N until pH > 8, the resulting suspension was filtered through Celite ®. The solvent was removed in vacuo and the residue was suspended in water, extracted with EtOAc and dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue was triturated with ether to give the product as a yellow solid (2.5g, 45%).

6-chloro-3, 4-dihydro-2H-benzo [ b ] [1, 4] oxazin-7-amine

Borane reduction was performed using the general procedure described above for 3, 4-dihydro-2H-benzo [ b ] [1, 4] oxazin-6-amine, but using 7-amino-6-chloro-2H-benzo [ b ] [1, 4] oxazin-3 (4H) -one as starting material.

Intermediate 49

Preparation of (6-amino-3H-imidazo [4, 5-b ] pyridin-2-yl) -methanol

(6-nitro-3H-imidazo [4, 5-b ] pyridin-2-yl) -methanol

Solid 2, 3-diamino-5-nitropyridine (prepared according to J. Med. chem.1997, 40, 3679-3686; 610mg, 0.0040mol) and solid glycolic acid (750mg, 0.0099mol) were mixed in a lock tube (kept open), heated to 145 ℃ and stirred for about 30-45 minutes (the solids were fused together, liquefied and then re-solidified). After cooling to room temperature the solid was extracted with 1n hcl. The aqueous mixture was concentrated in vacuo to a crude solid, which was washed with concentrated NH₄The OH solution alkalifies the solid. The aqueous ammonia solution was concentrated in vacuo to a crude solid, which was loaded onto silica and purified by column chromatography (using an ISCO system) to give a solid (450mg) which was used directly in the next step.

(6-amino-3H-imidazo [4, 5-b ] pyridin-2-yl) -methanol

Tin chloride dihydrate (1.6g, 0.0070mol) was added to (6-nitro-3H-imidazo [4, 5-b ] in 10% aqueous hydrochloric acid (20mL) at once at 50 ℃ with stirring]Pyridin-2-yl) -methanol (450mg, 0.0023 mol). The mixture was stirred at 50 ℃ for about 2 hours and then allowed to cool to room temperature. The mixture was further cooled to 0 ℃ and then treated with concentrated NH ₄The OH is basified to about pH 8. The aqueous layer was then filtered through Celite ® to remove the tin salt, and the filtrate was concentrated in vacuo toA crude solid (380 mg; assuming the same yield) was obtained which was used directly in the next step (amide formation).

Intermediate 50

Preparation of (3-aminoquinolin-7-yl) methanol (prepared using the general procedure described in J.Am.chem.Soc.1997, 119, 5591)

3- [3- (hydroxymethyl) phenylamino ] -2-nitroacrolein

3-aminobenzyl alcohol (4.97g, 0.0404mol) was dissolved in 4mL concentrated HCl. Sodium nitropropionaldehyde monohydrate (prepared from mucobromic acid as described in "organic Synthesis", volume IV, p 844, 1963) (4.25g, 0.0269mol) was dissolved in 35mL of water and an amine solution (yellow precipitate formed immediately) was added, followed by 80mL of water to aid stirring. After 10 min the precipitate was filtered off, washed with water and air dried overnight to give the product as a yellow solid (4.3 g).

(3-nitroquinolin-7-yl) methanol

3- (3- (hydroxymethyl) phenylamino) -2-nitroacrolein (4.3g, 19.4mmol) was added to 20 mLHOAc. 4.8g of 3-aminobenzyl alcohol (4.8g, 38.7mmol) are dissolved in 5mL of concentrated HCl and 20mL of HOAC are added to the HCl solution. This mixture was added to a reaction flask containing a solution of 3- (3- (hydroxymethyl) phenylamino) -2-nitroacrolein in HOAc. The mixture was heated to reflux under nitrogen and after 20 min thiophenol (0.19mL, 0.19mmol) was added. The mixture was refluxed for 28 hours (m/z 208.1). After cooling, the acid was removed under vacuum. The residue was dissolved in EtOAc/MeOH and loaded onto a silica gel column. Purification by column chromatography on silica gel with hexanes/EtOAc (0-50%) and 10% MeOH/EtOAc as eluent afforded the product as a brown solid (500mg, 9%).

(3-aminoquinolin-7-yl) methanol

(3-Nitro-quinolin-7-yl) methanol (1.2g, 0.0059mol) and 400mg Pd/C (10% wt) were added to 60mL of anhydrous THF. The mixture was stirred under hydrogen (balloon) overnight. The reaction was filtered through Celite ® and the filtrate was concentrated to an oil. Purifying by silica gel column chromatography with MeOH/CH₂Cl₂(0-10%) was used as eluent to give 0.9 g of oily product, m/z 216.9(+ acetic acid). The product was suspended in MeOH and K was added₂CO₃(200 mg). The mixture was stirred at room temperature for 4 hours. And m/z is 175.1. The mixture was filtered and the filtrate was concentrated in vacuo to give the product as a moist solid (172mg, 19%).¹HNMR(d₄-MeOD)δ 8.32(1H，d)，7.69(1H，s)，7.55(1H，d)，7.34(1H，dd)，7.23(1H，d)，5.40(2H，s)。

Intermediate 51

Preparation of (6-amino-1H-indazol-3-yl) methanol

6-Nitro-1H-indazole-3-carboxaldehyde (500mg, 0.003mol) was dissolved in 50mL THF. Lithium tetrahydroaluminate (400mg, 0.01mol) was added in 3 portions and the reaction mixture was stirred at room temperature overnight. Water (400. mu.L), 15% NaOH solution (400. mu.L) and then water (1.2mL) were added and the yellow-brown crystalline precipitate was filtered off. The filtrate was concentrated to an oil, which was used in the next step without further purification. And m/z is 164.0.¹HNMR(d₄-MeOH)δ 7.2(1H，d)，7.05(1H，d)，6.85(1H，dd)，4.74(2H，s)。

Intermediate body 52

Preparation of (7-aminoquinolin-3-yl) methanol

2-dimethylaminomethylene-1, 3-bis (dimethyllimonoi) propane bis (tetrafluoroborate)

In a three-necked flask equipped with a reflux condenser were charged bromoacetic acid (25g, 0.18mol) and phosphorus oxychloride (50mL, 0.54 mol). The solution was cooled to 0 ℃ and N, N-dimethylformamide (84mL, 1.1mol) was added dropwise over 30 minutes. The resulting solution was heated at 110 ℃ for 3 hours. The mixture begins to release heat and CO when heated₂. The mixture was then cooled to 0 ℃ and a solution of 50% aqueous tetrafluoroboric acid (63g, 0.36mol) in MeOH (100mL) was slowly added over 1 hour through an addition funnel. To the thick dark solution was added isopropanol (100 mL). A solid precipitated out and the slurry was stirred at 0 ℃ for 2 hours. The solid was collected by filtration to give the product as a light yellow solid (64g, 72%).

3-Aminophenylcarbamic acid benzyl ester

At 0 ℃ with stirring, m-phenylenediamine (5.0g, 0.046mol) and N, N-diisopropylethylamine (8.0mL, 0.046mol) in CH₂Cl₂To the solution (150mL) was added slowly benzyl chloroformate (6.6mL, 0.046 mol). The mixture was stirred at 0 ℃ for 2 hours and then allowed to return to room temperature over 2 hours. Adding NaHCO₃The aqueous solution was separated and the organic phase was washed with brine and dried (Na)₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel to give the desired product (8.0g, 71%) as a slurry. LC-MS: 2.11 min, 243.0(M + 1).

3-Formylquinolin-7-ylcarbamic acid benzyl ester

A slurry of benzyl 3-aminophenylcarbamate (8.0g, 0.033mol) and 2-dimethylaminomethylene-1, 3-bis (dimethyllimonoio) propane bis (tetrafluoroborate) (31g, 0.087mol) in ethanol (400mL) was heated at reflux for 24 hours. The solution was concentrated in vacuo and the residue was dissolved in THF (200mL) and 1N HCl (200 mL). The reaction mixture was stirred at rt overnight, then poured into saturated sodium bicarbonate solution (200mL) and extracted with EtOAc (2 ×). The combined organic layers were washed with brineWashing and drying (Na)₂SO₄) And concentrated in vacuo to afford the desired product as a yellow solid (10.0g, 99%). LC-MS: 2.84 min, 307.1(M + 1).

3- (hydroxymethyl) quinolin-7-ylcarbamic acid benzyl ester

Sodium tetrahydroborate (0.25g, 0.0065mol) was added to a mixture of benzyl 3-formylquinolin-7-ylcarbamate (2.0g, 0.0065mol), THF (50mL), MeOH (50mL), and water (50mL) with stirring. The mixture was stirred at room temperature until LC-MS indicated no SM. The mixture was acidified with 1N HCl and concentrated in vacuo, then NaHCO₃Aqueous and EtOAc treatment. The organic layer was separated and washed with brine and dried (Na)₂SO₄) And evaporated. The residue was purified by column chromatography on silica gel with MeOH-EtOAc (0-10%) as eluent to give the product as a light yellow solid (1.3g, 64%). LC-MS: 1.83 min, 309.2(M + 1).

(7-aminoquinolin-3-yl) methanol

A mixture of benzyl 3- (hydroxymethyl) quinolin-7-ylcarbamate (480mg, 0.0016mol), 10% Pd-C (50mg), and MeOH (50mL) in H₂(1 atm) for 1 hour. The crystals were filtered off and the filtrate was concentrated to give the product as a yellow solid. LC-MS: 0.34 min, 175.1(M + 1).

Intermediate 53

Preparation of quinolin-7-amines

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

Intermediate body 54

Preparation of 5-amino-3-methylisoquinoline

5-amino-3-methylisoquinoline

A mixture of 3-methyl-5-nitroisoquinoline (1.3g, 0.0069mol, prepared according to the method of WO 2004/024710), 10% Pd-C (100mg) and MeOH (100mL) was stirred under hydrogen (1 atm) at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a pale yellow solid (1.1g, 100%). LC-MS: 0.64 min, 159.1(M + 1).

Intermediate 55

Preparation of 1-chloroisoquinolin-5-amine

1-chloro-5-nitroisoquinoline

At 0-5 deg.C, with fuming HNO₃Concentrated H (10mL) with Potassium nitrate (4.0g, 0.040mol) ₂SO₄(35mL) solution treatment of 1-chloroisoquinoline (6.0g, 0.037mol) and concentrated H₂SO₄(35 mL). The mixture was stirred at 0 ℃ for another 90 minutes 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+1)。

1-chloroisoquinolin-5-amines

A mixture of 1-chloro-5-nitroisoquinoline (450mg, 0.0022mol), tin chloride dihydrate (2.4g, 0.011mol), and EtOAc (50mL) was stirred at reflux under nitrogen for 3 hours. After cooling, the mixture was poured into ice water and washed with aq₂CO₃Basification to ph 10.0. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product as a pale yellow solid. LC-MS: 3.17 min, 179.2& 181.2(M+1)。

Intermediate 56

Preparation of 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 and 8-amino-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] oxazepin-3-ol

A mixture of 2-amino-5-nitrophenol (10.0g, 0.0649mol), potassium carbonate (13.4g, 0.0973mol), cesium fluoride (2.0g, 0.013mol), and 1-bromo-2, 3-epoxypropane (5.37mL, 0.0649mol) in DMF (120mL) was stirred overnight at room temperature under nitrogen and then heated at 100 ℃ for 10 hours. After cooling, the solvent was removed under vacuum and the residue was partitioned between water and EtOAc. The organic layer was washed with brine and dried (Na) ₂SO₄) And concentrated. The residue is substituted by CH₂Cl₂EtOAc (5% Et-containing)₃N) (0-40%) was purified by column chromatography to give an orange solid. LC-MS: 2.30 min, 211.1(M + 1).

7-amino-3, 4-dihydro-2I 7-benzo [ b ] [1, 4] oxazin-3-yl) methanol and 8-amino-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] oxazepin-3-ol

Reacting (3, 4-dihydro-7-nitro-2H-benzo [ b ]][1，4]Oxazin-3-yl) methanol (3.8g, 0.018mol) was hydrogenated over 10% Pd/C at 40Psi for 2 hours. The mixture was filtered through Celite ® and the filtrate was concentrated in vacuo to give the crude product. Purification by silica gel column chromatography (EtOAc) afforded the product as a dark brown oil. LC-MS: 0.36 min, 181.1(M + 1).¹H NMR(DMSO-d₆): 6.32(1H, d, J ═ 9.2Hz), 6.01-5.97(2H, m), 4.82-4.76(2H, m), 4.29(2H, s), 4.08(1H, dd, J ═ 10.4, 1.6Hz), 3.79(1H, dd, J ═ 10.4, 6.8Hz), 3.35(2H, m), 3.17(1H, m). Also isolated from the above process is 8-amino-2, 3, 4, 5-tetrahydrobenzo [ b][1，4]Oxazepin-3-ol as a minor by-product.

Intermediate 57

Preparation of (S) - (3, 4-dihydro-7-nitro-2H-benzo [ b ] [1, 4] oxazin-3-yl) methanol

(S) - (3, 4-dihydro-7-nitro-2H-benzo [ b ] [1, 4] oxazin-3-yl) methanol

Sodium hydride (0.810g, 0.0202mol) was added slowly to a mixture of 2-amino-5-nitrophenol (3.0g, 0.019mol) and dmf (50ml) at 0 ℃. The mixture was stirred at room temperature for 1 hour and then (r) - (oxiran-2-yl) methyl 3-nitrobenzenesulfonate (5.0g, 0.019mol) 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. Na for organic layer ₂CO₃Washed with aqueous solution and brine, dried (Na)₂SO₄) And concentrated in vacuo to give a brown solid (5.2 g). Mixing the above brown solid with K₂CO₃A mixture of (2.0g) and DMF (200ml) was stirred under nitrogen at 120 ℃ overnight. After cooling, the solvent was removed under vacuum and the residue was partitioned between water and EtOAc. The organic layer was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue is substituted by CH₂Cl₂EtOAc (5% Et-containing)₃N, 0-60%) was purified by silica gel column chromatography to give the product as a soft brown solid. LC-MS: 2.30 min, 211.1(m + 1).

(S) - (7-amino-3, 4-dihydro-2H-benzo [ b1[1, 4] oxazin-3-yl) methanol

A mixture of(s) - (3, 4-dihydro-7-nitro-2H-benzo [ b ] [1, 4] oxazin-3-yl) methanol (340mg, 0.0016mol), 10% PaVC (50mg) and MeOH (50ml) was stirred under hydrogen (1 atm) for 3H. LC-MS indicated the reaction was complete. The mixture was filtered and the filtrate was concentrated in vacuo to give 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(s) - (3, 4-dihydro-7-nitro-2H-benzo [ b ] [1, 4] oxazin-3-yl) methanol but using(s) - (oxiran-2-yl) methyl 3-nitrobenzenesulfonate as the starting material.

Intermediate 58

Preparation of (7-amino-2, 3-dihydro-benzo [1, 4] dioxin-2-yl) -methanol 9 see 43P-intermediate 19)

(7-nitro-2, 3-dihydro-benzo [1, 4] dioxin-2-yl) -methanol

3.0 g of sodium bicarbonate was suspended in 90mL of DMF. 5.15 g of 4-nitrocatechol solution were added dropwise at 0 ℃ over 15 minutes. 3.9 g of epichlorohydrin dissolved in 10ml of DMF were subsequently added over 15 minutes. Stirring was continued at room temperature and then at 80 ℃ overnight. The mixture was diluted with water and extracted three times with ethyl acetate and dried (anhydrous Na)₂SO₄) Filtered and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica eluting with EtOAc-hexanes (0-100% gradient) to give the product as a yellow solid (2.8 g))。

(7-amino-2, 3-dihydro-benzo [1, 4] dioxin-2-yl) -methanol

(7-Nitro-2, 3-dihydro-benzo [1, 4] dioxin-2-yl) -methanol (1.0g, 4.7mmol) was dissolved in methanol (30ml) and palladium on activated carbon (0.10g, 5% wt) was added. The mixture was shaken on a parr shaker under hydrogen (60psi) for 24 hours. The mixture was filtered through Celite ® and evaporated to give 722mg of material as a white solid (86%), which was used directly in the next step. M/z 182(M + 1). LC: 0.82 minute.

Intermediate 59

Preparation of (6-amino-2, 3-dihydro-benzo [1, 4] dioxin-2-yl) -methanol

(6-nitro-2, 3-dihydro-benzo [1, 4] dioxin-2-yl) -methanol

1.93 g of 60% sodium hydride are suspended in 90mL of DMF. 5.15 g of 4-nitrocatechol solution were added dropwise at 0 ℃ over 15 minutes. 3.9 g of epichlorohydrin dissolved in 10mL of DMF are subsequently added over 15 minutes. Stirring was continued at room temperature and then at 80 ℃ overnight. The mixture was diluted with water and extracted three times with ethyl acetate and dried (anhydrous Na)₂SO₄) Filtered and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica eluting with EtOAc-hexanes (0-100% gradient) to give the product as a yellow solid (2.3 g).

(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, 4.7mmol) was dissolved in methanol (30ml) and palladium on activated carbon (0.10g, 5% wt) was added. The mixture was shaken on a Parr shaker under hydrogen (60psi) for 24 hours. The mixture was filtered through Celite ® and evaporated to give 646mg of material as a white solid (77%) which was used directly in the next step. M/z 182(M + 1). LC: 0.82 minute.

Intermediate body 60

Preparation of (7-amino-3, 4-dihydro-2H-pyrido [3, 2-b ] [1, 4] oxazin-3-yl) methanol

2-amino-3-methoxy-5-nitropyridines

2-chloro-3-methoxy-5-nitropyridine (0.50g, 0.00265mol), concentrated ammonia (5mL, 0.1mol) and ethanol (20mL) were mixed in a 250mL sealed tube. The mixture was heated to 80 ℃ and stirred overnight. After cooling to room temperature the mixture was concentrated in vacuo and the residue was taken up in ethyl acetate (50mL) and washed with equal amounts of brine and water (1X 50mL each). The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo to give a solid (0.312g, 69%) which was used directly in the next step without further purification. LC-MS 1.94 min. M/z 171.0(M + 1).

2-amino-3-hydroxy-5-nitropyridines

In a 500mL round bottom flask was mixed 2-amino-3-methoxy-5-nitropyridine (0.300g, 0.00177mol) and solid pyridine hydrochloride (8.8g, 0.076 mol). The solid mixture was heated at 150 c (the solid melted on heating and also gas formed). The mixture was held at 150 ℃ for 3 hours and the reaction was deemed complete by LC-MS. After cooling to 80 ℃ the mixture was poured into ice and the aqueous layer was extracted with ethyl acetate (3X 100 ml). The combined organic extracts were washed with water (2X 100mL) and dried (Na) ₂SO₄) Filtered and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography using methanol: a gradient of dichloromethane (0-10%) was used as eluent to give the solid product (0.13)8g, 49%) the product was used directly in the next step. LC-MS 1.28 minutes. And M/z is 155.9(M + 1).

(7-nitro-3, 4-dihydro-2H-pyrido [3, 2-b ] [1, 4] oxazin-3-yl) methanol

In a 75mL stopcock were mixed 2-amino-3-hydroxy-5-nitropyridine (0.138g, 0.000890mol), N-dimethylformamide (4.1mL) and potassium carbonate (0.39g, 0.0028 mol). The mixture was stirred at room temperature for 10 minutes, and then 1-bromo-2, 3-epoxypropane (0.12g, 0.00089mol) was added in one portion. The flask was sealed and then heated to 110 ℃ and stirred overnight. After cooling the mixture was concentrated in vacuo to give a crude solid, which was dissolved in EtOAc (75mL), washed with water and brine, and then dried (Na)₂SO₄) Filtered and concentrated in vacuo to give a crude residue. The residue was purified by column chromatography on silica gel with MeOH/CH₂Cl₂(0-10% gradient) as eluent to give a solid (0.092g, 46%). LC-MS 1.92 minutes. M/z 212.0(M + 1).¹HNMR(d₄-DMSO)δ 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

A mixture of (7-nitro-3, 4-dihydro-2H-pyrido [3, 2-b ] [1, 4] oxazin-3-yl) methanol (0.320g, 0.00152mol), 10% palladium on carbon (0.06g, 0.0005mol) and methanol (50mL) was placed in a 500mL round bottom flask. The vessel was evacuated, then charged with hydrogen and the mixture was stirred overnight (at 1 atm gas pressure). The mixture was then filtered through Celite ® and the filtrate was concentrated in vacuo to give an oil (0.252g, 89%) which was used in the next step without further purification. (0.252g, 89%) LC-MS 0.29 min. M/z 181.9(M + 1).

Intermediate 61

Preparation of (5-amino-1H-indol-2-yl) methanol

2-ethoxycarbonyl-5-nitroindole (500mg, 0.002mol) was dissolved in 50mL of THF, and lithium tetrahydroaluminate (341mg, 0.00898mol) was added dropwise and stirred at room temperature overnight. Water (341. mu.L), 15% NaOH solution (341. mu.L) and water (1.1mL) were carefully added and the mixture was filtered. The filtrate was concentrated in vacuo to give the product as an oil (300mg, 98%). And m/z is 162.9.

Intermediate 62

Preparation of (5-amino-1H-indazol-3-yl ] methanol

5-Nitro 1H-indazole-3-carboxylic acid (500mg, 0.002mol) was dissolved in 50mL THF, lithium tetrahydroaluminate (366mg, 0.00964mol) was added dropwise and stirred at room temperature overnight. 65mg (15%). Water (366. mu.L), 15% NaOH solution (366. mu.L) and water (1.1mL) were carefully added and the mixture was filtered. The filtrate was concentrated in vacuo to give the product as an oil (65mg, 15%). And m/z is 160.0.

Preparation of amido Compounds

Formation of amides

The method A comprises the following steps: typical procedure for the synthesis of benzamides by the automated parallel synthesis

The appropriate benzoic acid (2mmol) was dissolved or suspended in 15ml chloroform and treated with 20mmol thionyl chloride. The reaction mixture was refluxed for 15 minutes and then the solvent was removed under vacuum. The residue was dissolved in 4ml of anhydrous chloroform and 60. mu.l (30. mu. mole) of this solution was added to each well of a 96-well glass plate. The appropriate amine (60. mu. mole) was then added to the corresponding well followed by n, n-diisopropylethylamine (120. mu. mole). The plate was then heated at 65 ℃ for 15 minutes. The solvent was removed using an ht-12 genevac centrifugal evacuator and 100. mu.l of dmso was added to each well before transferring the compound to a 96 well polypropylene reaction plate. The plates were then sealed with an abgene plate sealer and purified by lc-ms.

The method B comprises the following steps: typical procedure for the synthesis of benzamides by the automated parallel synthesis

To one well of a 96-well polypropylene reaction plate was added the appropriate benzoic acid (6.03mg, 30. mu. mol) dissolved in 15. mu.l of anhydrous pyridine. TFFH (TFFH is fluoro-N, N, N ', N' -tetramethyluronium hexafluorophosphate; 12mg, 45. mu. mol) was added to the reaction well followed by diisopropylethylamine (6.0mg, 45. mu. mol) and the appropriate amine (60. mu. mol). The reaction plate was heated at 50 ℃ for 15 minutes and the solvent was evaporated. The residue was dissolved in DMSO and purified by LC-MS based purification method (50mm × 10mm phenomenex Gemini column with 10-100% acetonitrile-water gradient).

The method C comprises the following steps:

in the presence of acid (0.4mmol), N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (0.8mmol), 1-hydroxybenzotriazole hydrate (0.24mmol) and CH₂Cl₂(5mL) to the mixture was added the appropriate amine (0.5mmol) and DIPEA (0.2 mL). The mixture was stirred at rt overnight, diluted with EtOAc, washed with brine and dried (Na)₂SO₄) And concentrated. The residue was purified by silica gel column chromatography to give the product.

The method D comprises the following steps:

in the presence of acid (1.0mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (385mg, 2.0mmol), 1-hydroxybenzotriazole hydrate (0.5-1.0mmol), DMF (2mL) and CH₂Cl₂To the mixture (5mL) was added amine (1.2mmol) and diisopropylethylamine (0.5 mL). The mixture was stirred at rt overnight, diluted with EtOAc, washed with brine and dried (Na)₂SO₄) And concentrated. The residue was purified by column chromatography to give an amide.

The method E comprises the following steps:

at 0 ℃ under stirring in anhydrous CH as acid (1.0mmol)₂Cl₂To a solution of (10mL) and DMF (2 drops) was added oxalyl chloride (1.5 mmol). The mixture was stirred at 0 ℃ for 1 hour and then allowed to stand at room temperature for 3 hours. The solvent was removed in vacuo. The obtained acid chloride CH is reacted at 0 DEG C₂Cl₂(2mL) solution amine (1.0mmol) in CH was added₂Cl₂(3mL) and pyridine (2 mL). The reaction mixture was stirred at rt overnight and then diluted with EtOAc. NaHCO for organic phase ₃Washed with aqueous solution and brine, dried (Na)₂SO₄) And concentrated. The residue was purified by chromatography to give an amide.

Method F:

0 ℃ with stirring in acid (0.25mmol) in dry THF or CH₂Cl₂To a solution of (5mL) and DMF (1 drop) was added oxalyl chloride (0.40 mmol). The mixture was stirred at 0 ℃ for 1 hour and then returned to room temperature. The solvent was removed in vacuo. The obtained acid chloride CH is reacted at 0 DEG C₂Cl₂(2mL) solution amine (0.25mmol) in CH was added₂Cl₂(10mL)、Et₃N (0.2mL), DMAP (5 mg). The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc (100 mL). NaHCO for organic phase₃The aqueous solution and brine were washed, dried, and concentrated. The residue was purified by chromatography to give an amide.

Method G:

CH of an appropriate acid (1 equivalent) with cooling (0 ℃ C.) and thorough stirring₂Cl₂To a solution of (ca. 3mL/mmol) and DMF (catalytic amount) was slowly added oxalyl chloride (1.5 eq.) dropwise and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo and the residue was resuspended in CH₂Cl₂. The appropriate amine (0.5-1.0 equiv.) is then added and the mixture is stirred for 1-48 hours before it is allowed to form a solution and purified.

Method H:

2-methyl-4- (3, 3-dimethyl-formamide (about 3mL per 0.5mmol of starting acid) in 2-methyl-4- (3, 3-dimethyl-formamide with stirring at room temperature To a mixture of but-1-ynyl) benzoic acid (1 eq) and N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (1.05 eq) was added N, N-diisopropylethylamine (1 eq) in one portion. The mixture was stirred at room temperature for about 2 hours, then a solution of the appropriate amine (1 eq) in DMF (1mL) was added all at once. The mixture was stirred overnight and then poured into H₂O (30mL) and EtOAc (30mL) to form a solution. The aqueous and organic layers were separated and the aqueous layer was extracted with EtOAc (2X 30 mL). The combined organic extracts were washed with brine (1X 30mL) and dried (Na)₂SO₄) Filtered and the solvent removed under vacuum to give a crude residue. Appropriate purification is carried out to obtain the desired final compound.

The method I comprises the following steps:

a mixture of acid (1mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (3mmol), 1-hydroxybenzotriazole hydrate (1.5mmol) and amine (2mmol) was stirred in DMF at room temperature overnight. The mixture was partitioned between EtOAc and water. The organic layer was separated and saturated NaHCO₃The aqueous solution, water and brine were washed and dried (Na)₂SO₄) It is filtered and the filtrate is concentrated in vacuo to a residue which is purified by flash column chromatography.

Method J:

DIPEA (0.92mmol) was added to a solution of the appropriate acid (0.46mmol), the appropriate amine (0.69mmol) and TFFH (0.69mmol) in anhydrous pyridine (3mL) and the reaction mixture was stirred at 60 ℃ overnight. The volatiles were removed, the residue was suspended in water, extracted with EtOAc, and the organic phase was washed with water and brine, over Na₂SO₄Drying, removal of the solvent and chromatography of the residue to give the product.

Method K:

DIPEA (0.92mmol) was added to a solution of the appropriate acid (4.0mmol), the appropriate amine (3.2mmol) and TFFH (6.0mmol) in anhydrous pyridine (10mL) and the reaction mixture was stirred at 70 ℃ overnight. The volatiles were removed, the residue was suspended in EtOAc and the organic phase was washed with water, Na₂CO₃Washed with aqueous solution and brine, and Na₂SO₄Drying, removal of the solvent and chromatography of the residue to give the product.

The method L comprises the following steps:

in DMF (5mL) and CH in acid (0.5mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.0mmol), 1-hydroxybenzotriazole hydrate (1.0mmol)₂Cl₂To the solution (5mL) was added amine (0.75mmol) and diisopropylethylamine (1.0 mmol). The mixture was stirred at 40 ℃ overnight, then diluted with EtOAc, washed with brine, and Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give an amide.

Method M:

acid (1 eq), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1 eq), 4-N, N-dimethylaminopyridine (1 eq) and Et were stirred together₃CH of N (2 equivalents)₂Cl₂(about 3mL/0.125mmol) to the solution was added the amine (1 eq) in one portion and the mixture was stirred until the reaction was complete (typically left overnight). With a large amount of CH₂Cl₂(30mL) the mixture was diluted and washed with H₂O (1X 20mL) and then dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography or preparative thin layer chromatography.

Compound 54

Oxalyl chloride (0.10mL, 1.2mmol) was added to a solution of 4- (3, 3, 3-trifluoroprop-1-ynyl) benzoic acid (50mg, 0.23mmol) in THF (5mL) and DMF (1 drop) with stirring at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour and then returned to room temperature. Removing the solvent in vacuo and reacting the resulting acid chloride CH at 0 deg.C₂Cl₂(2mL) solution was added (5-aminobenzo [ d ]]Thiazol-2-yl) methanol (20mg, 0.11mmol) in CH₂Cl₂(5mL)、Et₃N (0.2mL), DMAP (5 mg). The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc (100 mL). NaHCO for organic phase₃Washed with aqueous solution and brine, dried (Mg)SO₄) And concentrated in vacuo. The residue was purified by silica gel column chromatography to give an ester. The ester was dissolved in MeOH (10mL) and K was added ₂CO₃(300 mg). The mixture was stirred at rt for 3 h, then treated with water and EtOAc. The organic layer was separated, washed with brine and dried (Na)₂SO₄) And concentrated. The residue was purified by preparative thin layer chromatography using acetone-hexane (1: 1) to give a white solid (10 mg).

Compound 69

N- (1-acetyl-3, 3-dimethylindolin-6-yl) -4- (3, 3-dimethylbut-1-ynyl) benzamide (20mg), CH₃A mixture of CN (3mL) and 5N aq. HCl (1mL) was refluxed at 80 ℃ for 10 hours. After cooling, the mixture is treated with aq₂CO₃The mixture was worked up and extracted with EtOAc. The combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by PLC to give a pale yellow solid (10 mg).

Compound 112

A mixture of 4- (2-cyclopentylethynyl) benzoic acid (42.6mg, 0.000199mol), (6-amino-2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methanol (36.2mg, 0.000200mol), EDCI (1 equivalent), and DIEA (2 equivalents) in 10ml DCM was stirred at 50 ℃ overnight. The reaction mixture was washed with brine and dried over sodium sulfate. The residue was separated by NP column after removal of the solvent. The product was obtained as a tan solid (53%).

Compound 116

Adding 10ml of CH₂Cl₂A mixture of 4- (2-cyclopentylethynyl) benzoic acid (23mg, 0.10mmol), EDCI (1 eq) and DIPEA (2 eq) in (D) was stirred at room temperature for 20 min. To this solution was added a solution of CH dissolved in 5ml ₂Cl₂Of (6-amino-2, 3-dihydrobenzo [ b ]][1，4]Dioxine-2-yl) methyl methanesulfonate (27mg, 0.10 mmol). The reaction mixture was then stirred at room temperature overnight. A yellow solid was obtained after solution formation and chromatographic separation as usual.

Compound 117

A mixture of 4- (2-cyclopentylethynyl) benzoic acid (43mg, 0.00020mol), 3, 4-dihydro-2H-benzo [ b ] [1, 4] oxazin-7-amine (35mg, 0.00020mol), EDC (1.0 equiv.) and HOBt (1.0 equiv.) in 20ml DCM was stirred at RT overnight. The reaction mixture was washed with brine and dried over sodium sulfate. The solvent was removed and the residue was isolated by chromatography. The product was obtained as a pale yellow solid (42 mg).

Compound 197

Reacting 2-methyl-N- (2-methylbenzo [ d ]]A mixture of thiazol-5-yl) -4- (3, 3-dimethylbut-1-ynyl) benzamide (50mg, 0.14mmol), selenium dioxide (46mg, 0.41mmol) and 1, 4-dioxane (10mL) was stirred under nitrogen at 80 ℃ overnight. After cooling, the mixture was filtered through Celite ® and the filtrate was taken up in aq NaHCO₃Treated and extracted with EtOAc. The organic layer was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was dissolved in THF-H₂O (2: 1) (10mL) and NaBH was added slowly₄(50 mg). The mixture was stirred at room temperature for 2 hours and then acidified with 1N HCl. With aq ₃After work-up the mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by preparative thin layer chromatography to give N- (benzo [ d ] as a pale yellow solid]Thiazol-5-yl) -2-methyl-4- (3, 3-dimethylbut-1-ynyl) benzamide (compound 198, 11mg) and N- (2- (hydroxymethyl) benzo [ d ] as a pale yellow solid]Thiazol-5-yl) -2-methyl-4- (3, 3-dimethylbut-1-ynyl) benzamide (compound 197, 27 mg).

Compound 225

Reacting (E) -4- (3, 3, 3-trifluoroprop-1-enyl) -2-methyl-N- (2-methylbenzo [ d ]]Thiazol-5-yl) benzamide (200mg, 0.0005mol) and selenium dioxide (177mg, 0.00160mol) were added to 20mL dioxane and the reaction was heated under nitrogen at 80 ℃ overnight. The reaction was cooled and passed through Celite ®And (5) filtering. The filtrate was washed with EtOAc and NaHCO₃Are distributed among the devices. The organic layer was separated, washed with water and brine, dried (Na)₂SO₄) And concentrated in vacuo. The residue was dissolved in THF/H₂O (2: 1; 20mL) and add NaBH in 3 portions₄(200mg, 5.3 mmol). The mixture was stirred at room temperature for 2 hours, and then 1N HCl was added to terminate the reaction. Adding saturated NaHCO₃The mixture was basified and extracted with EtOAc. The organic layer was washed with water and brine and dried (Na) ₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/hexane (0-100%) as eluent followed by MeOH/CH₂Cl₂(0-3%) as eluent to give the product as a solid (40mg), m/z 392.6. Further purification by preparative HPLC (water/acetonitrile) gave the product as a white solid (35mg), m/z 392.6.

Compound 228

(E) -4- (3, 3, 3-trifluoroprop-1-enyl) -2-methylbenzoic acid (0.20g, 0.87mmol) in CH with stirring at 0 deg.C₂Cl₂To a solution of (50mL) and DMF (2 drops) was added oxalyl chloride (0.11mL, 1.3 mmol). The mixture was stirred at 0 ℃ for 1 hour and then allowed to stand at room temperature for 2 hours. The solvent was removed in vacuo. The acid chloride was added to (7-aminoquinolin-3-yl) methanol (76mg, 0.43mmol) in CH₂Cl₂(5mL) and pyridine (10 mL). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was washed with EtOAc and NaHCO₃And (4) treating with an aqueous solution. The organic layer was separated, washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/hexanes (0-50%) as eluent to give the ester [95mg, m/z: 599.2(M +1)]. The ester was dissolved in MeOH (5mL) and K was added₂CO₃(200 mg). The mixture was stirred at room temperature for 3 hours, then methanol was removed under vacuum. The residue was treated with water and EtOAc. The organic layer was separated, washed with brine and dried (Na) ₂SO₄) And concentrated in vacuo. The residue is treated with acetone-CH₂Cl₂(1: 1) purified by preparative thin layer chromatography to give a white solid (43mg, 24%). LC-MS: 2.29 min, 387.7(M + 1).

Compound 229

Stirring the mixture at the temperature of 7, 8-dihydro-5H-pyrano [4, 3-b ]]To a solution of pyridin-3-ylamine (50mg, 0.3mmol) in anhydrous DMF (2mL) was added a solution of (E) -4- (3, 3, 3-trifluoroprop-1-enyl) -2-methylbenzoic acid (91.96mg, 0.4mmol), N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (76.59mg, 0.4mmol), HOBt (62.98mg, 0.46mmol), 4-N, N-dimethylaminopyridine (2mg, 0.02mmol) and DIPEA (139. mu.L, 0.8mmol) in anhydrous DMF (3 mL). The reaction was stirred overnight at room temperature. The reaction mixture was poured into saturated NaHCO₃The solution (50mL) was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (3X 50mL) and dried (MgSO)₄) Filtered and concentrated in vacuo. Purification by silica gel column chromatography (0-5% MeOH in 60 min, in DCM) afforded the desired product as a cream solid (39mg, 30%).

Universal method for automatic parallel LC-MS purification of product libraries

The product library was purified using a Perkin Elmer API100 mass spectrometer connected to a Shimadzu LC pump. Chromatography used a 10-100% acetonitrile-water gradient over 8 minutes at a flow rate of 6 ml/min. The column used was 10X 50mm YMC C C18 and the compounds were collected using a Gilson 204 flow collector.

The amide compounds of the present invention are prepared or may be prepared according to the methods described above and suitable reagents, starting materials and purification methods known to those skilled in the art.

The synthetic and biological examples herein are provided to illustrate the invention and are not intended to limit the scope of the invention in any way. In the following examples, all temperatures are in degrees celsius unless otherwise indicated.

The compounds which have been prepared according to the invention are listed in table 1 below. The synthesis of these representative compounds was performed as described above and the activity of the compounds was expressed as percent inhibition in the calcium uptake assay, the details of which are described below.

Calcium uptake assay.

Functional activity of compounds at the VR1 receptor was determined by measuring changes in intracellular calcium in hVR 1-expressing HEK293 cells. The ability of a compound to inhibit agonist-induced calcium influx is tested. Using FlexStation^®(Molecular Devices) the dye Fura2 was used as [ Ca ] in a 96-well format using a dual wavelength metering (ratiometric) dye²⁺]An indicator of the level.

Cell lines and culture conditions:

hVR1 was cloned into the Invitrogen pcDNA5/TO vector and stably transformed into the Invitrogen T-RexHEK293 cell line. HEK293 cells expressing hVR1 were grown to confluence (24 hours in culture) on PDL-coated 96-well black-wall plastic plates in DMEM medium containing 5% PenStrep, 5% Glutamax, 200. mu.g/mL hygromycin, 5. mu.g/mL blasticidin and 10% heat-inactivated FBS. Cells were transferred to DMEM medium containing 1. mu.g/mL doxycycline 24 hours prior to assay. Prior to assay, cells were added to a saline solution (130mM NaCl, 3mM KCl, 1mM CaCl) along with 5. mu.g/mL Fura-2(Molecular Probes) ₂、0.6mM MgCl₂10mM HEPES, 10mM glucose and 50mM sucrose, pH7.4), and incubated at 37 ℃ for 40 minutes. The dye was then aspirated and replaced with 100. mu.L saline, and the procedure was resumed at Flex Station^®Is measured.

Agonist concentration and compound dilution:

determination of EC for agonist at assay initiation₅₀And the combined concentration is equal to EC₅₀As a stimulator for the determination of Compound IC₅₀The test of (1). The agonist used is capsaicin (EC)₅₀2.5nM) and protons (saline solution +10mM citric acid, buffered to ph5.7 with HCl). The tested concentration of the compound was 10 nM-3.3. mu.M.

The test comprises two phases: a pretreatment stage and a treatment stage. To the cells, 50. mu.l of compound solution (pretreatment) was added. In some cases, 50 μ l of a saline solution of the test compound, ph5.1 (treatment) was added after pretreatment. Compounds were tested as follows: in the pretreatment stage, 50. mu.l of 3 Xconcentration saline solution of the test compound was added to 100. mu.l of cell-containing saline to give a final concentration of x. In the treatment phase, 50 μ l of test compound + agonist solution was added to the cells at the corresponding concentration at a predetermined time after pretreatment.

The recording was carried out at 340nm and 380nm wavelength at 4 second intervals and the fluorescence ratio was analyzed. The reaction is that the fluorescence ratio peak value after adding the compound-agonist is subtracted by the fluorescence ratio baseline value before treatment, and the fluorescence ratio baseline value is calculated by adopting SoftMaxPro software of molecular devices. The percent inhibition was calculated according to the following formula and is shown in table 1:

[00427] Table 1: amide compound

Acid stimulation test：

The change in acid-induced intracellular calcium concentration was monitored using fluorescence imaging system FDSS 6000(Hamamatsu Photonics, Japan). Cell suspensions in resting buffer (HBSS, pH7.4 supplemented with 10mM HEPES) were incubated with different concentrations of test compound or resting buffer (buffer control) at room temperatureLight preincubation for 15 minutes. Stimulation solution (HBSS with MES added, final assay buffer, ph5.8) was automatically added to the cells by FDSS 6000. IC of VR1 antagonist was determined from half the increase demonstrated by buffer control samples after acid challenge₅₀The values, results obtained and selected compounds of the invention are listed in table 2 below.

Table 2: IC of selected amido compounds₅₀Data of

Half-life in Human Liver Microsomes (HLM)

Exemplary compounds of the invention (1. mu.M) were tested and mixed with 3.3mM MgCl₂And 0.78mg/mLHLM (HL101) were incubated in 100mM potassium phosphate buffer (pH7.4) in 96 deep well plates at 37 ℃. The reaction mixture was divided into 2 groups: non-P450 group and P450 group. NADPH was added to the reaction mixture of the P450 group only. Aliquots of the P450 group samples were collected at time points 0, 10, 30 and 60 minutes, where the 0 minute time point represents the time at which NADPH addition to the reaction mixture of the P450 group was initiated. Aliquots of non-P450 group samples were collected at time points 10 and 65 minutes. Collected aliquots were extracted with acetonitrile solution containing an internal standard. The precipitated protein was spun off by centrifugation (2000rpm, 15 minutes). The concentration of the compound in the supernatant was determined by an LC/MS/MS system. The natural logarithm of the peak area ratio of compound/internal standard was plotted against time to obtain a half-life value (T) _1/2). The slope of the best fit line through each point is the metabolic rate (k). This is converted to a half-life value using the following equation: half-life is ln 2/k. Experimental results and corresponding T_1/2The values are listed in table 3 below.

Table 3: half-life of exemplary Compounds (Unit: hour)

Pharmacokinetic evaluation was performed after intravenous or oral administration of the compounds to rats.

Female Sprague-Dawley rats were acclimated for at least 24 hours prior to the start of the experiment. During the acclimation period, all animals had free access to food and water. However, food, but no water, was removed from the animal cage at least 12 hours before the start of the experiment. Animals were only allowed ad libitum access to water during the first 3 hours of the experiment. Intravenous and oral formulations at least 3 animals were tested each. For intravenous formulations, the compounds were dissolved (0.25-1mg/mL) in a mixture consisting of 3% dimethylsulfoxide, 40% PEG 400, leaving 40% aqueous Captisol solution (w/v). For oral formulations, the compounds of the invention were dissolved (2mg/mL) in a mixture consisting of 5% -10% aqueous Tween 80 (v/v) and 95% aqueous 0.5% methylcellulose (w/v). Animals were weighed prior to dosing. The measured body weight was used to determine the dose volume for each animal.

For intravenous administration: dose volume (mL/kg) ═ 1 mg/kg/formulation concentration (mg/mL).

For example, when the concentration of the formulation is less than 0.5mg/mL, the dosage volume is about 2 mL/kg. For PO rats, it is usually administered at 2.5mL/kg via a gavage tube to achieve a dose level of 5 mg/kg. For IV administration, blood samples were collected via jugular vein catheters (using pre-heparin treated needles) at 2, 5, 15, 30, 60, 120, 180, 300, 480 and 1440 minutes post administration. For PO administration, blood samples were collected via jugular vein catheters (using pre-heparin treated needles) at 5, 15, 30, 60, 120, 180, 300, 480, and 1440 minutes post administration. Approximately 250uL of blood was obtained from the animals at each time point. Blood was replaced with an equal volume of 0.9% saline to prevent dehydration. Whole blood samples were placed on ice until centrifugation. The blood samples were then centrifuged at 14,000rpm for 10 minutes at 4 ℃ and the plasma upper layer was transferred to a clean tube and stored at-80 ℃. The resulting plasma samples were then analyzed by liquid chromatography-tandem mass spectrometry. Measuring plasmaPlasma concentration-time curves were plotted after the samples and dosing solution. Calculate the area under the curve of the concentration-time curve extrapolated to infinity (AUC) _inf) As Plasma exposure (Plasma exposure). The AUC_infThe oral bioavailability (% F) of each animal was averaged and calculated according to the following formula:

AUC_inf(IV, mean)/AUC_inf(PO, normalized to their respective dosage levels). % F is the average% F of all orally administered animals.

Example 1

Calcium imaging assay

The VR1 protein is a thermally gated cation channel protein that exchanges 1 sodium ion for approximately 10 calcium ions, resulting in depolarization of neuronal membranes and elevated intracellular calcium levels. The functional activity of a compound at the VR1 receptor can therefore be determined by measuring changes in intracellular calcium levels within neurons such as the dorsal root ganglion.

DRG neurons were grown in PDL-coated 96-well black-wall plates in DMEM medium containing 5% PenStrep, 5% Glutamax, 200. mu.g/mL hygromycin, 5. mu.g/mL blasticidin, and 10% heat-inactivated FBS. Cells were added to a physiological saline solution together with Fura2 at 5. mu.g/ml and left at 37 ℃ for 40 minutes before the test. The cells were then washed with physiological saline to remove the dye, and the experiment was started.

The coated neurons were transferred to a chamber on the Nikon eclipse TE300 microscope stage, after which the experiment was restarted with appropriate fluorescent light for approximately 10 minutes. The test comprises two stages: a pretreatment stage and a treatment stage. First, test compound solutions were added to the cells using a multi-tube loading system and allowed to stand for 1 minute (pretreatment). Immediately thereafter, capsaicin (250nM) was added in the presence of the test compound (treatment), with a typical treatment period of 20-60 seconds.

Fura2 was excited at 340 and 380nm to indicate the relative concentration of calcium ions. The change in wavelength values was measured throughout the experiment. The fluorescence value measured at 340nm was divided by the fluorescence value measured at 380nm to calculate the fluorescence ratio. Data were collected using slideboot software from IntelligentImaging. All compounds that inhibited capsaicin-induced calcium influx by more than 75% were considered positive.

Table 4 provides the data obtained. Figure 1 shows the results obtained when compound 225 was administered with capsaicin. Reflecting a decrease in fluorescence of calcium influx.

TABLE 4

Compound numbering	Concentration of	Treatment time (seconds)	Inhibition of capsaicin-induced calcium influx%
Compound numbering	Concentration of	Treatment time (seconds)	Inhibition of capsaicin-induced calcium influx%	225	3nM	20	＞75

Example 2

High throughput analysis of VR1 antagonists using calcium imaging assays to determine in vitro efficacy

Inhibition of capsaicin response in the presence and absence of test compounds was measured and evaluated using the calcium uptake assay method described above, according to the data in table 1. These data are also presented in figures 2-6, where capsaicin response is significantly reduced in the presence of representative test compounds. No such reduction in reaction was observed in the absence of the test compound.

Example 3

Whole cell patch clamp electrophysiology

Dorsal Root Ganglion (DRG) neurons were removed from neonatal or adult rats and plated onto poly-D-lysine coated glass coverslips. The coated neurons were transferred into a measurement chamber for addition of drug solution to the cells using a computer controlled solenoid valve based loading system. Cell imaging was performed using standard DIC optics. The very thin glass electrode was inserted into the cell. Voltage-clamped electrophysiology experiments were performed using an Axon Instruments multiclad under the software amplification control of pCLAMP 8.

The cells were placed in whole cell voltage clamps and the membrane current was monitored in a gapless (gap-free) recording mode to maintain a voltage of-80 mV. 500nM capsaicin was added for 30 seconds as a control. Various concentrations of test compound were added to the cells for 1 minute before 30 seconds of capsaicin addition. The difference between the control test and the drug-positive capsaicin test is used to determine the efficacy of each test compound. All compounds that inhibited capsaicin-induced current by more than 50% were considered positive. The data obtained with compound 240 are shown in Table 5.

TABLE 5

Compound numbering	Concentration of	Treatment time (seconds)	Inhibition of capsaicin-induced currents%
Compound numbering	Concentration of	Treatment time (seconds)	Inhibition of capsaicin-induced currents%	240	100nM	20	50

All publications, patents, and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by 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 may be made thereto without departing from the spirit or scope of the appended claims. All such modifications which are within the scope of the appended claims are intended to be included within the scope of such claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers and tautomers thereof:

(1)，

wherein:

w, Z, Y and X are each independently N or CR⁴；

L is- (CR)⁵＝CR⁶) -or- (C ≡ C) -;

R¹is a bicyclic aryl or bicyclic heteroaryl substituted with: hydrogen, C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl radical, C₁-C₆Alkylamino radical, C₁-C₆Alkoxy, amino C₁-C₆Alkoxy, substituted amino C₁-C₆Alkoxy, di-C₁-C₆Alkylamino radical C₁-C₆Alkoxy, cycloalkyl C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkyl aryl amino, aryl C₁-C₆Alkoxy, amino, aryl C₁-C₆Alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid ester, azido, carboxyl, carbamoyl, cyano, cycloheteroalkyl, di-C₁-C₆Alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxy, nitro or thio;

R³is CR⁶’R⁷R⁸；

Each R⁴Independently of one another is hydrogen, C₁-C₆Alkyl, hydroxy C₁-C₆Alkyl radical, C₁-C₆Alkylamino radical, C₁-C₆Alkoxy, amino C₁-C₆Alkoxy, substituted amino C₁-C₆Alkoxy, di-C₁-C₆Alkylamino radical C₁-C₆Alkoxy, cycloalkyl C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkyl aryl amino, aryl C₁-C₆Alkoxy, amino, aryl C ₁-C₆Alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid ester, azido, carboxyl, carbamoyl, cyano, cycloheteroalkyl, di-C₁-C₆Alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxy, nitro or thio;

R⁵and R⁶Each independently is H, halo or C₁-C₆An alkyl group; and

R⁶' is hydrogen, halo or C₁-C₆An alkyl group; r⁷And R⁸Each independently is halo or C₁-C₆An alkyl group; or R⁷And R⁸Together form C₃-C₈A cycloalkyl ring;

wherein the compound is not selected from the group consisting of compounds numbered 1-39.

2. The compound of claim 1, wherein R⁵And R⁶Each independently is H, halo or C₁-C₆An alkyl group.

3. The compound of claim 1, wherein R¹The method comprises the following steps:

wherein A is¹、A²、A³、A⁴、B¹And B²Each independently is CR⁴' and N; and each R⁴' independently is H, C₁-C₆Alkyl, halo or hydroxy C₁-C₆An alkyl group.

4. The compound of claim 1, wherein R¹The method comprises the following steps:

A⁶And A⁷Each independently is CR⁴’、NR⁴’、CR⁴’R⁴' or CO; b is³And B⁴Each independently is CR⁴' and N; when R is⁴' when C is attached, each R⁴' independently is H, C₁-C₆Alkyl, halo or hydroxy C₁-C₆Alkyl, and when R⁴' when N is attached, each R ⁴' independently is H or C₁-C₆An alkyl group; and the dotted bond represents a single or double bond.

5. The compound of claim 1, wherein R¹The method comprises the following steps:

wherein A is⁹、A¹⁰And A¹¹Each independently is CR⁴’、CR⁴’R⁴’、CO、CS、N、NR⁴', O, S, SO or SO₂；B⁵And B⁶Each independently is CR⁴' and N;

each dotted bond independently represents a single or double bond.

6. The compound of claim 1, wherein R¹Is that

Wherein the ring may be substituted by R⁴' further substituted, and R⁴' as claimed in claim 4; and when applicable, ring N can be substituted by H or C₁-C₆Alkyl is further substituted.

7. The compound of claim 1, wherein R¹Is that

8. The compound of claim 1, wherein R¹Is that

Wherein A is¹、A²、A³、A⁴、B¹And B²Each independently is CH and N; and R⁴Is' a C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group.

9. The compound of claim 1, wherein R¹The method comprises the following steps:

wherein A is⁵And A⁸Each independently is CH₂CHMe, NH, NMe, O, S, SO or SO ₂(ii) a And R⁴Is' a C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group.

10. The compound of claim 1, wherein R¹The method comprises the following steps:

wherein A is⁹、A¹⁰And A¹¹Each independently is CH, CH₂N, NH, O or S; b is⁵And B⁶Each independently is CH and N;

each R⁴' independently is H, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group; and each dotted bond independently represents a single or double bond.

11. The compound of claim 1, wherein R¹Is that

And wherein R⁴' as claimed in claim 4.

12. The compound of any one of claims 9-11, wherein R⁴' is hydroxy C₁-C₆An alkyl group.

13. The compound of claim 12, wherein R⁴' is- (CH)₂)_n-OH; and wherein n is selected from 1-3.

14. The compound of claim 13, wherein R⁴' is CH₂OH。

15. The compound of claim 1, wherein R¹Is that

Wherein, when applicable, the ring N may be H or C₁-C₆Alkyl is further substituted.

16. The compound of claim 1, wherein W, X, Y and Z are each CR⁴。

17. The compound of claim 1, wherein one of W, X, Y and Z is N and the others are independently CR⁴。

18. The compound of claim 1, wherein W is N, X, Y and Z are each CR⁴。

19. The compound of claim 1, wherein W and X are each CR ⁴(ii) a And Y and Z are each CR⁴", and wherein, R⁴"is independently selected from hydrogen and C₁-C₆Alkyl, trihalo C₁-C₆Alkyl, sulfone, and halo.

20. The compound of claim 19, wherein each R⁴"independently is H, CH₃、CF₃Cl, F or SO₂Me。

21. The compound of claim 1, wherein W, X and Z are each CH; y is C-CH₃C-Cl or C-F.

22. The compound of claim 19, wherein R⁴Is H.

23. The compound of claim 1, wherein L is- (CR)⁵＝CR⁶) -; and wherein R⁵And R⁶Each independently is H, halo or C₁-C₆An alkyl group.

24. The compound of claim 1, wherein L is-CH ═ CH-.

25. The compound of claim 1, wherein L is-C ≡ C-.

26. The compound of claim 1, wherein R³Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

27. The compound of claim 1, wherein R³Is cyclopropyl or CF₃。

28. The compound of claim 1, wherein R³Is a tert-butyl group.

29. The compound of claim 1, wherein the compound is selected from the group consisting of:

4- [ (E) -3, 3-dimethylbut-1-enyl ] -N- (5-isoquinolinyl) benzamide;

4- [ (E) -3, 3-dimethylbut-1-enyl ] -N- (3-quinolinyl) benzamide;

4- [ (E) -3, 3-dimethylbut-1-enyl ] -N- (1-methylindol-5-yl) benzamide;

n- (2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) -4- (3, 3, 3-trifluoroprop-1-ynyl) benzamide;

6- (3, 3-dimethylbut-1-ynyl) -N- (1-methylindol-6-yl) pyridine-3-carboxamide;

n- (5-isoquinolinyl) -4- (3, 3, 3-trifluoroprop-1-ynyl) benzamide;

n- (3-quinolinyl) -4- (3, 3, 3-trifluoroprop-1-ynyl) benzamide;

4- (2-cyclopropylethynyl) -N- (3-quinolinyl) benzamide;

4- (2-cyclopropylethynyl) -N- (5-isoquinolinyl) benzamide;

4- (2-cyclopropylethynyl) -N- (2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

n- (2, 2-difluorobenzo [1, 3] dioxol-5-yl) -4- (3, 3-dimethylbut-1-ynyl) benzamide;

n- (2-methylbenzothiazol-5-yl) -4- (3, 3, 3-trifluoroprop-1-ynyl) benzamide;

n- (2-methylbenzothiazol-5-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- [2- (hydroxymethyl) benzothiazol-5-yl ] -4- (3, 3, 3-trifluoroprop-1-ynyl) benzamide;

n- [2- (hydroxymethyl) benzothiazol-5-yl ] -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- (2-methylbenzothiazol-5-yl) benzamide;

n- (9-oxo-7-oxa-10-azabicyclo [4.4.0] dec-2, 4, 11-trien-3-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (8, 8-dimethyl-9-oxo-7-oxa-10-azabicyclo [4.4.0] decan-2, 4, 11-trien-3-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- (1, 4, 4-trimethyl-2, 3-dihydroquinolin-7-yl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- (5-isoquinolinyl) -3- (2-morpholinoethoxy) benzamide;

n- (4-oxo-2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (5-oxa-2-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (8, 8-dimethyl-7-oxa-10-azabicyclo [4.4.0] decan-2, 4, 11-trien-3-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -3-ethoxy-N- (5-isoquinolinyl) benzamide;

2-chloro-6- (3, 3-dimethylbut-1-ynyl) -N- (5-isoquinolinyl) pyridine-3-carboxamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [3, 3-dimethyl-1- (2-morpholinoethyl) indolin-6-yl ] benzamide;

n- (1-acetyl-3, 3-dimethyl-indolin-6-yl) -4- (3, 3-dimethylbut-1-ynyl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- (3, 3-dimethylindolin-6-yl) benzamide;

n- (2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- (3, 3, 3-trifluoroprop-1-ynyl) benzamide;

n- (3, 3-dimethyl-4-oxo-2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (3, 3-dimethyl-2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (2-methyl-5-oxa-2-azabicyclo [4.4.0] dec-7, 9, 11-trien-8-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- (1-methyl-3, 4-dihydro-2H-quinolin-7-yl) benzamide;

n- (5-isoquinolinyl) -3-methyl-4- (3, 3, 3-trifluoroprop-1-ynyl) benzamide;

N- (5-isoquinolinyl) -4- [ (E) -3, 3, 3-trifluoro-1-methyl-prop-1-enyl ] benzamide;

n- (5-isoquinolinyl) -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] -N- (8, 8, 10-trimethyl-9-oxo-7-oxa-10-azabicyclo [4.4.0] dec-2, 4, 11-trien-3-yl) benzamide;

n- (1-methyl-3, 4-dihydro-2H-quinolin-7-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (2-cyclopropylethynyl) -N- (1-methyl-3, 4-dihydro-2H-quinolin-7-yl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [3- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] -N- (8, 8, 10-trimethyl-7-oxa-10-azabicyclo [4.4.0] dec-2, 4, 11-trien-3-yl) benzamide;

n- (10-methyl-9-oxo-7-oxa-10-azabicyclo [4.4.0] decan-2, 4, 11-trien-3-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

6- (3, 3-dimethylbut-1-ynyl) -N- (1-methyl-3, 4-dihydro-2H-quinolin-7-yl) pyridine-3-carboxamide;

4- (2-cyclopropylethynyl) -N- [3- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

4- (2-cyclopropylethynyl) -N- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

n- (10-methyl-7-oxa-10-azabicyclo [4.4.0] dec-2, 4, 11-trien-3-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (5-isoquinolinyl) -4- [ (E) -3, 3, 3-trifluoro-2-methyl-prop-1-enyl ] benzamide;

5- (3, 3-dimethylbut-1-ynyl) -N- (1-methyl-3, 4-dihydro-2H-quinolin-7-yl) pyridine-2-carboxamide;

5- (3, 3-dimethylbut-1-ynyl) -N- (5-isoquinolinyl) pyridine-2-carboxamide;

n- (1, 1-dioxobenzothien-6-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoro-2-methyl-prop-1-enyl ] benzamide;

4- (2-cyclopropylethynyl) -3- (cyclopropylmethoxy) -N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

2- (3, 3-dimethylbut-1-ynyl) -N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) pyrimidine-5-carboxamide;

N- (2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoro-1-methyl-prop-1-enyl ] benzamide;

n- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl ] -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (2-cyclopentylethynyl) -N- (1-methyl-3, 4-dihydro-2H-quinolin-7-yl) benzamide;

n- (2, 5-dioxabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoro-1-methyl-prop-1-enyl ] benzamide;

4- (2-cyclopentylethynyl) -N- (2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

4- (2-cyclopentylethynyl) -N- (5-isoquinolinyl) benzamide;

n- (2, 5-dioxabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoro-2-methyl-prop-1-enyl ] benzamide;

4- (2-cyclopropylethynyl) -N- [ (4S) -4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] benzamide;

4- (2-cyclopropylethynyl) -N- [ (4R) -4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] benzamide;

4- (2-cyclopentylethynyl) -N- (3-methylcinnolin-5-yl) benzamide;

4- (2-cyclopentylethynyl) -N- (5-oxa-2-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl) benzamide;

n- [ (4R) -4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- [ (4S) -4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (3-methylcinnolin-5-yl) -4- [ (E) -3, 3, 3-trifluoro-1-methyl-prop-1-enyl ] benzamide;

4- (2-cyclopropylethynyl) -N- (2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) -3- (2-hydroxy-2-methyl-propoxy) benzamide;

n- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] dec-6, 8, 10-trien-9-yl ] -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (2-cyclopentylethynyl) -N- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

n- (3-methylcinnolin-5-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (3-methyl-5-isoquinolinyl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n-quinoxalin-6-yl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (2-cyclopentylethynyl) -N- [8- (methylsulfonyloxymethyl) -7, 10-dioxabicyclo [4.4.0] decan-1, 3, 5-trien-3-yl ] benzamide;

4- (2-cyclopentylethynyl) -N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

2-methyl-N- (2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-chloro-6- (2-cyclopropylethynyl) -N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) pyridine-3-carboxamide;

2-methoxy-N- (2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (Z) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (2, 5-dioxabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -2-methoxy-4- [ (Z) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (2, 5-dioxabicyclo [4.4.0] dec-7, 9, 11-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] decan-6, 8, 10-trien-9-yl ] -2-methyl-benzamide;

4- (2-cyclopentylethynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] -2-methyl-benzamide;

4- (2-cyclopentylethynyl) -2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] benzamide;

4- (2-cyclopropylethynyl) -2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-methoxy-N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

4- (2-cyclopropylethynyl) -2, 6-difluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

4- (2-cyclopropylethynyl) -2, 6-difluoro-N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

n- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-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] decan-7, 9, 11-trien-9-yl ] -2-methyl-benzamide;

n- [4- (cyclopropylmethoxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] -4- (3, 3-dimethylbut-1-ynyl) -2-methyl-benzamide;

2-fluoro-N- (2-oxa-5-azabicyclo [4.4.0] dec-6, 8, 10-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-fluoro-N- (2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (Z) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (8-chloro-2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-fluoro-N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

4- (2-cyclopentylethynyl) -2-methyl-N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

4- (2-cyclopentylethynyl) -N- (2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) -2-methyl-benzamide;

4- (2-cyclopentylethynyl) -N- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] -2-methyl-benzamide;

n- (2, 5-dioxabicyclo [4.4.0] dec-6, 8, 10-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] decan-7, 9, 11-trien-9-yl) benzamide;

2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl ] -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (2-cyclopropylethynyl) -N- (2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) -2-fluoro-benzamide;

2-chloro-4- (3, 3-dimethylbut-1-ynyl) -N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

2-chloro-4- (2-cyclopropylethynyl) -N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

2-chloro-N- (2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-fluoro-N- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl ] -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (2-cyclopropylethynyl) -2-fluoro-N- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

4- (2-cyclopropylethynyl) -N- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] -2-methyl-benzamide;

4- (2-cyclopropylethynyl) -N- (2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) -2-methyl-benzamide;

4- (2-cyclopropylethynyl) -2-methyl-N- (2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-fluoro-N- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- (2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) -2-fluoro-benzamide;

2-chloro-4- (2-cyclopropylethynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

2-chloro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl ] -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-chloro-4- (3, 3-dimethylbut-1-ynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl ] benzamide;

4- (2-cyclopentylethynyl) -N- (2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl) -2-methylsulfonyl-benzamide;

2-fluoro-N- (5-isoquinolinyl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-chloro-4- (3, 3-dimethylbut-1-ynyl) -N- (5-isoquinolinyl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-methyl-N- (2-methylbenzothiazol-5-yl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- (5-isoquinolinyl) -2-methyl-benzamide;

2-chloro-4- (3, 3-dimethylbut-1-ynyl) -N- (3-quinolinyl) benzamide;

2-chloro-4- (3, 3-dimethylbut-1-ynyl) -N- (2-methylbenzothiazol-5-yl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2, 6-difluoro-N- (5-isoquinolinyl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4, 4.0] decan-7, 9, 11-trien-9-yl ] -2-methyl-benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2, 6-difluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

4- (2-cyclopropylethynyl) -2-fluoro-N- [ (4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-fluoro-N- [ (4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] benzamide;

4- (2-cyclopropylethynyl) -2-fluoro-N- [ (4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-fluoro-N- [ (4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-fluoro-N- (2-methylbenzothiazol-5-yl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-fluoro-N- (3-quinolinyl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-fluoro-N- (5-isoquinolinyl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-fluoro-N- (5-isoquinolinyl) -3-methoxy-benzamide;

2-fluoro-N- (2-methylbenzothiazol-5-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-fluoro-N- (3-quinolinyl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2, 6-difluoro-N- (3-quinolinyl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2, 6-difluoro-N- (2-methylbenzothiazol-5-yl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-methyl-N- (3-quinolinyl) benzamide;

2-chloro-4- (3, 3-dimethylbut-1-ynyl) -N- [ (4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] benzamide;

2-chloro-4- (3, 3-dimethylbut-1-ynyl) -N- [ (4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] dec-6, 8, 10-trien-9-yl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [ (4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] -2-methyl-benzamide;

n- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl ] -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] -2-methyl-benzamide;

2-methyl-N- (3-quinolinyl) -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] undec-8, 10, 12-trien-10-yl) -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (2, 5-dioxabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-chloro-4- (3, 3-dimethylbut-1-ynyl) -5-fluoro-N- [4- (hydroxymethyl) -2, 5-dioxabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- (1H-indol-7-yl) -2-methyl-benzamide;

2-fluoro-N- [ (4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl ] -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [ (4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-6, 8, 10-trien-9-yl ] -2-methyl-benzamide;

n- [ (4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl ] -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-methyl-N- (3-methyl-5-isoquinolinyl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [2- (hydroxymethyl) benzothiazol-5-yl ] -2-methyl-benzamide;

n-benzothiazol-5-yl-4- (3, 3-dimethylbut-1-ynyl) -2-methyl-benzamide;

n- (1-chloro-5-isoquinolinyl) -4- (3, 3-dimethylbut-1-ynyl) -2-methyl-benzamide;

n- (1-chloro-5-isoquinolinyl) -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

4- [ (E) -3, 3-dimethylbut-1-enyl ] -2-methyl-N- (3-quinolinyl) benzamide;

n- (2, 9-diazabicyclo [4.3.0] non-1, 3, 5, 7-tetraen-4-yl) -4- (3, 3-dimethylbut-1-ynyl) -2-methyl-benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- (1, 3-dioxoisoindolin-5-yl) -2-methyl-benzamide;

n- (1H-benzoimidazol-5-yl) -4- (3, 3-dimethylbut-1-ynyl) -2-methyl-benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-methyl-N- (2-methyl-1H-benzoimidazol-5-yl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [7- (hydroxymethyl) -3-quinolinyl ] -2-methyl-benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2-methyl-N- (2-oxo-3H-benzoxazol-6-yl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [8- (hydroxymethyl) -2, 7, 9-triazabicyclo [4.3.0] non-2, 4, 7, 10-tetraen-4-yl ] -2-methyl-benzamide;

2-methyl-N- (8-quinolinyl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-methyl-N- (6-quinolinyl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-methyl-N- (5-quinolinyl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-methyl-N- (7-quinolinyl) -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;

n- [3- (hydroxymethyl) -7-quinolinyl ] -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-methyl-N- (5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-3-yl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- (5, 7-diazabicyclo [4.3.0] non-1, 3, 5, 8-tetraen-3-yl) -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide, 2-methyl-3- (hydroxymethyl) -1H-indazol-6-yl ] -benzamide;

n- (1H-indol-6-yl) -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n- [3- (hydroxymethyl) -5-oxa-2, 10-diazabicyclo [4.4.0] dec-7, 9, 11-trien-8-yl ] -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide, 2-methyl-3- (hydroxymethyl) -1H-indazol-5-yl ] -benzamide;

n- [2- (hydroxymethyl) -1H-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-1-enyl ] benzamide;

2-methyl-N-tetralin-1-yl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

2-methyl-N- (2-methyl-6-quinolyl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide.

30. The compound of claim 1, wherein the compound is selected from the group consisting of:

N- (5-isoquinolinyl) -4- (3, 3, 3-trifluoroprop-1-ynyl) benzamide;

n- (2-oxa-5-azabicyclo [4.4.0] dec-7, 9, 11-trien-9-yl) 4- (3, 3, 3-trifluoroprop-1-ynyl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -2, 6-difluoro-N- (5-isoquinolinyl) benzamide;

4- (3, 3-dimethylbut-1-ynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] decan-7, 9, 11-trien-9-yl ] -2-methyl-benzamide;

2-methyl-N- (3-quinolinyl) -4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide;

n-benzothiazol-5-yl-4- (3, 3-dimethylbut-1-ynyl) -2-methyl-benzamide;

n- (1-acetylindolin-6-yl) -4- (3, 3-dimethylbut-1-ynyl) -2-methyl-benzamide;

4- [ (E) -3, 3-dimethylbut-1-enyl ] -2-methyl-N- (3-quinolinyl) benzamide;

n- (1H-benzoimidazol-5-yl) -4- (3, 3-dimethylbut-1-ynyl) -2-methyl-benzamide;

n- [3- (hydroxymethyl) -5-oxa-2, 10-diazabicyclo [4.4.0] dec-7, 9, 11-trien-8-yl ] -2-methyl-4- [ (E) -3, 3, 3-trifluoroprop-1-enyl ] benzamide.

31. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers and tautomers thereof:

wherein: w, Z, Y and X are each independently N or CR⁴；

L is- (CR)⁵＝CR⁶) -or- (C ≡ C) -;

R¹is substituted or unsubstituted:

B³and B⁴Each independently is CR⁴' or N; a. the¹And A⁴Independently is CR⁴’R⁴’、NR⁴', O, S, SO or SO₂；

R⁴Is' a C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group;

R³is CR⁶’R⁷R⁸；

Each R⁴Independently of one another is hydrogen, C ₁-C₆Alkyl, hydroxy C₁-C₆Alkyl radical, C₂-C₆Acyl radical, C₂-C₆Acylamino group, C₁-C₆Alkylamino radical, C₁-C₆Alkylthio radical, C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkyl aryl amino, aryl C₁-C₆Alkoxy, amino, aryl C₁-C₆Alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxyl, carbamoyl, cyano, cycloheteroalkyl, di-C₁-C₆Alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxy, nitro or thio;

R⁵and R⁶Each independently is H, halo, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group;

R⁶' is hydrogen, halo, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group; r⁷And R⁸Each independently is halo, C₁-C₆Alkyl or hydroxy C₁-C₆An alkyl group; or R⁷And R⁸Together form a substituted or unsubstituted C₃-C₈A cycloalkyl ring; and

wherein the compound is not selected from the group consisting of compounds No. 1, 11, 38, and 42.

32. The compound of claim 29, wherein R⁴' is hydroxy C₁-C₆An alkyl group.

33. The compound of claim 29, wherein R⁴' is- (CH)₂)_n-OH; and wherein n is selected from 1 to 6.

34. The compound of claim 29, wherein R⁴' is CH₂OH。

35. The compound of claim 29, wherein W and X are each CR ⁴(ii) a And Y and Z are each CR⁴", and wherein R⁴"is independently selected from hydrogen and C₁-C₆Alkyl, trihalo C₁-C₆Alkyl and halo.

36. The compound of claim 35, wherein each R⁴"independently is H, CH₃、CF₃Cl or F.

37. The compound of claim 29, wherein W, X and Z are each CH; and Y is C-CH₃C-C1 or C-F.

38. The compound of claim 35, wherein R⁴Is H.

39. The compound of claim 29, wherein R¹Is that

And wherein, when applicable, said ring N may be H or C₁-C₆Alkyl is further substituted.

40. The compound of claim 29, wherein R¹Is that

41. The compound of claim 29 of formula (IV) or (V):

42. a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers and tautomers thereof:

wherein:

w, Z, Y and X are each independently N or CR⁴；

L is substituted or unsubstituted- (CR)⁵＝CR⁶) -or- (C ≡ C) -;

R¹is substituted or unsubstituted:

A¹、A²and A³Each independently is CR⁴’、CR⁴’R⁴’、CO、CS、N、NR⁴', O, S, SO or SO₂；

Each R⁴' independently is H, substituted or unsubstituted C₁-C₆An alkyl or aryl group;

each dotted bond represents a single or double bond;

R³is CR⁶’R⁷R⁸；

Each R⁴Independently hydrogen, substituted or unsubstituted C ₁-C₆Alkyl, acyl, acylamino, C₁-C₆Alkylamino radical, C₁-C₆Alkylthio radical, C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkyl aryl amino, aryl C₁-C₆Alkoxy, amino, aryl C₁-C₆Alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxyl, carbamoyl, cyano, cycloheteroalkyl, di-C₁-C₆Alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxy, nitro or thio;

R⁵and R⁶Each independently of the others being H, halo or substituted or unsubstituted C₁-C₆Alkyl radical, C₂-C₆Alkylene radical, C₂-C₆Alkenyl radical, C₂-C₆Alkenylene radical, C₂-C₆Alkynyl, heteroalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

R⁶' is hydrogen, halo or substituted or unsubstituted C₁-C₆An alkyl group; r⁷And R⁸Each independently being halo or substituted or unsubstituted C₁-C₆An alkyl group; or R⁷And R⁸Together form a substituted or unsubstituted C₃-C₈A cycloalkyl ring;

wherein the compound is not selected from the group consisting of compounds Nos. 2, 4, 9-10, 16-17, 25-29, 33, 37-38, or 39.

43. The compound of claim 42, wherein W and X are each CR⁴(ii) a And Y and Z are each CR⁴", and wherein, R ⁴"is independently selected from hydrogen and C₁-C₆Alkyl, trihalo C₁-C₆Alkyl and halo.

44. The compound of claim 43, wherein each R⁴Independently of one anotherIs H, CH₃、CF₃Cl or F.

45. The compound of claim 42, wherein W, X and Z are each CH; y is C-CH₃C-Cl or C-F.

46. The compound of claim 43, wherein R⁴Is H.

47. The compound of claim 42, wherein R¹Is substituted or unsubstituted

48. A compound of formula (VI) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers and tautomers thereof:

wherein:

w, Z, Y and X are each independently N or CR⁴；

L is substituted or unsubstituted- (CR)⁵＝CR⁶) -or- (C ≡ C) -;

R³is CR⁶’R⁷R⁸；

Each R⁴Independently hydrogen, substituted or unsubstituted C₁-C₆Alkyl, acyl, acylamino, C₁-C₆Alkylamino radical, C₁-C₆Alkylthio radical, C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkyl aryl aminoAryl radical C₁-C₆Alkoxy, amino, aryl C₁-C₆Alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxyl, carbamoyl, cyano, cycloheteroalkyl, di-C ₁-C₆Alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxy, nitro or thio;

R⁴' is substituted or unsubstituted C₁-C₆An alkyl group; and

R⁶' is hydrogen, halo or substituted or unsubstituted C₁-C₆An alkyl group; r⁷And R⁸Each independently being halo or substituted or unsubstituted C₁-C₆An alkyl group; or R⁷And R⁸Together form a substituted or unsubstituted C₃-C₈A cycloalkyl ring.

49. The compound of claim 48, wherein W and X are each N or CR⁴(ii) a And Y and Z are each N or CR⁴", and wherein, R⁴"is independently selected from hydrogen and C₁-C₆Alkyl, trihaloalkyl and halo.

50. The compound of claim 49, wherein each R⁴"independently is H, CH₃、CF₃Cl or F.

51. The compound of claim 48, wherein W, X and Z are each N or CH; y is C-CH₃C-Cl or C-F.

52. The compound of claim 49, wherein R⁴Is H.

53. The compound of claim 48, wherein R⁴' is hydroxy-substituted C₁-C₆An alkyl group.

54. The compound of claim 48, wherein R ⁴' is- (CH)₂)_n-OH; and wherein n is selected from 1-6.

55. The compound of claim 48, wherein R⁴' is CH₂OH。

56. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of any one of claims 1-55.

57. The pharmaceutical composition of claim 56, wherein the carrier is a parenteral carrier, an oral carrier, or a topical carrier.

58. A method of preventing, treating, ameliorating, or managing a disease or condition, the method comprising administering to a patient in need of such prevention, treatment, amelioration, or management a prophylactically or therapeutically effective amount of a compound of any one of claims 1-55 or a pharmaceutical composition of claim 56 or 57.

59. A method of making a compound of any one of claims 1-55, the method comprising reacting formula R under conditions sufficient to form a compound of any one of claims 1-55³-L-Cy-COCl compound contact R¹R²A compound of NH; and wherein Cy is aryl or heteroaryl.

60. A compound of any one of claims 1-55, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament or medicament.

61. Use of a compound as defined in any one of claims 1 to 55, or a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of a disease for which a VR1 antagonist is indicated.

62. The use of claim 61, wherein the disease is selected from the group consisting of: acute cerebral ischemia, pain, chronic pain, acute pain, nociceptive pain, neuropathic pain, inflammatory pain, post-herpetic neuralgia, neuropathy, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid joint pain, osteoarticular pain, burn, back pain, visceral pain, cancer pain, toothache, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, sciatica, menstrual pain, bladder diseases such as incontinence, micturition disorders, renal colic and cystitis, inflammation such as burn, rheumatoid arthritis and osteoarthritis, neurodegenerative diseases such as stroke, post-stroke pain and multiple sclerosis, pulmonary diseases such as asthma, cough, Chronic Obstructive Pulmonary Disease (COPD) and bronchoconstriction, gastrointestinal disorders such as gastroenterological 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 cancer chemotherapy-induced emesis and obesity.

63. A method of treatment of a mammal, including a human being, suffering from a disease for which an VR1 antagonist is indicated, which method comprises treating said mammal with an effective amount of a compound as defined in any one of claims 1 to 57, or with a pharmaceutically acceptable salt, solvate or composition thereof.

64. A combination of a compound as defined in any one of claims 1 to 55 and another pharmaceutically active agent.