KR20070119655A - Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same - Google Patents

Abstract

Compounds are disclosed that have a formula represented by the following: 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, and Pharmaceutical Compositions and Methods Using Them (01) Amid Derivates AS ION-CHANNEL LIGANDS AND PHARMACEUTICAL COMPOSITIONS AND METHODS OF USING THE SAME

The present invention relates to novel compounds and pharmaceutical compositions containing said compounds. The invention also provides for pain and inflammation-related symptoms in mammals using the compounds and pharmaceutical compositions of the invention, such as but not limited to arthritis, Parkinson's disease, Alzheimer's disease, Stroke, uveitis, asthma, myocardial infarction, treatment and prevention of pain syndromes (acute and chronic, or neuropathic), traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease, incontinence, A method for preventing and / or treating chronic obstructive pulmonary disease, irritable bowel disease, osteoarthritis and autoimmune disorders.

The study of signaling pathways in the body showed the presence of ion channels and tried to explain their role. Ion channels are opened and closed by two distinct properties, i.e., specific signals (e.g., membrane voltage, or direct binding of chemical ligands), and once opened, they have a property of transporting ions across the cell membrane at a very high rate. Reproductive membrane protein.

There are many types of ion channels. Based on their selectivity to ions, they can be classified into calcium channels, potassium channels, sodium channels and the like. Calcium channels are more permeable to calcium ions than other types of ions, potassium channels select potassium ions than other ions, and so on. In addition, ion channels can be classified according to their opening and closing mechanism. In voltage-gated ion channels, the likelihood of opening depends on the membrane voltage, while in ligand-gated ion channels, the opening potential is regulated by the binding of molecules (ligands) that are less open. Because ligand-gated ion channels receive signals from ligands, they can also be considered "receptors" for ligands.

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

Transient receptor potential (TRP) channel proteins make up a large and diverse family of proteins expressed in many tissues and cell types. This group of channels mediates responses to nerve growth factors, pheromones, olfactory, vascular strain and metabolic stress, and channels are found in a variety of organisms, tissues and cell types (including non-exciting smooth muscle and neuronal cells). In addition, TRP-related channel proteins are involved in several diseases, such as various tumors and neurodegenerative disorders, etc. (see, eg, 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 pain. Receptors in these cells can be activated by various chemical or physical adverse stimuli. Essential functions of nociceptors include the transmission of harmful stimuli to depolarization that trigger action potentials, conduction of action potentials from the primary sensory site to the synapse in the central nervous system, and neurotransmission of action potentials at the presynaptic terminal. There is a transition to mass release, all of which depend on the ion channel.

Of particular interest is the TRP channel protein is a vanilloid receptor. Vanilloid receptors, also known as VR1, are activated or sensitized by a series of various stimuli, including capsaicin, heat and acid stimuli, and products of lipid bilayer metabolism (anandamide), and lipoxygenase metabolites. Is a non-selective cation channel (see, eg, Smith, et al., Nature, 418: 186-190 (2002)). VR1 does not discriminate monovalent cations, but exhibits notable preference for divalent cations in the order of permeability of Ca ^{2 +} > Mg ^{2 +} > Na ⁺ = K ⁺ = Cs ⁺ . Extracellular Ca ^{2 +} is desensitized screen, that is, the neurons by reducing the neurons in the overall reaction for a particular chemical or physical signal because it mediates the process of such adapted for a particular stimulus, Ca ^{2 +,} are particularly important for VR1 function . VR1 is highly expressed in primary sensory neurons in rats, mice and humans and stimulates many visceral organs including the dermis, bone, bladder, gastrointestinal tract and lungs. In addition, VR1 is expressed in other neurons and non-neuronal tissues including the CNS, nucleus, kidney, stomach and T-cells. The VR1 channel has six membrane-spanning domains and is a member of the ion channel macro group with the highest homology to the TRP group of ion channels.

VR1 gene knockout mice have been found to have reduced sensory sensitivity to thermal and acid stimuli (see, eg, Catrina, et al. Science, 14: 306-313 (2000)). . This supports the concept that VR1 contributes not only to the occurrence of pain response but also to the maintenance of the basal activity of the sensory nerves. VR1 agonists and antagonists are useful as analgesics for the treatment of pain of various origins or etiologies, such as acute, inflammatory and neuropathic pain, toothaches and headaches (eg, migraine, cluster headaches and tension headaches). In addition, VR1 agonists and antagonists can treat and prevent anti-inflammatory agents for the treatment of arthritis, Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, pain syndromes (acute and chronic [neuropathic]), Traumatic brain injury, spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease, irritable bowel disease and autoimmune disorders, kidney disorders, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleep disorders, cognitive disorders, It is useful as an agent for the treatment of depression, anxiety, blood pressure, lipid disorders, osteoarthritis and atherosclerosis.

Accordingly, compounds, such as compounds of the present invention that interact with vanilloid receptors, may serve to treat, prevent or alleviate the above symptoms.

Various vanilloid compounds of different structures are known in the art and are described, for example, in European Patent Applications EP 0 347 000 and EP 0 401 903, British Patent Application GB 2226313 and International Patent Publication WO 92 /. 09285. Examples of particularly notable vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N-vanyl-6-nonenamide, capsazepine isolated from pepper plants (Tetrahedron, 53, 1997). , 4791), and olvanil or N- (4-hydroxy-3-methoxybenzyl) oleamide (J. Med. Chem., 36, 1993, 2595).

International Patent Publication No. WO 02/08221 discloses diaryl piperazine and related compounds that bind to vanilloid receptors, in particular type I vanilloid receptors (also known as capsaicin or VR1 receptors) with high selectivity and high affinity. The compounds are said to be useful in the treatment of chronic and acute pain symptoms, itching and incontinence.

International Patent Publications WO 02/16317, WO 02/16318 and WO 02/16319 suggest that compounds with high affinity for vanilloid receptors are useful for treating gastric-duodenal ulcers.

International Patent Publication No. WO 2005/046683 (published May 25, 2005, jointly owned by Applicant) demonstrates its activity as a VR-1 antagonist and is believed to be useful for the treatment of symptoms associated with VR-1 activity. A series of compounds is disclosed.

Both US Pat. Nos. 3,424,760 and US 3,424,761 describe a series of 3-ureidopyrrolidines known to exhibit analgesic, central nervous system and psychopharmacological activity. These patents include compounds 1- (1-phenyl-3-pyrrolidinyl) -3-phenyl urea and 1- (1-phenyl-3-pyrrolidinyl) -3- (4-methoxyphenyl) urea, respectively. Specifically disclosed. International Patent Publications WO 01/62737 and WO 00/69849 disclose a series of pyrazole derivatives which are mentioned as useful for the treatment of disorders and diseases associated with NPY receptor subtype Y5, such as obesity. WO 01/62737 specifically discloses compound 5-amino-N-isoquinolin-5-yl-1- [3- (trifluoromethyl) phenyl] -1H-pyrazole-5-carboxamide. WO 00/69849 discloses compound 5-methyl-N-quinolin-8-yl-1- [3- (trifluoromethyl) phenyl] -1H-pyrazole-3-carboxamide, 5-methyl-N-quinoline -7-yl-1- [3- (trifluoromethyl) phenyl] -1H-pyrazole-3-carboxamide, 5-methyl-N-quinolin-3-yl-1- [3- (trifluoro Rhomethyl) phenyl] -1H-pyrazole-3-carboxamide, N-isoquinolin-5-yl-5-methyl-1- [3- (trifluoromethyl) phenyl] -1H-pyrazole-3 -Carboxamide, 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-pyra Sol-3-carboxamide, 1- (3-fluorophenyl) -N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide, 1- (2-chloro-5 -Trifluoromethylphenyl) -N-isoquinolin-5-yl-5-methyl-1N-pyrazole-3-carboxamide, 5-methyl-N- (3-methylisoquinolin-5-yl) -1 -[3- (trifluorome ) Phenyl] -1N-pyrazole-3-carboxamide, 5-methyl-N- (1,2,3,4-tetrahydroisoquinolin-5-yl) -1- [3- (trifluoromethyl ) Phenyl] -1H-pyrazole-3-carboxamide is specifically disclosed.

German patent application 2502588 describes a series of piperazine derivatives. This application contains the compound N- [3- [2- (diethylamino) ethyl] -1,2-dihydro-4-methyl-2-oxo-7-quinolinyl] -4-phenyl-1-piperazine Carboxamides are specifically disclosed.

We have found in the present invention that certain compounds have surprising efficacy and selectivity as VR-1 antagonists. The compounds of the present invention are considered to be particularly beneficial as VR-1 antagonists because certain compounds exhibit improved water solubility and metabolic stability.

Summary of the Invention

It has been found herein that compounds, such as the compounds described herein, can modify mammalian ion channels, such as the VR1 cation channel. Accordingly, the present compounds are potent VR1 antagonists with analgesic activity by systemic administration. Compounds of the present invention may exhibit low toxicity, good absorption, good half-life, good solubility, low protein binding affinity, low drug-drug interactions, reduced inhibitory activity in HERG channels, reduced QT prolongation and good metabolic stability have. This finding led to novel compounds of therapeutic value. In addition, this has resulted in pharmaceutical compositions having the compounds of the invention as active ingredients and have a wide range of symptoms in mammals, such as but not limited to pain of various origins or etiologies, for example acute, chronic, inflammatory and The use of such materials for the treatment, prevention or alleviation of neuropathic pain, toothaches and headaches (eg migraine, cluster headaches and tension headaches) has been obtained.

Accordingly, in a first aspect of the invention, a compound having Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers and tautomers thereof, that can modify ion channels in vivo is disclosed. It became.

(In the meal,

W, Z, Y and X are each independently N or CR ⁴ ;

L is-(CR ⁵ = CR ⁶ )-or-(C≡C)-;

R ¹ is substituted or unsubstituted bicycloaryl or bicycloheteroaryl;

R ³ is C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, heteroalkyl, aryl, cycloalkyl, cycloheteroalkyl, heteroaryl, aralkyl or heteroaralkyl;

Each R ⁴ is independently hydrogen, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, C ₂ -C ₆ acyl, C ₂ -C ₆ acylamino, C ₁ -C ₆ alkylamino, C _1- C ₆ alkylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylarylamino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl , Sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfate ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxy, carbamoyl, carboxyl, cyano, cyclo Heteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio;

R ⁵ and R ⁶ are each independently H, halo, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, hetero C ₁ -C ₆ alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.

In a further embodiment of the invention of the compound of formula IA, hereinafter referred to as the compound of formula IA ′, R ³ -L represents the residue CR ³ R ⁶ = CR ⁵ .

<Formula IA '>

Wherein R ³ is as defined for the compound of formula I, R ⁵ and R ⁶ are hydrogen, halo, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, hetero C ₁ -C ₆ Independently selected from alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl).

In certain particular compounds, R ³ is C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aral Is selected from Kiel; R ⁵ and R ⁶ are each independently selected from hydrogen, halo and substituted or unsubstituted C ₁ -C ₆ alkyl; 0 to 3 groups selected from W, Z, X and Y represent N.

In the compounds of the formula (IA ′), R ⁵ and R ⁶ independently represent, for example, hydrogen, halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl. It is preferable that R ⁵ and R ⁶ represent hydrogen.

In another specific embodiment of the compound of formula (IA), hereinafter referred to as the compound of formula (IA "), R ³ -L represents the residue R ³ C≡C-.

<Formula IA ">

In the compounds of the formulas I, IA 'and IA ", W, Z, X and Y may each represent CR ⁴ , in particular CH. Alternatively, X represents N and W, Z and Y are Each may represent CR ^{4. In} another example of a group of compounds, X, Y and Z each represent CR ⁴ , in particular CH. In another example of a group of compounds, W is N. In the example, Y is N.

In general, in the compounds of formula (I), L is preferably-(C = C)-or -C≡C-. Thus, in one example of a group of compounds, L represents-(C = C)-. In another example of a group of compounds, L represents -C≡C-.

In the compounds of the formulas I, IA 'and IA ", R ¹ is for example substituted or unsubstituted bicycloaryl or bicycloheteroaryl such as substituted naphthyl, quinoline, isoquinoline or tetrahydroquinoline Examples of substituents include alkyl, alkyl (OH), -COOH, C (Me) ₃ , CH (Me) ₂ , halo, CF ₃ , cyano and methoxy Alternatively, R ¹ is substituted Or unsubstituted tetrahydroisoquinoline or benzodioxane.

In the compounds of the formulas I, IA 'and IA ", R ³ is for example CR ^6' R ⁷ R ⁸ , wherein R ^{6 '} is hydrogen, halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl; R ⁷ and R ⁸ are each independently halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl; or R ⁷ and R ⁸ together or unsubstituted C ₃ -C ₈ may form a cycloalkyl ring, for example, R ⁷ may represent lower alkyl (eg, methyl) For example, R ⁸ may represent lower alkyl (eg, methyl) In certain instances, R ^{6 ′} may represent hydrogen and R ⁷ and R ⁸ may represent methyl Alternatively, R ^{6 ′} , R ⁷ and R ⁸ may each represent methyl. Alternatively, R ^{6 '} , R ⁷ and R ⁸ may each represent fluoro Alternatively, R ^6' may represent hydrogen and R ⁷ and R ⁸ together may form a cyclopropyl ring.

In further embodiments of compounds of Formulas (I), (IA), (IA ′) and (IA ″), R ³ may represent, for example, substituted or unsubstituted aryl or heteroaryl.

의 기 (여기서, R^2'는 수소 또는 알킬이고; 여기서, 2개의 R^2'는 함께 결합하여 3 내지 8개의 원자를 갖는 시클로알킬 또는 시클로헤테로알킬 고리를 형성할 수 있고; 제공된 2개 이상의 R^2'는 알킬임)이다.In a first alternative embodiment of the compound of formula (IA), R ³ is CF ₃ , n-propyl, or formula

Wherein R ^{2 ′} is hydrogen or alkyl, wherein two R ^{2 ′} can be joined together to form a cycloalkyl or cycloheteroalkyl ring having 3 to 8 atoms; two or more R provided ^{2 '} is alkyl).

In the case of compounds of formula (I), R ¹ may be substituted or unsubstituted naphthyl or, alternatively, may be substituted or unsubstituted tetrahydronaphthyl. Additionally, R ¹ may also be substituted or unsubstituted bicycloheteroaryl, and in certain embodiments, the bicycloheteroaryl is tetrahydroquinoline, tetrahydroisoquinoline, benzodioxane, benzopyran, indole and benzimi It may be selected from the group consisting of dozol. More particularly, the bicycloheteroaryl can be quinoline, isoquinoline, benzodioxane and benzoxazine. In certain embodiments, the substitution on bicycloheteroaryl is selected from the group consisting of hydrogen, alkyl, trifluoromethyl, halo, methoxy, trifluoromethoxy, amino and carboxy. In a still further particular embodiment, the substitution on bicyclohetero aryl is selected from the group consisting of tert-butyl, cyano, trifluoroalkyl, halo, nitro, methoxy, amino and carboxy.

In another specific embodiment, for compounds of Formula (I), R ¹ may be substituted or unsubstituted isoquinolin-5-yl, quinolin-3-yl, benzodioxan-6-yl or benzoxazine-6-yl have.

In another specific embodiment, for compounds of Formula (I), R ¹ is substituted or unsubstituted

일 수 있다 (여기서, 가능한 경우, 고리 N은 H 또는 알킬로 더 치환될 수 있음).

(Where possible, ring N may be further substituted with H or alkyl).

In another specific embodiment, for compounds of Formula (I), R ¹ is substituted or unsubstituted

일 수 있다 (여기서, 가능한 경우, 고리 N은 H 또는 알킬로 더 치환될 수 있음).

(Where possible, ring N may be further substituted with H or alkyl).

In another specific embodiment, for compounds of Formula (I), R ¹ is substituted or unsubstituted

일 수 있다 (여기서, 가능한 경우, 고리 N은 H 또는 알킬로 더 치환될 수 있음).

(Where possible, ring N may be further substituted with H or alkyl).

In another specific embodiment, for compounds of Formula (I), R ³ can be substituted or unsubstituted cyclopropyl.

In yet further specific embodiments, for a compound of Formula (I), R ³ can be CF ₃ .

In still further particular embodiments, the compounds of the present invention may be selected from a comprehensive list of compounds described and described later in Table 1 herein. The table contains more than 200 synthetic or synthetic compounds that have groups that exhibit activity in their ability to modify ion channels in vivo and thereby serve for the therapeutic uses described herein in connection with capsaicin and vanilloid receptors. Compound is contained.

In a further aspect of the invention, compounds having the formula (I-I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, and stereoisomers and tautomers thereof, that can modify ion channels in vivo are disclosed.

<Formula I-I>

(In the meal,

W, Z, Y and X are each independently N or CR ⁴ ;

L is substituted or unsubstituted-(CR ⁵ = CR ⁶ )-or-(C≡C)-;

R ¹ is substituted bicycloaryl or bicycloheteroaryl;

R ³ is C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, heteroalkyl, aryl, cycloalkyl, cycloheteroalkyl, heteroaryl, aralkyl or heteroaralkyl;

Each R ⁴ is independently hydrogen, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, acylamino, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl , Arylalkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfuric ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxy, carbamoyl, cyano, cyclo Heteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio;

R ⁵ and R ⁶ are each independently H, halo, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, heteroalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.

In a further embodiment of the invention of the compound of formula (I-IA) hereinafter referred to as compound (IA ′), R ³ -L represents residues CR ³ R ⁶ = CR ⁵ .

<Formula IA '>

Wherein R ³ is as defined for the compound of formula I, R ⁵ and R ⁶ are hydrogen, halo, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, cycloalkyl, heteroalkyl, Independently selected from aryl, heteroaryl, aralkyl and heteroaralkyl).

In certain particular compounds, R ³ is C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aral Is selected from Kiel; R ⁵ and R ⁶ are each independently selected from hydrogen, halo and substituted or unsubstituted C ₁ -C ₆ alkyl; 0 to 3 groups selected from W, Z, X and Y represent N.

In the compounds of the formula (IA ′), R ⁵ and R ⁶ may, for example, independently represent hydrogen, halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl. It is preferable that R ⁵ and R ⁶ represent hydrogen.

In another particular embodiment of a compound of Formula (I-IA), hereinafter referred to as a compound of Formula (IA), R ³ -L represents the residue R ³ C≡C—.

<Formula IA ">

In the compounds of the formulas II, IA 'and IA ", W, Z, X and Y may each represent CR ⁴ , in particular CH. Alternatively, X represents N and W, Z and Y are Each may represent CR ^{4. In} another example of a group of compounds, X, Y and Z each represent CR ⁴ , in particular CH. In another example of a group of compounds, W is N. In the example, Y is N.

In another group of examples of formulas II, IA 'and IA ", W, X and Z each represent CR ⁴ , in particular CH and Y represents CR ^{4 "} . In this group of examples, R ^{4 ″} may represent, for example, substituted alkyl, halo, sulfone, alkoxy or amino. In particular, R ^{4 ″} may represent substituted alkyl or halo. More particularly, R ^{4 ″} may be methyl, chloro, trifluoromethyl or fluoro.

In examples of another group of compounds of Formulas II, IA 'and IA ", W and X each represent CR ⁴ , in particular CH, and Y and Z each represents CR ^{4 "} . In this group of examples, R ^{4 ″} may each represent, for example, substituted alkyl, halo, alkoxy or amino. In particular, R ^{4 ″} may represent substituted alkyl or halo. More particularly, R ^{4 ″} may be methyl, trifluoromethyl, chloro or fluoro.

In general, in the compounds of formula (I-I), L is preferably-(C = C)-or -C≡C-. Thus, in one example of a group of compounds, L represents-(C = C)-. In another example of a group of compounds, L represents -C≡C-.

In the compounds of the formulas II, IA 'and IA ", R ¹ is for example substituted bicycloaryl or bicycloheteroaryl, for example substituted benzopyranyl, benzoxazine, benzothiazine, indolyl, Zolyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, carbazolyl, naphthalene, tetrahydronaphthalene, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinyl or dihydroisoquinolin may represent a carbonyl. Examples of the substituents are the alkyl, (OH), -COOH, C ( Me) 3, CH (Me) 2, halo, CF _3, cyano, and methoxy. Alternatively, R ¹ May represent substituted or unsubstituted benzoxazine, dihydrobenzoxazine, benzodioxine or benzodioxane.

In compounds of formula (II), (IA ′ and IA ″), R ³ is for example CR ^{6 ′} R ⁷ R ⁸ , wherein R ^{6 ′} is hydrogen, halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl; R ⁷ and R ⁸ are each independently halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl; or R ⁷ and R ⁸ together or unsubstituted C ₃ -C ₈ may form a cycloalkyl ring, for example R ⁷ may represent lower alkyl (eg methyl) For example, R ⁸ may also represent lower alkyl (eg methyl In certain instances, R ^{6 ′} may represent hydrogen and R ⁷ and R ⁸ may represent methyl Alternatively, R ^{6 ′} , R ⁷ and R ⁸ may each represent methyl. Alternatively, R ^{6 '} , R ⁷ and R ⁸ may each represent fluoro Alternatively, R ^6' may represent hydrogen and R ⁷ and R ⁸ together may form a cyclopropyl ring.

In further embodiments of compounds of Formula (II), (IA), (IA ′) and (IA ″), R ³ may represent, for example, substituted or unsubstituted aryl or heteroaryl.

의 기 (여기서, R^2'는 수소 또는 알킬이고; 여기서, 2개의 R^2'는 함께 결합하여 3 내지 8개의 원자를 갖는 시클로알킬 또는 시클로헤테로알킬 고리를 형성할 수 있고; 제공된 2개 이상의 R^2'는 알킬임)이다.In a first alternative embodiment of the compound of formula (IA), R ³ is CF ₃ , n-propyl, or formula

Wherein R ^{2 ′} is hydrogen or alkyl, wherein two R ^{2 ′} can be joined together to form a cycloalkyl or cycloheteroalkyl ring having 3 to 8 atoms; two or more R provided ^{2 '} is alkyl).

For compounds of formula II, IA 'and IA ", R ¹ may be substituted naphthyl, or, alternatively, substituted tetrahydronaphthyl. Additionally, R ¹ may also be substituted bicycloheteroaryl and In certain embodiments, the bicycloheteroaryl is selected from the group consisting of tetrahydroquinoline, tetrahydroisoquinoline, benzoxazine, dihydrobenzoxazine, benzodioxine, dihydrobenzodioxine, benzopyran, indole and benzimidazole More particularly, the bicycloheteroaryl may be quinoline, isoquinoline, benzodioxin and benzoxazine In certain embodiments, the substitution on the bicycloheteroaryl is hydrogen, alkyl, trifluoromethyl, halo. , Methoxy, trifluoromethoxy, amino and carboxy In a further particular embodiment, the substitution on the bicycloheteroaryl is substituted alkyl, Ano, trifluoroalkyl, halo, nitro, methoxy, amino and carboxy More particularly, the substitution on the bicycloheteroaryl is selected from alkyl substituted with hydroxyl or amino. Substitutions on cycloheteroaryl are hydroxyalkyl, for example hydroxymethyl, hydroxyethyl or hydroxypropyl.

(여기서, A¹, A², A³, A⁴, B¹ 및 B²는 각각 독립적으로 CR^4' 및 N이고; R^4'는 각각 독립적으로 H, 치환되거나 치환되지 않은 저급 알킬, 할로, 히드록실, 알콕시, 치환된 알콕시, 아미노, 치환된 아미노, 또는 히드록시알킬임)일 수 있다. 더욱 특히, R¹은 치환되거나 치환되지 않은

일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted or unsubstituted

Wherein A ¹ , A ² , A ³ , A ⁴ , B ¹ and B ² are each independently CR ^{4 ′} and N; R ^{4 ′} is each independently H, substituted or unsubstituted lower alkyl, halo, Hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino, or hydroxyalkyl). More particularly, R ¹ is substituted or unsubstituted

Can be.

(여기서, A⁵ 및 A⁸은 각각 독립적으로 CR^4'R^4', NR^4', O, S, SO 또는 SO₂이고; A⁶ 및 A⁷은 각각 독립적으로 CR^4', NR^4', CR^4'R^4' 또는 CO이고; B³ 및 B⁴는 각각 독립적으로 CR^4' 및 N이고; R^4'가 C에 부착되는 경우, R^4'는 각각 독립적으로 H, C₁-C₆ 알킬, 할로, 또는 히드록시 C₁-C₆ 알킬이고, R^4'가 N에 부착되는 경우, R^4'는 각각 독립적으로 H 또는 C₁-C₆ 알킬이고; 점선으로 된 결합은 단일 또는 이중 결합을 나타냄)일 수 있다. 더욱 특히, R¹은 치환되거나 치환되지 않은

일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted

Wherein A ⁵ and A ⁸ are each independently CR ^{4 ′} R ^{4 ′} , NR ^{4 ′} , O, S, SO or SO ₂ ; A ⁶ and A ⁷ are each independently CR ^{4 ′} , NR ^{4 ′} , CR ^{4 ′} R ^{4 ′} or CO; B ³ and B ⁴ are each independently CR ^{4 ′} and N; and when R ^{4 ′} is attached to C, R ^{4 ′} is each independently H, C ₁ -C ₆ Alkyl, halo, or hydroxy C ₁ -C ₆ alkyl and when R ^{4 ′} is attached to N, R ^{4 ′} is each independently H or C ₁ -C ₆ alkyl; the dotted bond is single or double Indicative of binding). More particularly, R ¹ is substituted or unsubstituted

Can be.

일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted or unsubstituted

Can be.

(여기서, A⁹, A¹⁰ 및 A¹¹은 각각 독립적으로 CR^4', CR^4'R^4', CO, CS, N, NR^4', O, S, SO 또는 SO₂이고; B⁵ 및 B⁶은 각각 독립적으로 CR^4' 및 N이고; R^4'가 C에 부착되는 경우, R^4'는 각각 독립적으로 H, C₁-C₆ 알킬, 할로, 또는 히드록시 C₁-C₆ 알킬이고, R^4'가 N에 부착되는 경우, R^4'는 각각 독립적으로 H 또는 C₁-C₆ 알킬이고; 점선으로 된 결합은 각각 독립적으로 단일 또는 이중 결합을 나타냄)일 수 있다. 더욱 특히, R¹은 치환되거나 치환되지 않은

일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted or unsubstituted

Wherein A ⁹ , A ¹⁰ and A ¹¹ are each independently CR ^{4 ′} , CR ^{4 ′} R ^{4 ′} , CO, CS, N, NR ^{4 ′} , O, S, SO or SO ₂ ; B ⁵ and B ⁶ are each independently CR ^{4 ′} and N; when R ^{4 ′} is attached to C, R ^{4 ′} is each independently H, C ₁ -C ₆ alkyl, halo, or hydroxy C ₁ -C ₆ alkyl; When R ^{4 ′} is attached to N, R ^{4 ′} is each independently H or C ₁ -C ₆ alkyl; the dotted bonds each independently represent a single or double bond). More particularly, R ¹ is substituted or unsubstituted

Can be.

(여기서, A¹, A², A³, A⁴, B¹ 및 B²는 각각 독립적으로 CH 및 N이고; R^4'는 치환되거나 치환되지 않은 저급 알킬임. 더욱 특히, R^4'는 C₁-C₆ 알킬 또는 히드록시 C₁-C₆ 알킬임)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted or unsubstituted

Wherein A ¹ , A ² , A ³ , A ⁴ , B ¹ and B ² are each independently CH and N; R ^{4 ′} is substituted or unsubstituted lower alkyl. More particularly, R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl.

(여기서, A⁵ 및 A⁸은 각각 독립적으로 CH₂, CHMe, NH, NMe, O, S, SO 또는 SO₂이고; R^4'는 C₁-C₆ 알킬 또는 히드록시 C₁-C₆ 알킬임)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted

Wherein A ⁵ and A ⁸ are each independently CH ₂ , CHMe, NH, NMe, O, S, SO or SO ₂ ; R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl May be).

(여기서, R^4'는 치환된 알킬임. 더욱 특히, R^4'는 C₁-C₆ 알킬 또는 히드록시 C₁-C₆ 알킬임)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted

Wherein R ^{4 ′} is substituted alkyl. More particularly, R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl.

(여기서, R^4'는 치환된 알킬임. 더욱 특히, R^4'는 C₁-C₆ 알킬 또는 히드록시 C₁-C₆ 알킬임)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted

Wherein R ^{4 ′} is substituted alkyl. More particularly, R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl.

(여기서, R^4'는 치환된 알킬임. 더욱 특히, R^4'는 C₁-C₆ 알킬 또는 히드록시 C₁-C₆ 알킬임)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted

Wherein R ^{4 ′} is substituted alkyl. More particularly, R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl.

(여기서, R^4'는 치환된 알킬임. 더욱 특히, R^4'는 C₁-C₆ 알킬 또는 히드록시 C₁-C₆ 알킬임)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted

Wherein R ^{4 ′} is substituted alkyl. More particularly, R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl.

(여기서, A⁹, A¹⁰ 및 A¹¹은 각각 독립적으로 CH, CH₂, N, NH, O 또는 S이고; B⁵ 및 B⁶은 각각 독립적으로 CH 및 N이고; R^4'는 각각 독립적으로 H, C₁-C₆ 알킬 또는 히드록시 C₁-C₆ 알킬이고; 점선으로 된 결합은 각각 독립적으로 단일 또는 이중 결합을 나타냄)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted

Wherein A ⁹ , A ¹⁰ and A ¹¹ are each independently CH, CH ₂ , N, NH, O or S; B ⁵ and B ⁶ are each independently CH and N; and R ^{4 ′} is each independently H, C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl; the dashed bonds each independently represent a single or double bond).

(여기서, R^4'는 독립적으로 H, C₁-C₆ 알킬, 할로, 또는 히드록시 C₁-C₆ 알킬임)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted

Wherein R ^{4 ′} is independently H, C ₁ -C ₆ alkyl, halo, or hydroxy C ₁ -C ₆ alkyl.

In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ may be substituted dihydrobenzodioxin-6-yl or dihydrobenzoxazine-6-yl.

(여기서, 가능한 경우, 고리 N은 H 또는 C₁-C₆ 알킬로 더 치환될 수 있음)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted or unsubstituted

Where ring N may be further substituted with H or C ₁ -C ₆ alkyl.

(여기서, 가능한 경우, 고리 N은 H 또는 C₁-C₆ 알킬로 더 치환될 수 있음)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted or unsubstituted

Where ring N may be further substituted with H or C ₁ -C ₆ alkyl.

(여기서, 가능한 경우, 고리 N은 H 또는 알킬로 더 치환될 수 있음)일 수 있다.In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ¹ is substituted or unsubstituted

Where ring N may be further substituted with H or alkyl, where possible.

In another specific embodiment, for compounds of Formula (II), IA ′ and IA ″, R ^{4 ′} can be hydroxy C ₁ -C ₆ alkyl. In more particular embodiments, R ^{4 ′} is-(CH ₂ ) _n -OH (n may be selected from 1 to 3.) In a further embodiment thereof, R ^{4 ′} may be —CH ₂ OH.

일 수 있다.In another specific embodiment, for compounds of Formula (II), IA ′ and IA ″, R ¹ is

Can be.

일 수 있다.In another specific embodiment, for compounds of Formula (II), IA ′ and IA ″, R ¹ is

Can be.

일 수 있다.In another specific embodiment, for compounds of Formula (II), IA ′ and IA ″, R ¹ is

Can be.

In another specific embodiment, for compounds of Formulas II, IA 'and IA ", R ³ may be substituted or unsubstituted cycloalkyl. More particularly, R ³ may be substituted or unsubstituted cyclopropyl, cyclobutyl , Cyclopentyl or cyclohexyl.

In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ³ can be cyclopropyl.

In yet further specific embodiments, for compounds of Formula (II), (IA ′ and IA ″), R ³ may be CF ₃ or CHF _2. More particularly, R ³ may be CF ₃ .

In another specific embodiment, for compounds of Formula (II), (IA ′ and IA ″), R ³ can be t-Bu or isopropyl. More particularly, R ³ can be t-Bu.

In another embodiment, the present invention provides an amide compound according to formula II.

(In the meal,

R ³ is t-Bu, CF ₃ or cyclopropyl;

Z and Y are independently CH, CF, C-Cl, C-Me, C-SO ₂ Me or C-OMe;

B ³ and B ⁴ are independently CR ^{4 ′} or N;

A ⁵ and A ⁸ are each independently CR ^{4 ′} R ^{4 ′} , NR ^{4 ′} , O, S, SO or SO ₂ ;

A ⁶ and A ⁷ are each independently CR ^{4 ′} , NR ^{4 ′} , CR ^{4 ′} R ^{4 ′} or CO;

Each R ^{4 '} is independently H, substituted or unsubstituted alkyl or aryl;

The dotted bond represents a single or double bond). In one particular embodiment, each R ^{4 '} is independently H, substituted or unsubstituted alkyl.

In another embodiment, the present invention provides an amide compound according to formula III.

(In the meal,

R ³ is t-Bu, CF ₃ or cyclopropyl;

Z and Y are independently CH, CF, C-Cl, C-Me, C-SO ₂ Me or C-OMe;

B ³ and B ⁴ are independently CR ^{4 ′} or N;

A ⁵ and A ⁸ are each independently CR ^{4 ′} R ^{4 ′} , NR ^{4 ′} , O, S, SO or SO ₂ ;

A ⁶ and A ⁷ are each independently CR ^{4 ′} , NR ^{4 ′} , CR ^{4 ′} R ^{4 ′} or CO;

Each R ^{4 '} is independently H, substituted or unsubstituted alkyl or aryl;

The dotted bond represents a single or double bond). In one particular embodiment, each R ^{4 '} is independently H, substituted or unsubstituted alkyl.

In another embodiment, the present invention provides an amide compound according to formula IV.

(In the meal,

R ³ is t-Bu, CF ₃ or cyclopropyl;

Z and Y are independently CH, CF, C-Cl, C-Me, C-SO ₂ Me or C-OMe;

B ³ and B ⁴ are independently CR ^{4 ′} or N;

A ⁵ and A ⁸ are independently O or NH).

In one particular embodiment, for compounds of Formula IV, R ³ may be t-Bu. In other specific embodiments, for compounds of Formula IV, R ³ can be CF ₃ . In other specific embodiments, for compounds of Formula IV, R ³ can be cyclopropyl.

In one particular embodiment, for compounds of Formula (IV), both Y and Z can be C-H. In other specific embodiments, for compounds of Formula IV, Y is C-H and Z is C-F or C-Cl. In other specific embodiments, for compounds of Formula IV, Y is C-H and Z is C-F. In other specific embodiments, for compounds of Formula IV, Y is C-H and Z is C-Cl. In further specific embodiments, for compounds of Formula IV, Y is C-H and Z is C-Me or C-OMe. In one particular embodiment, for compounds of Formula (IV), both Y and Z can be C-F. In one particular embodiment, for compounds of Formula (IV), both Y and Z can be C-Cl. In another specific embodiment, for compounds of Formula (IV), both Y and Z can be C-Me.

In one specific embodiment, for compounds of Formula (IV), both A ⁵ and A ⁸ can be O. In one particular embodiment, for compounds of Formula (IV), both A ⁵ and A ⁸ can be NH. In one particular embodiment, for compounds of Formula (IV), A ⁵ can be O and A ⁸ can be NH. In one specific embodiment, for compounds of Formula (IV), A ⁵ can be NH and A ⁸ can be O.

In another embodiment, the present invention provides an amide compound according to formula V.

(In the meal,

R ³ is t-Bu, CF ₃ or cyclopropyl;

Z and Y are independently CH, CF, C-Cl, C-Me, C-SO ₂ Me or C-OMe;

B ³ and B ⁴ are independently CR ^{4 ′} or N;

A ⁵ and A ⁸ are independently O or NH).

In one particular embodiment, for compounds of Formula (V), R ³ may be t-Bu. In other specific embodiments, for compounds of Formula (V), R ³ can be CF ₃ . In other specific embodiments, for compounds of Formula (V), R ³ can be cyclopropyl.

In certain embodiments, for compounds of Formula (V), both Y and Z can be C-H. In other specific embodiments, for compounds of Formula (V), Y is C-H and Z is C-F or C-Cl. In other specific embodiments, for compounds of Formula (V), Y is C-H and Z is C-F. In a further particular embodiment, for compounds of Formula (V), Y is C-H and Z is C-Cl. In other specific embodiments, for compounds of Formula (V), Y is C-H and Z is C-Me or C-OMe.

In certain embodiments, for compounds of Formula (V), both Y and Z can be C-F. In one particular embodiment, for compounds of Formula (V), both Y and Z can be C-Cl. In another particular embodiment, for compounds of Formula (V), both Y and Z can be C-Me.

In one particular embodiment, for compounds of Formula (V), both A ⁵ and A ⁸ can be O. In one particular embodiment, for compounds of Formula (V), both A ⁵ and A ⁸ can be NH. In one particular embodiment, for compounds of Formula (V), A ⁵ can be O and A ⁸ can be NH. In one specific embodiment, for compounds of Formula (V), A ⁵ can be NH and A ⁸ can be O.

In a further aspect, the present invention provides a compound according to Formula VI, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers and tautomers thereof.

(In the meal,

W, Z, Y and X are each independently N or CR ⁴ ;

B ⁷ , B ⁸ and B ⁹ are each independently N or CR ⁴ ;

L is-(CR ⁵ = CR ⁶ )-or-(C≡C)-;

R ³ is C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, heteroalkyl, aryl, cycloalkyl, cycloheteroalkyl, heteroaryl, aralkyl or heteroaralkyl;

Each R ⁴ is independently hydrogen, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, C ₂ -C ₆ acyl, C ₂ -C ₆ acylamino, C ₁ -C ₆ alkylamino, C _1- C ₆ alkylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylarylamino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl , Sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfate ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxy, carbamoyl, cyano, cycloheteroalkyl, Di C ₁ -C ₆ alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio;

R ⁵ and R ⁶ are each independently H, halo, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, heteroalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;

R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl.

In certain embodiments according to formula VI, R ³ is CR ^{6 ′} R ⁷ R ⁸ , wherein R ^{6 ′} is hydrogen, halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl; R ⁷ and Each R ⁸ is independently halo or substituted or unsubstituted C ₁ -C ₆ alkyl; or R ⁷ and R ⁸ together form a substituted or unsubstituted C ₃ -C ₈ cycloalkyl ring. For example, R ⁷ can represent lower alkyl (eg methyl). For example, R ⁸ may also represent lower alkyl (eg methyl). In certain instances, R ^{6 ′} may represent hydrogen and R ⁷ and R ⁸ may represent methyl. Alternatively, R ^{6 '} , R ⁷ and R ⁸ may each represent methyl. Alternatively, R ^{6 '} , R ⁷ and R ⁸ may each represent fluoro. Alternatively, R ^{6 '} represents hydrogen and R ⁷ and R ⁸ together can form a cyclopropyl ring. In certain embodiments, R ³ is selected from the group consisting of CF ₃ , t-Bu and cycloalkyl. In certain embodiments, R ³ is CF ₃ . In certain embodiments, R ³ is t-Bu. In certain embodiments, R ³ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ³ is cyclopropyl.

In the compounds of formula VI, R ⁵ and R ⁶ independently represent, for example, hydrogen, halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl. It is preferable that R ⁵ and R ⁶ represent hydrogen. In general, in the compounds of formula VI, L is preferably-(C = C)-or -C≡C-. Thus, in one example of a group of compounds, L represents-(C = C)-. In another example of a group of compounds, L represents -C≡C-.

In certain embodiments according to formula VI, B ⁷ , B ⁸ and B ⁹ are each N or CR ⁴ , wherein R ⁴ is selected from the group consisting of substituted alkyl, halo, alkoxy or amino. In certain embodiments, B ⁷ , B ⁸ and B ⁹ are each CR ⁴ . In certain embodiments, R ⁴ is independently H, CH ₃ , CF ₃ , Cl or F. In certain embodiments, each R ⁴ is H.

In the compounds of formula VI, W, Z, X and Y can for example represent CR ⁴ , in particular CH. Alternatively, X may represent N and W, Z and Y may each represent CR ⁴ . In another example of a group of compounds, X, Y and Z each represent CR ⁴ , in particular CH. In another example of a group of compounds, W is N. In another example of a group of compounds, Y is N.

In another group of examples of compounds of Formula VI, W, X and Z each represent CR ⁴ , in particular CH and Y represents CR ^{4 "} . In the examples of the group, R ^{4 "} is for example substituted Alkyl, halo, alkoxy or amino. In particular, R ^{4 ″} may represent substituted alkyl or halo. More particularly, R ^{4 ″} may be methyl, chloro or fluoro.

In another example of a group of compounds of Formula VI, W and X each represent CR ⁴ , particularly CH and Y and Z each represent CR ^{4 "} . In the examples of the group, R ^{4 "} is each, eg, Substituted alkyl, halo, alkoxy or amino. In particular, R ^{4 ″} may represent substituted alkyl or halo and, more particularly, may represent methyl, chloro or fluoro.

In certain embodiments according to Formula VI, W and X are each N or CR ⁴ , Y and Z are each N or CR ^{4 ″} and R ^{4 ″} are each independently from hydrogen, alkyl, trihaloalkyl and halo Is selected. In certain embodiments, R ^{4 ″} are each independently H, CH ₃ , CF ₃ , Cl, or F. In certain embodiments, R ⁴ is each H.

In certain embodiments according to formula VI, W, X and Z are each N or CH and Y is C-CH ₃ , C-Cl or CF.

In certain embodiments according to formula VI, R ^{4 ′} is hydroxyl substituted alkyl. In certain embodiments according to _formula VI, R ^{4 ′} is-(CH ₂ ) _n -OH, wherein n is selected from 1-6. In certain embodiments according to formula VI, R ^{4 ′} is CH ₂ OH.

In certain embodiments according to formula VI, L is-(C = C)-or -C≡C-; W, X and Y are each CH; Z is CR ^{4 ″} where R ^{4 ″} is lower alkyl; R ³ is selected from the group consisting of CF ₃ , t-Bu and cyclopropyl; R ^{4 '} is hydroxyl substituted alkyl. In certain embodiments according to formula VI, L is-(C = C)-or -C≡C-; W, X and Y are each CH; Z is CR ^{4 ″} where R ^{4 ″} is methyl; R ³ is selected from the group consisting of CF ₃ , tBu and cyclopropyl; R ^{4 '} is hydroxyl substituted alkyl.

In certain embodiments according to formula VI, L is-(C = C)-or -C≡C-; W, X and Y are each CH; Z is CR ^{4 ″} where R ^{4 ″} is methyl; R ³ is selected from the group consisting of CF ₃ , t-Bu and cyclopropyl; R ^{4 '} is-(CH ₂ ) _n -OH where n is an integer from 1 to 6. In certain embodiments according to formula VI, L is-(C = C)-or -C≡C-; W, X and Y are each CH; Z is CR ^{4 ″} where R ^{4 ″} is methyl; R ³ is selected from the group consisting of CF ₃ , t-Bu and cyclopropyl; R ^{4 '} is CH ₂ OH.

In certain embodiments according to formula VI, L is-(C = C)-or -C≡C-; W, X and Y are each CH; Z is CR ^{4 ″} where R ^{4 ″} is methyl; R ³ is CF ₃ ; R ^{4 '} is CH ₂ OH. In certain embodiments according to formula VI, L is-(C = C)-or -C≡C-; W, X and Y are each CH; Z is CR ^{4 ″} where R ^{4 ″} is methyl; R ³ is t-Bu; R ^{4 '} is CH ₂ OH. In certain embodiments according to formula VI, L is-(C = C)-or -C≡C-; W, X and Y are each CH; Z is CR ^{4 ″} where R ^{4 ″} is methyl; R ³ is cyclopropyl; R ^{4 '} is CH ₂ OH.

In still further particular embodiments, the compounds of the present invention may be selected from a comprehensive list of compounds described and described later in Table 1 herein. The table above has been synthesized or can be synthesized and has a proven activity in the ability to modify ion channels in vivo as a group of compounds, thereby functioning for the therapeutic uses described herein in connection with capsaicin and vanilloid receptors. Contains over 200 compounds.

The compounds of the present invention are useful for the treatment of inflammatory pain and related hyperalgesia and allodynia. In addition, the compounds can be used for neuropathic pain and related hyperalgesia and allodynia (e.g., trigeminal or herpes neuralgia, diabetic neuropathy, burning pain, sympathetic persistent pain and afferent blockade syndromes such as brachial plexus avulsion) Useful for the treatment of)). In addition, the compounds of the present invention are anti-inflammatory agents for the treatment of arthritis, and Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, traumatic brain injury, spinal cord injury, neurodegenerative disorders, alopecia (hair loss), It is useful as an agent for treating inflammatory bowel disease and autoimmune disorders, kidney disorders, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleep disorders, cognitive disorders, depression, anxiety, blood pressure, lipid disorders and atherosclerosis.

In one aspect, the invention provides a compound capable of modifying ion channels in vivo. Representative ion channels modified by such compounds include voltage-gated channels and ligand-gated channels (including cation channels such as vanilloid channels).

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

In a further aspect of the invention, among the symptoms listed herein, comprising administering an effective amount of one or more of the pharmaceutical compositions described above, for example, arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, Methods for treating mammals (including human and lower mammalian species) susceptible to or suffering from alopecia (hair loss), inflammatory bowel disease and autoimmune disorders are disclosed.

In another aspect of the method of treatment, the present invention provides a method for treating a mammal susceptible to, or suffering from, a symptom that induces a pain response or an imbalance in the maintenance of basal activity of the sensory nerves. . Such compounds may be used as pains of various origins or etiologies, such as acute, inflammatory pain (eg, pain associated with osteoarthritis and rheumatoid arthritis); Various neuropathic pain syndromes (e.g. postherpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb pain, pain after mastectomy, peripheral neuropathy) , HIV neuropathy, and chemotherapy-induced and other irtogenic neuropathy); For the treatment of visceral pain (eg, gastroesophageal reflux disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and pain associated with various gynecological and urological disorders), toothaches and headaches (eg, migraine, cluster headaches and tension headaches) It has a use as an analgesic agent.

In terms of additional methods of treatment, the present invention relates to neurodegenerative diseases and disorders, including Parkinson's disease, Alzheimer's disease and multiple sclerosis, comprising administering a symptomatically-effective amount or symptomatically-effective amount of one or more of the pharmaceutical compositions described above; Neuroinflammatory disorders such as diseases and disorders mediated by or causing such neuroinflammatory disorders, such as traumatic brain injury, stroke and encephalitis; Central-mediated psychiatric diseases and disorders such as mood swings, bipolar disorders, anxiety, schizophrenia, eating disorders, sleep disorders and cognitive disorders; Epilepsy and seizure disorders; Prostate, bladder and bowel dysfunctions such as urinary incontinence, delayed urination, irritability, stool incontinence, benign prostatic hyperplasia and inflammatory bowel disease; Irritable bowel syndrome, irritable bladder, respiratory and airway diseases and disorders such as allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; Inflammations such as rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis and atherosclerosis, diseases and disorders mediated by or causing such inflammation; Itching, such as psoriasis; Alopecia (hair loss); obesity; Lipid disorders; cancer; Blood pressure; Spinal cord injury; And a method of treating a stray animal susceptible to, or suffering from, a kidney disorder.

In a further aspect, the present invention provides a method for synthesizing a compound of the present invention in conjunction with the representative synthetic protocols and routes disclosed herein below.

Other objects and advantages will become apparent to those skilled in the art from a review of the following detailed description, together with the following illustrative drawings.

1: Graph shows significant inhibition of capsaicin-induced intracellular calcium response by 3 nM of compound 225 under the described experimental conditions.

2: Graph shows significant inhibition of capsaicin-induced intracellular calcium response by 3 nM of compound 187 under the described experimental conditions.

3: Graph shows significant inhibition of capsaicin-induced intracellular calcium response by 3 nM of Compound 96 under the described experimental conditions.

4: Graph shows significant inhibition of capsaicin-induced intracellular calcium response by 3 nM of compound 45 under the described experimental conditions.

5: Graph shows significant inhibition of capsaicin-induced intracellular calcium response by 3 nM of compound 233 under the described experimental conditions.

6: Graph shows significant inhibition of capsaicin-induced intracellular calcium response by 3 nM of compound 167 under the described experimental conditions.

Justice

When describing compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions, the following terms have the following meanings unless indicated otherwise. In addition, it is to be understood that any residue to be defined below may be substituted with a variety of substituents, and that each definition is intended to include such substituted residues within its scope. Non-limiting examples of such substituents include, for example, halo (eg, fluoro, chloro, bromo), -CN, -CF ₃ , -OH, -OCF ₃ , C ₂ -C ₆ alkenyl , C ₃ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, aryl and di-C ₁ -C ₆ alkylamino.

"Acyl" refers to the radical -C (O) R wherein R is 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” is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, wherein R 'is hydrogen, alkyl, alkoxy as defined herein. And a radical -NR'C (O) R which is 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, wherein R is hydrogen, alkyl, aryl, or cycloalkyl.

"Substituted alkenyl" includes groups mentioned in the definition of "substituted" herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted Amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, Consisting of substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and aryl-S (O) _2- Alkenyl groups having one or more substituents selected from the group, for example 1 to 5 substituents, in particular 1 to 3 substituents.

"Alkoxy" refers to the group -OR where R is alkyl. In particular, as the alkoxy group, 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 groups mentioned in the definition of "substituted" herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino , Aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, hydroxyl, keto, nitro, thio Alkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and aryl-S (O) _2- It represents an alkoxy group having at least one substituent selected from the group consisting of 1 to 5 substituents, in particular 1 to 3 substituents.

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

"Alkali" refers to a hydrocarbyl organic compound or group that is characterized by its linear, branched or cyclic arrangement of constituent carbon atoms, and the absence of aromatic unsaturation. Aliphatics include, but are not limited to, alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene. Typically, aliphatic groups have 1 or 2 to about 12 carbon atoms.

"Alkyl" denotes a monovalent saturated aliphatic hydrocarbyl group having, in particular, up to about 11 carbon atoms, more particularly lower alkyl, having from 1 to 8 carbon atoms, even more particularly from 1 to 6 carbon atoms. Hydrocarbon chains may be straight or branched. The term is exemplified by groups such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like. The term "lower alkyl" denotes an alkyl group having 1 to 6 carbon atoms. The term "alkyl" also includes "cycloalkyl" as defined below.

"Substituted alkyl" includes groups mentioned in the definition of "substituted" herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino , Aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, heteroaryl, keto, nitro, thio Alkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and aryl-S (O) _2- An alkyl group having at least one substituent selected from the group consisting of 1 to 5 substituents, in particular 1 to 3 substituents.

"Alkylene" denotes a divalent saturated aliphatic hydrocarbyl group having, in particular, up to 11 carbon atoms, more particularly 1 to 6 carbon atoms, which may be straight or branched. The term includes, for example, methylene (-CH _2- ), ethylene (-CH ₂ CH _2- ), propylene isomers (eg -CH ₂ CH ₂ CH ₂ -and -CH (CH ₃ ) CH _2- ) and the like. Illustrated with the same groups.

"Substituted alkylene" includes groups mentioned in the definition of "substituted" herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted Amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy At least one substituent selected from the group consisting of thioketo, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and aryl-S (O) _2- , For example, alkylene groups having 1 to 5 substituents, in particular 1 to 3 substituents.

"Alkenyl" preferably has up to about 11 carbon atoms, in particular 2 to 8 carbon atoms, more particularly 2 to 6 carbon atoms, which may be straight or branched, and at least one, in particular 1 to The monovalent olefinic unsaturated hydrocarbyl group which has two olefin unsaturated sites is shown. Specific alkenyl groups include ethenyl (-CH = CH ₂ ), n-propenyl (-CH ₂ CH = CH ₂ ), isopropenyl (-C (CH ₃ ) = CH ₂ ), vinyl and substituted vinyl, and the like. There is this.

"Alkenylene" is a divalent olefin, in particular having up to about 11 carbon atoms, more particularly 2 to 6 carbon atoms, which may be straight or branched, and having at least one, in particular 1 to 2, olefin unsaturated sites A series unsaturated hydrocarbyl group is shown. The term includes, for example, ethenylene (-CH = CH-), propenylene isomers (eg, -CH = CHCH ₂ -and -C (CH ₃ ) = CH- and -CH = C (CH ₃ )- And the like.

"Alkynyl" is an acetylene-based, in particular having up to about 11 carbon atoms, more particularly 2 to 6 carbon atoms, which may be straight or branched, and having at least one, in particular 1 to 2 alkynyl unsaturated sites An unsaturated hydrocarbyl group is shown. Examples of certain non-limiting alkynyl groups include acetylene, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), and the like.

"Substituted alkynyl" includes groups mentioned in the definition of "substituted" herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted Amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, Consisting of substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and aryl-S (O) _2- Alkynyl groups having one or more substituents selected from the group, for example 1 to 5 substituents, in particular 1 to 3 substituents.

As used herein, “alkanoyl” or “acyl” refers to the group R—C (O) —, wherein R is hydrogen or alkyl as defined above.

"Aryl" denotes a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include aceanthryl, acenaphthylene, acefenanthryl, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-in Sen, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, penalene, phenanthrene , But are not limited to, groups derived from pysene, playaden, pyrene, pyrantrene, rubicene, triphenylene, trinaphthalene and the like. In particular, the aryl group contains 6 to 14 carbon atoms.

"Substituted aryl" includes groups mentioned in the definition of "substituted" herein, in particular acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, Substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted Cycloalkyl, halogen, hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and Aryl-S (O) ₂ -represents an aryl group which may be optionally substituted with one or more substituents selected from the group consisting of 1 to 5 substituents, in particular 1 to 3 substituents.

"Fused aryl" refers to an aryl having two common ring carbons with a second aryl ring or aliphatic ring.

"Alkaryl" refers to an aryl group as defined above substituted with one or more alkyl groups as defined above.

"Aralkyl" or "arylalkyl" refers to an alkyl group as defined above substituted with one or more aryl groups as defined above.

"Aryloxy" refers to an -O-aryl group in which "aryl" is defined above.

"Alkylamino" refers to the group alkyl-NR'R ", wherein R 'and R" are each independently selected from hydrogen and alkyl.

"Arylamino" refers to the group aryl-NR'R ", wherein R 'and R" are each independently selected from hydrogen, aryl and heteroaryl.

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

"Alkoxycarbonyl" refers to the radical -C (O) -alkoxy where alkoxy is defined herein.

"Alkylarylamino" refers to the radical -NRR 'wherein R represents an alkyl or cycloalkyl group and R' is aryl as defined herein.

"Alkylsulfonyl" refers to the radical -S (O) ₂ R wherein R is an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

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

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

"Amino" refers to the radical -NH ₂ .

"Substituted amino" includes groups mentioned in the definition of "substituted" herein, in particular R is each hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl And independently selected from the group consisting of cycloalkyl, substituted cycloalkyl, both R groups represent a group -N (R) ₂ , which is bonded to form an alkylene group. When both R groups are hydrogen, -N (R) ₂ is an amino group.

“Aminocarbonyl” refers to the group —C (O) NRR, wherein each R is independently hydrogen, alkyl, aryl, or cycloalkyl, or wherein the R groups combine to form an alkylene group.

“Aminocarbonylamino” refers to the group —NRC (O) NRR, wherein each R is independently hydrogen, alkyl, aryl, or cycloalkyl, or two R groups combine to form an alkylene group.

“Aminocarbonyloxy” refers to the group —OC (O) NRR, wherein each R is independently hydrogen, alkyl, aryl, or cycloalkyl, or wherein the R groups combine to form an alkylene group.

"Arylalkyloxy" refers to an -O-arylalkyl radical in which arylalkyl is defined herein.

"Arylamino" means a radical -NHR in which R represents an aryl group as defined herein.

“Aryloxycarbonyl” refers to a radical —C (O) —O-aryl where aryl is as defined herein.

“Arylsulfonyl” refers to the radical —S (O) ₂ R wherein R is an aryl or heteroaryl group as defined herein.

"Azido" refers to the radical -N ₃ .

"Bicycloaryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system. Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene and the like. In particular, the aryl group contains 8 to 11 carbon atoms.

"Bicycloheteroaryl" refers to a monovalent bicycloheteroaromatic group derived by removing one hydrogen atom from a single atom of the parent bicycloheteroaromatic ring system. Typical bicycloheteroaryl groups include benzofuran, benzimidazole, benzidazole, benzdioxane, chromen, chromman, cinnoline, phthalazine, indole, indolin, indolizin, isobenzofuran, isocro Men, isoindole, isoindolin, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quino There are groups derived from norizine, quinoxaline, benzomorphane, tetrahydroisoquinoline, tetrahydroquinoline and the like, but are not limited thereto. Bicycloheteroaryl groups which are 9 to 11 membered bicycloheteroaryl are preferred, and bicycloheteroaryl groups having 5 to 10 membered heteroaryl are particularly preferred. Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.

“Carbamoyl” refers to the radical —C (O) N (R) ₂ , wherein the R groups are each independently hydrogen, alkyl, cycloalkyl, or aryl, as defined herein.

"Carboxy" represents the radical -C (O) OH.

"Carboxyamino" refers to the radical -N (H) C (O) OH.

"Cycloalkyl" is a cyclic hydro having 3 to 10 carbon atoms, optionally substituted with 1 to 3 alkyl groups, and having a single cyclic ring or multiple condensed rings (including fused and bridged ring systems) It represents a carbyl group. Such cycloalkyl groups include, for example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ring structures, Adamantanyl and the like.

"Substituted cycloalkyl" includes groups mentioned in the definition of "substituted" herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted Amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, Consisting of substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and aryl-S (O) _2- Cycloalkyl groups having one or more substituents selected from the group, for example 1 to 5 substituents, in particular 1 to 3 substituents.

"Cycloalkoxy" refers to the group -OR where R is cycloalkyl. As said cycloalkoxy group, cyclopentoxy, cyclohexoxy, etc. are mentioned, for example.

"Cycloalkenyl" has 3 to 10 carbon atoms and has a single cyclic ring or multiple condensed rings (including fused and bridged ring systems) and at least one, in particular one to two, olefin unsaturated sites A cyclic hydrocarbyl group having Such cycloalkenyl groups include, for example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl and the like.

"Substituted cycloalkenyl" includes groups mentioned in the definition of "substituted" herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted Amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy , Substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and aryl-S (O) _2- Cycloalkenyl groups having one or more substituents selected from the group consisting of, for example, 1 to 5 substituents, in particular 1 to 3 substituents.

"Fused cycloalkenyl" refers to cycloalkenyl having a second aliphatic or aromatic ring and two common ring carbon atoms and an olefin unsaturation positioned to impart aromaticity to the cycloalkenyl ring.

"Cyanato" refers to the radical -OCN.

"Cyano" refers to the radical -CN.

"Dialkylamino" is an alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or R and R 'are independently defined herein The radical -NRR 'which represents a substituted heteroaryl group.

"Ethenyl" represents substituted or unsubstituted-(C = C)-.

"Ethylene" represents substituted or unsubstituted-(C-C)-.

"Ethynyl" represents-(C≡C)-.

"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo. Preferred halo group is fluoro or chloro.

"Hydroxy" refers to the radical -OH.

"Nitro" refers to the radical -NO ₂ .

"Substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent (s). By conventional substituents are ^{-X, -R 14, -O -,} = 0, -OR 14, -SR 14, -S -, = S, -NR 14 R 15, = NR 14, -CX 3, -CF _{3, -CN, -OCN, -SCN,} -NO, -NO 2, = N 2, -N 3, -S (O) 2 O -, -S (O) 2 OH, -S (O) 2 R _{^{14, -OS (O 2) O}} -, -OS (O) 2 R 14, -P (O) (O -) 2, -P (O) (OR 14) (O -), -OP (O) ^{(OR 14) (OR 15)} , -C (O) R 14, -C (S) R 14, -C (O) OR 14, -C (O) NR 14 R 15, -C (O) O - , -C (S) OR ¹⁴ , -NR ¹⁶ C (O) NR ¹⁴ R ¹⁵ , -NR ¹⁶ C (S) NR ¹⁴ R ¹⁵ , -NR ¹⁷ C (NR ¹⁶ ) NR ¹⁴ R ¹⁵ and -C (NR ¹⁶⁾ NR ¹⁴ R ¹⁵ (wherein, X is halogen, each ^{independently; R 14, R 15, R} 16 and R ¹⁷ are each independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted Arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, -NR ¹⁸ R ¹⁹ , —C (O) R ¹⁸ or —S (O) ₂ R ¹⁸ ; R ¹⁸ and R ^{1 9} independently 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, or optionally R ¹⁸ and R ¹⁹ together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring, This is not restrictive.

가 있다.Examples of representative substituted aryls are

There is.

In the above formula, one of R ^{6 '} and R ^7' may be hydrogen, at least one of R ^{6 '} and R ^7' is alkyl, alkenyl, alkynyl, cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, Heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR ¹⁰ COR ¹¹ , NR ¹⁰ SOR ¹¹ , NR ¹⁰ SO ₂ R ¹⁴ , COOalkyl, COOaryl, CONR ¹⁰ R ¹¹ , CONR ¹⁰ OR ¹¹ , NR ¹⁰ R ¹¹ , SO ₂ NR ¹⁰ R ¹¹ , S-alkyl, SOalkyl, SO ₂ alkyl, S-aryl, SOaryl, S0 ₂ aryl, each independently selected; Or R ^{6 '} and R ^7' combine to form a cyclic ring (saturated or unsaturated) having 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group of N, O or S. R ¹⁰ , R ¹¹ and R ¹² are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl, substituted or heteroalkyl and the like.

“Hetero” when used to describe a compound, or a group present on a compound, means that one or more carbon atoms in the compound have been replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero may be any hydrocarbyl group described above, such as alkyl, for example heteroalkyl, cycloalkyl, for example cycloheteroalkyl, aryl, for example heteroaryl, cycloalkenyl, cycloheteroalkenyl, and 1-5 It can be applied to dogs, especially those having 1 to 3 heteroatoms.

"Heteroaryl" refers to a monovalent heteroaromatic group derived by removing one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include acridine, arcindol, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indolin, indolizin, isobenzofuran, Isochromen, isoindole, isoindolin, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, phthalene Teridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidinine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene Groups derived from, triazole, xanthene, and the like, but are not limited thereto. Heteroaryl groups which are 5 to 20 membered heteroaryl are preferred, and heteroaryl groups having 5 to 10 membered heteroaryl are particularly preferred. Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

Examples of representative heteroaryls are

가 있다 (여기서, Y는 각각 카르보닐, N, NR⁴, O 및 S로부터 선택됨).

Where Y is selected from carbonyl, N, NR ⁴ , O and S, respectively.

Examples of representative cycloheteroalkyls are

가 있다 (여기서, X는 각각 CR⁴ ₂, NR⁴, O 및 S이고; Y는 각각 NR⁴, O 및 S로부터 선택되고, R^6'는 R²임).

Where X is CR ⁴ ₂ , NR ⁴ , O and S, respectively; Y is selected from NR ⁴ , O and S, and R ^{6 ′} is R ² .

Examples of representative cycloheteroalkenyls are

가 있다 (여기서, X는 각각 CR⁴, NR⁴, O 및 S로부터 선택되고; Y는 각각 카르보닐, N, NR⁴, O 및 S로부터 선택됨).

Where X is selected from CR ⁴ , NR ⁴ , O and S, respectively; Y is selected from carbonyl, N, NR ⁴ , O and S, respectively.

이 있다 (여기서, X는 각각 C-R⁴, CR⁴ ₂, NR⁴, O 및 S로부터 선택되고; Y는 각각 카르보닐, NR⁴, O 및 S로부터 선택됨).Examples of representative aryls having hetero atoms containing substitutions include

Where X is selected from CR ⁴ , CR ⁴ ₂ , NR ⁴ , O and S, respectively; Y is selected from carbonyl, NR ⁴ , O and S, respectively.

"Hetero substituent" is "substituted" present in, or compound, or may be present as R ⁴ in R ⁴ C group is present as a direct substituent on the A, B, W, X, Y or Z of the compound of the present invention Halo, O, S or N atom-containing functional groups which may be present as substituents on aryl and aliphatic groups.

Examples of hetero substituents are

Halo,

-NO ₂ , -NH ₂ , -NHR, -N (R) ₂ ,

-NRCOR, -NRSOR, -NRSO ₂ R, OH, CN,

-CO ₂ H,

-R-OH, -O-R, -COOR,

-CON (R) ₂ , -CONROR,

-SO ₃ H, -RS, -SO ₂ N (R) ₂ ,

-S (O) R, -S (O) ₂ R, wherein each R is independently, optionally substituted aryl or aliphatic. Among the hetero substituents containing an R group, materials having aryl and alkyl R groups as defined herein are preferred. Preferred hetero substituents are those listed above.

As used herein, the term “cycloheteroalkyl” refers to stable heterocyclic non-aromatic rings and fused rings containing one or more heteroatoms independently selected from N, O and S. Fused heterocyclic ring systems can include carbocyclic rings and are required to include only one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl, but not limited to acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxy Carbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl , Keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and aryl- The following illustrative examples are shown optionally substituted with one or more groups selected from the group consisting of S (O) _2- .

Substituents are, for example, carbonyl or thiocarbonyl, which provide lactams and urea derivatives. In this example, M is CR ⁷ , NR ² , O or S; Q is O, NR ² or S. R ⁷ and R ⁸ are acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl , Aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl- Independently selected from the group consisting of S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and aryl-S (O) _2- .

"Dihydroxyphosphoryl" refers to the radical -PO (OH) ₂ .

"Substituted dihydroxyphosphoryl" refers to a dihydroxyphosphoryl radical which includes the groups mentioned in the definition of "substituted" herein and in particular one or both hydroxyl groups are substituted. Suitable substituents are described in detail below.

"Aminohydroxyphosphoryl" refers to the radical -PO (OH) NH ₂ .

"Substituted aminohydroxyphosphoryl" refers to aminohydroxyphosphoryl, which includes groups mentioned in the definition of "substituted" herein, in which the amino group is substituted with one or two substituents. Suitable substituents are described in detail below. In certain embodiments, hydroxyl groups may also be substituted.

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

"Substituted thioalkoxy" includes groups mentioned in the definition of "substituted" herein and in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted Amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, Consisting of substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) ₂ -and aryl-S (O) _2- Thioalkoxy groups having at least one substituent selected from the group, for example 1 to 5 substituents, in particular 1 to 3 substituents.

"Sulfanyl" refers to the radical HS-. "Substituted sulfanyl" R represents a radical such as RS-, which is any substituent described herein.

"Sulfonyl" refers to a divalent radical -S (O ₂ )-. "Substituted sulfonyl" refers to a radical where R is any substituent described herein, such as R- (O ₂ ) S-. "Aminosulfonyl" or "sulfonamide" refers to the radical H ₂ N (O ₂ ) S-, and "substituted aminosulfonyl""substitutedsulfonamide" is a radical in which R is independently any substituent described herein. For example, R ₂ N (O ₂ ) S—.

"Sulfone" refers to the group -SO ₂ R. In certain embodiments, R is selected from H, lower alkyl, alkyl, aryl and heteroaryl.

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

"Thioketo" represents the group = S.

"Thiol" represents the group -SH.

One skilled in the art of organic synthesis knows that the maximum number of heteroatoms in a stable and chemically possible heterocyclic ring is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms, regardless of whether they are aromatic or non-aromatic. Will know. In general, heterocyclic rings may have from 1 to 4 heteroatoms, as long as the heteroaromatic ring is chemically possible and stable.

“Pharmaceutically acceptable” means approved by a federal or state government agency for use in an animal, more particularly a human, or contained in a US pharmacopoeia or other generally known pharmacopoeia.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. The salts include (1) inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; Or 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, camphor Sulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid Acid addition salts formed with hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; Or (2) acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions or aluminum ions; Or salts formed when coordinating with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. By way of example only, salts further include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like; When the compound contains a basic functional group, there are salts of nontoxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to a cationic counter-ion of an acidic functional group that is nontoxic and acceptable. The cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations and the like.

"Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the present invention is administered.

"Preventing" or "prevention" is intended to reduce the risk of obtaining a disease or disorder (ie, may be susceptible to or prone to disease, but does not occur in a subject who has yet suffered from or has not shown symptoms). Causing one or more clinical symptoms of the disease).

A “prodrug” refers to a compound of the invention (including derivatives of the compound) which has a cleavable group and becomes a compound of the invention by solvolysis or under physiological conditions and is pharmaceutically active in raw vegetables. Such materials include, but are not limited to, N-alkyl morpholine esters, such as choline ester derivatives.

"Solvate" generally refers to the form of a compound associated with a solvent by a solvolysis reaction. Typical solvents include water, ethanol, acetic acid and the like. The compounds of the present 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 further stoichiometric and non-stoichiometric solvates.

"Subject" includes humans. The terms "human", "patient" and "subject" are used interchangeably herein.

A “therapeutically effective amount” refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient for that treatment for the disease to be effective. A "therapeutically effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, and the like of the subject being treated.

"Treating" or "treatment" of any disease or disorder refers to alleviating (ie, inhibiting or reducing the development of the disease or one or more of its clinical symptoms) in one embodiment. In other embodiments, “treating” or “treatment” refers to alleviating one or more physical parameters that may not be recognized by a subject. In another embodiment, "treating" or "treatment" means physically (eg, stabilizing a recognizable symptom), physiologically (eg, stabilizing a physical parameter) or both, a disease or disorder. To control everything. In another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.

Other derivatives of the compounds of the present invention have activity in both their acid and acid derivative forms, while in acid sensitive forms often provide the benefits of solubility, histocompatibility or delayed release in mammalian organisms (Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with substituted or unsubstituted amines, or acid anhydrides, Or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic group pendants on the compounds of the present invention are preferred as prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkylesters. Preferred are C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, aryl, C ₇ -C ₁₂ substituted aryl, and C ₇ -C ₁₂ arylalkyl esters of the compounds of the invention.

It is also to be understood that compounds having the same molecular formula, but differing in the nature or order of bonding of atoms, or in the arrangement of atoms in space, are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers".

Stereoisomers that are not mirror images of one another are termed "diastereomers", and stereoisomers that are not superimposed of one another are named "enantiomers". If the compound has an asymmetric center, for example when it is bound to four different groups, a pair of enantiomers are possible. Enantiomers can be characterized by the absolute arrangement of their asymmetric centers, and the R- and S-series rules of Cahn and Prelog, or the way in which molecules rotate the plane of polarization (right turn or It is described as left turnability (ie, represented as (+) or (-)-isomer, respectively). Chiral compounds may exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".

"Tautomers" are interconvertible forms of a particular compound structure and refer to compounds that depend on the movement of hydrogen atoms and electrons. Thus, both structures may be in equilibrium through the movement of π electrons and atoms (generally H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with acids or bases. Other examples of tautomers are the axi- and nitro-forms of phenylnitromethane, which are similarly formed by treatment with acids or bases. Representative enol-keto structures and equilibria are illustrated below.

Tautomeric forms may be associated with achieving optimal chemical reactivity and biological activity of the compound of interest.

Compounds of the invention may have one or more asymmetric centers; The compounds can thus be prepared as individual (R)-or (S) -stereoisomers, or mixtures thereof. Unless otherwise indicated, the description and naming of specific compounds in the specification and claims are intended to include both individual enantiomers and mixtures, racemates or the like thereof. Methods for the determination of stereochemistry and the identification of stereoisomers are well known in the art.

compound

As previously described herein, the compounds of the present invention have a wide range of symptoms in mammals, including arthritis, Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, pain syndrome (acute and chronic, or neuropathic). Treatment and prevention, traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease and autoimmune disorders or symptoms.

In order that the present invention described herein may be more fully understood, the following structures representing typical compounds of the present invention have been described. It is to be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

Thus, additional groups of specific compounds have been provided. Accordingly, as discussed previously herein, suitable compounds capable of modifying ion channels in vivo can be selected from those listed in Tables 1-1 and 1-2 below, and they are compounds listed in Tables, or Pharmaceutically acceptable salts, solvates or prodrugs; And their stereoisomers and tautomers. All such variants are contemplated herein and are within the scope of the present invention.

In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the above formulas. Prodrugs are derivatives of the compounds of the present invention which have a cleavable group and become compounds of the invention by solvolysis or under physiological conditions and are pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives, and N-alkyl morpholine esters.

Other derivatives of the compounds of the present invention have activity in both their acid and acid derivative forms, while in acid sensitive forms often provide the benefits of solubility, histocompatibility or delayed release in mammalian organisms (Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with substituted or unsubstituted amines, or acid anhydrides, Or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic group pendants on the compounds of the present invention are preferred as prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkylesters. Preferred are C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, aryl, C ₇ -C ₁₂ substituted aryl, and C ₇ -C ₁₂ arylalkyl esters of the compounds of the invention.

Analytical Method

Chronic stenosis injury model CCI  Model):

Male Sprague-Dawley rats (270-300 g; B.W., Charles River, Tsukuba, Japan) were used. Chronic stenosis injury (CCI) surgery was performed according to the method described by Bennett and Xie (Bennett, G.J. and Xie, Y.K. Pain, 33: 87-107, 1988). In summary, animals were anesthetized with sodium pentobarbital (64.8 mg / kg, intraperitoneal) and exposed to medial femoral levels by blunt dissection of the left common sciatic nerve through the biceps. The sciatic nerve proximal portion of his three branches was removed from the adherent tissue and loosely tied around it with about 1 mm space with four ligations (4-0 silk). A sham operation was performed identically to CCI surgery except for sciatic nerve ligation. Two weeks after surgery, mechanical allodynia was evaluated by applying von Frey hair (VFH) to the posterior plantar surface. The lowest amount of VFH force required to elicit a response was recorded as the paw atrophy threshold (PWT). VFH testing was performed at 0.5, 1 and 2 hours post dose. Experimental data were obtained using the Kruskal-Wallis test, followed by the Dunn's test (for multiple comparisons) or the Mann-Whitney U-test (for pair comparisons). Analyzed.

Caco -2 transmittance

Caco-2 permeability was measured according to the method described in Shiiyin Yee, Pharmaceutical Research, 763 (1997).

Caco-2 cells were incubated for 14 days on a filter support (Falcon HTS multiwell insertion system). The culture medium was removed from both the tip and basolateral compartments and the monolayer was preincubated at 37 ° C. for 0.75 hours with 0.3 ml of pre-warmed tip buffer and 1.0 ml of basolateral buffer in 50 cycles of shaker bath per minute. It was. The tip buffer consists of Hanks' equilibrium salt solution, 25 mM D-glucose monohydrate, 20 mM MES biological buffer, 1.25 mM CaCl ₂ and 0.5 mM MgCl ₂ (pH 6.5). The basolateral buffer consists of Hanks' equilibrium salt solution, 25 mM D-glucose monohydrate, 20 mM HEPES biological buffer, 1.25 mM CaCl ₂ and 0.5 mM MgC1 ₂ (pH 7.4). At the end of the preincubation, the medium was removed and a test compound solution (10 [mu] M) in buffer was added to the tip compartment. Inserts were transferred to wells containing fresh basolateral buffer and incubated for 1 hour. Drug concentration in the buffer was determined by LC / MS analysis.

The flux rate (F, mass / hour) was calculated from the slope of the cumulative appearance of the substrate on the receiver side, and the apparent permeability coefficient (Papp) was calculated from the following equation.

Papp (cm / sec) = (F × VD) / (SA × MD)

Where SA is the surface area for transport (0.3 cm ² ), VD is the donor volume (0.3 ml) and MD is the total amount of drug on the donor side at t = 0. All data represent the average of two inserts. Monolayer integrity was determined by Lucifer Yellow transport.

human Dofetilide  ( dofetilide ) Combination

The cell paste of HEK-293 cells expressing the HERG product was diluted 10-fold with 50 mM Tris buffer (adjusted to pH 7.5) with 2M HCl containing 1 mM MgCl ₂ , 10 mM KCl at 25 ° C. Could be suspended. Cells were homogenized using a Polytron homogenizer (20 seconds at full power) and centrifuged at 48,00 g for 20 minutes at 4 ° C. The pellet was resuspended, homogenized and centrifuged once more in the same manner. The resulting supernatant was discarded and the final pellet was resuspended (10-fold volume of 50 mM Tris buffer) and homogenized for 20 seconds at full power. The membrane homogenate was aliquoted and stored at -80 ° C until use. Aliquots were used for protein concentration determination using Protein Assay Rapid Kit and ARVO SX Plate Reader (Wallac). All manipulations, stocks and instruments were always kept on ice. For saturation analysis, experiments were performed at a total volume of 200 μl. At the final concentration for total binding or nonspecific binding (20 μl), in the absence or presence of 10 μM dofetilide, 20 μl of [3H] -dofetilide and membrane homogenate (20-30 μg of protein per well) 160 Saturation was respectively determined by incubating μL at room temperature for 60 minutes. All incubations were terminated by rapid vacuum filtration through polyetherimide (PEI) wet glass fiber filter paper using a Skatron cell harvester, followed by washing twice with 50 mM Tris buffer (pH 7.5 at 25 ° C.). . Receptor-bound radioactivity was quantified by counting liquid scintillation using a Packard LS counter.

For competitive analysis, compounds were diluted in 96-well polypropylene plates as 4-point dilutions in semi-log format. All dilutions were performed first in DMSO, then transferred to 50 mM Tris buffer (pH 7.5 at 25 ° C.) containing 1 mM MgCl ₂ , 10 mM KCl to bring the final DMSO concentration to 1%. Compounds were dispensed in triplicate in assay plates (4 μl). Total binding and nonspecific binding wells were set up in 6 wells as vehicle and 10 μM dofetilide at final concentration, respectively. Radioligands were prepared at a final concentration of 5.6 × and the solution was added to each well (36 μl). The assay was initiated by adding YSi poly-L-lysine scintillation proximity assay (SPA) beads (50 μl, 1 mg / well) and membrane (110 μl, 20 μg / well). Incubation was continued for 60 minutes at room temperature. Plates were incubated for an additional 3 hours at room temperature until the beads settled. Receptor-bound radioactivity was quantified by counting with a Wallac MicroBeta plate counter.

HERG  Method

HEK 293 cells stably expressing HERG potassium channels were used for electrophysiological studies. Methodologies for stable transfection of these channels in HEK cells can be found elsewhere (Z. Zhou et al., 1998, Biophysical Journal, 74, pp230-241). Prior to the experimental day, cells were harvested from the culture flasks and plated on cover glass in standard minimal essential medium (MEM) with 10% fetal bovine serum (FCS). The plated cells were stored in an incubator maintained at 95 ° C. in an atmosphere of 95% O ₂ /5% CO ₂ . Cells were studied 15-28 hours after harvest.

HERG currents were studied using standard patch clamp techniques in a whole-cell mode. During the experiment, cells were superfused with a standard external solution of the following composition: 130 mM NaCl, 4 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM glucose, 5 mM HEPES (pH 7.4 with NaOH). I was. When filled with a standard internal solution of the following compositions: 130 mM KCl, 5 mM MgATP, 1.0 mM MgCl ₂ , 10 mM HEPES, 5 mM EGTA (pH 7.2 with KOH), the whole-cells are patch clamp amplifiers, and 1-3 Recordings were made using a patch pipette with a resistance of M0hm. Only cells with access resistance less than 15 MΩ and seal resistance greater than 1 GΩ were allowed for further experiments. Series resistance compensation was applied below 80% of maximum value. There was no reduction by short circuit. However, the permissible access resistance depends on the magnitude of the recorded current and the series resistance compensation that can be used safely. As a result of the full-cell morphology, and sufficient time (greater than 5 minutes) for cell dialysis into the pipette solution, standard voltage protocols were applied to the cells to induce membrane currents. The voltage protocol is as follows. The membrane was negated for 1000 milliseconds from a retention potential of -80 mV to +40 mV. This led to a downward voltage ramp (rate of 0.5 mV / millisecond) back to the holding potential. The voltage protocol was applied to the cells continuously (0.25 Hz) every 4 seconds throughout the experiment. The amplitude of the peak current induced by about -40 mV during the ramp was measured. Once a stable induced current response was obtained in the external solution, the vehicle (0.5% DMSO in standard external solution) was applied for 10-20 minutes by a transfer pump. If a minimum change in the amplitude of the induced current response under vehicle control conditions is provided, 0.3, 1, 3 or 10 mM test compound is applied for a 10 minute period. The 10 minute period includes the time the feed solution passes as a pump through the tube from the solution reservoir to the recording chamber. The exposure time of the cells to the compound solution is greater than 5 minutes after the drug concentration in the chamber well reaches the intended concentration. Subsequent washes were conducted for a period of 10-20 minutes to assess reversibility. Finally, to measure insensitive endogenous currents, cells were exposed to high doses of dofetilide (5 mM), a specific IKr blocker.

All experiments were performed at room temperature (23 ± 1 ° C.). Using a patch clamp amplifier and specific data analysis software, the induced membrane currents were recorded on-line on a computer, filtered at 500-1 KHz (Bessel-3 dB) and sampled at 1-2 KHz. The peak current amplitude, which typically occurs at about -40 mV, was measured off-line on a computer.

The arithmetic mean of the 10 amplitude values was calculated under the presence of drug and vehicle control conditions. The percent reduction of IN in each experiment is normalized using the formula: IN = (1-ID / IC) x lOO, where ID is the average current value in the presence of the drug and IC is the average current value under control conditions. The obtained current value was obtained. Individual experiments were performed for each drug concentration or time-macthed control and the arithmetic mean in each experiment was defined as the result of the study.

Human liver microsomes ( HLM Half-life at)

Test compounds (1 μM) were incubated at 96 ° C. on 96-deep well plates with 0.78 mg / mL HLM (HL101) and 3.3 mM MgCl ₂ in 100 mM potassium phosphate buffer, pH 7.4. The reaction mixture was divided into two groups, non-P450 and P-450 groups. NADPH was added only to the reaction mixture of the P450 group. Aliquot samples from the P450 group were collected at 0, 10, 30 and 60 minute time points, where the 0 minute time point indicated the time when NADPH was added to the reaction mixture of the P450 group. Aliquot samples from the non-P450 group were collected at the −10 and 65 minute time points. The collected aliquots were extracted with acetonitrile solution containing internal standard. The precipitated protein was spun down in a centrifuge (2000 rpm, 15 minutes). Compound concentration in the supernatant was measured by LC / MS / MS system.

Half-life values were obtained by plotting the natural logarithm of the peak area ratio of compound / internal standard to time. The metabolic rate (k) was calculated from the slope of the best fitted line through the points. This was converted to a half-life value using the following formula, ie half-life = ln 2 / k.

Mono Iodoacetate  ( MIA )-cause OA  Model

Six-week-old male Sprague-Dawley (SD, Japan SLC or Charles River Japan) rats were anesthetized with pentobarbital. The injection site (knee) of MIA was shaved and cleared with 70% ethanol. 25 ml of MIA solution or saline was injected into the right knee joint using a 29G needle. The effect of joint damage on the weight distribution through the right (injured) and left (untreated) knees was assessed using an inactivity tester (Linton Instrumentation, Norfolk, UK). The force exerted by each hind limb was measured in g. Weight-load (WB) deficiency was determined by the weight difference loaded on each foot. Rats were trained to measure WB once weekly, up to 20 days after MIA-injection. The analgesic effect of the compound was measured 21 days after MIA injection. Prior to compound administration, the "preliminary value" of WB deficiency was measured. After administration of the compound, attenuation of WB deficiency was judged as an analgesic effect.

In rats  very Freind  Supplements ( complete Freund's adjuvant ) ( CFA ) -Induced thermal and mechanical Hyperalgesia

Thermal Hyperalgesia

Six week old male rats were used. Rats were treated with Mycobacterium Tuberculosis H37RA (Difco, MI 300 mg) in 100 μl of complete Freund's adjuvant (CFA, liquid paraffin (Wako, Osaka, Japan). Injected into the plantar surface. On day 2 after CFA-injection, heat hyperalgesia was determined by the method described previously (Hargreaves et al., 1988) using the plantar test device (Ugo-Basil, Varese, Italy). . Rats were acclimated to the test environment for at least 15 minutes prior to any stimulation. Radiant heat was applied to the posterior plantar surface and foot atrophy incubation (PWL, seconds) was determined. The intensity of radiant heat was adjusted to provide a stable PWL of 10-15 seconds. Test compounds were administered in a volume of 0.5 mL per 100 g body weight. PWL was measured 1, 3 or 5 hours after drug administration.

Mechanical Hyperalgesia

Male SD rats at 4 weeks of age were used. CFA (300 mg of Mycobacterium tuberculosis H37RA (Diffco, MI) in 100 μl of liquid paraffin (Wako, Osaka, Japan)) was injected into the rat's hind paw. On day 2 after CFA-injection, mechanical hyperalgesia was tested by measuring with analgesy-meter (Ugo-Basil, Varese, Italy) to measure the paw atrophy threshold (PWT, g). The animals were carefully restrained and a steadily increasing pressure was applied to the dorsal side of the hind paw through the plastic tip. The pressure required to induce foot atrophy was determined. Test compounds were administered in a volume of 0.5 mL per 100 g body weight. PWT was measured 1, 3 or 5 hours after drug administration.

Pharmaceutical composition

When used as a medicament, the amide compound of the invention is usually administered in the form of a pharmaceutical composition. Such compositions may be prepared in a manner well known in the pharmaceutical art and comprise one or more active compounds.

In general, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of compound actually administered will typically be determined by the physician in view of the situation, including the condition being treated, the route of administration chosen, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

Pharmaceutical compositions of the invention can be administered by a variety of routes including, but not limited to, oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Depending on the intended route of delivery, the compounds of the invention are preferably formulated as ointments, lotions or patches for injection or oral compositions, or for transdermal administration.

Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More generally, however, the composition is present in unit dosage form to facilitate precise administration. The term “unit dosage form” refers to physically discrete units suited as unitary dosages for human subjects and other mammals, each unit having a predetermined amount calculated to provide the desired therapeutic effect with a suitable pharmaceutical excipient. Contains the active substance of. Typical unit dosage forms include prefilled and premeasured ampoules or syringes, or pills, tablets, capsules, etc., in solid compositions, in liquid compositions. In such compositions, the furansulfonic acid compound is generally a minor component (about 0.1 to about 50 weight percent or preferably about 1 to about 40 weight percent) and the remainder is a variety of vehicles or carriers that assist in forming the desired dosage form, And processing aids.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles with buffers, suspending agents and preparations, coloring agents, flavoring agents, and the like. In solid form, for example, binders such as microcrystalline cellulose, gum tragacanth or gelatin; Excipients such as starch or lactose; Disintegrants such as alginic acid, Primogel or corn starch; Lubricants such as magnesium stearate; Glidants, such as clausable silicon dioxide; Sweetening agents such as sucrose or saccharin; Or a flavoring agent such as peppermint, methyl salicylate or any of the orange flavors, or compounds of similar nature.

Injectable compositions are typically based on sterile saline or phosphate-buffered saline for injection or other injectable carriers known in the art. As before, the active compound in the composition is often minor components, often from about 0.05 to 10% by weight, the remainder being an injectable carrier and the like.

Transdermal compositions are typically topical ointments or creams containing the active ingredient (s) (generally from about 0.01 to about 20 weight percent, preferably from about 0.1 to about 20 weight percent, preferably from about 0.1 to about 10 weight percent And more preferably in an amount ranging from about 0.5% to about 15% by weight. When formulated as an ointment, the active ingredient will typically be combined with a paraffinic or water miscible ointment base. Alternatively, the active ingredient may be formulated in a cream, for example using an oil-in-water cream base. Such transdermal formulations are well known in the art and generally comprise additional ingredients for enhancing the skin penetration stability of the active ingredient or formulation. All such known transdermal formulations and components are within the scope of the present invention.

In addition, the compounds of the present invention can be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using patches of reservoir or porous membrane type, or solid matrix varieties.

The above-described ingredients for compositions for oral, injectable or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

In addition, the compounds of the present invention may be administered in a 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 present invention. However, the present invention is not limited to the following pharmaceutical compositions.

Formulation 1-Tablet

The compound of formula (I) was mixed with dry gelatin binder in a weight ratio of approximately 1: 2 as dry powder. A small amount of magnesium stearate was added as a lubricant. The mixture was formulated into 240-270 mg tablets (80-90 mg of active compound per party) in a tablet press.

Formulation 2- Capsule

The compound of formula (I) was mixed with the starch diluent in a weight ratio of approximately 1: 1 as a dry powder. The mixture was filled into 250 mg capsules (125 mg of active compound per capsule).

Formulation 3- Liquid

Compound (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) of formula (I) were blended and Messier No. 10 U.S. After passing through a sieve, it was mixed with a solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in premade water. Sodium benzoate (10 mg), flavor and colorant were diluted with water and added with stirring. Thereafter, sufficient water was added to prepare a total volume of 5 mL.

Formulation 4-Tablet

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

Formulation 5-Injection

Compounds of formula (I) were dissolved or suspended in buffered sterile saline injectable aqueous medium at a concentration of approximately 5 mg / ml.

Formulation 6- Topical

After stearyl alcohol (250 g) and white petrolatum (250 g) are melted at about 75 ° C., the compound of formula I (50 g), methylparaben (0.25 g), propylparaben (0.15 g), dissolved in water, A mixture of sodium lauryl sulfate (10 g) and propylene glycol (120 g) was added and the resulting mixture was stirred until solidified.

How to treat

The compounds are used as therapeutic agents for the treatment of symptoms in mammals. Accordingly, the compounds and pharmaceutical compositions of the present invention are used as therapeutic agents for preventing and / or treating neurodegenerative, autoimmune and inflammatory symptoms in mammals, including humans.

In terms of the method of treatment, the present invention comprises administering an effective amount of one or more of the pharmaceutical compositions described above, arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, alopecia (hair loss), inflammatory bowel disease And a method for treating a mammal susceptible to or suffering from an autoimmune disorder.

In another aspect of the treatment, the present invention provides a method for treating a mammal susceptible to, or suffering from, a symptom that induces a pain response or an imbalance in the maintenance of basal activity of the sensory nerves. do. Such compounds may be used as pains of various origins or etiologies, such as acute, inflammatory pain (eg, pain associated with osteoarthritis and rheumatoid arthritis); Various neuropathic pain syndromes (e.g. postherpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Julian Barre syndrome, fibromyalgia, annular limb pain, pain after mastectomy, peripheral neuropathy, HIV neuropathy , And chemotherapy-induced and other iatrogenic neuropathy); For the treatment of visceral pain (eg, gastroesophageal reflux disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and pain associated with various gynecological and urological disorders), toothaches and headaches (eg, migraine, cluster headaches and tension headaches) It has a use as an analgesic agent.

In terms of additional methods of treatment, the present invention relates to neurodegenerative diseases and disorders, including Parkinson's disease, Alzheimer's disease and multiple sclerosis, comprising administering a symptomatically-effective amount or symptomatically-effective amount of one or more of the pharmaceutical compositions described above; Neuroinflammatory disorders such as diseases and disorders mediated by or causing such neuroinflammatory disorders, such as traumatic brain injury, stroke and encephalitis; Central-mediated psychiatric diseases and disorders such as mood swings, bipolar disorders, anxiety, schizophrenia, eating disorders, sleep disorders and cognitive disorders; Epilepsy and seizure disorders; Prostate, bladder and bowel dysfunctions such as urinary incontinence, delayed urination, irritability, stool incontinence, benign prostatic hyperplasia and inflammatory bowel disease; Respiratory and airway diseases and disorders such as allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; Inflammations such as rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis and atherosclerosis, diseases and disorders mediated by or causing such inflammation; Itching, such as psoriasis; Alopecia (hair loss); obesity; Lipid disorders; cancer; Blood pressure; Spinal cord injury; And methods of treating mammals susceptible to or suffering from kidney disorders.

Injection level levels range from about 0.1 mg / kg to 10 mg / kg or more per hour, all for about 1 to about 120 hours, and especially for 24 to 96 hours. Preloading bolus from about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve appropriate steady state levels. The total maximum dose is not expected to exceed about 2 g per day for 40-80 kg human patients.

For the prophylaxis and / or treatment of long-term symptoms such as neurodegenerative and autoimmune symptoms, treatment regimens generally extend over months or years, so oral administration is preferred for patient convenience and patience. In addition to oral administration, oral administration of 1 to 5, and especially 2 to 4, and usually 3 times per day are representative therapies. Using this dosage pattern, each dose provides about 0.01 to about 20 mg / kg of the compound or derivative thereof, and provides about 0.1 to about 10 mg / kg, and especially about 1 to about 5 mg / kg. desirable.

Transdermal doses are generally selected to provide a blood level that is similar or lower than that achieved using the dosage.

When used to prevent the onset of neurodegenerative, autoimmune or inflammatory symptoms, the compounds of the present invention or derivatives thereof are typically administered to a patient at risk of developing symptoms at the dosage levels described above under the diagnostic and management of a physician. Will be administered. Patients at risk for the development of certain symptoms generally include those who have a family history of the symptoms or who have been identified as being particularly prone to developing the symptoms by genetic testing or screening.

The chemicals of the present invention can be administered as the sole active agent or in combination with other agents (including other active derivatives). VR1 antagonists may be usefully combined with other pharmacologically active compounds, or two or more other pharmacologically active compounds, especially in the treatment of pain. For example, a VR1 antagonist, in particular a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof (as defined above) may be used in combination with one or more agents selected from: and pharmaceutically acceptable salts and solvates thereof. May be administered simultaneously, sequentially or separately in combination.

Opiate analgesics, for example morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine ( meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone Naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

Nonsteroidal anti-inflammatory drugs (NSAIDs), for example aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenprofen, fenoprofen, flufeny Flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid (mefenamic acid), meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxalazine (oxaprozin), phenylbutazone, pyroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

Barbiturate sedatives, for example amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metabital ( metharbital, metohexital, pentobarbital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental ;

Benzodiazepine with sedative action, for example chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazzepam, oxazepam, themes Temazepam or triazolam;

H1 antagonists with sedative action, for example diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

Sedatives such as glutethimide, meprobamate, metaqualone or dichloralphenazone;

Skeletal muscle relaxants, for example baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, metocarbamol or orphrenadine ;

NR2B antagonists, eg ifenprodil, traxoprodil or (-)-(R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy NMDA receptor antagonists, including -1-piperidinyl] -1-hydroxyethyl-3,4-dihydro-2 (1H) -quinolinone, for example dextromethorphan ((+) -3-hydroxy-N-methylmorphinan or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, Pyrroloquinolinequinine, cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), morphine and dextromethor Combination formulation of plates), topiramate, neramexane or perzinfotel;

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

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

Anticonvulsants, for example carbamazepine, lamotrigine, topiratmate or valproate;

Tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, for example (aR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl ] -8,9,10, l1-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, dapitant or 3-[[2-methoxy-5- (trifluoromethoxy) phenyl] -methylamino] -2-phenylpiperidine (2S, 3S );

Muscarinic antagonists such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, Temiverine and ipratropium;

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

Coal-tar analgesics, in particular paracetamol;

Neuroleptics such as droperidol, chlorpromazine, haloperidol, perphenazine, thiolidazine, mesoridazine, trifluoroperazine ( trifluoperazine, fluphenazine, clozapine, olanzapine, osperzadone, risperidone, ziprasidone, quetiapine, quetiapine, sertindole, aripiprazole, Sonepiprazole, blonanserin, iloperidone, perospirone, laclopriride, zolopine, bifeprunox, bifeprunox, ah Senapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant ), Meclinertant, Miraxion (registered trademark) or sarizotan;

Beta-adrenergic agents such as propranolol;

Local anesthetics such as mexiletine;

Corticosteroids such as dexamethasone;

5-HT receptor agonists or antagonists, in particular 5-HT1B / 1D agonists such as eletriptan, sumatriptan, naratriptan, zolmitriptan or liztriptan ( rizatriptan);

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

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

Tramadol (registered trademark);

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) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6,1] -pyrido [3,4-b] indole-1,4-dione (IC-351 or tadalafil ( 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-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- (5-acetyl-2-propoxy-3 -Pyridinyl) -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] pyrimi -7-one, 4-[(3-chloro-4-methoxybenzyl) amino] -2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- (pyrimidine 2-ylmethyl) pyrimidine-5-carboxamide, 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidine -5-yl) -N- [2- (1-methylpyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide;

Alpha-2-delta ligands such as gabapentin, pregabalin, 3-methylgabapentin, (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-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] oxadiazole-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;

Cannabinoids;

Serotonin reuptake inhibitors such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), flufluxetine Fluvoxamine, paroxetine, citalopram, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d, l-fenfluramine (d, l-fenfluramine ), Femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone ( trazodone);

Noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, geomcetin ( tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), in particular Selective noradrenaline reuptake inhibitors such as reboxetine, in particular (S, S) -reboxetine;

Dual serotonin-noradrenaline reuptake inhibitors such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, 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-heptenic acid, 2-[[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) -Butyl] thio] -5-chloro-3-pyridinecarbonitrile; 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-thiazolebutanol,

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] carb Carbonyl} amino) ethyl] benzoic acid;

Leukotriene B4 antagonists; 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] -valeric 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.

Because it may be desirable to administer a combination of active compounds, for example for the purpose of treating a particular disease or condition, two or more pharmaceutical compositions (at least one containing a compound according to the invention) are co-administered of the compositions It can be conveniently combined in the form of a kit suitable for.

Preparation of the compound

Compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that given the usual or preferred process conditions (ie reaction temperature, time, mole ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise specified. Optimum reaction conditions may vary depending on the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent unwanted reactions from occurring in certain functional groups. The selection of suitable protecting groups for particular functional groups and suitable conditions for protection and deprotection is well known in the art. For example, myriad protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

 The target compound is synthesized by known reactions summarized in the following scheme. The product is isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography or HPLC.

In this specification, in particular "general synthesis" and "example", the following abbreviations may be used.

DCM dichloromethane

EtOAc ethyl acetate

DME 1,2-dimethoxyethane, dimethoxyethane

EtOH Ethanol

DMF N, N-dimethylformamide

MeOH Methanol

DMSO dimethyl sulfoxide

THF tetrahydrofuran

EDC 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrogen chloride)

TFA trifluoroacetic acid

HOBt 1-hydroxybenzotriazole

Preparation of Acid Constituent Units

Preparation of Substituted Benzoic Acid

Intermediate 1

(E) -4- (3,3- Dimethyl Boot -One- Enil Production of benzoic acid

33.3 mmol of neopentyl magnesium chloride in hexane is added to a cooled (0 ° C.) well stirred suspension of 4-carboxy benzaldehyde (2.O g, 13.32 mmol) in anhydrous THF (90 mL) for 20 minutes and the mixture is added After stirring for an additional 2 hours at the same temperature, it was quenched with saturated ammonium chloride solution. Most of THF was evaporated and the aqueous mixture was treated with concentrated HCl (50 mL) and the mixture was heated to reflux for 2 hours. Thereafter, the mixture was cooled to room temperature, extracted with methylene chloride (2 x 100 mL), and the organic layer was dried over sodium sulfate and concentrated to give the desired compound.

Intermediate 2

(E) -4- (3- Methyl Boot -One- Enil Production of benzoic acid

4-carboxybenzaldehyde (1.O g, 6.66 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to 0 ° C. Isobutylmagnesium chloride (16 mL, 32 mmol, 2.0 M solution in THF) was added to the mixture. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was acidified with 50% sulfuric acid in water and THF was removed in vacuo. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and evaporated to afford the desired compound (950 mg) as a gray powder. m / z = 192 (M + 1).

Intermediate 3

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

4-carboxybenzaldehyde (1.O g, 6.66 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to 0 ° C. 2,2-dimethylpropanemagnesium chloride (10.7 mL, 32 mmol, 3.0 M solution in diethyl ether) was added to the mixture. 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 in vacuo. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a gray powder. The gray powder was dissolved in acetone (10 mL) and Jones's Reagent was added (10 mL). The solvent was evaporated and the residue was dissolved in diethyl ether, washed with brine and water, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a white solid. White solid (730 mg) was resuspended in anhydrous THF. Methylmagnesium bromide (3.3 mL, 10 mmol, 3.0 M solution in diethyl ether) was added to the solution. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was acidified with 50% sulfuric acid in water and THF was removed in vacuo. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and evaporated in vacuo to give the product as a gray powder (600 mg). m / z = 219 (M + 1).

Intermediate 4

6- (3,3- Dimethyl Boot -One- Inil The manufacturing method of nicotinic acid

6-Chloronicotinic acid methyl ester (500 mg; 2.93 mmol) was suspended in 1,4-dioxane (3 ml) in a reaction vial (5 ml). Dichlorobis (triphenylphosphine) palladium (II) (70 mg; 3 mol%), copper iodide (12 mg), n, n-diisopropylethylamine (0.63 ml; 3.5 mmol) and 3,3-dimethyl But-1-in (0.44 ml; 3.5 mmol) was added to the vessel. The vessel was sealed and the mixture heated at 80 ° C. for 24 h. The solvent was evaporated to dryness and 20 ml of tetrahydrofuran and 20 ml of 10 N NaOH were added. The mixture was stirred at rt for 30 min 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, dried over Na ₂ SO ₄ , filtered and evaporated to afford the desired product as a brown powder (590 mg; 99%).

Intermediate 5

4- (3,3- Dimethyl Boot -One- Inil Production of benzoic acid

4-iodobenzoic acid methyl ester (500 mg; 1.9 mmol) was suspended in 1,4-dioxane (3 mL) in a reaction vial (5 mL). Dichlorobis (triphenylphosphine) palladium (II) (44 mg; 3 mol%), copper iodide (7.5 mg), N, N-diisopropylethylamine (0.39 mL; 3.5 mmol) and 3,3-dimethyl But-1-in (0.275 mL; 3.5 mmol) was added to the vessel. The vessel was sealed and the mixture heated at 80 ° C. for 24 h. The solvent was evaporated to dryness and 20 mL of tetrahydrofuran and 20 mL of 10 N NaOH were added. The mixture was stirred at rt for 30 min 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, dried over Na ₂ SO ₄ , filtered and evaporated to afford the desired product as a brown powder (210 mg; 28%). m / z = 203 (M + 1).

Intermediate 6

4-( Cyclopentylethynyl Production of benzoic acid

The same procedure was followed as for 4- (3,3-dimethylbut-1-ynyl) benzoic acid except that ethynylcyclopentane was used instead of 3,3-dimethylbut-1-yne.

Intermediate 7

4- (3,3,3- Trifluoropropenyl Production of benzoic acid

A mixture of ethyl diphenylphosphonite (1.98 g; 5.8 mmol) and 2,2,2-trifluoroethyl iodide (6.1 g; 29 mmol) was stirred at room temperature under nitrogen for 24 hours. Excess reagent was removed in vacuo. The residue was purified on silica gel using a hexane-ethyl acetate gradient from 0 to 100% to give the target as a white powder (800 mg; 49%). m / z = 286 (M + 1).

4mm molecular sieve (7 g; active powder) was suspended in 8.8 ml of 1.0 M TBAF in THF and stirred overnight at room temperature under nitrogen. Methyl 4-formylbenzoate (160 mg; 0.97 mmol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (415 mg; 1.46 mmol) in 10 ml of dry THF were added to the solution. After stirring overnight, the solvent was evaporated to dryness. The residue was dissolved in EtOAc and washed with water and brine. The organics were dried over Na ₂ S0 ₄ , filtered and evaporated. The residue was dissolved in 10 ml of THF and 10 ml of 1 N NaOH and refluxed for 30 minutes. The mixture was acidified with concentrated HCl and extracted three times with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to afford the desired product as a brown powder (125 mg; 60%). m / z = 217 (m + 1).

Intermediate 8

4- (3,3,3- Trifluoroprop -One- Inil Production of benzoic acid

(3,3,3- Trifluoroprop -One- Inil ) Triphenylstannan .

Triphenylstannan derivatives were prepared using a modified procedure of Brisdon (Chem. Commun. 2002, 2420-2421). Thus, 1,1,1,3,3-pentafluoropropane (2.0 g, 14.9 mmol) was condensed in a three necked round bottom flask (500 mL) containing ether (20 mL) cooled to -15 ° C. I was. The mixture was kept below −10 ° C. during the addition of n-BuLi (2.5 M in hexane, 16.08 mL, 40.2 mmol). The reaction was stirred at −10 ° C. for 10 minutes before triphenyl tin chloride (5 g, 13.4 mmol) was added as a solution in ether while maintaining −10 ° C. The mixture was slowly warmed to room temperature and allowed to stir for an additional 4 hours. After addition of excess hexane (300 mL), the precipitated mixture was filtered through Celite®. The filtered solution was concentrated in vacuo to give a light yellow solid, which was purified by column chromatography (SiO ₂ : ether / hexane, 1:10) to give 5.2 g (78%) of triphenylstannan derivative as an off-white solid.

methyl  4- (3,3,3- Trifluoroprop -One- Inil ) Benzoate .

Methyl 4-iodobenzoate (1 g, 3.8 mmol), toluene (5 mL), tetrakis (triphenylphosphine) Pd (O) (0.44 g, 0.38 mmol) and (3,3,3-trifluoro Roprov-1-ynyl) triphenylstannan (2.52 g, 5.7 mmol) was added to the microwave reaction vial (20 mL). The mixture was heated at 120 ° C. for 30 minutes, allowed to cool and the volume reduced in vacuo. The remaining residue was dissolved in ethyl acetate (20 mL), washed with water (2 x 50 mL) and brine (2 x 50 mL), and column chromatography (SiO ₂ : ethyl acetate / hexanes, 1:10) Purification gave 0.680 g (78%) of benzoate as a yellow oil.

4- (3,3,3- Trifluoroprop -One- Inil Benzoic acid.

4- (3,3,3-trifluoroprop-1-ynyl) benzoate (0.68 g, 2.9 mmol), lithium hydroxide (0.71 g, 29 mmol), and methanol (30 mL): water (10 mL) Was added to a round bottom flask (100 mL). The mixture was stirred at rt for 30 min, heated to reflux for 1 h and the volume reduced in vacuo. Water (10 mL) was added and the mixture was cooled to 0 ° C. HCl (10 N) was added slowly to the solution until the pH of the stirred solution reached 5. A yellow precipitate formed which was filtered off, washed with cold water (3 × 100 mL) and dried under vacuum to give 0.540 g of 4- (3,3,3-trifluoroprop-1-ynyl) benzoic acid as a pale yellow solid. (86%) was obtained.

Intermediate 9

4-( Cyclopropylethynyl Production of benzoic acid

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

Intermediate 10

4- (3,3- Dimethyl Boot -One- Inil ) -3- (2- Morpholinoethoxy Production of benzoic acid

Ethyl 3- (2- Morpholinoethoxy )-4- Bromobenzoate .

Ethyl 4-bromo-3-hydroxybenzoate (1.5 g, 6.12 mmol), potassium carbonate (2.5 g, 18.37 mmol) and 4- (2-chloroethyl) morpholine hydrochloride (1.4 g, 7.35 mmol) Placed in 50 mL of DMF and the reaction was heated at 80 ° C. for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated to an oil. Purification by column chromatography on silica gel using 0-50% EtOAc / hexane eluent gave the product as a colorless oil (1.O g, 47%).

Ethyl 3- (2- Morpholinoethoxy ) -4- (3,3- Dimethyl Boot -One- Inil ) Benzoate .

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

4- (3,3- Dimethyl Boot -One- Inil ) -3- (2- Morpholinoethoxy Benzoic acid.

Ethyl 3- (2-morpholinoethoxy) -4- (3,3-dimethylbut-1-ynyl) benzoate (0.34 g, 0.95 mmol) and LiOH (68 mg, 2.84 mmol) were added to methanol: water. : 1 mixture (30 mL) and heated at 60 ° C. for 3.5 h. The reaction was cooled down and concentrated in vacuo to a volume of 20 mL. The mixture was placed in an ice-water bath and acidified to pH 5 with concentrated HCl. A white solid precipitated out, which was filtered off and washed thoroughly with water. The solid was dried in a vacuum oven to give the product as a solid (0.24 g, 70%). m / z = 330.1 (M−1).

Intermediate 11

4- (3,3- Dimethyl Boot -One- Inil ) -3- Ethoxybenzoic acid  quite

Ethyl 4- Bromo -3- Ethoxybenzoate .

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

Ethyl-3- Ethoxy -4- (3,3- Dimethyl Boot -One- Inil ) Benzoate .

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

4- (3,3- Dimethyl Boot -One- Inil ) -3- Ethoxybenzoic acid .

The compound was prepared using the same procedure as described above for 4- (3,3-dimethylbut-1-ynyl) -3- (2-morpholinoethoxy) benzoic acid. m / z = 244 (M−1).

Intermediate 12

4- (3,3- Dimethyl Boot -One- Inil ) -3- (2-hydroxy-2- Methylpropoxy Production of benzoic acid

Ethyl 3- (2-hydroxy-2- Methylpropoxy )-4- Bromobenzoate .

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

Ethyl 3- (2-hydroxy-2- Methylpropoxy ) -4- (2- Cyclopropylethynyl ) Benzoate .

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

4- (3,3- Dimethyl Boot -One- Inil ) -3- (2-hydroxy-2- Methylpropoxy Benzoic acid.

The compound was prepared using the same procedure as described above for 4- (3,3-dimethylbut-1-ynyl) -3- (2-morpholinoethoxy) benzoic acid to give the product as a solid (0.15 g, 95%) was obtained. m / z = 272.8 (M−1).

Intermediate 13

2- Chloro -6- (3,3- Dimethyl Boot -One- Inil The manufacturing method of nicotinic acid

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

Intermediate 14

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

(E)- methyl  4- (4,4,4- Trifluoroboot -2-en-2-yl) Benzoate .

A mixture of methyl 4-iodobenzoate (2.62 g, 10 mmol), Et ₃ N (5 ml), acetonitrile (6 ml), Pd (OAc) ₂ (100 mg, 0.4 mmol) was prepared in 1,1,1 -Trifluoro-2-butene (2.20 g, 20 mmol) was added, sealed and heated at 125 ° C. for 20 h. After cooling, the mixture was treated with saturated aqueous Na ₂ CO ₃ solution and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography on silica gel 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 was obtained.

(E) -4- (4,4,4- Trifluoroboot -2-en-2-yl) benzoic acid.

(E) -4- (4,4,4-trifluorobut-2-en-2-yl) benzoic acid [LC-MS: t _R = 3.03 min, m / z = 229 (m-1)] and 4- (4,4,4-Trifluorobut-1-en-2-yl) benzoic acid [LC-MS: t _R = 2.82 min, m / z = 229 (m-1)] to (e)- Prepared from the corresponding methyl ester according to the general saponification procedure for the preparation of 4- (3,3,3-trifluoro-2-methylprop-1-enyl) benzoic acid.

Intermediate 15

(E) -2- methyl -4- (3,3,3- Trifluoroprop -One- Enil Production of benzoic acid

4-bromo-2-methylbenzoic acid (25 g, 0.12 mol), tri-o-tolylphosphine (7.1 g, 0.023 mol), tetra-N-butylammonium chloride (9.7 g, 0.035 mol), potassium acetate ( 22.8 g, 0.232 mol), 3,3,3-trifluoroprop-1-ene (89 g, 0.93 mol), palladium acetate (1.3 g, 0.0058 mol) and N, N-dimethylacetamide (150 mL, 1.6 mol) of the mixture was sealed in a Parr instrument and stirred at 180 ° C. for 120 hours. After cooling, the reaction mixture was filtered through Celite (R) and the filtrate was partitioned between EtOAc and 1N HCl (pH 2-3). The organic layer was separated, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the 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. The methyl ester was saponified to give pure acid (16.5 g, 62%) as a white solid.

Intermediate 16

(e) -4- (3,3,3- Trifluoro -2- Methylprop -One- Enil Production of benzoic acid

(E)- methyl  4- (3,3,3- Trifluoro -2- Methylprop -One- Enil ) Benzoate .

2-trifluoromethylpropene (2.20 g, 20 mmol) was dissolved in methyl 4-iodobenzoate (2.62 g, 10 mmol), Et ₃ N (5 mL), acetonitrile (6 mL), Pd (OAc) ₂ (100 mg, 0.4 mmol) was added to the mixture. The mixture was sealed and heated at 125 ° C. for 20 hours. After cooling, the mixture was treated with saturated aqueous Na ₂ CO ₃ solution and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography on silica gel to give methyl (E) -4- (3,3,3-trifluoro-2-methylprop-1-enyl) benzoate.

(E) -4- (3,3,3- Trifluoro -2- Methylprop -One- Enil Benzoic acid.

2 N NaOH solution (1 mL) was dissolved in THF (5 mL) and MeOH (5 mL) in methyl (E) -4- (3,3,3-trifluoro-2-methylprop-1-enyl) benzo To a stirred mixture of ate (60 mg, 0.25 mmol). The mixture was stirred at rt for 10 h. After the organic solvent was removed in vacuo, the mixture was treated with water and acidified to pH 2-3 with 1 N HCl. The mixture was extracted with EtOAc (20 mL × 3). The combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by column to give (E) -4- (3,3,3-trifluoro-2-methylprop-1-enyl) benzoic acid as a white solid. LC-MS: t _R = 3.04 min, m / z = 229 (M-1).

Intermediate 17

5- (3,3- Dimethyl Boot -One- Inil The manufacturing method of picolinic acid

methyl  5- (3,3- Dimethyl Boot -One- Inil ) Picolinate .

Methyl 5-bromopyridine-2-carboxylate (5 g, 23 mmol), copper iodide (I) (0.43 g, 2.3 mmol), bis (triphenylphosphine) palladium (II) chloride (3.23 g, 4.6 mmol) and triethylamine (80 mL) were added to the sealing reaction vessel (250 mL). The mixture was allowed to stir for approximately 10 minutes upon addition of 3,3-dimethylbut-1-yne (2.83 g, 34.5 mmol). The tube was sealed, stirred overnight at room temperature and heated at 60 ° C. for 1 hour. After allowing the mixture to cool, it was concentrated to a residue under vacuum. The residue was purified by column chromatography on silica gel using EtOAc / hexane (1:10) eluent to give the product as a tan solid (4.62 g, 92%) (used directly in the next step).

5- (3,3- Dimethyl Boot -One- Inil Picolinic acid.

Methyl 5- (3,3-dimethylbut-1-ynyl) picolinate (4.5 g, 21 mmol), lithium hydroxide (5.02 g, 210 mmol), methanol (80 mL) and water (3O mL) To the flask (500 mL). The mixture was stirred at rt for 30 min, heated to reflux for 1 h and then concentrated in vacuo. Water (100 mL) was added and the mixture was cooled to 0 ° C. Concentrated HCl was added slowly to the stirred solution until the pH of the solution reached 6. An off white precipitate formed which was filtered off, washed with cold water (3 × 100 mL) and dried under vacuum to give the product as an off white solid (3.97 g, 95%). LC-MS 2.76 min, 202.9 (M-1).

Intermediate 18

4-( Cyclopropylethynyl ) -3- ( Cyclopropylmethoxy Production of benzoic acid

Ethyl 4- Bromo -3- ( Cyclopropylmethoxy ) Benzoate .

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

Ethyl 4- (2- Cyclopropylethynyl ) -3- ( Cyclopropylmethoxy ) Benzoate .

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

4-( Cyclopropylethynyl ) -3- ( Cyclopropylmethoxy Benzoic acid.

Ethyl 4- (2-cyclopropylethynyl) -3- (cyclopropylmethoxy) benzoate (0.47 g, 1.65 mmol) and LiOH (120 mg, 4.96 mmol) in a methanol: water 3: 1 mixture (50 mL) And heated at 60 ° C. for 3.5 h. The reaction was cooled and concentrated in vacuo to a volume of 20 mL, then placed in an ice-water bath and acidified to pH 5 with concentrated HCl. A white solid precipitated out, which was filtered off and washed thoroughly with water. The solid was dried in a vacuum oven to give the product (0.44 g, 98%). m / z = 257.1 (M + 1).

Intermediate 19

2- (3,3- Dimethyl Boot -One- Inil Pyrimidine-5- Carboxylic acid  quite

5- Bromo -2- Iodo Pyrimidine.

The title compound was prepared following the procedure given in The Journal of Organic Chemistry, 2002, 67, 6550-6552. 57% Hydrogen iodide (aqueous) precooled to 0 ° C. was added to a solid 5-bromo-2-chloro-pyrimidine (3.36 g, 0.0174 mol) in a round bottom flask (100 ml). The mixture was vigorously stirred at 0 ° C., after 4 h, allowed to warm to rt and stirred overnight. Thereafter, the mixture was poured onto ice and carefully neutralized by adding solid sodium bicarbonate. Solid sodium hydrogen sulfite was added until the mixture was colorless, then the mixture was extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give 4.2 g of a white solid (used without further purification).

5- Bromo -2- (3,3- Dimethyl Boot -One- Inil Pyrimidine.

5-Bromo-2-iodo-pyrimidine (2.53 g, 0.00888 mol) in triethylamine (25 mL, 0.18 mol), copper iodide (I) (0.169 g, 0.000888 mol), 3,3-dimethyl- A mixture of 1-butyne (1.17 mL, 0.00977 mol) and bis (triphenylphosphine) palladium (II) chloride (0.623 g, 0.000888 mol) was heated at 50 ° C. in a sealing reaction vessel (150 mL). After 16 hours, the mixture was cooled to room temperature, 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 column chromatography on silica gel using ethyl acetate: hexanes (gradient from 0 to 100%) eluent gave the product as a solid (1.9 g).

2- (3,3- Dimethyl Boot -One- Inil Pyrimidine-5- Carbonitrile .

For sealing a mixture of 5-bromo-2- (3,3-dimethylbut-1-ynyl) pyrimidine (2.5 g, 0.010 mol) and copper cyanide (1.4 g, 0.016 mol) in N-methyl pyrrolidine The tube was heated at 200 ° C. for 24 hours. The mixture was allowed to cool to rt, filtered through celite (R) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate: hexanes (gradient from 0 to 50%) to give the product (1.25 g).

2- (3,3- Dimethyl Boot -One- Inil Pyrimidine-5- Carboxylic acid .

2- (3,3-dimethylbut-1-ynyl) pyrimidine-5-carbonitrile (1.0 g, 0.005 mol) and potassium hydroxide (2.8 g, 0.05 mol) in isopropanol (40 mL) and water (10 mL) The mixture of was heated to reflux for 3 hours. The mixture was allowed to cool to rt and concentrated in vacuo. Water (200 mL) was added and the mixture was cooled to 0 ° C., then concentrated HCl was added until pH 6 was obtained. The resulting off-white precipitate was collected by filtration and washed with water to give the product as a solid. m / z = 205 (M + 1).

Intermediate 20

4-( Cyclopentylethynyl )-2- Fluorobenzoic acid  quite

methyl  4-( Cyclopentylethynyl )-2- Fluorobenzoate .

4-bromo-2-fluorobenzoic acid methyl ester (1.O g, 4.0 mmol) was dissolved in triethylamine (5 mL). Copper iodide (38 mg, 5 mol%) was added to the mixture, followed by PdCl ₂ (PPh ₃ ) ₂ (140 mg, 5 mol%) and ethynylcyclopentane (0.85 mL, 6.3 mmol). The mixture was heated at 80 ° C. for 3 hours in a sealing pressure tube. After the reaction was complete, triethylamine was removed in vacuo and the residue was dissolved in EtOAc and filtered through Celite®. The organic layer was washed with water, brine, dried (Na ₂ SO ₄ ), filtered and the mixture concentrated in vacuo. The residue was purified by column chromatography on silica using EtOAc-hexane (gradient from 0 to 100%) eluent to afford the product (0.92 g).

4-( Cyclopentylethynyl )-2- Fluorobenzoic acid .

Methyl 4- (cyclopentylethynyl) -2-fluorobenzoate was dissolved in 10 mL of MeOH and 10 mL of 2N LiOH and the mixture was refluxed overnight. MeOH was removed in vacuo and the basic layer was washed with EtOAc, acidified and reextracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the desired product (645 mg) as a beige solid. m / z = 233 (M + 1).

Intermediate 21

2- Chloro -6- ( Cyclopropylethynyl The manufacturing method of nicotinic acid

Ethyl 2,6- Dichloropyridine -3- Carboxylate .

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

Ethyl 2- Chloro -6- (2- Cyclopropylethynyl Pyridine-3- Carboxylate .

Ethyl 2,6-dichloropyridine-3-carboxylate (2.0 g, 9.1 mmol), ethynylcyclofropanane (1.6 mL of 70% w / v solution in toluene, 13.63 mmol), copper iodide (1) mg, 0.9 mmol), bis (triphenylphosphine) palladium (II) chloride (1.28 g, 1.82 mmol) were stirred in 40 mL of triethylamine for 24 hours at room temperature. 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 (0.7 g, 31%). m / z = 250 (M + 1).

2- Chloro -6- ( Cyclopropylethynyl Nicotinic acid.

The ester was hydrolyzed as follows. Ethyl 2-chloro-6- (2-cyclopropylethynyl) pyridine-3-carboxylate (0.7 g, 2.8 mmol) and lithium hydroxide (0.4 g, 16.86 mmol) were added to a mixture of 30 mL of MeOH and 10 mL of water. It was refluxed. The mixture was cooled down and methanol was removed in vacuo. The remaining solution was acidified to pH 2 with 1 M HCl at 0 ° C. The precipitate was filtered off and dried to give 0.4 g (57%) of the title compound. m / z = 222.4 (M + l).

Intermediate 22

(Z) -2- Methoxy -4- (3,3,3- Trifluoroprop -One- Enil Preparation of benzoic acid and (E) -2-methoxy-4- (3,3,3- Trifluoromethylprop -One- Enil Production of benzoic acid

methyl  4- Formyl -2- Methoxybenzoate .

The slow stream of CO was extracted from methyl 4-bromo-2-methoxybenzoate (2.4 g, 0.010 mol), bis (triphenylphosphine) palladium (II) chloride (140 mg, 0.00020 mol), sodium formate (1.02 g, 0.0150 mol) and a suspension of anhydrous DMF (10 mL). The mixture was vigorously stirred at 110 ° C. for 2 hours. After cooling, the mixture was treated with aqueous Na ₂ CO ₃ solution and extracted with EtOAc. The extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography on silica gel using AcOEt-hexane eluent (0-50%) to give a colorless oil.

methyl  (E) -4- (3,3,3- Trifluoroprop -One- Enil )-2- Methoxybenzoate  And methyl  (Z) -4- (3,3,3-t ripple Luoroprop-1- Enil )-2- Methoxybenzoate .

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

(E) -4- (3,3,3- Trifluoroprop -One- Enil )-2- Methoxybenzoic acid .

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

(Z) -4- (3,3,3- Trifluoroprop -One- Enil )-2- Methoxybenzoic acid .

(Z) -methyl 4- (3,3,3-trifluoroprop-1-enyl) -2-methoxybenzoate (60.0 mg, 0.000230 mol), MeOH (10 mL) and 2N aqueous NaOH solution (0.5 mL) was stirred at 65 ° C. for 5 hours. After cooling the mixture, the solvent was removed under reduced pressure. The residue was treated with water, acidified to pH 2-3 with 1 N HCl and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the product as a syrup (which becomes an off-white solid when left at room temperature for a long time). LC-MS: 2.49 min, 244.8 (M-1).

Intermediate 23

4-( Cyclopropylethynyl )-2- Methylbenzoic acid  quite

methyl -4- Bromo -2- Methylbenzoate .

4-bromo-2-methylbenzoic acid (5.0 g, 23 mmol) was suspended in methanol (30 mL). A solution of HCl in diethyl ether (1.0 M, 30 mL) was added to the mixture. The mixture was refluxed for 24 hours and concentrated to dryness. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the desired compound (5.5 g) as a brown oil.

4-( Cyclopropylethynyl )-2- Methylbenzoic acid .

Methyl 4-bromo-2-methylbenzoate (1.O g, 4.4 mmol) was dissolved in triethylamine (5 mL). Copper iodide (43 mg, 5 mol%) was added to the mixture, followed by PdCl ₂ (PPh ₃ ) ₂ (157 mg, 5 mol%) and ethynylcyclopropane (1.43 ml, 12 mmol). The mixture was heated at 80 ° C. for 3 hours in a sealing pressure tube. After the reaction was complete, triethylamine was evaporated and the residue was dissolved in EtOAc and filtered through Celite®. The organic layer was washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc-hexane (gradient from 0 to 100%) eluent to afford the desired product (630 mg). The product was dissolved in 10 mL of MeOH and 10 mL of 2N LiOH and the mixture was refluxed overnight. MeOH was evaporated and the basic layer was washed with EtOAc, acidified and reextracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the desired product (461 mg) as a beige solid. m / z 201 (M + 1).

Intermediate 24

4-( Cyclopropylethynyl )-2- Fluorobenzoic acid  quite

The compound was prepared using the same method as for 4- (3,3-dimethylbut-1-ynyl) -2-methylbenzoic acid, except that cyclopropylacetylene was used as the alkyne coupling partner.

Intermediate 25

4- (3,3- Dimethyl Boot -One- Inil )-2- Methoxybenzoic acid  quite

methyl  2- Methoxy -4- (3,3- Dimethyl Boot -One- Inil ) Benzoate .

Methyl 4-bromo-2-methoxybenzoate (1.2 g, 0.0049 mol) in Et ₃ N (10 mL), copper iodide (I) (0.093 g, 0.00049 mol), 3,3-dimethyl-1-butyne A mixture of (0.70 mL, 0.0059 mol) and bis (triphenylphosphine) palladium (II) chloride (0.34 g, 0.00049 mol) was heated in a sealing reaction vessel (50 mL) at 100 ° C. for 16 h. After cooling, the mixture was filtered through Celite (R) and the filter cake was washed repeatedly with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel to give a viscous oil (1.10 g, 91%).

2- Methoxy -4- (3,3- Dimethyl Boot -One- Inil Benzoic acid.

A mixture of methyl 2-methoxy-4- (3,3-dimethylbut-1-ynyl) benzoate (1.10 g, 0.00447 mol), MeOH (20 mL) and a 2 N aqueous NaOH solution (5 mL) at 65 ° C. Stir overnight. After allowing to cool, the mixture was concentrated in vacuo. The residue was treated with water and extracted with hexanes. The aqueous layer was acidified to pH 2-3 with 1 N HCl and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the product as a white solid (870 mg, 84%). LC-MS: 3.22 min, 233.4 (M + 1).

Intermediate 26

4-( Cyclopropylethynyl ) -2,6- Difluorobenzoic acid  quite

4-bromo-2,6-difluoro-benzoic acid methyl ester (200 mg, O.8 mmol) is dissolved in triethylamine (5 mL) and dichloropalladium (bis) triphenylphosphine (29 mg, 5 mol%) was added followed by copper iodide (8 mg, 5 mol%) and cyclopropylacetylene (0.09 mL, 0.96 mmol). The mixture was heated to reflux for 1 hour in a sealing tube. The mixture was cooled to rt, filtered through celite (R) and evaporated. The residue was dissolved in dichloromethane and purified using a EtOAc / hexane gradient from 0 to 100% to give 178 mg (94%) of ester compound. m / z = 237 (M + 1). The esters were hydrolyzed using the methodology outlined for 4- (cyclopentylethynyl) -2-fluorobenzoic acid to afford the desired acid product.

Intermediate 27

4-( Cyclopentylethynyl )-2- Methylbenzoic acid  quite

methyl  4-( Cyclopentylethynyl )-2- Methylbenzoate .

Methyl 4-bromo-2-methylbenzoate (1.O g, 4.4 mmol) was dissolved in triethylamine (5 mL). Copper iodide (43 mg, 5 mol%) was added to the mixture, followed by PdCl ₂ (PPh ₃ ) ₂ (157 mg, 5 mol%) and ethynylcyclopentane (0.75 mL, 5.3 mmol). The mixture was heated at 80 ° C. for 3 hours in a sealing pressure tube. After the reaction was complete, triethylamine was evaporated and the residue was dissolved in EtOAc and filtered through Celite®. The organic layer was washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc-hexane (gradient from 0 to 100%) eluent to afford the desired product.

4-( Cyclopentylethynyl )-2- Methylbenzoic acid .

The product from step 1 was dissolved in 10 mL of MeOH and 10 mL of 2N LiOH and the mixture was refluxed overnight. MeOH was evaporated and the basic layer was washed with EtOAc, acidified and reextracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the desired product (461 mg) as a beige solid. m / z = 243 (M + 1).

Intermediate 28

4- (3,3- Dimethyl Boot -One- Inil )-2- Methylbenzoic acid  quite

Ethyl 4- Bromo -2- Methylbenzoate .

4-bromo-2-methylbenzoic acid (10 g, 46.5 mmol) was dissolved in 200 mL of EtOH, 5 mL of concentrated H ₂ SO ₄ was added and the mixture was refluxed for 18 h. The reaction volume was reduced to 50 mL in vacuo, neutralized to pH 7 with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated to give the product as an oil (6.5 g).

Ethyl 2- methyl -4- (3,3- Dimethyl Boot -One- Inil ) Benzoate .

Ethyl 4-bromo-2-methylbenzoate (6 g, 0.02 mol), 3,3-dimethyl-1-butyne (4.56 mL, 0.0382 mol) copper iodide (I) (0.47 g, 0.0025 mol) and bis ( Triphenylphosphine) palladium (II) chloride (3.46 g, 0.00493 mol) was added to 40 mL of triethylamine and stirred overnight at room temperature in a sealing tube. 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 eluent to afford the product as a brown oil (4.8 g, 42%).

4- (3,3- Dimethyl Boot -One- Inil )-2- Methylbenzoic acid .

Ethyl 2-methyl-4- (3,3-dimethylbut-1-ynyl) benzoate (4.8 g, 0.020 mol) and lithium hydroxide (2.8 g, 0.058 mol) were added to a methanol: water 3: 1 mixture (80 mL). In and heated at 60 ° C. for 3.5 h. TLC and LCMS showed the formation of the product. The reaction was cooled down and concentrated in vacuo to a volume of 20 mL. The mixture was placed in an ice water bath and acidified to pH 5 with concentrated HCl. Filter and wash thoroughly with water to give a white solid. The solid was dried in a vacuum oven to give the product as a solid (4.1 g, 97%). m / z = 215.1 (M−1).

Intermediate 29

(E) -2- Fluoro -4- (3,3,3- Trifluoroprop -One- Enil Production of benzoic acid

methyl -2- Fluoro -4- Bromobenzoate .

4-Bromo-2-fluorobenzoyl chloride (45.0 g, 0.190 mol) is added slowly to a solution of methanol (31 mL, 0.76 mol) and triethylamine (53 mL, 0.38 mol) at 0 ° C., and the mixture Was stirred at rt overnight. MeOH was removed in vacuo and the residue dissolved in CH ₂ Cl ₂ (500 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to give a white solid.

(E) -2- Fluoro -4- (3,3,3- Trifluoroprop -One- Enil Benzoic acid.

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

Intermediate 30

(E) -2- Fluoro -4- (3,3,3- Trifluoroprop -One- Enil ) Benzoic acid and (Z) -2- Fluoro -4- (3,3,3- Trifluoroprop -One- Enil Production of benzoic acid

tert -Butyl 4- Bromo -2- Fluorobenzoate .

DMF (0.1 mL) and oxalyl chloride (1.5 mL, 0.018 mol) were added to a stirred solution of 4-bromo-2-fluorobenzoic acid (3.0 g, 0.014 mol) in THF (50 mL) at 0 ° C. . The mixture was stirred at 0 ° C. for 1 h and then warmed to rt. The solvent was removed under reduced pressure. The resulting acid chloride was added to a mixture of tert-butyl alcohol (5.0 g, 0.067 mol), pyridine (10 mL) and CH ₂ Cl ₂ (50 mL) at 0 ° C. The mixture was stirred at rt for 3 h and then at 50 ° C. overnight. The mixture was washed with water, 2N NaOH and brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column to give a colorless oil (1.5 g, 45%).

tert -Butyl 2- Fluoro -4- Formylbenzoate .

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

(E)- tert -Butyl 2- Fluoro -4- (3,3,3- Trifluoroprop -One- Enil ) Benzoate  And (Z)- tert -Butyl 2- Fluoro -4- (3,3,3- Trifluoroprop -One- Enil ) Benzoate .

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

(E) -2- Fluoro -4- (3,3,3- Trifluoroprop -One- Enil Benzoic acid.

(E) -tert-butyl 2-fluoro-4- (3,3,3-trifluoroprop-1-enyl) benzoate (500 mg) in CH ₂ Cl ₂ (10 mL) and TFA (1.0 mL) , 0.002 mol) solution was stirred at room temperature for 2 hours. 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 -One- Enil Benzoic acid.

(Z) -tert-butyl 2-fluoro-4- (3,3,3-trifluoroprop-1-enyl) benzoate (35 mg in CH ₂ Cl ₂ (5 mL) and TFA (0.5 mL) , 0.12 mmol) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give a white solid. LC-MS: 2.86 min, 233.2 (M-1).

Intermediate 31

4- (3,3- Dimethyl Boot -One- Inil )-2- Fluorobenzoic acid  quite

4- Bromo -2- Fluoro -Benzoic acid methyl  ester.

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

4- (3,3-dimethyl- Boot -One- Inil )-2- Fluoro -Benzoic acid methyl  ester.

Bis (triphenylphosphine) palladium (II) chloride (1.03 g, 0.00145 mol), N, N-diisopropylethylamine (9.0 mL, 0.050 mol), copper iodide (I) (0.353 g, 0.00186 mol) and 1,4-dioxane (70 mL) was added in this order to the sealing reaction vessel. 3,3-Dimethyl-1-butyne (6.1 mL, 0.050 mol) was added and the vessel was allowed to stir at room temperature for 24 hours. The mixture was filtered through Celite (R) and concentrated in vacuo. The mixture was chromatographed using a 0 to 20% ethyl acetate: hexanes gradient. The combined pure fractions were reduced in volume in vacuo and dried over high vacuum to give a pale brown solid.

4- (3,3-dimethyl- Boot -One- Inil )-2- Fluoro Benzoic acid.

Methyl 2-fluoro-4- (3,3-dimethylbut-1-ynyl) benzoate (8.2 g, 0.035 mol) is suspended in a 3: 1 mixture of H ₂ O and methanol, containing lithium hydroxide (2.5 g, 0.10 mol) was added all at once and the mixture was shaken at room temperature overnight. Thereafter, the mixture was concentrated to 3/4 volume and acidified with 1N HCl until the pH was adjusted to acidic. The white precipitate was filtered off, washed with water and vacuum dried at 80 ° C. for several hours. m / z = 218.9 (M−1).

Intermediate 32

2- Chloro -4- (3,3- Dimethyl Boot -One- Inil Production of benzoic acid

methyl  2- Chloro -4- (3,3- Dimethyl Boot -One- Inil ) Benzoate .

Methyl 4-bromo-2-chlorobenzoate (400 mg, 0.0016 mol) in copper Et ₃ N (5 mL) and DMF (2 mL) (30 mg, 0.00016 mol), 3,3- A mixture of dimethyl-1-butyne (0.29 mL, 0.0024 mol) and bis (triphenylphosphine) palladium (II) chloride (110 mg, 0.00016 mol) was sealed in a reaction vessel (50 mL) for 32 hours at 100 ° C. Heated. After cooling, the mixture was filtered through Celite (R) and the filter cake was washed repeatedly with ethyl acetate. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the product as pale yellow oil (330 mg, 82%).

2- Chloro -4- (3,3- Dimethyl Boot -One- Inil Benzoic acid.

Of methyl 2-chloro-4- (3,3-dimethylbut-1-ynyl) benzoate (330 mg, 0.0013 mol), 2N aqueous NaOH (3.0 mL), THF (5 mL) and MeOH (5 mL) The mixture was stirred at rt for 5 h. The mixture was concentrated in vacuo, the residue treated with water, acidified to pH 2-3 with 1 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the product as a white solid (305 mg, 98%). t _R = 3.56 min, 234.9 and 236.9 (M-1).

Intermediate 33

2- Chloro -4-( Cyclopropylethynyl Production of benzoic acid

methyl  2- Chloro -4- (2- Cyclopropylethynyl ) Benzoate .

Methyl 4-bromo-2-chlorobenzoate (450 mg, 0.0018 mol), copper iodide (I) (34 mg, 0.00018 mol), a 70% solution of cyclopropylacetylene (0.26 g, 0.0027 mol) in toluene, and A mixture of bis (triphenylphosphine) palladium (II) chloride (130 mg, 0.00018 mol) in Et ₃ N (5 mL) and DMF (3 mL) was sealed for 36 h at 100 ° C. in a reaction vessel (50 mL) for sealing. Heated during. After cooling, the mixture was filtered through Celite (R) and the filter cake was washed repeatedly with ethyl acetate. The organic phase was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the product as a brown oil (320 mg, 76%).

2- Chloro -4- (2- Cyclopropylethynyl Benzoic acid.

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

Intermediate 34

(E) -2- Chloro -4- (3,3,3- Trifluoroprop -One- Enil Production of benzoic acid

methyl  2- Chloro -4- Formylbenzoate .

The CO's documents were methyl 4-bromo-2-chlorobenzoate (1.50 g, 0.00601 mol), bis (triphenylphosphine) palladium (II) chloride (80 mg, 0.0001 mol), sodium formate (613 mg, 0.00902 mol) and a suspension of anhydrous DMF (10 mL). The mixture was vigorously stirred at 110 ° C. for 2 hours. After cooling, the mixture was treated with aqueous Na ₂ CO ₃ solution and extracted with EtOAc. The extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was chromatographed on silica gel with AcOEt-hexanes to give the product as a colorless oil which became a white solid when stored in the refrigerator.

2- Chloro -4-((E) -3,3,3- Trifluoroprop -One- Enil Benzoic acid.

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

Intermediate 35

4-( Cyclopropylethynyl )-2-( Methylsulfonyl Production of benzoic acid

4-bromo-2-methanesulfonyl acid methyl ester (250 mg, 0.85 mmol) was dissolved in triethylamine (5 mL). Copper iodide (9.0 mg, 5 mol%) was added to the mixture, followed by PdCl ₂ (PPh ₃ ) ₂ (32 mg, 5 mol%) and ethynylcyclopentane (0.135 ml, 1.O mmol). . The mixture was heated at 80 ° C. for 3 hours in a sealing pressure tube. After the reaction was complete, triethylamine was removed in vacuo and the residue was dissolved in EtOAc and filtered through Celite®. The organic layer was washed with water, brine and dried (Na ₂ SO ₄ ). After filtration and concentration in vacuo, the residue was purified by column chromatography on silica gel using EtOAc-hexane (gradient from 0 to 100%) eluent to methyl 4- (cyclopropylethynyl) -2- (methylsulphur). Ponyl) benzoate (240 mg) was obtained. The product was dissolved in 10 mL of MeOH and 10 mL of 2N LiOH and the mixture was refluxed overnight. MeOH was evaporated and the basic layer was washed with EtOAc, acidified and reextracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the product as a beige solid (165 mg). m / z = 293 (M + 1).

Intermediate 36

4- (3,3- Dimethyl Boot -One- Inil ) -2,6- Difluorobenzoic acid  quite

methyl  4- Bromo -2,6- Difluorobenzoate .

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

methyl  2,6- Difluoro -4- (3,3- Dimethyl Boot -One- Inil ) Benzoate .

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

4- (3,3- Dimethyl Boot -One- Inil ) -2,6- Difluorobenzoic acid .

Methyl 2,6-difluoro-4- (3,3-dimethylbut-1-ynyl) benzoate (1.0 g, 0.004 mol) and lithium hydroxide (0.57 g, 0.012 mol) in a 3: 1 mixture of methanol: water (60 mL) and heated at 60 ° C. for 3.5 h. The reaction was cooled down and concentrated in vacuo to a volume of 20 mL. The mixture was placed in an ice water bath and acidified to pH 5 with concentrated HCl. Filter and wash thoroughly with water to give a white solid. The solid was dried in a vacuum oven to give the product as a solid (0.79 g, 84%). m / z = 237.1 (M−1).

Intermediate 37

4- (3,3-dimethyl-1- Inil )-2- Fluoro -3- Methoxybenzoic acid  quite

methyl  2- Fluoro -3- Methoxy -4- (3,3- Dimethyl Boot -One- Inil ) Benzoate .

Methyl 4-bromo-2-fluoro-3-methoxybenzoate (960 mg, 3.5 mmol), copper iodide (I) (70 mg, 0.4 mmol) and bis (triphenylphosphine) palladium (II) chloride (300 mg, 0.4 mmol) was suspended in Et ₃ N (10 mL) and DMF (4 mL). 3,3-dimethyl-1-butyne (440 mg, 5.2 mmol) was added and the mixture was heated in a sealing tube at room temperature to 100 ° C. for 60 hours. The solvent was removed and the residue was dissolved in EtOAc, washed with water, brine and dried over Na ₂ SO ₄ . Purification by column chromatography on silica gel gave the product as a pale yellow oil (760 mg, 79%).

2- Fluoro -3- Methoxy -4- (3,3- Dimethyl Boot -One- Inil Benzoic acid.

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

Intermediate 38

2- Chloro -4- (3,3- Dimethyl Boot -One- Inil ) -5- Fluorobenzoic acid  quite

methyl  2- Chloro -5- Fluoro -4- (3,3- Dimethyl Boot -One- Inil ) Benzoate .

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

2- Chloro -5- Fluoro -4- (3,3- Dimethyl Boot -One- Inil Benzoic acid.

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

Intermediate 39

(E) -4- (3,3- Dimethyl Boot -One- Enil )-2- Methylbenzoic acid  quite

4- Bromo -2- methyl -Benzoic acid methyl  ester.

Thionyl chloride (28 g, 0.23 mol) is added to a suspension of 4-bromo-2-methylbenzoic acid (10.0 g, 0.0465 mol) in 1,2-dichloroethane (60 mL) and the mixture is added for 1 hour. Heated to reflux. The mixture was concentrated to dryness and vacuum dried. The crude acid chloride was dissolved in methanol (100 mL) and the solution was treated with triethylamine (4.7 g, 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- Dimethyl Boot -One- Enil )-2- Methylbenzoic acid methyl  ester.

Methyl 4-bromo-2-methylbenzoate (10.0 g, 0.0436 mol), tri-o-tolylphosphine (1.31 g, 0.00429 mol), cesium carbonate (6.99 g, 0.0214 mol), tetra-N-butylchloride A mixture of ammonium (1.79 g, 0.00644 mol), 3,3-dimethyl-1-butene (20 g, 0.2 mol), palladium acetate (0.24 g, 0.0011 mol) was sealed in a glass vessel and 96 hours at 150 ° C. Stirred. After cooling, the reaction mixture was filtered through Celite (R) and the filtrate was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was chromatographed with hexane-EtOAc to afford the title compound as a white solid.

(E) -4- (3,3-dimethyl- Boot -One- Enil )-2- Methylbenzoic acid .

(E) -4- (3,3-dimethylbut-1-enyl) -2-methylbenzoic acid methyl ester (6.5 g, 0.028 mol) in a mixture of methanol (50 mL, 1 mol) and water (150 mL) and A solution of lithium hydroxide (3.4 g, 0.14 mol) was heated to reflux for 3 hours. Most of the methanol was removed 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

3- methyl -4- (3,3,3- Trifluoroprop -One- Inil Production of benzoic acid

This method was based on the procedure detailed in Yondada et al in Bulletin Chemical Society Japan 1990, 63, 2124-2126. A solution of n-butyl lithium (2.5 M in hexane; 1 equiv) was carefully added to a solution of 3,3,3-trifluoroprop-1-yne (1 equiv) in THF at −78 ° C. under nitrogen. The mixture was stirred at −78 ° C. for 30 minutes, then a solution of ZnCl ₂ (3 equiv) in THF was added slowly. The mixture was allowed to warm to room temperature and stirred for 30 minutes before Pd (Ph ₃ P) ₄ (5 mol%) was added followed by 4-iodo-3-methylbenzoic acid (0.5 equiv). The mixture was heated to 50 ° C., stirred for 15 hours, then further heated at 80 ° C. for 5 hours, and finally at 100 ° C. overnight. After allowing to cool to room temperature, the mixture was concentrated in vacuo to a crude residue. The residue was purified by column chromatography on silica gel to give the product as a solid. m / z = 227 (M−1).

Preparation of Amine Structural Unit

Intermediate 41

2-(( Cyclopropylmethoxy ) methyl ) -2,3- Dihydrobenzo [b] [1,4] dioxin -6- Amine  quite

2-(( Cyclopropylmethoxy ) methyl ) -2,3- Dehydro -6- Nitrobenzo [b] [1,4] dioxin .

(2,3-dihydro-6-nitrobenzo [b] [1,4] dioxin-2-yl) methanol (500 mg, 0.002 mol) and sodium hydride (0.28 g, 0.0070 mol) in a flask under nitrogen Put in. The flask was placed in an ice bath and 25 mL of DMF was added. The reaction was stirred at 0 ° C. for 10 minutes before (chloromethyl) cyclopropane (440 μl, 0.0048 mol) was added. After the mixture was allowed to warm to room temperature over 20 minutes, tetra-N-butylammonium bromide (1.53 g, 0.00475 mol) was added to the mixture and the reaction stirred at room temperature overnight. The reaction was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated in vacuo to an oil. The oil was purified by column chromatography on silica gel using EtOAc / hexane (10%) eluent to afford a yellow solid (0.33 g, 50%). m / z = 266 (M + 1).

2-(( Cyclopropylmethoxy ) methyl ) -2,3- Dihydrobenzo [b] [1,4] dioxin -6-amine.

2-((cyclopropylmethoxy) methyl) -2,3-dihydro-6-nitrobenzo [b] [1,4] dioxine (0.33 g, 0.0012 mol) was dissolved in 20 mL of dioxane. Sodium dithionite (2.2 g, 0.013 mol) was suspended in water (4 mL) and NH ₄ OH (2 mL) and then added to the dioxane solution. The reaction was stirred at rt for 6 h. 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 and used without further purification in the next reaction. 0.29 g (98%) of the title compound were obtained. m / z = 235.8 (M + 1).

Intermediate 42

One- methyl -1,2,3,4- Tetrahydroquinoline -7- Monoamine  quite

7-nitro-1,2,3,4- Tetrahydroquinoline .

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

One- methyl -7-nitro-1,2,3,4- Tetrahydroquinoline .

Potassium carbonate (15 g) is added to a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (4.5 g, 25.25 mmol) in DMF (50 mL), followed by iodomethane (5.54 g, 39.0 mmol) was added and the mixture was shaken at room temperature overnight. The mixture was poured onto water and extracted with ether (3 x 200 mL). The combined etheric extracts were washed with brine, dried and concentrated to give the crude product, which was purified by column chromatography on silica-gel to give the title compound as an orange liquid.

One- methyl -1,2,3,4- Tetrahydroquinoline -7- Monoamine .

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

Intermediate 43

3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -6- Amine  quite

6-nitro-2H- Benzo [b] [1,4] oxazines -3 (4H) -on.

Bromoacetyl bromide (4.84 g, 24 mmol, in 10 mL of CHCl ₃ ) was added with ice bath cooling to 2-amino-4-nitrophenyl (3.08 g, 20 mmol) in 30 mL CHCl ₃ , benzyltriethylammonium chloride ( TEBA, 4.56 g, 20 mmol) and NaHCO ₃ (6.72 g, 80 mmol) were added dropwise. The mixture was stirred for 1.5 h with ice bath cooling, then at 60 ° C. overnight. Solvent was removed in vacuo and water was added to the residue. A solid precipitated out, which was filtered and dried under vacuum to give the product as a beige solid (3.45 g, 89%).

6-amino-2H- Benzo [b] [1,4] oxazines -3 (4H) -on.

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

3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -6-amine.

6-amino-2H-benzo [b] [1,4] oxazin-3 (4H) -one (590 mg, 3.6 mmol) was added to a THF solution of borane tetrahydrofuran complex (9 mL, 1 M solution) And the reaction mixture was refluxed for 2.5 h. EtOH (2 mL) was added and stirred at 70 ° C. for 1 h, followed by 1 mL of concentrated HCl. After the mixture was stirred at 80 ° C. overnight, the volatiles were removed in vacuo to afford a crude residue. The residue was dissolved in water, NaOH was added until the pH was about 10 and the mixture was extracted with CH ₂ Cl ₂ . The organic phase was washed with water and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel to give the product as a colorless oil (274 mg, 51%).

Intermediate 44

3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -7-amine

This material is identical to that for 3,4-dihydro-2H-benzo [b] [1,4] oxazin-6-amine, except that 2-amino-5-nitrophenol was used as starting material. Prepared using the procedure.

Intermediate 45

4- methyl -3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -7- Amine  quite

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

Intermediate 46

6-amino-2,2-dimethyl-2H- Benzo [b] [1,4] oxazines -3 (4H) -one and 2,2-dimethyl-3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -6- Amine  quite

2,2-dimethyl-6-nitro-2H- Benzo [b] [1,4] oxazines -3 (4H) -on.

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

The rest of the synthesis (borane reduction of lactam after hydrogenation of nitro groups) was carried out using the general procedure described for 3,4-dihydro-2H-benzo [b] [1,4] oxazin-6-amine.

Intermediate 47

7-amino-2,2-dimethyl-2H- Benzo [b] [1,4] oxazines -3 (4H) -one and 2,2-dimethyl-3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -7- Amine  quite

The material is 6-amino-2,2-dimethyl-2H-benzo [b] [1,4] oxazine-3 (4H), except that 2-amino-5-nitrophenol was used as starting material. Prepared using the same procedure for -one and 2,2-dimethyl-3,4-dihydro-2H-benzo [b] [1,4] oxazine-6-amine.

Intermediate 48

6- Chloro -3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -7- Amine  quite

6- Chloro -7-nitro-2H- Benzo [b] [1,4] oxazines -3 (4H) -on

The compound is the 2,2-dimethyl-6-nitro-2H-benzo [b] [1,4] oxazine, except that 2-amino-4-chloro-5-nitrophenol was used as starting material. Prepared using the general procedure described for -3 (4H) -one.

7-amino-6- Chloro -2H- Benzo [b] [1,4] oxazines -3 (4H) -on.

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

6- Chloro -3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -7-amine.

Borane reduction is 3,4-dihydro-2H, except that 7-amino-6-chloro-2H-benzo [b] [1,4] oxazin-3 (4H) -one is used as starting material. -Benzo [b] [1,4] oxazine-6-amine was carried out using the general procedure described above.

Intermediate 49

(6-amino-3H- Imidazo [4,5-b] pyridine 2-yl) -Methanol Preparation

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

Solid 2,3-diamino-5-nitropyridine (prepared according to J. Med. Chem. 1997, 40, 3679-3686); 610 mg, 0.0040 mol) and solid glycolic acid (750 mg, 0.0099 mol ) Were combined in a sealing tube (opened), heated to 145 ° C. and stirred for approximately 30 to 45 minutes (solids fuse together and re-stock after liquefaction). After allowing to cool to room temperature, the solid was extracted with 1 N HCl. The aqueous mixture was concentrated in vacuo to afford a crude solid which was basified with concentrated NH ₄ OH solution. The ammonia solution was concentrated in vacuo to give a crude solid which was dry-loaded onto silica and purified by column chromatography (using the ISCO system) to give a solid (450 mg) which was used directly in the next step.

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

Tin chloride dihydrate (1.6 g, 0.0070 mol) was added (6-nitro-3H-imidazo [4,5-b] pyridin-2-yl) -methanol (450 in 10% aqueous hydrochloric acid (20 mL) at 50 ° C. mg, 0.0023 mol) was added in portions to the stirred solution. The mixture was stirred at 50 ° C. for approximately 2 hours and then allowed to cool to room temperature. After further cooling the mixture to 0 ° C., it was basified to about pH 8 with concentrated NH ₄ OH. The aqueous layer was then filtered through Celite® to remove tin salts, and the filtrate was concentrated in vacuo to yield a crude solid (380 mg; assuming quantitative yield), which was used directly in the next step. (Amide formation).

Intermediate 50

(3- Aminoquinoline Preparation of -7-yl) methanol (J. Am . Chem . Soc . Prepared using the general procedure from 1997, 119, 5591).

3- [3- ( Hydroxymethyl ) Phenylamino ]-2- Nitroacrylaldehyde .

3-aminobenzyl alcohol (4.97 g, 0.0404 mol) was dissolved in 4 mL concentrated HCl. Sodium nitromalonaldehyde monohydrate (prepared from mucobromic acid according to the procedure in Organic Syntheses Vol IV, pp 844, 1963) (4.25 g, 0.0269 mol) is dissolved in 35 mL of water and added to the amine solution (Yellow precipitate formed immediately)-80 mL of additional water was added to aid stirring. After 10 minutes, the precipitate was filtered off, washed with water and air and dried overnight to give the product as a yellow solid (4.3 g).

(3- Nitroquinoline -7-yl) methanol.

3- (3- (hydroxymethyl) phenylamino) -2-nitroacrylaldehyde (4.3 g, 19.4 mmol) was added to 20 mL of HOAc. After dissolving 4.8 g of 3-aminobenzyl alcohol (4.8 g, 38.7 mmol) in 5 mL concentrated HCl, 20 mL HOAc was added to the HCl solution. The mixture was added to a reaction flask containing 3- (3- (hydroxymethyl) phenylamino) -2-nitroacrylaldehyde in HOAc. The mixture was heated to reflux under nitrogen and after 20 minutes, benzene thiol (0.19 mL, 0.19 mmol) was added. The mixture was refluxed for 28 h (m / z = 208.1). After allowing to cool, the acid was removed under vacuum. The residue was dissolved in EtOAc / MeOH and loaded onto a silica gel cartridge. Purification by column chromatography on silica gel using hexanes / EtOAc (0-50%), followed by 10% MeOH / EtOAc eluent gave the product as a brown solid (500 mg, 9%).

(3- Aminoquinoline -7-yl) methanol.

400 mg of (3-nitroquinolin-7-yl) methanol (1.2 g, 0.0059 mol) and Pd / C (10% by weight) were added to 60 mL of dry THF. The mixture was stirred overnight under a hydrogen atmosphere (balloon). The reaction was filtered through Celite® and the filtrate was concentrated to oil. Purification by column chromatography on silica gel using MeOH / CH ₂ Cl ₂ (0-10%) eluent gave 0.9 g of an oily product. m / z = 216.9 (+ acetic acid). The product was suspended in MeOH and K ₂ CO ₃ (200 mg) was added. The mixture was stirred at rt for 4 h. m / z = 175.1. The mixture was filtered and the filtrate was concentrated in vacuo to give the product as a wet solid (172 mg, 19%).

Intermediate 51

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

6-nitro-1H-indazole-3-carbaldehyde (500 mg, 0.003 mol) was dissolved in 50 mL of THF. Lithium tetrahydroaluminate (400 mg, 0.01 mol) was added in three portions and the reaction mixture was stirred at rt overnight. After addition of water (400 μl), 15% NaOH solution (400 μl), then water (1.2 mL), the crystalline brown-yellow precipitate was filtered off. The filtrate was concentrated to an oil and used directly in the next step without further purification. m / z = 164.0.

Intermediate 52

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

2- Dimethylaminomethylene -1,3- Bis (dimethylimmonio) propane  Vis ( Tetrafluoroborate ).

Bromoacetic acid (25 g, 0.18 mol) and phosphoryl chloride (50 mL, 0.54 mol) were added to a three neck flask with reflux condenser. The solution was cooled to 0 ° C. and N, N-dimethylformamide (84 mL, 1.1 mol) was added dropwise over 30 minutes. The resulting solution was heated at 110 ° C. for 3 hours. As the mixture was heated, an exothermic reaction began and CO ₂ began to diverge. Thereafter, the mixture was cooled to 0 ° C. and an aqueous solution of 50% tetrafluoroboric acid (63 g, 0.36 mol) in MeOH (100 mL) was added slowly through the dropping funnel over 1 hour. Isopropanol (100 mL) was added to the dark viscous solution. A solid precipitated out and the slurry was stirred at 0 ° C. for 2 hours. The solid was collected by filtration to give the product as a pale yellow solid (64 g, 72%).

Benzyl 3- Aminophenylcarbamate .

Benzyl chloroformate (6.6 mL, 0.046 mol) was added m-phenylenediamine (5.0 g, 0.046 mol) and N, N-diisopropylethylamine (8.0 mL, in CH ₂ Cl ₂ (150 mL) at 0 ° C. 0.046 mol) was added slowly to the stirred solution. The mixture was stirred at 0 ° C. for 2 hours and then warmed to room temperature for 2 hours. NaHCO ₃ aqueous solution was added and the organic phase was separated, washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography on silica gel to give the desired product (8.O g, 71%) as a syrup. LC-MS: 2.11 min, 243.0 (M + 1).

Benzyl 3- Formylquinoline -7- Ilcarbamate .

Benzyl 3-aminophenylcarbamate (8.0 g, 0.033 mol) and 2-dimethylaminomethylene-1,3-bis (dimethylimmonio) propane bis (tetrafluoroborate) in ethanol (400 mL) (31 g, 0.087 mol) of slurry was heated to reflux for 24 hours. The solution was concentrated in vacuo and the residue was dissolved in THF (200 mL) and 1N HCl (200 mL). The reaction mixture was stirred at rt overnight, then poured into saturated sodium bicarbonate (200 mL) solution and extracted with EtOAc (2 ×). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the desired product (10.0 g, 99%) as a yellow solid. LC-MS: 2.84 min, 307.1 (M + 1).

Benzyl 3- ( Hydroxymethyl Quinoline-7- Ilcarbamate .

Sodium tetrahydroborate (0.25 g, 0.0065 mol) was converted to benzyl 3-formylquinoline-7-ylcarbamate (2.O g, 0.0065 mol), THF (50 mL), MeOH (50 mL) and water (50 mL) was added to the stirred mixture. The mixture was stirred at room temperature until no starting material (SM) appeared in LC-MS. The mixture was acidified with 1 N HCl and concentrated in vacuo, then treated with aqueous NaHCO ₃ solution and EtOAc. The organic layer was separated, washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by column chromatography on silica gel using MeOH-EtOAc (0 to 10%) eluent to afford the product as a pale yellow solid (1.3 g, 64%). LC-MS: 1.83 min, 309.2 (M + l).

(7- Aminoquinoline -3-yl) methanol.

A mixture of benzyl 3- (hydroxymethyl) quinoline-7-ylcarbamate (480 mg, 0.0016 mol), 10% Pd-C (50 mg) and MeOH (50 mL) was added under H ₂ (1 atm). Stir for hours. The catalyst was 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

Quinoline-7- Amine  quite

A mixture of 7-nitroquinoline (0.30 g, 0.0017 mol; Specs, Inc.), 10% Pd-C (50 mg) and MeOH (20 mL) under H ₂ (1 atm) for 2 hours Was stirred. The mixture was filtered and the filtrate was concentrated to give a yellow solid (235 mg, 95%). LC-MS: 0.33 min, 145.1 (M + 1).

Intermediate 54

5-amino-3- Methylisoquinoline  quite

5-amino-3- Methylisoquinoline .

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

Intermediate 55

One- Chloroisoquinoline -5- Amine  quite

One- Chloro -5- Nitroisoquinoline .

Of concentrated H ₂ SO ₄ (35 mL) of 1-chloro-isoquinoline concentrated H ₂ SO a mixture of (6.0 g, 0.037 mol) at 0 to 5 ℃ ₄ (35 mL) of fuming HNO ₃ (10 mL) and potassium nitrate (4.0 g, 0.040 mol) in solution. The mixture was stirred at 0 ° C. for an additional 90 minutes and then poured on ice. The precipitate was collected, washed and dried to give the product as a yellow solid. LC-MS: 3.68 min, 209.2 and 211.1 (M + 1).

One- Chloroisoquinoline -5-amine.

A mixture of 1-chloro-5-nitroisoquinoline (450 mg, 0.0022 mol), tin chloride dihydrate (2.4 g, 0.011 mol) and EtOAc (50 mL) was stirred under reflux for 3 hours under a nitrogen atmosphere. After cooling, the mixture was poured into ice-water and basified to pH 10.0 with aqueous Na ₂ CO ₃ . The organic phase is separated and the aqueous phase is extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the product as a pale yellow solid. LC-MS: 3.17 min, 179.2 and 181.2 (M + 1).

Intermediate 56

7-amino-3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -3-yl) methanol and 8-amino-2,3,4,5-te Trahydrobenzo [b] [1,4] Preparation of Oxazepine-3-ol

3,4- Dehydro -7-nitro-2H- Benzo [b] [1,4] oxazines -3-yl) methanol and 8-amino-2,3,4,5-te Trahydrobenzo [b] [1,4] Oxazin-3-ol.

2-amino-5-nitrophenol (10.0 g, 0.0649 mol), potassium carbonate (13.4 g, 0.0973 mol), cesium fluoride (2.0 g, 0.013 mol) and 1-bromo-2 in DMF (120 mL), A mixture of 3-epoxypropane (5.37 mL, 0.0649 mol) was stirred overnight at room temperature under N ₂ , then heated at 100 ° C. for 10 hours. After cooling, the solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column using CH ₂ Cl ₂ -EtOAc (containing 5% Et ₃ N) (0-40%) to give an orange solid. LC-MS: 2.30 min, 211.1 (M + 1).

7-amino-3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -3-yl) methanol and 8-amino-2,3,4,5-te Trahydrobenzo [b] [1,4] Oxazin-3-ol.

(3,4-Dihydro-7-nitro-2H-benzo [b] [1,4] oxazin-3-yl) methanol (3.8 g, 0.018 mol) was added to 10% Pd / C at 40 PSi for 2 hours. Hydrogenated. The mixture was filtered through Celite (R) and the filtrate was concentrated in vacuo to afford the crude product. Purification by column chromatography on silica-gel (EtOAc) gave the product as a dark brown oil. LC-MS: 0.36 min, 181.1 (M + 1).

8-amino-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepin-3-ol was also isolated from the procedure as a minor byproduct.

Intermediate 57

(S)-(3,4- Dehydro -7-nitro-2H- Benzo [b] [1,4] oxazines Preparation of -3-yl) methanol

(S)-(3,4- Dehydro -7-nitro-2H- Benzo [b] [1,4] oxazines -3-yl) methanol

Sodium hydride (0.810 g, 0.0202 mol) was added slowly to a mixture of 2-amino-5-nitrophenol (3.0 g, 0.019 mol) in DMF (50 ml) at 0 ° C. The mixture was stirred at rt for 1 h before (r)-(oxirane-2-yl) methyl 3-nitrobenzenesulfonate (5.0 g, 0.019 mol) was added. After the mixture was stirred at rt overnight, the DMF was removed in vacuo. The residue was partitioned between water and EtOAc. The organic layer was washed with Na ₂ CO ₃ aqueous solution, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a brown solid (5.2 g). The mixture of the brown solid, K ₂ CO ₃ (2.0 g) and DMF (200 ml) was stirred overnight at 120 ° C. under N ₂ . After cooling, the solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ -EtOAc (containing 5% Et ₃ N-0 to 60%) to give the product as a light brown solid. LC-MS: 2.30 min, 211.1 (m + 1).

(S)-(7-amino-3,4- Dehydro -2H- Benzo [b] [1,4] oxazines -3-yl) methanol

(S)-(3,4-dihydro-7-nitro-2H-benzo [b] [1,4] oxazin-3-yl) methanol (340 mg, 0.0016 mol), 10% Pd / C (50 mg) and MeOH (50 ml) were stirred under hydrogen atmosphere (1 atm) for 3 hours. LC-MS indicated completion of reaction. The mixture was filtered and the filtrate was concentrated in vacuo to give the product as a brown syrup. LC-MS: 0.36 min, 181.1 (m + 1).

(R)-(7-amino-3,4-dihydro-2H-benzo [b] [1,4] oxazin-3-yl) methanol is (S)-(oxirane-2-yl) methyl 3 (S)-(3,4-dihydro-7-nitro-2H-benzo [b] [1,4] oxazin-3-yl), except that nitrobenzenesulfonate was used as starting material Prepared using the same procedure as for methanol.

Intermediate 58

(7-amino-2,3- Dehydro - Benzo [1,4] dioxin Preparation of 2-yl) -methanol (see Intermediate 19)

(7-nitro-2,3- Dehydro - Benzo [1,4] dioxin -2-yl) -methanol.

3.0 g of sodium bicarbonate was suspended in 90 mL of DMF. At 0 ° C., a solution of 4-nitrocatechol (5.15 g) was added dropwise over 15 minutes. Subsequently, 3.9 g of epichlorohydrin in 10 mL of DMF was added over 15 minutes. After continuing stirring at room temperature, the mixture was stirred overnight at 80 ° C. The mixture was diluted with water, extracted three times with ethyl acetate, dried (anhydrous Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel using EtOAc-hexanes (gradient from 0 to 100%) to give the product as a yellow solid (2.8 g).

(7-amino-2,3- Dehydro - Benzo [1,4] dioxin -2-yl) -methanol.

(7-nitro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methanol (1.0 g, 4.7 mmol) was dissolved in methanol (30 ml) and palladium on activated carbon Added (0.10 g, 5% by weight). The mixture was shaken for 24 hours under H ₂ (gas) atmosphere (60 psi) on a wave shaker. The mixture was filtered through Celite® and evaporated to afford the material (722 mg, 86%) as a white solid which was used as such in the next step. m / z = 182 (m + 1). LC: 0.82 min.

Intermediate 59

(6-amino-2,3- Dehydro - Benzo [1,4] dioxin 2-yl) -Methanol Preparation

(6-nitro-2,3- Dehydro - Benzo [1,4] dioxin -2-yl) -methanol.

1.93 g of 60% sodium hydride was suspended in 90 mL of DMF. At 0 ° C., a solution of 4-nitrocatechol (5.15 g) was added dropwise over 15 minutes. Subsequently, 3.9 g of epichlorohydrin in 10 mL of DMF was added over 15 minutes. After continuing stirring at room temperature, the mixture was stirred overnight at 80 ° C. The mixture was diluted with water, extracted three times with ethyl acetate, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel using EtOAc-hexanes (gradient from 0 to 100%) to give the product as a yellow solid (2.3 g).

(6-amino-2,3- Dehydro - Benzo [1,4] dioxin -2-yl) -methanol.

(6-nitro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methanol (1.0 g, 4.7 mmol) was dissolved in methanol (30 mL) and palladium on activated carbon Added (0.10 g, 5% by weight). The mixture was shaken on a wave shaker for 24 hours under H ₂ (gas) atmosphere (60 PSI). The mixture was filtered through Celite® and evaporated to afford the material (646 mg, 77%) as a white solid which was used as such in the next step. m / z = 182 (M + 1). LC: 0.82 min.

Intermediate 60

(7-amino-3,4- Dehydro -2H- Pyrido [3,2-b] [1,4] oxazines Preparation of -3-yl) methanol

2-amino-3- Methoxy -5- Nitropyridine .

2-Chloro-3-methoxy-5-nitropyridine (0.50 g, 0.00265 mol), concentrated ammonium hydroxide (5 mL, 0.1 mol) and ethanol (20 mL) were combined in a sealing tube (250 mL). The mixture was heated to 80 ° C. and stirred overnight. After allowing to cool to room temperature, the mixture was reduced in volume in vacuo and the residue dissolved in ethyl acetate (50 mL) and then washed with an equal amount of brine and water (1 × 50 mL each). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a solid (0.312 g, 69%) which was used directly in the next step without further purification. LC-MS 1.94 min. m / z = 171.0 (M + l).

2-amino-3-hydroxy-5- Nitropyridine .

2-amino-3-methoxy-5-nitropyridine (0.300 g, 0.00177 mol) and solid pyridine hydrochloride (8.8 g, 0.076 mol) were combined in a round bottom flask (500 mL). The solid mixture was heated at 150 ° C. (as solids fuse, gas evolution is also pronounced). As the reaction was deemed complete by LC-MS, the mixture was left at 150 ° C. for 3 hours. After allowing to cool to 80 ° C., the mixture was poured onto ice and the aqueous layer was extracted with ethyl acetate (3 × 100 ml). The combined organic extracts were washed with water (2 × 100 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford a crude residue. The residue was purified by column chromatography on silica gel using methanol: methylene chloride (gradient from 0 to 10%) eluent to afford the product as a solid (0.138 g, 49%), which was used directly in the next step. LC-MS 1.28 min. m / z = 155.9 (M + 1).

(7-nitro-3,4- Dehydro -2H- Pyrido [3,2-b] [1,4] oxazines -3-yl) methanol.

Tube for sealing 2-amino-3-hydroxy-5-nitropyridine (0.138 g, 0.000890 mol), N, N-dimethylformamide (4.1 mL) and potassium carbonate (0.39 g, 0.0028 mol) (75 mL) Combined. After allowing the mixture to stir at room temperature for 10 minutes, 1-bromo-2,3-epoxypropane (0.12 g, 0.00089 mol) was added in one portion. After the flask was sealed, it was heated to 110 ° C. and stirred overnight. After allowing to cool, the mixture was concentrated in vacuo to afford a crude solid which was dissolved in EtOAc (75 mL), washed with water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. To give a crude residue. The residue was purified by column chromatography on silica gel using MeOH / CH ₂ Cl ₂ (gradient from 0 to 10%) eluent to afford a solid (0.092 g, 46%). LC-MS 1.92 min. m / z = 212.0 (M + l).

(7-amino-3,4- Dehydro -2H- Pyrido [3,2-b] [1,4] oxazines -3-yl) methanol.

(7-nitro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-3-yl) methanol (0.320 g, 0.00152 mol), 10% palladium on carbon (0.06 g, 0.0005 mol) and methanol (50 mL) were combined into a round bottom flask (500 mL). After the apparatus was evacuated, hydrogen was introduced and the mixture was allowed to stir overnight (at 1 atm). The mixture was then filtered through Celite® and the filtrate was concentrated in vacuo to give an oil (0.252 g, 89%) which was used directly in the next step without further purification. LC-MS 0.29 min. m / z = 181.9 (M + 1).

Intermediate 61

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

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

Intermediate 62

(5-amino-1H- Indazole Preparation of -5-yl) methanol

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

Preparation of Amido Compounds

Amide formation

Method A: Using the Automatic Parallel Synthesis Method Benzamide  Representative Synthesis

Appropriate benzoic acid (2 mmol) was dissolved or suspended in 15 mL of chloroform and treated with 20 mmol thionyl chloride. The reaction mixture was refluxed for 15 minutes and the solvent was removed in vacuo. The residue was dissolved in 4 ml of anhydrous chloroform and 60 μl (30 μmole) of this solution was added to each well of a 96 well glass plate. Thereafter, the appropriate amine was added to the corresponding wells (60 μmole) followed by n, n-diisopropylethylamine (120 μmole). The plate was then heated at 65 ° C. for 15 minutes. Solvent was removed using an ht-12 genevac centrifugal aspirator, 100 μl of DMSO was added to each well and the compound was transferred to a 96-well polypropylene reaction plate. The plate was then sealed using an abgene plate sealer and LC-MS purified.

Method B: Using the Automatic Parallel Synthesis Method Benzamide  Representative Synthesis

Appropriate benzoic acid (6.03 mg, 30 μmol) in pyridine anhydride (15 μl) was added to one well of a 96-well polypropylene reaction plate. TFFH (TFFH is fluoro-N, N, N ', N'-tetramethylformamidinium hexafluorophosphate; 12 mg, 45 μmol) was added to the reaction followed by diisopropylethylamine (6.0 mg, 45 μmol), then the appropriate amine (60 μmol) is added. The reaction plate was heated at 50 ° C. for 15 minutes and the solvent was evaporated. The residue was dissolved in DMSO and purified using LC-MS based purification (50 mm × 10 mm Phenomenex Gemini column with acetonitrile-water gradient from 10 to 100%).

Method C:

Suitable amine (0.5 mmol) and DIPEA (0.2 mL) were converted to acid (0.4 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (0.8 mmol), 1-hydroxybenzotriazole. To a mixture of hydrate (0.24 mmol) and CH ₂ Cl ₂ (5 mL). The mixture was stirred at rt overnight, diluted with EtOAc, washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography on silica gel to give the product.

Method D:

Amines (1.2 mmol) and diisopropylethylamine (0.5 mL) were acid (1.0 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (385 mg, 2.0 mmol), 1 -To a mixture of hydroxybenzotriazole hydrate (0.5-1.0 mmol), DMF (2 mL) and CH ₂ Cl ₂ (5 mL). The mixture was stirred at rt overnight, diluted with EtOAc, washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column to give amide.

Method E:

Oxalyl chloride (1.5 mmol) was added to a stirred solution of acid (1.0 mmol) in anhydrous CH ₂ Cl ₂ (10 mL) and DMF (2 drops) at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour and then warmed at room temperature for 3 hours. The solvent was removed in vacuo. CH ₂ Cl _{2 (2} mL) and a solution of the obtained acid chloride of from 0 ℃ was added to a solution of amine (1.0 mmol) in CH ₂ Cl ₂ (3 mL) and pyridine (2 mL). The reaction mixture was stirred at rt overnight then diluted with EtOAc. The organic phase was washed with aqueous NaHCO ₃ solution and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography to give the amide.

Method F:

Oxalyl chloride (0.40 mmol) was added to a stirred solution of anhydrous THF or CH ₂ Cl ₂ (5 mL), and acid (0.25 mmol) in DMF (1 drop) at 0 ° C. The mixture was stirred at 0 ° C. for 1 h and then warmed to rt. The solvent was removed in vacuo. A solution of the obtained acid chloride in CH ₂ Cl ₂ (2 mL) was added to a solution of CH ₂ Cl ₂ (10 mL), Et ₃ N (0.2 mL), amine (0.25 mmol) in DMAP (5 mg) at 0 ° C. It was. The reaction mixture was stirred at rt overnight, then diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO ₃ solution and brine, dried and concentrated. The residue was purified by chromatography to give the amide.

Method G:

Oxalyl chloride (1.5 equiv) is slowly added dropwise to a cooled (0 ° C.) well stirred suspension of the appropriate acid (1 equiv) in CH ₂ Cl ₂ (about 3 mL per mmol) and DMF (catalyst amount), the mixture Was shaken for 1 hour. The mixture was concentrated in vacuo and the residue was resuspended in CH ₂ Cl ₂ . Thereafter, the appropriate amine (0.5-1.0 equiv) is added and the mixture is stirred for 1-48 hours before workup and purification.

Method H:

N, N-diisopropylethylamine (1 equiv) in 2-methyl-4- (3,3-dimethylbut-1- in N, N-dimethylformamide (about 3 mL per 0.5 mmol of starting acid) at room temperature To a stirred mixture of inyl) benzoic acid (1 equiv) and N, N, N ', N'-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (1.05 equiv) It was added at once. After the mixture was stirred at room temperature for approximately 2 hours, a solution of the appropriate amine (1 equiv) in DMF (1 mL) was added in one portion. The mixture was stirred overnight and then worked up by pouring into H ₂ O (30 mL) and EtOAc (30 mL). The aqueous and organic layers were partitioned and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine (1 × 30 mL), dried (Na ₂ SO ₄ ), filtered and the solvent removed in vacuo to afford a crude residue. Appropriate purification was used to obtain the desired final compound.

Method I:

A mixture of acid (1 mmol), N- (3-dimethylaminopropyl) -N'ethylcarbodiimide hydrochloride (3 mmol), 1-hydroxybenzotriazole hydrate (1.5 mmol) and amine (2 mmol) Stir overnight at room temperature in DMF. The mixture was partitioned between EtOAc and water. The organic layer was separated, washed with saturated aqueous NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by flash column chromatography.

Method J:

DIPEA (0.92 mmol) was added to a solution of the appropriate acid (0.46 mmol), the appropriate amine (0.69 mmol) and TFFH (0.69 mmol) in anhydrous pyridine (3 mL), and the reaction mixture was stirred at 60 ° C. overnight. The volatiles are removed, the residue is suspended in water, extracted with EtOAc, the organic phase is washed with water, brine, dried over Na ₂ SO ₄ , the solvent is removed and the residue is chromatographed to give the product. Got it.

Method K:

DIPEA (0.92 mmol) was added to a solution of the appropriate acid (4.0 mmol), the appropriate amine (3.2 mmol) and TFFH (6.0 mmol) in anhydrous pyridine (10 mL), and the reaction mixture was stirred at 70 ° C. overnight. The volatiles are removed, the residue is dissolved in EtOAc, the organic phase is washed with water, aqueous Na ₂ CO ₃ solution, brine, dried over Na ₂ SO ₄ , the solvent is removed and the residue is chromatographed to give the product. Obtained.

Method L:

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

Method M:

Amines (1 equiv) in CH ₂ Cl ₂ (about 3 mL per 0.125 mmol) acid (1 equiv), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (1 equiv), 4 To a stirred solution of -N, N-dimethylaminopyridine (1 equiv) and Et ₃ N (2 equiv) was added in one portion and the mixture was stirred until the reaction was complete (usually left overnight). The mixture was diluted with additional CH ₂ Cl ₂ (30 mL), washed with H ₂ O (1 × 20 mL), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel or preparative thin layer chromatography.

Compound 54

Oxalyl chloride (0.10 mL, 1.2 mmol) was added 4- (3,3,3-trifluoroprop-1-ynyl) benzoic acid (50 mg, 0.23) in THF (5 mL) and DMF (1 drop) at 0 ° C. mmol) was added to the stirred solution. The mixture was stirred at 0 ° C. for 1 h and then warmed to rt. The solvent was removed in vacuo and the acid chloride in CH ₂ Cl ₂ (2 mL) obtained was washed with CH ₂ Cl ₂ (5 mL), Et ₃ N (0.2 mL), DMAP (5 mg) at 0 ° C. To a solution of benzo [d] thiazol-2-yl) methanol (20 mg, 0.11 mmol). The reaction mixture was stirred at rt overnight, then diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO ₃ solution and brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give ester. The ester was dissolved in MeOH (10 mL) and K ₂ CO ₃ (300 mg) was added. The mixture was stirred at rt for 3 h and then treated with water and EtOAc. The organic layer was separated, washed with brine, dried (Na ₂ SO ₄ ) 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 (20 mg), CH ₃ CN (3 mL) and 5 A mixture of N aqueous HCl (1 mL) was refluxed at 80 ° C. for 10 h. After cooling, the mixture was treated with aqueous Na ₂ CO ₃ and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by PLC to give a pale yellow solid (10 mg).

Compound 112

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

Compound 116

A mixture of 4- (2-cyclopentylethynyl) benzoic acid (23 mg, 0.10 mmol), EDCI (1 equiv) and DIPEA (2 equiv) in 10 mL of CH ₂ Cl ₂ was stirred at room temperature for 20 minutes. (6-amino-2,3-dihydrobenzo [b] [1,4] dioxin-2-yl) methyl methanesulfonate (27 mg, 0.10 mmol) in 5 ml of CH ₂ Cl ₂ was added to the solution It was. Thereafter, the reaction mixture was stirred at room temperature overnight. After usual workup and chromatographic separation, a yellow solid was obtained.

Compound 117

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

Compound 197

2-methyl-N- (2-methylbenzo [d] thiazol-5-yl) -4- (3,3-dimethylbut-1-ynyl) benzamide (50 mg, 0.14 mmol), selenium dioxide (46 mg, 0.41 mmol) and 1,4-dioxane (10 mL) were stirred overnight at 80 ° C. under a nitrogen atmosphere. After cooling, the mixture was filtered through Celite (R) and the filtrate was treated with aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in THF-H ₂ O (2: 1) (10 mL) and NaBH ₄ (50 mg) was added slowly. The mixture was stirred at rt for 2 h and then acidified with 1 N HCl. After treatment with aqueous NaHCO ₃ , the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by preparative thin layer chromatography to give N- (benzo [d] thiazol-5-yl) -2-methyl-4- (3,3-dimethylbut-1-ynyl) benzamide as a pale yellow solid. Compound 198-11 mg) and N- (2- (hydroxymethyl) benzo [d] thiazol-5-yl) -2-methyl-4- (3,3-dimethylbut-1-ynyl) as a pale yellow solid Benzamide (Compound 197-27 mg) was obtained.

Compound 225

(E) -4- (3,3,3-trifluoroprop-1-enyl) -2-methyl-N- (2-methylbenzo [d] thiazol-5-yl) benzamide (200 mg, 0.0005 mol) and selenium dioxide (177 mg, 0.00160 mol) were placed in 20 mL of dioxane and the reaction was heated at 80 ° C. under nitrogen overnight. The reaction was cooled and filtered through Celite®. The filtrate was partitioned between EtOAc and NaHCO ₃ . The organic layer was separated, washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in THF / H ₂ O (2: 1; 20 mL) and NaBH ₄ (200 mg, 5.3 mmol) was added in three batches. The mixture was stirred at rt for 2 h and then quenched by addition of 1 N HCl. The mixture was basified by addition of saturated NaHCO ₃ and extracted with EtOAc. The organic layer was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc / hexane (0 to 100%) eluent followed by column chromatography on silica gel using MeOH / CH ₂ Cl ₂ (0 to 3%) eluent. Purification to afford the product as a solid (40 mg). m / z = 392.6. Further purification by preparative HPLC (water / acetonitrile) gave the product as a white solid (35 mg). m / z = 392.6.

Compound 228

Oxalyl chloride (0.11 mL, 1.3 mmol) was added (E) -4- (3,3,3-trifluoroprop-1-enyl in CH ₂ Cl ₂ (50 mL) and DMF (2 drops) at 0 ° C. To a stirred solution of) -2-methylbenzoic acid (0.20 g, 0.87 mmol). The mixture was stirred at 0 ° C. for 1 h and then warmed to rt for 2 h. The solvent was removed in vacuo. The acid chloride was added to a solution of (7-aminoquinolin-3-yl) methanol (76 mg, 0.43 mmol) in CH ₂ Cl ₂ (5 mL) and pyridine (10 mL). The reaction mixture was stirred at rt overnight, then concentrated in vacuo. The residue was treated with EtOAc and aqueous NaHCO ₃ solution. The organic layer was separated, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc / hexane (0-50%) eluent to afford the ester [95 mg, m / z: 599.2 (M + 1)]. The ester was dissolved in MeOH (5 mL) and K ₂ CO ₃ (200 mg) was added. After the mixture was stirred at room temperature for 3 hours, methanol was removed in vacuo. The residue was treated with water and EtOAc. The organic layer was separated, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by preparative thin layer chromatography using acetone-CH ₂ Cl ₂ (1: 1) to give a white solid (43 mg, 24%). LC-MS: 2.29 min, 387.7 (M + l).

Compound 229

(E) -4- (3,3,3-trifluoroprop-1-enyl) -2-methylbenzoic acid (91.96 mg, 0.4 mmol), N- (3-dimethylaminopropyl in anhydrous DMF (3 mL) ) -N'-ethylcarbodiimide hydrochloride (76.59 mg, 0.4 mmol), HOBt (62.98 mg, 0.46 mmol), 4-N, N-dimethylaminopyridine (2 mg, 0.02 mmol) and DIPEA (139 μl, 0.8 mmol) of the stirred solution was stirred with anhydrous DMF (2 mL) of 7,8-dihydro-5H-pyrano [4,3-b] pyridin-3-ylamine (50 mg, 0.3 mmol). Was added. The reaction was stirred at rt overnight. The reaction mixture was poured into saturated NaHCO ₃ solution (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were washed with brine (3 × 50 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by column chromatography on silica gel (0-5% MeOH in DCM over 60 minutes) afforded the desired product as an off-white solid (39 mg, 30%).

library ( library Auto parallel LC - MS  General method for purification

The library was purified using a Perkin Elmer API100 mass spectrometer connected to a Shimadzu LC pump. Chromatography used a gradient of 10 to 100% of acetonitrile over water over 8 minutes at a flow rate of 6 ml per minute. The column used 10 × 50 mm YMC C18 and the compounds were collected using a Gilson 204 preparative device.

According to the methods described above, and appropriate reagents, starting materials and purification methods known to those skilled in the art, the amide compounds of the present invention can be prepared or prepared.

The synthetic and biological examples presented herein are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any way. In the examples below, unless otherwise indicated, all temperatures are degrees Celsius.

The compounds prepared according to the invention are shown in Table 1 below. Synthesis of these representative compounds was performed according to the methods described above, and the activity of the compounds was determined as percent inhibition in the calcium uptake assay detailed below.

Calcium Absorption Assay.

The functional activity of the compound against the VR1 receptor was determined by measuring changes in intracellular calcium in HEK 293 cells expressing hVR1. The ability of the compounds to inhibit agonist-induced calcium influx was investigated. A dual wavelength measurement dye, Fura2 ratio was used as a measure of the relative level of flex station (Flex Station, R) the 96-well format (Molecular Devices ISIS (Molecular Devices)) in [Ca ^{2 +]} used.

Cell line and culture conditions:

hVR1 was cloned into pcDNA5 / TO vector (Invitrogen) and stably transformed into T-REx HEK 293 cell line (Invitrogen). HEK 293 cells expressing hVR1 were treated with 5% PenStrep, 5% Glutamax, 200 μg / mL Hygromycin, 5 μg / mL Blastisidin, and 10%. In the presence of DMEM medium containing heat inactivated FBS, growth (24 hours incubation) to confluency was performed on PDL-coated plastic 96-well black-walled plates. 24 hours prior to analysis, cells were transferred to DMEM medium containing 1 μg / mL doxycycline. Prior to analysis, 5 μg / mL in saline solution (130 mM NaCl, 3 mM KCl, 1 mM CaCl ₂ , 0.6 mM MgCl ₂ , 10 mM HEPES, 10 mM glucose and 50 mM sucrose pH 7.4) at 37 ° C. for 40 minutes. Fura-2 (Molecular Probes) was loaded into cells. The dye was then aspirated off and replaced with 100 μl of brine and the assay was initiated at the Flex station.

Agonists  Concentration and Dilution of Compounds:

Agonist EC ₅₀ was determined at the start of the assay and Compound IC ₅₀ experiments were performed using an agonist concentration equivalent to its EC ₅₀ as a stimulus. The agonists used were capsaicin (EC ₅₀ = 2.5 nM) and protons (saline solution + 10 mM citric acid (buffered to pH 5.7 with HCl)). Compounds were tested at concentrations ranging from 10 nM to 3.3 μM.

The analysis consists of two steps, pre-process followed by process. 50 μl of compound solution was added to the cells (pre-treatment). In some cases, following pre-treatment, 50 μl of test compound (pH 5.1) in saline solution was added (treatment). The compound was tested as follows. For the pre-treatment phase, 50 μl of 3 × concentration of test compound in saline was added to cells containing 100 μl of saline to achieve final concentration x. For the treatment phase, at defined times after pre-treatment, 50 μl of test compound plus agonist solution was added to the cells at the corresponding concentrations.

Recordings were performed at 4 second intervals at wavelengths of 340 nm and 380 nm, and analyzed fluorescence ratios. The reaction was measured by subtracting the fluorescence ratio reference value before treatment from the fluorescence ratio peak after compound-agonist addition and calculated using SoftMaxPro software (Molecular Devices). % Inhibition was calculated as follows and shown in Table 1.

Acid Stimulation Assay:

Acid-induced changes in intracellular calcium concentrations were monitored using the FDSS 6000 (Hamamatsu Photonics, Japan), a fluorescence imaging system. Cell suspensions in resting buffer (HBSS, pH 7.4, supplemented with 10 mM HEPES) were pre-incubated with various concentrations of test compound, or resting buffer (buffer control), for 15 minutes at room temperature under dark conditions. It was. Stimulation solution (HBSS supplemented with MES, final assay buffer pH 5.8) was automatically added to the cells by FDSS 6000. The IC ₅₀ value of the VR1 antagonist was determined from half of the increase demonstrated by the buffer control sample after acidic stimulation, and the results obtained using the selected compounds of the invention are described in Table 2 below.

Human liver microsomes ( HLM Half-life at)

Tested with exemplary compounds of the invention (1 μM) and incubated on 96-deep well plates with 0.78 mg / mL HLM (HL101) and 3.3 mM MgCl ₂ at 100 ° C. in 100 mM potassium phosphate buffer (pH 7.4). . The reaction mixture was divided into two groups, non-P450 and P450 groups. NADPH was added only to the reaction mixture of the P450 group. Aliquot samples from the P450 group were collected at 0, 10, 30 and 60 minute time points, where the 0 minute time point indicated the time when NADPH was added to the reaction mixture of the P450 group. Aliquot samples from the non-P450 group were collected at the −10 and 65 minute time points. The collected aliquots were extracted with acetonitrile solution containing internal standard. The precipitated protein was spun down in a centrifuge (2000 rpm, 15 minutes). Compound concentration in the supernatant was measured by LC / MS / MS system. Half-life values (T _1/2) is obtained by plotting the natural logarithm of the peak area ratio of compounds / internal standard time. The metabolic rate (k) was calculated from the slope of the best fitted line through the points. This was converted to a half-life value using the following formula, ie half-life = ln 2 / k. To the results of the test and the corresponding T _1/2 values that were described in Table 3.

In rats Intravenous  And pharmacokinetic evaluation of the compound following oral administration.

Male Spray-Dawley rats were acclimated for at least 24 hours prior to the start of the experiment. During the acclimation period, all animals were given free food and water intake. However, food was removed from the animal cages with only water remaining at least 12 hours before the start of the experiment. During the first three hours of the experiment, animals were allowed only free water. At least three animals each were tested for intravenous and oral administration. For intravenous formulations, the compounds of the present invention are dissolved (0.25-1 mg) in a mixture of 3% dimethyl sulfoxide, 40% PEG 400, and 40% Captisol (w / v) in 57% water. / mL). For oral formulations, the compounds of the present invention are dissolved in a mixture of 10% Tween 80 (v / v) in 5% water, and 0.5% methyl cellulose (w / v) in 95% water ( 2 mg / mL). Animals were weighed prior to dosing. The measured body weight was used to calculate the dosage for each animal.

For intravenous administration, the dose (mL / kg) = 1 mg / kg / formulation concentration (mg / mL).

If the formulation concentration is less than 0.5 mg / mL, the dosage is about 2 mL / kg. Oral Dosing Rats were commonly administered via oral gavage at 2.5 mL / kg to achieve a dose level of 5 mg / kg. For intravenous administration, blood samples were collected at 2, 5, 15, 30, 60, 120, 180, 300, 480 and 1440 minutes after administration via a jugular catheter (using a pre-heparinized syringe). For oral administration, blood samples were collected before and after 5, 15, 30, 60, 120, 180, 300, 480 and 1440 minutes after administration via a jugular catheter (using a pre-heparinized syringe). About 250 μl of blood was obtained at each time point from the animals. Replace with equal volume of 0.9% normal saline to prevent dehydration. All blood samples were kept on ice until centrifuged. The blood samples were then centrifuged at 14,000 rpm for 10 minutes at 4 ° C. and the upper plasma layer was transferred to clean vials and stored at −80 ° C. The resulting plasma sample was then analyzed by liquid chromatography-tandem mass spectroscopy. After measuring the plasma sample and the dosing solution, the plasma concentration-time curve was plotted. Plasma exposure was calculated as the area under the concentration-time curve extrapolated to infinite time (AUC _inf ). AUC _inf was averaged and oral bioavailability (% F) for individual animals was calculated as follows.

AUC _inf (intravenous, mean) / AUC _inf (oral) (normalized for their respective dose level).

% F is reported as the average% F of all animals administered orally.

Example  One

Calcium Imaging Assay

VR1 protein is a heat-gated cation channel that exchanges approximately 10 calcium ions for every sodium ion, leading to neuronal membrane depolarization and high intracellular calcium levels. Accordingly, the functional activity of a compound at the VR1 receptor can be determined by measuring changes in intracellular calcium levels in neurons such as spinal cord ganglia.

DRG neurons were PDL coated 96- in the presence of DMEM medium containing 5% penstrep, 5% glutamax, 200 μg / ml hygromycin, 5 μg / ml blastidide and 10% heat inactivated FBS. Cultured on well assay wall plates. Prior to analysis, cells were loaded with 5 μg / ml of Fura2 in saline solution at 37 ° C. for 40 minutes. Thereafter, cells were washed with saline to remove the dye prior to the start of the experiment.

After the plated neurons were transferred to a chamber on the microscope stand of a Nikon eclipse TE300 microscope, the neurons were allowed to achieve stable fluorescence for about 10 minutes before the start of the experiment. The analysis consists of two steps, pre-process followed by process. First, a solution of test compound was added to the cells from a multivalve perfusion system for 1 minute (pre-treatment). Immediately thereafter, (treatment) capsaicin (250 nM) was added in the presence of the test compound for a specific period of 20 to 60 seconds.

Fura2 was excited at 340 and 380 nm to show relative calcium ion concentrations. Wavelength measurements changed throughout the experiment. Fluorescence ratio was calculated by dividing the fluorescence measured at 340 nm by the fluorescence measured at 380 nm. Data was collected using Intelligent Imaging's Slidebook software. All compounds that inhibited capsaicin induced calcium influx by more than 75% were judged positive.

The data obtained are provided in Table 4. 1 shows the results obtained when Compound 225 was administered with capsaicin. Fluorescence reflecting calcium ion influx decreased.

Example  2

Calcium Imaging Assay In vitro  For measuring efficacy VR1  Antagonist High throughput  Method

Inhibition of the capsaicin response in the presence or absence of test compounds was measured and analyzed using the method for calcium uptake analysis (described above in connection with the data presented in Table 1). In addition, the data are shown graphically in FIGS. 2-6, where a significant decrease in capsaicin response was observed in the presence of representative test compounds. In the absence of the test compound no such decrease in reaction was observed.

Example  3

Whole-cell Patch Clamp Electrophysiology

Spinal ganglion (DRG) neurons were isolated from neonatal or adult rats and plated onto poly-D-lysine coated cover glass. The plated neurons were transferred to the chamber to allow drug solution to be added to the cells using a computer-controlled solenoid-valve based sparging system. Cells were imaged using standard DIC optics. Cells were connected using finely separated glass electrodes. Voltage-clamp electrophysiology experiments were performed using Axon Instruments Multiclamp, which is controlled and amplified by pCLAMP8 software.

The cells were placed in a full-cell voltage clamp and the voltage of −80 mV was maintained while monitoring the membrane current in spaced recording mode. 50 nM capsaicin was added for 30 seconds as a control. Thirty seconds before capsaicin application, various concentrations of test compound were added to the cells for 1 minute. The difference between the control and drug positive capsaicin experiments was used to determine the efficacy of each test compound. All compounds that inhibited capsaicin induced currents by more than 50% were judged positive. The data obtained for compound 240 are described in Table 5.

As specifically and individually stated that each individual document or patent application is hereby incorporated by reference, all documents, patents, and patent applications cited herein are hereby incorporated by reference.

Although the present invention has been described in some detail as examples and embodiments for purposes of clarity and understanding, it is to be understood that certain changes and modifications may be made therein without departing from the spirit and scope of the appended claims. In light of this, it will be readily apparent to those skilled in the art. All such modifications falling within the scope of the appended claims are intended to be included herein.

Claims (64)

Compounds of formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, and stereoisomers and tautomers thereof. <Formula I>

In the formula, W, Z, Y and X are each independently N or CR ⁴ ; L is-(CR ⁵ = CR ⁶ )-or-(C≡C)-; R ¹ is hydrogen, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkoxy, amino C ₁ -C ₆ alkoxy, substituted amino C _1- C ₆ alkoxy, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, cycloalkyl C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylarylamino, aryl C _1- C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfuric ester, azido, carboxy, carbamoyl, cyano, Bicycloaryl or bicycloheteroaryl substituted with cycloheteroalkyl, di C ₁ -C ₆ alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio; R ³ is CR ^{6 ′} R ⁷ R ⁸ ; Each R ⁴ is independently hydrogen, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkoxy, amino C ₁ -C ₆ alkoxy, substituted amino C ₁ -C ₆ alkoxy, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, cycloalkyl C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylarylamino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfuric ester, azido, carboxy, carbamoyl, Cyano, cycloheteroalkyl, di C ₁ -C ₆ alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio; R ⁵ and R ⁶ are each independently H, halo or C ₁ -C ₆ alkyl; R ^{6 '} is hydrogen, halo or C ₁ -C ₆ alkyl; R ⁷ and R ⁸ are each independently halo or C ₁ -C ₆ alkyl; Or R ⁷ and R ⁸ together form a C ₃ -C ₈ cycloalkyl ring; Here, the compound is not selected from the group consisting of compounds 1 to 39. The compound of claim 1, wherein R ⁵ and R ⁶ are each independently H, halo or C ₁ -C ₆ alkyl. The compound of claim 1, wherein R ¹ is

Wherein A ¹ , A ² , A ³ , A ⁴ , B ¹ and B ² are each independently CR ^{4 ′} and N; R ^{4 ′} is each independently H, C ₁ -C ₆ alkyl, halo Or hydroxy C ₁ -C ₆ alkyl. The compound of claim 1, wherein R ¹ is

Wherein A ⁵ and A ⁸ are each independently CR ^{4 ′} R ^{4 ′} , NR ^{4 ′} , O, S, SO or SO ₂ ; A ⁶ and A ⁷ are each independently CR ^{4 ′} , NR ^{4 '} , CR ^4' R ^{4 '} or CO; B ³ and B ⁴ are each independently CR ^4' and N; when R ^{4 '} is attached to C, R ^4' is each independently H, C _1- When C ₆ alkyl, halo or hydroxy C ₁ -C ₆ alkyl, and R ^{4 ′} is attached to N, R ^{4 ′} is each independently H or C ₁ -C ₆ alkyl; the dotted bond is single or Represents a double bond). The compound of claim 1, wherein R ¹ is

Wherein A ⁹ , A ¹⁰ and A ¹¹ are each independently CR ^{4 ′} , CR ^{4 ′} R ^{4 ′} , CO, CS, N, NR ^{4 ′} , O, S, SO or SO ₂ ; B ⁵ And B ⁶ are each independently CR ^{4 ′} and N; and when R ^{4 ′} is attached to C, R ^{4 ′} is each independently H, C ₁ -C ₆ alkyl, halo or hydroxy C ₁ -C ₆ alkyl And when R ^{4 ′} is attached to N, R ^{4 ′} is each independently H or C ₁ -C ₆ alkyl; the dotted bonds each independently represent a single or double bond). The compound of claim 1, wherein R ¹ is

(In the formula, ring R ^{4 'and} may further be substituted by (R ^4' is same as the case described in claim 4), possible, that the ring is N may further be substituted by H, or C ₁ -C ₆ alkyl ) Compound. The compound of claim 1, wherein R ¹ is

(In the formula, ring R ^{4 'and} may further be substituted by (R ^4' is same as the case described in claim 4), possible, that the ring is N may further be substituted by H, or C ₁ -C ₆ alkyl ) Compound. The compound of claim 1, wherein R ¹ is

Wherein A ¹ , A ² , A ³ , A ⁴ , B ¹ and B ² are each independently CH and N; R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl Im). The compound of claim 1, wherein R ¹ is

Wherein A ⁵ and A ⁸ are each independently CH ₂ , CHMe, NH, NMe, O, S, SO or SO ₂ ; R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl). The compound of claim 1, wherein R ¹ is

Wherein A ⁹ , A ¹⁰ and A ¹¹ are each independently CH, CH ₂ , N, NH, O or S; B ⁵ and B ⁶ are each independently CH and N; and R ^{4 ′} is each Independently H, C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl; the dashed bonds each independently represent a single or double bond). The compound of claim 1, wherein R ¹ is

(Wherein R ^{4 ′} is as described in claim 4). The compound of any one of claims 9-11, wherein R ^{4 ′} is hydroxy C ₁ -C ₆ alkyl. The compound of claim 12, wherein R ^{4 ′} is — (CH ₂ ) _n —OH, wherein n is selected from 1-3. The compound of claim 13, wherein R ^{4 ′} is CH ₂ OH. The compound of claim 1, wherein R ¹ is

Wherein, where possible, ring N may be further substituted with H or C ₁ -C ₆ alkyl. The compound of claim 1, wherein W, X, Y and Z are each CR ⁴ . The compound of claim 1, wherein one of W, X, Y and Z is N, and the other is CR ⁴ independently. The compound of claim 1, wherein W is N and X, Y and Z are each CR ⁴ . The compound of claim 1, wherein W and X are each CR ⁴ , and Y and Z are each CR ^{4 "} , wherein R ^{4 "} is hydrogen, C ₁ -C ₆ alkyl, trihalo C ₁ -C ₆ alkyl, sulfone And independently selected from halo). The compound of claim 19, wherein each R ^{4 ″} is independently H, CH ₃ , CF ₃ , Cl, F or SO ₂ Me. The compound of claim 1, wherein W, X and Z are each CH and Y is C-CH ₃ , C-Cl or CF. The compound of claim 19, wherein R ⁴ is H. 20. The compound of claim 1, wherein L is-(CR ⁵ = CR ⁶ )-, wherein R ⁵ and R ⁶ are each independently H, halo or C ₁ -C ₆ alkyl. The compound of claim 1, wherein L is —CH═CH—. The compound of claim 1, wherein L is -C≡C-. The compound of claim 1, wherein R ³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. The compound of claim 1, wherein R ³ is cyclopropyl or CF ₃ . The compound of claim 1, wherein R ³ is t-Bu. The method of claim 1, 4-[(E) -3,3-dimethylbut-1-enyl] -N- (5-isoquinolyl) benzamide; 4-[(E) -3,3-dimethylbut-1-enyl] -N- (3-quinolyl) benzamide; 4-[(E) -3,3-dimethylbut-1-enyl] -N- (1-methylindol-5-yl) benzamide; N- (2,5-dioxabicyclo [4.4.0] deca-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-isoquinolyl) -4- (3,3,3-trifluoroprop-1-ynyl) benzamide; N- (3-quinolyl) -4- (3,3,3-trifluoroprop-1-ynyl) benzamide; 4- (2-cyclopropylethynyl) -N- (3-quinolyl) benzamide; 4- (2-cyclopropylethynyl) -N- (5-isoquinolyl) benzamide; 4- (2-cyclopropylethynyl) -N- (2,5-dioxabicyclo [4.4.0] deca-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] deca-2,4,11-trien-3-yl) -4-[(E) -3,3,3-tree Fluoroprop-1-enyl] benzamide; N- (8,8-dimethyl-9-oxo-7-oxa-10-azabicyclo [4.4.0] deca-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-isoquinolyl) -3- (2-morpholinoethoxy) benzamide; N- (4-oxo-2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -4-[(E) -3,3,3-tree Fluoroprop-1-enyl] benzamide; N- (5-oxa-2-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -4-[(E) -3,3,3-trifluoroprop- 1-enyl] benzamide; N- (2-oxa-5-azabicyclo [4.4.0] deca-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] deca-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-isoquinolyl) benzamide; 2-chloro-6- (3,3-dimethylbut-1-ynyl) -N- (5-isoquinolyl) 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] deca-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] deca-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] deca-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] deca-7,9,11-trien-8-yl) -4-[(E) -3,3,3-tri Fluoroprop-1-enyl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -N- (1-methyl-3,4-dihydro-2H-quinolin-7-yl) benzamide; N- (5-isoquinolyl) -3-methyl-4- (3,3,3-trifluoroprop-1-ynyl) benzamide; N- (5-isoquinolyl) -4-[(E) -3,3,3-trifluoro-1-methyl-prop-1-enyl] benzamide; N- (5-isoquinolyl) -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] deca-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] deca-7,9,11-triene- 9-yl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -N- [3- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9,11-triene- 9-yl] benzamide; 4-[(E) -3,3,3-trifluoroprop-1-enyl] -N- (8,8,10-trimethyl-7-oxa-10-azabicyclo [4.4.0] deca-2 , 4,11-trien-3-yl) benzamide; N- (10-methyl-9-oxo-7-oxa-10-azabicyclo [4.4.0] deca-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] deca-7,9,11-trien-9-yl] Benzamide; 4- (2-cyclopropylethynyl) -N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl] Benzamide; N- (10-methyl-7-oxa-10-azabicyclo [4.4.0] deca-2,4,11-trien-3-yl) -4-[(E) -3,3,3-tri Fluoroprop-1-enyl] benzamide; N- (5-isoquinolyl) -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-isoquinolyl) pyridine-2-carboxamide; N- (1,1-dioxobenzothiophen-6-yl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- (2-oxa-5-azabicyclo [4.4.0] deca-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] deca-7,9,11-trien-9-yl ) Benzamide; 2- (3,3-dimethylbut-1-ynyl) -N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) pyrimidine-5 Carboxamide; N- (2-oxa-5-azabicyclo [4.4.0] deca-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] deca-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] deca-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] deca-7,9,11-trien-9-yl) benzamide; 4- (2-cyclopentylethynyl) -N- (5-isoquinolyl) benzamide; N- (2,5-dioxabicyclo [4.4.0] deca-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] deca-6,8,10-triene- 9-yl] benzamide; 4- (2-cyclopropylethynyl) -N-[(4R) -4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-6,8,10-triene- 9-yl] benzamide; 4- (2-cyclopentylethynyl) -N- (3-methylcinnoline-5-yl) benzamide; 4- (2-cyclopentylethynyl) -N- (5-oxa-2-azabicyclo [4.4.0] deca-6,8,10-trien-9-yl) benzamide; N-[(4R) -4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-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] deca-6,8,10-trien-9-yl] -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- (3-methylcinnoline-5-yl) -4-[(E) -3,3,3-trifluoro-1-methyl-prop-1-enyl] benzamide; 4- (2-cyclopropylethynyl) -N- (2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -3- (2-hydroxy -2-methyl-propoxy) benzamide; N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-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] deca-7,9,11-trien-9-yl] Benzamide; N- (3-methylcinnoline-5-yl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- (3-methyl-5-isoquinolyl) -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] deca-1,3,5-triene-3- General] benzamide; 4- (2-cyclopentylethynyl) -N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) benzamide; 2-methyl-N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -4-[(E) -3,3,3-tri Fluoroprop-1-enyl] benzamide; 2-chloro-6- (2-cyclopropylethynyl) -N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) pyridine-3- Carboxamides; 2-methoxy-N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -4- [(Z) -3,3,3- Trifluoroprop-1-enyl] benzamide; N- (2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -2-methoxy-4-[(Z) -3,3,3- Trifluoroprop-1-enyl] benzamide; N- (2,5-dioxabicyclo [4.4.0] deca-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] deca-6,8,10-trien-9-yl] -2-methyl-benzamide; 4- (2-cyclopentylethynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6,8,10-trien-9-yl] -2-methyl-benzamide; 4- (2-cyclopentylethynyl) -2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6,8,10-triene -9-yl] benzamide; 4- (2-cyclopropylethynyl) -2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6,8,10-triene -9-yl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-methoxy-N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl ) Benzamide; 4- (2-cyclopropylethynyl) -2,6-difluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7,9,11 -Trien-9-yl] benzamide; 4- (2-cyclopropylethynyl) -2,6-difluoro-N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) Benzamide; N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-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] deca-7,9,11-triene-9- Il] -2-methyl-benzamide; N- [4- (cyclopropylmethoxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl] -4- (3,3-dimethyl But-1-ynyl) -2-methyl-benzamide; 2-fluoro-N- (2-oxa-5-azabicyclo [4.4.0] deca-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] deca-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] deca-7,9,11-trien-9-yl) -4-[(E) -3,3,3-tri Fluoroprop-1-enyl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- (2-oxa-5-azabicyclo [4.4.0] deca-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] deca-7,9, 11-trien-9-yl] benzamide; 4- (2-cyclopentylethynyl) -2-methyl-N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) benzamide; 4- (2-cyclopentylethynyl) -N- (2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -2-methyl-benzamide; 4- (2-cyclopentylethynyl) -N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl ] -2-methyl-benzamide; N- (2,5-dioxabicyclo [4.4.0] deca-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] deca-7,9,11-trien-9-yl) benzamide; 2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-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] deca-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] deca-7,9,11-trien-9-yl) Benzamide; 2-chloro-4- (2-cyclopropylethynyl) -N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) benzamide; 2-chloro-N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -4-[(E) -3,3,3-tri Fluoroprop-1-enyl] benzamide; 2-fluoro-N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl] -4-[(E ) -3,3,3-trifluoroprop-1-enyl] benzamide; 4- (2-cyclopropylethynyl) -2-fluoro-N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9,11-triene -9-yl] benzamide; 4- (2-cyclopropylethynyl) -N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl] -2-methyl-benzamide; 4- (2-cyclopropylethynyl) -N- (2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -2-methyl-benzamide; 4- (2-cyclopropylethynyl) -2-methyl-N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-7,9, 11-trien-9-yl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -N- (2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -2-fluoro Rho-benzamide; 2-Chloro-4- (2-cyclopropylethynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-triene- 9-yl] benzamide; 2-chloro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-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] deca-7,9,11 -Trien-9-yl] benzamide; 4- (2-cyclopentylethynyl) -N- (2,5-dioxabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -2-methylsulfonyl-benz amides; 2-fluoro-N- (5-isoquinolyl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-chloro-4- (3,3-dimethylbut-1-ynyl) -N- (5-isoquinolyl) benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-methyl-N- (2-methylbenzothiazol-5-yl) benzamide; 4- (3,3-dimethylbut-1-ynyl) -N- (5-isoquinolyl) -2-methyl-benzamide; 2-chloro-4- (3,3-dimethylbut-1-ynyl) -N- (3-quinolyl) 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-isoquinolyl) benzamide; 4- (3,3-dimethylbut-1-ynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-triene- 9-yl] -2-methyl-benzamide; 4- (3,3-dimethylbut-1-ynyl) -2,6-difluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7 , 9,11-trien-9-yl] benzamide; 4- (2-cyclopropylethynyl) -2-fluoro-N-[(4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-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] deca- 6,8,10-trien-9-yl] benzamide; 4- (2-cyclopropylethynyl) -2-fluoro-N-[(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6,8, 10-trien-9-yl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N-[(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca- 6,8,10-trien-9-yl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- (2-methylbenzothiazol-5-yl) benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- (3-quinolyl) benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- (5-isoquinolyl) benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- (5-isoquinolyl) -3-methoxy-benzamide; 2-fluoro-N- (2-methylbenzothiazol-5-yl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-fluoro-N- (3-quinolyl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -2,6-difluoro-N- (3-quinolyl) 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-quinolyl) benzamide; 2-chloro-4- (3,3-dimethylbut-1-ynyl) -N-[(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6 , 8,10-trien-9-yl] benzamide; 2-chloro-4- (3,3-dimethylbut-1-ynyl) -N-[(4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6 , 8,10-trien-9-yl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -N-[(4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6,8,10 -Trien-9-yl] -2-methyl-benzamide; N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-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] deca-7,9,11-triene- 9-yl] -2-methyl-benzamide; 2-methyl-N- (3-quinolyl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (2-methylbenzothiazol-5-yl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- (4-hydroxy-2-oxa-6-azabicyclo [5.4.0] 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] deca-7,9,11-trien-9-yl) -2-methyl-4-[(E) -3,3,3-tri Fluoroprop-1-enyl] benzamide; 2-chloro-4- (3,3-dimethylbut-1-ynyl) -5-fluoro-N- [4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca- 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] deca-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] deca-6,8,10 -Trien-9-yl] -2-methyl-benzamide; N-[(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl] -2-methyl-4- [(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (3-methyl-5-isoquinolyl) -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-isoquinolyl) -4- (3,3-dimethylbut-1-ynyl) -2-methyl-benzamide; N- (1-chloro-5-isoquinolyl) -2-methyl-4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 4-[(E) -3,3-dimethylbut-1-enyl] -2-methyl-N- (3-quinolyl) benzamide; N- (2,9-diazabicyclo [4.3.0] nona-1,3,5,7-tetraen-4-yl) -4- (3,3-dimethylbut-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-quinolyl] -2-methyl-benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-methyl-N- (2-oxo-3H-benzooxazol-6-yl) benzamide; 4- (3,3-dimethylbut-1-ynyl) -N- [8- (hydroxymethyl) -2,7,9-triazabicyclo [4.3.0] nona-2,4,7,10- Tetraen-4-yl] -2-methyl-benzamide; 2-methyl-N- (8-quinolyl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (6-quinolyl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (5-quinolyl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (7-quinolyl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- [2- (hydroxymethyl) benzothiazol-5-yl] -2-methyl-4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- [3- (hydroxymethyl) -7-quinolyl] -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] nona-1,3,5,8-tetraen-3-yl) -2-methyl-4-[(E) -3,3,3- Trifluoroprop-1-enyl] benzamide; N- [3- (hydroxymethyl) -1H-indazol-6-yl] -2-methyl-4-[(E) -3,3,3-trifluoroprop-1-enyl] 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] deca-7,9,11-trien-8-yl] -2-methyl-4- [ (E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- [3- (hydroxymethyl) -1H-indazol-5-yl] -2-methyl-4-[(E) -3,3,3-trifluoroprop-1-enyl] 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; And 2-methyl-N- (2-methyl-6-quinolyl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide Compound selected from. The method of claim 1, N- (5-isoquinolyl) -4- (3,3,3-trifluoroprop-1-ynyl) benzamide; N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -4- (3,3,3-trifluoroprop-1-ynyl) Benzamide; N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -4-[(E) -3,3,3-trifluoro-1 -Methyl-prop-1-enyl] benzamide; N-[(4R) -4- (hydroxymethyl) -2,5-dioxabicyclo [4.4.0] deca-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] deca-6,8,10-trien-9-yl] -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6,8,10-trien-9-yl] -4-[(E) -3,3 , 3-trifluoroprop-1-enyl] benzamide; 2-methyl-N- (2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl) -4-[(E) -3,3,3-tri Fluoroprop-1-enyl] benzamide; 4- (2-cyclopropylethynyl) -2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-6,8,10-triene -9-yl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7,9, 11-trien-9-yl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -2,6-difluoro-N- (5-isoquinolyl) benzamide; 4- (3,3-dimethylbut-1-ynyl) -N- [4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-triene- 9-yl] -2-methyl-benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N-[(4R) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca- 6,8,10-trien-9-yl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N-[(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca- 6,8,10-trien-9-yl] benzamide; 4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- (5-isoquinolyl) -3-methoxy-benzamide; 2-methyl-N- (3-quinolyl) -4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; 2-fluoro-N-[(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-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] deca-6,8,10 -Trien-9-yl] -2-methyl-benzamide; N-[(4S) -4- (hydroxymethyl) -2-oxa-5-azabicyclo [4.4.0] deca-7,9,11-trien-9-yl] -2-methyl-4- [(E) -3,3,3-trifluoroprop-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-acetylindolin-6-yl) -4- (3,3-dimethylbut-1-ynyl) -2-methyl-benzamide; 4-[(E) -3,3-dimethylbut-1-enyl] -2-methyl-N- (3-quinolyl) benzamide; N- (1H-benzoimidazol-5-yl) -4- (3,3-dimethylbut-1-ynyl) -2-methyl-benzamide; N- [2- (hydroxymethyl) benzothiazol-5-yl] -2-methyl-4-[(E) -3,3,3-trifluoroprop-1-enyl] benzamide; And N- [3- (hydroxymethyl) -5-oxa-2,10-diazabicyclo [4.4.0] deca-7,9,11-trien-8-yl] -2-methyl-4- [ (E) -3,3,3-trifluoroprop-1-enyl] benzamide Compound selected from. Compounds of formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, and stereoisomers and tautomers thereof. <Formula I>

In the formula, W, Z, Y and X are each independently N or CR ⁴ ; L is-(CR ⁵ = CR ⁶ )-or-(C≡C)-; R ¹ is substituted or unsubstituted

ego; B ³ and B ⁴ are each independently CR ^{4 ′} or N; A ¹ and A ⁴ are independently CR ^{4 ′} R ^{4 ′} , NR ^{4 ′} , O, S, SO or SO ₂ ; R ^{4 '} is C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl; R ³ is CR ^{6 ′} R ⁷ R ⁸ ; Each R ⁴ is independently hydrogen, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, C ₂ -C ₆ acyl, C ₂ -C ₆ acylamino, C ₁ -C ₆ alkylamino, C _1- C ₆ alkylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylarylamino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl , Sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfate ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxy, carbamoyl, cyano, cycloheteroalkyl, Di C ₁ -C ₆ alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio; R ⁵ and R ⁶ are each independently H, halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl; R ^{6 '} is hydrogen, halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl; R ⁷ and R ⁸ are each independently halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl; Or R ⁷ and R ⁸ together form a substituted or unsubstituted C ₃ -C ₈ cycloalkyl ring; Wherein the compound is not selected from the group consisting of compounds 1, 11, 38 and 42. The compound of claim 29, wherein R ^{4 ′} is hydroxyl C ₁ -C ₆ alkyl. The compound of claim 29, wherein R ^{4 ′} is — (CH ₂ ) _n —OH, wherein n is selected from 1-6. The compound of claim 29, wherein R ^{4 ′} is CH ₂ OH. 30. The compound of claim 29, wherein W and X are each CR ⁴ , and Y and Z are each CR ^{4 "} , wherein R ^{4 "} is hydrogen, C ₁ -C ₆ alkyl, trihalo C ₁ -C ₆ alkyl, and halo. Independently selected from). The compound of claim 35, wherein each R ^{4 ″} is independently H, CH ₃ , CF ₃ , Cl, or F. 38. 30. The compound of claim 29, wherein W, X and Z are each CH and Y is C-CH ₃ , C-Cl or CF. 36. The compound of claim 35, wherein R ⁴ is H. The compound of claim 29, wherein R ¹ is

Wherein, where possible, ring N may be further substituted with H or C ₁ -C ₆ alkyl. The compound of claim 29, wherein R ¹ is

Phosphorus compounds. 30. A compound according to claim 29 according to formula IV or V. <Formula IV>

<Formula V>

Compounds of formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, and stereoisomers and tautomers thereof. <Formula I>

In the formula, W, Z, Y and X are each independently N or CR ⁴ ; L is substituted or unsubstituted-(CR ⁵ = CR ⁶ )-or-(C≡C)-; R ¹ is substituted or unsubstituted

ego; A ¹ , A ² and A ³ are each independently CR ^{4 ′} , CR ^{4 ′} R ^{4 ′} , CO, CS, N, NR ^{4 ′} , O, S, SO or SO ₂ ; Each R ^{4 ′} is independently H, substituted or unsubstituted C ₁ -C ₆ alkyl or aryl; The dotted bonds each represent a single or double bond; R ³ is CR ^{6 ′} R ⁷ R ⁸ ; Each R ⁴ is independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, acyl, acylamino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylarylamino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, aryl Sulfonyl, sulfuric acid, sulfate ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxy, carbamoyl, cyano, cycloheteroalkyl, di C ₁ -C ₆ alkylamino, halo, heteroaryloxy , Heteroaryl, heteroalkyl, hydroxyl, nitro or thio; R ⁵ and R ⁶ are each independently H, halo, or substituted or unsubstituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkylene, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkenylene, C ₂ -C ₆ alkynyl, heteroalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R ^{6 '} is hydrogen, halo or substituted or unsubstituted C ₁ -C ₆ alkyl; R ⁷ and R ⁸ are each independently halo or substituted or unsubstituted C ₁ -C ₆ alkyl; Or R ⁷ and R ⁸ together form a substituted or unsubstituted C ₃ -C ₈ cycloalkyl ring; Wherein the compound is not selected from the group consisting of compounds 2, 4, 9-10, 16-17, 25-29, 33, 37-38 and 39. 43. The compound of claim 42, wherein W and X are each CR ⁴ , and Y and Z are each CR ^{4 "} , wherein R ^{4 "} is hydrogen, C ₁ -C ₆ alkyl, trihalo C ₁ -C ₆ alkyl, and halo. Independently selected from). The compound of claim 43, wherein each R ^{4 ″} is independently H, CH ₃ , CF ₃ , Cl, or F. 45. 43. The compound of claim 42, wherein W, X and Z are each CH and Y is C-CH ₃ , C-Cl or CF. 44. The compound of claim 43, wherein R ⁴ is H. The compound of claim 42, wherein R ¹ is substituted or unsubstituted.

Wherein, where possible, ring N may be further substituted with H or C ₁ -C ₆ alkyl. Compounds of Formula VI, or pharmaceutically acceptable salts, solvates or prodrugs thereof, and stereoisomers and tautomers thereof. <Formula VI>

In the formula, W, Z, Y and X are each independently N or CR ⁴ ; L is substituted or unsubstituted-(CR ⁵ = CR ⁶ )-or-(C≡C)-; R ³ is CR ^{6 ′} R ⁷ R ⁸ ; Each R ⁴ is independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, acyl, acylamino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylarylamino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, aryl Sulfonyl, sulfuric acid, sulfuric ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxy, carbamoyl, cyano, cyclo heteroalkyl, di C ₁ -C ₆ alkylamino, halo, heteroaryloxy , Heteroaryl, heteroalkyl, hydroxyl, nitro or thio; R ⁵ and R ⁶ are each independently H, halo, or substituted or unsubstituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkylene, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkenylene, C ₂ -C ₆ alkynyl, heteroalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R ^{4 ′} is substituted or unsubstituted C ₁ -C ₆ alkyl; R ^{6 '} is hydrogen, halo or substituted or unsubstituted C ₁ -C ₆ alkyl; R ⁷ and R ⁸ are each independently halo or substituted or unsubstituted C ₁ -C ₆ alkyl; Or R ⁷ and R ⁸ together form a substituted or unsubstituted C ₃ -C ₈ cycloalkyl ring. 49. The compound of claim 48, wherein W and X are each N or CR ⁴ and Y and Z are each N or CR ^{4 "} , wherein R ^{4 "} is selected from hydrogen, C ₁ -C ₆ alkyl, trihaloalkyl and halo. Independently selected). The compound of claim 49, wherein each R ^{4 ″} is independently H, CH ₃ , CF ₃ , Cl or F. 51. 49. The compound of claim 48, wherein W, X and Z are each N or CH and Y is C-CH ₃ , C-Cl or CF. 50. The compound of claim 49, wherein R ⁴ is H. 49. The compound of claim 48, wherein R ^{4 '} is hydroxyl substituted C ₁ -C ₆ alkyl. 49. The compound of claim 48, wherein R ^{4 '} is-(CH ₂ ) _n -OH, wherein n is selected from 1-6. 49. The compound of claim 48, wherein R ^{4 '} is CH ₂ OH. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound of any one of claims 1-55. The pharmaceutical composition of claim 56, wherein the carrier is a parenteral carrier, oral or topical carrier. The administration of a prophylactically effective amount or therapeutically effective amount of a compound of any one of claims 1 to 55 or a pharmaceutical composition of claim 56 or 57 to a patient in need of preventing, treating, alleviating or managing a disease or condition. A method for preventing, treating, alleviating, or managing a disease or condition. Any one of claims 1 to 55 wherein the compound of formula R ³ -L-Cy-COCl under conditions sufficient to form a compound of according to any one of (wherein, Cy is aryl or heteroaryl) the formula R ¹ R ² NH 56. A process for preparing the compound of any one of claims 1 to 55, comprising contacting with a compound of. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament or a medicament. 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 wherein a VR1 antagonist is prescribed. 62. The method of claim 61, wherein the disease is acute cerebral ischemia, pain, chronic pain, acute pain, invasive pain, neuropathic pain, inflammatory pain, post shingles neuralgia, neuropathy, neuralgia, diabetic neuropathy, HIV-related Neuropathy, nerve damage, rheumatoid arthritis pain, osteoarthritis pain, burns, back pain, visceral pain, cancer-induced pain, toothache, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica Neuralgia, pelvic hypersensitivity, pelvic pain, dysmenorrhea, bladder diseases such as incontinence, urination disorders, renal colic and cystitis, inflammation such as burns, rheumatoid arthritis and osteoarthritis, neurodegenerative diseases such as stroke, post-stroke pain and Multiple sclerosis, lung diseases such as asthma, cough, chronic obstructive pulmonary disease (COPD) and bronchial contractions, gastrointestinal disorders such as gastroesophageal reflux disease (GERD), dysphagia, ulcers, irritable bowel syndrome (IBS), Inflammatory bowel disease (IBD), colitis and Crohn's disease, ischemia such as cerebrovascular ischemia, vomiting such as chemotherapy-induced vomiting and obesity. 58. A method for treating a disease for which a VR1 antagonist is prescribed, comprising treating the mammal with an effective amount of a compound as defined in any one of claims 1 to 57, or a pharmaceutically acceptable salt, solvate or composition thereof. A method of treating said mammal, including humans. A combination of a compound as defined in any one of claims 1 to 55 with another pharmacologically active agent.

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