WO2007056046A1 - P2x7 receptor antagonists and methods of use - Google Patents

P2x7 receptor antagonists and methods of use Download PDF

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WO2007056046A1
WO2007056046A1 PCT/US2006/042777 US2006042777W WO2007056046A1 WO 2007056046 A1 WO2007056046 A1 WO 2007056046A1 US 2006042777 W US2006042777 W US 2006042777W WO 2007056046 A1 WO2007056046 A1 WO 2007056046A1
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alkyl
triazole
compound
dichlorophenyl
formula
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William A. Carroll
Alan S. Florjancic
Arturo Perez-Medrano
Sridhar Peddi
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Abbott Laboratories
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Priority to CA002627114A priority patent/CA2627114A1/en
Publication of WO2007056046A1 publication Critical patent/WO2007056046A1/en

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Abstract

The invention is directed to compounds that are P2X7 antagonist and have the formula (I) or (II) or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or a combination thereof, wherein R1, R2, and R3 are defined in the specification. The invention is also directed to a method of selectively inhibiting P2X7 activity comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (III), (IV) or (V) wherein R6, R7, R8, R9, R10, and R11 are defined in the specification.

Description

P2X7 RECEPTOR ANTAGONISTS AND METHODS OF USE
BACKGROUND OF THE INVENTION This invention relates to aminotriazole analogues that are antagonists of P2X7 receptors, and to the use of such compounds for treating conditions related to P2X7 receptor activation.
P2X receptors are ionotropic receptors activated by ATP. The importance of P2X receptors in nociception is underscored by the variety of pain states in which this endogenous ligand can be released. Of the seven P2X receptors, the P2X7 is distinguished by its ability to form a large pore upon prolonged or repeated agonist stimulation. It is partially activated by saturating concentrations of ATP, whereas it is fully activated by the synthetic ATP analog benzoylbenzoic ATP (BzATP) (Bianchi et al, Eur. J. Pharmacol. Vol. 376, pages 127-138, 1999). The P2X7 receptor is expressed by presynaptic terminals in the central and peripheral nervous systems, antigen-presenting cells including macrophages, human epidermal Langerhans' cells, microglial cells and a number of tumor cell lines of varying origin (Jacobson KA, et al. "Adenosine and Adenine Nucleotides: From Molecular Biology to Intefirative Physiology". L. Belardinelli and A. Pelleg (eds.), Kluwer, Boston, pages 149 - 166, 1995). Recent studies demonstrated the participation of P2X7 receptors in the modulation of electrical stimulation and ATP-evoked GABA and glutamate release from mouse hippocampal slices (Papp et al, Neuropharmacology and Neurotoxicology Vol. 15, pages 2387-2391, 2004)). In the central nervous system, the P2X7 receptor is predominately expressed by microglia, the resident macrophages of the brain. On glial cells, the P2X7 receptor has been shown to mediate release of glutamate (Anderson C. et al. Drug Dev. Res. Vol. 50. page 92, 2000). Upregulation of the P2X7 receptor, most likely on activated microglia, was reported in association with ischemic damage and necrosis induced by occlusion of middle cerebral artery in rat brain (Collo G. et al. Neuropharmacology, Vol. 36, pages 1277-1283, 1997). Recent studies indicate a role of the P2X7 receptor in the generation of superoxide in microglia, and upregulation of P2X7 receptors around β-amyloid plaques in a transgenic mouse model for Alzheimer's disease (Parvathenani et al, J. Biol. Chemistry, Vol.278. pages 13300-13317, 2003) and in multiple sclerosis lesions from autopsy brain sections (Narcisse et al, Glia, Vol. 49, pages 245-258 (2005).
Activation of the P2X7 receptor on cells of the immune system (macrophages, mast cells and lymphocytes) leads to release of interleukin-lβ (IL- lβ), giant cell formation, degranulation, and L-selectin shedding. ATP has been shown to increase local release and processing of IL-I β following lipopolysaccharide S (LPS) intraperitoneal injections in rats through a P2X7 receptor mediated mechanism (Griffiths et al, J. Immunology Vol. 154, pages 2821-2828 (1995); Solle et al, J. Biol. Chemistry. Vol. 276. pages 125-132, (2001)). Oxidized ATP (oATP), a nonselective and irreversible P2X7 antagonist, was recently reported to possess peripherally mediated antinociceptive properties in inflamed rats
(DeU' Antonio et al. Neuroscience Lett.. Vol. 327. pages 87-90, 2002). Activation of P2X7 receptors localized on presynaptic terminals in the central and peripheral nervous systems (Deuchars et al J. Neuroscience, Vol. 21, pages 7143-7152, 2001) induced release of the excitatory amino acid neurotransmitter glutamate. Studies from mice lacking the P2X7 receptor resulted in absence of inflammatory and neuropathic hypersensitivity to mechanical and thermal stimuli, indicating a link between a P2X7 purinoceptor gene and inflammatory and neuropathic pain (Chessell et al, Pain, VoI 114. pages 386-396 (2005)).
Antagonists to the P2X7 receptor significantly improved functional recovery and decreased cell death in spinal cord injury (SCI) animal models. Rats with SCI were administered P2X7 receptor irreversible antagonists oATP and PPADS with a resulting decrease of histological injury and improved recovery of motor function after the lesions (Wang et al, Nature Medicine Vol. 10, pages B21-B27, 2004).
Taken together, these findings indicate that compounds acting at the P2X7 receptor may have utility in the treatment of pain, including neuropathic pain, inflammatory processes, and degenerative conditions associated with disease states such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, multiple sclerosis, meningitis, osteoporosis, burn injury, ischemic heart disease, stroke and varicose veins. In view of the above facts, there is a need for selective P2X7 antagonist that can be efficiently used in preventing, treating, or ameliorating states as neuropathic pain, chronic inflammatory pain, inflammation and neurodegenerative conditions associated with several progressive CNS disorders, including, but not limited to, Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bodies, multiple sclerosis as well as diminished CNS function resulting from traumatic brain injury.
SUMMARY OF THE INVENTION The invention is directed to aminotriazole analog compounds as well as compositions comprising such compounds, and method of using the same to selectively inhibit P2X7 receptor activity. Compounds of the invention are P2X7 antagonists and have the formula (I) or (II)
Figure imgf000005_0001
(I) , (U) ; or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or a combination thereof, wherein
Ri is hydrogen, alkyl, haloalkyl or -CN;
R2 is -N(H)-(CRURV)-R2a, -N(ET)-Ra or R2b; and R3 is
Figure imgf000005_0002
; or
Figure imgf000005_0003
wherein R2a is a group of formula (a) or (b);
Figure imgf000006_0001
(a) (b) ;
R2b is a group of formula (c), (d) or (e)
Figure imgf000006_0002
(C) (d) or (e) ; Z1 at each occurrence is independently C, C(H), C(H)2, O, S, S(O), S(O)2,
N(H), N(alkyl) or N(acyl);
Z2 at each occurrence is independently C, C(H), or N; Z3 at each occurrence is independently O, S, S(O), S(O)2, N(H), N(alkyl) or N(acyl); R4 at each occurrence is independently halo, alkyl, -CN, -ORA, -SRA,
-N(RA)(RB) or haloalkyl;
R5 at each occurrence is independently alkyl, halo or haloalkyl; m at each occurrence is independently O, 1, 2 or 3; n at each occurrence is independently 0, 1, 2 or 3; ' Ra and Rb at each occurrence are each independently halo, -CN, haloalkyl, haloalkoxy or alkyl;
R0 at each occurrence is independently hydrogen, halo, haloalkyl, alkoxy, haloalkoxy or alkyl; each of R11 and Rv at each occurrence is independently hydrogen, alkyl or haloalkyl;
A1, A2, A3 and A4 are -C(RW); or one or two OfA1, A2, A3 and A4 are N, and the others are -C(RW); or one of A1, A2, A3 and A4 is N+-O" and the others are -C(RW); wherein Rw at each occurrence is independently hydrogen, halo, alkyl, alkenyl, -ORA, -SRA, -N(RA)(RB) or haloalkyl; A5 is N, A6 is O or S and A7 is C(H) or C(alkyl), or
A5 is N, A6 is C(H) or C(alkyl), and A7 is O or S, or one ofA5, A6 and A7 is S and the others are independently C(H) or C(alkyl);
G is -W2 or -L2-W2; or
G is hydrogen, alkyl, -Oalkyl, -NH2, -N(H)(alkyl), -N(alkyl)2, -S(O)alkyl, -S(O)2alkyl, -S(O)2NH2, -S(O)2N(H)(alkyl), -S(O)2N(alkyl)2, -C(O)NH2, -C(O)N(H)(alkyl), -C(O)N(alkyl)2, -W2 or -L2-W2, when one of A1, A2, A3 and A4 is
N;
L2 is N(H), N(alkyl), O, S, S(O), S(O)2, S(O)2N(H), SO2N(alkyl), N(H)S(O)2, N(alkyl)S(O)2, CON(H), CON(alkyl), N(H)CO, N(alkyl)CO); and W2 at each occurrence is independently aryl, heteroaryl or heterocycle; and each W2 is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of =0, halo,-CN, -NO2, alkyl, alkenyl, -0RA, -SRA, -S(O)2RA, -S(O)2N(RA)(RB), -N(RA)(RB), -C(0)RA, -C(0)N(RA)(RB), -C(0)0RA, haloalkyl, -alkyl-ORA, -alkyl-SRA, -alkyl-S(O)2RA, -alkyl-S(O)2N(RA)(RB), -alkyl-N(RA)(RB), -alkyl-C(O)RA, -alkyl-C(O)N(RA)(RB), and -alkyl-C(O)ORA; RA at each occurrence is independently hydrogen, alkyl, alkenyl or haloalkyl; and
RB at each occurrence is independently hydrogen, alkyl, or haloalkyl.
Another aspect of the invention relates to a method of selectively inhibiting P2X7 activity comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (III), (IV) or (V)
Figure imgf000007_0001
or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
R6 is hydrogen, alkyl, haloalkyl or -CN; R7 is
Figure imgf000008_0001
and R8 is -W, -C(RxRy)-W1, -C(RxRy)-W1-W2, or
Figure imgf000008_0002
or
R8 is
Figure imgf000008_0003
and R7 is -W, -N(H)-W, -L1-Wi, -Li-Wi-W2, or
Figure imgf000008_0004
Rio is Rn is -C(RxRy)-Wi; and Rg is hydrogen, alkyl, haloalkyl or-
CN; or
Rn is Rio is -C(RxRy)-Wi; and Rg is hydrogen, alkyl, haloalkyl or -
CN; or
Rg is
Figure imgf000008_0005
Rio is -C(RxRy)-W1; and Rn is hydrogen; wherein
R3 and Rb at each occurrence are each independently halo, -CN, haloalkyl, haloalkoxy or alkyl;
R0 at each occurrence is independently hydrogen, halo, haloalkyl, alkoxy, haloalkoxy or alkyl; L1 at each occurrence is independently -C(RxRy), or -N(H)-C(RURV)P-; p is l or 2; each of Ru, Rv, Rx and Ry at each occurrence is independently hydrogen, alkyl or haloalkyl;
W is
Figure imgf000009_0001
wherein
A is a five or six membered monocyclic ring selected from the group consisting of cyclo alkyl and heterocycle and is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halo and haloalkyl;
B is phenyl or monocyclic heteroaryl, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, alkyl, -CN, -ORA, -SRA,
-N(RA)(RB) and haloalkyl; q is 0 or 1 ; Rz is W2 or -L2-W2;
L2 at each occurrence is independently O, N(H), or N(alkyl), S, S(O), S(O)2, S(O)2N(H), SO2N(alkyl), N(H)S(O)2, N(alkyl)S(O)2, CON(H), CON(alkyl), N(H)CO,
N(alkyl)CO);
Wi at each occurrence is independently phenyl or monocyclic heteroaryl, wherein each Wi is optionally fused with a monocyclic, five or six-membered ring selected from the group consisting of phenyl, heteroaryl, heterocycle, cycloalkyl and cycloalkenyl;
W2, at each occurrence is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; each of Wi and W2, at each occurrence, is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, CN, NO2, halo, =0, -0RA, -SRA, -S(O)RA, -S(O)2RA, -S(O)2N(RA)(RB),
-N(RA)(RB), -C(O)RA, -C(O)ORA, -C(O)N(RA)(RB), haloalkyl, -alkyl-ORA, -alkyl-SRA, -alkyl-S(O)RA, -alkyl-S(O)2RA, -alkyl-S(O)2N(RA)(RB), -alkyl-N(RA)(RB), -alkyl-C(O)RA, -alkyl-C(O)ORA, and -alkyl-C(O)N(RA)(RB);
RA at each occurrence is independently hydrogen, alkyl, alkenyl or haloalkyl; and RB at each occurrence is independently hydrogen, alkyl, or haloalkyl. DETAILED DESCRIPTION OF THE INVENTION
All references contained herein are fully incorporated by reference. a) Definition of terms
The term "acyl" as used herein, means -C(O)CH3. The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl. The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n- heptyl, n-octyl, n-nonyl, and n-decyl.
The term "aryl" as used herein, means phenyl or a bicyclic aryl. The bicyclic aryl is naphthalenyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl. The phenyl and the bicyclic aryl groups of the present invention are unsubstituted or substituted. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic aryl. Representative examples of the aryl groups include, but are not limited to, dihydroindenyl, 2,3-dihydro-lH-inden-l-yl, naphthalenyl, dihydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalen-l-yl.
The term "cycloalkyl" or "cycloalkane" as used herein, means a monocyclic or bicyclic cycloalkyl. The monocyclic cycloalkyl has three to eight carbon atoms, zero heteroatom and zero double bond. The monocyclic cycloalkyl can be attached to the parent molecular moiety through any substitutable atom contained within the monocyclic cycloalkyl. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl. The bicyclic cycloalkyl can be attached to the parent molecular moiety through any substitutable atom contained within the bicyclic cycloalkyl. The monocyclic and bicyclic cycloalkyl groups of the present invention can be unsubstituted or substituted.
The term "cycloalkenyl" or "cycloalkene" as used herein, means a monocyclic or a bicyclic hydrocarbon ring system. The monocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms and zero heteroatom. The four-membered ring systems have one double bond, the five-or six-membered ring systems have one or two double bonds, and the seven- or eight-membered ring systems have one, two or three double bonds. The monocyclic cycloalkenyl can be attached to the parent molecular moiety through any substitutable atom contained within the monocyclic cycloalkenyl. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclop entenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. The bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group. The bicyclic cycloalkenyl can be attached to the parent molecular moiety through any substitutable atom contained within the bicyclic cycloalkenyl. Representative examples of the bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl and 1,6- dihydro-pentalene. The monocyclic and bicyclic cycloalkenyl groups of the present invention can be unsubstituted or substituted. The term "halo" or "halogen" as used herein, means -Cl, -Br, -I or -F.
The term "haloalkoxy" as used herein, means an alkoxy group, as defined herein, in which one, two, three or four hydrogen atoms are replaced by halogen. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, 2-chloro-3-fluoropentyloxy, and pentafluoroethoxy. The term "haloalkyl" as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl. The term "heterocycle" or "heterocyclic" as used herein, means a monocyclic heterocycle or a bicyclic heterocycle. The monocyclic heterocycle is a three-, four-, five-, six- or seven-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four membered ring contains zero or one double bond, and one heteroatom selected from, the group consisting of O, N and S. The five- membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The seven-membered ring contains zero, one, two, or three double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The monocyclic heterocycle can be unsubstituted or substituted and is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, [l,4]diazepan-l-yl, 1,3-dioxanyl, 1,3- dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroaryl. The bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heterocycle and can be unsubstituted or substituted. Representative examples of bicyclic heterocycle include, but are not limited to, benzodioxinyl, benzopyranyl, thiochromanyl, 2,3-dihydroindolyl, indolizinyl, pyranopyridinyl, 1, 2,3, A- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, thiopyranopyridinyl, 2-oxo-l,3- benzoxazolyl, 3-oxo-benzoxazinyl, 3-azabicyclo[3.2.0]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl, hexahydro-lH-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4- cjpyrrolyl, 2,3-dihydrobenzofuran-7-yl, 2,3-dihydrobenzofuran-3-yl, and 3,4-dihydro-2H- chromen-4-yl. The monocyclic or bicyclic heterocycles as defined herein may have two of the non-adjacent carbon atoms connected by a heteroatom selected from nitrogen, oxygen or sulfur, or an alkylene bridge of between one and three additional carbon atoms.
>
Representative examples of monocyclic or bicyclic heterocycles that contain such connection between two non- adjacent carbon atoms include, but are not limited to, 2- azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl, 2- azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2- azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.1.1]heptyl, 6-oxa-3- azabicyclo[3.1.1]heptyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 1,4- diazabicyclo[3.2.2]nonyl, l,4-diazatricyclo[4.3.1.13)8]undecyl, 3,10-diazabicyclo[4.3.1]decyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, octahydro-lH-4,7-methanoisoindolyl, and octahydro-lif- 4,7-epoxyisoindolyl. The nitrogen heteroatom may or may not be quaternized, and may or may not be oxidized to the N-oxide. In addition, the nitrogen containing heterocyclic rings may or may not be N-protected.
The term "heteroaryl" as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a five- or six-membered ring. The five-membered ring consists of two double bonds, and one sulfur, nitrogen or oxygen atom. Alternatively, the five-membered ring has two double bonds, and one, two, three or four nitrogen atoms and optionally one additional heteroatom selected from oxygen or sulfur. The six-membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl. The monocyclic and the bicyclic heteroaryl are connected to the parent molecular moiety through any substitutable atom contained within the monocyclic or the bicyclic heteroaryl. The monocyclic and bicyclic heteroaryl groups of the present invention can be substituted or unsubstituted. hi addition, the nitrogen heteroatom may or may not be quaternized, and may or may not be oxidized to the N-oxide. Also, the nitrogen containing rings may or may not be N-protected. Representative examples of monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridine-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. Representative examples of bicyclic heteroaryl groups include, but not limited to, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, 6,7-dihydro-l,3-benzothiazolyl, imidazo[l,2-a]pyridinyl, indazolyl, 1Η- indazol-3-yl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyrido imidazolyl, quinolinyl, quinolin-8-yl, and 5,6,7,8-tetrahydroquinolin-5-yl. The term "heteroatom" as used herein, refers to nitrogen, oxygen or sulfur atom.
b) Compounds, Methods and Compositions of the Invention
Compounds of the invention can have the formula (I) or (II) as described above. More particularly, compounds of formula (I) can include, but are not limited to, compounds wherein R1 is hydrogen, alkyl, haloalkyl or -CN; R3 is substituted phenyl; and R2 is -
Figure imgf000014_0001
N(H)-(CRURV)-R2a, wherein R2a is selected from (a) or (b) (a) (b)
Preferred compounds are those in which R2a is a six-membered ring such as phenyl or pyridine and G is aryl or heteroaryl. Other preferred compounds are those in which R2a is phenyl or pyridine and G is -L2-W2. Preferred compounds are those in which L2 is O and W2 is aryl or heteroaryl. Other compounds of the present invention include those in which R2a is a five membered ring as defined above.
The present invention also comprises compounds of formula (I) in which R1 is hydrogen, alkyl, haloalkyl or -CN; R3 is substituted phenyl; and R2 is -N(H)-R2b wherein R2b is selected from groups (c), (d) and (e)
Figure imgf000014_0002
(C) (d) or (e)
Other compounds of the present invention include those of formula (I) in which Ri is hydrogen, alkyl, haloalkyl or -CN; R3 is substituted phenyl; and R2 is R2b wherein R2b is selected from groups (c), (d) and (e) depicted above.
The present invention also comprises compounds of formula (I) in which Ri is hydrogen, alkyl, haloalkyl or -CN; R3 is R2b selected from groups (c), (d) and (e) as depicted above; and R2 is substituted phenyl. Preferred compounds are those in which R2bhas formula (C) or (d). The present invention also comprises compounds of formula (II) that can include, but are not limited to, compounds wherein Ri is hydrogen, alkyl, haloalkyl or -CN; R3 is substituted phenyl and R2 is -N(H)-(CRURV)-R2a- Preferred compounds are those in which R2a is phenyl or pyridine, independently substituted with G, and G is an alkoxy group or hydrogen. Other preferred compounds include those in which G is -W2 or -L2-W2; wherein -L2 is preferably oxygen and W2 is selected from aryl, heteroaryl or heterocycle; being independently unsubstituted or substituted. Other compounds of the present invention include those in which R2a is a carbocyclic or heterocyclic five-membered ring.
Other compounds of the present invention are those of formula (II) that can include, but are not limited to, compounds wherein Ri is hydrogen, alkyl, haloalkyl or -CN; R3 is substituted phenyl and R2 is -N(H)-R2V Wherein -R2b is selected from the groups (c), (d) and (e) described above. Also included are compounds of formula (II) in which Ri is hydrogen, alkyl, haloalkyl or -CN; R3 is substituted phenyl and R2 is -R2b; wherein -R2b is selected from the groups (c), (d) and (e) described above. Other compounds included in the present invention are those having formula (II) wherein Ri is hydrogen, alkyl, haloalkyl or -CN; R2 is substituted phenyl and R3 is R2b; wherein -R2b is selected from the groups (c), (d) and (e) described above.
The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) or (II) in combination with a pharmaceutically acceptable carrier. The compositions comprise compounds of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
The term "pharmaceutically acceptable carrier," as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of one skilled in the art of formulations. The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.
The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. The term "pharmaceutically acceptable prodrug" or "prodrug," as used herein, represents those prodrugs of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Prodrugs of the invention can be rapidly transformed in vivo to a parent compound of formula (I), for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).
The invention contemplates pharmaceutically active compounds either chemically synthesized or formed by in vivo biotransformation to compounds of formula (I). Compounds and compositions of the invention are useful for modulating the activation of P2X7 receptors. The compounds of the invention, including but not limited to those specified in the examples, possess an affinity for P2X7 receptors, and block P2X7 receptor activity. As P2X7 receptor antagonists, the compounds of the invention can be useful for the treatment and prevention of a number of P2X7 receptors -mediated diseases or conditions including but not limited to neuropathic pain, chronic inflammatory pain, inflammation and neurodegenerative conditions associated with several progressive CNS disorders, including, but not limited to, Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bodies, multiple sclerosis as well as diminished CNS function resulting from traumatic brain injury. . The present invention also includes a method of use for inhibiting P2X7 activity comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (III), (IV) or (V) or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof. More particularly, methods of use administering compounds of formula (III) can include, but are not limited to methods using compounds wherein R6 is hydrogen, alkyl, haloalkyl or -CN; R7 is substituted phenyl; and R8
is — W; wherein W is
Figure imgf000017_0001
In a preferred embodiment A is a five or six membered monocyclic ring selected from the group consisting of cycloalkyl and heterocycle and is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halo and haloalkyl; and B is phenyl or monocyclic heteroaryl, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, alkyl, -CN, -ORA, -SRA, -N(RA)(RB) and haloalkyl; q is 0 or 1; and Rz is W2 or -L2-W2. Preferred methods are those using compounds in which A is a five or six membered monocyclic ring that is cycloalkyl which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halo and haloalkyl, and B is phenyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, alkyl, -CN, -ORA, -SRA, -N(RA)(RB) and haloalkyl. Another preferred method uses compounds in which A is a five or six membered monocyclic ring that is cycloalkyl which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halo and haloalkyl, and B is a pyridine group. Other methods included in the present invention are those using compounds of formula (III) in which R6 is hydrogen, alkyl, haloalkyl or -CN; R7 is substituted phenyl; and R8 is -C(RxRy)-W1. Preferred ones are those using compounds in which Wi is phenyl, or a monocyclic heteroaryl. Other preferred methods use compounds wherein Wi is optionally fused with a monocyclic, five or six- membered ring selected from the group consisting of phenyl, heteroaryl, heterocycle, cycloalkyl and cycloalkenyl.
Other methods comprised in the present invention include those using compounds of formula (III) wherein R6 is hydrogen, alkyl, haloalkyl or -CN; R7 is substituted phenyl and R8 is selected from the group of -C(RxRy)-Wi-W2 and -C(RxRy)-Wi-L2-W2.
Other methods included in the present invention include those using compounds of formula (III) in which R6 is hydrogen, alkyl, haloalkyl or -CN; R8 is substituted phenyl and R7 is -W, wherein W is selected from any of the groups described above. Other methods that are part of the present invention include those using compounds of formula (III) wherein R6 is hydrogen, alkyl, haloalkyl or -CN; R8 is substituted phenyl and R7 is selected from the group consisting of -N(H)-W, -Li-Wi, -Li-Wi-W2, or -Li-Wi-L2-W2. Preferred methods are those using compounds of formula (111) wherein R6 is hydrogen, alkyl, haloalkyl or -CN; Rg is substituted phenyl and R7 is -Li-Wi, wherein -Wi is preferably phenyl or heteroaryl.
The present invention also includes methods of use as described above using compounds of formula (IV) wherein R6 is hydrogen, alkyl, haloalkyl or -CN; R7 is substituted phenyl; and Rg is selected from the group consisting of-W, -C(RxRy)-Wi, -C(RxRy)-Wi-W2, or -C(RxRy)-Wi-L2-W2. . Preferred compounds to be used in these methods of use are those in which R8 is — W, most preferably W is a five-membered ring fused to a phenyl group. Also preferred compounds include those in which R8 is -C(RxRy)-Wi, and Wi is phenyl.
Other methods of use contemplated in the present invention are those using compounds of formula (IV) in which R6 is hydrogen, alkyl, haloalkyl or -CN;
R8 is substituted phenyl, and R7 is -W. Preferred compounds are those in which W is a five- membered ring fused to a phenyl group. Also included are methods using compounds of formula (FV) in which R6 is hydrogen, alkyl, haloalkyl or -CN; R8 is substituted phenyl, and R7 is -L1-W1. Preferred compounds used in this method of use are those in which W1 is a phenyl, heteroaryl or heterocycle. Other methods of use contemplated in the present invention are those using compounds of formula (IV) in which R6 is hydrogen, alkyl, 5. haloalkyl or -CN; R8 is substituted phenyl, and R7 is -L1-W1-W2. Preferred compounds in this group are those in which W1 is heteroaryl and -W2 is heterocycle. Other methods of use contemplated in the present invention are those using compounds of formula (IV) in which R6 is hydrogen, alkyl, haloalkyl or -CN; R8 is phenyl, and R7 is -L1-Wi-L2-W2. Preferred compounds to be used include those in which -Wi is phenyl or heteroaryl, L2 is oxygen and 0 -W2 is pyridine. Also included are methods using compounds of formula (IV) in which R6 is hydrogen, alkyl, haloalkyl or -CN; R8 is substituted phenyl, and R7 is -W2.
The present invention also includes methods of use as described above using compounds of formula (V), wherein Rg is hydrogen, alkyl, haloalkyl or -CN; R10 is phenyl; and Rn is -C(RxRy)-W1, preferably wherein Rx and Ry are hydrogen and Wi is phenyl. The 5 present invention also contemplates methods of use with compounds of formula (V) in which R9 is hydrogen, alkyl, haloalkyl or -CN;
Rn is substituted phenyl; and R10 is -C(RxRy)-W1 wherein Rx , Ry and W1. Also included are methods using compounds of formula (FV) in which R9 is substituted phenyl; Ri0 is — C(RxRy)-Wi; and Rn is hydrogen, wherein Rx ,preferably wherein Rx and Ry are hydrogen 0 and Wi is phenyl.
c) Preparation of the Compounds of the Invention
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes, which illustrate the methods by which the 5 compounds of the invention may be prepared. Starting materials can be obtained from commercial sources or prepared by well-established literature methods known to those of ordinary skill in the art.
Scheme 1
Figure imgf000020_0001
(1 ) (3a)
Figure imgf000020_0002
Triazoles of formula (3) wherein G1 is W1, W1-W2 or Wi-L2-W2 and W1, W2, L2, Rx, Ry, Ra, Rb, R0 and R6 are as defined in formula (III), can be prepared by reacting amines of formula (2) with suitably substituted oxadiazoles of formula (1) at a temperature from about
100°C to about 150 0C. The reaction can be conducted optionally in a solvent such as, but not limited to, toluene, xylene, acetonitrile or ethanol.
Compounds of formula (3 a) wherein G2 is Ri or R6, Ga is R2b or W and R2b, W, Ra, Rb, Rς, Ri and R6 are as defined in formula (I) or (III) can be prepared from compounds of formula (1) and amines of formula (2a) using similar conditions for the conversion of compounds of formula (1) to (3).
Amines of formula (2a) are either commercially available or can be prepared using known methodologies. Literature references that outline synthesis of amines of formula (2a) include, but are not limited to, Kaluza et al Chem. Ber. 1955, 88, 597; Bennett et al J. Chem.
Soc. 1931; 1692, Sagorewskii et all Gen. Chem. USSR 1964; 34, 2294, Pratap et al Indian J.
Chem. Sect. B 1981; 20; 1063, WO2005/42533, pl21; Braun et al Chem. Ber. 1929, 62,
2420; Tikk et alActa CHm. Hung. 1986, 121, 255; and Bernabeu et al Synth. Commun. 2004,
34, 137. Oxadiazoles of formula (1) can be prepared in two steps from benzoic acid esters
(either commercially available or made by known methodologies from corresponding benzoic acids) of formula (4) wherein Pi is alkyl or benzyl. Reaction of the benzoic acid esters of formula (4) with hydrazine in a solvent such as but not limited to ethanol, at a temperature of about room temperture to about the reflux temperature of the solvent employed provides acyl hydrazides of formula (5). Reaction of acyl hydrazides of formula (5) with an orthoester such as triethylortho formate affords oxadiazoles of formula (1). The conversion is effected in the presence of catalytic amount of p-toluenesulfonic acid in a solvent such as, but not limited to, toluene at the reflux temperature of the solvent used.
Scheme IA
Figure imgf000021_0001
One particular example of amines of formula can be prepared from its corresponding ketone as shown in Scheme IA.
Furo[2,3-6]pyridin-3(2H)-one (prepared using procedures as described in Morita, Hiroyuki; Shiotani, Shunsaku; J Heterocycl. Chem.; 23; 1986; 1465-1469) and the hydrochloride salt of methoxylamine can be converted into the methyloxime by reacting at room temperature in a solvent such as pyridine over a period of 24 hours. The intermediate methyloxime, in turn, can be reduced to the corresponding amine by catalytic hydrogenation over Raney Nickel at 4 atmospheres for 6 hours at room temperature in the presence of aqueous ammonia and in an alcoholic solvent such as methanol or ethanol.
Scheme IB
Figure imgf000021_0002
(6) (7) (8)
Figure imgf000022_0001
(6) (7a) (8a)
G3-COOH Ga-COOP1 G3-CONHNH2 (7a) (i)
Similarly, triazoles of formula (8) wherein Gi is Wi, Wi-W2 or Wi-L2-W2 and Wi, W2, L2, Rx, Ry, Ra, Rb, R0 and R6 are as defined in formula (III), and compounds of formula (8a) wherein G2 is Ri or R6, Ga is R2b or W and R2b, W, Ra, Rb, R0, Ri and R6 are as defined in formula (I) or (III), can be obtained under similar reaction conditions as mentioned in Scheme 1 from amines of formula (6) and oxadiazoles of formula (7) or (7a) respectively.
Oxidazoles of formula (7a) can be prepared from carboxylic esters of formula (ii) (prepared from esterification of acids of formula (i) using similar reaction conditions^ for the synthesis of compounds of formula (1) from esters of formula (4) as shown in Scheme 1.
Acids of formula (i) can be purchased or prepared using various known methodologies. Literature references describing the synthesis of acids of formula (i) include, but are not limited to, Weidel Monatsh. Chem. 1882, 3, 66; Weidel Monatsh. Chem. 1881, 2, 29; Cohen et al J. Pharm ScL 1987, 76, 848; Maiti et al Synthesis 1987, 9, 806; Belletaire et al Synth. Commun. 1982, 12, 763; Cohen et al J Pharm Sd. 1987, 76, 848; Belletaire et al Synth. Commun. 1982, 12, 763; Fredga^cto Chem. Scand. 1955, 9, 719; Wolf HeIv. Chim. Acta 1972, 55, 2919; Scapecchi et al Farmaco 1998, 53, 764; Bernabeu Synth. Commun. 2004, 34, 137; andUS3975431.
Scheme 2
Figure imgf000022_0002
(9) (10) (11)
Figure imgf000023_0001
(11a)
Triazoles of formula (11) wherein G1 is W1, W1-W2 or W1-L2-W2 and W1, W2, L2, Rx, Ry, Ra, Rb, and R0 are as defined in formula (IV), can be prepared as outlined in Scheme 2. Benzamides of formula (9), purchased or prepared by known methodologies, and dimethylformamide dimethylacetal when heated neat at reflux provide acylamidines of formula (10). Compounds of formula (10) and hydrazines of formula (2b), in the presence of additives such as acetic acid and sodium acetate, can be heated in a solvent such as, but not limited to, dioxane to afford triazoles of formula (11).
Similarly, compounds of formula (1 Ia) wherein Ga is R2b or W, and W, R2b, Ra, Rb, and R0 are as defined in formula (II) or (IV) can be prepared from compounds of formula (10) and hydrazines of formula (2c). Hydrazines of formula (2c) can be synthesized using procedures described in literature references (for example, Sauter et al Arch. Pharm. 1981, 314, 567).
Scheme 3
Figure imgf000023_0002
t
O O G3^NH2 G OH
(iv) (i) Triazoles of formula (14) wherein Gi is Wi, Wi-W2 or Wi-L2-W2 and Wi, W2, L2, Rx, Ry, Ra, Rb, Rc and R6 are as defined in formula (IV), or compounds of formula (14a) wherein Ga is Rib or W, G2 is Ri or R6 and W, R2b, Ra, Rt, Rc, Ri, and R6 are as defined in formula (II) or (IV), can be prepared using the chemistry outlined in Scheme 3. Substituted hydrazines of formula (12) can be reacted with compounds of formula (13) or (13a) respectively, in refluxing glacial acetic acid to provide the desired triazole product.
Compounds of formula (13) or (13a) can be prepared from the corresponding carboxylic acid by (a) reacting with isobutyl chloro formate in the presence of a base such as, but not limited to, diisopropyl ethyl amine; (b) reacting the product of step (a) with ammonium hydroxide to provide amides such as those of formula (iv); and (c) acylation of amides from step (b) with acid chlorides of formula G2C(O)Cl, in the presence of a base such as, but not limited to, sodium hydride provides compounds of formula (13) and (13a) respectively.
Alternatively, amides obtained from step (b) can be formylated by reacting with N,N,- dimethylformamide dimethylacetal at elevated temperature (for example, at about 100 0C to about 130 0C), followed by stirring in an acid such as acetic acid at about 0 0C to about room temperature, to provide compounds of formula (13) and (13a) respectively wherein R6 and G2 are hydrogen.
Figure imgf000024_0001
(15) (16) (17)
Triazoles of formula (17) wherein Gi is Wi, Wi-W2 or Wi-L2-W2 and Wi, W2, L2, Rx, Ry, Ra, Rb, Rc and Rg are as defined in formula (V) can be prepared from the reaction of azides of formula (15) with acetylenes of formula (16), in the presence of a solvent such as, but not limited to, toluene. The transformation is generally performed at the reflux temperature of the solvent employed. Scheme 5
Figure imgf000025_0001
(18) (19) (20)
Triazoles of formula (20) wherein G1 is W1, W1-W2 or W1-L2-W2 and W1, W2, L2, Rx, Ry, Ra, Rb, R0 and R9 are as defined in formula (V) can be prepared from azides of formula (18) and acetylenes of formula (19). The conversion is generally conducted by heating the mixtures in a solvent such as, but not limited to, ethanol at reflux to provide a mixture of triazole regioisomers, from which the triazoles of formula (20) can be isolated by chromatography.
Scheme 6
Figure imgf000025_0002
Triazoles of formula (23) wherein G1 is R2a, W1, W1-W2 or W1-L2-W2 when t is 1 or 2, or G1 is R2b when t is 0, and G2 is R1 or R6, wherein R2a, R2b, W1, W2, L2, Ra, Rb, R0, R1, R6, Ru and Rv are as defined in formula (II) or (IV), can be prepared using the chemistry outlined in Scheme 6. Triazoles of formula (21) can be brominated using N-bromosuccinimide in the presence of a catalytic amount of benzoyl peroxide in a refluxing solvent such as carbon tetrachloride. The resultant bromotriazoles of formula (22) can be reacted with amines of formula G1-(CRuRy)4-NH2, either neat at 100-150 0C or in solvents such as toluene, xylene, acetonitrile or ethanol at reflux.
Scheme 7
Figure imgf000026_0001
Triazoles of formula (28) wherein G1 is R2a, W1, W1-W2 or W1-L2-W2 when t is 1 or 2, or Gi is R2^, when t is 0, and G2 is Ri or R6, wherein Wi, W2, L2, R2a, R2b, Ra, Rb, Rc, Ri , R6, R11 and Rv are as defined in formula (I) or (III), can be prepared using the chemistry outlined in Scheme 7. Isothiocyanates of formula (24) and amines of formula Gr(CRuRv)t-NH2 can be reacted in a solvent such as, but not limited to, tetrahydrofuran, with or without heating to provide thioureas of formula (25). The thioureas of formula (25) can be converted to compounds of formula (26) by reacting with hydrazine in a solvent such as, but not limited to, tetrahydrofuran in the presence of a base such as triethylamine and a mercury salt such as mercuric chloride. The reaction can be accomplished either at room temperture or at elevated temperature. Triazoles of formula (28) can be synthesized from compounds of formula (26) by reacting with orthoesters of formula (27) (for example, triethylorthoformate and the like) in the presence of an acid catalyst such as, but not limited to, formic acid. The reaction can be effected with heating to reflux in a solvent such as, but not limited to, tetrahydrofuran.
Scheme 8
Figure imgf000026_0002
(29) (30) (31) (32) Azides of formula (31) and amines of formula (32) wherein G1 is R2a, W1, W1-W2 or W1-L2-W2, when t is 1 or 2, or G1 is R2b when t is 0, and wherein W1, W2, L2, R11, Rv, R2a and R2b are as defined in formula (I) -(V)3 can be prepared by a variety of methods known to one skilled in the art. One example of such preparations is outlined in Scheme 8. Alcohols of formula (29) can be reacted with neat thionyl chloride, with or without a solvent at about room temperature to provide chlorides of formula (30) wherein X'" is Cl. Examples of solvents used are, but not limited to, dichloromethane and chloroform. Alternatively, compounds of formula (31) wherein X'" is methyl sulfonate (mesylate) can be prepared from alcohols of formula (29) with methane sulfonyl chloride, in the presence of a base such as, but not limited to, triethylamine.
Displacement of chlorides or mesylates of formula (30) with sodium azide in a solvent such as, but not limited to, N,N-dimethylformamide or acetone, provides azides of formula (30), which can be reduced to amines of formula (32) in the presence of a reducing agent such as, but not limited to, palladium/carbon or PtCVcarbon. The reaction can be performed in a solvent such as, but not limited to, ethanol, methanol or ethyl acetate at about room temperature.
Scheme 9
Figure imgf000027_0001
(33) (34) (35) (36) Amines of formula (36) wherein Gi is R2a, Wi, Wi-W2 or Wi-L2-W2, and R2a, Wi,
W2, and L2 are as defined in formula (I) -(V), can be prepared from the corresponding aldehydes of formula (33) as depicted in Scheme 9. Reaction of the aldehydes of formula (33) with hydroxylamine hydrochloride in an alcoholic solvent such as, but not limited to, ethanol, provides oximes of formula (34). Oximes of formula (34) can be converted to nitriles of formula (35) in the presence of acetic anhydride and a base such as, but not limited to, potassium hydroxide or sodium hydroxide. Reduction of the nitriles of formula (35) with Raney/nickel and ammonia provides amines of formula (36). The reduction can be performed in an alcoholic solvent such as, but not limited to, methanol. Certain nitriles of formula (35) can be purchased (for example 2-amino nicotinonitrile) or prepared using procedures described in literature reference such as, but not limited to, Aimed et al, Indian Chem. Soc, 1996, 73, 141.
Nitriles of formula (35) can be prepared from the reaction of the corresponding bromides with zinc cyanide in the presence of a palladium catalyst, such as but not limited to, bis(triphenylphosρine)palladium (II) chloride and in a solvent such as N,N- dimethylformamide.
Scheme 10
N≡≡— W1- X' + "X-W2 *- N≡≡_Wi_L2 — W2 *- H2NH2C-W1-L2 — W2
(37) (38) (39) (40)
Compounds of formula (39) wherein L2 is O, N(H) or N(alkyl) and W1 and W2 are as defined in formula (I)-(V) can be prepared by reaction of nitriles of formula (37) wherein X' is OH, NH2 or N(H)(alkyl) with halides of formula (38) wherein X" is fluoro or chloro, in the presence of a base such as, but not limited to, sodium hydride or potassium carbonate. The reaction can be conducted in a solvent such as tetrahydrofuruan, dimethylformamide or dioxane at a temperature from about room temperature to about 15O0C.
Conversely, compounds of formula (39) wherein L2 is O, N(H) or N(alkyl) and Wi, and W2 are as defined in formula (I)-(V) can also be prepared by reaction of nitriles of formula (37) wherein X' is fluoro and compounds of formula (38) wherein X" is -NH2, -N(H)(alkyl), or OH under the abovementioned conditions.
Amines of formula (40) can be prepared from nitriles of formula (39) using the transformation conditions for the conversion of compounds of formula (35) to (36) as outlined in Scheme 9.
Scheme 11 N≡≡— W1- X' + "X — W2 *- N=^-AV1-W2 »- H2NH2C-W1-W2
(37) (38) (41) (42)
Nitriles of formula (41) wherein W1 and W2 are as defined in formula (I)-(V), can be prepared by reaction of nitriles of formula (37) wherein X' is Cl, Br, I or triflate with boronic acid or ester of formula (38) wherein X" is -B(OR1OO2 ^d R10I is hydrogen or alkyl, in the presence of a palladium catalyst, such as but not limited to, bis(triphenylphospine)palladium (II) chloride and a base such as triethylamine or sodium carbonate. The reaction can be effected by heating from 50-90 0C in solvents such as isopropanol, ethanol, dimethoxyethane, water or dioxane. Alternatively, this transformation can be accomplished by reacting nitriles of formula (37) wherein X' is Cl, Br, I or triflate with tin reagents of formula (38) wherein X" is -Sn(alkyl)3, with a palladium catalyst such as, but not limited to, tetrakis(triphenylphospine)palladium (0) , and cesium fluoride and heating in a solvent such as dioxane. These transformations can also be effected by heating in a microwave reactor.
The transformation can also be accomplished by reacting compounds of formula (38) wherein X" is Cl, Br, I or triflate with compounds of formula (37) wherein X' is -Sn(alkyl)3 or -B(OR1Oi)2 and R1Oi is hydrogen or alkyl using the abovementioned reaction conditions.
Amines of formula (42) can be obtained from nitriles of formula (41) using using the transformation conditions for the conversion of compounds of formula (35) to (36) as outlined in Scheme 9.
Scheme 12
Figure imgf000029_0001
Alcohols of formula (29) can be prepared by various methodologies known to one skilled in the art. One such method is shown in Scheme 12.
The aldehyde of formula (43) can be reduced with sodium borohydride then protected as the t-butyldimethylsilyl ether, followed by mono-debromination with n-butyl lithium. The mono-bromothiazole of formula (46) can then be reacted with compounds of formula (38) wherein X" is -Sn(alkyl)3 or -B(ORiOi)2 and R1Oi is hydrogen or alkyl using the reaction conditions outlined in Scheme 11, followed by removal of the t-butyldimethyl silyl group using reaction conditions known to one skilled in the art, to provide compounds of formula (47).
Scheme 13
Figure imgf000030_0001
Triazoles of formula (50) wherein Ra, Rb, Rc, Rn, Rx5 Ry and W1 are as defined in formula (V) can be prepared from substituted acetylenes of formula (48) and azide reagents of formula (49) (for example, trimethylsilylazide, methylazide, ethylazide and the like). The reaction is generally conducted with or without a solvent such as, but not limited to, dioxane, toluene or xylene, at a temperature from about 100 0C to about 150 °C.
Scheme 14
Figure imgf000030_0002
(51 ) (52) (53) (54)
1 . nBuLi
Figure imgf000030_0003
Figure imgf000030_0004
Figure imgf000030_0005
(55) (52) (56) (57) Triazoles of formula (54) wherein G2 is R1 or R6 and G1 is W1, W1-W2 or Wj-L2-W2, and R1, R6, W1, W2, L2, Ra, Rb and Rς are as defined in formula (II) or (IV) can be prepared using the chemistry shown in Scheme 14. Triazoles of formula (51) can be lithiated with alkyllithium reagents like n-butyl lithium, sec-butyl lithium or tert-butyl lithium in solvents such as tetrahydrofuran or diethylether at temperatures from -100 °C to about room temperature, followed by addition of aldehydes of formula (52) to provide alcohols of formula (53). The alcohol can then be converted to an intermediate thiocarbonate using phenyl chlorothionoformate and a catalyst such as 4-(dimethylamino)pyridine, in a solvent such as acetonitrile followed by radical deoxygenation with a tin reagent such as tributyltinhydride with AIBN in a solvent such as toluene to provide triazoles of formula (54).
Similarly, triazoles of formula (57) wherein G2 is R1 or R6 and G1 is W1, Wi-W2 or Wi-L2-W2, and R1, R6, W1, W2, L2, Ra, Rb and R0 are as defined in formula (I) or (III) can be prepared from triazoles of formula (55).
d) Reference Examples
The following Examples are intended as an illustration of and not a limitation upon the scope of the invention as defined in the appended claims.
Example 1
4-benzyl-3-(2,3-dichlorophenvD-4H-l,2,4-triazole
Example IA 5-f2,3-dichlorophenvD-lH-tetrazole
A 2.0 M solution of A1(CH3)3 in toluene (35 mL) was treated with 2,3- dichlorobenzonitrile (8.00 g, 37.2 mmol), azidotrimethylsilane (5.14 g, 44.6 mmol) slowly, and heated at 80 0C for 16 hours behind a blast shield. The mixture was cooled to 0 0C and treated with 2N HCl (100 mL) dropwise over 1 hour. The mixture was allowed to warm to ambient temperature and extracted twice with ethyl acetate (100 mL). The combined organic phases were dried over Na2SO4, filtered through a 1/2" pad of silica gel, and the filtrate was evaporated under reduced pressure. The residue was purified by recrystallization from ethyl acetate/hexanes to provide the title compound. MS (DCITNH3) m/z 215 (M)+; 1H NMR (DMSO-d6) δ 7.59 (t, IH, J=8.0 Hz), 7.79 (dd, IH, J=7.8, 1.7 Hz), 7.92 (dd, IH, J=8.1, 1.7 Hz). Example IB ethyl 5-(2,3-dichlorophenyl)-l,3,4-oxadiazole-2-carboxylate
Example IA (6.45 g, 30.0 mmol) and ethyl chlorooxoacetate (3.4 mL, 30.4 mmol) in toluene (150 mL) were heated at reflux for 2 hours, cooled, the solvent was evaporated, and the crude material was recrystallized from ethanol to provide the title compound. MS
(DCITNH3) m/z 287 (M+H)+; 1H NMR (CDCl3) δ 1.49 (t, 3H), 4.57 (q, 2H), 7.40 (t, IH), 7.72 (dd, IH)5 7.96 (dd, IH).
Example 1C 2-(2,3-dichlorophenyl)-1.3,4-oxadiazole
Example IB (5.75 g, 20.0 mmol) and potassium hydroxide (1.2 g, 20.7 mmol) were combined in ethanol (200 mL) and heated at reflux for 2 hours. The mixture was allowed to cool to room temperature, acidified with IN hydrochloric acid (50 mL), concentrated under reduced pressure, and the residue was partitioned between methylene chloride and water. The organic phase was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography over silica gel, eluting with hexanes/ethyl acetate (2:1). MS (DClTNH3) m/z 215 (M+H)+; 1H NMR (CDCl3) δ 7.37 (t, IH), 7.69 (dd, IH), 7.90 (dd, IH), 8.58 (s, IH).
Example ID
4-benzyl-3-(2,3-dichlorophenylV4H-l,2,4-triazole
Example 1C (216 mg, 1.01 mmol) and benzylamine (0.13 mL, 1.2 mmol) were heated in xylenes (0.25 mL) at 140 0C in a sealed tube for 72 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (40mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 12 minutes (15 minute run time) at a flow rate of 70 mL/minute to provide the title compound. MS (DCI/NH3) m/z 304 (M+H)+; 1HNMR (CDCl3) δ 5.00 (s, 2H), 7.01 (m, 2H), 7.24-7.34 (m, 5H), 7.63 (m, IH), 8.22 (s, IH). Anal calcd for C15HnCl2N3: C, 59.23; H, 3.65; N, 13.81. Found: C, 58.93; H, 3.41; N, 13.64. Example 2
3-(2,3-dichlorophenyl)-4-r3-fluoro-5-rtrifluoromethvDbenzyl]-4H-l,2.4-txiazole The title compound was prepared using the procedure as described in Example ID substituting 3-fluoro-5-(trifluoromethyl)benzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 390 (M+H)+; 1H NMR (DMSOd6) δ 5.26 (s, 2H), 7.09 (s, IH), 7.18 (d, IH), 7.41 (dd, IH), 7.46 (t, IH), 7.59 (d, IH), 7.82 (dd, IH), 8.88 (s, IH).
Example 3
3-(2,3-dichlorophenyl)-4-r4-('trifluororαethoxy)benzyl1-4H-l,2,4-triazole The title compound was prepared using the procedure as described in Example ID substituting 4-(trifluoromethoxy)benzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 388 (M+H)+; 1H NMR (DMSOd6) δ 5.17 (s, 2H), 7.06 (d, 2H), 7.23 (d, 2H), 7.38 (d, IH), 7.44 (t, IH), 7.82 (d, IH), 8.84 (s, IH).
Example 4
3-(2,3-dichlorophenylV4-r3-(trifluoromethvDbenzvn-4H-L2,4-triazole The title compound was prepared using the procedure as described in Example ID substituting 3-(trifluoromethyl)benzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 372 (M+H)+; 1H NMR (DMSOd6) δ 5.25 (s, 2H), 7.21 (s, IH), 7.28 (d, IH), 7.37 (dd, IH), 7.44 (t, IH), 7.49 (t, IH), 7.61 (d, IH), 7.81 (dd, IH), 8.78 (s, IH). Example 5
3-(2,3-dichlorophenyl)-4-[4-(trifluoromethyl)benzyl]-4H-l,2,4-triazole The title compound was prepared using the procedure as described in Example ID substituting 4-(trifluoromethyl)benzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 372 (M+H)+; 1H NMR (DMSO-d6) δ 5.25 (s, 2H), 7.16 (d, 2H), 7.39 (dd, IH), 7.44 (t, IH), 7.61 (d, 2H), 7.82 (dd, IH), 8.86 (s, IH).
Example 6
3-(2,3-dichlorophenyl)-4-r3-ftrifluoromethoxy)benzyl1-4H-L2,4-triazole The title compound was prepared using the procedure as described in Example ID substituting 3-(trifluoromethoxy)benzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 388 (M+H)+; 1H NMR (DMSOd6) δ 5.20 (s, 2H), 6.93 (s, IH), 6.97 (d, 1H),7.25 (d, IH), 7.38 (m, 2H), 7.44 (t, IH), 7.82 (dd, IH), 8.87 (s, IH).
Example 7
4-(4-tert-butylbenzyl)-3-(2,3-dichloroρhenvD-4H-L2,4-triazole The title compound was prepared using the procedure as described in Example ID substituting 4-(tert-butyl)benzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 360 (M+H)+;1H NMR (DMSOd6) δ 1.22 (s, 9H), 5.07 (s, 2H), 6.86 (d, 2H), 7.24 (d, 2H), 7.39 (dd, IH), 7.46 (t, IH), 7.82 (dd, IH), 8.81 (s, IH). Example 8
3-(2.3-dichlorophenylV4-('2.3-dimethylbenzylV4H-l,2.4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2,3-dimethylbenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 332 (M+H)+; 1H NMR (DMSO-d6) δ 1.92 (s, 3H), 2.16 (s, 3H), 5.15 (s, 2H), 6.54 (d, IH), 6.90 (t, IH), 7.05 (d, IH), 7.37 (dd, IH), 7.42 (t, IH), 7.79 (dd, IH), 8.66 (s, IH).
Example 9
3-(2,3-dichlorophenyl)-4-(2,5-dimethylbenzylV4H-1.2.4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2,5-dimethylbenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 332 (M+H)+; 1H NMR (DMSOd6) δ 1.98 (s, 3H), 2.09 (s, 3H),5.11 (s, 2H), 6.41 (s, IH), 6.95 (m, 2H), 7.35 (d, IH), 7.41 (t, IH), 7.79 (dd, IH), 8.73 (s, IH).
Example 10
3-(23-dichlorophenylV4-f3.4-dimethylbenzylV4H-l,2.4-triazole The title compound was prepared using the procedure as described in Example ID substituting 3,4-dimethylbenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 332 (M+H)+; 1H NMR (DMSO-d6) δ 2.09 (s, 3H), 2.14 (s, 3H),5.02 (s, 2H), 6.67 (m, 2H), 6.99 (d, IH), 7.38 (d, IH), 7.47 (t, IH), 7.84 (d, IH), 8.80 (s, IH). Example 11
S-^.S-dichlorophenvD^-O^-dimethylbenzvD^H-l^^-triazole The title compound was prepared using the procedure as described in Example ID substituting 3,5-dimethylbenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 332 (M+H)+; 1H NMR (DMSO-d6) δ 2.14 (s, 3H), 2.50 (s, 3H),5.02 (s, 2H), 6.49 (s, 2H), 6.86 (s, IH), 7.38 (d, IH), 7.47 (t, IH), 7.84 (d, IH), 8.80 (s, IH).
Example 12
3-(2,3-dichlorophenyl')-4-(2,3-dimethoxybenzylV4H-l,2,4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2,3-dimethoxybenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 364 (M+H)+; 1H NMR (DMSO-de) δ 3.47 (s, 3H), 3.75 (s, 3H), 5.05 (s, 2H), 6.35 (d, IH), 6.90 (t, IH), 6.98 (dd, 1H),7.38 (dd, IH), 7.46 (t, IH), 7.83 (dd, IH), 8.68 (s, IH).
Example 13
3-(2,3-dichlorophenyl')-4-(2,5-dimethoxybenzylV4H-1.2.4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2,5-dimethoxybenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 364 (M+H)+; 1H NMR (DMSO-d6) δ 3.54 (s, 3H), 3.60 (s, 3H), 5.00 (s, 2H), 6.43 (d, IH), 6.82 (m, 2H), 7.38 (dd, IH), 7.48 (t, IH), 7.84 (dd, IH), 8.72 (s, IH). Example 14
4-r2,3-dichlorobenzylV3-α.3-dichloroph.enyl)-4H-1.2.4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2,3-dichlorobenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 374 (M+H)+; 1H NMR (DMSOd6) δ 5.29 (s, 2H), 6.88 (dd, IH), 7.22 (t, IH), 7.41 (dd, IH), 7.44 (t, IH), 7.56 (dd, IH), 7.81 (dd, IH), 8.81 (s, IH).
Example 15
4-(2,3-dichlorobenzylV3-(2.4-dichlorophenylV4H-L2,4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2,4-dichlorobenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 374 (M+H)+; 1H NMR (DMSOd6) δ 5.23 (s, 2H), 6.96 (d, IH), 7.30 (dd, IH), 7.40 (dd, IH), 7.45 (t, IH), 7.55 (d, IH), 7.82 (dd, IH), 8.79 (s, IH).
Example 16
4-(2.3-dichlorobenzvn-3 -C2.5-dichlorophenyl)-4H- 1 ,2.4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2,5-dichlorobenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute ran time) at a flow rate of 40 mL/minute. MS (ESI) m/z 374 (M+H)+; 1H NMR (DMSOd6) δ 5.24 (s, 2H), 6.93 (d, IH), 7.37-7.42 (m, 3H), 7.46 (t, IH), 7.82 (dd, IH), 8.83 (s, IH). Example 17
4-(2.3-dichlorobenzyl')-3-(3,4-dichlorophenylV4H-1.2.4-triazole The title compound was prepared using the procedure as described in Example ID substituting 3,4-dichlorobenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 374 (M+H)+; 1H NMR (DMSOd6) δ 5.14 (s, 2H), 6.95 (dd, IH), 7.18 (d, IH), 7.40 (dd, IH), 7.47 (t, IH), 7.51 (d, IH), 7.84 (dd, IH), 8.84 (s, IH).
Example 18
4-("2.3-dichlorobenzylV3-("3.5-dichlorophenylV4H-1.2.4-triazole The title compound was prepared using the procedure as described in Example ID substituting 3,5-dichlorobenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (ESI) m/z 374 (M+H)+; 1H NMR (DMSO-d6) δ 5.15 (s, 2H), 6.97 (d, 2H), 7.42 (dd, IH), 7.49 (t, IH), 7.50 (s, IH), 7.85 (dd, IH), 8.85 (s, IH).
Example 19
3-(2,3-dichlorophenyl>4-f2-metfaoxyberizvD-4H- 1 ,2.4-triazole The title compound was prepared using the procedure described in Example ID substituting 2-methoxybenzylamine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (DCITNH3) m/z 334 (M+H)+; 1H NMR (CDCl3) δ 3.75 (s, 3H), 4.99 (s, 2H), 6.81 (m, 3H), 7.30 (m, 3H), 7.65 (dd, IH), 8.27 (s, IH). Example 20
3-f2.3-dichlorophenvD-4-('2-methylbenzyl')-4H-l,2t4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2-rnethylbenzylarnine for benzylamine. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute. MS (DCIZNH3) m/z 318 (M+H)+; 1H NMR (CDCl3) δ 2.10 (s, 3H), 4.99 (s, 2H), 6.94 (d, IH), 7.15 (m, 2H), 7.23-7.32 (m, 3H), 7.64 (dd, IH), 8.06 (s, IH).
Example 21 r4-(2,3-Dichloro-phenylV4H-ri2.41triazol-3-vll-f2-(5-fluoro-pyridin-3-yloxyVpyridin-3- ylmethyi] -amine
Example 21 A
2-(5-Fluoro-pyridin-3-yloxyVnicotinonitrile
The title compound was prepared using the procedure as described in Example 109A substituting 5-fluoro-pyridin-3-ol for pyridin-3-ol. MS (ESI+) m/z 216 (M+H)+.
Example 21B
|2-[(5-fluoropyridin-3-yl)oxylpyridin-3-yl}methylamine
The title compound was prepared using the procedure as described in Example 109B substituting Example 21A for Example 109A. MS (ESI+) m/z 220 (M+H)+'
Example 21C r4-(2,3-Dichloro-phenylV4H-ri2.41triazol-3-yll-r2-(5-fluoro-pyridin-3-yloxyVpyridin-3- ylmethyl] -amine
The title compound was prepared using the procedure as described in Example 100 substituting Example 21B for 2-methylbenzylamine. MS (ESI+) m/z 431 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.51 (d, J=5.76 Hz, 2 H) 6.71 (dd, J=5.76 Hz, 1 H) 7.18 (dd,
/=7.46, 4.75 Hz, 1 H) 7.55 (t, J=7.97 Hz, 1 H) 7.61 - 7.66 (m, 1 H) 7.74 (dt, J=9.83, 2.37 Hz, 1 H) 7.82 (dd, J=I '.46, 1.70 Hz, 1 H) 7.86 (dd, J=8.14, 1.70 Hz, 1 H) 8.03 (dd, J=4.92, 1.86 Hz, 1 H) 8.19 (s, 1 H) 8.38 (dd, J=IJO, 1.02 Hz, 1 H) 8.48 (d, J=2.37 Hz, 1 H)
Example 22 3 -f 2.3 -dichloroρhenvD-4-f 1 -phenylethylV4H- 1.2.4-triazole
The title compound was prepared using the procedure as described in Example ID substituting 1-phenylethylamine for benzylamine. MS (DCI/NH3) m/z 318 (M+H)+; 1H NMR (CDCl3) δ 1.86 (d, 3H), 5.15 (q, IH), 6.98 (m, 2H), 7.10 (d, IH), 7.23 (t, IH), 7.27-7.32 (m, 3H), 7.61 (dd, IH), 8.40 (s, IH).
Example 23
3-(2.3-dichlorophenvD-4-(l -methyl- 1 -phenylethvD-4H- 1 ,2,4-triazole The title compound was prepared using the procedure as as described in Example ID substituting 1 -methyl- 1-phenylethylamine for benzylamine. MS (DCI/NH3) m/z 332 (M+H)+; 1R NMR (CDCl3) δ 1.65-1.98 (br s, 6H), 6.29 (dd, IH), 6.88 (t, IH), 7.00 (m, 2H), 7.18 (dd, IH), 7.23-7.30 (m, 3H), 7.44 (dd, IH), 8.50 (s, IH).
Example 24
1 -benzyl-5-(2,3-dichloroρhenyl)- IH- 1 ,2,4-triazole
Example 24A
2.3-dichloro-N-[fdimethylamino)methylene]benzamide
2,3-Dichlorobenzamide (4.96 g, 26.1 mmol) and dimethylformamide dimethylacetal (10 mL) were heated at reflux for 1.5 hours, allowed to cool to room temperature, concentrated under reduced pressure, and the residue was partitioned between diethyl ether and water. The organic phase was washed with water (2x), saturated sodium chloride, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate to provide the title compound. MS (DCIZNH3) m/z 245 (MH-H)+.
Example 24B l-benzyl-5-(2,3-dichlorophenylVlH-1.2.4-triazo1e Example 24A (269 mg, 1.10 mmol), sodium acetate monohydrate (360 mg, 3.6 mmol), 70% acetic acid (3 mL), and benzylhydrazine dihydrochloride (235 mg, 1.2 mmol) were combined in 1,4 dioxane (3 mL) and heated at reflux for 2 hours. The mixture was allowed to cool to room temperature, concentrated under reduced pressure, and the residue was partitioned between methylene chloride and water. The organic phase was washed with water, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate:hexanes (1 : 1) to provide the title compound. MS (DCITNH3) m/z 304 (M+H)+; 1H NMR (CDCl3) δ 5.20 (s, 2H), 7.00-7.07 (m, 2H), 7.18 (dd, IH), 7.23-7.30 (m, 4H), 7.62 (dd, IH), 8.05 (s, IH); Anal calcd for Ci5HnCl2N3: C, 59.23; H, 3.65; N, 13.81. Found: C, 59.47; H, 3.87; N, 13.70.
Example 25 l-benzyl-5-(2,3-dichlorophenyl)-lH-L2,3-triazole
Example 25A
[(2,3-dichlorophenyl)ethynyl](trimethyi)silane l,2-Dichloro-3-iodobenzene (4.95 g, 18.1 mmol), trimethylsilylacetylene (2 g, 20 mmol), bis(triphenylphosphine)palladium(II)chloride (245 mg, 0.35 mmol), and copper(I)iodide (45 mg, 0.24 mmol) were combined in triethylamine (120 mL) and heated at reflux for 45 minutes. The mixture was allowed to cool to room temperature and was then partitioned between diethyl ether and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was taken directly on to the next step.
Example 25B
1 ,2-dichloro-3-ethynylbenzene
Example 25A (4.0 g, 16.5 mmol) and potassium carbonate (2.28 g, 16.5 mmol) were combined in methanol (125 mL), stirred for 30 minutes, and the mixture was partitioned between diethyl ether and water. The organic phase was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with pentane: diethyl ether (9:1) to provide the title compound. 1H NMR (CDCl3) δ 3.41 (s, IH), 7.06 (t, IH), 7.44 (d, 2H).
Example 25C l-benzyl-5-(23-dichloroρhenylVlH-1.2.3-triazole
Example 25B (200 mg, 1.17 mmol) and benzylazide (130 mg, 0.98 mmol) were combined in ethanol (1 mL) and heated at 80 0C in a sealed tube for 16 hours. The mixture was treated with additional benzylazide (100 mg) and heated an additional 4 hours. The mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The crude residue was composed of a mixture of regioisomers that were purified by flash chromatography eluting with hexanes: ethyl acetate (3:1) to provide the title compound. MS (DCI/NH3) m/z 304 (M+H)+; 1H NMR (CDCl3) δ 5.43 (s, 2H), 6.90 (dd, IH), 6.94 (m, 2H), 7.13-7.24 (m, 4H), 7.55 (dd, IH), 7.71 (s, IH).
Example 26
5-benzyl-l-(2.3-dichlorophenyl)-lH-l,2,3-triazole l-Azido-2,3-dichlorobenzene (200 mg, 1.06 mmol) (Cambie J. Organomet. Chem. 1996, 507, 1) and 3 -phenyl- 1-propyne (150 μL, 1.1 equiv) were combined in toluene (0.2 mL) and heated at 100 0C for 18 hours, allowed to cool to room temperature, and then concentrated under reduced pressure to give a mixture of regioisomers. The residue was purified by flash chromatography eluting with hexanes -.ethyl acetate (3:1) to provide the title compound. MS (DCI/NH3) m/z 304 (M+H)+; 1H NMR (CDCl3) δ 3.87 (br s, 2H), 6.98 (m, 2H), 7.13 (dd, IH), 7.22 (m, 3H), 7.29 (t, IH), 7.56 (s, IH), 7.64 (dd, IH).
Example 27
4-benzyl-5-(2.3-dichlorophenylVlH-1.2.3-triazole
Example 27A
L2-dichloro-3-(3-phenylprop-l-vnyDbenzene l,2-Dichloro-3-iodobenzene (4.39 g, 16.1 mmol), benzylacetylene (1.96 g, 16.9 mmol), copper(I) iodide (26 mg, 0.14 mmol) and bistriphenylphosphinepalladium(II)chloride (113 mg, 0.16 mmol) were combined in triethylamine (100 mL) and heated at reflux for 2 hours. The reaction was allowed to cool to room temperature and then was partitioned between saturated sodium chloride and diethylether. The organic phase was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel (eluting with hexane) to provide the title compound. MS (DClTNH3) m/z 278 (M+NH4)+; 1H NMR (CDCl3) δ 3.90 (s, 2H), 7.13 (t, IH), 7.2-7.5 (m, 7H).
Example 27B
4-benzyl-5-(2,3-dichlorophenylVlH-1.2,3-triazole Example 27 A (294 mg, 1.13 mmol) and azidotrimethylsilane (0.16 mL, 1.2 mol) were combined and heated at 120 0C overnight, treated with additional azidotrimethylsilane (0.25 mL, 1.89 mmol) and heated for 3 days. The reaction was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:ethyl acetate, 3:1) to provide the title compound. MS (DCITNH3) m/z 304 (M+H)+; 1R NMR (CDCl3) δ 4.03 (s, 2H), 7.02-7.30 (m, 7H), 7.52 (dd, IH).
Example 28 3-r2-chloro-3-(trifluoromethvl)phenyll-4-(2-methylbenzylV4H-L2.4-triazole
Example 28A
2-[2-chloro-3 -(trifluoromethvDphenyl] -1,3 ,4-oxadiazole
2-Chloro-3-trifluoromethylbenzoic acid (10 g, 44.5 mmol) in sulfuric acid (1 mL) was heated at reflux in ethanol (50 mL) for 24 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was diluted with diethyl ether, washed with saturated sodium bicarbonate (3x), dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure to provide 9.65 g of the crude ester. The obtained ester was heated with hydrazine hydrate (9.4 mL 194 mmol) in ethanol (50 mL) for 3 hours, allowed to cool to room temperature, and concentrated under reduced pressure to provide the crude acylhydrazide. The obtained acylhydrazide was combined with triethylorthoformate (20 mL 120 mmol) and/>αra-toluenesulfonic acid monohydrate (530 mg 2.8 mmol) in toluene and heated at reflux for 2 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate, 3:2) to provide the title compound. MS (DClTNH3) m/z 249 (M+H)+; 1H NMR (CDCl3) δ 7.56 (t, IH), 7.93 (dd, IH), 8.15 (dd, IH), 8.61 (s, IH).
Example 28B 3-r2-chloro-3-αrifluoromethyl)phenyll-4-('2-methylbenzyl)-4H-L2,4-triazole
Example 28A (190 mg 0.76 mmol) and 2-methylbenzylamine (0.105 mL 0.85 mmol) were combined in toluene (0.125 mL), heated at 100 0C for 42 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (3% methanol/ethyl acetate) to provide the title compound. MS (DCI/NH3) m/z 352 (M+H)+; 1H NMR (CDCl3) δ 5.01 (s, 2H), 6.91 (d, IH), 7.07-7.27 (m, 3H), 7.45 (t, IH), 7.53 (dd, IH), 7.87 (dd, IH), 8.13 (s, IH).
Example 29
5-(2,3-dichlorophenyl)-l-(2,3-dihvdro-l-benzofuran-7-ylmethylVlH-l,2,3-triazole
Example 29A
2,3 -dihydro- 1 -benzofuran-7-ylmethanol
2,3-Dihydrobenzofuran carboxylic acid (5.047g, 30.77 mmol) in tetrahydrofuran at — 10 0C was treated dropwise with a solution of 1.0 M borane-tetrahydrofuran (20 mL 20 mmol). The temperature was allowed to warm to room temperature overnight, and was then treated with additional 1.0 M borane-tetrahydrofuran (10 mL 10 mmol), and stirred at room temperature for 2 hours. The mixture was cooled to 5 0C, slowly treated with methanol (20 mL), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate (2x), saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes: ethyl acetate, 3:2) to provide the title compound. MS (DCITNH3) m/z 168 (MH-NH4)VH NMR (CDCl3) δ 3.21 (t, 2H), 4.60 (t, 2H), 4.68 (s, 2H), 6.83 (t, IH), 7.08 (dd, IH), 7.14 (dd, IH). Example 29B
7-(bromomethyl)-2,3 -dihydro- 1 -benzofuran
Example 29 A (4.06 g, 27.1 mmol) and carbon tetrabromide (10.9 g, 32.8 mmol) were combined in methylene chloride (100 mL) at 0 0C and treated with triphenylphosphine (8.53 g, 32.6 mmol) portionwise. The mixture was allowed to warm to room temperature, was stirred overnight, concentrated under reduced pressure, and the residue was purified by flash chromatography (2% ethyl acetate/hexanes) to provide the title compound. 1H NMR (CDCl3) δ 3.22 (t, 2H), 4.50 (s, 2H), 4.65 (t, 2H), 6.81 (t, IH), 7.12 (m, 2H).
Example 29C
7-(azidomethylV2,3-dihydro-l-benzofuran
Example 29B (4.40 g, 20.7 mmol) in N,N-dimethylformamide (60 mL) at room temperature was treated in one portion with sodium azide (5.37 g, 82.6 mmol), stirred for 3 hours, poured into water and extracted with diethylether (2x100 mL). The organics were dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (5% ethyl acetate/hexane) to provide the title compound. 1H NMR (CDCl3) δ 3.23 (t, 2H), 4.31 (s, 2H), 4.60 (t, 2H), 6.85 (t, IH), 7.06 (d, IH), 7.19 (dd, IH).
Example 29D
5-(2,3-dichloroτ>henylVl-(23-dihvdro-l-benzofuran-7-ylmethvD-lH-l,2,3-triazole
Example 29C (710 mg, 4.06 mmol) and l,2-dichloro-3-ethynylbenzene (370 mg, 2.18 mmol) were combined in toluene and heated at 100 °C overnight in a sealed tube. The reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue composed of a mixture of regioisomers was purified by flash chromatography with gradient elution (3:1 to 1:1 hexane: ethyl acetate) to provide the title compound as the minor more polar regioisomer. MS (DCI/NH3) m/z 346 (M+H)+; 1H NMR (CDCl3) δ 3.08 (t, 2H), 4.34 (t, 2H), 5.41 (s, 2H), 6.69 (t, IH), 6.78 (d5 IH), 6.97 (dd, IH), 7.03 (dd, IH), 7.18 (t, IH), 7.54 (dd, IH), 7.70 (s, IH); Anal, calcd for CnHi3Cl2N3O: C, 58.98; H, 3.78; N, 12.14. Found: C, 58.92; H, 3.61; N, 12.16. Example 30
3-r2,3-dichlorophenylV4-|"2-ftrifluoromethvnbenzyll-4H-l,2,4-triazρle The title compound was prepared using the procedure as described in Example ID substituting 2-(trifluoromethyl)benzylamine for benzylamine. MS (DClTNH3) m/z 372 (M+H)+; 1H NMR (CDCl3) δ 5.23 (s, 2H), 7.03 (d, IH), 7.31 (m, 2H), 7.50 (m, 2H), 7.67 (m, 2H), 8.25 (s, IH).
Example 31
3-(2,3-dichlorophenyl)-4-["2-(difluoromethoxy)benzyl]-4H-l,2.4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2-(difluoromethoxy)benzylamine for benzylamine. MS (DClTNH3) m/z 370 (M+H)+; 1H NMR (CDCl3) δ 5.09 (s, 2H), 6.47 (t, IH, J=72.9 Hz), 6.93 (dd3 IH), 7.07-7.14 (m, 2H), 7.26-7.39 (m, 3H), 7.66 (dd, IH), 8.41 (s, IH).
Example 32
3-(2,3-dichlorophenyl)-4-["2-(trifluoromethoxy)benzyl]-4H-l,2,4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2-(trifluoromethoxy)benzylamine for benzylamine. MS (DCI/NH3) m/z 388 (M+H)+; 1H NMR (CDCl3) δ 5.12 (s, 2H), 6.96 (dd, IH), 7.18-7.43 (m, 5H), 7.66 (dd, IH), 8.36 (s, IH).
Example 33
3-(2,3-dichlorophenyl)-4-r2,3-difluorobenzyl)-4H-L2,4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2,3-difluorobenzylamine for benzylamine. MS (DClTNH3) m/z 340 (M+H)+; 1H NMR (CDCl3) δ 5.12 (s, 2H), 6.68 (t, IH), 6.99-7.07 (m, IH), 7.13-7.22 (m, IH), 7.29-7.38 (m, 2H), 7.69 (dd, IH), 8.43 (s, IH).
Example 34 3-(23-dichlorophenylV4-["2-('methylthio)benzyll-4H-L2,4-triazole
The title compound was prepared as a trifluoroacetic acid salt using the procedure as described in Example ID substituting 2-(methylthio)benzylamine for benzylamine. MS (DCI/NH3) m/z 349 (M+H)+; 1H NMR (CDCl3) δ 2.41 (s, 3H), 5.11 (s, 2H), 6.92 (dd, IH), 7.09 (td, IH), 7.23-7.37 (m, 4H), 7.66 (dd, IH), 8.34 (s, IH).
Example 35 3-(2,3-dichlorophenyl)-4-("2-ethoxybenzyl)-4H-l,2,4-triazole
The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 2-ethoxybenzylamine for benzylamine. MS (DCITNH3) m/z 348 (M+H)+; 1U NMR (CDCl3) δ 1.38 (t, 3H), 4.01 (q, 2H), 5.03 (s, 2H), 5.50 (br s, IH), 6.72-6.85 (m, 3H), 7.24-7.34 (m, 3H), 7.68 (dd, IH), 8.51 (s, IH).
Example 36
4-(3-chloro-2-fluorobenzyl')-3-(2,3-dichlorophenylV4H-l,2.4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 3-chloro-2-fluorobenzylamine for benzylamine. MS (DCI/NH3) m/z 356 (M+H)+; 1H NMR (CDCl3) δ 5.12 (s, 2H), 6.81 (t, IH), 7.02 (t, IH), 7.32-7.40 (m, 3H), 7.68 (dd, IH), 8.50 (s, IH).
Example 37
3-(23-dichlorophenγl)-4-r2-fluoro-3-ftrifluoromethyl)benzyll-4H-l,2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 2-fluoro-3-(trifluoromethyl)benzylamine for benzylamine. MS (DCI/NH3) m/z 390 (M+H)+; 1U NMR (CDCl3) δ 5.17 (s, 2H), 5.47 (br s, IH), 7.10-7.36 (m, 4H), 7.61 (m, IH), 7.68 (dd, IH), 8.51 (s, IH).
Example 38
3-r2.3-dichlorophenylV4-d-naphthylmethvD-4H-l,2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 1-naphthylmethylamine for benzylamine. MS (DCIZNH3) m/z 354 (M+H)+; 1H NMR (CDCl3) δ 3.70 (br s, IH), 5.47 (s, 2H), 7.20 (dd, IH), 7.29-7.62 (m, 6H), 7.64 (dd, IH), 7.88 (m, IH), 8.17 (s, IH). Example 39
3-C2,3-dichlorophenylV4-(thien-3-ylmethylV4H-l,2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting thien-3-yrmethylamine for benzylamine. MS (DCIMH3) m/z 310 (M+H)+; 1H NMR (CDCl3) δ 5.07 (s, 2H), 6.81 (dd, IH), 7.05 (d, IH), 7.31-7.34 (m, 3H), 7.66 (dd, IH), 8.46 (s, IH).
Example 40
3-(23-dichlorophenγlV4-(3-rurylmethylV4H-l,2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 3-furylmethylamine for benzylamine. MS (DCI/NH3) m/z 294 (M+H)+; 1H NMR (CDCl3) δ 4.95 (s, 2H), 6.22 (m, IH), 7.35 (s, IH), 7.39-7.43 (m, 3H), 7.69 (dd, IH), 8.46 (s, IH).
Example 41
3-(2,3-dichlorophenyl)-4-(2,5-difluorobenzylV4H-L2.4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 2,5-difluorobenzylamine for benzylamine. MS (DClTNH3) m/z 340 (M+H)+; 1HNMR (CDCl3) δ 5.07 (s, 2H), 6.58 (m, IH), 7.03 (m, 2H), 7.30-7.38 (m, 2H), 7.66 (dd, IH), 8.46 (s, IH).
Example 42
3-('2.3-dichlorophenylV4-[5-fluoro-2-ftrifluoromethyl)benzyll-4H-l,2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 5-fluoro-2-(trifluoromethyl)benzylamine for benzylamine. MS (DCI/NH3) m/z 390 (M+H)+; 1H NMR (CDCl3) δ 5.25 (s, 2H), 6.69 (dd, IH), 7.15 (m, IH), 7.61-7.72 (m, 2H), 8.33 (s, IH).
Example 43 4-f 5-chloro-2-methylbenzylV 3 -f2.3 -dichloroϋhenylV 4H- 1.2 ,4-triazole
The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 5-chloro-2-methylbenzylamine for benzylamine. MS (DCIZNH3) mZz 352 (M+H)+; 1H NMR (CDCl3) δ 2.08 (s. 3H), 5.00 (s, 2H), 6.87 (d, IH), 7.09 (d, IH), 7.21 (dd, IH), 7.28-7.34 (m, 2H), 7.66 (dd, IH), 8.26 (s, IH).
Example 44 3-(23-dichloroph.enyl)-4-[2-fluoro-5-(trifluoromethyl)benzyll-4H-1.2.4-triazole
The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 2-fluoro-5-(trifluoromethyl)benzylamine for benzylamine. MS (DCITNH3) m/z 390 (M+H)+; 1B. NMR (CDCl3) δ 5.16 (s, 2H), 7.05 (dd, IH), 7.15-7.25 (m, 2H), 7.31 (t, IH), 7.61 (m, IH), 7.68 (dd, IH), 8.48 (s, IH).
Example 45
4-|"2-chloro-5-(trifluoromethyl)benzyl1-3-(2,3-dichlorophenyl)-4H-l,2.4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 2-chloro-5-(trifluoromethyl)benzylamine for benzylamine. MS (DCIZNH3) m/z 406 (M+H)+; 1B NMR (CDCl3) δ 5.25 (s, 2H), 7.08 (s, IH), 7.23-7.33 (m, 2H), 7.52 (m, 2H), 7.66 (dd, IH), 8.51 (s, IH).
Example 46
3-(2,3-dichlorophenylV4-(5-fluoro-2-methylbenzyl)-4H-l,2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 5-fluoro-2-methylbenzylamine for benzylamine. MS (DC]TNH3) m/z 336 (M+H)+; 1H NMR (CDCl3) δ 2.08 (s, 3H), 5.02 (s, 2H), 6.66 (dd, IH), 6.97 (m, IH), 7.15 (dd, IH), 7.34 (m, 2H), 7.68 (t, IH), 8.33 (s, IH).
Example 47
4-(5-chloro-2-fluorobenzyl)-3-f2.3-dichlorophenyl')-4H-L2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 5-chloro-2-fluorobenzylamine for benzylamine. MS (DCIZNH3) m/z 356 (M+H)+; 1H NMR (CDCl3) δ 5.04 (s, 2H), 6.79 (dd, IH), 7.00 (t, IH), 7.28 (m, 2H), 7.35 (t, IH), 7.69 (dd, IH), 8.40 (s, IH). Example 48
4-(6-chloro-2-fluoro-3-methylbenzyl')-3-f2,3-dichlorophenyl')-4H-l,2,4-triazole The title compound was prepared as its trifiuoroacetic acid salt using the procedure as described in Example ID substituting 6-chloro-2-fluoro-3-methylbenzylamine for benzylamine. MS (DCITNH3) m/z 370 (M+H)+; 1B. NMR (CDCl3) δ 2.20 (d, 3H), 5.18 (d, 2H), 7.07-7.18 (m, 2H), 7.35 (m, 2H), 7.66 (dd, IH), 8.33 (s, IH).
Example 49
3-(23-dichlorophenylV4-(2,3,6-trifluorobenzylV4H-1.2.4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 2,3,6-trifluorobenzylarnine for benzylamine. MS (DCITNH3) mTz 358 (M+H)+; 1H NMR (CDCl3) δ 5.14 (s, 2H), 6.84 (m, IH), 7.17 (m, IH), 7.31-7.38 (m, 2H), 7.69 (dd, IH), 8.41 (s, IH).
Example 50
4-(2-chloro-3 ,6-difluorobenzyl)-3-(2,3-dichlorophenylV4H- 1.2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 2-chloro-3,6-difluorobenzylamine for benzylamine. MS (DCITNH3) m/z 374 (M+H)+; 1H NMR (CDCl3) δ 5.21 (d, 2H, J=IHz), 6.99 (dt, IH), 7.19 (m, IH), 7.35 (m, 2H), 7.67 (m, IH), 8.32 (s, IH).
Example 51
3-(2,3-dichlorophenyl)-4-(3-methoxybenzyl)-4H-l,2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 3-methoxybenzylamine for benzylamine. MS
(DCITNH3) mTz 334 (M+H)+; 1H NMR (CDCl3) δ 3.74 (s, 3H), 4.98 (d, 2H), 6.53 (t, IH), 6.60 (d, IH), 6.84 (dd, IH), 7.19-7.31 (m, 3H), 7.61-7.66 (m, IH), 8.32 (s, IH).
Example 52 . 4-r2-chloro-6-fluoro-3-methylbenzyl)-3-r2.3-dichlorophenylV4H-L2,4-triazole
The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 2-chloro-6-fluoro-3-methylbenzylamine for benzylamine. MS (DCImH3) m/z 370 (M+H)+; 1H NMR (CDCl3) δ 2.31 (s, 3H), 5.19 (d, 2H), 6.90 (t, IH), 7.23 (dd, IH), 7.35 (m, 2H), 7.66 (dd, IH), 8.26 (s, IH).
Example 53 3-f2,3-dichlorophenyl)-4-(l-phenylpropylV4H-l,2,4-triazole
The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 1-phenylpropylamine for benzylamine. MS (DCITNH3) m/z 332 (M+H)+; 1H NMR (CDCl3) δ 0.95 (t, 3H), 2.20-2.35 (m, 2H)5 4.82 (t, IH), 6.85-7.0 (m, 3H), 7.2-7.35 (m, 4H), 7.65 (dd, IH), 8.77 (s, IH).
Example 54
3-r2,3-dichloroρhenyl)-4-f2,3-dihvdro-lH-inden-l-yl)-4H-L2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 2,3-dihydro-lH-inden-l-ylamine for benzylamine. MS (DCI/NH3) m/z 330 (M+H)+; 1H NMR (CDCl3) δ 2.05-2.2 (m, IH), 2.57-2.7 (m, IH), 2.9-3.0 (m, IH), 3.08-3.2 (m, IH), 5.45 (t, IH), 7.1 (d, IH), 7.25-7.35 (m, 3H), 7.42 (t, IH), 7.49 (dd, IH), 7.71 (dd, IH), 8.11 (s, IH).
Example 55 3-f2,3-dichlorophenyl)-4-(2,3-dihvdro-l-benzofuran-7-ylmethylV4H-l,2,4-triazole
Example 55 A
2,3-dihydro-l-benzofuran-7-ylmethylamine
Example 29C (2.2 g, 12.6 mmol) in tetrahydrofuran (10 mL) was treated with lithium aluminum hydride (0.71 g, 18.7 mmol) in tetrahydrofuran (20 mL) at 0 0C dropwise. The mixture was stirred at 0 0C for 90 minutes then carefully treated in succession with water (0.7 mL), 15% sodium hydroxide (0.7 mL) and then water (2.1 mL). After stirring overnight, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran (70 mL), and the filtrate concentrated under reduced pressure. The crude was dissolved in diethylether, washed with water, and extracted with IN hydrochloric acid (2x20 mL). The acidic extracts were combined, basified with potassium carbonate, and extracted with methylene chloride (4x). The organic extracts were combined, dried (potassium carbonate), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (DCI/NH3) m/z 150 (MH-H)+J1HNMR (CDCl3) δ 3.21 (t, 2H), 3.82 (s, 2H), 4.59 (t, 2H), 6.81 (t, IH), 7.03 (d, IH), 7.10 (dd, IH).
Example 55B
3-f23-dichlorophenyl)-4-(2,3-dihvdro- 1 -benzofuran-7-ylmethylV4H- 1 ,2,4-triazole
The title compound was prepared using the procedure as described in Example ID substituting Example 55 A for benzylamine. The product was purified by flash chromatography (5% methanol/ethyl acetate) to provide the title compound. MS (DCI/NH3) m/z 346 (M+H)+; 1H NMR (CDCl3) δ 3.18 (t, 2H), 4.52 (t, 2H), 4.93 (s, 2H), 6.59 (d, IH), 6.71 (t, IH), 7.13 (d, IH), 7.24-7.34 (m, 2H), 7.63 (dd, IH), 8.34 (s, IH).
Example 56
3-(2,3-dichlorophenyl)-4-|"2,3-dihvdro-l-benzofuran-3-yll-4H-L2,4-triazole The title compound was prepared using the procedure as described in Example ID substituting 2,3-dihydro-l-benzofuran-3-ylamine (prepared using the procedure as described in Kaluza Chem.Ber. 1955; 88, 597) for benzylamine. MS (DCIMH3) m/z 332 (M+H)+; 1H NMR (CDCl3) δ 4.5 (br d, IH), 4.68 (m, IH), 5.58 (dd, IH), 6.98 (m, 2H), 7.17 (d, IH), 7.32- 7.48 (m, 3H), 7.71 (dd, IH), 7.96 (s, IH).
Example 57
3-(2,3-dichlorophenylV4-r(lR)-2,3-dihvdro-lH-inden-l-yll-4H-l,2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting (lR)-2,3-dihydro-lH-inden-l-ylamine for benzylamine. MS (APCI) m/z 330 (M+H)+; 1H NMR (CDCl3) δ 2.05-2.2 (m, IH), 2.57-2.7 (m, IH), 2.9-3.0 (m, IH), 3.08-3.2 (m, IH), 5.45 (t, IH), 7.1 (d, IH), 7.2-7.35 (m, 3H), 7.42 (t, IH), 7.49 (dd, IH), 7.71 (dd, IH), 8.11 (s, IH).
Example 58 3-f2,3-dichlorophenvn-4-rflS)-2,3-dihvdro-lH-inden-l-yll-4H-l,2,4-triazole
The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting (lS)-2,3-dihydro-lH-inden-l-ylamine for benzylamine. MS (APCI) m/z 330 (M+H)+; 1H NMR (CDCl3) δ 2.05-2.2 (m, IH), 2.57-2.7 (m, IH), 2.9- 3.0 (m, IH), 3.08-3.2 (m, IH), 5.43 (t, IH), 7.1 (d, IH), 7.2-7.35 (m, 3H), 7.42 (t, IH), 7.49 (d, IH), 7.70 (dd, IH), 8.05 (s, IH).
Example 59
3-(2,3-dichlorophenylV4-(l,2,3,4-tetrahvdronaphthalen-l-yl)-4H-1.2.4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 1,2,3,4-tetrahydronaphthalen-l-ylamine for benzylamine. MS (APCI) m/z 344 (M+H)+; 1H NMR (CDCl3) δ 1.7-1.95 (br m, 3H), 2.5 (br s, IH), 2.8 (dt, IH), 2.95 (dt, IH), 5.19 (t, IH), 6.99 (br s, IH), 7.18 (m, IH), 7.28 (m, IH), 7.40 (t, IH), 7.47 (dd, IH), 7.69 (dd, IH), 8.00 (s, IH).
Example 60
3-r2,3-dichlorophenyl)-4-('3-methyl-2,3-dihvdro-lH-inden-l-vD-4H-L2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 3-methylindan-l -amine for benzylamine. MS (APCI) m/z 344 (M+H)+; 1H NMR (CDCl3) δ 1.41 (d, 3H), 1.72 (m, IH), 2.89 (m, IH), 3.17 (m, IH), 5.39 (t, IH), 7.03 (m, IH), 7.26-7.32 (m, 2H), 7.38-7.43 (m, 2H), 7.73 (d, IH), 8.43 (s, IH).
Example 61
3-(2,3-dichlorophenγlV4-(4,4-dimethγl-l,2,3,4-tetrahvdronaphthalen-l-ylV4H-L2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 4,4-dimethyl-l,2,3,4-tetrahydronaphthalen-l-ylamine hydrochloride (prepared as described in Woods J.Org.Chem. 1954, 19; 1290) for benzylamine and also using diisopropylethylamine as a base. MS (APCI) m/z 372 (M+H)+; 1H NMR (CDCl3) δ 1.27 (s, 3H), 1.38 (s, 3H), 1.67 (m, 2H), 1.9 (br m, IH), 2.14 (br m, IH), 5.15 (t, IH), 6.95 (br m, IH), 7.17 (td, IH), 7.34 (t, IH), 7.39 (m, 2H), 7.44 (td, IH), 7.69 (dd, IH), 7.94 (s, IH). Example 63
3 -C2.3 -dichlorophenyr)-4-(3 ,4-dihvdro-2H-chromen-4- ylV4H- 1.2.4-triazole The title compound was prepared using the procedure as described in Example ID substituting 3,4-dihydro-2H-chromen-4-ylamine hydrochloride (prepared according to the procedure described in Fernandez Chem. Commun. 1997, 2.) for benzylamine and also using diisopropylethylamine. MS (DCITNH3) m/z 346 (M+H)+; 1H NMR (CDCl3) δ 2.08 (m, IH)5 2.28 (m, IH), 4.18 (m, 2H), 5.21 (t, IH), 6.93 (m, 3H), 7.28 (m, IH), 7.41 (t, IH), 7.47 (dd, IH), 7.70 (dd, IH), 8.01 (s, IH).
Example 64
3-r2-chloro-3-(trifluoromethvnphenγll-4-rriRV2.3-dihvdiO-lH-inden-l-yll-4H-1.2.4-triazole The title compound was prepared using the procedure as described in Example 28B substituting (lR)-2,3-dihydro-lH-inden-l-ylarnine for 2-methylbenzylamine. MS (DCI/NH3) m/z 364 (M+H)+; 1H NMR (CDCl3) δ 2.14 (m, IH), 2.62 (m, IH), 2.94 (m, IH), 3.1 (m, IH), 5.41 (t, IH), 7.11 (d, IH), 7.2-7.3 (m, 3H), 7.57 (t, IH), 7.73 (dd, IH), 7.93 (dd, IH), 8.01 (s,
IH).
Example 65
3-r2-chloro-3-(trifluoromethvπphenyl]-4-[2-(methγlthio)benzyll-4H-L2,4-triazole The title compound was prepared using the procedure as described in Example 28B substituting 2-(methylthio)benzylamine for 2-methylbenzylamine. MS (DCI/NH3) m/z 384 (M+H)+; 1H NMR (CDCl3) δ 2.40 (s, 3H), 5.14 (s, 2H), 6.92 (dd, IH), 7.07 (td, IH), 7.23 (dd, IH), 7.33 (td, IH), 7.48 (t, IH), 7.58 (dd, IH), 7.91 (dd, IH), 8.46 (s, IH).
Example 66
4-r3-chloro-2-metliylbenzyl)-3-(2,3-dichloroρhenyl)-4H-1.2.4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 3-chloro-2-methylbenzylamine for benzylamine. MS (DCIZNH3) m/z 352 (M+H)+; 1H NMR (CDCl3) δ 2.15 (s, 3H), 5.03 (s, 2H), 6.85 (d, IH), 7.09 (t, IH), 7.31 (m, 2H), 7.36 (d, IH), 7.64 (m, IH), 8.08 (s, IH).
Example 67 3-(23-dichlorophenylV4-{2-r(trifluoromethvπtMo]bepzyl>-4H-l,2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 2-[(trifluoromethyl)thio]benzylamine for benzylamine. MS (DCITNH3) m/z 404 (M+H)+; 1H NMR (CDCl3) δ 5.33 (s, 2H), 7.05 (dd, IH), 7.29 (m, 2H), 7.38-7.51 (m, 2H), 7.65 (dd, IH), 7.70 (d, IH), 8.28 (s, IH).
Example 68
3-(2,3-dichlorophenylV4-f4-fluoro-2,3-dihvdro-lH-inden-l-yl)-4H-l,2,4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 4-fluoro-2,3-dihydro-lH-inden-l-ylamine hydrochloride for benzylamine and also using diisopropylethylamine. MS (DCI/NH3) m/z 348 (M+H)+; 1H NMR (CDCl3) δ 2.18 (m, IH), 2.68 (m, IH), 2.95 (m, IH), 3.18 (m, IH), 5.45 (t, IH), 6.9 (d, IH), 7.05 (t, IH), 7.26 (m, IH), 7.41 (t, IH), 7.47 (dd, IH), 7.70 (dd, IH), 8.05 (s, IH).
Example 69
3 -(2,3 -dichlorophenvD-4-[ 5-(trifluoromethyl)-2,3 -dihydro- 1 H-inden- 1 - yl) -4H-1 ,2.4-triazole The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting 5-(trifluoromethyl)-2,3-dihydro-lH-inden-l-ylamine hydrochloride for benzylamine and also using diisopropylethylamine. MS (DClTNH3) m/z
398 (MH-H)+; 1H NMR (CDCl3) δ 2.1 (m, IH), 2.7 (m, IH), 3.0 (m, IH), 3.1 (m, IH)3 5.46 (t, IH), 7.22 (br d, IH), 7.41 (t, IH), 7.48 (dd, IH), 7.53 (d, IH), 7.60 (s, IH), 7.70 (dd, IH), 8.05 (s, IH).
Example 70
3-(r3-(2.3-dichlorophenyl)-4H-l,2,4-triazol-4-vnmethvU pyridine The title compound was prepared as its trifluoroacetic acid salt using the procedure as described in Example ID substituting pyridin-3-ylmethylamine for benzylamine. MS (DCI/NH3) m/z 305 (M+H)+; 1H NMR (CDCl3) δ 5.27 (s, 2H), 7.31 (dd, IH), 7.37 (t, IH), 7.60 (dd, IH), 7.72 (m, 2H), 8.54 (s, IH), 8.66 (s, IH), 8.68 (s, IH), 9.60 (br s, 2H).
Example 71 3-(2.3-dichlorophenylV4-(2-ethylbenzylV4H- 1.2.4-triazole
Example 71 A 2-ethylbenzylamine Lithium aluminum hydride (7.4 g 196 mmol) in tetrahydrofαran (130 mL) was slowly treated with 2-ethylbenzonitrile (4.99 g 38 mmol) in tetrahydrofuran (40 mL) at 0 0C under nitrogen. The mixture was stirred for 30 minutes at 0 0C, 2 hours at room temperature, recooled to 0 0C, and then slowly treated in succession with water (7.4 mL), 15% sodium hydroxide (7.4 mL) and water (22 mL). Additional tetrahydrofuran (50 mL) was added to facilitate stirring. The reaction mixture was filtered through celite, the filter cake was washed with tetrahydrofuran (150 mL), the filtrate was concentrated under reduced pressure, and the residue was partitioned between methylene chloride/saturated sodium chloride. The organic phase was dried (potassium carbonate), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (CDCl3) δ 1.24 (t, 3H), 2.69 (q, 2H), 3.89 (s, 2H), 7.20 (m, 3H), 7.32 (m, IH).
Example 7 IB
3-r2.3-dichlorophenyl)-4-(2-ethylbenzyl)-4H-L2,4-triazole
The title compound was prepared as a trifluoroacetic acid salt using the procedure as described in Example ID substituting Example 71 A for benzylamine. MS (DCI/NH3) m/z 332 (M+H)+; 1H NMR (CDCl3) δ 1.05 (t, 3H), 2.42 (q, 2H), 5.02 (s, 2H), 6.96 (dd, IH), 7.19 (td, IH), 7.22 (d, IH), 7.29-7.34 (m, 3H), 7.65 (m, IH), 8.10 (s, IH).
Example 72 5-[2-chloro-3-(trifluoromethvnphenyll-l-[2,3-dihvdro-lH-inden-l-yll-lH-L2,4-triazole
Example 72A
2-chloro-N-[(dimethylamino')methylenel-3-(trifluoromethyl>)benzamide Step A 2-Chloro-3-trifluoromethylbenzoic acid (4.52 g, 20.13 mmol) and thionylchloride (10 mL, 137 mmol) were heated to reflux in toluene (40 mL) for 3 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was treated with dry toluene and concentrated under reduced pressure (3x). Step B
A solution of 0.5 M ammonia in 1,4-dioxane (140 mL) at 5 °C was slowly treated with the obtained residue from step A in diethyl ether (30 mL) and then allowed to warm to room temperature overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between methylene chloride and water. The organic phase was washed with saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. Step C
The crude amide from step B (~20 mmol) and dimethylformamide dimethylacetal (10 mL) were combined and heated at reflux for 1.5 hours, allowed to cool to room temperature, concentrated under reduced pressure, and partitioned between water and diethyl ether. The organic phase was washed with water (2x), saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate to provide the title compound. MS (DCIZNH3) m/z 279 (M+H)+; 1H NMR (CDCl3) δ 3.18 (s, 3H), 3.23 (s, 3H), 7.38 (t, IH), 7.71 (dd, IH), 7.88 (dd, IH), 8.63 (s, IH).
Example 72B
S-fΣ-chloro^-ftrifluoromethvnphenyli-l-ri^-dihvdro-lH-inden-l-yll-lH-iαΛ-triazole
Example 72A (117 mg, 0.42 mmol) and indan-1-yl-hydrazine oxalate (Huebner J.Org.Chem. 1962, 27; 4465) (110 mg, 0.46 mmol) were combined in ethanol (5 mL) and heated at reflux for 1 hour, allowed to cool to room temperature, and partitioned between diethyl ether and saturated aqueous sodium bicarbonate. The organic phase was dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes: ethyl acetate (3:2) to provide the title compound. MS (DCITNH3) m/z 364 (M+H)+; 1H NMR (CDCl3) δ 2.6 (m, 2H), 2.92 (m, IH), 3.24 (m, IH), 5.60 (t, IH), 6.93 (m, IH), 7.17 (m, IH), 7.28 (m, 2H), 7.55 (t, IH), 7.67 (d, IH), 7.91 (dd, IH), 8.04 (s, IH); Anal, calcd for C18H13ClF3N3: C, 59.43; H, 3.60; N, 11.55. Found: C, 59.12; H, 3.38; N, 11.34. Example 73
3-[2-cMoro-3-(Mfluoromethyl')phenyl1-4-f2-ethylbenzvD-4H-1.2,4-triazole The title compound was prepared using the procedure as described in Example 28B substituting 2-ethylbenzylamine for 2-methylbenzylamine. MS (DCI/NH3) m/z 366 (M+H)+; 1H NMR (CDCl3) δ 1.03 (t, 3H), 2.41 (q, 2H), 5.04 (s, 2H), 6.90 (dd, IH), 7.13 (td, IH), 7.18 (d, IH), 7.28 (td, IH), 7.44 (td, IH), 7.53 (dd, IH), 7.86 (dd, IH), 8.12 (s, IH).
Example 74
5-benzyl-l -f2,3-dichloroρhenvD-lH-l ,2,4-triazole N-Formylphenylacetamide (Finkbeiner J. Org. Chem. 1965, 30; 2861) (200 mg, 1.22 mmol) and 2,3-dichlorophenylhydrazine hydrochloride (314 mg, 1.47 mmol) were combined in glacial acetic acid (8 mL) and refmxed under a nitrogen atmosphere for 1 hour and then concentrated under reduced pressure at 60 °C. The residue was purified by flash chromatography eluting with hexanes/ethyl acetate (6/1) to provide the title compound. MS (ESl+) m/z 305 (M+1H)+; 1H NMR (300 MHz, DMSOd6) δ ppm 4.02 (s, 2 H) 6.97 - 7.02
(m, 2 H) 7.16 - 7.25 (m, 3 H) 7.52 - 7.58 (m, 2 H) 7.88 (dd, J=6.8, 3.1 Hz, 1 H) 8.16 (s, 1 H).
Example 75
3-{|"l-f2.3-dichlorophenyl)-lH-L2.4-triazol-5-yl1methylipyridine
Example 75A
|"2-(2,3-dichlorophenyl)-2H-[L2,41-triazol-3-yl]-pyridin-3-yl-methanol To a solution of Example 83A (1.00 g, 4.67 mmol) in tetrahydrofuran (35 mL) was slowly added n-butyl lithium (2.24 mL, 5.61 mmol) at -78 0C. The reaction mixture was stirred for 1.5 hours at -78 0C and then nicotinaldehyde (612 mg, 5.61 mmol) in tetrahydrofuran (6 mL) was added dropwise. The reaction mixture was stirred for 12 hours at room temperature and then quenched with water (5 mL). The reaction mixture was extracted with EtOAc, dried with MgSO4, filtered and concentrated to provide 1.3 g of the title compound. MS (ESI/NH3) m/z 221 (M)+ Example 75B Thionocarbonic acid 6>,6>-bis-(r2-('2.3-dichlorophenvD-2iJr-rL2.4]-triazol-3-yll-Pyridm-3-yl- metyl) ester
To a solution of product of Example 75A (800 mg, 2.49 mmol) and 4-N,N- dimethylaminopyridine (1.08 g, 8.72 mmol) in CH3CN (30 mL) was added phenyl chlorothionocarbonate (645 mg, 3.74 mmol) under N2. The reaction mixture was stirred for 5 hours at room temperature and then concentrated under reduced pressure. The residue was purified by flash column chromatography on SiO2 (1% methanol/dichloromethane) to give the title compound. 1H NMR (300 MHz, DMSOd6) δ ppm 6.51 (s, 1 H) 7.45 (dd, J=8.0, 4.9 Hz, 1 H) 7.58 - 7.69 (m, 1 H) 7.70 - 7.77 (m, 1 H) 7.97 (dd, J=8.0, 1.5 Hz, 1 H) 8.06 (d, J=7.5 Hz, 1 H) 8.33 (s, 1 H) 8.57 (dd, J=4.7, 1.7 Hz, 1 H) 8.72 (d, J=2.4 Hz, 1 H).
Example 75 C 3-iri-r2,3-dichlorophenyl)-lH-L2,4-triazol-5-yllmethyl|pyridine A mixture of product from Example 75B (330 mg, 0.48 mmol), n-butyltin hydride
(0.3 mL, 1.08 mmol) and 2,2'-azobisobutylnitrile (24 mg, 0.15 mmol) in toluene (15 mL) was degassed under an oxygen free N2 atmosphere for 20 minutes. The reaction mixture was stirred 100 0C for 5 hours. The solvent was removed under vacuum and the residue purified by flash chromatography on SiO2 (gradient elution, 1 % to 2.5 % methanol/dichloromethane) ' to provide the title compound. MS (ESf) m/z 305 (M)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.05 - 4.08 (m, 2 H) 7.25 - 7.30 (m, 1 H) 7.48 - 7.54 (m, 1 H) 7.57 (t, J=8.1 Hz, 1 H) 7.65 (dd, J=9.0, 1.7 Hz, 1 H) 7.90 (dd, J-8.1, 1.7 Hz, 1 H) 8.17 (s, 1 H) 8.26 (d, J=2.0 Hz, 1 H) 8.41 (dd, J=4.7, 1.7 Hz, 1 H).
Example 76 l-(2.3-dichlorophenyl")-5-r2-methylbenzylVlH-L2,4-triazole
Example 76A
N-formyl-2-(o-methylphenyl)acetamide A mixture of 2-o-tolylacetamide (Lee, Dong-Ung; Mayer, Klaus K.; Wiegrebe,
Wolfgang; Lauber, Rolf; Schlunegger, Urs P.; Arch.Pharm. 1988, 321; 265-272) (320 mg, 2.15 mmol) and ΛζΛζ-dimethylformamide dimethylacetal (1.1 mL, 8.59 mmol) was stirred under N2 for 55 min at 120 0C. The excess of _V,N,-dimethylformamide dimethylacetal was eliminated under reduced pressure. The residue was dissolved in 3 mL of 70% aqueous acetic acid and stirred at 0 0C for 30 min. The precipitate was filtered, washed with water and dried to afford the title compound as a white solid. MS (DCI/NH3) m/z 195 (M+NH4)+.
Example 76B l-(2,3-dichlorophenylV5-(2-methylbenzylVlH-1.2.4-triazole The title compound was prepared using the procedure as described in Example 74 substituting Example 76A for N-formylphenylacetamide. MS (ESl+) m/z 318 (M); 1H NMR (300 MHz5 DMSO-d6) δ 2.09 (s, 3 H), 4.01 (s, 2 H), 6.77 (d, J=7.5 Hz, 1 H), 6.92-7.00 (m, 1 H), 7.06-7.10 (m, 2 H), 7.49-7.60 (m, 2 H), 7.83-7.88 (m, 1 H), 8.13 (s, 1 H); Anal, calcd for C16H13Cl2N3: C, 60.39; H, 4.12; N, 13.21. Found: C, 60.07; H, 4.04; N, 13.01.
Example 77 1 -(2,3 -dichlorophenyl)-5 -fthien-3- ylmethvD- 1 H- 1.2,4-triazole
Example 77A
7V-formyl-2-(thien-3 -vDacetamide
The title compound was prepared using the procedure as described in Example 76A substituting 2-thiophen-3-yl-acetamide (Schenck; Steinmetz; Justus Liebigs Ann. Chem. 1963, 668; 19, 26) for 2-o-tolylacetamide. MS (DCI/NH3) m/z 187 (M+NH4)+.
Example 77B
1 -(23-dichlorophenvD- 5 -fthien-3 -ylmethvD- 1 H- 1 ,2,4-triazole The title compound was prepared using the procedure as described in Example 74 substituting Example 77 A for N-formylphenylacetamide. MS (ESI+) m/z 311 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 4.02 (s, 2 H), 6.81-6.85 (m, 1 H), 7.02-7.06 (m, 1 H), 7.39- 7.43 (m, 1 H), 7.53-7.59 (m, 2 H), 7.86-7.91 (m, 1 H), 8.17 (s, 1 H); Anal, calcd for Ci3H9Cl2N3S: C, 50.33; H, 2.92; N, 13.55. Found: C, 50.51; H, 2.69; N, 13.55. Example 78
5-l[3-(2,3-dichlorophenyl')-4H-l,2,4-triazol-4-yllmethvUisoqumoline The title compound was prepared using the procedure as described in Example ID substituting isoquinolin-5-ylmethylamme (prepared using the procedure as in EP 13411) for benzylamine. MS (ESl+) m/z 356 (M+H)+; 1H NMR (300 MHz, DMSOd6) δ 5.66 (s, 2 H), 7.17 (d, J=7.1 Hz, 1 H), 7.31-7.40 (m, 2 H), 7.49 (t, J=7.5 Hz, 1 H), 7.65-7.76 (m, 2 H), 8.04 (d, J=8.1 Hz, 1 H), 8.46 (d, J=6.1 Hz, 1 H), 8.91 (s, 1 H) 9.29 (s, 1 H); Anal, calcd for C18Hi2Cl2N4 O-ICF3CO2H: C, 59.49; H, 3.34; N, 15.33. Found: C, 59.62; H, 3.24; N, 15.21.
Example 79
8-{r3-(2,3-dichlorophenvD-4H-l,2,4-triazol-4-vnmethyUquinoline
The title compound was prepared using the procedure as described in Example ID substituting quinolin-8-ylmethylamine for benzylamine. MS (ESI+) m/z 356 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 5.71 (s, 2 H), 7.28 (d, J=6.1 Hz, 1 H), 7.34-7.41 (m, 2 H),
7.45-7.57 (m, 2 H), 7.72-7.77 (m, 1 H), 7.92 (dd, J=8.1, 1.4 Hz, 1 H), 8.35 (dd, J=8.5, 1.7 Hz, 1 H), 8.77-8.80 (m, 1 H), 8.84 (s, 1 H); Anal, calcd for C18HI2CI2N5 O-OSCF3CO2H: C, 60.17; H, 3.37; N, 15.55. Found: C, 59.91; H, 3.59; N, 15.34.
Example 80
5-benzyl- 1 -phenyl- IH- 1 ,2,4-triazole
Phenylhydrazine hydrochloride (0.09 g, 0.6 mmol) in 5 mL glacial acetic acid was treated with triethylamine (0.06 g, 0.6 mmol), warmed to 70 0C, treated with N- formylphenylacetamide (0.1 g, 0.6 mmol), and heated at 90 0C for 1 hour. The mixture was then allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organics were washed with saturated NaHCO3, IM NaOH, water, and brine. The organics were then dried (MgSO4), and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40% hexanes/ethyl acetate) to provide the title compound. MS (ESI) m/e: 236 (M+H)+; 1H NMR (DMSO-d6) δ 4.2 (s, 2H), 7.05-7.1 (d, 2H), 7.17-7.3 (m, 3H), 7.45-7.6 (m, 5H), 8.1 (s, IH); Anal, calcd. for C: 76.57, H: 5.57, N: 17.86. Found C: 76.32, H: 5.81, N: 17.63. Example 81 l-r2-chloro-3-rtrifluoromethvDphenyll-5-(2-methylbenzylVlH-L2,4-triazole
Example 81 A l-r2-chloro-3-rtrifluoromethyl)phenyl1-5-r2-methylbenzylVlH-L2,4-triazole
The title compound was prepared using the procedure as described in Example 80 substituting 2-chloro-3-trifluoromethylphenylhydrazine hydrochloride for phenylhydrazine hydrochloride and substituting Example 76A for N-formylphenylacetamide. The residue was purified by flash chromatography (20% ethyl acetate/hexanes) to provide the title compound. MS (ESI) m/e: 352 (M+H); 1H NMR (DMSOd6) δ 2.05 (s, 3H), 4.05 (s, 2H), 6.7-6.75 (d, IH), 6.85-6.96 (m, IH), 7.04-7.1 (d, 2H), 7.7-7.75 (t, IH), 7.89-7.97 (d, IH), 8.05-8.1 (d, IH), 8.18 (s, IH); Anal, calcd. for C: 58.05, H: 3.73, N: 11.95. Found C: 58.10, H: 3.86, N: 11.68. The title compound (0.12 g, 0.34 mmol) in ethyl acetate (3 mL) was treated with IM HCl/diethyl ether (5 mL). After stirring for 1 hour, the mixture was diluted with diethyl ether, filtered, and the filter cake was dried under high vacuum to provide the title compound as a hydrochloride salt. MS (ESI) m/e: 352 (M+H)+; 1B NMR (DMSOd6) δ 2.05 (s, 3H), 4.05 (s, 2H), 6.7-6.75 (d, IH), 6.85-6.96 (m, IH), 7.04-7.1 (d, 2H), 7.7-7.75 (t, IH), 7.89-7.97 (d, IH), 8.05-8.1 (d, IH), 8.18 (s, IH); Anal, calcd. for C: 52.60, H: 3.63, N: 10.82. Found C: 52.54, H: 3.42, N: 10.79.
Example 82 l-r2-chloiO-3-(trifluoromethyl)phenyl1-5-('2,3-dihvdro-lH-inden-l-ylVlH-1.2.4-triazole
The title compound was prepared using the procedure as described in Example 80 substituting 2-chloro-3-trifluoromethylphenylhydrazine hydrochloride for phenylhydrazine hydrochloride and substituting N-formyl-2,3-dihydro-lH-indene-l-carboxamide (prepared using the procedure as described in Example 76 A, substituting from indan-1-carboxamide [Seidl Tetrahedron 1964, 20, 633] for 2-o-tolylacetamide) for N-formylphenylacetamide. The residue was purified by flash chromatography (40% ethyl acetate/hexanes) to provide the title compound. MS (ESI) m/e: 364 (M+H)+; 1H NMR (DMSOd6) δ 2.05-2.45 (m, 2H), 2.8- 3.05 (m, 2H), 4.29-4.35 (t, IH), 6.95-7.05 (bs, IH), 7.03-7.1 (t, IH), 7.1-7.21 (t, IH), 7.2-7.3 (d, IH), 7.78-7.82 (t, 2H), 8.0-8.01 (bs, 0.5H), 8.18 (s, IH), 8.22 (bs, 0.5H); Anal, calcd. for C: 59.43, H: 3.60, N: 11.55. Found C: 59.20, H: 3.34, N: 11.48 Example 83 BenzvH2-(2.3 -dichloro-phenviy 2H-F 1 ,2.41triazol-3 - yli -amine
Example 83A l-f2.3-Dichloro-phenyl)-lH-π.2.41triazole
A suspension of 2,3 dicholorophenylhydrazine hydrochloride (5g, 23 mmol) in 20 mL N,N-dimethyl foraiamide was heated at 180 0C for 12 hours. The reaction was cooled and the resulting solid was dissolved in ethyl acetate (50 mL). The organic layer was washed with water (3x30 mL), brine (1x20 mL), dried (MgSO4), filtered and concentrated to give 5 g of a chalky solid, used without further purification. MS (ESIZNH3) m/z 215 (M+H)+
Example 83B 5-Bromo-l-f2,3-dichloro-phenyl)-lH-ri,2,41triazole To Example 83 A (2 g, 8 mmol) in 25mL carbon tetrachloride was added N- bromosuccinimide (2.86 g, 16.2 mmol) and a catalytic amount of benzoyl peroxide. The solution was heated to reflux for 12 hours, then cooled and filtered through Celite, washing the solids with warm carbon tetrachloride (20 mL). The solvent was removed in vacuo and the residue purified by column chromatography (gradient elution, 20% to 35% ethyl acetate/hexanes) to give 1.2 g of the compound as an off-white solid. MS (ESITNH3) m/z 293 (M)+
Example 83C
Benzyl-f 2-(2,3-dichloro-phenyl')-2H-r 1 ,2.41triazol-3-vH-amine Example 83B (0.1 g, 0.34 mmol) was combined with 0.1 mL of benzylamine and heated to 100 0C for 24 hours, cooled and purified by column chromatography (gradient elution; 25% ethyl acetate/hexanes to 35%) to give 0.065g of the title compound as a white solid. MS (ESIZNH3) m/z 318 (M)+ 1H NMR (δ, DMSO-J6); 4.41-4.5 (d, 2H), 7.1-7.26 (m, 2H), 7.3-7.37 (m, 4H), 7.6 (s, IH), 7.8-7.9 (m, IH). Example 84 r2-(2J-Dichloro-phenyl)-2H-|"1.2.41triazol-3-yll-('2-methyl-benzylVamine The title compound was prepared using the procedure as described in Example 83C substituting 2-methylbenzylamine for benzylamine. MS (ESI/NH3) m/z 366 (M+H)+; 1H NMR (δ, DMSO-J6); 2.3 (s, 3H), 4.41-4.5 (d, 2H), 7.1-7.32 (m, 5H), 7.62 (m, 2H), 7.8-7.9 (d, IH), 8.0-8.09 (d, IH).
Example 85 r2-(2.3-Dichloro-phenylV2H-|"1.2,41triazol-3-yll-('2-trifluoromethyl-benzyl)-amme The title compound was prepared using the procedure as described in Example 83C substituting 2-trifluoromethylbenzylamine for benzylamine. MS (ESlTNH3) m/z 385 (M+H)+; 1H NMR (δ, DMSO-J6); 4.61-4.65 (d, 2H), 7.2-7.28 (t, IH), 7.41-7.5 (t, IH), 7.52- 7.78 (m, 6H), 7.8-7.88 (d, IH)
Example 86 r2-(2,3-Dichloro-phenyl)-2H-rL2,41triazol-3-yll-(3-methoxy-benzyl)-amine The title compound was prepared using the procedure as described in Example 83C substituting 3-methoxybenzylamine for benzylamine. MS (ESITNH3) m/z 348 (M+H)+; 1H NMR (δ, DMSO-J6); 4.38-4.41 (d, 2H), 6.75-6.79 (d, IH), 6.82-6.90 (m, 2H), 7.1-7.17 (t, IH), 7.19-7.21 (t, IH), 7.51-7.58 (d, 2H), 7.6 (s, IH), 7.8-7.85 (m, IH).
Example 87 r2-r2.3-Dichloro-plienylV2H-("l,2,4]triazol-3-yll-f2.3-dimethoxy-benzylVamine The title compound was prepared using the procedure as described in Example 83 C substituting 2,3-dimethoxybenzylamine for benzylamine. MS (ESIZNH3) m/z 379 (M); 1H NMR (δ, DMSO-J6); 3.7 (s, 3H), 3.8 (s, 3H), 4.41-4.5 (d, 2H), 6.8-7.05 (m, 4H), 7.5-7.6 (m, 3H), 7.8-7.85 (m, IH).
Example 88 [2-(2.3-Dichloro-phenyl)-2H-ri.2,41triazol-3-yl1-r2-methylsulfanyl-benzyl)-amine
The title compound was prepared using the procedure as described in Example 83 C substituting 2-thiomethylbenzylamine for benzylamine MS (ESITNH3) m/z 364 (M+H)+; 1H NMR (δ, DMSO-J6); 2.5 (s, 3H), 4.41-4.5 (d, 2H), 7.1-7.19 (m, 2H), 7.2-7.3 (m, 4H), 7.5-7.6 (m, 3H), 7.82-7.85 (m, IH).
Example 89 [2-(2,3-Dichloro-phenylV2H-ri,2,4]triazol-3-yll-r2-methanesulfonyl-benzyl)-amine
Example 88 (0.015 g, 0.041 mmol) was dissolved in 2 mL acetone and treated with OXONE (0.1 g, 0.16 mmol) for 24 hours. The resulting slurry was taken up in 25 mL ethyl acetate and washed with water (3x10 mL), brine (1x10 mL), then dried (MgSO4), filtered and concentrated to give 0.014 g of the title compound as a white solid. MS (ESI/NH3) m/z 398 (M+H)+; 1H NMR (δ, DMSO-J6); 3.4, (s, 3H), 4.8-4.85 (d, 2H), 7.28-7.39 (t, IH), 7.25-7.76 (m, 5H), 7.82-7.92 (m, 2H).
Example 90 r2-(2,3-Dichloro-phenyl)-2H-[l,2,41triazol-3-yl]-f2-methoxy-benzyl)-amine The title compound was prepared using the procedure as described in Example 83C substituting 2-methoxybenzylamine for benzylamine. MS (ESiyNH3) m/z 348 (M+H)+; 1H NMR (δ, DMSO-J6); 3.78 (s, 3H), 4.38-4.4 (d, 2H), 6.8-6.95 (m, 3H), 7.15-7.22 (m, 2H), 7.5- 7.59 (m, 3H), 7.81-7.85 (m, IH).
Example 91 r2-(2,3-Dichloro-phenylV2H-[L2,4]triazol-3-yl]-(2-ethoxy-benzyl)-amine The title compound was prepared using the procedure as described in Example 83C substituting 2-ethoxybenzylamine for benzylamine. MS (ESIZNH3) m/z 348 (M+H)+; 1H NMR (δ, DMSO-J6); 1.22-1.35 (t, 3H), 3.91-4.05 (q, 2H), 4.38-4.4 (d, 2H), 6.8-6.95 (m, 3H), 7.15-7.22 (m, 2H), 7.5-7.59 (m, 3H), 7.81-7.85 (m, IH).
Example 92 r2-(2,3-Dichloro-phenylV2H-|"L2,41triazol-3-yll-pyridin-3-ylmethyl-amine The title compound was prepared using the procedure as described in Example 83C substituting C-pyridin-3-yl-methylamine for benzylamine. MS (ESIZNH3) m/z 319 (M+H)+; 1HNMR (δ, DMSO-J6); 4.5-4.6 (d, 2H), 7.3-7.4 (t, IH), 7.5-7.65 (m, 3H), 7.8-7.9 (m, 2H), 8.25-8.3 (d, IH), 8.7-8.8 (m, 2H). Example 93 l-r23-dichlorophenylVJV-[(2-pyrrolidin-l-ylpyridin-3-yl>)methyll-lH-ri,2,41triazole-5-amine
Example 93A
2-pyrrolidin- 1 -yl-nicotinonitrile
To an oven-dried, N2-purged, 50-mL flask containing a magnetic stir bar were added 2-fluoronicotinonitrile (1.22 g, 10.0 mmol), anhydrous tetrahydrofuran (5 mL), and triethylamϊne (3.04 g, 4.19 mL, 30.0 mmol). The flask was sealed with a septum and cooled to 0 0C in an ice bath. Neat pyrrolidine (1.04 g, 1.24 mmol, 15.0 mmol) was added via syringe. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature overnight. Water (10 mL) was added and the mixture was transferred to a separatory funnel. The mixture was extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to a brown oil. The product was recrystallized from ethyl acetate/hexanes to give 1.29 g (75%) of the title compound as a tan powder. MS (ESI+) m/z 174.0 (M+Η)+; 1H NMR (DMSOd6) δ 1.91-1.95 (m, 4H), 3.63-3.68 (m, 4H), 6.68 (dd, J = 7.6, 4.6 Hz, IH), 7.91 (dd, J = 7.6, 1.9 Hz, IH), 8.31 (dd, J = 4.7, 2.0 Hz, IH).
Example 93B
C-(2-p yrrolidin- 1 -yl-pyridin-3-ylVmethylamine
To a thick-walled pressure bottle was added Raney nickel (~5 g) and ammonia- saturated methanol (100 mL). Example 93 A (866 mg, 5.00 mmol) was added, and the bottle was inserted into a Parr shaker. The bottle was charged with 60 psi of H2 gas, and the grey mixture was shaken under static hydrogen pressure at room temperature for 2 hours. After venting, the solids were removed by vacuum filtration through a glass frit covered with a nylon filter. The solvent/volatiles were removed by rotary evaporation to give ~900 mg of a pale green oil to give the title compound which was used without further purification for the next step. Example 93 C l-r2,3-dichlorophenyl)-N-[(2-pyrrolidin-l-ylpyridm-3-vDmethyl1-lH-["L2,41triazole-5-amme
The title compound was prepared using the procedure as described in Example 83 C substituting Example 93B for benzylamine. MS (ESITNH3) m/z 389 (M+H)+; 1H NMR (δ, DMSO-J6); 1.78-1.90 (m, 4H), 3.4-3.52 (m, 4H), 4.41-4.45 (d, 2H), 6.82-6.85 (m, IH), 6.98- 7.02 (t, IH), 7.4-7.6 (m, 4H), 7.79-7.85 (m, IH), 7.95-7.99 (d, IH).
Example 94
[2-(23-Dichloro-r)henylV2H-|"l,2,4]triazol-3-yll-[2-fpyridin-3-yloxyVbenzyl]-amine
Example 94A
2-(Pyridm-3-yloxy)-benzonitrile
To a solution of 3-hydoxypyridine sodium salt (purchased from Acros) (2.54 g, 26.71 mmol) in N,N-dimethyl formamide (50 mL) was added 2-fluoronicotinonitrile (3.32 g, 26.68 mmol) dropwise and the solution was heated at 100 0C for 2 hours. To the reaction mixture was added ethyl acetate (100 mL) and IM NaHCO3 (150 mL) and it was filtered to remove black tar. The filtrate was decolorized with activated charcoal and extracted with ethyl acetate (3x30 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography on silica gel using dichloromethane to give the title compound. MS (ESI+) m/z 197 (M+H)+.
Example 94B
2-(P yridin-3 -yloxyVbenzylamine
To a solution of Example 94A (4.28 g, 21.84 mmol) in 7N NH3 in methanol (200 ml) was added Raney nickel (12 g) under argon atmosphere. The reaction mixture was kept on a shaker under 60 psi H2 atmosphere. After 6 hours at room temperature, the reaction mixture was filtered through a micro pore filter and concentrated to give the title compound. MS (ESr") m/z 201 (M+H)+. Example 94C [2-(2,3-DicMoro-phenylV2H-[1.2^1triazol-3-yll-r2-fpyridin-3-yloxyVberi-zyll-arnine
The title compound was prepared using the procedure as described in Example 83 C substituting Example 94B for benzylamine. MS (ESlTNH3) m/z 412 (M+H)+; 1H NMR (δ, DMSOrZ6); 4.41-4.45 (d, 2H), 6.82-6.85 (d, IH), 6.98-7.02 (t, IH), 7.19-7.6 (m, 9H), 7.8- 7.85 (d, IH), 8.3-8.39 (m, 2H).
Example 95 r2-r2,3-Dichloro-phenylV2H-[1.2,41triazol-3-yll-r2-(pyridin-3-yloxyVρyridin-3-ylmethyll- amine
The title compound was prepared using the procedure as described in Example 83C substituting Example 109B for benzylamine. MS (ESITNH3) m/z 413 (M+H)+ 1H NMR (δ, DMSO-Cf6); 4.51-4.59 (d, 2H), 7.05-7.2 (m, 2H), 7.4-7.6 (m, 4H), 7.7-7.81 (m, 2H), 7.95-8.0 (d, IH), 8.4-8.48 (m, 2H)
Example 96 r2-(2.3-Dichloro-phenylV2H-ri,2,4]triazol-3-yll-("2-thiophen-3-yl-pyridin-3-ylmethyl)-amme
Example 96A 2-thiophen-3-ylnicotinonitrile
To an oven-dried, N2-purged , 50 mL, round-bottomed flask containing a magnetic stir bar were added potassium fluoride (767 mg, 13.2 mmol), bis(tri-t- butylphosphine)palladium (51.0 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 2-chloro-3-cyanopyridine (559 mg, 4.00 mmol), and 3-thiopheneboronic acid (819 mg, 6.4 mmol). The flask was sealed with a septum and purged with dry N2 atmosphere. Anhydrous dioxane (4 mL) was added via syringe. The reaction mixture was heated to ~ 90 0C in an oil bath for 18 hours. After cooling to room temperature, ethyl acetate (15 mL) was added and the mixture was filtered through a pad of silica. The filtrate was concentrated by rotary evaporation to give a brown oil. The product was purified by recrystallization from ethyl acetate/hexanes to give 417 mg (56%) of the title compound. MS (ESI-) m/z 186.9 (M+H)+; 1H NMR (CDCl3) δ 7.30 (7.8, 4.7 Hz, IH), 7.44 (dd, J = 5.3, 2.9 Hz, IH), 7.88 (dd, J = 5.1, 1.4 Hz, IH), 8.03 (dd, J = 8.0, 1.9 Hz, IH), 8.29 (dd, J = 3.0, 1.4 Hz, IH), 8.82 (dd, J = 4.7, 1.7 Hz, IH).
Example 96B C-(2-Thiophen-3-yl-pyridin-3-ylVmethylamine
The title compound was prepared using the procedure as described in Example 93B substituting Example 96A for Example 93A.
Example 96C 2-f2,3-Dichloro-phenylV2H-ri,2,41triazol-3-yll-(2-thiophen-3-yl-pγridin-3-ylmethyl)-amme
The title compound was prepared using the procedure as described in Example 83C substituting Example 96B for benzylamine. MS (ESITNH3) m/z 402 (M+H)+; 1H NMR (δ, DMSO-J6); 4.51-4.59 (d, 2H), 7.15-7.2 (t, IH), 7.3-7.36 (m, IH), 7.42-7.62 (m, 4H), 7.75- 7.81 (3H), 8.45-8.5 (m, IH)
Example 97 (2-Azetidm-l-yl-pyridin-3-ylmethylV[2-(23-dichloro-phenylV2H-ri,2,4]triazol-3-yll-amine
Example 97A 2- Azetidin- 1 -yl-nicotinonitrile
The title compound was prepared using the procedure as described in Example 93A, substituting azetidine hydrochloride for pyrrolidine. MS (ESI+) m/z 160.0 (M+H)+; 1H NMR (DMSO-40 δ 2.28-2.38 (m, 2H), 4.19-4.25 (m, 4H), 6.73 (dd, J = 7.6, 4.9 HZ, IH), 7.92 (dd, J = 7.7, 1.8 Hz, IH), 8.30 (dd, J - 4.9, 1.9 Hz, IH).
Example 97B
C-(2-Azetidin-l-yl-pγridin-3-ylVmethylamine
The title compound was prepared using the procedure as described in Example 93B, substituting Example 97A for Example 93 A.
Example 97C f2-Azetidin-l-yl-ρyridin-3-ylmethylVr2-(2.3-dichloro-DhenylV2H-["1.2,41triazol-3-yll-amine The title compound was prepared using the procedure as described in Example 83 C substituting Example 97B for benzylamine. MS (ESIZNH3) m/z 375 (M+H)+; 1H NMR (δ, DMSO-^6); 2.19-2.25 (m, 2H), 3.95-4.04 (m, 4H), 4.25-4.3 (d, 2H), 6.62-6.65 (m, IH), 6.98- 7.02 (t, IH), 7.4-7.6 (m, 4H)3 7.79-7.85 (m, IH), 7.95-7.99 (d, IH).
Example 98 l-(23-dichlorophenyl)-Ar-[(2-morpholin-4-ylpyridin-3-yl)methyl1-lH-[l,2.4]-triazol-5-amine
Example 98A 4-[3-(azidomethγl)pwidin-2-yl]morpholine
To a solution of (2-morpholino-3-pyridinyl)methanol (1 g, 5.01 mmol)(purchased from Maybridge) in dichloromethane (20 ml) was added thionyl chloride (3 ml) dropwise at 0 0C and allowed to warm to room temperature. After stirring at room temperature for 6 hours, the solvents were removed under reduced pressure and the residue was dissolved and concentrated repeatedly in dichloromethane to remove excess of thionyl chloride. The obtained crude chloride intermediate, (2-morpholino-3-pyridinyl)methylchloride, was immediately dissolved in acetone (25 ml) and sodium azide (1.63 g, 25.05 nrmol) was added at room temperature. The reaction was refluxed overnight, the solvents were removed under reduced pressure, dissolved in dichloromethane (25 ml) and washed with IM NaHCO3 (25 ml). The aqueous layer was extracted with dichloromethane (2x20 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated to yield 0.62 g (57%) of product as a thick yellowish liquid. MS (ESI+) m/z 220 (M+H)+;
Example 98B (2-morpholin-4-ylpyridin-3-yl)methylamine
To a solution of the product from Example 98A (0.62 g) in methanol (10 ml) was added Pd/C (0.06 g) under N2 atmosphere. The reaction mixture was stirred at room temperature under H2 atmosphere. After 6 hours, the reaction mixture was filtered through celite and concentrated to yield 0.42 g (78%) of product. MS (ESl+) m/z 194 (M+H)+;
Example 98C l-(2,3-dichlorophenvD-7V-[("2-morpholm-4-ylpyridm-3-yl)methyll-lJH-[1.2,4]-triazol-5-amine The title compound was prepared using the procedure as described in Example 83C substituting Example 98B for benzylamine. MS (ES]yNH3) m/z 403 (M+H)+; 1H NMR (δ, DMSO-J6); 2.95-2.99 (m, 4H), 3.65-3.72 (m, 4H), 4.39-4.43 (d, 2H), 6.98-7.01 (m, IH), 7.05-7.12 (t, IH), 7.44-7.65 (m, 4H), 7.79-7.85 (m, IH), 8.15-8.2 (d, 2H).
Example 99 r2-(2,3-Dichloro-ρhenylV2H-rL2,41triazol-3-yl]-('2-methyl-ρyridin-3-ylmethylVamme The title compound was prepared using the procedure as described in Example 83C substituting C-(2-Methyl-pyridin-3-yl)-methylamine (purchased from General Intermediates of Canada, Inc)for benzylamine. MS (ES]yNH3) m/z 333 (M+H)+; 1H NMR (δ, DMSO- J6); 3.5 (s, 3H), 4.39-4.42 (d, 2H), 7.01-7.2 (m, 2H), 7.45-7.6 (m, 3H), 7.79-7.82 (d, IH), 8.29- 8.33 (d, IH).
Example 100 [4-("23-Dichloro-phenylV4H-[l,2,41triazol-3-yll-(2-methyl-benzyl)-amine
To a solution of 2-methylbenzylamine (0.121 g, 1 mmol) in tetrahydrofuran (10 ml) was added 2,3-dichlorophenylisothiocyanate (0.204 g, 1 mmol) drop wise at room temperature and stirred for one hour. To the reaction mixture was added triethylamine (0.42 ml), mercuric chloride (0.326 g, 1.2 mmol), and 3 ml of IM hydrazine solution in tetrahydrofuran. After stirring at room temperature for 12 hours, the reaction mixture was filtered. To the filtrate was added triethylorthoformate (2.5 ml) and formic acid (0.1 ml). The reaction mixture was heated to reflux for 2 hours, cooled, and triturated in hexanes. The viscous precipitate was purified by preparative HPLC on a waters Symmetry C8 column (40 mm X 100 mm, 7 μm particle size) using a gradient of 10 % to 100 % acetonitrile: ammonium acetate (10 mM) over 15 min at a flow rate of 70 mL/min to yield 80 mg of the title compound. MS (ESI+) m/z 333 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.28 (s, 3 H) 4.35 (d, J=5.76 Hz, 2 H) 6.49 (t, J=5.76 Hz, 1 H) 7.05 - 7.18 (m, 3 H) 7.26 (t, J=3.90 Hz, 1 H) 7.55 (t, 2 H) 7.83 (dd, J=7.46, 2.37 Hz, 1 H) 8.14 (s, 1 H); Anal, calcd for C13Hi4Cl2N4: C, 57.67; H, 4.23; N, 16.81. Found: C, 57.11; H, 4.24; N, 16.37.
Example 101 [4-(2,3-Dichloro-phenyl)-4H-[l,2,41triazol-3-vn-pyridin-3-ylmethyl-amine The title compound was prepared using the procedure as described in Example 100 substituting 3-(ammornethyl)pyridine for 2-methylbenzylamine. MS (ESI+) m/z 320 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.40 (d, J=S H 6 Hz, 2 H) 6.69 (d, J=I 1.87 Hz, 1 H) 7.30 - 7.36 (m, 1 H) 7.51 - 7.63 (m, 2 H) 7.73 (dt, J=7.80, 1.86 Hz, 1 H) 7.85 (dd, /=7.63, 2.20 Hz, 1 H) 8.16 (s, 1 H) 8.43 (dd, /=4.75, 1.70 Hz, 1 H) 8.54 (d, /=1.70 Hz, 1 H).
Example 102 r4-(2,3-Dichloro-ρhenyl)-4H-|"L2,41triazol-3-yll-r2-methyl-ρyridin-3-ylmethyl)-amine The title compound was prepared using the procedure as described in Example 100 substituting C-(2-methyl-pyridm-3-yl)-methylamine for 2-methylbenzylamine. MS (ESI+) m/z 334 (M+H)+; 1H NMR (300 MHz, DMSOd6) δ 2.47 (s, 3 H) 4.37 (d, J=5.42 Hz, 2 H) 6.61 (t, J=5.76 Hz, 1 H) 7.16 (dd, J=7.63, 4.92 Hz, 1 H) 7.51 - 7.64 (m, 3 H) 7.85 (dd, J=7.63, 1.86 Hz, 1 H) 8.16 (s, 1 H) 8.30 (dd, J=4.75, 1.70 Hz, 1 H).
Example 103
[4-("2,3-Dichloro-phenyl)-5-methyl-4H-ri,2,41triazol-3-yl1-f2-methyl-benzyl)-amine
The title compound was prepared using the procedure as described in Example 100 substituting triethylorthoacetate for triethylorthoformate. MS (ESI*) m/z 347 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.96 (s, 3 H) 2.26 (s, 3 H) 4.31 (d, J=5.76 Hz, 2 H) 6.27 (t, J=5.76 Hz, 1 H) 7.07 - 7.16 (m, 3 H) 7.20 - 7.30 (m, 1 H) 7.51 - 7.61 (m, 2 H) 7,85 (dd, /=6.10, 3.73 Hz, I H).
Example 104 r4-(2J-Dichloro-phenvn-5-ethyl-4H-ri,2,41triazol-3-yl1-(2-methyl-benzyl)-amme The title compound was prepared using the procedure as described in Example 100 substituting triethylorthpropionate for triethylorthoformate. MS (ESI+) m/z 361 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.63 Hz, 3 H) 2.21 - 2.35 (m, 5 H) 4.22 - 4.39 (m, 2 H) 6.26 (t, J=5.76 Hz, 1 H) 7.07 - 7.16 (m, 3 H) 7.20 - 7.30 (m, 1 H) 7.50 - 7.64 (m, 2 H) 7.85 (dd, /=7.12, 2.37 Hz, 1 H).
Example 105 [4-f2,3-Dichloro-phenyl)-4H-ri.2,41triazol-3-yl]-r2-Cpyridin-2-yloxy)-benzyll-amine The title compound was prepared using the procedure as described in Example 100 substituting 2-(Pyridin-2-yloxy)benzylamine hydrochloride (purchased from Array Biopharma) for 2-methylbenzylamine. MS (ESt) m/z 412 (M+H)+; 1H NMR (300 MHz, DMSOd6) δ ppm 4.30 (d, J=5.76 Hz, 2 H) 6.44 (t, J=5.93 Hz, 1 H) 6.98 - 7.07 (m, 2 H) 7.11 (dd, J=6.78, 5.43 Hz, 1 H) 7.19 (td, J=7.38, 1.19 Hz, 1 H) 7.28 (td, J=7.63, 2.03 Hz, 1 H) 7.42 (dd, J=7.63, 1.53 Hz, 1 H) 7.49 - 7.58 (m, 2 H) 7.79 - 7.90 (m, 2 H) 8.08 (dd, J=5.09, 1.36 Hz, I H) 8.14 (s, I H).
Example 106 ["4-(2,3-Dichloro-phenyl)-4H-ri,2,4]triazol-3-yll-r2-pyrrolidin-l-yl-pyridin-3-ylmethyl)- amine
The title compound was prepared using the procedure as described in Example 100 substituting Example 93B for 2-methylbenzylamine. MS (ESI+) m/z 389 (M+H)+; 1H NMR (300 MHz, DMSOd6) δ ppm 1.76 - 1.89 (m, 4 H) 3.40 - 3.51 (m, 4 H) 4.38 (d, J=5.09 Hz, 2 H) 6.48 (t, 1 H) 6.65 (dd, J=7.46, 4.75 Hz, 1 H) 7.47 (dd, J=7.29, 1.86 Hz, 1 H) 7.50 - 7.60 (m, 2 H) 7.83 (dd, J-7.46, 2.37 Hz, 1 H) 7.97 (dd, J=4.75, 2.03 Hz, 1 H) 8.15 (s, 1 H).
Example 107
["4-(2,3-Dichloro-phenylV4H-[l,2,4]triazol-3-yl]-[2-(pyridin-3-γloxy)-benzyl]-amine The title compound was prepared using the procedure as described in Example 100 substituting Example 94B for 2-methylbenzylamine. MS (ESI+) m/z 412 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.41 (d, J=6.10 Hz, 2 H) 6.56 (t, J=6.10 Hz, 1 H) 6.92 (dd, J=8.14, 1.02 Hz, 1 H) 7.18 (td, J=7.46, 1.36 Hz, 1 H) 7.24 - 7.32 (m, 1 H) 7.32 - 7.37 (m, 1 H) 7.37 - 7.44 (m, 1 H) 7.46 (dd, J=7.80, 1.70 Hz, 1 H) 7.50 - 7.57 (m, 2 H) 7.79 - 7.88 (m, 1 H) 8.15 (s, 1 H) 8.29 - 8.38 (m, 2 H).
Example 108 r4-f2.3-Dichloro-phenylV4H-ri.2.41triazol-3-yll-r2-thiophen-3-yl-pyridin-3-ylmethyl)-amine
The title compound was prepared using the procedure as described in Example 100 substituting Example 96B for 2-methylbenzylamine. MS (ESI+) m/z 402 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.52 (d, J=5.76 Hz, 2 H) 6.71 (t, J=5.76 Hz, 1 H) 7.32 (dd, J=I '.80, 4.75 Hz, 1 H) 7.48 - 7.55 (m, 1 H) 7.56 - 7.61 (m, 2 H) 7.63 (dd, J=4.92, 2.88 Hz, 1 H) 7.80 - 7.87 (m, 3 H) 8.15 - 8.18 (m, 1 H) 8.50 (dd, J=4.58, 1.53 Hz, 1 H).
Example 109 r4-(2,3-Dichloro-ρhenylV4H-ri,2,41triazol-3-yll-r2-(υyridin-3-yloxyVpγridin-3-ylmethyll- amine
Example 109 A
2-(Pyridin-3-yloxyVnicotinonitrile To a solution of pyridin-3-ol (1.3 g, 10 mmol) in N,N-dimethyl formamide (25 ml) was added 60 % NaH in mineral oil (0.3 g, 15 mmol) and 2-chloronicotinonitrile (1.38 g, 10 mmol) and heated at 120 0C for overnight. The reaction mixture was quenched with IM NaHCO3 and extracted with ethyl acetate (3x30 ml). The combined organic extracts were washed with saturated NaCl (50 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography using dichloromethane to yield 1.1 g (50%) of product. MS (ESI+) m/z 198 (M+H)+.
Example 109B
C-[2-(Pyridin-3-yloxy)-pyridin-3-yl]-methylamine To a solution of Example 109. A (1.Og, 5.1 mmole) in 7N NH3 in methanol (1000 ml) was added Raney nickel (10 g) under argon atmosphere. The reaction mixture was kept on shaker under 60 psi H2 atmosphere. After 6 hours at room temperature, the reaction mixture was filtered through a micro pore filter and concentrated to yield 0.9 g (88%) of product. MS (ESI1") m/z 202 (M+H)+.
Example 109C [4-(2,3-Dichloro-phenyl)-4H-ri.2,41triazol-3-yl1-[2-(pyridin-3-yloxy)-pyridin-3-ylmethyll- amine
The title compound was prepared using the procedure as described in Example 100 substituting Example 109B for 2-methylbenzylamine. MS (ESI+) m/z 413 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.52 (d, J=5.76 Hz, 2 H) 6.71 (t, J=5.76 Hz, 1 H) 7.14 (dd, J=7.46, 4.75 Hz, 1 H) 7.47 (dd, J=8.14, 4.75 Hz, 1 H) 7.56 (t, J=7.97 Hz, 1 H) 7.60 - 7.67 (m, 2 H) 7.80 (dd, J=I..29, 1.86 Hz, 1 H) 7.86 (dd, J=7.80, 1.70 Hz, 1 H) 7.99 (dd, J=4.92, 1.86 Hz, 1 H) 8.19 (s, 1 H) 8.41 - 8.47 (m, 2 H).
Example 110 r4-C23-Dichloro-phenylV4H-ri.2Λltriazol-3-yll-r2-ri-methyl-pyrrolidm-3-yloxyVpyridin-3- ylmethyl] -amine
Example HOA
2-( 1 -Methyl-p yrrolidm-3 - yloxy)-nicotinonitrile The title compound was prepared using the procedure as described in Example 109A substituting l-Methyl-pyrrolidin-3-ol for ρyridin-3-oL MS (ESI*) m/z 204 (M+H)+.
Example 11 OB
C- \2-( 1 -Methyl-pyrrolidin-3 -ylox y) -p yridin-3 -yl] -methylamine The title compound was prepared using the procedure as described in Example 109B substituting Example HOA for Example 109A. MS (ESI+) m/z 208 (M+H)+.
Example HOC r4-(2.3-Dichloro-phenyl)-4H-ri.2,41triazol-3-yl1-r2-(l-methyl-pyrrolidin-3-yloxyVpyridin-3- ylmethyl] -amine
The title compound was prepared using the procedure as described in Example 100 substituting Example HOB for 2-methylbenzylamine. MS (ESI+) m/z 419 (M+H)+; 1H NMR (300 MHz, DMSOd6) δ ppm 1.72 - 1.86 (m, 1 H) 2.25 (s, 3 H) 2.27 - 2.40 (m, 2 H) 2.54 - 2.70 (m, 2 H) 2.80 (dd, J=10.51, 6.10 Hz, 1 H) 4.30 (d, J=5.76 Hz, 2 H) 5.36 (t, 1 H) 6.45 (t, J=5.93 Hz, 1 H) 6.92 (dd, J-7.29, 4.92 Hz, 1 H) 7.56 (t, J=7.97 Hz, 2 H) 7.61 - 7.67 (m, 1 H) 7.86 (dd, J=7.80, 1.70 Hz, 1 H) 8.00 (dd, J=4.92, 1.86 Hz, 1 H) 8.17 (s, 1 H).
Example 111 r4-f2J-Dichloro-phenyl)-5-methyl-4H-ri,2,41triazol-3-yll-(2-thiophen-3-yl-pyridin-3- ylmethyD-amine
The title compound was prepared using the procedure as described in Example 100 substituting Example 96B for 2-methylbenzylamine and triethylorthoacetate was for triethylorthoformate. MS (ESl+) m/z 416 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.97 (s, 3 H) 4.48 (d, J=5.76 Hz, 2 H) 6.50 (t, J=5.76 Hz, 1 H) 7.30 (dd, J=7.80, 4.75 Hz, 1 H) 7.50 (dd, J=5.09, 1.36 Hz, 1 H) 7.57 (s, 3 H) 7.77 - 7.90 (m, 3 H) 8.45 - 8.52 (m, J=4.75, 1.70 Hz, I H).
Example 112 tert-butyl 4-r3-({r4-r2,3-dichloroρhenylV4H-1.2.4-triazol-3-yllamino|methvDpyridin-2-yl1-
1 ,4-diazepane- 1 -carboxylate
Example 112A
4-(2-Cvano-phenyl)-["l,4]diazepane-l-carboxylic acid ferf-butyl ester 2-Chloro-nicotinonitrile(1.0 g, 7.215 mmol) was added to a mixture of
[l,4]Diazepane-l-carboxylic acid tert-butyl ester and potassium hydogencarbonate (0.87 g, 8.66 mmol) in N,N-dimethylformamide (20 mL). The mixture was heated at 9O0C overnight. The reaction mixture was poured onto ice and extracted with dichloromethane. The organic layer was washed with water and brine then dried over magnesium sulfate and filtered. The solvent was removed and the residue was purified by flash column chromatography on silica using ethyl acetate/heptane (50:50) mixture as the mobile phase to give 4-(2-Cyano-phenyl)- [l,4]diazepane-l-carboxylic acid fert-butyl ester. 1H-NMR (400 MHz, DMSCW6) ^ 1.25 (d, 27 Hz, 9H), 1.81 (m, IH), 1.87 (m,lH), 3.31(m,2H), 3.55(m,lH), 3.60 (m,lH), 3.84 (m, 2H), 3.94 (m, 2H), 6.75 (m,2H), 8.34 (m,lH).
Example 112B
4-(3-Aminomethyl-pyridin-2-yl)-[l,41diazepane-l-carboxylic acid tert-butyl ester
To a nitrogen-purged, thick-walled pressure vessel was added wet Raney nickel (~2 g). A solution of ammonia-saturated methanol (7.0N, 70 mL) was added, followed by Example 112A (7.215 mmol). The vessel was inserted into a Parr shaker and was charged with 60 psi ofH2 gas. The mixture was shaken at room temperature under static H2 pressure for 16 hours. The H2 gas was vented and the vessel was purged with nitrogen. The solids were removed by vacuum filtration through Celite ®. The solvent/volatiles were removed by rotary evaporator to give the title compound which was used without further purification. Example 112C 4-f3-([4-(2.3-Dichloro-phenylV4H-ri.2.41triazol-3-ylaminol-methyll-pyridin-2- yD[~l,41diazepane-l-carboxyric acid tert-butyl ester The title compound was prepared using the procedure as described in Example 100, substituting Example 112B for 2-methylbenzylamine. MS (ESI+) m/z 518.6 (M+H)+; 1H NMR (DMSOd6) δ 8,107 (s. IH); 8,075 (m,lH); 7,811(m,lH); 7,607(m,2H); 7,545(m,lH); 6.888(m,lH); 6.375(m,lH); 4,360 (m,2H); 3,509(m,2H); 3,410(m,2H); 3,378(m,2H); 3,288(m,2H); l,838(m,2H); l,383(s,9H).
Example 113
2-[4-(3-jr4-(2.3-Dichloro-phenylV4H-[L2,41triazol-3-ylamino1-methyll-pyridin-2-ylV r 1 ,4"jdiazepan-l -yl]-acetamide
Example 113A
N- { [2-(T ,4-diazepan- 1 - yl>pyridin-3-yllmethyl> -4-(2,3 -dichloroυhenyl)-4H- 1 ,2.4-triazol-3 - amine
Trifluoro acetic acid (15 mL) was added to a solution of Example 112C (2.0 g, 3.86 mmol) in dichloromethane (75 mL) at O0C. 5 minuted later, the ice bath was removed and the the reaction mixture was stirrred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane. The organic was washed with saturated sodium bicarbonate and the pH was adjusted to 9. The layers were separated and the aqueous layer was extracted with dichloromathane. The combined organic layer was washed with brine, dried over magnium sulfate, filtered and concentrated to yield the title compound that was used without further purification.
Example 113B 2-|"4-("3-{r4-(2,3-Dichloro-phenyl)-4H-|"l,2,41triazol-3-ylamino1-methyl|-ρvridin-2-vl)-
\ 1 ,4"]diazepan- 1 - vH-acetamide To a solution of Example 113A (250 mg, 0.597 mmol) in dimethylformamide (7 ml) was added potassium carbonate (165 mg, 1.194 mmol) and bromoacetamide (124 mg, 0.896 mmol). The reaction mixture was stirred at room temperature for 16 hours then poured onto ice water. The aqueous mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) to give the title compound (109 mg). MS (ESI+) m/z 475.6 (M+H)+;
Figure imgf000078_0001
1HNMR (DMSO-d«j) δ 8,170 (s, IH); 8,054 (d,lH) ; 7,832 (d,lH); 7,579(m,3H); 7,251 (s,lH); 7,112 (s,lH); 6,832 (dd,lH); 6,545 (t,lH); 4,338 (d, 2H); 3,423 (m,4H); 3,011 (s,2H); 2,772 (m,2H); 2,710 (m,2H); l,856(m,2H).
Example 114 4-(Z3-dichlorophenyl)-iV- 1 r2-(4-isopropyl- 1 ,4-diazepan- 1 - vDp yridin-3 - yl]methyl} -4H- 1 ,2,4- triazol-3-amine
To a solution of Example 113 A in 1,2-dichloroethane (10 ml) was added acetone (3 niL) and sodium triacetoxyborohydride (253 mg, 1.194 mmol). The reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) to give the title compound. MS (ESI+) m/z 460.6 (M+H)+; Rt=1.47. 1H NMR (DMSO-rf6) δ 8,171 (s.lH); 8,049 (d, IH); 7,831(d, IH); 7,586(m, 3H); 6,837 (dd, IH); 6,521 (t, IH); 4,353 (d, 2H); 3,377 (m, 4H); 3,289 (m, IH); 2,862 (m, 2H); 2,642 (m, 2H); 1,773 (m, 2H); 0,949 (m, 6H).
f) Biological Activity In Vitro Data
Tissue Culture: Cells of the THP-I monocytic cell line (American Type Culture Collection, Rockville, MD) were maintained in the log phase of growth in RPMI medium containing high glucose and 10% fetal calf serum (BRL, Grand Island, NY) according to established procedures (Humphrey and Dubyak, J. Immunol. Vol. 275. pages 26792-26798, 1996). Fresh vials of frozen THP-I cells were initiated for growth every eight weeks. To differentiate THP-I cells into a macrophage phenotype, a final concentration of 25 ng/ml of LPS and 10 ng/ml of IFNγ were added to the cells (Humphrey and Dubyak 1996) either for 3 hours for IL-lβ release assays or overnight (16 hours) for pore formation studies. 1321N1 cells stably expressing the recombinant human P2X7 receptor were grown and used according to previously published protocols (Bianchi, et al, Eur. J. Pharmacol. Vol. 376, pages 127-138, 1999; Lynch et ah. MoI. Pharmacol. Vol. 56. pages 1171-1181, 1999). For both the pore formation and IL-I β release assays, cell density and viability were routinely assessed prior to each experiment by trypan dye exclusion and cells found to be >90% viable following differentiation.
IL-lβ Release: THP-I cells were plated in 24-well plates at a density of 1 x 106 cells /well/ ml. On the day of the experiment, cells were differentiated with 25 ng/ml LPS and 10 ng/ml final concentration of γlFN for 3 hours at 37 0C. Solutions of antagonist compounds were prepared by serial dilutions of a 10 mM DMSO solution of the antagonist into the PBS solution, hi the presence of the differentiation media, the cells were incubated with the antagonists of the present invention for 30 minutes at 37 0C followed by a challenge with 1 mM BzATP for an additional 30 minutes at 37 0C. Supernatants of the samples were collected after a 5 minute centrifugation in microfuge tubes to pellet the cells and debris and to test for mature IL-lβ released into the supernatant using either R & D Systems Human IL- lβ ELISA assay or Endogen Human IL-lβ ELISA, following the manufacturer's instructions. The maximum IL-lβ release at each concentration of test compound was normalized to that induced by BzATP alone to determine the activity of the test compound. Antagonist potency was expressed as the concentration producing a 50% reduction in release of IL-lβ or IC50. Representative compounds of the present invention when tested with the above assay demonstrated antagonist activity at the P2X7 receptor with IC50 equal or less than 1 μM. In Vivo Data
Determination of Antinociceptive Effect Animal handling and experimental protocols were approved by the Institutional
Animal Care and Use Committee (IACUC) at Abbott Laboratories. For all surgical procedures, animals were maintained under halothane anesthesia (4% to induce, 2% to maintain), and the incision sites were sterilized using a 10% povidone-iodine solution prior to and after surgeries. CFA model: The capacity of the antagonists to reduce inflammatory hyperalgesia was evaluated using the complete Freund's adjuvant (CFA) model. In these experiments, animals were subjected to intraplantar injection of CFA 48 hours before administration of the P2X7 antagonists. Inhibition of thermal hyperalgesia was determined 30 minutes after antagonist administration by observation of paw withdrawal latency and comparison to response of the contralateral paw. Representative compounds were active in reducing tactile allodynia when administered subcutaneously using this model. Chung model: Efficacy in the reduction of neuropathic pain was evaluated using the
L5/L6 spinal nerve tight ligation (Chung) model in rats. In these experiments, spinal nerve ligation was performed 7-14 days prior to assay. Tactile allodynia was induced by application of a von Frey hair 30 minutes after intraperitoneal administration of the antagonist. Reduction in tactile allodynia was measured by determination of the paw withdrawal threshold and comparison to the contralateral paw. Representative compounds were active in reducing tactile allodynia when tested using this model. (Jarvis et ah, Proc. Natl. Acad. USA Vol. 99, pages 17179-17184, 2002).
Zymosan Method: Mice were dosed with experimental compounds orally or subcutaneously 30 minutes prior to injection of zymosan. Mice were then injected intraperitonealy with 2 mg/animal of zymosan suspended in saline. Four hours later the animals were euthanized by CO2 inhalation and the peritoneal cavities lavaged with 2 X 1.5 mL of ice cold phosphate buffered saline containing 10 units of heparin/ml. For IL- lβ determination the samples were spun at 10,000 x g in a refrigerated microfuge (4° C), supernatants removed and frozen until ELISAs (Enzyme Linked hnmuno-Assay) were performed. ELISAs were performed according to manufacture's instructions. IL-lβ was determined relative to vehicle control (Perretti M. et ah, Agents Actions VoI 35(1-2) pages 71-78 (1992); Torek K, et al, ftiflamm Res. VoI 44(6) pages 248-252 (1995)). Representative compounds of this invention were active as P2X7 antagonists in inhibiting IL- 1 β release in this assay when administered subcutaneously.

Claims

We claim
1. A compound having formula (I) or (II)
Figure imgf000081_0001
(D (II) or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or a combination thereof, wherein
R1 is hydrogen, alkyl, haloalkyl or -CN;
R2 is -N(H)-(CRuRv)-R2a, -N(H)-R2b or R2b; and R3 is
Figure imgf000081_0002
wherein R2a is a group of formula (a) or (b);
Figure imgf000081_0003
(a) (b) ; and
R2b is a group of formula (c), (d) or (e)
Figure imgf000081_0004
or
(C) (d) (e)
or
Figure imgf000081_0005
wherein R2b is a group of formula (c), (d) or (e)
Figure imgf000082_0001
(C) (d) or (e) ;
Zi at each occurrence is independently C, C(H), C(H)2, O, S, S(O), S(O)2, N(H), N(alkyl) or N(acyl); Z2 at each occurrence is independently C, C(H), or N;
Z3 at each occurrence is independently O, S, S(O), S(O)2, N(H), N(alkyl) or N(acyl);
R4 at each occurrence is independently halo, alkyl, -CN, -ORA, -SRA, -N(RA)(RB) or haloalkyl; R5 at each occurrence is independently alkyl, halo or haloalkyl; m at each occurrence is independently O, 1, 2 or 3; n at each occurrence is independently O, 1, 2 or 3;
R2 and Rb at each occurrence are each independently halo, -CN, haloalkyl, haloalkoxy or alkyl; R0 at each occurrence is independently hydrogen, halo, haloalkyl, alkoxy, haloalkoxy or alkyl; each of Ru and Rv at each occurrence is independently hydrogen, alkyl or haloalkyl;
Ai, A2, A3 and A4 are -C(RW); or one or two of Ai, A2, A3 and A4 are N, and the others are -C(RW); or one of
Ai, A2, A3 and A4 is N+-O" and the others are -C(RW); wherein Rw at each occurrence is independently hydrogen, halo, alkyl, alkenyl, -ORA, -SRA, -N(RA)(RB) or haloalkyl;
A5 is N, A6 is O or S and A7 is C(H) or C(alkyl), or
A5 is N, A6 is C(H) or C(alkyl), and A7 is O or S, or one of A5, A6 and A7 is S and the others are independently C(H) or C(alkyl);
G is -W2 or -L2-W2; or
G is hydrogen, alkyl, -Oalkyl, -NH2, -N(H)(alkyl), -N(alkyl)2, -S(O)alkyl, -S(O)2alkyl, -S(O)2NH2, -S(O)2N(H)(alkyl), -S(O)2N(alkyl)2, -C(O)NH2, -C(O)N(H)(alkyl), -C(O)N(alkyl)2, -W2 or -L2-W2, when one OfA1, A2, A3 and A4 is N;
L2 is N(H), N(alkyl), O, S, S(O)5 S(O)2, S(O)2N(H), SO2N(alkyl), N(H)S(O)2, N(alkyl)S(O)2, CON(H), CON(alkyl), N(H)CO, N(alkyl)CO); and W2 at each occurrence is independently aryl, heteroaryl or heterocycle; and each W2 is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of =0, halo,-CN, -NO2, alkyl, alkenyl, -0RA, -SRA, -S(O)2RA, -S(O)2N(RA)(RB), -N(RA)(RB), -C(O)RA, -C(O)N(RA)(RB), -C(O)ORA, haloalkyl, -alkyl-ORA, -alkyl-SRA, -alkyl-S(O)2RA, -alkyl-S(O)2N(RA)(RB), -alkyl-N(RA)(RB), -alkyl-C(O)RA, -alkyl-C(O)N(RA)(RB), and -alkyl-C(O)ORA;
RA at each occurrence is independently hydrogen, alkyl, alkenyl or haloalkyl; and
RB at each occurrence is independently hydrogen, alkyl, or haloalkyl.
2. The compound of claim 1 having formula (I)
Figure imgf000083_0001
(I) wherein R1 is hydrogen, alkyl, haloalkyl or - -CN;
Figure imgf000083_0002
R2 is -N(H)-(CRURV)-R2a.
3. The compound of claim 2 wherein R2a is
Figure imgf000083_0003
; and G is -W2, wherein W2 is independently aryl, heteroaryl or heterocycle, and is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of =0, halo,-CN, -NO2, alkyl, alkenyl, -ORA, -SRA, -S(O)2RA, -S(O)2N(RA)(RB), -N(RA)(RB), -C(O)RA, -C(O)N(RA)(RB), -C(O)ORA, haloalkyl, -alkyl-ORA, -alkyl-SRA, -alkyl-S(O)2RA, -alkyl-S(O)2N(RA)(RB), -alkyl-N(RA)(RB), -alkyl-C(O)RA, -alkyl-C(O)N(RA)(RB), and -alkyl-C(O)ORA.
4. The compound of claim 3 that is selected from the group consisting of [4-(2,3-Dichloro-ρhenyl)-4H-[l,2,4]triazol-3-yl]-(2-pyrrolidin-l-yl-pyridin-3-ylmethyl)- amine, tert-butyl 4-[3-({[4-(2,3-dichlorophenyl)-4H-l,2,4-triazol-3-yl]amino}methyl)pyridin-2-yl]-
1,4-diazepane-l-carboxylate;
2-[4-(3 - { [4-(2,3 -Dichloro-phenyl)-4H- [ 1 ,2,4] triazol-3 -ylamino] -methyl} -pyridin-2-yl)- [l,4]diazepan-l-yl]-acetamide;
4-(2,3-dichlorophenyl)-JV- { [2-(4-isopropyl- 1 ,4-diazepan- 1 -yl)pyridin-3 -yljmethyl} -4H- 1 ,2,4- triazol-3-amine;
[4-(2,3-Dichloro-ρhenyl)-4Η-[l,2,4]triazol-3-yl]-(2-thiophen-3-yl-pyridin-3-ylmethyl)- amine, and [4-(2,3-Dichloro-ρhenyl)-5-methyl-4H-[l ,2,4]triazol-3-yl]-(2-thiophen-3-yl-pyridin-3- ylmethyl)-amine.
5. The compound of claim 2 wherein R2a is
Figure imgf000084_0001
and G is G is hydrogen, alkyl, -Oalkyl, -NH2, -N(H)(alkyl), -N(alkyl)2, -S(O)alkyl, -S(O)2alkyl, -S(O)2NH2, -S(O)2N(H)(alkyl), -S(O)2N(alkyl)2, -C(O)NH2, -C(O)N(H)(alkyl), -C(O)N(alkyl)2, -W2 or -L2-W2, when one of A1, A2, A3 and A4 is N.
6. The compound of claim 5 that is selected from the group consisting of [4-(2,3-Dichloro-ρhenyl)-4H- [ 1 ,2,4] triazol-3 -yl] -pyridin-3 -ylmethyl- amine, and [4-(2,3-Dichloro-ρhenyl)-4H-[l,2,4]triazol-3-yl]-(2-methyl-pyridin-3-ylmethyl)-amine,
7. The compound of claim 2 wherein R2a is
Figure imgf000084_0002
8. The compound of claim 7 wherein L2 is O and W2 is selected from unsubstituted or substituted aryl, heteroaryl or heterocycle,
9. The compound of claim 8 that is selected from the group consisting of [4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-[2-(5-fluoro-pyridm-3-yloxy)-pyridin-3- ylmethyl] -amine,
[4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-[2-(pyridin-2-yloxy)-benzyl]-amine, [4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-benzyl]-amine, [4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-pyridin-3-ylmethyl]- amine, and
[4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-[2-(l-methyl-pyrrolidin-3-yloxy)-pyridin-3- yϊmethyl] -amine.
10. The compound of claim 2 wherein R2a is
Figure imgf000085_0001
or
G is hydrogen, alkyl, -Oalkyl, -NH2, -N(H)(alkyl), -N(alkyl)2, -S(O)alkyl, -S(O)2alkyl, -S(O)2NH2, -S(O)2N(H)(alkyl), -S(O)2N(alkyl)2, -C(O)NH2, -C(O)N(H)(alkyl), -C(O)N(alkyl)2, -W2 or -L2-W2, when one OfA1, A2, A3 and A4 is N;
11. The compound of claim 1 having formula (I)
herein Ri is hydrogen, alkyl, haloalkyl or -CN;
Figure imgf000085_0002
R2 is -N(H)-R2b.
12. The compound of claim 11 wherein
Figure imgf000086_0001
13. The compound of claim 11 wherein
Figure imgf000086_0002
14. The compound of claim 11 wherein
Figure imgf000086_0003
15. The compound of claim 1 having formula (I)
erein Ri is hydrogen, alkyl, haloalkyl or -CN;
Figure imgf000086_0004
R2 is R2b.
16. The compound of claim 15 wherein
Figure imgf000086_0005
17. The compound of claim 15 wherein
Figure imgf000087_0001
18. The compound of claim 15 wherein
Figure imgf000087_0002
19. The compound of claim 1 having formula (I)
Figure imgf000087_0003
W wherein R1 is hydrogen, alkyl, haloalkyl or -CN;
Figure imgf000087_0004
R3 is R2b.
20. The compound of claim 19 wherein
R3 is R2b, and
R2b is a group of formula (c)
Figure imgf000087_0005
(C)
21. The compound of claim 18 that is selected from the group consisting of
3-(2,3-dichlorophenyl)-4-(2,3-dihydro-lH-inden-l-yl)-4H-l,2,4-triazol,
3-(2,3-dichlorophenyl)-4-[2,3-dihydro-l-benzofuran-3-yl]-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-[(lR)-2,3-dihydro-lH-inden-l-yl]-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-[(lS)-2,3-dihydro-lH-inden-l-yl]-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-(3-metliyl-2,3-dihydro-lH-mden-l-yl)-4H-l,2,4-triazole, 3-[2-chloro-3-(trifluoromethyl)phenyl]-4-[(lR)-2,3-dihydro-lH-inden-l-yl]-4H-l52,4- triazole,-(2,3 -dichlorophenyl)-4-(4-fluoro-2,3 -dihydro- lH-inden- 1 -yl)-4H- 1 ,2,4-triazole, and 3-(2,3-dichlorophenyl)-4-[5-(trifluoromethyl)-2,3-dihydro-lH-inden-l-yl]-4H-l,2J4-triazole.
22. The compound of claim 19 wherein R2b is a group of formula (d)
Figure imgf000088_0001
(d)
23. The compound of claim 22 that is selected from the group consisting of
3-(2,3-dichlorophenyl)-4-(l,2,3,4-tetrahydronaphthalen-l-yl)-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(4,4-dimethyl-l,2,3,4-tetrahydronaphthalen-l-yl)-4H-l,2,4-triazole, and
3-(2,3-dichlorophenyl)-4-(3,4-dihydro-2H-chromen-4-yl)-4H-l,2,4-triazole.
24. The compound of claim 19 wherein R2b is a group of formula (e)
Figure imgf000088_0002
(e)
25. The compound of claim 1 having formula (II)
Figure imgf000088_0003
(H) ; wherein R1 is hydrogen, alkyl, haloalkyl or -CN; R2 is -N(H)-(CRuRv)-R2a; and
Figure imgf000089_0001
26. The compound of claim 25 wherein R2a is
Figure imgf000089_0002
A-i A2 . an(j Q js -W25 wherein W2 is independently aryl, heteroaryl or heterocycle, and is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of O, halo,-CN, -NO2, alkyl, alkenyl, -0RA, -SRA, -S(O)2RA, -S(O)2N(RA)(RB), -N(RA)(RB), -C(O)RA, -C(O)N(RA)(RB), -C(O)ORA, haloalkyl, -alkyl-ORA, -alkyl-SRA, -alkyl-S(O)2RA, -alkyl-S(O)2N(RA)(RB), -alkyl-N(RA)(RB), -alkyl-C(O)RA, -alkyl-C(O)N(RA)(RB), and -alkyl-C(O)ORA.
27. The compound of claim 26 selected from the group consisting of: l-(2,3-dichlorophenyl)-N-[(2-pyrrolidin-l-ylpyridin-3-yl)methyl]-lH-[l,2,4]triazole-5-amine, l-(2,3-dichlorophenyl)-iV-[(2-morpholin-4-ylpyridin-3-yl)methyl]-lH-[l,2,4]-triazol-5- amine,
[2-(2,3-Dichloro-phenyl)-2Η-[l,2,4]triazol-3-yl]-(2-thioρhen-3-yl-pyridin-3-ylmethyl)- amine, and
(2- Azetidin- 1 -yl-ρyridin-3 -ylmethyl)- [2-(2,3 -dichloro-ρhenyl)-2H-[ 1 ,2,4]triazol-3-yl] -amine.
28. The compound of claim 25 wherein R2a is
Figure imgf000089_0003
; and G is hydrogen, alkyl, -Oalkyl, -NH2, -N(H)(alkyl), -N(alkyl)2, -S(O)alkyl, -S(O)2alkyl, -S(O)2NH2, -S(O)2N(H)(alkyl)5 -S(O)2N(alkyl)2, -C(O)NH2, -C(O)N(H)(alkyl), or -C(O)N(alkyl)2.
29. The compound of claim 28 selected from the group consisting of: [2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-pyridm-3-ylmethyl-amine, and [2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-(2-methyl-pyridin-3-ylmethyl)-amine.
30. The compound of claim 25 wherein R2a is
Figure imgf000090_0001
31. The compound of claim 30 wherein L2 is O and W2 is aryl or heteroaryl.
32. The compound of claim 31 selected from the group consisting of: [2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-benzyl]-amine, and
[2-(2,3-Dichloro-ρhenyl)-2H-[l,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-pyridin-3- ylmethyl] -amine.
33. The compound of claim 25 wherein R2a is
Figure imgf000090_0002
34. The compound of claim 1 having formula (II)
Figure imgf000090_0003
(H) ; wherein R1 is hydrogen, alkyl, haloalkyl or -CN; R2 is -N(H)-Ra; and
Figure imgf000090_0004
35. The compound of claim 34 wherein R2b is a group of formula (c )
Figure imgf000091_0001
(C)
36. The compound of claim 34 wherein R2b is a group of formula (d)
Figure imgf000091_0002
(d)
37. The compound of claim 34 wherein R2b is a group of formula (e)
Figure imgf000091_0003
(e)
38. The compound of claim 1 having formula (II)
Figure imgf000091_0004
(H) ; wherein
R1 is hydrogen, alkyl, haloalkyl or -CN; R2 is -R2b; and
Figure imgf000091_0005
39. The compound of claim 38 wherein R2b is a group of formula (c)
Figure imgf000092_0001
(C)
40. The compound of claim 39 that is l-[2-chloro-3-(trifiuoromethyl)phenyl]-5-(2,3-dihydro-lH-inden-l-yl)-lH-l,2,4-triazole.
41. The compound of claim 38 wherein R2b is a group of formula (d)
Figure imgf000092_0002
(d)
42. The compound of claim 38 wherein R2b is a group of formula (e)
Figure imgf000092_0003
(e)
43. The compound of claim 1 having formula (II)
Figure imgf000092_0004
(H) ; wherein
R1 is hydrogen, alkyl, haloalkyl or -CN;
Figure imgf000092_0005
R3 is R2b.
44. The compound of claim 43 wherein R2b is a group of formula (c)
Figure imgf000093_0001
(G)
45. The compound of claim 44 that is S-p-chloro-S-Ctrifluoromethy^phenylJ-l-P^-dihydro-lH-inden-l-ylJ-lH-l^^-triazole.
46. The compound of claim 43 wherein R2b is a group of formula (d)
Figure imgf000093_0002
(d)
47. The compound of claim 43 wherein R2b is a group of formula (e)
Figure imgf000093_0003
(e)
48. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or formula (II) as described in claim 1, or a therapeutically acceptable salt, solvate, prodrug, salt of a prodrug, or combination thereof, and a pharmaceutically acceptable carrier.
49. A method of selectively inhibiting P2X7 activity in a mammal comprising administering an effective amount of a compound of of formula (I) or formula (II) as described in claim l,or a pharmaceutically acceptable salt thereof.
50. A method of treating or preventing a condition or disorder selected from the group consisting of pain, neuropathic pain, chronic inflammatory pain, inflammation, depression and neurodegenerative conditions associated with several progressive CNS disorders, including, but not limited to, Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bodies, multiple sclerosis as well as diminished CNS function resulting from traumatic brain injury, comprising the step of administering a compound of formula (I) or formula (II) as described in claim 1.
51. A method of use for treating or preventing a condition or disorder selected from the group consisting of pain, neuropathic pain, chronic inflammatory pain, inflammation and neurodegenerative conditions associated with several progressive CNS disorders comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (III), (IV) or (V)
Figure imgf000094_0001
or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
R6 is hydrogen, alkyl, haloalkyl or -CN;
l7 is
Figure imgf000094_0002
and R8 is -W, -C(RxRy)-W1, -C(RxRy)-W1-W2, or
Figure imgf000094_0003
Rs is d R7 is -W, -N(H)-W5 -L1-W1, -Li-Wi-W2, or -L1-W1-L2-W2;
Rio is Rn is -C(RxRy)-Wi; and Rg is hydrogen, alkyl, haloalkyl or -
CN; or
Rn is io is -C(RxRy)-Wi; and R9 is hydrogen, alkyl, haloalkyl or-
CN; or
Rg is
Figure imgf000095_0001
Rio is -C(RxRy)-Wi; and Rn is hydrogen; wherein
Ra and Rb at each occurrence are each independently halo, -CN, haloalkyl, haloalkoxy or alkyl;
Rc at each occurrence is independently hydrogen, halo, haloalkyl, alkoxy, haloalkoxy or alkyl;
Li at each occurrence is independently -C(RxRy), or -N(H)-C(RURV)P-; p is l or 2; each of Ru, Rv, Rx and Ry at each occurrence is independently hydrogen, alkyl or haloalkyl;
W is
Figure imgf000095_0002
wherein
A is a five or six membered monocyclic ring selected from the group consisting of cycloalkyl and heterocycle and is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halo and haloalkyl; B is phenyl or monocyclic heteroaryl, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, alkyl, -CN, -ORA, -SRA, -N(RA)(RB) and haloalkyl; q is O or 1; R2 is W2 or -L2-W2;
L2 at each occurrence is independently O, N(H), or N(alkyl), S, S(O), S(O)2, S(O)2N(H), SO2N(alkyl), N(H)S(O)2, N(alkyl)S(O)2, CON(H), CON(alkyl), N(H)CO, N(alkyl)CO);
W1 at each occurrence is independently phenyl or monocyclic heteroaryl, wherein each W1 is optionally fused with a monocyclic, five or six-membered ring selected from the group consisting of phenyl, heteroaryl, heterocycle, cycloalkyl and cycloalkenyl;
W2, at each occurrence is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; each of Wi and W2, at each occurrence, is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, CN, NO2, halo, =0, -0RA, -SRA, -S(O)RA, -S(O)2RA, -S(O)2N(RA)(RB), -N(RA)(RB), -C(0)RA, -C(0)0RA, -C(O)N(RA)(RB), haloalkyl, -alkyl-ORA, -alkyl-SRA, -alkyl-S(O)RA, -alkyl-S(O)2RA, -alkyl-S(O)2N(RA)(RB), -alkyl-N(RA)(RB), -alkyl-C(O)RA, -alkyl-C(O)ORA, and -alkyl-C(O)N(RA)(RB);
RA at each occurrence is independently hydrogen, alkyl, alkenyl or haloalkyl; and
RB at each occurrence is independently hydrogen, alkyl, or haloalkyl.
52. The method of use of claim 51, wherein the compound has formula (III),
Figure imgf000096_0001
(III)
R6 is hydrogen, alkyl, haloalkyl or -CN; R7 is
Figure imgf000097_0001
and R8 is -W, wherein W is
Figure imgf000097_0002
claim 48.
53. The method of use of claim 52 wherein A is a five or six membered monocyclic ring that is cycloalkyl or heterocycle, which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halo and haloalkyl, and B is phenyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, alkyl, -CN, -ORA, -SRA, -N(RA)(RB) and haloalkyl.
54. The method of use of claim 52 wherein A is a five membered monocyclic ring that is cycloalkyl or heterocycle, which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halo and haloalkyl, and B is heteroaryl, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, alkyl, -CN, -ORA, -SRA, -N(RA)(RB) and haloalkyl.
55. The method of use of claim 53 wherein the compound is selected from the group consisting of
3-(2,3-dichlorophenyl)-4-(2,3-dihydro-lH-inden-l-yl)-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-[2,3-dihydro-l-benzofuran-3-yl]-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-[(lR)-2,3-dihydro-lH-inden-l-yl]-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-[(lS)-2,3-dihydro-lH-inden-l-yl]-4H-l,2,4-triazole,
3-(2,3-diclilorophenyl)-4-(3-methyl-2,3-dihydro-lH-inden-l-yl)-4H-l,2,4-triazole, 3-[3-(2,3-dichlorophenyl)-4H4,2,4-triazol-4-yl]-lH-indazole,
3-[2-chloro-3-(trifluoromethyl)phenyl]-4-[(lR)-2,3-dihydro-lH-inden-l-yl]-4H-l,2,4- triazole, 3 -(2,3 -dichlorophenyl)-4-(4-fluoro-2,3 -dihydro-lH-inden- 1 -yl)-4H- 1 ,2,4-triazole, and
3-(2,3-dichlorophenyl)-4-[5-(trifluoromethyl)-2,3-dihydro-lH-inden-l-yl]-4H-l,2,4-triazole.
56. The method of use of claim 52 wherein A is a six membered monocyclic ring that is cycloalkyl or heterocycle, which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halo and haloalkyl, and B is phenyl, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, alkyl, -CN, -ORA, -SRAj -N(RA)(RB) and haloalkyl.
57. The method of use of claim 56, wherein the compound is selected from the group consisting of
3-(2,3-dichlorophenyl)-4-(l,2,3,4-tetrahydronaphthalen-l-yl)-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-(4,4-dimethyl-l,2,3,4-tetrahydronaρhthalen-l-yl)-4H-l,2,4-triazole, and
3-(2,3-dichlorophenyl)-4-(3,4-dihydro-2H-chiOmen-4-yl)-4H-l,2,4-triazole.
58. The method of use of claim 51, wherein the compound has formula (III),
Figure imgf000098_0001
(III)
R6 is hydrogen, alkyl, haloalkyl or -CN;
Figure imgf000098_0002
and Rg is -C(RxRy)-W1; wherein W1 at each occurrence is independently phenyl or monocyclic heteroaryl, wherein each W1 is optionally fused with a monocyclic, five or six-membered ring selected from the group consisting of phenyl, heteroaryl, heterocycle, cycloalkyl and cycloalkenyl; and Rx and Ry at each occurrence is independently hydrogen, alkyl or haloalkyl.
59. The method of use of claim 58, wherein Wi is phenyl independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, CN, NO2, halo, =0, -ORA, -SRA, -S(O)RA, -S(O)2RA, -S(O)2N(RA)(RB), -N(RA)(RB), -C(O)RA, -C(O)ORA, -C(O)N(RA)(RB), haloalkyl, -alkyl-ORA, -alkyl-SRA, -alkyl-S(O)RA, -alkyl-S(O)2RA, -alkyl-S(O)2N(RA)(RB)5 -alkyl-N(RA)(RB), -alkyl-C(O)RA, -alkyl-C(O)ORA, and -alkyl-C(O)N(RA)(RB);
60. The method of use of claim 59 wherein the compound is selected form the group consisting of
4-benzyl-3-(2,3-dichlorophenyl)-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-[3-fluoro-5-(trifluoromethyl)benzyl]-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-[4-(trifluoromethoxy)benzyl]-4H-l,2,4-triazole,
3 -(2,3-dichlorophenyl)-4- [3 -(trifluoromethyl)benzyl] -4H- 1 ,2,4-triazole,
3-(2,3-dichlorophenyl)-4-[4-(trifluoromethyl)benzyl]-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-[3-(trifluoromethoxy)benzyl]-4H-l,2,4-triazole,
4-(4-tert-butylbenzyl)-3-(2,3-dichlorophenyl)-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-(2,3-dimethylbenzyl)-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(2,5-dimethylbenzyl)-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(3,4-dimethylbenzyl)-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(3,5-dimethylbenzyl)-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(2,3-dimethoxybenzyl)-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-(2,5-dimethoxybenzyl)-4H-l,2,4-triazole,
4-(2,3-dichlorobenzyl)-3-(2,3-dichlorophenyl)-4H-l,2,4-triazole,
4-(2,3-dichlorobenzyl)-3-(2,4-dichlorophenyl)-4H-l,2,4-triazole,
4-(2,3-dichlorobenzyl)-3-(2,5-dichlorophenyl)-4H-l,2,4-triazole,
4-(2,3-dichlorobenzyl)-3-(3,4-dichlorophenyl)-4H-l,2,4-triazole, 4-(2,3-dichlorobenzyl)-3-(3,5-dichlorophenyl)-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(2-methoxybenzyl)-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(2-methylbenzyl)-4H- 1 ,2,4-triazole,
3 -(2,3 -dichlorophenyl)-4-(l -phenylethyl)-4H- 1 ,2,4-triazole,
3 -(2,3 -dichlorophenyl)-4-( 1 -methyl- 1 -phenylethyl)-4H- 1 ,2,4-triazole, 3-[2-chloro-3-(trifluoromethyl)phenyl]-4-(2-methylbenzyl)-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-[2-(trifluoromethyl)benzyl]-4H-l,2,4-triazole,
3 -(2,3 -dichlorophenyl)-4- [2-(difluoromethoxy)benzyl] -4H- 1 ,2,4-triazole,
3-(2,3-dichlorophenyl)-4-[2-(trifluoromethoxy)benzyl]-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(2,3-difluorobenzyl)-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-[2-(methylthio)benzyl]-4H-l,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(2-ethoxybenzyl)-4H- 1 ,2,4-triazole,
4-(3-chloro-2-fluorobenzyl)-3-(2,3-dichlorophenyl)-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-[2-fluoro-3-(trifluoromethyl)benzyl]-4H-l,2,4-triazole, 3-(2,3-dichlorophenyl)-4-(2,5-difluorobenzyl)-4H-l,2,4-triazole, 3 -(2,3 -dichlorophenyl)-4-(l -phenylpropyl)-4H- 1 ,2,4-triazole, 3-[2-chloro-3-(trifluoromethyl)phenyl]-4-[2-(methylthio)benzyl]-4H-l,2,4-triazole, 4-(3 -chloro-2-methylbenzyl)-3 -(2,3 -dichlorophenyl)-4H- 1 ,2,4-triazole,
3-(2,3-dichlorophenyl)-4- {2-[(trifluoromethyl)thio]benzyl} -4H- 1 ,2,4-triazole,
3-(2,3-dichlorophenyl)-4-(2-ethylbenzyl)-4H-l,2,4-triazole, and
3 -[2-chloro-3 -(trifluoromethyl)phenyl] -4-(2-ethylbenzyl)-4H- 1 ,2,4-triazole.
61. The method of use of claim 58, wherein Wi is phenyl optionally fused with a monocyclic, five or six-membered ring selected from the group consisting of phenyl, heteroaryl, heterocycle, cycloalkyl and cycloalkenyl.
62. The method of use of claim 61 wherein the compound is selected from the group consisting of
3 -(2,3 -dichlorophenyl)-4-( 1 -naphthylmethyl)-4H- 1 ,2,4-triazole, 3 -(2,3 -dichlorophenyl)-4-(2,3 -dihydro- 1 -benzofuran-7-ylmethyl)-4H- 1 ,2,4-triazole, 5-{[3-(2,3-dichlorophenyl)-4H-l,2,4-triazol-4-yl]methyl}isoquinoline, and 8- { [3 -(2,3 -dichlorophenyl)-4H- 1 ,2,4-triazol-4-yl]methyl} quinoline.
63. The method of use of claim 58, wherein Wi is monocyclic heteroaryl, independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, CN, NO2, halo, =0, -ORA, -SRA, -S(O)RA, -S(O)2RA, -S(O)2N(RA)(RB), -N(RA)(RB), -C(O)RA, -C(O)ORA, -C(O)N(RA)(RB), haloalkyl, -alkyl-ORA, -alkyl-SRA, - alkyl-S(O)RA, -alkyl-S(O)2RA, -alkyl-S(O)2N(RA)(RB), -alkyl-N(RA)(RB), -alkyl-C(O)RA, -alkyl-C(O)ORA, and -alkyl-C(O)N(RA)(RB);
64. The method of use of claim 63 wherein the compound is selected form the group consisting of 3-(2,3-dichloroρhenyl)-4-(thien-3-ylmethyl)-4H-l,2,4-triazole, 3 -(2,3 -dichlorophenyl)-4-(3 -furylmethyl)-4H- 1 ,2,4-triazole, and 3-{[3-(2,3-dichlorophenyl)-4H-l,2,4-triazol-4-yl]methyl}pyridine.
65. The method of use of claim 51, wherein the compound has formula (III),
Figure imgf000101_0001
(III)
R6 is hydrogen, alkyl, haloalkyl or -CN;
R7 is
Figure imgf000101_0002
and R8 is -C(RxRy)-W1-W2 as defined in claim 51.
66. The method of use of claim 51, wherein the compound has formula (III),
Figure imgf000101_0003
(III)
R6 is hydrogen, alkyl, haloalkyl or -CN;
R7 is
Figure imgf000101_0004
and R8 is -C(RxRy)-Wi-L2-W2, as defined in claim 51.
67. The method of use of claim 51, wherein the compound has formula (III),
Figure imgf000101_0005
(III)
R6 is hydrogen, alkyl, haloalkyl or -CN; R8 is
Figure imgf000102_0001
and R7 is -W as defined in claim 51.
68. The method of use of claim 51, wherein the compound has formula (III),
Figure imgf000102_0002
(III)
R6 is hydrogen, alkyl, haloalkyl or -CN;
R8 is
Figure imgf000102_0003
and R7 is -N(H)-W, as defined in claim 51.
69. The method of use of claim 51, wherein the compound has formula (III),
Figure imgf000102_0004
(III) R6 is hydrogen, alkyl, haloalkyl or -CN;
R8 is
Figure imgf000102_0005
and R7 is -L1-Wi, as defined in claim 51.
70. The method of use of claim 69 wherein the compound is selected from the group consisting of [4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-(2-methyl-benzyl)-amine, [4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-pyridin-3-ylmethyl-amine, [4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-(2-methyl-pyridin-3-ylmethyl)-amine, [4-(2,3-Dichloro-phenyl)-5-methyl-4H-[l,2,4]triazol-3-yl]-(2-methyl-benzyl)-amine, and [4- (2,3-Dichloro-phenyl)-5-ethyl-4H-[l,2,4]triazol-3-yl]-(2-methyl-benzyl)-amine.
71. The method of use of claim 51, wherein the compound has formula (III),
Figure imgf000103_0001
(Hi)
R6 is hydrogen, alkyl, haloalkyl or -CN;
R8 is
Figure imgf000103_0002
and R7 is -L1-W1-W2, as defined in claim 51.
72. The method of use of claim 71, wherein the compound is selected from the group consisting of
[4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-(2-pyrrolidin-l-yl-pyridin-3-ylmethyl)- amine,
[4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-(2-thiophen-3-yl-pyridin-3-ylmethyl)- amine, [4-(2,3-Dichloro-phenyl)-5-methyl-4H-[l ,2,4]triazol-3-yl]-(2-thiophen-3-yl-pyridin-3- ylmethyl)-amine, tert-butyl 4-[3-({[4-(2,3-dichlorophenyl)-4H-l,2,4-triazol-3-yl]amino}methyl)pyridin-2-yl]-
1 ,4-diazepane- 1 -carboxylate,
2-[4-(3-{[4-(2,3-Dichloro-phenyl)-4Η-[l,2,4]triazol-3-ylamino]-methyl}-pyridin-2-yl)- [l,4]diazepan-l-yl]-acetamide, and
4-(2,3-dichlorophenyl)-N- { [2-(4-isopropyl- 1 ,4-diazepan- 1 -yl)pyridin-3 -yl]methyl} -4H- 1 ,2,4- triazol-3-amine.
73. The method of use of claim 51, wherein the compound has formula (III),
Figure imgf000104_0001
(III)
R6 is hydrogen, alkyl, haloalkyl or -CN;
R8 is
Figure imgf000104_0002
and R7 is -L1-W1-L2-W2, as defined in claim 51.
74. The method of use of claim 73, wherein the compound is selected from the group consisting of
[4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-[2-(5-fiuoro-ρyridin-3-yloxy)-pyridin-3- ylmethyl] -amine,
[4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-[2-(pyridin-2-yloxy)-benzyl]-amine, [4-(2,3-Dichloro-phenyl)-4H-[ 1 ,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-benzyl]-amine,
[4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-pyridin-3-ylmethyl]- amine, and
[4-(2,3-Dichloro-phenyl)-4H-[l,2,4]triazol-3-yl]-[2-(l-methyl-pyrrolidin-3-yloxy)-pyridin-3- ylmethyl]-amine.
Figure imgf000104_0003
75. The method of use of claim 51, wherein the compound has formula (IV)
R6 is hydrogen, alkyl, haloalkyl or -CN;
Figure imgf000104_0004
and R8 is -W as defined in claim 51.
76. The method of claim 73 wherein the compound is 5-[2-chloro-3-(trifluoromethyl)ρhenyl]-l-[2,3-dihydro-lH-inden-l-yl]-lH-l,2,4-triazole.
Figure imgf000105_0001
77. The method of use of claim 51, wherein the compound has formula (IV) R6 is hydrogen, alkyl, haloalkyl or -CN;
R7 is
Figure imgf000105_0002
and R8 is -C(RxRy)-Wi as defined in claim 51.
78. The method of claim 77 wherein the compound is l-benzyl-5-(2,3-dichlorophenyl)-lH-l,2,4-triazole.
Figure imgf000105_0003
79. The method of use of claim 51, wherein the compound has formula (IV) R6 is hydrogen, alkyl, haloalkyl or -CN;
R7 is
Figure imgf000105_0004
and R8 is -C(RxRy)-W1-W2.
Figure imgf000105_0005
80. The method of use of claim 51 , wherein the compound has formula (IV) R6 is hydrogen, alkyl, haloalkyl or -CN;
R7 is
Figure imgf000106_0001
and R8 is -C(RxRy)-W1-L2-W2.
Figure imgf000106_0002
81. The method of use of claim 51 , wherein the compound has formula (IV) R6 is hydrogen, alkyl, haloalkyl or -CN;
R8 is
Figure imgf000106_0003
and R7 is -W as defined in claim 51.
82. The method of claim 81 wherein the compound is
[2-chloro-3 -(trifluoromethyl)phenyl] -5-(2,3-dihydro- 1 H-inden- 1 -yl)- 1 H- 1 ,2,4-triazole.
Figure imgf000106_0004
83. The method of use of claim 51, wherein the compound has formula (IV) R6 is hydrogen, alkyl, haloalkyl or -CN;
R8 is
Figure imgf000106_0005
and R7 is -N(H)-W as defined in claim 51.
84. The method of use of claim 51, wherein
Figure imgf000107_0001
the compound has formula (IV)
R6 is hydrogen, alkyl, haloalkyl or -CN;
R8 is
Figure imgf000107_0002
and R7 is -Lj-W1, wherein -L1 and -Wi are as defined in claim 51.
85. The method of claim 83 wherein the compound is selected from the group consisting of 5-benzyl-l-(2,3-dichlorophenyl)-lH-l,2,4-triazole, 3-{[l-(2,3-dichlorophenyl)-lH-l,2,4-triazol-5-yl]methyl}pyridine, 1 -(2,3-dichlorophenyl)-5 -(2-methylbenzyl)- IH- 1 ,2,4-triazole, l-(2,3-dichlorophenyl)-5-(thien-3-ylmethyl)-lH-l,2,4-triazole, l-[2-chloro-3-(trifluoromethyl)phenyl]-5-(2-methylbenzyl)-lH-l,2,4-triazole, Benzyl-[2-(2,3-dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-amine, [2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-(2-methyl-benzyl)-amine, [2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-(2-trifluoromethyl-benzyl)-amine, [2-(2,3-Dichloro-phenyl)-2H-[l ,2,4]triazol-3-yl]-(3-methoxy-benzyl)-amine,
[2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-(2,3-dimethoxy-benzyl)-amine, [2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-(2-methylsulfanyl-benzyl)-amine, [2-(2,3-Dichloro-ρhenyl)-2H-[l,2,4]triazol-3-yl]-(2-methanesulfonyl-benzyl)-amine, [2-(2,3 -Dichloro-phenyl)-2H-[ 1 ,2,4]triazol-3 -yl] -(2-methoxy-benzyl)-amine, [2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-(2-ethoxy-benzyl)-amine,
[2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-pyridin-3-ylmethyl-amine, and [2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-(2-methyl-ρyridin-3-ylmethyl)-amine.
Figure imgf000108_0001
86. The method of use of claim 51, wherein the compound has formula ^
R6 is hydrogen, alkyl, haloalkyl or -CN;
R8 is
Figure imgf000108_0002
and R7 is -L1-W1-W2, wherein -L1 , -W1 and -W2 are as defined in claim
51.
87. The method of claim 86 wherein the compound is selected from the group consisting of
[2-(2,3-Dichloro-ρhenyl)-2H-[l,2,4]triazol-3-yl]-(2-thiophen-3-yl-ρyridin-3-ylmethyl)- amine,
(2-Azetidin-l-yl-pyridin-3-ylmethyl)-[2-(2,3-dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-amine, l-(2,3-dichlorophenyl)-N-[(2-morpholm-4-ylpyridin-3-yl)methyl]-lH-[l,2,4]-triazol-5- amine, and l-(2,3-dichlorophenyl)-N-[(2-pyrrolidin-l--ylpyridin-3-yl)methyl]-lH-[l,2,4]triazole-5-amine.
Figure imgf000108_0003
88. The method of use of claim 51, wherein the compound has formula (IV) R6 is hydrogen, alkyl, haloalkyl or -CN;
Rg is
Figure imgf000108_0004
and R7 is -L1-W1-L2-W2;, wherein -L1, -L2, -Wi and -W2 are as defined in claim 51.
89. The method of claim 88 wherein the compound is selected from the group consisting of [2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-benzyl]-amine, and [2-(2,3-Dichloro-phenyl)-2H-[l,2,4]triazol-3-yl]-[2-(pyridin-3-yloxy)-ρyridin-3-ylmethyl]- amine.
90. The method of use of claim 51, wherein the compound has formula
Figure imgf000109_0001
wherein Rg is hydrogen, alkyl, haloalkyl or -CN;
Rio is
Figure imgf000109_0002
and Rn is -C(RxRy)-Wi wherein Rx , Ry and Wi are as defined in claim 51.
91. The method of claim 90 wherein the compound is l-benzyl-5-(2,3-dichlorophenyl)-lH-l,2,3-triazole, and
5 -(2,3 -dichlorophenyl)- 1 -(2,3 -dihydro- 1 -benzofuran-7-ylmethyl)- 1 H- 1 ,2,3 -triazole.
92. The method of use of claim 61, wherein the compound has formula
Figure imgf000109_0003
; wherein R9 is hydrogen, alkyl, haloalkyl or -CN;
Rn is
Figure imgf000109_0004
and Ri0 is -C(RxRy)-Wi wherein Rx , Ry and Wi are as defined in claim 51.
93. The method of use of claim 92 wherein the compound is 5-benzyl-l-(2,3-dichlorophenyl)-lH-l,2,3-triazole.
94. The method of use of claim 51, wherein the compound has formula
Figure imgf000110_0001
wherein
R-9 is
Figure imgf000110_0002
Rio is -C(RxRy)-Wi ; and Ru is hydrogen, wherein Rx , Ry and Wi are as defined in claim 51.
95. The method of claim 94 wherein the compound is 4-benzyl-5-(2,3-dichlorophenyl)-lH-l,2,3-triazole.
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US9133204B2 (en) 2007-07-19 2015-09-15 H. Lundbeck A/S 5-membered heterocyclic amides and related compounds

Families Citing this family (3)

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Publication number Priority date Publication date Assignee Title
KR100898159B1 (en) * 2007-06-26 2009-05-19 포항공과대학교 산학협력단 Mechanism of inhibiting activity of p2x7 receptor on doparminergic neuronal cells
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058731A1 (en) * 2002-12-31 2004-07-15 Pfizer Products Inc. Benzamide inhibitors of the p2x7 receptor

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3975431A (en) 1972-07-13 1976-08-17 The Upjohn Company Preparing carboxylic acids from glycidonitriles through enol acylates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058731A1 (en) * 2002-12-31 2004-07-15 Pfizer Products Inc. Benzamide inhibitors of the p2x7 receptor

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