HK1018621A - Quinoxalinediones - Google Patents

Description

Quinoxalinedione compound

The present invention relates to 2,3(1H,4H) -quinoxalinedione derivatives which are selective antagonists of the N-methyl-D-aspartate receptor. In particular, the present invention relates to 5-heteroaryl-2, 3(1H,4H) -quinoxalinedione derivatives and their preparation, compositions containing them, their use and intermediates used in their synthesis.

L-glutamate is an excitatory amino acid neurotransmitter whose physiological role in the brain involves interaction with four receptors, three of which are named according to the selective agonists NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainic acid. The fourth receptor is called the metabotropic receptor. In addition to having a binding site for glutamate, NMDA receptors also have a binding site for dissociative anesthetics (e.g., ketamine), polyamines (e.g., spermine), glycine, and some metal ions (e.g., Mg)²⁺,Zn²⁺) Has high affinity binding sites. Glutamate antagonists are useful as functional NMDA antagonists because the NMDA receptor must bind glutamate for activation to occur.

For example, in the area of cerebral infarction, hypoxia results in the release of abnormally high concentrations of glutamate, which in turn causes overstimulation of NMDA receptors, leading to neuronal degeneration and death. Thus, NMDA receptor antagonists which have been shown to block the neurotoxic effects of glutamate in vitro and in vivo may be used for the treatment and/or prevention of pathological conditions in which NMDA receptor activation is important. Examples of such diseases include acute neurodegenerative diseases caused by conditions such as stroke, transient ischemic attack, peripheral surgical ischemia, global ischemia (after cardiac arrest) and traumatic head injury to the brain or spinal cord. In addition, NMDA antagonists are useful in the treatment of certain chronic neurological disorders such as Alzheimer's disease, Parkinson's disease and Alzheimer's disease. They also have utility in conditions in which peripheral nerve function is being tested, such as retinal and macular degeneration.

In addition, NMDA antagonists have been shown to have anticonvulsant and anxiolytic activity and are therefore useful in the treatment of epilepsy and anxiety. NMDA antagonists may also reduce the effects of alcohol withdrawal in physically dependent animals (k.a. grant et al, journal of pharmacology and experimental therapeutics 260,1017(992)), and thus NMDA antagonists may be useful in the treatment of alcohol addiction and pain. NMDA antagonists may also be useful in the treatment of hearing disorders (e.g., tinnitus), migraine and psychiatric disorders.

EP-A-0572852 describes pyrrol-1-yl-substituted 2,3(1H,4H) -quinoxalinedione derivatives suitable for the treatment of neurodegenerative diseases of the central nervous system and neurotoxic disorders.

EP-A-0556393 discloses, inter aliｃA, imidazolyl-or triazolyl-substituted 2,3(1H,4H) -quinoxalinedione derivatives having glutamate receptor antagonistic activity, in particular NMDA-glycine receptor and AMPA receptor antagonistic activity. However, no 5-triazolyl-substituted compound is specifically described in this document.

The compounds of the present invention are potent NMDA (glycine site) receptor antagonists. In addition, the compounds of the present invention are highly selective antagonists of NMDA (glycine site) receptors compared to AMPA receptors, to which the compounds of the present invention have low, if any, affinity.

The present invention relates to compounds of the formula:wherein:

r is a 5-membered ring heteroaryl group containing 3 or 4 nitrogen heteroatoms, which heteroaryl group is attached to the quinoxalinedione ring by a ring carbon or a ring nitrogen atom; or a 6-membered ring heteroaryl group containing 1-3 nitrogen heteroatoms, the heteroaryl group being attached to the quinoxalinedione ring by a ring carbon atom; any of the groups are optionally benzo-fused and they (including benzo-fused moieties) may be optionally substituted with 1 or 2 substituents each independently selected from: c₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₃-C₇Cycloalkyl, halogen, hydroxy, C₁-C₄Alkoxy radical, C₃-C₇Cycloalkoxy, -COOH, C₁-C₄Alkoxycarbonyl, -CONR³R⁴,-NR³R⁴,-S(O)_p(C₁-C₄Alkyl), -SO₂NR³R⁴Aryl, aryloxy, aryl (C)₁-C₄) Alkoxy and het, said C₁-C₄Alkyl is optionally substituted by C₃-C₇Cycloalkyl, halogen, hydroxy, C₁-C₄Alkoxy, halo (C)₁-C₄) Alkoxy radical, C₃-C₇Cycloalkoxy, C₃-C₇Cycloalkyl (C)₁-C₄) Alkoxy, -COOH, C₁-C₄Alkoxycarbonyl, -CONR³R⁴,-NR³R⁴,-S(O)_p(C₁-C₄Alkyl), -SO₂(aryl group), -SO₂NR³R⁴Morpholino, aryl, aryloxy, aryl (C)₁-C₄) Alkoxy or het substitution, and said C₂-C₄Alkenyl is optionally substituted with aryl;

R¹and R²Each independently selected from H, fluorine, chlorine, bromine and C₁-C₄Alkyl and halo (C)₁-C₄) An alkyl group;

R³and R⁴Each independently selected from H and C₁-C₄Alkyl, or they together represent C₅-C₇An alkylene group;

p is 0,1 or 2;

"aryl" as used in the definition of R and "het" means phenyl or naphthyl, each of which is selected from C by 1 or 2 independently of one another₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy, halogen, halo (C)₁-C₄Alkyl) and-NR³R⁴The substituent(s) is optionally substituted; "het" as used in the definition of R means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl(ii) azolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, all of which are each optionally benzo-fused and which (including benzo-fused moieties) may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: c₁-C₄Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₄Alkoxy, halogen, hydroxy, -COOH, C₁-C₄Alkoxycarbonyl, allyloxycarbonyl, -CONR³R⁴,-NR³R⁴,-S(O)_p(C₁-C₄Alkyl), -SO₂NR³R⁴Halo (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl radical, C₁-C₄Alkoxy (C)₁-C₄) Alkyl radical, R³R⁴NCO(C₁-C₄) Alkyl, aryl, aralkyl, het¹And het¹(C₁-C₄) Alkyl, and/or when "het" includes pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, the ring nitrogen heteroatom of which is optionally substituted by an oxygen substituent; "het" as used in the definition of "het¹"means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is substituted by 1 or 2C₁-C₄The alkyl substituents are optionally substituted.

In the above definitions, "halogen" means fluorine, chlorine, bromine or iodine, alkyl, alkoxy and alkylene groups having three or more carbon atoms and alkenyl groups having 4 or more carbon atoms may be straight-chain or branched.

Definition of "C₁-C₄Alkyl "includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. Definition of "C₁-C₄Alkoxy "includes the corresponding alkoxy.

When R is a 5-membered ring heteroaryl, this definition includes 1,2, 3-triazolyl, 1,2, 4-triazolyl and tetrazolyl.

When R is a 6-membered ring heteroaryl this definition specifically includes 2-, 3-and 4-pyridyl, 3-or 4-pyridazinyl, 2-, 4-or 5-pyrimidinyl and 2-pyrazinyl.

When "het" represents a benzo-fused heteroaryl group, that group is attached to the remainder of the molecule through the heteroaryl or benzo-fused portion of the "het" group.

Preferably R is triazolyl or tetrazolyl, each of which is substituted by 1 or 2 substituents independently of one another and selected from C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₃-C₇Cycloalkyl, halogen, hydroxy, C₁-C₄Substituted by alkoxycarbonyl, aryl and het substituents, said C₁-C₄Alkyl substituted by halogen, hydroxy, C₁-C₄Alkoxy, halo (C)₁-C₄) Alkoxy radical, C₃-C₇Cycloalkyl (C)₁-C₄) Alkoxy, -COOH, C₁-C₄Alkoxycarbonyl, -NR³R⁴,-SO₂(aryl), morpholino, aryl, aryloxy, aryl (C)₁-C₄) Alkoxy or het is optionally substituted; or is pyridyl or pyrimidinyl.

More preferably R is 1,2, 3-triazol-4-yl, 1,2, 4-triazol-3-yl, 1,2, 4-triazol-4-yl or tetrazol-5-yl, each of which is substituted by 1 or 2 substituents independently of one another selected from C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₃-C₇Cycloalkyl, halogen, hydroxy, C₁-C₄Substituted by alkoxycarbonyl, aryl and het substituents, said C₁-C₄Alkyl substituted by halogen, hydroxy, C₁-C₄Alkoxy, halo (C)₁-C₄) Alkoxy radical, C₃-C₇Cycloalkyl (C)₁-C₄) Alkoxy, -COOH, C₁-C₄Alkoxycarbonyl, -NR³R⁴,-SO₂(aryl), morpholino, aryl, aryloxy, aryl (C)₁-C₄) Alkoxy or het is optionally substituted; or is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidinePyridin-5-yl.

More preferably R is 1,2, 3-triazol-4-yl, 1,2, 4-triazol-3-yl, 1,2, 4-tetrazol-4-yl or tetrazol-5-yl, each of which is substituted by 1 or 2 substituents independently of one another selected from the group consisting of methyl, ethyl, propyl, allyl, cyclopropyl, cyclohexyl, bromo, hydroxy, ethoxycarbonyl, 2-chlorophenyl, 3-chlorophenyl, 4-dimethylaminophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, phenyl, 4-trifluoromethylphenyl, 2-amino-1, 3, 4-oxadiazol-5-yl, 2-carboxypyridin-5-yl, 1, 5-dimethyl-1H-pyrazol-3-yl, 1H-imidazol-1-yl, 1-methylimidazol-2-yl, 1-methylimidazol-4-yl, 1-methylimidazol-5-yl, 3-methylisothiazol-4-yl, 4-methyl-1H-imidazol-5-yl, 3-methyl-1, 2, 4-oxadiazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 5-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl, 1-pyrid-3-yl oxide, 2-methylpyridin-3-yl, 2-methylpyridin-5-yl, 1-phenylimidazol-4-yl, 5-phenylpyridin-3-yl, 2-phenylpyridin-5-yl, 1-methylpyrrole-2-yl, 4-methyl-1, 2, 3-thiadiazol-5-yl, 2-methylthiazol-4-yl, 1-methyl-1H-1, 2, 4-triazol-5-yl, 3- (propan-1-yl) -1H-pyrazol-5-yl, pyrazin-2-yl, 1H-pyrazol-4-yl, pyridazin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, thiophen-2-yl, 1H-1,2, 4-triazol-5-yl, 1H-1,2, 3-triazol-5-yl, quinolin-3-yl, and quinolin-6-yl, wherein said methyl, ethyl, or propyl is optionally substituted with fluoro, hydroxy, methoxy, ethoxy, 2,2, 2-trifluoroethoxy, cyclohexylmethoxy, cyclopentylmethoxy, -COOH, methoxycarbonyl, dimethylamino, 4-chlorophenylsulfonyl, morpholino, phenyl, phenoxy, benzyloxy, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl; or R is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-5-yl.

Examples of R include:

1- (2-hydroxyethyl) -5-phenyl-1, 2, 3-triazol-4-yl,

1- (2-hydroxyethyl) -4-phenyl-1, 2, 3-triazol-5-yl,

2- (2-hydroxyethyl) -5-phenyl-1, 2, 3-triazol-4-yl,

1-methyl-5-phenyl-1, 2, 3-triazol-4-yl,

1-methyl-4-phenyl-1, 2, 3-triazol-5-yl,

2-methyl-5-phenyl-1, 2, 3-triazol-4-yl,

5-phenyl-1H-1, 2, 3-triazol-4-yl,

1-methyl-1H-1, 2, 4-triazol-3-yl,

2-methyl-2H-1, 2, 4-triazol-3-yl,

4- (2-hydroxyethyl) -4H-1,2, 4-triazol-3-yl,

4-methyl-4H-1, 2, 4-triazol-3-yl,

3- (2-amino-1, 3, 4-oxadiazol-5-yl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3-benzyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-benzyloxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-bromo-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3- (3-carboxyprop-1-yl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3- (2-carboxypyridin-5-yl) -5-methoxymethyl-4H-1, 2, 4-triazol-4-yl,

3- (2-chlorophenyl) -5-methoxymethyl-4H-1, 2, 4-triazol-4-yl,

3- (2-chlorophenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (3-chlorophenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (4-chlorophenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (4-chlorobenzenesulfonylmethyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3-cyclohexylmethoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-cyclopentylmethoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-cyclopropyl-5-methyl-4H-1, 2, 4-triazol-4-yl,

3, 5-bis (methoxymethyl) -4H-1,2, 4-triazol-4-yl,

3- (N, N-dimethylaminomethyl) -5-ethyl-4H-1, 2, 4-triazol-4-yl,

3- (N, N-dimethylaminomethyl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3- (4-dimethylaminophenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (1, 5-dimethyl-1H-pyrazol-3-yl) -5-methoxymethyl-4H-1, 2, 4-triazol-4-yl,

3- (1, 5-dimethyl-1H-pyrazol-3-yl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3, 5-dimethyl-4H-1, 2, 4-triazol-4-yl,

3, 5-diphenyl-4H-1, 2, 4-triazol-4-yl,

3- (2-ethoxyethyl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-ethoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-ethoxycarbonyl-4H-1, 2, 4-triazol-4-yl,

3-ethyl-5- (2-chlorophenyl) -4H-1,2, 4-triazol-4-yl,

3-ethyl-5- (2-methoxyphenyl) -4H-1,2, 4-triazol-4-yl,

3-ethyl-5- (1-methylpyrazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-ethyl-5-methyl-4H-1, 2, 4-triazol-4-yl,

3-ethyl-5-morpholinomethyl-4H-1, 2, 4-triazol-4-yl,

3-ethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-ethyl-4H-1, 2, 4-triazol-4-yl,

3- (2-hydroxyethyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3-hydroxymethyl-5-methyl-4H-1, 2, 4-triazol-4-yl,

3-hydroxymethyl-5-phenyl-4H-1, 2, 4-triazol-4-yl,

3-hydroxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-hydroxymethyl-4H-1, 2, 4-triazol-4-yl,

3-hydroxy-5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (2-hydroxyphenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (1H-imidazol-1-yl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (2-methoxyethyl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (2-methylpyridin-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (2-methylthiazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (1-oxidopyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (1-phenylimidazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (5-phenylpyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (2-phenylpyridin-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (pyridin-3-ylmethyl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (quinolin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (quinolin-6-yl) -4H-1,2, 4-triazol-4-yl,

3- (2-methoxyphenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (3-methoxyphenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (4-methoxyphenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3-methyl-5- (1-methylimidazol-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methylimidazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methylimidazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3- (3-methylisothiazol-4-yl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3-methyl-5- (4-methyl-1H-imidazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (2-methylpyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (2-methylpyridin-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methylpyrazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (5-methyl-1H-pyrazol-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (2-methylphenyl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methylpyrrole-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (4-methyl-1, 2, 3-thiadiazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (2-methylthiazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methyl-1H-1, 2, 4-triazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methyl-1H-pyrazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3- (3-methyl-1, 2, 4-oxadiazol-5-yl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5-phenyl-4H-1, 2, 4-triazol-4-yl,

3-methyl-5- (3- [ prop-1-yl ] -1H-pyrazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyrazin-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1H-pyrazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl, 3-methyl-5- (pyridin-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-2-ylmethyl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-3-ylmethyl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-4-ylmethyl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridazin-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyrimidin-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (thien-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-4H-1, 2, 4-triazol-4-yl,

3-methyl-5- (1H-1,2, 3-triazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1H-1,2, 4-triazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-morpholinomethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-phenoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3- (2-phenylethyl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3- (pyridin-3-yl) -5- (2,2, 2-trifluoroethoxy) methyl-4H-1, 2, 4-triazol-4-yl,

3- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (4-trifluoromethylphenyl) -4H-1,2, 4-triazol-4-yl,

1-allyltetrazol-5-yl group,

1-benzyltetrazol-5-yl group,

1-carboxymethyltetrazol-5-yl group,

1-cyclohexyltetrazol-5-yl group,

1-ethyltetrazol-5-yl group,

1- (2-hydroxyethyl) tetrazol-5-yl,

1- (3-hydroxypropyl) tetrazol-5-yl,

1-methoxycarbonylmethyltetrazol-5-yl,

1- (2-methoxyethyl) tetrazol-5-yl,

1-methyltetrazol-5-yl group,

1- (2-phenylethyl) tetrazol-5-yl,

1-phenyltetrazol-5-yl group,

1- (propan-2-yl) tetrazol-5-yl,

1- (2,2, 2-trifluoroethyl) tetrazol-5-yl,

(ii) a pyridin-2-yl group,

(ii) a pyridin-3-yl group,

(ii) a pyridin-4-yl group,

pyrimidin-2-yl, and

pyrimidin-5-yl.

Most preferred R is:

1- (3-hydroxypropyl) tetrazol-5-yl,

4-methyl-4H-1, 2, 4-thiazol-3-yl,

1- (2-hydroxyethyl) -5-phenyl-1, 2, 3-triazol-4-yl,

3-methyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-3-ylmethyl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (quinolin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (quinolin-6-yl) -4H-1,2, 4-triazol-4-yl,

or 3- (1, 5-dimethyl-1H-pyrazol-3-yl) -5-methyl-4H-1, 2, 4-triazol-4-yl.

Preferably R¹And R²Each independently selected from chlorine and C₁-C₄Alkyl, especially methyl or ethyl.

Most preferred is R¹And R²Each being chlorine.

Preferably R³And R⁴Each independently selected from H and C₁-C₄An alkyl group.

Most preferred is R³And R⁴Are each independentlyA methyl group.

Preferably "aryl" represents phenyl optionally substituted with 1 or 2 substituents each independently selected from methyl, methoxy, hydroxy, chloro, trifluoromethyl and dimethylamino.

Examples of "aryl" include 2-chlorophenyl, 3-chlorophenyl, 4-dimethylaminophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, phenyl and 4-trifluoromethylphenyl.

Preferably "het" represents thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is optionally benzo-fused and is substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, -COOH, -NR and³R⁴and phenyl, and/or the ring nitrogen heteroatom of said pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl is optionally substituted with an oxygen substituent.

Examples of "het" include thiophen-2-yl, 1-methylpyrrol-2-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrrol-4-yl, 5-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl, 1, 5-dimethyl-1H-pyrazol-3-yl, 3- (propan-1-yl) -1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1-methylimidazol-2-yl, 1-methylimidazol-4-yl, 1-methylimidazol-5-yl, 4-methyl-1H-imidazol-5-yl, 1-phenylimidazol-4-yl, 1H-1,2, 3-triazol-5-yl, 1H-1,2, 4-triazol-5-yl, 1-methyl-1H-1, 2, 4-triazol-5-yl, 2-methylthiazol-4-yl, 3-methylisothiazol-4-yl, 2-amino-1, 3, 4-oxadiazol-5-yl, 3-methyl-1, 2, 4-oxadiazol-5-yl, 4-methyl-1, 2, 3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-3-yl, 2-methylpyridin-5-yl, 1-oxidopyridin-3-yl, 2-carboxypyridin-5-yl, 5-phenylpyridin-3-yl, 2-phenylpyridin-5-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, quinolin-3-yl and quinolin-6-yl.

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts, examples of which include hydrochloride, hydrobromide, sulphate, bisulphate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate.

Suitable basic salts are formed from bases which form non-toxic salts, examples of which include the calcium, lithium, magnesium, potassium, sodium, zinc, ethanolamine, diethanolamine and triethanolamine salts.

For a review of suitable salts, see Berge et al, J.Pharm.Sci., 66,1-19 (1977).

The compounds of formula (i) may contain one or more asymmetric carbon atoms and may therefore exist as two or more stereoisomers, or they may exist as tautomers. The invention includes single stereoisomers and tautomers of the compounds of formula (i) and mixtures thereof.

Diastereomeric separation of a mixture of stereoisomers of a compound of formula (i) or a suitable salt or derivative thereof may be effected by conventional techniques, for example by fractional crystallisation, chromatography or HPLC. The single enantiomers of the compounds of formula (i) may also be prepared from the corresponding optically pure intermediates, or by resolution of the corresponding racemates using suitable chiral supports, for example by HPLC techniques, or by fractional crystallization of the diastereomeric salts formed by reaction of the corresponding racemates with a suitable optically active acid or base.

Certain compounds of formula (I) may exist in the form of specific stereoisomers, referred to as atropisomers. Atropisomers are separable isomers simply because rotation about a single bond is limited or greatly slowed (see Advanced Organic Chemistry, third edition, Jerry March, John Wiley and Sons (1985)). They may be separated using conventional methods such as those described in the preceding paragraph. The invention includes single atropisomers of the compounds of formula (I) and mixtures thereof.

Preferred examples of compounds of formula (I) are those wherein; r is 1- (3-hydroxypropyl) tetrazol-5-yl¹Is chlorine and R²Is chlorine; (ii) R is 4-methyl-4H-1, 2, 4-triazol-3-yl, R¹Is chlorine and R²Is chlorine; (iii) R is 1- (2-hydroxyethyl) -5-phenyl-1, 2, 3-triazole-4-

Radical, R¹Is chlorine and R²Is chlorine; (iv) R is 3-methyl-5- (pyridin-3-yl) -4H-1,2, 4-triazole

-4-yl, R¹Is chlorine and R²Is chlorine; (v) R is 3-methyl-5- (pyridin-3-ylmethyl) -4H-1,2, 4-triazol-4-yl, R¹Is chlorine and R²Is chlorine; (vi) R is 3-methoxymethyl-5- (pyridin-3-yl) -4H-1,2,4-

Triazol-4-yl radical, R¹Is chlorine and R²Is chlorine; (vii) R is 3- (1, 5-dimethyl-1H-pyrazol-3-yl) -5-methyl-

4H-1,2, 4-triazol-4-yl, R¹Is chlorine and R²Is chlorine; (viii) R is 3-methoxymethyl-5- (pyridin-3-yl) -4H-1,2,4-

Triazol-4-yl radical, R¹Is chlorine and R²Is methyl; (ix) R is 3-methoxymethyl-5- (pyridin-3-yl) -4H-1,2,4-

Triazol-4-yl radical, R¹Is methyl and R²Is chlorine; (x) R is 3-methoxymethyl-5- (quinolin-3-yl) -4H-1,2, 4-tris

Oxazol-4-yl, R¹Is chlorine and R²Is chloro, or (xi) R is 3-methoxymethyl-5- (quinolin-6-yl) -4H-1,2,4-

Triazol-4-yl radical, R¹Is chlorine and R²Is chlorine;

or a single stereoisomer or pharmaceutically acceptable salt of any of these compounds.

Particularly preferred compounds of formula (i) include: (i) R- (-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridinyl) -4H-1,2, 4-triazol-4-yl ] -2,3(1H,4H) -quinoxalinedione or a pharmaceutically acceptable salt thereof, and (ii) the sodium salt of R- (-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridinyl) -4H-1,2, 4-triazol-4-yl ] -2,3(1H,4H) -quinoxalinedione.

All compounds of formula (I) can be prepared by hydrolysis of a compound of formula (II) with an acid or a base:wherein R, R¹And R²Are as defined above for compounds of formula (I), R⁵And R⁶Independently or together represent a group which can be cleaved hydrolytically under acidic or basic conditions to give the quinoxalinediones of formula (I). Such groups are conventional and suitable examples thereof are also well known to the skilled person.

Preferably R⁵And R⁶Each independently selected from C₁-C₄Alkyl (preferably methyl or ethyl) and optionally substituted by 1 to 3 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen, nitro and trifluoromethyl substituted benzyl; or they together represent C₁-C₆Alkylene, CH (phenyl), CH (4-methoxyphenyl) or CH (3, 4-dimethoxyphenyl).

The above reaction is preferably carried out by acid hydrolysis of the compound of formula (II).

In a typical process, the compound of formula (ii) is treated with a suitable acid, such as an aqueous solution of a mineral acid (e.g. hydrochloric acid), optionally in the presence of a suitable organic co-solvent such as 1, 4-dioxane. The reaction is usually accomplished by heating the mixture up to the reflux temperature of the solvent.

The intermediates of formula (II) may be prepared by a variety of conventional methods, for example as described hereinafter. (a) Compounds of formula (II) wherein R is substituted tetrazol-5-yl may be prepared according to the scheme shown in scheme I: reaction scheme IWherein R is¹,R³,R⁵And R⁶Is as defined in formula (II)A compound of formula (I), and R^CAre suitable substituents as described above for the moiety of the R group in the compounds of formula (i).

In a typical process, the compound of formula (III) is deprotected first with a suitable base, such as lithium diisopropylamide, in a suitable solvent, such as tetrahydrofuran, and the resulting carbanion is then treated with carbon dioxide. The resulting carboxylic acid of formula (iv) is then converted to the corresponding acid chloride using oxalyl chloride and a catalytic amount of N, N-dimethylformamide in a suitable solvent (e.g. dichloromethane) and further converted to the secondary amide of formula (v) by in situ treatment with an amine of the formula:

R^CNH₂.

the amide of formula (V) is first treated with phosphorus pentachloride in a suitable solvent, such as toluene, and the resulting intermediate is then reacted in situ with azidotrimethylsilane to prepare the compound of formula (IIA). (b) Compounds of formula (II) wherein R is an optionally benzo-fused/substituted 5-or 6-membered ring heteroaryl attached to the quinoxaline ring via a ring carbon atom may be prepared according to the route shown in scheme II: reaction scheme IIWherein R is¹,R²,R⁵And R⁶Is as defined above for a compound of formula (II), and R^DIs an optionally benzo-fused/substituted 5-or 6-membered ring heteroaryl as described above in the section for the R group in the compounds of formula (I), which group is attached to the quinoxaline through a ring carbon atom.

In a typical procedure, the compound of formula (III) is deprotected first as described in process (a) above, followed by treatment in situ with trimethyl borate, followed by acid hydrolysis in a post-treatment procedure to give a boronic acid of formula (VI); this compound is then reacted with a compound of the formula:

R^Dx wherein X is bromo, iodo, or trifluoromethanesulfonyloxy, and R^DIs as defined above, fromTo give the compound of formula (IIB). (c) Compounds of formula (II) wherein R is optionally 4-substituted-4H-1, 2, 4-triazol-3-yl are prepared as follows: the compound of formula (v) is first treated with phosphorus pentachloride in a suitable solvent such as toluene, followed by reaction of the resulting intermediate in situ with a formyl hydrazine in the presence of a suitable base such as triethylamine. (d) Wherein R is 1-or 2- (optionally substituted C)₁-C₄The preparation of the alkyl) -substituted-1, 2, 4-triazol-3-yl compounds of formula (II) is as follows: by N, N-di (C)₁-C₄Alkyl) formamide di (C)₁-C₄Alkyl alcohol) (preferably N, N-dimethylformamide dimethyl acetal) treatment wherein R^CA compound of formula (V) which is H, followed by reaction of the resulting intermediate formamidine with hydrazine in the presence of a suitable acid (e.g. acetic acid), followed by treatment of the resulting tautomeric mixture of 5- (1H-and 2H-1,2, 4-triazol-3-yl) -substituted quinolines with a suitable base (e.g. sodium hydride) in a suitable solvent (e.g. N, N-dimethylformamide), followed by the appropriate optional substitution of C₁-C₄Alkyl halide treatment (e.g., with methyl iodide to produce an N-methyl-substituted product).

Resulting 1-and 2- (optionally substituted C)₁-C₄The alkyl) -substituted-1, 2, 4-triazol-3-yl product mixture can be isolated by conventional methods (e.g., chromatography). (e) Compounds of formula (II) wherein R is optionally substituted 1,2, 4-triazol-4-yl may be prepared according to the scheme shown in scheme III: reaction scheme IIIWherein R is¹,R²,R⁵And R⁶Is as defined above for a compound of formula (II), R^AAnd R^BEach independently being H or a suitable substituent as described above for the R moiety in the compounds of formula (I).

In a typical process, the 5-aminoquinoxaline of formula (VII) is reacted in a suitable solvent (e.g. toluene or dichloromethane), optionally in the presence of a suitable acid acceptor (e.g. pyridine), with a compound of the formula:

R^ACOX¹wherein X¹Is a suitable leaving groupSuch as chlorine or bromine.

Amides of formula (VIII) may be converted to thioamides of formula (IX) by treatment with 2, 4-bis (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphobutylene-2, 4-disulfide (Lawesson's reagent) in a suitable solvent, such as toluene or tetrahydrofuran.

Thioamides of formula (IX) can be converted to compounds of formula (IIC) as follows: treating with a compound of the formula:

R^BCONHNH₂(f) compounds of formula (II) wherein R is an optionally benzo-fused/substituted 5-or 6-membered ring heteroaryl attached to the quinoxaline ring via a ring carbon atom may be prepared as follows: in the presence of a suitable catalyst such as tetrakis (triphenylphosphine) palladium (O), under suitable conditions, a compound of the formula:wherein R is¹,R²,R⁵And R⁶Are as defined above for compounds of formula (II), with formula R^EX²Coupling of compounds in which X²Is Sn (C)₁-C₄Alkyl radical)₃ZnCl, ZnBr, ZnI or-B (OH)₂,R^EIs as defined for R in the process. (g) Compounds of formula (II) wherein R is optionally substituted 1,2, 3-triazol-4-yl may be prepared according to the scheme shown in scheme IV: reaction scheme IVWherein R is¹,R²,R⁵And R⁶Is as defined above for a compound of formula (II), R^FIs H, or R^FAnd R^GEach independently represents a suitable substituent as described above for the R group portion of the compounds of formula (I).

In a typical procedure, a 5-iodoquinoxaline compound of formula (X) is coupled under suitable conditions (e.g., using bis (triphenylphosphine) palladium (II) chloride, copper (I) iodide and triethylamine) with an acetylide of the formula:

R^F-C ≡ CH the resulting compound of formula (XI) is then reacted with azidotrimethylsilane to give the compound of formula (IID), which is then converted to the compound of formula (IIE) using conventional methods, for example, when R is^GIs C₁-C₄When alkyl, the compound of formula (IID) can be deprotonated by a suitable base (e.g., sodium hydride) followed by reaction with C₁-C₄Alkyl halides (e.g., methyl iodide) are reacted to effect the above conversion. If a mixture of 1-, 2-and 3-substituted-1, 2, 3-triazol-4-yl isomers of the compound of formula (IIE) is obtained, these compounds can be separated by conventional methods, such as chromatography.

It will be appreciated that certain compounds of formula (I) or (II) may be converted to corresponding other compounds of formula (I) or (II) by conventional methods such as functional group interconversion.

All of the above reactions and the preparation of the novel starting materials used in the preceding methods are conventional reactions and the appropriate reagents and reaction conditions for the implementation or preparation and isolation of the desired product steps are well known to those skilled in the art by reference to the previous literature and the examples and preparations herein.

Pharmaceutically acceptable acid addition or base salts of the compounds of formula (I) can be readily prepared, where appropriate, by mixing together a solution of the compound of formula (I) and the desired acid or base. The salt may be precipitated from the solution and collected by filtration or recovered by evaporation of the solvent.

Their binding affinity to the glycine site of the NMDA receptor was determined by testing the ability of the compounds of formula (i) and salts thereof to displace a selective glycine site radioligand from rat brain membranes as described in british journal of pharmacy (brit. j. pharm., 104,74 (1991). In a variation of this method, the well-washed membrane protein is contacted with the [2 ], [ solution ] using a tris-acetate buffer solution (pH7.4)³H]L-689,560 for 90 minutes (mol. Pharmacol.,41,923 (1992)). Using a range of concentrations of test compound in place of radioligand to determine IC₅₀(50% inhibitory concentration) value.

Functional NMDA antagonism in vitro was tested for the ability of the compound to inhibit depolarization in NMDA-induced rat brain cortex sections according to methods similar to those described in j.med.chem.,33,789(1990) and brit.j.pharm.,84,381 (1985). In a variation of this method, the response to a standard NMDA concentration is measured in the presence of a series of test compounds, and the results used to determine EC₅₀(50% effective concentration) value.

Displacement of radioligand from brain membranes of rats by testing the Compound of the invention³H]-AMPA capacity, determining their binding affinity to AMPA receptors. The membrane homogenate was incubated with radioligand (10nM) at 4 ℃ for 45 min in the presence or absence of various concentrations of test compound. Free and bound radiolabel was separated by rapid filtration and radioactivity was determined by liquid scintillation counting.

The compounds of formula (i) and salts thereof may be administered to a subject alone, but will generally be administered in admixture with a pharmaceutically acceptable diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally (including sublingually) in the form of tablets containing excipients such as starch or lactose, capsules or eggs prepared alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents. They may also be administered by injection by the parenteral (e.g. intravenous, intramuscular or subcutaneous) route. For parenteral administration, they are best used in the form of sterile aqueous solutions which may contain other substances, for example, enough salts or glucose to keep the solution isotonic with blood.

The compounds of the invention have the potential to be absorbed through the gastrointestinal tract and may therefore also be administered in sustained release formulations.

Generally, the therapeutically active daily dose of a compound of formula (I) or a salt thereof will be from about 0.1 to about 100mg, preferably from about 1 to about 20mg/kg of body weight of the subject, and the daily dose for intravenous administration will be from about 0.01 to about 20mg, preferably from about 0.1 to about 20mg/kg of body weight of the subject. The compounds of formula (I) and salts thereof may also be administered by intravenous infusion in a dosage of about 0.01 to 10 mg/kg/hr.

Tablets or capsules of the compounds of the invention may, where appropriate, be administered in each case in a single tablet (granule) or in two tablets (granules) or more.

The effective dosage most suitable for a particular patient will be determined by the attending physician and will vary with the age, weight and response to the drug of the particular patient. The above doses are typical of the average case. There are, of course, specific cases where higher or lower dosage ranges are desired, and such dosages are within the scope of the invention.

Alternatively, the compounds of formula (I) may be administered by inhalation, or in the form of suppositories or pessaries, or they may be administered topically in the form of lotions, solutions, ointments or powders. Another transdermal application is the use of skin patches. For example, the compounds of the present invention may be incorporated into emulsifiable concentrates formed from aqueous emulsions of polyethylene glycol or liquid paraffin. They may also be incorporated in ointments consisting of a white wax or white petrolatum base, and possibly stabilizers and preservatives, at concentrations of 1-10 wt.%.

It is understood that treatment includes both prevention and alleviation of established symptoms of the disease.

Accordingly, the present invention further provides: i) a pharmaceutical composition comprising a compound of formula (i) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable diluent or carrier; ii) a compound of formula (I) or a pharmaceutically acceptable salt or combination thereof for use as a medicament; iii) the use of a compound of formula (I), or a pharmaceutically acceptable salt or combination thereof, in the manufacture of a medicament for the treatment of a disease state by antagonism at the NMDA receptor; iv) the use as described in (iii), wherein the disease is acute neurodegeneration or a chronic neurological disorder; v) a method of treating a disease in a mammal by producing antagonism at the NMDA receptor, which method comprises treating said mammal with an effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof or a combination thereof; vi) the method as in (v), wherein the disease is acute neurodegenerative or chronic neurological disorder; and vii) compounds of formula (II).

The following examples and preparations are illustrative of the preparation of the compounds of formula (I) and intermediates used in their synthesis.

Melting points were measured in glass capillaries using a Buchi apparatus and were uncorrected. Low Resolution Mass Spectrometry (LRMS) values were recorded using a Fisons Trio 1000 mass spectrometer (thermal spray method using ammonium acetate/methanol in water as the carrier, or atmospheric pressure chemical ionization method using methanol to acetic acid in a volume ratio of 97.5: 2.5, using nitrogen as the carrier). NMR values were recorded using a Bruker AC300 or Varian Unity 300 NMR instrument (both 300MHz) or a UNity inova-400(400MHz) instrument and were consistent with the determined structure. Flash chromatography was performed using Kieselgel 60(230-400 mesh) from E.Merck, Darmstadt and Thin Layer Chromatography (TLC) using Kieselgel 60F from E.Merck₂₅₄Plates and compounds were developed using UV light or chloroplatinic acid/potassium iodide solutions. When the compound was analyzed as a hydrate, the presence of water was confirmed by the strong peak of water appearing in the proton NMR spectrum. The purity of the compound was carefully determined by analytical TLC and proton NMR (300MHz), and the latter technique was also used to calculate the solvent content in the solvated samples. In a multi-step series, the purity and structure of the intermediate was determined spectroscopically using proton NMR. Proton NMR shifts are expressed in parts per million downfield from tetramethylsilane.

Certain abbreviations familiar to those skilled in the art are used in the examples and preparations.

Example 16, 7-dichloro-5- (4-pyridyl) -2,3(1H,4H) -quinoxalinebis

Ketones

A mixture of 6, 7-dichloro-2, 3-dimethoxy-5- (4-pyridyl) quinoxaline (preparation 2,110mg,0.327mmol),2M aqueous hydrochloric acid (1ml) and 1, 4-dioxane (7ml) was heated under reflux for 2 hours and cooledThen, the mixture was concentrated under reduced pressure. The resulting solid residue was triturated with water, collected by filtration and washed with water and diethyl ether to give the title compound (17mg, 17%) as a white solid, mp > 300 ℃. m/z (thermal spraying) 308 (MH)⁺) Elemental analysis (%): measured value: c, 49.58; h, 2.36; n,12.93.C₁₃H₇Cl₂N₃O₂.0.5H₂Calculated value of O: c, 49.24; h, 2.54; and N,13.25.

Examples 2 to 107

Following a similar procedure to example 1, the following formula was prepared:the following table shows examples in which the corresponding 2, 3-dimethoxyquinoxaline derivative shown is used and the reaction time is the approximate time required to determine complete exhaustion of the starting material by TLC detection. In examples 8,82 and 84, an ester hydrolysis reaction was accompanied, whereas in example 104-106, the trityl group was cleaved.

TABLE 1Note 1) the reaction was carried out as described in example 1, but at 50 ℃ for 9 hours. The crude product was purified by flash chromatography on silica gel eluting first with 95: 5(v/v) dichloromethane: methanol and then with 80: 20: 1 (v/v) dichloromethane: methanol: acetic acid. 2) The resulting solid was dissolved in hot water (4mL), cooled to 0 ℃ and collected by filtration. 3) The product was obtained as an orange oil, which was dissolved in distilled water (4ml) and lyophilized. 4) The starting material was prepared analogously to preparation 27 and the hydrazide intermediate was prepared analogously to the preparation 27.

Example 1086, 7-dichloro-5- (1-methoxycarbonylmethyltetrazol-5-yl) -

2,3(1H,4H) -quinoxalinediones

Under nitrogen atmosphere, 6, 7-dichloro-5- (1-carboxymethyltetrazol-5-yl) -2,3(1H,4H) -quinoxalinedione (realgar)Example 8,42mg,0.12mmol) in a saturated solution of methanolic hydrogen chloride (5ml) were heated to reflux for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water (10ml) and dichloromethane (10 ml). The aqueous phase was separated and extracted with dichloromethane (2X 25 ml). Drying (MgSO)₄) And the combined organic extracts were concentrated under reduced pressure. The residue was triturated with ether and filtered to give the title compound (24mg, 55%) as a pale grey solid, mp281-283 ℃.¹H-NMR(300MHz,DMSO-d₆) δ =3.60(3H, s),5.32(2H, m),7.44(1H, s),11.60(1H, brs),1.212(1H, brs) m/z (thermal spraying) 371 (MH)⁺).

Example 109

6-chloro-7-methyl-5- [ 5-methoxymethyl-3- (3-pyridyl) -

4H-1,2, 4-triazol-4-yl]-2,3(1H,4H) -quinoxalinedione

Similar to the procedure described in example 1, 6-chloro-2, 3-dimethoxy-7-methyl-5- [ 5-methoxymethyl-3- (pyridyl) -4H-1,2, 4-triazol-4-yl]Quinoxaline (preparation 114) in place of 6, 7-dichloro-2, 3-dimethoxy-5- (4-pyridyl) quinoxaline was used to prepare the title compound. The residue obtained after concentrating the reaction mixture was dissolved in 1M aqueous sodium hydroxide solution, and the pH of the mixture was adjusted to 6 with 2M aqueous hydrochloric acid solution, followed by cooling to 0 ℃. The solid formed was collected by filtration and washed with water to give an off-white solid, mp229-231 ℃ elemental analysis (%): measured value: c, 51.33; h, 4.16; n,19.99.C₁₈H₁₅ClN₆O₃.0.25H₂Calculated value of O: c, 51.31; h, 4.19; and N,19.95.

Example 110

7-chloro-6-methyl-5- [ 5-methoxymethyl-3- (3-pyridyl) -

4H-1,2, 4-triazol-4-yl]-2,3(1H,4H) -quinoxalinedione

The title compound is synthesized in analogy to the procedure described in example 1 using 7-chloro-2, 3-dimethoxy-6-methyl-5- [ 5-methoxymethyl-3- (pyridyl) -4H-1,2, 4-triazol-4-yl]Quinoxaline (preparation 115) was prepared in place of 6, 7-dichloro-2, 3-dimethoxy-5- (4-pyridyl) quinoxaline. The residue obtained after concentrating the reaction mixture was dissolved in 1M aqueous sodium hydroxide solution, and the pH of the mixture was adjusted to 6 with 2M aqueous hydrochloric acid solution, followed by cooling to 0 ℃. The solid formed was collected by filtration and washed with water to give a pale yellow solid, mp > 300 ℃ m/z (thermal spray) 399 (MH)⁺) Elemental analysis (%): measured value: c, 52.60; h, 3.91; n,20.34.C₁₈H₁₅ClN₆O₃.0.75H₂Calculated value of O: c, 52.43; h, 4.03; and N,20.38.

Example 111

(+) -, (-) -and (+) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl]-2,3(1H,4H) -quinoxalinedione(a) Methoxyacetyl chloride (27.3mL,32.4g,0.30mol) was added to a mixture of 5-amino-6, 7-dichloro-2, 3-dimethoxyquinoxaline (preparation 26,73.8g,0.27mol) and pyridine (26.4mL,25.8g,0.33mol) in dichloromethane (1.2L) at room temperature under nitrogen with stirring. After stirring at room temperature for 18 hours, the mixture was washed successively with 2M aqueous hydrochloric acid and brine, followed by drying (MgSO)₄) And concentrated under reduced pressure. The residue was triturated with methanol and filtered to give 6, 7-dichloro-2, 3-dimethoxy-5-methoxyacetamidoquinoxaline (82.0g, 88%) as an off-white solid, mp171-173 ℃. Elemental analysis (%): measured value: c, 44.97; h, 3.75; n,12.03.C₁₃H₁₃Cl₂N₃O₄Calcd for C, 45.11; h, 3.79; n,12.14.(b) to a solution of 6, 7-dichloro-2, 3-dimethoxy-5-methoxyacetamidoquinoxaline (27g,78mmol) in tetrahydrofuran (480mL) was added 2, 4-bis (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetanyl-2, 4-disulfide (Lawesson's reagent) (19.5g,48.2mmol) and the mixture was stirred at room temperature for 18h and then evaporated under reduced pressure.The residue was purified by flash chromatography on silica gel with gradient elution using hexane: dichloromethane (1: 1 → 1: 4, volume ratio) as eluent to give 6, 7-dichloro-2, 3-dimethoxy-5-methoxythioacetamidoquinoxaline (29.1g, > 100%) as a white solid, mp198-200 ℃ containing a small amount of impurities. Elemental analysis (%): measured value: c, 43.06; h, 3.65; n,11.59.C₁₃H₁₃Cl₂N₃O₃S calculated value: c, 43.11; h, 3.62; n,11.60.(c) a mixture of 6, 7-dichloro-2, 3-dimethoxy-5-methoxythioacetamidoquinoxaline (25.3g,69.9mmol), nicotinic acid hydrazide (19.3g,140.8mmol), mercury (ii) oxide (15.1g,69.7mmol) and 1, 4-dioxane (600ml) was heated at reflux for 18 h. After cooling, it was filtered through ARBOCEL (trade name) filter aid and the residue was washed with dichloromethane. The filtrate was concentrated under reduced pressure to give a bright brown solid which was partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The layers were separated and the aqueous layer was extracted with dichloromethane (2X 500mL, 4X 100mL) and dried (MgSO)₄) And the combined dichloromethane extracts were concentrated under reduced pressure. Recrystallizing the residue with ethyl acetate/methanol to obtain (+ -) -6, 7-dichloro-2, 3-dimethoxy-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl group]Quinoxaline (11.6g, 37%) as a pale yellow solid, mp189-191 ℃ elemental analysis (%): measured value: c, 50.10; h, 3.57; n,18.53.C₁₉H₁₆Cl₂N₆O₃.0.5H₂Calculated value of O: c, 50.01; h, 3.76; n,18.42.(d) reacting (. + -.) -6, 7-dichloro-2, 3-dimethoxy-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl]A mixture of quinoxaline (3.0g,6.7mmol),2M aqueous hydrochloric acid (10mL) and 1, 4-dioxane (50mL) was heated at reflux for 9h, cooled and concentrated under reduced pressure. The residue was dissolved in 1M aqueous sodium hydroxide solution, acidified with concentrated hydrochloric acid to pH4.5 to give a white viscous precipitate, collected by filtration and washed with water to give (+ -) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl ester]-2,3(1H,4H) -quinoxalinedione (2.0g, 68%) as off-white solid, mp230-232 ℃ elemental analysis (%): measured value: c, 46.23; h, 2.93; n,19.00.C₁₇H₁₂Cl₂N₆O₃.1.25H₂Calculated value of O: c, 46.22; h,3.31; n,19.02.(e) (i) to (. + -.) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl ] was added under stirring at room temperature]Suspension of (E) -2,3(1H,4H) -quinoxalinedione (1.9g,4.3mmol) in ethyl acetate (400mL) was added (-) -N-methylephedrine (0.88g,4.9mmol) followed by methanol (66 mL). The mixture is heated to its boiling point. The mixture was filtered and the filtrate was concentrated to 3/4 of its volume and then cooled to room temperature. The resulting solid was collected by filtration and washed with ethyl acetate. The solid was crystallized from ethyl acetate/methanol to give a single diastereomer of the quinoxalinedione starting material as (-) -N-crystalline ephedrine salt (1.28g, 43%), mp162-164 ℃. Elemental analysis (%): measured value: c, 55.74; h, 5.38; n,14.38.C₂₈H₂₉Cl₂N₇O₄.CH₃CO₂C₂H₅Calculated values: c, 55.98; h, 5.43; n,14.28]²⁵D-135 ° (c =0.1, ethanol) · (ii) a suspension of (-) -N-methylephedrine salt (1.2g,1.7mmol) from fraction (e) (i) in water (13ml) was acidified to pH5 with concentrated hydrochloric acid at room temperature and the suspension was stirred for 1 hour. The resulting solid was collected by filtration, washed with water and crystallized from water/ethanol to give (-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl ester]-2,3(1H,4H) -quinoxalinedione (0.48g, 62%) as a white solid, mp220-222 ℃ elemental analysis (%): measured value: c, 45.49; h, 3.21; n,18.72.C₁₇H₁₂Cl₂N₆O₃.1.5H₂Calculated value of O: c, 45.76; h, 3.39; n,18.83.[ alpha ]]²⁵D-214 ° (c =0.1, ethanol) · (iii) combine part (e) (i) of the filtrate and concentrate to dryness. The residue was dissolved in water (20mL), acidified to pH3 with concentrated hydrochloric acid, the resulting solid collected by filtration, washed with water and dried. To a suspension of this solid (0.80g,1.87mmol) in ethyl acetate (170mL) was added (+) -N-methylephedrine (0.37g,2.06mmol) and methanol (28mL) sequentially with stirring at room temperature, and the mixture was heated to its boiling point. The mixture was filtered, concentrated to its volume of 3/4, and then cooled to room temperature. The resulting solid was collected by filtration and washed with ethyl acetate. The solid was crystallized from ethyl acetate/methanol to give a single diastereomer of the quinoxalinedione starting material, which was (+) -N-crystalline ephedrine salt (0.93g, 32%), mp165-167 ℃. Elemental analysis (%): measured in factThe value: c, 55.88; h, 5.40; n,14.31.C₂₈H₂₉Cl₂N₇O₄.0.8CH₃CO₂C₂H₅Calculated values: c, 56.01; h, 5.33; n,14.66.[ alpha ]]²⁵D +127 ° (c =0.1, ethanol) · (iv) a suspension of part (e) (iii) of (+) -N-methylephedrine salt (0.90g,1.35mmol) in water (10ml) was acidified to pH5 with concentrated hydrochloric acid at room temperature and the suspension was stirred for 1 hour. The obtained solid is collected by filtration and washed with water to obtain (+) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl]-2,3(1H,4H) -quinoxalinedione (0.41g, 69%) as a white solid, mp222-224 ℃. elemental analysis (%): measured value: c, 46.44; h, 3.18; n,19.01.C₁₇H₁₂Cl₂N₆O₃.1.25H₂Calculated value of O: c, 46.22; h, 3.31; n,19.02]²⁵D +212 ° (c =0.1, ethanol).

Example 112

6-chloro-7-ethyl-5- [ 3-methoxymethyl-5- (3-pyridyl) -

4H-1,2, 4-triazol-4-yl]-2,3(1H,4H) -quinoxalinedione

The title compound was prepared in analogy to example 109 using the starting materials shown above (which starting materials were prepared from 6-chloro-7-ethyl-5-nitro-2, 3(1H,4H) -quinoxalinedione (cf. WO-A-95/12417) in analogy to the methods described in preparation 113, steps (c), (d) and (e), preparation 114 and preparation 115). The yellow foam was isolated. Elemental analysis (%): measured value: c, 48.68; h, 4.18; n,17.60.C₁₉H₁₇N₆O₃Cl.HCl.H₂Calculated value of O: c, 48.83; h, 4.31; n,17.98.m/z (thermal spraying) 413.0 (MH)⁺).

Example 113

7-chloro-6-ethyl-5- [ 3-methoxymethyl-5- (3-pyridyl) -

4H-1,2, 4-triazol-4-yl]-2,3(1H,4H) -quinoxalinediones

The title compound was prepared in analogy to example 109 using the starting materials shown above (wherein the starting materials were prepared from 7-chloro-6-ethyl-5-nitro-2, 3(1H,4H) -quinoxalinedione (cf. WO-A-95/12417) in analogy to the methods described in preparation 113, steps (c), (d) and (e), preparation 114 and preparation 115). The yellow foam was isolated. Elemental analysis (%): measured value: c, 46.28; h, 4.17; n,16.70.C₁₉H₁₇N₆O₃Cl.2HCl.1/3H₂Calculated value of O: c, 46.41; h, 4.03; n,17.09.m/z (thermal spray method) 413.0 (MH)⁺).

Example 114

(-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (1-oxidopyridin-3-yl) -4H-

1,2, 4-triazol-4-yl]-2,3(1H,4H) -quinoxalinedione

A solution of 3-chloroperbenzoic acid (0.85g,4.93mmol) in acetone (20ml) was added in one portion to (-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl]-2,3(1H,4H) -quinoxalinedione (see example 111) (1.0g,2.24mmol) in acetone (40ml) so that all solids are dissolved. The reaction was stirred at room temperature for 40 minutes, after which a white solid began to form, and the reaction mixture was stirred at room temperature for 3 days. The white solid was collected by filtration and purified by flash chromatography on silica gel using dichloromethane: methanol: glacial acetic acid (90: 10: 1, vol.) as eluent, the appropriate fractions were combined and concentrated to give the title compound (0.16g, 17%) as a white solid, m.p. > 310 ℃. [ alpha. ]]²⁵D-235 ° (c =1.0, ethanol).

Example 115-129

The following general formula was prepared in a similar manner to example 1：The following table shows examples in which the corresponding 2, 3-dimethoxyquinoxaline derivative was used and the reaction time means the approximate time required to determine complete exhaustion of the starting material by TLC detection.

TABLE 2

Example 130

(-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl ] -

2,3(1H,4H) -Quinoxalinedione sodium salt

Stirring and stirring the mixture at (-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl]To a suspension of (E) -2,3(1H,4H) -quinoxalinedione (see example 111) (0.428g,0.959mmol) in water (10ml) was added sodium hydroxide (0.959ml,1M in water, 0.959mmol) and the mixture was stirred for 0.5H. The resulting solution was filtered and the filtrate was lyophilized to give the title compound as a white solid (0.43g, 94%), mp260 deg.C (decomposition). Elemental analysis (%): measured value: c, 42.90; h, 2.89; n,17.76.C₁₇H₁₁Cl₂N₆NaO₃.1.5H₂Calculated value of O: c, 42.78; h, 3.17; n,17.61.[ alpha ]]²⁵D-228 ° (c =0.1, ethanol).

Example 131

(-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl ] -

Intravenous formulations of 2,3(1H,4H) -quinoxalinedione sodium salt

Using (-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl]-2,3(1H,4H) -quinoxalinedione sodium salt. 1.5H₂O (see example 130) (22.4 mg/unit dose), sodium chloride (9.0 mg/unit dose) and water for injection (to 1.0ml) to prepare a formulation containing 20mg/ml of active ingredient suitable for intravenous administration.

To prepare the formulation, sodium chloride is dissolved in 75% by volume of water, based on the total volume of water, in a suitable container with stirring, and (-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl is added]-2,3(1H,4H) -quinoxalinedione sodium salt 1.5H₂And O is mixed and dissolved. Then add additional solution to the appropriate volume and filter through a clean 0.2 micron filter. The filtrate was aseptically filled into 10ml sterile ampoules using a tip-purge filter. The following preparations are illustrative of the synthesis of some of the intermediates used in the above examples.

Preparation example 1

6, 7-dichloro-2, 3-dimethoxyquinoxaline

To a suspension of 2,3,6, 7-tetrachloroquinoxaline (106g,400mmol) in methanol (1400mL) was added sodium methoxide solution (25% wt/v in methanol, 190mL,880mmol) at room temperature under nitrogen with stirring. After 3 days of reaction, further sodium methoxide solution (25% wt/v methanol solution, 40mL,190mmol) was added, followed by tetrahydrofuran (300 mL). The reaction mixture was heated to reflux for 5 minutes, cooled, concentrated at least volumetrically under reduced pressure, and poured into water (500 mL). The precipitate was collected by filtration and washed with water to give the title compound as a pink solid (97g, 95%), mp144-146 ℃.¹H-NMR(300MHz,CDCl₃) δ =4.14(6H, s),7.88(2H, s) m/z (thermal spraying) 259 (MH)⁺).

Preparation example 2

6, 7-dichloro-2, 3-dimethylOxy-5- (4-pyridyl) quinoxaline(a) To a suspension of 6, 7-dichloro-2, 3-dimethoxyquinoxaline (preparation 1, 2.9g,7.72mmol) in anhydrous tetrahydrofuran (150mL) was added lithium diisopropylamide mono (tetrahydrofuran) (1.5M cyclohexane solution, 6.18mL,9.26mmol) under nitrogen and stirring at-78 ℃. After 1 hour at-78 deg.C, trimethyl borate (1.47ml,2.0g,19.3mmol) was added. The solution was further stirred for 1 hour and then allowed to stand for 18 hours to warm to room temperature. Water (50mL) was added, the solution was acidified to pH1 with 2M aqueous hydrochloric acid and extracted with dichloromethane (3X 150 mL). Drying (MgSO)₄) The combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with gradient elution using dichloromethane: methanol (100: 0 → 99: 1, volume ratio) as eluent to give 6, 7-dichloro-2, 3-dimethoxyquinoxaline-5-boronic acid (0.610g, 26%) as a light brown solid.¹H-NMR(300MHz,DMSO-d₆) δ =3.97(3H, s),4.02(3H, s),7.88(1H, s),8.50(2H, s) m/z (thermal spraying) 303 (MH)⁺) (b) A mixture of 6, 7-dichloro-2, 3-dimethoxyquinoxaline-5-boronic acid (0.27g,0.89mmol), 4-bromopyridine (0.14g,0.89mmol) and tetrakis (triphenylphosphine) palladium (0) (0.031g,0.026mmol) in a mixture of 2M aqueous sodium carbonate (1mL), ethanol (0.5mL) and toluene (10mL) was heated at reflux for 24 hours under a nitrogen atmosphere. After cooling, the mixture was partitioned between water (20ml) and dichloromethane (20 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (3X 50 ml). Drying (MgSO)₄) And the combined organic extracts were concentrated under reduced pressure to give a brown solid which was purified by flash chromatography on silica gel eluting with hexane: ethyl acetate (3: 1, vol.) to give the title compound as a beige solid (0.113g, 38%).¹H-NMR(300MHz,CDCl₃) δ =3.80(3H, s),4.17(3H, s); 7.30(2H, d, J =5Hz),7.97(1H, s),8.73(2H, d, J =5Hz) m/z (thermal spraying) 336 (MH)⁺).

Preparation examples 3 to 5

Analogously to the process described in section b of preparation 2, 6, 7-dichloro-2, 3-dimethoxyquinoxaline-5-boronic acid was used,and the appropriate heterocyclic bromide (R-Br) was used in place of 4-bromopyridine to prepare the following compounds

Preparation example 6

6, 7-dichloro-2, 3-dimethoxyquinoxaline-5-carboxylic acid

To a suspension of 6, 7-dichloro-2, 3-dimethoxyquinoxaline (preparation 1,5.0g,19.3mmol) in anhydrous tetrahydrofuran (150mL) was added lithium diisopropylamide mono (tetrahydrofuran) (1.5M cyclohexane solution, 15.5mL,23.3mmol) under nitrogen with stirring at-78 ℃. The reaction mixture was stirred at this temperature for 1 hour, and then anhydrous carbon dioxide was passed through the solution at-78 ℃ for 1 hour. Saturated aqueous ammonium chloride (80ml) was added and the resulting mixture was warmed to room temperature, acidified to pH1 with 2M aqueous hydrochloric acid and extracted with ethyl acetate (3X 50 ml). The combined organic extracts were then extracted with 1M sodium hydroxide solution. The aqueous solution was acidified to pH1 with 2M aqueous hydrochloric acid and extracted with dichloromethane (3X 50 mL). Drying (MgSO)₄) And the combined dichloromethane extracts were concentrated under reduced pressure to give the title compound as a light brown solid (4.0g, 68%), mp 230-.¹H-NMR(300MHz,DMSO-d₆):δ=3.98(3H,s),4.04(3H,s),8.02(1H,s),13.85(1H,brs).

Preparation example 7

6, 7-dichloro-2, 3-dimethoxy-5- (N-methylcarbamoyl) quinoxaline

To a solution of 6, 7-dichloro-2, 3-dimethoxyquinoxaline-5-carboxylic acid (preparation 6,0.890g,2.93mmol) in dichloromethane (25ml) was added anhydrous N, N-dimethylformamide (50. mu.l, 47.2mg,0.64mmol) at room temperature under a nitrogen atmosphereOxalyl chloride (0.338ml,3.8mmol) was then added. After 0.5 h, the mixture was concentrated under reduced pressure. To the residue was added dichloromethane (10mL) under nitrogen atmosphere at room temperature, followed by methylamine (33% w/w ethanol solution, 10mL,80.3 mol). After 10 minutes of reaction, the mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (20ml) and 1M aqueous hydrochloric acid. Drying (MgSO)₄) And the organic extract was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel with a gradient elution using dichloromethane: methanol (100: 0 → 99: 1, vol.) as eluent, and the resulting solid was recrystallized from toluene to give the title compound as a white solid (0.570g, 61%).¹H-NMR(300MHz,CDCl₃) δ =3.11(3H, d, J =3Hz),4.10(3H, s),4.05(3H, s),5.87(1H, br d, J =3Hz),7.87(1H, s). m/z (thermal spraying).

Preparation example 8

6, 7-dichloro-2, 3-dimethoxy-5- (1-methyl-1H-tetrazol-5-yl) quinoxaline

To a solution of 6, 7-dichloro-2, 3-dimethoxy-5- (N-methylcarbamoyl) quinoxaline (preparation 7, 0.197g,0.62mmol) in toluene (7ml) was added phosphorus pentachloride (0.136g,0.65mmol), and the mixture was heated under nitrogen at reflux for 1 hour. The reaction was cooled to room temperature and azidotrimethylsilane (123. mu.l, 0.107g,0.93mmol) was added. After stirring at room temperature for 18 hours, a dilute aqueous ammonia solution (20ml) was added and the mixture was extracted with dichloromethane (3X 50 ml). Mixing the organic extracts, and drying (MgSO)₄) And the combined organic extracts were evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with dichloromethane to give the title compound as a white solid (0.080g, 38%).¹H-NMR(300MHz,CDCl₃) δ =3.84(3H, s),3.90(3H, s),4.14(3H, s),8.5(1H, s) m/z (thermal spraying) 341 (MH)⁺).

Preparation examples 9 to 17

In analogy to the procedures described in preparations 7 and 8, use 67-dichloro-2, 3-dimethoxyquinoxaline-5-carboxylic acid with a suitable primary amine (R-NH)₂) Instead of methylamine, the following representative compounds were prepared.

Preparation example 18

6, 7-dichloro-2, 3-dimethoxy-5- (N-allylcarbamoyl) quinoxaline

Quinoline (III)

The title compound was prepared in a similar manner to that described for preparation 7, using allylamine instead of methylamine.¹H-NMR(300MHz,CDCl₃) δ =4.10(3H, s); 4.14(3H, s),4.19(2H, m),5.20(1H, d, J =10Hz),5.38(1H, dd, J =2,10Hz),5.85(1H, br s),6.00(1H, m); 7.88(1H, s) m/z (thermal spraying) 342 (MH)⁺).

Preparation example 19

6, 7-dichloro-2, 3-dimethoxy-5- (1-allyl-1H-tetrazole-5)

-yl) quinoxalines

The title compound was prepared in a similar manner to preparation 8 using 6, 7-dichloro-2, 3-dimethoxy-5- (N-allylcarbamoyl) quinoxaline (preparation 18) in place of 6, 7-dichloro-2, 3-dimethoxy-5- (N-methylcarbamoyl) quinoxaline.¹H-NMR(300MHz,CDCl₃) δ =3.80(3H, s),4.14(3H, s),4.80(2H, m),5.02(1H, m),5..16(1H, m),5.80(1H, m),8.10(1H, s). m/z (thermal spraying) 367 (MH)⁺).

Preparation example 20

6, 7-dichloro-2, 3-dimethoxy-5- [1- (3-hydroxypropyl) -

1H-tetrazol-5-yl]Quinoxalines as inhibitors of tyrosine kinases

To a stirred suspension of 6, 7-dichloro-2, 3-dimethoxy-5- (1-allyl-1H-tetrazol-5-yl) quinoxaline (preparation 19, 0.67g,1.82mmol) in anhydrous tetrahydrofuran (15mL) at room temperature under a nitrogen atmosphere was added 9-borabicyclo [3.3.1]Nonane (0.5M in tetrahydrofuran, 9.1mL,4.55 mmol). The reaction mixture was heated under reflux for 18 hours, cooled, and to this trimethylamine-N-oxide (1.03g,13.7mmol) was added portionwise, and the reaction mixture was heated under reflux for 2 hours, and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of dichloromethane: methanol (100: 0 → 99.5: 0.5, vol.) to give the title compound as a white solid (0.510g, 73%), mp188-189 ℃.¹H-NMR(300MHz,CDCl₃) δ =2.04(2H, m),3.60(2H, m),3.82(3H, s),4.16(3H, s),4.30(2H, m),8.12(1H, s) m/z (thermal spraying) 769 (MH)⁺).

Preparation example 21

6, 7-dichloro-2, 3-dimethoxy-5- [1- (2-hydroxyethyl)

-1H-tetrazol-5-yl]Quinoxalines as inhibitors of tyrosine kinases

Diisobutylaluminum hydride (1M in tetrahydrofuran, 0.7ml,0.7mmol) was added dropwise to a solution of 6, 7-dichloro-2, 3-dimethoxy-5- (1-methoxycarbonylmethyl-1H-tetrazol-5-yl) quinoxaline (preparation 11, 0.126g,0.32mmol) in dichloromethane (15ml) at-78 ℃ under nitrogen and stirring. After 1h, the reaction mixture was warmed to room temperature, and diisobutylaluminum hydride (1M tetrahydrofuran solution, 0.7ml,0.7mmol) was added thereto, after 30 min, a further addition was madeDiisobutylaluminum hydride (1M tetrahydrofuran solution, 0.7ml,0.7 mmol). After a further reaction time of 0.25 h, a saturated ammonium chloride solution (20ml) was added to the mixture and the aqueous phase was extracted with dichloromethane (2X 25 ml). The combined organic extracts were washed with brine (50ml) and dried (MgSO)₄) And concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (99: 1, vol.) to give the title compound as a white solid (93mg, 79%).¹H-NMR(300MHz,CDCl₃) δ =3.84(3H, s),4.08(2H, m),4.18(3H, s),4.28(2H, m),8.14(1H, s) m/z (thermal spraying) 371 (MH)⁺).

Preparation example 22

6, 7-dichloro-2, 3-dimethoxy-5- [4- (2-hydroxyethyl) -4H-

1,2, 4-triazol-3-yl]Quinoxalines as inhibitors of tyrosine kinases(a) Phosphorus pentachloride (0.67g,3.22mmol) was added to a suspension of 6, 7-dichloro-2, 3-dimethoxy-5- (N-allylcarbamoyl) quinoxaline (preparation 18, 1.0g,2.93mmol) in toluene (40ml) with stirring at room temperature, followed by heating and refluxing for 1 hour. After cooling, formylhydrazine (0.585g,8.79mmol) and triethylamine (0.592g,8.79mmol) were added and the mixture was heated under reflux for 1 hour. After cooling, the mixture was partitioned between ethyl acetate (60ml) and 10% w/w aqueous potassium carbonate (60 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2X 40 ml). Drying (MgSO)₄) And the combined organic extracts were concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel, eluting with a gradient of toluene: ethyl acetate (1: 0 → 1: 1, vol.) to give 6, 7-dichloro-2, 3-dimethoxy-5- (4-allyl-4H-1, 2, 4-triazol-3-yl) quinoxaline (0.112g, 10%) as a white solid, mp206-208 ℃.¹H-NMR(300MHz,CDCl₃) δ =3.88(3H, s),4.14(3H, s),4.37(2H, d, J =3Hz),5.16(2H, m),5.79(1H, m),8.06(1H, s),8.34(1H, s) m/z (thermal spraying) 366 (MH)⁺) (b) 6, 7-dichloro-2, 3-dimethoxy-5- (4-allyl-4H-1, 2, 4-triazol-3-yl) quinoxaline (0.1g,0.273mmol) in dichloromethane (3ml)) The solution was cooled to-70 ℃ and an ozone/oxygen flow was applied for 0.5 hour. A stream of nitrogen was then passed for 0.25 h, followed by addition of methanol (3ml) and sodium borohydride (0.026g,0.683 mmol). After warming to room temperature, the mixture was partitioned between dichloromethane (10ml) and brine (10 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2X 10 ml). Drying (MgSO)₄) And the combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of ethyl acetate: methanol (100: 0 → 95: 5, vol.) to give the title compound (0.042g, 40%) as an off-white solid, mp212-214 ℃.¹H-NMR(300MHz,CDCl₃) δ =3.78(2H, m),3.87(3H, s),3.92(2H, m),4.18(3H, s),8.07(1H, s),8.63(1H, s) m/z (thermal spraying) 370 (MH)⁺).

Preparation example 23

6, 7-dichloro-2, 3-dimethoxy-5- (4-methyl-

4H-1,2, 4-triazol-3-yl) quinoxalines

The title compound was prepared according to a similar procedure as described in preparation 22, step (a) using 6, 7-dichloro-2, 3-dimethoxy-5- (N-methylcarbamoyl) quinoxaline (preparation 7) in place of 6, 7-dichloro-2, 3-dimethoxy-5- (N-allylcarbamoyl) quinoxaline. Purification by flash chromatography on silica gel eluting with a gradient of toluene: ethyl acetate (1: 1 → 0: 1, volume ratio) afforded an off-white solid.¹H-NMR(300MHz,CDCl₃) δ =3.52(3H, s),3.88(3H, s),4.17(3H),8.07(1H, s),8.37(1H, s) m/z (thermal spraying) 340 (MH)⁺).

Preparation example 24

6, 7-dichloro-2, 3-dimethoxyquinoxaline-5-carboxamide

Analogously to preparation 7The title compound was prepared using gaseous ammonia instead of methylamine to give a pale yellow solid (chromatography was not necessarily required during work-up).¹H-NMR(300MHz,DMSO-d₆) δ =4.00(3H, s),4.06(3H, s),7.80(1H, br.s),7.92(1H, br.s),8.00(1H, s) m/z (thermal spraying) 302 (MH)⁺).

Preparation examples 256, 7-dichloro-2, 3-dimethoxy-5- (2-methyl-2H-1, 2, 4-triazol-3-yl) quinoxaline (isomer 1) and 6, 7-dichloro-2, 3-dimethoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) quinoxaline (isomer 2)(a) A solution of 6, 7-dichloro-2, 3-dimethoxyquinoxaline-5-carboxamide (preparation 24,1.96g,6.49mmol) in N, N-dimethylformamide dimethyl acetal (25ml) was heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was triturated with ether to give N¹,N¹-dimethyl-N²- [6, 7-dichloro-2, 3-dimethoxyquinoxalin-5-ylcarbonyl]Formamidine (2.14g, 92%) as a pale yellow solid.¹H-NMR(300MHz,CDCl₃) δ =3.18(3H, s),3.24(3H, s),4.09(3H, s),4.15(3H, s),7.88(1H, s),8.62(1H, s) m/z (thermal spraying) 357 (MH)⁺) (b) reacting N¹,N¹-dimethyl-N²- [6, 7-dichloro-2, 3-dimethoxyquinoxalin-5-ylcarbonyl]A mixture of formamidine (2.14g,5.99mmol) and hydrazine hydrate (0.599g,11.98mmol) in glacial acetic acid (80ml) was heated at reflux for 2 h. After cooling, the solid was collected by filtration and washed with diethyl ether. A portion of this solid (1.108g) was taken and then suspended in anhydrous N, N-dimethylformamide (80ml) at room temperature under nitrogen and treated with sodium hydride (80% w/w oil dispersion, 0.122g,4.08 mmol). After stirring for 0.25 h, iodomethane (0.579g,4.08mmol) was added and the mixture was heated at 50 ℃ for 6 h. The mixture was cooled, filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane (80ml) and brine (80 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2X 80 ml). The residue is purified by flash chromatography on silica gel using a gradient of toluene: ethyl acetate (4: 1 → 1: 1, vol.)Elution gave the first eluted product, isomer 1, tentatively designated 6, 7-dichloro-2, 3-dimethoxy-5- (2-methyl-2H-1, 2, 4-triazol-3-yl) quinoxaline (0.18g, 10%) as a white solid, mp208-210 ℃.¹H-NMR(300MHz,CDCl₃) δ =3.73(3H, s),3.89(3H, s),4.18(3H, s),8.10(1H, s),8.13(1H, s) m/z (thermal spraying) 340 (MH)⁺).

The second eluted product (i.e., isomer 2) was obtained as a white solid (0.11g, 6%) and was tentatively designated 6, 7-dichloro-2, 3-dimethoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) quinoxaline at mp184-186 ℃.¹H-NMR(300MHz,CDCl₃) δ =3.90(3H, s),4.09(3H, s),4.16(3H, s),8.02(1H, s),8.28(1H, s) m/z (thermal spraying) 340 (MH)⁺).

Preparation example 26

5-amino-6, 7-dichloro-2, 3-dimethoxyquinoxaline(a) A mixture of 6, 7-dichloro-5-nitro-2, 3(1H,4H) -quinoxalinedione (example 1, 84g,0.34mol of WO-A-94/00124), thionyl chloride (840ml) and dimethylformamide (0.5ml) was heated under reflux for 3 hours, cooled and concentrated under reduced pressure. Ethyl acetate (300ml) was added and evaporated under reduced pressure, then this step was repeated with petroleum ether (bp100-120 ℃). The resulting solid residue was recrystallized from petroleum ether (bp100-120 ℃ C.) to give 2,3,6, 7-tetrachloro-5-nitroquinoxaline (78g, 73%) as a bright yellow solid.¹H-NMR(300MHz,CDCl₃) δ =8.6(1H, s) (b) to a solution of 2,3,6, 7-tetrachloro-5-nitroquinoxaline (96.2g,0.31mol) in ethyl acetate (1.8L) was added tin (ii) chloride dihydrate (346.3g,1.54 mol). The mixture was heated to reflux for 4 hours, cooled, and then carefully poured into an excess of saturated aqueous sodium bicarbonate. The mixture was filtered through CELITE (trade name) and washed thoroughly with ethyl acetate. The filter cake was further digested with ethyl acetate and the solid material was filtered off. The combined ethyl acetate phases were dried over magnesium sulfate and concentrated under reduced pressure to give 5-amino-2, 3,6, 7-tetrachloroquinoxaline (73.4 g)84%) as a yellow solid.¹H-NMR(300MHz,CDCl₃) δ =5.45(2H, br.s),7.47(1H, s) m/z (thermal spraying) 385 (MH)⁺) (in another manufacturing process, this reduction step may be carried out using iron filings in an aqueous acetic acid solution). (c) To a suspension of 5-amino-2, 3,6, 7-tetrachloroquinoxaline (72.4g,0.256mol) in anhydrous methanol (1L) was added a sodium methoxide solution (25% w/w methanol solution, 274ml,1.28mol), and the resulting mixture was heated under reflux for 30 minutes. The mixture was cooled, concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate (total volume 8L). Drying (MgSO)₄) And concentrating the organic extract under reduced pressure. The crude product was triturated with methanol, then dissolved in dichloromethane (2L) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (55.0g, 79%) as a yellow solid.¹H-NMR(300MHz,CDCl₃) δ =4.13(3H, s),4.14(3H, s),5.07(2H, br.s),7.26(1H, s) m/z (thermal spraying) 274 (MH)⁺).

Preparation example 27

6, 7-dichloro-2, 3-dimethoxy-5- [3- (3-chlorophenyl) -5-

methyl-4H-1, 2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases(a) To a suspension of 5-amino-6, 7-dichloro-2, 3-dimethoxyquinoxaline (preparation 26,20.49g,64.8mmol) in toluene (500ml) was added acetyl chloride (5.71ml,6.30g,80.3mmol) with vigorous stirring, and the resulting mixture was heated under reflux for 2 hours. After cooling, the product was collected by filtration, washed with toluene, and dried under suction for 15 hours to give 5-acetylamino-6, 7-dichloro-2, 3-dimethoxyquinoxaline (20.49g, 89%) as a beige solid.¹H-NMR(300MHz,DMSO-d₆) δ =2.11(3H, s),4.04(3H, s),4.05(3H, s),7.91(1H, s),9.80(1H, s) m/z (thermal spraying) 316 (MH)⁺) (b) to a stirred suspension of 2, 4-bis (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetanyl-2, 4-disulfide (Lawesson's reagent) (15.7g,38.9mmol) in toluene (432ml) at room temperature under nitrogen was added 5-acetylamino-6, 7-dichloro-2, 3-dimethoxyquinoxaline (20.49g,64.8 mmol). The mixture was heated to reflux for 25 minutesAnd held at reflux temperature for a further 90 minutes. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with dichloromethane. Yellow foam 6, 7-dichloro-2, 3-dimethoxy-5-thioacetamidoquinoxaline (17.54g, 81%) was obtained.¹H-NMR(300MHz,DMSO-d₆) δ =2.70(3H, s),3.99(3H, s),4.05(3H, s),8.05(1H, s),11.74(1H, s) m/z (thermal spraying) 332 (MH)⁺) (c) A mixture of 6, 7-dichloro-2, 3-dimethoxy-5-thioacetamidoquinoxaline (250mg,0.753mmol), 3-chlorobenzohydrazide (167mg,0.978mmol), mercuric (II) oxide (163mg,0.753mmol),4A molecular sieve powder (175mg) and n-butanol (7ml) was heated under reflux for 18 hours. After cooling, the mixture was filtered through an ARBOCEL (trade name) filter, and the residue was washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the resulting green solid was dissolved in dichloromethane, washed with 2M aqueous hydrochloric acid and brine in this order, and then dried (MgSO 2)₄) And concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (98: 2, vol.) to give the title compound (120mg, 35%) as a pale yellow solid.¹H-NMR(300MHz,CDCl₃) δ =2.21(3H, s),3.84(3H, s),4.14(3H, s),7.13(2H, s),7.25(1H, mask), 7.49(1H, s),8.08(1H, s) m/z (thermal spraying) 450 (MH)⁺).

Preparation examples 28 to 95

Following a similar procedure to preparation 27, 5-amino-6, 7-dichloro-2, 3-dimethoxyquinoxaline and the appropriate acid chloride (R)^ACOCl) and hydrazide (R)^BCONHNH₂) The following representative compounds were prepared.And (4) supplementary notes: 1) prepared using ethyl carbazate as the "hydrazide" starting material. The final crystallization was carried out by heating in xylene 2) the reaction of the hydrazide according to preparation 118, which was an unexpected product.

Preparation example 966, 7-dichloro-2, 3-dimethoxy-5- [3- (3-methyl-1, 2, 4-)

Oxadiazol-5-yl) -5- (3-pyridinyl) -4H-1,2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases

To 6, 7-dichloro-2, 3-dimethoxy-5- [ 3-ethoxycarbonyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl at room temperature under nitrogen with stirring]To a suspension of quinoxaline (preparation 94,250mg,0.53mmol) in dry toluene (15ml) was added acetamide oxime (120mg,1.62mmol) followed by sodium hydride (80% w/w oil dispersion, 8mg,0.27 mmol). The mixture was heated to reflux for 3.5 hours, cooled and the solution was partitioned between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate (2X 20ml) and dried (MgSO)₄) And the combined organic extracts were concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel eluting with a gradient of hexane: ethyl acetate (7: 3 → 1: 1, vol.) to give the title compound (21mg, 82%) as a white solid.¹H-NMR(300MHz,CDCl₃) δ =2.25(3H, s),3.77(3H, s),4.14(3H, s),7.28(1H, m, mask), 7.93(1H, m),8.10(1H, s),8.58(2H, m). m/z (thermal spraying) 485 (MH)⁺).

Preparation example 97

6, 7-dichloro-2, 3-dimethoxy-5- [ 5-methyl-3- (3-)

Methyl-1, 2, 4-oxadiazol-5-yl) -4H-1,2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases

Following a similar procedure to preparation 96, 6, 7-dichloro-2, 3-dimethoxy-5- (3-ethoxycarbonyl-5-methyl-4H-1, 2, 4-triazol-4-yl) quinoxaline (preparation 67) was used in place of 6, 7-dichloro-2, 3-dimethoxy-5- [ 3-ethoxycarbonyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl)]Quinoxaline the title compound is prepared. Purification by flash chromatography on silica gel eluting with a gradient of dichloromethane: methanol (1: 0 → 95: 5, vol.) afforded a white solid.¹H-NMR(300MHz,CDCl₃) δ =2.26(3H, s),2.33(3H, s),3.79(3H, s),4.20(3H, s),8.15(1H, s) m/z (thermal spraying) 422 (MH)⁺).

Preparation example 986, 7-dichloro-2, 3-dimethoxy-5- [3- (3-pyridyl) -4H-

1,2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases

To 6, 7-dichloro-2, 3-dimethoxy-5- [ 3-ethoxycarbonyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl at 10 ℃ with stirring]To a solution of quinoxaline (preparation 94,8.2g,17.25mmol) in 1, 4-dioxane (68ml) and water (50ml) was added dropwise a 1M aqueous sodium hydroxide solution (17.25ml,17.25 mmol). The solution was warmed to room temperature and stirred for 20 hours. Diluting with water (50ml), and diluting with iceAcidified with acetic acid, followed by extraction with ethyl acetate (1X 100ml, 2X 50 ml). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of dichloromethane: methanol (1: 0 → 9: 1, volume ratio) to give the title compound as a white solid (5.82g, 84%), mp206-207 ℃ elemental analysis (%): found C, 50.49; h, 3.06; n,20.44.C₁₇H₁₂Cl₂N₆O₂Calculated values: c, 50.63; h, 3.00; n,20.84.

Preparation example 996, 7-dichloro-2, 3-dimethoxy-5- [ 5-bromo-3- (3-pyridyl) -

4H-1,2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases

To a stirred mixture of 6, 7-dichloro-2, 3-dimethoxy-5- [3- (3-pyridyl) -4H-1,2, 4-triazol-4-yl at room temperature under a nitrogen atmosphere]To a suspension of quinoxaline (preparation 98,102mg,0.25mmol) in 1,1, 1-trichloroethane (6ml) was added N-bromosuccinimide (58mg,0.33mmol), and the mixture was heated under reflux for 18 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with a gradient of hexane: ethyl acetate (7: 3 → 1: 1, vol.) to give the title compound as a white solid (87mg, 71%).¹H-NMR(300MHz,CDCl₃) δ =3.86(3H, s),4.16(3H, s),7.28(1H, m, mask), 7.88(1H, m),8.12(1H, s),8.49(1H, m),8.58(1H, m) m/z (thermal spraying) 481 (MH)⁺).

Preparation example 1006, 7-dichloro-2, 3-dimethoxy-5- [3- (1-imidazolyl) -5-

methyl-4H-1, 2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases(a) Similar to preparation 99, 6, 7-dichloro-2, 3-dimethoxy-5- (3-methyl-4H-1, 2, 4-triazol-4-Yl) quinoxaline (preparation 78,50mg,0.147mmol) instead of 6, 7-dichloro-2, 3-dimethoxy-5- [3- (3-pyridyl) -4H-1,2, 4-triazol-4-yl]Quinoxaline preparation of 6, 7-dichloro-2, 3-dimethoxy-5- (3-bromo-5-methyl-4H-1, 2, 4-triazol-4-yl) quinoxaline, the product obtained as a light brown solid (53mg, 86%).¹H-NMR(300MHz,DMSO-d₆) δ =2.27(3H, s),3.91(3H, s),4.19(3H, s),8.16(1H, s) m/z (thermal spraying) 419 (MH)⁺) (b) A mixture of imidazole (78mg,1.15mmol) and 6, 7-dichloro-2, 3-dimethoxy-5- (3-bromo-5-methyl-4H-1, 2, 4-triazol-4-yl) quinoxaline (48mg,0.115mmol) was heated at 100 ℃ for 1 hour and then at 120 ℃ for 3 hours. After cooling, the mixture was partitioned between water (15ml) and dichloromethane (2X 15 ml). Drying (MgSO)₄) The combined organic extracts were filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of dichloromethane: methanol (98: 2 → 95: 5, vol.) to give the title compound as a brown solid (15mg, 32%).¹H-NMR(300MHz,DMSO-d₆) δ =2.27(3H, s),4.11(6H, s),7.16(2H, brs),7.79(1H, brs),7.95(1H, s) m/z (thermal spraying) 406 (MH)⁺).

Preparation example 1016, 7-dichloro-2, 3-dimethoxy-5- [ 3-hydroxymethyl-5- (3-pyridyl)

-4H-1,2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases

In a sealed container, adding 6, 7-dichloro-2, 3-dimethoxy-5- [3- (3-pyridyl) -4H-1,2, 4-triazol-4-yl]A suspension of quinoxaline (preparation 98, 1.008g,2.5mmol) and paraformaldehyde (0.75g,25mmol) in acetic acid (14ml) was heated at 125 ℃ for 3 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with a gradient of dichloromethane: methanol (1: 0 → 95: 5, volume ratio) to give the title compound as a white solid (0.60g, 56%), mp209-210 ℃ elemental analysis (%): measured value: c, 49.86; h, 3.31; n,19.18.C₁₈H₁₄Cl₂N₆O₃Calculated values: c, 49.90; h, 3.26; n,19.39.

Preparation example 1026, 7-dichloro-2, 3-dimethoxy-5- [ 3-hydroxymethyl-5-methyl-

-4H-1,2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases

Analogously to preparation 101, 6, 7-dichloro-2, 3-dimethoxy-5- (3-methyl-4H-1, 2, 4-triazol-4-yl) quinoxaline (preparation 78) was used in place of 6, 7-dichloro-2, 3-dimethoxy-5- [3- (3-pyridyl) -4H-1,2, 4-triazol-4-yl)]Quinoxaline to yield the title compound as a white solid.¹H-NMR(300MHz,DMSO-d₆) δ =2.20(3H, s),3.89(3H, s),4.18(3H, s),4.54(2H, s),8.11(1H, s) m/z (thermal spraying) 370 (MH)⁺).

Preparation example 1036, 7-dichloro-2, 3-dimethoxy-5- [ 3-dimethylaminomethyl-5- (3-)

Pyridyl) -4H-1,2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases

Mixing 6, 7-dichloro-2, 3-dimethoxy-5- [3- (3-pyridyl) -4H-1,2, 4-triazol-4-yl]A mixture of quinoxaline (preparation 98, 101mg,0.25mmol), paraformaldehyde (15mg,0.5mmol) and dimethylamine hydrochloride (22mg,0.27mmol) in acetic acid (5ml) was heated under reflux for 5 hours. After cooling, the mixture was concentrated under reduced pressure, water (20ml) was added, the solution was basified with aqueous potassium carbonate solution and extracted with ethyl acetate (3X 20 ml). Drying (MgSO)₄) And the combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of dichloromethane: methanol (1: 0 → 95: 5, vol.) to give the title compound as a white solid (75mg, 65%), mp192-194 ℃.¹H-NMR(300MHz,CDCl₃) δ =2.0(6H, s),3.48(2H, m),3.82(3H, s),4.15(3H, s),7.2(1H, m),7.85(1H, m),8.05(1H, s),8.5(2H, m) m/z (thermal spraying) 460 (MH)⁺).

Preparation 1046, 7-dichloro-2, 3-dimethoxy-5- [ 3-morpholinomethyl-5- (3-pyridone)

Pyridyl) -4H-1,2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases

The title compound was prepared in a similar manner to preparation 103 using morpholine hydrochloride instead of dimethylamine hydrochloride. The product was obtained as a white solid, mp178-179 ℃.¹H-NMR(300MHz,CDCl₃) δ =2.10(4H, s),3.10(4H, m),3.56(2H, m),3.80(3H, s),4.18(3H, s),7.21(1H, m),7.80(1H, m),8.05(1H, s),8.55(2H, m) m/z (thermal spraying) 502 (MH)⁺).

Preparation example 1056, 7-dichloro-2, 3-dimethoxy-5- (3-hydroxymethyl-5-phenyl-

4H-1,2, 4-triazol-4-yl) quinoxalines

Diisobutylaluminum hydride (1M in tetrahydrofuran, 2.5ml,2.5mmol) was added to a solution of 6, 7-dichloro-2, 3-dimethoxy-5- (3-ethoxycarbonyl-5-phenyl-4H-1, 2, 4-triazol-4-yl) quinoxaline (preparation 93,237mg,0.5mmol) in dichloromethane (10ml) at room temperature under a nitrogen atmosphere. After 1 hour, a further portion of diisobutylaluminum hydride (1M in tetrahydrofuran, 1ml,1mmol) was added. The mixture was further stirred for 1 hour, and then saturated aqueous ammonium chloride solution (10ml) was added. Dichloromethane (50ml) and water (50ml) were added and filtered through ARBOCEL (trade name) and the residue was washed with hot dichloromethane: methanol (9: 1, volume ratio, 100 ml). The organic layer was separated and dried (MgSO)₄) And evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of hexane: ethyl acetate: methanol (1: 0 → 0: 95: 5, vol.) to give the title compound as an off-white solid (70mg, 79%).¹H-NMR(300MHz,CDCl₃) δ =2.78(1H, s),3.85(3H, s),4.14(3H, s),4.6(2H, m),7.25(2H, m),7.32(2H, m),7.38(1H, m),8.08(1H, s) m/z (thermal spraying) 432 (MH)⁺).

Preparation example 106

6, 7-dichloro-2, 3-dimethoxy-5- (3-hydroxymethyl-4H-

1,2, 4-triazol-4-yl) quinoxalines

The title compound was obtained as an off-white solid in a similar manner to preparation 105 using 6, 7-dichloro-2, 3-dimethoxy-5- (3-ethoxycarbonyl-4H-1, 2, 4-triazol-4-yl) quinoxaline (preparation 92) in place of 6, 7-dichloro-2, 3-dimethoxy-5- (3-ethoxycarbonyl-5-phenyl-4H-1, 2, 4-triazol-4-yl) quinoxaline.¹H-NMR(300MHz,CDCl₃) δ =3.89(3H, s),4.14(3H, s),4.64(2H, m),8.08(1H, s),8.16(1H, s) m/z (thermal spraying) 356 (MH)⁺).

Preparation example 1076, 7-dichloro-2, 3-dimethoxy-5- [3- (2-hydroxyethyl) -

5-methyl-4H-1, 2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases

Analogously to preparation 105, 6, 7-dichloro-2, 3-dimethoxy-5- [ 3-ethoxycarbonylmethyl-5-methyl-4H-1, 2, 4-triazol-4-yl]Quinoxaline (preparation 68) in place of 6, 7-dichloro-2, 3-dimethoxy-5- (3-ethoxycarbonyl-5-phenyl-4H-1, 2, 4-triazol-4-yl) quinoxaline the title compound is prepared. The reaction was carried out in toluene instead of dichloromethane and purified by flash chromatography on silica gel, eluting with a gradient of dichloromethane: methanol (1: 0 → 95: 5, volume ratio). Crystallization from diisopropyl ether gave an off-white solid.¹H-NMR(300MHz,CDCl₃) δ =2.1(3H, s),2.5(2H, m),3.5(2H, m),3.9(3H, s),4.18(3H, s),8.1(1H, s) m/z (thermal spraying) 384 (MH)⁺).

Preparation example 108

6, 7-dichloro-2, 3-dimethoxy-5-iodoquineWoquinoline

To a mechanically stirred solution of 5-amino-6, 7-dichloro-2, 3-dimethoxyquinoxaline (preparation 26,38.12g,0.14mol) in acetone at 0 ℃ was added a 2M aqueous hydrochloric acid solution (396ml,0.79mol) followed by dropwise addition of a 1M aqueous sodium nitrite solution (208ml,0.28 mol). After 0.25 h at 0 ℃ 5M aqueous potassium iodide (278ml,1.39mol) was added maintaining the reaction temperature below 5 ℃. The mixture was then warmed to 10 ℃ over 0.5 h, acetone was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic extract was washed with 10% aqueous sodium bisulfite and then with saturated aqueous sodium bicarbonate, and dried (MgSO)₄) And concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with toluene to give the title compound (16.9g, 32%).¹H-NMR(300MHz,CDCl₃):δ=4.17(3H,s),4.24(3H,s),7.91(1H,s)

Preparation example 1096, 7-dichloro-2, 3-dimethoxy-5- (3-pyridyl) quinoxaline

A mixture of 6, 7-dichloro-2, 3-dimethoxy-5-iodoquinoxaline (preparation 108,0.2g,0.519mmol), 3-pyridineboronic acid (Rec. Trav. Chim. Pays-Bas.,84,439(1965)) (0.077g,0.623mmol), tetrakis (triphenylphosphine) palladium (0) (0.03g,0.026mmol) and potassium carbonate (0.143g,1.038mol) in 1, 4-dioxane (12ml) and water (4ml) was heated to reflux for 16 hours. After cooling, the mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (20ml) and water (20 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2X 40 ml). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of dichloromethane: methanol (1: 0 → 99: 1, vol.) to give the title compound as a yellow solid (0.051g, 29%).¹H-NMR(300MHz,CDCl₃) δ =3.84(3H, s),4.18(3H, s),7.42(1H, m),7.75(1H, m),7.99(1H, s),8.63(2H, m) m/z (thermal spraying) 336 (MH)⁺).

Preparation example 110

6, 7-dichloro-2, 3-dimethoxy-5- [ 5-phenyl-1H-

1,2, 3-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases(a) A mixture of 6, 7-dichloro-2, 3-dimethoxy-5-iodoquinoxaline (preparation 108,5.0g,13mmol), phenylacetylene (3.98g,39mmol), bis (triphenylphosphine) palladium (II) chloride (0.913g,1.3mmol) and copper (I) iodide (0.248g,1.3mmol) in triethylamine (100ml) was heated under reflux for 4 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (200ml) and brine (200 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2X 100 ml). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of hexane: dichloromethane (1: 0 → 1: 1, vol.) to give 6, 7-dichloro-2, 3-dimethoxy-5- (2-phenylethynyl) quinoxaline (3.60g, 77%) as a yellow solid, mp170-172 ℃.¹H-NMR(300MHz,CDCl₃) δ =4.14(3H, s),4.26(3H, s),7.39(3H, m),7.67(2H, m),7.87(1H, s) m/z (thermal spraying) 359 (MH)⁺) (b) A mixture of 6, 7-dichloro-2, 3-dimethoxy-5- (2-phenylethynyl) quinoxaline (2.0g,5.57mmol) and azidotrimethylsilane (20ml) was heated at 170 ℃ for 18 hours in a sealed vessel. After cooling, 20ml of water were added, followed by 50ml of saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate (3X 50 ml). Drying (MgSO)₄) And the combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of dichloromethane: methanol (1: 0 → 98: 2, vol.) to give the title compound (1.3g, 58%) as a brown foam.¹H-NMR(300MHz,CDCl₃) δ =3.67(3H, s),4.13(3H, s),7.23(3H, m),7.40(2H, m),8.02(1H, s) m/z (thermal spraying) 402 (MH)⁺).

Preparation 1116, 7-dichloro-2, 3-dimethoxy-5- [ 2-methyl-5-phenyl-2H-1, 2, 3-triazol-4-yl]Quinoxaline (isomer 1)6, 7-dichloro-2, 3-dimethoxy-5- [ 1-methyl-5-phenyl-1H-1, 2, 3-triazol-4-yl]Quinoxaline (isomer 2) and 6, 7-dichloro-2, 3-dimethoxy-5- [ 1-methyl-4-phenyl-1H-1, 2, 3-triazol-5-yl]Quinoxaline (isomer 3)

At 0 deg.C under nitrogen and with stirring, in 6, 7-dichloro-2, 3-dimethoxy-5- [ 5-phenyl-1H-1, 2, 3-triazol-4-yl]To a solution of quinoxaline (preparation 110,0.5g,1.24mmol) in anhydrous N, N-dimethylformamide (20ml) was added sodium hydride (80% w/w oil dispersion, 0.041g,1.37 mmol). After 0.5 hour reaction at 0 deg.C, methyl iodide (0.194g,1.37mmol) was added. The mixture was stirred at 0 ℃ for 0.5 hour and then at room temperature for 0.5 hour. 50ml of brine were added and the mixture was extracted with dichloromethane (3X 50 ml). Drying (MgSO)₄) And the combined organic extracts were concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel using toluene/ethyl acetate (1: 0 → 9: 1, vol.) to give the first eluting product, isomer 1, tentatively designated 6, 7-dichloro-2, 3-dimethoxy-5- [ 2-methyl-5-phenyl-2H-1, 2, 3-triazol-4-yl]Quinoxaline (0.19g, 37%) as a pale yellow solid, mp233-235 ℃.¹H-NMR(300MHz,CDCl₃) δ =3.67(3H, s),4.14(3H, s),4.38(3H, s),7.23(3H, m),7.38(2H, m),8.05(1H, s) m/z (thermal spraying) 416 (MH)⁺).

The second eluted product (i.e., isomer 2) was obtained as a pale yellow solid (0.135g, 26%) and was tentatively designated 6, 7-dichloro-2, 3-dimethoxy-5- [ 1-methyl-5-phenyl-1H-1, 2, 3-triazol-4-yl]Quinoxaline, mp 189-.¹H-NMR (300MHz,CDCl₃) δ =3.75(3H, s),3.84(3H, s),4.17(3H, s),7.26(3H, m),7.48(2H, m),8.13(1H, s) m/z (thermal spraying) 416 (MH)⁺).

The third eluted product (i.e., isomer 3) was obtained as an orange oil (0.046g, 9%) which was tentatively designated 6, 7-dichloro-2, 3-dimethoxy-5- [ 1-methyl-4-phenyl-1H-1, 2, 3-triazol-5-yl]Quinoxaline.¹H-NMR(300MHz,CDCl₃) δ =3.84(3H, s),4.11(3H, s),4.16(3H, s),7.20(3H, m),7.33(2H, m),7.96(1H, s) m/z (thermal spraying) 416 (MH)⁺).

Preparation examples 1126, 7-dichloro-2, 3-dimethoxy-5- [ 5-phenyl-2- (2- (triphenylmethoxy) ethyl) -2H-1,2, 3-triazol-4-yl ] quinoxaline (isomer 1),6, 7-dichloro-2, 3-dimethoxy-5- [ 5-phenyl-1- (2- (triphenylmethoxy) ethyl) -1H-1,2, 3-triazol-4-yl ] quinoxaline (isomer 2) and 6, 7-dichloro-2, 3-dimethoxy-5- [ 4-phenyl-1- (2- (triphenylmethoxy) ethyl) -1H-1,

2, 3-triazol-5-yl]Quinoxaline (isomer 3)

The title compound is prepared analogously to preparation 111 by using 2- (triphenylmethoxy) ethyl bromide (Liebigs Ann.,635,3(1960)) instead of iodomethane, and purifying by flash chromatography on silica gel eluting with a gradient of toluene to diethyl ether (1: 0 → 9: 1, vol.) to give the first eluting product as a white solid, isomer 1(0.336g, 45%), which is tentatively designated 6, 7-dichloro-2, 3-dimethoxy-5- [ 5-phenyl-2- (2- (triphenylmethoxy) ethyl) -2H-1,2, 3-triazol-4-yl]Quinoxaline.¹H-NMR(300MHz,CDCl₃) δ =3.32(3H, s),3.73(2H, m),4.11(3H, s),4.73(2H, m),7.22(12H, m),7.40(6H, m),7.47(2H, m),8.02(1H, s). m/z (thermal spraying) 688 (MH)⁺).

The second eluted product (i.e., isomer 2) was obtained as a white solid (0.104g, 14%) which was tentatively designated 6, 7-dichloro-2, 3-dimethoxy-5- [ 5-phenyl-1- (2- (triphenylmethoxy) ethyl) -1H-1,2, 3-triazol-4-yl]Quinoxaline.¹H-NMR(300MHz,CDCl₃) δ =3.40(2H, m),3.44(3H, s),4.17(3H, s),4.25(2H, m),7.22(18H, m),7.39(2H, m),8.02(1H, s) m/z (thermal spraying) 688(MH, m)⁺).

The third eluted product (i.e., isomer 3) was obtained as an off-white solid (0.037g, 5%) which was tentatively designated 6, 7-dichloro-2, 3-dimethoxy-5- [ 4-phenyl-1- (2- (triphenylmethoxy) ethyl) -1H-1,2, 3-triazol-4-yl]Quinoxaline.¹H-NMR(300MHz,CDCl₃):δ=3.47(3H,s),3.73(2H,m),4.10(3H, s),4.58(2H, m),7.24(20H, m),7.94(1H, s) m/z (thermal spray) 688 (MH)⁺).

Preparation 1135-amino-6-chloro-2, 3-dimethoxy-7-methylquinoxaline and 5-amino-7-methylquinoxaline

-chloro-2, 3-dimethoxy-6-methylquinoxaline(a) A mixture of 1, 2-diamino-4-chloro-5-methylbenzene hydrochloride (1.90g,9.84mmol), oxalic acid (1.24g,13.8mmol) and 4M aqueous hydrochloric acid (49ml) was heated under reflux for 4.5 hours. After cooling, the solid precipitate was collected by filtration, washed thoroughly with water and then dried under reduced pressure at 80 ℃ to give 6-chloro-7-methyl-2, 3(1H,4H) -quinoxalinedione (1.68g, 81%) as a dark gray solid, mp > 330 ℃. Measured value: c, 51.58; h.2.98; n,13.27.C₉H₇ClN₂O₂Calculated C, 51.32; h, 3.35; n,13.30.(b) 6-chloro-7-methyl-2, 3(1H,4H) -quinoxalinedione (1.26g,5.98mmol) was added portionwise to strongly stirred concentrated nitric acid (10ml, d =1.42) over 3 minutes at room temperature. The resulting heterogeneous mixture was then warmed to 40 ℃ and stirred for 12 hours. After cooling, the yellow mixture was poured into ice water (100ml) and stirred for 30 minutes. The resulting yellow precipitate was collected by filtration, washed with water and dried under suction to give a mixture of 6-chloro-7-methyl-5-nitro-2, 3(1H,4H) -quinoxalinedione and 7-chloro-6-methyl-5-nitro-2, 3(1H,4H) -quinoxalinedione (molar ratio 1: 2,1.35g, 88%) as a yellow solid.¹H-NMR(300MHz,CDCl₃) δ =2.23(2H, s),2.35(1H, s),7.19(0.3H, s),7.30(0.7H, s),11.9-12.25(2H, brm) (c) the above mixture of 6-chloro-7-methyl-5-nitro-2, 3(1H,4H) -quinoxalinedione and 7-chloro-6-methyl-5-nitro-2, 3(1H,4H) -quinoxalinedione (1.35g,5.73mmol), thionyl chloride (12.5ml,20.4g,0.172mol) and dimethylformamide (44 μ l,42mg,0.573mmol) were heated together under reflux for 4 hours. After cooling, the mixture was carefully added to vigorously stirred ice water (300 ml). Filtering and collecting the obtained precipitate, washing with water, and suction-drying to obtain a mixture of 2,3, 7-trichloro-6-methyl-5-nitroquinoxaline and 2,3, 6-trichloro-7-methyl-5-nitroquinoxaline (2: 1)1 molar ratio, 1.45g, 87%) as a grass yellow powder. For characterization purposes, this mixture was very difficult to separate by flash chromatography on silica gel, eluting with a hexane: dichloromethane (9: 1 → 3: 1, volume ratio) gradient to give the first eluting isomer, 2,3, 7-trichloro-6-methyl-5-nitroquinoxaline, as a white solid, mp164-165 ℃ elemental analysis (%): measured value: c, 36.76; h, 1.37; n,14.43.C₉H₄Cl₃N₃O₂Calculated values: c, 36.96; h, 1.38; n,14.37.

The second eluting isomer, 2,3, 6-trichloro-7-methyl-5-nitroquinoxaline, was obtained as a grass yellow solid, mp121-122 ℃ elemental analysis (%): c, 39.78; h, 2.02; n,13.23.C₉H₄Cl₃N₃O₂0.22 Hexane: calculated values: c, 39.80; h, 2.29; n,13.49.(d) A mixture of the above-mentioned 2,3, 7-trichloro-6-methyl-5-nitroquinoxaline and 2,3, 6-trichloro-7-methyl-5-nitroquinoxaline (250mg,0.855mmol) and tin chloride dihydrate (1.35g,5.98mmol) were heated under reflux in ethyl acetate (8.5ml) for 3 hours under a nitrogen atmosphere. After cooling, the mixture was diluted with ethyl acetate (50ml) and washed with 10% aqueous sodium carbonate (2X 25ml), brine (25ml) and dried (MgSO)₄) Filtration and concentration under reduced pressure gave a mixture of 5-amino-2, 3, 7-trichloro-6-methylquinoxaline and 5-amino-2, 3, 6-trichloro-7-methylquinoxaline (2: 1 molar ratio, 217mg, 97%) as an orange solid.¹H-NMR(300MHz,CDCl₃) δ =2.41(2H, s),2.55(1H, s),5.03(1.3H, brs),5.08(0.7H, brs),7.23(0.3H, s),7.44(0.7H, s) m/z (thermal spraying) 262 (MH)⁺) (e) 25% w/w sodium methoxide/methanol solution (433. mu.l), 1.89mmol, was added dropwise to a solution of the above mixture (200mg,0.788mol) of 5-amino-2, 3, 7-trichloro-6-methylquinoxaline and 5-amino-2, 3, 6-trichloro-7-methylquinoxaline in anhydrous tetrahydrofuran (7.9ml) at 0 ℃ under a nitrogen atmosphere. The mixture was stirred for 3h, then diluted with ethyl acetate (30ml), washed successively with water (2X 10ml) and brine (10ml), dried (MgSO)₄) Filtered and concentrated under reduced pressure. The solid residue was purified by flash chromatography on silica gel using a gradient elution with hexane/ethyl acetate (95: 5 → 1: 1, vol.) to give the first eluting isomer-5-amino-6-chloro-2, 3-dimethoxy-7-methylquinoxaline (48mg, 25%) as an off-white solid, mp169-170 ℃. elemental analysis (%): measured value: c, 53.80; h, 5.16; n,16.18.C₁₁H₁₂ClN₃O₂0.15 Hexane calcd: c, 53.61; h, 5.33; n,15.75.

The second eluting isomer obtained, 5-amino-7-chloro-2, 3-dimethoxy-6-methylquinoxaline (85mg, 44%) was an orange solid, mp181-182 ℃. Measured value: c, 52.55; h, 4.72; n,16.61.C₁₁H₁₂ClN₃O₂0.05 Hexane calcd: c, 52.61; h, 4.96; n,16.29.

Preparation example 114

6-chloro-2, 3-dimethoxy-7-methyl-5- [ 5-methoxymethyl-

3- (3-pyrazoyl) -4H-1,2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases(a) Methoxyacetyl chloride (2.16ml,2.57g,23.66mmol) was added to a solution of 5-amino-6-chloro-2, 3-dimethoxy-7-methylquinoxaline (preparation 113,5g,19.72mmol) and pyridine (1.91ml,1.89g,23.66mmol) in dichloromethane (80ml) at 0 ℃. After further reaction at this temperature for 1 hour, the mixture was washed with 2M aqueous hydrochloric acid and brine, and dried (MgSO)₄) And concentrated under reduced pressure. The residue was triturated with diisopropyl ether and filtered to give 6-chloro-2, 3-dimethoxy-5-methoxyacetylamino-7-methylquinoxaline (6.06g, 98%) as an off-white solid, mp170-171 ℃.¹H-NMR(300MHz,CDCl₃) δ =2.55(3H, s),3.6(3H, s),4.1(3H, s),4.13(3H, s),4.18(2H, s),7.61(1H, s),8.47(1H, brs) m/z (thermal spraying) 326 (MH)⁺) (b) to a solution of 6-chloro-2, 3-dimethoxy-5-methoxyacetylamino-7-methylquinoxaline (6g,18.43mmol) in tetrahydrofuran (120ml) was added 2, 4-bis (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetanyl-2, 4-disulfide (Lawesson's reagent) (4.47g,11.06mmol) and the mixture was stirred for 18h and then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using hexane: dichloromethane (1: 1 → 1: 4 → 0: 1, in bulkVolume ratio) to give 6-chloro-2, 3-dimethoxy-5-methoxythioacetamido-7-methylquinoxaline (5.48g, 87%) as a yellow foam, mp174-176 ℃.¹H-NMR(300MHz,CDCl₃) δ =2.55(3H, s),3.65(3H, s),4.05(3H, s),4.15(3H, s),4.55(2H, s),7.7(1H, s),9.65(1H, brs) m/z (thermal spraying) 342 (MH)⁺) (c) A mixture of 6-chloro-2, 3-dimethoxy-5-methoxythioacetamido-7-methylquinoxaline (1.45g,4.25mmol), nicotinhydrazide (1.16g,8.5mmol), mercury (II) oxide (1.84g,8.5mmol), 4A molecular sieve powder (1.06g) and n-butanol (60ml) was heated under reflux for 8 hours. After cooling, the mixture was filtered through an ARBOCEL (trade name) filter aid and the residue was washed with dichloromethane. The filtrate was concentrated under reduced pressure to give a bright brown solid which was then portioned into ethyl acetate and 2M aqueous hydrochloric acid. The aqueous layer was extracted with dichloromethane (4X 50ml) and dried (MgSO)₄) And the combined dichloromethane extracts were concentrated under reduced pressure. The residue was crystallized from diisopropyl ether/methanol to give a solid (394 mg). The mother liquor was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel using ethyl acetate as eluent to give a further quantity of solid (364mg) after trituration with diisopropyl ether. The two solid batches were combined to give the title compound (740mg, 41%) as a pale yellow solid, mp183-184 ℃.¹H-NMR(300MHz,CDCl₃) δ =2.5(3H, s),3.18(3H, s),3.8(3H, s),4.16(3H, s),4.45(2H, m),7.58(1H, m),7.86(1H, s),8.35(1H, m),8.45(1H, m),8.65(1H, m). m/z (thermal spraying) 427 (MH)⁺).

Preparation example 115

7-chloro-2, 3-dimethoxy-6-methyl-5- [ 5-methoxymethyl-3-

(3-pyridyl) -4H-1,2, 4-triazol-4-yl]Quinoxalines as inhibitors of tyrosine kinases

The title compound was prepared in a similar manner to preparation 114 using 5-amino-7-chloro-2, 3-dimethoxy-6-methylquinoxaline (preparation 113) in place of 5-amino-6-chloro-2, 3-dimethoxy-7-methylquinoxaline. Off-white solid is obtained，mp166-168℃.¹H-NMR(300MHz,CDCl₃) δ =2.25(3H, s),3.2(3H, s),3.78(3H, s),4.15(3H, s),4.35(2H, m),7.2(1H, m),7.82(1H, m),8.0(1H, s),8.45(1H, m),8.55(1H, m) m/z (thermal spraying) 427 (MH)⁺).

Preparation example 116

2-methoxycarbonylpyridine-5-carboxylic acid hydrazide

A mixture of 2-methoxycarbonylpyridine-5-carboxylic acid (chem. Abstr.68,68840h (1968)) (0.40g,2.2mmol) and N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (0.60g,2.4mmol) in dichloromethane (10ml) was stirred at room temperature under nitrogen for 0.75 h. Hydrazine hydrate (0.110ml,2.2mmol) was then added and after 5 minutes the precipitate formed was collected by filtration, washed with dichloromethane and dried to give the title compound as a white solid (0.349g, 81%), mp177-180 ℃.¹H-NMR(300MHz,DMSO-d₆) δ =4.90(3H, s),5.00(2H, br s),8.10(1H, d, J =10Hz),8.27(1H, dd, J =2 and 10Hz),9.05(1H, d, J =2Hz),10.05(1H, br) m/z (thermal spraying) 196 (MH)⁺).

Preparation example 117

Pyrimidine-2-carboxylic acid hydrazides

A mixture of pyrimidine-2-carboxylic acid ethyl ester (Ann. Chim.,5,351(1960)) (0.866g,5.7mmol) and hydrazine hydrate (0.332ml,6.8mmol) in ethanol (20ml) was heated under reflux for 3 hours and then concentrated under reduced pressure. The residue was triturated with ether, collected by filtration and washed with ethyl acetate to give the title compound as a yellow solid (0.542g, 69%), mp173-175 ℃.¹H-NMR(300MHz,DMSO-d₆) δ =4.20(2H, br s),7.50(1H, t, J =4Hz),8.83(2H, d, J =4Hz),9.93(1H, br). m/z (thermal spraying) 139 (MH)⁺).

Preparation example 118-

Analogously to preparation 117, hydrazine hydrate and the appropriate ethyl ester (R) are used^BCO₂C₂H₅) The following representative compounds were prepared.

Preparation 1332-phenylpyridine-5-carboxylic acid ethyl ester2-Bromopyridine-5-carboxylic acid ethyl ester

A mixture of 2-bromopyridine-5-carboxylic acid (J.org.chem.,12,456(1947)) (2.32g,11.49mmol) and N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (3.12g,12.64mmol) in dichloromethane (30ml) was stirred at room temperature under a nitrogen atmosphere for 1 hour. Anhydrous ethanol (5ml) was added, and the mixture was stirred for 30 minutes, followed by concentration under reduced pressure. The residue was partitioned between dichloromethane (40ml) and 10% w/w aqueous potassium carbonate (40 ml). The aqueous layer was extracted with dichloromethane (25ml) and dried (MgSO)₄) And the combined organic layers were concentrated under reduced pressure. Flash chromatography on silica eluting with dichloromethane afforded ethyl 2-bromopyridine-5-carboxylate (2.18g, 83%) as a colorless oil. Elemental analysis (%): measured value: c, 41.57; h, 3.45; n,5.98.C₈H₈NO₂Calculated Br: c, 41.77; h, 3.50; n,6.09. (ii) 2-phenylpyridine-5-carboxylic acid ethyl ester

A mixture of ethyl 2-bromopyridine-5-carboxylate (see section (i)) (1.855g,8.065mmol), phenyltrimethyltin (3.89g,16.13mmol), bis (triphenylphosphine) palladium (II) chloride (371mg) and lithium chloride (1.03g,24.95mmol) in dry dimethylformamide (40ml) was heated at 100 ℃ for 1.5 hours under a nitrogen atmosphere.After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with hexane: ethyl acetate (10: 1, vol.) to give the title compound as a white solid (0.843g, 46%).¹H-NMR(300MHz,CDCl₃) δ =1.43(3H, t, J =8Hz),4.42(2H, q, J =8Hz),7.49(3H, m),7.80(1H, m),8.07(2H, m),8.36(1H, m),9.29(1H, m). m/z (thermal spraying) 228 (MH)⁺).

Preparation example 134

1-Phenylimidazole-4-carboxylic acid ethyl ester1- (4-Nitrophenyl) imidazole-4-carboxylic acid ethyl ester

A mixture of ethyl 1H-imidazole-4-carboxylate (J.het.chem.,19,253(1982)) (584mg,4.17mmol), 4-fluoronitrobenzene (588mg,4.17mmol) and anhydrous sodium carbonate (487mg,4.59mmol) in anhydrous dimethylformamide (100ml) was heated at 50 ℃ for 24 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was poured into ice-cold water (60ml), the resulting solid collected by filtration, washed with water and dried at 60 ℃ under reduced pressure to give ethyl 1- (4-nitrophenyl) imidazole-4-carboxylate (980mg, 90%) as an off-white solid, mp198-200 ℃. Elemental analysis (%): measured value: c, 55.06; h, 4.21; n,15.99.C₁₂H₁₁N₃O₄Calculated values: c, 55.17; h, 4.24; n,16.08. (ii) 1- (4-aminophenyl) imidazole-4-carboxylic acid ethyl ester

A mixture of ethyl 1- (4-nitrophenyl) imidazole-4-carboxylate (see section (i)) (950mg,3.64mmol) and tin (II) chloride (4.11g,18.2mmol) in absolute ethanol (30ml) was heated at reflux for 30 minutes under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure and then partitioned between ethyl acetate (30ml) and a saturated sodium bicarbonate solution (20 ml). The aqueous layer was extracted with ethyl acetate (30ml), and dried (MgSO)₄) And the combined organic layers were concentrated under reduced pressure to give ethyl 1- (4-aminophenyl) imidazole-4-carboxylate (810mg, 96%) as a yellow oil.¹H-NMR(300MHz,CDCl₃):δ=1.40(3H,t,J=7Hz),2.86(2H,brs),4.39(2H,q,J=7Hz),6.76(2H,d,J=9Hz),7.18(2H, d, J =9Hz),7.72(1H, s),7.83(1H, s) m/z (thermal spraying) 232 (MH)⁺) (iii) 1-phenylimidazole-4-carboxylic acid ethyl ester

A solution of tert-butyl nitrite (535mg,5.19mmol) in anhydrous dimethylformamide (15ml) was heated to 65 ℃ under nitrogen and a solution of ethyl 1- (4-aminophenyl) imidazole-4-carboxylate (see section (ii)) (800mg,3.463mmol) in anhydrous dimethylformamide (5ml) was added dropwise over a period of 10 minutes. The mixture was further heated at 65 ℃ for 20 minutes and then cooled to room temperature. The mixture was poured into saturated brine (50ml) and extracted with dichloromethane (3X 20 ml). Drying (MgSO)₄) And the combined organic layers were concentrated under reduced pressure. After purification by flash chromatography on silica gel (using dichloromethane as eluent), the title compound was obtained (520mg, 70%) as an off-white solid.¹H-NMR(400MHz,CDCl₃) δ =1.43(3H, t, J =7Hz),4.42(2H, q, J =7Hz),7.45(3H, m),7.54(2H, m),7.88(1H, s),7.98(1H, s) m/z (thermal spraying) 217 (MH)⁺).

Preparation example 135-149

In a similar manner to that described in preparation 27, 5-amino-6, 7-dichloro-2, 3-dimethoxyquinoxaline and the appropriate acid chloride (R)^ACOCl) and hydrazide (R)^BCONHNH₂) The following representative compounds were prepared.

Preparation example 1505-amino-6, 7-dichloro-2, 3-dimethoxyquinoxaline(a) To a suspension of 2,3,6, 7-tetrachloroquinoxaline (175g,0.653mol) in methanol (1.4L) at reflux temperature was added 25% w/w sodium methoxide methanol solution (700ml,5.15mol) and the mixture was kept at this temperature for 4 hours. The mixture was cooled and 2.1L of water was added. The slurry was filtered and the solid washed with water (0.35L) and isopropanol (0.175L) to give 6, 7-dichloro-2, 3-dimethoxyquinoxaline (159g, 94%) as a beige solid, m.p.146-148 ℃.¹H-NMR(300MHz,CDCl₃) δ =4.13(6H, s),7.83(2H, s) (b) fuming nitric acid (0.113L) was precooled to-5 ℃, to which 6, 7-dichloro-2, 3-dimethoxyquinoxaline (25g,0.096mol) was added in portions. The solution was warmed to 10 ℃ and stirred for 2 hours. The solution was then poured into an ice/water mixture (0.5L). The slurry was filtered and the resulting solid washed with water and isopropanol (0.05L) to give 6, 7-dichloro-2, 3-dimethoxy-5-nitroquinoxaline (27g, 92%) as an off-white solid at m.p.184-186 ℃.¹H-NMR(300MHz,CDCl₃) δ =4.12(3H, s),4.17(3H, s),7.98(1H, s) (c) 6, 7-dichloro-2, 3-dimethoxy-5-nitroquinoxaline (20g,0.066mol) and 5% w/w palladium-on-charcoal (50% humidity) (1.2g) were suspended in a mixture of tetrahydrofuran (0.12L) and ethyl acetate (0.12L). The mixture was hydrogenated at 60 ℃ and 414 kPa (60psi) for 22 hours, cooled, diluted with dichloromethane (0.48L) and the catalyst filtered off through celite (trade name) filter aid. The solution was concentrated under reduced pressure while gradually adding toluene. The mixture was then filtered and the solid washed with toluene (20ml) to give the title compound as a brown solid (14.2g, 78%), m.p.182-4 ℃.¹H-NMR(300MHz,CDCl₃):δ=4.13(3H,s),4.14(3H,s),5.07(2H,brs),7.26(1H,s).

Pharmacological data

The term "used in page 20 of the present specification³H]The method of L-689,560, determining the binding affinity of selected example compounds to the glycine site of the NMDA receptor. The results obtained are shown in the table below.

Examples	IC50(nM)
		5	3
20	19
		73	4

Claims (28)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:wherein;

r represents a 5-membered ring heteroaryl group containing 3 or 4 nitrogen heteroatoms, which heteroaryl group is attached to the quinoxalinedione ring by a ring carbon or a ring nitrogen atom; or represents a 6-membered ring heteroaryl group containing 1-3 nitrogen heteroatoms, which heteroaryl group is linked to the quinoxalinedione ring via a ring carbon atom; any of said groups being optionally benzo-fused, and they, including the benzo-fused moiety, are each independently 1 or 2Optionally substituted with a substituent selected from: c₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₃-C₇Cycloalkyl, halogen, hydroxy, C₁-C₄Alkoxy radical, C₃-C₇Cycloalkoxy, -COOH, C₁-C₄Alkoxycarbonyl, -CONR³R⁴,-NR³R⁴,-S(O)_P(C₁-C₄Alkyl), -SO₂NR³R⁴Aryl, aryloxy, aryl (C)₁-C₄) Alkoxy and het, said C₁-C₄Alkyl is optionally substituted by C₃-C₇Cycloalkyl, halogen, hydroxy, C₁-C₄Alkoxy, halo (C)₁-C₄) Alkoxy radical, C₃-C₇Cycloalkoxy, C₃-C₇Cycloalkyl (C)₁-C₄) Alkoxy, -COOH, C₁-C₄Alkoxycarbonyl, -CONR³R⁴,-NR³R⁴,-S(O)_p(C₁-C₄Alkyl), -SO₂(aryl group), -SO2NR³R⁴Morpholino, aryl, aryloxy, aryl (C)₁-C₄) Alkoxy or het substitution, and said C₂-C₄Alkenyl is optionally substituted with aryl;

R¹and R²Each independently selected from H, fluorine, chlorine, bromine and C₁-C₄Alkyl and halo (C)₁-C₄) An alkyl group;

R³and R⁴Each independently selected from H and C₁-C₄Alkyl, or they together represent C₅-C₇An alkylene group;

p is 0,1 or 2;

"aryl" as used in the definition of R and "het" means phenyl or naphthyl, each of which is selected from C by 1 or 2 independently of one another₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy, halogen, halo (C)₁-C₄Alkyl) and-NR³R⁴The substituent(s) is optionally substituted;

"het" as used in the definition of R means furalPyranyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, all of which are each optionally benzo-fused, and which, including benzo-fused moieties, may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: c₁-C₄Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₄Alkoxy, halogen, hydroxy, -COOH, C₁-C₄Alkoxycarbonyl, allyloxycarbonyl, -CONR³R⁴,-NR³R⁴,-S(O)_p(C₁-C₄Alkyl), -SO₂NR³R⁴Halo (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl radical, C₁-C₄Alkoxy (C)₁-C₄) Alkyl radical, R³R⁴NCO(C₁-C₄) Alkyl, aryl, aralkyl, het¹And het¹(C₁-C₄) Alkyl, and/or when "het" includes pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, the ring nitrogen heteroatom of which is optionally substituted by an oxygen substituent; and "het" as used in the definition of "het¹"means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is substituted by 1 or 2C₁-C₄The alkyl substituents are optionally substituted.

2. A compound according to claim 1, wherein R is triazolyl or tetrazolyl, each of which is substituted by 1 or 2 substituents independently selected from C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₃-C₇Cycloalkyl, halogen, hydroxy, C₁-C₄Substituted by alkoxycarbonyl, aryl and het substituents, said C₁-C₄Alkyl being optionally substituted by halogen, hydroxy, C₁-C₄An alkoxy group,halo (C)₁-C₄) Alkoxy radical, C₃-C₇Cycloalkyl (C)₁-C₄) Alkoxy, -COOH, C₁-C₄Alkoxycarbonyl, -NR³R⁴,-SO₂(aryl), morpholino, aryl, aryloxy, aryl (C)₁-C₄) Alkoxy or het substitution; or is pyridyl or pyrimidinyl.

3. A compound according to claim 1 or 2, wherein R is 1,2, 3-triazol-4-yl, 1,2, 4-triazol-3-yl, 1,2, 4-triazol-4-yl or tetrazol-5-yl, each of which is substituted by 1 or 2 substituents independently selected from C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₃-C₇Cycloalkyl, halogen, hydroxy, C₁-C₄Substituted by alkoxycarbonyl, aryl and het substituents, said C₁-C₄Alkyl substituted by halogen, hydroxy, C₁-C₄Alkoxy, halo (C)₁-C₄) Alkoxy radical, C₃-C₇Cycloalkyl (C)₁-C₄) Alkoxy, -COOH, C₁-C₄Alkoxycarbonyl, -NR³R⁴,-SO₂(aryl), morpholino, aryl, aryloxy, aryl (C)₁-C₄) Alkoxy or het is optionally substituted; or is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-5-yl.

4. A compound according to any one of the preceding claims wherein R³And R⁴Each independently selected from H and C₁-C₄An alkyl group.

5. A compound according to any one of the preceding claims wherein "aryl" represents phenyl optionally substituted by 1 or 2 substituents each independently selected from methyl, methoxy, hydroxy, chloro, trifluoromethyl and dimethylamino.

6. A compound according to any one of the preceding claims wherein "het" represents thiopheneA radical, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is optionally benzo-fused and may be selected from C by 1 or 2 independently of one another₁-C₄Alkyl, -COOH, -NR³R⁴And phenyl, and/or the ring nitrogen heteroatom of said pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl is optionally substituted with an oxygen substituent.

7. A compound according to any one of the preceding claims wherein R is 1,2, 3-triazol-4-yl, 1,2, 4-triazol-3-yl, 1,2, 4-triazol-4-yl or tetrazol-5-yl, each of which is substituted by 1 or 2 substituents independently selected from methyl, ethyl, propyl, allyl, cyclopropyl, cyclohexyl, bromo, hydroxy, ethoxycarbonyl, 2-chlorophenyl, 3-chlorophenyl, 4-dimethylaminophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, phenyl, 4-trifluoromethylphenyl, 2-amino-1, 3, 4-oxadiazol-5-yl, 2-carboxypyridin-5-yl, 1, 5-dimethyl-1H-pyrazol-3-yl, 1H-imidazol-1-yl, 1-methylimidazol-2-yl, 1-methylimidazol-4-yl, 1-methylimidazol-5-yl, 3-methylisothiazol-4-yl, 4-methyl-1H-imidazol-5-yl, 3-methyl-1, 2, 4-oxadiazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 5-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl, 1-pyrid-3-oxide-yl, 2-methylpyridin-3-yl, 2-methylpyridin-5-yl, 1-phenylimidazol-4-yl, 5-phenylpyridin-3-yl, 2-phenylpyridin-5-yl, 1-methylpyrrole-2-yl, 4-methyl-1, 2, 3-thiadiazol-5-yl, 2-methylthiazol-4-yl, 1-methyl-1H-1, 2, 4-triazol-5-yl, 3- (propan-1-yl) -1H-pyrazol-5-yl, pyrazin-2-yl, 1H-pyrazol-4-yl, pyridazin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, thiophen-2-yl, 1H-1,2, 4-triazol-5-yl, 1H-1,2, 3-triazol-5-yl, quinolin-3-yl and quinolin-6-yl, wherein said methyl, ethyl or propyl is optionally substituted with fluoro, hydroxy, methoxy, ethoxy, 2,2, 2-trifluoroethoxy, cyclohexylmethoxy, cyclopentylmethoxy, -COOH, methoxycarbonyl, dimethylamino, 4-chlorobenzenesulfonyl, morpholino, phenyl, phenoxy, benzyloxy, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or R is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-5-yl.

8. The compound of any one of the preceding claims, wherein R is:

1- (2-hydroxyethyl) -5-phenyl-1, 2, 3-triazol-4-yl,

1- (2-hydroxyethyl) -4-phenyl-1, 2, 3-triazol-5-yl,

2- (2-hydroxyethyl) -5-phenyl-1, 2, 3-triazol-4-yl,

1-methyl-5-phenyl-1, 2, 3-triazol-4-yl,

1-methyl-4-phenyl-1, 2, 3-triazol-5-yl,

2-methyl-5-phenyl-1, 2, 3-triazol-4-yl,

5-phenyl-1H-1, 2, 3-triazol-4-yl,

1-methyl-1H-1, 2, 4-triazol-3-yl,

2-methyl-2H-1, 2, 4-triazol-3-yl,

4- (2-hydroxyethyl) -4H-1,2, 4-triazol-3-yl,

4-methyl-4H-1, 2, 4-triazol-3-yl,

3- (2-amino-1, 3, 4-oxadiazol-5-yl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3-benzyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-benzyloxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-bromo-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3- (3-carboxyprop-1-yl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3- (2-carboxypyridin-5-yl) -5-methoxymethyl-4H-1, 2, 4-triazol-4-yl,

3- (2-chlorophenyl) -5-methoxymethyl-4H-1, 2, 4-triazol-4-yl,

3- (2-chlorophenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (3-chlorophenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (4-chlorophenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (4-chlorobenzenesulfonylmethyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3-cyclohexylmethoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl group,

3-cyclopentylmethoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-cyclopropyl-5-methyl-4H-1, 2, 4-triazol-4-yl,

3, 5-bis (methoxymethyl) -4H-1,2, 4-triazol-4-yl,

3- (N, N-dimethylaminomethyl) -5-ethyl-4H-1, 2, 4-triazol-4-yl,

3- (N, N-dimethylaminomethyl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3- (4-dimethylaminophenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (1, 5-dimethyl-1H-pyrazol-3-yl) -5-methoxymethyl-4H-1, 2, 4-triazol-4-yl,

3- (1, 5-dimethyl-1H-pyrazol-3-yl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3, 5-dimethyl-4H-1, 2, 4-triazol-4-yl,

3, 5-diphenyl-4H-1, 2, 4-triazol-4-yl,

3- (2-ethoxyethyl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-ethoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-ethoxycarbonyl-4H-1, 2, 4-triazol-4-yl,

3-ethyl-5- (2-chlorophenyl) -4H-1,2, 4-triazol-4-yl,

3-ethyl-5- (2-methoxyphenyl) -4H-1,2, 4-triazol-4-yl,

3-ethyl-5- (1-methylpyrazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-ethyl-5-methyl-4H-1, 2, 4-triazol-4-yl,

3-ethyl-5-morpholinomethyl-4H-1, 2, 4-triazol-4-yl,

3-ethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-ethyl-4H-1, 2, 4-triazol-4-yl,

3- (2-hydroxyethyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3-hydroxymethyl-5-methyl-4H-1, 2, 4-triazol-4-yl,

3-hydroxymethyl-5-phenyl-4H-1, 2, 4-triazol-4-yl,

3-hydroxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-hydroxymethyl-4H-1, 2, 4-triazol-4-yl,

3-hydroxy-5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (2-hydroxyphenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (1H-imidazol-1-yl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (2-methoxyethyl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (2-methylpyridin-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (2-methylthiazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (1-oxidopyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (1-phenylimidazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (5-phenylpyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (2-phenylpyridin-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (pyridin-3-ylmethyl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (quinolin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (quinolin-6-yl) -4H-1,2, 4-triazol-4-yl,

3- (2-methoxyphenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (3-methoxyphenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3- (4-methoxyphenyl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3-methyl-5- (1-methylimidazol-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methylimidazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methylimidazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3- (3-methylisothiazol-4-yl) -5-methyl-4H-1, 2, 4-triazol-4-yl,

3-methyl-5- (4-methyl-1H-imidazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (2-methylpyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (2-methylpyridin-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methylpyrazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (5-methyl-1H-pyrazol-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (2-methylphenyl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methylpyrrole-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (4-methyl-1, 2, 3-thiadiazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (2-methylthiazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methyl-1H-1, 2, 4-triazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1-methyl-1H-pyrazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3- (3-methyl-1, 2, 4-oxadiazol-5-yl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5-phenyl-4H-1, 2, 4-triazol-4-yl,

3-methyl-5- (3- [ prop-1-yl ] -1H-pyrazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyrazin-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1H-pyrazol-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-2-ylmethyl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-3-ylmethyl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-4-ylmethyl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridazin-4-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyrimidin-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (thien-2-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-4H-1, 2, 4-triazol-4-yl,

3-methyl-5- (1H-1,2, 3-triazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (1H-1,2, 4-triazol-5-yl) -4H-1,2, 4-triazol-4-yl,

3-morpholinomethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-phenoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3- (2-phenylethyl) -5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3- (pyridin-3-yl) -5- (2,2, 2-trifluoroethoxy) methyl-4H-1, 2, 4-triazol-4-yl,

3- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (4-trifluoromethylphenyl) -4H-1,2, 4-triazol-4-yl,

1-allyltetrazol-5-yl group,

1-benzyltetrazol-5-yl group,

1-carboxymethyltetrazol-5-yl group,

1-cyclohexyltetrazol-5-yl group,

1-ethyltetrazol-5-yl group,

1- (2-hydroxyethyl) tetrazol-5-yl,

1- (3-hydroxypropyl) tetrazol-5-yl,

1-methoxycarbonylmethyltetrazol-5-yl,

1- (2-methoxyethyl) tetrazol-5-yl,

1-methyltetrazol-5-yl group,

1- (2-phenylethyl) tetrazol-5-yl,

1-phenyltetrazol-5-yl group,

1- (propan-2-yl) tetrazol-5-yl,

1- (2,2, 2-trifluoroethyl) tetrazol-5-yl,

(ii) a pyridin-2-yl group,

(ii) a pyridin-3-yl group,

(ii) a pyridin-4-yl group,

pyrimidin-2-yl, and

pyrimidin-5-yl.

9. The compound of claim 1, wherein R is:

1- (3-hydroxypropyl) tetrazol-5-yl,

4-methyl-4H-1, 2, 4-triazol-3-yl,

1- (2-hydroxyethyl) -5-phenyl-1, 2, 3-triazol-4-yl,

3-methyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methyl-5- (pyridin-3-ylmethyl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (pyridin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (quinolin-3-yl) -4H-1,2, 4-triazol-4-yl,

3-methoxymethyl-5- (quinolin-6-yl) -4H-1,2, 4-triazol-4-yl,

or 3- (1, 5-dimethyl-1H-pyrazol-3-yl) -5-methyl-4H-1, 2, 4-triazol-4-yl.

10. A compound according to any one of the preceding claims wherein R¹And R²Each independently selected from chlorine and C₁-C₄An alkyl group.

11. A compound according to any one of the preceding claims wherein R1 and R2 are each chloro.

12. The compound of claim 1, wherein: r is 1- (3-hydroxypropyl) tetrazol-5-yl¹Is chlorine and R²Is chlorine; (ii) R is 4-methyl-4H-1, 2, 4-triazol-3-yl, R¹Is chlorine and R²Is chlorine; (iii) R is 1- (2-hydroxyethyl) -5-phenyl-1, 2, 3-triazole-4-

Radical, R¹Is chlorine and R²Is chlorine; (iv) R is 3-methyl-5- (pyridine-3-yl) -4H-1,2, 4-triazoles

-4-yl, R¹Is chlorine and R²Is chlorine; (v) R is 3-methyl-5- (pyridin-3-ylmethyl) -4H-1,2, 4-triazol-4-yl, R¹Is chlorine and R²Is chlorine; (vi) R is 3-methoxymethyl-5- (pyridin-3-yl) -4H-1,2,4-

Triazol-4-yl radical, R¹Is chlorine and R²Is chlorine; (vii) R is 3- (1, 5-dimethyl-1H-pyrazol-3-yl) -5-methyl-

4H-1,2, 4-triazol-4-yl, R¹Is chlorine and R²Is chlorine; (viii) R is 3-methoxymethyl-5- (pyridin-3-yl) -4H-1,2,4-

Triazol-4-yl radical, R¹Is chlorine and R²Is methyl; (ix) R is 3-methoxymethyl-5- (pyridin-3-yl) -4H-1,2,4-

Triazol-4-yl radical, R¹Is methyl and R²Is chlorine; (x) R is 3-methoxymethyl-5- (quinolin-3-yl) -4H-1,2, 4-tris

Oxazol-4-yl, R¹Is chlorine and R²Is chloro, or (xi) R is 3-methoxymethyl-5- (quinolin-6-yl) -4H-1,2,4-

Triazol-4-yl radical, R¹Is chlorine and R²Is chlorine;

or a single stereoisomer or pharmaceutically acceptable salt of any of these compounds.

13. The compound of claim 1, which is: r- (-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl ] -2,3(1H,4H) -quinoxalinedione or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, which is: sodium salt of R- (-) -6, 7-dichloro-5- [ 3-methoxymethyl-5- (3-pyridyl) -4H-1,2, 4-triazol-4-yl ] -2,3(1H,4H) -quinoxalinedione.

15. A pharmaceutical composition which comprises a compound of formula (i), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-14, in association with a pharmaceutically-acceptable diluent or carrier.

16. A compound of formula (i), or a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 14 and claim 15, respectively, for use as a medicament.

17. The use of a compound of formula (i), or a pharmaceutically acceptable salt thereof, or a combination thereof, as claimed in any one of claims 1 to 14 and 15 respectively, in the manufacture of a medicament for the treatment of a disease or condition by antagonism at the NMDA receptor.

18. The use according to claim 17, wherein the disease is an acute neurodegenerative or chronic neurological disorder.

19. The use of a compound of formula (i), or a pharmaceutically acceptable salt thereof, or a composition thereof, as claimed in any one of claims 1 to 14 and 15, respectively, in the manufacture of a medicament for the treatment of stroke, transient ischemic attack, peripheral surgical ischemia or traumatic head injury.

20. A method of treating a disease in a mammal by producing antagonism at the NMDA receptor which comprises treating said mammal with an effective amount of a compound of formula (i), or a pharmaceutically acceptable salt thereof, or a combination thereof, as claimed in any one of claims 1 to 14 and claim 15, respectively.

21. The method of claim 20, wherein the disease is an acute neurodegenerative or chronic neurological disorder.

22. A method of treating stroke, transient ischemic attack, peripheral surgical ischemia or traumatic head injury in a mammal, which comprises treating said mammal with an effective amount of a compound of formula (i), or a pharmaceutically acceptable salt thereof, or a composition thereof, as claimed in any one of claims 1 to 14 and 15, respectively.

23. A compound of formula (II):wherein R, R¹And R²A compound of the formula (I) as defined in claim 1, R⁵And R⁶Independently or together represent a group which can be cleaved hydrolytically under acidic or basic conditions to give a compound of formula (i) according to claim 1.

24. The compound of claim 23, wherein R⁵And R⁶Each independently selected from C₁-C₄Alkyl and optionally substituted by 1 to 3 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen, nitro and trifluoromethyl substituted benzyl; or they together represent C₁-C₆Alkylene, CH (phenyl), CH (4-methoxyphenyl) or CH (3, 4-dimethoxyphenyl).

25. A process for the preparation of a compound of formula (I) as claimed in claim 1 wherein R, R¹And R²As defined in claim 1, which process comprises hydrolysing a compound of formula (ii):wherein R, R¹And R²A compound of formula (I), as defined in the claims, R⁵And R⁶Independently or together represent a group which can be cleaved hydrolytically under acidic or basic conditions to give a compound of formula (I); the resulting compound of formula (I) is then optionally converted to form a pharmaceutically acceptable salt thereof.

26. The method of claim 25, wherein R⁵And R⁶Each independently selected from C₁-C₄Alkyl and optionally substituted by 1 to 3 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen, nitro and trifluoromethyl substituted benzyl; or they together represent C₁-C₆Alkylene, CH (phenyl), CH (4-methoxyphenyl) or CH (3, 4-dimethoxyphenyl).

27. The process of claim 25 or 26, wherein the reaction is carried out by acid hydrolysis of a compound of formula (ii).

28. A compound according to claim 1 wherein R represents a 5-membered ring heteroaryl group containing 3 or 4 nitrogen heteroatoms, which heteroaryl group is attached to the quinoxalinedione ring by a ring carbon or ring nitrogen atom; or represents a 6-membered ring heteroaryl group containing 1-3 nitrogen heteroatoms, which heteroaryl group is linked to the quinoxalinedione ring via a ring carbon atom; any of the groups are optionally benzo-fused and they, including the benzo-fused moiety, are optionally substituted with 1 or 2 substituents each independently selected from: c₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₃-C₇Cycloalkyl, halogen, hydroxy, C₁-C₄Alkoxy radical, C₃-C₇Cycloalkoxy, -COOH, C₁-C₄Alkoxycarbonyl, -CONR³R⁴,-NR³R⁴,-S(O)_p(C₁-C₄Alkyl), -SO₂NR³R⁴Aryl, aryloxy, aryl (C)₁-C₄) Alkoxy and het, wherein said C₁-C₄Alkyl is optionally substituted by C₃-C₇Cycloalkyl, halogen, hydroxy, C₁-C₄Alkoxy radical, C₃-C₇Cycloalkoxy, -COOH, C₁-C₄Alkoxycarbonyl, -CONR³R⁴,-NR³R⁴,-S(O)_p(C₁-C₄Alkyl), -SO₂(aryl group), -SO₂NR³R⁴Morpholino, aryl, aryloxy, aryl (C)₁-C₄) Alkoxy or het substitution, and said C₂-C₄Alkenyl is optionally substituted with aryl; r¹And R²Each independently selected from H, fluoro, chloro, bromo and C₁-C₄An alkyl group; r³And R⁴Each independently selected fromH and C₁-C₄Alkyl, or they together represent C₅-C₇An alkylene group; p is 0,1 or 2; "aryl" as used in the definition of R and "het" means phenyl or naphthyl, each of which is selected from C by 1 or 2 independently of one another₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy, halogen, halo (C)₁-C₄Alkyl) and-NR³R⁴The substituent(s) is optionally substituted; "het" as used in the definition of R means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is optionally substituted by 1 or 2 substituents independently selected from the group consisting of: c₁-C₄Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₄Alkoxy, halogen, hydroxy, -COOH, C₁-C₄Alkoxycarbonyl, allyloxycarbonyl, -CONR³R⁴,-NR³R⁴,-S(O)_p(C₁-C₄Alkyl), -SO₂NR³R⁴Halo (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl radical, C₁-C₄Alkoxy (C)₁-C₄) Alkyl radical, R³R⁴NCO(C₁-C₄) Alkyl, aryl, aralkyl, het¹And het¹(C₁-C₄) An alkyl group; and "het" as used in the definition of "het¹"means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is substituted by 1 or 2C₁-C₄The alkyl substituents are optionally substituted.