GLYCINE B ANTAGONISTS

FIELD OF THE INVENTION

[0001] The present invention relates to novel naphthalene derivatives which may act as glycine B antagonists, methods for their synthesis and the treatment and/or prevention of various diseases and disorders, including neurological disorders, by administration of such substances.

BACKGROUND OF THE INVENTION

[0002] Glutamate is a major excitatory transmitter in the central nervous system and is believed to be involved in many pathological and excitotoxic processes; therefore, there is a great deal of interest in the development of glutamate antagonists for therapeutic uses. Glutamate activates three major types of ionotropic receptors: α-amino-3- hydroxy-5-methyl-4-isoazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) as well as several types of metabotropic receptors. Antagonism of NMDA receptors potentially has a wide range of therapeutic applications. Functional inhibition of NMDA receptors may be achieved through actions at different recognition sites, such as the primary transmitter site, the strychnine insensitive glycine site (glycine B), the polyamine site, and the phencyclidine site located inside the cation channel.

[0003] Receptor desensitization may represent a physiological process serving as an endogenous control mechanism to prevent long term neurotoxic activation of glutamate receptors but allow their transient physiological activation. In the case of the NMDA receptor, the co-agonist glycine is an endogenous ligand inhibiting such desensitization via activation of the glycine B site. It is noteworthy that ischemia increases not only the concentration of extracellular glutamate but also that of glycine and, although this latter effect is less pronounced, it actually persists for a longer period of time. Thus, glycine B antagonists may restore normal synaptic transmission under such conditions by increasing NMDA receptor desensitization to its physiological level. It has been suggested that glycine B antagonists may offer a better therapeutic window than agents acting at other recognition sites of the NMDA receptor complex. [0004] Therefore, glycine B antagonists, such as glycine B antagonists restricted to action in the peripheral nervous system (PNS), may be useful for the treatment and/or prevention of pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).

[0005] Glycine B antagonists may also be useful for the treatment and/or prevention of acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia;

chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ^' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration;

neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity;

psychological/psychiatric disorders, including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children;

drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse;

skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis;

diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation;

diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS);

eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration;

diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease;

migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.

THE PRESENT INVENTION

[0006] We have determined that certain naphthalene derivatives are glycine B antagonists. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve excitotoxicity and malfunctioning of glutamatergic neurotransmission. These substances may be administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.

OBJECTS OF THE INVENTION

[0007] It is an object of the present invention to provide novel pharmaceutical compounds which are glycine B antagonists and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, or ameliorating undesirable conditions, including CNS conditions, associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission by employing a compound of the invention or a pharmaceutical composition containing the same. [0008] An additional object of the invention is the provision of processes for producing the naphthalene derivatives.

[0009] Yet additional objects will become apparent hereinafter, and still further objects will be apparent to one skilled in the art.

SUMMARY OF THE INVENTION

[0010] What we therefore believe to be comprised by our invention may be summarized inter alia in the following words:

A compound selected from those of Formula I:

wherein

R ¹ represents hydrogen, halogen, nitro, acylamino, trifluoromethyl, d-βalkyl, C-i-βalkoxy, hydroxy-C"i _-6 alkyl, or Ci- ₆ alkoxy-Ci _-6 alkyl;

R ² represents hydrogen, halogen, nitro, trifluoromethyl, Ci _-6 alkyl, or Ci _-6 alkoxy;

R ³ represents halogen, nitro, trifluoromethyl, or d-βalkyl;

R ⁴ represents hydrogen, CONH ₂ , Ci _-6 alkyl, C _3-6 alkenyl, C ₃ - ₆ alkynyl, hydroxy-Ci _-6 alkyl, carboxy-Ci _-6 alkyl, d-βalkoxy-Ci-ealkyl, carbamoyl-Ci _-6 alkyl, aryl, heteroaryl, cyclo- C _3-12 alkyl, cyclo-Ca-^alkyl-Ci-βalkyl, cyclo-C _3- i ₂ alkoxy-C-|. ₆ alkyl, aryl-Ci _-6 alkyl, heteroaryl- C-i-βalkyl, aryloxy-Ci-βalkyl, heteroaryloxy-Ci _-6 alkyl, aryl-C-i-ealkoxy-Ci-βalkyl, heteroaryl- Ci _-6 alkoxy-Ci- ₆ alkyl, arylamino-Ci-βalkyl, heteroarylamino-Ci-βalkyl, cyclo-C ₃ -i ₂ alkyl- amino-Ci. ₆ alkyl, C^βalkylaminocarbonyl-Ci-ealkyl, cyclo-C _3- i ₂ alkylaminocarbonyl- Ci _-6 alkyl, arylaminocarbonyl-Ci. ₆ alkyl, heteroarylaminocarbonyl-Ci-βalkyl, carboxy- Ci-ealkylamino-Ci-βalkyl, acylamino-C _1-6 alkyl; arylsulfonylamino-Ci-βalkyl,

Ci-βalkylsulfonylamino-Ci-βalkyl, cyclo-Cs-^alkyl-Ci-ealkylaminocarbonyl-C^-ealkyl, aryl- Ci-βalkylaminocarbonyl-Ci-βalkyl, heteroaryl-Ci-βalkylaminocarbonyl-Ci-βalkyl, hydroxy- Ci-ealkylaminocarbonyl-Ci-βalkyl, dKCi-βalkyOaminocarbonyl-C-i-ealkyl, aryKCi-ealkyOaminocarbonyl-Ci-βalkyl, or heteroaryKCi-ealkyOaminocarbonyl-C-i-ealkyl;

R ⁵ represents hydrogen or C-i-βalkyl;

R ⁶ represents hydroxy, C _1-6 alkoxy, hydroxy-Ci _-6 alkoxy, aryl, heteroaryl, or NR ⁷ R ⁸ ;

R ⁷ and R ⁸ , which may be the same or different, each independently represent hydrogen, Ci _-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, Ci _-6 alkylamino, arylamino, di(Ci. ₆ alkyl)amino, aryl(Ci _-6 alkyl)amino, Ci- ₆ alkoxycarbonyl, d-βalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, Ci _-6 alkyl-carbamoyl, cyclo-Cs-^alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, di-(Ci _-6 alkyl)aminocarbonyl, aryl(C _1-6 alkyl)aminocarbonyl, heteroaryl(Ci- ₆ alkyl)aminocarbonyl, hydroxy-C-i-βalkyl, hydroxy(aryl)-Ci _-6 alkyl, carboxy-Ci _-6 alkyl, Ci-βalkoxycarbonyl-Ci-βalkyl, carboxy(aryl)- Ci _-6 alkyl, carboxy(aryl-Ci. ₆ alkyl)-Ci- ₆ alkyl, Ci. ₆ alkoxy-Ci _-6 alkyl, carbamoyl-Ci. ₆ alkyl, aryl, heteroaryl, cyclo-C ₃ -i ₂ alkyl, cyclo-Ca-^alkyl-Ci-ealkyl, aryl-Ci _-6 alkyl, heteroaryl-Ci-βalkyl, aryl-cyclo-Cs-^alkyl, heteroaryl-cyclo-Ca-iaalkyl, cyclo-Cs-^alkoxy-Ci-βalkyl, aryloxy- Ci-βalkyl, heteroaryloxy-Ci-βalkyl, aryl-Ci-βalkoxy-Ci-βalkyl, heteroaryl-Ci-βalkoxy- C-i-βalkyl, arylamino-Ci _-6 alkyl, heteroarylamino-Ci-βalkyl, cyclo-Ca-^alkyl-amino-Ci-βalkyl, Ci-βalkylaminocarbonyl-Ci-ealkyl, cyclo-C _3- i ₂ alkylaminocarbonyl-C-ι- ₆ alkyl, arylaminocarbonyl-Ci-βalkyl, heteroarylaminocarbonyl-Ci-βalkyl, carboxy-Ci-βalkylamino- Ci _-6 alkyl, acylamino-Ci-βalkyl; Ci-βalkylsulfonylamino-Ci-ealkyl, arylsulfonylamino- Ci _-6 alkyl, cyclo-Ca-^alkyl-Ci-βalkylaminocarbonyl-Ci-βalkyl, aryl-C _1-6 alkylaminocarbonyl- Ci _-6 alkyl, heteroaryl-Ci-βalkylaminocarbonyl-Ci-βalkyl, hydroxy-Ci-βalkylaminocarbonyl- C _1-6 alkyl, dKCi-βalkyOaminocarbonyl-Ci-ealkyl, aryKCi-βalkyOaminocarbonyl-Ci-βalkyl, or heteroaryKCi-βalkyOaminocarbonyl-Ci-ealkyl;

or R ⁷ and R ⁸ together represent -(CH ₂ ) _n - wherein n is 3, 4, 5 or 6;

or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to aromatic or heteroaromatic ring selected from phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, nitro, acylamino, trifluoromethyl, C-i-βalkyl, Ci _-6 alkoxy, hydroxy-Ci _-6 alkyl, Ci _-6 alkoxy-Ci _-6 alkyl, COOH, CONH ₂ , Ci- ₆ alkoxycarbonyl, Ci-βalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, di-(Ci _-6 alkyl)aminocarbonyl, carboxy-Ci _-6 alkyl, Ci-βalkoxycarbonyl-d-βalkyl, carbamoyl- Ci _-6 alkyl, cyclo-C ₃ .i ₂ alkyl, aryl, heteroaryl, aryl-Ci _-6 alkyl, and heteroaryl-Ci _-6 alkyl;

or R ⁴ and R ⁷ together with the carbon and nitrogen atoms to which they are attached represent a 5- or 6-membered ring, wherein the ring may be optionally substituted by one or more substituents selected from Ci- ₆ alkyl, aryl, heteroaryl, COOH, Ci _-6 alkoxycarbonyl, and CONH ₂ ;

wherein

the term "aryl" represents phenyl or naphthyl, or phenyl substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH ₂ , Ci-βalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, hydroxy- Ci- ₆ alkylaminocarbonyl, di-(Ci- ₆ alkyl)aminocarbonyl, trifluoromethyl, C _h alky!, heteroaryl, Ci _-6 alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-C ₃ -i ₂ alkoxy, aryloxy, heteroaryloxy, aryl-C _1-6 alkoxy, heteroaryl-Ci _-6 alkoxy, amino-Ci-βalkyl, hydroxy-Ci-βalkyl, carboxy-Ci-βalkyl, carbamoyl-C-i-βalkyl, cyano-Ci-βalkyl, Ci- ₆ alkoxycarbonylamino- Ci _-6 alkyl, hydroxy-Ci _-6 alkoxy, carboxy-Ci-βalkoxy, acyl-C-i-βalkoxy, Ci- ₆ alkoxycarbonyl, Ci- ₆ alkylamino, cyclo-Ca-^alkylamino, arylamino, heteroarylamino, aryl-Ci-βalkylamino, heteroaryl-Ci-βalkylamino, hydroxy-Ci _-6 alkylamino, carboxy-d-βalkylamino, di-(Ci- ₆ alkyl)amino, acylamino, di^Ci-ealkylJamino-Ci-βalkyl, di-(Ci- ₆ alkyl)amino- Ci _-6 alkylamino-Ci- ₆ alkyl, heterocyclyl-Ci-βalkyl, Ci-βalkoxycarbonyl-Ci-βalkyl, heterocyclyl-Ci-βalkyl, cyano-Ci. ₆ alkoxy, heterocyclyl-Ci-βalkoxy, Ci _-6 alkylamino- Ci _-6 alkoxy, di-(Ci _-6 alkyl)amino-Ci _-6 alkoxy, carboxy-Ci-βalkylamino-Ci-βalkoxy,

Ci-ealkoxycarbonyl-C-i.ealkoxy, heteroarylaminocarbonyl-C-i-βalkoxy,

Ci _-6 alkylsulfonylamino, arylsulfonylamino, C _1-6 alkyl-aminosulfonyl, di-(Ci _-6 alkyl)aminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,

Ci-βalkylaminocarbonyl-Ci-βalkyl, cyclo-Ca-^alkylaminocarbonyl-d-βalkyl, arylaminocarbonyl-Ci-βalkyl, heteroarylaminocarbonyl-d- ₆ alkyl, hydroxy-

Ci-ealkylaminocarbonyl-Ci-βalkyl, carboxy-d-ealkylaminocarbonyl-d-βalkyl, and di-(d- ₆ alkyl)aminocarbonyl-d- ₆ alkyl;

and

the term "heteroaryl" represents an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group containing a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or with a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH ₂ , d-βalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, hydroxy-d-βalkylaminocarbonyl, di-(Ci. ₆ alkyl)aminocarbonyl, trifluoromethyl, Ci _-6 alkyl, heteroaryl, Ci _-6 alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-C _3- i ₂ alkoxy, aryloxy, heteroaryloxy, aryl-d-βalkoxy, heteroaryl-d-βalkoxy, amino- Ci _-6 alkyl, hydroxy-d-βalkyl, carboxy-d-βalkyl, carbamoyl-d-βalkyl, cyano-d-βalkyl, C _M -βalkoxycarbonylamino-Ci-βalkyl, hydroxy-d-βalkoxy, carboxy-Ci _-6 alkoxy, acyl- Ci _-6 alkoxy, d-βalkoxycarbonyl, d-βalkylamino, cyclo-Cs-^alkylamino, arylamino, heteroarylamino, aryl-Ci-βalkylamino, heteroaryl-Ci _-6 alkylamino, hydroxy-Ci _-6 alkylamino, carboxy-Ci _-6 alkylamino, di-(Ci _-6 alkyl)amino, acylamino, di-(Ci- ₆ alkyl)amino-Ci _-6 alkyl, di^Ci-βalkyOamino-Ci-βalkylamino-Ci-βalkyl, heterocyclyl-Ci-βalkyl, Ci-βalkoxycarbonyl- Ci _-6 alkyl, heterocyclyl-Ci-βalkyl, cyano-Ci _-6 alkoxy, heterocyclyl-Ci-βalkoxy, C-i-βalkylamino-Ci-βalkoxy, di-(Ci- ₆ alkyl)amino-Ci- ₆ alkoxy, carboxy-Ci _-6 alkylamino- Ci _-6 alkoxy, d-ealkoxycarbonyl-Ci-βalkoxy, heteroarylaminocarbonyl-d-βalkoxy, Ci _-6 alkylsulfonylamino, arylsulfonylamino, Ci _-6 alkyl-aminosulfonyl, di-(Ci _-6 alkyl)aminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, d-βalkylaminocarbonyl-d-βalkyl, cyclo-Ca-^alkylaminocarbonyl-Ci-βalkyl, arylaminocarbonyl-d-βalkyl, heteroarylaminocarbonyl-Ci-βalkyl, hydroxy-

Ci-βalkylaminocarbonyl-Ci-ealkyl, carboxy-Ci-βalkylaminocarbonyl-d-ealkyl, and di-(d _-6 alkyl)aminocarbonyl-d-6alkyl; and optical isomers, polymorphs, analogs, derivatives, prodrugs, and pharmaceutically- acceptable acid and base addition salts and hydrates and solvates thereof.

[0011] Such a compound of Formula I, wherein R ¹ and R ³ each independently represent hydrogen or halogen.

[0012] Such a compound of Formula I, wherein R ¹ and R ³ each independently represent hydrogen or chlorine.

[0013] Such a compound of Formula I, wherein R ¹ and R ³ each represent chlorine.

[0014] Such a compound of Formula I, wherein R ² represents hydrogen.

[0015] Such a compound of Formula I, wherein R ⁴ represents hydrogen, C-i-βalkyl, or aryl, and R ⁵ represents hydrogen.

[0016] Such a compound of Formula I, wherein R ⁶ represents hydroxy, aryl, or NR ⁷ R ⁸ .

[0017] Such a compound of Formula I, wherein R ⁶ represents phenyl optionally substituted by methoxy.

[0018] Such a compound of Formula I, wherein R ⁶ represents NR ⁷ R ⁸ and R ⁷ and R ⁸ each independently represent hydrogen, C _h alky!, aryl, heteroaryl, arylC _1-6 alkyl, arylsulfonyl, carboxyCi _-6 alkyl, carboxy(aryl)Ci _-6 alkyl, hydroxy(aryl)Ci _-6 alkyl; or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent a 5- or 6-membered ring which may be saturated or unsaturated, and wherein the ring in addition to nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to a phenyl ring, wherein the ring may be optionally substituted by a carboxy group.

[0019] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA:

wherein R ,1 , r R>2 , _D R3 ₁ R _D 4 , and R are as defined above for Formula I.

[0020] Such a compound of Formula IA, wherein R ⁴ represents hydrogen or phenyl.

[0021] A further aspect of the invention relates to a compound of Formula I, which is selected from those of formula IB:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , and R ⁸ are as defined above for Formula I.

[0022] Such a compound of Formula IB, wherein R ⁷ and R ⁸ each independently represent hydrogen, Ci _-6 alkyl, aryl, heteroaryl, arylCi- ₆ alkyl, arylsulfonyl, carboxy- Ci _-6 alkyl, carboxy(aryl)Ci _-6 alkyl, hydroxy(aryl)Ci. ₆ alkyl; or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent a 5- or 6-membered ring which may be saturated or unsaturated, and wherein the ring in addition to nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to a phenyl ring, wherein the ring may be optionally substituted by a carboxy group.

[0023] Such a compound of Formula IB, wherein R ⁷ represents hydrogen or methyl and R ⁸ represents phenyl which may be substituted with one or more substituents selected from d-βalkoxy, carboxy-Ci _-6 alkyl, hydroxy, hydroxy-Ci _-6 alkyl, carboxy, and carboxy- Ci-βalkoxy; benzyl; or phenysulfonyl which is substituted by methyl, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent a pyrrolidinyl, piperidinyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl, or 1 ,2,3,4-tetrahydro-isoquinolinyl ring which may be optionally substituted by carboxy.

[0024] Specific compounds of Formula I within the present invention include but are not limited to:

4-Carboxymethoxy-5,7-dichloro-naphthalene-2-carboxylic acid,

4-[(3-Carboxymethoxy-phenylcarbamoyl)-methoxy]-5,7-dichlo ro-naphthalene-2- carboxylic acid,

4-[(2-Carboxy-phenylcarbamoyl)-methoxy]-5,7-dichloro-naph thalene-2-carboxylic acid,

5,7-Dichloro-4-[2-(4-methoxy-phenyl)-2-oxo-ethoxy]-naphth alene-2-carboxylic acid,

5,7-Dichloro-4-[(2-hydroxymethyl-phenylcarbamoyl)-methoxy ]-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[(3-methoxy-phenylcarbamoyl)-methoxy]-naph thalene-2-carboxylic acid,

4-[(4-Carboxymethyl-phenylcarbamoyl)-methoxy]-5,7-dichlor o-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[(4-hydroxy-phenylcarbamoyl)-methoxy]-naph thalene-2-carboxylic acid,

5,7-Dichloro-4-[(4-hydroxymethyl-phenylcarbamoyl)-methoxy ]-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[(3-hydroxymethylφhenylcarbamoyl)-methoxy ]-naphthalene-2- carboxylic acid,

4-{[3-(tert-Butoxycarbonylamino-methyl)-phenylcarbamoyl]- methoxy}-5,7-dichloro- naphthalene-2-carboxylic acid,

4-[(3-Aminomethyl-phenylcarbamoyl)-methoxy]-5,7-dichloro- naphthalene-2- carboxylic acid,

4-[(3-Carboxymethyl-phenylcarbamoyl)-methoxy]-5,7-dichlor o-naphthalene-2- carboxylic acid,

4-{[(4-Carboxy-phenyl)-methyl-carbamoyl]-methoxy}-5,7-dic hloro-naphthalene-2- carboxylic acid, 4-[(2-Carboxymethyl-phenylcarbamoyl)-methoxy]-5,7-dichloro-n aphthalene-2- carboxylic acid, δ.Z-Dichloro-^JI^^hydroxymethyl-phenylcarbamoyO-ethoxyj-nap hthalene^- carboxylic acid,

5,7-Dichloro-4-[1-(2-hydroxymethyl-phenylcarbamoyl)-ethox y]-naphthalene-2- carboxylic acid,

4-(Benzylcarbamoyl-methoxy)-5,7-dichloro-naphthalene-2-ca rboxylic acid,

4-[(Carboxymethyl-phenyl-carbamoyl)-methoxy]-5,7-dichloro -naphthalene-2- carboxylic acid,

4-{[(2-Carboxy-phenyl)-methyl-carbamoyl]-methoxy}-5,7-dic hloro-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-(phenethylcarbamoyl-methoxy)-naphthalene-2 -carboxylic acid,

5,7-Dichloro-4-[(3-hydroxymethyl-benzylcarbamoyl)-methoxy ]-naphthalene-2- carboxylic acid,

7-Chloro-4-[(2-hydroxymethyl-phenylcarbamoyl)-methoxy]-na phthalene-2- carboxylic acid,

4-[(1-Carboxy-2-phenyl-ethylcarbamoyl)-methoxy]-5,7-dichl oro-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[1-(3-hydroxymethyl-phenylcarbamoyl)-ethox y]-naphthalene-2- carboxylic acid,

4-[(3-Carboxymethyl-phenylcarbamoyl)-methoxy]-7-chloro-na phthalene-2- carboxylic acid,

4-{[(Carboxy-phenyl-methyl)-carbamoyl]-methoxy}-5,7-dichl oro-naphthalene-2- carboxylic acid,

7-Chloro-4-[(3-hydroxymethyl-phenylcarbamoyl)-methoxy]-na phthalene-2- carboxylic acid,

5,7-Dichloro-4-[((R)-2-hydroxy-1-phenyl-ethylcarbamoyl)-m ethoxy]-naphthalene-2- carboxylic acid,

1-[2-(3-Carboxy-6,8-dichloro-naphthalen-1-yloxy)-acetyl]- piperidine-3-carboxylic acid,

4-{[(3-Carboxy-phenyl)-methyl-carbamoyl]-methoxy}-5,7-dic hloro-naphthalene-2- carboxylic acid,

4-(Carboxy-phenyl-methoxy)-5,7-dichloro-naphthalene-2-car boxylic acid,

5,7-Dichloro-4-phenylcarbamoylmethoxy-naphthalene-2-carbo xylic acid, 4-[(4-Aminomethyl-2-carboxymethoxy-phenylcarbamoyl)-methoxy] -5,7-dichloro- naphthalene-2-carboxylic acid,

1-[2-(3-Carboxy-6,8-dichloro-naphthalen-1-yloxy)-acetyl]- pyrrolidine-2-carboxylic acid,

5,7-Dichloro-4-[2-oxo-2-(toluene-4-sulfonylamino)-ethoxy] -naphthalene-2- carboxylic acid,

4-[(1-Carboxymethyl-2-phenyl-ethylcarbamoyl)-methoxy]-5,7 -dichloro- naphthalene-2-carboxylic acid,

2-[2-(3-Carboxy-6,8-dichloro-naphthalen-1-yloxy)-acetyl]- 1 ,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid,

4-{[(2-Carboxy-phenyl)-methyl-carbamoyl]-methoxy}-6,7-dic hloro-naphthalene-2- carboxylic acid,

4-{[(3-Carboxymethyl-phenyl)-methyl-carbamoyl]-methoxy}-5 ,7-dichloro- naphthalene-2-carboxylic acid,

4-{[(4-Carboxymethyl-phenyl)-methyl-carbamoyl]-methoxy}-5 ,7-dichloro- naphthalene-2-carboxylic acid,

4-[(2-Carboxymethoxy-phenylcarbamoyl)-methoxy]-5,7-dichlo ro-naphthalene-2- carboxylic acid,

4-[2-(3-Carboxy-6,8-dichloro-naphthalen-1-yloxy)-acetyl]- 3,4-dihydro-2H- benzo[1 ,4]oxazine-2-carboxylic acid,

4-[(4-Carboxymethoxy-phenylcarbamoyl)-methoxy]-5,7-dichlo ro-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[(2-methoxycarbonyl-phenylcarbamoyl)-metho xy]-naphthalene-2- carboxylic acid,

4-[(6-Carboxymethyl-pyridin-3-ylcarbamoyl)-methoxy]-5,7-d ichloro-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-{[3-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl carbamoyl]-methoxy}- naphthalene-2-carboxylic acid, i-^S-Carboxy-θ.β-dichloro-naphthalen-i-yloxyJ-acetyπ^.S-d ihydro-I H-indole^- carboxylic acid, i-^^S-Carboxy-β.δ-dichloro-naphthalen-i-yloxyJ-acetyπ-I ^.S^-tetrahydro- quinoline-2-carboxylic acid,

5,7-Dichloro-4-[2-(3,4-dihydro-2H-quinolin-1-yl)-2-oxo-et hoxy]-naphthalene-2- carboxylic acid, δJ-Dichloro-^p^β.Z-dimethoxy-S^-dihydro-I H-isoquinolin^-yl^-oxo-ethoxy]- naphthalene-2-carboxylic acid,

5,7-Dichloro-4-[2-(3,4-dihydro-1 H-isoquinolin-2-yl)-2-oxo-ethoxy]-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-{[2-(2,2,2-trifluoro-ethoxy)-phenylcarbamo yl]-methoxy}- naphthalene-2-carboxylic acid,

5,7-Dichloro-4-{[2-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl carbamoyl]-methoxy}- naphthalene-2-carboxylic acid,

5,7-Dichloro-4-{[4-(2 _I 2 _> 2-trifluoro-ethoxy)-phenylcarbamoyl]-methoxy}- naphthalene-2-carboxylic acid,

5 _I 7-Dichloro-4-[(4-trifluoromethoxy-phenylcarbamoyl)-met hoxy]-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[(2-trifluoromethoxy-phenylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-(2-oxo-2-pyridin-2-yl-ethoxy)-naphthalene- 2-carboxylic acid,

4-[(2-Carboxymethoxy-benzylcarbamoyl)-methoxy]-5,7-dichlo ro-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-{[2-(1 H-tetrazol-5-ylmethoxy)-phenylcarbamoyl]-methoxy}- naphthalene-2-carboxylic acid,

5,7-Dichloro-4-[(2-trifluoromethoxy-benzylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[(3-trifluoromethoxy-benzylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[(4-trifluoromethoxy-benzylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[(1 H-tetrazol-5-ylcarbamoyl)-methoxy]-naphthalene-2-carboxylic acid,

5,7-Dichloro-4-(2-oxo-1-phenyl-pyrrolidin-3-yloxy)-naphth alene-2-carboxylic acid,

5,7-Dichloro-4-[(frans-2-phenyl-cyclopropylcarbamoyl)-met hoxy]-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-(2-methoxy-1-phenylcarbamoyl-ethoxy)-napht halene-2-carboxylic acid,

4-(1-Carboxy-1-methyl-ethoxy)-5,7-dichloro-naphthalene-2- carboxylic acid, 5,7-Dichloro-4-{[2-(2-dimethylamino-ethoxy)-phenylcarbamoyl] -methoxy}- naphthalene-2-carboxylic acid ,

4-(1-Benzyl-2-oxo-pyrrolidin-3-yloxy)-5,7-dichloro-naphth alene-2-carboxylic acid,

5,7-Dichloro-4-[(2-methoxy-phenylcarbamoyl)-methoxy]-naph thalene-2-carboxylic acid,

4-[(2,6-Bis-carboxymethoxy-phenylcarbamoyl)-methoxy]-5,7- dichloro-naphthalene-

2-carboxylic acid,

5,7-Dichloro-4-[(2-cyanomethoxy-phenylcarbamoyl)-methoxy] -naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[2-methoxy-1-(2-methoxy-phenylcarbamoyl)-e thoxy]-naphthalene-

2-carboxylic acid,

5,7-Dichloro-4-[1-(2-methoxy-phenyl)-2-oxo-pyrrolidin-3-y loxy]-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-[(2-hydroxymethyl-6-methoxy-phenylcarbamoy l)-methoxy]- naphthalene-2-carboxylic acid,

5,7-Dichloro-4-(indan-1-ylcarbamoylmethoxy)-naphthalene-2 -carboxylic acid,

5,7-Dichloro-4-[2-(8-hydroxymethyl-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-2-oxo- ethoxy]-naphthalene-2-carboxylic acid,

4-[(5-Aminomethyl-2-carboxymethoxy-phenylcarbamoyl)-metho xy]-5,7-dichloro- naphthalene-2-carboxylic acid, δ^-Dichloro^-KI ^.S^-tetrahydro-naphthalen-i-ylcarbamoyO-methoxy]- naphthalene-2-carboxylic acid,

4-{[2-(1-Carboxy-1-methyl-ethoxy)-phenylcarbamoyl]-methox y}-5,7-dichloro- naphthalene-2-carboxylic acid,

5,7-Dichloro-4-[(2-cyano-phenylcarbamoyl)-methoxy]-naphth alene-2-carboxylic acid,

4-[(2,4-Bis-carboxymethoxy-phenylcarbamoyl)-methoxy]-5,7- dichloro-naphthalene-

2-carboxylic acid,

5,7-Dichloro-4-[(4-cyano-phenylcarbamoyl)-methoxy]-naphth alene-2-carboxylic acid,

5,7-Dichloro-4-{[2-(1 H-tetrazol-5-yl)-phenylcarbamoyl]-methoxy}-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-{[4-(1 H-tetrazol-5-ylmethyl)-phenylcarbamoyl]-methoxy}- naphthalene-2-carboxylic acid, δJ-Dichloro-^μ-Ca-dimethylamino-ethoxyJ-S-hydroxymθthyl-p henylcarbamoyl]- methoxy}-naphthalene-2-carboxylic acid,

5,7-Dichloro-4-{[4-(1 H-tetrazol-5-ylmethoxy)-phenylcarbamoyl]-methoxy}- naphthalene-2-carboxylic acid, δJ-Dichloro-^^I H-tetrazol-δ-yO-phenylcarbamoylJ-methoxyJ-naphthalene^- carboxylic acid,

5,7-Dichloro-4-{[3-(1 H-tetrazol-5-ylmethyl)-phenylcarbamoyl]- methoxy}naphthalene-2-carboxylic acid,

5,7-Dichloro-4-[(2-methylcarbamoylmethoxy-phenylcarbamoyl )-methoxy]- naphthalene-2-carboxylic acid,

5,7-Dichloro-4-{[3-(1 H-tetrazol-5-ylmethoxy)-phenylcarbamoyl]-methoxy}- naphthalene-2-carboxylic acid,

4-[(3-Carbamoylmethoxy-phenylcarbamoyl)-methoxy]-5,7-dich loro-naphthalene-2- carboxylic acid,

4-[(2-Carboxymethoxy-5-hydroxymethyl-phenylcarbamoyl)-met hoxy]-5,7-dichloro- naphthalene-2-carboxylic acid,

4-[(2-Carbamoylmethoxy-phenylcarbamoyl)-methoxy]-5,7-dich loro-naphthalene-2- carboxylic acid,

4-{[3-(2-Carboxy-ethyl)-phenylcarbamoyl]-methoxy}-5,7-dic hloro-naphthalene-2- carboxylic acid,

4-[(2-Aminomethyl-4-carboxymethoxy-phenylcarbamoyl)-metho xy]-5,7-dichloro- naphthalene-2-carboxylic acid,

5,7-Dichloro-4-[(3-cyano-phenylcarbamoyl)-methoxy]-naphth alene-2-carboxylic acid,

5 , 7-Dich loro-4-{2-oxo-2-[2-( 1 H-tetrazol-5-yl)-2 , 3-d i hyd ro-i ndol- 1 -yl]-ethoxy}- naphthalene-2-carboxylic acid, δJ-Dichloro^-I^^I H-tetrazol-δ-ylmethylJ-phenylcarbamoyll-methoxy}- naphthalene-2-carboxylic acid, δy-Dichloro^tS-CI H-tetrazol-δ-ylJ-phenylcarbannoyll-methoxyJ-naphthalene^- carboxylic acid,

5,7-Dichloro-4-[(2-dimethylcarbamoylmethoxy-phenylcarbamo yl)-methoxy]- naphthalene-2-carboxylic acid, δJ-Dichloro^Kpyridin^-ylmethyO-carbamoylJ-methoxyJ-naphthal ene^- carboxylic acid, 5,7-Dichloro-4-{[(pyridin-3-ylmethyl)-carbamoyl]-methoxy}-na phthalene-2- carboxylic acid,

SJ-Dichloro-^Kpyridin-^ylmethyO-carbamoyπ-methoxyJ-napht halene^- carboxylic acid,

5,7-Dichloro-4-{[2-(1 H-tetrazol-5-yl)-benzylcarbamoyl]-methoxy}-naphthalene-2- carboxylic acid,

SJ-Dichloro-^P^I H-tetrazol-δ-yO-benzylcarbamoyll-methoxyJ-naphthalene^- carboxylic acid,

5,7-Dichloro-4-{[4-(1 H-tetrazol-5-yl)-benzylcarbamoyl]-methoxy}-naphthalene-2- carboxylic acid,

5,7-Dichloro-4-({2-[(2-dimethylamino-ethylcarbamoyl)-meth oxy]-phenylcarbamoyl}- methoxy)-naphthalene-2-carboxylic acid ,

5,7-Dichloro-4-[(2-{[(2-dimethylamino-ethyl)-methyl-carba moyl]-methoxy}- phenylcarbamoyl)-methoxy]-napthalene-2-carboxylic acid,

4-[(2-Carboxymethoxy-4-methylaminomethyl-phenylcarbamoyl) -methoxy]-5,7- dichloro-naphthalene-2-carboxylic acid, δJ-Dichloro^-^-cyanomethyl-phenylcarbamoyO-methoxyJ-naphtha lene^- carboxylic acid,

4-[(3-Carbamoyl-phenylcarbamoyl)-methoxy]-5,7-dichloro-na phthalene-2- carboxylic acid,

4-[(4-Carbamoyl-phenylcarbamoyl)-methoxy]-5,7-dichloro-na phthalene-2- carboxylic acid,

7-[2-(3-Carboxy-6,8-dichloro-naphthalen-1-yloxy)-acetylam ino]-benzofuran-2- carboxylic acid,

4-[(4-Aminomethyl-2-methylcarbamoylmethoxy-phenylcarbamoy l)-methoxy]-5,7- dichloro-naphthalene-2-carboxylic acid,

5,7-Dichloro-4-[(4-cyano-benzylcarbamoyl)-methoxy]-naphth alene-2-carboxylic acid,

5,7-Dichloro-4-{[2-(1 H-tetrazol-5-ylmethyl)-benzylcarbamoyl]-methoxy}- naphthalene-2-carboxylic acid, δJ-Dichloro^fS^I H-tetrazol-δ-ylmethyO-benzylcarbamoyll-methoxy}- naphthalene-2-carboxylic acid, δJ-Dichloro^^i H-tetrazol-S-ylmethyO-benzylcarbamoyπ-methoxy}- naphthalene-2-carboxylic acid, 5,7-Dichloro-4-{[3-(1 H-tetrazol-5-ylmethoxy)-benzylcarbamoyl]-methoxy}- naphthalene-2-carboxylic acid,

4-[(2-Carboxymethoxy-4-hydroxymethyl-phenylcarbamoyl)-met hoxy]-5,7-dichloro- naphthalene-2-carboxylic acid,

4-[(4-Aminomethyl-2-dimethylcarbamoylmethoxy-phenylcarbam oyl)-methoxy]-5,7- dichloronaphthalene^-carboxylic acid ,

5,7-Dichloro-4-{[2-(2-hydroxy-ethoxy)-3-hydroxymethyl-phe nylcarbamoyl]- methoxy}-naphthalene-2-carboxylic acid, δJ-Dichloro^^-CI H-tetrazol-δ-ylmethoxyJ-benzylcarbamoyπ-methoxy}- naphthalene-2-carboxylic acid, δJ-Dichloro^^^i H-tetrazol-δ-ylmethoxyJ-benzylcarbamoyπ-methoxy}- naphthalene-2-carboxylic acid,

5,7-Dichloro-4-(pyridin-3-ylcarbamoylmethoxy)-naphthalene -2-carboxylic acid,

4-{[2,3-Bis-(1 H-tetrazol-5-ylmethoxy)-phenylcarbamoyl]-methoxy}-5,7-dichlo ro- naphthalene-2-carboxylic acid,

5,7-Dichloro-4-(pyridin-2-ylcarbamoylmethoxy)-naphthalene -2-carboxylic acid,

5,7-Dichloro-4-[(4-methyl-thiazol-2-ylcarbamoyl)-methoxy] -naphthalene-2- carboxylic acid,

4-[1-(2-Carboxymethoxy-phenylcarbamoyl)-2-methoxy-ethoxy] -5,7-dichloro- naphthalene-2-carboxylic acid, δy-Dichloro^-Kδ-methyl^.δ.ej-tetrahydro-thiazolo^.S-clpyr idin^-ylcarbamoyl)- methoxy]-naphthalene-2-carboxylic acid,

5,7-Dichloro-4-[(5-methyl-thiazol-2-ylcarbamoyl)-methoxy] -naphthalene-2- carboxylic acid,

5,7-Dichloro-4-({2-[(2-hydroxy-ethylcarbamoyl)-methoxy]-p henylcarbamoyl}- methoxy)-naphthalene-2-carboxylic acid,

5,7-Dichloro-4-[(4,5-dimethyl-thiazol-2-ylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid,

4-[(5-Carbamoyl-1 H-imidazol-4-ylcarbamoyl)-methoxy]-5,7-dichloro-naphthalene-

2-carboxylic acid,

5,7-Dichloro-4-[(2-cyanomethyl-phenylcarbamoyl)-methoxy]- naphthalene-2- carboxylic acid and optical isomers, polymorphs, analogs, derivatives, prodrugs, and pharmaceutically- acceptable acid and base addition salts, hydrates, and solvates thereof.

[0025] Moreover, the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for the treatment or prevention of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including for the conditions selected from those described earlier in the description.

[0026] Such conditions include pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV) ₁ traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).

[0027] Such conditions also include acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug- induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia;

chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ^' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity;

psychological/psychiatric disorders, including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children;

drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis;

diseases of the gastro-intestinal tract and metabolic diseases including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation;

diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS);

eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration;

diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease;

migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.

[0028] Further, the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for use in the treatment or prevention of NMDA excitotoxicity or malfunctioning glutamatergic neurotransmission.

[0029] Further, the invention relates to the use of a compound of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically- acceptable acid or base addition salt, hydrate, or solvate thereof for the manufacture of a medicament for the prevention and/or treatment of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission. Such a use includes the use of such a compound for the manufacture of a medicament for the prevention and/or treatment of a condition in an animal including a human being which condition is associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description.

[0030] Moreover, the invention relates to a method for treating or preventing a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description, such method comprising administering to a living animal, including a human, a therapeutically effective amount of a compound selected from those of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof.

[0031] A further aspect of the invention relates to such a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising at least one compound of Formula I in combination with one or more pharmaceutically- acceptable diluents, excipients, or carriers.

[0032] The compounds of the invention are suitable for administration in monotherapy or for combination therapy with other pharmaceutically active compounds. Examples of suitable other pharmaceutically active compounds include immunomodulators and agents active against central nervous system disorders such as other NMDA agonists or antagonists including glycine B antagonists.

[0033] Further, the invention relates to a pharmaceutical composition comprising as active ingredient at least one compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable excipients or vehicles.

[0034] The invention also relates to a process for the synthesis or preparation of a compound selected from those of Formula IA ¹ :

wherein

R ¹ represents hydrogen, halogen, nitro, acylamino, trifluoromethyl, Ci _-6 alkyl, Ci _-6 alkoxy, hydroxy-Ci _-6 alkyl, or Ci-βalkoxy-Ci-βalkyl;

R ² represents hydrogen, halogen, nitro, trifluoromethyl, C-i-βalkyl, or Ci-βalkoxy;

R ³ represents halogen, nitro, trifluoromethyl, or C-|. ₆ alkyl;

R ⁴ represents hydrogen, CONH ₂ , Ci _-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, hydroxy-Ci. ₆ alkyl, carboxy-Ci _-6 alkyl, Ci-ealkoxy-C-i-βalkyl, carbamoyl-Ci _-6 alkyl, aryl, heteroaryl, cyclo- C _3- i ₂ alkyl, cyclo-Cs-^alkyl-C-i-βalkyl, aryl-Ci _-6 alkyl, heteroaryl-Ci _-6 alkyl, cyclo-C ₃ .i ₂ alkoxy- Ci _-6 alkyl, aryloxy-Ci-βalkyl, heteroaryloxy-C-i-βalkyl, aryl-Ci-βalkoxy-Ci-βalkyl, heteroaryl- Ci-βalkoxy-Ci-βalkyl, arylamino-Ci-βalkyl, heteroarylamino-Ci-βalkyl, cyclo-C _3- i ₂ alkyl- amino-Ci-βalkyl, Ci-βalkylaminocarbonyl-Ci-βalkyl, cyclo-C _3- i ₂ alkylaminocarbonyl- C _1-6 alkyl, arylaminocarbonyl-Ci-βalkyl, heteroarylaminocarbonyl-Ci-βalkyl, carboxy- Ci _-6 alkylamino-Ci _-6 alkyl, acylamino-Ci. ₆ alkyl, arylsulfonylamino-d-βalkyl,

Ci-βalkylsulfonylamino-Ci-ealkyl, cyclo-Cs-^alkyl-Ci-βalkylaminocarbonyl-Ci-βalkyl, aryl- Ci-βalkylaminocarbonyl-Ci-ealkyl, heteroaryl-Ci-βalkylaminocarbonyl-Ci-βalkyl, hydroxy- Ci-βalkylaminocarbonyl-Ci-βalkyl, di^Ci-βalkyOaminocarbonyl-Ci-ealkyl, aryKCi-βalkyOaminocarbonyl-Ci-ealkyl, or heteroaryKCi-βalkyOaminocarbonyl-Ci-βalkyl; and

R ⁵ represents hydrogen;

and optical isomers, polymorphs, analogs, derivatives, prodrugs, and pharmaceutically- acceptable acid and base addition salts and hydrates and solvates thereof; comprising reaction of a compound of Formula II:

with 2-(triphenylphosphoranylidene)-succinic acid diethyl ester in an appropriate solvent (e.g., benzene) to yield a compound of Formula III:

which compound of Formula III is treated with a concentrated acid (e.g., concentrated sulfuric acid) to yield a compound of Formula IV:

which compound of Formula IV is treated with an appropriate reagent or combination of reagents (e.g., thionyl chloride/methanol) to yield an ester of Formula V:

wherein R represents Ci _-6 alkyl or arylCi _-6 alkyl (e.g., Me, Et, t-Bu, PMB), which compound of Formula V is reacted with a compound of Formula Vl:

wherein X represents chlorine, bromine, or iodine and AIk represents d-βalkyl, in a polar solvent (e.g., acetonitrile, DMF, DMSO, or NMP) in the presence of a base (e.g., sodium carbonate or potassium carbonate) and, optionally, in the presence of a phase transfer catalyst (e.g., TBAI) to yield a compound of Formula VII: which compound of Formula VII is subjected to appropriate hydrolysis conditions (e.g., TFA/CH ₂ CI ₂ or UOH/THF-H2O) to yield a compound of Formula IA ^* , which may be converted, if desired, into an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable salt, hydrate or solvate.

[0035] The invention also relates to a process for the synthesis or preparation of a compound selected from those of Formula IA":

wherein

R ¹ represents hydrogen, halogen, nitro, acylamino, trifluoromethyl, Ci _-6 alkyl, Ci _-6 alkoxy, hydroxy-Ci _-6 alkyl, or Ci _-6 alkoxy-Ci- ₆ alkyl;

R ² represents hydrogen, halogen, nitro, trifluoromethyl, Ci _-6 alkyl, or Ci _-6 alkoxy;

R ³ represents halogen, nitro, trifluoromethyl, or d-βalkyl;

R ⁴ represents hydrogen, CONH ₂ , C _h alky!, Ca-βalkenyl, Ca-βalkynyl, hydroxy-d-βalkyl, carboxy-Ci-βalkyl, Ci- ₆ alkoxy-C _1-6 alkyl, carbamoyl-C-i-βalkyl, aryl, heteroaryl, cyclo- C _3- i2alkyl, cyclo-Ca-^alkyl-Ci-βalkyl, aryl-Ci-βalkyl, heteroaryl-Ci _-6 alkyl, cyclo-C _3- i ₂ alkoxy- Ci _-6 alkyl, aryloxy-C _1-6 alkyl, heteroaryloxy-Ci _-6 alkyl, aryl-Ci-βalkoxy-Ci-βalkyl, heteroaryl- Ci _-6 alkoxy-Ci- ₆ alkyl, arylamino-Ci-βalkyl, heteroarylamino-Ci _-6 alkyl, cyclo-C ₃ -i ₂ alkyl- amino-Ci _-6 alkyl, Ci-βalkylaminocarbonyl-C^ealkyl, cyclo-Ca-^alkylaminocarbonyl- Ci _-6 alkyl, arylaminocarbonyl-Ci-βalkyl, heteroarylaminocarbonyl-d-ealkyl, carboxy- Ci-βalkylamino-Ci-ealkyl, acylamino-Ci- ₆ alkyl, arylsulfonylamino-Ci-βalkyl,

Ci-βalkylsulfonylamino-Ci-βalkyl, cyclo-Ca-^alkyl-Ci-ealkylaminocarbonyl-C-i-ealkyl, aryl- Ci-βalkylaminocarbonyl-Ci-ealkyl, heteroaryl-Ci-ealkylaminocarbonyl-Ci-ealkyl, hydroxy- Ci-βalkylaminocarbonyl-Ci-βalkyl, dKCi-βalkyOaminocarbonyl-C-i-ealkyl, aryKCi-βalkyOaminocarbonyl-Ci-ealkyl, or heteroaiγKCi-ealkyOaminocarbonyl-Ci-βalkyl; and

R ⁵ represents Ci _-6 alkyl;

and optical isomers, polymorphs, analogs, derivatives, prodrugs, and pharmaceutically- acceptable acid and base addition salts and hydrates and solvates thereof;

comprising reaction of a compound of Formula II:

with 2-(triphenylphosphoranylidene)-succinic acid diethyl ester in an appropriate solvent (e.g., benzene) to yield a compound of Formula III:

which compound of Formula III is treated with a concentrated acid (e.g., concentrated sulfuric acid) to yield a compound of Formula IV:

which compound of Formula IV is treated with an appropriate reagent or combination of reagents (e.g., thionyl chloride/methanol) to yield an ester of Formula V: wherein R represents d-βalkyl or arylCi _-6 alkyl (e.g., Me, Et, t-Bu, PMB), which compound of Formula V is reacted with a compound of Formula Vl:

wherein X represents chlorine, bromine, or iodine and AIk represents Ci-βalkyI, in a polar solvent (e.g., acetonitrile, DMF, DMSO, or NMP) in the presence of a base (e.g., sodium carbonate or potassium carbonate) and, optionally, in the presence of a phase transfer catalyst (e.g., TBAI) to yield a compound of Formula VII:

which compound of Formula VII is reacted with a compound of formula VIII:

R ⁵ — x VlIl in an appropriate solvent (e.g., THF or DMF) in the presence of a base (e.g., LDA or NaH) to yield a compound of Formula IX:

which compound of Formula IX is subjected to appropriate hydrolysis conditions (e.g., TFA/CH ₂ CI ₂ or LiOH/THF-H2θ) to yield a compound of Formula IA", which may be converted, if desired, into an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable salt, hydrate or solvate. [0036] The invention also relates to a process for the synthesis or preparation of a compound selected from those of Formula IB as defined above, comprising reaction of a compound of Formula X:

wherein R represents Ci _-6 alkyl or arylCi _-6 alkyl (e.g., Me, Et, t-Bu, PMB), with a compound of Formula Xl: in an appropriate solvent (e.g., DMF) in the presence of a condensing agent (e.g., EDCI or HOBT) to yield a compound of formula XII:

which compound of Formula XII is subjected to appropriate hydrolysis conditions (e.g., TFA/CH ₂ CI ₂ or LiOH/THF-H ₂ O) to yield a compound of Formula IB, which may be converted, if desired, into an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable salt, hydrate or solvate.

[0037] The invention also relates to a process for the synthesis or preparation of a compound selected from those of Formula IB as defined above, comprising reaction of a compound of Formula X:

wherein R represents Ci _-6 alkyl or arylCi _-6 alkyl (e.g., Me, Et, t-Bu, PMB), with thionyl chloride to yield a compound of Formula XIII:

s reacted with a ( Domi in an appropriate solvent (e.g., CH ₂ CI ₂ ) in the presence of base (e.g., triethylamine) to yield a compound of Formula XII:

which compound of Formula XII is subjected to appropriate hydrolysis conditions (e.g., TFA/CH ₂ CI ₂ or LiOH/TH F-H ₂ O) to yield a compound of Formula IB, which may be converted, if desired, into an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable salt, hydrate or solvate.

[0038] The invention also relates to a process for the synthesis or preparation of a compound selected from those of Formula IB as defined above, comprising reaction of a compound of Formula XIV:

wherein X represents chlorine or bromine, with a compound of Formula Xl:

in an appropriate solvent or solvent system (e.g., ethyl acetate/water) in the presence of a base (e.g., potassium carbonate) to yield a compound of Formula XV:

which compound of Formula XV is reacted with a compound of Formula XVI:

wherein R represents Ci-βalkyl or arylC-i-βalkyl (e.g., Me, Et, t-Bu, PMB), in a polar solvent (e.g., acetonitrile, DMF, DMSO, or NMP) in the presence of a base (e.g., sodium carbonate or potassium carbonate) and, optionally, in the presence of a phase transfer catalyst (e.g., TBAI) to yield a compound of Formula XII:

which compound of Formula XII is subjected to appropriate hydrolysis conditions (e.g., TFA/CH ₂ CI ₂ or LiOH/TH F-H ₂ O) to yield a compound of Formula IB, which may be converted, if desired, into an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable salt, hydrate or solvate.

DETAILED DESCRIPTION OF THE INVENTION

[0039] For the purpose of the present invention, the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Q-J indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, Ci _-3 alkyl refers to alkyl of one to three carbon atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof. [004O]As used herein and as far as it is not defined in a different manner elsewhere in this description or the accompanying claims, the term "d-βalkyl" represents straight or branched chain alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms, examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl, tert- butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, 2-methylbutyl, tert-amyl, n-hexyl, 2-hexyl, 3-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2- dimethylbutyl, 3-dimethylbutyl, 2-ethylbutyl, and 3-ethylbutyl. Further, such alkyl groups may optionally be substituted by one or more fluorine, chlorine and/or bromine atoms and/or a carboxy or carbamoyl moiety; examples of halogenated alkyl moieties include -CF ₃ , -C ₂ F ₅ , -CBr ₃ , and -CCI ₃ . The term "C^-βalkenyl" represents straight or branched chain alkenyl groups having 2, 3, 4, 5 or 6 carbon atoms. The term "cycloCs-^alkyl" represents monocyclic or bicyclic, or tricyclic alkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantanyl, wherein the "cycloC _3-12 alkyr'-ring is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) fluorine, chlorine, and/or bromine atoms. In the context of the present invention the term "di-(Ci- ₆ alkyl)amino" refers to an amino moiety in which the nitrogen atom of the amino group is substituted with two C-|. ₆ alkyl groups, which may be the same or different, as defined above. Examples of di- Ci _-6 alkylamino groups include dimethylamino, diethylamino and N-methyl-N- isopropylamino. The term "aryl" represents phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) substituents, which may be the same or different, selected independently from halogen, amino, hydroxy, nitro, cyano, COOH, CONH ₂ , d-βalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, hydroxy-d-ealkylaminocarbonyl, di-(Ci- ₆ alkyl)aminocarbonyl, trifluoromethyl, d-βalkyl, heteroaryl, d-βalkoxy, difluoromethoxy, trifluoromethoxy, cyclo-C _3- i ₂ alkoxy, aryloxy, heteroaryloxy, aryl-Ci-6alkoxy, heteroaryl-d-βalkoxy, amino- Ci _-6 alkyl, hydroxy-Ci _-6 alkyl, carboxy-d-βalkyl, carbamoyl-Ci _-6 alkyl, cyano-Ci _-6 alkyl, d-ealkoxycarbonylamino-d-βalkyl, hydroxy-d-βalkoxy, carboxy-d-βalkoxy, acyl- C _1-6 alkoxy, Ci _-6 alkoxycarbonyl, d-βalkylamino, cyclo-Cs-^alkylamino, arylamino, heteroarylamino, aryl-d-βalkylamino, heteroaryl-Ci _-6 alkylamino, hydroxy-Ci _-6 alkylamino, carboxy-d- ₆ alkylamino, di-(C ₁ . ₆ alkyl)amino, acylamino, di-(d- ₆ alkyl)amino-d- ₆ alkyl, di-(d- ₆ alkyl)amino-d- ₆ alkylamino-d- ₆ alkyl, heterocyclyl-d-βalkyl, d-βalkoxycarbonyl- Ci _-6 alkyl, heterocyclyl-d-εalkyl, cyano-Ci _-6 alkoxy, heterocyclyl-d _-6 alkoxy, Ci-ealkylamino-C-i-βalkoxy, dKCi-βalkylJamino-Ci-βalkoxy, carboxy-Ci _-6 alkylamino- Ci. ₆ alkoxy, Ci-βalkoxycarbonyl-Ci-βalkoxy, heteroarylaminocarbonyl-Ci-βalkoxy, Ci. ₆ alkylsulfonylamino, arylsulfonylamino, Ci-βalkyl-aminosulfonyl, di-(Ci- ₆ alkyl)aminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,

Ci-ealkylaminocarbonyl-Ci-βalkyl, cyclo-Ca-^alkylaminocarbonyl-d-ealkyl, arylaminocarbonyl-Ci-ealkyl, heteroarylaminocarbonyl-Ci-βalkyl, hydroxy-

Ci-βalkylaminocarbonyl-Ci-ealkyl, carboxy-d-ealkylaminocarbonyl-d-ealkyl, and di^Ci-ealkylJaminocarbonyl-Ci-ealkyl. The term "heteroaryl" represents an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen or a bicyclic ring system having one 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) substituents, which may be the same or different, selected independently from halogen, amino, hydroxy, nitro, cyano, COOH, CONH ₂ , d-βalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, hydroxy-d-βalkylaminocarbonyl, di-(Ci- ₆ alkyl)aminocarbonyl, trifluoromethyl, d-βalkyl, heteroaryl, d-βalkoxy, difluoromethoxy, trifluoromethoxy, cyclo-C ₃ -i ₂ alkoxy, aryloxy, heteroaryloxy, aryl- Ci _-6 alkoxy, heteroaryl-Ci. ₆ alkoxy, amino-Ci _-6 alkyl, hydroxy-Ci _-6 alkyl, carboxy-C-|. ₆ alkyl, carbamoyl-Ci-βalkyl, cyano-d-βalkyl, Ci-βalkoxycarbonylamino-Ci-ealkyl, hydroxy- d-βalkoxy, carboxy-Ci _-6 alkoxy, 8CyI-C _{1 -6} a I koxy, Ci _-6 alkoxycarbonyl, C _1-6 alkylamino, cyclo-Ca-^alkylamino, arylamino, heteroarylamino, aryl-Ci-βalkylamino, heteroaryl- Cvβalkylamino, hydroxy-d-βalkylamino, carboxy-Ci- ₆ alkylamino, di-(Ci- ₆ alkyl)amino, acylamino, di(C-ι- ₆ alkyl)amino-Ci- ₆ alkyl, di(Ci _-6 alkyl)amino-Ci _-6 alkylamino-Ci _-6 alkyl, heterocyclyl-Ci-βalkyl, d-βalkoxycarbonyl-Ci-ealkyl, heterocyclyl-Ci-βalkyl, cyano- Ci _-6 alkoxy, heterocyclyl-Ci-βalkoxy, d-βalkylamino-Ci-ealkoxy, di-(Ci- ₆ alkyl)amino- Ci _-6 alkoxy, carboxy-Ci-βalkylamino-d-ealkoxy, Ci-ealkoxycarbonyl-Ci-ealkoxy, heteroarylaminocarbonyl-d-ealkoxy, Ci-βalkylsulfonylamino, arylsulfonylamino, d-βalkyl-aminosulfonyl, di-(Ci-6alkyl)aminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, Ci-βalkylaminocarbonyl-Ci-ealkyl, cyclo-

Ca-^alkylaminocarbonyl-Ci-βalkyl, arylaminocarbonyl-Ci-βalkyl, heteroarylaminocarbonyl-d-βalkyl, hydroxy-d-ealkylaminocarbonyl-d-ealkyl, carboxy- Ci-βalkylaminocarbonyl-d-ealkyl, and dKCi-ealkyOaminocarbonyl-d-βalkyl; examples of such heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl. The term "acyl" represents Ci- ₆ alkylcarbonyl, trifluoroacetyl, hydroxy-d-βalkylcarbonyl, carboxy- Ci _-6 alkylcarbonyl, Ci-βalkoxy-Ci-βalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C _3- i ₂ alkylcarbonyl, aryl-Ci-βalkylcarbonyl, heteroaryl-C-i-βalkylcarbonyl, arylamino- Ci-βalkylcarbonyl, heteroarylamino-C-i-ealkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci-βalkylcarbonyl. The term "heterocyclyl" represents a saturated 4-7 membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, examples of such heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuryl, thiazolidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. The term "halogen" represents fluorine, chlorine, bromine and iodine.

[0041] The compounds of the present invention are named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour or hours, and "rt" for room temperature).

[0042] The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule (such as 4-hydroxy-naphthalene-2-carboxylic acid), but has been modified in a targeted and controlled manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule. Synthesis and screening of analogs (e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.

[0043] In addition, using methods known to those skilled in the art, analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc. [0044] The term "prodrug" is used herein in the conventional pharmaceutical sense, to refer to a molecule which undergoes a transformation in vivo (e.g., an enzymatic or chemical transformation) to release an active parent drug. Prodrugs of the compounds of Formula I of the present invention may be prepared by chemically modifying a functional group present in the compound of Formula I such that the chemically modified compound may undergo a transformation in vivo (e.g., enzymatic hydrolysis) to provide the compound of Formula I. Examples of functional groups present in the compounds of Formula I which may be modified to produce prodrugs include carboxy, hydroxy, amino, and thio groups. Prodrugs of the compounds of Formula I of the present invention may be prepared according to conventional techniques which have been described in the art (see, for example, Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007).

[0045] The phrase "pharmaceutically acceptable", as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human). The term "pharmaceutically acceptable" may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[0046] Compounds of the present invention may be in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.

[0047] It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention ecompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein.

[0048] Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occurs stereoselective^. Stereoisomeric forms of Formula I are obviously intended to be included within the scope of this invention.

ADDITION SALTS

[0049] For therapeutic use, salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention. The pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g. hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2- hydroxybenzoic and like acids. Conversely, the salt may be converted to the free base by treatment with alkali. Compounds of Formula I can form pharmaceutically acceptable salts with various basic compounds. Suitable base salts include, but are not limited to, ammonium, calcium, potassium, sodium, and choline salts. PHARMACEUTICAL COMPOSITIONS

[0050] The active ingredients of the compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, or thin films/flash doses, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient of the compounds of the present invention commensurate with the intended daily dosage range to be employed. Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.

[0051] The term "excipient" applied to pharmaceutical compositions of the invention refers to an adjuvant, carrier, diluent, or vehicle with which a compound of the present invention is administered. Such pharmaceutical excipients may be sterile or non-sterile excipients commonly used for the formulation and production of solid, semi solid, liquid and sterile pharmaceutical compositions. These excipients may also be liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A.R. Gennaro, 20 ^th Edition, describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy". The excipients may also be combinations of solids and liquids.

METHOD OF TREATING

[0052] Due to their high degree of activity and their low toxicity, together presenting a most favorable therapeutic index, the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, including concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, including in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount. Suitable dosage ranges are 1-1000 milligrams daily, optionally 10-500 milligrams daily, and optionally 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.

[0053] The term "treat" is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject. Within the meaning of the present invention, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.

[0054] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.

[0055] The compounds of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route. The compounds of the present invention may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20 ^th Edition). The orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion- controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices. [0056] For oral administration in the form of a tablet or capsule, the glycine B antagonist active component may be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like. For oral administration in liquid form, the glycine B antagonist active components may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.

[0057] The tablets may be coated by methods well known in the art. The compounds of the present invention may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA). Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.

[0058] The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known. [0059] The compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The instant compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the instant compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.

[0060] For administration by inhalation, the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0061] The formulations comprising the compounds of the present invention may be delivered parenterally, i.e., by intravenous (Lv.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient of the compounds of the present invention can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [0062] The compounds of the present invention may also be formulated for rectal administration, e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).

[0063] The compositions comprising glycine B antagonists of the present invention may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The glycine B antagonists of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0064] As disclosed herein, the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient. A specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease. The appropriate dose and dosage times under certain conditions can be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.

[0065] Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD ₅₀ (the dose lethal to 50% of the population) and the ED ₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD _5O /ED ₅ o. Compositions that exhibit large therapeutic indices are preferred.

[0066] Schemes 1 and 2 describe the preparation of compounds of Formula I of the present invention. All of the starting materials are prepared by procedures described in these schemes, by procedures well known to one of ordinary skill in organic chemistry or can be obtained commercially. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which procedures would be well known to one of ordinary skill in organic chemistry. All of the variables used in the schemes are as defined below or as in the claims.

Scheme 1 - Synthesis of starting materials 4 and 8, and compounds of Formula IA

[0067] The compounds of general Formula I (wherein R ⁵ is hydrogen) may be prepared in two steps from an appropriately substituted ester of 4-hydroxynaphthalene-3- carboxylic acid 4 (Scheme 1). Thus, naphthoic acid ester 6 (wherein R ⁶ represents aryl, heteroaryl or OAIk) may be obtained by reacting compound 4 with compound 5 in the presence of an appropriate base (e.g., sodium carbonate or potassium carbonate) in a polar solvent (e.g., acetonitrile, DMF, DMSO or NMP). Addition of a phase transfer catalyst such as TBAI may facilitate this alkylation reaction. The ester group of compound 6 may be hydrolyzed by well known procedures to yield compound IA. For example, a lower alkyl (e.g., methyl or ethyl) ester group may be hydrolyzed using reagents such as aqueous lithium hydroxide or sodium hydroxide. tert-Butyl and PMB (para-methoxybenzyl) esters may easily be cleaved by TFA in methylene chloride solution. Alternatively, PMB esters may also be cleaved by hydrogenation in the presence of an appropriate Pd catalyst.

[0068] The compounds of Formula IA, wherein R ⁵ is Ci _-6 -alkyl, may be prepared by alkylation of compound 6 (wherein R ⁶ represents OAIk) and subsequent hydrolysis of ester groups as described above. The alkylation reaction may be carried out in the presence of a strong base such as lithium diisopropylamide in THF or sodium hydride in DMF.

Scheme 2 - Synthesis of compounds of Formula IB, General procedures A, B, C and D

[0069] The compounds of formula IB may be prepared by hydrolysis of the ester group of naphthoic acid derivatives 13. The naphthoic acid derivatives 13 (Scheme 2) may, in turn, be synthesized by reaction of ester 4 with halogenated acetamide derivative 12 (Procedure A) analogously to the synthesis of esters 6 (Scheme 1). An alternative synthesis of naphthoic acid derivatives 13 is via an amide bond formation reaction (Procedure B) which involves reaction of carboxylic acid 8 with amine 10 in the presence of condensing agent (e.g., EDCI and HOBT) in an appropriate solvent (e.g., DMF). Alternatively, carboxylic acid 8 may be transformed to acyl chloride 9 by common procedures, for example, by reaction with thionyl chloride or oxalyl chloride. Reaction of acyl chloride 9 with amine 10 yields compound 13 which, after hydrolysis of the ester groups, affords compound IB.

[0070] It will be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions. The reaction products may be isolated and purified by standard laboratory techniques, such as extraction, chromatography and crystallization. Products isolated as a free base may be further converted into a hydrochloride or any other pharmaceutically acceptable salt according to known procedures. Products isolated as a free carboxylic acid may be converted into sodium salt or any other pharmaceutically acceptable salt according to known procedures.

[0071] It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry.

EXPERIMENTAL PART

[0072] The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.

[0073] Hereinafter, "DMF" is defined as N,N-dimethylforrnamide, "HCI" as hydrochloric acid, "DMSO" as dimethyl sulfoxide, "NH ₄ OH" as ammonium hydroxide solution, "TBAI" as tetrabutylammonium iodide, "TFA" as trifluoroacetic acid, "TEA" as triethylamine, "MeCN" as acetonitrile, "AcOH" as acetic acid, "TLC" as thin layer chromatography, "HOBT" as 1-hydroxybenzotriazole, "EDCI" as 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, "EtOH" as ethanol and "MeOH" as methanol. Example 1 4-Carboxymethoxy-5,7-dichloronaphthalene-2-carboxylic acid

a) 2-[1-(3,5-Dichlorophenyl)-meth-(E)-ylidene]-succinic acid diethyl ester (2a).

[0074] A mixture of 2-(triphenylphosphoranylidene)-succinic acid diethyl ester (40.410 g, 93.01 mmol) [Prepared according to: Bacaloglu, R.; Blasko, A.; Bunton, C. A.; Cerichelli, G.; Castaneda, F.; Rivera, E. J. Chem. Soc, Perkin Trans. 2. 1995 (2) 965-972] and 3,5-dichlorobenzaldehyde (1a) (16.603 g, 94.87 mmol) in dry benzene (150 ml_) is stirred at rt for 24 h. Saturated aqueous NaHCθ ₃ is added, the organic layer separated and the aqueous layer is extracted with diethyl ether (2 x 15 ml_). The organic extracts are combined, dried over Na2SO ₄ and evaporated under reduced pressure. The product is purified by flash chromatography on silica gel (eluent - CH ₂ CI ₂ ) to give the title compound 2a (20,54 g, 66%). ¹ H NMR (CDCI ₃ ), δ (ppm): 1.25-1.36 (m, 6H); 3.45 (s, 2H); 4.10-4.33 (m, 4H); 7.24 (d, 2 Hz, 2H); 7.34 (t, 2 Hz, 1 H) and 7.73 (s, 1 H).

b) 5 J-Dichloro^-hydroxynaphthalene-^-carboxylic acid (3a).

[0075] A mixture of 2-[1-(3,5-dichlorophenyl)-meth-(E)-ylidene]-succinic acid diethyl ester (2a) (20.540 g, 62.02 mmol) and cone. H ₂ SO ₄ (150 mL) is stirred at 80 ⁰ C for 8 h. Resulting dark green mixture is poured into 1 L of ice-water, the precipitated dark brown solid is collected on filter and dried to give the title compound 3a (13.23 g, 82%). ¹ H NMR (DMSO-de), δ (ppm): 7.42 (d, 2 Hz, 1 H); 7.64 (d, 2 Hz, 1 H); 8.03 (d, 2 Hz, 1 H); 8.14 (d, 2 Hz, 1 H) and 10.72 (s, 1 H).

c) 5,7-Dichloro-4-hydroxynaphthalene-2-carboxylic acid methyl ester (4a).

[0076] A mixture of 5,7-dichloro-4-hydroxy-naphthalene-2-carboxylic acid (3a) (13.0 g, 50.57 mmol) and thionyl chloride (15 mL) in methanol (60 mL) is heated at 80 ⁰ C for 6 h. Additional thionyl chloride (8 mL) is added and heating is continued for 10 h. After evaporation of solvent under reduced pressure water is added to the residue, the precipitated solid is collected on filter and dried to give the title compound 4a (12.38 g, 90%). ¹ H NMR (DMSO-de), δ (ppm): 3.87 (s, 3H); 7.43 (d, 2 Hz, 1 H); 7.66 (d, 2 Hz, 1 H); 8.07 (s, 1H); 8.18 (s, 1 H) and 10.80 (s, 1 H). d) 4-Ethoxycarbonylmethoxy-5,7-dichloronaphthalene-2-carboxylic acid methyl ester (6a)

[0077] A mixture of 5,7-dichloro-4-hydroxynaphthalene-2-carboxylic acid methyl ester (4a) (150 mg, 0.553 mmol), potassium carbonate (92 mg, 0.664 mmol) and TBAI (10 mg, 0.027 mmol) in DMF (5 mL) is stirred at rt for 30 min. Then ethyl bromoacetate (5a) (74 μl_, 0.664 mmol) is added and stirring is continued for 48 h. The reaction mixture is diluted with water (5 mL), the precipitated solid collected on filter, washed with water and dried at 55 ⁰ C. The product is purified by flash chromatography (eluent - CH ₂ Cb) to give the title compound 6a (151 mg, 76 %). ¹ H NMR (DMSO-d ₆ ), δ (ppm): 1.21 (t, 7 Hz ₁ 3H); 3.90 (s, 3H); 4.19 (q, 7 Hz, 2H); 5.03 (s, 2H); 7.35 (s, 1 H); 7.80 (d 2 Hz, 1 H) and 8.29 (s, 1 H).

e) 4-Carboxymethoxy-5,7-dichloronaphthalene-2-carboxylic acid

[0078] A suspension of 4-ethoxycarbonylmethoxy-5,7-dichloronaphthalene-2-carboxylic acid methyl ester (6a) (91 mg, 0.254 mmol) and LiOH ^* H ₂ O (22 mg, 0.533 mmol) in THF/water (4 ml, 1 :1 ) is stirred at rt for 2 h (TLC control). The reaction mixture is acidified by addition of 1 M aqueous HCI and stirred for 30 min. The precipitated solid is collected by filtration, washed with water and dried at 55 ⁰ C to give the title compound (63 mg, 79%). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.92 (s, 2H), 7.32 (s, 1 H), 7.77 (d, 2.2 Hz ₁ 1 H) ₁ 8.23 (s, 1 H), 8.26 (d, 2.2 Hz ₁ 1 H).

Example 2

4-[(3-Carboxymethoxyphenylcarbamoyl)-methoxy]-5,7-dichlor onaphthalene-2- carboxylic acid

a) 4-tert-Butoxycarbonylmethoxy-5,7-dichloronaphthalene-2-carbo xylic acid methyl ester (6b)

[0079] A mixture of δj-dichloro^-hydroxynaphthalene^-carboxylic acid methyl ester (4a) (2.7796 g, 10.25 mmol), potassium carbonate (3.1175 g, 22.56 mmol) and TBAI (0.1894 g, 0.51 mmol) in DMF (5 mL) is stirred at rt for 30 min. Then tert-butyl bromoacetate (5b) (1.65 mL, 11.28 mmol) is added and stirring continued for 24 h. Reaction mixture is diluted with water (5 mL), the precipitated solid is collected on filter, washed with water and dried at 55 ⁰ C to give the title compound 6b (3.687 g, 93%). b) 4-Carboxymethoxy-5,7-dichloronaphthalene-2-carboxylic acid methyl ester (8a)

[008O]A mixture of 4-tert-butoxycarbonylmethoxy-5,7-dichloro-naphthalene-2-carb oxylic acid methyl ester (6b) (3.6870 g, 9.57 mmol) and TFA (10 mL) in CH ₂ CI ₂ (30 mL) is stirred at rt for 30 min (TLC control; CHCb). After evaporation of the solvent under reduced pressure diethyl ether is added to the residue, the precipitated solid is collected on filter and dried at 55 ⁰ C to give the title compound 8a (3.015 g, 95%). ¹ H NMR (DMSO-d ₆ ), δ (ppm): 3.90 (s, 3H); 4.94 (s, 2H); 7.33 (s, 1 H); 7.79 (d 1.4 Hz, 1 H) and 8.27-8.30 (m, 2H).

c) 5,7-Dichloro-4-chlorocarbonylmethoxynaphthalene-2-carboxylic acid methyl ester (9a)

[0081] A mixture of 4-carboxymethoxy-5,7-dichloronaphthalene-2-carboxylic acid methyl ester (8a) (0.7670 g, 2.33 mmol) and thionyl chloride (3.4 mL) is refluxed for 2 h. After cooling the reaction mixture is concentrated under reduced pressure to give the title compound 9a (750 mg, 92%). Product is used in the next step without purification.

d) SJ-Dichloro^-^S-ethoxycarbonylmethoxyphenylcarbamoyO-methoxy ]- naphthalene-2-carboxylic acid methyl ester (13aa) (General procedure C)

[0082] A mixture of (3-aminophenoxy)-acetic acid ethyl ester (10aa) (88.5 mg, 0.45 mmol) and triethylamine (0.12 mL) in methylene chloride (2 mL) is stirred at rt for 20 min. Then 5,7-dichloro-4-chlorocarbonylmethoxynaphthalene-2-carboxylic acid methyl ester (9a) is added (150 mg) and stirring is continued for 24 h. The resulting mixture is evaporated under reduced pressure and purified by flash chromatography (eluent CH ₂ CI ₂ : MeOH, 20:1 ) to give the title compound 13aa (168 mg, 77%). ¹ H NMR (DMSO- d ₆ ), δ (ppm): 1.18 (t, 7 Hz, 3H); 3.89 (s, 3H); 4.14 (q, 7 Hz, 2H); 4.72 (s, 2H); 4.94 (s, 2H); 6.64 (d 5.4 Hz, 1 H); 7.17-7.30 (m, 3H); 7.43 (s, 1 H); 7.83 (d 2.4 Hz, 1 H); 8.30 (s, 1 H); 8.32 (s, 1 H) and 10.16 (s, 1 H).

e) 4-[(3-Carboxymethoxyphenylcarbamoyl)-methoxy]-5,7-dichlorona phthalene-2- carboxylic acid

[0083] A mixture of δ^-dichloro^-KS-ethoxycarbonylmethoxyphenylcarbamoyl)- methoxy]-naphthalene-2-carboxylic acid methyl ester (13aa) (150 mg, 0,30 mmol) and 1 M aqueous NaOH (0.7 mL) in THF/water (5 ml_) is stirred for 3 days. The reaction mixture is evaporated under reduced pessure, diluted with water (5 mL) and acidified by addition of 1 M aqueous HCI. The precipitated solid is collected on filter, washed with water and hot acetonitrile and dried at 55 ⁰ C to give the title compound (84 mg, 61 %). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.62 (s, 2H), 4.93 (s, 2H), 6.60-6.66 (m, 1 H), 7.16-7.28 (m, 3H), 7.44 (s, 1 H), 7.81 (d, 1.2 Hz, 1 H), 8.26 (s, 1 H), 8.29 (d, 2.4 Hz, 1 H), 10.16 (s, 1 H).

Example 3

4-[(2-Carboxy-phenylcarbamoyl)-methoxy]-5,7-dichloro-naph thalene-2-carboxylic acid

a) 2-(2-Chloro-acetylamino)-benzoic acid methyl ester (12aa).

[0084] A mixture of methyl anthranilate (10ab) (1.0 g, 6.61 mmol) and K ₂ CO ₃ (2.28 g, 16.53 mmol) in ethyl acetate/water (1 :1 ) (30 mL) is stirred at rt for 20 min, then chloroacetyl chloride (11a) (0.63 mL, 7.94 mmol) is added dropwise. The resulting mixture is stirred at rt for 24 h. The organic phase is separated, washed with water and dried over Na ₂ SO ₄ . Solvent is evaporated under reduced pressure to give the title compound 12ab (1.412 g, 94%) of. ¹ H NMR (CDCI ₃ ), δ (ppm): 3.96 (s, 3H); 4.21 (s, 2H); 7.15 (t, 8 Hz, 1 H); 7.58 (t, 8 Hz, 1 H); 8.07 (d, 8 Hz, 1 H); 8.71 (d, 8 Hz, 1 H) and 11.88 (s, 1 H).

b) 5,7-Dichloro-4-[(2-methoxycarbonylphenylcarbamoyl)-methoxy]- naphthalene-2- carboxylic acid methyl ester (13ab). (General procedure A)

[0085] A mixture of 5,7-dichloro-4-hydroxynaphthalene-2-carboxylic acid methyl ester (4a) (150 mg, 0.55 mmol), K ₂ CO ₃ (168 mg, 1.22 mmol) and TBAI (10 mg, 0,03 mmol) in DMF (2 mL) is stirred at rt for 30 min. Then 2-(2-chloroacetylamino)-benzoic acid methyl ester (12ab) (151 mg, 0.66 mmol) is added and stirring is continued for 24 h. The resulting reaction mixture is diluted with water, precipitated solid is collected on filter, washed with water and dried at 55 ⁰ C. The residue is recrystallized from CHCIs/hexane to give the title compound 13ab (221 mg, 82%). ¹ H NMR (DMSO-d ₆ ), δ (ppm): 3.69 and 3.89 (both s, both 3H); 5.02 (s, 2H); 7.22 (t, 8 Hz ₁ 1 H); 7.55 (s, 1 H); 7.65 (t, 8 Hz, 1H); 7.87 (s, 1 H); 7.91 (d, 8 Hz, 1 H); 8.30 (s, 2H); 8.44 (d, 8 Hz, 1 H) and 11.23 (s, 1 H). c) 4-[(2-Carboxyphenylcarbamoyl)-methoxy]-5,7-dichloronaphthale ne-2- carboxylic acid (General procedure D)

[0086] A mixture of 5,7-dichloro-4-[(2-methoxycarbonylphenylcarbamoyl)-methoxy]- naphthalene-2-carboxylic acid methyl ester (13ab) (100 mg, 0.22 mmol) and LiOI-PH ₂ O (20 mg, 0.47 mmol) in THF/water (1 :1 ) (2 ml_) is stirred at rt for 20 h. The reaction mixture is diluted with water (5 ml_) and acidified by addition of 1 M aqueous HCI solution. The precipitated solid is collected on filter, washed with water and dried at 55 ⁰ C to give the title compound (0.077 g, 82%). ¹ H NMR (DMSO-d ₆ ), δ (ppm): 5.00 (s, 2H); 7.17 (t, 8 Hz, 1 H); 7.47 (s, 1 H); 7.62 (t, 8 Hz, 1 H); 7.83 (s, 1 H); 7.94 (d, 8 Hz, 1 H); 8.30 (s, 2H); 8.63 (d, 8 Hz, 1 H) and 11.88 (s, 1 H).

Example 4 5,7-Dichloro-4-[2-(4-methoxyphenyl)-2-oxo-ethoxy]-naphthalen e-2-carboxylic acid

a) 5,7-dichloro-4-[2-(4-methoxyphenyl)-2-oxo-ethoxy]-naphthalen e-2-carboxylic acid methyl ester (6c)

[0087] A mixture of δy-dichloro^-hydroxynaphthalene^-carboxylic acid methyl ester (4a) (150 mg, 0.55 mmol), K ₂ CO ₃ (92 mg, 0.664 mmol) and TBAI (10 mg, 0,03 mmol) in DMF (2 ml_) is stirred at rt for 20 min, then 2-bromo-1-(4-methoxyphenyl)-ethanone (5c) (151 mg, 0.66 mmol) is added and stirring continued for 3 days. The resulting mixture is diluted with water, precipitated solid is collected on filter, washed with water and dried at 55 ⁰ C to give the title compound 6c (192 mg, 83%). ¹ H NMR (DMSO-d ₆ ), δ (ppm): 3.87 (s, 6H); 5.80 (s, 2H); 7.10 (d 8.4 Hz, 2H); 7.38 (s, 1 H); 7.80 (d 1.5 Hz, 1 H); 8.05 (d, 8.4 Hz, 1 H); 8.27 (s, 1 H) and 8.29 (d, 1.5 Hz,1 H).

b) 5,7-Dichloro-4-[2-(4-methoxyphenyl)-2-oxo-ethoxy]-naphthalen e-2-carboxylic acid

[0088] A mixture of 5,7-dichloro-4-[2-(4-methoxyphenyl)-2-oxoethoxy]-naphthalene -2- carboxylic acid methyl ester (6c) (120 mg, 0.286 mmol) and 1 M aqueous NaOH (0.4 mL) in THF/water (1 :1) (4 ml_) is refluxed for 2 h. After cooling, the reaction mixture is acidified by addition of 1 M aqueous HCI. The precipitated solid is collected on filter, washed with water and dried at 55 ⁰ C to give the title compound (91 mg, 78%). ¹ H-NMR (200 MHz, DMSO-de), δ (ppm) 3.85 (s, 3H) ₁ 5.75 (s, 2H), 7.08 (d, 9.4 Hz, 2H), 7.35 (s, 1 H), 7.76 (d, 2.0 Hz, 1 H), 8.04 (d, 9.0 Hz, 2H), 8.19 (s, 1 H), 8.24 (d, 2.2 Hz, 1 H).

Example 5

5,7-Dichloro-4-[(2-hydroxymethylphenylcarbamoyl)-methoxy] -naphthalene-2- carboxylic acid

[0089] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 2-aminobenzyl alcohol (10ac) with chloroacetyl chloride gives 2-chloro-N-(2-hydroxymethyl-phenyl)- acetamide (12ac) in 94% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-chloro-N-(2-hydroxymethylphenyl)-acetamide (12ac) gives 5,7-dichloro-4-[(2-hydroxymethylphenylcarbamoyl)-methoxy]-na phthalene- 2-carboxylic acid methyl ester (13ac); c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[(2-hydroxymethyl- phenylcarbamoyl)-methoxy]-naphthalene-2-carboxylic acid methyl ester (13ac) with LiOH gives the title compound in 90% yield. ¹ H NMR (DMSO-d ₆ ), δ (ppm): 4.41 (d, 5 Hz, 2H); 4.96 (s, 2H); 5.31 (t, 5 Hz, 1 H); 7.13 (t, 8 Hz, 1 H); 7.21 (d, 8 Hz, 1 H); 7.31 (t, 8 Hz, 1 H); 7.50 (s, 1 H); 7.69 (d, 8 Hz, 1 H); 7.80; (s, 1 H); 8.28 (s, 2H) and 9.76 (s, 1 H).

Example 6

5,7-Dichloro-4-[(3-methoxyphenylcarbamoyl)-methoxy]-napht halene-2-carboxylic acid

[0090] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 3- methoxyphenylamine (10ad) with chloroacetyl chloride gives 2-chloro-N-(3- methoxyphenyl)-acetamide (12ad); b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-chloro-N-(3-methoxyphenyl)-acetamide (12ad) gives 5,7-dichloro-4-[(3-methoxy-phenylcarbamoyl)-methoxy]-naphtha lene-2-carboxylic acid methyl ester (13ad) in 58% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[(3-methoxy- phenylcarbamoyl)-methoxy]-naphthalene-2-carboxylic acid methyl ester (13ad) with LiOH gives the title compound in 74% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.71 (s, 3H), 4.92 (s, 2H), 6.66 (d, 8.2 Hz ₁ 1 H), 7.10-7.30 (m, 3H), 7.44 (s, 1 H), 7.80 (d, 2.0 Hz, 1 H) ₁ 8.25 (s, 1 H) ₁ 8.28 (d, 2.0 Hz, 1 H), 10.14 (s, 1 H).

Example 7

4-[(4-Carboxymethylphenylcarbamoyl)-methoxy]-5,7-dichloro naphthalene-2- carboxylic acid

[0091] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of (4-aminophenyl)- acetic acid ethyl ester (10ae) with chloroacetyl chloride gives [4-(2-chloro-acetylamino)- phenyl]-acetic acid ethyl ester (12ae); b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with [4-(2-chloroacetylamino)-phenyl]-acetic acid ethyl ester (12ae) gives 4-[(4-carboxymethylphenylcarbamoyl)-methoxy]-5,7-dichloro- naphthalene-2-carboxylic acid methyl ester (13ae) in 72% yield; c) in analogy to the procedure D hydrolysis of 4-[(4-carboxymethylphenylcarbamoyl)- methoxy]-5,7-dichloronaphthalene-2-carboxylic acid methyl ester (13ae) with LiOH gives the title compound in 45% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.50 (s, 2H), 4.93 (S ₁ 2H), 7.20 (d, 8.6 Hz, 2H) ₁ 7.45 (s, 1 H), 7.54 (d, 8.0 Hz, 2H) ₁ 7.80 (s, 1 H) ₁ 8.26 (s, 1 H), 8.28 (s, 1 H) ₁ 10.12 (s, 1 H)

Example 8

5,7-Dichloro-4-[(4-hydroxyphenylcarbamoyl)-methoxy]-napht halene-2-carboxylic acid

[0092] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 4-aminophenol (10af) with chloroacetyl chloride gives 2-chloro-N-(4-hydroxyphenyl)-acetamide (12af); b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-chloro-N-(4-hydroxyphenyl)-acetamide (12af) gives 5,7-dichloro-4-[(4-hydroxyphenylcarbamoyl)-methoxy]-naphthal ene-2-carboxylic acid methyl ester (13af) in 46% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[(4- hydroxyphenylcarbamoyO-methoxyJ-naphthalene^-carboxylic acid methyl ester (13af) with LiOH gives the title compound in 67% yield. ¹ H-NMR (200 MHz ₁ DMSO-d ₆ ), δ (ppm) 4.88 (S, 2H), 6.70 (d, 9.0 Hz, 2H), 7.37 (d, 9.0 Hz ₁ 2H) ₁ 7.44 (s, 1 H) ₁ 7.80 (s, 1 H), 8.25 (s, 1 H), 8.27 (s, 1 H), 9.26 (s, 1 H), 9.86 (s, 1 H).

Example 9

5,7-Dichloro-4-[(4-hydroxymethyl-phenylcarbamoyl)-methoxy ]-naphthalene-2- carboxylic acid

[0093] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 4- aminophenylmethanol (10ag) with chloroacetyl chloride gives 2-chloro-N-(4- hydroxymethylphenyl)-acetamide (12ag) in 99% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-chloro-N-(4-hydroxymethylphenyl)-acetamide (12ag) gives 5,7-dichloro-4-[(4-hydroxymethyl-phenylcarbamoyl)-methoxy]- naphthalene-2-carboxylic acid methyl ester (13ag) in 58% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[(4-hydroxymethyl- phenylcarbamoylj-methoxyl-naphthalene^-carboxylic acid methyl ester (13ag) with LiOH gives the title compound in 43% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.43 (s, 2H), 4.93 (s, 2H), 7.26 (d, 8.8 Hz, 2H), 7.45 (s, 1 H), 7.55 (d, 7.8 Hz, 2H), 7.80 (s, 1 H), 8.26 and 8.27 (both s, total 2H), 10.10 (s, 1 H), 13.20-13.60 (br s, 1 H).

Example 10

5,7-Dichloro-4-[(3-hydroxymethylphenylcarbamoyl)-methoxy] -naphthalene-2- carboxylic acid

[0094] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 3- aminophenylmethanol (10ah) with chloroacetyl chloride gives 2-chloro-N-(3- hydroxymethylphenyl)-acetamide (12ah) in 99% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-chloro-N-(3-hydroxymethylphenyl)-acetamide (12ah) gives δJ-dichloro^-KS-hydroxymethylphenylcarbamoylJ-methoxyl-naph thalene- 2-carboxylic acid methyl ester (13ah) in 62% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[(3-hydroxymethyl- phenylcarbamoyl)-methoxy]-naphthalene-2-carboxylic acid methyl ester (13ah) with LiOH gives the title compound in 43% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.46 (d, 3.8 Hz, 2H), 4.93 (s, 2H), 5.18-5.22 ( br s, 1H), 7.01 (d, 7.0 Hz, 1 H), 7.22-7.30 (m, 1 H), 7.40-7.50 (m, 2H), 7.59 (s, 1 H), 7.80 (s, 1 H), 8.26 and 8.28 (both s, total 2H), 10.12 (s, 1 H).

Example 11

4-{[3-(tert-Butoxycarbonylaminomethyl)-phenylcarbamoyl]-m ethoxy}-5,7- dichloronaphthalene-2-carboxylic acid

[0095] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of (3-aminobenzyl)- carbamic acid tert-butylester (10ai) with chloroacetyl chloride gives [3-(2- chloroacetylamino)-benzyl]-carbamic acid tert-butylester (12ai) in 99% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with [3-(2-chloroacetylamino)-benzyl]-carbamic acid tert-butylester (12ai) gives 4-{[3-(tert-butoxycarbonylaminomethyl)-phenylcarbamoyl]- methoxy}-5,7-dichloronaphthalene-2-carboxylic acid methyl ester (13ai) in 25% yield; c) in analogy to the procedure D hydrolysis of 4-{[3-(tert-butoxycarbonylaminomethyl)- phenylcarbamoyl]-methoxy}-5,7-dichloronaphthalene-2-carboxyl ic acid methyl ester (13ai) with LiOH gives the title compound in 75% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 1.36 (s, 9H), 4.07 (d, 6.0 Hz, 2H), 4.93 (s, 2H), 6.94 (d, 7.8 Hz, 1 H), 7.21-7.29 (m, 1 H), 7.35-7.42 (m, 1 H), 7.45-7.50 (m, 3H), 7.79 (d, 2.0 Hz, 1H), 8.26 (s, 1 H), 8.28 (d, 1.4 Hz, 1 H), 10.13 (s, 1 H).

Example 12

4-[(3-Aminomethylphenylcarbamoyl)-methoxy]-5,7-dichloro-n aphthalene-2- carboxylic acid [0096] In analogy to the procedure described in Example 2(b), 4-{[3-(tert- butoxycarbonylaminomethyO-phenylcarbamoyll-rnethoxyJ-δJ-dic hloro-naphthalene^- carboxylic acid (Example 11) is treated with TFA to give the title compound in 88 % yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.92 and 4.01 (both s, total 2H), 4.70 and 4.99 (both s, total 2H), 7.18 (d, 8.2 Hz), 7.38-7.52 (m), 7.84 (d, 8.4 Hz), 8.13 (s) and 8.30 (s) (total 8H) ₁ 10.30 (s, 1 H).

Example 13

4-[(3-Carboxymethylphenylcarbamoyl)-methoxy]-5,7-dichloro naphthalene-2- carboxylic acid

[0097] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 3- aminophenylacetic acid ethyl ester (10ak) with chloroacetyl chloride gives [3-(2- chloroacetylamino)-phenyl]-acetic acid ethyl ester (12ak) in 80% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with [3-(2-chloroacetylamino)-phenyl]-acetic acid ethyl ester (12ak) gives δJ-dichloro^-KS-ethoxycarbonylmethylphenylcarbamoyO-methoxy ]- naphthalene-2-carboxylic acid methyl ester (13ak) in 95% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[(3- ethoxycarbonylmethylphenylcarbamoyl)-methoxy]-naphthalene-2- carboxylic acid methyl ester (13ak) with LiOH gives the title compound in 53% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.52 (s, 2H), 4.93 (s, 2H), 6.96 (d, 8.4 Hz, 1 H), 7.21-7.29 (m, 1 H) ₁ 7.44-7.52 (m, 3H), 7.80 (d, 2.2 Hz, 1 H), 8.25 (s, 1 H), 8.28 (d, 2.2 Hz, 1 H), 10.14 (s, 1 H).

Example 14

4-{[(4-Carboxy-phenyl)-methylcarbamoyl]-methoxy}-5,7-dich loronaphthalene-2- carboxylic acid

[0098] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 4- methylaminobenzoic acid methyl ester (1OaI) with chloroacetyl chloride gives 4-[(2- chloroacetyl)-methylamino]-benzoic acid methyl ester (12al) in 98% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 4-[(2-chloroacetyl)-methylamino]-benzoic acid methyl ester (12al) gives 5,7-dichloro-4-{[(4-methoxycarbonylphenyl)-methyl- carbamoyl]-methoxy}-naphthalene-2-carboxylic acid methyl ester (13al) in 92% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-{[(4- methoxycarbonylphenyl)-methylcarbamoyl]-methoxy}-naphthalene -2-carboxylic acid methyl ester (13al) with LiOH gives the title compound in 40% yield. ¹ H-NMR (200 MHz, DMSO-dβ), δ (ppm) 4.91 (br s, 2H), 7.27 (s, 1 H), 7.53 (d, 8.6 Hz, 2H), 7.72 (d, 2.2 Hz, 1 H), 7.95 (d, 8.0 Hz, 2H), 8.20 (s, 1 H), 8.23 (d, 2.2 Hz, 1 H).

Example 15

4-[(2-Carboxymethylphenylcarbamoyl)-methoxy]-5,7-dichloro naphthalene-2- carboxylic acid

[0099] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of (2-aminophenyl)- acetic acid methyl ester (10am) with chloroacetyl chloride gives [2-(2- chloroacetylamino)-phenyl]-acetic acid methyl ester (12am) in 94% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with [2-(2-chloroacetylamino)-phenyl]-acetic acid methyl ester (12am) gives 5,7-dichloro-4-[(2-methoxycarbonylmethyl-phenylcarbamoyl)- methoxy]-naphthalene-2-carboxylic acid methyl ester (13am) in 32% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[(2- methoxycarbonylmethylphenylcarbamoyl)-methoxy]-naphthalene-2 -carboxylic acid methyl ester (13am) with LiOH gives the title compound in 21 % yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.54 (s, 2H), 4.95 (s, 2H), 7.12-7.26 (m, 3H), 7.43-7.49 (m, 2H), 7.79 (d, 2.0 Hz, 1 H), 8.28 (s, 2H), 9.62 (s, 1 H).

Example 16

5,7-Dichloro-4-[1-(4-hydroxymethylphenylcarbamoyl)-ethoxy ]-naphthalene-2- carboxylic acid

[00100] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of (4-aminophenyl)- methanol (10ag) with 2-bromopropionyl chloride (11b) gives 2-bromo-N-(4- hydroxymethylphenyl)-propionamide (12an) in 99% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-bromo-N-(4-hydroxymethylphenyl)- propionamide (12an) gives 5,7-dichloro-4-[1-(4-hydroxymethylphenylcarbamoyl)- ethoxy]-naphthalene-2-carboxylic acid methyl ester (13an) in 97% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[1-(4- hydroxymethylphenylcarbamoylj-ethoxyj-naphthalene^-carboxyli c acid methyl ester (13an) with LiOH gives the title compound in 34% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 1.68 (d, 6.4 Hz, 3H), 4.43 (d, 4.8 Hz ₁ 2H), 5.05-5.20 (m, 2H), 7.25 (d, 8.2 Hz, 2H), 7.41 (s, 1 H), 7.53 (d, 8.4 Hz, 2H), 7.81 (d, 1.4 Hz, 1 H), 8.23 (s, 1 H), 8.28 (d, 2.4 Hz, 1 H), 10.28 (s, 1 H).

Example 17

5,7-Dichloro-4-[1-(2-hydroxymethylphenylcarbamoyl)-ethoxy ]-naphthalene-2- carboxylic acid

[00101] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 2- aminophenylmethanol (10ac) with 2-bromopropionyl chloride (11b) gives 2-bromo-N-(2- hydroxymethylphenyl)-propionamide (12ao) in 58% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-bromo-N-(2-hydroxymethylphenyl)- propionamide (12ao) gives 5,7-dichloro-4-[1-(2-hydroxymethylphenylcarbamoyl)- ethoxy]-naphthalene-2-carboxylic acid methyl ester (13ao) in 69% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[1-(2- hydroxymethylphenylcarbamoyl)-ethoxy]-naphthalene-2-carboxyl ic acid methyl ester (13ao) with LiOH gives the title compound in 67% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 1.69 (d, 6.6 Hz, 3H), 4.20-4.28 (m, 1 H), 4.37-4.46 (m, 1 H), 5.12 (q, 6.6 Hz, 1 H), 5.20-5.30 (br s, 1 H), 7.08-7.33 (m, 3H), 7.44 (s, 1 H), 7.60 (d, 8.0 Hz, 1 H), 7.78 (d, 2.0 Hz, 1 H), 8.25 (s, 1 H), 8.27 (d, 1.6 Hz, 1 H), 9.92 (s, 1 H). Example 18 4-(Benzylcarbamoylmethoxy)-5,7-dichloro-naphthalene-2-carbox ylic acid

[00102] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of benzylamine (10an) with chloroacetyl chloride gives N-benzyl-2-chloroacetamide (12ap) in 99% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with N-benzyl-2-chloroacetamide (12ap) gives 4- (benzylcarbamoylmethoxy)-5,7-dichloronaphthalene-2-carboxyli c acid methyl ester (13ap) in 47% yield; c) in analogy to the procedure D hydrolysis of 4-(benzylcarbamoylmethoxy)-5,7- dichloronaphthalene-2-carboxylic acid methyl ester (13ap) with LiOH gives the title compound in 84% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.36 (d, 6.0 Hz, 2H) ₁ 4.81 (s, 2H) ₁ 7.20-7.40 (m, 5H), 7.42 (s, 1H), 7.78 (d, 1.6 Hz, 1H), 8.22-8.30 (m, 2H), 8.51 (t, 5.9 Hz, 1 H).

Example 19

4-[(Carboxymethylphenylcarbamoyl)-methoxy]-5,7-dichloro-n aphthalene-2- carboxylic acid

[00103] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of N-phenylglycine ethyl ester (10ao) with chloroacetyl chloride gives N-chloroacetyl-N-phenylglycine ethyl ester (12aq) in 71% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with N-chloroacetyl-N-phenylglycine ethyl ester (12aq) gives δJ-dichloro^-KethoxycarbonylmethylphenylcarbamoyO-methoxyJ- naphthalene^- carboxylic acid methyl ester (13aq) in good yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4- [(ethoxycarbonylmethylphenylcarbamoyl)-methoxy]-naphthalene- 2-carboxylic acid methyl ester (13aq) with LiOH gives the title compound in 26% yield. ¹ H-NMR (200 MHz, DMSO-de), δ (ppm) 4.30 (s, 2H), 4.72 (s, 2H), 7.21 (s, 1 H), 7.40-7.60 (m, 5H), 7.73 (d, 2.0 Hz, 1 H), 8.19 (s, 1 H), 8.23 (s, 1 H). Example 20

^{^-CarboxyphenyO-methylcarbamoyll-methoxy^SJ-dichloronap hthalene-Z- carboxylic acid (l-B-18)

[00104] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 2- methylaminobenzoic acid methyl ester (10ap) with chloroacetyl chloride gives 2-[(2- chloroacetyl)-methylamino]-benzoic acid methyl ester (12ar) in 84% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-[(2-chloroacetyl)-methylamino]-benzoic acid methyl ester (12ar) gives 5,7-dichloro-4-{[(2-methoxycarbonylphenyl)-methylcarbamoyl]- methoxy}-naphthalene-2-carboxylic acid methyl ester (13ar) in 66% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-{[(2- methoxycarbonylphenyl)-methylcarbamoyl]-methoxy}-naphthalene -2-carboxylic acid methyl ester (13ar) with LiOH gives the title compound in 71 % yield. ¹ H-NMR (200 MHz, DMSO-de), δ (ppm) 3.10 (s, 3H), 4.47 (d, 14.5 Hz, 1 H) ₁ 4.57 (d, 14.5 Hz, 1 H), 7.25 (s, 1 H), 7.48-7.57 (m, 2H) ₁ 7.66 (d, 7.4 Hz, 1 H), 7.72 (d, 1.6 Hz, 1 H) ₁ 7.96 (d, 8.0 Hz, 1 H), 8.19 (s, 1 H), 8.22 (d, 1.4 Hz, 1 H).

Example 21 5,7-Dichloro-4-(phenethylcarbamoylmethoxy)-naphthalene-2-car boxylic acid

[00105] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of phenethylamine (10aq) with chloroacetyl chloride gives 2-chloro-N-phenethylacetamide (12as) in 99% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-chloro-N-phenethylacetamide (12as) gives 5,7- dichloro-4-(phenethylcarbamoylmethoxy)-naphthalene-2-carboxy lic acid methyl ester (13as) in 85% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4- (phenethylcarbamoylmethoxyj-naphthalene^-carboxylic acid methyl ester (13as) with LiOH gives the title compound in 35% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 2.74 (t, 7.4 Hz ₁ 2H), 3.30-3.45 (m, 2H), 4.70 (s, 2H), 7.16-7.29 (m, 5H) ₁ 7.39 (d, 1.4 Hz, 1 H), 7.78 (d, 2.2 Hz, 1 H), 7.99 (t, 5.5 Hz, 1 H), 8.25 (s, 1 H), 8.27 (d, 2.4 Hz, 1 H).

Example 22

5,7-Dichloro-4-[(3-hydroxymethylbenzylcarbamoyl)-methoxy] -naphthalene-2- carboxylic acid

[00106] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of (3- aminomethylphenyl)-methanol (10ar) with chloroacetyl chloride gives 2-chloro-N-(3- hydroxymethylbenzyl)-acetamide (12at) in 32% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-chloro-N-(3-hydroxymethylbenzyl)-acetamide (12at) gives δy-dichloro^-KS-hydroxymethylbenzylcarbamoylJ-methoxyl-naph thalene- 2-carboxylic acid methyl ester (13at) in 70% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[(3- hydroxymethylbenzylcarbamoylj-methoxyj-naphthalene^-carboxyl ic acid methyl ester (13at) with LiOH gives the title compound in 35% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.35 (d, 6.2 Hz, 2H), 4.45 (s, 2H), 4.80 (s, 2H), 5.10-5.20 (m, 1 H), 7.10-7.28 (m, 4H), 7.42 (s, 1 H), 7.79 (s, 1 H), 8.26 (s, 2H), 8.49 (t, 6.1 Hz, 1 H).

Example 23

7-Chloro-4-[(2-hydroxymethylphenylcarbamoyl)-methoxy]-nap hthalene-2- carboxylic acid

[00107] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure A acylation of 7-chloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4b) with 2-chloro-N-(2-hydroxymethylphenyl)-acetamide (12ac) gives 7-chloro-4-[(2-hydroxymethylphenylcarbamoyl)-methoxy]-naphth alene-2- carboxylic acid methyl ester (13au) in 41% yield; b) in analogy to the procedure D hydrolysis of 7-chloro-4-[(2- hydroxymethylphenylcarbamoyO-methoxyJ-naphthalene^-carboxyli c acid methyl ester (13au) with LiOH gives the title compound in 69% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.54 (d, 5.0 Hz, 2H), 4.99 (s, 2H), 5.70 (t, 5.0 Hz, 1 H), 7.12 (t, 6.8 Hz, 1 H), 7.25-7.35 (m, 2H), 7.43 (s, 1 H), 7.64 (dd, 8.9 and 2.1 Hz, 1 H), 7.88 (d, 8.2 Hz ₁ 1 H), 8.25 (s, 2H), 8.51 (d, 8.6 Hz, 1 H), 10.08 (s, 1 H).

Example 24

4-[(1-Carboxy-2-phenylethylcarbamoyl)-methoxy]-5,7-dichlo ronaphthalene-2- carboxylic acid

[00108] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of phenylalanine methyl ester (10as) with chloroacetyl chloride gives 2-(2-chloroacetylamino)-3- phenylpropionic acid methyl ester (12au) in 92% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-(2-chloroacetylamino)-3-phenylpropionic acid methyl ester (12au) gives δJ-dichloro^-KI-methoxycarbonyl^-phenyl-ethylcarbamoyl)- methoxy]-naphthalene-2-carboxylic acid methyl ester (13av) in 69% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[(1-methoxycarbonyl-2- phenylethylcarbamoyl)-methoxy]-naphthalene-2-carboxylic acid methyl ester (13av) with LiOH gives the title compound in 31 % yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 2.92-3.16 (m, 2H), 4.56-4.67 (m, 1 H), 4.75 (s, 2H), 7.10-7.25 (m, 5H), 7.40 (s, 1 H), 7.77 (d, 2.2 Hz, 1 H), 8.06 (d, 8.2 Hz, 1 H), 8.25 (s, 1 H), 8.27 (d, 2.2 Hz, 1 H).

Example 25

5,7-Dichloro-4-[1-(3-hydroxymethylphenylcarbamoyl)-ethoxy ]-naphthalene-2- carboxylic acid

[00109] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 2- aminophenylmethanol (10ac) with 2-bromopropionyl chloride (11b) gives 2-bromo-N-(3- hydroxymethylphenyl)-propionamide (12av) in 80% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-bromo-N-(3-hydroxymethyl-phenyl)- propionamide (12av) gives 5,7-dichloro-4-[1-(3-hydroxymethylphenylcarbamoyl)- ethoxy]-naphthalene-2-carboxylic acid methyl ester (13aw) in 16% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[1-(3- hydroxymethylphenylcarbamoyO-ethoxyl-naphthalene^-carboxylic acid methyl ester (13aw) with LiOH gives the title compound in 38% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 1.66 (d, 6.4 Hz, 3H), 4.44 (d, 5.0 Hz, 2H), 5.01-5.21 (m, 2H), 6.99 (d, 8.4 Hz, 1 H), 7.23 (t, 8.1 Hz, 1 H), 7.38 (s, 1 H), 7.45 (d, 8.0 Hz, 1 H), 7.56 (s, 1 H), 7.79 (s, 1 H), 8.21 (s, 1 H), 8.25 (s, 1 H), 10.28 (s, 1 H).

Example 26

4-[(3-Carboxymethylphenylcarbamoyl)-methoxy]-7-chloro-nap hthalene-2- carboxylic acid

[00110] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure A acylation of 7-chloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4b) with [3-(2-chloroacetylamino)-phenyl]-acetic acid ethyl ester (12ak) gives 7-chloro-4-[(3-ethoxycarbonylmethyl-phenylcarbamoyl)-methoxy ]- naphthalene-2-carboxylic acid methyl ester (13ax) in 84% yield; b) in analogy to the procedure D hydrolysis of 7-chloro-4-[(3-ethoxycarbonylmethyl- phenylcarbamoyl)-methoxy]-naphthalene-2-carboxylic acid methyl ester (13ax) with LiOH gives the title compound in 29% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm)

3.54 (s, 2H), 4.99 (s, 2H), 6.98 (d, 7.4 Hz, 1H), 7.27 (t, 8.0 Hz, 1 H), 7.38 (s, 1 H), 7.50-

7.55 (m, 2H), 7.68 (dd, 8.6 and 2.2 Hz, 1 H) ₁ 8.22 (s, 1 H), 8.25 (d, 2.2 Hz, 1 H), 8.34 (d, 9.0 Hz, 1 H), 10.28 (s, 1 H).

Example 27

4-{[(Carboxyphenylmethyl)-carbamoyl]-methoxy}-5,7-dichlor onaphthalene-2- carboxylic acid

[00111] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of phenylglycine methyl ester (10at) with chloroacetyl chloride gives (2-chloroacetylamino)-phenylacetic acid methyl ester (12aw) in 62% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with (2-chloroacetylamino)-phenylacetic acid methyl ester (12aw) gives δ.Z-dichloro-^KmethoxycarbonylphenylmethyO-carbamoyl]- methoxy}-naphthalene-2-carboxylic acid methyl ester (13ay) in 30% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4- {[(methoxycarbonylphenylmethyl)-carbamoyl]-methoxy}-naphthal ene-2-carboxylic acid methyl ester (13ay) with LiOH gives the title compound in 19% yield. ¹ H-NMR (200 MHz, DMSO-de), δ (ppm) 4.84 (d, 4.8 Hz, 2H), 5.34-5.44 (m, 1 H), 7.30-7.45 (m, 6H), 7.82 (d, 2.2 Hz, 1 H), 8.26 (s, 1 H), 8.28 (s, 1 H), 8.60 (d, 7.4 Hz, 1 H).

Example 28

7-Chloro-4-[(3-hydroxymethylphenylcarbamoyl)-methoxy]-nap hthalene-2- carboxylic acid

[00112] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure A acylation of 7-chloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4b) with 2-chloro-N-(3-hydroxymethylphenyl)-acetamide (12ah) gives 7-chloro-4-[(3-hydroxymethylphenylcarbamoyl)-methoxy]-naphth alene-2- carboxylic acid methyl ester (13az) in 51 % yield; b) in analogy to the procedure D hydrolysis of 7-chloro-4-[(3- hydroxymethylphenylcarbamoyO-methoxyJ-naphthalene^-carboxyli c acid methyl ester (13az) with LiOH gives the title compound in 66% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.45 (d, 5.6 Hz, 2H), 4.98 (s, 2H), 5.20 (t, 5.6 Hz, 1 H), 7.00 (d, 8.2 Hz, 1 H), 7.22 (t, 7.7 Hz, 1 H), 7.35 (s, 1 H), 7.49 (d, 9.2 Hz, 1 H), 7.59 (s, 1 H), 7.68 (dd, 8.8 and 2.2 Hz, 1 H), 8.22 (s, 1 H), 8.25 (d, 1.6 Hz, 1 H) ₁ 8.33 (d, 9.0 Hz, 1 H), 10.25 (s, 1 H).

Example 29

5,7-Dichloro-4-[((R)-2-hydroxy-1-phenylethylcarbamoyl)-me thoxy]-naphthalene-2- carboxylic acid

[00113] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of (R)-(-)-2- phenylglycinol (10au) with chloroacetyl chloride gives 2-chloro-N-((R)-2-hydroxy-1- phenylethyl)-acetamide (12ax) in 30% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-chloro-N-((R)-2-hydroxy-1-phenylethyl)- acetamide (12ax) gives 5,7-dichloro-4-[((R)-2-hydroxy-1-phenylethylcarbamoyl)- methoxy]-naphthalene-2-carboxylic acid methyl ester (13ba) in 93% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[((R)-2-hydroxy-1- phenylethylcarbamoyO-methoxyl-naphthalene^-carboxylic acid methyl ester (13ba) with LiOH gives the title compound in 14% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.60-3.70 (m, 2H), 4.72-5.04 (m, 4H), 7.20-7.35 (m, 5H), 7.44 (s, 1 H), 7.81 (d, 2.4 Hz, 1 H), 8.26 (s, 1 H), 8.28 (d, 2.2 Hz, 1 H), 8.37 (d, 8.0 Hz, 1 H).

Example 30

1-[2-(3-Carboxy-6,8-dichloronaphthalen-1-yloxy)-acetyl]-p iperidine-3-carboxylic acid

[00114] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of piperidine-3- carboxylic acid ethyl ester (10av) with chloroacetyl chloride gives 1 -(2-chloro-acetyl)- piperidine-3-carboxylic acid ethyl ester (12ay) in 46% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 1-(2-chloroacetyl)-piperidine-3-carboxylic acid ethyl ester (12ay) gives 1-[2-(6,8-dichloro-3-methoxycarbonylnaphthalen-1-yloxy)- acetyl]-piperidine-3-carboxylic acid ethyl ester (13bb) in good yield; c) in analogy to the procedure D hydrolysis of 1-[2-(6,8-dichloro-3- methoxycarbonylnaphthalen-1-yloxy)-acetyl]-piperidine-3-carb oxylic acid ethyl ester (13bb) with LiOH gives the title compound in 42% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 1.50-2.40 (m, 3H), 2.60-3.10 (m, 2H), 3.80-3.90 (m, 2H), 4.35 (dd, 12 and 3 Hz, 1 H), 5.03-5.22 (m, 3H), 7.39 (s, 1 H), 7.77 (s, 1 H), 8.21 (s, 1H) and 8.25 (s, 1 H).

Example 31

4-{[(3-Carboxyphenyl)-methylcarbamoyl]-methoxy}-5,7-dichl oronaphthalene-2- carboxylic acid

[00115] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of 3-methylamino- benzoic acid methyl ester (10aw) with chloroacetyl chloride gives 3-[(2-chloroacetyl)- methylamino]-benzoic acid methyl ester (12az) in 57% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 3-[(2-chloroacetyl)-methylamino]-benzoic acid methyl ester (12az) gives 5,7-dichloro-4-{[(3-methoxycarbonylphenyl)-methyl- carbamoyl]-methoxy}-naphthalene-2-carboxylic acid methyl ester (13bc) in 83% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-{[(3- methoxycarbonylphenyl)-methylcarbamoyl]-methoxy}-naphthalene -2-carboxylic acid methyl ester (13bc) with LiOH gives the title compound in 44% yield. ¹ H-NMR (200 MHz ₁ DMSO-de), δ (ppm) 4.65-4.80 (br s, 2H), 7.20-7.40 (br s, 1 H), 7.53 (t, 7.7 Hz, 1 H), 7.60-7.75 (m, 2H), 7.80-7.90 (m, 2H), 8.19 (s, 1 H), 8.22 (s, 1 H).

Example 32 4-(Carboxyphenylmethoxy)-5,7-dichloronaphthalene-2-carboxyli c acid

[00116] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with bromophenylacetic acid methyl ester (5d) gives 5,7-dichloro-4-(methoxycarbonylphenylmethoxy)-naphthalene-2- carboxylic acid methyl ester (6d) in 40% yield; b) in analogy to the procedure D hydrolysis of 5,7-dichloro-4- (methoxycarbonylphenylmethoxy)-naphthalene-2-carboxylic acid methyl ester (6d) with LiOH gives the title compound in 64% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 6.09 (S ₁ 1 H), 7.38-7.50 (m, 4H), 7.69-7.78 (m, 3H), 8.24 (s, 1 H), 8.27 (d, 2.2 Hz, 1 H).

Example 33 5,7-Dichloro-4-phenylcarbamoylmethoxynaphthalene-2-carboxyli c acid

[00117] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of aniline (10ax) with chloroacetyl chloride gives 2-chloro-N-phenylacetamide (12ba) in 97% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 2-chloro-N-phenylacetamide (12ba) gives 5,7- dichloro-4-phenylcarbamoylmethoxynaphthalene-2-carboxylic acid methyl ester (13bd) in 40% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4- phenylcarbamoylmethoxynaphthalene-2-carboxylic acid methyl ester (13bd) with LiOH gives the title compound in 86% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.94 (s, 2H), 7.08 (t, 7.3 Hz, 1 H), 7.32 (t, 7.3 Hz, 2H), 7.46 (s, 1 H), 7.60 (d, 8.0 Hz, 2H), 7.81 (s, 1 H) ₁ 8.26 (s, 1 H), 8.28 (s, 1 H), 10.14 (s, 1 H).

Example 34

4-[(4-Aminomethyl-2-carboxymethoxyphenylcarbamoyl)-methox y]-5,7- dichloronaphthalene-2-carboxylic acid

[00118] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of [2-amino-5-(tert- butoxycarbonylaminomethyl)-phenoxy]-acetic acid tert-butyl ester (10ay) [Katayama, Seiji; Ae, Nobuyuki; Nagata, Ryu; J. Org. Chem. 2001, 66 (10), 3474-3483.] with chloroacetyl chloride gives 5-(tert-butoxycarbonylaminomethyl)-2-(2-chloroacetylamino)- phenoxy]-acetic acid tert-butyl ester (12bb) in 36% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with [5-(tert-butoxycarbonylaminomethyl)-2-(2- chloroacetylamino)-phenoxy]-acetic acid tert-butyl ester (12bb) provides 4-{[4-(tert- butoxycarbonylamino-methyl)-2-tert-butoxycarbonylmethoxy-phe nylcarbamoyl]- methoxy}-5,7-dichloro-naphthalene-2-carboxylic acid methyl ester (13be-1), c) in analogy to the procedure described in Example 2(b), 4-{[4-(tert- butoxycarbonylamino-methyO^-tert-butoxycarbonylmethoxy-pheny lcarbamoyl]- methoxy}-5,7-dichloro-naphthalene-2-carboxylic acid methyl ester (13be-1) is treated with TFA to give 4-[(4-aminomethyl-2-carboxymethoxyphenylcarbamoyl)-methoxy]- 5,7- dichloro-naphthalene-2-carboxylic acid methyl ester (13be-2) in good yield. d) in analogy to the procedure D hydrolysis of 4-[(4-aminomethyl-2- carboxymethoxyphenylcarbamoyl)-methoxy]-5,7-dichloronaphthal ene-2-carboxylic acid methyl ester (13be-2) with LiOH gives the title compound in 77% yield. ¹ H-NMR (200 MHz, DMSO-de), δ (ppm) 3.90-4.00 (m, 2H), 4.81 (s, 2H), 5.00 (s, 2H), 7.08 (d, 8.0 Hz, 1 H), 7.26 (s, 1 H), 7.52 (s, 1 H), 7.81 (d, 1.4 Hz, 1 H), 8.22-8.43 (m, 5H), 9.42 (s, 1 H). Example 35

1-[2-(3-Carboxy-6,8-dichloronaphthalen-1-yloxy)-acetyl]-p yrrolidine-2-carboxylic acid

[00119] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of L-proline methyl ester (10az) with chloroacetyl chloride gives 1-(2-chloroacetyl)-pyrrolidine-2-carboxylic acid methyl ester (12bc) in 41% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 1-(2-chloroacetyl)-pyrrolidine-2-carboxylic acid methyl ester (12bc) gives 1-[2-(6,8-dichloro-3-methoxycarbonylnaphthalen-1-yloxy)- acetyl]-pyrrolidine-2-carboxylic acid methyl ester (13bf) in 78% yield. c) in analogy to the procedure D hydrolysis of 1-[2-(6,8-dichloro-3- methoxycarbonylnaphthalen-1-yloxy)-acetyl]-pyrrolidine-2-car boxylic acid methyl ester (13bf) with LiOH gives the title compound in 56% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 1.80-2.00 (m, 2H) ₁ 2.10-2.20 (m, 2H), 3.63 (t, 6.5 Hz, 2H), 4.25 (dd, 8.2 and 3.6 Hz, 1 H), 5.01 (s, 2H), 7.39 (s, 1 H), 7.75 (d, 2.2 Hz, 1 H), 8.21 (s, 1 H), 8.24 (d, 1.2 Hz, 1 H).

Example 36

5,7-Dichloro-4-[2-oxo-2-(toluene-4-sulfonylamino)-ethoxy] -naphthalene-2- carboxylic acid

[00120] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of p- toluenesulfonamide (10ba) with chloroacetyl chloride gives N-(2-chloroacetyl)-p- toluenesulfonamide (12bd) in 35% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with N-(2-chloroacetyl)-p-toluenesulfonamide (12bd) gives 5,7-dichloro-4-[2-oxo-2-(toluene-4-sulfonylamino)-ethoxy]-na phthalene-2- carboxylic acid methyl ester (13bg) in 36% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[2-oxo-2-(toluene-4- sulfonylamino)-ethoxy]-naphthalene-2-carboxylic acid methyl ester (13bg) with LiOH gives the title compound in 20% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 2.36 (s, 3H), 4.86 (s, 2H), 7.21 (s, 1 H), 7.37 (d, 8.0 Hz, 2H), 7.75-7.80 (m, 3H) ₁ 8.21 (s, 1 H), 8.25 (d, 2.2 Hz, 1 H).

Example 37

4-[(1-Carboxymethyl-2-phenylethylcarbamoyl)-methoxy]-5,7- dichloronaphthalene- 2-carboxylic acid

[00121] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of homophenylalanine ethyl ester (10bb) with chloroacetyl chloride gives 3-(2-chloro- acetylamino)-4-phenylbutyric acid ethyl ester (12be) in 73% yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 3-(2-chloroacetylamino)-4-phenylbutyric acid ethyl ester (12be) gives 4-[(1-benzyl-2-ethoxycarbonylethylcarbamoyl)-methoxy]-5,7- dichloronaphthalene-2-carboxylic acid methyl ester (13bh) in 62% yield; c) in analogy to the procedure D hydrolysis of 4-[(1-benzyl-2- ethoxycarbonylethylcarbamoyl)-methoxy]-5,7-dichloro-naphthal ene-2-carboxylic acid methyl ester (13bh) with LiOH gives the title compound in 61% yield. ¹ H-NMR (200 MHz, DMSO-de), δ (ppm) 2.41 (d, 5.6 Hz, 2H), 2.80 (d, 7.4 Hz, 2H), 4.35 (dd, 7.4 and 5.6 Hz, 1 H), 4.65 (s, 2H), 7.15-7.30 (m, 5H), 7.38 (s, 1 H), 7.79 (d, 2.0 Hz, 1 H), 7.93 (d, 8.6 Hz, 1 H), 8.26 (s, 1H), 8.28 (d, 1.6 Hz, 1 H).

Example 38

2-[2-(3-Carboxy-6,8-dichloronaphthalen-1-yloxy)-acetyl]-1 , 2,3,4- tetrahydroisoquinoline-3-carboxylic acid

[00122] The title compound is prepared by the following reaction sequence: a) a mixture of 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride (10bc) (108 mg, 0.47 mmol), 5,7-dichloro-4- chlorocarbonylmethoxynaphthalene-2-carboxylic acid methyl ester (9a) (150 mg, 0.43 mmol) and TEA (0.21 mL, 5.51 mmol) in CH ₂ CI ₂ (4 ml_) is stirred at rt for 3 days. After evaporation under reduced pressure, the residue is purified by flash chromatography to give 2-[2-(6,8-dichloro-3-methoxycarbonylnaphthalen-1 -yloxy)-acetyl]-1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid methyl ester (13bi) (207 mg, 95%). b) in analogy to the procedure D hydrolysis of 2-[2-(6,8-dichloro-3- methoxycarbonylnaphthalen-1-yloxy)-acetyl]-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester (13bi) with LiOH gives the title compound in 47% yield. ¹ H-NMR (200 MHz, DMSO-de), δ (ppm) 3.10-3.40 (m, 2H), 4.74-5.04 (m, 2H), 5.10-5.35 (m, 3H), 7.10- 7.30 (m, 4H), 7.45 (s, 1 H), 7.76 (s, 1 H), 8.22 (s, 1 H), 8.25 (d, 1.6 Hz, 1 H).

Example 39

4-{[(2-Carboxyphenyl)-methyl-carbamoyl]-methoxy}-6,7-dich loronaphthalene-2- carboxylic acid

[00123] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure A acylation of 6,7-dichloro-4-hydroxy-naphthalene-2- carboxylic acid methyl ester (4c) with 2-[(2-chloroacetyl)-methylamino]-benzoic acid methyl ester (12ar) (Example 22(a)) gives 6,7-dichloro-4-{[(2-methoxycarbonylphenyl)- methylcarbamoyl]-methoxy}-naphthalene-2-carboxylic acid methyl ester (13bj) in 83% yield; c) in analogy to the procedure D hydrolysis of 6,7-dichloro-4-{[(2- methoxycarbonylphenyl)-methylcarbamoyl]-methoxy}-naphthalene -2-carboxylic acid methyl ester (13bj) with LiOH gives the title compound in 69% yield. ¹ H-NMR (200 MHz, DMSO-de), δ (ppm) 3.10 (s, 3H), 4.53-4.71 (m, 2H), 7.18 (s, 1 H), 7.50-7.60 (m, 2H), 7.62-7.67 (m, 1 H), 7.96 (d, 8.2 Hz, 1 H), 8.12 (s, 1 H), 8.19 (s, 1 H), 8.46 (s, 1 H).

Example 40

4-{[(3-Carboxymethylphenyl)-methyl-carbamoyl]-methoxy}-5, 7- dichloronaphthalene-2-carboxylic acid

[00124] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of (3- methylaminophenyl)-acetic acid ethyl ester (10bd) with chloroacetyl chloride gives {3- [(2-chloroacetyl)-methylamino]-phenyl}-acetic acid ethyl ester (12bf) in good yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxy-naphthalene-2- carboxylic acid methyl ester (4a) with {3-[(2-chloroacetyl)-methylamino]-phenyl}-acetic acid ethyl ester (12bf) gives 5,7-dichloro-4-{[(3-ethoxycarbonylmethylphenyl)- methylcarbamoyll-methoxyj-naphthalene^-carboxylic acid methyl ester (13bk) in 62% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-{[(3- ethoxycarbonylmethylphenyl)-methylcarbamoyl]-methoxy}-naphth alene-2-carboxylic acid methyl ester (13bk) with LiOH gives the title compound in 93% yield. ¹ H-NMR (200

MHz ₁ DMSO-de), δ (ppm) 3.21 (s, 3H), 3.59 (s, 2H), 4.68 (s, 2H), 7.10-7.50 (m, 5H),

7.73 (s, 1 H), 8.20 (s, 1 H), 8.23 (s, 1 H).

Example 41

4-{[(4-Carboxymethylphenyl)-methylcarbamoyl]-methoxy}-5,7 - dichloronaphthalene-2-carboxylic acid

[00125] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of (4- methylaminophenyl)-acetic acid ethyl ester (10be) with chloroacetyl chloride gives {4- [(2-chloroacetyl)-methylamino]-phenyl}-acetic acid ethyl ester (12bg) in good yield; b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxy-naphthalene-2- carboxylic acid methyl ester (4a) with {4-[(2-chloroacetyl)-methylamino]-phenyl}-acetic acid ethyl ester (12bg) gives 5,7-dichloro-4-{[(4-ethoxycarbonylmethylphenyl)-methyl- carbamoyl]-methoxy}-naphthalene-2-carboxylic acid methyl ester (13bl) in 49% yield; c) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-{[(4- ethoxycarbonylmethylphenyl)-methylcarbamoyl]-methoxy}-naphth alene-2-carboxylic acid methyl ester (13bl) with LiOH gives the title compound in 72% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.20 (s, 3H), 3.60 (s, 2H), 4.68 (s, 2H), 7.19-7.41 (m, 5H), 7.73 (d, 2.0 Hz, 1 H), 8.20 (s, 1 H), 8.23 (d, 2.4 Hz, 1 H).

Example 42

4-[(2-Carboxymethoxyphenylcarbamoyl)-methoxy]-5,7-dichlor onaphthalene-2- carboxylic acid

[00126] The title compound is prepared by the following reaction sequence: a) a solution of 2-nitrophenol (1 g, 7.19 mmol) in THF (5 mL) is added to a solution of NaH (345 mg, 8.63 mmol) in THF (5 mL) and the reaction mixture stirred at rt in an argon atmosphere for 30 min. Then tert-butyl bromoacetate (1.26 mL, 8.63 mmol) is added and the resulting mixture is refluxed for 6 h. After cooling, the reaction mixture is stirred at rt for 17 h and filtered. The filtrate is evaporated under reduced pressure. The residue is dissolved in CH ₂ CI ₂ , washed with saturated aqeous NaHCθ ₃ , 1 N aqeous HCI, brine, dried over MgSO ₄ and evaporated under reduced pressure to give (2- nitrophenoxy)-acetic acid tert-butyl ester (1.82 g, 99%). b) a mixture of (2-nitrophenoxy)-acetic acid tert-butyl ester (500 mg, 1.97 mmol) and Pd/C (50 mg) in EtOH (5 mL) is stirred at rt in atmosphere of H ₂ for 26 h. Then the mixture is filtered through a pad of celite and purified by flash chromatography (eluent - CH ₂ CI ₂ IMeOH, 100:1 ) to give 344 mg of 1 :1 mixture of (2-aminophenoxy)-acetic acid tert-butyl ester (10bf) and 4H-benzo[1 ,4]oxazin-3-one. The mixture is used in the next step without further purification. c) in analogy to the procedure described in Example 3(a), acylation of 1 :1 mixture of (2- aminophenoxy)-acetic acid tert-butyl ester (10bf) and 4H-benzo[1 ,4]oxazin-3-one with chloroacetyl chloride and purification by flash chromatography (eluent - CH ₂ CI ₂ :MeOH, 100:1 ) gives [2-(2-chloroacetylamino)-phenoxy]-acetic acid tert-butyl ester (12bh) in good yield; d) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxy-naphthalene-2- carboxylic acid methyl ester (4a) with [2-(2-chloroacetylamino)-phenoxy]-acetic acid tert- butyl ester (12bh) gives 4-[(2-tert-butoxycarbonylmethoxyphenylcarbamoyl)-methoxy]- 5,7-dichloronaphthalene-2-carboxylic acid methyl ester (13bm) in 58% yield; e) in analogy to the procedure D hydrolysis of 4-[(2-tert- butoxycarbonylmethoxyphenylcarbamoyO-methoxyl-δJ-dichloro-n aphthalene^- carboxylic acid methyl ester (13bm) with LiOH gives the title compound in 61% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.80 (s, 2H), 5.00 (s, 2H), 6.93-7.11 (m, 3H), 7.53 (s, 1 H), 7.83 (d, 2.0 Hz, 1 H), 8.24 (d, 7 Hz, 1 H); 8.30 (s, 2H) and 9.62 (s, 1 H).

Example 43

4-[2-(3-Carboxy-6,8-dichloronaphthalen-1-yloxy)-acetyl]-3 ,4-dihydro-2H- benzo[1 ,4]oxazine-2-carboxylic acid

[00127] The title compound is prepared by the following reaction sequence: a) a mixture of methyl 2,3-dibromopropionate (0.7 mL, 5.49 mmol), o-aminophenol (500 mg, 4.58 mmol) and K ₂ CO ₃ (1.39 g, 10.08 mmol) in 2-propanone (10 mL) is refluxed for 64 h. After cooling, precipitated solid is collected on filter and filtrate is evaporated under reduced pressure to give 3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid methyl ester (10bg) in good yield. b) in analogy to the procedure described in Example 3(a), acylation of 3,4-dihydro-2H- benzo[1 ,4]oxazine-2-carboxylic acid methyl ester (10bg) with chloroacetyl chloride gives 4-(2-chloroacetyl)-3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid methyl ester (12bi) in good yield; c) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxynaphthalene-2- carboxylic acid methyl ester (4a) with 4-(2-chloroacetyl)-3,4-dihydro-2H- benzo[1 ,4]oxazine-2-carboxylic acid methyl ester (12bi) gives 4-[2-(6,8-dichloro-3- methoxycarbonylnaphthalen-1-yloxy)-acetyl]-3,4-dihydro-2H-be nzo[1 ,4]oxazine-2- carboxylic acid methyl ester (13bn) in 91% yield; d) in analogy to the procedure D hydrolysis of 4-[2-(6,8-dichloro-3- methoxycarbonylnaphthalen-1-yloxy)-acetyl]-3,4-dihydro-2H-be nzo[1 ,4]oxazine-2- carboxylic acid methyl ester (13bn) with LiOH gives the title compound in 35% yield. ¹ H- NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.95 (d, 14 Hz, 1 H), 4.26 (d, 14 Hz, 1 H); 5.10-5.30 (m, 3H), 6.80-7.15 (m, 3H), 7.47 (s, 1 H), 7.45-7.78 (m, 1H), 7.78 (d, 1.6 Hz, 1 H) and 8.26 (s, 2H).

Example 44

4-[(4-Carboxymethoxy-phenylcarbamoyl)-methoxy]-5,7-dichlo ro-naphthalene-2- carboxylic acid

[00128] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 42(a), alkylation of 4-nitrophenol with tert-butyl bromoacetate gives (4-nitrophenoxy)-acetic acid tert-butyl ester in 99% yield, b) in analogy to the procedure described in Example 42(b),hydrogenation of (2- nitrophenoxy)-acetic acid tert-butyl ester over Pd/C gives (4-aminophenoxy)-acetic acid tert-butyl ester (10bh) in 99% yield, c) in analogy to the procedure described in Example 3(a), acylation of (4- aminophenoxy)-acetic acid tert-butyl ester (10bh) with chloroacetyl chloride gives [4-(2- chloroacetylamino)-phenoxy]-acetic acid tert-butyl ester (12bj) in 97% yield, d) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxy-naphthalene-2- carboxylic acid methyl ester (4a) with [4-(2-chloroacetylamino)-phenoxy]-acetic acid tert- butyl ester (12bj) gives 4-[(4-tert-butoxycarbonylmethoxyphenylcarbamoyl)-methoxy]- 5,7-dichloronaphthalene-2-carboxylic acid methyl ester (13bo) in 66% yield, e) in analogy to the procedure D hydrolysis of 4-[(2-tert- butoxycarbonylmethoxyphenylcarbamoyO-methoxyl-δJ-dichloro-n aphthalene^- carboxylic acid methyl ester (13bo) with LiOH; followed by f) treatment with TFA in CH ₂ CI ₂ in analogy to the procedure described in Example 2(b), gives the title compound in 60% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.62 (s, 2H), 4.90 (s, 2H), 6.88 (d, 8.4 Hz, 2H), 7.45 (s, 1H), 7.50 (d, 8.4 Hz, 1H), 7.79 (s, 1H), 8.26 (s, 2H) and 10.02 (s, 1 H).

Example 45

5,7-Dichloro-4-[(2-methoxycarbonyl-phenylcarbamoyl)-metho xy]-naphthalene-2- carboxylic acid

[00129] The title compound is prepared by the following reaction sequence: a) Sodium carbonate (21 mg, 0.195 mmol) and molecular sieves were added to a solution of 5,7-dichloro-4-hydroxynaphthalene-2-carboxylic acid (3a) (50 mg, 0.195 mmol) in 1 -methyl-2-pyrrolidone (1 ml_). The reaction mixture is flushed thoroughly with argon then 4-methoxybenzyl chloride (33.5 mg, 0.214 mmol) is added. The mixture is stirred at rt for 3 weeks then water is added. Solid is collected by filtration, washed with water, dried and purified by flash chromatography (eluent - CHCI ₃ ) to give 5,7-dichloro- 4-hydroxy-naphthalene-2-carboxylic acid 4-methoxy-benzyl ester (4d) as light yellow solid (42 mg, 57%). ¹ H-NMR (200 MHz, CDCI ₃ ), δ (ppm) 3.83 (s, 3H) ₁ 5.33 (s, 2H) ₁ 6.94 (dd, 8.7 and 2.2 Hz, 2H), 7.41 (d, 8.7 Hz, 2H), 7.49 (d, 2.2 Hz, 1 H) ₁ 7.58 (d, 1.5 Hz ₁ 1 H), 7.81 (d, 2.2 Hz ₁ 2H), 7.93 (s, 1 H) and 8.05 (d, 1.5 Hz, 1 H). b) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxy-naphthalene-2- carboxylic acid 4-methoxy-benzyl ester (4d) with 2-(2-chloro-acetylamino)-benzoic acid methyl ester (12ab) gives 5,7-dichloro-4-[(2-methoxycarbonyl-phenylcarbamoyl)- methoxy]-naphthalene-2-carboxylic acid 4-methoxy-benzyl ester (13bp) in 66% yield, c) in analogy to the procedure described in Example 2(b), treatment of 5,7-dichloro-4- [(2-methoxycarbonyl-phenylcarbamoyl)-methoxy]-naphthalene-2- carboxylic acid 4- methoxy-benzyl ester (13bp) with TFA in CH ₂ CI ₂ gives the title compound in 88% yield. ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.69 (s, 3H), 5.00 (s, 2H) ₁ 7.18 (t, 7.7 Hz, 1 H), 7.54 (d, 1.4 Hz, 1 H), 7.65 (td, 7.7 and 1.4 Hz, 1 H), 7.84 (d, 2.2 Hz, 1 H), 7.94 (dd, 8.0 and 1.4 Hz, 1 H), 8.31 (s and d, 2H), 8.45 (d, 9 Hz, 1 H) and 11.26 (s, 1 H).

Example 46

4-[(6-Carboxymethyl-pyridin-3-ylcarbamoyl)-methoxy]-5,7-d ichloro-naphthalene-2- carboxylic acid

[00130] The title compound is prepared by the following reaction sequence: a) (Procedure B) To a solution of 4-carboxymethoxy-5,7-dichloronaphthalene-2- carboxylic acid methyl ester (8a) (150 mg, 0.46 mmol), (5-amino-pyridin-2-yl)-acetic acid ethyl ester (10bi) (90.3 mg, 0.50 mmol) and diisopropylethylamine (88.4 mg, 0.11 ml_, 0.68 mmol) in DMF (2 mL) is added EDCI (131 mg, 0.68 mmol) and HOBt (105 mg, 0.68 mmol). The mixture is stirred at rt for 4 days (TLC control). Reaction mixture is poured onto ice cold water and extracted with ethyl acetate. The extract is washed with aqueous sodium bicarbonate, brine and water, dried over MgSO ₄ , and concentrated under reduced pressure. The residue is purified by flash chromatography (eluent: CHCI ₃ ) on silica gel (R _f =0.52; CH ₂ CI ₂ :MeOH, 20:1 ) to give 83 mg (37%) of 5,7-dichloro- 4-[(6-ethoxycarbonylmethyl-pyridin-3-ylcarbamoyl)-methoxy]-n aphthalene-2-carboxylic methyl ester (13bq). b) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-[(6-ethoxycarbonylmethyl- pyridin-S-ylcarbamoyO-methoxyl-naphthalene^-carboxylic methyl ester (13bq) with LiOH gives the title compound in 48% yield.

¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.71 (s, 2H), 4.97 (s, 2H), 7.35 (d, 9 Hz, 1 H), 7.45 (s, 1 H), 7.80 (d, 2 Hz, 1 H), 8.02 (dd, 9 and 2.5 Hz, 1 H), 8.26-8.29 (m, 2H), 8.68 (d, 2.5 Hz, 1 H) and 10.43 (s, 1 H).

Example 47

5,7-Dichloro-4-{[3-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl carbamoyl]-methoxy}- naphthalene-2-carboxylic acid

[00131] The title compound is prepared by the following reaction sequence: a) condensation of (3-nitrophenoxy)-acetic acid with morpholine in the presence of 1 ,1- carbonyldiimidazole provides 1-morpholin-4-yl-2-(3-nitro-phenoxy)-ethanone in 96% yield, b) in analogy to the procedure described in Example 42(b), hydrogenation of 1- morpholin-4-yl-2-(3-nitro-phenoxy)-ethanone in the presence of Pd/C gives 2-(3-amino- phenoxy)-1-morpholin-4-yl-ethanone (10bj) in 86% yield, c) in analogy to the procedure described in Example 3(a), acylation of 2-(3-amino- phenoxy)-1-morpholin-4-yl-ethanone (10bj) with chloroacetyl chloride gives 2-chloro-N- [3-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl]-acetamide (12bk) in 73% yield, d) in analogy to the procedure A acylation of 5,7-dichloro-4-hydroxy-naphthalene-2- carboxylic acid methyl ester (4a) with 2-chloro-N-[3-(2-morpholin-4-yl-2-oxo-ethoxy)- phenyl]-acetamide (12bk) gives 5,7-dichloro-4-{[3-(2-morpholin-4-yl-2-oxo-ethoxy)- phenylcarbamoyl]-methoxy}-naphthalene-2-carboxylic acid methyl ester (13br) in 82% yield, e) in analogy to the procedure D hydrolysis of 5,7-dichloro-4-{[3-(2-morpholin-4-yl-2- oxo-ethoxyj-phenylcarbamoylj-methoxyj-naphthalene^-carboxyli c acid methyl ester (13br) with LiOH gives the title compound in 81% yield. ¹ H-NMR (200 MHz ₁ DMSO-d ₆ ), δ (ppm) 3.43 (br s, 2H) ₁ 3.54 (br s, 2H), 4.78 (s, 2H), 4.93 (s, 2H), 6.65 (d, 8 Hz, 1 H), 7.11-7.28 (m, 3H); 7.44 (s, 1 H), 7.80 (d, 2.2 Hz, 1 H), 8.26 (s, 1H); 8.28 (s, 1H) and 10.13 (s, 1 H).

[00132] The compounds represented by following examples are prepared in analogy to the procedures used for the above-described examples and according to Scheme 1 and Scheme 2. All of the starting materials may be obtained commercially or are prepared by procedures well known to one of ordinary skill in organic chemistry.

Example 48 i-^S-Carboxy-β.δ-dichloro-naphthalen-i-yloxyJ-acetyll^.a-d ihydro-IH-indole^- carboxylic acid

[00133] LCMS m/z 458 (M-1 ). ¹ H NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.53-3.67 (m, 2H); 4.85 (d, 15 Hz, 1 H); 5.32-5.43 (m, 2H); 7.04 (t, 8 Hz, 1 H); 7.18 (t, 8 Hz, 1 H); 7.28 (d, 8 Hz, 1 H); 7.47 (s, 1 H); 7.80 (d, 2 Hz, 1 H); 8.01 (d, 8 Hz, 1 H); 8.24 (s, 1 H) and 8.26 (d, 2 Hz, 1 H). Example 49 i-^S-Carboxy-e.β-dichloro-naphthalen-i-yloxyJ-acetyll-I^.S. A-tetrahydro- quinoline-2-carboxylic acid

[00134] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 2.48-2.75 (m, 4H); 4.80-4.97 (m, 2H); 5.41 (d, 14 Hz, 1 H); 7.10-7.21 (m, 4H); 7.52 (d, 8 Hz, 1 H); 7.72 (d, 2 Hz ₁ 1 H); 8.18 (s, 1 H) and 8.22 (d, 2 Hz, 1 H).

Example 50

5,7-Dichloro-4-[2-(3,4-dihydro-2H-quinolin-1-yl)-2-oxo-et hoxy]-naphthalene-2- carboxylic acid

[00135] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 1.89 (quint, 2H); 2.73 (t, 2H); 3.73 (t, 2H); 5.20 (s, 2H); 7.05-7.19 (m, 4H); 7.50-7.60 (m, 1 H); 7.74 (d, 2 Hz, 1 H); 8.19 (s, 1 H) and 8.23 (d, 2 Hz, 1 H).

Example 51

5,7-Dichloro-4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinol in-2-yl)-2-oxo-ethoxy]- naphthalene-2-carboxylicacid

[00136] ¹ H-NMR (200 MHz ₁ DMSO-d ₆ ), δ (ppm) 2.65-2.83 (m, 2H); 3.69-3.75 (m, 8H); 4.54 (s, 1H); 4.68 (s, 1 H); 5.17 (s, 2H); 6.73 (s, 1H); 6.79 (s, 1H); 7.43 (s, 1H); 7.77 (d, 2 Hz, 1 H); 8.22 (s, 1 H) and 8.26 (s, 1 H).

Example 52

5,7-Dichloro-4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo -ethoxy]-naphthalene-2- carboxylic acid

[00137] LCMS m/z 428 (M-1 ). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 2.76-2.88 (m, 2H); 3.68-3.79 (m, 2H); 4.61 (s, 1 H); 4.76 (s, 1 H); 5.17 (s, 2H); 7.16 (s, 4H); 7.42 (s, 1 H); 7.75-7.77 (m, 1 H); 8.21 (s, 1 H) and 8.24 (s, 1 H). Example 53

5,7-Dichloro-4-{[2-(2,2,2-trifluoro-ethoxy)-phenylcarbamo yl]-methoxy}- naphthalene-2-carboxylic acid

[00138] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.80 (q, 2H); 5.00 (s, 2H); 7.00- 7.24 (m, 3H); 7.52 (s, 1 H); 7.80 (s, 1 H); 8.10 (d, 8 Hz, 1 H); 8.29 (s, 2H) and 9.20 (s, 1 H).

Example 54

5,7-Dichloro-4-{[2-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl carbamoyl]-methoxy}- naphthaIene-2-carboxylic acid

[00139] LCMS m/z 531 (M-1). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.40-3.53 (m, 8H); 4.94 (s, 2H); 5.00 (s, 2H); 6.96-7.03 (m, 3H); 7.51 (s, 1 H); 7.81 (s, 1 H); 8.16 (d, 8 Hz, 1 H); 8.30 (s, 2H) and 9.60 (s, 1 H). LCMS m/z 531.1 (M-1 ).

Example 55

5,7-Dichloro-4-{[4-(2,2,2-trifluoro-ethoxy)-phenylcarbamo yl]-methoxy}- naphthalene-2-carboxylic acid

[00140] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.70 (q, 2H); 4.92 (s, 2H); 7.03 (d, 8 Hz ₁ 2H); 7.45 (s, 1 H); 7.56 (d, 8 Hz, 2H); 7.81 (s, 1 H); 8.27 and 8.28 (both s, 2H) and 10.10 (s, 1 H).

Example 56

5,7-Dichloro-4-[(4-trifluoromethoxy-phenylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid

[00141] LCMS m/z 472 (M-1 ). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.96 (s, 2H); 7.34 (d, 8 Hz, 2H); 7.44 (s, 1 H); 7.72 (d, 8 Hz, 2H); 7.80 (d, 2 Hz, 1 H); 8.27 and 8.28 (both s, 2H) and 10.38 (s, 1 H). Example 57

5,7-Dichloro-4-[(2-trifluoromethoxy-phenylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid

[00142] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 5.95 (s, 2H); 7.24-7.48 (m, 4H); 7.83 (d, 2.6 Hz, 1 H); 7.99 (d, 8 Hz ₁ 1 H); 8.28 (d, 2.6 Hz ₁ 1 H); 8.30 (s, 1 H) and 9.81 (s, 1 H).

Example 58 5,7-Dichloro-4-(2-oxo-2-pyridin-2-yl-ethoxy)-naphthalene-2-c arboxylic acid

[00143] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 5.95 (s, 2H); 7.36 (s, 1 H); 7.70- 7.80 (m, 2H); 7.99-8.11 (m, 2H); 8.23 (s, 1 H); 8.27 (d, 2 Hz, 1 H) and 8.79 (d, 2 Hz, 1 H).

Example 59

4-[(2-Carboxymethoxy-benzylcarbamoyl)-methoxy]-5,7-dichlo ro-naphthalene-2- carboxylic acid

[00144] LCMS m/z 476 (M-1 ). ¹ H-NMR (200 MHz ₁ DMSO-d ₆ ), δ (ppm) 4.39 (d, 5 Hz ₁ 2H); 4.70 (s, 2H); 4.82 (s, 2H); 6.84-6.91 (m, 2H); 7.16-7.22 (m, 2H); 7.43 (d, 2 Hz, 1 H); 7.78 (d, 2 Hz ₁ 1 H) and 8.26-8.31 (m, 3H).

Example 60

5,7-Dichloro-4-{[2-(1H-tetrazol-5-ylmethoxy)-phenylcarbam oyl]-methoxy}- naphthalene-2-carboxylic acid

[00145] LCMS m/z 486 (M-1 ). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.99 (s, 2H); 5.58 (s, 2H); 6.97-7.32 (m, 4H); 7.50 (s, 1 H); 7.61 (d, 2 Hz ₁ 1 H); 8.20 (d, 6 Hz ₁ 1 H); 8.28 and 8.29 (both s, 2H) and 9.29 (s, 1 H). Example 61

5,7-Dichloro-4-[(2-trifluoromethoxy-benzylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid

[00146] LCMS m/z 486 (M-1 ). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.42 (d, 6 Hz, 2H); 4.84 (s, 2H); 7.26-7.42 (m, 5H); 7.78 (d, 2 Hz, 1 H); 8.26 and 8.28 (both s, 2H) and 8.54 (t, 6 Hz, 1 H).

Example 62

5,7-Dichloro-4-[(3-trifluoromethoxy-benzylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid

[00147] LCMS m/z 486 (M-1). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.40 (d, 6 Hz, 2H); 4.82 (s, 2H); 7.20-7.30 (m, 3H); 7.37-7.46 (m, 2H); 7.78 (d, 2 Hz ₁ 1 H); 8.26- 8.28 (m, 2H) and 8.63 (t, 5 Hz, 1 H).

Example 63

5,7-Dichloro-4-[(4-trifluoromethoxy-benzylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid

[00148] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.38 (d, 6 Hz, 2H); 4.82 (s, 2H); 7.26 (d, 8 Hz, 2H); 7.37 (d, 8 Hz, 3H); 7.78 (d, 2 Hz, 1H); 8.26 and 8.27 (both s, 2H) and 8.62 (t, 6 Hz, 1 H).

Example 64

5,7-Dichloro-4-[(1H-tetrazol-5-ylcarbamoyl)-methoxy]-naph thalene-2-carboxylic acid

[00149] LCMS m/z 380 (M-1). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 5.14 (s, 2H); 7.43 (s, 1 H); 7.80 (s, 1 H); 8.27 (s, 2H); 10.90 (s, 1 H) and 12.36 (s, 1 H). Example 65 δJ-Dichloro-A^-oxo-i-phenyl-pyrrolidin-S-yloxy^naphthalene^ -carboxylic acid

[00150] LCMS m/z 414 (M-1 ). ¹ H-NMR (200 MHz, DMSO-Cl ₆ ), δ (ppm) 2.30-2.39 (m, 1 H); 2.58-2.74 (m, 1 H); 3.86-3.95 (m, 2H); 5.55 (t, 7 Hz ₁ 1 H); 7.17 (t, 8 Hz, 1 H); 7.40 (t, 8 Hz, 2H); 7.69-7.76 (m, 3H); 7.84 (s, 1 H) and 8.26 and 8.27 (both s, 2H).

Example 66

5,7-Dichloro-4-[(frans-2-phenyl-cyclopropylcarbamoyl)-met hoxy]-naphthalene-2- carboxylic acid

[00151] LCMS m/z 428 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 1.19-1.25 (m, 2H); 1.99-2.03 (m, 1 H); 2.87-2.92 (m, 1 H); 4.73 (s, 2H); 7.10-7.17 (m, 3H); 7.25 (t, 8 Hz ₁ 2H); 7.39 (s, 1H); 7.80 (d, 2 Hz, 1H); 8.26 (d, 1 Hz, 1 H); 8.28 (d, 1 Hz, 1H); 8.41 (d, 4 Hz, 1 H) and 13.41 (s, 1 H).

Example 67

5,7-Dichloro-4-(2-methoxy-1-phenylcarbamoyl-ethoxy)-napht halene-2-carboxylic acid

[00152] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 3.75 (s, 3H); 3.90-4.00 (m, 2H); 5.21-5.23 (m, 1 H); 7.07 (t, 8 Hz, 1 H); 7.32 (t, 8 Hz, 2H); 7.46 (s, 1 H); 7.58 (d, 8 Hz, 2H); 7.80 (d, 2 Hz, 1 H); 8.25 (s, 1 H); 8.28 (d, 2 Hz, 1 H); 10.38 (s, 1 H) and 13.34 (s, 1 H).

Example 68 4-(1-Carboxy-1-methyl-ethoxy)-5,7-dichloro-naphthalene-2-car boxylic acid

[00153] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 1.66 (s, 6H); 7.32 (d, 1 Hz, 1 H); 7.77 (d, 2 Hz ₁ 1 H); 8.23 (d, 1 Hz, 1 H); 8.26 (d, 2 Hz ₁ 1 H) and 13.36 (s, 1 H). Example 69

5,7-Dichloro-4-{[2-(2-dimethylamino-ethoxy)-phenylcarbamo yl]-methoxy}- naphthalene-2-carboxylic acid

[00154] LCMS m/z475 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 2.81 (s, 6H); 3.52 (t, 5 Hz, 2H); 4.39 (t, 5 Hz, 2H); 5.14 (s, 2H); 6.97-7.01 (m, 1H); 7.13 (d, 4 Hz, 2H); 7.49 (s, 1H); 7.83 (d, 2 Hz, 1H); 8.02 (d, 8 Hz, 1H); 8.28 (d, 1 Hz, 1H); 8.30 (d, 2 Hz, 1H) and 9.73 (s, 1H).

Example 70 4-(1-Benzyl-2-oxo-pyrrolidin-3-yloxy)-5,7-dichloro-naphthale ne-2-carboxylic acid

[00155] ¹ H-NMR (400 MHz ₁ CDCI ₃ ), δ (ppm) 2.05-2.40 (m, 1H); 2.55-2.63 (m, 1H); 3.30-3.36 (m, 1H); 3.48-3.54 (m, 1H); 4.51 (d, 15 Hz, 1H); 4.65 (d, 15 Hz, 1H); 5.29- 5.32 (m, 1H); 7.30-7.39 (m, 5H); 7.58 (d, 2 Hz, 1H); 7.71 (d, 2 Hz, 1H); 7.81 (s, 1H) and 8.00(s, 1H).

Example 71

5,7-Dichloro-4-[(2-methoxy-phenylcarbamoyl)-methoxy]-naph thalene-2-carboxylic acid

[00156] ¹ H-NMR (400 MHz ₁ DMSO-d ₆ ), δ (ppm) 3.87 (s, 3H); 5.00 (s, 2H); 6.96 (dt, 2 and 8 Hz, 1H); 6.98-7.14 (m, 2H); 7.53 (s, 1H); 7.88 (d, 2 Hz, 1H); 8.23 (d, 8 Hz, 1H); 8.30 (s, 1 H); 8.32 (d, 2 Hz, 1 H) and 9.30 (s, 1 H).

Example 72

4-[(2,6-Bis-carboxymethoxy-phenylcarbamoyl)-methoxy]-5,7- dichloro- naphthalene-2-carboxylic acid

[00157] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.68 and 4.94 (both s, 6H); 6.62 (d, 8 Hz, 2H); 7.17 (s, 1H); 7.53 (s, 1H); 7.80 (s, 1H); 8.29 (s, 2H) and 9.13 (s, 1H). Example 73

SJ-Dichloro-A-^-cyanomethoxy-phenylcarbamoylJ-methoxyl-na phthalene^- carboxylic acid

[00158] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 5.02 (s, 2H); 5.27 (s, 2H); 7.10 (dt, 2 and 8 Hz, 1H); 7.20 (dt, 2 and 8 Hz, 1H); 7.26 (dd, 2 and 8 Hz, 1H); 7.53 (s, 1H); 7.84 (d, 2 Hz, 1H); 8.17 (d, 8 Hz ₁ 1H); 8.30 (s, 1H); 8.32 (d, 2 Hz, 1H) and 9.40 (s, 1H).

Example 74

5,7-Dichloro-4-[2-methoxy-1-(2-methoxy-phenylcarbamoyl)-e thoxy]-naphthalene- 2-carboxylic acid

[00159] LCMS m/z 464 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 3.74 (s, 3H); 3.82-3.89 (m, 1H); 3.95-3.99 (m, 1H); 5.46-5.48 (m, 1H); 6.90 (dt, 2 and 8 Hz, 1H); 7.02 (dd, 2 and 8 Hz, 1H); 7.08 (dt, 2 and 8 Hz, 1H); 7.55 (d, 1 Hz, 1H); 7.86 (d, 2 Hz, 1H); 8.05 (dd, 2 and 8 Hz, 1H); 8.27 (d, 1 Hz, 1H); 8.30 (d, 2 Hz, 1H) and 9.38 (s, 1H).

Example 75

5,7-Dichloro-4-[1-(2-methoxy-phenyl)-2-oxo-pyrrolidin-3-y loxy]-naphthalene-2- carboxylic acid

[00160] LCMS m/z 444 (M-1). ¹ H-NMR (400 MHz, CDCI ₃ ), δ (ppm) 2.32-2.43 (m, 1H); 2.66-2.76 (m, 1H); 3.72-3.79 (m, 2H); 3.82 (s, 3H); 5.47 (t, 7 Hz, 1H); 7.01 (dt, 2 and 8 Hz, 1H); 7.14 (d, 8 Hz, 1H); 7.29 (dd, 2 and 8 Hz, 1H); 7.33 (dt, 2 and 8 Hz, 1H); 7.78 (d, 2 Hz, 1H); 7.87 (s, 1H) and 8.27-8.28 (m, 2H).

Example 76

5,7-Dichloro-4-[(2-hydroxymethyl-6-methoxy-phenylcarbamoy l)-methoxy]- naphthalene-2-carboxylic acid

[00161] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 3.75 (s, 3H); 4.40 (s, 2H); 4.95 (s, 2H); 5.04 (s, 1H); 6.95 (d, 8 Hz, 1H); 7.09 (d, 8 Hz, 1H); 7.26 (t, 8 Hz, 1H); 7.53 (s, 1H); 7.81 (d, 2 Hz, 1 H); 8.29 (s, 2H) and 9.24 (s, 1 H). Example 77 5,7-Dichloro-4-(indan-1-ylcarbamoylmethoxy)-naphthalene-2-ca rboxylic acid

[00162] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 1.76-1.91 (m, 1 H); 2.33-2.45 (m, 1 H); 2.78-2.86 (m, 1 H); 2.90-2.97 (m, 1 H); 2.81 (dd, 14 and 20 Hz, 2H); 5.39 (dd, 8 and 16 Hz, 1 H); 7.14-7.26 (m, 4H); 7.45 (s, 1 H); 7.78 (d, 2 Hz, 1 H); 8.26 (s, 1 H); 8.27 (d, 2 Hz, 1 H) and 8.39 (d, 8 Hz, 1 H).

Example 78

5,7-Dichloro-4-[2-(8-hydroxymethyl-2,3-dihydro-benzo[1,4] oxazin-4-yl)-2-oxo- ethoxy]-naphthalene-2-carboxylic acid

[00163] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 3.93 (t, 4 Hz, 2H); 4.35 (t, 4 Hz, 2H); 4.48 (d, 4 Hz, 2H); 5.04 (s, 1 H); 5.32 (s, 2H); 6.86 (t, 8 Hz, 1 H); 7.18 (d, 8 Hz, 1 H); 7.39 (br s, 1 H); 7.78 (d, 2 Hz, 1 H); 8.24 (s, 1 H); 8.27 (d, 2 Hz, 1 H) and 13.37 (br s, 1 H).

Example 79

4-[(5-Aminomethyl-2-carboxymethoxy-phenylcarbamoyl)-metho xy]-5,7-dichloro- naphthalene-2-carboxylic acid

[00164] LCMS m/z 491 (M-1 ). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 3.94 (d, 7 Hz, 2H); 4.84 (s, 2H); 5.04 (s, 2H); 7.05 (d, 8 Hz, 1 H); 7.18 (d, 8 Hz, 1 H); 7.53 (s, 1 H); 7.82 (s, 1 H); 8.18-8.38 (m, 5H) and 9.42 (s, 1 H).

Example 80

5,7-Dichloro-4-[(1,2,3,4-tetrahydro-naphthalen-1-ylcarbam oyl)-methoxy]- naphthalene-2-carboxylic acid

[00165] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 1.71-1.95 (m, 4H); 2.67-2.78 (m, 2H); 4.77-4.86 (m, 2H); 5.04-5.10 (m, 1 H); 7.08-7.21 (m, 4H); 7.77 (d, 2 Hz 1 H); 8.25 (d, 1 Hz, 1 H); 8.27 (d, 2 Hz, 1 H) and 8.37 (d, 8 Hz, 1 H). Example 81

^{^-(i-Carboxy-i-methyl-ethoxyJ-phenylcarbamoyll-methoxyJ -SJ-dichloro- naphthalene-2-carboxylic acid

[00166] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 1.43 (s, 6H); 5.01 (s, 2H); 6.85 (dd, 2 and 8 Hz ₁ 1 H); 6.98-7.07 (m, 2H); 7.53 (s, 1 H); 7.86 (d, 2 Hz, 1 H); 8.17 (d, 8 Hz, 1 H); 8.32 (s, 2H) and 9.33 (s, 1 H).

Example 82

5,7-Dichloro-4-[(2-cyano-phenylcarbamoyl)-methoxy]-naphth alene-2-carboxylic acid

[00167] Mp >250 ⁰ C; ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 5.04 (s, 2H); 7.37- 7.41 (m, 1H); 7.53 (s, 1 H); 7.72 (d, 2 Hz, 2H); 7.82-7.86 (m, 2H); 8.29 (s, 2H) and 10.32 (s, 1 H).

Example 83

4-[(2,4-Bis-carboxymethoxy-phenylcarbamoyl)-methoxy]-5,7- dichloro- naphthalene-2-carboxylic acid

[00168] Mp >220 ⁰ C (decomp.); LCMS m/z 538 (M-1 ). ¹ H-NMR (200 MHz ₁ DMSO- d _β ), δ (ppm) 4.64 (s, 2H); 4.81 (s, 2H); 4.97 (s, 2H); 6.53 (d, 9 Hz, 1 H); 6.64 (d, 2 Hz, 1 H); 7.53 (s, 1 H); 7.82 (d, 3 Hz, 1 H); 8.06 (d, 9 Hz, 1 H); 8.31 (s, 2H) and 9.26 (s, 1 H).

Example 84

5,7-Dichloro-4-[(4-cyano-phenylcarbamoyl)-methoxy]-naphth alene-2-carboxylic acid

[00169] ¹ H-NMR (200 MHz ₁ DMSO-d ₆ ), δ (ppm) 5.01 (s, 2H); 7.45 (s, 1 H); 7.81 (br s, 5H); 8.28 (br s, 2H) and 10.65 (s, 1 H). Example 85

5,7-Dichloro-4-{[2-(1H-tetrazol-5-yl)-phenylcarbamoyl]-me thoxy}-naphthalene-2- carboxylic acid

[00170] Mp 247-248 ⁰ C; LCMS m/z 456.4 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 5.04 (s, 2H); 7.34 (t, 8 Hz ₁ 1 H); 7.49 (s, 1 H); 7.60 (t, 8 Hz, 1 H); 7.80 (d, 3 Hz, 1 H); 7.94 (d, 8 Hz, 1 H); 8.28-8.29 (m, 2H); 8.50 (d, 8 Hz, 1 H) and 11.37 (s, 1 H).

Example 86

5,7-Dichloro-4-{[4-(1H-tetrazol-5-ylmethyl)-phenylcarbamo yl]-methoxy}- naphthalene-2-carboxylic acid

[00171] LCMS m/z 470.4 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.24 (s, 2H); 4.94 (s, 2H); 7.24 (d, 8 Hz, 2H); 7.46 (s, 1 H); 7.58 (d, 8 Hz, 2H); 7.81 (s, 1 H); 8.27 and 8.29 (both s, 2H); 10.17 (s, 1 H).

Example 87

5,7-Dichloro-4-{[4-(2-dimethylamino-ethoxy)-3-hydroxymeth yl-phenylcarbamoyl]- methoxy}-naphthalene-2-carboxylic acid

[00172] LCMS m/z 505.6 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 2.31 (s, 6H); 2.74 (s, 2H); 4.08 (s, 2H); 4.47 (s, 2H); 4.90 (s, 2H); 6.93 (d, 9 Hz, 1 H); 7.48-7.58 (m, 3H); 8.23 and 8.25 (both s, 2H); 10.00 (s, 1 H).

Example 88

5,7-Dichloro-4-{[4-(1H-tetrazol-5-ylmethoxy)-phenylcarbam oyl]-methoxy}- naphthalene-2-carboxylic acid

[00173] LCMS m/z 486.4 (M-1). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.93 (s, 2H); 5.45 (s, 2H); 7.05 (d, 9 Hz, 2H); 7.46 (s, 1 H); 7.56 (d, 9 Hz, 2H); 7.81 (s, 1 H); 8.27 and 8.29 (both s, 2H); 10.11 (s, 1 H). Example 89

5,7-Dichloro-4-{[4-(1H-tetrazol-5-yl)-phenylcarbamoyl]-me thoxy}-naphthalene-2- carboxylic acid

[00174] LCMS m/z 456.5 (M-1 ). ¹ H-NMR (400 MHz, DMSO-Cl ₆ ), δ (ppm) 5.01 (s, 2H); 7.49 (s, 1 H); 7.82-7.85 (m, 3H); 8.01 (d, 8.8 Hz ₁ 2H); 8.32 (s, 1 H); 8.35 (d, 2 Hz, 1 H); 10.49 (S ₁ 1 H).

Example 90

5,7-Dichloro-4-{[3-(1H-tetrazol-5-ylmethyl)-phenylcarbamo yl]- methoxy}naphthalene-2-carboxylic acid

[00175] LCMS m/z 470.5 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.27 (s, 2H); 4.93 (s, 2H); 6.99 (d, 8 Hz ₁ 1H); 7.30 (t, 8 Hz, 1H); 7.45 (s, 1H); 7.51-7.53 (m, 2H);

7.81 (S ₁ 1 H); 8.29 and 8.29 (both s, 2H); 10.18 (s, 1 H).

Example 91

5,7-Dichloro-4-[(2-methylcarbamoylmethoxy-phenylcarbamoyl )-methoxy]- naphthalene-2-carboxylic acid

[00176] LCMS m/z 475.5 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 2.54 (s, 3H); 4.58 (s, 2H); 5.02 (s, 2H); 6.98 and 7.00 (both d, 8 Hz, 2H); 7.10 (t, 7 Hz ₁ 1 H); 7.54 (s, 1 H); 7.81 (d, 2 Hz, 1 H); 8.05-8.09 (m, 2H); 8.30 and 8.31 (both s, 2H); 9.57 (s, 1 H).

Example 92

5,7-Dichloro-4-{[3-(1H-tetrazol-5-ylmethoxy)-phenylcarbam oyl]-methoxy}- naphthalene-2-carboxylic acid

[00177] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.95 (s, 2H); 5.44 (s, 2H); 6.82 (dd, 2 and 8 Hz, 1 H); 7.21 (d, 8 Hz, 1 H); 7.29 (t, 8 Hz ₁ 1 H); 7.44 and 7.46 (both s, 2H);

7.82 (d, 2 Hz, 1 H); 7.95 (s, 1 H); 8.28 (s, 1 H); 8.29 (d, 2 Hz, 1 H); 10.20 (s, 1 H). Example 93

^[(S-Carbamoylmethoxy-phenylcarbamoylJ-methoxyl-SJ-dichlo ro-naphthalene^- carboxylic acid

[00178] LCMS m/z 462 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.39 (s, 2H);

4.96 (s. 2H); 6.68 (dd, 2 and 8 Hz, 1 H); 7.17 (d, 8 Hz, 1 H); 7.24 (t, 8 Hz, 1 H); 7.34 (br s, 2H); 7.45 (s, 1 H); 7.51 (br s, 1 H); 7.81 (d, 2Hz ₁ 1 H); 8. 22 - 8.28 (m, 2H); 10.15 (s, 1 H).

Example 94

4-[(2-Carboxymethoxy-5-hydroxymethyl-phenylcarbamoyl)-met hoxy]-5,7-dichloro- naphthalene-2-carboxylic acid

[00179] Mp 185-187 ⁰ C (decomp.); ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.42 (s, 2H); 4.80 (s, 2H); 5.02 (s, 2H); 5.16 (br s, 1 H); 6.92- 7.04 (m, 2H); 7.55 (s, 1H); 7.85 (d, 2 Hz, 1 H); 8.25 (s, 1 H); 8.32 (s, 1 H); 8.33 (s, 1 H); 9.38 (s, 1 H).

Example 95

4-[(2-Carbamoylmethoxy-phenylcarbamoyl)-methoxy]-5,7-dich loro-naphthalene-2- carboxylic acid

[00180] LCMS m/z 461 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.55 (s, 2H);

4.97 (s, 2H); 6.96-7.00 (m, 2H); 7.10 (t, 8 Hz, 1 H); 7.39 (br s, 1 H); 7.58 (s, 1 H); 7.67 (br s, 1 H); 7.74 (d, 2Hz, 1H): 8.07 (d, 8 Hz, 1 H); 8.16-8.20 (m, 2H); 9.58 (s, 1 H).

Example 96

4-{[3-(2-Carboxy-ethyl)-phenylcarbamoyl]-methoxy}-5,7-dic hloro-naphthalene-2- carboxylic acid

[00181] Mp >230 ⁰ C (decomp.); LCMS m/z 460.4 (M-1 ). ¹ H-NMR (200 MHz, DMSO-de), δ (ppm) 2.52 (t, 7.3 Hz, 2H); 2.80 (t, 7.3 Hz, 2H); 4.95 (s, 2H); 6.96 (d, 8.0 Hz, 1 H); 7.24 (t, 8.0 Hz, 1 H); 7.41 - 7.51 (m, 3H); 7.82 (d, 1.5 Hz ₁ 1 H); 8.27 (s, 1 H); 8.29 (s, 1 H) and 10.11 (s, 1 H). Example 97

4-[(2-Aminomethyl-4-carboxymethoxy-phenylcarbamoyl)-metho xy]-5,7-dichloro- naphthalene-2-carboxylic acid

[00182] Isolated as trifluoroacetate salt. Mp >169 ⁰ C; LCMS m/z 491.5 (M-1 ). ¹ H- NMR (200 MHz, DMSO-CJ ₆ ), δ (ppm) 3.86 - 3.98 (m, 2H); 4.70 (s, 2H); 5.00 (s, 2H); 6.98 (dd, 8.8 and 2.9 Hz, 1 H); 7.13 (d, 2.9 Hz, 1 H); 7.25 (d, 8.8 Hz, 1 H); 7.51 (s, 1 H); 7.82 (d, 1.5 Hz, 1 H); 8.06 (br. s, 3H); 8.30 (d, 1.5 Hz, 1H); 8.32 (s, 1 H) and 9.90 (s, 1 H).

Example 98

5,7-Dichloro-4-[(3-cyano-phenylcarbamoyl)-methoxy]-naphth alene-2-carboxylic acid

[00183] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.99 (s, 2H); 7.47 (s, 1 H); 7.55 - 7.61 (m, 2H); 7.78 - 7.91 (m, 2H); 8.11 (s, 1 H); 8.25 - 8.32 (m, 2H) and 10.54 (s, 1 H).

Example 99

5,7-Dichloro-4-{2-oxo-2-[2-(1H-tetrazol-5-yl)-2,3-dihydro -indol-1-yl]-ethoxy}- naphthalene-2-carboxylic acid

[00184] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 1.08 (t, 7.3 Hz ₁ 1 H); 3.90 (t, 7.3 Hz, 1 H); 3.70 - 3.93 (m, 1 H); 4.89 - 5.08 (m, 1 H); 5.39 - 5.57 (m, 1 H); 6.26 - 6.42 (m, 1 H); 7.09 (t, 7.4 Hz, 1 H); 7.16 - 7.38 (m, 2H); 7.47 (s, 1 H); 7.77 (s, 1 H); 7.93 - 8.06 (m, 1 H); 8.25 (s, 1 H) and 8.26 (s, 1 H).

Example 100

5,7-Dichloro-4-{[2-(1H-tetrazol-5-ylmethyl)-phenylcarbamo yl]-methoxy}- naphthalene-2-carboxylic acid

[00185] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.25 (s, 2H); 4.97 (s, 2H); 7.07 (d, 7.3 Hz, 1 H); 7.21 (t, 7.3 Hz, 1 H); 7.31 (t, 7.3 Hz, 1 H); 7.40 (d, 7.3 Hz, 1 H); 7.50 (s, 1 H); 7.79 (s, 1 H); 8.27 (br. s, 2H) and 9.86 (s, 1 H). Example 101

5,7-Dichloro-4-{[3-(1H-tetrazol-5-yl)-phenylcarbamoyl]-me thoxy}-naphthalene-2- carboxylic acid

[00186] ¹ H-NMR (400 MHz ₁ DMSO-d ₆ ), δ (ppm) 5.02 (s, 2H); 7.48 (s, 1 H); 7.57 (t, 8.1 Hz, 1 H); 7.72 - 7.81 (m, 2H); 7.82 (d, 2.2 Hz, 1 H); 8.28 (s, 1 H); 8.29 (d, 2.2 Hz, 1 H); 8.45 (s, 1 H) and 10.49 (S ₁ 1 H).

Example 102

5,7-Dichloro-4-[(2-dimethylcarbamoylmethoxy-phenylcarbamo yl)-methoxy]- naphthalene-2-carboxylic acid

[00187] LCMS m/z 489.5 (M-1 ). ¹ H-NMR (400 MHz ₁ DMSO-d ₆ ), δ (ppm) 2.71 (s, 3H); 2.94 (s, 3H); 4.81 and 4.92 (both s, total 2H); 5.00 (s, 2H); 6.90-7.10 (m, 3H); 7.52 (s, 1 H); 7.82 (d, 6 Hz ₁ 1 H); 8.10-8.30 (m, 3H); 9.38 and 9.61 ( both s, total 1 H).

Example 103

5,7-Dichloro-4-{[(pyridin-2-ylmethyl)-carbamoyl]-methoxy} -naphthalene-2- carboxylic acid

[00188] Mp >240 ⁰ C (decomp.); LCMS m/z 403 (M-1 ). ¹ H-NMR (200 MHz ₁ DMSO- d ₆ ), δ (ppm) 4.52 (d, 5.8 Hz ₁ 2H); 4.86 (s, 1 H); 7.27 - 7.44 (m, 2H); 7.45 (s, 1 H); 7.75 (d, 8.1 Hz ₁ 1 H); 7.80 (d, 2.2 Hz ₁ 1 H); 8.27 (br. s, 2H); 8.52 (d, 4.4 Hz ₁ 1 H) and 8.63 (t, 5.8 Hz ₁ I H).

Example 104

5,7-Dichloro-4-{[(pyridin-3-ylmethyl)-carbamoyl]-methoxy} -naphthalene-2- carboxylic acid

[00189] ¹ H-NMR (200 MHz ₁ DMSO-d ₆ ), δ (ppm) 4.41 (d, 5.1 Hz ₁ 2H); 4.82 (s, 2H); 3.71 - 3.40 (m, 1 H); 3.40 (s, 1 H); 3.72 (dm, 8.1 Hz, 1 H); 7.79 (d, 2.2 Hz ₁ 1 H); 8.27 (br. s, 2H); 8.48 (dd, 5.1 and 1.5 Hz ₁ 1 H); 8.52 (s, 1 H) and 8.64 (t, 5.1 Hz ₁ 1 H). Example 105

5,7-Dichloro-4-{[(pyridin-4-ylmethyl)-carbamoyl]-methoxy} -naphthalene-2- carboxylic acid

[00190] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.41 (d, 5.1 Hz ₁ 2H); 4.82 (s, 2H); 3.71 - 3.40 (m, 1 H); 3.40 (s, 1 H); 3.72 (dm, 8.1 Hz, 1 H); 7.79 (d, 2.2 Hz, 1 H); 8.27 (br. s, 2H); 8.48 (dd, 5.1 and 1.5 Hz, 1 H); 8.52 (s, 1 H) and 8.64 (t, 5.1 Hz, 1 H).

Example 106

5,7-Dichloro-4-{[2-(1H-tetrazol-5-yl)-benzylcarbamoyl]-me thoxy}-naphthalene-2- carboxylic acid

[00191] LCMS m/z 470 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.65 (d, 6 Hz, 2H); 4.82 (s, 2H); 7.41 (s, 1 H); 7.45 - 7.55 ( m, 3H); 7.72-7.76 (m, 2H); 8.23-8.27 (m, 2H); 8.52 (t, 6 Hz, 1 H).

Example 107

5,7-Dichloro-4-{[3-(1H-tetrazol-5-yl)-benzylcarbamoyl]-me thoxy}-naphthalene-2- carboxylic acid

[00192] LCMS m/z 470 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.49 (d, 6 Hz, 2H); 4.84 (s, 2H); 7.45 (s, 1 H); 7.48 -7.56 (m, 2H); 7.78 (d, 2 Hz, 1 H); 7.91 (d, 8 Hz, 1 H); 7.98 (s, 1 H); 8.22-8.26 (m, 2H); 8.65 (t, 6 Hz, 1 H).

Example 108

5,7-Dichloro-4-{[4-(1H-tetrazol-5-yl)-benzylcarbamoyl]-me thoxy}-naphthalene-2- carboxylic acid

[00193] LCMS m/z 470 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.45 (d, 6 Hz, 2H); 4.86 (s, 2H); 7.43 (d, 8 Hz, 2H); 7.46 (s, 1 H); 7.79 (d, 2 Hz, 1 H); 7.96 (d, 8 Hz, 2H); 8.27 (s, 2H); 8.63 (t, 6 Hz, 1 H). Example 109

5,7-Dichloro-4-({2-[(2-dimethylamino-ethylcarbamoyl)-meth oxy]- phenylcarbamoyl}-methoxy)-naphthalene-2-carboxylic acid

[00194] LCMS m/z 532 (M-1 ). ¹ H-NMR (400 MHz, DMSO-de), δ (ppm) 2.44 (s, 6H); 2.68-2.72 (m, 2H); 3.28-3.34 (m, 2H); 4.52 (s, 2H); 4.98 (s, 2H); 6.96-7.01 (m, 2H); 7.12 (t, 8 Hz, 1 H); 7.64 (s, 1 H); 7.72 (d, 2 Hz, 1 H); 7.80 (d, 7 Hz, 1 H); 8.15-8.22 (m, 3H); 9.72 (s, 1 H).

Example 110

5,7-Dichloro-4-[(2-{[(2-dimethylamlno-ethyl)-methyl-carba moyl]-methoxy}- phenylcarbamoyl)-methoxy]-napthalene-2-carboxylic acid

[00195] LCMS m/z 546 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 2.30 and 2.35 (both s, total 6H); 2.54 and 2.64 (both t, 6 Hz, total 2H); 2.76 and 2.93 (both s, total 3H); 3.36-3.48 (m, 2H); 4.82 (s), 4.97 (s), 4.99 (s) and 5.01 (s) - total 4H); 6.93-6.99 and 7.04-7.09 (both m, total 3H); 7.56 and 7.59 (both s, total 1 H); 7.72 and 7.74 (both d, 2 Hz, total 1 H); 7.88 and 7.90 (both d, 7 Hz, total 1 H); 8.21-8.25 (m, 2H); 9.69 and 9.71 (both s, total 1 H).

Example 111

4-[(2-Carboxymethoxy-4-methylaminomethyl-phenylcarbamoyl) -methoxy]-5,7- dichloro-naphthalene-2-carboxylic acid

[00196] LCMS m/z 505.5 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 2.55 (br s, 3H); 4.07 (br s. 2H); 4.82 (s, 2H); 5.04 (s, 2H); 7.09 (dd, 2 and 8 Hz 1 H); 7.17 (s, 1 H); 7.84 (d, 2 Hz, 1 H); 8.30-8.34 (m, 3H); 8.68 (br s, 1 H); 9.46 (s, 1 H); 14.27 (br s, 1 H). Example 112

SJ-Dichloro-A-^-cyanomethyl-phenylcarbamoyO-methoxyl-naph thalene^- carboxylic acid

[00197] LCMS m/z 427 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 3.99 (s, 2H); 4.96 (s, 2H); 7.32 (d, 8 Hz, 2H); 7.47 (s, 1 H); 7.64 (d, 8 Hz, 2H); 7.82 (d, 2 Hz, 1 H); 8.24-8.32 (m, 2H); 10.25 (s, 1 H).

Example 113

4-[(3-Carbamoyl-phenylcarbamoyl)-methoxy]-5,7-dichloro-na phthalene-2- carboxylic acid

[00198] Mp >250 ⁰ C; ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.97 (s, 2H); 7.33 - 7.48 (m, 3H); 7.58 (d, 7.3 Hz, 1 H); 7.74 - 7.83 (m, 2H); 7.95 (br. s, 1 H); 8.08 (s, 1 H); 8.28 (br. s, 2H) and 10.27 (s, 1 H).

Example 114

4-[(4-Carbamoyl-phenylcarbamoyl)-methoxy]-5,7-dichloro-na phthalene-2- carboxylic acid

[00199] ¹ H-NMR (200 MHz ₁ DMSO-d ₆ ), δ (ppm) 4.99 (s, 2H); 7.26 (br. s, 1H); 7.47 (s, 1 H); 7.68 (d, 8.8 Hz, 2H); 7.82 (s, 1 H); 7.86 (d, 8.8 Hz, 2H); 8.28 (s, 1 H); 8.29 (s, 1 H) and 10.39 (s, 1 H).

Example 115

7-[2-(3-Carboxy-6,8-dichloro-naphthalen-1-yloxy)-acetylam ino]-benzofuran-2- carboxylic acid

[00200] LCMS m/z 472 (M-1 ). ¹ H-NMR (400 MHz ₁ DMSO-d ₆ ), δ (ppm) 5.13 (s, 2H); 7.33 (t, 8 Hz, 1 H); 7.53 (d, 1 Hz, 1 H); 7.57 (dd, 1 and 8 Hz ₁ 1 H); 7.73 (s, 1 H); 7.80 (d, 2 Hz, 1 H); 8.06 (d, 8 Hz ₁ 1 H); 8.29 (d, 1 Hz, 1 H); 8.30 (d, 2 Hz, 1 H) and 10.29 (s, 1 H). Example 116

4-[(4-Aminomethyl-2-methylcarbamoylmethoxy-phenylcarbamoy l)-methoxy]-5,7- dichloro-naphthalene-2-carboxylic acid

[00201] Isolated as hydrochloride. Mp 233-235 ⁰ C; ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 2.52 (m, 3H); 3.97 (s, 2H); 4.57 (s, 2H); 5.00 (br. s, 2H); 7.06 (d, 8 Hz, 1H); 7.18 (s, 1 H); 7.54 (s, 1 H); 7.70 - 7.78 (m, 1 H); 8.08 (d, 8 Hz ₁ 1 H); 8.15 - 8.30 (m, 3H) and 9.67 (s, 1 H).

Example 117

5,7-Dichloro-4-[(4-cyano-benzylcarbamoyl)-methoxy]-naphth alene-2-carboxylic acid

[00202] LCMS m/z 427 (M-1). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.45 (d, 5.8 Hz, 2H); 4.85 (s, 2H); 7.40 - 7.48 (m, 3H); 7.73 - 7.80 (m, 3H); 8.27 (s, 2H) and 8.70 (t, 5.8 Hz, 1 H).

Example 118

5,7-Dichloro-4-{[2-(1H-tetrazol-5-ylmethyl)-benzylcarbamo yl]-methoxy}- naphthalene-2-carboxylic acid

[00203] Mp 239-240 ⁰ C; LCMS m/z 484 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.23 (s, 2H); 4.47 (d, 6 Hz, 2H); 4.79 (s, 2H); 7.01 -7.06 (m, 1 H); 7.13-7.18 (m, 2H); 7.25-7.28 (m, 1 H); 7.47 (s, 1 H); 7.72 (d, 2 Hz, 1 H); 8.19 (s, 1 H); 8.21 (d, 2 Hz, 1 H); 8. 64 (t, 6 Hz, 1 H).

Example 119

5,7-Dichloro-4-{[3-(1H-tetrazol-5-ylmethyl)-benzylcarbamo yl]-methoxy}- naphthalene-2-carboxylic acid

[00204] Mp 243-244 ⁰ C; LCMS m/z 484 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) ) 4.23 (s, 2H); 4.35 (d, 6 Hz ₁ 2H); 4.81 (s, 2H); 7.11 -7.16 (m, 2H); 7.20 (s, 1 H); 7.25 (t, 8 Hz, 1 H); 7.47(s, 1 H); 7.76 (d, 2 Hz, 1 H); 8.24 (d, 2 Hz, 1 H); 8.26 (d, 2 Hz ₁ 1 H); 8.57 (t, 6 Hz, 1 H). Example 120

5,7-Dichloro-4-{[4-(1H-tetrazol-5-ylmethyl)-benzylcarbamo yl]-methoxy}- naphthalene-2-carboxylic acid

[00205] Mp 247-248 ⁰ C; LCMS m/z 484 (M-1). ¹ H-NMR (400 MHz, DMSO-CJ ₆ ), δ (ppm) 4.25 (s, 2H); 4.35 (d, 6 Hz, 2H); 4.80 (s, 2H); 7.20 (d, 8 Hz, 2H); 7.24 (d, 8 Hz, 2H); 7.43 (s, 1H); 7.78 (d, 2 Hz, 1H); 8.26-8.28 ( m, 2H); 8.50 (t, 6 Hz, 1 H).

Example 121

5,7-Dichloro-4-{[3-(1H-tetrazol-5-ylmethoxy)-benzylcarbam oyl]-methoxy}- naphthalene-2-carboxylic acid

[00206] ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.46 (d, 5.9 Hz, 2H); 4.82 (s, 2H); 5.45 (s, 2H); 6.90 - 6.98 (m, 4H); 7.25 (t, 7.8 Hz, 1 H); 7.43 (s, 1 H); 7.79 (d, 2.2 Hz, 1 H); 8.25 - 8.30 (m, 2H) and 8.51 (t, 5.9 Hz, 1 H).

Example 122

4-[(2-Carboxymethoxy-4-hydroxymethyl-phenylcarbamoyl)-met hoxy]-5,7-dichloro- naphthalene-2-carboxylic acid

[00207] Mp 244-245 ⁰ C; LCMS m/z 492 (M-1). ¹ H-NMR (200 MHz, DMSO-d ₆ ), δ (ppm) 4.44 (d, 4 Hz, 2H): 4.78 (s, 2H); 5.00 (s, 2H); 5.19 (t, 4Hz, 1 H); 6.93 ( d, 8 Hz, 1 H); 6.95 (s, 1 H); 7.55 (s, 1 H); 7.84 (d, 2 Hz, 1 H); 8.18 (d, 8 Hz, 1 H); 8.30-8.33 (m, 2H); 9.37 (s, 1 H).

Example 123

4-[(4-Aminomethyl-2-dimethylcarbamoylmethoxy-phenylcarbam oyl)-methoxy]-5,7- dichloronaphthalene-2-carboxylic acid

[00208] Isolated as hydrochloride. LCMS m/z 518 (M-1). ¹ H-NMR (200 MHz, DMSO-de), δ (ppm) 2.72 (s, 3H); 2.95 (s, 3H); 3.95 (s, 2H); 4.94 (s, 2H); 5.03 (s, 2H); 7.07 (d, 8 Hz, 1 H); 7.21 (s, 1 H); 7.53 (s, 1 H); 7.81 (d, 2.2 Hz, 1 H); 8.22 (d, 8 Hz, 1 H); 8.30 (br. s, 2H) and 9.65 (s, 1 H). Example 124

5,7-Dichloro-4-{[2-(2-hydroxy-ethoxy)-3-hydroxymethyl-phe nylcarbamoyl]- methoxy}-naphthalene-2-carboxylic acid

[00209] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 3.70 (m, 2H); 3.90 (m, 2H); 4.60 (s, 2H); 5.00 (s, 2H); 7.12 (t, 8 Hz, 1 H); 7.19 (d, 8 Hz, 1 H); 7.48 (s, 1 H); 7.82 (s, 1 H); 8.05 (d, 8 Hz, 1 H); 8.25 (s, 1 H); 8.30 (s, 1 H). LCMS m/z 478.05 (M-1 ).

Example 125

5,7-Dichloro-4-{[2-(1H-tetrazol-5-ylmethoxy)-benzylcarbam oyl]-methoxy}- naphthalene-2-carboxylic acid

[00210] LCMS m/z 500 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.42 (d, 6 Hz, 2H); 4.84 (s, 2H); 5.48 (s, 2H); 6.94 (t, 7.4 Hz, 1 H); 7,14 (d, 8 Hz, 1H); 7.22-7.27 (m, 2H); 7.44 (s, 1 H); 7.75 (d, 2 Hz, 1 H): 8.25 (s, 1 H); 8.27 (d, 2 Hz, 1 H); 8.40 ( t, 6 Hz, 1 H).

Example 126

5,7-Dichloro-4-{[4-(1H-tetrazol-5-ylmethoxy)-benzylcarbam oyl]-methoxy}- naphthalene-2-carboxylic acid

[00211] Mp >236 ⁰ C (decomp.); LCMS m/z 500.4 (M-1 ). ¹ H-NMR (400 MHz, DMSO-de), δ (ppm) 4.32 (d, 6 Hz, 2H); 4.80 (s, 2H); 5.46 (s, 2H); 7.00 (d, 8 Hz, 2H); 7.24 (d, 8 Hz, 2H); 7.43 (s, 1 H); 7.79 (d, 2 Hz, 1 H); 8.26 (s, 1 H); 8.28 (d, 2 Hz, 1 H); 8.45 (t, 6 Hz, 1 H).

Example 127 5,7-Dichloro-4-(pyridin-3-ylcarbamoylmethoxy)-naphthalene-2- carboxylic acid

[00212] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 5.00 (s, 2H); 7.37-7.40 (m, 1 H); 7.48 (s, 1 H); 7.81 (d, 2 Hz, 1 H); 8.07 (d, 8 Hz, 1 H); 8.28 - 8.31 (m, 3H); 8.77 (d, 2 Hz, 1 H); 10.42 (s, 1 H). Example 128

^{^.S-Bis^iH-tetrazol-S-ylmethoxyJ-phenylcarbamoyll-metho xy^SJ-dichloro- naphthalene-2-carboxylic acid

[00213] Mp 246-247 ⁰ C; LCMS m/z 584 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 4.98 (s, 2H); 5.41 (s, 2H); 5.56 (s, 2H); 7.04 (d, 8 Hz, 1H); 7.12 (t, 8 Hz ₁ 1H); 7.51 (s, 1H); 7.71 (s, 1H); 7.81 (d, 8 Hz, 1H); 8.29 (s, 2H); 9.52 (s, 1H).

Example 129 5,7-Dichloro-4-(pyridin-2-ylcarbamoylmethoxy)-naphthalene-2- carboxylic acid

[00214] ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 5.03 (s, 2H); 7.15-7.18 (m, 1H); 7.49 (s, 1H); 7.78 -7.86 (m, 2H); 8.11 (d, 8 Hz ₁ 1H); 8.23 (s, 1H); 8.26 (d, 2 Hz ₁ 1H); 8.36 (d, 4 Hz, 1H); 10.42 (s, 1H).

Example 130

5,7-Dichloro-4-[(4-methyl-thiazol-2-ylcarbamoyl)-methoxy] -naphthalene-2- carboxylic acid

[00215] ¹ H-NMR (400 MHz ₁ DMSO-d ₆ ), δ (ppm) 2.27 (s, 3H); 5.09 (s, 2H); 6.81 (s, 1H); 7.41 (S ₁ 1H); 7.82 (s, 1H); 8.27 (s, 1H); 8.29 (d, 2 Hz ₁ 1H); 12.26 (br s, 1H); 13.39 (br.s, 1H).

Example 131

4-[1-(2-Carboxymethoxy-phenylcarbamoyl)-2-methoxy-ethoxy] -5,7-dichloro- naphthalene-2-carboxylic acid

[00216] Mp 224-225 ⁰ C; LCMS m/z 506 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 3.34 (S ₁ 3H); 3.90 (dd, 3.6 and 11.2 Hz ₁ 1H); 3.99 (dd, 5.2 and 11.2 Hz, 1H); 4.66 (d, 16.8 Hz, 1H); 4.68 (d, 16.8 Hz, 1H); 5.44-5.46 (m, 1H); 6.93 - 6.97 (m, 2H); 7.03- 7.07 (m, 1H); 7.56 (s, 1H); 7.82 (d, 2 Hz ₁ 1H); 8.08 (dd, 2 and 8 Hz, 1H); 8.27-8.29 (m, 2H); 9.49 (s, 1 H); 13.00 (br s, 1 H); 13.38 (br S ₁ 1 H). Example 132

SJ-Dichloro^-^S-methyl^.S.ej-tetrahydro-thiazolo^.S-clpyr idin^-ylcarbamoyl)- methoxy]-naphthalene-2-carboxylic acid

[00217] Mp 242-243 ⁰ C; LCMS m/z 464 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 2.51 and 2.52 (both br s, total 3H); 2.72-2.77 (m, 2H): 2.90-2.95 (m, 2H); 3.74 (s, 2H); 5.09 (s, 2H); 7.41 (s, 1 H); 7.81 (d, 2 Hz, 1 H); 8.27 (s, 1 H); 8.29 (d ,2 Hz, 1 H); 12.27 (br s, 1 H).

Example 133

5,7-Dichloro-4-[(5-methyl-thiazol-2-ylcarbamoyl)-methoxy] -naphthalene-2- carboxylic acid

[00218] Mp >250 ⁰ C; ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 2.34 (s, 3H); 5.06 (s, 2H); 7.16 (s, 1 H); 7.46 (s, 1 H); 7.74 (s, 1 H); 8.20-8.22 (m, 2H); 12.20 (br s, 1 H).

Example 134

5,7-Dichloro-4-({2-[(2-hydroxy-ethylcarbamoyl)-methoxy]-p henylcarbamoyl}- methoxy)-naphthalene-2-carboxylic acid

[00219] Mp 217-218 ⁰ C; LCMS m/z 505 (M-1 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 3.07-3.12 (m, 2H); 3.32-3.36 (m, 3H); 4.60 (s, 2H); 5.01 (s, 2H); 6.96-7.02 (m, 2H); 7.07-7.12 (m, 1 H); 7.53 (s, 1 H); 7.80 (d, 2 Hz ₁ 1 H); 8.06-8.13 (m, 2H); 8.28-8.32 (m, 2H); 9.58 (s, 1 H).

Example 135

5,7-Dichloro-4-[(4,5-dimethyl-thiazol-2-ylcarbamoyl)-meth oxy]-naphthalene-2- carboxylic acid

[00220] Mp >250 ⁰ C; ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 2.17 (s, 3H); 2.24 (s, 3H); 5.06 (s, 2H); 7.40 (s, 1 H); 7.81 (s, 1 H); 8.27-8.29 (both s, total 2H); 12.10 (br s, 1 H); 13.00-13.80 (br s, 1 H). Example 136

^[(S-Carbamoyl-IH-imidazol^-ylcarbamoyO-methoxyl-SJ-dichl oro-naphthalene- 2-carboxylic acid

[00221] Mp >250 ⁰ C; LCMS m/z 421 (M-1). ¹ H-NMR (400 MHz, DMSO-Cl ₆ ), δ (ppm) 5.11 (s, 2H); 7.21 (br s, 1 H); 7.32 (br s, 1 H); 7.35 (s, 1 H); 7.54 (s, 1 H); 7.83 (s, 1 H); 8.28-8.34 (m, 2H); 10.71 (s, 1 H); 12.72 (s, 1 H); 13.30-13.60 (br s, 1 H).

Example 137

5,7-Dichloro-4-[(2-cyanomethyl-phenylcarbamoyl)-methoxy]- naphthalene-2- carboxylic acid

[00222] Mp 246-247 ⁰ C; LCMS m/z 427 (M-1). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm) 3.95 (s, 2H); 5.00 (s, 2H); 7.30-7.38 (m, 3H); 7.46 (d, 7.6 Hz, 1 H); 7.52 (s, 1 H); 7.80 (d, 2Hz, 1 H): 8.28 (s and d, 2 Hz, total 2H); 9.98 (s, 1 H).

Table 1

Table 2

EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS

[00223] With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes. Representative pharmaceutical compositions follow.

(a) Tablets suitable for oral administration, which contain the active ingredient, may be prepared by conventional tabletting techniques.

(b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature. (c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.

[00224] Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.

FORMULATION EXAMPLES

[00225] The following examples are again given by way of illustration only and are not to be construed as limiting.

EXAMPLE 1

Tablet Formulation

A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows:

EXAMPLE 2

Tablet Formulation Another suitable formulation for a tablet containing 100 mg is as follows:

EXAMPLE 3

Capsule Formulation

A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:

filled in a gelatin capsule.

EXAMPLE 4

Solution for injection A suitable formulation for an injectable solution is as follows:

EXAMPLE 5

Liquid oral formulation

A suitable formulation for 1 liter of an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:

EXAMPLE 6

Liquid oral formulation

Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:

EXAMPLE 7

Liquid oral formulation

Another suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:

EXAMPLE 8

Aerosol formulation 180 g aerosol solution contain:

15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar.

EXAMPLE 9

TDS formulation 100 g solution contain:

1.8 ml of the solution are placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before use.

EXAMPLE 10

Nanoparticle formulation 10 g of polybutylcyanoacrylate nanoparticles contain:

Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum.

PHARMACOLOGY

[00226] The active principles of the present invention, and pharmaceutical compositions thereof and method of treating therewith, are characterized by unique and advantageous properties, rendering the "subject matter as a whole", as claimed herein, unobvious. The compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics:

METHODS

BINDING ASSAYS FOR THE CHARACTERIZATION OF GLYCINE B ANTAGONIST PROPERTIES

[ ³ H]MDL-105,519 Displacement Studies

[00227] For the evaluation of the binding affinity of the test compounds on the glycine binding pocket of the NMDA receptor, [ ³ H]-MDL-105,519 (GE Healthcare, Freiburg, Germany) displacement studies are performed using a 96-well plate robotic platform. MDL-105,519 (Baron et al., J Pharmacol Exp Ther 1996, 279(1 ), 62-68; Baron et al., European Journal of Pharmacology, 1997, 323(2-3), 181-192; Hoffner & Wanner, Neuroscience Letters, 1997, 226(2), 79-82) is a selective, high affinity antagonist at the NMDA receptor glycine site.

Preparation of cortical membranes:

[00228] Tissue preparation is performed according to Foster & Wong (Br J Pharmacol, 1987, 91 , 403-409) with some modifications. Anaesthetised male Sprague- Dawley rats (200-250 g, Janvier, Le Genest-lsle, France) are decapitated and their brains removed rapidly. The cortex is dissected out and processed as described by Parsons, et al. (J Pharmacol Exp Ther, 1997, 283(3), 1264-1275). For isolation of the cell membranes, the cortices are homogenized in 20 volumes of ice-cold 0.32 M sucrose (Sigma-Aldrich, Taufkirchen, Germany) using a glass-Teflon homogenizer. The homogenate is centrifuged at 1000 x g for 10 minutes, the pellet is discarded and the supernatant centrifuged at 20,000 x g for 20 minutes. The resulting pellet is re- suspended in 20 volumes of distilled water and centrifuged for 20 minutes at 8000 x g. The supernatant and the buffy coat are then centrifuged three times (48,000 x g for 20 minutes) in the presence of 50 mM Tris-HCI, pH 8.0 (assay buffer). All centrifugation steps are carried out at 4°C. After resuspension in 5 volumes of 50 mM Tris-HCI, pH 7.5, the membrane suspension is frozen rapidly at -80 ⁰ C. On the day of assay, the membranes are thawed and washed four times by resuspension in 50 mM Tris-HCI, pH 7.5, and centrifugation at 48,000 x g for 20 minutes. The final pellet is suspended in assay buffer. The amount of protein in the final membrane preparation is determined according to the method of Lowry, et al. (J. Biological Chemistry, 1951 , 193, 256-275) with some modifications (Hartree, Analytical Biochemistry, 1972, 48, 422-427). The final protein concentration used for our studies is 400 μg/ ml.

Displacement studies

[00229] A robotic system designed for binding assays (Tecan Deutschland GmbH, Crailsheim, Germany) is loaded with the membrane solution, solutions for bound control (buffer/DMSO 20%), unlabeled glycine (1 mM) for evaluation of non-specific binding, all compounds to be tested (at 20-fold concentrations), radioligand and respective 96-well plates.

[00230] Before performing displacement studies, saturation experiments are performed to determine the equilibrium dissociation constant (K _d ) of [ ³ H]-MDL-105,519, which is a parameter for the affinity of the radioligand to the binding site. The protein/receptor concentration is held constant whereas the amount of specific bound radioligand is determined using increasing concentrations of ligand.

[00231] On the basis of the saturation experiments, a final [ ³ H]-MDL-105,519 concentration of 2 nM is selected. Firstly, the assay plates are loaded with membrane solution and are shaken at 4°C. The mother plates are then prepared by pipetting the compounds into assay buffer/20% DMSO to obtain the desired final concentrations (dose response curve with five different concentrations, e.g. 10, 3, 1 , 0.3, and 0.1 μM). After transferring radioligand into the assay plates, the compounds are added (including the bound and the non-specific binding control). The final DMSO concentration is 1 %. The assay plates are incubated and shaken at 4°C for 1 h, before the mixture is exhausted as rapidly as possible via a vacuum manifold using the Multiscreen HTS glass fibre (type B) filter plates (Millipore, Schwalbach, Germany) under a constant vacuum of 450 mbar. The membranes are washed four times with cold assay buffer (100 μL). 50 μL of Ultima Gold scintillation cocktail (PerkinElmer, Rodgau-Jϋgesheim, Germany) is added to the wet filter plates and incubated at room temperature overnight before counting the disintegration per minutes using a liquid scintillation counter (MicroBeta, PerkinElmer, Rodgau-Jϋgesheim, Germany). Analysis of data

[00232] For the evaluation of the binding affinity of the test compound to the glycine B binding site and its potency to displace [ ³ H]-MDL-105,519, the measured radioactivity of the radioligand alone is set as 100 % bound control and the non-specific binding of the radioligand (which could not be displaced by glycine, 1 mM) represented the 0 % control. The residual radioactivity after displacement of the test compound (n = 5) is then corrected with respect to the set controls.

FUNCTIONAL SCREENING FOR THE CHARACTERIZATION OF GLYCINE B ANTAGONIST PROPERTIES

[00233] Antagonistic potencies of the test compounds are functionally evaluated using electrophysiological whole cell patch-clamp recordings and/or fluorometric intracellular Ca ²⁺ -imaging (FLIPR) screens.

Whole cell patch-clamp recordings

Preparation and cultivation of rat hippocampal neurons

[00234] Cell preparation is performed as described by Parsons, et al. (Neuropharmacology, 1998, 37(6), 719-727). The female Sprague-Dawley rat is anaesthetised by placing in a saturated Cθ ₂ -euthanasia chamber under further quiet Cθ ₂ -influx. Under these conditions the rat loses consciousness after a few seconds and is then sacrificed by cervical dislocation. After opening the abdominal cavity, embryos (E20) are removed and stored in ice cold Ca ²⁺ - and Mg ²⁺ -free Hank's Buffered Salt Solution (pH 7.3), containing 4 g/l glucose (HBSS-CMF). Hippocampi are then isolated from the brains of at least 8 embryos after decapitation, transferred into ice cold HBSS- CMF and washed 3 to 4 times.

[00235] Hippocampi are pre-incubated for 8 min with a 0.66% trypsin (Sigma- Aldrich) and 0.1% (20 U/ml) DNAase solution (Sigma-Aldrich) in Ca ²⁺ -free Phosphate Buffered Saline (PBS-CF) and washed 3 times with HBSS-CMF. Cells are then mechanically dissociated by trituration in a PBS-CF solution containing 0.05% (10 U/ml) DNAase and 0.3% of the trypsin inhibitor ovomucoid (all from Sigma-Aldrich). The cells are then centrifuged at 180 x g for 10 minutes, and the cell pellet re-suspended in basal Minimum essential medium (MEM, Invitrogen, Karlsruhe, Germany), again carefully triturated to ensure maximal dissociation and finally plated in the flexiPERM inserts (Thermo Fisher Scientific, Langenselbold, Germany) at a density of 15 x 10 ³ cells/cm ² (0.5 ml/insert) onto poly-DL-ornithine (Sigma) and mouse laminin (Invitrogen) pre- coated plastic petri dishes. After 1 hour the cells become attached to the bottom of the dish and the inserts may be removed. The cells are then nourished with 2 ml MEM supplemented with 5% foetal calf serum (FCS) and 5% horse serum and incubated at 37 ⁰ C with 95% air and 5% CO ₂ at 95% humidity. After 4 days in vitro (DIV) further glial mitosis is inhibited by adding 10 μl of AraC (5 μM endconcentration). The medium is completely exchanged after an additional 2 DIV and again, but only partly (50 %), after 8 DIV. The cells are used for electrophysiological recordings after 11-15 DIV.

Evaluation of peripheral antagonistic potencies

[00236] For the peripheral glycine B site antagonistic potency evaluation, compounds are functionally tested using dorsal root ganglia (DRG) neurons, modified from Li et al. (Pain, 2004, 109, 443-452).

Whole cell patch clamp recordings

[00237] Cells are visualised using an inverted microscope and selected for patching based upon their position and morphology. Voltage clamp recordings are made in the whole cell configuration of the patch clamp technique at a holding potential of -70 mV with the aid of an EPC-10 amplifier in combination with pipette manipulator. Patch clamp pipettes are pulled from borosilicate glass using a horizontal puller (P-97 Puller, Sutter Instruments, USA) and, when filled with intracellular solution, have resistances of 1 - 4 MΩ.

[00238] Solutions are delivered via a home-made gravity driven very fast perfusion system (< 10 ms) including valves to switch flow on and off in combination with a stepper motor-driven double-barrelled theta glass application pipette in order to expose cells to either agonist-free or agonist-containing solutions in presence or absence of antagonist. [00239] The intracellular solution used consists of: 120 mM CsCI, 10 mM EGTA, 1 mM MgCb, 200 μM CaCI ₂ , 10 mM glucose and 22 mM tetraethyl ammonium chloride (TEA-CL). The corresponding extracellular bath solution contains: 140 mM NaCI, 3 mM KCI, 10 mM glucose, 10 mM HEPES, 1.5 mM CaCI ₂ and 4.5 mM sucrose (all from Sigma-Aldrich) pH 7.3, and is supplemented with 0.3 μM tetrodotoxin (TTX, Tocris, Bristol, U.K.) to block voltage-activated sodium channels and 0.25 μM bicuculline (Sigma-Aldrich) to block GABA _A receptors.

[00240] For the determination of concentration-dependency of blockade, 5 control traces are recorded with application of NMDA (200 μM) and D-Serine (1 μM) for 5 seconds in order to reduce the effect of rundown, then the highest concentration of the test-substance is applied for 1 minute before applying the agonists for 5 seconds in the presence of antagonist. Three recordings are made in the presence of the antagonist and 3 recovery traces are recorded after it's removal. The procedure is repeated for three to four further concentrations of antagonist with declining concentrations e.g. 10, 3, 1 , 0.3, and 0.1 μM. For the final recovery, agonists are again applied five times after wash-out of the test substance.

Analysis of data

[00241] Data are analysed using TIDA 5.0 (Heka, Lambrecht, Germany). With the help of Microsoft Excel, data are pooled and finally GraFit software (Erithacus Software Ltd., Surrey, U.K.) is used to fit the data e.g. with the four parameter logistic equation for determining IC _5O values. For all data points, the value given is the mean ± S. E. M. (standard error of the mean) of results from at least 4 individual cells per concentration.

Calcium FLIPR studies

Preparation and cultivation of rat cortical neurons

[00242] Primary neurons are prepared from cortices of embryonal rats at day 17 of pregnancy as described by Dichter (Brain Res., 1987, 149, 279). Sprague-Dawley rat embryos (E 17) are decapitated and neocortices are dissected, trypsinized and carefully triturated. The cell suspension is plated on poly-D-lysine pre-coated 96-well Plates (Greiner, Frickenhausen, Germany) at a cell density of 55.000 cells /well. The neurons are cultivated in Neurobasal media containing B27-Supplement and 0.5 μM L-Glutamine (Biochrom) at 37 ⁰ C in a humidified atmosphere of 5% CO ₂ / 95% air. Medium is exchanged completely at day 4 and to 50% on day 7. At the time of experiments neurons are 11 - 13 days in vitro.

Calcium FLIPR studies

[00243] The increase of intracellular calcium after stimulation with 30 μM NMDA and 1 μM D-Serine is measured using the fluorometric imaging plate reader (FLIPR) and the Calcium-4-Kit (both Molecular Devices, Ismaning, Germany). Prior to addition of agonist or antagonist (5 different concentrations, n = 5) the medium is aspirated and cells are washed once before loading with 150 μl_ of loading buffer (1 h at room temperature), consisting of Ca-4 sensitive dye reconstituted in extracellular bath solution, pH 7.3. Subsequently, plates are transferred to FLIPR to detect increases in intracellular calcium after the addition of agonist, measured as relative fluorescence units (RFU). Antagonists are pre-incubated with the cells for 10 min at room temperature before the addition of the agonist and co-agonist.

Data analysis

[00244] The fluorescence signal increase after addition of agonist reflects the increase of intracellular calcium. Inconsistencies in the amount of cells per well are normalised by using the spatial uniformity correction of the FLIPR software (Screenworks, Molecular Devices). The mean of replicated temporal data (n=5) is calculated and used for graphical representation. For the evaluation of the antagonistic potency, the calcium changes in response to different concentrations of antagonist are determined using an area under the curve (AUC) calculation. All responses (RFU- values) are determined as percentage of control (= maximum response at 30 μM NMDA and 1 μM D-Serine). IC ₅₀ values are calculated according the four parameter logistic equation using GraFit (Erithacus Software).

[00245] Results for respresentative compounds of the invention are shown in Tables 3-5. Table 4 - Patch Clamp Studies

CONCLUSIONS

[00246] In conclusion, from the foregoing, it is apparent that the present invention provides novel, valuable, and unpredictable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith, all possessed of the foregoing more specifically-enumerated characteristics and advantages.

[00247] The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in lower animals. Clinical evaluation in human beings has not been completed, however. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies, such as the U.S. Federal Food and Drug Administration, which are responsible for and authorized to pass judgment on such questions.

[00248] The instant naphthalene derivatives represent a novel class of glycine B antagonists. In view of their potency, they will be useful therapeutics in a wide range of disorders, including CNS disorders, which involve excessive glutamate induced excitation.

[00249] These compounds accordingly find application in the treatment of the following disorders of a living animal body, especially a human: pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).

[00250] These compounds also find application in the treatment of the following disorders of a living animal body, especially a human: acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia;

chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ^' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration;

neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity;

psychological/psychiatric disorders, including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse;

skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis;

diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation;

diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS);

eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration;

diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease;

migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.

[00251] The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated. [00252] Use of the compounds of the present invention in the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a glycine B is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.

[00253] Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.

_{* * * * *}

[00254] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description.

[00255] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.