88625-23-4

According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by Mycobacterium tuberculosis against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino-N-phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against Mycobacterium tuberculosis H37Ra and four other mycobacterial strains (M. aurum, M. smegmatis, M. kansasii, M. avium) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against M. tuberculosis H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, N-(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (3c, MIC = 3.91 μg/mL or 13.02 μM, SI > 38) and 5-(heptylamino)-N-(p-tolyl)pyrazine-2-carboxamide (4e, MIC = 0.78 μg/mL or 2.39 μM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the Candida genus.

The current study is focused on a series of sorafenib analogs as potential antitumor agents. We have designed and synthesized nine novel pyrazine analogs 6a–i differing in amide and/or urea regions. Two alternative strategies for the preparation of title

Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ‘‘partial” GK activators. The structure-activity relationship studies starting from a “full GK activator” 11, which culminated in the discovery of the “partial GK activator” 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.

The invention provides a lappaconitine derivative with analgesic activity, and a preparation method and application thereof. The structure of the lappaconitine derivative is as shown in formula I in the specification. The lappaconitine derivative provided by the invention is high in analgesic activity, good in water solubility and low in biotoxicity, can be used for preparing low-toxicity analgesic drugs, and is wide in application prospect.

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.

Provided herein are certain compounds useful as HTT modulators. Such compound are useful in the treatment of Huntington's disease.

The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.

The present invention provides flavone derivatives having the general formula (I) which are useful for the treatment of Hepatitis B Virus infection (HBV). The compounds act as cccDNA (covalently closed circular DMA) inhibitors.

The present invention provides compounds of Formula (Ia) or (Ib) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein wherein X1, X2, X3, and X4 are each independently CR6 or N; provided that no more than two of X1, X2, X3, or X4 are N; L is C1-4 alkylene substituted with 0 to 4 R7; R1 is (-CH2)aR9; a is an integer of 0 or 1; R2 is each independently halo, cyano, hydroxyl, amino, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyi, hydroxyalkyi, aminoalkyi, alkoxy, alkoxyalkyi, haloalkoxyallcyl, or haloalkoxy; n is an integer of 0, 1, or 2; R3 is hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, haloalkyi, hydroxyalkyi, aminoalkyi, alkoxyalkyi, haloalkoxyalkyl, alkoxy, or haloalkoxy, and the alkyl, by itself or as part of other moiety, is optionally substituted with deuterium partially or fully; R4 is C1-10 alkyl, C1-10 deuterated alkyl, C1-10 haloalkyi, C1-10 alkenyl, C3-8 cycloalkyl, 6 to 10-membered aryl, 3 to 8-membered heterocyclyl, -(C1-6 alkylene)-(C3-8 cycloalkyl), -(C1-6 alkylene)-(6 to 10-membered aryl), -(C1-6 alkylene)-(3 to 8-membered heterocyclyl), or -(C1-6 alkylene)-(5 to 6-membered heteroaryl); wherein each of the alkyl, alkylene, alkenyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, by itself or as part of other moiety, is independently substituted with 0 to 3 R8; or alternatively, R3 and R4, taken together with the N atom to which they are attached, form a 4 to 9-membered heterocyclic ring moiety which is substituted with 0 to 3 R; R5 and R6 are each independently hydrogen, halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R7 is halo, oxo, cyano, hydroxyl, amino, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R8 are each independently deuterium, halo, hydroxyl, amino, cyano, C1-6 alkyl, C1-6 deuterated alkyl, C2-6 alkenyl, C2-6 alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5 to 6-membered heteroaryl; or alternatively, two R8, taken together with the atoms to which they are attached, form a 3 to 6-membered carbocyclic ring or a 3 to 6-membered heterocyclic ring each of which is independently substituted with 0 to 3 R12; R9 is selected from -CN, -C(O)OR10, -C(O)NR11aR11b, -CO-NH-CO-Re, -CO-NH-SO2-Re, -CO-NH-SO-Re, -SO2-OH, -SO2-NH-CO-Re, -P(O)(OH)2, tetrazol-5-yl, -CH2-CO-NH-CO-Re, -CH2-CO-NH-SO2-Re, CH2-CO-NH-SO-Re, -CH2-SO2-OH, -CH2-SO2-NH-CO-Re, -CH2-P(O)(OH)2, tetrazol-5-ylmethylene; Re is C1-6 alkyl, C3 -6 cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl; R10 is hydrogen or C1-10 alkyl; and R11a and R11b are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; and R12 is halo, cyano, hydroxyl, amino, C1-6alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5 to 6-membered heteroaryl. These compounds are selective LPA receptor inhibitors.

The present invention provides compounds of Formula (Ia) and (Ib): (Ia) or (Ib), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.

The present disclosure relates to novel compounds including formula (X) and pharmaceutical compositions thereof, and methods for inhibiting the activity of SHP2 phosphatase with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with SHP2 deregulation with the compounds and compositions of the disclosure.

Commercial route definition for a glucokinase activator called for a re-evaluation of the synthesis and processes used to access multikilogram quantities of a pyrazine building block. The processes developed allowed a literature route to sodium 6-oxo-1H-pyrazine-3-carboxylate to be leveraged. One of these processes consisted of a highly selective decarboxylation that allowed the target building block to be accessed with complete regioselectivity in standard batch processing equipment. The presence of an azetidine ring in the target required the mitigation of impurity liabilities arising from the use of the hydrochloride salt of azetidine as an input material.

Hybrid compounds based on a combination of the first-line antitubercular pyrazinamide (PZA) and a formerly identified antimycobacterial scaffold of 4-arylthiazol-2-amine were designed. Eighteen compounds were prepared, characterized and tested for in vitro growth inhibition activity against M. tuberculosis H37Rv, M. kansasii, M. avium and M. smegmatis by Microplate Alamar Blue Assay at neutral pH. Active compounds were tested for in vitro cytotoxicity in the human hepatocellular carcinoma cell line (HepG2). The most active 6-chloro-N-[4-(4-fluorophenyl)thiazol-2-yl]pyrazine-2-carboxamide (9b) also had the broadest spectrum of activity and inhibited M. tuberculosis, M. kansasii, and M. avium with MIC = 0.78 μg mL-1 (2.3 μM) and a selectivity index related to HepG2 cells of SI > 20. Structure-activity relationships within the series are discussed. Based on its structural similarity to known inhibitors and the results of a molecular docking study, we suggest mycobacterial beta-ketoacyl-(acyl-carrier-protein) synthase III (FabH) as a potential target.

The present invention relates to compounds of general formula (I), wherein the groups R, R1, R2, R3, m and n are defined as in claim 1, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.

The present invention relates to compounds of formula I, wherein the groups R, R1, R2, R3, m and n are defined herein, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2. Furthermore, the invention relates to novel intermediates, useful for the synthesis of compounds of formula I.

The present invention relates to compounds of general formula (I), wherein the groups R, R1, R2, R3, m and n are defined as in claim 1, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.

Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development.

The molecular structural parameters and vibrational frequencies of 5-chloro-N-(3-nitrophenyl)pyrazine-2-carboxamide have been obtained using density functional theory technique in the B3LYP approximation and CC-pVDZ (5D, 7F) basis set. Detailed vibrationa

A series of 6-hetaryloxy benzoxaborole compounds was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the changes in antimalarial activity which result from 6-aryloxy structural variation, substituent modification on the pyrazine ring, and optimization of the side chain ester group. This SAR study discovered highly potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 27-34) with IC50s = 0.2-22 nM against cultured Plasmodium falciparum W2 and 3D7 strains. Compound 9 also demonstrated excellent in vivo efficacy against P. berghei in infected mice (ED90 = 7.0 mg/kg).

The present invention relates to amino-substituted isothiazoles of general formula (I): in which A, R1 and R2 are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

[Problem] A compound which is useful as an active ingredient of a pharmaceutical composition for treating storage dysfunctions, voiding dysfunctions, and lower urinary tract diseases is provided. [Means for Solution] The present inventors have found that a thiazole derivative having pyrazine-2-carbonylamino substituted at the 2-position is an excellent muscarinic M 3 receptor positive allosteric modulator, and is useful as an agent for preventing and/or treating bladder or urinary tract diseases, related to bladder contraction by a muscarinic M 3 receptor, thereby completing the present invention. The 2-acylaminothiazole derivative or a salt thereof of the present invention can be used as an agent for preventing and/or treating bladder or urinary tract diseases, related to bladder contraction by a muscarinic M 3 receptor, for example, voiding dysfunctions such as underactive bladder.

A series of alkylamino derivatives of N-benzylpyrazine-2-carboxamide was designed, synthesized and assayed in vitro for their antimycobacterial, antibacterial, antifungal as well as antiviral activities. Final structures were prepared from 6-chloro (1), 5-chloro (2) or 3-chloro (3) derivatives of N-benzylpyrazine-2-carboxamide by nucleophilic substitution of chlorine with n-alkylamines in the range from butylamine to octylamine (labelled a-e). Series 1a-e and 2a-e exerted higher activity against Mycobacterium tuberculosis H37Rv compared to the corresponding pattern compounds and the reference compound pyrazinamide. The most active derivatives reached an activity MIC = 4.6-10 μM (M. tbc H37Rv). More importantly, activity was also observed against other tested mycobacterial strains (including drug-resistant strains). Substitution of 3-chlorine was disadvantageous and led to completely inactive compounds 3a-e. Some compounds showed activity against Gram-positive bacterial strains (including MRSA) or influenza virus, but no antifungal activity was observed.

Abstract In the Mycobacterium genus over one hundred species are already described and new ones are periodically reported. Species that form colonies in a week are classified as rapid growers, those requiring longer periods (up to three months) are the mostly pathogenic slow growers. More recently, new emerging species have been identified to lengthen the list, all rapid growers. Of these, Mycobacterium abscessus is also an intracellular pathogen and it is the most chemotherapy-resistant rapid-growing mycobacterium. In addition, the cases of multidrug-resistant Mycobacterium tuberculosis infection are also increasing. Therefore there is an urgent need to find new active molecules against these threatening strains. Based on previous results, a series of salicylanilides, salicylanilide 5-chloropyrazinoates and carbamates was designed, synthesized and characterised. The compounds were evaluated for their in vitro activity on M. abscessus, susceptible M. tuberculosis H37Rv, multidrug-resistant (MDR) M. tuberculosis MDR A8, M. tuberculosis MDR 9449/2006 and on the extremely-resistant Praha 131 (XDR) strains. All derivatives exhibited a significant activity with minimum inhibitory concentrations (MICs) in the low micromolar range. Eight salicylanilide carbamates and two salicylanilide esters exhibited an excellent in vitro activity on M. abscessus with MICs from 0.2 to 2.1 μM, thus being more effective than ciprofloxacin and gentamicin. This finding is potentially promising, particularly, as M. abscessus is a threateningly chemotherapy-resistant species. M. tuberculosis H37Rv was inhibited with MICs from 0.2 μM, and eleven compounds have lower MICs than isoniazid. Salicylanilide esters and carbamates were found that they were effective also on MDR and XDR M. tuberculosis strains with MICs ≥1.0 μM. The in vitro cytotoxicity (IC50) was also determined on human MonoMac-6 cells, and selectivity index (SI) of the compounds was established. In general, salicylanilide derivatives substituted by halogens on both salicyl and aniline rings showed better activity, than 4-benzoylaniline derivatives. The ester or carbamate bond formation of parent salicylanilides mostly retained or improved antimycobacterial potency with moderate selectivity.

Compounds of formula (I) or (II) wherein Rx, Rz, R9, R10, R14, R14′, R15, R15′, A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

The present invention provides a compound of Formula III: wherein A is: and Z, R1, R2, R3, and R4 are as defined herein, or a pharmaceutically acceptable salt thereof.

A series of pyrazinamide derivatives with alkylamino substitution was designed, synthesized and tested for their ability to inhibit the growth of selected mycobacterial, bacterial and fungal strains. The target structures were prepared from the corresponding 5-chloro (1) or 6-chloropyrazine-2-carboxamide (2) by nucleophilic substitution of chlorine by various non-aromatic amines (alkylamines). To determine the influence of alkyl substitution, corresponding amino derivatives (1a, 2a) and compounds with phenylalkylamino substitution were prepared. Some of the compounds exerted antimycobacterial activity against Mycobacterium tuberculosis H37Rv significantly better than standard pyrazinamide and corresponding starting compounds (1 and 2). Basic structure-activity relationships are presented. Only weak antibacterial and no antifungal activity was detected.

The present invention relates to a novel berbamine derivative of formula I or a pharmaceutically acceptable salt thereof, a process for preparation of the same, a pharmaceutical composition comprising said compound and its use in manufacture of an antitumor medicament.

The present invention relates to a novel berbamine derivative of formula I or a pharmaceutically acceptable salt thereof, a process for preparation of the same, a pharmaceutical composition comprising said compound and its use in manufacture of an antitumor medicament.

To develop new potential antimycobacterial drugs, a series of pyrazinamide derivatives was designed, synthesized and tested for their ability to inhibit the growth of selected mycobacterial strains (Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii

5-Chloropyrazinamide (5-Cl-PZA) is an inhibitor of mycobacterial fatty acid synthase I with a broad spectrum of antimycobacterial activity in vitro. Some N-phenylpyrazine-2-carboxamides with different substituents on both the pyrazine and phenyl core possess significant in vitro activity against Mycobacterium tuberculosis. To test the activity of structures combining both the 5-Cl-PZA and anilide motifs a series of thirty 5-chloro-N-phenylpyrazine-2-carboxamides with various substituents R on the phenyl ring were synthesized and screened against M. tuberculosis H37Rv, M. kansasii and two strains of M. avium. Most of the compounds exerted activity against M. tuberculosis H37Rv in the range of MIC = 1.56-6.25 μg/mL and only three derivatives were inactive. The phenyl part of the molecule tolerated many different substituents while maintaining the activity. In vitro cytotoxicity was decreased in compounds with hydroxyl substituents, preferably combined with other hydrophilic substituents. 5-Chloro-N-(5- chloro-2-hydroxyphenyl)pyrazine-2-carboxamide (21) inhibited all of the tested strains (MIC = 1.56 μg/mL for M. tuberculosis; 12.5 μg/mL for other strains). 4-(5-Chloropyrazine-2- carboxamido)-2-hydroxybenzoic acid (30) preserved good activity (MIC = 3.13 μg/mL M. tuberculosis) and was rated as non-toxic in two in vitro models (Chinese hamster ovary and renal cell adenocarcinoma cell lines; SI = 47 and 35, respectively).

Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3- yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy.

Compounds of formula (I) wherein Rx, Rz, R9, R10, R14, R14', R15, R15', A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are particularly useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.

[Problem] A compound which is useful as a GK activator is provided. [Means for Solution] The present inventors have conducted studies on compounds having a GK activating action, which are promising as active ingredients of pharmaceutical compositions for

A series of twelve amides was synthesized via aminolysis of substituted pyrazinecarboxylic acid chlorides with substituted benzylamines. Compounds were characterized with analytical data and assayed in vitro for their antimycobacterial, antifungal, antibacterial and photosynthesis-inhibiting activity. 5-tert-Butyl-6-chloro-N-(4-methoxybenzyl)pyrazine-2-carboxamide (12) has shown the highest antimycobacterial activity against Mycobacterium tuberculosis (MIC = 6.25 μg/mL), as well as against other mycobacterial strains. The highest antifungal activity against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 5-chloro-N-(3- trifluoromethylbenzyl)- pyrazine-2-carboxamide (2, MIC = 15.62 μmol/L). None of the studied compounds exhibited any activity against the tested bacterial strains. Except for 5-tert-butyl-6-chloro-N-benzylpyrazine-2-carboxamide (9, IC50 = 7.4 μmol/L) and 5-tert-butyl-6-chloro-N-(4-chlorobenzyl) pyrazine-2-carboxamide (11, IC50 = 13.4 μmol/L), only moderate or weak photosynthesis-inhibiting activity in spinach chloroplasts (Spinacia oleracea L.) was detected.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein A is hydrogen, C1-4alkyl, C3-6cycloalkyl, C1-3alkoxy, C1-3alkoxy C1-4alkyl, C1-2fluoroalkyl, halogen, NR6 R7, optionally substituted heteroaryl (Het), or optionally substituted phenyl, and R1, R2, R3, R4, R5, R6 and R7 are as defined in the description. The compounds or salts are thought to modulate P2X7 receptor function and to be capable of antagonizing the effects of ATP at the P2X7 receptor. The invention also provides the use of the compound or salt in the treatment or prophylaxis of, for example, inflammatory pain, neuropathic pain, visceral pain, rheumatoid arthritis, osteoarthritis or neurodegenerative disorders.

The present invention provides compounds of Formula (I) that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase.

The present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein R1, R4, R6, X, Y and Z are as defined herein. The compounds of Formula (I) have been found to act as glucokinase activators. Consequently, the compounds of Formula (I) and the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucokinase.

Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described. Ring A is selected from formula (a), (b) or (b'):

A process for preparing pharmaceutically active compounds of formula (I) or a salt thereof wherein R1, n, m, R3, R6, X1, X2, X3 and X4 are as defined in the specification, is described. Novel intermediates are also described and claimed.

Certain substituted pyrazinyl amide compounds are histamine H3 receptor modulators useful in the treatment of histamine H3 receptor-mediated diseases.

The invention relates to a novel group of compounds of Formula (I) or a salt thereof: wherein R1, R2, R3, n, A and HET-1 are as described in the specification, which may be useful in the treatment or prevention of a disease or medical condition mediated through glucokinase (GLK) such as type 2 diabetes. The invention also relates to pharmaceutical compositions comprising said compounds, methods of treatment of diseases mediated by GLK using said compounds and methods for preparing compounds of Formula (I).

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Compounds of Formula (I), wherein R1- R10, A and X1 to X3 are as described in the specification, and their salts and pro-drugs, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. Processes for preparing compounds of formula (I) are also described.

The present invention relates to a melanin concentrating hormone antagonist compound of formula (I); wherein Ar1, L1, R1, q, X, R2, R3, R4, and R5 are as defined, or a pharmaceutically acceptable salt, solvate, or enantiomer thereof useful in the treatment, prevention or amelioration of symptoms associated with obesity and related diseases.

4-Amino-5,7-disubstituted pyridopyrimidines are potent, non-nucleoside inhibitors of adenosine kinase (AK). We recently identified a potent, orally efficacious analog, 4 containing a 7-pyridylmorpholine substituted ring system as the key structural element of this template. In this report, we disclose the pharmacologic effects of five- and six-membered heterocyclic ring replacements for the pyridine ring in 4. These replacements were found to have interesting effects on in vivo efficacy and genotoxicity as well as in vitro potency. We discovered that the nitrogen in the heterocyclic ring at C(7) is important for the modulation of mutagenic side effects (Ames assay).