PYRROLOPYRIDAZINES AS POTASSIUM ION CHANNEL INHIBITORS

A compound of formula (I) wherein A, R 1 , R 3 , and R 24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment of arrhythmia, I Kur -associated disorders, and other disorders mediated by ion channel function.

Pyrrolopyridazines as potassium ion channel inhibitors

A compound of formula (I) wherein A, R 1 , R 3 , and R 24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment of arrhythmia, I Kur -associated disorders, and other disorders mediated by ion channel function.

PHOSPHORYLATED POLYOLS, PYROPHOSPHATES, AND DERIVATIVES THEREOF HAVING BIOLOGICAL ACTIVITY

The present invention provides phosphorylated and pyrophosphate derivatives of polyols, and structural derivatives of these compounds, and provides pharmaceutical compositions comprising the same. The compounds and compositions disclosed herein have various biological activities, including for example, as allosteric effectors of hemoglobin and/or as kinase inhibitors. The present invention further provides methods for therapy in human or mammalian patients, and methods for synthesis of biologically active compounds and their intermediates. 1. A method for treating a patient having a condition associated with PI3 kinase activity , comprising administering to the patient an effective amount of a PI3K inhibitor having a pyrophosphoryl ring , or structural mimetic thereof.2. The method of claim 1 , wherein the patient's condition is associated with claim 1 , or characterized by claim 1 , an amplification claim 1 , somatic mutation claim 1 , chromosomal rearrangement claim 1 , overexpression claim 1 , or overactivity of a PI3K.3. The method of claim 2 , wherein the PI3K is one or more of a class I PI3K claim 2 , class II PI3K claim 2 , class III claim 2 , and class IV PI3K.4. The method of any one of claim 1 , wherein the patient has a mutation or alteration in a PI3K pathway gene.5. The method of claim 4 , wherein the condition is associated with an inactivation of the tumor suppressor PTEN.6. The method of claim 1 , wherein the condition is an allergic disease claim 1 , inflammation claim 1 , heart disease claim 1 , autoimmunity claim 1 , diabetes mellitus claim 1 , or cancer.7. The method of claim 6 , wherein the condition is cancer claim 6 , and the cancer is one or more of ovarian claim 6 , cervical claim 6 , endometrial claim 6 , colorectal claim 6 , breast claim 6 , pancreatic claim 6 , gastric claim 6 , glioblastoma claim 6 , melanoma claim 6 , liver claim 6 , prostate claim 6 , leukemia claim 6 , lymphoma claim 6 , head and neck claim 6 , gastric claim 6 , ...

PYRROLOTRIAZINES AS POTASSIUM ION CHANNEL INHIBITORS

A compound of formula (I), wherein A, R, R, and Rare described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, I-associated disorders, and other disorders mediated by ion channel function. 3. The compound claim 2 , of claim 2 , or salt thereof wherein:{'sup': 13', '14', '14', '14', '14', '14', '14', '14', '14', '14', '14', '14', '14b', '14b', '14', '14', '14', '14', '14', '4', '14', '14a, 'sub': 1-6', '1-6', '1-6', '3-6', '2', '2', 'm', '2', '2', '2', 'm', '2', '2', '2', '2', '2, 'R, at each occurrence, is independently H, —OH, F, Cl, Br, I, Calkyl, Calkoxy, haloCalkyl, Ccycloalkyl, phenyl, a 4- to 12-membered heteroaryl, wherein the heteroaryl is selected from tetrazolyl, —CN, —NO, —(CH)—SOR, —NRSOR, —CONRR, —(CH)—SONRR, —NRCONRR, NRCONRR, —NRCOR, —NRCOR, —COR, or —NRR, wherein the alkyl, cycloalkyl, phenyl, and heteroaryl may be substituted with 0-2 R, and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;'}{'sup': 14', '14a, 'sub': 1-6', '3-6, 'R, at each occurrence, is independently selected from hydrogen, Calkyl, Ccycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, and phenyl, may be substituted with 0-3 R; or'}{'sup': '14b', 'sub': '1-6', "alternatively, two R's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring is morpholinyl, piperidinyl, or piperazinyl, and may be substituted with 0-1 Calkyl; and"}{'sup': '14a', 'sub': 1-6', '1-6', '3-6, 'R, at each occurrence, is independently selected from F, Cl, Br, I, Calkyl, haloCalkyl, phenyl, or Ccycloalkyl.'}4. The compound of claim 3 , or salt thereof wherein:{'sub': 2', 'm', '2', '2', 'n-1', '2', 'n-1', '2', '2', 'n-1', '2, 'sup': 2', '26', '2', '25', '2', '26', '2', '25', '2, 'A is —(CH)—R, —CH(R)—R, —(CH)—O—R, —(CH)—NR—R, —CH(R)—CO—R, or —(CH)—NR—CO—R;'}{'sup': 2', '2a, 'Ris ...

CYCLITOLS AND THEIR DERIVATIVES AND THEIR THERAPEUTIC APPLICATIONS

The present invention is directed to polyphosphorylated and pyrophosphate derivatives of cyclitols. More particularly, the invention relates to polyphosphorylated and pyrophosphate derivatives of inositols. The invention also relates to compositions of the polyphosphorylated and pyrophosphate derivatives of inositol and other similar, more lipophilic derivatives, and their use as allosteric effectors, cell-signaling molecule analogs, and therapeutic agents. 131.-. (canceled)32. A composition comprising a pyrophosphate inositol which reduces hemoglobin's oxygen affinity , wherein:the pyrophosphate is an internal pyrophosphate;the inositol is cis-inositol, epi-inositol, allo-inositol, muco-inositol, neo-inositol, scyllo-inositol, (+) chiro-inositol, or (−) chiro-inositol, and wherein the pyrophosphate inositol is monopyrophosphate, bispyrophosphate, or trispyrophosphate; andthe pyrophosphate inositol comprises a derivatized hydroxyl selected from alkoxy (—OR) or acyloxy (—OCOR),where R is selected from alkyl, aryl, acyl, aralkyl, alkenyl, alkynyl, heterocyclyl, polycyclyl, carbocycle, amino, acylamino, amido, alkylthio, sulfonate, alkoxyl, or sulfoxido, or a salt thereof.33. The composition of claim 32 , wherein the pyrophosphate inositol is complexed with a cation to form a salt claim 32 , and wherein the cation is an alkali metal cation claim 32 , an alkaline metal cation claim 32 , an ammonium claim 32 , or an organic cation.34. The composition of claim 32 , wherein R is a lower alkyl.35. The composition of claim 34 , where R is methyl.36. The composition of claim 32 , wherein the inositol is scyllo-inositol.37. The composition of claim 32 , wherein the inositol is monopyrophosphate.38. The composition of claim 32 , wherein the inositol is bispyrophosphate.39. A pharmaceutical composition claim 32 , comprising a pyrophosphate inositol wherein:the pyrophosphate is an internal pyrophosphate;the inositol is cis-inositol, epi-inositol, allo-inositol, muco-inositol, neo ...

CYCLITOLS AND THEIR DERIVATIVES AND THEIR THERAPEUTIC APPLICATIONS

The present invention is directed to polyphosphorylated and pyrophosphate derivatives of cyclitols. More particularly, the invention relates to polyphosphorylated and pyrophosphate derivatives of inositols. The invention also relates to compositions of the polyphosphorylated and pyrophosphate derivatives of inositol and other similar, more lipophilic derivatives, and their use as allosteric effectors, cell-signaling molecule analogs, and therapeutic agents. 18.-. (canceled)9. A pyrophosphate inositol , wherein the pyrophosphate is an internal pyrophosphate and the inositol is cis-inositol , epi-inositol , allo-inositol , muco-inositol , neo-inositol , scyllo-inositol , (+) chiro-inositol , or (−) chiro-inositol , and wherein the pyrophosphate inositol is monopyrophosphate , bispyrophosphate , or trispyrophosphate , and comprises a derivatized hydroxyl selected from alkoxy (—OR) or acyloxy (—OCOR) , where R is selected from alkyl , aryl , acyl , aralkyl , alkenyl , alkynyl , heterocyclyl , polycyclyl , carbocycle , amino , acylamino , amido , alkylthio , sulfonate , alkoxyl , sulfonyl , or sulfoxido , or a salt thereof.10. The pyrophosphate inositol of claim 9 , wherein the pyrophosphate inositol is complexed with a cation to form a salt claim 9 , and wherein the cation is an alkali metal cation claim 9 , an alkaline metal cation claim 9 , an ammonium claim 9 , or an organic cation.11. A pharmaceutical composition comprising the pyrophosphate inositol of .1231.-. (canceled)32. The pyrophosphate inositol of claim 9 , wherein R is a lower alkyl.33. The pyrophosphate inositol of claim 32 , where R is methyl.34. The pyrophosphate inositol of claim 9 , wherein the inositol is scyllo-inositol.35. The pyrophosphate inositol of claim 9 , wherein the inositol is monopyrophosphate.36. The pyrophosphate inositol of claim 9 , wherein the inositol is bispyrophosphate.37. A pharmaceutical composition comprising a pyrophosphate inositol wherein the pyrophosphate is an internal ...

ISOQUINOLINES AS POTASSIUM ION CHANNEL INHIBITORS

A compound of formula (I) (I) wherein A, R1, R1a, R3 and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.

Pyrrolotriazines as potassium ion channel inhibitors

A compound of formula (I), wherein A, R1, R3, and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.

Cyclitols and Their Derivatives and Their Therapeutic Applications

The present invention is directed to polyphosphorylated and pyrophosphate derivatives of cyclitols. More particularly, the invention relates to polyphosphorylated and pyrophosphate derivatives of inositols. The invention also relates to compositions of the polyphosphorylated and pyrophosphate derivatives of inositol and other similar, more lipophilic derivatives, and their use as allosteric effectors, cell-signaling molecule analogs, and therapeutic agents.

Isoquinolines as potassium ion channel inhibitors

A compound of formula (I) (I) wherein A, R1, R1a, R3 and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.

Hepatitis C virus inhibitors

The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

Hepatitis C Virus Inhibitors

The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection. 2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Q is phenyl.3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein X and Y are each CH.4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Rand Rare each hydrogen.8. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.9. The composition of further comprising one or two additional compounds having anti-HCV activity.10. The composition of wherein at least one of the additional compounds is an interferon or a ribavirin.11. The composition of wherein the interferon is selected from interferon alpha 2B claim 10 , pegylated interferon alpha claim 10 , pegylated interferon lambda claim 10 , consensus interferon claim 10 , interferon alpha 2A claim 10 , and lymphoblastiod interferon tau.12. The composition of wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease claim 9 , HCV serine protease claim 9 , HCV polymerase claim 9 , HCV helicase claim 9 , HCV NS4B protein claim 9 , HCV entry claim 9 , HCV assembly claim 9 , HCV egress claim 9 , HCV NS5A protein claim 9 , and IMPDH for the treatment of an HCV infection.13. A method of treating an HCV infection in a patient claim 1 , comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.14. The method of further comprising administering one or two additional compounds having anti-HCV activity prior to claim 1 , after or simultaneously with ...

Hepatitis C Virus Inhibitors

The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein. 1. A combination comprising an NS5A-targeting compound and an NS5A synergist , which , when administered , provides synergistic anti-HCV activity against variants that contain mutation(s) conferring resistance to the NS5A-targeting compound alone.2. The combination of which comprises two or more pharmaceutically acceptable carriers.3. The combination of wherein the NS5A-targeting compound and the NS5A synergist are combined in the same pharmaceutically acceptable carrier.19. A composition comprising a combination of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.20. The composition of further comprising one or two additional compounds having anti-HCV activity.21. The composition of wherein at least one of the additional compounds is an interferon or a ribavirin.22. The composition of wherein the interferon is selected from interferon alpha 2B claim 21 , pegylated interferon alpha claim 21 , pegylated interferon lambda claim 21 , consensus interferon claim 21 , interferon alpha 2A claim 21 , and lymphoblastoid interferon tau.23. The composition of wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV protease claim 20 , HCV polymerase claim 20 , HCV helicase claim 20 , HCV NS4B protein claim 20 , HCV entry claim 20 , HCV assembly claim 20 , HCV egress claim 20 , HCV NS5A protein claim 20 , and IMPDH for the treatment of an HCV infection.24. A method of treating an HCV infection in a patient claim 1 , comprising administering to the patient a therapeutically effective amount of a combination of claim 1 , or a pharmaceutically ...

PYRROLOTRIAZINES AS POTASSIUM ION CHANNEL INHIBITORS

A compound of formula (I)

HEPATITIS C VIRUS INHIBITORS

The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein. 2. The combination of which comprises two or more pharmaceutically acceptable carriers.3. The combination of wherein the NS5A-targeting compound and the NS5A synergist are combined in the same pharmaceutically acceptable carrier.4. A composition comprising a combination of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.5. The composition of further comprising one or two additional compounds having anti-HCV activity.6. The composition of wherein at least one of the additional compounds is an interferon or a ribavirin.7. The composition of wherein the interferon is selected from interferon alpha 2B claim 6 , pegylated interferon alpha claim 6 , pegylated interferon lambda claim 6 , consensus interferon claim 6 , interferon alpha 2A claim 6 , and lymphoblastoid interferon tau.8. The composition of wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV protease claim 5 , HCV polymerase claim 5 , HCV helicase claim 5 , HCV NS4B protein claim 5 , HCV entry claim 5 , HCV assembly claim 5 , HCV egress claim 5 , HCV NS5A protein claim 5 , and IMPDH for the treatment of an HCV infection.9. A method of treating an HCV infection in a patient claim 1 , comprising administering to the patient a therapeutically effective amount of a combination of claim 1 , or a pharmaceutically acceptable salt thereof.10. The method of further comprising administering one or two additional compounds having anti-HCV activity prior to claim 9 , after or simultaneously with the combination claim 9 , or a pharmaceutically acceptable salt thereof.11. The method of ...

PHTHALAZINES AS POTASSIUM ION CHANNEL INHIBITORS

A compound of formula (I) 3. The compound claim 2 , of claim 2 , wherein:{'sup': 13', '14', '14', '14', '14', '14', '14', '14', '14', '14', '14', '14', '14b', '14b', '14', '14', '14', '14', '14', '14', '14', '14a, 'sub': 1-6', '1-6', '1-6', '3-6', '2', '2', 'm', '2', '2', '2', 'm', '2', '2', '2', '2', '2, 'R, at each occurrence, is independently H, —OH, F, Cl, Br, I, Calkyl, Calkoxy, haloCalkyl, Ccycloalkyl, phenyl, a 4- to 12-membered heteroaryl, wherein the heteroaryl is selected from tetrazolyl, —CN, —NO, —(CH)—SOR, —NRSOR, —CONRR, —(CH)—SONRR, —NRCONRR, —NRCONRR, —NRCOR, —NRCOR, —COR, or —NRR, wherein the alkyl, cycloalkyl, phenyl, and heteroaryl may be substituted with 0-2 R, and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;'}{'sup': 14', '14a, 'sub': 1-6', '3-6, 'R, at each occurrence, is independently selected from hydrogen, Calkyl, Ccycloalkyl, phenyl, wherein the alkyl, cycloalkyl, and phenyl, may be substituted with 0-3 R; or'}{'sup': '14b', 'sub': '1-6', "alternatively, two R's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring is morpholinyl, piperidinyl, or piperazinyl, and may be substituted with 0-1 Calkyl;"}{'sup': '14a', 'sub': 1-6', '1-6', '3-6, 'R, at each occurrence, is independently selected from F, Cl, Br, I, Calkyl, haloCalkyl, phenyl, Ccycloalkyl.'}4. The compound of claim 3 , wherein:{'sub': 2', 'm', '2', '2', 'n−1', '2', '2', 'n−1', '2', '2', '2', 'n−1', '2, 'sup': 2', '26', '25', '26', '2', '25', '2, 'A is —(CH)—R, —CH(R)—R, —(CH)—O—R, —(CH)—NR—R, —CH(R)—CO—R, or —(CH)—NR—CO—R;'}{'sup': 2', '2a, 'Ris phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, or pyridinone, any of which are substituted with 0-2 R; or'}{'sup': 2a', '14', '14, 'sub': 1-6', '1-6', '2, 'R, at each occurrence, is independently H, —OH, F, Calkyl, Calkoxy, 6-SONRR.'}6. The compound of claim 5 , wherein:{'sup ...

Hepatitis c virus inhibitors

The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

Hepatitis C virus inhibitors

The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.

Hepatitis c virus inhibitors

The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.

Hepatitis c virus inhibitors

The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.

Hepatitis c virus inhibitors

Pyrrolotriazines as potassium ion channel inhibitors

A compound of formula (I), wherein A, R1, R3, and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.

Phthalazines as potassium ion channel inhibitors

A compound of formula (I), wherein A, R1, R3, and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.