Compounds as modulators of GPR-119

The present invention relates to novel compounds of formula (A) and (B) as modulators of GPR-119, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of GPR-119 mediated diseases or disorders with them.

Modulators of calcium release-activated calcium channel

Disclosed are novel calcium release-activated calcium (CRAC) channel inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods of treatment using them. The present disclosure also relates to methods for treating non-small cell lung cancer (NSCLC) with CRAC inhibitors, and to methods for identifying therapeutics for treating and of diagnosing cancer.

Pharmaceutical compositions containing a PDE4 inhibitor and a PI3 delta or dual PI3 delta-gamma kinase inhibitor

This present invention relates to a method of treating a autoimmune, respiratory and/or inflammatory disease or condition (e.g., psoriasis, rheumatoid arthritis, asthma, COPD). The method comprises administering a PI3K Delta inhibitor or a dual PI3K Delta-Gamma inhibitor and a PDE4 inhibitor. The present invention also relates to pharmaceutical compositions containing a PI3K Delta or dual PI3K Delta-Gamma inhibitor and a PDE4 inhibitor.

Immunomodulator and anti-inflammatory compounds

The present invention provides dihydroorotate dehydrogenase inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders wherein the inhibition of Dihydroorotate dehydrogenase is known to show beneficial effect.

Kinase modulators

The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

METHODS OF TREATING AUTOIMMUNE, RESPIRATORY AND INFLAMMATORY DISORDERS BY INHALATION OF ROFLUMILAST N-OXIDE

The present disclosure relates to pharmaceutical compositions useful for (and to a method of) treating autoimmune, respiratory and/or inflammatory diseases and conditions. The method involves administering to a subject in need thereof roflumilast N-oxide by inhalation. The present disclosure particularly relates to the treatment of asthma and chronic obstructive pulmonary disease (COPD) by administering roflumilast N-oxide by inhalation. 1. A method of treating an autoimmune , respiratory or inflammatory disease or condition in a subject in need thereof comprising pulmonary administration of an effective amount of roflumilast N-oxide or a pharmaceutically acceptable salt thereof.2. The method of claim 1 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered by inhalation.3. The method of claim 1 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered by inhalation as a dry powder claim 1 , solution or suspension.4. The method of claim 3 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered as a dry powder.5. The method of claim 3 , wherein roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered as a solution or suspension.6. The method of claim 1 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered at a single dose of about 5 μg to about 2000 μg.7. The method of claim 6 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered at a single dose of about 20 μg to about 1200 μg.8. The method of claim 6 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered at a single dose of 50 μg to 1000 μg.9. The method of claim 6 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered at a single dose of 100 μg to 800 μg.10. The method of claim 6 , wherein the roflumilast N-oxide or ...

Glutaminase inhibitors

The present disclosure provides compounds of formula (I) to (III) as glutaminase inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders involving glutamine.

Selective dual inhibitors of PI3 delta and gamma protein kinases

The present invention relates to a selective dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them.

SELECTIVE DUAL INHIBITORS OF PI3 DELTA AND GAMMA PROTEIN KINASES

The present invention relates to a selective dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)-N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them. 126-. (canceled)27. A method of inhibiting a catalytic activity of a PI3 δ kinase in a cell , comprising contacting the cell with an effective amount of (S)-N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 ,4-d]pyrimidin-3-y1)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof.28. A method of inhibiting a catalytic activity of a PI3 γ kinase in a cell , comprising contacting the cell with an effective amount of (S)-N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 ,4-d]pyrimidin-3-y1)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof.29. A method of inhibiting a catalytic activity of a PI3δ kinase and PI3γ kinase in a cell , comprising contacting the cell with an effective amount of (S)-N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 ,4-d]pyrimidin-3-y1)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof.30. The method of claim 27 , wherein the inhibition takes place in a subject suffering from a disease claim 27 , disorder or condition selected from a proliferative disease claim 27 , a bone disorder claim 27 , an inflammatory disease claim 27 , an immune disease claim 27 , a nervous system disease claim 27 , a metabolic disease claim 27 , a respiratory disease claim 27 , thrombosis claim 27 , and cardiac disease.31. A method of treating leukemia in a patient in need thereof claim 27 , comprising administering to the ...

Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast N-oxide

The present disclosure relates to pharmaceutical compositions useful for (and to a method of) treating autoimmune, respiratory and/or inflammatory diseases and conditions. The method involves administering to a subject in need thereof roflumilast N-oxide by inhalation. The present disclosure particularly relates to the treatment of asthma and chronic obstructive pulmonary disease (COPD) by administering roflumilast N-oxide by inhalation.

METHODS OF TREATING AUTOIMMUNE, RESPIRATORY AND INFLAMMATORY DISORDERS BY INHALATION OF ROFLUMILAST N-OXIDE

The present disclosure relates to pharmaceutical compositions useful for (and to a method of) treating autoimmune, respiratory and/or inflammatory diseases and conditions. The method involves administering to a subject in need thereof roflumilast N-oxide by inhalation. The present disclosure particularly relates to the treatment of asthma and chronic obstructive pulmonary disease (COPD) by administering roflumilast N-oxide by inhalation. 133-. (canceled)34. Roflumilast N-oxide having a dof less than about 10 microns.35. The roflumilast N-oxide of claim 34 , wherein the dis less than about 6 microns.36. Roflumilast N-oxide having a dequal to or less than 10 microns suitable for administration by inhalation.37. The roflumilast N-oxide of claim 36 , having a dof less than about 6 microns.38. The roflumilast N-oxide of claim 34 , wherein the roflumilast N-oxide is in the form of a dry powder suitable for administration by inhalation.39. The roflumilast N-oxide of claim 34 , wherein roflumilast N-oxide is in the form of a suspension.40. A pharmaceutical composition comprising micronized particles of roflumilast N-oxide or pharmaceutically acceptable salts thereof and claim 34 , optionally claim 34 , one or more pharmaceutically acceptable carriers and/or excipients claim 34 , wherein the composition is suitable for administration by inhalation.41. The pharmaceutical composition of claim 40 , wherein the pharmaceutical composition is in the form of an inhalable dry powder comprising micronized particles of roflumilast N-oxide or a pharmaceutically acceptable salt thereof as an active ingredient and particles of a physiologically acceptable pharmacologically inert solid carrier.42. The pharmaceutical composition of claim 40 , wherein the pharmaceutical composition is in the form of an aerosol comprising micronized particles of roflumilast N-oxide or a pharmaceutically acceptable salt thereof as an active ingredient claim 40 , a propellant and claim 40 , optionally claim 40 ...

FORMS OF A PI3K DELTA SELECTIVE INHIBITOR FOR USE IN PHARMACEUTICAL FORMULATIONS

The present invention relates to solid state forms of a p-toluenesulfonic acid salt (PTSA) of the selective PI3K delta inhibitor (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (TGR-1202). The present invention also relates to methods of preparing the same, pharmaceutical compositions containing them, and methods of treating a PI3K kinase mediated disease or disorder, such as cancer, by administering the same. 110-. (canceled)12. The salt of claim 11 , wherein the salt exhibits an XRPD pattern substantially as shown in .13. The salt of claim 11 , wherein the salt has a d(0.5) of from about 1 to about 10 μm.14. The salt of claim 11 , wherein the salt has a d(0.5) of from about 2 to about 5 μm.15. (canceled)16. The salt of claim 11 , wherein the salt has a d(0.9) of from about 5 to about 25 μm.17. The salt of claim 11 , wherein the salt has a d(0.9) of from about 5 to about 15 μm.18. The salt of claim 11 , wherein the salt has a d(0.1) of from about 0.5 to about 1.5 μm.19. The salt of claim 11 , wherein the salt has a d(0.1) of from about 0.5 to about 1.0 μm.2022-. (canceled)23. The salt of claim 11 , wherein the salt is substantially free of other solid state forms of the p-toluenesulfonic acid salt.24. The salt of claim 11 , wherein the salt contains less than 5% of other solid state forms of the p-toluenesulfonic acid salt.25. A pharmaceutical composition comprising a salt of and a pharmaceutically acceptable excipient.26. A method of inhibiting a catalytic activity of a PI3 δ kinase present in a cell claim 11 , comprising contacting the cell with an effective amount of a salt of .27. The method of claim 26 , wherein the inhibition takes place in a subject suffering from a disease or disorder which is cancer claim 26 , bone disorder claim 26 , inflammatory disease claim 26 , immune disease claim 26 , nervous system disease claim 26 , metabolic disease claim 26 , respiratory ...

METHOD OF TREATMENT AND COMPOSITIONS COMPRISING A DUAL P13K DELTA-GAMMA KINASE INHIBITOR AND A CORTICOSTEROID

This present disclosure relates to a method of treating autoimmune, respiratory and/or inflammatory diseases or conditions, e.g., asthma, COPD, rheumatoid arthritis and idiopathic pulmonary fibrosis (IPF). The method comprises administering a dual PI3K delta and gamma inhibitor and a corticosteroid. The present invention also relates to pharmaceutical compositions containing a dual PI3K delta and gamma inhibitor and a corticosteroid. 1. A method of treating an autoimmune , respiratory and/or inflammatory disease or condition , the method comprising administering to a subject in need thereof a therapeutically effective amount of (i) a dual PI3K delta and gamma inhibitor , and (ii) a corticosteroid.3. The method according to claim 1 , wherein the corticosteroid is selected from the group consisting of dexamethasone claim 1 , betamethasone claim 1 , prednisolone claim 1 , methyl prednisolone claim 1 , prednisone claim 1 , hydrocortisone claim 1 , fluticasone claim 1 , triamcinolone claim 1 , budesonide or cortisone prednisolone claim 1 , methylprednisolone claim 1 , naflocort claim 1 , deflazacort claim 1 , halopredone acetate claim 1 , budesonide claim 1 , beclomethasone dipropionate claim 1 , hydrocortisone claim 1 , triamcinolone acetonide claim 1 , fluocinolone acetonide claim 1 , fluocinonide claim 1 , clocortolone pivalate claim 1 , methylprednisolone aceponate claim 1 , dexamethasone palmitoate claim 1 , tipredane claim 1 , hydrocortisone aceponate claim 1 , prednicarbate claim 1 , alclometasone dipropionate claim 1 , halometasone claim 1 , methylprednisolone suleptanate claim 1 , mometasone furoate claim 1 , rimexolone claim 1 , prednisolone farnesylate claim 1 , ciclesonide claim 1 , deprodone propionate claim 1 , fluticasone propionate claim 1 , halobetasol propionate claim 1 , loteprednol etabonate claim 1 , betamethasone butyrate propionate claim 1 , flunisolide claim 1 , prednisone claim 1 , dexamethasone sodium phosphate claim 1 , triamcinolone claim 1 , ...

NOVEL GLUTAMINASE INHIBITORS

The present disclosure provides compounds of formula (I) to (III) as glutaminase inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders involving glutamine. 9. A compound of claim 1 , wherein P and Q are each independently selected from —NRC(═O)—(CRR)— claim 1 , —(CRR)—C(═O)—NR— claim 1 , —C(═O)NR—(CRR)— claim 1 , —(CRR)—NR—C(═O)— claim 1 , —NH—C(═O)—C(RR)— claim 1 , —(CRR)—C(═O)—NH— claim 1 , —NRC(═O)— claim 1 , —NRC(═S)— claim 1 , —NRS(═O)— claim 1 , —C(═O)NR— claim 1 , —C(═S)NR— claim 1 , or —NR—.10. A compound of claim 1 , wherein P and Q are each independently selected from —NRC(═O)—(CRR)— claim 1 , —(CRR)—C(═O)—NRC(═O)— or —NR— claim 1 , wherein Rand R are independently selected from hydrogen claim 1 , substituted or unsubstituted Calkyl claim 1 , halogen claim 1 , hydroxy and substituted or unsubstituted Calkoxy.11. A compound of claim 1 , wherein P and Q are each independently selected from —NH—C(═O)—(CRR)— claim 1 , —(CRR)—C(═O)—NH— claim 1 , —NH—C(═O)— or —NH— claim 1 , wherein Rand Rare hydrogen.12. A compound of claim 1 , wherein{'sub': 2', '2, '(i) each of P and Q are independently —NH—C(═O)—(CH)—, —(CH)—C(═O)—NH—, —NH—C(═O)— or —NH—;'}{'sub': 2', '2, '(ii) P is —(CH)—C(═O)—NH— and Q is —NH—C(═O)—CH—, —NH—C(═O)— or —NH—;'}{'sub': 2', '2, '(iii) P is —(CH)—C(═O)—NH—, —NH—C(═O)— or —NH— and Q is —NH—C(═O)—CH—; or'}{'sub': 2', '2, '(iv) P is —(CH)—C(═O)—NH— and Q is —NH—C(═O)—CH—.'}13. A compound of claim 1 , wherein both P and Q are independently selected from —NH—C(═O)—CH— or —CH—C(═O)—NH—.15. A compound of claim 1 , wherein{'sub': 1', '1-6', '1-3, 'sup': x', 'x, 'Lis absent, substituted or unsubstituted Calkyl or NR, wherein Ris hydrogen or Calkyl;'}{'sub': '2', 'Lis substituted or unsubstituted 3 to 10 membered heterocyclyl; and'}{'sub': 3', '1-6', '1-3, 'sup': x', 'x, 'Lis absent, substituted or unsubstituted Calkyl or NR, wherein Ris hydrogen ...

DUAL SELECTIVE PI3 DELTA AND GAMMA KINASE INHIBITORS

The present invention relates to dual delta (δ) and gamma (γ) PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of Pi3K kinase mediated diseases or disorders with them. 121-. (canceled)22. A method of treating T-cell lymphoma in a patient in need thereof , the method comprising administering to the patient an effective amount of 2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof.23. A method of treating T-cell lymphoma in a patient in need thereof , the method comprising administering to the patient an effective amount of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof.24. A method of treating T-cell lymphoma in a patient in need thereof , the method comprising administering to the patient an effective amount of a compound that is (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof , wherein the compound contains less than about 5% by weight of (R)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof.25. The method of claim 24 , wherein the compound contains less than about 2.5% by weight of (R)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof.26. The method of claim 24 , wherein the compound contains less than about 1% by weight of (R)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof.27. The method of claim 24 , wherein the compound contains less than about 0.1% by weight of (R)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof.28. The method of claim 22 , wherein the patient is a human patient.29. The ...

PROCESS FOR PREPARATION OF OPTICALLY PURE AND OPTIONALLY SUBSTITUTED 2-(1-HYDROXY-ALKYL)-CHROMEN-4-ONE DERIVATIVES AND THEIR USE IN PREPARING PHARMACEUTICALS

The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives represented by formula (IA) and (IB), processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals. 114-. (canceled)17. (canceled)1920-. (canceled)23. (canceled)27. A process of wherein R′ is 4-Chloro phenyl.2836-. (canceled)39. The composition of claim 37 , wherein the compound of formula (IA) or (IB) is present in an amount up to 0.2% by weight claim 37 , based upon the total of components (a) and (b).40. A process of claim 26 , wherein R′ is 4-chlorophenyl.43. The composition of claim 38 , wherein the compound of formula (IA) or (IB) is present in an amount up to 0.2% by weight claim 38 , based upon the total of components (a) and (b). This application claims the benefit of Indian Provisional Patent Application No. 1737/CHE/2012 dated 4 May 2012 and U.S. Provisional Patent Application No. 61/671,956 dated 16 Jul. 2012; each of which is hereby incorporated by reference.The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives, processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals.International Publication No. WO 2011/055215, International Publication No. WO2012151525A1, U.S. Publication No. 2011/0118257, U.S. Publication No. 2012/0289496, Indian Provisional Patent Application Nos. 1542/CHE/2011 dated 4 May ...

NOVEL 3,5-DISUBSTITUTED-3H-IMIDAZO[4,5-B]PYRIDINE AND 3,5- DISUBSTITUTED -3H-[1,2,3]TRIAZOLO[4,5-B] PYRIDINE COMPOUNDS AS MODULATORS OF C-MET PROTEIN, ETC

The present invention provides compounds useful as c-Met protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of c-Met kinase mediated disease or disorders with them. 145-. (canceled)48. A compound of claim 46 , wherein Cyis substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.51. A compound of claim 46 , wherein Lis —CRR—.52. A compound of claim 51 , wherein Lis —CH— claim 51 , —CH(OH)— claim 51 , —CHF— claim 51 , —CF— claim 51 , —CH(CH)— or —C(CH)—.53. A compound of claim 46 , wherein Lis —CH.56. A compound of claim 47 , wherein Xand Xare CRand Xis independently selected from —CR═CRand —S—.57. A compound of claim 56 , wherein Xis CH claim 56 , Xis CRand Xis —CR═CR claim 56 , wherein Ris hydrogen claim 56 , halogen or substituted or unsubstituted Calkyl.62. A compound of claim 60 , wherein each occurrence of Ris selected from hydrogen claim 60 , halogen and substituted or unsubstituted alkyl.63. A compound of claim 54 , wherein each occurrence of Ris selected from hydrogen claim 54 , fluoro claim 54 , chloro claim 54 , methyl and CFand each occurrence of Ris selected from hydrogen and fluoro.64. A compound of claim 46 , wherein each of Rand Ris hydrogen claim 46 , alkyl or halogen claim 46 , X is N or CRand Ris H claim 46 , substituted or unsubstituted Calkyl claim 46 , NH claim 46 , OH claim 46 , CN or CONH.65. A compound of claim 46 , wherein(a) X is N;{'sup': '2', '(b) Ris H;'}{'sup': a', 'b, 'claim-text': [{'sup': a', 'b, '(ii) Ris methyl and Ris hydrogen,'}, {'sup': a', 'b, '(iii) Ris fluoro and Ris hydrogen,'}, {'sup': a', 'b, '(iv) Rand Rboth are fluoro, or'}, {'sup': a', 'b, '(v) Rand Rboth are methyl; and'}], '(c) (i) both Rand Rare hydrogen,'}{'sup': 'c', '(d) Z is CR, N, S, O, HC═CH— or —N═CH—;'}{'sub': '1', '(e) Zis CH or N;'}{'sub': '2', '(f) Zis C; and'}{'sub': '3', '(g) Zis C or N.'}66. A compound of claim 54 , wherein{'sub': ...

NOVEL GLUTAMINASE INHIBITORS

The present disclosure provides compounds of formula (I) to (III) as glutaminase inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders involving glutamine. 9. (canceled)10. A compound of claim 1 , wherein P and Q are each independently selected from —NRC(═O)—(CRR)— claim 1 , —(CRR)—C(═O)—NR— claim 1 , —NRC(═O)— or —NR— claim 1 , wherein Rand Rare independently selected from hydrogen claim 1 , substituted or unsubstituted Calkyl claim 1 , halogen claim 1 , hydroxy and substituted or unsubstituted Calkoxy.11. A compound of claim 1 , wherein P and Q are each independently selected from —NH—C(═O)—(CRR)— claim 1 , —(CRR)—C(═O)—NH— claim 1 , —NH—C(═O)— or —NH— claim 1 , wherein Rand Rare hydrogen.12. A compound of claim 1 , wherein{'sub': 2', '2, '(i) each of P and Q are independently —NH—C(═O)—(CH)—, —(CH)—C(═O)—NH—, —NH—C(═O)— or —NH—;'}{'sub': 2', '2, '(ii) P is —(CH)—C(═O)—NH— and Q is —NH—C(═O)—CH—, —NH—C(═O)— or —NH—;'}{'sub': 2', '2, '(iii) P is —(CH)—C(═O)—NH—, —NH—C(═O)— or —NH— and Q is —NH—C(═O)—CH—; or'}{'sub': 2', '2, '(iv) P is —(CH)—C(═O)—NH— and Q is —NH—C(═O)—CH—.'}13. A compound of claim 1 , wherein both P and Q are independently selected from —NH—C(═O)—CH— or —CH—C(═O)—NH—.15. A compound of claim 1 , wherein{'sub': 1', '1-6', '1-3, 'sup': x', 'x, 'Lis absent, substituted or unsubstituted Calkyl or NR, wherein Ris hydrogen or Calkyl;'}{'sub': '2', 'Lis substituted or unsubstituted 3 to 10 membered heterocyclyl; and'}{'sub': 3', '1-6', '1-3, 'sup': x', 'x, 'Lis absent, substituted or unsubstituted Calkyl or NR, wherein Ris hydrogen or Calkyl.'}16. A compound of claim 1 , wherein{'sub': 1', '1-6, 'Lis absent or substituted or unsubstituted Calkyl;'}{'sub': '2', 'Lis substituted or unsubstituted 3 to 10 membered heterocyclyl; and'}{'sub': 3', '1-6, 'Lis absent or substituted or unsubstituted Calkyl.'}17. (canceled)18. (canceled)19. A compound of ...

NOVEL 3,5-DISUBSTITUTED-3H-IMIDAZO[4,5-B]PYRIDINE AND 3,5-DISUBSTITUTED-3H-[1,2,3]TRIAZOLO[4,5-B] PYRIDINE COMPOUNDS AS MODULATORS OF C-MET PROTEIN KINASES

The present invention provides compounds useful as c-Met protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of c-Met kinase mediated disease or disorders with them. 3. A compound of claim 1 , wherein Cyis substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.5. (canceled)6. A compound of claim 1 , wherein Lis —CRR—.7. A compound of claim 6 , wherein Lis —CH— claim 6 , —CH(OH)— claim 6 , —CHF— claim 6 , —CF— claim 6 , —CH(CH)— or —C(CH)—.8. (canceled)11. A compound of claim 2 , wherein Xand Xare CRand Xis independently selected from —CR═CRand —S—.12. (canceled)14. (canceled)1719-. (canceled)20. A compound of claim 9 , wherein{'sup': a', 'b, 'each of Rand Ris hydrogen, alkyl or halogen; and'}{'sup': 'c', 'Ris hydrogen or fluoro.'}21. (canceled)22. A compound of claim 9 , wherein{'sup': 'c', 'Z is CR, N, S, O, —HC═CH— or —N═CH—;'}{'sub': '1', 'Zis CH or N;'}{'sub': '2', 'Zis C; and'}{'sub': '3', 'Zis C or N.'}2324-. (canceled)25. A compound of claim 9 , wherein X is N or CRand Ris H claim 9 , substituted or unsubstituted Calkyl claim 9 , NH claim 9 , OH claim 9 , CN or CONH.2630-. (canceled)31. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.32. The pharmaceutical composition of claim 31 , further comprising one or more additional therapeutic agents and mixtures thereof.33. The pharmaceutical composition of claim 32 , wherein the one or more additional therapeutic agent is an anti-cancer agent claim 32 , anti-inflammatory agent claim 32 , immunosuppressive agent claim 32 , steroid claim 32 , non-steroidal anti-inflammatory agent claim 32 , antihistamine claim 32 , analgesic claim 32 , or a mixture thereof.3435-. (canceled)36. A method of inhibiting the HGF/c-Met kinase signaling pathway in a cell comprising contacting said cell with a compound of .37. A method of inhibiting the proliferative ...

NOVEL PROCESS FOR PREPARATION OF OPTICALLY PURE AND OPTIONALLY SUBSTITUTED 2-(1-HYDROXY-ALKYL)-CHROMEN-4-ONE DERIVATIVES AND THEIR USE IN PREPARING PHARMACEUTICALS

The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives represented by formula (IA) and (IB), processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals. 2. A process of claim 1 , wherein the reaction in step (a) is performed in the presence of HATU claim 1 , HBTU claim 1 , TBTU claim 1 , COMU claim 1 , TOTU claim 1 , HCTU claim 1 , TCTU claim 1 , TATU claim 1 , TSTU or TDBTU.3. A process of claim 1 , wherein in the deprotection reaction of step (b) is performed with aluminium chloride claim 1 , boron tribromide claim 1 , or a combination thereof claim 1 , or by hydrogenation.9. A process of claim 7 , wherein the reaction in step (a) is performed in the presence of HATU claim 7 , HBTU claim 7 , TBTU claim 7 , COMU claim 7 , TOTU claim 7 , HCTU claim 7 , TCTU claim 7 , TATU claim 7 , TSTU claim 7 , or TDBTU.10. A process of claim 7 , wherein the deprotection reaction of step (b) is performed with aluminium chloride claim 7 , boron tribromide claim 7 , or a combination thereof claim 7 , or by hydrogenation.27. A process of or wherein Ris 4-Chloro phenyl29. A compound of claim 28 , wherein R is alkyl or halogen.30. A compound of or claim 28 , wherein R is chloro claim 28 , fluoro or methyl.3130. A compound of any one of - claims 28 , wherein Cyis a monocyclic group selected from substituted or unsubstituted aryl.3332. A compound of any one of - claims 28 , wherein Ris methyl or ethyl.3433. A compound of - claim 28 , wherein n is 1.3524. A compound of any one of - claims 28 , wherein the compound has an enantiomeric excess of at least 75% claims 28 , 90% claims 28 , 95% claims 28 , 97% claims 28 , or 98%.36. A compound ...

PHARMACEUTICAL COMPOSITIONS CONTAINING A PDE4 INHIBITOR AND A PI3 DELTA OR DUAL PI3 DELTA-GAMMA KINASE INHIBITOR

This present invention relates to a method of treating a autoimmune, respiratory and/or inflammatory disease or condition (e.g., psoriasis, rheumatoid arthritis, asthma, COPD). The method comprises administering a PI3K Delta inhibitor or a dual PI3K Delta-Gamma inhibitor and a PDE4 inhibitor. The present invention also relates to pharmaceutical compositions containing a PI3K Delta or dual PI3K Delta-Gamma inhibitor and a PDE4 inhibitor. 134-. (canceled)35. A method of treating an autoimmune , respiratory and/or inflammatory disease or condition selected from asthma , chronic obstructive pulmonary disease , rheumatoid arthritis , inflammatory bowel disease , glomerulonephritis , neuroinflammatory diseases , multiple sclerosis , uveitis , psoriasis , arthritis , vasculitis , dermatitis , osteoarthritis , inflammatory muscle disease , allergic rhinitis , vaginitis , interstitial cystitis , scleroderma , osteoporosis , eczema , allogeneic or xenogeneic transplantation (organ , bone marrow , stem cells and other cells and tissues) graft rejection , graft-versus-host disease , lupus erythematosus , inflammatory disease , type I diabetes , pulmonary fibrosis , dermatomyositis , Sjogren's syndrome , thyroiditis , myasthenia gravis , autoimmune hemolytic anemia , cystic fibrosis , chronic relapsing hepatitis , primary biliary cirrhosis , allergic conjunctivitis , atopic dermatitis , and combinations thereof ,the method comprising administering to a subject in need thereof a therapeutically effective amount of (i) a dual PI3K Delta and Gamma inhibitor, and (ii) a PDE4 inhibitor, whereinthe dual PI3K Delta and Gamma inhibitor is (+)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof; andthe PDE4 inhibitor is selected from roflumilast, apremilast, and pharmaceutically acceptable salts thereof.36. The method according to claim 35 , wherein the PDE4 ...

PROCESS FOR PREPARATION OF OPTICALLY PURE AND OPTIONALLY SUBSTITUTED 2-(1-HYDROXY-ALKYL)-CHROMEN-4-ONE DERIVATIVES AND THEIR USE IN PREPARING PHARMACEUTICALS

The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives represented by formula (IA) and (IB), processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals. 114-. (canceled)17. (canceled)1920-. (canceled)23. (canceled)27. The process of claim 25 , wherein R′ is 4-chlorophenyl.29. The compound of claim 28 , wherein R is alkyl or halogen; Cyis a monocyclic group selected from substituted or unsubstituted aryl; and n is 1.3132-. (canceled)33. A compound of claim 28 , wherein Ris methyl or ethyl.34. A compound of claim 28 , wherein n is 1.35. A compound of claim 28 , wherein the compound has an enantiomeric excess of at least 75% claim 28 , 90% claim 28 , 95% claim 28 , 97% claim 28 , or 98%.38. (canceled)39. The composition of claim 37 , wherein the compound of formula (IA) or (IB) is present in the composition in an amount up to 0.2% by weight claim 37 , based upon the total of components (a) and (b) in the composition. This application claims the benefit of Indian Provisional Patent Application No. 1737/CHE/2012 dated 4 May 2012 and U.S. Provisional Patent Application No. 61/671,956 dated 16 Jul. 2012; each of which is hereby incorporated by reference.The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives, processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals. ...

SUBSTITUTED CHROMENONES AS MODULATORS OF PROTEIN KINASES

The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. 2. A compound of claim 1 , wherein R is independently selected from halogen claim 1 , cyano claim 1 , substituted or unsubstituted Calkyl claim 1 , substituted or unsubstituted alkoxy claim 1 , substituted or unsubstituted Calkenyl claim 1 , substituted or unsubstituted Calkynyl claim 1 , substituted or unsubstituted Ccycloalkyl claim 1 , and substituted or unsubstituted heterocyclic group.3. A compound of claim 2 , wherein R is fluoro claim 2 , methyl claim 2 , methoxy or morpholine.4. A compound of claim 1 , wherein Cyis selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.6. A compound of claim 1 , wherein Rand Rindependently represent hydrogen or substituted or unsubstituted Calkyl.7. A compound of claim 1 , wherein Li is absent or selected from S(═O)— or —NR—.8. A compound of claim 7 , wherein q is 0 claim 7 , Lis absent or Lis —NH—.9. A compound of claim 1 , wherein Cyis selected from substituted or unsubstituted heterocyclic group and substituted or unsubstituted heteroaryl.15. A compound of claim 10 , wherein Ris hydrogen claim 10 , halogen claim 10 , cyano claim 10 , substituted or unsubstituted alkyl claim 10 , substituted or unsubstituted alkynyl claim 10 , substituted or unsubstituted heterocyclyl claim 10 , substituted or unsubstituted aryl claim 10 , or substituted or unsubstituted heteroaryl.18. A compound of claim 13 , wherein each of R′ and R″ is selected from hydrogen or Calkyl claim 13 , or —NR′R″ together are joined to form a substituted or unsubstituted claim 13 , saturated or unsaturated 3-10 membered ring claim 13 , which may optionally include heteroatoms which may be the same or different and are selected from O claim 13 , NR(wherein Ris hydrogen or substituted or ...

NOVEL COMPOUNDS AS MODULATORS OF PROTEIN KINASES

The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. 2. A compound of claim 1 , wherein R is independently selected from halogen claim 1 , cyano claim 1 , substituted or unsubstituted Calkyl claim 1 , substituted or unsubstituted alkoxy claim 1 , substituted or unsubstituted Calkenyl claim 1 , substituted or unsubstituted Calkynyl claim 1 , substituted or unsubstituted Ccycloalkyl claim 1 , and substituted or unsubstituted heterocyclic group.3. A compound of claim 2 , wherein R is fluoro claim 2 , methyl claim 2 , methoxy or morpholine.4. A compound of claim 1 , wherein Cyis selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.6. A compound of claim 1 , wherein Rand Rindependently represent hydrogen or substituted or unsubstituted Calkyl.7. A compound of claim 1 , wherein Li is absent or selected from S(═O)— or —NR—.8. A compound of claim 7 , wherein q is 0 claim 7 , Lis absent or Lis —NH—.9. A compound of claim 1 , wherein Cyis selected from substituted or unsubstituted heterocyclic group and substituted or unsubstituted heteroaryl.15. A compound of claim 10 , wherein Ris hydrogen claim 10 , halogen claim 10 , cyano claim 10 , substituted or unsubstituted alkyl claim 10 , substituted or unsubstituted alkynyl claim 10 , substituted or unsubstituted heterocyclyl claim 10 , substituted or unsubstituted aryl claim 10 , or substituted or unsubstituted heteroaryl.18. A compound of claim 13 , wherein each of R′ and R″ is selected from hydrogen or Calkyl claim 13 , or —NR′R″ together are joined to form a substituted or unsubstituted claim 13 , saturated or unsaturated 3-10 membered ring claim 13 , which may optionally include heteroatoms which may be the same or different and are selected from O claim 13 , NR(wherein Ris hydrogen or substituted or ...

IMPROVED FORMS OF A PI3K DELTA SELECTIVE INHIBITOR FOR USE IN PHARMACEUTICAL FORMULATIONS

The present invention relates to solid state forms of a p-toluenesulfonic acid salt (PTSA) of the selective PI3K delta inhibitor (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (TGR-1202). The present invention also relates to methods of preparing the same, pharmaceutical compositions containing them, and methods of treating a PI3K kinase mediated disease or disorder, such as cancer, by administering the same. 2. The salt of claim 1 , wherein the salt has a d(0.9) of from about 5 to about 25 μm.3. The salt of claim 1 , wherein the salt has a d(0.9) of from about 5 to about 15 μm.4. The salt of claim 1 , wherein the salt has a d(0.5) of from about 1 to about 10 μm.5. The salt of claim 1 , wherein the salt has a d(0.5) of from about 2 to about 5 μm.6. The salt of claim 1 , wherein the salt has a d(0.1) of from about 0.5 to about 1.5 μm.7. The salt of claim 1 , wherein the salt has a d(0.1) of from about 0.5 to about 1.0 μm.8. The salt of claim 1 , wherein the salt exhibits a XRPD pattern having one or more peaks selected from 5.0 claim 1 , 10.1 claim 1 , 22.1 claim 1 , and 24.5±0.2° 2Θ.9. The salt of claim 1 , wherein the salt exhibits a differential scanning calorimeter (DSC) pattern with a characteristic endothermic peak at about 146° C.12. The salt of claim 11 , wherein the salt exhibits an XRPD pattern substantially as shown in .13. The salt of claim 11 , wherein the salt has a d(0.5) of from about 1 to about 10 μm.14. The salt of claim 11 , wherein the salt has a d(0.5) of from about 2 to about 5 μm.15. The salt of claim 11 , wherein the salt has a d(0.9) of from about 5 to about 50 μm.16. The salt of claim 11 , wherein the salt has a d(0.9) of from about 5 to about 25 μm.17. The salt of claim 11 , wherein the salt has a d(0.9) of from about 5 to about 15 μm.18. The salt of claim 11 , wherein the salt has a d(0.1) of from about 0.5 to about 1.5 μm.19. The salt of claim 11 , ...

NOVEL 3,5-DISUBSTITUTED-3H-IMIDAZO[4,5-B]PYRIDINE AND 3,5-DISUBSTITUTED -3H-[1,2,3]TRIAZOLO[4,5-B] PYRIDINE COMPOUNDS AS MODULATORS OF PROTEIN KINASES

The present invention provides, inter alia, compounds of formula I as protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. 2. A compound of claim 1 , wherein Cyis substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.5. A compound of claim 4 , wherein claim 4 , D is substituted with one to five substituents selected from halogen claim 4 , substituted or unsubstituted alkyl claim 4 , substituted or unsubstituted alkoxy claim 4 , —COR claim 4 , —CONRR claim 4 , —S(O)NRRor —NRR claim 4 , wherein{'sup': x', 'y', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'y', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'z', 'x', 'y', 'z', 'z, 'sub': 2', '2', '2', '2, 'each occurrence of Rand Ris independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COOR, —C(O)R, —C(S)R, —C(O)NRR, —C(O)ONRR, —NRR, —NRCONRR, —N(R)SOR, —N(R)SOR, —(═N—N(R)R), —NRC(O)OR, —NRC(O)R—, —NRC(S)R—NRC(S)NRR, —SONRR—, —SONRR—, —OR, —ORC(O)NRR, —ORC(O)OR—, —OC(O)R, —OC(O)NRR, —RNRC(O)R, —ROR, —RC(O)OR, —RC(O)NRR, —RC(O)R, —RC(O)R, —SR, —SOR, —SOR, ...

METHODS OF TREATING AUTOIMMUNE, RESPIRATORY AND INFLAMMATORY DISORDERS BY INHALATION OF ROFLUMILAST N-OXIDE

The present disclosure relates to pharmaceutical compositions useful for (and to a method of) treating autoimmune, respiratory and/or inflammatory diseases and conditions. The method involves administering to a subject in need thereof roflumilast N-oxide by inhalation. The present disclosure particularly relates to the treatment of asthma and chronic obstructive pulmonary disease (COPD) by administering roflumilast N-oxide by inhalation. 1. A method of treating an autoimmune , respiratory or inflammatory disease or condition in a subject in need thereof comprising pulmonary administration of an effective amount of roflumilast N-oxide or a pharmaceutically acceptable salt thereof.2. The method of claim 1 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered by inhalation.3. The method of claim 1 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered by inhalation as a dry powder claim 1 , solution or suspension.4. The method of claim 3 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered as a dry powder.5. (canceled)6. The method of claim 1 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered at a single dose of about 5 μg to about 2000 μg.7. (canceled)8. (canceled)9. The method of claim 6 , wherein the roflumilast N-oxide or pharmaceutically acceptable salt thereof is administered at a single dose of 100 μg to 800 μg.10. (canceled)11. The method of claim 1 , wherein the disease or condition is selected from asthma claim 1 , COPD claim 1 , chronic obstructive bronchiolitis claim 1 , acute bronchitis claim 1 , chronic bronchitis claim 1 , emphysema claim 1 , allergic rhinitis and non-allergic rhinitis.12. The method of claim 1 , wherein the disease or condition is asthma.13. The method of claim 1 , wherein the disease or condition is COPD.14. The method of claim 1 , wherein the roflumilast N-oxide or ...

NOVEL MODULATORS OF CALCIUM RELEASE-ACTIVATED CALCIUM CHANNEL

Disclosed are novel calcium release-activated calcium (CRAC) channel inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods of treatment using them. The present disclosure also relates to methods for treating non-small cell lung cancer (NSCLC) with CRAC inhibitors, and to methods for identifying therapeutics for treating and of diagnosing cancer. 7. A compound of claim 1 , wherein Land Ltogether represent —NH—C(═O)— claim 1 , —NH—S(═O)— claim 1 , —C(═O)NH— or NH—CH—.8. A compound of claim 7 , wherein Land Ltogether represent —NH—C(═O)— claim 7 , —C(═O)NH— or S(═O)NH— claim 7 , —NH—CH—.9. A compound of claim 1 , wherein A is absent or is selected from —(CR′R″)— or —NR.10. A compound of claim 9 , wherein A is —CH— or —CHMe— claim 9 , (CR′R″)— claim 9 , where R′ and R″ are joined to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring claim 9 , which may optionally include one or more heteroatoms which are the same or different and are selected from O claim 9 , NRand S.16. A compound of claim 15 , wherein{'sub': 1', '2, 'Land Ltogether represent —NH—C(O)—; and'}Cy is selected from monocyclic substituted or unsubstituted aryl, and monocyclic substituted or unsubstituted heteroaryl.17. A compound of claim 15 , wherein both Rand Rrepresent cyclopropyl.18. A compound of claim 15 , wherein one of Rand Ris CFand the other is independently cyclopropyl claim 15 , CHF or CHF.19. A compound of claim 15 , wherein T claim 15 , U claim 15 , V claim 15 , and W are independently CH claim 15 , CF or N.20. A compound of claim 19 , wherein T is CF or N and each of U claim 19 , V and W is CH.21. A compound of claim 19 , wherein each of T and V is independently CF or N and each of U and W is CH.22. A compound of claim 15 , wherein Land Ltogether represent —NH—C(═O)— claim 15 , —NH—S(═O)— claim 15 , —C(═O)NH— or NH—CH—.23. A compound of claim 15 , wherein A is absent claim 15 , —NH— claim 15 , or —CH—.24. A compound of ...

NOVEL KINASE MODULATORS

The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. 136-. (canceled)38. The method of claim 37 , wherein the inhibition takes place in a subject suffering from a disease or disorder which is cancer claim 37 , bone disorder claim 37 , inflammatory disease claim 37 , immune disease claim 37 , nervous system disease claim 37 , metabolic disease claim 37 , respiratory disease claim 37 , thrombosis claim 37 , or cardiac disease.40. The method of claim 39 , further comprising the step of administering simultaneously or sequentially to a subject in need thereof at least one other anti-cancer agent claim 39 , anti-inflammatory agent claim 39 , immunosuppressive agent claim 39 , steroid claim 39 , non-steroidal anti-inflammatory agent claim 39 , antihistamine claim 39 , analgesic claim 39 , or a mixture thereof.41. The method of claim 39 , wherein the PI3K associated disease claim 39 , disorder or condition is selected from the group consisting of chronic obstructive pulmonary disease claim 39 , asthma claim 39 , rheumatoid arthritis claim 39 , chronic bronchitis claim 39 , inflammatory bowel disease claim 39 , allergic rhinitis claim 39 , lupus erythematosus and ulcerative colitis.42. The method of claim 39 , wherein the PI3K associated disease claim 39 , disorder or condition is selected from the group consisting of hematopoietic tumors of lymphoid lineage claim 39 , leukemia claim 39 , acute lymphocytic leukemia claim 39 , acute lymphoblastic leukemia claim 39 , B-cell lymphoma claim 39 , T-cell lymphoma claim 39 , Hodgkin's lymphoma claim 39 , hairy cell lymphoma claim 39 , Burkett's lymphoma claim 39 , hematopoietic tumors of myeloid lineage claim 39 , chronic myelogenous leukemias claim 39 , myelodysplastic syndrome claim 39 , promyelocytic leukemia claim 39 , nonsecretory myeloma ...

NOVEL SELECTIVE PI3K DELTA INHIBITORS

The present invention relates to selective inhibitors of PI3K delta protein kinases, methods of preparing them, pharmaceutical compositions containing them and methods of treatment and/or prevention of kinase mediated diseases or disorders with them. 120. -. (canceled)21. (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 ,4-d]-pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4-methylbenzenesulfonate having an enantiomeric excess of at least 95%.22. A pharmaceutical composition comprising a compound of and at least one pharmaceutically acceptable carrier.23. The pharmaceutical composition of claim 22 , wherein the compound has an enantiomeric excess of at least 98%.24. A method for the treatment of leukemia comprising administering to a subject in need thereof an effective amount of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo└3 claim 22 ,4-d┘pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4-methylbenzenesulfonate having an enantiomeric excess of at least 95%.25. The method of claim 24 , wherein (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 24 ,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4-methylbenzenesulfonate has an enantiomeric excess of at least 98%.26. The method of claim 24 , further comprising the step of administering simultaneously or sequentially to a subject in need thereof at least one other anti-cancer agent.27. The method of claim 24 , wherein the leukemia is selected from acute leukemia claim 24 , acute lymphocytic leukemia claim 24 , acute lymphoblastic leukemia claim 24 , acute myelocytic leukemia claim 24 , acute myelogenous leukemia claim 24 , chronic myelogenous leukemia claim 24 , myelodysplastic syndrome claim 24 , promyelocytic leukemia claim 24 , chronic lymphocytic leukemia claim 24 , acute myeloid leukemia claim 24 , chronic granulocytic leukemia claim 24 , hairy-cell leukemia and erythroleukemia.28. A method of treating ...

SELECTIVE DUAL INHIBITORS OF PI3 DELTA AND GAMMA PROTEIN KINASES

The present invention relates to a selective dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them. 126-. (canceled)30. A pharmaceutical composition comprising a compound according to and at least one pharmaceutically acceptable carrier.31. A pharmaceutical composition comprising a compound according to and at least one pharmaceutically acceptable carrier.32. A pharmaceutical composition comprising a compound according to and at least one pharmaceutically acceptable carrier.33. A method of treating asthma or chronic obstructive pulmonary disease in a patient in need thereof claim 27 , the method comprising administering to the patient an effective amount of a compound of .34. A method of treating asthma or chronic obstructive pulmonary disease in a patient in need thereof claim 28 , the method comprising administering to the patient an effective amount of a compound of .35. A method of treating asthma or chronic obstructive pulmonary disease in a patient in need thereof claim 29 , the method comprising administering to the patient an effective amount of a compound of .36. A method of treating rheumatoid arthritis claim 27 , psoriasis claim 27 , lupus or experimental autoimmune encephalomyelitis (EAE) in a patient in need thereof claim 27 , the method comprising administering to the patient an effective amount of a compound of .37. A method of treating rheumatoid arthritis claim 28 , psoriasis claim 28 , lupus or experimental autoimmune encephalomyelitis (EAE) in a patient in need thereof claim 28 , the method comprising administering to the patient an effective amount of a compound of .38. A method of treating rheumatoid arthritis ...

SELECTIVE DUAL INHIBITORS OF PI3 DELTA AND GAMMA PROTEIN KINASES

The present invention relates to a selective dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them. 126-. (canceled)27. A method of inhibiting a catalytic activity of a PI3 δ kinase in a cell comprising contacting the cell with an effective amount of (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 ,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof.28. A method of inhibiting a catalytic activity of a PI3 γ kinase in a cell comprising contacting the cell with an effective amount of (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 ,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof.29. A method of inhibiting a catalytic activity of a PI3 δ kinase and PI3 γ kinase in a cell comprising contacting the cell with an effective amount of (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 ,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof.30. The method of claim 27 , wherein the inhibition takes place in a subject suffering from a disease claim 27 , disorder or condition selected from a proliferative disease claim 27 , a bone disorder claim 27 , an inflammatory disease claim 27 , an immune disease claim 27 , a nervous system disease claim 27 , a metabolic disease claim 27 , a respiratory disease claim 27 , thrombosis claim 27 , cardiac disease claim 27 , and any combination thereof.31. The method of claim 28 , wherein the inhibition takes place in a subject ...

NOVEL MODULATORS OF CALCIUM RELEASE-ACTIVATED CALCIUM CHANNEL

Disclosed are novel calcium release-activated calcium (CRAC) channel inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods of treatment using them. The present disclosure also relates to methods for treating non-small cell lung cancer (NSCLC) with CRAC inhibitors, and to methods for identifying therapeutics for treating and of diagnosing cancer. 167-. (canceled)69. The method of claim 68 , wherein the autoimmune disorder is multiple sclerosis claim 68 , chronic obstructive pulmonary disease claim 68 , chronic obstructive airway disease claim 68 , or psoriasis.70. The method of claim 68 , wherein the subject is a human subject.71. The method of claim 69 , wherein the subject is a human subject.72. A method of modulating store-operated calcium (SOC) channel activity comprising contacting the SOC channel complex claim 69 , or portion thereof claim 69 , with a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.73. A method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering to the mammal a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.74. A method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal comprising administering to the mammal a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.75. A method of decreasing cytokine release by inhibiting the SOCE activation of NFAT in a mammal comprising administering to the mammal a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.76. A method of inhibiting immune cell ...

NOVEL 3,5-DISUBSTITUTED-3H-IMIDAZO[4,5-B]PYRIDINE AND 3,5-DISUBSTITUTED -3H-[1,2,3]TRIAZOLO[4,5-B] PYRIDINE COMPOUNDS AS MODULATORS OF PROTEIN KINASES

The present invention provides, inter alia, compounds of formula I as protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. 166-. (canceled)69. The method of claim 67 , wherein each occurrence of Rand Ris hydrogen.70. The method of claim 67 , wherein Lis —CH— claim 67 , —CH(CH)— or —C(CH)—.71. The method of claim 67 , wherein Lis —CH— or —C(CH)—.72. The method of claim 67 , wherein Cyis substituted aryl or substituted or unsubstituted bicyclic heteroaryl. This application claims the benefit of Indian Provisional Patent Application No. 1377/CHE/2010 dated 17 May 2010 which is hereby incorporated by reference.The present invention provides, inter alia, compounds of formula I as protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.In the recent past immense research has been dedicated to the discovery and understanding of the structure and functions of enzymes and bio-molecules associated with various diseases. One such important class of enzymes that has been the subject of extensive research is Protein Kinase.In general, protein kinases represent a set of structurally related phosphoryl transferases, having conserved structures and catalytic functions. These enzymes modify proteins by chemically adding phosphate groups (phosphorylation). Phosphorylation involves the removal of a phosphate group from ATP and covalently attaching it to amino acids that have a free hydroxyl group such as serine, threonine or tyrosine. Phosphorylation usually results in a functional change of the target protein (substrate) by altering enzyme activity, cellular localization or association with other proteins. Up to 30% of all proteins may be modified by kinase activity.This class of ...

NOVEL 3,5-DISUBSTITUTED-3H-IMIDAZO[4,5-B]PYRIDINE AND 3,5-DISUBSTITUTED-3H-[1,2,3]TRIAZOLO[4,5-B] PYRIDINE COMPOUNDS AS MODULATORS OF PROTEIN KINASES

The present invention provides, inter alia, compounds of formula I as protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. 166.-. (canceled)70. The method of claim 68 , wherein the substituted or unsubstituted alkyl in Lis —CRCR— claim 68 , wherein{'sup': a', 'b', 'a', 'b', 'c, 'sub': 1-6', '2-6', '2-6', '3-6', '3-6', '3-6, 'each occurrence of Rand Rmay be the same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted Calkyl, substituted or unsubstituted Calkenyl, substituted or unsubstituted Calkynyl, substituted or unsubstituted Ccycloalkyl, substituted or unsubstituted Ccycloalkylalkyl, and substituted or unsubstituted Ccycloalkenyl, or when two Rand/or Rsubstituents are directly bound to a common atom, they may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NRor S, and'}{'sup': 'c', 'sub': 1-6', '2-6', '2-6', '3-6', '3-6', '3-6, 'each occurrence of Ris independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted Calkyl, substituted or unsubstituted Calkenyl, substituted or unsubstituted Calkynyl, substituted or unsubstituted Ccycloalkyl, substituted or unsubstituted Ccycloralkylalkyl, and substituted or unsubstituted Ccycloalkenyl.'}71. The method of claim 68 , wherein Lis —CH— claim 68 , —CH(OH)— claim 68 , —CHF— claim 68 , —CF— claim 68 , —CH(CH)— or —C(CH)—.72. The method of claim 68 , wherein Lis —CH— or —CH(CH)—.73. The method of claim 68 , wherein Cyis substituted or unsubstituted aryl or substituted or unsubstituted bicyclic heteroaryl.76. The method of claim 68 , wherein the compound of formula (IA-1) is selected from(3-(3-(quinolin-6-ylmethyl)-3H-[ ...

PHARMACEUTICAL COMPOSITIONS CONTAINING A PDE4 INHIBITOR AND A P13 DELTA OR DUAL P13 DELTA-GAMMA KINASE INHIBITOR

This present invention relates to a method of treating a autoimmune, respiratory and/or inflammatory disease or condition (e.g., psoriasis, rheumatoid arthritis, asthma, COPD). The method comprises administering a PI3K Delta inhibitor or a dual PI3K Delta-Gamma inhibitor and a PDE4 inhibitor. The present invention also relates to pharmaceutical compositions containing a PI3K Delta or dual PI3K Delta-Gamma inhibitor and a PDE4 inhibitor. 1. A method of treating an autoimmune , respiratory and/or inflammatory disease or condition , the method comprising administering to a subject in need thereof a therapeutically effective amount of (i) a PI3K Delta inhibitor or a dual PI3K Delta and Gamma inhibitor , and (ii) a PDE4 inhibitor.2. The method according to claim 1 , comprising administering a PI3K Delta inhibitor.3. The method according to claim 1 , comprising administering a dual PI3K Delta and Gamma inhibitor.9. The method according to claim 1 , wherein the PDE-4 inhibitor is selected from the group consisting of enprofylline claim 1 , theophylline claim 1 , aminophylline claim 1 , oxtriphylline claim 1 , apremilast claim 1 , roflumilast claim 1 , cilomilast claim 1 , tofimilast claim 1 , pumafentrine claim 1 , lirimilast claim 1 , arofylline claim 1 , atizorame claim 1 , oglemilastum claim 1 , D-4418 claim 1 , Bay-198004 claim 1 , BY343 claim 1 , CP-325 claim 1 ,366 claim 1 , D-4396 (Sch-351591) claim 1 , AWD-12-281 (GW-842470) claim 1 , NCS-613 claim 1 , CDP-840 claim 1 , D-4418 claim 1 , PD-168787 claim 1 , T-440 claim 1 , T-2585 claim 1 , V 1 1294A claim 1 , CI-1018 claim 1 , CDC-801 claim 1 , CDC-3052 claim 1 , D-22888 claim 1 , YM-58997 claim 1 , Z-15370 claim 1 , N-(3 claim 1 ,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide claim 1 , (−)-p-[(4aR* claim 1 ,10bS*)-9-ethoxy-1 claim 1 ,2 claim 1 ,3 claim 1 ,4 claim 1 ,4a claim 1 ,10b-hexahydro-8-methoxy-2-methylbenzo[s][1 claim 1 ,6]-naphthyridin-6-yl]-N claim 1 ,N-diiso-propylbenzamid ...

NOVEL KINASE MODULATORS

The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. 617-. (canceled)19. A compound of claim 3 , wherein X is CRand each occurrence of Ris independently hydrogen claim 3 , halogen claim 3 , hydroxyl or NH.20. A compound of claim 19 , wherein Ris hydrogen.21. A compound selected from:2-[(6-Amino-9H-purin-9-yl) methyl]-6-bromo-3-phenyl-4H-chromen-4-one;6-Bromo-2-(morpholinomethyl)-3-phenyl-4H-chromen-4-one;6-Bromo-2-(morpholinomethyl)-3-phenyl-4H-chromen-4-one hydrochloride;2-[(6-Amino-9H-purin-9-yl) methyl]-3-phenyl-4H-chromen-4-one;2-(Morpholinomethyl)-3-phenyl-4H-chromen-4-one;2-(Morpholinomethyl)-3-phenyl-4H-chromen-4-one hydrochloride;2-[(1H-Benzo[d]imidazol-1-yl) methyl]-6-bromo-3-phenyl-4H-chromen-4-one;6-Bromo-2-[(4-methyl-1H-benzo[d]imidazol-1-yl) methyl]-3-phenyl-4H-chromen-4-one;2-[(1H-benzo[d]imidazol-1-yl) methyl]-3-phenyl-4H-chromen-4-one;2-[(4-methyl-1H-benzo[d]imidazol-1-yl)methyl]-3-phenyl-4H-chromen-4-one;2-[(6-Chloro-9H-purin-9-yl)methyl]-3-phenyl-4H-chromen-4-one;6-Bromo-2-[(6-chloro-9H-purin-9-yl)methyl]-3-phenyl-4H-chromen-4-one;2-((9H-Purin-6-ylthio)methyl)-3-phenyl-4H-chromen-4-one;2-[(1H-Imidazol-1-yl)methyl]-3-phenyl-4H-chromen-4-one;2-[(9H-Purin-6-ylthio)methyl]-6-bromo-3-phenyl-4H-chromen-4-one;2-((4-Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-bromo-3-phenyl-4H-chromen-4-one;2-[(6-Amino-9H-purin-9-yl)methyl]-6-bromo-3-(4-fluorophenyl)-4H-chromen-4-one;2-[(6-Amino-9H-purin-9-yl)methyl]-3-(4-fluorophenyl)-4H-chromen-4-one;6-Bromo-3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-one;6-Bromo-3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-one hydro chloride;3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-one;3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-one hydrochloride;2-[(6-Amino-9H-purin-9-yl)methyl]-6-bromo-3-o-tolyl-4H-chromen ...

PHARMACEUTICAL COMPOSITIONS CONTAINING A PDE4 INHIBITOR AND A PI3 DELTA OR DUAL PI3 DELTA-GAMMA KINASE INHIBITOR

This present invention relates to a method of treating a autoimmune, respiratory and/or inflammatory disease or condition (e.g., psoriasis, rheumatoid arthritis, asthma, COPD). The method comprises administering a PI3K Delta inhibitor or a dual PI3K Delta-Gamma inhibitor and a PDE4 inhibitor. The present invention also relates to pharmaceutical compositions containing a PI3K Delta or dual PI3K Delta-Gamma inhibitor and a PDE4 inhibitor. 1. A method of treating an autoimmune , respiratory and/or inflammatory disease or condition , the method comprising administering to a subject in need thereof a therapeutically effective amount of (i) a PI3K Delta inhibitor or a dual PI3K Delta and Gamma inhibitor , and (ii) a PDE4 inhibitor.2. The method according to claim 1 , comprising administering a PI3K Delta inhibitor.3. The method according to claim 1 , comprising administering a dual PI3K Delta and Gamma inhibitor.9. The method according to claim 1 , wherein the PDE-4 inhibitor is selected from the group consisting of enprofylline claim 1 , theophylline claim 1 , aminophylline claim 1 , oxtriphylline claim 1 , apremilast claim 1 , roflumilast claim 1 , cilomilast claim 1 , tofimilast claim 1 , pumafentrine claim 1 , lirimilast claim 1 , arofylline claim 1 , atizorame claim 1 , oglemilastum claim 1 , D-4418 claim 1 , Bay-198004 claim 1 , BY343 claim 1 , CP-325 claim 1 ,366 claim 1 , D-4396 (Sch-351591) claim 1 , AWD-12-281 (GW-842470) claim 1 , NCS-613 claim 1 , CDP-840 claim 1 , D-4418 claim 1 , PD-168787 claim 1 , T-440 claim 1 , T-2585 claim 1 , V 1 1294A claim 1 , CI-1018 claim 1 , CDC-801 claim 1 , CDC-3052 claim 1 , D-22888 claim 1 , YM-58997 claim 1 , Z-15370 claim 1 , N-(3 claim 1 ,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide claim 1 , (−)-p-[(4aR* claim 1 ,10bS*)-9-ethoxy-1 claim 1 ,2 claim 1 ,3 claim 1 ,4 claim 1 ,4a claim 1 ,10b-hexahydro-8-methoxy-2-methylbenzo[s][1 claim 1 ,6]-naphthyridin-6-yl]-N claim 1 ,N-diiso-propylbenzamid ...

Process for preparation of optically pure and optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives and their use in preparing pharmaceuticals

The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives represented by formula (IA) and (IB), processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals.

DUAL SELECTIVE PI3 DELTA AND GAMMA KINASE INHIBITORS

The present invention relates to dual delta (δ) and gamma (γ) PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of Pi3K kinase mediated diseases or disorders with them. 1. A compound selected from 2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one and pharmaceutically acceptable salts thereof.2. A compound selected from (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one and pharmaceutically acceptable salts thereof.3. The compound according to claim 2 , wherein the compound is substantially free of (R)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one claim 2 , and pharmaceutical acceptable salts thereof.4. The compound of claim 2 , wherein the compound has an enantiomeric excess greater than about 95%.5. (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one.6. The compound of claim 5 , wherein the compound is substantially free of (R)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one.7. The compound of claim 5 , wherein the compound has an enantiomeric excess greater than about 95%.8. A pharmaceutical composition comprising a compound of and at least one pharmaceutically acceptable carrier.9. A method of inhibiting a catalytic activity of a PI3 δ kinase present in a cell claim 2 , comprising contacting the cell with an effective amount of a compound of .10. A method of inhibiting a catalytic activity of a PI3 γ kinase present in a cell claim 2 , comprising contacting the cell with an effective amount of a compound of .11. A method of inhibiting a catalytic activity of a PI3 δ kinase and PI3 γ kinase present in a cell claim 2 , comprising contacting the cell with an effective amount of a compound of .12. The method of claim 9 , wherein the inhibition takes place in a subject suffering from a disease claim 9 , disorder or condition selected from cancer claim 9 , a ...

Combination of Anti-CD20 Antibody and PI3 Kinase Selective Inhibitor

Highly effective combinations of a compound of formula A (a PI3Kδ selective inhibitor) and anti-CD20 antibodies are provided herein for the treatment and amelioration of PI3Kδ and/or CD20 mediated diseases and disorders. In particular, the combination can be used to treat cancers and autoimmune diseases. More particularly, the invention provided for a combination of a compound of formula A, or stereoisomers thereof, and ublituximab for the treatment and/or amerioration of hematological malignancies such as leukemia and lymphoma. 159.-. (canceled)61. The method of claim 60 , wherein said antibody or fragment comprises the VH CDR1 claim 60 , CDR2 and CDR3 region of sequences SEQ ID NO:1 claim 60 , 2 claim 60 , and 3 claim 60 , and the VL CDR1 claim 60 , CDR2 and CDR3 region of sequences SEQ ID NO:6 claim 60 , 7 claim 60 , and 8.62. The method of claim 61 , wherein the anti-CD20 antibody or antigen-binding fragment thereof comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:9.63. The method of claim 60 , wherein said compound of formula A is (RS)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 60 ,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one; (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 60 ,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one; or (R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 60 ,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and said anti-CD20 antibody is ublituximab.64. The method of claim 60 , wherein said compound of formula A is (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 60 ,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and said anti-CD20 antibody is ublituximab.65. A method of inhibiting proliferation of a cell population comprising contacting the population with a combination comprising (i) at least one compound selected from the group consisting of (RS)-2-(1 ...

METHOD OF TREATMENT AND COMPOSITIONS COMPRISING A DUAL PI3K DELTA-GAMMA KINASE INHIBITOR AND A CORTICOSTEROID

This present disclosure relates to a method of treating autoimmune, respiratory and/or inflammatory diseases or conditions, e.g., asthma, COPD, rheumatoid arthritis and idiopathic Pulmonary Fibrosis (IPF). The method comprises administering a dual PI3K delta and gamma inhibitor and a corticosteroid. The present invention also relates to pharmaceutical compositions containing a dual PI3K delta and gamma inhibitor and a corticosteroid. 1. A method of treating an autoimmune , respiratory and/or inflammatory disease or condition , the method comprising administering to a subject in need thereof a therapeutically effective amount of (i) a dual PI3K delta and gamma inhibitor , and (ii) a corticosteroid.3. The method according to claim 1 , wherein the corticosteroid is selected from the group consisting of dexamethasone claim 1 , betamethasone claim 1 , prednisolone claim 1 , methyl prednisolone claim 1 , prednisone claim 1 , hydrocortisone claim 1 , fluticasone claim 1 , triamcinolone claim 1 , budesonide or cortisone prednisolone claim 1 , methylprednisolone claim 1 , naflocort claim 1 , deflazacort claim 1 , halopredone acetate claim 1 , budesonide claim 1 , beclomethasone dipropionate claim 1 , hydrocortisone claim 1 , triamcinolone acetonide claim 1 , fluocinolone acetonide claim 1 , fluocinonide claim 1 , clocortolone pivalate claim 1 , methylprednisolone aceponate claim 1 , dexamethasone palmitoate claim 1 , tipredane claim 1 , hydrocortisone aceponate claim 1 , prednicarbate claim 1 , alclometasone dipropionate claim 1 , halometasone claim 1 , methylprednisolone suleptanate claim 1 , mometasone furoate claim 1 , rimexolone claim 1 , prednisolone farnesylate claim 1 , ciclesonide claim 1 , deprodone propionate claim 1 , fluticasone propionate claim 1 , halobetasol propionate claim 1 , loteprednol etabonate claim 1 , betamethasone butyrate propionate claim 1 , flunisolide claim 1 , prednisone claim 1 , dexamethasone sodium phosphate claim 1 , triamcinolone claim 1 , ...

NOVEL SELECTIVE PI3K DELTA INHIBITORS

The present invention relates to selective inhibitors of PI3K delta protein kinases, methods of preparing them, pharmaceutical compositions containing them and methods of treatment and/or prevention of kinase mediated diseases or disorders with them. 120.-. (canceled)21. (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 ,4-d]-pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one.22. A pharmaceutical composition comprising a compound of and at least one pharmaceutically acceptable carrier.23. The pharmaceutical composition of claim 22 , wherein the compound has an enantiomeric excess of at least 98%.24. A method treating indolent non-Hodgkin's lymphoma in a human subject in need thereof comprising administering to the human subject an effective amount of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 22 ,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt thereof.25. The method of claim 24 , wherein an effective amount of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 24 ,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4-methylbenzenesulfonate is administered.26. The method of claim 25 , wherein the (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 25 ,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4-methylbenzenesulfonate has an enantiomeric excess of at least 95%.27. The method of claim 25 , wherein the (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 25 ,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4-methylbenzenesulfonate has an enantiomeric excess of at least 98%.28. The method of claim 24 , further comprising the step of administering simultaneously or sequentially to the subject at least one other anti-cancer agent.29. A method of treating follicular lymphoma in a human subject in need thereof comprising administering to ...

NOVEL COMPOUNDS AS MODULATORS OF PROTEIN KINASES

The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. 137-. (canceled)38. A method of inhibiting a catalytic activity of a phosphoinositol 3-kinase present in a cell comprising contacting the cell with an effective amount of a compound selected from 2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 ,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt , N-oxide or tautomer thereof.39. The method of claim 38 , wherein the inhibition takes place in a subject suffering from a disease or disorder selected from cancer claim 38 , a bone disorder claim 38 , an inflammatory disease claim 38 , an immune disease claim 38 , a nervous system disease claim 38 , a metabolic disease claim 38 , a respiratory disease claim 38 , thrombosis claim 38 , and a cardiac disease.40. A method of treating asthma in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound selected from 2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 38 ,4-d]pyrimidin-1-yl) ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt claim 38 , N-oxide or tautomer thereof.41. A method of treating chronic obstructive pulmonary disease in a subject claim 38 , comprising administering to the subject in need thereof a therapeutically effective amount of a compound selected from 2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 38 ,4-d]pyrimidin-1-yl) ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt claim 38 , N-oxide or tautomer thereof.42. A method of inhibiting a catalytic activity of a phosphoinositol 3-kinase present in a cell claim 38 , comprising contacting the cell with an effective amount of a ...

Combination of Anti-CD20 Antibody and PI3 Kinase Selective Inhibitor

Highly effective combinations of a compound of formula A (a PI3Kδ selective inhibitor) and anti-CD20 antibodies are provided herein for the treatment and amelioration of PI3Kδ and/or CD20 mediated diseases and disorderes. In particular, the combination can be used to treat cancers and autoimmune diseases. More particularly, the invention provided for a combination of a compound of formula A, or stereoisomers thereof, and ublituximab for the treatment and/or amerioration of hematological malignancies such as leukemia and lymphoma. 1. A method of inhibiting proliferation of a CD20-positive cell population comprising contacting the population with a combination comprising(i) a compound selected from the group consisting of 2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, or a pharmaceutically acceptable salt, solvate, or prodrug of said compound; and(ii) an anti-CD20 antibody or antigen-binding fragment thereof.2. The method of claim 1 , wherein said anti-CD20 antibody or fragment thereof is selected from the group consisting of antibodies and fragments thereof that bind to the same epitope as rituximab claim 1 , ofatumumab claim 1 , ocrelizumab claim 1 , veltuzumab claim 1 , GA101 claim 1 , AME-133v claim 1 , PRO131921 claim 1 , tositumomab claim 1 , hA20 claim 1 , and PRO70769.3. The method of claim 2 , wherein said compound is (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3 claim 2 ,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one.4. The method of claim 1 , wherein the population is contacted with(i) a first composition comprising a compound selected from the group consisting of 2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and ...

NOVEL COMPOUNDS AS MODULATORS OF PROTEIN KINASES

The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. 124-. (canceled)26. The method of claim 25 , wherein the inhibition takes place in a subject suffering from a disease or disorder which is cancer claim 25 , bone disorder claim 25 , inflammatory disease claim 25 , immune disease claim 25 , nervous system disease claim 25 , metabolic disease claim 25 , respiratory disease claim 25 , thrombosis claim 25 , or cardiac disease.2728-. (canceled)30. A method of claim 29 , further comprising the step of administering simultaneously or sequentially to a subject in need thereof at least one other anti-cancer agent claim 29 , anti-inflammatory agent claim 29 , immunosuppressive agent claim 29 , steroid claim 29 , non-steroidal anti-inflammatory agent claim 29 , antihistamine claim 29 , analgesic claim 29 , or a mixture thereof.31. A method of claim 29 , wherein the PI3K associated disease claim 29 , disorder or condition is an immune system-related disease claim 29 , a disease or disorder involving inflammation claim 29 , cancer or other proliferative disease claim 29 , a hepatic disease or disorder claim 29 , or a renal disease or disorder.32. A method of claim 29 , wherein the PI3K associated disease claim 29 , disorder or condition is selected from inflammation claim 29 , glomerulonephritis claim 29 , uveitis claim 29 , hepatic diseases or disorders claim 29 , renal diseases or disorders claim 29 , chronic obstructive pulmonary disease claim 29 , rheumatoid arthritis claim 29 , inflammatory bowel disease claim 29 , vasculitis claim 29 , dermatitis claim 29 , osteoarthritis claim 29 , inflammatory muscle disease claim 29 , allergic rhinitis claim 29 , vaginitis claim 29 , interstitial cystitis claim 29 , scleroderma claim 29 , osteoporosis claim 29 , eczema claim 29 , allogeneic or ...

NOVEL KINASE MODULATORS

The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. 136-. (canceled)39. The method of claim 38 , wherein the PI3K associated diseases or disorders does not include chronic lymphocytic leukemia (CLL) claim 38 , non-Hodgkin's lymphoma (NHL) claim 38 , acute myeloid leukemia (AML) claim 38 , multiple myeloma (MM) claim 38 , and small lymphocytic lymphoma (SLL).40. The method of claim 38 , wherein the PI3K associated disease claim 38 , disorder or condition is selected from the group consisting of chronic obstructive pulmonary disease claim 38 , asthma claim 38 , rheumatoid arthritis claim 38 , chronic bronchitis claim 38 , inflammatory bowel disease claim 38 , allergic rhinitis claim 38 , lupus erythematosus and ulcerative colitis.41. The method of claim 38 , where the compound of formula (I) is selected from the group consisting of:2-((9H-Purin-6-ylthio)methyl)-3-phenyl-4H-chromen-4-one;2-[(9H-Purin-6-ylthio)methyl]-6-bromo-3-phenyl-4H-chromen-4-one;2-(1-(9H-Purin-6-ylthio)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-6-bromo-3-phenyl-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-3-phenyl-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-3-(2-fluorophenyl)-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;(S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;(R)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one;(S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenyl-4H-chromen-4-one;(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-((9H-purin-6-ylamino ...

NOVEL GLUTAMINASE INHIBITORS

The present disclosure provides compounds of formula (I) to (III) as glutaminase inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders involving glutamine. 9. A compound of claim 1 , wherein P and Q are each independently selected from —NRC(═O)—(CRR)— claim 1 , —(CRR)—C(═O)—NR— claim 1 , —C(═O)NR—(CRR)— claim 1 , —(CRR)—NR—C(═O)— claim 1 , —NH—C(═O)—C(RR)— claim 1 , —(CRR)—C(═O)—NH— claim 1 , —NRC(═O)— claim 1 , —NRC(═S)— claim 1 , —NRS(═O)— claim 1 , —C(═O)NR— claim 1 , —C(═S)NR— claim 1 , or —NR—.10. A compound of claim 1 , wherein P and Q are each independently selected from —NRC(═O)—(CRR)— claim 1 , —(CRR)—C(═O)—NR claim 1 , —NRC(═O)— or —NR— claim 1 , wherein Rand Rare independently selected from hydrogen claim 1 , substituted or unsubstituted Calkyl claim 1 , halogen claim 1 , hydroxy and substituted or unsubstituted Calkoxy.11. A compound of claim 1 , wherein P and Q are each independently selected from —NH—C(═O)—(CRR)— claim 1 , —(CRR)—C(═O)—NH— claim 1 , —NH—C(═O)— or —NH— claim 1 , wherein Rand Rare hydrogen.12. A compound of claim 1 , wherein{'sub': 2', '2, '(i) each of P and Q are independently —NH—C(═O)—(CH)—, —(CH)—C(═O)—NH—, —NH—C(═O)— or —NH—;'}{'sub': 2', '2, '(ii) P is —(CH)—C(═O)—NH— and Q is —NH—C(═O)—CH—, —NH—C(═O)— or —NH—;'}{'sub': 2', '2, '(iii) P is —(CH)—C(═O)—NH—, —NH—C(═O)— or —NH— and Q is —NH—C(═O)—CH—; or'}{'sub': 2', '2, '(iv) P is —(CH)—C(═O)—NH— and Q is —NH—C(═O)—CH—.'}13. A compound of claim 1 , wherein both P and Q are independently selected from —NH—C(═O)—CH— or —CH—C(═O)—NH—.15. A compound of claim 1 , wherein{'sub': 1', '1-6', '1-3, 'sup': x', 'x, 'Lis absent, substituted or unsubstituted Calkyl or NR, wherein Ris hydrogen or Calkyl;'}{'sub': '2', 'Lis substituted or unsubstituted 3 to 10 membered heterocyclyl; and'}{'sub': 3', '1-6', '1-3, 'sup': x', 'x, 'Lis absent, substituted or unsubstituted Calkyl or NR, wherein ...

NOVEL MODULATORS OF CALCIUM RELEASE-ACTIVATED CALCIUM CHANNEL

Disclosed are novel calcium release-activated calcium (CRAC) channel inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods of treatment using them. The present disclosure also relates to methods for treating non-small cell lung cancer (NSCLC) with CRAC inhibitors, and to methods for identifying therapeutics for treating and of diagnosing cancer. 167-. (canceled)68. A method of modulating store-operated calcium (SOC) channel activity comprising contacting the SOC channel complex , or portion thereof , with a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-2-methylbenzamide or a pharmaceutically acceptable salt thereof.69. A method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering to the mammal a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-2-methylbenzamide or a pharmaceutically acceptable salt thereof.70. A method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal comprising administering to the mammal a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-2-methylbenzamide or a pharmaceutically acceptable salt thereof.71. A method of decreasing cytokine release by inhibiting the SOCE activation of NFAT in a mammal comprising administering to the mammal a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-2-methylbenzamide or a pharmaceutically acceptable salt thereof.72. A method of inhibiting immune cell activation comprising administering to an immune cell a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-2-methylbenzamide or a pharmaceutically acceptable salt thereof.73. A method of inhibiting T-cell and/or B-cell proliferation in response to an antigen , comprising administering to a T-cell and/or B-cell cell a compound N-{6-[5-cyclopropyl-3-( ...

Pharmaceutical compositions containing a pde4 inhibitor and a pi3 delta or dual pi3 delta-gamma kinase inhibitor

This present invention relates to a method of treating a autoimmune, respiratory and/or inflammatory disease or condition (e.g., psoriasis, rheumatoid arthritis, asthma, COPD). The method comprises administering a PI3K Delta inhibitor or a dual PI3K Delta-Gamma inhibitor and a PDE4 inhibitor. The present invention also relates to pharmaceutical compositions containing a PI3K Delta or dual PI3K Delta-Gamma inhibitor and a PDE4 inhibitor.

DUAL SELECTIVE PI3 DELTA AND GAMMA KINASE INHIBITORS

The present invention relates to dual delta (δ) and gamma (γ) PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of Pi3K kinase mediated diseases or disorders with them. 1. A compound selected from 2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one and pharmaceutically acceptable salts thereof.2. A compound selected from (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one and pharmaceutically acceptable salts thereof.3. The compound according to claim 2 , wherein the compound is substantially free of (R)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one claim 2 , and pharmaceutical acceptable salts thereof.4. The compound of claim 2 , wherein the compound has an enantiomeric excess greater than about 95%.5. (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one.6. The compound of claim 5 , wherein the compound is substantially free of (R)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one.7. The compound of claim 5 , wherein the compound has an enantiomeric excess greater than about 95%.8. A pharmaceutical composition comprising a compound of and at least one pharmaceutically acceptable carrier.9. A method of inhibiting a catalytic activity of a P13 δ kinase present in a cell claim 2 , comprising contacting the cell with an effective amount of a compound of .10. A method of inhibiting a catalytic activity of a P13 γ kinase present in a cell claim 2 , comprising contacting the cell with an effective amount of a compound of .11. A method of inhibiting a catalytic activity of a PI3 δ kinase and PI3 γ kinase present in a cell claim 2 , comprising contacting the cell with an effective amount of a compound of .12. The method of claim 9 , wherein the inhibition takes place in a subject suffering from a disease claim 9 , disorder or condition selected from cancer claim 9 , a ...

Combination of Anti-CD20 Antibody and PI3 Kinase Selective Inhibitor

Highly effective combinations of a compound of formula A (a PI3Kδ selective inhibitor) and anti-CD20 antibodies are provided herein for the treatment and amelioration of PI3Kδ and/or CD20 mediated diseases and disorders. In particular, the combination can be used to treat cancers and autoimmune diseases. More particularly, the invention provides for a combination of a compound of formula A, or stereoisomers thereof, and ublituximab for the treatment and/or amerioration of hematological malignancies such as leukemia and lymphoma. The invention also provides for a combination of a compound of formula A, or stereoisomers thereof, and anti-CD20 antibodies, including ublituximab for the treatment and/or amelioration of multiple scelrosis. 1. A method of treating multiple sclerosis which comprises administering to a subject an effective amount of a combination of(i) a compound selected from the group consisting of (RS)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, or a pharmaceutically acceptable salt, solvate, or prodrug of said compound; and(ii) an anti-CD20 antibody or antigen-binding fragment thereof.2. The method of claim 1 , wherein said anti-CD20 antibody or fragment thereof is selected from the group consisting of antibodies and fragments that are or bind the same epitope as ublituximab claim 1 , rituximab claim 1 , ofatumumab claim 1 , ocrelizumab claim 1 , veltuzumab claim 1 , obinutuzumab claim 1 , ocaratuzumab claim 1 , PRO131921 and tositumomab.3. The method of claim 1 , wherein said antibody or fragment thereof comprises the VH CDR1 claim 1 , CDR2 and CDR3 region of sequences SEQ ID NO:1 claim 1 , 2 claim 1 , and 3 claim 1 , and the VL CDR1 claim 1 , CDR2 and CDR3 region of sequences SEQ ID NO:6 claim 1 , 7 claim 1 , and 8.4. The method ...

Novel compounds as modulators of gpr-119

The present invention relates to novel compounds of formula (A) and (B) as modulators of GPR-119, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of GPR-119 mediated diseases or disorders with them.

NOVEL COMPOUNDS AS MODULATORS OF GPR-119

The present invention relates to novel compounds of formula (A) and (B) as modulators of GPR-119, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of GPR-119 mediated diseases or disorders with them. 133-. (canceled)37. The method of claim 34 , wherein{'sub': '3', '(a) Z is NH, N—CH, O or S'}{'sup': 1', '1', '1, '(b) Xis CRor N, and Ris H or Halogen'}{'sup': '2', '(c) Xis CH'}{'sup': '3', '(d) Xis CH'}{'sup': 4', '4', '4, '(e) Xis CRor N, and Ris H or Halogen and'}(f) X is CR or N38. The method of claim 35 , wherein(a) Z is O or S{'sup': 1', '1', '1, '(b) Xis CRor N, and Ris H or Halogen'}{'sup': '2', '(c) Xin compound of formula is CH'}{'sup': '3', '(d) Xis CH'}{'sup': 4', '4', '4, '(e) Xis CRor N, and Ris H or Halogen and'}(f) X is CR or N42. The method of wherein{'sup': 1', '1', '1, '(a) Xis CRor N and Ris H or Halogen'}{'sup': '2', '(b) Xis CH'}{'sup': '3', '(c) Xis CH'}{'sup': 4', '4', '4, '(d) Xis CRor N, and Ris H or Halogen'}(e) X is CR or N and(f) p is 0 or 144. The method of claim 43 , wherein Ris —C(O)OC(CH)or —C(O)OCH(CH).45. The method of claim 40 , wherein Ris halogen claim 40 , substituted or unsubstituted alkyl or —OR; wherein Ris substituted or unsubstituted alkyl.46. The method of claim 45 , wherein Ris —F claim 45 , —CH claim 45 , —CFor —OCH.49. The method of claim 47 , wherein Xis CH or CF; X is N or CH and Z is S or O.50. The method of claim 49 , wherein Xis CH or CF; X is N or CH and Z is O.51. The method of wherein{'sup': 1', '1', '1, '(a) Xis CRor N and Ris H or Halogen'}{'sup': '2', '(b) Xis CH'}{'sup': '3', '(c) Xis CH'}{'sup': 4', '4', '4, '(d) Xis CRor N, and Ris H or Halogen'}(e) X is CR or N and(f) p is 0 or 153. The method of claim 52 , wherein Ris —C(O)OC(CH)or —C(O)OCH(CH).54. The method of claim 41 , where Ris halogen claim 41 , substituted or unsubstituted alkyl or —OR; wherein Ris substituted or unsubstituted alkyl.55. The method of claim 54 , wherein ...

SELECTIVE DUAL INHIBITORS OF PI3 DELTA AND GAMMA PROTEIN KINASES

The present invention relates to a selective dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them. 1. A compound selected from N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 ,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide and pharmaceutically acceptable salts thereof.3. A compound selected from (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 ,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide and pharmaceutically acceptable salts thereof.4. The compound according to claim 3 , wherein the compound is substantially free of (R)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 claim 3 ,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide and pharmaceutically acceptable salt thereof.5. The compound of claim 3 , wherein the compound has an enantiomeric excess greater than about 95%.6. (S)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 claim 3 ,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide.7. The compound of claim 6 , wherein the compound is substantially free of (R)—N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3 claim 6 ,4-d]pyrimidin-3-yl)-2-methoxyphenyl)methanesulfonamide.8. The compound of claim 6 , wherein the compound has an enantiomeric excess greater than about 95%.9. A pharmaceutical composition comprising a compound according to and at least one pharmaceutically acceptable carrier.10. A method of inhibiting a catalytic activity of a PI3 δ kinase in a cell claim 1 , comprising contacting ...

FORMS OF A PI3K DELTA SELECTIVE INHIBITOR FOR USE IN PHARMACEUTICAL FORMULATIONS

The present invention relates to solid state forms of a p-toluenesulfonic acid salt (PTSA) of the selective PI3K delta inhibitor (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (TGR-1202). The present invention also relates to methods of preparing the same, pharmaceutical compositions containing them, and methods of treating a PI3K kinase mediated disease or disorder, such as cancer, by administering the same. 127-. (canceled)29. The method of claim 28 , further comprising the step of administering simultaneously or sequentially to a subject in need thereof at least one other anti-cancer agent claim 28 , anti-inflammatory agent claim 28 , immunosuppressive agent claim 28 , steroid claim 28 , non-steroidal antiinflammatory agent claim 28 , antihistamine claim 28 , analgesic claim 28 , or a mixture thereof.30. The method of claim 28 , wherein the PI3K associated disease claim 28 , disorder or condition is an immune system-related disease claim 28 , a disease or disorder involving inflammation claim 28 , cancer or other proliferative disease claim 28 , a hepatic disease or disorder claim 28 , or a renal disease or disorder.31. The method of claim 28 , wherein the PI3K associated disease claim 28 , disorder or condition is selected from inflammation claim 28 , glomerulonephritis claim 28 , uveitis claim 28 , hepatic diseases or disorders claim 28 , renal diseases or disorders claim 28 , chronic obstructive pulmonary disease claim 28 , rheumatoid arthritis claim 28 , inflammatory bowel disease claim 28 , vasculitis claim 28 , dermatitis claim 28 , osteoarthritis claim 28 , inflammatory muscle disease claim 28 , allergic rhinitis claim 28 , vaginitis claim 28 , interstitial cystitis claim 28 , scleroderma claim 28 , osteoporosis claim 28 , eczema claim 28 , allogeneic or xenogeneic transplantation claim 28 , graft rejection claim 28 , graft-versus-host disease claim 28 , lupus ...

Novel compounds of 3H-imidazo [4,5-b] pyridine-3,5-disubstituted and 3H- [1,2,3] triazolo [4,5-b] pyridine 3,5-disubstituted as protein kinase modulators

Un compuesto de la fórmula **Fórmula** o un tautómero, estereoisómero, enantiómero, diastereómero, sal o N-óxido del mismo, donde D es arilo monocíclico sustituido o sin sustituir, sustituido por de uno a cinco sustituyentes seleccionados de entre halógeno, alquilo sustituido o sin sustituir o - CONRxRy; cada aparición de Rx y Ry se selecciona independientemente de entre hidrógeno, hidroxi, alquilo sustituido o sin sustituir, alcoxi sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, anillo heterocíclico sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, y heteroarilalquilo sustituido o sin sustituir, o dos cualesquiera de Rx y Ry que están directamente unidos a un átomo común pueden unirse para formar (i) un grupo oxo (C=O), tio (C=S) o imino (C=NR') (donde R' es H o alquilo) o (ii) un anillo de 3-14 miembros, sustituido o sin sustituir, saturado o insaturado, que puede incluir opcionalmente uno o más heteroátomos que pueden ser iguales o diferentes y se seleccionan de entre O, NR' (donde R' es H o alquilo) o S; cada aparición de R2 es hidrógeno; L2 es -CRaRb-; X es N; Cy2 es **Fórmula** cada aparición de Ra y Rb puede ser igual o diferente y se seleccionan independientemente de entre hidrógeno, halógeno, alquilo C1-6 sustituido o sin sustituir, alquenilo C2-6 sustituido o sin sustituir, alquinilo C2-6 sustituido o sin sustituir, cicloalquilo C3-6 sustituido o sin sustituir, cicloalquilalquilo C3-6 sustituido o sin sustituir, y cicloalquenilo C3-6 sustituido o sin sustituir, o cuando dos sustituyentes Ra y/o Rb están unidos directamente a un átomo común, pueden unirse para formar un anillo de 3-10 miembros sustituto o sin sustituir, saturado o insaturado, que puede incluir opcionalmente uno o más heteroátomos que pueden ser iguales o diferentes y se seleccionan de entre O, NRc o S; y cada aparición de Rc se selecciona independientemente de ...

Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases

The present disclosure provides, inter alia, compounds of formula IA and III as protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. Compounds of the disclosure include:3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldehyde, N-(2-Hydroxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl) benzamide, Lithium 4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate and tert-Butyl 4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)piperidine-1-carboxylate

3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases

The present invention provides, inter alia, compounds of formula ??,??? and III as protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

Selective dual inhibitors of PI3 delta and gamma protein kinases

The present invention relates to a selective dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)-N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them.

Combination of anti-cd20 antibody and pi3 kinase selective inhibitor

Dual selective PI3 delta and gamma kinase inhibitors

The present invention relates to dual delta (δ) and gamma (γ) PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of Pi3K kinase mediated diseases or disorders with them.

Substituted chromenones as modulators of protein kinases

The present invention provides PI3K protein kinase modulators of formula wherein R, Cy 1 , R 1 , R 2 , L 1 and Cy 2 are as defined herein. The present invention also relates to methods of preparing compounds of formula (I) to pharmaceutical compositions containing them and to methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

Dual selective pi3 delta and gamma kinase inhibitors

The present invention relates to dual delta (δ) and gamma (γ) PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of Pi3K kinase mediated diseases or disorders with them.

Dual selective PI3 delta and gamma kinase inhibitors

The present invention relates to dual delta (δ) and gamma (γ) PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of Pi3K kinase mediated diseases or disorders with them.

Dual selective pi3 delta and gamma kinase inhibitors

The present invention relates to dual delta (d) and gamma (?) PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of Pi3K kinase mediated diseases or disorders with them.

Combination of anti-cd20 antibody and pi3 kinase selective inhibitor

Highly effective combinations of a compound of formula A (a PI3Kδ selective inhibitor) and anti-CD20 antibodies are provided herein for the treatment and amelioration of PI3Kδ and/or CD20 mediated diseases and disorderes. In particular, the combination can be used to treat cancers and autoimmune diseases. More particularly, the invention provided for a combination of a compound of formula A, or stereoisomers thereof, and ublituximab for the treatment and/or amerioration of hematological malignancies such as leukemia and lymphoma.

Dual selective pi3 delta and gamma kinase inhibitors

The present invention relates to dual delta (.delta.) and gamma (.gamma.) PI3K protein kinase modulators, as reproduced below, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of Pi3K kinase mediated diseases or disorders with them: (see above formula)

compound, compound for use and pharmaceutical composition

a presente invenção refere-se a moduladores de proteína quinase delta (d) e gama (¿) pi3k duplos, métodos de preparação dos mesmos, composições farmacêuticas que contêm os mesmos e métodos de tratamento, prevenção e/ou melhora de doenças ou distúrbios mediados por pi3k quinase com os mesmos. the present invention relates to double delta (d) and gamma (¿) pi3k protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treating, preventing and / or ameliorating mediated diseases or disorders by pi3k kinase with them.

Combination of anti-CD20 antibody and PI3 kinase selective inhibitor

Highly effective combinations of a compound of formula A (a PI3Kδ selective inhibitor) and anti-CD20 antibodies are provided herein for the treatment and amelioration of PI3Kδ and/or CD20 mediated diseases and disorderes. In particular, the combination can be used to treat cancers and autoimmune diseases. More particularly, the invention provided for a combination of a compound of formula A, or stereoisomers thereof, and ublituximab for the treatment and/or amerioration of hematological malignancies such as leukemia and lymphoma.

Kinase modulators

The present invention provides PI3K protein kinase modulators of Formula (I) wherein R, R 1 ,R 2 ,L 1 , Cy 1 and Cy 2 are as disclosed herein, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases

The present disclosure provides, compounds of formula III and IV as protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them. Compounds of the disclosure include: N’-(1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene)acetohydrazide

Dual selective PI3 delta and gamma kinase inhibitors

The present invention relates to dual delta (δ) and gamma (γ) PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of Pi3K kinase mediated diseases or disorders with them.

Combination of anti-cd20 antibody and pi3 kinase selective inhibitor

Dual selective pi3 delta and gamma kinase inhibitors

Συνδυασμος αντισωματος αντι-cd20 και εκλεκτικου αναστολεα κινασης p13

Ιδιαιτέρως αποτελεσματικοί συνδυασμοί μιας ένωσης του τύπου Α (εκλεκτικός αναστολέας ΡΙ3Κδ) και αντι-CD20 αντισωμάτων παρέχονται στο παρόν για τη θεραπεία και βελτίωση προκαλούμενων από ΡΙ3Κδ ή/και CD20 ασθενειών και διαταραχών. Ιδιαιτέρως, ο συνδυασμός μπορεί να χρησιμοποιηθεί για να θεραπεύονται καρκίνοι και αυτοάνοσες ασθένειες. Ειδικότερα, η εφεύρεση παρέχεται για συνδυασμό μιας ένωσης του τύπου Α, ή στερεοϊσομερών αυτής, και ουμπλιτουξιμάμπης για τη θεραπεία ή/και βελτίωση αιματολογικών κακοηθειών όπως λευχαιμίας και λεμφώματος.

Kinase modulators

The present invention provides PI3K protein kinase modulators of Formula (I) wherein R, n, R 1 , R 2 , L 1 , Cy 1 and Cy 2 are as defined herein, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

Forms of a PI3K delta selective inhibitor for use in pharmaceutical formulations

The present invention relates to solid state forms of a p-toluenesulfonic acid salt (PTSA) of the selective PI3K delta inhibitor (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (TGR-1202). The present invention also relates to methods of preparing the same, pharmaceutical compositions containing them, and methods of treating a PI3K kinase mediated disease or disorder, such as cancer, by administering the same.

Modulators of calcium release-activated calcium channel

Disclosed are novel calcium release-activated calcium (CRAC) channel inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods of treatment using them. The present disclosure also relates to methods for treating non-small cell lung cancer (NSCLC) with CRAC inhibitors, and to methods for identifying therapeutics for treating and of diagnosing cancer.

3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of c-Met protein kinases

The present invention provides compounds useful as c-Met protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of c-Met kinase mediated disease or disorders with them.

Combination of anti-CD20 antibody and PI3 kinase selective inhibitor

Highly effective combinations of a compound of formula A (a PI3Kδ selective inhibitor) and anti-CD20 antibodies are provided herein for the treatment and amelioration of PI3Kδ and/or CD20 mediated diseases and disorders. In particular, the combination can be used to treat cancers and autoimmune diseases. More particularly, the invention provided for a combination of a compound of formula A, or stereoisomers thereof, and ublituximab for the treatment and/or amerioration of hematological malignancies such as leukemia and lymphoma.