MST1 kinase inhibitors and methods of their use

Compounds for the inhibition of mammalian Ste20-like kinase 1 (MST1) are disclosed, along with compositions comprising them and methods of their use in the treatment, management or prevention of an inflammatory or autoimmune diseases or disorders. Particular compounds are of the formula: ...

Inhibitors of sodium glucose transporter 1 for constipation

Inhibitors of sodium glucose cotransporter 1 (SGLT1), compositions comprising them, and methods of their use to treat diseases and disorders such as diabetes are disclosed. Particular compounds are of the formula: the various substituents of which are defined herein.

Inhibitors of sodium glucose cotransporter 1

Inhibitors of sodium glucose cotransporter 1 (SGLT1), compositions comprising them, and methods of their use to treat diseases and disorders such as diabetes are disclosed. Particular compounds are of the formula: the various substituents of which are defined herein.

Aryl alkenamides derivatives as MCP-1 antagonists

Aryl alkenamides derivatives of Formula I or a pharmaceutically acceptable salt thereof are novel MCP-1 antagonists and are thus useful in the treatment of inflammation, atherosclerosis, restenosis, and immune disorders such as arthritis and transplant rejectionwhereV=O,S, NH or a bond;Ar can be unsubstituted or substituted benzimidazole, phenyl, biphenyl, pyridyl, naphthyl, quinoline or isoquinoline. The other meanings for the terms are recited in the specification below.

4H-thieno[3,2-C]chromene-based inhibitors of Notum Pectinacetylesterase and methods of their use

Compounds that may be used to inhibit Notum Pectinacetylesterase are described, as well as compositions comprising them, and methods of their use to treat diseases and disorders affecting bone.

Pyrazolo[1,5-a]pyrimidine-based compounds, compositions comprising them, and methods of their use

Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: are disclosed, wherein R 1 , R 2 and R 3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by adaptor associated kinase 1 activity are also disclosed.

MST1 KINASE INHIBITORS AND METHODS OF THEIR USE

Compounds for the inhibition of mammalian Ste20-like kinase 1 (MST1) are disclosed, along with compositions comprising them and methods of their use in the treatment, management or prevention of an inflammatory or autoimmune diseases or disorders.

Inhibitors of sodium glucose cotransporter 1

Inhibitors of sodium glucose cotransporter 1 (SGLT1), compositions comprising them, and methods of their use to treat diseases and disorders such as diabetes are disclosed. Particular compounds are of the formula: the various substituents of which are defined herein.

Imidazo[1,2-b]pyridazine-based compounds, compositions comprising them, and methods of their use

Imidazo[1,2-b]pyridazine-based compounds of the formula: are disclosed, wherein R1, R2 and R3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by mediated by adaptor associated kinase 1 activity are also disclosed.

4H-THIENO[3,2-C]CHROMENE-BASED INHIBITORS OF NOTUM PECTINACETYLESTERASE AND METHODS OF THEIR USE

Compounds that may be used to inhibit Notum Pectinacetylesterase are described, as well as compositions comprising them, and methods of their use to treat diseases and disorders affecting bone. 2. The compound of claim 1 , wherein X is C(R).3. The compound of claim 2 , wherein at least one Ris H.4. The compound of claim 1 , wherein the bond between X and Cis a single bond.5. The compound of claim 1 , wherein X is 0.6. The compound of claim 1 , wherein X is S claim 1 , S(O) claim 1 , or S(O).7. The compound of claim 1 , wherein at least one Ris R.8. The compound of claim 1 , wherein Ris halo.9. The compound of claim 1 , wherein Ris cyano.10. The compound of claim 1 , wherein Ris nitro.11. The compound of claim 1 , wherein Ris C(O)OH.12. The compound of claim 1 , wherein Ris optionally substituted 5- or 6-membered heterocycle.13. The compound of claim 1 , wherein Ris —OR claim 1 , —N(R) claim 1 , —CHNO claim 1 , —CHOR claim 1 , or —CHCN.14. The compound of claim 1 , wherein Ris optionally substituted 5- or 6-membered heterocycle.15. The compound of claim 1 , wherein n is 2.16. The compound of claim 1 , wherein n is 3.17. The compound of claim 1 , wherein m is 0.18. The compound of claim 1 , wherein m is 1 and Ris methyl.19. A formulation comprising a compound of and a pharmaceutically acceptable excipient.2027-. (canceled) This application claims priority to U.S. provisional patent application No. 61/490,839, filed May 27, 2011, the entirety of which is incorporated herein by reference.This invention relates small molecule inhibitors of Notum Pectinacetylesterase, compositions comprising them, and methods of their use.Bone health depends on the coordinated activities of bone forming osteoblasts and bone resorbing osteoclasts. “Bone turnover reflects a balance between these anabolic and catabolic cellular functions and ensures that the mature skeleton can repair itself when damaged and sustain its endocrine function by release of minerals such as calcium and ...

IMIDAZO[1,2-b]PYRIDAZINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE

Imidazo[1,2-b]pyridazine-based compounds of the formula: 147-. (canceled)49. The compound of claim 48 , further provided that Ris not optionally substituted phenyl or pyridinyl.53. The compound of claim 48 , wherein at least one Ris halo.54. The compound of claim 48 , wherein at least one Ris —OR.55. The compound of claim 54 , wherein Ris optionally substituted Chydrocarbyl (e.g. claim 54 , Chydrocarbyl claim 54 , Chydrocarbyl).56. The compound of claim 48 , wherein Ris —C(O)OR claim 48 , —C(O)N(R) claim 48 , or —N(R)C(O)OR.57. The compound of claim 48 , wherein Ris —C(O)R.58. The compound of claim 56 , wherein each Ris independently hydrogen or Chydrocarbyl (e.g. claim 56 , Chydrocarbyl claim 56 , Chydrocarbyl).59. The compound of claim 56 , wherein at least one Ris optionally substituted Chydrocarbyl claim 56 , which optional substitution is with one or more of amino claim 56 , cyano claim 56 , halo claim 56 , hydroxyl.60. The compound of claim 56 , wherein Ris 2-12-membered heterocarbyl comprising at least one nitrogen atom.6166-. (canceled)67. The compound of claim 57 , wherein each Ris independently hydrogen or Chydrocarbyl (e.g. claim 57 , Chydrocarbyl claim 57 , Chydrocarbyl).68. The compound of claim 57 , wherein at least one Ris optionally substituted Chydrocarbyl claim 57 , which optional substitution is with one or more of amino claim 57 , cyano claim 57 , halo claim 57 , hydroxyl.69. The compound of claim 57 , wherein Ris 2-12-membered heterocarbyl comprising at least one nitrogen atom.70. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient or diluent. This application claims priority to U.S. provisional patent application No. 61/608,758, filed Mar. 9, 2012, the entirety of which is incorporated herein by reference.This invention is directed to imidazo[1,2-b]pyridazine-based compounds useful as inhibitors of adaptor associated kinase 1 (AAK1), compositions comprising them, and methods of their use.Adaptor ...

PYRAZOLO[1,5-a]PYRIMIDINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE

Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: 145-. (canceled)50. The compound of claim 46 , wherein at least one R claim 46 , is halo.51. The compound of claim 46 , wherein at least one Ris —OR.52. The compound of claim 51 , wherein Ris optionally substituted Chydrocarbyl.53. The compound of any of claim 46 , wherein Ris —C(O)OR claim 46 , —C(O)N(R) claim 46 , or —N(R)C(O)OR.54. The compound of claim 46 , wherein Ris —C(O)R.55. The compound of claim 53 , wherein each Ris independently hydrogen or Chydrocarbyl.56. The compound of claim 53 , wherein at least one Ris optionally substituted Chydrocarbyl claim 53 , which optional substitution is with one or more of amino claim 53 , cyano claim 53 , halo claim 53 , hydroxyl.57. The compound of claim 53 , wherein Ris 2-12-membered heterocarbyl comprising at least one nitrogen atom.5863-. (canceled)64. The compound of claim 54 , wherein each Ris independently hydrogen or hydrocarbyl.65. The compound of claim 54 , wherein at least one Ris optionally substituted Chydrocarbyl claim 54 , which optional substitution is with one or more of amino claim 54 , cyano claim 54 , halo claim 54 , hydroxyl.66. The compound of claim 54 , wherein Ris 2-12-membered heterocarbyl comprising at least one nitrogen atom. This application claims priority to U.S. provisional patent application No. 61/608,765, filed Mar. 9, 2012, the entirety of which is incorporated herein by reference.This invention is directed to pyrazolo[1,5-a]pyrimidine-based compounds useful as inhibitors of adaptor associated kinase 1 (AAK1), compositions comprising them, and methods of their use.Adaptor associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases. AAK1 mRNA exists in two splice forms termed short and long. The long form predominates and is highly expressed in brain and heart (Henderson and Conner, 2007, 18, 2698-2706). AAK1 is enriched in synaptosomal preparations and is co-localized with endocytic structures in ...

Mst1 kinase inhibitors and methods of their use

Compounds for the inhibition of mammalian Ste20-like kinase 1 (MST1) are disclosed, along with compositions comprising them and methods of their use in the treatment, management or prevention of an inflammatory or autoimmune diseases or disorders.

IMIDAZO[1,2-b]PYRIDAZINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE

Imidazo[1,2-b]pyridazine-based compounds of the formula: 141-. (canceled)43. The compound of claim 42 , with the provision that Ris not optionally substituted phenyl or pyridinyl.4866-. (canceled)67. The compound of claim 42 , wherein each Ris independently hydrogen or Chydrocarbyl.68. The compound of claim 67 , wherein at least one Ris optionally substituted Chydrocarbyl claim 67 , which optional substitution is with one or more of amino claim 67 , cyano claim 67 , halo claim 67 , hydroxyl.69. The compound of claim 67 , wherein Ris 2-12-membered heterocarbyl comprising at least one nitrogen atom.70. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient or diluent. This application claims priority to U.S. patent application Ser. No. 13/785,271, filed Mar. 5, 2013, which claims priority to provisional patent application No. 61/608,758, filed Mar. 9, 2012, the entireties of which are incorporated herein by reference.This invention is directed to imidazo[1,2-b]pyridazine-based compounds useful as inhibitors of adaptor associated kinase 1 (AAK1), compositions comprising them, and methods of their use.Adaptor associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases. AAK1 mRNA exists in two splice forms termed short and long. The long form predominates and is highly expressed in brain and heart (Henderson and Conner, 2007, 18, 2698-2706). AAK1 is enriched in synaptosomal preparations and is co-localized with endocytic structures in cultured cells. AAK1 modulates clatherin coated endocytosis, a process that is important in synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 associates with the AP2 complex, a hetero-tetramer which links receptor cargo to the clatherin coat. The binding of clatherin to AAK1 stimulates AAK1 kinase activity (Conner et. al., 2003, 4, 885-890; Jackson et. al., 2003, 163, 231-236). AAK1 phosphorylates the mu-2 subunit of AP-2, which promotes the binding ...

IMIDAZO[1,2-b]PYRIDAZINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE

Imidazo[1,2-b]pyridazine-based compounds of the formula: 141-. (canceled)43. The compound of claim 42 , with the provision that Ris not optionally substituted phenyl or pyridinyl.44. (canceled)4866-. (canceled)67. The compound of claim 42 , wherein each Ris independently hydrogen or Chydrocarbyl.68. The compound of claim 67 , wherein at least one Ris optionally substituted Chydrocarbyl claim 67 , which optional substitution is with one or more of amino claim 67 , cyano claim 67 , halo claim 67 , hydroxyl.69. The compound of claim 67 , wherein Ris 2-12-membered heterocarbyl comprising at least one nitrogen atom.70. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient or diluent. This application is a continuation of U.S. patent application Ser. No. 14/631,097, filed Feb. 25, 2015, which is a continuation of U.S. patent application Ser. No. 13/785,271, filed Mar. 5, 2013, which claims priority to provisional patent application No. 61/608,758, filed Mar. 9, 2012, the entireties of which are incorporated herein by reference.This invention is directed to imidazo[1,2-b]pyridazine-based compounds useful as inhibitors of adaptor associated kinase 1 (AAK1), compositions comprising them, and methods of their use.Adaptor associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases. AAK1 mRNA exists in two splice forms termed short and long. The long form predominates and is highly expressed in brain and heart (Henderson and Conner, 2007, 18, 2698-2706). AAK1 is enriched in synaptosomal preparations and is co-localized with endocytic structures in cultured cells. AAK1 modulates clatherin coated endocytosis, a process that is important in synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 associates with the AP2 complex, a hetero-tetramer which links receptor cargo to the clatherin coat. The binding of clatherin to AAK1 stimulates AAK1 kinase activity (Conner et. al., 2003, 4, 885-890; ...

PYRAZOLO[1,5-a]PYRIMIDINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE

Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: 163-. (canceled)65. The compound of claim 64 , wherein Ris —C(O)OR.66. The compound of claim 65 , wherein Ris Chydrocarbyl.67. The compound of claim 65 , wherein Ris 2-12-membered heterocarbyl.71. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient or diluent.72. A method of inhibiting AAK1 activity claim 64 , which comprises contacting AAK1 with a compound of .73. A method of treating or managing a disease or disorder mediated by AAK1 activity claim 64 , which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of .74. The method of claim 73 , wherein the disease or disorder is Alzheimer's disease claim 73 , bipolar disorder claim 73 , pain claim 73 , Parkinson's disease claim 73 , or schizophrenia.75. The method of claim 74 , wherein the pain is neuropathic pain.76. The method of claim 75 , wherein the neuropathic pain is fibromyalgia or peripheral neuropathy.77. The method of claim 76 , wherein the peripheral neuropathy is diabetic neuropathy. This application is a continuation of U.S. patent application Ser. No. 14/483,898, filed Sep. 11, 2014, which is a continuation of U.S. patent application Ser. No. 13/785,355, filed Mar. 5, 2013, and now U.S. Pat. No. 8,946,415, which claims priority to provisional patent application No. 61/608,765, filed Mar. 9, 2012, the entireties of which are incorporated herein by reference.This invention is directed to pyrazolo[1,5-a]pyrimidine-based compounds useful as inhibitors of adaptor associated kinase 1 (AAK1), compositions comprising them, and methods of their use.Adaptor associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases. AAK1 mRNA exists in two splice forms termed short and long. The long form predominates and is highly expressed in brain and heart (Henderson and Conner, 2007, 18, 2698-2706). AAK1 is enriched in synaptosomal ...

4H-THIENO[3,2-C]CHROMENE-BASED INHIBITORS OF NOTUM PECTINACETYLESTERASE AND METHODS OF THEIR USE

Compounds that may be used to inhibit Notum Pectinacetylesterase are described, as well as compositions comprising them, and methods of their use to treat diseases and disorders affecting bone.

PYRAZOLO[1,5-a]PYRIMIDINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE

Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: are disclosed, wherein R 1 , R 2 and R 3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by mediated by adaptor associated kinase 1 activity are also disclosed.

INHIBITORS OF NOTUM PECTINACETYLESTERASE AND METHODS OF THEIR USE

Compounds are disclosed for the treatment, management and prevention of diseases and disorders affecting the bone. Particular compounds are potent inhibitors of Notum Pectinacetylesterase, and are of the formula: 3. The compound of claim 2 , wherein n is 0;4. The compound of claim 1 , wherein X is OR.5. The compound of claim 1 , wherein Ris hydrogen or optionally substituted alkyl or aryl.6. The compound of claim 5 , wherein Ris hydrogen or alkyl.7. The compound of claim 1 , wherein Ris hydrogen or optionally substituted alkyl.8. The compound of claim 1 , wherein Ris alkyl or halo.9. The compound of claim 8 , wherein Ris chloro.10. The compound of claim 1 , wherein Ris alkyl or halo.11. The compound of claim 10 , wherein Ris C-alkyl.12. A compound or a pharmaceutically acceptable salt thereof claim 10 , which compound is 2-((5 claim 10 ,6-dimethylthieno[2 claim 10 ,3-d]pyrimidin-4-yl)thio)acetic acid claim 10 , 2-((5-chloro-6-isopropylthieno[2 claim 10 ,3-d]pyrimidin-4-yl)thio)acetic acid claim 10 , 2-((6-chloro-7-cyclopropylthieno[3 claim 10 ,2-d]pyrimidin-4-yl)thio)acetic acid claim 10 , or 2-((6-chloro-7-methylthieno[3 claim 10 ,2-d]pyrimidin-4-yl)thio)acetic acid.13. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient or diluent. This application claims priority to U.S. patent application Ser. No. 13/231,653, filed Sep. 13, 2011, and U.S. provisional patent application No. 61/382,526, filed Sep. 14, 2010, the entireties of which are incorporated herein by reference.This invention relates small molecule inhibitors of Notum Pectinacetylesterase, compositions comprising them, and methods of their use.Bone health depends on the coordinated activities of bone forming osteoblasts and bone resorbing osteoclasts. “Bone turnover reflects a balance between these anabolic and catabolic cellular functions and ensures that the mature skeleton can repair itself when damaged and sustain its endocrine function by release of minerals ...

INHIBITORS OF SODIUM GLUCOSE COTRANSPORTER 1

Inhibitors of sodium glucose cotransporter 1 (SGLT1), compositions comprising them, and methods of their use to treat diseases and disorders such as diabetes are disclosed. Particular compounds are of the formula: 2. The compound of claim 1 , wherein Ris optionally substituted C-alkyl.3. The compound of claim 1 , wherein n is 0.4. The compound of claim 1 , wherein Ris OR.5. The compound of claim 4 , wherein at least one Ris hydrogen.6. The compound of claim 1 , wherein Ris optionally substituted C-alkyl.7. The compound of claim 1 , wherein Ris halo.8. The compound of claim 1 , wherein Ris optionally substituted C-alkoxy.9. The compound of claim 1 , wherein p is 1.10. The compound of claim 1 , wherein Ris R.11. The compound of claim 1 , wherein Ris —OR.14. The compound of claim 13 , wherein Ris C-alkyl.15. The compound of claim 13 , wherein Ris methyl.16. The compound of claim 13 , wherein Ris R.17. The compound of claim 13 , wherein Ris —OR.18. The compound of or claim 13 , wherein Ris:{'sub': 1-10', '4C', '2, '—C-alkyl-N(R);'}{'sub': 1-10', '4C', '4C, '—C-alkyl-N(R)C(O)R;'}{'sub': 1-10', '4C', '2, '—C-alkyl-C(O)N(R);'}{'sub': 1-10', '4C', '0-6', '4C, '—C-alkyl-C(O)N(R)—C-alkyl-C(O)R;'}{'sub': 1-10', '4C', '0-6', '4C', '2, '—C-alkyl-C(O)N(R)—C-alkyl-C(O)N(R);'}{'sub': 1-10', '4C', '0-6', '4C', '2, '—C-alkyl-N(R)C(O)—Calkyl-N(R); or'}{'sub': 1-10', '4C', '0-6', '4C', '4C, '—C-alkyl-N(R)C(O)—Calkyl-N(R)C(O)R.'}19. A pharmaceutical composition comprising a compound of any of the preceding claims and a pharmaceutically acceptable excipient or diluent.20. A method of treating or managing a disease or disorder claim 13 , which comprises administering to a patient in need thereof a therapeutically effective amount of a compound or composition of any of the preceding claims claim 13 , which disease or disorder is a cardiovascular or metabolic disease or disorder. This application claims priority to U.S. provisional patent application No. 61/728,373, filed Nov. 20, 2012, the ...

INHIBITORS OF SODIUM GLUCOSE COTRANSPORTER 1

Inhibitors of sodium glucose cotransporter 1 (SGLT1), compositions comprising them, and methods of their use to treat diseases and disorders such as diabetes are disclosed. Particular compounds are of the formula: 120-. (canceled) This application is a continuation of U.S. patent application Ser. No. 14/943,505, filed Nov. 17, 2015, which is a continuation of U.S. patent application Ser. No. 14/082,786, filed Nov. 18, 2013, and now U.S. Pat. No. 9,200,025, which claims priority to provisional patent application No. 61/728,373, filed Nov. 20, 2012, the entireties of which are incorporated herein by reference.This invention relates to compounds that can be used to inhibit sodium glucose cotransporter 1 (SLGT1), compositions comprising them, and methods of their use.Type 2 diabetes mellitus is a chronic disease characterized by hyperglycemia caused by hepatic glucose production, a deficiency in insulin secretion, and/or peripheral insulin resistance. In recent years, considerable effort has been directed towards discovering ways of treating the disease. One relatively new approach is inhibition of the sodium glucose cotransporter (SLGT), which lowers blood glucose levels by removing glucose from the bloodstream.Under normal conditions, plasma glucose is filtered in the kidney glomerulus and in healthy individuals is almost completely reabsorbed. Obermeier, M., et al., 38(3):405-414, 406 (2010). That reabsorption is mediated by two sodium-dependent glucose cotransporters: SGLT1 and SGLT2. SGLT1 is expressed in the gut, heart, and kidney, while SGLT2 is expressed primarily in the proximal tubule of the nephron. Id. Although compounds that inhibit both transporters have been described, research has largely focused on discovering selective SGLT2 inhibitors. This is due, in part, to the discovery that a defective SGLT1 transporter in the gut is responsible for some glucose and galactose malabsorption disorders, and the belief that inhibition of SGLT1 would therefore be ...

INHIBITORS OF SODIUM GLUCOSE COTRANSPORTER 1

Inhibitors of sodium glucose cotransporter 1 (SGLT1), compositions comprising them, and methods of their use to treat diseases and disorders such as diabetes are disclosed. Particular compounds are of the formula: 2. The compound of claim 1 , wherein Ris optionally substituted C-alkyl.3. The compound of claim 1 , wherein n is 0.4. The compound of claim 1 , wherein Ris OR.5. The compound of claim 4 , wherein at least one Ris hydrogen.6. The compound of claim 1 , wherein Ris optionally substituted C-alkyl.7. The compound of claim 1 , wherein Ris halo.8. The compound of claim 1 , wherein Ris optionally substituted C-alkoxy.9. The compound of claim 1 , wherein p is 1.10. The compound of claim 1 , wherein Ris R.11. The compound of claim 1 , wherein Ris —OR.14. The compound of claim 13 , wherein Ris C-alkyl.15. The compound of claim 13 , wherein Ris methyl.16. The compound of claim 13 , wherein Ris R.17. The compound of claim 13 , wherein Ris —OR.18. The compound of or claim 13 , wherein Ris:{'sub': 1-10', '4C', '2, '—C-alkyl-N(R);'}{'sub': 1-10', '4C', '4C, '—C-alkyl-N(R)C(O)R;'}{'sub': 1-10', '4C', '2, '—C-alkyl-C(O)N(R);'}{'sub': 1-10', '4C', '0-6', '4C, '—C-alkyl-C(O)N(R)—C-alkyl-C(O)R;'}{'sub': 1-10', '4C', '0-6', '4C', '2, '—C-alkyl-C(O)N(R)—C-alkyl-C(O)N(R);'}{'sub': 1-10', '4C', '0-6', '4C', '2, '—C-alkyl-N(R)C(O)—C-alkyl-N(R); or'}{'sub': 1-10', '4C', '0-6', '4C', '4C, '—C-alkyl-N(R)C(O)—C-alkyl-N(R)C(O)R.'}19. A pharmaceutical composition comprising a compound of any of the preceding claims and a pharmaceutically acceptable excipient or diluent.20. A method of treating or managing a disease or disorder claim 13 , which comprises administering to a patient in need thereof a therapeutically effective amount of a compound or composition of any of the preceding claims claim 13 , which disease or disorder is a cardiovascular or metabolic disease or disorder. This application claims priority to U.S. patent application Ser. No. 14/082,786, filed Nov. 18, 2013, which ...

Sodium glucose co-transporter 1 inhibitors.

Bu buluş, sodyum glikoz birlikte taşıyıcı 1'i (SLGT1) inhibe etmek için kullanılabilen bileşikler, bunları içeren kompozisyonlar ve bunların kullanım yöntemleri ile ilgilidir. The present invention relates to compounds that can be used to inhibit sodium glucose co-carrier 1 (SLGT1), compositions containing them, and methods of using them.

Mst1 kinase inhibitors and methods of their use

Compounds for the inhibition of mammalian Ste20-like kinase 1 (MST1) are disclosed, along with compositions comprising them and methods of their use in the treatment, management or prevention of an inflammatory or autoimmune diseases or disorders.

Inhibitors of notum pectinacetylesterase and methods of their use

4H-thieno[3,2-c]chromene-based inhibitors of Notum Pectinacetylesterase and methods of their use

Compounds that may be used to inhibit Notum Pectinacetylesterase are described, as well as compositions comprising them, and methods of their use to treat diseases and disorders affecting bone.

MST1 kinase inhibitors and methods of their use

Notum pectin acetylesterase inhibitors and methods for their use

Un compuesto de la fórmula:**Fórmula** o una sal farmacéuticamente aceptable del mismo, en la que: X es OR1B o N(R1B)2; cada R1B es independientemente hidrógeno, o alquilo, arilo, heteroalquilo o heterociclo opcionalmente sustituidos; R2 es hidrógeno, halo, -CO2R2A, -C(O)N(R2A)2, -SR2A, -OR2A, -N(R2A)2, o alquilo, arilo, heteroalquilo o heterociclo opcionalmente sustituidos; cada R2A es independientemente hidrógeno, o alquilo, arilo, heteroalquilo o heterociclo opcionalmente sustituidos; R3 es hidrógeno, halo, ciano, -CO2R3A, -C(O)N(R3A)2, -SR3A, -OR3A, -N(R3A)2, o alquilo, arilo, heteroalquilo o heterociclo opcionalmente sustituidos; cada R3A es independientemente hidrógeno, o alquilo, arilo, heteroalquilo o heterociclo opcionalmente sustituidos; R5 es hidrógeno, halo, -CO2R5A, -C(O)N(R5A)2, -SR5A, -OR5A, -N(R5A)2, o alquilo, arilo, heteroalquilo o heterociclo opcionalmente sustituidos; cada R5A es independientemente hidrógeno, o alquilo, arilo, heteroalquilo o heterociclo opcionalmente sustituidos; y n es 1 o 2; en el que "opcionalmente sustituidos" significa opcionalmente sustituidos con uno o más de alcoxi, alquilo, amino (incluyendo alquilamino, dialquilamino), arilo, ácido carboxílico, ciano, halo, haloalquilo, heterociclo o hidroxilo. A compound of the formula: ** Formula ** or a pharmaceutically acceptable salt thereof, wherein: X is OR1B or N (R1B) 2; each R1B is independently hydrogen, or optionally substituted alkyl, aryl, heteroalkyl or heterocycle; R2 is hydrogen, halo, -CO2R2A, -C (O) N (R2A) 2, -SR2A, -OR2A, -N (R2A) 2, or optionally substituted alkyl, aryl, heteroalkyl or heterocycle; each R2A is independently hydrogen, or optionally substituted alkyl, aryl, heteroalkyl or heterocycle; R3 is hydrogen, halo, cyano, -CO2R3A, -C (O) N (R3A) 2, -SR3A, -OR3A, -N (R3A) 2, or optionally substituted alkyl, aryl, heteroalkyl or heterocycle; each R3A is independently hydrogen, or optionally substituted alkyl, aryl, heteroalkyl or heterocycle; R5 is ...

Pyrazolo[1,5-a]pyrimidine-based compounds, compositions comprising them, and methods of their use

Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: are disclosed, wherein R1, R2 and R3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by mediated by adaptor associated kinase 1 activity are also disclosed.

Imidazo [1, 2 - b] pyridazine - based compounds, compositions comprising them, and uses thereof

Imidazo[1,2-b]pyridazine-based compounds of the formula (I): are disclosed, wherein R

Inhibitors of sodium glucose cotransport 1

MST1 kinase inhibitors and methods of their use

Compounds for the inhibition of mammalian Ste20-like kinase 1 (MST1) are disclosed, along with compositions comprising them and methods of their use in the treatment, management or prevention of an inflammatory or autoimmune diseases or disorders.

Imidazo [1, 2 - b] pyridazine - based compounds, compositions comprising them, and uses thereof

Imidazo[1,2-b]pyridazine-based compounds of the formula (I): are disclosed, wherein R1, R2 and R3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by mediated by adaptor associated kinase 1 activity are also disclosed.

Inhibitors of notum pectinacetylesterase and methods of their use

Compounds are disclosed for the treatment, management and prevention of diseases and disorders affecting the bone. Particular compounds are potent inhibitors of Notum Pectinacetylesterase, and are of the formula: wherein E, G, Y, Z, R1, R2, and R3 are defined herein.

MST1 kinase inhibitors and methods for use

Un compuesto de la fórmula:**Fórmula** o una sal farmacéuticamente aceptable del mismo, en la que: A es arilo o heterociclo de 4-7 miembros; D es un heterociclo no aromático de 5-7 miembros; X es N o CH; cada uno de Y1 e Y2 es independientemente N o CH; cada R1 es independientemente R1A, -(R1B)nSOpR1C, -(R1B)nSOpN(R1C)2, -(R1B)nNR1cSOpR1C, -(R1B)nC(O)N(R1C)2, o -(R1B)nNR1CC(O)R1C, o hidrocarbilo C1-12 opcionalmente sustituido o heterocarbilo de 2-12 miembros, cuya sustitución opcional es con uno o más de R1A; cada R1A es independientemente amino, alcoxilo, carboxilo, ciano, halo, o hidroxilo; cada R1B es independientemente hidrocarbilo C1-12 opcionalmente sustituido con uno o más de amino, alcoxilo, carboxilo, ciano, halo, o hidroxilo; cada R1C es independientemente hidrógeno o hidrocarbilo C1-12 opcionalmente sustituido o heterocarbilo de 2-12 miembros, cuya sustitución opcional es con uno o más de amino, alcoxilo, carboxilo, ciano, halo, o hidroxilo; cada R3A es independientemente amino, alcoxilo, carboxilo, ciano, halo, o hidroxilo; k es 0 o 1; m es 0-3; n es 0 o 1; p es 0-2; y q es 0-2. A compound of the formula: ** Formula ** or a pharmaceutically acceptable salt thereof, wherein: A is 4-7 membered aryl or heterocycle; D is a 5-7 membered non-aromatic heterocycle; X is N or CH; each of Y1 and Y2 is independently N or CH; each R1 is independently R1A, - (R1B) nSOpR1C, - (R1B) nSOpN (R1C) 2, - (R1B) nNR1cSOpR1C, - (R1B) nC (O) N (R1C) 2, or - (R1B) nNR1CC (O ) R1C, or optionally substituted C1-12 hydrocarbyl or 2-12 membered heterocarbyl, whose optional substitution is with one or more of R1A; each R1A is independently amino, alkoxy, carboxyl, cyano, halo, or hydroxyl; each R1B is independently C1-12 hydrocarbyl optionally substituted with one or more of amino, alkoxy, carboxyl, cyano, halo, or hydroxyl; each R1C is independently hydrogen or optionally substituted C1-12 hydrocarbyl or 2-12 membered heterocarbyl, the optional substitution of which is one or more ...

Pyrazolo[1,5-a]pyrimidine-based compounds, compositions comprising them, and methods of their use

Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: are disclosed, wherein R

Imidazo[1,2-b]pyridazine-based compounds, compositions comprising them, and uses thereof

Aryl alkenamides derivatives as mcp-1 antagonists

Aryl alkenamides derivatives of Formula I or a pharmaceutically acceptable salt thereof are novel MCP-1 antagonists and are thus useful in the treatment of inflammation, atherosclerosis, restenosis, and immune disorders such as arthritis and transplant rejection V=O, S, NH or a bond; Ar can be unsubstituted or substituted benzimidazole, phenyl, biphenyl, pyridyl, naphthyl, quinoline, isoquinoline or indole; n=2-6; m=1-3; X=O (oxygen), S (sulfur), ═CH 2 , ═NH or H 2 ; R 1 and R 2 can independently be hydrogen, lower alkyl of from 1-4 carbon atoms, —(CH 2 ) n OR 6 , —(CH 2 ) n NR 3 R 4 , —(CH 2 ) n ′CONR 3 R 4 , —(CH 2 ) n ′COOR 6 , —(CH 2 ) r Ar′, where n′=0-6 r=0-4 R 3 and R 4 can independently be hydrogen, lower alkyl of from 1-4 carbon atoms, —(CH 2 ) n OR 6 , or —(CH 2 ) m —Ar′, which can be unsubstituted or substituted with up to 3 substitutents, where “Ar′” is phenyl, pyridyl, or indole; R 3 and R 4 may also be taken together to form a cyclic ring of 3-8 atoms which may also contain oxygen or the group NR 5 where R 5 can be hydrogen, lower alkyl of from 1-4 carbon atoms, cycloalkyl of from 5-12 carbon atoms, or —(CH 2 ) m -Phenyl, which can be unsubstituted or substituted with up to 3 substitutents; R 6 can be hydrogen, lower alkyl or (CH 2 ) m -Phenyl; m=1-3; R 1 and R 2 may be also taken together to form a ring of 3-8 atoms which may also contain oxygen or the group NR 5 , which ring may be substituted on one or more carbon atoms with the group NR 3 R 4 ; the subtituents are defined as: halogen, nitro, CF 3 , alkyl of from 1-12 carbon atoms; —(CH 2 ) r OR 6 —(CH 2 ) r NR 3 R 4 —(CH 2 ) r CONR 3 R 4 —(CH 2 ) r C(O)OR 6 or —(CH 2 ) r SO 2 —OR 6 ; R 7 , R 8 , R 9 and R 10 can each independently be hydrogen, lower alkyl or aryl; and R 7 and R 8 or R 9 and R 10 or X or R 2 when taken together can form a 5-7 membered ring including cycloalkyl, cycloalkenyl, aryl, or heteroaryl containing nitrogen, oxygen or sulfur.