This invention relates to compounds of Formula (I) wherein Cy.sup.1, L.sup.1, Y, R.sup.1, L.sup.2, and Ar2 are defined herein, for the treatment of cancers, inflammatory disorders, and neurological conditions. ##STR00001##

This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.

This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.

An impurity A, an impurity B and an impurity G and preparation methods therefor, and an application as a reference standard for quality control of a compound as represented by formula VI are described.

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An impurity A, an impurity B and an impurity G and preparation methods therefor, and an application as a reference standard for quality control of a compound as represented by formula VI are described.

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A method of enhancing p53 activity of a p53 mutant polypeptide is provided. The method includes interacting a compound to an open L1/S3 binding site of the p53 mutant polypeptide, where the p53 activity of the p53 mutant polypeptide is enhanced in the presence of the compound. Compounds were identified from databases of compounds for virtual drug screening. Methods of screening for compounds that enhance p53 activity by binding to the open L1/S3 binding site, and methods of treatment using the identified compounds, are also provided.

A method of enhancing p53 activity of a p53 mutant polypeptide is provided. The method includes interacting a compound to an open L1/S3 binding site of the p53 mutant polypeptide, where the p53 activity of the p53 mutant polypeptide is enhanced in the presence of the compound. Compounds were identified from databases of compounds for virtual drug screening. Methods of screening for compounds that enhance p53 activity by binding to the open L1/S3 binding site, and methods of treatment using the identified compounds, are also provided.

Provided are compounds that are inhibitors of both rho kinase and of a monoamine transporter (MAT) act to improve the disease state or condition. Further provided are compositions comprising the compounds. Further provided are methods for treating diseases or conditions, the methods comprising administering compounds according to the invention. One such disease may be glaucoma for which, among other beneficial effects, a marked reduction in intraocular pressure (IOP) may be achieved.

This disclosure concerns compounds and a method for modulating the activity of calcium ion channels, including Ca.sup.2+-induced (or Ca.sup.2+-activated) calcium release channels and conformationally coupled calcium release channels such as ryanodine receptors. Some of the compounds have a structure according to formula I, or a stereoisomer, tautomer, hydrate, solvate, prodrug, or pharmaceutically acceptable salt thereof. ##STR00001##

Novel tetrahydroisoquinoline derivative compounds are disclosed herein that may be used as an active ingredient for a pharmaceutical composition, and in particular, for a pharmaceutical composition useful for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere. This may be accomplished, for example, by modulation of the troponin complex of the fast skeletal muscle sarcomere through one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. The tetrahydroisoquinoline derivative compounds can thus be used as an agent for preventing or treating 1) neuromuscular disorders, 2) disorders of voluntary muscle, 3) CNS disorders in which muscle weakness, atrophy, and fatigue are prominent symptoms, 4) muscle symptoms stemming from systemic disorders, and 5) dysfunctions of pelvic floor and urethral/anal sphincter muscle.