The present invention provides bicyclic heterocyclyl kinase enzyme inhibitor compounds of formula (I), which are therapeutically useful as kinase inhibitors, particularly IRAK4 inhibitors. ##STR00001##
wherein A, Y, Z, X.sub.1, X.sub.2, X.sub.3, R.sub.1, R.sub.3, ‘m’, ‘n’ and ‘p’ have the meanings given in the specification and pharmaceutically acceptable salt or stereoisomer thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder mediated by kinase enzyme, particularly IRAK4 enzyme. The present invention also provides pharmaceutical composition comprising at least one of the compounds of compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

The invention relates to Spirocyclic ether derivatives of pyrazolo[1,5-a]pyrimidine-3-carboxyamide of general formula (I) which are inhibitors of phosphodiesterase 2, useful in treating central nervous system diseases and other diseases. In addition, the invention relates to processes for preparing pharmaceutical compositions as well as processes for manufacture the compounds according to the invention.

The present invention relates to the method of treating heavy menstrual bleeding in a subject with or without uterine fibroids and in need of treatment by administering an effective amount of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof, in combination with estrogens and progestogens.

The present invention relates to the method of treating heavy menstrual bleeding in a subject with or without uterine fibroids and in need of treatment by administering an effective amount of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof, in combination with estrogens and progestogens.

The present invention relates to the intravaginal use of sex steroid precursor (e.g. DHEA) for the reduction of the incidence or recurrence of breast cancer in postmenopausal women. The dosage of sex steroid precursor is limited to 25 mg per day or less. Further administration of selective estrogen receptor modulator is disclosed for the above-reduction.

The present invention relates to the intravaginal use of sex steroid precursor (e.g. DHEA) for the reduction of the incidence or recurrence of breast cancer in postmenopausal women. The dosage of sex steroid precursor is limited to 25 mg per day or less. Further administration of selective estrogen receptor modulator is disclosed for the above-reduction.

High penetration compositions (HPC) of a parent compound, which are capable of crossing biological barriers with high penetration efficiency. The HPCs are capable of being converted to parent drugs or parent drug-related compounds such as metabolites after crossing one or more biological barriers and thus can render treatments for the conditions that the parent drugs or parent drug-related compounds can. Additionally, the HPCs are capable of reaching areas that their parent drugs or parent drug-related compounds may not be able to access or to render a sufficient concentration at the target areas HPCs of NSAIA, for example, have demonstrated indications such as treating hair loss. A HPC can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

The present invention relates to methods of treating ovarian cancer in a subject by administering to the subject by evaluating the subject's expression levels of specific biomarkers or angiogenic an anti-activin-A compound, such as an anti-activin-A antibody or an activin-A-binding receptor. In some embodiments, at least two compounds are administered to the subject, where the first compound is an anti-activin A compound, and the second compound is a chemotherapeutic compound, for example capecitabine. The invention further relates to methods of identifying subjects for treatment factors.

A Panax plant extract and a pharmaceutical composition and the use thereof. The mass ratio of Rk1 and Rg5 in the Panax plant extract is 1:1.0-1.5, and the content of Rg3, Rg5 and Rk1 in the extract is relatively high. The extract can be used to prepare a drug for treating chronic heart failure, coronary stable angina, arrhythmia, diabetes and complications thereof, Meniere's disease, hyperlipemia, fatty liver, Alzheimer's disease, dymenorrhea, metabolic syndrome, gout, tumours or vascular leak syndrome.

A Panax plant extract and a pharmaceutical composition and the use thereof. The mass ratio of Rk1 and Rg5 in the Panax plant extract is 1:1.0-1.5, and the content of Rg3, Rg5 and Rk1 in the extract is relatively high. The extract can be used to prepare a drug for treating chronic heart failure, coronary stable angina, arrhythmia, diabetes and complications thereof, Meniere's disease, hyperlipemia, fatty liver, Alzheimer's disease, dymenorrhea, metabolic syndrome, gout, tumours or vascular leak syndrome.