Provided herein are compounds of formula (I-A), (I-B), (I-C), or (I-D), pharmaceutical compositions comprising the compounds, and methods of use thereof. The compounds provided herein modulate kinase activity, including PI3 kinase activity, and are useful for treating diseases and conditions associated with kinase activity, including diseases and conditions associated with PI3 kinase activity. ##STR00001##

The invention relates to compounds of formula I ##STR00001##
wherein is a bond or is absent, V is CH, CR.sup.6 or N; R.sup.0 is H or, if is a bond, may also be alkoxy; R.sup.1 is H or halogen; U is CH or N when is a bond, or, if is absent, U is CH.sub.2, NH or NR.sup.9; R.sup.2 is H, alkylcarbonyl or —CH.sub.2—R.sup.3; R.sup.3 is H, alkyl or hydroxyalkyl; R.sup.4 is H or, if n is not 0 and R.sup.5 is H, may also be OH; R.sup.5 is H, alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, carboxy or alkoxycarbonyl; R.sup.6 is hydroxyalkyl, carboxy, alkoxycarbonyl or —(CH.sub.2).sub.q—NR.sup.7R.sup.8, q being 1, 2 or 3 and each of R.sup.7 and R.sup.8 independently being H or alkyl or R.sup.7 and R.sup.8 forming with the N atom bearing them a ring; R.sup.9 is alkyl or hydroxyalkyl; A is —(CH.sub.2).sub.p—, —CH.sub.2CH.sub.2CH(OH)— or —COCH.sub.2CH(OH)—; G is substituted phenyl or G.sup.1 or G.sup.2 ##STR00002##
wherein Q is O or S and X is CH or N; and Y.sup.1, Y.sup.2 and Y.sup.3 may each be CH or N; and n is 0 when A is —CH.sub.2CH.sub.2CH(OH)— or —COCH.sub.2CH(OH)—, and n is 0, 1 or 2 when A is —(CH.sub.2).sub.p—, p being 1, 2, 3 or 4, with the proviso that the sum of n and p is then 2, 3 or 4; and to salts thereof.

Dosing regimen for transdermal delivery of hormones comprising a variable treatment cycle and a variable rest interval.

Dosing regimen for transdermal delivery of hormones comprising a variable treatment cycle and a variable rest interval.

The invention discloses a method for preparing Palbociclib (I). The preparation method comprises the steps of: causing a ring-closing reaction of 2-acetyl-2-butenoic acid methyl ester and malononitrile to occur in an alkaline condition to generate 1,4,5,6-tetrahydro-2-methoxyl-4-methyl-5-acetyl-6-oxy-3-pyridine carbonitrile (II); causing a substitution reaction of the intermediate(II) and halogenated cyclopentane(III) to occur under the effect of acid binding agent to generate N-cyclopentyl-1,4,5,6-tetrahydro-2-methoxyl-4-methyl-5-acetyl-6-oxy-3-pyridinecarbonitrile (IV); causing a condensation reaction of the intermediate(IV) and N-[5-(1-piperazinyl)-2-pyridinyl]guanidine (V) to occur to generate 6-acetyl-8-cyclopentyl-5,8-dihydro-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]-pyrido[2,3-d]pyrimidin-7(6H)-one (VI); and causing a dehydrogenation reaction of the intermediate(VI) and sodium selenate to occur to prepare Palbociclib(I).The preparation method has readily available raw materials and a simple process, is economical and environmentally friendly, and is suitable for industrial production.

The invention discloses a method for preparing Palbociclib (I). The preparation method comprises the steps of: causing a ring-closing reaction of 2-acetyl-2-butenoic acid methyl ester and malononitrile to occur in an alkaline condition to generate 1,4,5,6-tetrahydro-2-methoxyl-4-methyl-5-acetyl-6-oxy-3-pyridine carbonitrile (II); causing a substitution reaction of the intermediate(II) and halogenated cyclopentane(III) to occur under the effect of acid binding agent to generate N-cyclopentyl-1,4,5,6-tetrahydro-2-methoxyl-4-methyl-5-acetyl-6-oxy-3-pyridinecarbonitrile (IV); causing a condensation reaction of the intermediate(IV) and N-[5-(1-piperazinyl)-2-pyridinyl]guanidine (V) to occur to generate 6-acetyl-8-cyclopentyl-5,8-dihydro-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]-pyrido[2,3-d]pyrimidin-7(6H)-one (VI); and causing a dehydrogenation reaction of the intermediate(VI) and sodium selenate to occur to prepare Palbociclib(I).The preparation method has readily available raw materials and a simple process, is economical and environmentally friendly, and is suitable for industrial production.

Dermatological compositions (methods of making and using) that include one or more anesthetic agents and/or one or more anti-inflammatory agents and/or a combination of ammonium, sodium, and potassium salts, preferably of an alpha-hydroxy acid.

Dermatological compositions (methods of making and using) that include one or more anesthetic agents and/or one or more anti-inflammatory agents and/or a combination of ammonium, sodium, and potassium salts, preferably of an alpha-hydroxy acid.

The present invention provides compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein A, B, W, X and Y are as defined herein. ##STR00001##

The present invention relates to certain heteroaryl amide compounds, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia, fronto-temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, and multiple system atrophy, and cancer and melanoma.