This invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins and novel methods of identifying such variants. Of particular interest are inhibitors and activators of endogenous protein variants, encoded by genes which have mutated, which variants often arise or are at least first identified as having arisen following exposure to a chemical agent which is known to be an inhibitor or activator of the corresponding unmutated endogenous protein.

This invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins and novel methods of identifying such variants. Of particular interest are inhibitors and activators of endogenous protein variants, encoded by genes which have mutated, which variants often arise or are at least first identified as having arisen following exposure to a chemical agent which is known to be an inhibitor or activator of the corresponding unmutated endogenous protein.

Provided herein are isotopologues of Compound A, which are enriched with isotopes such as, for example, deuterium. Pharmaceutical compositions comprising the isotope-enriched compounds, and methods of using such compounds are also provided.

Provided herein are isotopologues of Compound A, which are enriched with isotopes such as, for example, deuterium. Pharmaceutical compositions comprising the isotope-enriched compounds, and methods of using such compounds are also provided.

Compounds and methods for treating diseases mediated by a P2X.sub.3 and/or a P2X.sub.2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

##STR00001##

or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein X is O, D, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined herein.

Compounds and methods for treating diseases mediated by a P2X.sub.3 and/or a P2X.sub.2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

##STR00001##

or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein X is O, D, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined herein.

Compounds within the scope of the present invention have a Formula 1

##STR00001##

or a salt or produg thereof, where ring A is selected from cycloaliphatic; ring B is aryl; R.sup.1 is selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, halo, aryl, and heteroaryl; and R.sup.2 and R.sup.3 are independently selected from hydrogen and (C1-C6)alkyl. Disclosed compounds may have an IRAK4 IC.sub.50 of from 0.003 μM to 3.7 μM; a TAK1 IC.sub.50 of from 0.008 μM to 132 μM; and/or an IRAK4/TAK1 selectivity of from 1 to 450. Particular compounds may have an IRAK4/TAK1 selectivity of from 100 to 500. Disclosed compositions may be formulated as pharmaceutical compositions. A method for using the compounds and/or compositions also are disclosed. The method may comprise administering to a subject an effective amount of a compound within the scope of the present invention, particularly to selectively inhibit IRAK 1 and/or IRAK4 over TAK1.

Compounds within the scope of the present invention have a Formula 1

##STR00001##

or a salt or produg thereof, where ring A is selected from cycloaliphatic; ring B is aryl; R.sup.1 is selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, halo, aryl, and heteroaryl; and R.sup.2 and R.sup.3 are independently selected from hydrogen and (C1-C6)alkyl. Disclosed compounds may have an IRAK4 IC.sub.50 of from 0.003 μM to 3.7 μM; a TAK1 IC.sub.50 of from 0.008 μM to 132 μM; and/or an IRAK4/TAK1 selectivity of from 1 to 450. Particular compounds may have an IRAK4/TAK1 selectivity of from 100 to 500. Disclosed compositions may be formulated as pharmaceutical compositions. A method for using the compounds and/or compositions also are disclosed. The method may comprise administering to a subject an effective amount of a compound within the scope of the present invention, particularly to selectively inhibit IRAK 1 and/or IRAK4 over TAK1.

The present disclosure provides pharmaceutical compounds, compositions and methods, especially as they are related to compositions and methods for the treatment of tumors and related diseases related to the dysregulation of kinase (such as EGFR (including HER), Alk, PDGFR, but not limited to) pathways.

The present disclosure provides pharmaceutical compounds, compositions and methods, especially as they are related to compositions and methods for the treatment of tumors and related diseases related to the dysregulation of kinase (such as EGFR (including HER), Alk, PDGFR, but not limited to) pathways.