Heteroaromatic compounds as PI3 kinase modulators and methods of use

摘要

The present invention provides heteroaromatic derivatives and pharmaceutical acceptable salts and formulations thereof useful in modulating the protein kinase activity, especially phosphatidylinositol 3-kinases (PI3 kinases) and mTOR, and in modulating inter- and/or intra-cellular signaling activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.

主权项

1. A compound having Formula (I): or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a pharmaceutically salt or a prodrug thereof, wherein:
each of W1, W2 and W3 is independently N or CRc;Z is D, CN, N3, or X is H, D, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, —(C1-C4)alkylene-(C3-C6)cycloalkyl, —(C1-C4)alkylene-(C3-C6)heterocyclyl, (C6-C10)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each of the (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, —(C1-C4)alkylene-(C3-C6)cycloalkyl, —(C1-C4)alkylene-(C3-C6)heterocyclyl, (C6-C10)aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, —C(═O)NRaRb, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C1-C4)alkylene-CN, —(C1-C4)alkylene-ORa, —(C1-C4)alkylene-NRaRb, (C6-C10)aryl, and 5-10 membered heteroaryl; Y is (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, —(C1-C4)alkylene-(C3-C6)cycloalkyl, —(C1-C4)alkylene-(C3-C6)heterocyclyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each of the (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, —(C1-C4)alkylene-(C3-C6)cycloalkyl, —(C1-C4)alkylene-(C3-C6)heterocyclyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, —C(═O)NRaRb, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C1-C4)alkylene-CN, —(C1-C4)alkylene-ORa, —(C1-C4)alkylene-NRaRb, (C6-C10)aryl, and 5-10 membered heteroaryl; R1 is H, D, Cl, ORa, NRaRb, (C1-C6)aliphatic, or (C3-C6)cycloalkyl, wherein each of the (C1-C6)aliphatic and (C3-C6)cycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, ORa, SRa, and NRaRb; each Ra and Rb is independently H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, (C6-C10)aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, —(C1-C4)alkylene-(C6-C10)aryl, —(C1-C4)alkylene-(5-10 membered heteroaryl), or Ra and Rb are taken together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic ring, wherein each of the above substituents is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, OH, NH2, (C1-C6)alkoxy, and (C1-C6)alkylamino; and each Rc is independently H, D, F, Cl, Br, I, N3, CN, OH, NH2, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylamino, (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, (C6-C10)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each of the (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylamino, (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, (C6-C10)aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, OH, NH2, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C1-C6)alkylamino.