FUSED PYRIMIDINES AS INHIBITORS OF P97 COMPLEX

摘要

Fused pyrimidine compounds having a saturated, unsaturated or aromatic A ring fused to a pyrimidine ring and having a complex substituents at the 2 position and a substituted amine at the 4 position of the pyrimidine ring as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the pyrimidine ring and A ring are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.

主权项

1. A fused pyrimidine compound of Formula I Wherein: A is CH2, NR1, O or S; m is an integer of 1-3; n is 0 or an integer of 1-2; the ring containing A is a five or six member ring; Y is selected from the group consisting of hydrogen, halogen, Rc, ORc, CN, CO2H, CON(Rc)2, C(NRc)N(Rc)2, CH2N(Rc)2, SO2N(Rc)2 and SO2Rc wherein each Rc is independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and any combination thereof; Z is selected from the group consisting of halogen, unsubstituted alkyl of 1 to 6 carbons, substituted alkyl or alkenyl of 1 to 4 carbons, and substituted alkoxy of 1 to 4 carbons; wherein The substituted alkyl or alkenyl group is substituted with ORa, SRa, OC(O) Ra, C(O)Ra, C(O)ORa, OC(O)N(Ra)2, C(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)Ra, N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, N(Ra)S(O)tRa, S(O)tORa, S(O)tN(Ra)2, N(Ra)2 or PO3(Ra)2 wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl or any combination thereof; and, The substituted alkoxy group is substituted with ORb, Rb, OC(O)Rb, N(Rb)2, C(O)Rb, C(O)ORb, OC(O)N(Rb)2, C(O)N(Rb)2, N(Rb)C(O)ORb, N(Rb)C(O)Rb, N(Rb)C(O)N(Rb)2, N(Rb)C(NRb)N(Rb)2, N(Rb)S(O)tRb, S(O)tORb, S(O)tN(Rb)2, N(Rb)2 or PO3(Rb)2 wherein each Rb is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl or any combination thereof; R1 is selected from a group consisting of hydrogen, unsubstituted alkyl of 1 to 6 carbons, substituted alkyl of 1 to 4 carbons and —C(O)Rd; wherein, The substituted alkyl is substituted with ORd, SRd, OC(O) Rd, C(O)Rd, C(O)ORd OC(O)N(Rd)2, C(O)N(Rd)2, N(Rd)C(O)ORd, N(Rd)C(O)Rd, N(Rd)C(O)N(Rd)2, N(Rd)C(NRd)N(Rd)2, N(Rd)S(O)tR, S(O)tORd, S(O)tN(Rd)2, N(Rd)2 or PO3(Rd)2; and wherein each Rd is independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl alkenyl, alkynyl or any combination thereof; Each t is independently selected from an integer of 1 or 2; and, Ar is a phenyl, thiophenyl, pyridinyl, pyrrolyl, furanyl, or a substituted version thereof wherein the substituent is optional, independent and optionally multiple and is an aliphatic, functional or aromatic component.