Fused pyrimidines as inhibitors of p97 complex

摘要

Disclosed are fused pyrimidine compounds having scaffolds composed of left and right rings, the left ring being a saturated carbocyclic or heterocyclic ring and the right ring being a pyrimidine ring. The left saturated ring is fused to the pyrimidine ring at the 5 and 6 carbons of the pyrimidine. The saturated ring may be 5 or 6 members in size and may be all carbon or may contain a single oxygen, sulfur or nitrogen atom as one of the non-fused members of the ring. The pyrimidine ring is substituted at the two position by a 5:6 bicyclic aromatic heterocycle such as indole, benzimidazole or benzopyrazole and at the four position by an aryl methyl amino group. The 5:6 bicyclic aromatic heterocycle is substituted at its 2 position by hydrogen or an aliphatic or functional aliphatic group and at the 4 position by a functional group as described herein. The aryl methyl amino group may be aminobenzyl or aminomethyl-substituted phenyl. These fused pyrimidine compounds are inhibitors of the AAA proteosome complex containing the enzyme complex p97 and are effective medicinal agents for the treatment of diseases associated with p97 bioactivity such as cancer.

主权项

1. A fused pyrimidine compound of Formula I or a pharmaceutically acceptable salt thereof, 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 and the sum of m and n is no greater than 2; Y is selected from the group consisting of halogen, ORc, CN, CO2H, CON(Rc)2, C(NRc)N(Rc)2, CH2N(Rc)2, SO2N(Rc)2, tetrazolyl, SO2Rc and SO3H wherein each Rc is independently selected from the group consisting of hydrogen and alkyl of 1 to 4 carbons; Z is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, methoxy, ethoxy, propoxy, methoxymethyl, methoxyethyl, methoxymethoxy, methoxyethoxy, morpholinyl, piperidinyl, piperazinyl, pyrrolidonyl, pyrrolidinyl, trifluoromethyl, pentafluoroethyl; R1 is selected from a group consisting of hydrogen and unsubstituted alkyl of 1 to 6 carbons; and, Ar is phenyl or fluorophenyl.