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Publication Number
US-9828363-B2
Publication Date
2017-11-28
Expiration Date
Abstract
The present invention is directed to certain fused pyrimidines having a homo or hetero cyclopentyl, cyclohexyl or cycloheptyl ring as the pyrimidine fusion partner; having an amino benzyl or substituted amino benzyl group at the 4 position of the pyrimidine ring; and a 5:6 heterobicyclo ring with at least one N, O or S at the 2 position of the pyrimidine ring. These compounds are useful for treatment of cancer by inhibition of the p97 complex.
Core Innovation
The disclosed invention relates to fused pyrimidine inhibitors of the p97 (Valosin containing protein) AAA ATPase. The compounds are defined by a Formula I framework that includes a fused pyrimidine core and specific fusion partner and substitution patterns. The core scaffold selection and attachment connectivity are specified so that the valence bonds marked by squiggles correspond to the bond to HET at position 2 and the bond to NHCH2Ar at position 4.
The compounds feature a cyclopentyl/cyclohexyl/cycloheptyl fusion partner to a fused pyrimidine, with the 4-position substituted by an amino/substituted amino benzyl group. At the 2-position, a 5:6 heterobicyclic HET ring is incorporated, where HET is a 5:6 bicyclic aromatic group having one or two nitrogens or one oxygen in the 5 member ring, and is selected from Formula H4, Formula H5, Formula H8, Formula H10, Formula H13, and Formula H22.
The invention further specifies variability of substituents through enumerated substituent definitions R1–R7 and limits for Ar being phenyl or fluorophenyl. The disclosed compounds inhibit p97 ATPase activity and are described as binding the active site, in reversible or covalent manners. The patent also provides pharmaceutical compositions and medical treatment rationale for treating neoplastic diseases, grounded in the described p97 ATPase inhibition and active-site binding.
Claims Coverage
The consolidated claim coverage centers on one independent claim directed to a Formula I compound. The claim defines three main inventive features: selected scaffold attachment to HET and NHCH2Ar, restricted HET selection, and enumerated substituent constraints on Y, Ar, R1, R2, R3, R5, R6, and R7.
Formula I compound with defined scaffold connectivity to HET and NHCH2Ar
A compound of Formula I in which the selected Formula Scaffold has valence bonds marked by squiggles that are respectively the bond to HET at position 2 and the bond to NHCH2Ar at position 4.
Defined HET bicyclic aromatic group
HET is a 5:6 bicyclic aromatic group having one or two nitrogens or one oxygen in the 5 member ring and is selected from Formula H4, Formula H5, Formula H8, Formula H10, Formula H13, and Formula H22.
Enumerated substituent constraints with Ar restricted
Y is NR5 or O; Ar is phenyl or fluorophenyl; R1 is selected from the enumerated groups; R2 is hydrogen; R3 is hydrogen or alkyl of 1 to 4 carbons; R5 is hydrogen or alkyl of 1 to 4 carbons; each R6 is independently selected from the enumerated substituent groups; and R7 is hydrogen or alkyl of 1 to 4 carbons.
The claim scope is defined by the scaffold selection and attachment pattern, the named HET options, and the restricted substituent set for the remaining variables, with Ar limited to phenyl or fluorophenyl.
Stated Advantages
Inhibit p97 ATPase activity.
Bind the active site, in reversible or covalent inhibition.
Treat neoplastic diseases via pharmaceutical compositions.
Documented Applications
Treating neoplastic diseases using pharmaceutical compositions comprising the described p97 (Valosin containing protein) AAA ATPase inhibitors.
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