US 2016/0355503 A1Published application

NITROGEN HEXACYCLE COMPOUNDS AS INHIBITORS OF p97 COMPLEX

AssigneeCleave Biosciences, Inc.

InventorsHan-Jie Zhou, David Wustrow

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Abstract

Nitrogen hexacycle compounds having an arylalkyl amine substituent at the P4 position and a substituted 5:6 bicyclic group at the P2 position of the nitrogen hexacycle as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the nitrogen hexacycle, the aryl alkyl group and the 5:6 bicyclic group 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.

Claims40

Dependent claims

A nitrogen hexacycle compound of Formula I

Wherein:
One of X and Y is nitrogen and the other is CR2;
One of O1 and Q2 is nitrogen and the other is CR2′, or both of Q1 and Q2 are nitrogen;
The bicyclic ADEGZ group is a P2 group;
The five member ring of the P2 group is partially saturated or aromatic;
The six member ring of the P2 group is aromatic;
A, D and E each are independently C or nitrogen, the carbon of C being an sp2 carbon and A additionally may be CR6, the carbon of CR6 being an sp3 carbon;
The squiggle bond between D and E is a single bond if one of either of D and E is nitrogen, and the squiggle bond between D and E is a double bond if both of D and E are carbon;
The dotted bonds of the five member ring may be single or double bonds depending upon the valence and electon configuration of the bonded atom(s).
G and Z are each independently nitrogen, NR3, CR4, C(R5)2, oxygen or sulfur, the carbon of CR4 being an sp2 carbon and the carbon of C(R5)2 being an sp3 carbon, provided that:
when one of G and Z is oxygen or sulfur, each of A, D and E is an sp2 carbon;
G and Z are not together a combination of oxygen and sulfur and are not both oxygen or both sulfur;
when G and Z are both C(R5)2, A is CR6 or N and D and E are both sp2 carbons;
when G and Z are both CR4, A is CR6 or N and D and E are both sp2 carbons;
R1 is selected from hydrogen, an aliphatic group optionally substituted by a functional group or a functional group;
R2, R2′, Rn, R4 and each of R5 are each independently selected from hydrogen, an aliphatic group optionally substituted by a functional group, an optionally substituted aromatic group and a functional group with one of R5 preferably being hydrogen;
R3 is hydrogen, an aliphatic group optionally substituted by a functional group and a functional group;
R6 is hydrogen or an alkyl group of 1 to 3 carbons;
n is 0 or an integer of 1 or 2;
Ar is an aryl group optionally substituted by a functional group or an aliphatic group;
The number of boronic acid or boronic ester groups bonded anywhere to Formula I is one, the boronic acid and boronic ester groups being specific groups of a functional group.

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Dependencies are inferred from the claim text.

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Abstract

A nitrogen hexacycle compound of Formula I

Wherein:
One of X and Y is nitrogen and the other is CR2;
One of O1 and Q2 is nitrogen and the other is CR2′, or both of Q1 and Q2 are nitrogen;
The bicyclic ADEGZ group is a P2 group;
The five member ring of the P2 group is partially saturated or aromatic;
The six member ring of the P2 group is aromatic;
A, D and E each are independently C or nitrogen, the carbon of C being an sp2 carbon and A additionally may be CR6, the carbon of CR6 being an sp3 carbon;
The squiggle bond between D and E is a single bond if one of either of D and E is nitrogen, and the squiggle bond between D and E is a double bond if both of D and E are carbon;
The dotted bonds of the five member ring may be single or double bonds depending upon the valence and electon configuration of the bonded atom(s).
G and Z are each independently nitrogen, NR3, CR4, C(R5)2, oxygen or sulfur, the carbon of CR4 being an sp2 carbon and the carbon of C(R5)2 being an sp3 carbon, provided that:
when one of G and Z is oxygen or sulfur, each of A, D and E is an sp2 carbon;
G and Z are not together a combination of oxygen and sulfur and are not both oxygen or both sulfur;
when G and Z are both C(R5)2, A is CR6 or N and D and E are both sp2 carbons;
when G and Z are both CR4, A is CR6 or N and D and E are both sp2 carbons;
R1 is selected from hydrogen, an aliphatic group optionally substituted by a functional group or a functional group;
R2, R2′, Rn, R4 and each of R5 are each independently selected from hydrogen, an aliphatic group optionally substituted by a functional group, an optionally substituted aromatic group and a functional group with one of R5 preferably being hydrogen;
R3 is hydrogen, an aliphatic group optionally substituted by a functional group and a functional group;
R6 is hydrogen or an alkyl group of 1 to 3 carbons;
n is 0 or an integer of 1 or 2;
Ar is an aryl group optionally substituted by a functional group or an aliphatic group;
The number of boronic acid or boronic ester groups bonded anywhere to Formula I is one, the boronic acid and boronic ester groups being specific groups of a functional group.

18 more elements