US 7,115,598 B2Granted

Substituted 1,4-diazepines and uses thereof

AssigneeOrtho-McNeil Pharmaceutical, Inc.

InventorsTianbao Lu, Karen L. Milkiewicz, Pierre Raboisson, Maxwell David Cummings, Raul R. Calvo, Daniel J. Parks, Louis V. Lafrance, III, Juan Jose Marugan Sanchez, Joan Gushue, Kristi Leonard

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Abstract

The present invention is directed to novel 1,4-diazepines, pharmaceutical compositions thereof, and the use thereof as inhibitors of HDM2-p53 interactions. Compounds have Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: R1, R2, R9, R10, Ra, Rd and M are defined herein; X is a bivalent radical of: an alkane, a cycloalkane, an optionally-substituted arene, an optionally-substituted heteroarene, an optionally-substituted arylalkane or an optionally-substituted heteroarylalkane; and R3 is —CO2Rd, —CO2M, —OH, —NHRd, —SO2Rd, —NHCONHRd, optionally-substituted amidino or optionally-substituted guanidino; or R3—X— is hydrogen or an electron pair; R4 is oxygen or —NR9R10; R5 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted; and R6, R7 and R8 are independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkylalkyl, aralkyl or heteroarylalkyl, each of which is optionally substituted; or R6 and R7, together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic ring optionally substituted 1 to 3 times with Ra.

Claims62

Dependent claims

A compound of Formula II:

or a pharmaceutically acceptable salt thereof;
wherein:
each instance of Ra is independently halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cyano, C3-8 cycloalkyl, hydroxy, C1-6 alkoxy, carboxy, (C1-6 alkoxy)carbonyl, C1-6 acyl, carbamoyl, (C1-6 alkyl)aminocarbonyl, alkylthio, amino or nitro;
n is 0;
or n is 1 and Ra occurs at the 7- or 8-position;
or n is 2 and Ra occurs at the 7- and 8-positions;
X is a bivalent radical of:
a C1-6 alkane, an optionally-substituted C6-10 arene, an optionally-substituted 5- to 7-membered heteroarene wherein 1 or 2 ring atoms are heteroatoms, an optionally-substituted (C6-10 aryl)C1-6 alkane, or an optionally-substituted heteroaryl(C1-6) alkane in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms;
R3 is —CO2Rd or —CO2M, where Rd is hydrogen, C1-6 alkyl or optionally-substituted C3-8 cycloalkyl, and M is a cation;
R5 is C3-8 cycloalkyl, C6-10 aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C3-8 cycloalkyl)alkyl, (C6-10 aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;
R6 is C3-8 cycloalkyl, C6-10 aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C3-8 cycloalkyl)alkyl, (C6-10 aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;
R7 is hydrogen, C1-6 alkyl, C3-8 cycloalkyl or (C3-8 cycloalkyl)alkyl;
and
R8 is hydrogen or C1-6 alkyl.

11 more elements

A compound of Formula III:

or a pharmaceutically acceptable salt thereof;
wherein:
each instance of Ra is independently halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cyano, C3-8 cycloalkyl, hydroxy, C1-6 alkoxy, carboxy, (C1-6 alkoxy)carbonyl, C1-6 acyl, carbamoyl, (C1-6 alkyl)aminocarbonyl, amino, alkylthio or nitro;
n is 0;
or n is 1 and Ra occurs at the 7- or 8-position;
or n is 2 and Ra occurs at the 7- and 8-positions;
R5 is C3-8 cycloalkyl, C6-10 aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C3-8 cycloalkyl)alkyl, (C6-10 aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;
R6 is C3-8 cycloalkyl, C6-10 aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C3-8 cycloalkyl)alkyl, (C6-10 aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;
R7 is hydrogen, C1-6 alkyl, C3-8 cycloalkyl or (C3-8 cycloalkyl)alkyl;
R8 is hydrogen or C1-6 alkyl;
R9 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, hydroxy(C1-6) alkyl, amino(C1-6) alkyl, carboxy(C1-6) alkyl, (C1-6 alkoxy)carbonyl, (C1-6 alkoxy)carbonyl(C1-6) alkyl, carbamoyl, carbamoyl(C1-6) alkyl, (C1-6 alkylamino)carbonyl or (C1-6 alkylamino)carbonyl(C1-6) alkyl;
and
R10 is hydrogen or C1-6 alkyl.

10 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/829,040Filed 21 Apr 2004 · us provisional application
Priority: 25 Apr 2003
Published: US 2004/0220179 A14 Nov 2004
Granted: 3 Oct 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 243/14
Condensed with carbocyclic rings or ring systems: 1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
A61P 35/00
Antineoplastic agents
A61P 37/02
Drugs for immunological or allergic disorders: immunomodulators
C07D
Heterocyclic compounds