US 2006/0235007 A1 · Substituted 1,4-diazepines and uses thereof

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.

Claims20

Dependent claims

1-56. (canceled)

A pharmaceutical composition, comprising:

(a) a compound of Formula II:
or a solvate, hydrate or 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 alkyl, 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,
or a salt or prodrug thereof;
(b)) one or more pharmaceutically-acceptable excipients;
and
(c) at least one additional substance selected from the group consisting of synergists, stabilizing substances, antineoplastic agents, anticancer agents, and cytostatic agents.

16 more elements

A method of inhibiting the binding of p53 to a protein encoded by hdm2, comprising

contacting p53 or one or more proteins encoded by hdm2, with one or more compounds of Formula II:
or a solvate, hydrate or 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;
or a salt or prodrug thereof.

13 more elements

A method of treating a condition that results from the inhibition of one or more functions of a cellular protein that induces apoptosis, induces cellular death, or regulates the cell cycle by an HDM2 protein, comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a compound of Formula II:

or a solvate, hydrate or 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;
or a salt or prodrug thereof.

12 more elements

A method of inducing apoptosis, comprising

contacting an animal with a composition comprising a pharmaceutically-effective amount of at least one compound of Formula II:
or a solvate, hydrate or 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;
or a salt or prodrug thereof.

13 more elements

A method of preventing or treating cancer or a condition that results from the uncontrolled proliferation of cells, comprising contacting an animal with (a) a composition comprising a pharmaceutically-effective amount of an antineoplastic agent, and (b) a compound of Formula II:

or a solvate, hydrate or 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;
or a salt or prodrug thereof.

12 more elements

A method of treating an inflammatory condition, comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a compound of Formula II:

or a solvate, hydrate or 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 alkyl, 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;
or a salt or prodrug thereof.

12 more elements

A method of treating an autoimmune disease or condition, comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a compound of Formula II:

or a solvate, hydrate or 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;
or a salt or prodrug thereof.

12 more elements

Dependencies are inferred from the claim text.

Substituted 1,4-diazepines and uses thereof

Life of this patent

Substituted 1,4-diazepines and uses thereof

Life of this patent

Abstract

Claims20