Substituted 1,4-benzodiazepines and uses thereof

A pharmaceutical composition, comprising a compound of Formula I:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2—or —C(S)—;
• R1, R3, and R4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl:
• or R3 and R4 are taken together to form —(CH2)u—, where u is 3-6. —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• R2 is hydrogen, halo, C1-4 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, acetylamino, C1-6 alkoxy, phenyl, halophenyl, hydroxyphenyl, C1-6 alkoxyphenyl, C1-6 alkylphenyl, aminophenyl, C1-6 alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C1-6 alkylthienyl, furanyl, pyrrolyl, amino, C1-6 hydroxyalkyl or cyano;
• R5 is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl:
• R6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;
• R7 and R8 are independently hydrogen or alkyl:
• R9 is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted;
• and
• R10 is —(CH2)n—CO2Rb, —(CH2)m—CO2M, —(CH2)i—OH or —(CH2)j—CONRcRd where
• Rb is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;
• M is a cation;
• Rc and Rd are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle;
• and
• n is 0-8, m is 0-8, i is 1-8 and j is 0-8;
• and
• (b) one or more pharmaceutically-acceptable excipients, further comprising:
• (c) at least one additional substance selected from the group consisting of synergists, stabilizing substances, antineoplastic agents, anticancer agents, and cytostatic agents.

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 a compound of Formula I:
• or a pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R3, and R4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;
• or R3 and R4 are taken together to form —(CH2)u—, where u is 3-6, —CH═CH—CH═CH— or —CH2CH═CHCH2.
• R2 is hydrogen, halo, C1-4 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, acetylamino, C1-6 alkoxy, phenyl, halophenyl, hydroxyphenyl C1-6 alkoxyphenyl, C1-6 alkylphenyl, aminophenyl, C1-6 alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C1-6alkylthienyl, furanyl, pyrrolyl, amino, C1-6 hydroxyalkyl or cyano:
• R5 is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;
• R6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;
• R7 and R8 are independently hydrogen or alkyl;
• R9 is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted;
• and
• R10 is —(CH2)n—CO2Rb, —(CH2)m, —CO2M, —(CH2)i—OH or —(CH2)j—CONRcRd where
• Rb is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;
• M is a cation:
• Rc and Rd are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle;
• and
• n is 0-8, m is 0-8, i is 1-8 and j is 0-8.

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:

• or a pharmaceutically acceptable salt thereof, wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R3, and R4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;
• or R3 and R4 are taken together to form —(CH2)u—, where u is 3-6, —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• R2 is hydrogen, halo, C1-4 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl acetylamino, C1-6 alkoxy, phenyl, halophenyl, hydroxyphenyl, C1-6 alkoxyphenyl, C1-6 alkylphenyl, aminophenyl, C1-6 alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C1-6alkylthienyl, furanyl, pyrrolyl, amino, C1-6 hydroxyalkyl or cyano;
• R5 is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;
• R6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;
• R7 and R8 are independently hydrogen or alkyl;
• R9 is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted;
• and
• R10 is —(CH2)n—CO2Rb, —(CH2)m—CO2M, —(CH2)i—OH or —(CH2)j—CONRcRd where
• Rb is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;
• M is a cation;
• Rc and Rd are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle;
• and
• n is 0-8, m is 0-8, i is 1-8 and j is 0-8.

A method of inducing apoptosis, comprising contacting an animal with a composition comprising a pharmaceutically-effective amount of at least one compound of Formula I:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R3, and R4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;
• or R3 and R4 are taken together to form —(CH2)u—, where u is 3-6, —CH═CH—CH═CH— or —CH2CH=CHCH2—;
• R2 is hydrogen, halo, C1-4 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, acetylamino, C1-6 alkoxy, phenyl, halophenyl, hydroxyphenyl, C1-6 alkoxyphenyl, C1-6 alkylphenyl, aminophenyl, C1-6 alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C1-6 alkylthienyl, furanyl, pyrrolyl, amino, C1-6 hydroxyalkyl or cyano;
• R5 is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;
• R6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;
• R7 and R8 are independently hydrogen or alkyl;
• R9 is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted;
• and
• R10 is —(CH2)n—CO2Rb, —(CH2)m—CO2M, —(CH2)i—OH or —(CH2)j—CONRcRd where
• Rb is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;
• M is a cation;
• Rc and Rd are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle;
• and
• n is 0-8, m is 0-8, i is 1-8 and j is 0-8.

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 I:
• or a pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R3, and R4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;
• or R3 and R4 are taken together to form —(CH2)u—, where u is 3-6. —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• R2 is hydrogen, halo, C1-4 alkyl, C3-7 cycloalkyl, C2-6 alkelyl, C2-6 alkynyl, acetylamino, C1-6 alkoxy, phenyl, halophenyl, hydroxyphenyl C1-6 alkoxyphenyl, C1-6 alkylphenyl, aminophenyl, C1-6 alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C1-6 alkylthienyl, furanyl, pyrrolyl, amino, C1-6 hydroxyalkyl or cyano;
• R5 is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;
• R6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;
• R7 and R8 are independently hydrogen or alkyl;
• R9 is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted;
• and
• R10 is —(CH2)n—CO2Rb , —(CH2)m—CO2M, —(CH2)i—or —(CH2)j—CONRcRd where
• Rb is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;
• M is a cation;
• Rc and Rd are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle;
• and
• n is 0-8, m is 0-8, i is 1-8 and j is 0-8.

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 I:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R3, and R4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;
• or R3 and R4 are taken together to form —(CH2)u—, where u is 3-6, —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• R2 is hydrogen, halo, C1-4 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, acetylamino, C1-6 alkoxy, phenyl, halophenyl, hydroxyphenyl. C1-6 alkoxyphenyl, C1-6 alkylphenyl, aminophenyl, C1-6 alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C1-6 alkylthienyl, furanyl, pyrrolyl, amino, C1-6 hydroxyalkyl or cyano;
• R5 is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;
• R6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;
• R7 and R8 are independently hydrogen or alkyl;
• R9 is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted;
• and
• R10 is —(CH2)n—CO2Rb, —(CH2)m—CO2M, —(CH2)i—OH or —(CH2)j—CONRcRd where
• Rb is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;
• M is a cation;
• Rc and Rd are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle;
• and
• n is 0-8, m is 0-8, i is 1-8 and j is 0-8.

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 I:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R3, and R4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl;
• or R3 and R4 are taken together to form —(CH2)u—, where u is 3-6, —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• R2 is hydrogen, halo, C1-4 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, acetylamino, C1-6 alkoxy, phenyl, halophenyl, hydroxyphenyl, C1-6 alkoxyphenyl, C1-6 alkylphenyl, aminophenyl, C1-6 alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C1-6 alkylthienyl, furanyl, pyrrolyl, amino, C1-6 hydroxyalkyl or cyano;
• R5 is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;
• R6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;
• R7 and R8 are independently hydrogen or alkyl;
• R9 is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted;
• and R10 is —(CH2)n—CO2Rb, —(CH2)m—CO2M, —(CH2)i—OH or —(CH2)j—CONRcRd where
• Rb is hydrogen, alkyl, optionally substituted cycloalkyl, or optionally substituted, saturated or partially unsaturated heterocycle;
• M is a cation:
• Rc and Rd are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and an optionally substituted, saturated or partially unsaturated heterocycle;
• and
• n is 0-8, m is 0-8, i is 1-8 and j is 0-8.