Substituted 1,4-benzodiazepines and uses thereof

A compound of Formula I:

• or 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 iodo, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, ethynyl, acetylamino, methoxy, 3-chlorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 4-methylphenyl, 3-methylphenyl, 3-isopropylphenyl, 3-aminophenyl, 3,4-methylenedioxyphenyl, 4-hydroxycarbonylphenyl thien-3-yl, 4-methylthien-2-yl, furan-2-yl, 1H-pyrrol-3-yl, amino, 2-hydroxyethyl, hydroxymethyl, furan-3-yl, or vinyl;
• 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 compound of Formula I:

• or pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R2, 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 R1 and R2 are taken together to form —(CH2)u—, where u is 3–6, —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• R3 is hydrogen, alkyl, phenyl, fluoro, chloro, iodo or methyl;
• 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 compound of Formula I:

• or pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R2, 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 R1 and R2, or R2 and R3,-or R3 and R4 are taken together to form —(CH2)u—, where u is 3–6, —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• 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 trifluoromethylphenyl, halophenyl, C1-6 alkoxyphenyl, halo(C1-4)alkoxyphenyl, naphthyl, benzyloxyphenyl, phenoxyphenyl, dihydrobenzodioxinyl, trifluoromethyl-halophenyl, pyridyl, thienyl, C1-6 alkylthienyl, halothienyl, bithienyl, C1-6 alkylbenzothienyl, (halophenyl)furanyl, quinolinyl, biphenyl, indolyl, (trifluoromethylsulfanyl)phenyl, (trifluoromethylphenyl)furanyl, halo(C1-4)alkoxyphenyl, benzofuranyl, cyanophenyl, halopyridyl, (methylsulfanyl)phenyl, pyrrolidinylphenyl, C2-6 alkenyl(C3-7)cycloalkenyl, cubanyl or halocubanyl;
• 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 compound of Formula I:

• or pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R2, 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 R1 and R2, or R2 and R3, -or R3 and R4 are taken together to form —(CH2)u—, where u is 3–6, —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• 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 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 4-ethylphenyl, 4-trifluoromethoxyphenyl, 4-isopropylphenyl, phenyl, 4-methoxy-phenyl, naphthalen-2-yl, 4-tert-butylphenyl, 4-benzyloxyphenyl, 4-phenoxyphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 4-bromo-2-fluorophenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-chloro-3-fluorophenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-3-yl, 5-methylthien-2-yl, 3-methylthien-2-yl, 4-bromothien-2-yl, 5-[2,2′]bithienyl, 3-methylbenzo[b]thiophen-2-yl, 5-(2-chlorophenyl)-furan-2-yl, 5-(3-chlorophenyl)-furan-2-yl, quinolin-3-yl, biphen-4-yl, indol-2-yl, indol-3-yl, 4-trifluoromethylsulfanylphenyl, 5-(3-trifluoromethylphenyl)furan-2-yl, 4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-difluoromethoxyphenyl, benzofuran-2-yl, 4-cyanophenyl, 6-chloropyrid-3-yl, 4-methylsulfanylphenyl, 4-pyrrolidin-1-ylphenyl, 5-chlorothien-2-yl, 4-isopropenylcyclohex-1-enyl or 1-chlorocuban-4-yl;
• 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 compound of Formula I:

• or pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R2, 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 R1 and R2, or R2 and R3, or R3 and R4 are taken together to form —(CH2)u—, where u is 3–6, —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• 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, hetroaryl, cycloalkylalkyl, hetroarylalkyl, or a saturated or partially unsaturated hetrocycle, each of which is optionally substituted;
• 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 compound of Formula I:

• or pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R2, 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 R1 and R2, or R2 and R3, -or R3 and R4 are taken together to form —(CH2)u—, where u is 3–6, —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• 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, hetroaryl, cycloalkylalkyl, hetroarylalkyl, or a saturated or partially unsaturated hetrocycle, each of which is optionally substituted;
• R7 and R8 are independently hydrogen or alkyl;
• wherein R9 is optionally substituted C6-10 aryl or optionally substituted C6-10 ar(C1-6)alkyl;
• 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 compound of Formula I:

• or pharmaceutically acceptable salt thereof;
• wherein:
• X and Y are independently —C(O)—, —CH2— or —C(S)—;
• R1, R2, 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 R1 and R2, or R2 and R3, or R3 and R4 are taken together to form —(CH2)u—, where u is 3–6, —CH═CH—CH═CH— or —CH2CH═CHCH2—;
• 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, hetroaryl, cycloalkylalkyl, hetroarylalkyl, or a saturated or partially unsaturated hetrocycle, 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 —COORb or —CH2—COORb, where Rb is hydrogen or C1-6 alkyl;
• or R10 is —COOM, or —CH2—COOM, where M is Na+ or K+.