Substituted Tetracycline Compounds

A substituted tetracycline compound of formula II:

• wherein
• X is CHC(R13Y′Y), CR6′R6, C═CR6′R6, S, NR6, or O;
• J is NR7mR7n, OR7o or heteroaryl;
• R2, R2′, R4′, R4a and R4b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, hetero aromatic or a prodrug moiety;
• R3, R10, R11 and R12 are each hydrogen or a prodrug moiety;
• R4 is NR4aR4b, alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
• R5 and R5′ are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
• R6 and R6′ are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
• R7l, R7m, R7n and R7o are each independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, amino, alkylamino, amino alkyl, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy;
• R8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
• R9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, aminoalkyl, amido, arylalkenyl, arylalkynyl, thionitroso or —(CH2)0-3(NR9c)0-1C(═Z′)ZR9a;
• Z is CR9dR9e, S, NR9b or O;
• Z′ is O, S, or NR9f;
• R9a, R9b, R9c, R9d, R9e and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
• and
• Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of formula IIIa:

• wherein
• R4p is —N(CH3)2 or hydrogen;
• R7p′ is hydrogen, amino, acyl, heteroaryl, aminoalkyl;
• R10a′ is hydrogen, heteroaryl, alkoxycarbonyl, carboxylate, cyano, alkyl or alkoxy;
• and pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of formula IVa:

• wherein
• L* is O, NH or S;
• *M is N, CH or CR7ps″;
• R7ps″ is aminoalkyl;
• and pharmaceutically acceptable salts thereof.

A compound of formula Va:

• wherein
• Q is —CH2 or —C+CH2;
• R4 is hydrogen;
• R4′ is hydrogen or alkylamino;
• R5a′ is hydrogen or hydroxyl;
• R7qa is —N(CH3)2 or hydrogen;
• R9q is CR9g′NR9h′ or CR9j′NR9k′R9l′;
• R9g′, R9h′, R9i′, Rj′, R9k′ and R9l′ are each independently hydrogen, alkyl, hydroxyl, amino, urea or alkoxy, or R9k′ and R9l′ are joined to form a ring;
• and pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of formula VI:

• wherein
• X is CHC(R13Y′Y), CR6′R6, C═CR6′R6, S, NR6, or O;
• p is a single bond or a double bond;
• Q is CR7s when p is a double bond or Q is CR7s′R7s″ when p is a single bond;
• R2, R2′, R4′, R4a and R4b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R3, R10, R11 and R12 are each hydrogen or a prodrug moiety;
• R4 is NR4aR4b, alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
• R5 and R5′ are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
• R6 and R6′ are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
• R7s, R7s′ and R7s″ are each hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, aminoalkyl, alkylamino, aryl, acyl, arylalkyl, alkyl carbonyloxy, or arylcarbonyloxy;
• R8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
• R9 is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, aminoalkyl, amido, arylalkenyl, aryldkynyl, thionitroso —(CH2)0-3(NR9c)0-1C(═Z′)ZR9a;
• Z is CR9dR9e, S, NR9b or O;
• Z′ is O, S, or NR9f;
• R9a, R9b, R9c, R9d, R9e and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
• R13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
• and
• Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of formula (VIIa):

• wherein
• X is CR6*′R6*;
• Rs* is hydrogen;
• R5*′ is hydrogen or hydroxyl;
• R6*′ is hydrogen or alkyl;
• R6* is hydrogen;
• R7r* is hydrogen, alkyl, hetero, acyl or alkylamino;
• R9m* is aminoalkyl, a heterocyclic moiety, aryl, —CONR9maR9mb;
• —COR9m*, —COOR9m*″, alkyl, cycloalkyl or hydrogen;
• R9m*′ is aminoalkyl, aryl, or alkyl;
• R9m*″ alkyl, alkoxyalkyl or hydroxyalkyl;
• R9ma and R9mb are each hydrogen, hydroxyl, alkyl, hydrocyalkyl, aryl or alkoxy or are linked to form a ring;
• and pharmaceutically acceptable salts thereof.

A substituted tetracycline compounds of formula (VIIIa);

• wherein
• T* is N or CH;
• R4* is hydrogen or alkylamino;
• R7ta* is hydrogen or halogen;
• R7tb* is hydrogen, —CH═CHCN, hydroxyalkyl, —CONR7tbaR7tbb;
• —NHCOR7tbd;
• R7tba and R7tbb are linked to form a ring;
• or R7tba is hydrogen, or alkyl and R7tbb is hydrogen, alkoxy, alkyl or —(CH2)xR7tbc;
• R7tbc is amino, alkyl, alkoxycarbonyl, alkoxy, hydroxyl, aryl, a heterocyclic moiety or alkoxycarbonylamino;
• R7tbd is —(CH2)yR7tbe, wherein R7tbe is amino;
• R7tc* is hydrogen, —O(CH2)zRtca;
• —CONHRtcb or —NHCOR7td;
• wherein Rtcb is —(CH2)wRtcc and Rtca and Rtcc are each amino;
• R7td is alkoxy;
• or
• R7tb* and R7tc* are linked to join a ring;
• w, x, y and z are each, independently, an integer of between 0 and 5;
• and
• pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of Formula (IXa):

• wherein
• R7u* is hydrogen;
• R7u*′ is alkyl or —(CH2)dR7ua, wherein d is an integer from between 0 and 5 and R7ua is an amino;
• or
• R7u* and R7u*′ are linked to form a ring;
• and pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of formula (Xa):

• wherein
• R7v* is alkyl, hydrogen or allyl;
• R7v*′ is arylalkyl or —COO(CH2)fR7va;
• or
• R7v* and R7v*′ are linked to form a ring;
• F is an integer from between 0 and 5;
• R7va is alkylcarbonyloxy;
• and pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of formula XIa:

• wherein
• R7w* is cycloalkyl;
• R9w* is hydrogen or —CH2NR9waR9wb.
• R9wa is alkyl and R9wb is allyl;
• and pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of formula (XII):

• wherein
• h is an integer from between 0 and 5;
• R9* is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, aminoalkyl, amido, arylalkenyl, arylalkynyl, thionitroso, alkylcarbonyl, arylcarbonyl, carboxylate, alkoxycarbonyl, aryloxycarbonyl or aminocarbonyl;
• and pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of formula XIV:

• wherein
• Z is —C═CH2 or —CH2;
• R5y is hydrogen or hydroxyl;
• R7y is hydrogen or dimethylamino;
• R9y is hydrogen;
• R9y′ is —CH2-cycloalkyl or —CH2-substituted aryl;
• or
• R9y and R9y′ are linked to join a substituted piperidinyl ring or a tetracyclopyridinyl ring;
• and pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of formula (XV):

• wherein
• R9z is hydrogen;
• R9z′ is halogen substituted alkyl;
• or
• R9z and R9z′ are linked to form a substituted piperidinyl ring;
• and pharmaceutically acceptable salts thereof.

A substituted tetracycline compound of formula XVI:

• wherein
• R9z* is —(CH2)tR9za;
• t is an integer from 0-1;
• R9za is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylhio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, aminoalkyl, amido, arylalkenyl, arylalkynyl, thionitroso, alkylcarbonyl, arylcarbonyl, carboxylate, alkoxycarbonyl, aryloxycarbonyl or aminocarbonyl;
• and pharmaceutically acceptable salts thereof.