Imidazolothiazole compounds for the treatment of disease

A pharmaceutical composition comprising a compound and hydroxypropyl-beta-cyclodextrin, wherein the compound corresponds to formula (II):

• wherein:
• X is —S—, —N(R5)— or —O—;
• X1, X2, X3, X4 are each independently selected from —C(R10)—, —C(R10)2—, —N—, —N(R16)—, —O— and —S—, provided that no more than two of X1, X2, X3 and X4 are heteroatoms and wherein no two adjacent X's are both —O— or —S—;
• and each R10 is independently selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
• each R16 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
• n is an integer from 1 to 3;
• R0 is hydrogen, halo, hydroxy, optionally substituted alkyl, or optionally substituted alkoxy;
• each R1 is independently selected from the group consisting of halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, —R6OR7, —R6SR7, —R6S(O)tR8, —R6N(R7)2, —R6—OR9OR7, —R6CN, —R6C(O)R7, —R6C(S)R7, —R6C(NR7)R7, —R6C(O)OR7, —R6C(S)OR7, —R6C(NR7)OR7, —R6C(O)N(R7)2, —R6C(S)N(R7)2, —R6C(NR7)N(R7)2, —R6C(O)N(R7)R9N(R7)2, —R6C(O)SR8, —R6C(S)SR8, —R6C(NR7)SR8, —R6S(O)tOR7, —R6S(O)tN(R7)2, —R6S(O)tN(R7)N(R7)2, —R6S(O)tN(R7)N═C(R7)2, —R6S(O)tN(R7)C(O)R8, —R6S(O)tN(R7)C(O)N(R7)2, —R6S(O)tN(R7)C(NR7)N(R7)2, —R6N(R7)C(O)R8, —R6N(R7)C(O)OR8, —R6N(R7)C(O)SR8, —R6N(R7)C(NR7)SR8, —R6N(R7)C(S)SR8, —R6N(R7)C(O)N(R7)2, —R6N(R7)C(NR7)N(R7)2, —R6N(R7)C(S)N(R7)2, —R6N(R7)S(O)tR8, —R6OC(O)R8, —R6OC(NR7)R8, —R6OC(S)R8, —R6OC(O)OR8, —R6OC(NR7)OR8, —R6OC(S)OR8, —R6OC(O)SR8, —R6OC(O)N(R)2, —R6OC(NR7)N(R7)2, —R6OC(S)N(R7)2, —R6OR9N(R7)2, —R6SR9N(R7)2, —R6N(R7)R9N(R7)2, —R6C(O)R9C(O)R7, —R6C(O)R9C(S)R7, —R6C(O)R9C(NR7)R7, —R6C(O)R9C(O)OR7, —R6C(O)R9C(S)OR7, —R6C(O)R9C(NR7)OR7, —R6C(O)R9C(O)N(R7)2, —R6C(O)R9C(S)N(R7)2, —R6C(O)R9C(NR7)N(R7)2, —R6C(O)R9C(O)SR8, —R6C(O)R9C(S)SR8, —R6C(O)R9C(NR7)SR8, —R6OR9OR7, —R6C(O)R9N(R7)R9N(R7)2, —R6C(O)R9N(R7)R9OR7 and —R6C(O)N(R7)R9OR7;
• each R2 is independently selected from hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, and —N(R12)S(O)tR13;
• R3 is hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, or —N(R12)S(O)tR13;
• t is 1 or 2;
• and
• each R5 is independently hydrogen, or optionally substituted alkyl;
• each R6 is independently a direct bond, an optionally substituted alkylene chain, or an optionally substituted alkenylene chain;
• each R7 is independently selected from (i) or (ii) below
• (i) R7 is selected from a group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or
• (ii) two (R7)s together with the atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl;
• R8 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• each R9 is independently an optionally substituted alkylene chain or an optionally substituted alkenylene chain;
• each R12 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• and
• R13 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or as a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a compound and cyclodextrin, wherein the compound corresponds to formula (I),

• wherein
• bond b is a single bond or double bond;
• X is —S—, —N(R5)— or —O—;
• Z1 and Z3 are each independently —N(R5)—, —(CH2)q—, —O—, —S—, or a direct bond;
• Z2 is —C(O)— or —C(S)—;
• m is an integer from 1 to 2;
• n is an integer from 1 to 3;
• each q is independently an integer from 1 to 4;
• R0 is hydrogen, halo, hydroxy, optionally substituted alkyl, or optionally substituted alkoxy;
• each R1 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, —R6OR7, —R6SR7, —R6S(O)tR8, —R6N(R7)2, —R6—OR9OR7, —R6CN, —R6C(O)R7, —R6C(S)R7, —R6C(NR7)R7, —R6C(O)OR7, —R6C(S)OR7, —R6C(NR7)OR7, —R6C(O)N(R7)2, —R6C(S)N(R7)2, —R6C(NR7)N(R7)2, —R6C(O)N(R7)R9N(R7)2, —R6C(O)SR8, —R6C(S)SR8, —R6C(NR7)SR8, —R6S(O)tOR7, —R6S(O)tN(R7)2, —R6S(O)tN(R7)N(R7)2, —R6S(O)tN(R7)N═C(R7)2, —R6S(O)tN(R7)C(O)R8, —R6S(O)tN(R7)C(O)N(R7)2, —R6S(O)tN(R7)C(NR7)N(R7)2, —R6N(R7)C(O)R8, —R6N(R7)C(O)OR8, —R6N(R7)C(O)SR8, —R6N(R7)C(NR7)SR8, —R6N(R7)C(S)SR8, —R6N(R7)C(O)N(R7)2, —R6N(R7)C(NR7)N(R7)2, —R6N(R7)C(S)N(R7)2, —R6N(R7)S(O)tR8, —R6OC(O)R8, —R6OC(NR7)R8, —R6OC(S)R8, —R6OC(O)OR8, —R6OC(NR7)OR8, —R6OC(S)OR8, —R6OC(O)SR8, —R6OC(O)N(R7)2, —R6OC(NR7)N(R7)2, —R6OC(S)N(R7)2, —R6OR9N(R7)2, —R6SR9N(R7)2, —R6N(R7)R9N(R7)2, —R6C(O)R9C(O)R7, —R6C(O)R9C(S)R7, —R6C(O)R9C(NR7)R7, —R6C(O)R9C(O)OR7, —R6C(O)R9C(S)OR7, —R6C(O)R9C(NR7)OR7, —R6C(O)R9C(O)N(R7)2, —R6C(O)R9C(S)N(R7)2, —R6C(O)R9C(NR7)N(R7)2, —R6C(O)R9C(O)SR8, —R6C(O)R9C(S)SR8, —R6C(O)R9C(NR7)SR8, —R6OR9OR7, —R6C(O)R9N(R7)R9N(R7)2, —R6C(O)R9N(R7)R9OR7 and —R6C(O)N(R7)R9OR7;
• t is 1 or 2;
• each R2 is independently selected from hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, and —N(R12)S(O)tR13;
• R3 is hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, or —N(R12)S(O)tR13;
• R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, and optionally substituted aryl;
• each R5 is independently hydrogen, or optionally substituted alkyl;
• each R6 is independently a direct bond, an optionally substituted alkylene chain, or an optionally substituted alkenylene chain;
• each R7 is independently selected from (i) or (ii) below
• (i) R7 is selected from a group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or
• (ii) two R7 groups together with the atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl;
• R8 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• each R9 is independently an optionally substituted alkylene chain or an optionally substituted alkenylene chain;
• each R12 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• and
• R13 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• with the proviso that,
• (i) if —Z1Z2Z3R4 is —NHC(O)Bu then R1 may not be ethoxy;
• (ii) if —Z1Z2Z3R4 is —C(O)ORp, where Rp is methyl, or ethyl, then R1 may not be hydroxyl, methoxy or methoxycarbonyl;
• (iii) if —Z1Z2Z3R4 is —NHC(O)C(O)ORp, where Rp is methyl, or ethyl, then R1 may not be methoxy;
• (iv) if —Z1Z2Z3R4 is —CH2C(O)ORp, where Rp is methyl, or ethyl, then R1 may not be methoxy or ethoxy;
• (v) if —Z1Z2Z3R4 is —OC(O)CH3, then R1 may not be methyl, methoxy or ethoxy;
• as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or as a pharmaceutically acceptable salt thereof.