RAF kinase modulator compounds and methods of use thereof

A compound having formula (I):

• or a pharmaceutically acceptable salt, solvate, clathrate or hydrate thereof, wherein
• X is O or S(O)t;
• Ra is O or S;
• each R1 is independently selected from (i) or (ii) below:
• i) each R1 is independently selected from a group consisting of halo, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —R6OR7, —R6SR7, —R6S(O)tR8, —R6N(R7)2, —R6OR9OR7, —R6OR9SR7, —R6OR9S(O)tR8, —R6OR9S(O)tN(R7)2, —R6OR9N(R7)2, —R6SR9OR7, —R6SR9SR7, —R6SR9N(R7)2, —R6N(R7)R9N(R7)2, —R6N(R7)R9OR7, —R6N(R7)R9SR7, —R6CN, —R6C(O)R7, —R6C(O)OR7, —R6C(O)OR9OR7, —R6C(O)N(R7)2, —R6C(O)N(R7)OR7, —R6C(NR7)N(R7)2, —R6C(O)N(R7)R9N(R7)2, —R6C(O)N(R7)R9OR7, —R6C(O)N(R7)R9SR7, —R6C(O)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)N(R7)2, —R6N(R7)C(NR7)N(R7)2, —R6N(R7)C(S)N(R7)2, and —R6N(R7)S(O)tR8, or
• ii) any two adjacent R1 groups together form an alkylenedioxy group;
• each R6 is independently a direct bond, alkylene chain or alkenylene chain;
• each R7 is independently selected from (i) or (ii) below:
• (i) each R7 is selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or
• (ii) two R7 groups together with the N atom to which they are attached form a heterocyclyl or heteroaryl;
• each R8 is independently selected from a group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl;
• each R9 is independently an alkylene chain or an alkenylene chain;
• R2 is hydrogen, halo, alkyl, amino or alkylamino;
• R3 is halo or alkyl;
• R4 and R5 are selected as follows:
• a) R4 and R5 are each independently hydrogen or alkyl, or
• b) R4 and R5, together with the N atom to which they are attached, form an oxo-substituted heterocyclyl;
• R11 is isoxazolyl;
• m is an integer from 0 to 4;
• n is an integer from 0 to 4;
• t is an integer from 0 to 2;
• R1, R2, R3, R4, R5, R6, R7, R8, R9 and R11 are optionally substituted with one, two or three substituents independently selected from Q1, wherein Q1 is nitro, halo, azido, cyano, oxo, thioxo, imino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, —RuORx, —RuORuORx, —RuORuN(Ry)(Rz), —Ru N(Ry)(Rz), —RuSRx, —RuC(J)Rx, —RuC(J)ORx, —RuC(J)N(Ry)(Rz), —RuC(J)SRx, —RuS(O)tRw, —RuOC(J)Rx, —RuOC(J)ORx, —RuOC(J)N(Ry)(Rz), —RuOC(J)SRx, —RuN(Rx)C(J)Rx, —RuN(Rx)C(J)ORx, —RuN(Rx)C(J)N(Ry)(Rz), —RuN(Rx)C(J)SRx, —RuSi(Rw)3, —RuN(Rx)S(O)tRw, —RuN(Rx)RuS(O)2Rw, —RuN(Rx)S(O)2N(Ry)(Rz), —RuS(O)2N(Ry)(Rz), —RuP(O)(Rv)2, —RuOP(O)(Rv)2, —RuC(J)N(Rx)S(O)2Rw, —RuC(J)N(Rx)N(Rx)S(O)2Rw, —RuC(Rx)═N(ORx) or —RuC(Rx)═NN(Ry)(Rz);
• when Q1 is alkyl, alkenyl or alkynyl, each Q1 is optionally substituted with halo, cyano, hydroxy or alkoxy;
• when Q1 is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each Q1 is optionally substituted with halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkoxy or hydroxyl;
• each Ru is independently alkylene or a direct bond;
• each Rv is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, —ORx or —N(Ry)(Rz);
• Rw is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
• each Rx is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
• Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
• Ry and Rz, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl;
• and
• J is O, NRx or S.