The present disclosure provides a benzene fused heterocyclic derivative of Formula (I): is a single or double bond; n is an integer of 0 or 1; A is CH.sub.2, CH(OH), or C(O); G is C or N; X is CH.sub.2, O, or C(O); Y is alkyl, aryl, or heterocyclic alkyl optionally substituted with at least one substituent independently selected from a group consisting of: H, halogen, alkyl, alkyl substituted with at least one halogen, aryl, aryl substituted with at least one halogen, NR.sub.y1R.sub.y2, OR.sub.y1, R.sub.y1C(O)R.sub.y3, C(O)R.sub.y1, C(O)OR.sub.y2, C(O)OR.sub.y2Ry3, NR.sub.y1C(O)R.sub.y2, NR.sub.y1C(O)NR.sub.y2R.sub.y3, NR.sub.y1C(O)OR.sub.y2R.sub.y3, NR.sub.y1C(O)R.sub.y2OR.sub.y3, C(O)NR.sub.y1(R.sub.y2R.sub.y3), C(O)NR.sub.y1(R.sub.y2OR.sub.y1), OR.sub.y2R.sub.y3, and OR.sub.y2OR.sub.y3, wherein each of R.sub.y1 and R.sub.y2 is independently selected from a group consisting of H, oxygen, alkyl, and aryl, and R.sub.y3 is aryl optionally substituted with at least one halogen; Z is NR.sub.z1R.sub.z2, NR.sub.z1R.sub.z3, OR.sub.z1, OR.sub.z1R.sub.z3, C(O)R.sub.z1R.sub.z3, C(O)OR.sub.z1R.sub.z3, NR.sub.z1C(O)R.sub.z2R.sub.z3, NR.sub.z1C(O)OR.sub.z2R.sub.z3, C(O)NR.sub.z1R.sub.z3, or OR.sub.z2OR.sub.z3, wherein each of R.sub.z1 and R.sub.z2 is independently selected from a group consisting of H, oxygen, alkyl and aryl, and R.sub.z3 is aryl optionally substituted with at least one substituent independently selected from a group consisting of halogen, OH, R.sub.zaCOOR.sub.zb, OR.sub.zaCOOR.sub.zb, R.sub.zaSO.sub.2R.sub.zb, R.sub.zaSO.sub.2NR.sub.zbR.sub.zcR.sub.zd, R.sub.zaC(O)R.sub.zbR.sub.zc, R.sub.zaC(O)NR.sub.zbR.sub.zcR.sub.zd, RZ.sub.aC(O)NR.sub.zbSO.sub.2R.sub.zc, wherein Rza is nil or alkyl, R.sub.zb is H or alkyl, each of R.sub.zb and R.sub.zc is independently selected from a group consisting of H, OH, alkyl, aryl, alkoxyl, or NR.sub.zbR.sub.zc is a nitrogen-containing heterocyclic alkyl ring, R.sub.zd is nil or a sulfonyl alkyl group.

##STR00001##

The present invention provides a process of producing a trifluoromethoxylated aryl or trifluoromethoxylated heteroaryl having the structure: ##STR00001##
wherein
A is an aryl or heteroaryl, each with or without substitution; and
R.sub.1 is H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), NH-(alkyl), N(alkyl).sub.2, NH-(alkenyl), NH-(alkynyl) NH-(aryl), NH-(heteroaryl), O-(alkyl), O-(alkenyl), O-(alkynyl), O-(aryl), O-(heteroaryl); S-(alkyl), S-(alkenyl), S-(alkynyl), S-(aryl), or S-(heteroaryl), comprising:
(a) reacting a compound having the structure: ##STR00002##
with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure: ##STR00003##
and
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure: ##STR00004##

The present invention provides a process of producing a trifluoromethoxylated aryl or trifluoromethoxylated heteroaryl having the structure: ##STR00001##
wherein
A is an aryl or heteroaryl, each with or without substitution; and
R.sub.1 is H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), NH-(alkyl), N(alkyl).sub.2, NH-(alkenyl), NH-(alkynyl) NH-(aryl), NH-(heteroaryl), O-(alkyl), O-(alkenyl), O-(alkynyl), O-(aryl), O-(heteroaryl); S-(alkyl), S-(alkenyl), S-(alkynyl), S-(aryl), or S-(heteroaryl), comprising:
(a) reacting a compound having the structure: ##STR00002##
with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure: ##STR00003##
and
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure: ##STR00004##

Inhibitors of mTOR, MEK, JAK and PI3K and compositions containing the same are disclosed. Methods of using the inhibitors in the treatment of a variety of diseases and conditions wherein inhibition of one or more of mTOR, MEK, JAK and PI3K provides a benefit also are disclosed. Methods of using chemical attachment moieties and linkers for the purposes of modifying compound solubility and/or lymphatic absorption are also disclosed.

Inhibitors of mTOR, MEK, JAK and PI3K and compositions containing the same are disclosed. Methods of using the inhibitors in the treatment of a variety of diseases and conditions wherein inhibition of one or more of mTOR, MEK, JAK and PI3K provides a benefit also are disclosed. Methods of using chemical attachment moieties and linkers for the purposes of modifying compound solubility and/or lymphatic absorption are also disclosed.

Disclosed are compounds of formulae: (I), and (II) and pharmaceutically acceptable salts thereof, wherein the variables, R, R.sub.1, R.sub.2, R.sub.3, R.sub.21, R.sub.22, R.sub.23, R.sub.34, R.sub.37, R.sub.33, R.sub.39, D, Q, Y, X, X.sub.1, X.sub.3, and X.sub.4 are defined herein. These compounds are useful for treating Gram-negative bacteria infections. ##STR00001##

The present invention provides a compound having the structure: ##STR00001## wherein R.sub.1 is halogen, NR.sub.5R.sub.6, NR.sub.5C(O)R.sub.6, NHC(O)OR.sub.7, OR.sub.7, NO.sub.2, CN, SR.sub.7, SO.sub.2R.sub.7, CO.sub.2R.sub.7, CF.sub.3, SOR.sub.7, POR.sub.7, C(S)R.sub.7, C(O)NR.sub.5R.sub.6, CH.sub.2C(O)NR.sub.5R.sub.6, C(NR.sub.5)R.sub.6, P(O)(OR.sub.5)(OR.sub.6), P(OR.sub.5)(OR.sub.6), C(S)R.sub.7, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, aryl, heteroaryl, or heterocyclyl, wherein R.sub.5, R.sub.6, and R.sub.7 and are each, independently, H, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl; Ar.sub.1 is phenyl or thiophene; wherein when Ar.sub.1 is phenyl, then R.sub.1 is other than C(O)NR.sub.5R.sub.6, where one of R.sub.5 or R.sub.6 is phenyl or quinoline and the other of R.sub.5 or R.sub.6 is hydroxyalkyl, or where one of R.sub.5 or R.sub.6 is quinoline and the other of R.sub.5 or R.sub.6 is H; and wherein when Ar.sub.1 is phenyl, then R.sub.1 is other than NR.sub.5C(O)R.sub.6, where one of R.sub.5 is H and R.sub.6 is quinoline,
or a pharmaceutically acceptable salt thereof.

The present invention provides a compound having the structure: ##STR00001## wherein R.sub.1 is halogen, NR.sub.5R.sub.6, NR.sub.5C(O)R.sub.6, NHC(O)OR.sub.7, OR.sub.7, NO.sub.2, CN, SR.sub.7, SO.sub.2R.sub.7, CO.sub.2R.sub.7, CF.sub.3, SOR.sub.7, POR.sub.7, C(S)R.sub.7, C(O)NR.sub.5R.sub.6, CH.sub.2C(O)NR.sub.5R.sub.6, C(NR.sub.5)R.sub.6, P(O)(OR.sub.5)(OR.sub.6), P(OR.sub.5)(OR.sub.6), C(S)R.sub.7, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, aryl, heteroaryl, or heterocyclyl, wherein R.sub.5, R.sub.6, and R.sub.7 and are each, independently, H, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl; Ar.sub.1 is phenyl or thiophene; wherein when Ar.sub.1 is phenyl, then R.sub.1 is other than C(O)NR.sub.5R.sub.6, where one of R.sub.5 or R.sub.6 is phenyl or quinoline and the other of R.sub.5 or R.sub.6 is hydroxyalkyl, or where one of R.sub.5 or R.sub.6 is quinoline and the other of R.sub.5 or R.sub.6 is H; and wherein when Ar.sub.1 is phenyl, then R.sub.1 is other than NR.sub.5C(O)R.sub.6, where one of R.sub.5 is H and R.sub.6 is quinoline,
or a pharmaceutically acceptable salt thereof.

Disclosed are compounds of formulae (I), (II), and (II)I: and pharmaceutically acceptable salts thereof, wherein the variables, R, R.sub.1, R.sub.2, R.sub.3, R.sub.101, L, D, Q, Y, X, and Z are defined herein. These compounds are useful for treating Gram-negative bacteria infections. ##STR00001##

Disclosed are compounds of formulae (I), (II), and (II)I: and pharmaceutically acceptable salts thereof, wherein the variables, R, R.sub.1, R.sub.2, R.sub.3, R.sub.101, L, D, Q, Y, X, and Z are defined herein. These compounds are useful for treating Gram-negative bacteria infections. ##STR00001##