The present disclosure relates generally to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.

The present disclosure relates generally to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.

Compounds and pharmaceutically acceptable salts and solvates thereof are described. The compounds relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology and organic chemistry.

Compounds and pharmaceutically acceptable salts and solvates thereof are described. The compounds relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology and organic chemistry.

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: ##STR00001##
wherein R.sub.1, is a group of formula (IA): —Ar.sup.1-(Alk.sup.1).sub.p-(Z).sub.r-(Alk.sup.2).sub.s-Q, wherein in any compatible combination Ar.sup.1 is an optionally substituted aryl or heteroaryl radical, Alk.sup.1 and Alk.sup.2 are optionally substituted divalent C.sub.1-C.sub.6 alkylene or C.sub.2-C.sub.6 alkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NR.sup.A—, —C(═S) NR.sup.A—, —SO.sub.2NR.sup.A—, —NR.sup.AC(═O)—, —NR.sup.ASO.sub.2— or —NR.sup.A— wherein R.sup.A is hydrogen or C.sub.1-C.sub.6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R.sub.2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk.sup.1)p-(Z).sub.r-(Alk.sup.2).sub.s-Q wherein Q, Alk.sup.1, Alk.sup.2, Z, p, r and s are as defined above in relation to group (IA); and R.sub.3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkenyl, or C.sub.1-C.sub.6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: ##STR00001##
wherein R.sub.1, is a group of formula (IA): —Ar.sup.1-(Alk.sup.1).sub.p-(Z).sub.r-(Alk.sup.2).sub.s-Q, wherein in any compatible combination Ar.sup.1 is an optionally substituted aryl or heteroaryl radical, Alk.sup.1 and Alk.sup.2 are optionally substituted divalent C.sub.1-C.sub.6 alkylene or C.sub.2-C.sub.6 alkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NR.sup.A—, —C(═S) NR.sup.A—, —SO.sub.2NR.sup.A—, —NR.sup.AC(═O)—, —NR.sup.ASO.sub.2— or —NR.sup.A— wherein R.sup.A is hydrogen or C.sub.1-C.sub.6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R.sub.2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk.sup.1)p-(Z).sub.r-(Alk.sup.2).sub.s-Q wherein Q, Alk.sup.1, Alk.sup.2, Z, p, r and s are as defined above in relation to group (IA); and R.sub.3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkenyl, or C.sub.1-C.sub.6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

Disclosed are compounds which may be utilized to inhibit transcription by RNA Polymerase II (Pol II), and in particular to disrupt the Super Elongation Complex (SEC). The compounds may be utilized in pharmaceutical compositions and methods for treating diseases and disorders associated with the biological activity of SEC, and in particular, diseases and disorders that are associated with high levels of expression of genes whose expression is SEC-dependent and that promote, support, or otherwise are required for the disease or disorder such as cancers.

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: ##STR00001##
wherein R.sub.1, is a group of formula (IA): —Ar.sup.1-(Alk.sup.1).sub.p-(Z).sub.r-(Alk.sup.2).sub.s-Q, wherein in any compatible combination Ar.sup.1 is an optionally substituted aryl or heteroaryl radical, Alk.sup.1 and Alk.sup.2 are optionally substituted divalent C.sub.1-C.sub.6 alkylene or C.sub.2-C.sub.6 alkenylene radicals, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NR.sup.A—, —C(═S)NR.sup.A—, —SO.sub.2NR.sup.A—, —NR.sup.AC(═O)—, —NR.sup.ASO.sub.2— or —NR.sup.A— wherein R.sup.A is hydrogen or C.sub.1-C.sub.6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R.sub.2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk.sup.1)p-(Z).sub.r-(Alk.sup.2).sub.s-Q wherein Q, Alk.sup.1, Alk.sup.2, Z, p, r and s are as defined above in relation to group (IA); and R.sub.3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkenyl, or C.sub.1-C.sub.6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: ##STR00001##
wherein R.sub.1, is a group of formula (IA): —Ar.sup.1-(Alk.sup.1).sub.p-(Z).sub.r-(Alk.sup.2).sub.s-Q, wherein in any compatible combination Ar.sup.1 is an optionally substituted aryl or heteroaryl radical, Alk.sup.1 and Alk.sup.2 are optionally substituted divalent C.sub.1-C.sub.6 alkylene or C.sub.2-C.sub.6 alkenylene radicals, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NR.sup.A—, —C(═S)NR.sup.A—, —SO.sub.2NR.sup.A—, —NR.sup.AC(═O)—, —NR.sup.ASO.sub.2— or —NR.sup.A— wherein R.sup.A is hydrogen or C.sub.1-C.sub.6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R.sub.2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk.sup.1)p-(Z).sub.r-(Alk.sup.2).sub.s-Q wherein Q, Alk.sup.1, Alk.sup.2, Z, p, r and s are as defined above in relation to group (IA); and R.sub.3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkenyl, or C.sub.1-C.sub.6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

The present disclosure relates generally to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.