TGF-Beta Inhibitors

A method for treating a disease or condition mediated by GDF 8, TGF-β, and/or activin in a subject in need thereof, comprising administering an effective amount of a compound, wherein the compound has the structure of formula (I°):

• or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
• wherein
• X is —S— or —N(R′)—;
• R′ is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkyloxy, —(C0-C12alkyl)-Cak or —(C0-C6alkyl)-Hca, each optionally substituted with 1 to 3 moieties that are each independently C1-C6alkyl, halogen, C1-C6haloalkyl, —ORS0, C1-C6alkyl-ORS0′, —C(O)ORS0, —C(O)RS0, —C(O)NRS02, —RS0 or cyano;
• wherein each RS0 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• R1 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkyloxy, —ORS1, —NRS12, —SRS1 or —N(RS1)C(O)RS1, each optionally substituted with 1 to 3 moieties that are each independently C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• wherein each RS1 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• or R′ and R1 combined with the atoms to which they are attached form a five- to eight-membered ring;
• A is phenyl optionally substituted with one to five R2 groups, wherein
• each R2 is independently halogen, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, —NO2, —N(RS2)C(O)RS2, —ORS2, —C(O)NRS22, —N(RS2)S(O)2RS2, —S(O)2RS2, —(C0-C6alkyl)-Ar or —CN, wherein each alkyl, haloalkyl and alkoxy are optionally substituted with 1, 2, 3, or 4 groups that are each independently halogen, cyano, nitro, —ORS2, —SRS2, —NRS22, —C(O)ORS2, —C(O)NRS22, —C(O)RS2, —S(O)RS2, —S(O)2RS2, —S(O)ORS2, —S(O)2ORS2, —S(O)NRS22, —S(O)2NRS22, —OC(O)RS2, —OC(O)ORS2, —OC(O)NRS22, —N(RS2)C(O)RS2, —N(RS2)C(O)ORS2, —N(RS2)C(O)NRS22, —N(RS2)S(O)RS2, —N(RS2)S(O)2RS2, C1-C6alkyl, or C1-C6haloalkyl;
• wherein each RS2 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• Z is
• a fused bicyclic ring of the formula,
• wherein
• ring A is Ar or 5- or 6-membered Het,
• ring B is 5- or 6-membered Het,
• wherein
• Z is optionally substituted by one or two —RZ groups that are each independently halogen, cyano, C1-6alkyl, C1-6alkenyl, C1-6haloalkyl, —C1-C6alkoxy, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Hca, —ORS3, —SR, —NRS32, —C(O)RS3, —C(O)ORS3, —C(O)NRS32, —C(NRS3)NRS3ORS3, —S(O)2NRS32, —S(O)2RS3, —OC(O)RS3, —N(RS3)C(O)RS3, —OC(O)ORS3, —OC(O)NRS32, —N(RS3)C(O)ORS3, —N(RS3)C(O)NRS32, —N(RS3)S(O)2RS3, —OP(O)(ORS3)2 or —CH2—OP(O)(ORS3), wherein each alkyl, haloalkyl and alkoxy is optionally substituted by one or two —RZ2 groups;
• wherein each RS3 is independently hydrogen, —NRS32, —ORS3, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl, —C(O)NRS42 or cyano;
• and
• each —RZ2 is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —ORS4, —SRS4, —NRS42, —C(O)RS4, —C(O)ORS4, —C(O)NRS42, —S(O)2NRS42, —S(O)2RS4, —OC(O)RS4, —N(RS4)C(O)RS4, —OC(O)ORS4, —OC(O)NRS42, —N(RS4)C(O)ORS4, —N(RS4)C(O)NRS42, —N(RS4)S(O)2RS4, —OP(O)(ORS4)2 or —CH2—OP(O)(ORS4);
• and
• wherein each RS4 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with one or two C1-C6alkyl, halogen, C1-C6haloalkyl or cyano.

A method for treating cancer in a subject in need thereof, comprising administering an effective amount of a TGF-β superfamily inhibiting compound, wherein the compound has the structure of formula (I°):

• or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
• wherein
• X is —S— or —N(R′)—;
• R′ is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkyloxy, —(C0-C12alkyl)-Cak or —(C0-C6alkyl)-Hca, each optionally substituted with 1 to 3 moieties that are each independently C1-C6alkyl, halogen, C1-C6haloalkyl, —ORS0, C1-C6alkyl-ORS0′, —C(O)ORS0, —C(O)RS0, —C(O)NRS02, —RS0 or cyano;
• wherein each RS0 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• R1 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkyloxy, —ORS1, —NRS12, —SRS1 or —N(RS1)C(O)RS1, each optionally substituted with 1 to 3 moieties that are each independently C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• wherein each RS1 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• or R′ and R1 combined with the atoms to which they are attached form a five- to eight-membered ring;
• A is phenyl optionally substituted with one to five R2 groups, wherein
• each R2 is independently halogen, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, —NO2, —N(RS2)C(O)RS2, —ORS2, —C(O)NRS22, —N(RS2)S(O)2RS2, —S(O)2RS2, —(C0-C6alkyl)-Ar or —CN, wherein each alkyl, haloalkyl and alkoxy are optionally substituted with 1, 2, 3, or 4 groups that are each independently halogen, cyano, nitro, —ORS2, —SRS2, —NRS22, —C(O)ORS2, —C(O)NRS22, —C(O)RS2, —S(O)RS2, —S(O)2RS2, —S(O)ORS2, —S(O)2ORS2, —S(O)NRS22, —S(O)2NRS22, —OC(O)RS2, —OC(O)ORS2, —OC(O)NRS22, —N(RS2)C(O)RS2, —N(RS2)C(O)ORS2, —N(RS2)C(O)NRS22, —N(RS2)S(O)RS2, —N(RS2)S(O)2RS2, C1-C6alkyl, or C1-C6haloalkyl;
• wherein each RS2 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• Z is
• a fused bicyclic ring of the formula,
• wherein
• ring A is Ar or 5- or 6-membered Het,
• ring B is 5- or 6-membered Het,
• wherein
• Z is optionally substituted by one or two —RZ groups that are each independently halogen, cyano, C1-6alkyl, C1-6alkenyl, C1-6haloalkyl, —C1-C6alkoxy, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Hca, —ORS3, —SRS3, —NRS32, —C(O)RS3, —C(O)ORS3, —C(O)NRS32, —C(NRS3)NRS3ORS3, —S(O)2NRS32, —S(O)2RS3, —OC(O)RS3, —N(RS3)C(O)RS3, —OC(O)ORS3, —OC(O)NRS32, —N(RS3)C(O)ORS3, —N(RS3)C(O)NRS32, —N(RS3f)S(O)2RS3, —OP(O)(ORS3)2 or —CH2—OP(O)(ORS3), wherein each alkyl, haloalkyl and alkoxy is optionally substituted by one or two —RZ2 groups;
• wherein each RS3 is independently hydrogen, —NRS32, —ORS3, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl, —C(O)NRS42 or cyano;
• and
• each —RZ2 is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —ORS4, —SRS4, —NRS42, —C(O)RS4, —C(O)ORS4, —C(O)NRS42, —S(O)2NRS42, —S(O)2RS4, —OC(O)RS4, —N(RS4)C(O)RS4, —OC(O)ORS4, —OC(O)NRS42, —N(RS4)C(O)ORS4, —N(RS4)C(O)NRS42, —N(RS4)S(O)2RS4, —OP(O)(ORS4)2 or —CH2—OP(O)(ORS4);
• and
• wherein each RS4 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with one or two C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• in combination with the administration of a therapeutically effective amount of one or more chemotherapeutic or immuno-oncology agents.

A method of inhibiting GDF 8, TGF-β, and/or activin comprising contacting the GFD-8, TGF-β, and/or activin with a compound of structural formula (I°):

• or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
• wherein
• X is —S— or —N(R′)—;
• R′ is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkyloxy, —(C0-C12alkyl)-Cak or —(C0-C6alkyl)-Hca, each optionally substituted with 1 to 3 moieties that are each independently C1-C6alkyl, halogen, C1-C6haloalkyl, —ORS0, C1-C6alkyl-ORS0′, —C(O)ORS0, —C(O)RS0, —C(O)NRS02, —RS0 or cyano;
• wherein each RS0 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• R1 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkyloxy, —ORS1, —NRS12, —SRS1 or —N(RS1)C(O)RS1, each optionally substituted with 1 to 3 moieties that are each independently C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• wherein each RS1 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• or R′ and R1 combined with the atoms to which they are attached form a five- to eight-membered ring;
• A is phenyl optionally substituted with one to five R2 groups, wherein
• each R2 is independently halogen, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, —NO2, —N(RS2)C(O)RS2, —ORS2, —C(O)NRS22, —N(RS2)S(O)2RS2, —S(O)2RS2, —(C0-C6alkyl)-Ar or —CN, wherein each alkyl, haloalkyl and alkoxy are optionally substituted with 1, 2, 3, or 4 groups that are each independently halogen, cyano, nitro, —ORS2, —SRS2, —NRS22, —C(O)ORS2, —C(O)NRS22, —C(O)RS2, —S(O)RS2, —S(O)2RS2, —S(O)ORS2, —S(O)2ORS2, —S(O)NRS22, —S(O)2NRS22, —OC(O)RS2, —OC(O)ORS2, —OC(O)NRS22, —N(RS2)C(O)RS2, —N(RS2)C(O)ORS2, —N(RS2)C(O)NRS22, —N(RS2)S(O)RS2, —N(RS2)S(O)2RS2, C1-C6alkyl, or C1-C6haloalkyl;
• wherein each RS2 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
• Z is
• a fused bicyclic ring of the formula,
• wherein
• ring A is Ar or 5- or 6-membered Het,
• ring B is 5- or 6-membered Het,
• wherein
• Z is optionally substituted by one or two —RZ groups that are each independently halogen, cyano, C1-6alkyl, C1-6alkenyl, C1-6haloalkyl, —C1-C6alkoxy, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Hca, —ORS3, —SR, —NRS32, —C(O)RS3, —C(O)ORS3, —C(O)NRS32, —C(NRS3)NRS3ORS3, —S(O)2NRS32, —S(O)2RS3, —OC(O)RS3, —N(RS3)C(O)RS3, —OC(O)ORS3, —OC(O)NRS32, —N(RS3)C(O)ORS3, —N(RS3)C(O)NRS32, —N(RS3)S(O)2RS3, —OP(O)(ORS3)2 or —CH2—OP(O)(ORS3), wherein each alkyl, haloalkyl and alkoxy is optionally substituted by one or two —RZ2 groups;
• wherein each RS3 is independently hydrogen, —NRS32, —ORS3, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl, —C(O)NRS42 or cyano;
• and
• each —RZ2 is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —ORS4, —SRS4, —NRS42, —C(O)RS4, —C(O)ORS4, —C(O)NRS42, —S(O)2NRS42, —S(O)2RS4, —OC(O)RS4, —N(RS4)C(O)RS4, —OC(O)ORS4, —OC(O)NRS42, —N(RS4)C(O)ORS4, —N(RS4)C(O)NRS42, —N(RS4)S(O)2RS4, —OP(O)(ORS4)2 or —CH2—OP(O)(ORS4);
• and
• wherein each RS4 is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with one or two C1-C6alkyl, halogen, C1-C6haloalkyl or cyano.