Tryptanthrin derivatives and uses thereof

A compound of Formula (II):

• or a pharmaceutically acceptable salt thereof;
• wherein
• R51 is selected from fluoro, chloro, bromo, iodo, hydroxyl, —C1-6 alkyl, —C1-6 haloalkyl, —N(R61)2, —OR61, —SR61, —C(O)R61, —C(O)OR61, —OC(O)R61, —OC(O)N(R61)2, —C(O)N(R61)2, —N(R61)C(O)R61, —N(R61)C(O)OR61, —N(R61)C(O)N(R61)2, —N(R61)S(O)2(R61), —S(O)2R61, —S(O)2N(R61)2, —NO2, and —CN;
• when R51 is fluoro, chloro, or iodo, R52 is selected from
• bromo, iodo, —N(R71)2, —OR71, —SR71, —C(O)R71, —C(O)OR71, —OC(O)R71, —OC(O)N(R71)2, —C(O)N(R71)2, —N(R71)C(O)R71, —N(R71)C(O)OR71, —N(R71)C(O)N(R71)2, —N(R71)S(O)2(R71), N(R71)SO2N(R71)2, —N(R71)P(O)(OR71)R71, —S(O)R71, —S(O)2R71, —S(O)2N(R71)2, —NO2, and —CN;
• C1 alkyl substituted with one or more substituent independently selected from R80, and C2-6 alkyl optionally substituted with one or more substituent independently selected from R80;
• and
• C3-6 carbocycle and 3- to 5-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R80;
• when R51 is C1 alkyl or —NO2, R52 is selected from
• fluoro, iodo, —OR72, —SR72, —N(R72)2, —C(O)R72, —C(O)OR72, —OC(O)R72, —OC(O)N(R72)2, —C(O)N(R72)2, —N(R72)C(O)R72, —N(R72)C(O)OR72, —N(R72)C(O)N(R72)2, —N(R72)S(O)2(R72), —N(R72)SO2N(R72)2, —N(R72)P(O)(OR72)R72, —S(O)R72, —S(O)2R72, —S(O)2N(R72)2, —NO2, and —CN;
• C1-6 alkyl, optionally substituted with one or more substituent independently selected from R80;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R80;
• when R51 is selected from bromo, hydroxyl, —C2-6 alkyl, —C1-6 haloalkyl, —N(R61)2, —OR61, —SR61, —C(O)R61, —C(O)OR61, —OC(O)R61, —OC(O)N(R61)2, —C(O)N(R61)2, —N(R61)C(O)R61, —N(R61)C(O)OR61, —N(R61)C(O)N(R61)2, —N(R61)S(O)2(R61), —S(O)2R61, —S(O)2N(R61)2, and —CN, R52 is selected from
• halogen, —OR73, —SR73, —N(R73)2, —C(O)R73, —C(O)OR73, —OC(O)R73, —OC(O)N(R73)2, —C(O)N(R73)2, —N(R73)C(O)R73, —N(R73)C(O)OR73, —N(R73)C(O)N(R73)2, —N(R73)S(O)2(R73), —N(R73)SO2N(R73)2, —N(R73)P(O)(OR73)R73, —S(O)R73, —S(O)2R73, —S(O)2N(R73)2, —NO2, and —CN;
• C1-6 alkyl, optionally substituted with one or more substituent independently selected from R80;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R80;
• R53 and R54 are each independently selected at each occurrence from
• halogen, —OR64, —SR64, —N(R64)2, —N(R64)C(O)R64, —C(O)R64, —C(O)OR64, —C(O)N(R64)2, —NO2, and —CN;
• C1-4 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OR64, —SR64, —N(R64)2, —N(R64)C(O)R64, —C(O)R64, —C(O)OR64, —C(O)N(R64)2, —NO2, and —CN;
• and
• C3-4 carbocycle and 3- to 4-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR64, —SR64, —N(R64)2, —N(R64)C(O)R64, —C(O)R64, —C(O)OR64, —C(O)N(R64)2, —NO2, and —CN;
• R55 and R55′ are each independently selected from hydrogen and hydroxyl;
• or R55 and R55′ taken together are ═O;
• R56 and R56′ are each independently selected from hydrogen and hydroxyl;
• or R56 and R56′ taken together are ═O, ═N—OR64, or ═NR26;
• p is selected from 0, 1, 2, and 3;
• q is selected from 0, 1, 2, and 3;
• R61 and R64 are each independently selected at each occurrence from hydrogen;
• C1-6 alkyl optionally substituted with one or more substituent independently selected from R81;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R81;
• R71, R72, and R73 are each independently selected at each occurrence from hydrogen;
• C1-6 alkyl optionally substituted with one or more substituents independently selected from R82;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from C1-4 alkyl, C1-4 haloalkyl, and R82;
• R80, R81, and R82 are each independently selected at each occurrence from halogen, —OR91, —SR91, —N(R91)2, —C(O)R91, —C(O)OR91, —OC(O)R91, —OC(O)N(R91)2, —C(O)N(R91)2, —N(R91)C(O)R91, —N(R91)C(O)OR91, —N(R91)C(O)N(R91)2, —N(R91)S(O)2(R91), —N(R91)SO2N(R91)2, —N(R91)P(O)(OR91)R91, —S(O)R91, —S(O)2R91, —S(O)2N(R91)2, —NO2, ═O, ═S, —CN, C3-6 carbocycle, and 3- to 7-membered heterocycle;
• and
• R91 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C1-6 hydroxyalkyl.

A compound of Formula (III):

• or a pharmaceutically acceptable salt thereof;
• wherein
• R101 is selected from fluoro, chloro, bromo, hydroxyl, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —N(R111)2, —OR112, —SR111, —C(O)R111, —C(O)OR111, —OC(O)R111, —OC(O)N(R111)2, —C(O)N(R111)2, —N(R11)C(O)R111, —N(R111)C(O)OR111, —N(R111)C(O)N(R11)2, —N(R111)S(O)2(R111), —S(O)2R111, —S(O)2N(R111)2, —NO2, and —CN;
• when R101 is fluoro, R102 is selected from
• chloro, bromo, iodo, —N(R121)2, —OR122, —SR121, —C(O)R121, —C(O)OR121, —OC(O)R121, —OC(O)N(R121)2, —C(O)N(R121)2, —N(R121)C(O)R121, —N(R21)C(O)OR121, —N(R121)C(O)N(R121)2, —N(R121)S(O)2(R121), —N(R121)SO2N(R121)2, —N(R121)P(O)(OR121)R121, —S(O)R121, —S(O)2R121, —S(O)2N(R121)2, —NO2, and —CN;
• C1 alkyl substituted with one or more substituent independently selected from R123, and C2-6 alkyl optionally substituted with one or more substituent independently selected from R130;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R130;
• when R101 is bromo, iodo, hydroxyl, —O—C1 alkyl, —C(O)OR111, —C(O)N(H)(C2 alkyl), —S(O)2R111, or —S(O)2N(R111)2, R102 is selected from
• fluoro, —N(R124)2, —OR125, —SR124, —C(O)R124, —C(O)OR124, —OC(O)R124, —OC(O)N(R124)2, —C(O)N(R124)2, —N(R124)C(O)R124, —N(R124)C(O)OR124, —N(R124)C(O)N(R124)2, —N(R124)S(O)2(R124), —N(R124)SO2N(R124)2, —N(R124)P(O)(OR124)R124, —S(O)R124, —S(O)2R124, —S(O)2N(R124)2, —NO2, and —CN;
• C1-6 alkyl, optionally substituted with one or more substituent independently selected from R130;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R130;
• when R101 is chloro, —C1-6 alkyl, —C1-6 haloalkyl, —O—C2-6 alkyl, —O—C1-6 haloalkyl, —OR112, —SR111, —N(R111)2, —C(O)R111, —OC(O)R111, —C(O)N(R113)2, —OC(O)N(R111)2, —N(R111)C(O)R111, —N(R111)C(O)OR111, —N(R111)C(O)N(R111)2, —N(R111)S(O)2(R111), —NO2, or —CN, R102 is selected from
• halogen, —OR126, —SR126, —N(R126)2, —C(O)R126, —C(O)OR126, —OC(O)R126, —OC(O)N(R126)2, —C(O)N(R126)2, —N(R126)C(O)R126, —N(R126)C(O)OR126, —N(R126)C(O)N(R126)2, —N(R126)S(O)2(R126), —N(R126)SO2N(R126)2, —N(R126)P(O)(OR126)R126, —S(O)R126, —S(O)2R126, —S(O)2N(R126)2, —NO2, and —CN;
• C1-6 alkyl, optionally substituted with one or more substituent independently selected from R130;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R130;
• provided that (i) when R101 is NO2, R102 cannot be methyl;
• (ii) when R101 is methyl, R102 cannot be chloro;
• and (iii) when R101 is chloro, R102 cannot be bromo;
• R103 and R104 are each independently selected at each occurrence from
• halogen, —OR114, —SR114, —N(R114)2, —N(R114)C(O)R114, —C(O)R114, —C(O)OR114, —C(O)N(R114)2, —NO2, and —CN;
• C1-4 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OR114, —SR114, —N(R114)2, —N(R114)C(O)R114, —C(O)R114, —C(O)OR114, —C(O)N(R114)2, —NO2, and —CN;
• and
• C3-4 carbocycle and 3- to 4-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR114, —SR114, —N(R114)2, —N(R114)C(O)R114, —C(O)R114, —C(O)OR114, —C(O)N(R114)2, —NO2, and —CN;
• R105 and R105′ are each independently selected from hydrogen and hydroxyl;
• or R105 and R105′ taken together are ═O;
• R106 and R106′ are each independently selected from hydrogen and hydroxyl;
• or R106 and R106′ taken together are ═O, ═N—OR114, or ═NR114;
• r is selected from 0, 1, 2, and 3;
• s is selected from 0, 1, 2, and 3;
• R111 and R114 are each independently selected at each occurrence from hydrogen;
• C1-6 alkyl optionally substituted with one or more substituent independently selected from R131;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R131;
• R112 is selected at each occurrence from
• C1-6 alkyl substituted with one or more substituent independently selected from R132;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R133;
• R113 is selected at each occurrence from
• hydrogen;
• C1 alkyl and C3-6 alkyl optionally substituted with one or more substituent independently selected from R134, and C2 alkyl substituted with one or more substituent independently selected from R134;
• and
• C3-5 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R134;
• R121, R124, and R126 are each independently selected at each occurrence from
• hydrogen;
• C1-6 alkyl optionally substituted with one or more substituents independently selected from R134;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from C1-4 alkyl, C1-4 haloalkyl, and R134;
• R122 and R125 are each independently selected at each occurrence from
• C2-6 alkyl optionally substituted with one or more substituents independently selected from R134;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from C1-4 alkyl, C1-4 haloalkyl, and R134;
• R123 is independently selected at each occurrence from
• hydrogen;
• C1-6 alkyl optionally substituted with one or more substituents independently selected from R134;
• and
• C3-5 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from C1-4 alkyl, C1-4 haloalkyl, and R134;
• R130, R131, R132, R133, and R134 are each independently selected at each occurrence from halogen, —OR141, —SR141, —N(R141)2, —C(O)R141, —C(O)OR141, —OC(O)R141, —OC(O)N(R141)2, —C(O)N(R141)2, —N(R141)C(O)R141, —N(R141)C(O)OR141, —N(R141)C(O)N(R141)2, —N(R141)S(O)2(R141), —N(R141)SO2N(R141)2, —N(R141)P(O)(OR141)R141, —S(O)R141, —S(O)2R141, —S(O)2N(R141)2, —NO2, ═O, ═S, —CN, C3-6 carbocycle, and 3- to 7-membered heterocycle;
• and
• R141 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C1-6 hydroxyalkyl.

A compound of Formula (IV):

• or a pharmaceutically acceptable salt thereof;
• wherein
• R151 is selected from fluoro, bromo, —N(R161)2, —C(O)R161, —C(O)OR161, —OC(O)R161, —OC(O)N(R161)2, —C(O)N(R161)2, —N(R161)C(O)R161, —N(R161)C(O)OR161, —N(R161)C(O)N(R161)2, —N(R161)S(O)2(R161), —N(R161)S(O)2N(R161)2, —SR161, —S(O)R161, —S(O)2R161, —S(O)2N(R161)2, —CN, —NO2, —C1-6 haloalkyl, —O—C2-6 alkyl, —O—C1-6 haloalkyl, —OR3-6 carbocycle, and —OR3-6 heterocycle;
• and
• each of which is optionally substituted with one or more substituent independently selected from R171;
• when R151 is fluoro, R152 is selected from
• iodo, —NHR192, —OR171, —SR171, —C(═NR196)N(R196)2, —C(O)R171, —C(O)OR171, —OC(O)R171, —OC(O)N(R171)2, —C(O)N(R171)2, —N(R193)C(O)R171, —N(H)C(O)R194, —N(R193)C(O)OR171, —N(R171)C(O)N(R171)2, —N(R171)S(O)2(R171), —N(R171)SO2N(R171)2, —N(R171)P(O)(OR171)R171, —S(O)R171, —S(O)2R171, —S(O)2N(R171)2, —NR196(C═NR196)N(R196)2, —N3, and —CN;
• C1 alkyl substituted with one or more substituent independently selected from R195, and C2-6 alkyl optionally substituted with one or more substituent independently selected from R180;
• and
• C3-6 carbocycle, 3-membered heterocycle, 4-membered heterocycle,
• and 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R180;
• when R151 is
• —SR161, —S(O)R161, —S(O)2R161, —S(O)2N(R161)2, or —CN, R152 is selected from
• halogen, —N(R174)2, —OR174, —SR174, —C(O)R174, —C(O)OR174, —OC(O)R174, —OC(O)N(R174)2, —C(O)N(R174)2, —N(R174)C(O)R174, —N(R174)C(O)OR174, —N(R174)C(O)N(R174)2, —N(R174)S(O)2(R174), —N(R124)SO2N(R174)2, —N(R174)P(O)(OR174)R174, —S(O)R174, —S(O)2R174, —S(O)2N(R174)2, —NO2, and —CN;
• C1-6 alkyl, optionally substituted with one or more substituent independently selected from R180;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R180;
• when R151 is bromo or —NO2, R152 is selected from
• iodo, —OR197, —SR176, —NHR178, —C(O)R176, —C(O)OR176, —OC(O)R176, —OC(O)N(R176)2, —C(O)N(R176)2, —N(R176)C(O)R176, —N(R176)C(O)OR176, —N(R176)C(O)N(R176)2, —N(R176)S(O)2(R176), —N(R176)SO2N(R176)2, —N(R176)P(O)(OR176)R176, —S(O)R176, —S(O)2R176, —S(O)2N(R176)2, —NO2, and —CN;
• C1 alkyl substituted with one or more substituent independently selected from R180, C1 alkyl substituted with one or more substituent independently selected from R198, and C2-6 alkyl, optionally substituted with one or more substituent independently selected from R180:
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R180;
• and
• provided that (i) when R151 is NO2, R152 cannot be C1 alkyl substituted with one or more substituent independently selected from R180;
• and (ii) when R151 is NO2, R152 cannot be ethyl;
• when R151 is —C1-6 haloalkyl, —O—C2-6 alkyl, —O—C1-6 haloalkyl, —OR3-6 carbocycle, —OR3-6 heterocycle, —N(R161)2, —C(O)R161, —OC(O)R161, —C(O)N(R161)2, —OC(O)N(R161)2, —N(R161)C(O)R161, —N(R161)C(O)OR161, —N(R161)C(O)N(R161)2, —N(R161)S(O)2(R161), or —N(R161)S(O)2N(R161)2, R152 is selected from
• halogen, —OR176, —SR176, —N(R176)2, —C(O)R176, —C(O)OR176, —OC(O)R176, —OC(O)N(R176)2, —C(O)N(R176)2, —N(R176)C(O)R176, —N(R176)C(O)OR176, —N(R176)C(O)N(R176)2, —N(R176)S(O)2(R176), —N(R176)SO2N(R176)2, —N(R176)P(O)(OR176)R176, —S(O)R176, —S(O)2R176, —S(O)2N(R176)2, —NO2, and —CN;
• C1-6 alkyl, optionally substituted with one or more substituent independently selected from R177;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R177;
• R153 and R154 are each independently selected at each occurrence from halogen, —OR164, —NHR178, —N(R164)C(O)R164, —C(O)R164, —C(O)OR164, —C(O)N(R164)2, —NO2, and —CN;
• C1-4 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OR164, —SR164, —N(R164)2, —N(R164)C(O)R164, —C(O)R164, —C(O)OR164, —C(O)N(R164)2, —NO2, and —CN;
• and
• C3-6 carbocycle and 3- to 5-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR164, —SR164, —N(R164)2, —N(R164)C(O)R164, —C(O)R164, —C(O)OR164, —C(O)N(R164)2, —NO2, and —CN;
• R155 and R155′ are each independently selected from hydrogen, hydroxyl, and methyl;
• or R155 and R155′ taken together are ═O;
• R156 and R156′ are each independently selected from hydrogen, hydroxyl, and methyl;
• or R156 and R156′ taken together are ═O, ═N—OR171, or ═NR171;
• t is selected from 0, 1, 2, and 3;
• u is selected from 0, 1, 2, and 3;
• R161 and R164 are each independently selected at each occurrence from hydrogen;
• C1-6 alkyl optionally substituted with one or more substituent independently selected from R177;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R177;
• R171, R174, and R176 are each independently selected at each occurrence from hydrogen;
• C1-6 alkyl optionally substituted with one or more substituents independently selected from R180;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from C1-4 alkyl, C1-4 haloalkyl, and R180;
• R177 and R180 are each independently selected at each occurrence from halogen, —OR191, —SR191, —N(R191)2, —C(O)R191, —C(O)OR191, —OC(O)R191, —OC(O)N(R191)2, —C(O)N(R191)2, —N(R191)C(O)R191, —N(R191)C(O)OR191, —N(R191)C(O)N(R191)2, —N(R191)S(O)2(R191), —N(R191)SO2N(R191)2, —N(R191)P(O)(OR191)R191, —NR196(C═NR196)N(R196)2, —S(O)R191, —S(O)2R191, —S(O)2N(R191)2, —NO2, ═O, ═S, —CN, C1-6 alkyl, C3-6 carbocycle, and 3- to 7-membered heterocycle;
• R178 is selected at each occurrence from
• C1-6 alkyl optionally substituted with one or more substituents independently selected from R180;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R180:
• R191 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C1-6 hydroxyalkyl.
• R192 is selected at each occurrence from C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from R180;
• R193 is selected at each occurrence from
• C1-6 alkyl optionally substituted with one or more substituents independently selected from R180;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from C1-4 alkyl, C1-4 haloalkyl, and R180;
• R194 is selected at each occurrence from
• C1-6 alkyl substituted with one or more substituents independently selected from R180;
• R195 is independently selected at each occurrence from halogen, —NH2, —NHR192, —NR196(C═NR196)N(R196)2, —OR171, —SR171, —C(O)R171, —C(O)OR171, —OC(O)R171, —OC(O)N(R171)2, —C(O)N(R171)2, —N(R171)C(O)R171, —N(R171)C(O)R171, —N(R193)C(O)OR171, —N(R171)C(O)N(R171)2, —N(R171)S(O)2(R171), —N(R171)S(O)2N(R171)2, —N(R171)P(O)(OR171)R171, —S(O)R171, —S(O)2R171, and —S(O)2N(R171)2;
• C1-6 alkyl optionally substituted with one or more substituents independently selected from R180;
• and
• C5-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from C1-4 alkyl, C1-4 haloalkyl, and R180;
• R196 is selected at each occurrence from hydrogen, —CN, and OR171;
• C1-6 alkyl optionally substituted with one or more substituents independently selected from R180;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from C1-4 alkyl, C1-4 haloalkyl, and R180;
• R197 is selected at each occurrence from hydrogen;
• C2-6 alkyl optionally substituted with one or more substituents independently selected from R180;
• and
• C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from C1-4 alkyl, C1-4 haloalkyl, and R180;
• R198 is independently selected at each occurrence from fluoro, chloro, iodo, —NH2, —NHR192, —NR196(C═NR196)N(R196)2, —OR171, —SR171, —C(O)R171, —C(O)OR171, —OC(O)R171, —OC(O)N(R171)2, —C(O)N(R171)2, —N(R171)C(O)R171, —N(R171)C(O)R171, —N(R193)C(O)OR171, —N(R171)C(O)N(R171)2, —N(R171)S(O)2(R171), —N(R171)SO2N(R171)2, —N(R171)P(O)(OR171)R171, —S(O)R171, —S(O)2R171, and —S(O)2N(R171)2;
• C2-6 alkyl optionally substituted with one or more substituents independently selected from R180;
• and
• C5-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituent independently selected from C1-4 alkyl, C1-4 haloalkyl, and R180.