STAT3 INHIBITORS FOR USE IN THE TREATMENT OF NON-VIRAL LIVER CANCER

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, for use in a method of treating a subject diagnosed with a non-viral liver cancer, the method comprising administering to the subject an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

X is selected from the group consisting of hydrogen, phenylsulfanyl, hydroxy-naphthalenyl, quinolin-8-ylsulfanyl, triazol-3-yl sulfanyl, and benzothiazol-2-ylsulfanyl; and

Y is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4 dioxine, fluoro, trifluoro methoxy, acetyl, trifluoro methyl, propyl, cyclohexene, methoxy-phenoxy, chloro phenoxy, tolyloxy, and phenoxy.

2 . The compound for use of claim 1 , wherein the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.

3 . The compound for use of claim 1 , wherein the non-viral liver cancer is hepatocellular carcinoma, fibrolamellar carcinoma, bile duct cancer, angiosarcoma, or hepatoblastoma.

4 . The compound for use of claim 1 , wherein the non-viral liver cancer is hepatocellular carcinoma.

5 . The compound for use of claim 1 , wherein the subject has alcoholic liver disease, alcoholic cirrhosis, autoimmune disease, metabolic disease, alcoholic steatohepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, diabetes, obesity, iron overload syndrome, autoimmune hepatitis, primary biliary cholangitis, cryptogenic liver disease, alcohol use, tobacco use, oral contraceptive use, pesticide exposure, aflatoxin exposure, or betel quid chewing.

6 . The compound for use of claim 1 , wherein the subject is negative for hepatitis B virus.

7 . The compound for use of claim 1 , wherein the subject is negative for hepatitis B surface antigen.

8 . The compound for use of claim 1 , wherein the subject is negative for hepatitis C virus.

9 . The compound for use of claim 1 , wherein the subject is negative for anti-HCV antibody.

10 . The compound for use of claim 1 , wherein the subject has been administered one or more prior cancer therapy.

11 . The compound for use of claim 10 , wherein the prior cancer therapy is sorafenib, pembrolizumab, nivolumab, lenvatinib, bevacizumab, atezolizumab, ramucirumab, cabozantinib, infigratinib, pemigatinib, regorafenib, tremelimumab, or durvalumab, or pharmaceutically acceptable salts thereof, or any combination thereof.

12 . The compound for use of claim 10 , wherein the prior cancer therapy is sorafenib, pembrolizumab, nivolumab, lenvatinib, or bevacizumab.

13 . The compound for use of claim 1 , wherein the non-viral liver cancer has progressed from, or the subject was intolerant to, a prior first line cancer therapy.

14 . The compound for use of claim 1 , wherein the non-viral liver cancer has progressed from, or the subject was intolerant to, a prior second line cancer therapy.

15 . The compound for use of claim 1 , wherein the non-viral liver cancer has progressed from, or the subject was intolerant to, a prior third line cancer therapy.

16 . The compound for use of claim 1 , wherein about 1 mg/kg/day to about 50 mg/kg/day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject.

17 . The compound for use of claim 16 , wherein about 5 mg/kg/day to about 30 mg/kg/day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject.

18 . The compound for use of claim 16 , wherein about 5 mg/kg/day to about 8 mg/kg/day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject.

19 . The compound for use of claim 16 , wherein about 10 mg/kg/day to about 15 mg/kg/day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject.

20 . The compound for use of claim 16 , wherein about 20 mg/kg/day to about 30 mg/kg/day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject.

21 . The compound for use of claim 1 , wherein about 0.5 mg/kg/dose to about 25 mg/kg/dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject.

22 . The compound for use of claim 21 , wherein about 2.5 mg/kg/dose to about 15 mg/kg/dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject.

23 . The compound for use of claim 21 , wherein about 2.5 mg/kg/day to about 4 mg/kg/day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject.

24 . The compound for use of claim 21 , wherein about 5 mg/kg/day to about 7.5 mg/kg/day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject.

25 . The compound for use of claim 21 , wherein about 10 mg/kg/day to about 15 mg/kg/day of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject.

26 . The compound for use of any one of claims 21-25 , wherein the subject is dosed twice daily of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

27 . The compound for use of claim 1 , wherein the subject is dosed twice daily of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, at about 1.6 mg/kg/dose.

28 . The compound for use of claim 1 , wherein the subject is dosed twice daily of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, at about 3.2 mg/kg/dose.

29 . The compound for use of claim 1 , wherein the subject is dosed twice daily of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, at about 6.4 mg/kg/dose.

30 . The compound for use of claim 1 , wherein the subject is dosed twice daily of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, at about 12.8 mg/kg/dose.

31 . The compound for use of claim 1 , wherein about 200 mg to about 2000 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject per day.

32 . The compound for use of claim 31 , wherein about 400 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject per day.

33 . The compound for use of claim 31 , wherein about 800 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject per day.

34 . The compound for use of claim 31 , wherein about 800 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject per day.

35 . The compound for use of claim 31 , wherein about 1200 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject per day.

36 . The compound for use of claim 31 , wherein about 1600 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject per day.

37 . The compound for use of claim 1 , further comprising administering to the subject one or more additional agent.

38 . The compound for use of claim 37 , wherein the additional agent is an angiogenesis inhibitor, an anti-PD-1 antibody, or an anti-PD-L1 antibody.

39 . The compound for use of claim 38 , wherein the additional agent is an anti-PD-1 antibody, wherein the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, sasanlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717.

40 . The compound for use of claim 39 , wherein the anti-PD-1 antibody is pembrolizumab.

41 . The compound for use of claim 38 , wherein the additional agent is an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, envafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072.

42 . The compound for use of claim 41 , wherein the anti-PD-L1 antibody is atezolizumab.

43 . The compound for use of claim 38 , wherein the additional agent is an angiogenesis inhibitor, wherein the angiogenesis inhibitor is bevacizumab, sorafenib, sunitinib, nilotinib, pazopanib, dasatinib, regorafenib, cabozantinib, lenvatinib, ponatinib, ziv-aflibercept, axitinib, tivozanib, everolimus, lenalidomide, thalidomide, vandetanib, orvandetanib, or ramucirumab.

44 . The compound for use of claim 43 , wherein the angiogenesis inhibitor is bevacizumab.

45 . The compound for use of claim 37 , wherein the additional agents are angiogenesis inhibitor and anti-PD-L1 antibody.

46 . The compound for use of claim 45 , wherein the additional agents are a atezolizumab and bevacizumab.

47 . A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, for use in a method of treating a subject diagnosed with a non-viral liver cancer, the method comprising administering to the subject an effective amount of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein

each occurrence of R 1 is independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , ORa, SRa, C(═O)Ra, OC(═O)Ra, C(═O)ORa, NRbRc, NRbC(═O)Rc, C(═O)NRbRc, NRbC(═O)ORc, OC(═O)NRbRc, NRaC(═O)NRbRc, alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle;

n 1 is 0, 1, 2, 3, or 4;

each occurrence of R 2 is independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , ORa, SRa, C(═O)Ra, OC(═O)Ra, C(═O)ORa, NRbRc, NRbC(═O)Rc, C(═O)NRbRc, NRbC(═O)ORc, OC(═O)NRbRc, NRaC(═O)NRbRc, alkyl, alkenyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted aryloxyl, or optionally substituted heterocycle;

n 2 is 0, 1, 2, 3, 4, or 5;

R 3 is hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , ORa, SRa, OC(═O)Ra, alkyl, alkenyl, cycloalkyl, or optionally substituted aryl or heteroaryl;

R 4 is hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , ORa, SRa, NRbRc, OC(═O)Ra, alkyl, alkenyl, or cycloalkyl;

each occurrence of R 5 , R 6 , and R 7 is independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , ORa, SRa, C(═O)Ra, OC(═O)Ra, C(═O)ORa, NRbRc, NRbC(═O)Rc, C(═O)NRbRc, NRbC(═O)ORc, OC(═O)NRbRc, NRaC(═O)NRbRc, alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle;

n 3 is 0, 1, 2, 3, or 4; and

each occurrence of Ra, Rb, and Rc is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; or said Rb and Rc together with the nitrogen atom to which they are bonded optionally form a heterocycle comprising 1-4 heteroatoms.

48 . The compound for use of claim 47 , wherein the compound of Formula (II) is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof.

49 . The compound for use of claim 48 , wherein the compound of Formula (III) is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof.

50 . The compound for use of claim 47 , wherein the non-viral liver cancer is hepatocellular carcinoma, fibrolamellar carcinoma, bile duct cancer, angiosarcoma, or hepatoblastoma.

51 . The compound for use of claim 47 , wherein the non-viral liver cancer is hepatocellular carcinoma.

52 . The compound for use of claim 47 , wherein the subject has alcoholic liver disease, alcoholic cirrhosis, autoimmune disease, metabolic disease, alcoholic steatohepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, diabetes, obesity, iron overload syndrome, autoimmune hepatitis, primary biliary cholangitis, cryptogenic liver disease, alcohol use, tobacco use, oral contraceptive use, pesticide exposure, aflatoxin exposure, or betel quid chewing.

53 . The compound for use of claim 47 , wherein the subject is negative for hepatitis B virus.

54 . The compound for use of claim 47 , wherein the subject is negative for hepatitis B surface antigen.

55 . The compound for use of claim 47 , wherein the subject is negative for hepatitis C virus.

56 . The compound for use of claim 47 , wherein the subject is negative for anti-HCV antibody.

57 . The compound for use of claim 47 , wherein the subject has been administered one or more prior cancer therapy.

58 . The compound for use of claim 57 , wherein the prior cancer therapy is sorafenib, pembrolizumab, nivolumab, lenvatinib, bevacizumab, atezolizumab, ramucirumab, cabozantinib, infigratinib, pemigatinib, regorafenib, tremelimumab, or durvalumab, or pharmaceutically acceptable salts thereof, or any combination thereof.

59 . The compound for use of claim 57 , wherein the prior cancer therapy is sorafenib, pembrolizumab, nivolumab, lenvatinib, or bevacizumab.

60 . The compound for use of claim 47 , wherein the non-viral liver cancer has progressed from, or the subject was intolerant to, a prior first line cancer therapy.

61 . The compound for use of claim 47 , wherein the non-viral liver cancer has progressed from, or the subject was intolerant to, a prior second line cancer therapy.

62 . The compound for use of claim 47 , wherein the non-viral liver cancer has progressed from, or the subject was intolerant to, a prior third line cancer therapy.

63 . The compound for use of claim 47 , wherein about 1 mg/kg/day to about 50 mg/kg/day of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is administered to the subject.

64 . The compound for use of claim 63 , wherein about 5 mg/kg/day to about 30 mg/kg/day of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is administered to the subject.

65 . The compound for use of claim 47 , wherein about 200 mg to about 2000 mg of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is administered to the subject per day.

66 . The compound for use of claim 47 , further comprising administering to the subject one or more additional agent.

67 . The compound for use of claim 47 , wherein the additional agent is an angiogenesis inhibitor, an anti-PD-1 antibody, or an anti-PD-L1 antibody.

68 . The compound for use of claim 67 , wherein the additional agent is an anti-PD-1 antibody, wherein the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, sasanlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717.

69 . The compound for use of claim 68 , wherein the anti-PD-1 antibody is pembrolizumab.

70 . The compound for use of claim 67 , wherein the additional agent is an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, envafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072.

71 . The compound for use of claim 70 , wherein the anti-PD-L1 antibody is atezolizumab.

72 . The compound for use of claim 67 , wherein the additional agent is an angiogenesis inhibitor, wherein the angiogenesis inhibitor is bevacizumab, sorafenib, sunitinib, nilotinib, pazopanib, dasatinib, regorafenib, cabozantinib, lenvatinib, ponatinib, ziv-aflibercept, axitinib, tivozanib, everolimus, lenalidomide, thalidomide, vandetanib, orvandetanib, or ramucirumab.

73 . The compound for use of claim 72 , wherein the angiogenesis inhibitor is bevacizumab.

74 . The compound for use of claim 66 , wherein the additional agents are angiogenesis inhibitor and anti-PD-L1 antibody.

75 . The compound for use of claim 74 , wherein the additional agents are a atezolizumab and bevacizumab.