Benzimidazole derivatives as ERBB tyrosine kinase inhibitors for the treatment of cancer

1. A method for treating or ameliorating one or more symptoms of an EGFR-mediated proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula IV:

or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein:

R 1 is:

R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

L 1 is a bond, —O—, —S—, —N(R 1A )—, or —C(R 1A R 1B )—, wherein each R 1A and R 1B is independently hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

L 2 is C 3-10 cycloalkylene, C 6-14 arylene, C 7-15 aralkylene, heteroarylene, or heterocyclylene;

Z is NR 2A or CR 2A R 2B , wherein each R 2A and R 2B is independently hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

R 4 , R 5 , R 6 , and R 7 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)N 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; and

each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or R 1a and R 1c together with the C and N atoms to which they are attached form heterocyclyl; or R 1b and R 1c together with the N atom to which they are attached form heterocyclyl;

with the proviso that, when L 1 is a bond, at least one of R 4 , R 5 , R 6 , and R 7 is bromo, —OR 7a , or —NR 1b R 1c , wherein R 7a is C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OP(O)(OR a ) 2 , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR a )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q a ;

wherein each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R f , —C(O)OR f , —C(O)NR g R h , —C(NR f )NR g R h , —OC(O)R f , —OC(O)OR f , —OC(O)NR g R h , —OC(═NR f )NR g R h , —OP(O)(OR f ) 2 , —OS(O)R f , —OS(O) 2 R f , —OS(O)NR g R h , —OS(O) 2 NR g R h , —NR g R h , —NR f C(O)R k , —NR f C(O)OR k , —NR f C(O)NR g R h , —NR f C(═NR k )NR g R h , —NR f S(O)R k , —NR f S(O) 2 R k , —NR f S(O)NR g R h , —NR f S(O) 2 NR g R h , —SR f , —S(O)R f , —S(O) 2 R f , —S(O)NR g R h , and —S(O) 2 NR g R h ; wherein each R f , R g , R h , and R k is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R g and R h together with the N atom to which they are attached form heterocyclyl.

2. The method of claim 1 , wherein the compound has the structure of Formula VIII:

or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof; wherein R 7a is C 4-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

3. The method of claim 2 , wherein the compound has the structure of Formula XIa:

or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof; wherein R 2n is C 1-6 alkyl optionally substituted with one or more substituents Q or —OR 1a .

4. The method of claim 1 , wherein the compound has the structure of Formula XVIII:

or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof; wherein R 6a is (i) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (ii) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c .

5. The method of claim 4 , wherein the compound has the structure of Formula XIX:

or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof.

6. The method of claim 4 , wherein the compound has the structure of Formula XXa:

or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof wherein R 2n is C 1-6 alkyl optionally substituted with one or more substituents Q or —OR 1a .

7. A method for treating or ameliorating one or more symptoms of an EGFR-mediated proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound selected from:

and single enantiomers, racemic mixtures, mixtures of diastereomers, and isotopic variants thereof; and pharmaceutically acceptable salts and solvates thereof.

8. The method of claim 1 , wherein the proliferative disease is cancer.

9. The method of claim 8 , wherein the cancer is drug-resistant.

10. The method of claim 8 , wherein the cancer contains an EGFR variant.

11. The method of claim 10 , wherein the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 689, 700, 709, 715, 719, 720, 746-759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and 863.

12. The method of claim 10 , wherein the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 719, 746-751, 790, and 858.

13. The method of claim 10 , wherein the EGFR variant contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from G719C, G719S, G719A, ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), ΔD761-E762 (ins EAFQ), ΔS768-D770 (dup SVD), ΔV769-D770 (ins ASV), ΔD770-N771 (ins SVQ), ΔP772-H773 (ins PR), ΔH773-V774 (ins NPH), ΔH773-V774 (ins H), ΔH773-V774 (ins PH), and ΔH773-V774 (ins GNPH), T790M, and L858R.

14. The method of claim 10 , wherein the EGFR variant contains T790M, L858R, or a combination thereof.

15. The method of claim 8 , wherein the cancer is resistant to an EGFR inhibitor.

16. The method of claim 15 , wherein the cancer is resistant to afatinib, canertinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, neratinib, pelitinib, varlitinib, or a combination thereof.

17. The method of claim 8 , wherein the cancer is bladder cancer, brain tumor, breast cancer, cancer of the mouth and throat, colorectal cancer, lung cancer, or pancreatic cancer, prostate cancer, stomach cancer, or uterine cancer.

18. The method of claim 1 , wherein L 1 is a bond, —O—, —N(R 1A )—, or —C(R 1A R 1B )—.

19. The method of claim 1 , wherein L 1 is a bond, —O—, —NH—, or —CH 2 —.

20. The method of claim 1 , wherein L 1 is a bond.

21. The method of claim 1 , wherein L 2 is C 3-10 cycloalkylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more substituents Q.

22. The method of claim 1 , wherein L 2 is heterocyclylene, each of which is optionally substituted with one or more substituents Q.

23. The method of claim 1 , wherein R 2 is C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

24. The method of claim 1 , wherein R 2 is 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents Q.

25. The method of claim 1 , wherein R 2 is phenyl, pyridinyl, pyridazinyl, benzo[c][1,2,5]oxodiazolyl, or benzo[c][1,2,5]thiodiazolyl, each of which is optionally substituted with one or more substituents Q.

26. The method of claim 1 , wherein Z is NH.

27. The method of claim 2 , wherein R 7a is C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

28. The method of claim 2 , wherein R 7a is heterocyclyl, optionally substituted with one or more substituents Q.

29. The method of claim 2 , wherein R 7a is

30. The method of claim 3 , wherein R 2n is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, —OH, or —OCH 3 .

31. The method of claim 3 , wherein R 7a is heterocyclyl, optionally substituted with one or more substituents Q.

32. The method of claim 3 , wherein R 7a is

33. The method of claim 5 , wherein R 7 is chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, or —OR 1a .

34. The method of claim 5 , wherein R 7 is chloro.

35. The method of claim 5 , wherein R 6a is heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

36. The method of claim 5 , wherein R 6a is:

37. The method of claim 6 , wherein R 2n is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, —OH, or —OCH 3 .

38. The method of claim 6 , wherein R 7 is chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, or —OR 1a .

39. The method of claim 6 , wherein R 7 is chloro.

40. The method of claim 6 , wherein R 6a is heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

41. The method of claim 6 , wherein R 6a is: