Benzimidazole derivatives, and pharmaceutical compositions and methods of use thereof

1. A compound 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 a solvate thereof;

wherein each R 1 is independently selected from:

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;

each R 4 , R 5 , and R 7 is 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)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 , —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 ;

R 6a is C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;

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; and

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 d )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 , —SR a , —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 (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 , —OR f , —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 compound of claim 1 , having the structure of Formula XXa:

or a single enantiomer, a racemic mixture, a mixture of diastereomers, 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 .

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

4. The compound of claim 2 , wherein R 7 is chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, or —OR 1a .

5. The compound of claim 4 , wherein R 7 is chloro.

6. The compound of claim 2 , wherein R 6a is:

wherein:

p and q are each independently an integer of 0, 1, or 3, with the proviso that the total of p and q is no less than 1; and

each r is independently an integer of 0, 1, 2, 3, 4, 5, or 6.

7. The compound of claim 2 , wherein R 6a is:

8. The compound of claim 1 , wherein R 2 is 6- to 10-membered monocyclic or bicyclic aryl, optionally substituted with one or more substituents Q.

9. The compound 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.

10. The compound 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.

11. The compound of claim 1 , wherein R 4 is hydrogen.

12. The compound of claim 1 , wherein R 5 is hydrogen.

13. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient.

14. The pharmaceutical composition of claim 13 , wherein the composition is formulated for oral, nasal, bronchial, or topical administration.

15. The pharmaceutical composition of claim 13 , wherein the composition is formulated as a single dosage form.

16. The pharmaceutical composition of claim 13 , wherein the composition is formulated as oral, parenteral, nasal, respiratory, pulmonary, or intravenous dosage form.

17. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition is in an oral dosage form.

18. The pharmaceutical composition of claim 17 , wherein the oral dosage form is a tablet or capsule.

19. The pharmaceutical composition of claim 13 , further comprising a second therapeutic agent.

20. The compound of claim 1 , wherein the compound is

21. The compound of claim 1 , wherein the compound is a pharmaceutically acceptable salt of

22. The pharmaceutical composition of claim 13 , wherein the compound is

23. The pharmaceutical composition of claim 13 , wherein the compound is a pharmaceutically acceptable salt of