阅读说明：本技术 金属酶抑制剂化合物 (Metalloenzyme inhibitor compounds ) 是由 史蒂文·斯帕克斯 克里斯多夫·M·耶茨 塞米·R·谢弗 威廉·J·胡克斯特拉 于 2017-12-22 设计创作，主要内容包括：提供了具有金属酶调节活性的化合物、以及治疗由这些金属酶介导的疾病、病症或症状的方法。(Compounds having metalloenzyme modulating activity are provided, as are methods of treating diseases, disorders, or conditions mediated by such metalloenzymes.)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein

A is N or CR⁵；

W is N or CR⁶；

X is N or CR⁶；

Y is N or CR⁶；

Z is N or CR⁶；

Provided that no more than two of W, X, Y and Z are N;

R¹is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、S(O)R^d、S(O)₂R^d、CH₂OR^fOr CR^eR^fOH, wherein any R¹Optionally substituted by 1 to 3 independent substituents R⁷Substitution;

R²is hydrogen, halogen, cyano, alkyl or haloalkyl;

or R¹And R²Together with the atoms to which they are attached form an aryl, heterocycloalkyl, or cycloalkyl ring;

R³is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、CH₂OR^fOr CR^eR^fOH；

R⁴Is alkyl, cycloalkyl, haloalkyl or heteroalkyl;

R⁵is hydrogen, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

each occurrence of R⁶Independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl or carboxyl;

each occurrence of R⁷Independently halogen, alkyl, alkoxy, haloalkyl, carboxy, aryl substituted with 1 to 3 independent halogens, - (CH)₂)_nC(O)NR^gR^h、-S(O)₂Rⁱ、-CO₂R^jOr NR^gR^h，

Each n is independently 1,2, 3,4, 5,6,7,8, 9, or 10;

each occurrence of R^a、R^b、R^c、R^d、R^eAnd R^fIndependently hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC_1-6Alkyl, C (O) C_1-6An alkyl group, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R^aAnd R^bTogether with the atoms to which they are attached form a heterocycloalkyl ring; or R^eAnd R^fTogether with the atoms to which they are attached form a cycloalkyl ring; and

each occurrence of R^g、R^h、RⁱAnd R^jIndependently of each otherIs hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC_1-6Alkyl, C (O) C_1-6Alkyl, or R^gAnd R^hTogether with the atoms to which they are attached form a heterocycloalkyl ring.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹Is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、COR^fOr CR^eR^fOH; or R¹And R²Together with the atoms to which they are attached form an aromatic ring.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹Is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR^aR^b、CH₂NHSO₂R^dOr CR^eR^fOH; or R¹And R²Together with the atoms to which they are attached form an aromatic ring.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R¹is hydrogen, halogen, alkyl, haloalkyl, CH₂NHSO₂R^dOr NR^aR^b(ii) a And

R^a、R^band R^dIndependently hydrogen, alkyl or haloalkyl.

5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹Is a haloalkyl group.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen or alkyl.

7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹Is hydrogen, R²Is an alkyl group.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R⁴Is an alkyl or cycloalkyl group.

9. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R⁴Is C_1-4Alkyl or C_3-5A cycloalkyl group.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each R⁶Independently hydrogen, halogen, cyano, alkoxy, haloalkyl or carboxyl.

11. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each R⁶Independently hydrogen, halogen or cyano.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein a is CR⁵And R is⁵Is hydrogen, C_1-4Alkyl or C_3-5A cycloalkyl group.

13. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein a is N.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein no more than one of W, X, Y and Z is N.

15. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein W, X, Y and Z are each independently CR⁶。

16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Z is N.

17. The compound of claim 1, wherein the compound is of formula I-a:

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein a is N.

19. The compound of claim 1, wherein the compound is a compound of formula I-b:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound is a compound of formula I-c:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound is a compound of formula I-d:

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound is a compound of formula I-e:

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound is a compound of formula I-f:

or a pharmaceutically acceptable salt thereof.

24. A compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein R¹Is a haloalkyl group.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein each R⁶Independently a halogen.

26. The compound of claim 1, wherein the compound is of formula I-g:

or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1, selected from:

1-cyclopropyl-6-fluoro-2- (pyridazin-4-yl) -1H-benzo [ d ] imidazole (1);

5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carbonitrile (2);

2- (6-chloropyridazin-4-yl) -1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazole (3);

1-cyclopropyl-6-fluoro-2- (6-vinylpyridazin-4-yl) -1H-benzo [ d ] imidazole (4);

5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carboxylic acid methyl ester (5);

1-cyclopropyl-2- (6-ethylpyridazin-4-yl) -6-fluoro-1H-benzo [ d ] imidazole (6);

1- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -2,2, 2-trifluoroethyl-1-ol (7);

n- ((5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) propanamide (8);

(5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) carbamic acid ethyl ester (9);

4- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) morpholine (10);

1-cyclopropyl-6-fluoro-2- (6- (4- (4-fluorophenyl) piperazin-1-yl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (11);

2- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) propan-2-ol (12);

5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyridazin-3-amine (13);

4- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) cinnoline (14);

1-cyclopropyl-6-fluoro-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (15);

n- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethanesulfonamide (16);

2- (6-chloropyridazin-4-yl) -1-ethyl-1H-benzo [ d ] imidazole-6-carbonitrile (17);

2- (4- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazin-1-yl) -N-isopropylacetamide (18);

1-cyclopropyl-5, 6-difluoro-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (19);

2- (4- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazin-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one (20);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N-methylpyridazin-3-amine (21);

2- (6-chloropyridazin-4-yl) -1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazole (22);

1-cyclopropyl-5, 6-difluoro-2- (6-methoxypyridazin-4-yl) -1H-benzo [ d ] imidazole (23);

1-cyclopropyl-5, 6-difluoro-2- (6-isopropoxypyridazin-4-yl) -1H-benzo [ d ] imidazole (24);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N, N-dimethylpyridazin-3-amine (25);

1-ethyl-6-fluoro-2- (6-methylpyridazin-4-yl) -1H-indole (26);

1-cyclopropyl-5, 6-difluoro-2- (6- (2,2, 2-trifluoroethoxy) pyridazin-4-yl) -1H-benzo [ d ] imidazole (27);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N- (2-methoxyethyl) pyridazin-3-amine (28);

1-cyclopropyl-2- (6-methoxypyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (29);

1-cyclopropyl-6-fluoro-2- (6-methylpyridazin-4-yl) -1H-indole (30);

n- ((5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) ethanesulfonamide (31);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N- (2,2, 2-trifluoroethyl) pyridazin-3-amine (32);

1-cyclopropyl-2- (6-ethylpyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (33);

2- (6-chloropyridazin-4-yl) -1-cyclopropyl-1H-benzo [ d ] imidazole-6-carbonitrile (34);

1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (35);

1-cyclopropyl-5, 6-difluoro-2- (6- (4-methylpiperazin-1-yl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (36);

1- (4- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazin-1-yl) ethan-1-one (37);

1-cyclopropyl-5, 6-difluoro-2- (6- (4- (methylsulfonyl) piperazin-1-yl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (38);

4- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (39);

1-ethyl-2- (6-methoxypyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (40);

1-ethyl-2- (6-ethylpyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (41);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (42);

2- (6-cyclobutoxypyridazin-4-yl) -1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazole (43);

1-cyclopropyl-2- (6- (4, 4-difluoropiperidin-1-yl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (44);

5-chloro-3-cyclopropyl-2- (6-methylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (45);

1-cyclopropyl-2- (6- (3, 3-difluoropyrrolidin-1-yl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (46);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -2,2, 2-trifluoroethyl-1-ol (47);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -N, N-dimethylpyrrolidin-3-amine (48);

1-cyclopropyl-5, 6-difluoro-2- (6- (4-fluorophenyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (49);

1-cyclopropyl-5, 6-difluoro-2- (6- ((4-fluorophenyl) ethynyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (50);

1-cyclopropyl-5, 6-difluoro-2- (6-isopropylpyridazin-4-yl) -1H-benzo [ d ] imidazole (51);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) ethanesulfonamide (52);

1-cyclopropyl-5, 6-difluoro-2- (6- ((1,1, 1-trifluoropropan-2-yl) oxy) pyridazin-4-yl) -1H-benzo [ d ] imidazole (53);

3-cyclopropyl-2- (6-methylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (54);

1-cyclopropyl-5, 6-difluoro-2- (pyridazin-4-yl) -1H-benzo [ d ] imidazole (55);

1-cyclopropyl-5, 6-difluoro-2- (pyridazin-4-yl) -4- (trifluoromethyl) -1H-benzo [ d ] imidazole (56);

1-cyclopropyl-2- (6- (2, 2-difluoropropoxy) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (57);

1-cyclopropyl-5, 6-difluoro-2- (5-isopropylpyridazin-4-yl) -1H-benzo [ d ] imidazole (58);

1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (59);

2- (6-chloropyridazin-4-yl) -3-cyclopropyl-5-methoxy-3H-imidazo [4,5-b ] pyridine (60);

1-cyclopropyl-5, 6-difluoro-2- (6- (4-fluoro-2-methylphenyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (61);

1-cyclopropyl-2- (6- (2, 4-difluorophenyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (62);

1-cyclopropyl-2- (6- (3, 4-difluorophenyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (63);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethan-1-one (64);

2- (6-chloropyridazin-4-yl) -1-ethyl-5, 6-difluoro-1H-benzo [ d ] imidazole (65);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (66);

2- (6- (difluoromethyl) pyridazin-4-yl) -1-ethyl-5, 6-difluoro-1H-benzo [ d ] imidazole (67);

2- (6-chloropyridazin-4-yl) -1-ethyl-1H-benzo [ d ] imidazole-6-carbonitrile (68);

2- (6- (difluoromethyl) pyridazin-4-yl) -1-ethyl-1H-benzo [ d ] imidazole-6-carbonitrile (69);

1-cyclopropyl-2- (6- (1, 1-difluoroethyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (70);

1-cyclopropyl-5, 6-difluoro-2- (6- (2,2, 2-trifluoroethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (71);

2- (6-cyclopropylpyridazin-4-yl) -1-ethyl-5, 6-difluoro-1H-benzo [ d ] imidazole (72);

5-chloro-3-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (73);

1-cyclopropyl-5, 6-difluoro-2- (5-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (74);

1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (75);

3-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (76);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) methanesulfonamide (77);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) -N-methylmethanesulfonamide (78);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) propane-2-sulfonamide (79);

1-cyclopropyl-5, 6-difluoro-2- (6- (methylsulfonyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (80);

1-cyclopropyl-2- (6- (ethylsulfonyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (81);

1-cyclopropyl-5, 6-difluoro-2- (6- (methylsulfinyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (82);

1-cyclopropyl-2- (6- (ethylsulfinyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (83);

5-chloro-3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (84);

1-cyclopropyl-5, 6-difluoro-2- (6- (trifluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (85);

1-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (86);

3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (87);

2- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) isothiazolidine 1, 1-dioxide (88);

3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (89);

1-cyclopropyl-2- (6-methylpyridazin-4-yl) -6- (trifluoromethyl) -1H-benzo [ d ] imidazole (90);

and pharmaceutically acceptable salts thereof.

28. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein

A is N or CR⁵；

W is N or CR⁶；

X is N or CR⁶；

Y is N or CR⁶；

Z is N or CR⁶；

Provided that no more than two of W, X, Y and Z are N;

R¹is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CR^eR^fNHSO₂R^d、OR^f、SR^f、CO₂R^e、COR^f、S(O)R^d、S(O)₂R^d、CH₂OR^fOr CR^eR^fOH, wherein any R¹Optionally substituted by 1 to 3 independent substituents R⁷Substitution;

R²is hydrogen, halogen, cyano, alkyl or haloalkyl;

or R¹And R²Together with the atoms to which they are attached form an aryl, heterocycloalkyl, or cycloalkyl ring;

R³is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyHaloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、CH₂OR^fOr CR^eR^fOH；

R⁴Is alkyl, cycloalkyl, haloalkyl or heteroalkyl;

R⁵is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

each occurrence of R⁶Independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, OR^fOr a carboxyl group;

each occurrence of R⁷Independently halogen, alkyl, alkoxy, haloalkyl, carboxy, cycloalkyl, aryl substituted with 1 to 3 independent halogens, - (CH)₂)_nC(O)NR^gR^h、-S(O)₂Rⁱ、-CO₂R^jOr NR^gR^h，

Each n is independently 1,2, 3,4, 5,6,7,8, 9, or 10;

each occurrence of R^a、R^b、R^c、R^d、R^eAnd R^fIndependently hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC_1-6Alkyl, C (O) C_1-6An alkyl group, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R^aAnd R^bTogether with the atoms to which they are attached form a heterocycloalkyl ring; or R^eAnd R^fTogether with the atoms to which they are attached form a cycloalkyl ring; and

each occurrence of R^g、R^h、RⁱAnd R^jIndependently hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl,Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC_1-6Alkyl, C (O) C_1-6Alkyl, or R^gAnd R^hTogether with the atoms to which they are attached form a heterocycloalkyl ring.

29. A compound or pharmaceutically acceptable salt thereof according to claim 28, wherein R¹Is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CR^eR^fNHSO₂R^d、SR^f、COR^fOr CR^eR^fOH; or R¹And R²Together with the atoms to which they are attached form an aromatic or cycloalkyl ring.

30. A compound or pharmaceutically acceptable salt thereof according to claim 28, wherein R¹Is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR^aR^b、CR^eR^fNHSO₂R^d、SR^fOr CR^eR^fOH; or R¹And R²Together with the atoms to which they are attached form an aromatic or cycloalkyl ring.

31. A compound according to claim 28, or a pharmaceutically acceptable salt thereof, wherein:

R¹is hydrogen, halogen, alkyl, haloalkyl, CR^eR^fNHSO₂R^d、SR^fOr NR^aR^b(ii) a And

R^a、R^b、R^d、R^eand R^fIndependently hydrogen, alkyl or haloalkyl.

32. A compound or pharmaceutically acceptable salt thereof according to claim 28, wherein R¹Is a haloalkyl group.

33. The compound according to any one of claims 28 to 32, or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen or alkyl.

34. A compound or pharmaceutically acceptable salt thereof according to claim 28, wherein R¹Is hydrogen, R²Is an alkyl group.

35. The compound of any one of claims 28 to 34, or a pharmaceutically acceptable salt thereof, wherein R⁴Is an alkyl or cycloalkyl group.

36. The compound of any one of claims 28 to 34, or a pharmaceutically acceptable salt thereof, wherein R⁴Is C_1-4Alkyl or C_3-5A cycloalkyl group.

37. The compound of any one of claims 28 to 36, or a pharmaceutically acceptable salt thereof, wherein each R⁶Independently hydrogen, halogen, cyano, alkoxy, haloalkyl or carboxyl.

38. The compound of any one of claims 28 to 36, or a pharmaceutically acceptable salt thereof, wherein each R⁶Independently hydrogen, halogen or cyano.

39. The compound according to any one of claims 28 to 38, or a pharmaceutically acceptable salt thereof, wherein a is CR⁵And R is⁵Is hydrogen, C_1-4Alkyl or C_3-5A cycloalkyl group.

40. The compound of any one of claims 28 to 38, or a pharmaceutically acceptable salt thereof, wherein a is N.

41. The compound of any one of claims 28 to 40, or a pharmaceutically acceptable salt thereof, wherein no more than one of W, X, Y and Z is N.

42. The compound of any one of claims 28 to 41, or a pharmaceutically acceptable salt thereof, wherein W, X, Y and Z are each independently CR⁶。

43. The compound of any one of claims 28 to 41, or a pharmaceutically acceptable salt thereof, wherein Z is N.

44. The compound of claim 28, wherein the compound is of formula I-a:

or a pharmaceutically acceptable salt thereof.

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein A is N.

46. The compound of claim 28, wherein the compound is a compound of formula I-b:

or a pharmaceutically acceptable salt thereof.

47. The compound of claim 28, wherein the compound is a compound of formula I-c:

or a pharmaceutically acceptable salt thereof.

48. The compound of claim 28, wherein the compound is a compound of formula I-d:

or a pharmaceutically acceptable salt thereof.

49. The compound of claim 28, wherein the compound is a compound of formula I-e:

or a pharmaceutically acceptable salt thereof.

50. The compound of claim 28, wherein the compound is a compound of formula I-f:

or a pharmaceutically acceptable salt thereof.

51. A compound or pharmaceutically acceptable salt thereof according to claim 50, wherein R¹Is a haloalkyl group.

52. A compound or pharmaceutically acceptable salt thereof according to claim 50, wherein R⁶Independently a halogen.

53. The compound of claim 28, wherein the compound is of formula I-g:

or a pharmaceutically acceptable salt thereof.

54. A compound selected from:

1-cyclopropyl-6-fluoro-2- (pyridazin-4-yl) -1H-benzo [ d ] imidazole (1);

5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carbonitrile (2);

2- (6-chloropyridazin-4-yl) -1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazole (3);

1-cyclopropyl-6-fluoro-2- (6-vinylpyridazin-4-yl) -1H-benzo [ d ] imidazole (4);

5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carboxylic acid methyl ester (5);

1-cyclopropyl-2- (6-ethylpyridazin-4-yl) -6-fluoro-1H-benzo [ d ] imidazole (6);

1- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -2,2, 2-trifluoroethyl-1-ol (7);

n- ((5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) propanamide (8);

(5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) carbamic acid ethyl ester (9);

4- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) morpholine (10);

1-cyclopropyl-6-fluoro-2- (6- (4- (4-fluorophenyl) piperazin-1-yl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (11);

2- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) propan-2-ol (12);

5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyridazin-3-amine (13);

4- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) cinnoline (14);

1-cyclopropyl-6-fluoro-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (15);

n- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethanesulfonamide (16);

2- (6-chloropyridazin-4-yl) -1-ethyl-1H-benzo [ d ] imidazole-6-carbonitrile (17);

2- (4- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazin-1-yl) -N-isopropylacetamide (18);

1-cyclopropyl-5, 6-difluoro-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (19);

2- (4- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazin-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one (20);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N-methylpyridazin-3-amine (21);

2- (6-chloropyridazin-4-yl) -1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazole (22);

1-cyclopropyl-5, 6-difluoro-2- (6-methoxypyridazin-4-yl) -1H-benzo [ d ] imidazole (23);

1-cyclopropyl-5, 6-difluoro-2- (6-isopropoxypyridazin-4-yl) -1H-benzo [ d ] imidazole (24);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N, N-dimethylpyridazin-3-amine (25);

1-ethyl-6-fluoro-2- (6-methylpyridazin-4-yl) -1H-indole (26);

1-cyclopropyl-5, 6-difluoro-2- (6- (2,2, 2-trifluoroethoxy) pyridazin-4-yl) -1H-benzo [ d ] imidazole (27);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N- (2-methoxyethyl) pyridazin-3-amine (28);

1-cyclopropyl-2- (6-methoxypyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (29);

1-cyclopropyl-6-fluoro-2- (6-methylpyridazin-4-yl) -1H-indole (30);

n- ((5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) ethanesulfonamide (31);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N- (2,2, 2-trifluoroethyl) pyridazin-3-amine (32);

1-cyclopropyl-2- (6-ethylpyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (33);

2- (6-chloropyridazin-4-yl) -1-cyclopropyl-1H-benzo [ d ] imidazole-6-carbonitrile (34);

1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (35);

1-cyclopropyl-5, 6-difluoro-2- (6- (4-methylpiperazin-1-yl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (36);

1- (4- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazin-1-yl) ethan-1-one (37);

1-cyclopropyl-5, 6-difluoro-2- (6- (4- (methylsulfonyl) piperazin-1-yl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (38);

4- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (39);

1-ethyl-2- (6-methoxypyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (40);

1-ethyl-2- (6-ethylpyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (41);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (42);

2- (6-cyclobutoxypyridazin-4-yl) -1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazole (43);

1-cyclopropyl-2- (6- (4, 4-difluoropiperidin-1-yl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (44);

5-chloro-3-cyclopropyl-2- (6-methylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (45);

1-cyclopropyl-2- (6- (3, 3-difluoropyrrolidin-1-yl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (46);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -2,2, 2-trifluoroethyl-1-ol (47);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -N, N-dimethylpyrrolidin-3-amine (48);

1-cyclopropyl-5, 6-difluoro-2- (6- (4-fluorophenyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (49);

1-cyclopropyl-5, 6-difluoro-2- (6- ((4-fluorophenyl) ethynyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (50);

1-cyclopropyl-5, 6-difluoro-2- (6-isopropylpyridazin-4-yl) -1H-benzo [ d ] imidazole (51);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) ethanesulfonamide (52);

1-cyclopropyl-5, 6-difluoro-2- (6- ((1,1, 1-trifluoropropan-2-yl) oxy) pyridazin-4-yl) -1H-benzo [ d ] imidazole (53);

3-cyclopropyl-2- (6-methylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (54);

1-cyclopropyl-5, 6-difluoro-2- (pyridazin-4-yl) -1H-benzo [ d ] imidazole (55);

1-cyclopropyl-5, 6-difluoro-2- (pyridazin-4-yl) -4- (trifluoromethyl) -1H-benzo [ d ] imidazole (56);

1-cyclopropyl-2- (6- (2, 2-difluoropropoxy) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (57);

1-cyclopropyl-5, 6-difluoro-2- (5-isopropylpyridazin-4-yl) -1H-benzo [ d ] imidazole (58);

1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (59);

2- (6-chloropyridazin-4-yl) -3-cyclopropyl-5-methoxy-3H-imidazo [4,5-b ] pyridine (60);

1-cyclopropyl-5, 6-difluoro-2- (6- (4-fluoro-2-methylphenyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (61);

1-cyclopropyl-2- (6- (2, 4-difluorophenyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (62);

1-cyclopropyl-2- (6- (3, 4-difluorophenyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (63);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethan-1-one (64);

2- (6-chloropyridazin-4-yl) -1-ethyl-5, 6-difluoro-1H-benzo [ d ] imidazole (65);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (66);

2- (6- (difluoromethyl) pyridazin-4-yl) -1-ethyl-5, 6-difluoro-1H-benzo [ d ] imidazole (67);

2- (6-chloropyridazin-4-yl) -1-ethyl-1H-benzo [ d ] imidazole-6-carbonitrile (68);

2- (6- (difluoromethyl) pyridazin-4-yl) -1-ethyl-1H-benzo [ d ] imidazole-6-carbonitrile (69);

1-cyclopropyl-2- (6- (1, 1-difluoroethyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (70);

1-cyclopropyl-5, 6-difluoro-2- (6- (2,2, 2-trifluoroethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (71);

2- (6-cyclopropylpyridazin-4-yl) -1-ethyl-5, 6-difluoro-1H-benzo [ d ] imidazole (72);

5-chloro-3-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (73);

1-cyclopropyl-5, 6-difluoro-2- (5-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (74);

1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (75);

3-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (76);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) methanesulfonamide (77);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) -N-methylmethanesulfonamide (78);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) propane-2-sulfonamide (79);

1-cyclopropyl-5, 6-difluoro-2- (6- (methylsulfonyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (80);

1-cyclopropyl-2- (6- (ethylsulfonyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (81);

1-cyclopropyl-5, 6-difluoro-2- (6- (methylsulfinyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (82);

1-cyclopropyl-2- (6- (ethylsulfinyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (83);

5-chloro-3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (84);

1-cyclopropyl-5, 6-difluoro-2- (6- (trifluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (85);

1-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (86);

3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (87);

2- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) isothiazolidine 1, 1-dioxide (88);

3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (89);

1-cyclopropyl-2- (6-methylpyridazin-4-yl) -6- (trifluoromethyl) -1H-benzo [ d ] imidazole (90);

n- (1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethyl) methanesulfonamide (91);

1-cyclopropyl-5, 6-difluoro-2- (6- (fluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (92);

1-cyclopropyl-2- (5, 6-dimethylpyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (93);

(5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methanol (94);

5-chloro-3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (95);

n- (1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethyl) ethanesulfonamide (96);

2- (6-butylpyridazin-4-yl) -1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazole (97);

1-cyclopropyl-6-methyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (98);

1-cyclopropyl-5, 6-difluoro-2- (3-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (99);

1-cyclopropyl-2- (3, 6-dimethylpyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (100);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -6, 7-difluoro-1H-benzo [ d ] imidazole (101);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-thiol (102);

2- (6- (difluoromethyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (103);

2- (6- (difluoromethyl) pyridazin-4-yl) -5, 6-difluoro-1-methyl-1H-benzo [ d ] imidazole (104);

2- (6- (difluoromethyl) pyridazin-4-yl) -5, 6-difluoro-1-propyl-1H-benzo [ d ] imidazole (105);

4- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -5,6,7, 8-tetrahydrocinnoline (106);

1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole-5-carbonitrile (Ex.107)

1-cyclobutyl-5, 6-difluoro-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (108);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazol-6-ol (109);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carboxylic acid (110);

1-cyclopropyl-7-fluoro-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (111);

5-chloro-1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (112);

4-chloro-1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (113);

1-cyclopropyl-5, 6-difluoro-2- (6- (methoxymethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (114);

methyl 5- (6-cyano-1-cyclopropyl-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carboxylate (115);

5- (6-cyano-1-cyclopropyl-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carboxylic acid (116);

1-cyclopropyl-2- (6- (cyclopropylmethoxy) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (117);

1-cyclopropyl-2- (6- (2,2, 2-trifluoroethoxy) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (118);

6-chloro-1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5-fluoro-1H-benzo [ d ] imidazole (119);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5-fluoro-1H-benzo [ d ] imidazole-6-carbonitrile (120);

4- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -6, 7-dihydro-5H-cyclopenta [ c ] pyridazine (121);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -6-fluoro-1H-benzo [ d ] imidazole (122);

1-cyclopropyl-5, 6-difluoro-2- (6- (methylthio) pyridazin-4-yl) -1H-benzo [ d ] imidazole (123);

1-cyclopropyl-5, 6-difluoro-2- (6- (isopropylsulfanyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (124);

1-cyclopropyl-2- (6- ((difluoromethyl) thio) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (125);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-ol (126);

1-cyclopropyl-2- (6- (difluoromethoxy) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (127);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethan-1-ol (128);

1-cyclopropyl-5, 6-difluoro-2- (6- (1-fluoroethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (129);

1-cyclopropyl-5, 6-difluoro-2- (6- ((trifluoromethyl) thio) pyridazin-4-yl) -1H-benzo [ d ] imidazole (130)

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (131);

2- (6- (difluoromethyl) pyridazin-4-yl) -1-propyl-1H-benzo [ d ] imidazole (132);

1-cyclopropyl-2- (6- (difluoromethoxy) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (133);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1H-indole-3-carbonitrile (134);

2- (6- (difluoromethyl) pyridazin-4-yl) -1-methyl-1H-indole-3-carbonitrile (135);

1-cyclopropyl-2- (6- (1-fluoroethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (136);

and pharmaceutically acceptable salts thereof.

55. A compound selected from:

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (42);

3-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (76);

1-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (86);

and pharmaceutically acceptable salts thereof.

56. A method of inhibiting metalloenzyme activity, comprising contacting a compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, with a metalloenzyme.

57. The method of claim 56, wherein the contacting is performed in vivo.

58. The method of claim 56, wherein said contacting is performed in vitro.

59. The method of claim 56, wherein said metalloenzyme comprises a metal atom that is iron, zinc, heme iron, manganese, magnesium, iron sulfide cluster, nickel, molybdenum, or copper.

60. The method of claim 56, wherein the metalloenzyme is a member of an enzyme class selected from cytochrome P450 family, cyclooxygenase and nitric oxide synthase.

61. The method of claim 56, wherein said metalloenzyme is aldosterone synthase (CYP11B 2).

62. The method of claim 56, wherein the metalloenzyme is aromatase (CYP19), a cyclooxygenase family member, lanosterol demethylase (CYP51), a nitric oxide synthase family member, thromboxane synthase (CYP5a), thyroid peroxidase, 17-alpha hydroxylase/17, 20-lyase (CYP17), cytochrome P4502A6(CYP2A6), heme oxygenase, indoleamine 2, 3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P4503A5(CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P4504F2(CYP4F2), myeloperoxidase, and 11-beta-hydroxylase (CYP11B 1).

63. The method of claim 56, further comprising administering the compound to a human subject.

64. A method of modulating metalloenzyme activity in a subject, comprising contacting the subject with a compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, in an amount and under conditions sufficient to modulate metalloenzyme activity.

65. A method of treating a subject suffering from or susceptible to a disorder or disease, wherein the subject has been identified as in need of treatment for the disorder or disease, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof.

66. A method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof.

67. A method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme-related disorder or disease, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to 55, such that the subject is receiving treatment for the disorder or disease.

68. A method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1-54, such that metalloenzyme activity in the subject is modulated (e.g., down-regulated, inhibited).

69. The method of any one of claims 65 to 68, wherein the disorder or disease is mediated by aromatase (CYP19), a cyclooxygenase family member, lanosterol demethylase (CYP51), a nitric oxide synthase family member, thromboxane synthase (CYP5a), thyroid peroxidase, 17-alpha hydroxylase/17, 20-lyase (CYP17), cytochrome P4502A6(CYP2A6), heme oxygenase, indoleamine 2, 3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P4503A5(CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P4504F2(CYP4F2), myeloperoxidase, or 11-beta-hydroxylase (CYP11B 1).

70. The method of any one of claims 65-69, wherein the disorder or disease is cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, Central Nervous System (CNS) disease, urological disease, or gastrointestinal disease.

71. The method of any one of claims 65-70, wherein the disorder or disease is hypertension, refractory hypertension, disorders associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction syndrome, coronary heart disease, fibrosis, diseases characterized by increased collagen formation following hypertension, fibrosis and matrix remodeling, diseases characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, cardiovascular diseases such as atherosclerosis, atrial fibrillation, renal dysfunction, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, nephropathy, or a combination thereof, Neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necroptosis, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall thickening, endothelial thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, liver cirrhosis, non-alcoholic fatty liver disease, kidney disease, diabetic nephropathy or stroke.

72. A pharmaceutical composition comprising a compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

73. The pharmaceutical composition of claim 72, further comprising an additional therapeutic agent.

74. The pharmaceutical composition of claim 72, further comprising an additional therapeutic agent that is an anti-cancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, a metabolic disease therapeutic agent, an ophthalmic disease therapeutic agent, a Central Nervous System (CNS) disease therapeutic agent, a urological disease therapeutic agent, or a gastrointestinal disease therapeutic agent.

75. The method of claim 65, wherein the subject is an animal other than a human.

Background

Aldosterone is a steroid hormone secreted from the adrenal gland that binds to and activates the Mineralocorticoid Receptor (MR). In primary cells of the renal distal tubules and renal collecting ducts, MR activation leads to retention of sodium and water with potassium excretion, causing expansion of plasma volume, resulting in increased Blood Pressure (BP). The excess aldosterone measured in the circulation is called Primary Aldosteronism (PA) and occurs when the renin-angiotensin-aldosterone system (RAAS) deregulates aldosterone production. PA was originally found in adrenal adenoma patients, and recent evidence suggests an increased prevalence associated with obesity. PA is a common cause of secondary hypertension, with prevalence ranging from 14% to 21% of patients with Refractory Hypertension (RHTN), a condition in which blood pressure is above target despite concurrent use of 3 antihypertensive drugs of different classes including diuretics. Recent studies have shown a correlation between excess aldosterone, RHTN, and Obstructive Sleep Apnea (OSA) that is exacerbated by aldosterone-mediated fluid retention.

In several severe disease states, local overproduction of aldosterone has been noted even if no significant plasma elevation was observed. In patients with chronic Congestive Heart Failure (CHF), aldosterone levels in failing heart tissue are higher than aldosterone levels in peripheral plasma. In animal models of renal disease, it is hypothesized that local production of aldosterone in the renal cortex contributes to disease progression. In both states, locally elevated aldosterone levels produce deleterious effects through MR-dependent and MR-independent mechanisms, including the production of reactive oxygen species and endothelial dysfunction, which lead to inflammation and stimulation of cell growth and proliferation, while up-regulated collagen deposition leads to fibrosis.

Antagonists of MR, including spironolactone and eplerenone, have been widely used to block the effects of aldosterone binding to MR. The use of these drugs in combination with Angiotensin Converting Enzyme (ACE) inhibitors and diuretics (RALES and ephsus tests) demonstrated a significant reduction in morbidity and mortality in patients with heart failure or myocardial infarction. Both drugs have side effects including hyperkalemia, where non-selective spironolactones also cause gynecomastia through nonselective modulation of progesterone and androgen receptors. In addition, the rise in renin and aldosterone is caused by MR antagonism, and thus the MR independent (non-genomic) effect of aldosterone is exacerbated.

In contrast to MR antagonists, inhibition of the key enzyme in aldosterone biosynthesis, CYP11B2 (aldosterone synthase), should provide a beneficial effect of MR antagonism without the deleterious accumulation of aldosterone leading to activation of MR-dependent inflammation and fibrotic states. CYP11B2 is a mitochondrial cytochrome P450 enzyme that converts 11-deoxycorticosterone to aldosterone. Selective inhibition of CYP11B2 represents a promising therapeutic approach for aldosterone-related diseases.

The highly homologous metalloenzyme CYP11B1 (11-beta-steroid-hydroxylase) catalyzes the formation of 11-deoxycorticosterol to the major glucocorticoid cortisol. In view of the high degree of homology (93%) between CYP11B2 and CYP11B1, the development of selective CYP11B2 inhibitors has been a significant challenge. The inhibitor, osildorostat (LCI-699), was developed as a CYP11B2 inhibitor for the treatment of hypertension, but was abandoned due to its potent inhibition of CYP11B 1. Described herein are selective compounds that block aldosterone production by CYP11B2 without inhibiting cortisol production by CYP11B 1.

Organisms have developed a tightly regulated process that specifically imports metals, transports them to intracellular storage sites, and ultimately to sites of use. One of the most useful functions of metals (e.g., zinc and iron) in biological systems is to make metalloenzymes active. Metalloenzymes are enzymes that bind metal ions to the active site of an enzyme and utilize the metal as part of the catalytic process. Over one third of the characterized enzymes are metalloenzymes.

The function of metalloenzymes is highly dependent on the presence of metal ions in the active site of the enzyme. It is well known that agents that bind to and inactivate active site metal ions significantly reduce the activity of the enzyme. Nature employs the same strategy to reduce the activity of certain metalloenzymes during periods when enzyme activity is not required. For example, the protein TIMP (tissue inhibitor of metalloproteinases) binds to zinc ions in the active site of various matrix metalloproteinases, thereby preventing enzymatic activity. The pharmaceutical industry uses the same strategy in the design of therapeutic agents. For example, the azole antifungal agents fluconazole and voriconazole contain a 1- (1,2, 4-triazole) group that binds to heme iron present in the active site of the target enzyme lanosterol demethylase, thereby inactivating the enzyme. Another example includes zinc-binding hydroxamic acid groups, which have been incorporated into most of the disclosed matrix metalloproteinase and histone deacetylase inhibitors. Another example is a zinc-bound carboxylic acid group, which has been incorporated into most of the disclosed angiotensin converting enzyme inhibitors.

In the design of clinically safe and effective metalloenzyme inhibitors, it is desirable to use appropriate metal binding groups for any particular target and clinical indication. If weakly bound metal binding groups are used, the efficacy may be sub-optimal. On the other hand, if very tightly bound metal binding groups are used, the selectivity of the target enzyme for the relevant metalloenzyme may not be optimal. The lack of optimal selectivity may be a cause of clinical toxicity due to unintended inhibition of these off-target metalloenzymes. An example of such clinical toxicity is the unintended inhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19 and CYP3a4 by currently available azole antifungals such as fluconazole and voriconazole. This off-target inhibition is believed to be primarily due to indiscriminate binding of the currently used 1- (1,2, 4-triazole) to iron in the CYP2C9, CYP2C19 and CYP3a4 active sites. Another example of clinical toxicity is joint pain observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity is thought to be related to the inhibition of off-target metalloenzymes, which is caused by the indiscriminate binding of hydroxamic acid groups to zinc in the deoxy active site.

Thus, the search for metal binding groups that can achieve a better balance of potency and selectivity remains an important goal and is of great significance in the implementation of therapeutic agents and methods to address the unmet need in the treatment and prevention of diseases, disorders and conditions at present.

Disclosure of Invention

The present invention relates to compounds (e.g., any of the compounds described herein; any of the formulae described herein), methods of modulating metalloenzyme activity, and methods of treating diseases, disorders, or conditions thereof. The methods may include the compounds herein.

It is to be understood that the embodiments of the invention discussed below with respect to the selection of preferred variables may be used alone or in combination with one or more embodiments of the invention or the preferred variable selections as if each combination were explicitly listed herein.

In one aspect, there is provided a compound of formula I:

or a pharmaceutically acceptable salt, co-crystal (co-crystal), tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein:

a is N or CR⁵；

W is N or CR⁶；

X is N or CR⁶；

Y is N or CR⁶；

Z is N or CR⁶；

Provided that no more than two of W, X, Y and Z are N;

R¹is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、S(O)R^d、S(O)₂R^d、CH₂OR^fOr CR^eR^fOH, wherein any R¹Optionally substituted by 1 to 3 independent substituents R⁷Substitution;

R²is hydrogen, halogen, cyano, alkyl or haloalkyl;

or R¹And R²Together with the atoms to which they are attached form an aryl, heterocycloalkyl, or cycloalkyl ring;

R³is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、CH₂OR^fOr CR^eR^fOH；

R⁴Is alkyl, cycloalkyl, haloalkyl or heteroalkyl;

R⁵is hydrogen, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

each occurrence of R⁶Independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl or carboxyl;

each occurrence of R⁷Independently halogen, alkyl, alkoxy, haloalkyl, carboxy, aryl substituted with 1 to 3 independent halogens, - (CH)₂)_nC(O)NR^gR^h、-S(O)₂Rⁱ、-CO₂R^jOr NR^gR^h；

Each n is independently 1,2, 3,4, 5,6,7,8, 9, or 10;

each occurrence of R^a、R^b、R^c、R^d、R^eAnd R^fIndependently hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC_1-6Alkyl, C (O) C_1-6Alkyl, nitrogen when bound to a nitrogen atomA protecting group, or an oxygen protecting group when attached to an oxygen atom; or R^aAnd R^bTogether with the atoms to which they are attached form a heterocycloalkyl ring; or R^eAnd R^fTogether with the atoms to which they are attached form a cycloalkyl ring; and

each occurrence of R^g、R^h、RⁱAnd R^jIndependently hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC_1-6Alkyl, C (O) C_1-6Alkyl, or R^gAnd R^hTogether with the atoms to which they are attached form a heterocycloalkyl ring.

In certain embodiments, R¹Is aryl, heteroaryl or heterocycloalkyl, wherein any R¹May optionally be substituted with 1 to 3 independent substituents R⁷And (4) substitution.

In certain embodiments, R¹Is aryl, heteroaryl or heterocycloalkyl, wherein any R¹May optionally be substituted with 1 to 3 independent substituents R⁷Is substituted, and each R⁷Independently halogen, alkyl, alkoxy, haloalkyl, carboxyl, - (CH)₂)_nC(O)NR^gR^h、-S(O)₂Rⁱ、-CO₂R^jOr NR^gR^hAnd each R is^gAnd R^hIndependently hydrogen, alkyl, C (O) C_1-6Alkyl, or R^gAnd R^hTogether with the atoms to which they are attached form a heterocycloalkyl ring.

In certain embodiments, R¹Is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、COR^fOr CR^eR^fOH; or R¹And R²Together with the atoms to which they are attached form an aromatic ring.

In certain embodiments, R¹Is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR^aR^b、CH₂NHSO₂R^dOr CR^eR^fOH; or R¹And R²Together with the atoms to which they are attached form an aromatic ring.

In certain embodiments, R¹Is hydrogen, halogen, alkyl, haloalkyl, CH₂NHSO₂R^dOr NR^aR^b；R^a、R^bAnd R^dIndependently hydrogen, alkyl or haloalkyl.

In certain embodiments, R¹Is an alkyl or haloalkyl group.

In certain embodiments, R¹Is C_1-6Alkyl or C_1-6A haloalkyl group.

In certain embodiments, R¹Is a haloalkyl group.

In certain embodiments, R¹Is C_1-6A haloalkyl group.

In certain embodiments, R¹Is a fluoroalkyl group. In certain embodiments, R¹Is C_1-6A fluoroalkyl group. In certain embodiments, R¹Is C_1-3A fluoroalkyl group. In certain embodiments, R¹Is difluoromethyl or trifluoromethyl. In certain embodiments, R¹Is difluoromethyl. In certain embodiments, R¹Is trifluoromethyl.

In certain embodiments, R²Is hydrogen or alkyl.

In certain embodiments, R²Is hydrogen or C_1-6An alkyl group.

In certain embodiments, R²Is hydrogen or C_1-3An alkyl group.

In certain embodiments, R²Is an alkyl group. In certain embodiments, R²Is C_1-6An alkyl group. In certain embodiments, R²Is C_1-3An alkyl group. In certain embodiments, R²Is hydrogen.

In certain embodiments, R¹Is hydrogen and R²Is an alkyl group. In certain embodiments, R¹Is hydrogen and R²Is C_1-6An alkyl group. In certain embodiments, R¹Is hydrogen and R²Is C_1-3An alkyl group.

In certain embodiments, R⁴Is an alkyl or cycloalkyl group.

In certain embodiments, R⁴Is C_1-4Alkyl or C_3-5A cycloalkyl group.

In certain embodiments, R⁴Is C_1-4An alkyl group. In certain embodiments, R⁴Is C_3-5A cycloalkyl group. In certain embodiments, R⁴Is cyclopentyl. In certain embodiments, R⁴Is a cyclobutyl group. In certain embodiments, R⁴Is cyclopropyl.

In certain embodiments, each R is⁶Independently hydrogen, halogen, cyano, alkoxy, haloalkyl or carboxyl.

In certain embodiments, each R is⁶Independently hydrogen, halogen or cyano.

In certain embodiments, each R is⁶Independently hydrogen, chloro, fluoro or cyano.

In certain embodiments, each R is⁶Independently hydrogen, fluoro or cyano.

In certain embodiments, each R is⁶Independently hydrogen or halogen.

In certain embodiments, each R is⁶Independently hydrogen, chlorine or fluorine.

In certain embodiments, each R is⁶Independently hydrogen or fluorine.

In certain embodiments, each R is⁶Independently hydrogen or cyano.

In certain embodiments, each R is⁶Is a halogen. In certain embodiments, each R is⁶Is chlorine or fluorine. In certain embodiments, each R is⁶Is fluorine. In certain embodiments, each R is⁶Is cyano.

In certain embodiments, A is CR⁵And R is⁵Is hydrogen, C_1-4Alkyl or C_3-5A cycloalkyl group.

In certain embodiments, a is N.

In certain embodiments, no more than one of W, X, Y and Z is N.

In certain embodiments, W, X, Y and Z are each CR⁶。

In certain embodiments, Z is N.

In certain embodiments, the compound of formula I is a compound of formula I-a:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R²、R⁴、R⁶A, X and Z are as defined herein.

In certain embodiments, the compound of formula I is a compound of formula I-b:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R²、R⁴W, X, Y and Z are as defined herein.

In certain embodiments, the compound of formula I is a compound of formula I-c:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, or polymorph thereofA polymorph, isotopically enriched derivative or prodrug thereof, wherein R¹、R²、R⁴、R⁶And Z is as defined herein.

In certain embodiments, the compound of formula I is a compound of formula I-d:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R²、R⁴、R⁶And Z is as defined herein.

In certain embodiments, the compound of formula I is a compound of formula I-e:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R⁴、R⁶And Z is as defined herein.

In certain embodiments, the compound of formula I is a compound of formula I-f:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R⁴And R⁶As defined herein.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; r⁶Is hydrogen or halogen, wherein at least one R⁶Is halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; r⁶Is a halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; r⁶Is hydrogen or halogen, wherein at least one R⁶Is halogen; r¹Is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、CH₂OR^fOr CR^eR^fOH。

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; r⁶Is hydrogen or halogen, wherein at least one R⁶Is halogen; r¹Is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycloalkyl.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is alkyl or haloalkyl; r⁴Is alkyl or cycloalkyl; r⁶Is hydrogen or halogen, wherein at least one R⁶Is halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is alkyl or haloalkyl; r⁴Is alkyl or cycloalkyl; r⁶Is a halogen.

In certain embodiments, the compound of formula I is a compound of formulae I-g:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R⁴And R⁶As defined herein.

In certain embodiments, the aforementioned compounds of formula I-g are the following:

wherein R is⁴Is alkyl or cycloalkyl; r⁶Is hydrogen or halogen, wherein at least one R⁶Is halogen.

In certain embodiments, the aforementioned compounds of formula I-g are the following:

wherein R is⁴Is alkyl or cycloalkyl; r⁶Is a halogen.

In certain embodiments, the aforementioned compounds of formula I-g are the following:

wherein R is⁴Is alkyl or cycloalkyl; r⁶Is hydrogen or halogen, wherein at least one R⁶Is halogen; r¹Is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、CH₂OR^fOr CR^eR^fOH。

In certain embodiments, the aforementioned compounds of formula I-g are the following:

wherein R is⁴Is alkyl or cycloalkyl; r⁶Is hydrogen or halogen, wherein at least one R⁶Is halogen; r¹Is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycloalkyl.

In another aspect, compounds of formula I are provided:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein:

a is N or CR⁵；

W is N or CR⁶；

X is N or CR⁶；

Y is N or CR⁶；

Z is N or CR⁶；

Provided that no more than two of W, X, Y and Z are N;

R¹is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CR^eR^fNHSO₂R^d、OR^f、SR^f、CO₂R^e、COR^f、S(O)R^d、S(O)₂R^d、CH₂OR^fOr CR^eR^fOH, wherein any R¹Optionally substituted by 1 to 3 independent substituents R⁷Substitution;

R²is hydrogen, halogen, cyano, alkyl or haloalkyl;

or R¹And R²Together with the atoms to which they are attached form an aryl, heterocycloalkyl, or cycloalkyl ring;

R³is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、CH₂OR^fOr CR^eR^fOH；

R⁴Is alkyl, cycloalkyl, haloalkyl or heteroalkyl;

R⁵is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

each occurrence of R⁶Independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, OR^fOr a carboxyl group;

each occurrence of R⁷Independently halogen, alkyl, alkoxy, haloalkyl, carboxy, cycloalkyl, aryl substituted with 1 to 3 independent halogens, - (CH)₂)_nC(O)NR^gR^h、-S(O)₂Rⁱ、-CO₂R^jOr NR^gR^h；

Each n is independently 1,2, 3,4, 5,6,7,8, 9, or 10;

each occurrence of R^a、R^b、R^c、R^d、R^eAnd R^fIndependently hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC_1-6Alkyl, C (O) C_1-6An alkyl group, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R^aAnd R^bTogether with the atoms to which they are attached form a heterocycloalkyl ring; or R^eAnd R^fTogether with the atoms to which they are attached form a cycloalkyl ring; and

each occurrence of R^g、R^h、RⁱAnd R^jIndependently hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC_1-6Alkyl, C (O) C_1-6Alkyl, or R^gAnd R^hTogether with the atoms to which they are attached form a heterocycloalkyl ring.

In certain embodiments, R¹Is aryl, heteroarylOr heterocycloalkyl, wherein any R¹May optionally be substituted with 1 to 3 independent substituents R⁷And (4) substitution.

In certain embodiments, R¹Is aryl, heteroaryl or heterocycloalkyl, wherein any R¹May optionally be substituted with 1 to 3 independent substituents R⁷Is substituted, and each R⁷Independently halogen, alkyl, alkoxy, haloalkyl, carboxyl, - (CH)₂)_nC(O)NR^gR^h、-S(O)₂Rⁱ、-CO₂R^jOr NR^gR^hAnd each R is^gAnd R^hIndependently hydrogen, alkyl, C (O) C_1-6Alkyl, or R^gAnd R^hTogether with the atoms to which they are attached form a heterocycloalkyl ring.

In certain embodiments, R¹Is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CR^eR^fNHSO₂R^d、SR^f、COR^fOr CR^eR^fOH; or R¹And R²Together with the atoms to which they are attached form an aromatic or cycloalkyl ring.

In certain embodiments, R¹Is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR^aR^b、CR^eR^fNHSO₂R^d、SR^fOr CR^eR^fOH; or R¹And R²Together with the atoms to which they are attached form an aromatic or cycloalkyl ring.

In certain embodiments, R¹Is hydrogen, halogen, alkyl, haloalkyl, CR^eR^fNHSO₂R^d、SR^fOr NR^aR^b；R^a、R^b、R^d、R^eAnd R^fIndependently hydrogen, alkyl or haloAn alkyl group.

In certain embodiments, R¹Is SR^f. In certain embodiments, R¹Is SR^f；R^fIs hydrogen, alkyl or haloalkyl.

In certain embodiments, R¹Is an alkyl or haloalkyl group.

In certain embodiments, R¹Is C_1-6Alkyl or C_1-6A haloalkyl group.

In certain embodiments, R¹Is a haloalkyl group.

In certain embodiments, R¹Is C_1-6A haloalkyl group.

In certain embodiments, R¹Is a fluoroalkyl group. In certain embodiments, R¹Is C_1-6A fluoroalkyl group. In certain embodiments, R¹Is C_1-3A fluoroalkyl group. In certain embodiments, R¹Is difluoromethyl or trifluoromethyl. In certain embodiments, R¹Is difluoromethyl. In certain embodiments, R¹Is trifluoromethyl.

In certain embodiments, R²Is hydrogen or alkyl.

In certain embodiments, R²Is hydrogen or C_1-6An alkyl group.

In certain embodiments, R²Is hydrogen or C_1-3An alkyl group.

In certain embodiments, R²Is an alkyl group. In certain embodiments, R²Is C_1-6An alkyl group. In certain embodiments, R²Is C_1-3An alkyl group. In certain embodiments, R²Is hydrogen.

In certain embodiments, R¹Is hydrogen and R²Is an alkyl group. In certain embodiments, R¹Is hydrogen and R²Is C_1-6An alkyl group. In certain embodiments, R¹Is hydrogen and R²Is C_1-3An alkyl group.

In certain embodiments, R¹And R²With itThe atoms to which they are attached together form an aromatic or cycloalkyl ring. In certain embodiments, R¹And R²Together with the atoms to which they are attached form an aromatic ring. In certain embodiments, R¹And R²Together with the atoms to which they are attached form a cycloalkyl ring.

In certain embodiments, R⁴Is an alkyl or cycloalkyl group.

In certain embodiments, R⁴Is C_1-4Alkyl or C_3-5A cycloalkyl group.

In certain embodiments, R⁴Is C_1-4An alkyl group. In certain embodiments, R⁴Is C_3-5A cycloalkyl group. In certain embodiments, R⁴Is cyclopentyl. In certain embodiments, R⁴Is a cyclobutyl group. In certain embodiments, R⁴Is cyclopropyl.

In certain embodiments, each R is⁶Independently hydrogen, halogen, cyano, alkoxy, haloalkyl or carboxyl.

In certain embodiments, each R is⁶Independently hydrogen, halogen or cyano.

In certain embodiments, each R is⁶Independently hydrogen, chloro, fluoro or cyano.

In certain embodiments, each R is⁶Independently hydrogen, fluoro or cyano.

In certain embodiments, each R is⁶Independently hydrogen or halogen.

In certain embodiments, each R is⁶Independently hydrogen, chlorine or fluorine.

In certain embodiments, each R is⁶Independently hydrogen or fluorine.

In certain embodiments, each R is⁶Independently hydrogen or cyano.

In certain embodiments, each R is⁶Is a halogen. In certain embodiments, each R is⁶Is chlorine or fluorine. In certain embodiments, each R is⁶Is fluorine. In certain embodiments, each R is⁶Is cyano。

In certain embodiments, A is CR⁵And R is⁵Is hydrogen, cyano, C_1-4Alkyl or C_3-5A cycloalkyl group.

In certain embodiments, a is N.

In certain embodiments, no more than one of W, X, Y and Z is N.

In certain embodiments, W, X, Y and Z are each independently CR⁶。

In certain embodiments, Z is N.

In certain embodiments, the compound of formula I is a compound of formula I-a:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R²、R⁴、R⁶A, X and Z are each independently as defined herein.

In certain embodiments, the compound of formula I is a compound of formula I-b:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R²、R⁴W, X, Y and Z are each independently as defined herein.

In certain embodiments, the compound of formula I is a compound of formula I-c:

or a pharmaceutically acceptable salt, co-crystal, tautomer thereofA body, a stereoisomer, a solvate, a hydrate, a polymorph, an isotopically enriched derivative or a prodrug thereof, wherein R¹、R²、R⁴、R⁶And Z are each independently as defined herein.

In certain embodiments, the compound of formula I is a compound of formula I-d:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R²、R⁴、R⁶And Z are each independently as defined herein.

In certain embodiments, the compound of formula I is a compound of formula I-e:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R⁴、R⁶And Z are each independently as defined herein.

In certain embodiments, the compound of formula I is a compound of formula I-f:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R⁴And R⁶Each independently as defined herein.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen or halogen, wherein at least one R⁶Is halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently a halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds: wherein R is⁴Is C_1-4Alkyl or C_3-5A cycloalkyl group; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is a cycloalkyl group; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is C_3-5A cycloalkyl group; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is a cycloalkyl group; each R⁶Independently a halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is C_3-5A cycloalkyl group; each R⁶Independently a halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen, cyano or halogen;R¹is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、CH₂OR^fOr CR^eR^fOH。

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen or halogen, wherein at least one R⁶Is halogen; r¹Is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、CH₂OR^fOr CR^eR^fOH。

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen or halogen, wherein at least one R⁶Is halogen; r¹Is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycloalkyl.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is alkyl or haloalkyl; r⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen or halogen, wherein at least one R⁶Is halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is alkyl or haloalkyl; r⁴Is alkyl or cycloalkyl; each R⁶Independently a halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is alkyl or haloalkyl; r⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is C_1-4Alkyl or C_3-5A cycloalkyl group; each R₆Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is a cycloalkyl group; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is C_3-5A cycloalkyl group; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is a cycloalkyl group; each R⁶Independently a halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is C_3-5A cycloalkyl group; each R⁶Independently a halogen.

In certain embodiments, the compound of formula I is a compound of formulae I-g:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof¹、R⁴And R⁶Each independently as defined herein.

In certain embodiments, the aforementioned compounds of formula I-g are the following:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen or halogen, wherein at least one R⁶Is halogen.

In certain embodiments, the aforementioned compounds of formula I-g are the following:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently a halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is C_1-4Alkyl or C_3-5A cycloalkyl group; each R₆Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is a cycloalkyl group; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is C_3-5A cycloalkyl group; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is a cycloalkyl group; each R⁶Independently hydrogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is C_3-5A cycloalkyl group; each R⁶Independently hydrogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is a cycloalkyl group; each R⁶Independently a halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is C_3-5A cycloalkyl group; each R⁶Independently a halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen, cyano or halogen; r¹Is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、CH₂OR^fOr CR^eR^fOH。

In certain embodiments, the aforementioned compounds of formula I-g are the following:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen or halogen, wherein at least one R⁶Is halogen; r¹Is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR^aR^b、NHSO₂R^c、CH₂NR^aR^b、CH₂NHSO₂R^d、CO₂R^e、COR^f、CH₂OR^fOr CR^eR^fOH。

In certain embodiments, the aforementioned compounds of formula I-g are the following:

wherein R is⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen or halogen, wherein at least one R⁶Is halogen; r¹Is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycloalkyl.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is alkyl or haloalkyl; r⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is alkyl or haloalkyl; r⁴Is C_1-4Alkyl or C_3-5A cycloalkyl group; each R₆Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is alkyl or cycloalkyl; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is C_1-4Alkyl or C_3-5A cycloalkyl group; each R₆Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is a cycloalkyl group; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is C_3-5A cycloalkyl group; each R⁶Independently hydrogen, halogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is a cycloalkyl group; each R⁶Independently hydrogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is C_3-5A cycloalkyl group; each R⁶Independently hydrogen or cyano.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is a cycloalkyl group; each R⁶Independently a halogen.

In certain embodiments, the aforementioned compounds of formula I-f are the following compounds:

wherein R is¹Is a haloalkyl group; r⁴Is C_3-5A cycloalkyl group; each R⁶Independently a halogen.

In certain embodiments, the compound of formula I is a compound selected from the group consisting of:

1-cyclopropyl-6-fluoro-2- (pyridazin-4-yl) -1H-benzo [ d ] imidazole (1);

5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carbonitrile (2);

2- (6-chloropyridazin-4-yl) -1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazole (3);

1-cyclopropyl-6-fluoro-2- (6-vinylpyridazin-4-yl) -1H-benzo [ d ] imidazole (4);

5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carboxylic acid methyl ester (5);

1-cyclopropyl-2- (6-ethylpyridazin-4-yl) -6-fluoro-1H-benzo [ d ] imidazole (6);

1- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -2,2, 2-trifluoroethyl-1-ol (7);

n- ((5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) propanamide (8);

(5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) carbamic acid ethyl ester (9);

4- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) morpholine (10);

1-cyclopropyl-6-fluoro-2- (6- (4- (4-fluorophenyl) piperazin-1-yl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (11);

2- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) propan-2-ol (12);

5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyridazin-3-amine (13);

4- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) cinnoline (14);

1-cyclopropyl-6-fluoro-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (15);

n- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethanesulfonamide (16);

2- (6-chloropyridazin-4-yl) -1-ethyl-1H-benzo [ d ] imidazole-6-carbonitrile (17);

2- (4- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazin-1-yl) -N-isopropylacetamide (18);

1-cyclopropyl-5, 6-difluoro-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (19);

2- (4- (5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazin-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one (20);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N-methylpyridazin-3-amine (21);

2- (6-chloropyridazin-4-yl) -1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazole (22);

1-cyclopropyl-5, 6-difluoro-2- (6-methoxypyridazin-4-yl) -1H-benzo [ d ] imidazole (23);

1-cyclopropyl-5, 6-difluoro-2- (6-isopropoxypyridazin-4-yl) -1H-benzo [ d ] imidazole (24);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N, N-dimethylpyridazin-3-amine (25);

1-ethyl-6-fluoro-2- (6-methylpyridazin-4-yl) -1H-indole (26);

1-cyclopropyl-5, 6-difluoro-2- (6- (2,2, 2-trifluoroethoxy) pyridazin-4-yl) -1H-benzo [ d ] imidazole (27);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N- (2-methoxyethyl) pyridazin-3-amine (28);

1-cyclopropyl-2- (6-methoxypyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (29);

1-cyclopropyl-6-fluoro-2- (6-methylpyridazin-4-yl) -1H-indole (30);

n- ((5- (1-cyclopropyl-6-fluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) ethanesulfonamide (31);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -N- (2,2, 2-trifluoroethyl) pyridazin-3-amine (32);

1-cyclopropyl-2- (6-ethylpyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (33);

2- (6-chloropyridazin-4-yl) -1-cyclopropyl-1H-benzo [ d ] imidazole-6-carbonitrile (34);

1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (35);

1-cyclopropyl-5, 6-difluoro-2- (6- (4-methylpiperazin-1-yl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (36);

1- (4- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazin-1-yl) ethan-1-one (37);

1-cyclopropyl-5, 6-difluoro-2- (6- (4- (methylsulfonyl) piperazin-1-yl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (38);

4- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (39);

1-ethyl-2- (6-methoxypyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (40);

1-ethyl-2- (6-ethylpyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (41);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (42);

2- (6-cyclobutoxypyridazin-4-yl) -1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazole (43);

1-cyclopropyl-2- (6- (4, 4-difluoropiperidin-1-yl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (44);

5-chloro-3-cyclopropyl-2- (6-methylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (45);

1-cyclopropyl-2- (6- (3, 3-difluoropyrrolidin-1-yl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (46);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -2,2, 2-trifluoroethyl-1-ol (47);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -N, N-dimethylpyrrolidin-3-amine (48);

1-cyclopropyl-5, 6-difluoro-2- (6- (4-fluorophenyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (49);

1-cyclopropyl-5, 6-difluoro-2- (6- ((4-fluorophenyl) ethynyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (50);

1-cyclopropyl-5, 6-difluoro-2- (6-isopropylpyridazin-4-yl) -1H-benzo [ d ] imidazole (51);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) ethanesulfonamide (52);

1-cyclopropyl-5, 6-difluoro-2- (6- ((1,1, 1-trifluoropropan-2-yl) oxy) pyridazin-4-yl) -1H-benzo [ d ] imidazole (53);

3-cyclopropyl-2- (6-methylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (54);

1-cyclopropyl-5, 6-difluoro-2- (pyridazin-4-yl) -1H-benzo [ d ] imidazole (55);

1-cyclopropyl-5, 6-difluoro-2- (pyridazin-4-yl) -4- (trifluoromethyl) -1H-benzo [ d ] imidazole (56);

1-cyclopropyl-2- (6- (2, 2-difluoropropoxy) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (57);

1-cyclopropyl-5, 6-difluoro-2- (5-isopropylpyridazin-4-yl) -1H-benzo [ d ] imidazole (58);

1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (59);

2- (6-chloropyridazin-4-yl) -3-cyclopropyl-5-methoxy-3H-imidazo [4,5-b ] pyridine (60);

1-cyclopropyl-5, 6-difluoro-2- (6- (4-fluoro-2-methylphenyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (61);

1-cyclopropyl-2- (6- (2, 4-difluorophenyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (62);

1-cyclopropyl-2- (6- (3, 4-difluorophenyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (63);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethan-1-one (64);

2- (6-chloropyridazin-4-yl) -1-ethyl-5, 6-difluoro-1H-benzo [ d ] imidazole (65);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (66);

2- (6- (difluoromethyl) pyridazin-4-yl) -1-ethyl-5, 6-difluoro-1H-benzo [ d ] imidazole (67);

2- (6-chloropyridazin-4-yl) -1-ethyl-1H-benzo [ d ] imidazole-6-carbonitrile (68);

2- (6- (difluoromethyl) pyridazin-4-yl) -1-ethyl-1H-benzo [ d ] imidazole-6-carbonitrile (69);

1-cyclopropyl-2- (6- (1, 1-difluoroethyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (70);

1-cyclopropyl-5, 6-difluoro-2- (6- (2,2, 2-trifluoroethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (71);

2- (6-cyclopropylpyridazin-4-yl) -1-ethyl-5, 6-difluoro-1H-benzo [ d ] imidazole (72);

5-chloro-3-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (73);

1-cyclopropyl-5, 6-difluoro-2- (5-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (74);

1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (75);

3-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (76);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) methanesulfonamide (77);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) -N-methylmethanesulfonamide (78);

n- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) propane-2-sulfonamide (79);

1-cyclopropyl-5, 6-difluoro-2- (6- (methylsulfonyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (80);

1-cyclopropyl-2- (6- (ethylsulfonyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (81);

1-cyclopropyl-5, 6-difluoro-2- (6- (methylsulfinyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (82);

1-cyclopropyl-2- (6- (ethylsulfinyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (83);

5-chloro-3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (84);

1-cyclopropyl-5, 6-difluoro-2- (6- (trifluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (85);

1-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (86);

3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (87);

2- ((5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) isothiazolidine 1, 1-dioxide (88);

3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine-5-carbonitrile (89);

1-cyclopropyl-2- (6-methylpyridazin-4-yl) -6- (trifluoromethyl) -1H-benzo [ d ] imidazole (90);

n- (1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethyl) methanesulfonamide (91);

1-cyclopropyl-5, 6-difluoro-2- (6- (fluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (92);

1-cyclopropyl-2- (5, 6-dimethylpyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (93);

(5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methanol (94);

5-chloro-3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3H-imidazo [4,5-b ] pyridine (95);

n- (1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethyl) ethanesulfonamide (96);

2- (6-butylpyridazin-4-yl) -1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazole (97);

1-cyclopropyl-6-methyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (98);

1-cyclopropyl-5, 6-difluoro-2- (3-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (99);

1-cyclopropyl-2- (3, 6-dimethylpyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (100);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -6, 7-difluoro-1H-benzo [ d ] imidazole (101);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-thiol (102);

2- (6- (difluoromethyl) pyridazin-4-yl) -5, 6-difluoro-1-methyl-1H-benzo [ d ] imidazole (104);

2- (6- (difluoromethyl) pyridazin-4-yl) -5, 6-difluoro-1-propyl-1H-benzo [ d ] imidazole (105);

4- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -5,6,7, 8-tetrahydrocinnoline (106);

1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole-5-carbonitrile (Ex.107)

1-cyclobutyl-5, 6-difluoro-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (108);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazol-6-ol (109);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carboxylic acid (110);

1-cyclopropyl-7-fluoro-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (111);

5-chloro-1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (112);

4-chloro-1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1H-benzo [ d ] imidazole (113);

1-cyclopropyl-5, 6-difluoro-2- (6- (methoxymethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (114);

methyl 5- (6-cyano-1-cyclopropyl-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carboxylate (115);

5- (6-cyano-1-cyclopropyl-1H-benzo [ d ] imidazol-2-yl) pyridazine-3-carboxylic acid (116);

1-cyclopropyl-2- (6- (cyclopropylmethoxy) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (117);

1-cyclopropyl-2- (6- (2,2, 2-trifluoroethoxy) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (118);

6-chloro-1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5-fluoro-1H-benzo [ d ] imidazole (119);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5-fluoro-1H-benzo [ d ] imidazole-6-carbonitrile (120);

4- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) -6, 7-dihydro-5H-cyclopenta [ c ] pyridazine (121);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -6-fluoro-1H-benzo [ d ] imidazole (122);

1-cyclopropyl-5, 6-difluoro-2- (6- (methylthio) pyridazin-4-yl) -1H-benzo [ d ] imidazole (123);

1-cyclopropyl-5, 6-difluoro-2- (6- (isopropylsulfanyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (124);

1-cyclopropyl-2- (6- ((difluoromethyl) thio) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (125);

5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-ol (126);

1-cyclopropyl-2- (6- (difluoromethoxy) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (127);

1- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethan-1-ol (128);

1-cyclopropyl-5, 6-difluoro-2- (6- (1-fluoroethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (129);

1-cyclopropyl-5, 6-difluoro-2- (6- ((trifluoromethyl) thio) pyridazin-4-yl) -1H-benzo [ d ] imidazole (130)

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole (131);

2- (6- (difluoromethyl) pyridazin-4-yl) -1-propyl-1H-benzo [ d ] imidazole (132);

1-cyclopropyl-2- (6- (difluoromethoxy) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (133);

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1H-indole-3-carbonitrile (134);

2- (6- (difluoromethyl) pyridazin-4-yl) -1-methyl-1H-indole-3-carbonitrile (135);

1-cyclopropyl-2- (6- (1-fluoroethyl) pyridazin-4-yl) -1H-benzo [ d ] imidazole-6-carbonitrile (136); pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives and prodrugs thereof.

In another aspect, 2- (6- (difluoromethyl) pyridazin-4-yl) -5, 6-difluoro-1H-benzo [ d ] imidazole (103), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, is provided.

In one aspect, the compound of formula I is a compound wherein the compound inhibits (or is identified to inhibit) aldosterone synthase (CYP11B 2).

Compounds herein include those compounds identified therein that at least partially gain affinity for metalloenzymes by forming one or more than one of the following types of chemical interactions or bonds with metals: sigma bonds, covalent bonds, coordinate covalent bonds, ionic bonds, pi bonds, delta bonds, or anti-bond interactions. The compounds may also acquire affinity by weaker interactions with metals, by, for example, van der waals interactions, pi cation interactions, pi anion interactions, dipole-dipole interactions, ion-dipole interactions. In one aspect, the compound is identified as having a bonding interaction with a metal through a pyridazine moiety.

Methods for assessing metal-ligand binding interactions are known in the art, as exemplified in the references, including, for example, "Principles of bioinformatic Chemistry", university science Books, (1994), by Lippard and Berg; basolo and Pearson John Wiley & Sons Inc. "mechanics of organic Reactions"; version 2 (1967 month 9); ivano Bertini, Harry Gray, Ed Stiefel, "Biological organic Chemistry" by Joan valence, University Science Books (2007); xue et al, "Nature Chemical Biology", vol.4, No.2,107-109 (2008).

In another aspect, pharmaceutical compositions are provided comprising a compound of formula I and a pharmaceutically acceptable carrier.

In another aspect, there is provided a method of modulating metalloenzyme activity in a subject, comprising contacting the subject with a compound of formula I in an amount and under conditions sufficient to modulate metalloenzyme activity.

In another aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease, wherein the subject has been identified as in need of treatment for the disorder or disease, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of formula I, such that the subject is treated for the disorder.

In another aspect, the subject is an animal other than a human.

In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutical composition.

In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, wherein the subject has been identified as in need of treatment for the metalloenzyme-related disorder or disease, the method comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition of formula I, such that the subject is treated for the disorder.

In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, wherein the subject has been identified as in need of treatment for the metalloenzyme-mediated disorder or disease, the method comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition of formula I such that metalloenzyme activity in the subject is modulated (e.g., down-regulated, inhibited).

The diseases or conditions in the methods encompassed herein are those mediated by any one of aromatase (CYP19), a member of the cyclooxygenase family, lanosterol demethylase (CYP51), a member of the nitric oxide synthase family, thromboxane synthase (CYP5a), thyroid peroxidase, 17-alpha hydroxylase/17, 20-lyase (CYP17), cytochrome P4502 a6(CYP2a6), heme oxygenase, indoleamine 2, 3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P4503 a5(CYP3a5), cholesterol 24-hydroxylase (CYP46), cytochrome P4504F 2(CYP4F2), myeloperoxidase, or 11-beta-hydroxylase (CYP11B 1).

The methods herein include those wherein the disease or disorder is cancer, cardiovascular disease, inflammatory disease, infectious disease, metabolic disease, ophthalmic disease, Central Nervous System (CNS) disease, urinary disease, or gastrointestinal disease.

The methods herein include wherein the disease or disorder is hypertension, refractory hypertension, a disorder associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction syndrome, coronary heart disease, fibrosis, a disease characterized by increased collagen formation following hypertension, fibrosis and matrix remodeling, a disease characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, a cardiovascular disease such as atherosclerosis, atrial fibrillation, renal dysfunction, liver disease, non-alcoholic steatohepatitis, a vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, Myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes mellitus, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic fatty liver disease, kidney disease, diabetic nephropathy or stroke.

The methods described herein include methods wherein a subject is identified as in need of a particular such treatment. Identification of a subject in need of such treatment can be at the discretion of the subject or a health care professional, and can be subjective (e.g., opinion) or objective (e.g., as measured by testing or diagnostic methods).

Detailed Description

Definition of

For ease of understanding the present invention, certain terms are first defined herein for convenience.

As used herein, the term "treating" a disease includes preventing, ameliorating, alleviating and/or managing the disease and/or the conditions that may lead to the disease. The terms "treat" and "treatment" refer to a method of alleviating or alleviating a disease and/or its attendant symptoms. According to the present disclosure, "treating" includes preventing, blocking, inhibiting, attenuating, protecting, modulating, reversing, and reducing the effects of a disease, e.g., the deleterious effects of a disease.

As used herein, "inhibit" includes preventing, reducing and halting progression. Note that "enzyme inhibition" (e.g., metalloenzyme inhibition) is distinguished and described below.

The term "modulate" refers to an increase or decrease in the activity of an enzyme in response to exposure to a compound of the present disclosure.

The terms "isolated," "purified," or "biologically pure" refer to a substance that is substantially free of components that normally accompany it in its natural state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. In particular, in embodiments, the compound is at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

The term "administering" or "administering" includes the route by which a compound is introduced into a subject to achieve its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal and transdermal.

The term "effective amount" includes an effective amount to achieve the desired result in the necessary dosage and period of time. An effective amount of a compound may vary depending on factors such as the disease state, age, and weight of the subject, as well as the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the inhibitor compound are outweighed by the therapeutically beneficial effects.

The phrases "systemic administration," "peripheral administration," and "peripheral administration" as used herein refer to the administration of a compound, drug, or other substance such that it enters the patient's system and thus undergoes metabolism and other similar processes.

The term "therapeutically effective amount" means an amount of a compound administered sufficient to prevent or to reduce to some extent the development of one or more symptoms of the disease or disorder being treated.

A therapeutically effective amount (i.e., effective dose) of the compound may be from about 0.005 μ g/kg body weight to about 200mg/kg body weight, preferably from about 0.01mg/kg body weight to about 200mg/kg body weight, more preferably from about 0.015mg/kg body weight to about 30mg/kg body weight. In other embodiments, the therapeutically effective amount may be from about 1.0pM to about 10 μ M. One skilled in the art will appreciate that certain factors may affect the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Furthermore, treatment of a subject with a therapeutically effective amount of a compound may comprise a monotherapy, or preferably may comprise a series of therapies. In one example, a subject is treated with about 0.005 μ g/kg body weight to about 200mg/kg body weight of the compound once per day for about 1 week to 10 weeks, preferably 2 weeks to 8 weeks, more preferably about 3 weeks to 7 weeks, even more preferably about 4 weeks, 5 weeks, or 6 weeks. In another example, in the case of a chronic condition or disease, the subject may be treated daily for years. It is also understood that the effective dose of the compound for treatment may be increased or decreased during the course of a particular treatment.

The term "chiral" refers to a molecule having the property that mirror image molecules are not superimposable, while the term "achiral" refers to a molecule that is superimposable on a mirror image molecule.

The term "diastereomer" refers to stereoisomers having two or more asymmetric centers, whose molecules are not mirror images of each other.

The term "enantiomer" refers to two stereoisomers of a compound that are nonsuperimposable mirror images of each other. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate"

The term "isomer" or "stereoisomer" refers to compounds that are identical in chemical composition but differ in the arrangement of atoms or groups in space.

The term "prodrug" includes compounds having moieties that are metabolized in vivo. Typically, prodrugs are metabolized in vivo by esterases or other mechanisms to active drugs. Examples of prodrugs and uses thereof are well known in the art (see, e.g., Berge et al (1977) "Pharmaceutical Salts", J.pharm.Sci.66: 1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or hydroxyl form with a suitable esterifying agent. The hydroxyl group can be converted to an ester by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionate), lower alkenyl esters, di-lower alkylamino lower alkyl esters (e.g., dimethylaminoethyl ester), amido lower alkyl esters (e.g., acetoxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl lower alkyl esters (e.g., benzyl esters), substituted (e.g., substituted with methyl, halogen, or methoxy) aryl and aryl lower alkyl esters, amides, lower alkylamides, di-lower alkylamides, and hydroxyamides. Preferred prodrug moieties are propionates and acyl esters. Prodrugs that are converted to the active form by other mechanisms in the body are also included. In some aspects, the compounds of the present disclosure are prodrugs of any of the formulae herein.

The term "subject" refers to an animal, such as a mammal, including but not limited to a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, and the like. In some embodiments, the subject is a human.

The use of the terms "a" or "an" or "the" preceding non-limiting words in this application, including the claims, means "one or more than one". Thus, for example, reference to "a sample" includes a plurality of samples, unless the context clearly contradicts that (e.g., plurality of samples), and so forth.

Throughout the specification and claims, the words "comprise", "comprising" and "contain" are used in a non-exclusive sense unless the context requires otherwise.

As used herein, the term "about," when referring to a value, is meant to encompass variations based on the specified amount, in some embodiments ± 20%, in some embodiments ± 10%, in some embodiments ± 5%, in some embodiments ± 1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1%, as such variations are suitable for performing the disclosed methods or using the disclosed compositions.

The use of the term "inhibitor" herein means a molecule that exhibits inhibition of metalloenzyme activity. By "inhibiting" herein is meant that the activity of the metalloenzyme is reduced compared to the activity of the metalloenzyme in the absence of the inhibitor. In some embodiments, the term "inhibit" refers to a decrease in metalloenzyme activity of at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibition refers to a decrease in metalloenzyme activity of about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibition refers to a decrease in metalloenzyme activity of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. This reduction can be measured using various techniques recognized by those skilled in the art. Specific tests for measuring the activity of an individual are described below.

Further, the compounds of the present disclosure include olefins having the following geometry: "Z" refers to the so-called "cis" (ipsilateral) configuration, while "E" refers to the so-called "trans" (contralateral) configuration. For the nomenclature of the chiral center, the terms "d" and "l" configuration are as defined in the IUPAC recommendation. With regard to the use of the terms diastereomer, racemate, epimer and enantiomer, these will be used in their usual context to describe the stereochemistry of formulations.

As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon group containing from 1 to 12 carbon atoms. The term "lower alkyl" refers to a C1 to C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl and n-pentyl. Alkyl groups may be optionally substituted with one or more substituents.

The term "haloalkyl" refers to an alkyl group substituted with one or more than one halogen substituent. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl and 2,2, 2-trifluoroethyl.

The term "alkenyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. An alkenyl group may be optionally substituted with one or more substituents.

The term "arylalkenyl" refers to an unsaturated hydrocarbon chain, which may be straight-chain or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond, wherein one or more than one sp of the alkenyl unit²The hybridized carbon is attached to the aryl moiety. An alkenyl group may be optionally substituted with one or more substituents.

The term "alkynyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

The term "arylalkynyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond, wherein one or more than one sp hybridized carbon of the alkynyl unit is attached to the aryl moiety. Alkynyl groups may be optionally substituted with one or more substituents.

Sp of alkenyl²The carbon or and the sp carbon of the alkynyl group, respectively, may optionally be the point of attachment of the alkenyl or alkynyl group.

The term "alkoxy" refers to an-O-alkyl substituent.

The terms "halogen", "halo", as used herein, refer to-F, -C1, -Br, or-I.

The term "alkylthio" refers to the-S-alkyl substituent.

The term "alkoxyalkyl" refers to an-alkyl-O-alkyl substituent.

The term "haloalkoxy" refers to an-O-alkyl group substituted with one or more halogen substituents. Examples of haloalkoxy groups include trifluoromethoxy and 2,2, 2-trifluoroethoxy.

The term "haloalkoxyalkyl" refers to-alkyl-O-alkyl ', wherein alkyl' is substituted with one or more halogen substituents.

The term "haloalkylaminocarbonyl" refers to-c (o) -amino-alkyl, wherein the alkyl is substituted with one or more than one halogen substituent.

The term "haloalkylthio" refers to-S-alkyl substituted with one or more halogen substituents. Examples of the haloalkylthio group include a trifluoromethylthio group and a 2,2, 2-trifluoroethylthio group.

The term "haloalkylcarbonyl" refers to-c (o) -alkyl substituted with one or more halogen substituents. Examples of haloalkylcarbonyl groups include trifluoroacetyl.

The term "cycloalkyl" refers to a hydrocarbon 3-to 8-membered monocyclic or 7-to 14-membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have some degree of unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1,2, 3, or 4 atoms per ring of a cycloalkyl group may be substituted with a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

The term "cycloalkoxy" refers to an-O-cycloalkyl substituent.

The term "cycloalkoxyalkyl" refers to an-alkyl-O-cycloalkyl substituent.

The term "cycloalkylalkoxy" refers to an-O-alkyl-cycloalkyl substituent.

The term "cycloalkylaminocarbonyl" refers to the substituent-C (O) -NH-cycloalkyl.

The term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1,2, 3,4, 5, or 6 atoms per ring of the aryl group may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

The term "aryloxy" refers to the-O-aryl substituent.

The term "arylalkoxy" refers to an-O-alkyl-aryl substituent.

The term "arylalkylthio" refers to the group-S-alkyl-aryl substituents.

The term "arylthioalkyl" refers to an-alkyl-S-aryl substituent.

The term "arylalkylaminocarbonyl" refers to the-c (o) -amino-alkyl-aryl substituent.

The term "arylalkylsulfonyl" refers to the group-S (O)₂-alkyl-aryl substituents.

The term "arylalkylsulfinyl" refers to the group-s (o) -alkyl-aryl substituents.

The term "aryloxyalkyl" refers to an-alkyl-O-aryl substituent.

The term "alkylaryl" refers to an-aryl-alkyl substituent.

The term "arylalkyl" refers to an-alkyl-aryl substituent.

The term "heteroaryl" refers to an aromatic 5-to 8-membered monocyclic, 8-to 12-membered bicyclic, or 11-to 14-membered tricyclic ringThe ring system, if monocyclic, has from 1 to 4 ring heteroatoms, if bicyclic, from 1 to 6 heteroatoms, or if tricyclic, from 1 to 9 heteroatoms selected from O, N or S, the remaining ring atoms being carbon (with appropriate hydrogen atoms unless otherwise specified). Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1,2, 3, or 4 atoms per ring of the heteroaryl group may be substituted with a substituent. Examples of heteroaryl groups include pyridyl, furyl, thienyl, pyrrolyl, and the like,

Azolyl group,

Oxadiazolyl, imidazolyl, thiazolyl, isoxazolylOxazolyl, quinolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolyl, indazolyl, and the like.

The term "heteroarylalkyl" refers to an-alkyl-heteroaryl substituent.

The term "heteroaryloxy" refers to an-O-heteroaryl substituent.

The term "heteroarylalkoxy" refers to an-O-alkyl-heteroaryl substituent.

The term "heteroaryloxyalkyl" refers to an-alkyl-O-heteroaryl substituent.

The term "nitrogen-containing heteroaryl" refers to heteroaryl groups having 1 to 4 ring nitrogen heteroatoms if monocyclic; if bicyclic, having 1 to 6 ring nitrogen heteroatoms; or, if tricyclic, 1 to 9 ring nitrogen heteroatoms.

The term "heterocycloalkyl" refers to a non-aromatic 3-to 8-membered monocyclic, 7-to 12-membered bicyclic, or 10-to 14-membered tricyclic ring system containing 1 to 3 heteroatoms in the case of a monocyclic ring, 1 to 6 heteroatoms in the case of a bicyclic ring, or 1 to 9 heteroatoms in the case of a tricyclic ring, said heteroatoms selected from O, N, S, B, P or Si, wherein the non-aromatic ring system is fully saturated. The heterocycloalkyl group can be optionally substituted with one or more than one substituent. In one embodiment, 0, 1,2, 3, or 4 atoms per ring of the heterocycloalkyl group can be substituted with a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1, 3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thiacyclopropenyl (thiirenyl), and the like.

The term "heterocycloalkylalkyl" refers to an-alkyl-heterocycloalkyl substituent.

The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more than one amino group. The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more than one hydroxyl group. The alkyl or aryl moieties of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

Acids and bases useful in the methods herein are known in the art. The acid catalyst is any acidic chemical, which may be inorganic in nature (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic in nature (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate). The acid is used in catalytic or stoichiometric amounts to promote the chemical reaction. The base is any basic chemical, which may be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic in nature (e.g., triethylamine, pyridine). The base is used in catalytic or stoichiometric amounts to promote the chemical reaction.

An alkylating agent is any agent capable of effecting alkylation of the functional group in question (e.g., oxygen atom of an alcohol, nitrogen atom of an amino group). Alkylating agents are known in the art, are included in the references cited herein, and include alkyl halides (e.g., methyl iodide, benzyl bromide, or benzyl chloride), alkyl sulfate salts (e.g., methyl sulfate), or other alkyl-A combination of leaving groups. Leaving groups are any stable species that can be separated from a molecule during a reaction (e.g., elimination, substitution) and are known in the art, including in the references cited herein, and include halides (e.g., I-, Cl-, Br-, F-), hydroxyls, alkoxys (e.g., -OMe, -Ot-Bu), acyloxyanions (e.g., -OAc, -OC (O) CF)₃) Sulfonates (e.g., methylsulfonyl, tosyl), acetamides (e.g., -NHC (O) Me), carbamates (e.g., N (Me) C (O) Ot-Bu), phosphonates (e.g., -OP (O) (OEt)₂) Water or alcohol (protic conditions), etc.

In certain embodiments, a substituent on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be on any atom of that group, wherein any substitutable group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be optionally substituted with one or more substituents (which can be the same or different), each substituent replacing a hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, oxo (i.e., carbonyl), carboxy, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino substituted aryl; arylalkylamino, aralkylaminocarbonyl, acylamino, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, ureido, carbamoyl, thioureido, thiocyano, sulfonamido, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxyamidino, or N' -aryl, N "-hydroxyamidino.

The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis. If it is desired to minimize competing by-products, the reaction conditions should be optimized, and methods for optimizing reaction conditions are known in the art. Reaction optimization and amplification may advantageously utilize high-speed parallel Synthesis equipment and computer-controlled microreactors (e.g., Design analysis in Organic Synthesis, second edition, Carlson R, Ed, 2005; Elsevier science Ltd.;k et al, Angew43406; and references therein). Those skilled in the art can use commercially available database software with searchable structure, for example

(CAS division of the American chemical society) and Cross fire

(Elsevier MDL), or by appropriate keyword searching using an internet search engine such as Google or a keyword database such as the us patent and trademark office text database.

As will be appreciated by those skilled in the art, methods of synthesizing the compounds of the formulae herein will be apparent to those of ordinary skill in the art, including in the schemes and examples herein. In addition, the various synthetic steps may be performed in alternating order or in sequence to give the desired compound. In addition, the solvents, temperatures, reaction durations, etc. described herein are for illustrative purposes only, and one of ordinary skill in the art will recognize that variations in reaction conditions may produce the desired compounds of the present disclosure.

The compounds herein may also contain a linking group (e.g., a carbon-carbon bond), wherein bond rotation is limited by a particular bond, e.g., a limitation caused by the presence of a ring or double bond. Thus, all cis/trans and E/Z isomers are expressly included in this disclosure. The compounds herein may also be represented in multiple tautomeric forms, in which case the disclosure expressly includes all tautomeric forms of the compounds described herein, although only a single tautomeric form may be shown. All such isomeric forms of these compounds are expressly included in the present disclosure. All crystalline forms and polymorphs of the compounds described herein are expressly included in the present disclosure. Extracts and fractions containing the compounds of the disclosure are also embodied. The term isomer is intended to include diastereomers, enantiomers, regioisomers, structural isomers, rotamers, tautomers and the like. For compounds containing one or more than one stereocenter, e.g., chiral compounds, the methods of the present disclosure can be performed with enantiomerically enriched compounds, racemates, or mixtures of diastereomers.

Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or more than 50%, more preferably the compound has an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more than 99%. In a preferred embodiment, only one enantiomer or diastereomer of a chiral compound of the invention is administered to a cell or subject.

Method of treatment

In one aspect, there is provided a method of treating a subject suffering from or susceptible to a disease or disorder, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutical composition.

In other aspects, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of formula I, such that the subject is treated for the disorder.

In one aspect, there is provided a method of modulating metalloenzyme activity in a cell in a subject, comprising contacting the subject with a compound of formula I in an amount and under conditions sufficient to modulate metalloenzyme activity.

In one embodiment, the modulation is inhibition.

In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutical composition.

In other aspects, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme-related disorder or disease, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of formula I, such that the subject is treated for the disorder.

In certain embodiments, methods of treating a disease, disorder or condition thereof are provided, wherein the disorder is cancer, a cardiovascular disease, an endocrine disease, an inflammatory disease, an infectious disease, a gynecological disease, a metabolic disease, an ophthalmic disease, a Central Nervous System (CNS) disease, a urinary disorder or a gastrointestinal disorder. In certain embodiments, the disease is hypertension, refractory hypertension, conditions associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction syndrome, coronary heart disease, fibrosis, diseases characterized by increased collagen formation following hypertension, fibrosis and matrix remodeling, diseases characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, cardiovascular diseases such as atherosclerosis, atrial fibrillation, renal dysfunction, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, inflammatory bowel disease, Myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes mellitus, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic steatohepatitis, kidney disease, diabetic nephropathy or stroke.

In certain embodiments, the subject is a mammal, preferably a primate or a human.

In another embodiment, there is provided a method as described above, wherein the effective amount of the compound of formula I is as described above.

In another embodiment, there is provided the method as described above, wherein the compound of formula I is administered intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally or topically.

In another embodiment, methods as described herein are provided wherein the compound of formula I exhibits selectivity for a range of activities of a target enzyme (e.g., aldosterone synthase (CYP11B2) IC₅₀<1.0μM)。

In other embodiments, there are provided methods as described above, wherein a compound of formula I is administered alone or in combination with one or more other therapeutic agents. In a further embodiment, the additional therapeutic agent is an anti-cancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, a therapeutic agent for a metabolic disease, a therapeutic agent for an ophthalmic disease, an agent for a Central Nervous System (CNS) disease, a therapeutic agent for a urological disease, or a therapeutic agent for a gastrointestinal disease.

In certain embodiments, the additional therapeutic agent is an agent for treating hypertension, an agent for treating primary aldosteronism, an agent for treating nephropathy, an agent for treating congestive heart failure, an agent for treating an atherosclerotic condition, an agent for treating diabetes, an agent for treating obesity, or an agent for treating a metabolic disease.

Exemplary additional therapeutic agents include, but are not limited to, renin inhibitors, Angiotensin Converting Enzyme (ACE) inhibitors, dual inhibitors of Angiotensin Converting Enzyme (ACE) and Neutral Endopeptidase (NEP), angiotensin II receptor blockers (ARBs), Mineralocorticoid Receptor Antagonists (MRAs), neutral endopeptidase inhibitors (NEPs), enkephalinase inhibitors, calcium channel blockers, alpha-adrenergic blockers, beta-adrenergic blockers, diuretics (including loop diuretics), potassium channel activators, endothelin receptor antagonists, endothelin 1 receptor agonists, soluble guanylate cyclase stimulators, vasodilators, HMG-CoA reductase inhibitors, niacin and niacin receptor agonists, niemann-pick C1-like 1(NPC1L1) inhibitors, insulin or insulin analogs, biguanides (e.g., metformin), Sulfonylureas, peroxisome proliferator-activated receptor (PPAR) agonists and partial agonists including PPAR γ agonists and other PPAR ligands, dipeptidyl peptidase 4(DPP4) inhibitors, glucagon-like peptide 1(GLP-1), GLP-1 receptor agonists, and sodium-glucose co-transporter 2(SGLT2) inhibitors.

Another object of the present disclosure is the use of a compound described herein (e.g., a compound of formula I) in the manufacture of a medicament for the treatment of a metalloenzyme-mediated disorder or disease. Another object of the present disclosure is the use of a compound as described herein (e.g., a compound of formula I) for the treatment of a metalloenzyme-mediated disorder or disease. Another object of the present disclosure is the use of a compound as described herein (e.g., a compound of formula I) in the preparation of an agricultural composition for the treatment or prevention of a metalloenzyme-mediated disorder or disease in an agricultural or agricultural environment.

Pharmaceutical composition

In one aspect, there is provided a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.

In another embodiment, a pharmaceutical composition is provided that further comprises an additional therapeutic agent. In a further embodiment, the additional therapeutic agent is an anti-cancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, a metabolic disease agent, an ophthalmic disease agent, a Central Nervous System (CNS) disease agent, a urological disease therapeutic agent, or a gastrointestinal disease therapeutic agent.

In certain embodiments, the additional therapeutic agent is an agent for treating hypertension, an agent for treating primary aldosteronism, an agent for treating nephropathy, an agent for treating congestive heart failure, an agent for treating an atherosclerotic condition, an agent for treating diabetes, an agent for treating obesity, or an agent for treating a metabolic disease.

Exemplary additional therapeutic agents include, but are not limited to, renin inhibitors, Angiotensin Converting Enzyme (ACE) inhibitors, dual inhibitors of Angiotensin Converting Enzyme (ACE) and Neutral Endopeptidase (NEP), angiotensin II receptor blockers (ARBs), Mineralocorticoid Receptor Antagonists (MRAs), neutral endopeptidase inhibitors (NEPs), enkephalinase inhibitors, calcium channel blockers, alpha-adrenergic blockers, beta-adrenergic blockers, diuretics (including loop diuretics), potassium channel activators, endothelin receptor antagonists, endothelin 1 receptor agonists, soluble guanylate cyclase stimulators, vasodilators, HMG-CoA reductase inhibitors, niacin and niacin receptor agonists, niemann-pick C1-like 1(NPC1L1) inhibitors, insulin or insulin analogs, biguanides (e.g., metformin), Sulfonylureas, peroxisome proliferator-activated receptor (PPAR) agonists and partial agonists including PPAR γ agonists and other PPAR ligands, dipeptidyl peptidase 4(DPP4) inhibitors, glucagon-like peptide 1(GLP-1), GLP-1 receptor agonists, and sodium-glucose co-transporter 2(SGLT2) inhibitors.

In one aspect, a kit is provided comprising an effective amount of a compound of formula I in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to a metalloenzyme-mediated disease or disorder, including cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, Central Nervous System (CNS) disease, urological disease, or gastrointestinal disease. In other embodiments, the disease, disorder, or symptom thereof is hypertension, refractory hypertension, a disorder associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, renal disease, post-myocardial infarction syndrome, coronary heart disease, fibrosis, a disease characterized by increased collagen formation following hypertension, fibrosis and matrix remodeling, a disease characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, a cardiovascular disease such as atherosclerosis, atrial fibrillation, renal dysfunction, liver disease, non-alcoholic steatohepatitis, a vascular disease, retinopathy, neuropathy, insulinopathy, Endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall thickening, endothelial thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic steatohepatitis, kidney disease, diabetic nephropathy or stroke.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" is meant to include salts of the active compounds which are prepared with relatively non-toxic acids or bases depending on the particular substituents present on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired base, which may be pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired acid, which may be pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, bicarbonate, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric, bisulfate, hydroiodic, or phosphorous acids, and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are amino acid salts such as arginine salts and the like, and organic acid salts such as glucuronic acid or galacturonic acid and the like (see, for example, Berge et al, Journal of pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into base addition salts or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in the present disclosure.

The neutral form of the compounds may be recovered by contacting the salt with a base or acid and isolating the parent compound in conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this disclosure the salts are equivalent to the parent form of the compound.

In addition to salt forms, the present invention also provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to a compound of the present disclosure when placed in a transdermal patch container with a suitable enzyme or chemical agent.

Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to fall within the scope of the present disclosure.

The present disclosure also provides pharmaceutical compositions comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In embodiments, the compound of formula I is administered to the subject using a pharmaceutically acceptable formulation, e.g., the pharmaceutically acceptable formulation delivers the compound to the subject for at least 12 hours, 24 hours, 36 hours, 48 hours, 1 week, 2 weeks, 3 weeks, or 4 weeks after administration of the pharmaceutically acceptable formulation to the subject.

The actual dose level and time of administration of the active ingredient in the pharmaceutical compositions of the present disclosure can be varied to obtain an effective amount of the active ingredient which will achieve the desired therapeutic response for a particular patient, composition, and mode of administration, and which will not be toxic (or unacceptably toxic) to the patient.

In use, at least one compound according to the invention is administered to a subject in need thereof in a pharmaceutically effective amount in a pharmaceutical carrier by intravenous, intramuscular, subcutaneous or intracerebroventricular injection or by oral or topical administration. In accordance with the present disclosure, a compound of the present disclosure may be administered alone or in combination with a second, different therapeutic agent. "administered in combination with … …" means administered together substantially simultaneously or sequentially. In one embodiment, a compound of the disclosure is administered acutely. Thus, the compounds of the present invention may be administered for a short term treatment, e.g., for about 1 day to about 1 week. In another embodiment, the compounds of the present disclosure may be administered over a longer period of time to ameliorate a chronic condition, for example for about one week to several months depending on the condition to be treated.

As used herein, a "pharmaceutically effective amount" refers to an amount of a compound of the present disclosure that is high enough to significantly positively modify the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The pharmaceutically effective amount of a compound of the present disclosure will vary with the particular goal to be achieved, the age and physical condition of the patient being treated, the severity of the underlying disease, the duration of the treatment, the nature of the concurrent therapy, and the particular compound used. For example, a therapeutically effective amount of a compound of the invention administered to a child or neonate will be proportionally reduced according to sound medical judgment. Thus, an effective amount of a compound of the present disclosure will be the minimum amount that provides the desired effect.

A decisive practical advantage of the present disclosure is that the compounds can be administered in a convenient manner, for example by intravenous, intramuscular, subcutaneous, oral or intracerebroventricular injection routes or by topical administration, for example in the form of creams or gels. Depending on the route of administration, it may be desirable to coat the active ingredient comprising a compound of the present disclosure in a material to protect the compound from enzymes, acids, and other natural conditions that may inactivate the compound. To administer the compounds of the present invention by means other than parenteral administration, the compounds may be coated with or co-administered with inactivation-preventing materials.

The compounds may be administered parenterally or intraperitoneally. Dispersants may also be prepared, for example, in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils.

Some examples of substances that can be used as pharmaceutical carriers are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and a phosphate buffer solution; skimmed milk powder; and other non-toxic compatible substances used in pharmaceutical preparations, such as vitamin C, estrogens and echinacea purpurea (echinacea). Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives, may also be present. Solubilizers including, for example, Cremaphore and beta-cyclodextrin can also be used in the pharmaceutical compositions herein.

Pharmaceutical compositions comprising the active compounds of the present disclosure (or prodrugs thereof) may be prepared by conventional mixing, dissolving, granulating, dragee-making, milling, emulsifying, encapsulating, entrapping or lyophilizing processes. The compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.

The pharmaceutical compositions of the presently disclosed subject matter can take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, and the like, or a form suitable for administration by inhalation or insufflation.

For topical administration, the active compounds or prodrugs can be formulated as solutions, gels, ointments, creams, suspensions, and the like.

Systemic formulations include those designed for administration by injection, for example, subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or respiratory administration.

Useful injectable formulations include sterile suspensions, solutions or emulsions of the active compounds in aqueous or oily vehicles. The composition may also contain formulating agents such as suspending, stabilizing and/or dispersing agents. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, and may contain an added preservative.

Alternatively, the injectable formulations can be provided in powder form for constitution with a suitable vehicle, including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, and the like, before use. To this end, the active compound may be dried by any technique known in the art, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional methods together with pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art, for example with sugar coatings or enteric coatings.

Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. These liquid preparations may be prepared by a conventional method with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous carriers (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl parabens or sorbic acid). The formulations may also suitably contain buffer salts, preservatives, flavouring agents, colouring agents and sweetening agents.

Formulations for oral administration may be suitably formulated to provide controlled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compounds may be formulated as solutions (for retention enemas), suppositories, or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation or insufflation, the active compound or prodrug may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbon, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit is determined by providing a valve to deliver a metered amount. Capsules and kits for use in an inhaler or insufflator, e.g., capsules and kits composed of gelatin, may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

Specific examples of aqueous suspension formulations suitable for nasal administration using commercially available nasal spray devices include the following: an active compound or prodrug (0.5mg/ml to 20 mg/ml); benzalkonium chloride (0.1mg/mL to 0.2 mg/mL); polysorbate 80 (C)

80; 0.5mg/ml to 5 mg/ml); sodium carboxymethylcellulose or microcrystalline cellulose (1mg/ml to 15 mg/ml); phenethyl alcohol (1mg/ml to 4 mg/ml); and dextrose (20mg/ml to 50 mg/ml). The pH of the final suspension may be adjusted to about pH5 to pH7, with a typical pH of about 5.5.

For ophthalmic administration, the active compounds or prodrugs can be formulated as solutions, emulsions, suspensions, and the like, suitable for administration to the eye. Various carriers suitable for administering the compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. patent nos. 6261547; U.S. patent No. 6197934; U.S. patent No. 6056950; U.S. patent No. 5800807; U.S. patent No. 5776445; U.S. patent No. 5698219; U.S. patent No. 5521222; U.S. patent No. 5403841; U.S. patent No. 5077033; U.S. patent No. 4882150; U.S. patent No. 4738851, each of which is incorporated herein by reference in its entirety.

For prolonged delivery, the active compounds or prodrugs can be formulated as long acting formulations for administration by implantation or intramuscular injection. The active ingredient may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives such as a sparingly soluble salt. Alternatively, transdermal delivery systems that are manufactured as adhesive discs or patches that slowly release the active compound for transdermal absorption may be used. To this end, penetration enhancers may be used to facilitate transdermal penetration of the active compound. Suitable transdermal patches are described, for example, in U.S. patent nos. 5407713; U.S. patent No. 5352456; U.S. patent No. 5332213; U.S. patent No. 5336168; U.S. patent No. 5290561; U.S. patent No. 5254346; U.S. patent No. 5164189; U.S. patent No. 5163899; U.S. patent No. 5088977; U.S. patent No. 5087240; U.S. patent No. 5008110; U.S. patent No. 4921475, each of which is incorporated herein by reference in its entirety.

Alternatively, other drug delivery systems may be used. Liposomes and emulsions are well known examples of delivery vehicles which can be used to deliver the active compound or prodrug. Certain organic solvents, such as dimethyl sulfoxide (DMSO), may also be used.

If desired, the pharmaceutical composition may be presented in a pack or dispenser device which may contain one or more than one unit dosage form containing the active compound. The package may for example comprise a metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

The active compounds or prodrugs or compositions thereof of the present disclosure are generally used in amounts effective to achieve the desired result, e.g., in amounts effective to treat or prevent the particular disease being treated. The compound may be administered therapeutically to obtain a therapeutic benefit or prophylactically to obtain a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more symptoms associated with the underlying disorder such that the patient reports an improvement in sensation or condition, although the patient may still be afflicted with the underlying disorder. For example, administration of a compound to a patient suffering from an allergy not only provides therapeutic benefit in eradicating or ameliorating the underlying allergic response, but also when the patient reports a reduction in the severity or duration of symptoms associated with the allergy following exposure to the allergen. As another example, therapeutic benefits for asthma include improved breathing after the onset of an asthma attack, or a reduction in the frequency or severity of an asthma attack. Therapeutic benefits also include halting or slowing the progression of the disease, whether or not improvement is achieved.

For prophylactic administration, the compound may be administered to a patient at risk of developing one of the above-mentioned diseases. A patient at risk of developing a disease may be a patient with the characteristic of placing the patient in a designated risk patient group, as defined by an appropriate medical professional or group. A patient at risk may also be a patient who is normally or routinely in an environment where potential disease may occur, which potential disease may be treated by administering a metalloenzyme inhibitor according to the present disclosure. In other words, a patient at risk is often or routinely exposed to a disease or pathogenic condition, or may be acutely exposed for a limited time. Alternatively, prophylactic administration may be applied to avoid symptoms in patients diagnosed with an underlying disorder.

The amount of the compound administered will depend on a variety of factors including, for example, the particular indication being treated, the mode of administration, whether prophylactic or therapeutic benefit is desired, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound, and the like. Determination of an effective dose is well within the capability of those skilled in the art.

The effective dose can be estimated initially from in vitro assays. For example, an initial dose for an animal can be formulated such that the circulating blood or serum concentration of the active compound is at or above the IC of the particular compound measured in an in vitro assay₅₀E.g. in vitro fungal MIC or MFC and other in vitro tests described in the examples section. It is well within the ability of the skilled person to calculate the dose to achieve such circulating blood or serum concentrations, taking into account the bioavailability of the particular compound. For guidance, refer to Fingl&Woodbury, "General Principles," Goodman and Gilman's the pharmaceutical Basis of Therapeutics, Chapter 1, pp.1-46, latest edition, PagamononPress, and references cited therein, which are incorporated herein by reference.

Initial doses can also be estimated from in vivo data, such as animal models. Animal models for testing the efficacy of a compound to treat or prevent the various diseases described above are well known in the art.

The dose is typically from about 0.0001 mg/kg/day or 0.001 mg/kg/day or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower depending, inter alia, on the following factors: the activity of the compound, its bioavailability, the mode of administration, and the various factors described above. The dosage amounts and intervals may be adjusted individually to provide plasma levels of the compound sufficient to maintain a therapeutic or prophylactic effect. In the case of topical administration or selective uptake, e.g. topical administration, the effective local concentration of the active compound may be independent of the plasma concentration. The skilled person will be able to optimize effective topical dosages without undue experimentation.

The compound may be administered once a day, several times or several times a day, or even more times a day, depending on, inter alia, the indication being treated and the judgment of the prescribing physician, etc.

Preferably, the compounds will provide therapeutic or prophylactic benefit without causing substantial toxicity. Toxicity of the compounds can be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effects is the therapeutic index. Compounds with high therapeutic indices are preferred.

In any definition of a variable herein, recitation of a list of chemical groups includes definitions of that variable as any single group or combination of groups listed. Recitation of embodiments herein for variables includes such embodiments as any single embodiment, or combinations of such embodiments with any other embodiments or portions thereof. Recitation of embodiments herein includes the embodiment as any single embodiment or combination of the embodiment with any other embodiments or portions thereof.