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1. (WO2018165520) METALLOENZYME INHIBITOR COMPOUNDS
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

What is claimed:

1. A compound of Formula I:


I,

or a pharmaceutically acceptable salt thereof; wherein

A is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, or alkyl, wherein each A is optionally substituted with 1-3 independent substituents R5;

X is NR4 or O;

each of R 1 and R 2 is, independently, hydrogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl, heterocycloalkylalkyl, -(CRhRi)n-E-NRaC(0)Rb, -C(0)NRaRb, -(CRhRi)n-E-NRdS02Rd, -(CRhRi)n-G-S02Rd,-C02Re, - COR f , or -CH2OR f , wherein each R 1 and R2 is optionally substituted with 1-3 independent substituents R5;

or R1 and A together with the atoms to which they are attached form a heterocycloalkyl ring or fused bicyclic ring;

R3 is haloalkyl or -ORg;

R4 is hydrogen, alkyl, -(CRhRi)„C(0)NRaRb, -C(0)(CRhRi)„NRaRb, -C(0)0(CRhRi)nC(0)NRaRb, or -(CRhRi)nOP(0)(ORa)2;

each occurrence of R5 is, independently, halogen, cyano, alkyl, haloalkyl, -NRaRb, -NHS02Rc, -(CH2)nNRaRb, -(CH2)nC(0)NRaRb, -(CH2)nNRdS02Rd, -S(0)Rd, -S(0)2Rd, -C02Re, -CORf, -(CReRf)nORf, -ORf, or aryl substituted with 0-3 independent halogen, -NRaRb, -NHS02Rc, -(CH2)nNRaRb, -(CH2)nC(0)NRaRb, -(CH2)nNRdS02Rd, -S(0)Rd, -S(0)2Rd, -C02Re, -CORf, -(CReRf)nORf, or -ORf; or two occurrences of R5, together with the atoms to which they are attached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

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

each E is independently a bond, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

each G is independently heteroaryl or heterocycloalkyl;

each occurrence of Ra, Rb, Rc, Rd, Re, and Rf is, independently, hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or Ra and Rb together with the atoms to which they are attached form a heterocycloalkyl ring; or Re and Rf together with the atoms to which they are attached form a cycloalkyl ring; or 2 instances of Rd together with the atoms to which they are attached form a heterocycloalkyl ring;

Rg is haloalkyl; and

each occurrence of Rh and R1 is, independently, hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or heterocycloalkylalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein each A is optionally substituted with 1-3 independent substituents R5.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is aryl, heteroaryl, or cycloalkyl, wherein each A is optionally substituted with 1-3 independent substituents R5.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is aryl or heteroaryl, wherein each A is optionally substituted with 1-3 independent substituents

R5.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is aryl optionally substituted with 1-3 independent substituents R5.

6. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 2 is, independently, hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, -CH2ORf, -(CH2)nNRaC(0)Rb, -C(0)NRaRb, or -(CRhRi)n-E-NRdS02Rd, wherein each R1 and

R 2 is optionally substituted with 1-3 independent substituents R 5.

7. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 2 is, independently, hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, -CH2ORf, -CH2NRaC(0)Rb, -C(0)NRaRb, or -CH2NHS02Rd, wherein each R1 and R2 is optionally substituted with 1-3 independent substituents R5

8. The compound of any of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1 is -(CRhRi)nNRdS02Rd

9. The compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R1 is -(CH2)nNRdS02Rd

10. The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R1 and A together with the atoms to which they are attached form a fused bicyclic ring; and

R is hydrogen.

12. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R is haloalkyl.

13. The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3 is -CF3, -CHF2, or CH2F.

14. The compound of any of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein X is NR4.

15. The compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein X is NH.

16. The compound of claim 1, wherein the compound is of Formula I-a:


l a,

or a pharmaceutically acceptable salt thereof.

The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein A is heteroaryl, wherein each A is optionally substituted with 1-3 independent substituents R5.

18. The compound of claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein:

R1 is -(CRhRi)n-E-NRdS02Rd;

E is a bond or aryl;

each occurrence of Rd is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2 instances of Rd together with the atoms to which they are attached form a heterocycloalkyl ring;

each occurrence of Rh and R1 is, independently, hydrogen, halogen, haloalkyl, or alkyl; and

R is hydrogen.

19. The compound of any of claims 16-18, or a pharmaceutically acceptable salt thereof, wherein R is haloalkyl.

20. The compound of claim 1 rmula I-b:


l b,

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R 5 is, independently, halogen, cyano, alkyl, haloalkyl, or -OR f .

22. The compound of claim 20 or 21, or a pharmaceutically acceptable salt thereof,

wherein

R1 is -(CRhRi)n-E-NRdS02Rd;

E is a bond or aryl;

each occurrence of Rd is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2 instances of Rd together with the atoms to which they are attached form a heterocycloalkyl ring; and

each occurrence of Rh and R1 is, independently, hydrogen, halogen, haloalkyl, or alkyl; and

R is hydrogen.

23. The compound of any of claims 20-22, or a pharmaceutically acceptable salt thereof, wherein R is haloalkyl.

The compound of claim 1, wherein the compound is of Formula I-d:


or a pharmaceutically acceptable salt thereof.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein A is aryl or heteroaryl, wherein each A is optionally substituted with 1-3 independent substituents R5.

26. The compound of claim 24 or 25, or a pharmaceutically acceptable salt thereof, wherein:

R1 is -(CRhRi)n-E-NRdS02Rd;

E is a bond or aryl;

each occurrence of Rd is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2 instances of Rd together with the atoms to which they are attached form a heterocycloalkyl ring;

each occurrence of Rh and R1 is, independently, hydrogen, halogen, haloalkyl, or alkyl; and

2

R is hydrogen.

27. The compound of claim 1, wherein the compound is of Formula I-g:


or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3.

29. The compound of claim 27 or 28, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R 5 is, independently, halogen, cyano, alkyl, haloalkyl, or -OR f ; and R is independently alkyl or haloalkyl.

30. The compound of any of claims 27-29, or a pharmaceutically acceptable salt thereof, wherein at least one R5 is halogen.

31. The compound of any of claims 27-30, or a pharmaceutically acceptable salt thereof, wherein:

R1 is -(CRhRi)n-E-NRdS02Rd;

E is a bond or aryl;

each occurrence of Rd is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2 instances of Rd together with the atoms to which they are attached form a heterocycloalkyl ring;

each occurrence of Rh and R1 is, independently, hydrogen, halogen, haloalkyl, or alkyl; and

2

R is hydrogen.

32. The compound of claim 1, wherein the compound is of Formula I-h:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein R5a is halogen;

each occurrence of R 5 is, independently, halogen, cyano, alkyl, haloalkyl, or -OR f ; R is independently alkyl or haloalkyl; and

p is 0 or 1.

34. The compound of claim 32 or 33, or a pharmaceutically acceptable salt thereof, wherein:

R1 is -(CRhRi)n-E-NRdS02Rd;

E is a bond or aryl;

each occurrence of Rd is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2 instances of Rd together with the atoms to which they are attached form a heterocycloalkyl ring; and

each occurrence of Rh and R1 is, independently, hydrogen, halogen, haloalkyl, or alkyl; and

R is hydrogen.

35. The compound of claim 1 wherein the compound is of Formula I-j:


or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or 4.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein A is aryl or heteroaryl, wherein each A is optionally substituted with 1-3 independent substituents R5.

37. The compound of claim 35 or 36, or a pharmaceutically acceptable salt thereof, wherein:

each occurrence of Rd is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2 instances of Rd together with the atoms to which they are attached form a heterocycloalkyl ring; and

Rh is, hydrogen, halogen, haloalkyl, or alkyl.

38. The compound of any of claims 35-37, or a pharmaceutically acceptable salt thereof, wherein R is haloalkyl.

39. The compound of claim 1, wherein the compound is of Formula I-i:


I i,

or a pharmaceutically acceptable salt thereof.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein A is aryl or heteroaryl, wherein each A is optionally substituted with 1-3 independent substituents R5.

41. The compound of claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein:

each occurrence of Rd is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2 instances of Rd together with the atoms to which they are attached form a heterocycloalkyl ring.

A compound selected from the group consisting of:

N-(l-phenylethyl)-5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (2); N-((6-methylpyridin-2-yl)methyl)-5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (3);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-phenylethyl)pyrimidin-2-amine (6); N-benzhydryl-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (7); 5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)cyclopropyl)-N-methylpyrimidin-2-amine (8);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(2-(4-fluorophenyl)propan-2-yl)pyrimidin-2-amine (9);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,6-difluorophenyl)cyclopropyl)pyrimidin-2-amine (11);

2-(difluoromethyl)-5-(2-(l-phenylcyclopropoxy)pyrimidin-5-yl)-l,3,4-oxadiazole (12); 5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-l-(4-fluorophenyl)propyl)pyrimidin-2-amine (13);

(+)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-l-(4-fluorophenyl)propyl)pyrimidin-2-amine (13(+));

(-)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-l-(4-fluorophenyl)propyl)pyrimidin-2-amine (13(-));

5-(5-(difluoromethyl)- 1 ,3 ,4-oxadiazol-2-yl)-N-( 1 -(4'-fluoro-[ 1 , 1 '-biphenyl] -2-yl)cyclopropyl)pyrimidin-2-amine (14);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(2,2,2-trifluoro-l-(4-fluorophenyl)ethyl)pyrimidin-2-amine (15);

5-(5-(difluoromethyl)- 1 ,3 ,4-oxadiazol-2-yl)-N-( 1 -(4'-fluoro-[ 1 , l'-biphenyl] -4-yl)cyclopropyl)pyrimidin-2-amine (16);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(4-(4-fluorophenyl)-l-phenylpiperidin- 4- yl)pyrimidin-2-amine (17);

5- (5-(difluoromethyl)- 1 ,3 ,4-oxadiazol-2-yl)-N-( 1 -(4'-fluoro-[ 1 , l'-biphenyl] -3-yl)cyclopropyl)pyrimidin-2-amine (18);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-phenoxyethyl)pyrimidin-2-amine (19);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)ethyl)pyrimidin-2-amine (20);

(+)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)ethyl)pyrimidin-2-amine (20(+));

(-)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)ethyl)pyrimidin-2-amine (20(-));

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-methoxyethyl)pyrimidin-2-amine (21);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)propyl)pyrimidin-2-amine (22);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)butyl)pyrimidin-2-amine (23);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine (24);

5-(l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)picolinonitrile (25);

l-(4-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-4-(4-fluorophenyl)piperidin- 1 -yl)ethanone (26);

N-(l-cyclohexylcyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (27);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-isopropylcyclopropyl)pyrimidin-2-amine (28);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-lH-inden-l-yl)pyrimidin-2-amine (29);

2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)- 1-morpholinoethanone (30);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(5-fluoropyridin-2-yl)ethyl)pyrimidin-2-amine (31);

N-(l-(4-(difluoromethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (32);

N-(l-(4-(difluoromethoxy)-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (33);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(6-fluoro-l,2,3,4-tetrahydronaphthalen- 1- yl)pyrimidin-2-amine (34);

2- ((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-N-phenylacetamide (35);

N-(cyclopropyl(4-fluorophenyl)methyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (36);

N-(4,4-difluoro-l-(4-fluorophenyl)cyclohexyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (37);

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide (38);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide (38(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide (38(-));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)benzenesulfonamide (39) ;

N-(l-(2-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (40);

N-(l-(3-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (41);

N-(l-(4-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (42);

N-(l-(4-bromophenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (47);

4- (l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)benzonitrile (48);

N-(l-(2-chlorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (52);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(3- (trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine (53);

5- (5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine (54) ;

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine (55);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2-(trifluoromethyl)phenyl)cyclopropyl)pyrimidin-2-amine (58);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,3-difluorophenyl)cyclopropyl)pyrimidin-2-amine (60);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,5-difluorophenyl)cyclopropyl)pyrimidin-2-amine (61);

N-(l-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (62);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluoro-2-(trifluoromethyl)phenyl)cyclopropyl)pyrimidin-2-amine (63);

N-(l-(6-bromopyridin-3-yl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (64);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(pyridin-3-yl)cyclopropyl)pyrimidin-2-amine (65);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(5-fluoropyridin-2-yl)cyclopropyl)pyrimidin-2-amine (67);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pyrimidin-2-amine (68);

N-(4-(l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)benzyl)methanesulfonamide (69);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2-fluoro-4- (trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine (70);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)pyrimidin-2-amine (71);

N-(l-(3-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (73);

5-(5-(difluoromethyl)- 1,3, 4-oxadiazol-2-yl)-N-(l -(2,4,6-trifluorophenyl)cyclopropyl)pyrimidin-2-amine (74);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2-fluoro-5-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine (75);

N-(l-(5-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (76);

N-(l-(2-chloro-3-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (77);

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl) acetamide (78 ) ;

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl) acetamide (78(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)acetamide (78(-));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)benzamide (79) ;

N-(l-(2-chloro-5-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (80);

N-(l-(2-chloro-5-(trifluoromethyl)phenyl)cyclopropyl)-5-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (81 ) ;

N-(l-(2-bromopyridin-4-yl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (82);

4- (l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)picolinonitrile (83);

5- (5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pyrimidin-2-amine (84);

N-(l-(2-chloro-3-(trifluoromethyl)phenyl)cyclopropyl)-5-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (85);

N-(l-(2-chloro-3-(difluoromethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (86) ;

N-(l-(2-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (87);

N-(l-(2-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (89);

N-(l-(2-chloro-5-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (90);

N-(l-(2-chloro-3-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (91);

l-(4-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-4-isopropylpiperidin-l-yl)ethanone (92);

l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-l-(2,4-difluorophenyl)propan-2-ol (93);

Nl-(5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-l-(4-fluorophenyl)-N2,N2-dimethylethane- 1 ,2-diamine (94);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(4-(2,4-difluorophenyl)-l-methylpiperidin-4-yl)pyrimidin-2-amine (95);

Nl-(5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-l-(4-fluorophenyl)ethane- 1 ,2-diamine (96);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(2-(2,4-difluorophenyl)propan-2-yl)pyrimidin-2-amine (97);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(2-(2,6-difluorophenyl)propan-2-yl)pyrimidin-2-amine (98);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,4-difluorophenyl)ethyl)pyrimidin-2-amine (99);

5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]-N-[(lR)-l-(2,4-difluorophenyl)ethyl]pyrimidin-2-amine (99-R);

5-[5-(difluoromethyl)-l,3,4-oxadiazol-2-yl]-N-[(lS)-l-(2,4-difluorophenyl)ethyl]pyrimidin-2-amine (99-S);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,6-difluorophenyl)ethyl)pyrimidin-2-amine (100);

(+)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,6-difluorophenyl)ethyl)pyrimidin-2-amine (100(+));

(-)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,6-difluorophenyl)ethyl)pyrimidin-2-amine (100(-));

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,4-difluorophenyl)-3,3,3-trifluoropropyl)pyrimidin-2-amine (101);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,6-difluorophenyl)-3,3,3-trifluoropropyl)pyrimidin-2-amine (102);

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide (103);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide (103(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide (103(-));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,6-difluorophenyl)ethyl)methanesulfonamide (104);

N-(l-(2-(difluoromethoxy)-6-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (105);

N-(l-(2,6-difluoro-4-methoxyphenyl)cyclopropyl)-5-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (106);

N-(l-(2,6-difluoro-4-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (107);

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)ethanesulfonamide (108);

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)propane-2-sulfonamide (109);

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanesulfonamide (110);

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)propane- 1 -sulfonamide (111);

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-2-methylpropane- 1 -sulfonamide (112);

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl) -N-methylmethanesulf onamide (113);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylmethanesulfonamide (113(+));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-2,2,2-trifluoroacetamide (114);

N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (115);

(+)-N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (115(+));

(-)-N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (115(-));

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (116);

(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (116(+));

(-)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (116(-));

N-(2-(4-(difluoromethoxy)-2,6-difluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (117);

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (118);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (118(+));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-2,2,2-trifluoroethanesulfonamide (119);

2-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)isothiazolidine 1,1-dioxide (120);

(+)-2-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)isothiazolidine 1,1-dioxide (120(+));

(-)-2-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)isothiazolidine 1,1-dioxide (120(-));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4,6-trifluorophenyl)ethyl)methanesulfonamide (121);

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide (122);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide (122(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide (122(-));

N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (123);

(+)-N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (123(+));

(-)-N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (123(-));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(tetrahydro-2H-pyran-4-yl)ethyl)methanesulfonamide (124);

N-(3-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-3-(4-fluorophenyl)propyl)methanesulfonamide (125);

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-((4-fluorophenyl)(l-(methylsulfonyl)azetidin-3-yl)methyl)pyrimidin-2-amine (126);

N-(l-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-l-(4-fluorophenyl)propan-2-yl)methanesulfonamide (127);

N-(3-(((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide (128);

N-(4-(((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide (129);

N-(2-(((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide (130);

N-(2-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide ( 131 ) ;

N-(3-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide (132);

N-(4-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide (133);

N-(2-cyclopropoxy-l-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)-5-(5- (difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (135);

(+)-N-(2-cyclopropoxy-l-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)-5-(5- (difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (135(+));

(-)-N-(2-cyclopropoxy-l-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)-5-(5- (difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (135(-));

N-(2-cyclopropoxy-l-(4-(trifluoromethoxy)phenyl)ethyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (136);

(+)-N-(2-cyclopropoxy-l-(4-(trifluoromethoxy)phenyl)ethyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (136(+));

(-)-N-(2-cyclopropoxy-l-(4-(trifluoromethoxy)phenyl)ethyl)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-amine (136(-));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylmethanesulfonamide (137);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylmethanesulfonamide (137(+));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (138);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (138(+));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)ethanesulfonamide (139);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)ethanesulfonamide (139(+));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylethanesulfonamide (140);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylethanesulfonamide (140(+));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide (141);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide (141(+));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)cyclopropanesulfonamide (142);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)cyclopropanesulfonamide (142(+));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylcyclopropanesulfonamide (143);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylcyclopropanesulfonamide (143(+));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide (144);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide (144(+));

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol- 2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylmethanesulfonamide (145);

(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylmethanesulfonamide (145(+));

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol- 2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (146);

(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (146(+));

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)ethanesulfonamide (147);

(+)-N-(2-(4-(dMuoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)ethanesulfonamide (147(+));

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylethanesulfonamide (148);

(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylethanesulfonamide (148(+)); N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide (149); (+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide (149(+));

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)cyclopropanesulfonamide (150);

(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)cyclopropanesulfonamide (150(+));

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylcyclopropanesulfonamide (151);

(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylcyclopropanesulfonamide

(151(+));

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol- 2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide

(152);

(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide (152(+));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylmethanesulfonamide (153);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylmethanesulfonamide (153(+));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (154); (+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (154(+));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)ethanesulfonamide (155);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)ethanesulfonamide (155(+));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylethanesulfonamide (156);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylethanesulfonamide (156(+));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide (157); (+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide (157(+)); N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)cyclopropanesulfonamide (158);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)cyclopropanesulfonamide (158(+));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylcyclopropanesulfonamide (159);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylcyclopropanesulfonamide (159(+));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide (160);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4- (trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide

(160(+));

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine (161);

(+)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine (161(+));

(-)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine (161(-));

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine (162);

(+)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine (162(+));

(-)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine (162(-));

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine (163);

(+)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine (163(+));

(-)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine (163(-));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide (164);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide (164(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide (164(-));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide (165);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide (165(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide (165(-));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide (166);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl) -N-methylacetamide ( 166(+) ) ;

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide (166(-));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide (167);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide (167(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide (167(-));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide (168);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide (168(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide (168(-));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide (169);

(+)-N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide (169(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide (169(-));

N-(2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide (170);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide (170(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide (170(-));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide (171);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide (171(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide (171(-));

N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (172);

(+)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (172(+));

(-)-N-(2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (172(-));

N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (173);

(+)-N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide (173(+));

(-)-N-(2-(4-chlorophenyl)-2-((5-(5-(dilluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2 yl)amino)ethyl)methanesulfonamide (173(-));

N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (174);

(+)-N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl) ,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (174(+));

(-)-N-(2-(4-chlorophenyl)-2-((5-(5-(dilluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2 yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (174(-));

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(4-(trifluoromethyl)- IH-imidazol- l-yl)ethyl)pyrimidin-2-amine (175);

(+)-5-(5-(dilluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(4-(trifluoromethyl)- IH-imidazol- l-yl)ethyl)pyrimidin-2-amine (175(+));

(-)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(4-(trifluoromethyl)- IH-imidazol- l-yl)ethyl)pyrimidin-2-amine (175(-));

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(4-(trifluoromethyl)- lH-pyrazol- l-yl)ethyl)pyrimidin-2-amine (176);

(+)-5-(5-(dilluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(4-(trifluoromethyl)- lH-pyrazol- l-yl)ethyl)pyrimidin-2-amine (176(+));

(-)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(4-(trifluoromethyl)- lH-pyrazol- l-yl)ethyl)pyrimidin-2-amine (176(-));

1- (2-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one (177);

(+)- 1 -(2-((5-(5-(dilluoromethyl)- 1 ,3 ,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one (177(+));

(-)-l-(2-((5-(5-(diiluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one (177(-));

5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(3-(trifluoromethyl)- lH-pyrrol- l-yl)ethyl)pyrimidin-2-amine (178);

(+)-5-(5-(dilluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(3-(trifluoromethyl)- lH-pyrrol- l-yl)ethyl)pyrimidin-2-amine (178(+));

(-)-5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-N-(l-(4-fluorophenyl)-2-(3-(trifluoromethyl)- lH-pyrrol- l-yl)ethyl)pyrimidin-2-amine (178(-));

2- ((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(l-(4-fluorophenyl)cyclopropyl)amino)-N,N-dimethylacetamide (179);

fluorophenyl)cyclopropyl)amino)-N,N-diethylacetamide (180);

2-(dimethylamino)-2-oxoethyl (5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin- 2-yl)(l-(4-fluorophenyl)cyclopropyl)carbamate (181);

2-(diethylamino)-2-oxoethyl (5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2- yl)(l-(4-fluorophenyl)cyclopropyl)carbamate (182);

2-amino-N-(5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-N-(l-(4- fluorophenyl)cyclopropyl)acetamide (183); or

((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(l-(4- fluorophenyl)cyclopropyl)amino)methyl dihydrogen phosphate (184) and

pharmaceutically acceptable salts thereof.

43. A method of inhibiting metalloenzyme activity comprising contacting a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, with a metalloenzyme.

44. The method of claim 43, wherein the contacting is in vivo.

45. The method of claim 43, wherein the contacting is in vitro.

46. The method of claim 43, wherein the metalloenzyme comprises a metal atom that is iron, zinc, heme iron, manganese, magnesium, iron sulfide cluster, nickel, molybdenum, or copper.

47. The method of claim 43, wherein the metalloenzyme is a histone deacetylase (HDAC).

48. The method of claim 43, wherein the metalloenzyme is HDAC6.

49. The method of claim 43, further comprising administering the compound, or pharmaceutically acceptable salt thereof, to a subject.

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

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, comprising administering to said subject in need thereof, an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

52. 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 claim 1, or a pharmaceutically acceptable salt thereof.

53. 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, comprising administering to said subject in need thereof, an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, such that said subject is treated for said disorder or disease.

54. 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, comprising administering to said subject in need thereof, an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, such that metalloenzyme activity in said subject is modulated (e.g., down regulated, inhibited).

55. The method of any of claims 51-54, wherein the disorder or disease is cancer, a proliferative disease, a neurodegenerative disease, pain, an autoimmune or inflammatory disorder, an infection, a metabolic disorder, an hematologic disorder, a cardiovascular disease, or a combination thereof.

56. The method of any of claims 51-55, wherein the disorder or disease is cancer or a proliferative disease, wherein the cancer or proliferative disease includes a carcinoma, a sarcoma, a leukemia, a blastoma, a lymphoma, a myeloma, or a melanoma, or a combination thereof.

57. The method of any of claims 51-56, wherein the disorder or disease is multiple myeloma, melanoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, hepatocellular cancer, renal cancer, leukemia, T-cell lymphoma, cardiac cancer, bone cancer, glioblastoma, neuroblastoma, oral squamous cell carcinoma, urothelial cancer, lung cancer, cervical cancer, rectal cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, stomach cancer, skin cancer, colon cancer, head and neck squamous cell carcinoma, Burkitt's Lymphoma, esophageal cancer, Hodgkin's lymphoma, bladder cancer, or gastric cancer, or a combination thereof.

58. The method of any of claims 51-55, wherein the disorder or disease is rheumatoid arthritis, spondylitis arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus

erythematosus, inflammatory bowel disease, graft versus host disease, transplant rejection, fibrotic disease, Crohn's Disease, type-1 diabetes, eczema, psoriasis, sepsis, airway hyperresponsiveness, or ulcerative colitis, or a combination thereof.

59. The method of any of claims 51-55, wherein the disorder or disease is peripheral neuropathy, chemotherapy induced peripheral neuropathy, diabetic peripheral neuropathy, neuropathy, neuralgia, trigeminal neuralgia, postherpetic neuralgia, autoimmune peripheral neuropathy, Leber's hereditary optic neuropathy, POEMS syndrome, Cattleman disease, pain due to tumor infiltration, HIV related peripheral neuropathy, post-amputation phantom pain syndrome, Charcot-Marie Tooth disease, medication induced peripheral neuropathy, or a combination thereof.

60. The method of any of claims 51-55, wherein the disorder or disease is epilepsy, attention deficit disorder, depression, anxiety, Alzheimer's disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal muscular atrophy, essential tremor, central nervous system trauma, multiple sclerosis, Charcot-Marie-Tooth (MCT), cerebral ischemia, stroke, Gulf War Illness, or a combination thereof.

61. The method of any of claims 51-55, wherein the disorder or disease is an infection caused by virus, fungus, or bacteria, or a combination thereof.

62. The method of any of claims 51-55, wherein the disorder or disease is metabolic syndrome, diabetes, obesity, high blood pressure, heart failure, cyst growth in autosomal dominant polycystic kidney disease (ADPKD), or a combination thereof.

63. The method of any of claims 51-55, wherein the disorder or disease is cardiovascular stress, pressure overload, chronic ischemia, infarction-reperfusion injury, hypertension, atherosclerosis, peripheral artery disease, heart failure, hypertrophy, angina, arrhythmias, hypercholesterolemia, atherosclerosis, or stroke, or a combination thereof.

64. A pharmaceutical composition comprising a compound of any of claims 1-42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

65. The pharmaceutical composition of claim 64 further comprising an additional therapeutic agent.

66. The pharmaceutical composition of claim 64 further comprising an anti-cancer agent.

67. The pharmaceutical composition of claim 65, wherein the additional therapeutic agent is selected from the group consisting of platinum-based chemotherapeutic agents, vinca alkaloids, Akt inhibitors, alkylating agents, androgen receptor antagonists, anti-estrogens, Bcl-2 inhibitors, BRAF kinase inhibitors, BTK inhibitors, CAR-T Cells, anti-CD38 antibodies, CDK inhibitors, anti-CTLA-4 antibodies, ERK/MAPK inhibitors, farnesyltransferase inhibitors, IL-6 inhibitors, immunomodulatory agents, immuno-oncology agents, JAK2/FLT3 inhibitors, kinesin spindle protein inhibitors, MEK inhibitors, anti-PD-1 antibodies, anti-PD-Ll antibodies, PI3K inhibitors, proteasome inhibitors, radiation (sensitizer), radioisotopes (sensitizer), synthetic retinoids (AM80), taxanes, tyrosine kinase inhibitors, VDR agonists, VEGF inhibitors, and oncolytic viruses.

68. The pharmaceutical composition of claim 65, wherein the additional therapeutic agent is selected from the group consisting of all trans tetinoic acid (ATRA), arsenic trioxide, berberine, bevacizumab, bortezomib, cabazitaxel, carfilzomib, cisplatin, carboplatin, oxaliplatin, clarithromycin, cyclophosphamide, cytarabine, darzalex, dexamethasone, docetaxel, elotuzumab, enzalutamide, epirubicin, fluorouracil (5-FU), gefitinib, gemcitabine hydrochloride, ibrutinib, idelalisib, indatuximab, ixazomib, ravtansine, ipilimumab, lenalidomide, lonafarnib, methotrexate, nab-paclitaxel, nivolumab, paclitaxel, pacritinib, pomalidomide, sorafenib, temozolomide, thalidomide, vemurafenib, vinblastine, vindesine, vinorelbine, and vincristine.

The method of claim 50, wherein the subject is an animal other than a human.