Isoxazole hydroxamic acids as histone deacetylase 6 inhibitors

1. A compound having Formula I:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

X is selected from the group consisting of:

R 1 is selected from the group consisting of hydrogen and C 1-4 alkyl;

R 2 is selected from the group consisting of optionally substituted C 6 -C 14 aryl and aralkyl;

R 3 is —C(═O)NR d R e ;

R 4a , R 4b , R 4e and R 4f are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NR a R b , —C(═O)NR a R b , —C(═O)R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, and haloalkoxy;

R 4c and R 4d are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or

R 4c and R 4d taken together form a —C(═O)— with the carbon atom to which they are attached;

R 5a , R 5b , R 5c , and R 5d are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NR a R b , —C(═O)NR a R b , —C(═O)R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, and haloalkoxy;

Z is selected from the group consisting of —O—, —N(R 8 )—, and —C(═O)—; or

Z is absent;

R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 6 -C 14 aryl, aralkyl, optionally substituted 5- to 14-membered heteroaryl, and heteroaralkyl;

m is 0, 1, or 2;

n is 1, 2, 3, 4, 5, or 6;

represents a single or double bond;

R a and R b are independently selected from the group consisting of hydrogen, C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 6 -C 14 aryl, and optionally substituted 5- to 14-membered heteroaryl; or

R a and R b taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo;

R d and R e are independently selected from the group consisting of C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, and optionally substituted C 6 -C 14 aryl; or

R d and R e taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo; and

R c is C 1-4 alkyl.

2. A compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having Formula II:

wherein:

R 6a , R 6b , R 6c , R 6d and R 6e are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NR a R b , —C(═O)NR a R b , —C(═O)R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, and optionally substituted 5- or 6-membered heterocyclo;

R a and R b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or

R a and R b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclo;

R c is C 1-4 alkyl; and

n is 1, 2, or 3.

3. The compound of claim 2 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NR a R b , —C(═O)NR a R b , —C(═O)R c , C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, and C 1-4 alkoxy.

5. A compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from the group consisting of:

5-(2-benzamidoethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(3,4-dichlorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(2-naphthamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-([1,1′-biphenyl]-3-carboxamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(4-(5,6-dichloro-1H-indol-1-yl)butyl)-N-hydroxyisoxazole-3-carboxamide;

5-(4-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide;

5-(4-(6-chloro-4,4-dimethyl-3,4-dihydroquinolin-1(2H)-yl)butyl)-N-hydroxyisoxazole-3-carboxamide;

5-(3-(3,4-dichlorophenoxy)propyl)-N-hydroxyisoxazole-3-carboxamide;

5-(4-(2,8-dichloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)butyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(4-bromobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(4-fluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(4-chlorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

N-hydroxy-5-(2-(4-methoxybenzamido)ethyl)isoxazole-3-carboxamide;

5-(2-(4-(dimethylamino)benzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(4-cyclopropylbenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(3,4-difluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(3-chloro-4-fluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(4-chloro-3-fluorobenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(3-(dimethylamino)benzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

N-hydroxy-5-(2-(3-(pyridin-3-yl)benzamido)ethyl)isoxazole-3-carboxamide;

5-(3-benzamidopropyl)-N-hydroxyisoxazole-3-carboxamide;

N-hydroxy-5-(2-(4-(trifluoromethoxy)benzamido)ethyl)isoxazole-3-carboxamide;

5-(2-(4,5-dichloroindoline-1-carboxamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-((6,7-dichloroisoquinolin-3-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide;

543-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)propyl)-N-hydroxyisoxazole-3-carboxamide;

5-(24(5,6-dichloro-1-methyl-1H-benzo[d]imidazol-2-yl)oxy)ethyl)-N-hydroxyisoxazole-3-carboxamide;

N-hydroxy-5-(2-(4-((trifluoromethyl)thio)benzamido)ethyl)isoxazole-3-carboxamide;

5-(4-(4,5-dichloroindolin-1-yl)-4-oxobutyl)-N-hydroxyisoxazole-3-carboxamide;

5-(24(6,7-dichloroquinolin-2-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(3-(5,6-dichlorobenzo[d]thiazol-2-yl)propyl)-N-hydroxyisoxazole-3-carboxamide;

5-(3-(5,6-dichlorobenzo[d]oxazol-2-yl)propyl)-N-hydroxyisoxazole-3-carboxamide;

N-hydroxy-5-(2-(4-(trifluoromethyl)benzamido)ethyl)isoxazole-3-carboxamide;

2-(3-(hydroxycarbamoyl)isoxazol-5-yl)ethyl 4,5-dichloroindoline-1-carboxylate;

5-(2-((6,7-dichloronaphthalen-2-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-((5,6-dichlorobenzo[d]thiazol-2-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide;

N-hydroxy-5-(2-(phenanthridin-6-ylamino)ethyl)isoxazole-3-carboxamide;

5-(2-(2-(3,4-dichlorophenyl)acetamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(6,7-dichloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-((5,6-dichloroisoquinolin-1-yl)amino)ethyl)-N-hydroxyisoxazole-3-carboxamide;

N-hydroxy-5-(2-(2-phenylacetamido)ethyl)isoxazole-3-carboxamide;

2-(3-(hydroxycarbamoyl)isoxazol-5-yl)ethyl(3,4-dichlorophenyl)(methyl) carbamate;

5-(2-((5,6-dichloroisoquinolin-1-yl)oxy)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(2-(N-butylbenzamido)ethyl)-N-hydroxyisoxazole-3-carboxamide;

5-(4-((3,4-dichlorophenyl)amino)butyl)-N-hydroxyisoxazole-3-carboxamide;

5-(3-((3,4-dichlorophenyl)amino)propyl)-N-hydroxyisoxazole-3-carboxamide;

N-hydroxy-5-(3-(naphthalen-1-ylamino)propyl)isoxazole-3-carboxamide;

N-hydroxy-5-(3-(quinolin-8-ylamino)propyl)isoxazole-3-carboxamide;

5-(4-(8-chloro-2-methyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)butyl)-N-hydroxyisoxazole-3-carboxamide;

5-(4-((4-chlorophenyl)(cyclohexyl)amino)butyl)-N-hydroxyisoxazole-3-carboxamide;

5-(4-(bis(4-chlorophenyl)amino)butyl)-N-hydroxyisoxazole-3-carboxamide;

5-(4-((4-chlorobenzyl)(4-chlorophenyl)amino)butyl)-N-hydroxyisoxazole-3-carboxamide;

N-hydroxy-5-(3-(naphthalen-1-yloxy)propyl)isoxazole-3-carboxamide; and

N-hydroxy-5-(3-(quinolin-8-yloxy)propyl)isoxazole-3-carboxamide.

6. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient and/or carrier.

7. A composition comprising:

(a) a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof;

(b) a second therapeutic agent; and

(c) an optional excipient and/or pharmaceutically acceptable carrier.

8. A method of making the compound of claim 1 , the method comprising:

(1) contacting a compound having Formula VI:

wherein:

X is selected from the group consisting of:

R 1 is selected from the group consisting of hydrogen and C 1-4 alkyl;

R 2 is selected from the group consisting of optionally substituted C 6 -C 14 aryl and aralkyl;

R 3 is —C(═O)NR d R e ;

R 4a , R 4b , R 4e , and R 4f are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NR a R b , —C(═O)NR a R b , —C(═O)R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, and haloalkoxy;

R 4c and R 4d are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or

R 4c and R 4d taken together form a —C(═O)— with the carbon atom to which they are attached;

R 5a , R 5b , R 5c , and R 5d are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —C(═O)NR a R b , —C(═O)R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, and haloalkoxy;

Z is selected from the group consisting of —O—, —N(R 8 )—, and —C(═O)—; or

Z is absent;

R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 6 -C 14 aryl, aralkyl, optionally substituted 5- to 14-membered heteroaryl, and heteroaralkyl;

R 9 is C 1-4 alkyl;

m is 0, 1, or 2;

n is 1, 2, 3, 4, 5, or 6;

represents a single or double bond;

R a and R b are independently selected from the group consisting of hydrogen, C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 6 -C 14 aryl, and optionally substituted 5- to 14-membered heteroaryl; or

R a and R b taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo;

R d and R e are independently selected from the group consisting of C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, and optionally substituted C 6 -C 14 aryl; or

R d and R e taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo; and

R c is C 1-4 alkyl,

with NH 2 OH in the presence of a solvent; and,

(2) isolating the compound having Formula I.