Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
The present invention relates to novel pyrimidine hydroxy amide compounds, and the use of such compounds in the inhibition of HDAC6 and in the treatment of various diseases, disorders or conditions related to HDAC6.
1. A compound of formula VI:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
R x and R y together with the carbon to which each is attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, oxozolidinyl, or imidazolidinyl;
each R A is independently alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, haloalkoxy, halo, OH, —NO 2 , —CN, or —NH 2 ; and
m is 0, 1, or 2.
2. The compound of claim 1 , wherein R x and R y together with the carbon to which each is attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or tetrahydropyranyl.
3. The compound of claim 1 , wherein m is 1 or 2, and each R A is independently methyl, phenyl, F, Cl, methoxy, OCF 3 , or CF 3 .
4. The compound of claim 1 , wherein m is 0.
5. The compound of claim 1 , selected from the following:
73
81
82
84
97
87
88
90
91
93
94
95
100
101
117
120
121
122
123
124
125
126
127
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
155
or a pharmaceutically acceptable salt, ester or prodrug thereof.
6. The compound of claim 5 , selected from the following:
73
81
82
84
97
87
88
90
91
93
94
95
or a pharmaceutically acceptable salt, ester or prodrug thereof.
7. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable ester, salt, or prodrug thereof, together with a pharmaceutically acceptable carrier.
8. A kit comprising a compound selected from one or more compounds of formula VI
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
R x and R y together with the carbon to which each is attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, oxozolidinyl, or imidazolidinyl;
each R A is independently alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, haloalkoxy, halo, OH, —NO 2 , —CN, or —NH 2 ; and
m is 0, 1, or 2;
and instructions for use in treating multiple myeloma.
9. The compound of claim 1 , which is
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
10. The compound of claim 1 , which is
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
11. A pharmaceutical composition comprising the compound 84 or 101:
or a pharmaceutically acceptable salt, ester or prodrug thereof, together with a pharmaceutically acceptable carrier.
12. The compound 73,
or a pharmaceutically acceptable salt, ester or prodrug thereof.
13. A pharmaceutical composition comprising the compound of claim 12 , or a pharmaceutically acceptable salt, ester or prodrug thereof, together with a pharmaceutically acceptable carrier.
14. The compound 84:
15. The compound 101:
16. The compound 73: