HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS
Compounds that are fatty acid synthesis modulators are provided. The compounds may be used to treat disorders characterized by disregulation of the fatty acid synthase function by modulating the function and/or the fatty acid synthase pathway. Methods are provided for treating such disorders including viral infections, such as hepatitis C infection, cancer and metabolic disorders.
1 - 104 . (canceled)
105 . A pharmaceutical composition comprising:
(i) a compound of Formula (IX):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:
C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is halogen, or C 1 -C 2 alkyl;
R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein:
t is 0 or 1;
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
L 1 is CR 23 or N;
L 2 is CH or N;
at least one of L 1 or L 2 is N; and
R 23 is H or C 1 -C 4 straight or branched alkyl; and
(ii) one or more other active agent.
106 . The pharmaceutical composition of claim 105 , wherein R 24 is C 1 -C 4 straight or branched alkyl or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein t is 0 or 1.
107 . The pharmaceutical composition of claim 106 wherein R 24 is C 1 -C 4 straight or branched alkyl.
108 . The pharmaceutical composition of claim 107 wherein R 24 is methyl.
109 . The pharmaceutical composition of claim 105 wherein both L 1 and L 2 are N.
110 . The pharmaceutical composition of claim 105 wherein R 21 is halogen, C 1 -C 4 straight or branched alkyl or C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom.
111 . The pharmaceutical composition of claim 110 wherein R 21 is C 3 -C 5 cycloalkyl.
112 . The pharmaceutical composition of claim 111 wherein R 21 is cyclobutyl.
113 . The pharmaceutical composition of claim 105 wherein R 22 is H, methyl or ethyl.
114 . The pharmaceutical composition of claim 113 wherein R 22 is methyl.
115 . The pharmaceutical composition of claim 105 wherein R 3 is H or halogen.
116 . The pharmaceutical composition of claim 105 wherein R 3 is H.
117 . The pharmaceutical composition of claim 105 wherein each R 2 is H.
118 . The pharmaceutical composition of claim 105 wherein R 1 is halogen, —CN or C 1 -C 2 haloalkyl.
119 . The pharmaceutical composition of claim 118 wherein R 1 is —CN.
120 . The pharmaceutical composition of claim 105 wherein R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
121 . The pharmaceutical composition of claim 120 wherein R 21 is C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
122 . The pharmaceutical composition of claim 121 wherein R 24 is C 1 -C 2 alkyl.
123 . The pharmaceutical composition of claim 105 wherein R 1 is —CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, L 1 and L 2 are N, and R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
124 . The pharmaceutical composition of claim 105 wherein the compound of Formula (IX) is selected from the group consisting of:
125 . The pharmaceutical composition of claim 105 wherein the compound of Formula (IX) is
126 . The pharmaceutical composition of claim 105 wherein the compound of Formula (IX) is
127 . The pharmaceutical composition of claim 105 wherein the compound of Formula (IX) is
128 . The pharmaceutical composition of claim 105 wherein the compound of Formula (IX) is
129 . The pharmaceutical composition of claim 105 wherein the one or more other active agent is an agent having a therapeutic effect for a viral infection.
130 . The pharmaceutical composition of claim 105 wherein the one or more other active agent is a cancer therapeutic.
131 . The pharmaceutical composition of claim 130 wherein the one or more other active agent is selected from the group consisting of paclitaxel, doxorubicin, vincristine, actinomycin D, altretamine, asparaginase, bleomycin, busulphan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitozantrone, oxaliplatin, procarbazine, steroids, streptozocin, taxotere, tamozolomide, thioguanine, thiotepa, tomudex, topotecan, treosulfan, uracil-tegufur, vinblastine, and vindesine.
132 . The pharmaceutical composition of claim 130 wherein the one or more other active agent is paclitaxel.
133 . The pharmaceutical composition of claim 130 wherein the one or more other active agent is cisplatin.
134 . The pharmaceutical composition of claim 130 wherein the one or more other active agent is gemcitabine.
135 . The pharmaceutical composition of claim 130 wherein the one or more other active agent is irinotecan.
136 . The pharmaceutical composition of claim 130 wherein the one or more other active agent is taxotere.
137 . A method of treating cancer in a subject, the method comprising administering to the subject in need thereof, a therapeutically effective amount of the pharmaceutical composition of claim 105 .
138 . The method of claim 137 wherein the one or more other active agent is a cancer therapeutic.
139 . The method of claim 137 wherein the one or more other active agent is selected from the group consisting of paclitaxel, doxorubicin, vincristine, actinomycin D, altretamine, asparaginase, bleomycin, busulphan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitozantrone, oxaliplatin, procarbazine, steroids, streptozocin, taxotere, tamozolomide, thioguanine, thiotepa, tomudex, topotecan, treosulfan, uracil-tegufur, vinblastine, and vindesine.
140 . The method of claim 137 wherein the one or more other active agent is paclitaxel.
141 . The method of claim 137 wherein the one or more other active agent is cisplatin.
142 . The method of claim 137 wherein the one or more other active agent is gemcitabine.
143 . The method of claim 137 wherein the one or more other active agent is irinotecan.
144 . The method of claim 137 wherein the one or more other active agent is taxotere.
145 . The method of claim 137 wherein the cancer is lung cancer.
146 . The method of claim 137 wherein the cancer is breast cancer.
147 . The method of claim 137 wherein the cancer is ovarian cancer.
148 . The method of claim 137 wherein the cancer is prostate cancer.
149 . The method of claim 137 wherein the cancer is colon cancer.
150 . The method of claim 137 wherein the cancer is pancreatic cancer.
151 . A method of treating cancer in a subject, the method comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (IX):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:
C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein:
t is 0 or 1;
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
L 1 is CR 23 or N;
L 2 is CH or N;
at least one of L 1 or L 2 is N; and
R 23 is H or C 1 -C 4 straight or branched alkyl.
152 . The method of claim 151 wherein R 1 is —CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, L 1 and L 2 are N, and R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
153 . The method of claim 151 wherein the compound having structure (IX) is selected from the group consisting of:
154 . The method of claim 151 wherein the compound having structure (IX) is:
155 . The method of claim 151 wherein the compound having structure (IX) is:
156 . The method of claim 151 wherein the compound having structure (IX) is:
157 . The method of claim 151 wherein the compound having structure (IX) is:
158 . The method of claim 151 wherein the cancer is lung cancer.
159 . The method of claim 151 wherein the cancer is breast cancer.
160 . The method of claim 151 wherein the cancer is ovarian cancer.
161 . The method of claim 151 wherein the cancer is prostate cancer.
162 . The method of claim 151 wherein the cancer is colon cancer.
163 . The method of claim 151 wherein the cancer is pancreatic cancer.
164 . A method of treating a viral infection in a subject, the method comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (IX):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:
C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 15 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein:
t is 0 or 1;
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
L 1 is CR 23 or N;
L 2 is CH or N;
at least one of L 1 or L 2 is N; and
R 23 is H or C 1 -C 4 straight or branched alkyl.
165 . The method of claim 164 wherein R 1 is —CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, L 1 and L 2 are N, and R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
166 . The method of claim 164 wherein the compound of Formula (IX) is selected from the group consisting of:
167 . The method of claim 164 wherein the compound having structure (IX) is:
168 . The method of claim 164 wherein the compound having structure (IX) is:
169 . The method of claim 164 wherein the compound having structure (IX) is:
170 . The method of claim 164 wherein the compound having structure (IX) is:
171 . The method of claim 164 wherein the viral infection is a hepatitis C infection.
172 . The method of claim 164 wherein the viral infection is a respiratory syncytial virus infection.
173 . A method of treating a condition characterized by disregulation of a fatty acid synthase pathway in a subject, the method comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (IX):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:
C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH, or halogen;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is H, halogen, or C 1 -C 2 alkyl;
R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein:
t is 0 or 1;
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
L 1 is CR 23 or N;
L 2 is CH or N;
at least one of L 1 or L 2 is N; and
R 23 is H or C 1 -C 4 straight or branched alkyl.
174 . The method of claim 173 wherein R 1 is —CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, L 1 and L 2 are N, and R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
175 . The method of claim 173 wherein the compound of Formula (IX) is selected from the group consisting of:
176 . The method of claim 173 wherein the compound having structure (IX) is:
177 . The method of claim 173 wherein the compound having structure (IX) is:
178 . The method of claim 173 wherein the compound having structure (IX) is:
179 . The method of claim 173 wherein the compound having structure (IX) is:
180 . The method of claim 173 wherein the condition characterized by disregulation of a fatty acid synthase pathway is a metabolic disease.
181 . The method of claim 173 wherein the condition characterized by disregulation of a fatty acid synthase pathway is diabetes.