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US 2004/0176395 A1Published application
Anti-cancer medicaments
AssigneeDeciphera Pharmaceuticals, LLC
InventorsDaniel L. Flynn, Peter A. Petillo
Life of this patent
Estimating the term…
Abstract
Novel compounds and methods of using those compounds for the treatment of oncological conditions are provided. In a preferred embodiment, modulation of the activation states of abl or bcr-abl α-kinase proteins comprises the step of contacting the kinase proteins with the novel compounds.
Claims32
A compound having the formula
- 189
- wherein:
- R1 is selected from the group consisting of aryls and heteroaryls;
- each X and Y is individually selected from the group consisting of —O—, —S—, —NR6—, —NR6SO2—, —NR6CO—, alkynyls, alkenyls, alkylenes, —O(CH2)h—, and —NR6(CH2)h—, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —O(CH2)h—, and —NR6(CH2)h—, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that with —O(CH2)h—, the introduction of the side-chain oxo group does not form an ester moiety;
- A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
- D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrr-olyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl;
- E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
- L is selected from the group consisting of —C(O)—, —S(O)2—, —N(R6)CO—, —N(R6)SO2—, —N(R6)CON(R6)—;
- j is 0 or 1;
- m is 0 or 1;
- n is 0 or 1;
- p is 0 or 1;
- q is 0 or 1;
- t is 0 or 1;
- Q is selected from the group consisting of
- 190 191 192 193 194 195
- each R4 group is individually selected from the group consisting of —H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
- when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
- each R5 is individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros;
- each R6 is individually selected from the group consisting of —H, alkyls, allyls, and β-trimethylsilylethyl;
- each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
- each R9 group is individually selected from the group consisting of —H, —F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
- G is selected from the group consisting of —O—, —S—, and —N(R4)—;
- k is 0 or 1;
- each Z is individually selected from the group consisting of —O— and —N(R4)—;
- and
- each ring of formula (I) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls;
- except that:
- when Q is Q-3 or Q-4, then the compound of formula (I) is not
- 196
- when Q is Q-7, then the compound of formula (I) is not
- 197
- when Q is Q-7, R5 is —OH, Y is —O—, —S—, or —CO—, m is 0, n is 0, p is 0, q is 0, and E is phenyl, then D is not thienyl, thiazolyl, or phenyl;
- when Q is Q-7, then the compound of formula (I) is not
- 198
- when Q is Q-9, then the compound of formula (I) is not
- 199
- when Q is Q-10, then the compound of formula (I) is not
- 200
- wherein there is a bond between Q and
- 201
- of formula (I), and when Q is Q-11, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy in relation to said bond;
- when Q is Q-11, then the compound of formula (I) is not
- 202
- when Q is Q-15, then the compound of formula (I) is not
- 203
- when Q is Q-16, then the compound of formula (I) is not
- 204 205 206
- when Q is Q-17, then the compound of formula (I) is not
- 207
- when Q is Q-21, then the compound of formula (I) is not
- 208
- when Q is Q-22, then the compound of formula (I) is selected from the group consisting of
- 209 210
- but excluding
- 211 212
- when Q is Q-23, then the compound of formula (I) is not
- 213 214
- when Q is Q-24, Q-25, Q-26, or Q-31, then
- 215
- is selected from the group consisting of
- 216
- wherein each W is individually selected from the group consisting of —CH— and —N—;
- and
- 217
- where * denotes the point of attachment to Q-24, Q-25, Q-26, or Q-31;
- when Q is Q-31, then the compound of formula (I) is not
- 218
- when Q is Q-28, then the compound of formula (I) is not
- 219
- when Q is Q-32, then
- 220
- is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl;
- when Q is Q-32, then the compound of formula (I) is not
- 221
- when Q is Q-35 as shown
- 222
- wherein G is selected from the group consisting of —O—, —S—, and —NR4—, k is 0 or 1, and u is 1, 2, 3, or 4, then
- 223
- is selected from the group consisting of
- 224
- except that the compound of formula (I) is not
- 225 226 227
80 more elements
A method of modulating the activation state of abl or bcr-abl α-kinase comprising the step of contacting said kinase with a molecule having the formula
- 229
- wherein:
- R1 is selected from the group consisting of aryls and heteroaryls;
- each X and Y is individually selected from the group consisting of —O—, —S—, —NR6—, —NR6SO2—, —NR6CO—, alkynyls, alkenyls, alkylenes, —O(CH2)h—, and —NR6(CH2)h—, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —O(CH2)h—, and —NR6(CH2)h—, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that with —O(CH2)h—, the introduction of the side-chain oxo group does not form an ester moiety;
- A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
- D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl;
- E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
- L is selected from the group consisting of —C(O)—, —S(O)2—, —N(R6)CO—, —N(R6)SO2—, —N(R6)CON(R6)—;
- j is 0 or 1;
- m is 0 or 1;
- n is 0 or 1;
- p is 0 or 1;
- q is 0 or 1;
- t is 0 or 1;
- Q is selected from the group consisting of
- 230 231 232 233 234 235
- each R4 group is individually selected from the group consisting of —H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
- when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
- each R5 is individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros;
- each R6 is individually selected from the group consisting of —H, alkyls, allyls, and β-trimethylsilylethyl;
- each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
- each R9 group is individually selected from the group consisting of —H, —F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
- G is selected from the group consisting of —O—, —S—, and —N(R4)—;
- k is 0 or 1;
- each Z is individually selected from the group consisting of —O— and —N(R4)—;
- and
- each ring of formula (I) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls;
- and thereby causing modulation of said activation state.
25 more elements
An adduct comprising a molecule binding with a kinase, said molecule having the formula
- 236
- wherein:
- R1 is selected from the group consisting of aryls and heteroaryls;
- each X and Y is individually selected from the group consisting of —O—, —S—, —NR6—, —NR6SO2—, —NR6CO—, alkynyls, alkenyls, alkylenes, —O(CH2)h—, and —NR6, (CH2)h—, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —O(CH2)h—, and —NR6(CH2)h—, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that with —O(CH2)h—, the introduction of the side-chain oxo group does not form an ester moiety;
- A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
- D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl;
- E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
- L is selected from the group consisting of —C(O)—, —S(O)2—, —N(R6)CO—, —N(R6)SO2—, —N(R6)CON(R6)—;
- j is 0 or 1;
- m is 0 or 1;
- n is 0 or 1;
- p is 0 or 1;
- q is 0 or 1;
- t is 0 or 1;
- Q is selected from the group consisting of
- 237 238 239 240 241 242
- each R4 group is individually selected from the group consisting of —H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
- when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
- each R5 is individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros;
- each R6 is individually selected from the group consisting of —H, alkyls, allyls, and β-trimethylsilylethyl;
- each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
- each R9 group is individually selected from the group consisting of —H, —F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered-ring;
- G is selected from the group consisting of —O—, —S—, and —N(R4)—;
- k is 0 or 1;
- each Z is individually selected from the group consisting of —O— and —N(R4)—;
- and
- each ring of formula (I) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls.
24 more elements
Dependencies are inferred from the claim text.