Bi-aryl meta-pyrimidine inhibitors of kinases
AssigneeTargeGen, Inc.
InventorsGlenn Noronha, Chi Ching Mak, Jianguo Cao, Joel Renick, Andrew McPherson, Binqi Zeng, Ved P. Pathak, Daniel L. Lohse, John D. Hood, Richard M. Soll
Life of this patent
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Abstract
The invention provides biaryl meta-pyrimidine compounds having the general structure (A). The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the Jak kinase family, and various other specific receptor and non-receptor kinases.
Claims31
A compound having the structure (A):
- wherein:
- X is selected from a group consisting of a bond, O, and CH2;
- Y is selected from a group consisting of a bond or NR9;
- or X and Y taken together is a bond;
- each of R1 and R2 is independently selected from a group consisting of H, C1-C6 substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
- or R1 and R2 taken together is a bond;
- or R1 and R2 taken together form a moiety selected from a group consisting of (CH2)m, (CH2)r—S—(CH2)m, (CH2)r—SO—(CH2)m, (CH2)r—SO2—(CH2)m, (CH2)r—NR9—(CH2)m, and (CH2)r—O—(CH2)m;
- each of p, q, r, n, m is independently an integer having the value between 0 and 6,
- R9 is selected from a group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 branched alkyl, C1-C6 substituted alkyl, C1-C6 aminoalkyl, and C1-C6 hydroxyalkyl;
- G0 is selected from a group consisting of N, O, H, and CH,
- with the proviso that if G0 is N, then:
- each of R3 and R4 is independently selected from a group consisting of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R3 and R4 taken together form a moiety selected from a group consisting of (CH2)m, (CH2)r—S—(CH2)m, (CH2)r—SO—(CH2)m, (CH2)r—SO2—(CH2)m, (CH2)r—NR9—(CH2)m, and (CH2)r—O—(CH2)m, or R3 and R4 are taken together with G0 to form an aromatic, heteroaromatic, cyclic or heterocyclic ring system;
- with the further proviso that if G0 is O, then:
- R3 is selected from a group consisting of H, C1-C6 alkyl and C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cycloalkyl, substituted heterocyclic connected through carbon or nitrogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl connected through carbon or nitrogen, with no group R4;
- or R1 and R3 taken together form a moiety selected from a group consisting of (CH2)m, (CH2)r—S—(CH2)m, (CH2)r—SO—(CH2)m, (CH2)r—SO2—(CH2)m, (CH2)r—NR9—(CH2)m, and (CH2)r—O—(CH2)m;
- with the further proviso that if G0=CH, then:
- each of R3 and R4 is independently selected from a group consisting of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle connected through carbon or nitrogen, and substituted or unsubstituted heteroaryl connected through carbon or nitrogen, or R3 and R4 taken together form a moiety selected from a group consisting of (CHR9)r—(CHR9)m—(CHR9)p, (CHR9)r—S—(CHR9)m, (CHR9)r—SO—(CHR9)m, (CHR9)r—SO2—(CHR9)m, (CHR9)r—NR9—(CHR9)m, and (CHR9)r—O—(CHR9)m;
- each G is independently N or CR6, or C when bonded to X, provided that not more than two groups G can be N, and each R6 is independent of each other group R6;
- R5 is methyl;
- each of R6, R7, R8 is independently selected from a group consisting of H, C2-C6 substituted or unsubstituted alkenyl, C2-C6 substituted or unsubstituted alkynyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl connected through carbon or a heteroatom, a halogen, CF3, —OCF3, SO2H, SO2(C1-C6 alkyl), SO2-heterocycle, SO2-cycloalkyl, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)(C1-C6 alkyl), SO2NH(C3-C6 cycloalkyl), SO2NH-heterocycle, SO2NH(C3-C6 branched alkyl), NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), NO2, CN, CONH2, CONH(C1-C6 alkyl), CON(C1-C6 alkyl)(C1-C6 alkyl), CO(C1-C6 alkyl), CO-heterocycle, COOH, COO(C1-C6 alkyl), NHCO—(C1-C6 alkyl), and NHCONH-aryl, or any of R6 and R7 taken together, or R7 and R8 taken together, or R6 and R8 taken together form a moiety independently selected from a group consisting of —HN—CH═CH—, —HN—N═CH—, —HN—N═N—, —O(CH2)O—, —S(CH2)nS—, —N═CH—S—, —CH═N—O—, —CH═N—S—, —N═CH—O—, —C═N—O—, CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—, —O—CH═CH, and —S—CH═CH;
- A is selected from a group consisting of O, NH, N—(C1-C6 alkyl), CH2, S, SO, and SO2;
- G1 is selected from a group consisting of CH, N, NH, S, and O;
- G2 is selected from a group consisting of CR7, N, NH, S, and O, with each group R7 being independent of every other group R7;
- and if G1 or G2 is NH, S, or O, then Q is a five membered heteroaromatic ring, optionally fused to a six member aromatic or non-aromatic ring;
- and if G1 or G2 is N, then Q is a five or a six membered aromatic ring, optionally fused to a six member aromatic or non-aromatic ring;
- or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.
A compound comprising a first moiety chemically connected to a second moiety, or a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, wherein the first moiety is selected from the group consisting of:
- and wherein the second moiety is selected from the group consisting of:
A compound selected from the group consisting of compounds having formulae I-CLXII:
- or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.
6-74. (canceled)
76-93. (canceled)
95-97. (canceled)
100-103. (canceled)
A compound having the structure (B):
- wherein:
- X is selected from a group consisting of a bond, O, and CH2;
- Y is selected from a group consisting of a bond or NR9;
- or X and Y taken together is a bond;
- R9 is selected from a group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 branched alkyl, C1-C6 substituted alkyl, C1-C6 aminoalkyl, and C1-C6 hydroxyalkyl;
- each of R1 is independently selected from a group consisting of H, C1-C6 substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
- each of n, or p is independently an integer having the value between 0 and 6;
- Q1 is a 4-7 membered heterocycle connected through carbon or nitrogen, with one or more heteroatoms in the heterocyle, and each carbon or nitrogen in the heterocycle is optionally substituted independently with C1-C6 substituted or unsubstituted alkyl, C2-C6 substituted or unsubstituted alkenyl, C2-C6 substituted or unsubstituted alkynyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C1-C6 substituted or unsubstituted branched alkyl, C1-C6 substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl connected through carbon or a heteroatom, substituted or unsubstituted heteroaryl connected through carbon or a heteroatom, a halogen, CF3, —OCF3, NO2, CN, OH, CONR3R4, and COR3;
- each of R6, R7, R8 is independently selected from a group consisting of H, C1-C6 substituted or unsubstituted alkyl, C2-C6 substituted or unsubstituted alkenyl, C2-C6 substituted or unsubstituted alkynyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted branched alkyl, C3-C6 substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl connected through carbon or a heteroatom, C1-C6 alkoxy, a halogen, CF3, —OCF3, SO2R3, SO2NR3R4, NR3R4, NO2, CN, OH, CONR3R4, COR3, COOR3, NR3COR4, NR3CONR3R4, and OCONR3R4;
- or any of R6 and R7 taken together, or R7 and R8 taken together, or R6 and R8 taken together form a moiety independently selected from a group consisting of —HN—CH═CH—, —HN—N═CH—, —HN—N═N—, —O(CH2)nO—, —S(CH2)nS—, —N═CH—S—, —CH═N—O—, —CH═N—S—, —N═CH—O—, —C═N—O—, CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—, —O—CH═CH, and —S—CH═CH—;
- each of R3 and R4 is independently selected from a group consisting of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl
- with the further provisos that:
- (a) at least one of R6, R7 and R8 is not hydrogen;
- (b) R6 and R7, or R6 and R8, or R7 and R8 are substituted with non-hydrogen atoms, or if only one of R6, R7 and R8 is substituted, then the substitution contains at least three non-hydrogen atoms;
- (c) any one of R6, R7 or R8 optionally comprises a heteroatom selected from a group consisting of O, N and S;
- (d) the moiety connected through X excludes aromatic or hetero-aromatic cyclic rings,
- or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide, thereof.
105-112. (canceled)
114-125. (canceled)
A method of treating a myeloproliferative disorder, comprising administering to a subject in need thereof an effective amount of the compound:
- or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.
127-130. (canceled)
A method of treating chronic myelogenous leukemia (CML), comprising administering an effective amount of the compound to a subject in need thereof:
- or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide, thereof.
(canceled)
135-143. (canceled)
A method for treating a disease selected from systemic sclerosis, rheumatoid arthritis, mastocytosis, chronic myelogenous leukemia, and chronic eosinophilic leukemia comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound comprising a first moiety chemically connected to a second moiety, or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof, wherein the first moiety is selected from the group consisting of:
- and wherein the second moiety is selected from the group consisting of:
145-151. (canceled)
A method of treating systemic sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by:
- or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.
A method of treating rheumatoid arthritis, comprising administering to a subject in need thereof a therapeutically effective amount of:
- or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.
A compound, or a salt thereof, wherein the compound is of the formula selected from the group consisting of:
A method for making a compound of the formula XLV:
- comprising reacting 3-bromo-N-tert-butyl-benzenesulfonamide with a compound of the formula 32:
A method for making a compound of the formula LVII:
- comprising reacting 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine with a compound of the formula 33:
Dependencies are inferred from the claim text.