The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
대표청구항▼
1. A compound of Formula IO: or a pharmaceutically acceptable salt or complex thereof, or a racemic or scalemic mixture, diastereomer, or enantiomer thereof, whereinX is optionally substituted phenyl;Y is NH2;Ra is H or halogen;Z is phenyl optionally substituted with one or more groups independently
1. A compound of Formula IO: or a pharmaceutically acceptable salt or complex thereof, or a racemic or scalemic mixture, diastereomer, or enantiomer thereof, whereinX is optionally substituted phenyl;Y is NH2;Ra is H or halogen;Z is phenyl optionally substituted with one or more groups independently selected from C1-C7alkyl, hydroxy, C1-C7alkoxy, halo, CN and amino; andR is —(CR32R33)s—N(R30)(R31), —Y31—X30, —O-heterocyclyl, —O—C2-C4alkyl-N(R30)(R31), or —(CH2)s—N(R30)(R31);whereins is an integer from 0 to 6;R32 and R33 are each independently selected from the group consisting of hydrogen, halo, hydroxyl, —C0-C3alkyl-aryl, —C0-C3alkyl-heteroaryl, —C0-C3alkyl-heterocyclyl, —C0-C3alkyl-cycloalkyl and C1-C4alkyl;R30 and R31 are each independently selected from the group consisting of hydrogen, cyano, oxo, hydroxyl, —C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkenyl, carboxamido, C1-C3alkyl-carboxamido-, carboxamido-C1-C3alkyl-, amidino, C2-C8hydroxyalkyl-, C1-C3alkylaryl-, aryl-C1-C3alkyl-, C1-C3alkylheteroaryl-, heteroaryl-C1-C3alkyl-, C1-C3alkylheterocyclyl-, heterocyclyl-C1-C3alkyl, C1-C3alkylcycloalkyl-, cycloalkyl-C1-C3alkyl-, C2-C8alkoxy, C2-C8alkoxy-C1-C4alkyl-, C1-C8alkoxycarbonyl-, aryloxycarbonyl, aryl-C1-C3alkoxycarbonyl-, heteroaryloxycarbonyl, heteroaryl-C1-C3alkoxycarbonyl-, C1-C8acyl, C0-C8alkyl-carbonyl-, aryl-C0-C8alkyl-carbonyl-, heteroaryl-C0-C8alkyl-carbonyl-, cycloalkyl-C0-C8alkyl-carbonyl-, C0-C8alkyl-NH-carbonyl-, aryl-C0-C8alkyl-NH-carbonyl-, heteroaryl-C0-C8alkyl-NH-carbonyl-, cycloalkyl-C0-C8alkyl-NH-carbonyl-, C0-C8alkyl-O-carbonyl-, aryl-C0-C8alkyl-O-carbonyl-, heteroaryl-C0-C8alkyl-O-carbonyl-, cycloalkyl-C0-C8alkyl-O-carbonyl-, C1-C8alkylsulfonyl-, arylalkylsulfonyl-, arylsulfonyl-, heteroarylalkylsulfonyl-, heteroarylsulfonyl-, C1-C8alkyl-NH-sulfonyl-, arylalkyl-NH-sulfonyl-, aryl-NH-sulfonyl-, heteroarylalkyl-NH-sulfonyl-, heteroaryl-NH-sulfonyl-, aroyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C1-C3alkyl-, cycloalkyl-C1-C3alkyl-, heterocyclyl-C1-C3alkyl-, heteroaryl-C1-C3alkyl- and a protecting group, wherein each of the foregoing is further optionally substituted with one more moieties selected from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino and guanidino; orR30 and R31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, cyano, carboxy, formyl, nitro, amino, amidino, guanidino, a protecting group, and (X30—Y31—), wherein said optional substituent is not spiro-fused to said heterocyclyl or heteroaryl, and wherein said heterocyclyl is optionally bridged with a methylene, ethylene or propylene bridge;X30 is selected from the group consisting of C1-C8alkyl-, C2-C8alkenyl-, C2-C8alkynyl-, C0-C3alkyl-C2-C8alkenyl-C0-C3alkyl-, C0-C3alkyl-C2-C8alkynyl-C0-C3alkyl-, C0-C3alkyl-O—C1-C3alkyl-, HO—C1-C3alkyl-, C0-C4alkyl-N(R30)—C0-C3alkyl-, N(R30)(R31)—C0-C3alkyl-, N(R30)(R31)—C0-C3alkenyl-, N(R30)(R31)—C0-C3alkynyl-, (N(R30)(R31))2—C═N—, C0-C3alkyl-S(O)0-2—C0-C3alkyl-, CF3—C0-C3alkyl-, C1-C8heteroalkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C1-C3alkyl-, cycloalkyl-C1-C3alkyl-, heterocyclyl-C1-C3alkyl-, heteroaryl-C1-C3alkyl- and N(R30)(R31)-heterocyclyl-C1-C3alkyl-, wherein the aryl, cycloalkyl, heteroaryl and heterocycyl are optionally substituted with from 1 to 3 substituents from halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino and guanidino; andY31 is selected from the group consisting of a direct bond, —N(R30)—, —C(O)—, —O—C(O)—, —C(O)—O—, —N(R30)—C(O)—, —C(O)—N(R30)—, —N(R30)—C(S)—, —C(S)—N(R30)—, —N(R30)—C(O)—N(R31)—, —N(R30)—C(NR30)—N(R31)—, —N(R30)—C(NR31)—, —C(NR31)—N(R30), —N(R30)—C(S)—N(R31)—, —N(R30)—C(O)—O—, —O—C(O)—N(R31)—, —N(R30)—C(S)—O—, —O—C(S)—N(R31)—, —S(O)0-2—, —SO2N(R31)—, —N(R31)—SO2— and —N(R30)—SO2N(R31)—;provided that Y31 and X30 are not linked to form —O—O— or —O—N—. 2. A compound having formula III or a pharmaceutically acceptable salt or complex thereof, or a racemic or scalemic mixture, diastereomer, or enantiomer thereof, whereinX is optionally substituted phenyl or optionally substituted thienyl;Ar is optionally substituted phenyl;Ra is H or halo;Rb, Rc and Rd are each independently hydrogen, C1-C8 alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or halo; orRb and Rc together with the atoms to which they are bonded, optionally form a 5- or 6-membered cycloalkyl or heteroalkyl having 1 or 2 annular heteroatoms; each of which is optionally substituted with from 1 to 3 substituents;Y is —NH2;Yb is —N— or —CH—;Ya is direct bond, —O—, —N(R34)—, —C(O)—, —OC(O)—, —C(O)O—, —N(R34)—C(O)—, —C(O)—N(R34)—, —N(R34) —C(S)—, —C(S)—N(R34)—, —N(R34)—C(O)—N(R35)—, —N(R34)—C(NR34)—N(R35)—, —N(R34)—C(NR35)—, —C(NR35)—N(R34)—, —N(R34)—C(S)—N(R35)—, —N(R34)—C(O)—O—, —O—C(O)—N(R34)—, —N(R34)—C(S)O—, —O—C(S)—N(R35)—, —S(O)0-2—, —SO2N(R35)—, —N(R35)—SO2—, N(R34)—S(O)2—N(R35)—, —O—C1-C3alkyl-, —N(R34)—C1-C3alkyl-, —C(O)—C1-C3alkyl- or —O—C(O)—C1-C3alkyl-;Xa is C1-C8alkyl-, C1-C8alkenyl-, C1-C8alkynyl-, C0-C3alkyl-C1-C8alkenyl-C0-C3alkyl-, C0-C3alkyl-C1-C8alkynyl-C0-C3alkyl-, C1-C3alkyl-O—C1-C3alkyl-, HO—C1-C3alkyl-, C1-C4alkyl-N(R34)—C0-C3alkyl-, N(R34)(R35)—C0-C3alkyl-, C1-C3alkyl-S(O)0-2—C1-C3alkyl-, CF3—C0-C3alkyl-, CF2H—C0-C3alkyl-, C1-C8heteroalkyl-, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C1-C3alkyl-, cycloalkyl-C1-C3alkyl-, heterocyclyl-C1-C3alkyl-, heteroaryl-C1-C3alkyl-, aryl-C0-C2alkyl-heterocyclyl-C0-C2alkyl-, heteroaryl-C0-C2alkyl-heterocyclyl-C0-C2alkyl-, N(R34)(R35)-heterocyclyl-C0-C3alkyl-, heteroaryl-C0-C3alkyl-heterocyclyl- or C1-C4alkyl-CH(N(R34)(R35))—C(O)—N(R34)-aryl-, wherein the aryl, cycloalkyl, heteroaryl and heterocycyl are optionally substituted with from 1 to 3 independently selected substituents;orXa—Ya— is selected from the group consisting of H—, halo-, HO—, HS—, HC(O)—, HOC(O)—, C1-C4alkyl-, H2N—, (R34)(R35)N—, C1-C4alkyl-NH—, (C1-C4alkyl)2-N—, HC(O)N(R34)—, (R34)(R35)N—S(O)2—N(R36)—, (R34)(R35)N—C(O)—, H2N—C(O)—, HC(S)N(R34)—, (R34)(R35)N—C(S)—, H2N—C(S)—, (R34)(R35)N—C(O)—O—, (R34)(R35)N—C(S)—O—, (R34)(R35)N—C(O)—N(R36)—, (C1-C3alkylN)2—C═N—, (R34)(R35)N—C(NR37)—N(R36)—, (R34)(R35)N—C(NR36)—, cycloalkyl-C0-C2alkyl-C(NR36)—, heterocyclyl-C0-C2alkyl-C(NR36)—, aryl-C0-C2alkyl-C(NR36)—, heteroaryl-C0-C2alkyl-C(NR36)—, C0-C3alkyl-C(NR36)—, C1-C4alkyl-S(O)2—N(R36)—, CF3—C0-C4alkyl-S(O)2—N(R36)—, CF3—C0-C4alkyl-C(O)—N(R36)—, aryl-C0-C4alkyl-S(O)2—N(R36)—, heteroaryl-C0-C4alkyl-S(O)2—N(R36)—, cycloalkyl-C0-C4alkyl-S(O)2—N(R36)—, heterocyclyl-C0-C4alkyl-S(O)2—N(R36)—, C1-C4alkyl-O—C(O)—NH—, C1-C4alkyl-O—C(O)—N(H)—C1-C4alkyl-, C1-C4alkyl-N(H)—C(O)—N(H)—, C1-C4alkyl-NH—C(O)—O—, C1-C4alkyl-C(O)—N(H)—, C1-C4alkyl-O—C(S)—N(H)—, C1-C4alkyl-N(H)—C(S)—N(H)—, C1-C4alkyl-N(H)—C(S)—O—, C1-C4alkyl-C(S)—N(H)—, Me-C(O)—O—, Me-C(O)—N(H)—, aryl-C0-C4alkyl-O—C(O)—N(H)—, aryl-C0-C4alkyl-O—C(O)—N(C1-C4alkyl)-, aryl-C0-C4alkyl-C(O)—N(H)—, heteroaryl-C0-C4alkyl-O—C(O)—N(H)—, heteroaryl-C0-C4alkyl-O—C(O)—N(C1-C4alkyl)-, heteroaryl-C0-C4alkyl-C(O)—N(H)—, aryl-C0-C4alkyl-N(H)—C(O)—O—, heteroaryl-C0-C4alkyl-N(H)—C(O)—O—, heterocyclyl-C0-C4alkyl-O—C(O)—N(H)—, heterocyclyl-C0-C4alkyl-O—C(O)—N(C1-C4alkyl)-, heterocyclyl-C0-C4alkyl-C(O)—N(H)—, cycloalkyl-C0-C4alkyl-O—C(O)—N(H)—, cycloalkyl-C0-C4alkyl-O—C(O)—N(C1-C4alkyl)-, cycloalkyl-C0-C4alkyl-C(O)—N(H)—, heterocyclyl-C0-C4alkyl-N(H)—C(O)—O—, cycloalkyl-C0-C4alkyl-N(H)—C(O)—O—, heterocyclyl-C0-C4alkyl-C(O)—N(H)—, aryl-C0-C4alkyl-N(H)—C(O)—N(H)—, aryl-C0-C4alkyl-N(H)—, aryl-C0-C4alkyl-O—, aryl-C0-C4alkyl-S(O)0-2—, heteroaryl-C0-C4alkyl-N(H)—C(O)—N(H)—, heteroaryl-C0-C4alkyl-N(H)—, heteroaryl-C0-C4alkyl-O—, heteroaryl-C0-C4alkyl-S(O)0-2, heterocyclyl-C0-C4alkyl-N(H)—C(O)—N(H)—, heterocyclyl-C0-C4alkyl-N(H)—, heterocyclyl-C0-C4alkyl-O—, heterocyclyl-C0-C4alkyl-S(O)0-2—, cycloalkyl-C0-C4alkyl-N(H)—C(O)—N(H)—, cycloalkyl-C0-C4alkyl-N(H)—, cycloalkyl-C0-C4alkyl-O—, cycloalkyl-C0-C4alkyl-S(O)0-2, aryl-C0-C4alkyl-C(S)—N(H)—, heteroaryl-C0-C4alkyl-C(S)—N(H)—, aryl-C0-C4alkyl-O—C(S)—N(H)—, heteroaryl-C0-C4alkyl-O—C(S)—N(H)—, aryl-C0-C4alkyl-N(H)—C(S)—O—, heteroaryl-C0-C4alkyl-N(H)—C(S)—O—, heterocyclyl-C0-C4alkyl-C(S)—N(H)—, cycloalkyl-C0-C4alkyl-C(S)—N(H)—, heterocyclyl-C0-C4alkyl-O—C(S)—N(H)—, cycloalkyl-C0-C4alkyl-O—C(S)—N(H)—, heterocyclyl-C0-C4alkyl-N(H)—C(S)—O—, cycloalkyl-C0-C4alkyl-N(H)—C(S)—O—, heterocyclyl-C0-C4alkyl-C(S)—N(H)—, aryl-C0-C4alkyl-N(H)—C(S)—NH—, heteroaryl-C0-C4alkyl-N(H)—C(S)—N(H)—, heterocyclyl-C0-C4alkyl-N(H)—C(S)—N(H)—, cycloalkyl-C0-C4alkyl-N(H)—C(S)—N(H)—, C1-C4alkyl-O—C1-C4alkyl-C(O)—N(H)—, C1-C4alkyl-O—C2-C4alkyl-O—C(O)—N(H)—, C1-C4alkyl-O—C2-C4alkyl-N(H)—C(O)—N(H)—, C1-C4alkyl-O—C2-C4alkyl-N(H)—, C1-C4alkyl-O—C2-C4alkyl-O—, C1-C4alkyl-O—C2-C4alkyl-N(H)—C(O)—O—, HO—C1-C4alkyl-C(O)—N(H)—, HO—C1-C4alkyl-N(H)—, HO—C1-C4alkyl-N(R3)—, HO—C1-C4alkyl-O—, HO—C1-C4alkyl-S(O)0-2—, HO—C2-C4alkyl-O—C(O)—N(H)—, HO—C2-C4alkyl-N(H)—C(O)—N(H)—, HO—C2-C4alkyl-N(H)—C(O)—O—, C1-C4alkyl-O—C1-C4alkyl-C(S)—N(H)—, C1-C4alkyl-O—C2-C4alkyl-O—C(S)—N(H)—, C1-C4alkyl-O—C2-C4alkyl-N(H)C(S)—N(H)—, C1-C4alkyl-O—C2-C4alkyl-N(H)—C(S)—O—, HO—C2-C4alkyl-O—C(S)—N(H)—, HO—C2-C4alkyl-N(H)—C(S)—N(H)—, HO—C2-C4alkyl-N(H)—C(S)—O—, (C1-C4alkyl)2N—C1-C4alkyl-C(O)—N(H)—, (C0-C4alkyl)-O—C1-C4alkyl-C(O)—N(H)—, (C0-C4alkyl)-O—C1-C4alkyl-C(S)—N(H)—, (C0-C4alkyl)-O—C1-C4alkyl-C(O)—O—, (C0-C4alkyl)-O—C2-C4alkyl-N(H)—C(O)—N(H)—, (C0-C4alkyl)-O—C2-C4alkyl-O—C(O)—N(H)—, (C0-C4alkyl)-O—C2-C4alkyl-N(H)—C(NH)—N(H)—, (C0-C4alkyl)-O—C2-C4alkyl-N(H)—C(O)—, (C1-C4alkyl)2N—C2-C4alkyl-O—C(O)—N(H)—, (C1-C4alkyl)2N—C2-C4alkyl-N(H)—, (C1-C4alkyl)2N—C2-C4alkyl-O—, (C1-C4alkyl)2N—C2-C4alkyl-S(O)0-2—, (C1-C4alkyl)2N—C2-C4alkyl-N(H)—C(O)—N(H)—, (C1-C4alkyl)2N—C2-C4alkyl-N(H)—C(O)—O—, (C1-C4alkyl)2N—C1-C4alkyl-C(S)—N(H)—, (C1-C4alkyl)2N—C2-C4alkyl-N(H)—C(S)—N(H)—, (C1-C4alkyl)2N—C2-C4alkyl-N(H)—C(S)—O—, (C1-C4alkyl)-O—C(O)C1-C8alkyl-C(O)—(H)—, HO—C(O)C1-C8alkyl-C(O)—N(H)—, HO—NH—C(O)C1-C8alkyl-C(O)—N(H)—, CF2H—C0-C4alkyl-C(O)—N(H)—, CF3—C0-C4alkyl-C(O)—N(H)—, CF3—C0-C4alkyl-N(H)—, CF3—C0-C4alkyl-N(R3)—, CF3—C0-C4alkyl-O—, CF3—C0-C4alkyl-S(O)0-2—, CF3—C0-C4alkyl-O—C(O)—N(H)—, CF3—C0-C4alkyl-N(H)C(O)—N(H)—, CF3—C0-C4alkyl-N(H)—C(O)—O—, CF3—C0-C4alkyl-O—C(S)—N(H)—, CF3—C0-C4alkyl-N(H)—C(S)—N(H)—, CF3—C0-C4alkyl-N(H)—C(S)—O—, CF3—C0-C4alkyl-C(S)—N(H)—, CF2H—C0-C4alkyl-N(H)—, CF2H—C0-C4alkyl-O—, CF2H—C0-C4alkyl-S(O)0-2—, CF2H—C0-C4alkyl-O—C(O)—N(H)—, CF2H—C0-C4alkyl-N(H)C(O)—N(H)—, CF2H—C0-C4alkyl-N(H)—C(O)—O—, CF2H—C0-C4alkyl-O—C(S)—N(H)—, CF2H—C0-C4alkyl-N(H)—C(S)—N(H)—, CF2H—C0-C4alkyl-N(H)—C(S)—O—, CF2H—C0-C4alkyl-C(S)—N(H)—, (H)(R34)N—C1-C3alkyl-, (H)(R34)N—C1-C3alkyl-, HO—C1-C3alkyl-, (H)(R34)N—S(O)2—N(R35)—, (H)(R35)N—S(O)2—, (H)(R34)N—C(S)—O—, (H)(R34)N—C(O)—O—, (H)(R34)N—C(S)—N(R35)—, (H)(R34)N—C(NR35)—, (H)(R34)N—C(NR34)—N(R38)—, (H)(R34)N—C(O)—N(R35)—, HO—C(O)—C1-C3alkyl-, C1-C4alkyl-S(O)2—NH— and ((R34)(R35)N)2—C═N—;m and n are independently 0, 1, 2 or 3;q is 0, 1 or 2;R34, R35, R36 and R37 are each independently selected from the group consisting of hydrogen, cyano, oxo, hydroxyl, —C1-C8alkyl, C1-C8heteroalkyl, C1-C8alkenyl, carboxamido, C1-C3alkyl-carboxamido-, carboxamido-C1-C3alkyl-, amidino, C2-C8hydroxyalkyl, C1-C3alkylaryl-, aryl-C1-C3alkyl-, C1-C3alkylheteroaryl-, heteroaryl-C1-C3alkyl-, C1-C3alkylheterocyclyl-, heterocyclyl-C1-C3alkyl-, C1-C3alkylcycloalkyl-, cycloalkyl-C1-C3alkyl-, C2-C8alkoxy-, C2-C8alkoxy-C1-C4alkyl-, C1-C8alkoxycarbonyl-, aryloxycarbonyl-, aryl-C1-C3alkoxycarbonyl-, heteroaryloxycarbonyl-, heteroaryl-C1-C3alkoxycarbonyl-, C1-C8acyl, C0-C8alkyl-carbonyl-, aryl-C0-C8alkyl-carbonyl-, heteroaryl-C0-C8alkyl-carbonyl-, cycloalkyl-C0-C8alkyl-carbonyl-, C0-C8alkyl-N(H)-carbonyl-, aryl-C0-C8alkyl-N(H)-carbonyl-, heteroaryl-C0-C8alkyl-N(H)-carbonyl-, cycloalkyl-C0-C8alkyl-N(H)-carbonyl-, C0-C8alkyl-O-carbonyl-, aryl-C0-C8alkyl-O-carbonyl-, heteroaryl-C0-C8alkyl-O-carbonyl-, cycloalkyl-C0-C8alkyl-O-carbonyl-, C1-C8 alkylsulfonyl-, arylalkylsulfonyl-, arylsulfonyl-, heteroarylalkylsulfonyl-, heteroarylsulfonyl-, C1-C8alkyl-N(H)-sulfonyl-, arylalkyl-N(H)-sulfonyl-, aryl-N(H)-sulfonyl-, heteroarylalkyl-N(H)-sulfonyl-, heteroaryl-N(H)-sulfonyl, aroyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C1-C3alkyl-, cycloalkyl-C1-C3alkyl-, heterocyclyl-C1-C3 alkyl-, heteroaryl-C1-C3 alkyl-, and a protecting group, wherein each of the foregoing is further optionally substituted with one more moieties; orR34 and R35 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents, wherein the heterocyclyl is optionally bridged with a methylene, ethylene or propylene bridge,provided that 1) when Yb is N, then m is not 0 if Ya is bound to the ring comprising Y, via a N, S or O in Ya, or 2) when m and n are both 0 then Yb is —CH—. 3. The compound of claim 1, wherein —Z—R is 4. A compound that is N-(4,4′-diaminobiphenyl-3-yl)-4-(pyridin-3-yl)benzamide,N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(pyridin-3-yl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(morpholinomethyl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(pyridin-3-yl)benzamide,N-(4-amino-4′-hydroxybiphenyl-3-yl)-4-(morpholinomethyl)benzamide,(R)—N-(4-aminobiphenyl-3-yl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)benzamide,(R)—N-(4-amino-4′-hydroxybiphenyl-3-yl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)benzamide,N-(4-amino-4′-chlorobiphenyl-3-yl)-4-(morpholinomethyl)benzamide,2-(dimethylamino)ethyl 4-(4-amino-4′-chloro-3′-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-3′-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-3′,4′-dichlorobiphenyl-3-ylcarbamoyl)phenylcarbamate,4-(4-amino-3′,4′-dichlorobiphenyl-3-ylcarbamoyl)phenyl acetate,2-(dimethylamino)ethyl 4-(4-amino-3′,4′-difluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,4-(4-amino-3′,4′-difluorobiphenyl-3-ylcarbamoyl)phenyl acetate,2-(dimethylamino)ethyl 4-(4-aminobiphenyl-3-ylcarbamoyl)phenylcarbamate,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-aminopyrrolidin-1-yl)benzamide,2-morpholinoethyl 4-(4-aminobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-3′-(trifluoromethoxy)biphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-(trifluoromethoxy)biphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-3′-fluoro-4′-methoxybiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-chlorobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-3′-fluoro-4′-hydroxybiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-2′,4′-difluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-(trifluoromethyl)biphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-2′-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-hydroxybiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-3′,4′,5′-trifluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-(dimethylamino)biphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-(methylthio)biphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-cyanobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-2′-fluoro-4′-methoxybiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-3′-fluoro-4′-methylbiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-2′,4′,5′-trifluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-(methylsulfinyl)biphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-2′-fluoro-4′-(trifluoromethyl)biphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-(methylsulfonyl)biphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4,4′-diaminobiphenyl-3-ylcarbamoyl)phenylcarbamate,2-(dimethylamino)ethyl 4-(4-amino-4′-ethoxybiphenyl-3-ylcarbamoyl)phenylcarbamate,(S)-4-(3-acetamidopyrrolidin-1-yl)-N-(4-aminobiphenyl-3-yl)benzamide,(S)-4-(3-acetamidopyrrolidin-1-yl)-N-(4-amino-4′-fluorobiphenyl-3-yl)benzamide,2-(dimethylamino)ethyl 4-(4-amino-4′-cyano-3′-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,(S)—N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(3-aminopyrrolidin-1-yl)benzamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-(bis(dimethylamino)methyleneamino)pyrrolidin-1-yl)benzamide,(S)—N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(3-(bis(dimethylamino)methyleneamino)pyrrolidin-1-yl)benzamide,N-(4-amino-3′,4′-difluorobiphenyl-3-yl)-4-(1,3-dioxoisoindolin-2-yl)benzamide,N-(4-aminobiphenyl-3-yl)-3-(pyridin-3-yl)benzamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-(methylsulfonamido)pyrrolidin-1-yl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(4-methylpiperazin-1-yl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(pyrrolidin-1-yl)benzamide,(R)—N-(4-aminobiphenyl-3-yl)-4-(3-aminopyrrolidin-1-yl)benzamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-(2,2,2-trifluoroacetamido)pyrrolidin-1-yl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(4-methylpiperazin-1-ylsulfonyl)benzamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-(dimethylamino)pyrrolidin-1-yl)benzamide,(R)—N-(4-aminobiphenyl-3-yl)-4-(3-hydroxypyrrolidin-1-yl)benzamide,(S)-methyl 1-(4-(4-aminobiphenyl-3-ylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamate,N-(4-aminobiphenyl-3-yl)-4-(4-ethylpiperazin-1-yl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(4-aminopiperidin-1-yl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(3-oxopiperazin-1-yl)benzamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-hydroxypyrrolidin-1-yl)benzamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-(ethylamino)pyrrolidin-1-yl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(1H-imidazol-1-yl)benzamide,(R)—N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(3-aminopyrrolidin-1-yl)benzamide,1-(4-(4-aminobiphenyl-3-ylcarbamoyl)phenyl)piperidine-4-carboxamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-fluoropyrrolidin-1-yl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(3,3-difluoropyrrolidin-1-yl)benzamide,(R)—N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(3-(2-methoxyacetamido)pyrrolidin-1-yl)benzamide,(R)—N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(3-(methylsulfonamido)pyrrolidin-1-yl)benzamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-(2-methoxyacetamido)pyrrolidin-1-yl)benzamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-(2-(dimethylamino)acetamido)pyrrolidin-1-yl)benzamide,(R)-4-(3-acetamidopyrrolidin-1-yl)-N-(4-amino-4′-fluorobiphenyl-3-yl)benzamide,(R)-methyl 1-(4-(4-amino-4′-fluorobiphenyl-3-ylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamate,N-(4-aminobiphenyl-3-yl)-4-(piperazin-1-yl)benzamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-(2-hydroxyethylamino)pyrrolidin-1-yl)benzamide,(S)—N-(4-aminobiphenyl-3-yl)-4-(3-(2,2,2-trifluoroethylamino)pyrrolidin-1-yl)benzamide,(R)—N-(4-aminobiphenyl-3-yl)-4-(3-(dimethylamino)pyrrolidin-1-yl)benzamide,(R)—N-(4-aminobiphenyl-3-yl)-4-(3-(ethylamino)pyrrolidin-1-yl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(hydroxymethyl)benzamide,(R)—N-(4-aminobiphenyl-3-yl)-4-(3-methoxypyrrolidin-1-yl)benzamide,N-(4-aminobiphenyl-3-yl)-4-(3-hydroxyazetidin-1-yl)benzamide,N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(3-hydroxyazetidin-1-yl)benzamide,(S)—N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(3-hydroxypyrrolidin-1-yl)benzamide,or a pharmaceutically acceptable salt thereof. 5. A compound that is N-(4-aminobiphenyl-3-yl)-4-(morpholinomethyl)benzamide;2-(dimethylamino)ethyl 4-(4-amino-3′,4′-difluorobiphenyl-3-ylcarbamoyl)phenylcarbamate;2-(dimethylamino)ethyl 4-(4-amino-3′-fluoro-4′-methoxybiphenyl-3-ylcarbamoyl)phenylcarbamate;2-(dimethylamino)ethyl 4-(4-amino-4′-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate;2-(dimethylamino)ethyl 4-(4-amino-2′,4′-difluorobiphenyl-3-ylcarbamoyl)phenylcarbamate;(S)—N-(4-aminobiphenyl-3-yl)-4-(3-hydroxypyrrolidin-1-yl)benzamide;(R)—N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(3-(2-methoxyacetamido)pyrrolidin-1-yl)benzamide;N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(3-hydroxyazetidin-1-yl)benzamide;(S)—N-(4-amino-4′-fluorobiphenyl-3-yl)-4-(3-hydroxypyrrolidin-1-yl)benzamide;or a pharmaceutically acceptable salt thereof. 6. The compound of claim 2, wherein X is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, oxo, hydroxy, C1-C3-hydrocarbyl, methoxy, HalCH2—O—, Hal2CH—O—, Hal3C—O— (preferably F3C—O—), NH2—, —N(C1-C3alkyl)2, —CN, —S(O)0-2—C1-C4alkyl, —CF3, and mono-, di-, or tri-halo substituted alkyl, or, when there are two optional substituents bonded to adjacent atoms of the phenyl, thienyl, or pyridyl they, together with the atoms to which they are bonded, optionally form a 5- or 6-membered cycloalkyl or heteroalkyl having 1, 2, or 3 annular heteroatoms. 7. The compound of claim 2, wherein Ar is optionally substituted with one or two substituents independently selected from the group consisting of halo, nitro, hydroxy, C1-C3-hydrocarbyl, methoxy, HalCH2—O—, Hal2CH—O—, Hal3C—O— (preferably F3C—O—), and mono-, di-, or tri-halo substituted alkyl. 8. The compound of claim 2, wherein Xa—Ya— is selected from the group consisting of CH3—SO2—, CF3—C(O)—NH—, CH3—C(O)—NH—, ((CH3)2N)2—C═N—, (CH3)2N—, CH3—O—CH2—C(O)—NH—, (CH3)2N—CH2—C(O)—NH—, CH3CH2—N(CH3)—, CF3CH2—NH—, H—, HO—, CH3—O—C(O)—NH—, H2N—, CH3CH2—NH—, H2N—C(O)—, phenyl-CH2—O—C(O)—N(CH2CH3)—, CH3CH2—NH—, F, CH3—O—CH2—C(O)—NH—, heterocyclyl-heterocyclyl, heterocyclyl-heteroaryl, aryl-NH—, heteroaryl-NH—, (CH3)2N—CH2—C(O)—NH— and HO—CH2CH2—NH—. 9. The compound of claim 2 of the formula: 10. The compound of claim 2 of the formula: 11. The compound of claim 2 of the formula: 12. The compound of claim 1 of the formula: 13. A composition comprising a compound according to any one of claims 1, 2, or 4-3, and a pharmaceutically acceptable carrier, excipient, or diluent.
Bing-Yan Zhu ; Penglie Zhang ; Lingyan Wang ; Wenrong Huang ; Erick A. Goldman ; Wenhao Li ; Jingmei Zuckett ; Yonghong Song ; Robert M. Scarborough, Benzamides and related inhibitors of factor Xa.
Saunders, Jeffrey O.; Elbaum, Daniel; Novak, Perry M.; Naegele, Douglas; Bethiel, Randy S.; Ronkin, Steven M.; Badia, Michael C.; Frank, Catharine; Stamos, Dean P.; Walters, William; Pearlman, David, Inhibitors of IMPDH enzyme technical field of the invention.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Weiershausen Ute (Gundelfingen DEX) Satzinger Gerhard (Denzlingen DEX) Vollmer Karl-Otto (Freiburg DEX) Herrmann Wolfgang (Merzhausen DEX), N-(2′-aminophenyl)-benzamide derivatives process for the preparation thereof and pharmaceutical compositions containing.
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