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US 8,133,992 B2Granted
Azepinoindole and pyridoindole derivatives as pharmaceutical agents
AssigneeExelixis, Inc.
InventorsRichard Martin, Tie-Lin Wang, Brenton T. Flatt, Xiao-Hui Gu, Ronald Griffith
Life of this patent
Estimating the term…
Abstract
Compounds, compositions and methods for modulating the activity of receptors are provided. In particular compounds and compositions are provided for modulating the activity of receptors and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder directly or indirectly related to the activity of the receptors.
Claims50
A method of making a compound having a formula 24:
- or a pharmaceutically acceptable derivative selected from the group consisting of salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, and hydrates thereof, the method comprising
- a) condensing a heteroar-3-yl-2-ethylamine of formula 1
- with a halopyruvate of Formula 6
- to produce a β-carboline intermediate of Formula 22,
- b) heating the β-carboline under basic conditions to produce an azepine of Formula 23
- c) optionally treating the azepine with an electrophile in the presence of a base to produce a compound of Formula 24
- wherein
- n is 0 to 4;
- A is —N(R9)—, —O— or —S(O)t—, where t is 0 to 2;
- R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted
- heteroaralkyl, —C(O)R10, —C(O)OR10, —S(O)2R10, —C(O)N(R11)R12, —C(O)N(R11)S(O)2R43, —C(O)N(R13)N(R11)R12, —C(O)N(R13)N(R11)S(O)2R43, —N(R13)C(O)R10, —N(R13)C(O)N(R11)R12, —N(R13)C(O)N(R11)S(O)2R43, —N(R10)C(O)N(R13)N(R11)R12, —N(R10)C(O)N(R13)N(R11)S(O)2R43, —N(R13)C(O)OR10, —P(O)OR10, or —P(O)(OR19)OR12;
- R4, R5, R6 and R7 are each independently selected from a group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted
- heteroaralkyl, —OR14, —SR14, —S(O)2R14, —N(R15)R16, —N(R15)S(O)2R43, —C(O)R18, —C(O)OR20, —C(O)N(R21)R22, —C(O)N(R21)S(O)2R43, C(O)N(R42)N(R21)R22, and —C(O)N(R42)N(R21)S(O)2R43;
- or
- R4 and R5, or R4 and R6, or R4 and R7, or R5 and R6, or R5 and R7, or R6 and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, an optionally substituted cycloalkenyl ring, or together form a double bond and the others of R4, R5, R6 and R7 are as described above;
- or R6 and R7 together form an oxo, thioxo, optionally substituted imine, optionally substituted oxime or an optionally substituted hydrazone, or R6 and R7, together with the carbon atom to which they are attached, form an optionally substituted exocyclic double bond, and R4 and R5 are as described above;
- R8 is each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, pseudohalo,
- nitro, —C(O)OR23, —C(O)N(R24)R25, —C(O)N(R24)S(O)2R43, —C(O)R26, —OR27, —SR27, —C(S)OR23, —C(O)SR23, —N(R28)R29, and —N(R28)S(O)2R43, or
- two adjacent R8 groups, together with the carbons to which they are attached, form an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl;
- R9 is hydrogen, optionally substituted alkyl, —C(O)R10 or —S(O)2R43;
- R10, R11, R12, R13 and R19 are selected as in (a) or (b) as follows:
- (a) R10, R11, R12, R13 and R19 each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- or (b) R11 and R12 or R12 and R19, together with the atoms to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;
- and the others of R10, R11, R12, R13 and R19 are selected as in (a), above;
- R14, R15, R16, and R18 are selected as in (a) or (b) as follows:
- (a) R14, R15, R16, and R18 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- or (b) R15 and R16, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R14, R15, R16, and R18 are selected as in (a) above,
- R20, R21, R22 and R42 are selected as in (a) or (b) as follows:
- (a) R20, R22 and R42 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- or (b) R21 and R22, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R20, R21, R22 and R42 are selected as in (a), above;
- R23, R24, R25 and R26 are selected as in (a) or (b) as follows:
- (a) R23, R24, R25 and R26 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- or (b) R24 and R25, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring, and the others of R23, R24, R25 and R26 are selected as in (a) above;
- R27, R28 and R29 are selected as in (a) or (b) as follows:
- (a) R27, R28 and R29 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted
- heteroaralkyl, —C(O)R30, —C(O)OR31, —C(O)N(R32)R33, —C(O)N(R32)S(O)2R43, —C(O)SR31, —C(S)OR31, or —C(S)N(R32)R33;
- or (b) R28 and R29 together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring, and the others of R27, R28 and R29 are selected as in (a) above;
- R30 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- R31 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- R32 and R33 are selected as in (a) or (b) as follows:
- (a) R32 and R33 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- or (b) R32 and R33, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring;
- R43 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- each of R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R42 and R43, when substituted, are substituted with one or more substituents, each independently selected from Q1;
- Q1 is halo, pseudohalo, hydroxy, oxo, thia, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl, containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, guanidino, isothioureido, amidino, alkylamidino, cycloalkylamidino, heterocyclylamidino, heterocyclylalkylamidino, arylamidino, aralkylamidino, heteroarylamidino, heteroaralkylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, cycloalkylamino, heterocyclylamino, heterocyclylalkylamino, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio,
- azido, —P(R37)2, —P(O)(R37)2, —OP(O)(R37)2, —N(R38)C(O)R39, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, cycloalkylthio, heterocyclylalkylthio, arylthio, aralkylthio, heteroaralkythio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, —SO2F when Q1 is on R10 or when Q1 is on the aryl group of R3 when R3 is —C(O)(aryl), alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl;
- or
- two Q1 groups, which substituted atoms in a 1,2 or 1,3 arrangement, together form alkylene, oxaalkylene, alkylenedioxy, thioalkylenoxy or alkylenedithioxy;
- or
- two Q1 groups, which substitute the same atom, together form alkylene;
- each Q1 is independently unsubstituted or substituted with one or more substituents each independently selected from Q2;
- each Q2 is independently halo, pseudohalo, hydroxy, oxo, thia, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl, containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxyaryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —P(R37)2, —P(O)(R37)2, —OP(O)(R37)2, —N(R38)C(O)R39, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl;
- or
- two Q2 groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylene, oxaalkylene, alkylenedioxy, thioalkylenoxy or alkylenedithioxy;
- or
- two Q2 groups, which substitute the same atom, together form alkylene,
- R37 is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR40R41;
- R38 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;
- and
- R39 is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —N(R40)R41;
- and
- R40 and R41 are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or
- R40 and R41 together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;
- with the proviso that when R14 of the —CO2R14 group is an unsubstituted alkyl and R3 is hydrogen, methyl, acetyl, benzyl, 1-phenylethyl, 1-(1-naphthyl)ethyl, —C(O)OCH2C6H5 or —C(O)OCH2CH3, then at least one of R6 and R7 is not hydrogen, and
- with the proviso that when R3 is hydrogen, then at least one of R6 and R7 is not hydrogen.
62 more elements
A method of making a compound having a formula 24:
- or a pharmaceutically acceptable derivative selected from the group consisting of salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, and hydrates thereof, the method comprising
- a) condensing a heteroar-3-yl-2-ethylamine of formula 1
- with a halopyruvate of Formula 6
- to produce a β-carboline intermediate of Formula 22,
- b) heating the β-carboline under basic conditions to produce an azepine of Formula 23
- d) treating the azepine with an electrophile in the presence of a base to produce a compound of Formula 24
- wherein:
- n is 0 to 4;
- A is —N(R9)—, —O— or —S(O)t—, where t is 0 to 2;
- R3 is —C(O)R10;
- R4, R5, R6 and R7 are each independently selected from a group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, —OR14, —SR14, —S(O)2R14, —N(R15)R16, —N(R15)S(O)2R43, —C(O)R18, —C(O)OR20, —C(O)N(R21)R22, —C(O)N(R21)R22, —C(O)N(R21)S(O)R43, —CC(O)N(R42)N(R21)R22, and —C(O)N(R42)N(R21)S(O)2R43;
- or
- R4 and R5, or R4 and R6, or R4 and R7, or R5 and R6, or R5 and R7, or R6 and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, an optionally substituted cycloalkenyl ring, or together form a double bond and the others of R4, R5, R6 and R7 are as described above;
- or R6 and R7 together form an oxo, thioxo, optionally substituted imine, optionally substituted oxime or an optionally substituted hydrazone, or R6 and R7 together with the carbon atom to which they are attached, form an optionally substituted exocyclic double bond, and R4 and R5 are as described above;
- R8 is each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halo, pseudohalo,
- nitro, —C(O)OR23, —C(O)N(R24)R25, —C(O)N(R24)S(O)2R43, —C(O)R26, —OR27, —SR27, —C(S)OR23, —C(O)SR23, —N(R28)R29, and —N(R28)S(O)2R43;
- or
- two adjacent R8 groups, together with the carbons to which they are attached, form an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl;
- R9 is hydrogen, optionally substituted alkyl, —C(O)R10 or —S(O)2R43;
- R10 is optionally substituted aryl or optionally substituted heteroaryl;
- R14, R15, R16 and R18 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- or
- R15 and R16, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring, and R14 is as described above;
- R20, R21 and R22 are each independently hydrogen or optionally substituted alkyl;
- or
- R21 and R22, together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;
- R23, R24, R25 and R26 are selected as in (a) or (b) as follows:
- (a) R23, R24, R25 and R26 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- or (b) R24 and R25, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring, and the others of R23, R24, R25 and R26 are selected as in (a) above;
- R27, R28 and R29 are each independently hydrogen, optionally substituted alkyl, optionally substituted aralkyl, —C(O)R30, —C(O)OR31 or —C(O)N(R32)R33,
- R30 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- R31 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- R32 and R33 are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl;
- or
- R32 and R33, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;
- R42 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- R43 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
- each of R3, R4, R5, R6, R7, R8, R9, R10, R14, R15, R16, R18, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R42 and R43, when substituted, are substituted with one or more substituents, each independently selected from Q1;
- Q1 is halo, pseudohalo, hydroxy, oxo, thia, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl, containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, guanidino, isothioureido, amidino, alkylamidino, cycloalkylamidino, heterocyclylamidino, heterocyclylalkylamidino, arylamidino, aralkylamidino, heteroarylamidino, heteroaralkylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, cycloalkylamino, heterocyclylamino, heterocyclylalkylamino, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio,
- azido-P(R37)2, —P(O)(R37)2, —OP(O)(R37)2, —N(R38)C(O)R39, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, cycloalkylthio, heterocyclylalkylthio, arylthio, aralkylthio, heteroaralkylhio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, —SO2F when Q1 is on R10 or when Q1 is on the aryl group of R3 when R3 is —C(O)(aryl), arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl;
- or
- two Q1 groups, which substituted atoms in a 1,2 or 1,3 arrangement, together form alkylene, oxaalkylene, alkylenedioxy, thioalkylenoxy or alkylenedithioxy;
- or
- two Q1 groups, which substitute the same atom, together form alkylene;
- each Q1 is independently unsubstituted or substituted with one or more substituents each independently selected from Q2;
- each Q2 is independently halo, pseudohalo, hydroxy, oxo, thia, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl, containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxyaryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —P(R37)2, —P(O)(R37)2, —OP(O)(R37)2, —N(R38)C(O)R39, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, or alkylarylaminosulfonyl;
- or
- two Q2 groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylene, oxaalkylene, alkylenedioxy, thioalkylenoxy or alkylenedithioxy;
- or
- two Q2 groups, which substitute the same atom, together form alkylene,
- R37 is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR40)R41;
- and
- R38 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;
- and
- R39 is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —N(R40)R41;
- and
- R40 and R41 are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or
- R40 and R41 together form alkylene, azaalkylene, oxaalkylene or thiaalkylene.
55 more elements
A method for making the compound,
- or a pharmaceutically acceptable derivative selected from the group consisting of salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, and hydrates thereof, the method comprising
- a) condensing a compound of the formula,
- with a halopyruvate of the formula
- wherein X is Cl or Br, to produce a β-carboline intermediate of the formula,
- b) heating the β-carboline under basic conditions to produce an azepine of the formula,
- c) treating the azepine with a compound of the formula,
- in the presence of a base to produce the compound of the formula
4 more elements
Dependencies are inferred from the claim text.