Patent Grant
9283222
This invention relates to inhibitors of poly(ADP-ribose)polymerase, ways to make them and methods of treating patients using them.
Poly(ADP-ribose)polymerase (PARP) is essential for facilitating DNA repair, controlling RNA transcription, mediating cell death and regulating immune response. This activity makes PARP inhibitors targets for a number of disorders. PARP inhibitors have shown utility for treating diseases such as ischemia reperfusion injury, inflammatory disease, retroviral infections, ischemia reperfusion injury, myocardial infarction, stroke and other neural trauma, organ transplantation, reperfusion of the eye, kidney, gut and skeletal muscle, arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis, and uveitis, diabetes and Parkinsons disease, liver toxicity following acetominophen overdose, cardiac and kidney toxicities from doxorubicin and platinum-based antineoplastic agents and skin damage secondary to sulfur mustards. PARP inhibitors have also been shown to potentiate radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, decreasing metastasis, and prolonging the survival of tumor-bearing animals.
US 2002/0183325 A1 describes phthalazinone derivatives as PARP inhibitors. US 2004/0023968 A1 describes phthalazinone derivatives as PARP inhibitors. US 2005/0085476 A1 describes fused pyridazine derivatives as PARP inhibitors. US 2005/0059663 A1 describes phthalazinone derivatives as PARP inhibitors. US 2006/0063767 A1 describes phthalazinone derivatives as PARP inhibitors. US 2006/0142293 A1 describes phthalazinone derivatives as PARP inhibitors. US 2006/0149059 A1 describes phthalazinone derivatives as PARP inhibitors. US 2007/0093489 A1 describes phthalazinone derivatives as PARP inhibitors.
There is therefore a need in the therapeutic arts for PARP inhibitors. Such compounds can be used to treat subjects suffering from cancer, and can further expand the range of treatment options available for such subjects.
One embodiment of this invention, therefore, pertains to compounds that inhibit the activity of poly(ADP-ribose) polymerase and have formula I
and pharmaceutically acceptable salts thereof, wherein
A1 is R1 or R2, wherein A1 is unsubstituted or substituted with one or two OH, CN, C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl, cycloalkane, ORA or NRARA;
RA is H or alkyl;
R1 is cycloalkane or cycloalkene each of which is unfused or fused with R1A;
R1A is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R2 is heterocycloalkane or heterocycloalkene; each of which is unfused or fused with R2A;
R2A is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
A2 is OR4, NHR4, N(R4)2, SR4, S(O)R4, SO2R4 or R5;
wherein each R4 is C1-alkyl, C2-alkyl or C3-alkyl; each of which is substituted with R10;
R5 is C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl or C5-alkyl; each of which is substituted with R10, and further unsubstituted or substituted with one or two or three of independently selected OR10, NHR10, N(R10)2, SR10, S(O)R10, SO2R10 or CF3;
wherein each R10 is R10A, R10B or R10C; each of which must be attached at a carbon atom;
R10A is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which are unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which are unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R10C is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein each R10 is independently unsubstituted or substituted with one or two or three of independently selected, R11, OR11, SR11, S(O)R11, SO2R11, NH2, NHR11, N(R11)2, C(O)R11, C(O)OR11, C(O)NH2, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NR11C(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NR11C(O)OR11, NHSO2NH2, NHSO2NHR11, NHSO2N(R11)2, SO2NH2, SO2NHR11, SO2N(R11)2, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)N(R11)2, NO2, OH, (O), C(O)H, C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I;
wherein each R11 is R12, R13, R14 or R15;
R12 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R13 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R14 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R15 is alkyl, alkenyl or alkynyl; each of which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NH2, C(O)NHR16, C(O)N(R16)2, NHC(O)R16, NR16C(O)R16, NHC(O)OR16, NR16C(O)OR16, OH, F, Cl, Br or I;
wherein each R16 is R17 or R17A;
R17 is alkyl, alkenyl or alkynyl; each of which is unsubstituted or substituted with one or two of independently selected R18, C(O)OH, NH2, NHR18 or N(R18)2, C(O)R18, C(O)NH2, C(O)NHR18, C(O)N(R18)2, NHC(O)R18, NR18C(O)R18, F, Cl, Br or I;
R17A is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein each R18 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
wherein each of the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, S(O)R19, SO2R19, C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, NHR19, N(R19)2, NHC(O)R19, NR19C(O)R19, NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)NHR19, NHC(O)N(R19)2, NR19(O)NHR19, NR19C(O)N(R19)2, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)NHOH, C(O)NHOR19, C(O)NHSO2R19, C(O)NR19SO2R19, SO2NH2, SO2NHR19, SO2N(R19)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR19, C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;
wherein each R19 is R20, R21, R22 or R23;
R20 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R21 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R23 is alkyl, alkenyl or alkynyl; each of which is unsubstituted or substituted with one or two of independently selected R24, OR24, SR24, S(O)2R24, C(O)OH, NH2, NHR24N(R24)2, C(O)R24, C(O)NH2, C(O)NHR24, C(O)N(R24)2, NHC(O)R24, NR24C(O)R24, NHC(O)OR24, NR24C(O)OR24, NHS(O)2R24, NR24S(O)2R24, OH, F, Cl, Br or I;
wherein each R24 is R24A or R24B;
R24A is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R24B is alkyl, alkenyl or alkynyl each of which is unsubstituted or substituted with one or two of independently selected R25, OR25, SR25, S(O)2R25, C(O)OH, NH2, NHR25N(R25)2, C(O)R25, C(O)NH2, C(O)NHR25, C(O)N(R25)2, NHC(O)R25, NR25C(O)R25, NHC(O)OR25, NR25C(O)OR25, OH, F, Cl, Br or I;
wherein each R25 is alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unsubstituted or substituted with NH2, NH(CH3), N(CH3)2, OH or OCH3;
wherein each of the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26, alkenyl, alkynyl, phenyl, OH, (O), C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; and
R26 is alkyl.
Still another embodiment comprises pharmaceutical compositions comprising a compound having formula I and an excipient.
Still another embodiment comprises methods of inhibiting PARP in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I
or a salt thereof, wherein
A1 is R1 or R2, wherein A1 is unsubstituted or substituted with one or two OH, CN, C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl, cycloalkane, ORA or NRARA;
RA is H or alkyl;
R1 is cycloalkane or cycloalkene each of which is unfused or fused with R1A;
R1A is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R2 is heterocycloalkane or heterocycloalkene; each of which is unfused or fused with R2A;
R2A is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
A2 is OR4, NHR4, N(R4)2, SR4, S(O)R4, SO2R4 or R5;
wherein each R4 is C1-alkyl, C2-alkyl or C3-alkyl; each of which is substituted with R10;
R5 is C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl or C5-alkyl; each of which is substituted with R10, and further unsubstituted or substituted with one or two or three of independently selected OR10, NHR10, N(R10)2, SR10, S(O)R10, SO2R10 or CF3;
wherein each R10 is R10A, R10B or R10C; each of which must be attached at a carbon atom;
R10A is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which are unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which are unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R10C is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein each R10 is independently unsubstituted or substituted with one or two or three of independently selected, R11, OR11, SR11, S(O)R11, SO2R11, NH2, NHR11, N(R11)2, C(O)R11, C(O)OR11, C(O)NH2, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NR11C(O)R11, NHSO2R11), NR11SO2R11, NHC11(O)OR11, NR11C(O)OR11, NHSO2NH2, NHSO2NHR11, NHSO2N(R11)2, SO2NH2, SO2NHR11, SO2N(R11)2, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)N(R11)2, NO2, OH, (O), C(O)H, C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I;
wherein each R11 is R12, R13, R14 or R15;
R12 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R13 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R14 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R15 is alkyl, alkenyl or alkynyl; each of which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NH2, C(O)NHR16, C(O)N(R16)2, NHC(O)R16, NR16C(O)R16, NHC(O)OR16, NR16C(O)OR16, OH, F, Cl, Br or I;
wherein each R16 is R17 or R17A;
R17 is alkyl, alkenyl or alkynyl; each of which is unsubstituted or substituted with one or two of independently selected R18, C(O)OH, NH2, NHRIS or N(R18)2, C(O)R18, C(O)NH2, C(O)NHR18, C(O)N(R18)2, NHC(O)R18, NR18C(O)R18, F, Cl, Br or I;
R17A is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein each R18 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
wherein each of the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, S(O)R19, SO2R19, C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, NHR19, N(R19)2, NHC(O)R19, NR19C(O)R19, NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)NHR19, NHC(O)N(R19)2, NR19C(O)NHR19, NR19C(O)N(R19)2, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)NHOH, C(O)NHOR19, C(O)NHSO2R19, C(O)NR19SO2R19, SO2NH2, SO2NHR19, SO2N(R19)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR19, C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;
wherein each R19 is R20, R21, R22 or R23;
R20 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R21 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R23 is alkyl, alkenyl or alkynyl; each of which is unsubstituted or substituted with one or two of independently selected R24, OR24, SR24, S(O)2R24, C(O)OH, NH2, NHR24N(R24)2, C(O)R24, C(O)NH2, C(O)NHR24, C(O)N(R24)2, NHC(O)R24, NR24C(O)R24, NHC(O)OR24, NR24C(O)OR24, NHS(O)2R24, NR24S(O)2R24, OH, F, Cl, Br or I;
wherein each R24 is R24A or R24B;
R24A is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R24B is alkyl, alkenyl or alkynyl each of which is unsubstituted or substituted with one or two of independently selected R25, OR25, SR25, S(O)2R25, C(O)OH, NH2, NHR25N(R25)2, C(O)R25, C(O)NH2, C(O)NHR25, C(O)N(R25)2, NHC(O)R25, NR25C(O)R25, NHC(O)OR25NR25C(O)OR25, OH, F, Cl, Br or I;
wherein each R25 is alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unsubstituted or substituted with NH2, NH(CH3), N(CH3)2, OH or OCH3;
wherein each of the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26, alkenyl, alkynyl, phenyl, OH, (O), C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; and
R26 is alkyl.
Still another embodiment comprises methods for decreasing tumor volume in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I
Still another embodiment comprises the use of a compound of Formula I for the preparation of a medicament for the treatment of cancer.
Still another embodiment comprises a method of treating leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast or cervical carcinomas in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises the use of a compound of Formula I for the preparation of a medicament for the treatment of leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast or cervical carcinomas.
Still another embodiment comprises methods for potentiation of cytotoxic cancer therapy in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises methods for potentiation of radiation therapy in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises methods of treating ischemia reperfusion injury associated with myocardial infarction, stroke, neural trauma or organ transplantation in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises methods of treating reperfusion of the eye, kidney, gut or skeletal muscle in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises methods of treating arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis or uveitis in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises a method of treating rheumatoid arthritis or septic shock in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises methods of treating diabetes or Parkinsons disease in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises methods of treating hypoglycemia in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises methods of treating retroviral infection in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises methods of treating liver toxicity following acetominophen overdose in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises a method of treating cardiac or kidney toxicities from doxorubicin or platinum based antineoplastic agents in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises methods of treating skin damage secondary to sulfur mustards in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having formula I.
Still another embodiment comprises the compounds
Variable moieties of compounds herein are represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and may be specifically embodied.
It is meant to be understood that proper valences are maintained for all combinations herein, that monovalent moieties having more than one atom are attached through their left ends.
It is also meant to be understood that a specific embodiment of a variable moiety may be the same or different as another specific embodiment having the same identifier.
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are:
BOC is Di-tert-butyl dicarbonate
C-18 is dimethyl-octadecylsilane
DCI for chemical ionization for direct introduction,
DME for 1,2-dimethoxyethane,
DMSO for dimethylsulfoxide,
ESI for electrospray ionization,
HATU for O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,
HPLC for high performance liquid chromatography,
MS for mass spectrometry,
TFA for trifluoroacetic acid,
As used in reference to 1H NMR, the symbol “δ” refers to a 1H NMR chemical shift.
As used in reference to 1H NMR, the abbreviation “br” refers to a broad 1H NMR signal.
As used in reference to 1H NMR, the abbreviation “d” refers to a doublet 1H NMR peak.
As used in reference to 1H NMR, the abbreviation “dd” refers to a doublet of doublets 1H NMR peak.
As used in reference to 1H NMR, the abbreviation “m” refers to a multiplet 1H NMR peak.
As used in reference to 1H NMR, the abbreviation “q” refers to a quartet 1H NMR peak.
As used in reference to 1H NMR, the abbreviation “s” refers to a singlet 1H NMR peak.
As used in reference to 1H NMR, the abbreviation “t” refers to a triplet 1H NMR peak.
The term “alkenyl,” as used herein, means monovalent, straight or branched chain hydrocarbon moieties having one or more than one carbon-carbon double bonds, such as C2-alkenyl, C3-alkenyl, C4-alkenyl, C5-alkenyl, C6-alkenyl and the like.
The term “alkyl,” as used herein, means monovalent, saturated, straight or branched chain hydrocarbon moieties, such as C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl, C6-alkyl and the like.
The term “alkynyl,” as used herein, means monovalent, straight or branched chain hydrocarbon moieties having one or more than one carbon-carbon triple bonds, such as C2-alkynyl, C3-alkynyl, C4-alkynyl, C5-alkynyl, C6-alkynyl and the like.
The term “cycloalkane,” as used herein, means saturated cyclic or bicyclic hydrocarbon moieties, such as C4-cycloalkane, C5-cycloalkane, C6-cycloalkane, C7-cycloalkane, C8-cycloalkane, C9-cycloalkane, C10-cycloalkane, C11-cycloalkane, C12-cycloalkane and the like.
The term “cycloalkyl,” as used herein, means monovalent, saturated cyclic and bicyclic hydrocarbon moieties, such as C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, C8-cycloalkyl, C9-cycloalkyl, C10-cycloalkyl, C11-cycloalkyl, C12-cycloalkyl and the like.
The term “cycloalkene,” as used herein, means cyclic and bicyclic hydrocarbon moieties having one or more than one carbon-carbon double bonds, such as C5-cycloalkene, C6-cycloalkene, C7-cycloalkene, C8-cycloalkene, C9-cycloalkene, C10-cycloalkene, C11-cycloalkene, C12-cycloalkene and the like.
The term “cycloalkenyl,” as used herein, means monovalent, cyclic hydrocarbon moieties having one or more than one carbon-carbon double bonds, such as C4-cycloalkenyl, C5-cycloalkenyl, C6-cycloalkenyl, C7-cycloalkenyl, C8-cycloalkenyl, C9-cycloalkenyl, C10-cycloalkenyl, C11-cycloalkenyl, C12-cycloalkenyl and the like.
The term “heteroarene,” as used herein, means furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1,3,4-thiadiazole, thiophene, triazine and 1,2,3-triazole.
The term “heteroaryl,” as used herein, means furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, 1,2,3-thiadiazoyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl.
The term “heterocycloalkane,” as used herein, means cycloalkane having one or two or three CH2 moieties replaced with independently selected O, S, S(O), SO2 or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkane having one or two or three CH2 moieties unreplaced or replaced with independently selected O, S, S(O), SO2 or NH and one or two CH moieties replaced with N.
The term “heterocycloalkene,” as used herein, means cycloalkene having one or two or three CH2 moieties replaced with independently selected O, S, S(O), SO2 or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkene having one or two or three CH2 moieties unreplaced or replaced with independently selected O, S, S(O), SO2 or NH and one or two CH moieties replaced with N.
The term “heterocycloalkyl,” as used herein, means cycloalkyl having one or two or three CH2 moieties replaced with independently selected O, S, S(O), SO2 or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkyl having one or two or three CH2 moieties unreplaced or replaced with independently selected O, S, S(O), SO2 or NH and one or two CH moieties replaced with N.
The term “heterocycloalkenyl,” as used herein, means cycloalkenyl having one or two or three CH2 moieties replaced with independently selected O, S, S(O), SO2 or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkenyl having one or two or three CH2 moieties unreplaced or replaced with independently selected O, S, S(O), SO2 or NH and one or two CH moieties replaced with N.
The term “cyclic moiety,” as used herein, means benzene, cycloalkane, cycloalkyl, cycloalkene, cycloalkenyl, heteroarene, heteroaryl, heterocycloalkane, heterocycloalkyl, heterocycloalkene, heterocycloalkenyl and phenyl.
Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms “R” and “S” are as defined in Pure Appl. Chem. (1976) 45, 13-10. Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those atoms. Atoms having excess of one configuration over the other are assigned the configuration in excess, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%. Accordingly, this invention is meant to embrace racemic mixtures, relative and absolute diastereoisomers and the compounds thereof.
Compounds of this invention may also contain carbon-carbon double bonds or carbon-nitrogen double bonds in the Z or E configuration, in which the term “Z” represents the larger two substituents on the same side of a carbon-carbon or carbon-nitrogen double bond and the term “E” represents the larger two substituents on opposite sides of a carbon-carbon or carbon-nitrogen double bond. The compounds of this invention may also exist as a mixture of “Z” and “E” isomers.
Compounds of this invention containing NH, C(O)H, C(O)OH, C(O)NH2, OH or SH moieties may have attached thereto prodrug-forming moieties. The prodrug-forming moieties are removed by metabolic processes and release the compounds having the freed NH, C(O)H, C(O)OH, C(O)NH2, OH or SH in vivo. Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance.
Metabolites of compounds having Formula I, produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases caused or exacerbated by unregulated or overexpressed poly(ADP-ribose)polymerase.
Certain precursor compounds of compounds having Formula I may be metabolized in vitro or in vivo to form compounds having Formula I and may thereby also have utility for treating diseases caused or exacerbated by unregulared or overexpressed poly(ADP-ribose)polymerase.
Compounds having Formula I may exist as acid addition salts, basic addition salts or zwitterions. Salts of compounds having Formula I are prepared during their isolation or following their purification. Acid addition salts are those derived from the reaction of a compound having Formula I with acid. Accordingly, salts including the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate and undecanoate salts of the compounds having Formula I are meant to be embraced by this invention. Basic addition salts of compounds are those derived from the reaction of the compounds having Formula I with the bicarbonate, carbonate, hydroxide, or phosphate of cations such as lithium, sodium, potassium, calcium and magnesium.
Compounds having Formula I may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperintoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally and vaginally.
Therapeutically effective amounts of a compound having Formula I depend on recipient of treatment, disease treated and severity thereof, composition comprising it, time of administration, route of administration, duration of treatment, potency, rate of clearance and whether or not another drug is co-administered. The amount of a compound having Formula I used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.001 to about 200 mg/kg body weight. Single dose compositions contain these amounts or a combination of submultiples thereof.
Compounds having Formula I may be administered with or without an excipient.
Excipients include, for example, encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
Compounds having Formula I may be radiolabeled with a radioactive isotope such as carbon (i.e. 13C), hydrogen (i.e. 3H), nitrogen (i.e. 15N), phosphorus (i.e. 32P), sulfur (i.e. 35S), iodide (i.e. 125I) and the like. Radioactive isotopes may be incorporated into the compounds having Formula I by reacting the same and a radioactive derivitizing agent or by incorporating a radiolabeled intermediate into their syntheses. The radiolabeled compounds of Formula I are useful for both prognostic and diagnostic applications and for in vivo and in vitro imaging.
Compounds having Formula I may be incorporated into devices such as, but not limited to, arterio-venous grafts, billiary stents, by-pass grafts, catheters, central nervous system shunts, coronary stents, drug delivery balloons, peripheral stents and ureteural stents, each of which may be used in areas such as, but not limited to, the vasculature for introduction of a compound having Formula I into selected tissues or organs in the body. One measure of the effectiveness of compounds having Formula I is reduction or elimination of device-associated thrombi and complications associated therewith.
Compounds having Formula I can used as a radiosensitizers which enhance the efficacy of radiotherapy. Examples of radiotherapy include, but are not limited to, external beam radiotherapy, teletherapy, brachtherapy and sealed and unsealed source radiotherapy.
Excipients for preparation of compositions comprising a compound having Formula I to be administered orally include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl celluose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof. Excipients for preparation of compositions comprising a compound having Formula I to be administered ophthalmically or orally include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Excipients for preparation of compositions comprising a compound having Formula I to be administered osmotically include, for example, chlorofluoro-hydrocarbons, ethanol, water and mixtures thereof. Excipients for preparation of compositions comprising a compound having Formula I to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof. Excipients for preparation of compositions comprising a compound having Formula I to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.
Compounds having formula I are also expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, aurora kinase inhibitors, Bcr-Abl kinase inhibitors, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors inhibitors, hormonal therapies, immunologicals, intercalating antibiotics, kinase inhibitors, mammalian target of rapomycin inhibitors, mitogen-activated extracellular signal-regulated kinase inhibitors, non-steroidal anti-inflammatory drugs (NSAID's), platinum chemotherapeutics, polo-like kinase inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids plant alkaloids, topoisomerase inhibitors and the like.
Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, Cloretazine™ (VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, treosulfan, trofosfamide and the like.
Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680 and the like.
Bcr-Abl kinase inhibitors include DASATINIBx (BMS-354825). GLEEVEC® (imatinib) and the like.
CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA® (valdecoxib), BMS347070, CELEBREX™ (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX® (rofecoxib) and the like.
EGFR inhibitors include ABX-EGF, anti-EGFr immunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB® (lapatinib) and the like.
ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib), Herceptin® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4, petuzumab), TAK-165, GW-572016 (ionafamib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB®, NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.
MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus and the like.
Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate), DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN® (nabumetone), FELDENE® (piroxicam) ibuprofin cream, ALEVE® and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.
PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin and the like.
Polo-like kinase inhibitors include BI-2536 and the like.
Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like.
VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788, ANGIOZYME™, axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, Macugen (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), (PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, vatalanib, ZACTIMA™ (vandetanib, ZD-6474) and the like.
Antimetabolites include ALIMTA® (premetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR, enocitabine, ethnylcytidine, fludarabine, hydroxyurea, 5-fluorouracil (5-FU) alone or in combination with leucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.
Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin), daunorubicin, CAELYX® or MYOCET® (doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and the like.
Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR® (irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine), diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin), etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.
Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies, chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab), IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX® (WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab and the like.
Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN® (exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE® (cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane), dexamethasone, DROGENIL®, (flutamide), EVISTA® (raloxifene), fadrozole, FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®, (letrozole), formestane, glucocorticoids, HECTOROL® or RENAGEL® (doxercalciferol), lasofoxifene, leuprolide acetate, MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide), NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), predisone, PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR® (luteinizing hormone releasing hormone (LHRH)), vantas, VETORYL®, (trilostane or modrastane), ZOLADEX® (fosrelin, goserelin) and the like.
Deltoids and retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol (KH 1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.
Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.
Proteasome inhibitors include VELCADE® (bortezomib), MG 132, NPI-0052, PR-171 and the like.
Examples of immunologicals include interferons and other immune-enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, ACTIMMUNE® (interferon gamma-1b), or interferon gamma-n 1, combinations thereof and the like. Other agents include ALFAFERONE®, BAM-002, BEROMUN® (tasonermin), BEXXAR® (tositumomab), CamPath® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010, melanoma vaccine, mitumomab, molgramostim, MY LOTARG™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OvaRex® (oregovomab), pemtumomab (Y-muHMFG1), PROVENGE®, sargaramostim, sizofilan, teceleukin, TheraCys®, ubenimex, VIRULIZIN®, Z-100, WF-10, PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomab tiuxetan) and the like.
Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity and include krestin, lentinan, sizofuran, picibanil PF-3512676 (CpG-8954), ubenimex and the like.
Pyrimidine analogs include cytarabine (ara C), cytosine arabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX® (ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.
Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL® (mercaptopurine).
Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940 (109881), patupilone, XRP-9881, vinflunine, ZK-EPO and the like.
Compounds of the present invention are also intended to be used as a radiosensitizer that enhances the efficacy of radiotherapy. Examples of radiotherapy include, but are not limited to, external beam radiotherapy, teletherapy, brachtherapy and sealed and unsealed source radiotherapy.
Additionally, compounds having formula I may be combined with other chemptherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN®, ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA), APTOSYN™ (exisulind), AREDIA® (pamidronic acid), arglabin, L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene), AVAGE® (tazarotne), AVE-8062, BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CeaVac™ (cancer vaccine), CELEUK® (celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX™ (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN® (hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CyPat™, combrestatin A4P, DAB(389)EGF or TransMID-107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposome lotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin, EP0906, GARDASIL® (quadrivalent human papillomavirus (Types 6, 11, 16, 18) recombinant vaccine), gastrimmune, genasense, GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide), lonafamib, 5,10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexate glucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme), ONCOPHAGE® (melanoma vaccine treatment), OncoVAX (IL-2 Vaccine), ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OvaRex® MAb (murine monoclonal antibody), paditaxel, PANDIMEX™ (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN® (bexarotene), Taxoprexin® (DHA-paclitaxel), TELCYTA™ (TLK286), temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline dihydrochloride), TNFerade™ (adenovector: DNA carrier containing the gene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide), VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandine plant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafin gadolinium), XINLAY® (atrasentan), XYOTAX™ (paclitaxel poliglumex), YONDELIS™ (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), zometa (zolendronic acid), zorubicin and the like.
In one embodiment, compounds having Formula I are used in a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of claim 1 in combination with a chemotherapeutic agent selected from temozolomide, dacarbazine, cyclophosphamide, carmustine, melphalan, lomustine, carboplatin, cisplatin, 5-FU+/−leucovorin, gemcitabine, methotrexate, bleomycin, irinotecan, camptothecin, or topotecan.
It is expected that compounds having formula I would also inhibit growth of cells derived from a pediatric cancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid tumor of the central nervous system, pediatric biphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing's family of tumors such as primitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorable histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cell cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and skin cancer and the like (commonly-owned U.S. application Ser. No. 10/988,338), Cancer Res., 2000, 60, 6101-10); and autoimmune disorders include, acquired immunodeficiency disease syndrome, autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, thrombocytopenia and the like (Current Allergy and Asthma Reports 2003, 3:378-384; Br. J. Haematol. 2000 September; 110(3): 584-90; Blood 2000 Feb. 15; 95(4):1283-92; and New England Journal of Medicine 2004 September; 351(14): 1409-1418).
PARP Enzyme Inhibition Assay
Nicotinamide[2,5′,8-3H]adenine dinucleotide and strepavidin SPA beads were purchased from Amersham Biosiences. Recombinant Human Poly(ADP-Ribose) Polymerase (PARP), purified from E. coli and 6-Biotin-17-NAD+, were purchase from Trevigen. NAD+, histone, aminobenzamide, 3-amino benzamide and Calf Thymus DNA (dcDNA) were purchased from Sigma. Stem loop oligonucleotide containing MCAT sequence was obtained from Qiagen. The oligos were dissolved to 1 mM in annealing buffer containing 10 mM Tris HCl pH 7.5, 1 mM EDTA, and 50 mM NaCl, incubated for 5 minutes at 95° C., and annealed at 45° C. for 45 minutes. Histone H1 (95% electrophoretically pure) was purchased from Roche. Biotinylated histone H1 was prepared by treating the protein with Sulfo-NHS-LC-Biotin from Pierce. The biotinylation reaction was conducted by slowly and intermittently adding 3 equivalents of 10 mM Sulfo-NHS-LC-Biotin to 100 μM Histone H1 in phosphate-buffered saline, pH 7.5, at 4° C. with gentle vortexing over 1 minute followed by subsequent 4° C. incubation for 1 hour. Streptavidin coated (FlashPlate Plus) microplates were purchased from Perkin Elmer.
PARP1 assay was conducted in PARP assay buffer containing 50 mM Tris pH 8.0, 1 mM DTT, 4 mM MgCl2. PARP reactions contained 1.5 μM [3H]-NAD+ (1.6 uCi/mmol), 200 nM biotinylated histone H1, 200 nM sIDNA, and 1 nM PARP enzyme. Auto reactions utilizing SPA bead-based detection were carried out in 100 μL volumes in white 96 well plates. Reactions were initiated by adding 50 μl of 2×NAD+ substrate mixture to 50 μL of 2× enzyme mixture containing PARP and DNA. These reactions were terminated by the addition of 150 μL of 1.5 mM benzamide (˜1000-fold over its IC50). 170 μL of the stopped reaction mixtures were transferred to streptavidin Flash Plates, incubated for 1 hour, and counted using a TopCount microplate scintillation counter. The EC50s for exemplified compounds of this invention are provided in Table 1.
Cellular PARP Assay:
C41 cells were treated with a compound of this invention for 30 minutes in 96 well plate. PARP was then activated by damaging DNA with 1 mM H2O2 for 10 minutes. The cells were then washed with ice-cold PBS once and fixed with pre-chilled methanol:acetone (7:3) at −20° C. for 10 minutes. After air-drying, the plates were rehydrated with PBS and blocked 5% non-fat dry milk in PBS-TWEEN20® (Sigma, St. Louis, Mo.) (0.05%) (blocking solution) for 30 minutes at room temperature. The cells were incubated with anti-PAR antibody 10H (1:50) in Blocking solution at 37° C. for 60 minutes followed by washing with PBS— TWEEN20® 5 times, and incubation with goat anti-mouse fluorescein 5(6)-isothiocyanate-coupled antibody (1:50) and 1 μg/ml 4′,6-diamidino-2-phenylindole (DAPI) in blocking solution at 37° C. for 60 minutes. After washing with PBS-TWEEN20® 5 times, the analysis was performed using an FMAX FLUORESCENCE MICROPLATE READER® (Molecular Devices, Sunnyvalle, Calif.), set at the excitation wavelength of 490 nm and emission wavelength of 528 nm fluorescein 5(6)-isothiocyanate (FITC) or the excitation wavelength of 355 nm and emission wavelength of 460 nm (DAPI). The PARP activity (FITC signal) was normalized with cell numbers (DAPI).
The cellular assay measures the formation of poly ADP-ribose by PARP within cells and demonstrates that compounds of this invention penetrate cell membranes and inhibit PARP in intact cells. Due to variability in the cellular assay, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide was run as a comparator in each assay and data reported as the ratio of test compound EC50 relative to the EC50 of 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide obtained in that particular assay. The mean EC50 of 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide for all assays carried out was 0.0032 μM (n=270) and generally ranged from 0.001 to 0.013 μM. (ratio EC50=EC50 test compound/EC50 comparator compound). The EC50 data (nM) are shown in TABLE 1.
Selected compounds of Formula I wherein A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, R5 is C1-alkyl were run in the PARP Enzyme Inhihition Assay and the PARP Cellular Assay described above. Compounds outside of Formula I wherein at the position of A2 is instead a bond also were run in the PARP Enzyme Inhihition Assay and the PARP Cellular Assay described above. The results of the assays are described in TABLE 2, below:
Selected compounds of Formula I wherein A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, R5 is C1-alkyl wherein R5 is substituted with R10, wherein R10 is phenyl, either with a para-substituted F, as shown in Formula (Is):
or without a para-substituted F were run in the PARP Enzyme Inhihition Assay and the PARP Cellular Assay described above. Results are shown in Table 3.
As PARP inhibitors, the compounds of this invention have numerous therapeutic applications related to ischemia reperfusion injury, inflammatory diseases, degenerative diseases, protection from adverse effects of cytotoxic compounds, and potentiation of cytotoxic cancer therapy. In particular, compounds of this invention potentiate radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, decreasing metastasis, and prolonging the survival of tumor-bearing mammals. Compounds having formula I can treat leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast, and cervical carcinomas.
Other therapeutic applications include retroviral infection, arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary fibrosis, uveitis, diabetes, Parkinsons disease, myocardial infarction, stroke, other neural trauma, organ transplantation, reperfusion of the eye, reperfusion of the kidney, reperfusion of the gut, reperfusion of skeletal muscle, liver toxicity following acetominophen overdose, cardiac and kidney toxicities from doxorubicin and platinum based antineoplastic agents, and skin damage secondary to sulfur mustards. (G. Chen et al. Cancer Chemo. Pharmacol. 22 (1988), 303; C. Thiemermann et al., Proc. Natl. Acad. Sci. USA 94 (1997), 679-683 D. Weltin et al. Int. J. Immunopharmacol. 17 (1995), 265-271; H. Kriger et al. Inflammation 20 (1996), 203-215; W. Ehrlich et al. Rheumatol. Int. 15 (1995), 171-172; C. Szabo et al., Proc. Natl. Acad. Sci. USA 95 (1998), 3867-3872; S. Cuzzocrea et al. Eur. J. Pharmacol. 342 (1998), 67-76; V. Burkhart et al., Nature Medicine (1999), 5314-19).
Compounds of Formula I
In one embodiment of formula I
or a salt thereof, wherein
A1 is R1 or R2, wherein A1 is unsubstituted or substituted with one or two OH, CN, C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl, cycloalkane, ORA or NRARA;
RA is H or alkyl;
R1 is cycloalkane or cycloalkene each of which is unfused or fused with R1A;
R1A is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R2 is heterocycloalkane or heterocycloalkene; each of which is unfused or fused with R2A;
R2A is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
A2 is OR4, NHR4, N(R4)2, SR4, S(O)R4, SO2R4 or R5;
wherein each R4 is C1-alkyl, C2-alkyl or C3-alkyl; each of which is substituted with R10;
R5 is C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl or C5-alkyl; each of which is substituted with R10, and further unsubstituted or substituted with one or two or three of independently selected OR10, NHR10, N(R10)2, SR10, S(O)R10, SO2R10 or CF3;
wherein each R10 is R10A, R10B or R10C; each of which must be attached at a carbon atom;
R10A is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which are unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R10B is
each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which are unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R10C is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein each R10 is independently unsubstituted or substituted with one or two or three of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, NHR11, N(R11)2, C(O)R11, C(O)OR11, C(O)NH2, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NR11C(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NR11C(O)OR11, NHSO2NH2, NHSO2NHR11, NHSO2N(R11)2, SO2NH2, SO2NHR11, SO2N(R11)2, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)N(R11)2, NO2, OH, (O), C(O)H, C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I;
wherein each R11 is R12, R13, R14 or R15;
R12 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R13 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R14 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R15 is alkyl, alkenyl or alkynyl; each of which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NH2, C(O)NHR16, C(O)N(R16)2, NHC(O)R16, NR16C(O)R16, NHC(O)OR16, NR16C(O)OR16, OH, F, Cl, Br or I;
wherein each R16 is R17 or R17A;
R17 is alkyl, alkenyl or alkynyl; each of which is unsubstituted or substituted with one or two of independently selected R18, C(O)OH, NH2, NHR18 or N(R18)2, C(O)Ris, C(O)NH2, C(O)NHR18, C(O)N(R18)2, NHC(O)R18, NR18C(O)R18, F, Cl, Br or I;
R17A is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein each R18 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
wherein each of the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, S(O)R19, SO2R19, C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, NHR19, N(R19), NHC(O)R19, NR19C(O)R19, NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)NHR19, NHC(O)N(R19)2, NR19C(O)NHR19, NR19C(O)N(R19)2, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)NHOH, C(O)NHOR19, C(O)NHSO2R19, C(O)NR19SOR19, SO2NH2, SO2NHR19, SO2N(R19)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR19, C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;
wherein each R19 is R20, R21, R22 or R23;
R20 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R21 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R23 is alkyl, alkenyl or alkynyl; each of which is unsubstituted or substituted with one or two of independently selected R24, OR24, SR24, S(O)2R24, C(O)OH, NH2, NHR24N(R24)2, C(O)R24, C(O)NH2, C(O)NHR24, C(O)N(R24)2, NHC(O)R24, NR24C(O)R24, NHC(O)OR24, NR14C(O)OR4, NHS(O)2R24, NR24S(O)2R24, OH, F, Cl, Br or I;
wherein each R24 is R24A or R24B,
R24A is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R24B is alkyl, alkenyl or alkynyl each of which is unsubstituted or substituted with one or two of independently selected R25, OR25, SR25, S(O)2R25, C(O)OH, NH2, NHR25N(R25)2, C(O)R25, C(O)NH2, C(O)NHR25, C(O)N(R25)2, NHC(O)R25, NR25C(O)R25, NHC(O)OR25, NR25C(O)OR25, OH, F, Cl, Br or I;
wherein each R25 is alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unsubstituted or substituted with NH2, NH(CH3), N(CH3)2, OH or OCH3;
wherein each of the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26, alkenyl, alkynyl, phenyl, OH, (O), C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; and
R26 is alkyl.
Embodiments of Formula I
Selected subclasses of compounds of interest that fall within the scope of the compounds of formula I are shown in the various embodiments described below, wherein A1, R1, RA, R1A, R2, R2A, A2, R4, R5, R10, R10A, R10B, R10C, R11, R12, R13, R14, R15, R16, R17, R17A, R18, R19, R20, R21, R22, R23, R24, R24A, R24B, R25 and R26 can be as defined for the compounds of Formula I and as defined in the various embodiments described throughout this specification.
Embodiments of A1
In one embodiment of formula I, A1 is R1 or R2, wherein R1 is an unfused cycloalkane and R2 is an unfused heterocycloalkane, wherein A1 is unsubstituted or is substituted with one or two OH, CN, C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl, cycloalkane, ORA or NRARA; wherein RA is H or alkyl. In another embodiment of formula I, A1 is R1 or R1, wherein R1 is cyclohexane and R2 is piperidinyl, wherein A1 is unsubstituted or is substituted with one or two CL-alkyl, C2-alkyl or C3-alkyl. In another embodiment of formula I, A1 is R1 or R2, wherein R1 is unsubstituted cyclohexane and R2 is unsubstituted piperidinyl. In another embodiment of formula I, A1 is R1, and R1 is unsubstituted cyclohexane, as shown in formula (Ia):
Embodiments of A2
In one embodiment of formula I, A2 is OR4, NHR4, N(R4)2, SR4, S(O)R4, SO2R4 or R5; wherein each R4 is C1-alkyl, C2-alkyl or C3-alkyl; each of which is substituted with R10 as described in Formula I; and R5 is C1-alkyl, C2-alkyl or C3-alkyl wherein R5 is substituted as described in formula I. In another embodiment of formula I, A2 is R5, and Rs is C1-alkyl, C2-alkyl or C3-alkyl wherein R5 is substituted as described in formula I. In another embodiment of formula I, A2 is R5, wherein R5 is C1-alkyl, which is substituted with R10, and further unsubstituted or substituted with one or two or three of independently selected NHR10, N(R10)2, SR10, S(O)R10, SO2R10 or CF3, wherein R10 is as described in formula I. In another embodiment of formula I, A2 is R5, wherein R5 is C1-alkyl, substituted with R10 as described in Formula I and further unsubstituted as shown in formula (Ib):
In another embodiment of formula I, A2 is R5, wherein R5 is C2-alkyl, substituted with R10 as described in Formula I and further unsubstituted as shown in formulas (Ic) and (Id):
In another embodiment of formula I, A2 is R5, wherein R5 is C3-alkyl, substituted with R10 as described in Formula I and further unsubstituted. In another embodiment of formula I, A2 is R5, wherein R5 is C1-alkyl or C2-alkyl; each of which are substituted with R10 as described in Formula I and further substituted with CF3.
Embodiments of R10
In one embodiment of formula I, R10 is R10A, R10B or R10C, wherein R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused heterocycloalkane, R10B is
and R10C is heterocycloalkyl, which is unfused, wherein R10 is optionally substituted as described in Formula I. In another embodiment of formula I, R10 is R10A, R10B or R10C, wherein R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused heterocycloalkane, R10B is
and R10C is heterocycloalkyl, which is unfused; wherein R10 is substituted with F and further unsubstituted or substituted with one or two of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br, wherein R11 is as described in Formula I. In another embodiment of formula I, R10 is R10A, R10B or R10C, wherein R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused heterocycloalkane, R10B is
and R10C is heterocycloalkyl, which is unfused; wherein R10 is substituted with F and further unsubstituted or substituted with one or two of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein each R11 is R12, R13, R14 or R15; wherein R12 is phenyl which is unfused or fused with benzene, heteroarene, heterocycloalkane or heterocycloalkene; R13 is heteroaryl, which is unfused; R14 is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, cycloalkane, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene; and R15 is alkyl which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I, wherein R16 is as described in Formula I. In another embodiment of formula I, R10 is R10A, R10B or R10C, wherein R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused heterocycloalkane, R10B is
and R10C is heterocycloalkyl, which is unfused; wherein R10 is substituted with F and further unsubstituted or substituted with one or two of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein each R11 is R12, R13, R14 or R15; wherein R12 is phenyl which is unfused or fused with benzene, heteroarene, heterocycloalkane or heterocycloalkene; R13 is heteroaryl, which is unfused; R14 is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, cycloalkane, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene; and R15 is alkyl which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl which is unsubstituted or substituted with R18; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane; and R18 is phenyl or heterocycloalkyl, which is unfused; wherein the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I, wherein R19 is as described in Formula I. In another embodiment of formula I, R10 is R10A, R10B or R10C, wherein R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused heterocycloalkane, R10B is
and R10C is heterocycloalkyl, which is unfused; wherein R10 is substituted with F and further unsubstituted or substituted with one or two of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein each R11 is R11, R13, R14 or R15; wherein R12 is phenyl which is unfused or fused with benzene, heteroarene, heterocycloalkane or heterocycloalkene; R13 is heteroaryl, which is unfused;
R14 is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, cycloalkane, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene; and R15 is alkyl which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl which is unsubstituted or substituted with R18; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane: R18 is phenyl or heterocycloalkyl, which is unfused; wherein the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl, which is unfused; R22 is heteroaryl, which is unfused; R23 is cycloalkyl or heterocycloalkyl; each of which is unfused or fused with benzene; and R23 is alkyl which is unsubstituted or substituted with R24, OR24, NHR24N(R24)2, NHS(O)R24 or OH, wherein R24 is as described in Formula I. In another embodiment of formula I, R10R10A, R10B or R10C, wherein R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused heterocycloalkane, R10B is
and R10B is heterocycloalkyl, which is unfused; wherein R10 is substituted with F and further unsubstituted or substituted with one or two of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein each R11 is R12, R13, R14 or R15; wherein R12 is phenyl which is unfused or fused with benzene, heteroarene, heterocycloalkane or heterocycloalkene; R13 is heteroaryl, which is unfused;
R14 is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, cycloalkane, heterocycloalkane or heterocycloalkene: each of which is unfused or fused with benzene; and R15 is alkyl which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl which is unsubstituted or substituted with R18; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane; R18 is phenyl or heterocycloalkyl, which is unfused; wherein the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl, which is unfused; R21 is heteroaryl, which is unfused; R22 is cycloalkyl or heterocycloalkyl; each of which is unfused or fused with benzene; and R23 is alkyl which is unsubstituted or substituted with R24, OR24, NHR24N(R24)2, NHS(O)2R24 or OH; wherein each R24 is R24A or R24B; R24A is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, which is unfused or fused with heterocycloalkane; R24B is alkyl, which is unsubstituted or substituted with OR25, OH, F, Cl, Br or I; R25 is alkyl, which is unsubstituted or substituted with NH2; wherein the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26 (O), F, Cl, Br or I; and R26 is alkyl. In another embodiment of formula I, R10 is R10A, R10B or R10C, wherein R10A is
R10B is
and R10C is
wherein R10 is optionally substituted as described in Formula I. In another embodiment of formula I, R10 is R10A, wherein R10A is phenyl which is unfused, wherein R10 is optionally substituted as described in Formula I. In another embodiment of formula I, R10 is R10A, wherein R10A is phenyl which is unfused, wherein R10 is substituted with F and further unsubstituted or substituted with one or two of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein each R11 is R12, R13, R14 or R15; wherein R12 is phenyl which is unfused or fused with benzene, heteroarene, heterocycloalkane or heterocycloalkene; R13 is heteroaryl, which is unfused;
R14 is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, cycloalkane, heterocycloalkane or heterocycloalkene: each of which is unfused or fused with benzene; and R15 is alkyl which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl which is unsubstituted or substituted with R18; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane; R18 is phenyl or heterocycloalkyl, which is unfused; wherein the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl, which is unfused; R21 is heteroaryl, which is unfused; R22 is cycloalkyl or heterocycloalkyl: each of which is unfused or fused with benzene; and R23 is alkyl which is unsubstituted or substituted with R24, OR24, NHR24N(R24)2, NHS(O)2R24 or OH; wherein each R24 is R24A or R24B; R24A is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, which is unfused or fused with heterocycloalkane; R24B is alkyl, which is unsubstituted or substituted with OR25, OH, F, Cl, Br or I; R25 is alkyl, which is unsubstituted or substituted with NH2; wherein the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26(O), F, Cl, Br or I; and R26 is alkyl. In another embodiment of formula I, R10 is R10A, wherein R10A is phenyl which is unfused, wherein R10 is substituted with F and further substituted with NHC(O)R11 wherein R11 is R15, wherein R16 is optionally substituted as described in Formula I. In another embodiment of formula I, R10 is R10A, wherein R10A is phenyl which is unfused, wherein R10 is substituted with F and further substituted with R11, wherein R11 is R12 or R14, wherein R14 is heterocycloalkyl which is unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I, wherein R19 is as described in Formula I. In another embodiment of formula I, R10 is R10A, wherein R10A is phenyl which is unfused, wherein R10 is substituted with F and further substituted with R11, wherein R11 is phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl, tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each of which are independently unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I wherein R19 is as described in Formula I. In another embodiment of formula I, R10 is R10A, wherein R10A is phenyl which is unfused, wherein R10 is substituted with F and further substituted with R11, wherein R11 is phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl, tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each of which are independently substituted with one or two (O). In another embodiment of formula I, R10 is R10A, wherein R10A is phenyl which is unfused, wherein R10 is substituted with F and further substituted with R11, wherein R11 is R14, wherein R14 is heterocycloalkyl which is unsubstituted or substituted with one or two (O). In another embodiment of formula I, R10 is R10A, wherein R10A is phenyl which is unfused, wherein R10 is substituted with F and further substituted with R11, wherein R11 is R14, wherein R14 is pyrrolidinyl which is substituted with one or two or three or four of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I wherein R19 is as described in Formula I and wherein R14 is substituted with at least one (O). In another embodiment of formula I, R10 is R10A, wherein R10A is phenyl which is unfused, wherein R10 is substituted with F and further substituted with R11, wherein R11 is R14, wherein R14 is pyrrolidinyl which is substituted with one or two (O).
Embodiments of Multiple Substituents
The following are additional embodiments of the compounds of Formula I. Unless otherwise specified, substituents are as described in Formula I.
In one embodiment of Formula I, R1 is cycloalkane, which is unfused; R2 is heterocycloalkane, which is unfused, and A1 is R5.
Embodiments where A1 is Cyclohexane, A2 is R5
In one embodiment of Formula I, A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, which is as described in Formula I. In another embodiment of Formula I, A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, R5 is C1-alkyl, C2-alkyl or C3-alkyl wherein R5 is substituted as described in Formula I. In another embodiment of Formula I, A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, R5 is C1-alkyl, C2-alkyl or C3-alkyl wherein R10 is R10A, wherein is R10A is phenyl which is unfused and substituted with F, and further substituted with NHC(O)R11, wherein R11 is R15. In another embodiment of Formula I, A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, R5 is C1-alkyl, C2-alkyl or C3-alkyl wherein R10 is R10A, wherein is R10A is phenyl which is unfused and substituted with F, and further substituted with NHC(O)R11, wherein R11 is R15 wherein R15 is alkyl, which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl, which is unsubstituted or substituted with one or two of independently selected R18; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane; wherein each R18 is phenyl or heterocycloalkyl; wherein each of the moieties represented by R17A and R18 are independently unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl which is unfused; R21 is heteroaryl which is unfused; R22 is cycloalkyl or heterocycloalkyl; each of which are unfused or fused with benzene; R23 is alkyl, which is unsubstituted or substituted with one or two of independently selected R24, OR24, NHR24N(R24)2, NHS(O)2R24 or OH; wherein each R24 is R24A or R24; R24A is unsubstituted phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with heterocycloalkane; R24B is alkyl, which is unsubstituted or substituted with one or two of independently selected OR25 or OH; wherein each R25 is alkyl unsubstituted or substituted with NH2; wherein each R20 is unsubstituted or substituted with one or two of independently selected R26, OR26, (O), F, Cl, Br or I; and R26 is alkyl. In another embodiment of Formula I, A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, R5 is C1-alkyl, C2-alkyl or C3-alkyl wherein R10 is substituted with F, and further substituted with R14 wherein each R10 is independently unsubstituted or substituted with one or two or three of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, NHR11, N(R11)2, C(O)R11, C(O)OR11, C(O)NH2, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NR11C(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NR11C(O)OR11, NHSO2NH2, NHSO2NHR11, NHSO2N(R11)2, SO2NH2, SO2NHR11, SO2N(R11)2, NHC(O)NH2, NHC(O)NHR11, NHC(O)N(R11)2, NR11C(O)N(R11)2, NO2, OH, (O), C(O)H, C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; wherein R14 is pyrrolidinyl, azetidinyl, pyrrolyl, 1,3-oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, tetrahydropyrimidin(2H)-yl, azabicyclo(2.2.1)heptyl or 1,6-dihydropyridazyl; each of which unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and wherein the moiety represented by R14 is substituted with one or two (O) substituents. In another embodiment of Formula I, A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, R5 is C1-alkyl, C2-alkyl or C3-alkyl wherein R5 is substituted with R10, and further unsubstituted or substituted with one or two or three of independently selected NHR10, N(R10)2, SR10, S(O)R10, SO2R10 or CF3, wherein R10 is as described in formula I. In another embodiment of Formula I, A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, R5 is C1-alkyl, C2-alkyl or C3-alkyl wherein R5 is substituted with R10, and further unsubstituted or substituted with one CF3, wherein R10 is as described in formula I. In another embodiment of Formula I, A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5 selected from the following Formulas (Ie), (If), (Ig), (Ih), (Ii) or (Ij):
In one embodiment of Formula (Ii), R10 is R10A, R10B or R10C; each of which must be attached at a carbon atom; R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused with heterocycloalkane; R10B is
R10C is heterocycloalkyl, which is unfused; wherein R10 is substituted with C(O)R11, C(O)NHR11, C(O)N(R11)2 or NHC(O)R11, and is further unsubstituted or substituted with one or two or three of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl, Br or I; wherein each R11 is R12, R13, R14 or R15; R12 is phenyl which is unfused or fused with benzene, heteroarene, heterocycloalkane or heterocycloalkene; R13 is heteroaryl, which is unfused; R14 is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, cycloalkane, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene; R15 is alkyl, which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl, which is unsubstituted or substituted with R15; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane; R18 is phenyl or heterocycloalkyl, which is unfused; wherein the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19), NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl, which is unfused; R21 is heteroaryl, which is unfused; R22 is cycloalkyl, or heterocycloalkyl each of which is unfused or fused with benzene; R23 is alkyl which is unsubstituted or substituted with one or two of independently selected R24, OR24, NHR24N(R24)2, NHS(O)2R24, OH, F, Cl, Br or I; wherein each R24 is R24A or R24B; R24A is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with heterocycloalkane; R24B is alkyl which is unsubstituted or substituted with OR25, OH, F, Cl, Br or I; R25 is alkyl each of which is unsubstituted or substituted with NH2; wherein the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26, (O), F, Cl, Br or I; and R16 is alkyl. In another embodiment of Formula I, A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, R5 is C1-alkyl wherein R5 is substituted with R10, wherein R10 is as described in formula I, as described in Formula (Ie)
In another embodiment of Formula I, A1 is R1, wherein R1 is unsubstituted cyclohexane which is unfused, and A2 is R5, R5 is unbranched C2-alkyl wherein R5 is substituted with R10, wherein R10 is as described in formula I, as described in Formula (If)
Embodiments of Formula (Ie)
In one embodiment of Formula (Ie), R10 is R10A, R10B or R10C, wherein R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused heterocycloalkane, R10B is
and R10C is heterocycloalkyl, which is unfused; wherein R10 is substituted as described in formula I. In another embodiment of Formula (Ie), R10 is R10A, R10B or R10C, wherein R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused heterocycloalkane, R10B is
and R10C is heterocycloalkyl, which is unfused; wherein R10 is substituted with one or two of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein R11 is as described in Formula I. In another embodiment of Formula (Ie), R10 is R10A, R10B or R10C, wherein R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused heterocycloalkane, R10B is
and R10C is heterocycloalkyl, which is unfused; wherein R10 is substituted with F and further unsubstituted or substituted with one or two of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein R11 is as described in Formula I. In another embodiment of Formula (Ie), R10 is R10A, R10B or R10C, wherein R10A is phenyl which is unfused or fused with heterocycloalkane, which is fused heterocycloalkane, R10B is
and R10C is heterocycloalkyl, which is unfused; wherein R10 is substituted with F and further unsubstituted or substituted with one or two of independently selected R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein R11 is R12, R13, R14 or R15; R12 is phenyl which is unfused or fused with benzene, heteroarene, heterocycloalkane or heterocycloalkene; R13 is heteroaryl, which is unfused; R14 is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, cycloalkane, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene; R15 is alkyl which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl which is unsubstituted or substituted with Ris; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane; R18 is phenyl or heterocycloalkyl, which is unfused; wherein the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl, which is unfused; R21 is heteroaryl, which is unfused; R22 is cycloalkyl or heterocycloalkyl; each of which is unfused or fused with benzene; R23 is alkyl which is unsubstituted or substituted with R24, OR24, NHR24N(R24)2, NHS(O)2R24 or OH; wherein each R24 is R24A or R24B; R24A is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, which is unfused or fused with heterocycloalkane; R24B is alkyl, which is unsubstituted or substituted with OR25, OH, F, Cl, Br or I; R25 is alkyl, which is unsubstituted or substituted with NH2; wherein the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26 (O), F, Cl, Br or T; and R26 is alkyl. In another embodiment of Formula (Ie), R10 is R10A, R10B or R10C, wherein R10A is phenyl which is unfused.
R10B is
and R10C is
wherein R10 is optionally substituted as described in Formula I. In another embodiment of Formula (Ie), R10 is R10A R10B or R10C as described in Formulas (Ik), (Il), (Im), (In), (Io) or (Ip)
wherein R101, R102, R103, R104, and R105, are independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein R11 is as described in Formula I.
In another embodiment of Formula (Ie), R10 is R10A or R10B, as described in Formulas (Ik), (Il), (Im), (In), (Io) or (Ip). In another embodiment of Formula (Ie), R10 is phenyl, as shown in Formula (Ik):
wherein R101, R102, R103, R104, and R105, are independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein R11 is as described in Formula I. In another embodiment of Formula (Ik), at least one of R101, R102, R103, R104, and R105 are F, and at least one is R11, wherein R11 is phenyl, pyrrolyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, 1,3-oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl, 1,6-dihydropyridazyl, tetrahydropyrimidin(2H)-yl or azabicylo(2.2.1)hept-2-yl; each of which are independently unsubstituted or substituted with one or two or three of independently selected R19, OR19SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl, which is unfused; R21 is heteroaryl, which is unfused; R22 is cycloalkyl, or heterocycloalkyl each of which is unfused or fused with benzene; R23 is alkyl which is unsubstituted or substituted with one or two of independently selected R24, OR24, NHR24N(R24)2, NHS(O)2R19, OH, F, Cl, Br or I; wherein each R24 is R24A or R24B; R24A is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with heterocycloalkane; R24B is alkyl which is unsubstituted or substituted with OR25, OH, F, Cl, Br or I; R25 is alkyl each of which is unsubstituted or substituted with NH2; wherein the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26, (O), F, Cl, Br or I; and R26 is alkyl. In another embodiment of Formula (Ik), R101, R104 and R105 are H, and R102 is R11, wherein R11 is selected from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolidinyl, piperidinyl, and azepanyl, wherein R102 is substituted with one or two (O) substituents. In another embodiment of Formula (Ik), R101, R104 and R105 are H, and R102 is R11, wherein R11 is pyrrolidinyl.
Further Embodiments of Formula (Ik)
In one embodiment of Formula (Ik), R102 is NHC(O)R11, as described in Formula (Iq):
wherein R101, R103, R104 and R105 are independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11, SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein R11 is as described in Formula I. In one embodiment of Formula (Iq), R11 is R15, wherein R16 is optionally substituted as described in Formula I and R101, R103, R104 and R105 are as described in Formula (Iq). In another embodiment of Formula (Iq), R103 is F, and R101, R104 and R105 are independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; and R11 is R15, wherein R16 is optionally substituted as described in Formula I. In another embodiment of Formula (Iq), one of R101, R103, R104 and R105 is F, R11 is R15, wherein R16 is optionally substituted as described in Formula I. In another embodiment of Formula (Iq), R101, R104 and R105 is F. In another embodiment of Formula (Iq), R103 is F. In another embodiment of Formula (Iq), one of R101, R103, R104 and R105 is F, R11 is R15, wherein R16 is alkyl, which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl, which is unsubstituted or substituted with one or two of independently selected R18: R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane; wherein each R18 is phenyl or heterocycloalkyl; wherein each of the moieties represented by R17A and R18 are independently unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl which is unfused; R21 is heteroaryl which is unfused; R22 is cycloalkyl or heterocycloalkyl; each of which are unfused or fused with benzene; R23 is alkyl, which is unsubstituted or substituted with one or two of independently selected R24, OR24, NHR24N(R24)2, NHS(O)2R24 or OH; wherein each R24 is R24A or R24BA; R24A is unsubstituted phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with heterocycloalkane; R24B is alkyl, which is unsubstituted or substituted with one or two of independently selected OR25 or OH; wherein each R25 is alkyl unsubstituted or substituted with NH2; wherein each R20 is unsubstituted or substituted with one or two of independently selected R26, OR26, (O), F, Cl, Br or I; and R26 is alkyl. In another embodiment of Formula (Iq), R103 is F, and R101, R104 and R105 are each H, R11 is R15, wherein R16 is optionally substituted as described in Formula I. In another embodiment of Formula (Iq), R11 is R12 or R14, wherein R14 is heterocycloalkyl which is unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein R19 is as described in Formula I. In another embodiment of Formula (Iq), R11 is selected from phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl, tetrahydropyrimidinyl or azabicylo(2.2.1)hept-2-yl; each of which are independently unsubstituted or substituted with one or two or three or four of independently selected R19OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein R19 is as described in Formula I.
In one embodiment of Formula (Ik), R102 is R11, wherein R11 is pyrrolidinyl as described in Formula (Ir):
wherein R101, R103, R104, and R105, are independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein R11 is as described in Formula I, and R201, R202, R203, and R204 are independently H, R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein R19 is as described in Formula I. In one embodiment of Formula (Ir), R103 is F, and R101, R104, and R105 are H, wherein R201, R202, R203, and R204 are independently H, R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein R19 is as described in Formula I. In one embodiment of Formula (Ir), one or two of R201, R202, R203, and R204 is (O). In another embodiment of Formula (Ir), two of R201, R202, R203, and R204 are (O). In another embodiment of Formula (Ir), R201 and R204 are (O) and R202 and R203 are H, as described in Formula (Ir1):
In one embodiment of Formula (Ir1), R103 is F and R101, R104, and R105, are independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein R11 is as described in Formula I.
In one embodiment of Formula (Ik), R103 is F, as described in Formula (Is):
wherein R101, R102, R104, and R105, are independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein R11 is as described in Formula I. In another embodiment of Formula (Is), R101, R102, R104, and R105, are independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSON(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein each R11 is R12, R13, R14 or R15; wherein R12 is phenyl which is unfused or fused with benzene, heteroarene, heterocycloalkane or heterocycloalkene; R13 heteroaryl, which is unfused; R14 is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, cycloalkane, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene; and R15 is alkyl which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R1A; R17 is alkyl which is unsubstituted or substituted with R's; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane: R18 is phenyl or heterocycloalkyl, which is unfused; wherein the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl, which is unfused; R21 is heteroaryl, which is unfused; R22 is cycloalkyl or heterocycloalkyl; each of which is unfused or fused with benzene; and R23 is alkyl which is unsubstituted or substituted with R24, OR24, NHR24N(R24)2, NHS(O)2R24 or OH; wherein each R24 is R24A or R24; R24A is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, which is unfused or fused with heterocycloalkane; R24B is alkyl, which is unsubstituted or substituted with OR25, OH, F, Cl, Br or I; R25 is alkyl, which is unsubstituted or substituted with NH2; wherein the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26 (O), F, Cl, Br or I; and R26 is alkyl. In another embodiment of Formula (Is), R11 is selected from phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl, tetrahydropyrimidinyl or azabicylo(2.2.1)hept-2-yl; each of which are independently unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein R19 is as described in Formula I. In another embodiment of Formula (Is), R102 is R11, wherein R11 is selected from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl and azepanyl, wherein R102 is substituted with one or two (O) substituents. In another embodiment of Formula (Is), R102 is R11, wherein R11 is selected from pyrrolidinyl substituted with one or two (O) substituents. In another embodiment of Formula (Is), R101, R104 and R105 are H, and R102 is selected from R11, OR11, NHC(O)R11, or C(O)NHR11; wherein R11 is as described in Formula I. In another embodiment of Formula (Is), wherein R101, R104 and R105 are H, and R102 is selected from R11, OR11, NHC(O)R11, or C(O)NHR11;
wherein R11 is phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl, tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each of which are independently unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I wherein R19 is as described in Formula I. In another embodiment of Formula (Is), wherein R101, R104 and R105 are H, and R102 is selected from R11, OR11, NHC(O)R11, or C(O)NHR11; wherein R11 is phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl, tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each of which are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I wherein R19 is as described in Formula I. In another embodiment of Formula (Is), wherein R101, R104 and R105 are H, and R102 is selected from R11, OR11, NHC(O)R11, or C(O)NHR11; wherein R11 is R15 and R15 is alkyl which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl which is unsubstituted or substituted with R18; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with benzene or heterocycloalkane; R18 is phenyl or heterocycloalkyl, which is unfused; wherein the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R21; R20 is phenyl, which is unfused; R21 is heteroaryl, which is unfused; R22 is cycloalkyl or heterocycloalkyl; each of which is unfused or fused with benzene; and R23 is alkyl which is unsubstituted or substituted with R24, OR24, NHR24N(R4)2, NHS(O)2R24 or OH; wherein each R24 is R24A or R24B; R24A is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, which is unfused or fused with heterocycloalkane; R24B is alkyl, which is unsubstituted or substituted with OR25, OH, F, Cl, Br or I; R25 is alkyl, which is unsubstituted or substituted with NH2; wherein the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26(O), F, Cl, Br or I; and R26 is alkyl.
In one embodiment, the compound of Formula (Is) is selected from:
In another embodiment, the compound of Formula (Is) is selected from
In one embodiment of Formula (Ik), R102 is C(O)R11, as described in Formula (It):
wherein R11 is as described in Formula I. In one embodiment of Formula (It), R101, R103, R104 and R105 are H. In another embodiment of Formula (It), R103 is F and R101, R104 and R105 are H. In another embodiment of Formula (It), R11 is R15 and R15 is alkyl which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl which is unsubstituted or substituted with R18; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane; R18 is phenyl or heterocycloalkyl, which is unfused; wherein the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl, which is unfused; R21 is heteroaryl, which is unfused; R22 is cycloalkyl or heterocycloalkyl; each of which is unfused or fused with benzene; and R23 is alkyl which is unsubstituted or substituted with R24, OR24, NHR24N(R24)2, NHS(O)2R24 or OH; wherein each R24 is R24A or R24B; R24A is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, which is unfused or fused with heterocycloalkane; R24B is alkyl, which is unsubstituted or substituted with OR25, OH, F, Cl, Br or I; R15 is alkyl, which is unsubstituted or substituted with NH2; wherein the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26 (O), F, Cl, Br or I; and R26 is alkyl. In another embodiment of Formula (It), R11 is phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl, tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each of which are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I wherein R19 is as described in Formula I.
In one embodiment of Formula (Ik), R102 is C(O)NHR11, as described in Formula (Iu):
wherein R11 is as described in Formula I. In one embodiment of Formula (Iu), R101, R103, R104 and R105 are H. In another embodiment of Formula (Iu), R103 is F and R101, R104 and R105 are H. In another embodiment of Formula (Iu), R11 is R15 and R15 is alkyl which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NHR16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl which is unsubstituted or substituted with R18; R17A is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heterocycloalkane; R18 is phenyl or heterocycloalkyl, which is unfused; wherein the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl, which is unfused; R21 is heteroaryl, which is unfused; R22 is cycloalkyl or heterocycloalkyl; each of which is unfused or fused with benzene; and R23 is alkyl which is unsubstituted or substituted with R24, OR24, NHR24N(R24)2, NHS(O)2R24 or OH; wherein each R24 is R24A or R24B; R24A is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl, which is unfused or fused with heterocycloalkane; R24B is alkyl, which is unsubstituted or substituted with OR25, OH, F, Cl, Br or I; R25 is alkyl, which is unsubstituted or substituted with NH2; wherein the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26 (O), F, Cl, Br or I; and R26 is alkyl. In another embodiment of Formula (Iu), R11 is phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl, tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each of which are independently unsubstituted or substituted with one or two of independently selected R19, OR19, SR19, SO2R19, C(O)R19, CO(O)R19, NHR19, N(R19)2, NHC(O)R19, NHS(O)2R19, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)H, OH, (O), CN, CF3, F, Cl, Br or I wherein R19 is as described in Formula I.
In one embodiment of Formula (Ik), R102 is phenyl which is unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, S(O)R19, SO2R19, C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, NHR19, N(R19)2, NHC(O)R19, NR19C(O)R19, NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)NHR19, NHC(O)N(R19)2, NR19C(O)NHR19, NR19C(O)N(R19)2, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)NHOH, C(O)NHOR19, C(O)NHSO2R19, C(O)NR19SO2R19, SO2NH2, SO2NHR19, SO2N(R19)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR19, C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I; wherein R19 is as described in Formula I.
In one embodiment of Formula (Ik), R102 is heterocycloalkyl which is unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, S(O)R19, SO2R19, C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, NHR19, N(R19)2, NHC(O)R19, NR19C(O)R19, NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)NHR19, NHC(O)N(R19)2, NR19C(O)NHR19, NR19C(O)N(R19)2, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)NHOH, C(O)NHOR19, C(O)NHSO2R19, C(O)NR19SOR19, SO2NH2, SO2NHR19, SO2N(R19)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR19, C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I; wherein R19 is as described in Formula I.
Embodiments where A102 is Piperidine, A2 is R5
In one embodiment of Formula (I) A1 is R2, wherein R2 is unsubstituted piperidine which is unfused, and A2 is R5, which is as described in Formula I. In another embodiment of Formula I, A1 is R2, wherein R2 is unsubstituted piperidine which is unfused, and A2 is R5, R5 is C1-alkyl, C2-alkyl or C3-alkyl wherein R5 is substituted with R10, and further unsubstituted or substituted with one or two or three of independently selected NHR10, N(R10)2, SR10, S(O)R10, SO2R10 or CF3, wherein R10 is as described in formula I. In another embodiment of Formula I, A1 is R2, wherein R1 is unsubstituted piperidine which is unfused, and A2 is R5, R5 is C1-alkyl, C2-alkyl or C3-alkyl wherein R5 is substituted with R10, and further unsubstituted or substituted with one CF3, wherein R10 is as described in formula I. In another embodiment of Formula I, A1 is R2, wherein R2 is unsubstituted piperidine which is unfused, A2 is C1-alkyl, and R10 is phenyl, as shown in Formula (Iv):
wherein R101, R102, R103, R104, and R105, are independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2, N(R11)2, C(O)R11, C(O)OR11, C(O)NHR11, C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; wherein each R11 is R12, R13, R14 or R15; R12 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R13 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R14 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R15 is alkyl, alkenyl or alkynyl; each of which is unsubstituted or substituted with one or two of independently selected R16, OR16, SR16, S(O)2R16, C(O)OH, NH2, NHR16N(R16)2, C(O)R16, C(O)NH2, C(O)NHR16, C(O)N(R16)2, NHC(O)R16, NR16C(O)R16, NHC(O)OR16, NR16C(O)OR16, OH, F, Cl, Br or I; wherein each R16 is R17 or R17A; R17 is alkyl, alkenyl or alkynyl: each of which is unsubstituted or substituted with one or two of independently selected R18, C(O)OH, NH2, NHR18 or N(R18)2, C(O)R18, C(O)NH2, C(O)NHR18, C(O)N(R18)2, NHC(O)R18, NR18C(O)R18, F, Cl, Br or I; R17A is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; wherein each R18 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; wherein each of the moieties represented by R12, R13, R14, R17A, and R18 are independently unsubstituted or substituted with one or two or three or four of independently selected R19, OR19, SR19, S(O)R19, SO2R19, C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, NHR19, N(R19)2, NHC(O)R19, NR19C(O)R19, NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)NHR19, NHC(O)N(R19)2, NR19C(O)NHR19, NR19C(O)N(R19)2, C(O)NH2, C(O)NHR19, C(O)N(R19)2, C(O)NHOH, C(O)NHOR19, C(O)NHSO2R19, C(O)NR19SO2R19, SO2NH2, SO2NHR19, SO2N(R19)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR19, C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I; wherein each R19 is R20, R21, R22 or R23; R20 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R21 is heteroaryl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R23 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected R24, OR24, SR24, S(O)2R24, C(O)OH, NH2, NHR24N(R24)2, C(O)R24, C(O)NH2, C(O)NHR4, C(O)N(R14)2, NHC(O)R14, NR2C(O)R24, NHC(O)OR4, NR14C(O)OR14, NHS(O)2R24, NR4S(O)2R24, OH, F, Cl, Br or I; wherein each R24 is R24A or R24B; R24A is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R24B is alkyl, alkenyl or alkynyl each of which is unsubstituted or substituted with one or two of independently selected R25, OR25, SR25, S(O)2R25, C(O)OH, NH2, NHR25N(R25)2, C(O)R25, C(O)NH2, C(O)NHR25, C(O)N(R25)2, NHC(O)R25, NR25C(O)R5, NHC(O)OR25, NR25C(O)OR2, OH, F, Cl, Br or I; wherein each R25 is alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; each of which is unsubstituted or substituted with NH2, NH(CH3), N(CH3)2, OH or OCH3; wherein each of the moieties represented by R20, R21, R22, and R24A are independently unsubstituted or substituted with one or two of independently selected R26, OR26, alkenyl, alkynyl, phenyl, OH, (O), C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; and R26 is alkyl. In another embodiment, the compound of Formula (Iv) is selected from
The starting materials used herein are commercially available or may be prepared by routine methods well known to those of ordinary skill in the art. The compounds of the present invention may be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes are presented for purposes of illustration and are not intended to be limiting.
As shown in Scheme 1, the bicyclic anhydride (1) can be reduced to the alcohol (2) using a reducing agent such as but not limited to sodium borohydride. The reaction is typically conducted in a solvent such as but not limited to tetrahydrofuran at below room temperature to reflux. Conversion of (2) to the phosphonium salt (3) may be carried out by reacting the former with a trialkyl phosphine such as but not limited to tri-n-butyl phosphine in the presence of hydrobromic acid. The reaction is typically conducted in a solvent such as but not limited to acetic acid at reflux. Reaction of (3) with a nitrobenzaldehyde of Formula (4), wherein R11A is a substituent on R10 as described herein, in the presence of a base such as but not limited to triethylamine will provide a lactone of Formula (5). The reaction is typically conducted in a solvent such as but not limited to dichloromethane at room temperature. Reduction of the nitro group of a compound of Formula (5) with a reducing agent such as but not limited to iron powder and NH4Cl will provide the corresponding aniline of Formula (6). The reaction is typically conducted in a solvent such as but not limited to ethanol at reflux. Reaction of the aniline of Formula (6) with hydrazine will provide a tetrahydrophthalazinone of Formula (7). The reaction is typically conducted in a solvent such as but not limited to ethanol at an elevated temperature. Reaction of a compound of Formula (7) with either an anhydride of Formula (8) or with an acid of Formula (11) under standard peptide coupling conditions known to those skilled in the art and widely available in the literature will provide compounds of Formula (9) and (12), respectively. An acid of Formula (9) may be further modified to an imide of Formula (10) using standard peptide coupling conditions including the use of 1,1′-carbonyldiimidazole (CDI) as the coupling agent.
Alternatively, as shown in Scheme 2, the phosphonium salt (3) can be reacted with a cyanobenzaldehyde of Formula (13) to provide a lactone of Formula (14). The reaction is typically conducted under basic conditions in a solvent such as but not limited to dichloromethane at room temperature. Hydrolysis of the nitrile of Formula (14) to the corresponding acid, followed by addition of hydrazine will provide the tetrahydrophthalazinone of Formula (15). The hydrolysis step is typically conducted with an aqueous base such as but not limited to sodium hydroxide at elevated temperatures. The second step is also conducted under aqueous conditions at elevated temperatures. Coupling the acid of Formula (15) with an amine of Formula (16), wherein each R11 is as described in Formula I herein or is H or is a heterocyclic amine R14, under standard peptide coupling conditions known to those skilled in the art and widely available in the literature, will provide an amide of Formula (17). Alternatively, a compound of Formula (14) can be converted to a tetrahydrophthalazinone using hydrazine as previously described, followed by reduction to the primary amine of Formula (18) under standard Raney-nickel reduction conditions. Treatment of compounds of Formula (18) under standard reductive amination conditions with an aldehyde R16CHO or ketone R16C(O)R16 and then optionally with a second aldehyde R16CHO or ketone R16C(O)R16, will provide secondary or tertiary amines of Formula (19) (wherein each R16 can be H or as defined in Formula (I)).
In a manner similar to the procedure described in Scheme I, the phosphonium salt (3) can be reacted with a benzaldehyde of Formula (20), wherein R11B is alkyl such as but not limited to ethyl and R11A is as previously defined in Scheme 1. Reaction of a compound of Formula (21) with hydrazine as described in Scheme 1, followed by hydrolysis using an aqueous acid such as but not limited to sulfuric acid will provide a compound of Formula (22). The reaction is typically performed at elevated temperatures in a solvent such as but not limited tot ethanol. Reaction of a compound of Formula (22) with an amine of Formula (23) under reductive amination conditions known to those skilled in the art and widely available in the literature will provide a tetrahydrophthalazinone of Formula (19).
As shown in Scheme 4, the phosphonium salt (3) can be reacted with a bromobenzaldehyde of Formula (24) to provide a compound of Formula (25) using the conditions described in Scheme 1. Reaction of a compound of Formula (25) with hydrazine as described in Scheme 1 will provide a tetrahydrophthalazinone of Formula (26), which can be coupled with stannane of Formula (27) or a borate of Formula (28) to provide a compound of Formula (29) wherein R11 is a substituted or unsubstituted phenyl or heteroaryl. Coupling conditions include those known by those skilled in the art and widely available in the literature for Suzuki and Stille type couplings.
A benzylic bromide of Formula (30) wherein R11 is as described herein, can be converted to a Grignard reagent and then added to a diester (31) to give a keto-ester of Formula (32) as shown in Scheme 5. The addition of the Grignard reagent is typically performed at cold temperatures, before warming up the reaction to room temperature. The reaction is typically performed in a solvent such as but not limited to tetrahydrofuran, ether and the like, or mixtures thereof. The Grignard reagent may be purchased commercially or prepared from Mg using standard conditions available in the literature. The addition of hydrazine to a compound of Formula (32) under conditions described in Scheme I at room temperature will provide a phthalazinone of Formula (33). The bromide can be converted to an ester of Formula (34) under palladium catalyzed carboxylation conditions. The transformation typically requires the use of a palladium catalyst and a base, such as but not limited to triethylamine, in addition to carbon monoxide and methanol. Typical palladium catalysts include [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane and the like. The reaction is typically conducted at elevated temperatures and may require the use of a solvent such as but not limited to N,N-dimethylformamide. The ester of Formula (34) can be converted to a primary amide of Formula (35) using ammonia, followed by a Hoffman rearrangement with bromine and aqueous potassium hydroxide to provide an aniline of Formula (36). The first step typically requires an elevated temperature, and the second step typically requires a decreased temperature for the additions, followed by heating. The pyridine ring can be reduced under catalytic conditions, such as but not limited to the use of hydrogen gas and platinum on carbon to provide a compound of Formula (37). Amide formation using either an acid chloride of Formula R11C(O)Cl or an acid of Formula R11C(O)OH under standard peptide coupling conditions known to those skilled in the art and widely available in the literature will provide compounds of Formula (38). Alternatively, an ester of Formula (34) can be reduced to a compound of Formula (39) using the conditions described above, followed by hydrolysis to provide an acid of Formula (40). Typical hydrolysis conditions include but are not limited to using an aqueous base such as lithium hydroxide at elevated temperatures. Amide formation using a primary or secondary amine of Formula NH2R11 or NH(R11)2 employing standard peptide coupling conditions known to those skilled in the art and widely available in the literature, will provide an amide of Formula (41).
The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The exemplified compounds were named using ACD/ChemSketch Version 5.06 (5 Jun. 2001, Advanced Chemistry Development Inc., Toronto, Ontario), except for Examples 160, 320 and 487, which were named using ChemDraw) Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.). Intermediates were named using IUPAC standards.
To a solution of 1-cyclohexene-1,2-dicarboxylic anhydride (25.2 g) in tetrahydrofuran (125 mL) at 0° C. was added sodium borohydride (1.51 g). The mixture was warmed to ambient temperature for 30 minutes, heated at reflux for 5 hours, cooled, treated with 1N hydrochloric acid and concentrated. The concentrate was partitioned between ethyl acetate and brine, and the organic layer was washed with brine and water and concentrated. The concentrate was purified by flash chromatography with 50% ethyl acetate in hexane.
A solution of EXAMPLE 1A (3 g) in acetic acid (10 mL) at ambient temperature was treated with tri-n-butyl phosphine (4.81 mL) and 33% hydrobromic acid in acetic acid (3.34 mL), heated at reflux for 21 hours, cooled and concentrated. The concentrate was purified by flash chromatography on silica gel with 10% methanol in dichloromethane.
To a solution of EXAMPLE 1B (3.05 g) in dichloromethane (30 mL) was added 2-fluoro-5-formylbenzonitrile (1.08 g) and triethylamine (1.02 mL). The mixture was stirred at ambient temperature for 16 hours and concentrated. The concentrate was partitioned between ethyl acetate and brine. The organic layer was washed with brine and concentrated. The concentrate was purified by flash chromatography on silica gel with 50% ethyl acetate in hexane.
To a suspension of EXAMPLE 1C (1.46 g) in water (15 mL) was added 50% sodium hydroxide. The mixture was heated at 90° C. for 1 hour. After cooling to 70° C., hydrazine monohydrate (0.54 mL) was added, and the solution was stirred at 70° C. for 17 hours. The solution was cooled to ambient temperature and brought to pH 4 with 6N hydrochloric acid. The precipitate was filtered, washed with water and dried. 1H NMR (DMSO-d6) δ1.55-1.69 (m, 4H), 2.31-2.42 (m, 4H), 3.93 (s, 2H), 7.24 (dd, J=10.8, 8.5 Hz, 1H), 7.40-7.48 (m, 1H), 7.68 (dd, J=6.9, 2.2 Hz, 1H), 12.61 (s, 1H), 13.22 (brs, 1H).
This example was prepared as described in EXAMPLE 1C by substituting 4-fluoro-3-nitrobenzaldehyde for 2-fluoro-5-formylbenzonitrile.
A solution of EXAMPLE 2A (2.25 g) and ammonium chloride (0.83 g) in ethanol (35 mL) and water (25 mL) at 70° C. was treated with iron powder (4.35 g), stirred for 3 hours and filtered through diatomaceous earth (CELITE®, World Minerals, Santa Barbara, Calif.) with hot ethanol. The filtrate was concentrated, and the concentrate was stirred with water for 30 minutes and filtered. The solid was washed with water and dried.
To a solution of EXAMPLE 2B (1.42 g) in ethanol (10 mL) was added hydrazine monohydrate (0.27 mL). The mixture stirred at reflux for 1 hour, cooled to 0° C., and filtered. The solid was washed with water and dried. 1H NMR (CD3OD) δ 1.63-1.75 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.53 (m, 2H), 3.84 (s, 2H), 6.42-6.49 (m, 1H), 6.64 (dd, J=8.6, 2.2 Hz, 1H), 6.86 (dd, J=11.2, 8.1 Hz, 1H).
To a solution of EXAMPLE 2 (872 mg) in acetonitrile was added succinic anhydride (370 mg). The mixture was heated at reflux for 17 hours, cooled and concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). 1H NMR (DMSO-d6) δ1.53-1.66 (m, 4H), 2.30-2.43 (m, 4H), 2.55-2.67 (m, 2H), 3.26-3.31 (m, 2H), 3.85 (s, 2H), 6.85-6.99 (m, 1H), 7.15 (dd, J=10.8, 8.5 Hz, 1H), 7.74 (d, J=6.4 Hz, 1H), 9.70 (brs, 1H), 12.09 (brs, 1H), 12.61 (s, 1H).
To EXAMPLE 3 (905 mg) in dichloromethane (30 mL) and N,N-dimethylformamide (6 mL) was added 1,1′-carbonyldiimidazole (785 mg). The mixture was stirred at ambient temperature for 3 hours and concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). 1H NMR (DMSO-d6): δ 1.57-1.69 (m, 4H), 2.32-2.42 (m, 4H), 2.78-2.89 (m, 4H), 3.93 (s, 2H), 7.09-7.13 (m, 1H), 7.32-7.33 (m, 1H), 7.34 (d, J=1.2 Hz, 1H), 12.62 (s, 1H).
To EXAMPLE 1 (294 mg) in 1:1 N,N-dimethylformamide/pyridine (6 mL) was added 1,1′-carbonyldiimidazole (166 mg). The mixture was stirred at ambient temperature for 30 minutes, and tert-butyl 1-homopiperazine carboxylate (189 μL) was added. The mixture was stirred for 18 hours and concentrated. The concentrate was purified by flash chromatography on silica gel with 5% methanol in ethyl acetate.
To a solution of EXAMPLE 5A (330 mg) in dichloromethane (8 mL) at 0° C. was added trifluoroacetic acid (8 mL). The solution was warmed to ambient temperature, and acetonitrile was added. The mixture was concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). The product was dissolved in methanol/dichloromethane and treated with 1M hydrochloric acid in diethyl ether and filtered to give the title compound as the hydrochloride salt. 1H NMR (CD3OD) δ 1.70-1.76 (m, 4H), 2.02-2.11 (m, 2H), 2.52 (d, J=27.5 Hz, 4H), 3.32-3.36 (m, 2H), 3.40-3.46 (m, 2H), 3.51 (t, J=6.1 Hz, 2H), 3.95-4.01 (m, 2H), 4.06 (s, 2H), 7.19 (t, J=9.0 Hz, 1H), 7.29-7.34 (m, 1H), 7.36-7.41 (m, 1H).
This example was prepared as described in EXAMPLE 2C by substituting EXAMPLE 1C for EXAMPLE 2B.
To a solution of EXAMPLE 6A (1.5 g) in 20% ammonia in methanol (150 mL) was added Raney nickel (15 g). The mixture was shaken under hydrogen (60 psi) at ambient temperature for 2 hours, filtered, and concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid) to give the title compound as the trifluoroacetate salt. 1H NMR (CD3OD) δ1.55-1.65 (m, 4H), 2.33-2.41 (m, 4H), 3.90 (s, 2H), 4.04 (s, 2H), 7.21-7.25 (m, 1H), 7.27-7.29 (m, 1H), 7.31 (d, J=7.0 Hz, 1H), 8.20-8.27 (brs, 2H).
To a solution of EXAMPLE 6 (75 mg) in methanol (8 mL) was added 37 wt % formaldehyde in water (39 μL) and triethylamine (36 μL). The solution was stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (49 mg) and zinc chloride (35 mg) were added, and the mixture was stirred for 60 hours and was concentrated. The concentrate was dissolved in trifluoroacetic acidimethanol and purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). The product was dissolved in methanol/dichloromethane and treated with 1M hydrochloric acid in diethyl ether to give the title compound as the hydrochloride salt. 1H NMR (CD3OD) δ1.68-1.80 (m, 4H), 2.50-2.60 (m, 4H), 2.88 (s, 6H), 4.10 (s, 2H), 4.39 (s, 2H), 7.22-7.27 (m, 1H), 7.40-7.44 (m, 1H), 7.46 (dd, J=6.9, 2.0 Hz, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 7 by substituting acetone for formaldehyde. 1H NMR (CD3OD) δ1.39 (d, J=6.7 Hz, 6H), 1.68-1.77 (m, 4H), 2.43-2.59 (m, 4H), 3.41-3.50 (m, 1H), 4.05 (s, 2H), 4.24 (s, 2H), 7.18-7.24 (m, 1H), 7.35-7.38 (m, 1H), 7.38-7.42 (m, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 7 by substituting cyclohexanone for formaldehyde. 1H NMR (CD3OD) δ 1.32-1.46 (m, 4H), 1.68-1.81 (m, 6H), 1.84-1.94 (m, 2H), 2.13-2.22 (m, 2H), 2.43-2.61 (m, 4H), 3.08-3.18 (m, 1H), 4.07 (s, 2H), 4.26 (s, 2H), 7.18-7.23 (m, 1H), 7.35-7.39 (m, 1H), 7.40-7.43 (m, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 7 by substituting tetrahydro-4H-pyran-4-one for formaldehyde. 1H NMR (CD3OD) δ 1.66-1.76 (m, 6H), 2.04-2.14 (m, 2H), 2.40-2.57 (m, 4H), 3.40-3.51 (m, 3H), 4.03 (s, 2H), 4.05 (d, J=4.6 Hz, 2H), 4.29 (s, 2H), 7.18-7.25 (m, 1H), 7.36-7.39 (m, 1H), 7.40 (d, J=1.8 Hz, 1H).
To a solution of EXAMPLE 6 (75 mg) in methanol (8 mL) was added 3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (104 mg) and triethylamine (36 μL). The mixture was stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (49 mg) and zinc chloride (35 mg) were added. The mixture was stirred for 60 hours and trifluoracetic acid was added and the mixture stirred for one hour and was concentrated. The concentrate was dissolved in water/acetonitrile and was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). The residue was treated as described above with 37 wt % formaldehyde in water (39 μL), followed by treatment with 1M hydrochloric acid in diethyl ether to obtain the title compound as the HCl salt. 1H NMR (CD3OD) δ1.69-1.74 (m, 6H), 1.80-1.88 (m, 3H), 2.10-2.20 (m, 2H), 2.44-2.58 (m, 6H), 3.10 (dd, J=11.4, 7.5 Hz, 2H), 3.22-3.26 (m, 1H), 3.34-3.38 (m, 2H), 3.52-3.56 (m, 1H), 4.03 (s, 2H), 4.31 (s, 2H), 7.18-7.23 (m, 1H), 7.35-7.39 (m, 1H), 7.49 (dd, J=6.9, 2.0 Hz, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 11 by substituting N-(tert-butoxycarbonyl)-D-prolinal for 3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H NMR (CD3OD) δ 1.74-1.83 (m, 4H), 1.95-2.07 (m, 1H), 2.10-2.28 (m, 2H), 2.52-2.70 (m, 5H), 2.91 (s, 3H), 3.04 (s, 3H), 3.21-3.29 (m, 1H), 3.63-3.69 (m, 1H), 3.73-3.81 (m, 1H), 3.90-4.00 (m, 1H), 4.05-4.13 (m, 1H), 4.20 (s, 2H), 4.50-4.62 (m, 2H), 7.27 (t, J=9.1 Hz, 1H), 7.44-7.49 (m, 1H), 7.64 (d, J=5.2 Hz, 1H).
This example was prepared as described in EXAMPLE 1C by substituting 3-(diethoxymethyl)benzaldehyde for 2-fluoro-5-formylbenzonitrile.
This example was prepared as described in EXAMPLE 2C by substituting EXAMPLE 13A for EXAMPLE 2B.
To a solution of EXAMPLE 13B (681 mg) in a 1:1 mixture of ethanol/water (20 mL) was added concentrated sulfuric acid (0.4 mL). The mixture was refluxed for 16 hours. The mixture was cooled and concentrated, and the concentrate was triturated with saturated sodium bicarbonate. The solid was filtered, washed with water and dried.
A solution of EXAMPLE 13C (80 mg) and cyclopropylamine (51 mg) in methanol (8 mL) was stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (57 mg) was added, and the solution was stirred for 18 hours and was concentrated. The concentrate was dissolved in methanol/trifluoroacetic acid and was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). The product was dissolved in methanol/dichloromethane and was treated with 1M hydrochloric acid in diethyl ether and concentrated to give the title compound as the hydrochloride salt. 1H NMR (CD3OD) δ 0.82-0.92 (m, 4H), 1.65-1.77 (m, 4H), 2.41-2.60 (m, 4H), 2.69-2.79 (m, 1H), 4.11 (s, 2H), 4.28 (s, 2H), 7.31 (d, J=6.7 Hz, 1H), 7.34-7.40 (m, 2H), 7.41-7.45 (m, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting isopropylamine for cyclopropylamine. 1H NMR (CD3OD) δ1.38 (d, J=6.7 Hz, 6H), 1.68-1.79 (m, 4H), 2.41-2.65 (m, 4H), 3.38-3.48 (m, 1H), 4.12 (s, 2H), 4.17 (s, 2H), 7.31 (d, J=7.1 Hz, 1H), 7.35-7.38 (m, 1H), 7.38-7.41 (m, 1H), 7.41-7.46 (m, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting morpholine for cyclopropylamine. 1H NMR (CD3OD) δ1.67-1.78 (m, 4H), 2.39-2.57 (m, 4H), 3.13-3.24 (m, 2H), 3.32-3.39 (m, 2H), 3.71-3.80 (m, 2H), 4.03 (dd, J=13.3, 3.2 Hz, 2H), 4.08 (s, 2H), 4.34 (s, 2H), 7.37 (d, J=6.7 Hz, 1H), 7.39-7.42 (m, 1H), 7.41-7.44 (m, 1H), 7.44-7.48 (m, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting pyrrolidine for cyclopropylamine. 1H NMR (CD3OD) δ1.67-1.79 (m, 4H), 1.95-2.07 (m, 2H), 2.11-2.24 (m, 2H), 2.44-2.65 (m, 4H), 3.09-3.26 (m, 2H), 3.41-3.54 (m, 2H), 4.15 (s, 2H), 4.35 (s, 2H), 7.32-7.37 (m, 1H), 7.39-7.47 (m, 3H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting cyclohexylamine for cyclopropylamine. 1H NMR (CD3OD) δ1.20-1.27 (m, 1H), 1.31-1.45 (m, 4H), 1.66-1.78 (m, 5H), 1.85-1.93 (m, 2H), 2.12-2.20 (m, 2H), 2.45-2.60 (m, 4H), 3.08 (dd, J=14.6, 7.6 Hz, 1H), 4.11 (s, 2H), 4.19 (s, 2H), 7.32 (d, J=7.0 Hz, 1H), 7.34-7.38 (m, 1H), 7.38-7.42 (m, 1H), 7.41-7.45 (m, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting 2M methylamine in methanol for cyclopropylamine. 1H NMR (CD3OD) δ1.69-1.78 (m, 4H), 2.45-2.59 (m, 4H), 2.70 (s, 3H), 4.13 (s, 2H), 4.16 (s, 2H), 7.30-7.33 (m, 1H), 7.33-7.37 (m, 1H), 7.37-7.40 (m, 1H), 7.43 (t, J=7.4 Hz, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting 2-Methylamine in methanol for cyclopropylamine. 1H NMR (CD3OD) δ1.33 (t, J=7.2 Hz, 3H), 1.66-1.80 (m, 4H), 2.42-2.62 (m, 4H), 3.10 (q, J=7.4 Hz, 2H), 4.13 (s, 2H), 4.16 (s, 2H), 7.31 (d, J=7.1 Hz, 1H), 7.34-7.37 (m, 1H), 7.38-7.40 (m, 1H), 7.41-7.45 (m, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting 4-methylpiperidine for cyclopropylamine. 1H NMR (CD3OD) δ0.99 (d, J=6.4 Hz, 3H), 1.39-1.54 (m, 2H), 1.67-1.76 (m, 5H), 1.83-1.95 (m, 2H), 2.44-2.63 (m, 4H), 2.92-3.04 (m, 2H), 3.35-3.46 (m, 2H), 4.15 (s, 2H), 4.26 (s, 2H), 7.34-7.37 (m, 1H), 7.40-7.44 (m, 2H), 7.44-7.47 (m, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting 3-(trifluoromethyl)phenethylamine for cyclopropylamine. 1H NMR (CD3OD) δ1.64-1.72 (m, 4H), 2.40-2.57 (m, 4H), 3.06-3.14 (m, 2H), 3.27-3.29 (m, 2H), 4.07 (s, 2H), 4.22 (s, 2H), 7.33 (d, J=7.3 Hz, 1H), 7.35-7.38 (m, 1H), 7.38-7.42 (m, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.55 (d, J=0.9 Hz, 1H), 7.55-7.58 (m, 1H), 7.59 (d, J=5.2 Hz, 1H), 7.60-7.62 (m, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting N-methyl cyclohexylamine for cyclopropylamine. 1H NMR (CD3OD) δ1.23-1.40 (m, 3H), 1.53-1.65 (m, 2H), 1.67-1.79 (m, 5H), 1.90-2.00 (m, 2H), 2.02-2.18 (m, 2H), 2.40-2.49 (m, 2H), 2.49-2.58 (m, 2H), 2.71 (s, 3H), 3.16-3.28 (m, 1H), 4.07 (s, 2H), 4.17 (d, J=12.9 Hz, 1H), 4.45 (d, J=13.2 Hz, 1H), 7.34-7.36 (m, 1H), 7.37-7.39 (m, 1H), 7.41 (s, 1H), 7.43-7.49 (m, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13 by substituting 2-ethylpyrrolidine for cyclopropylamine. 1H NMR (CD3OD) δ0.94 (t, J=7.5 Hz, 3H), 1.52-1.63 (m, 1H), 1.69-1.77 (m, 4H), 1.78-1.87 (m, 2H), 1.91-2.04 (m, 1H), 2.05-2.17 (m, 1H), 2.31-2.44 (m, 1H), 2.45-2.64 (m, 4H), 3.19-3.28 (m, 1H), 3.34-3.47 (m, 2H), 4.15 (s, 2H), 4.21 (d, J=12.9 Hz, 1H), 4.50 (d, J=13.2 Hz, 1H), 7.33-7.38 (m, 1H), 7.40-7.44 (m, 2H), 7.44-7.48 (m, 1H).
This example was prepared as described in EXAMPLE 1C by substituting 4-(diethoxymethyl)benzaldehyde for 2-fluoro-5-formylbenzonitrile.
This example was prepared as described in EXAMPLE 2C by substituting EXAMPLE 24A for EXAMPLE 2B.
This example was prepared as described in EXAMPLE 13C by substituting EXAMPLE 24B for EXAMPLE 13B.
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C. 1H NMR (CD3OD) δ0.82-0.88 (m, 2H), 0.89-0.94 (m, 2H), 1.62-1.77 (m, 4H), 2.35-2.44 (m, 2H), 2.45-2.55 (m, 2H), 2.70-2.82 (m, 1H), 4.02 (s, 2H), 4.27 (s, 2H), 7.30 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and 2-propylamine for cyclopropylamine. 1H NMR (CD3OD) δ1.38 (d, J=6.4 Hz, 6H), 1.65-1.72 (m, 4H), 2.37-2.45 (m, 2H), 2.46-2.52 (m, 2H), 3.39-3.50 (m, 1H), 4.01 (s, 2H), 4.17 (s, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and morpholine for cyclopropylamine. 1H NMR (CD3OD) δ1.65-1.76 (m, 4H), 2.43-2.48 (m, 2H), 2.49-2.58 (m, 2H), 3.13-3.24 (m, 2H), 3.33-3.37 (m, 2H), 3.36-3.41 (m, 1H), 3.70-3.80 (m, 2H), 3.99-4.03 (m, 1H), 4.06 (s, 2H), 4.34 (s, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and pyrrolidine for cyclopropylamine. 1H NMR (CD3OD) δ1.63-1.76 (m, 4H), 1.94-2.06 (m, 2H), 2.10-2.24 (m, 2H), 2.37-2.46 (m, 2H), 2.46-2.55 (m, 2H), 3.11-3.23 (m, 2H), 3.38-3.58 (m, 2H), 4.02 (s, 2H), 4.34 (s, 2H), 7.33 (d, J=7.7 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and cyclohexylamine for cyclopropylamine. 1H NMR (CD3OD) δ1.21-1.29 (m, 1H), 1.33-1.43 (m, 4H), 1.64-1.75 (m, 5H), 1.86-1.93 (m, 2H), 2.13-2.21 (m, 2H), 2.37-2.44 (m, 2H), 2.49 (t, J=4.9 Hz, 2H), 3.05-3.16 (m, 1H), 4.01 (s, 2H), 4.18 (s, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and 4-phenylpiperidine for cyclopropylamine. 1H NMR (CD3OD) δ1.64-1.76 (m, 4H), 1.93-2.03 (m, 2H), 2.05-2.15 (m, 2H), 2.40-2.49 (m, 2H), 2.48-2.55 (m, 2H), 2.81-2.94 (m, 1H), 3.10-3.23 (m, 2H), 3.54-3.64 (m, 2H), 4.04 (s, 2H), 4.33 (s, 2H), 7.19-7.22 (m, 1H), 7.24 (d, J=7.1 Hz, 2H), 7.28-7.33 (m, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.51 (d, J=7.7 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and 2M methylamine in methanol for cyclopropylamine. 1H NMR (CD3OD) δ1.64-1.73 (m, 4H), 2.38-2.44 (m, 2H), 2.47-2.54 (m, 2H), 2.71 (s, 3H), 4.02 (s, 2H), 4.15 (s, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and 2-Methylamine in methanol for cyclopropylamine. 1H NMR (CD3OD) δ61.32 (t, J=7.4 Hz, 3H), 1.64-1.72 (m, 4H), 2.37-2.44 (m, 2H), 2.45-2.52 (m, 2H), 3.10 (q, J=7.4 Hz, 2H), 4.01 (s, 2H), 4.15 (s, 2H), 7.30 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and 4-methylpiperidine for cyclopropylamine. 1H NMR (CD3OD) δ0.99 (d, J=6.4 Hz, 3H), 1.33-1.48 (m, 2H), 1.66-1.75 (m, 5H), 1.85-1.95 (m, 2H), 2.40-2.48 (m, 2H), 2.48-2.57 (m, 2H), 2.90-3.05 (m, 2H), 3.44 (d, J=12.3 Hz, 2H), 4.04 (s, 2H), 4.25 (s, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and 3-(trifluoromethyl)phenethylamine for cyclopropylamine. 1H NMR (CD3OD) δ1.62-1.72 (m, 4H), 2.38-2.44 (m, 2H), 2.46-2.52 (m, 2H), 3.06-3.14 (m, 2H), 3.27-3.35 (m, 2H), 4.02 (s, 2H), 4.22 (s, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.53-7.57 (m, 2H), 7.57-7.62 (m, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and N-methylcyclohexylamine for cyclopropylamine. 1H NMR (CD3OD) δ1.20-1.31 (m, 1H), 1.32-1.44 (m, 2H), 1.54-1.63 (m, 2H), 1.65-1.75 (m, 5H), 1.91-2.01 (m, 2H), 2.05-2.18 (m, 2H), 2.39-2.46 (m, 2H), 2.47-2.53 (m, 2H), 2.71 (s, 3H), 3.23-3.29 (m, 1H), 4.03 (s, 2H), 4.13 (d, J=13.2 Hz, 1H), 4.47 (d, J=13.2 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.43-7.46 (m, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and 2-methylpyrrolidine for cyclopropylamine. 1H NMR (CD3OD) δ1.39 (d, J=6.7 Hz, 3H), 1.66-1.78 (m, 5H), 1.93-2.02 (m, 1H), 2.03-2.13 (m, 1H), 2.29-2.38 (m, 1H), 2.39-2.45 (m, 2H), 2.47-2.53 (m, 2H), 3.15-3.27 (m, 1H), 3.34-3.40 (m, 1H), 3.51-3.62 (m, 1H), 4.02 (s, 2H), 4.09-4.17 (m, 1H), 4.43-4.55 (m, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and 1-methylhomopiperazine for cyclopropylamine. 1H NMR (CD3OD) δ1.68-1.79 (m, 4H), 2.29-2.42 (m, 2H), 2.46-2.53 (m, 2H), 2.53-2.62 (m, 2H), 2.97 (s, 3H), 3.35-3.44 (m, 1H), 3.47-3.65 (m, 2H), 3.67-3.96 (m, 5H), 4.11 (s, 2H), 4.46 (s, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 13D by substituting 1-methylhomopiperazine for cyclopropylamine. 1H NMR (CD3OD) δ1.68-1.81 (m, 4H), 2.29-2.41 (m, 2H), 2.44-2.53 (m, 2H), 2.55-2.64 (m, 2H), 2.98 (s, 3H), 3.33-3.40 (m, 1H), 3.40-3.56 (m, 2H), 3.58-3.72 (m, 1H), 3.73-3.97 (m, 4H), 4.15 (s, 2H), 4.46 (s, 2H), 7.37 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.51 (d, J=6.1 Hz, 2H).
This example was prepared as described in EXAMPLE 1C by substituting 3-bromo-4-fluorobenzaldehyde for 2-fluoro-5-formylbenzonitrile.
This example was prepared as described in EXAMPLE 2D by substituting EXAMPLE 38A for EXAMPLE 2B.
To EXAMPLE 38B (75 mg) in N,N-dimethylformamide (8 mL) was added 2-tributylstannylpyrimidine (81 mg), tris(dibenzylidineacetone)dipalladium(0) (20 mg), tri-o-tolylphosphine (20 mg) and triethylamine (92 μL). The mixture was stirred at 70° C. for 17 hours. After cooling, the mixture was filtered, and the filtrate was concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). The product was dissolved in methanol/dichloromethane and treated with 1M hydrochloric acid in diethyl ether and concentrated to provide the title compound as the hydrochloride salt. 1H NMR (CD3OD) δ1.69-1.78 (m, 4H), 2.48-2.60 (m, 4H), 4.11 (s, 2H), 7.27 (dd, J=10.8, 8.5 Hz, 1H), 7.43-7.50 (m, 1H), 7.61 (t, J=5.1 Hz, 1H), 7.87 (dd, J=7.1, 2.4 Hz, 1H), 9.01 (d, J=5.1 Hz, 2H).
To EXAMPLE 38B (75 mg), 3-pyridineboronic acid (54 mg) and dichlorobis(triphenylphosphine)palladium (II) (28 mg) in 7:3:2 1,2-dimethoxyethane/water/ethanol (3 mL) was added 2M sodium carbonate (0.22 mL). The mixture was stirred in a CEM Explorer® microwave reactor (Matthews, N.C.) for 10 minutes at 150° C. After cooling, the mixture was filtered, and the filtrate was concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). The product was dissolved in methanol/dichloromethane and was treated with 1M hydrochloric acid in diethyl ether and concentrated to provide the title compound as the hydrochloride salt. 1H NMR (CD3OD) δ1.70-1.80 (m, 4H), 2.50-2.62 (m, 4H), 4.17 (s, 2H), 7.33 (dd, J=10.7, 8.5 Hz, 1H), 7.40-7.48 (m, 1H), 7.60 (dd, J=7.3, 1.8 Hz, 1H), 8.22 (dd, J=8.2, 5.8 Hz, 1H), 8.87 (d, J=8.2 Hz, 1H), 8.90 (d, J=5.5 Hz, 1H), 9.12 (s, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 39 by substituting 4-pyridine boronic acid for 3-pyridine boronic acid. 1H NMR (CD3OD) δ1.68-1.84 (m, 4H), 2.46-2.64 (m, 4H), 4.15 (s, 2H), 7.35 (dd, J=11.0, 8.5 Hz, 1H), 7.48-7.53 (m, 1H), 7.69 (dd, J=7.2, 2.0 Hz, 1H), 8.32 (d, J=5.8 Hz, 2H), 8.91 (d, J=6.7 Hz, 2H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 39 by substituting (2-(N,N-diethylaminocarbonyl)phenyl)boronic acid for 3-pyridineboronic acid. 1H NMR (CD3OD) δ0.83 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H), 1.72-1.83 (m, 4H), 2.51-2.66 (m, 4H), 2.73-3.01 (m, 2H), 3.02-3.25 (m, 2H), 4.11 (s, 2H), 7.13-7.17 (m, 1H), 7.17-7.19 (m, 1H), 7.26-7.31 (m, 1H), 7.38-7.41 (m, 2H), 7.47-7.50 (m, 1H), 7.51-7.54 (m, 1H).
To 3-(1-piperidinyl)propionic acid (28 mg) in dichloromethane (3 mL) was added oxalyl chloride (24 μL) and a drop of N,N-dimethylformamide. The mixture was stirred at ambient temperature for 1 hour and concentrated. The concentrate was dissolved in dichloromethane (3 mL) and added to a solution of EXAMPLE 2C (50 mg) in tetrahydrofuran (3 mL). Triethylamine (31 μL) was also added. The mixture was stirred at ambient temperature for 16 hours and was concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). The product was dissolved in methanol/dichloromethane and treated with 1M hydrochloric acid in diethyl ether and was concentrated to provide the title compound as the hydrochloride salt. 1H NMR (CD3OD) δ1.50-1.59 (m, 1H), 1.68-1.75 (m, 4H), 1.76-1.87 (m, 3H), 1.92-2.01 (m, 2H), 2.41-2.57 (m, 4H), 2.94-2.98 (m, 2H), 2.98-3.03 (m, 2H), 3.45 (t, J=6.9 Hz, 2H), 3.57 (d, J=12.2 Hz, 2H), 3.99 (s, 2H), 6.99-7.05 (m, 1H), 7.11 (dd, J=10.4, 8.5 Hz, 1H), 7.81 (dd, J=7.3, 1.8 Hz, 1H).
This example was prepared as the hydrochloride salt as described in EXAMPLE 42 by substituting 3-(4-methylpiperazin-1-yl)propionic acid for 3-(1-piperidinyl)propionic acid. 1H NMR (CD3OD) δ 1.65-1.79 (m, 4H), 2.38-2.58 (m, 4H), 3.03 (s, 3H), 3.07 (t, J=6.7 Hz, 2H), 3.60-3.65 (m, 2H), 3.65-3.68 (m, 3H), 3.70-3.89 (m, 4H), 3.97-4.06 (m, 1H), 4.00 (s, 2H), 6.99-7.04 (m, 1H), 7.12 (dd, J=10.7, 8.5 Hz, 1H), 7.83 (dd, J=7.3, 1.8 Hz, 1H).
A solution of EXAMPLE 2 (50 mg) and Boc-L-glycine N-hydroxysuccinimide ester (54 mg) in tetrahydrofuran (4 mL) was stirred at ambient temperature for 16 hours and was concentrated. To this solid in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) and the mixture stirred at ambient temperature for 1 hour and concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid) to provide the title compound as the trifluoroacetate salt. 1H NMR (CD3OD) δ 1.65-1.74 (m, 4H), 2.38-2.55 (m, 4H), 3.89 (s, 2H), 3.96 (s, 2H), 7.00-7.06 (m, 1H), 7.09-7.16 (m, 1H), 7.87 (dd, J=7.4, 2.1 Hz, 1H).
This example was prepared as described in EXAMPLE 42 by substituting cyclohexanepropionic acid for 3-(1-piperidinyl)propionic acid. 1H NMR (CD3OD) δ 0.90-1.00 (m, 2H) 1.16-1.33 (m, 4H) 1.53-1.61 (m, 2H) 1.63-1.68 (m, 1H) 1.70-1.74 (m, 5H) 1.74-1.82 (m, 3H) 2.39-2.46 (m, 4H) 2.48-2.51 (m, 2H) 3.94 (s, 2H) 6.96-7.01 (m, 1H) 7.07 (dd, J=10.7, 8.5 Hz, 1H) 7.69 (dd, J=7.2, 1.7 Hz, 1H).
This example was prepared as the trifluoroacetate salt as described in EXAMPLE 42 by substituting 1-(tert-butoxycarbonyl)-3-piperidine carboxylic acid for 3-(1-piperidinyl)propionic acid. 1H NMR (CD3OD) δ 1.66-1.76 (m, 4H), 1.79-1.87 (m, 1H), 1.89-2.03 (m, 2H), 2.12 (dd, J=9.3, 4.9 Hz, 1H), 2.38-2.56 (m, 4H), 2.96-3.04 (m, 1H), 3.08-3.15 (m, 1H), 3.17-3.25 (m, 2H), 3.33-3.35 (m, 1H), 3.95 (s, 2H), 6.99-7.06 (m, 1H), 7.07-7.15 (m, 1H), 7.71 (dd, J=7.5, 2.0 Hz, 1H).
To a solution of EXAMPLE 2 (200 mg) in dichloromethane (5 mL) was added 4-chlorobutanoylchloride (103 mg) and triethylamine (0.12 mL). The solution was stirred at ambient temperature for 16 hours and was concentrated. The concentrate was dissolved in ethanol (2 mL) and added to a solution of 21 wt % sodium ethoxide in ethanol (0.47 mL). The mixture was stirred at ambient temperature for 16 hours, treated with 2M hydrochloric acid (1 mL) and concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). 1H NMR (CD3OD) δ 1.66-1.77 (m, 4H), 2.15-2.27 (m, 2H), 2.40-2.51 (m, 4H), 2.51-2.58 (m, 2H), 3.78-3.86 (m, 2H), 3.97 (s, 2H), 7.11-7.15 (m, 1H), 7.16-7.19 (m, 1H), 7.22-7.27 (m, 1H).
This example was prepared as the trifluoroacetate salt as described in EXAMPLE 42 by substituting 1-(tert-butoxycarbonyl)-3-azetidine carboxylic acid for 3-(1-piperidinyl)propionic acid. 1H NMR (CD3OD) δ 1.64-1.78 (m, 4H), 2.40-2.49 (m, 2H), 2.47-2.55 (m, 2H), 3.81-3.93 (m, 1H), 3.96 (s, 2H), 4.20-4.33 (m, 4H), 6.99-7.06 (m, 1H), 7.07-7.15 (m, 1H), 7.87 (dd, J=7.3, 2.2 Hz, 1H).
This example was prepared as described in EXAMPLE 1C by substituting methyl-3-formylbenzoate for 2-fluoro-5-formylbenzonitrile.
EXAMPLE 49A (6.09 g) in 1:1 tetrahydrofuran/water (60 mL) at ambient temperature was treated with lithium hydroxide monohydrate (1.8 g) and stirred for 16 hours. The mixture was acidified with 2N hydrochloric acid and partitioned between ethyl acetate and brine. The organic layer was washed with water and concentrated, and the concentrate was purified by flash chromatography on silica gel with ethyl acetate.
This example was prepared as described in EXAMPLE 2C by substituting EXAMPLE 49B for EXAMPLE 2B.
To a solution of EXAMPLE 49C (75 mg) in N,N-dimethylformamide (3 mL) was added N-isopropylethylenediamine (27 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg), 1-hydroxybenzotriazole hydrate (35 mg) and triethylamine (0.11 mL). The mixture was stirred at ambient temperature for 16 hours and was partitioned between brine and water. The organics were washed with brine and concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies. Santa Clara, Calif.], 0-100% acetonitrile/water with 0.10% trifluoroacetic acid) to provide the title compound as the trifluoroacetate salt. 1H NMR (CD3OD) δ 1.34 (d, J=6.7 Hz, 6H), 1.65-1.74 (m, 4H), 2.37-2.44 (m, 2H), 2.47-2.54 (m, 2H), 3.23 (t, J=5.9 Hz, 2H), 3.39-3.47 (m, 1H), 3.67 (t, J=5.9 Hz, 2H), 4.05 (s, 2H), 7.41-7.44 (m, 2H), 7.71-7.74 (m, 2H).
This example was prepared as the trifluoroacetate salt as described in EXAMPLE 41 by substituting morpholin-4-yl-acetic acid for 3-(1-piperidinyl)propionic acid. 1H NMR (CD3OD) δ 1.65-1.73 (m, 4H), 2.38-2.46 (m, 2H), 2.46-2.52 (m, 2H), 3.34-3.52 (m, 4H), 3.90-4.03 (m, 6H), 4.19 (s, 2H), 7.03-7.09 (m, 1H), 7.10-7.17 (m, 1H), 7.85 (dd, J=7.3, 2.1 Hz, 1H).
The title compound was prepared according to procedure for EXAMPLE 1 substituting 3-formylbenzonitrile for 2-fluoro-5-formylbenzonitrile in EXAMPLE 1C. MS (DCI/NH4) m z 285 (M+H)+.
To a solution of EXAMPLE 51A (75 mg, 0.26 mmol) in anhydrous dichloromethane (5 mL) was added 4-(2-aminoethyl)morpholine (68 mg, 0.52 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (271 mg, 0.52 mmol), and N,N′-diisopropylethylamine (0.18 mmol, 1.04 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 hours, and concentrated. The residue was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 397 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.64-1.75 (m, 4H), 2.37-2.45 (m, 2H), 2.45-2.55 (m, 2H), 3.15-3.27 (m, 2H), 3.40 (t, J=5.80 Hz, 2H), 3.63-3.71 (m, 2H), 3.74-3.81 (m, 4H), 4.02-4.13 (m, 4H), 7.42-7.46 (m, 2H), 7.71-7.75 (m, 2H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 1-(2-aminoethyl)pyrrolidine for 4-(2-aminoethyl)morpholine. MS (DCI/NH3) m/z 381 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.65-1.74 (m, 4H), 1.97-2.08 (m, 2H), 2.13-2.22 (m, 2H), 2.39-2.45 (m, 2H), 2.46-2.54 (m, 2H), 3.10-3.20 (m, 2H), 3.42 (t, J=5.80 Hz, 2H), 3.73 (t, J=5.95 Hz, 2H), 3.75-3.82 (m, 2H), 4.05 (s, 2H), 7.42-7.46 (m, 2H), 7.70-7.74 (m, 2H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 2-methylpyrrolidine for 4-(2-aminoethyl)morpholine. MS (DCI/NH3) m/z 352 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 0.86 (d, J=6.41 Hz, 1H), 1.33 (d, J=6.41 Hz, 2H), 1.60-1.67 (m, 2H), 1.70 (d, J=2.75 Hz, 3H), 1.73-1.80 (m, 1H), 1.90-1.99 (m, 1H), 2.11-2.22 (m, 1H), 2.39-2.47 (m, 2H), 2.46-2.56 (m, 2H), 3.43-3.51 (m, 1H), 3.57-3.67 (m, 1H), 4.02 (s, 2H), 4.21-4.28 (m, 1H), 7.24-7.33 (m, 2H), 7.33-7.36 (m, 1H), 7.37-7.42 (m, 1H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 1-aminohomopiperidine for 4-(2-aminoethyl)morpholine. MS (DCI/NH3) m/z 381 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.68-1.74 (m, 4H), 1.73-1.81 (m, 4H), 1.92-2.01 (m, 4H), 2.41-2.46 (m, 2H), 2.48-2.54 (m, 2H), 3.53-3.60 (m, 4H), 4.06 (s, 2H), 7.45-7.50 (m, 2H), 7.70-7.73 (m, 2H).
The title compound was prepared according to procedure for EXAMPLE 51 substituting tert-butyl 1-piperazine carboxylate for 4-(2-aminoethyl)morpholine. MS (DCI/NH3) m/z 453 (M+H)+.
To a solution of EXAMPLE 55A (480 mg, 1.76 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 1 hour, and was concentrated. The residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 353 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.68-1.74 (m, 4H), 2.43-2.48 (m, 2H), 2.48-2.54 (m, 2H), 3.19-3.29 (m, 3H), 3.67-3.97 (m, 5H), 4.04 (s, 2H), 7.30-7.33 (m, 1H), 7.33-7.36 (m, 1H), 7.36-7.39 (m, 1H), 7.44 (t, J=7.48 Hz, 1H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 55 substituting 3-amino-1-N-Boc-azetidine for tert-butyl 1-piperazine carboxylate. MS (DCI/NH3) m/z 339 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.63-1.76 (m, 4H), 2.37-2.45 (m, 2H), 2.46-2.55 (m, 2H), 4.05 (s, 2H), 4.28-4.37 (m, 4H), 4.76-4.82 (m, 1H), 7.41-7.45 (m, 2H), 7.69-7.74 (m, 2H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 55 substituting (+/−)-3-amino-1-N-Boc-piperidine for tert-butyl 1-piperazine carboxylate. MS (DCI/NH3) m/z 367 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.68-1.72 (m, 4H), 1.72-1.77 (m, 1H), 1.80-1.89 (m, 1H), 2.02-2.15 (m, 2H), 2.37-2.46 (m, 2H), 2.47-2.54 (m, 2H), 2.85-3.00 (m, 2H), 3.33-3.39 (m, 1H), 3.52 (dd, J=12.21, 4.27 Hz, 1H), 4.04 (s, 2H), 4.18-4.26 (m, 1H), 7.40-7.43 (m, 2H), 7.66-7.71 (m, 2H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting N,N-dimethyl-1,4-phenylenediamine for 4-(2-aminoethyl)morpholine. MS (DCI/NH3) m/z 403 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.67-1.73 (m, 4H), 2.42-2.48 (m, 2H), 2.47-2.55 (m, 2H), 3.28 (s, 6H), 4.08 (s, 2H), 7.43-7.45 (m, 1H), 7.45-7.49 (m, 1H), 7.55 (d, J=8.85 Hz, 2H), 7.77-7.80 (m, 1H), 7.79-7.82 (m, 1H), 7.89-7.93 (m, 2H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 2-(4-methyl-piperazin-1-yl)-ethylamine for 4-(2-aminoethyl)morpholine. MS (DCI/NH3) m/z 410 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.67-1.73 (m, 4H), 2.41-2.46 (m, 2H), 2.48-2.54 (m, 2H), 2.82 (t, J=6.41 Hz, 2H), 2.87 (s, 3H), 2.89-3.09 (m, 3H), 3.17-3.26 (m, 2H), 3.33-3.41 (m, 1H), 3.57 (t, J=6.26 Hz, 2H), 4.04 (s, 2H), 4.72-4.83 (m, 2H), 7.39-7.44 (m, 2H), 7.63-7.66 (m, 1H), 7.66-7.69 (m, 1H).
A solution of isoxazole-5-carboxylic acid (32 mg, 0.28 mmol) in a mixture of anhydrous N,N-dimethylformamide (2 mL) and pyridine (2 mL) was treated with 1,1′-carbonyldiimidazole (48 mg, 0.30 mmol) at 40° C. for 2 hours. EXAMPLE 55 (50 mg, 0.14 mmol) was added and the reaction mixture was heated at 60° C. for 3 hours. After cooling, the reaction mixture was concentrated on a rotary evaporator and the residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 448 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.65-1.76 (m, 4H), 2.41-2.47 (m, 2H), 2.48-2.56 (m, 2H), 3.51-3.66 (m, 3H), 3.66-3.79 (m, 3H), 3.79-3.94 (m, 2H), 4.04 (s, 2H), 7.27-7.30 (m, 1H), 7.32-7.35 (m, 1H), 7.36-7.39 (m, 1H), 7.43 (t, J=7.48 Hz, 1H), 7.61-7.66 (m, 1H), 7.86-7.91 (m, 1H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 4-phenylpiperidine for 4-(2-aminoethyl)morpholine. MS (DCI/NH3) m/z 428 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.54-1.65 (m, 1H), 1.64-1.71 (m, 4H), 1.72-1.82 (m, 2H), 1.91-1.99 (m, 1H), 2.40-2.45 (m, 2H), 2.49-2.51 (m, 2H), 2.80-2.89 (m, 1H), 2.89-2.98 (m, 1H), 3.15-3.26 (m, 1H), 3.71-3.82 (m, 1H), 4.04 (s, 2H), 4.72-4.81 (m, 1H), 7.16-7.20 (m, 1H), 7.22-7.26 (m, 3H), 7.27-7.30 (m, 2H), 7.30-7.32 (m, 1H), 7.34 (d, J=7.93 Hz, 1H), 7.42 (t, J=7.63 Hz, 1H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 55 substituting tert-butyl 2-(aminomethyl)piperidine-1-carboxylate for tert-butyl 1-piperazine carboxylate. MS (DCI/NH3) m/z 381 (M+H)+; 1H NMR (500 MHz, CD3OD): δ1.46-1.56 (m, 2H), 1.60-1.78 (m, 6H), 1.79-1.93 (m, 2H), 2.38-2.47 (m, 2H), 2.47-2.55 (m, 2H), 3.14 (dd, J=13.27, 4.42 Hz, 2H), 3.46-3.52 (m, 1H), 3.55-3.64 (m, 1H), 4.04 (s, 2H), 4.91-5.05 (m, 1H), 7.27-7.32 (m, 1H), 7.35-7.40 (m, 2H), 7.43 (t, J=7.48 Hz, 1H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 55 substituting 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester for tert-butyl 1-piperazine carboxylate. MS (DCI/NH3) m/z 381 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.40-1.52 (m, 2H), 1.64-1.74 (m, 4H), 1.91-2.03 (m, 3H), 2.37-2.47 (m, 2H), 2.47-2.55 (m, 2H), 2.93-3.02 (m, 2H), 3.32-3.36 (m, 2H), 3.37-3.44 (m, 2H), 4.04 (s, 2H), 7.38-7.43 (m, 2H), 7.65-7.69 (m, 2H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 51 substituting 2-(piperidin-1-yl)ethanamine for 4-(2-aminoethyl)morpholine. MS (DCI/NH3) m/z 395 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.50-1.58 (m, 1H), 1.67-1.73 (m, 4H), 1.76-1.88 (m, 3H), 1.97 (d, J=14.34 Hz, 2H), 2.38-2.47 (m, 2H), 2.46-2.54 (m, 2H), 2.93-3.04 (m, 2H), 3.32-3.37 (m, 2H), 3.68 (d, J=12.21 Hz, 2H), 3.74 (t, J=6.10 Hz, 2H), 4.05 (s, 2H), 7.42-7.45 (m, 2H), 7.70-7.74 (m, 2H).
To a solution of EXAMPLE 56 (25 mg, 0.07 mmol) in methanol (2 mL) was added formaldehyde (37% in water, 16 μL, 0.21 mmol) and triethylamine (10 μL, 0.07 mmol). The mixture was stirred at room temperature for 2 hours before sodium cyanoborohydride (13 mg, 0.21 mmol) and zinc chloride (10 mg) were added. The reaction mixture was stirred at room temperature for 16 hours, and concentrated. The residue was dissolved in 1:1 mixture of acetonitrile and water, and purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 353 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.63-1.74 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.53 (m, 2H), 3.01 (d, J=17.70 Hz, 3H), 4.06 (d, J=10.68 Hz, 2H), 4.21-4.28 (m, 1H), 4.31 (dd, J=11.44, 8.70 Hz, 1H), 4.56-4.66 (m, 2H), 5.51 (s, 1H), 7.41-7.44 (m, 1H), 7.44-7.48 (m, 1H), 7.70-7.78 (m, 2H).
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2-bromo-pyridine-4-carbaldehyde for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 307 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C substituting EXAMPLE 66A for EXAMPLE 2B. MS (DCI/NH3) m/z 321 (M+H)+.
A mixture of EXAMPLE 66B (800 mg, 2.5 mmol), dichloro(1,1′-ferrocenylbis(diphenyl-phosphine))palladium(II) dichloromethane (125 mg, 0.15 mmol) and triethylamine (1 ml) in a mixture of methanol (40 ml) and N,N-dimethylformamide (16 ml) was heated at 110° C. in a pressure vessel under 30 psi of carbon monoxide for 16 hours. After cooling, the solid material was filtered off, and the filtrate was concentrated. The residual solid was washed with methanol, and dried to provide the title compound. MS (DCI/NH3) m/z 300 (M+H)+.
A solution of EXAMPLE 66 (100 mg, 0.33 mmol) in methanol (5 ml) was treated with methylamine (2.0 N in methanol, 2 ml) at 50° C. for 24 hours, and concentrated. The residue was washed with methanol, and dried to provide the title compound. MS (DCI/NH3) m/z 299 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2-methylthio-4-pyrimidine-carboxyaldehyde for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 275 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 68A for EXAMPLE 2B. MS (DCI/NH3) m/z 289 (M+H)+.
To a suspension of EXAMPLE 68 (280 mg, 1 mmol) in methylene chloride (5 mL) was added m-chloroperoxybenzoic acid (256 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 4 hours, and concentrated. The residual solid was separated by flash chromatography on silica gel (80% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 321 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.61-1.89 (m, 4H), 2.37-2.71 (m, 4H), 3.32 (s, 3H), 4.29 (s, 2H), 7.65 (d, J=5.09 Hz, 1H), 8.88 (d, J=5.43 Hz, 1H).
The title compound was isolated as a side product in EXAMPLE 69. MS (ESI) m/z 305 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 3-bromoisonicotinaldehyde for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 306 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 71A for EXAMPLE 2B. MS (DCI/NH3) m/z 321 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 6-bromonicotinaldehyde for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 306 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 72A for EXAMPLE 2B. MS (DCI/NH3) m/z 321 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2-bromonicotinaldehyde for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 306 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 72A for EXAMPLE 2B. MS (DCI/NH3) m/z 321 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 6-bromo-pyridine-2-carbaldehyde for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 300 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 74A for EXAMPLE 2B. MS (DCI/NH3) m/z 321 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 66C, substituting EXAMPLE 74B for EXAMPLE 66B. MS (DCI/NH3) m/z 300 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 67, substituting ethylamine for methylamine. MS (ESI) m/z 313 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 67, substituting isopropyl amine for methyl amine. MS (ESI) m/z 327 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 67, substituting cyclohexanamine for methyl amine. MS (ESI) m/z 367 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.23-1.45 (m, 6H), 1.60-1.64 (m, 4H), 1.65-1.86 (m, 5H), 2.30-2.40 (m, 4H), 4.03 (s, 2H), 7.41 (dd, J=4.92, 1.86 Hz, 1H), 7.86 (s, 1H), 8.41 (d, J=8.82 Hz, 1H), 8.53 (d, J=5.09 Hz, 1H), 12.64 (s, 1H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 65, substituting EXAMPLE 62 for EXAMPLE 56. MS (DCI/NH3) m/z 409 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.47-1.57 (m, 1H), 1.58-1.67 (m, 1H), 1.67-1.77 (m, 6H), 1.77-1.87 (m, 1H), 1.85-1.95 (m, 1H), 2.43-2.51 (m, 2H), 2.53-2.63 (m, 2H), 2.99 (s, 3H), 3.08 (s, 3H), 3.26 (dd, J=13.73, 3.36 Hz, 2H), 3.51-3.61 (m, 1H), 3.95 (dd, J=13.27, 11.44 Hz, 1H), 4.13 (s, 2H), 5.11-5.24 (m, 1H), 7.35-7.40 (m, 2H), 7.41-7.47 (m, 2H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 65, substituting EXAMPLE 63 for EXAMPLE 56. MS (DCI/NH3) m/z 395 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.49-1.61 (m, 2H), 1.69-1.78 (m, 4H), 1.90-1.98 (m, 1H), 1.97-2.08 (m, 2H), 2.43-2.53 (m, 2H), 2.54-2.65 (m, 2H), 2.85 (s, 3H), 2.95-3.04 (m, 2H), 3.32-3.38 (m, 2H), 3.53 (dd, J=10.53, 1.98 Hz, 2H), 4.15 (s, 2H), 7.39-7.41 (m, 1H), 7.43 (t, J=7.63 Hz, 1H), 7.68 (s, 1H), 7.70-7.73 (m, 1H).
The title compound was prepared according to procedure for EXAMPLE 67, substituting EXAMPLE 74 for EXAMPLE 66. MS (ESI) m/z 299 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.61-1.81 (m, 4H), 2.38-2.61 (m, 4H), 2.95 (s, 3H), 4.22 (s, 2H), 7.41 (dd, J=7.46, 1.36 Hz, 1H), 7.88 (t, J=7.63 Hz, 1H), 7.91-7.98 (m, 1H).
The title compound was prepared according to procedure for EXAMPLE 67, substituting EXAMPLE 74 for EXAMPLE 66, and ethylamine for methylamine. MS (ESI) m/z 313 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 67, substituting EXAMPLE 74 for EXAMPLE 66, and isopropylamine for methylamine. MS (ESI) m/z 327 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 67, substituting EXAMPLE 74 for EXAMPLE 66, and cyclopropylamine for methylamine. MS (ESI) m/z 325 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 67, substituting EXAMPLE 74 for EXAMPLE 66, and cyclohexylamine for methylamine. MS (ESI) m/z 367 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 66C, substituting EXAMPLE 73B for EXAMPLE 66B. MS (DCI/NH3) m/z 300 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 66C, substituting EXAMPLE 72B for EXAMPLE 66B. MS (DCI/NH3) m/z 300 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 1C, substituting 5-bromothiophene-2-carbaldehyde for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 312 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 87A for EXAMPLE 2B. MS (DCI/NH3) m/z 326 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 1C, substituting 3-bromothiophene-2-carbaldehyde for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 312 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C substituting EXAMPLE 88A for EXAMPLE 2B. MS (DCI/NH3) m/z 326 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2, substituting 3-nitrobenzaldehyde for 4-fluoro-3-nitrobenzaldehyde in EXAMPLE 2A. MS (DCI/NH3) m/z 256 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.62-1.75 (m, 4H), 2.37-2.44 (m, 2H), 2.46-2.54 (m, 2H), 3.86 (s, 2H), 6.46-6.54 (m, 2H), 6.57 (dd, J=7.93, 1.98 Hz, 1H), 7.01 (t, J=7.73 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 2C. substituting 3-bromobenzaldehyde for 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 256 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.64-1.77 (m, 4H), 2.37-2.46 (m, 2H), 2.47-2.55 (m, 2H), 3.96 (s, 2H), 7.13-7.18 (m, 1H), 7.18-7.24 (m, 1H), 7.35-7.40 (m, 2H).
A mixture of EXAMPLE 87 (100 mg, 0.31 mmol) and acetamide (1 g) was stirred at 180° C. overnight. After cooling, the mixture was dissolved in methanol, and separated by HPLC (Zorbax® C-8 packing material [Agilent Technologies, Santa Clara, Calif.]0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound. MS (DCI/NH3) m/z 247 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 66C, substituting EXAMPLE 87 for EXAMPLE 66B. MS (DCI/NH3) m/z 305 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 67, substituting EXAMPLE 86 for 66. MS (ESI) m/z 299 (M+H)+, 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.51-1.73 (m, 4H), 2.40 (d, J=14.92 Hz, 4H), 2.81 (d, J=5.09 Hz, 3H), 4.02 (s, 2H), 7.75 (dd, J=7.97, 2.20 Hz, 1H), 7.96 (d, J=8.14 Hz, 1H), 8.49 (d, 11.70 Hz, 1H), 8.70 (d, J=4.75 Hz, 1H), 12.60 (s, 1H).
The title compound was prepared according to procedure for EXAMPLE 67, substituting EXAMPLE 86 for EXAMPLE 66, and ethylamine for methylamine. MS (ESI) m/z 313 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 67, substituting EXAMPLE 85 for 66. MS (ESI) m/z 299 (M+H)+, 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 1.53-1.79 (m, 4H), 2.29-2.44 (m, 4H), 2.73 (d, J=5.16 Hz, 3H), 4.35 (s, 2H), 7.50 (dd, J=7.73, 4.56 Hz, 1H), 7.66 (dd, J=7.93, 1.59 Hz, 1H), 8.49 (dd, J=4.36, 1.59 Hz, 1H), 8.65 (d, J=5.16 Hz, 1H), 12.35 (s, 1H).
The title compound was prepared according to procedure for EXAMPLE 67, substituting EXAMPLE 85 for EXAMPLE 66, and ethylamine for methylamine. MS (ESI) m/z 313 (M+H)+.
To a solution of EXAMPLE 89 (50 mg, 02 mmol) in dichloromethane (4 mL) was added dimethylsulfamoyl chloride (31 mg, 0.22 mmol) and pyridine (17 mL, 0.22 mol). The solution was stirred at room temperature for 16 hours, and was concentrated. The residue was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 363 (M+H)+; 1H NMR (400 MHz, CD3OD): δ 1.64-1.76 (m, 4H), 2.37-2.46 (m, 2H), 2.47-2.54 (m, 2H), 2.72 (s, 6H), 3.95 (s, 2H), 6.91-6.96 (m, 1H), 7.02-7.06 (m, 2H), 7.19-7.24 (m, 1H).
To a solution of 3-(piperidin-1-yl)propanoic acid (31 mg) in anhydrous dichloromethane (2 mL) was added oxalyl chloride (25.7 μL) and a drop of N,N-dimethylformamide. The solution was stirred for 1 hour, and was concentrated. The residue was re-dissolved in anhydrous dichloromethane (2 mL), and was quickly added to a solution of EXAMPLE 89 (50 mg) in anhydrous tetrahydrofuran (2 mL). Triethylamine (32.8 μL) was added, and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residual solid was separated on HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 395 (M+H)+; 1H NMR (400 MHz, CD3OD): δ 1.48-1.60 (m, 1H), 1.65-1.71 (m, 4H), 1.73-1.87 (m, 3H), 1.92-2.01 (m, 2H), 2.38-2.45 (m, 2H), 2.46-2.53 (m, 2H), 2.87 (t, J=6.60 Hz, 2H), 2.93-3.03 (m, 2H), 3.44 (t, J=6.75 Hz, 2H), 3.57 (d, J=12.58 Hz, 2H), 3.97 (s, 2H), 6.95-7.00 (m, 1H), 7.26 (t, J=7.83 Hz, 1H), 7.36-7.39 (m, 1H), 7.41-7.48 (m, 1H).
A solution of EXAMPLE 89 (150 mg, 0.59 mmol) and 4-chlorobutanoyl chloride (83 mg, 0.59 mmol) in dichloromethane (5 mL) was stirred at room temperature for 16 hours, and was concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated to provide the title compound. MS (DCI/NH3) m/z 360 (M+H)+; 1H NMR (400 MHz, CD3OD): δ 1.66-1.73 (m, 4H), 2.07-2.15 (m, 2H), 2.40-2.46 (m, 2H), 2.48-2.51 (m, 2H), 2.50-2.56 (m, 2H), 3.63 (t, J=6.44 Hz, 2H), 3.96 (s, 2H), 6.93 (d, J=7.67 Hz, 1H), 7.21-7.26 (m, 1H), 7.36 (s, 1H), 7.38-7.46 (m, 1H).
A suspension of EXAMPLE 90 (150 mg, 0.47 mmol), pyrrolidine-2-one (80 mg, 0.94 mmol), tris(dibenzylideneacetone)dipalladium(0) (43 mg, 0.05 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (41 mg, 0.07 mmol) and cesium carbonate (214 mg, 0.66 mmol) in anhydrous dioxane (2 mL) was heated in a CEM Explorer® microwave reactor (Matthews, N.C.) at 200° C. for 30 minutes. After cooling, the reaction mixture was concentrated. The residue was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies. Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 324 (M+H)+; 1H NMR (400 MHz, CD3OD): δ 1.65-1.75 (m, 4H), 2.11-2.23 (m, 2H), 2.41-2.47 (m, 2H), 2.48-2.53 (m, 2H), 2.57 (t, J=7.98 Hz, 2H), 3.83-3.92 (m, 2H), 3.99 (s, 2H), 7.01 (d, J=7.67 Hz, 1H), 7.31 (t, J=7.98 Hz, 1H), 7.38-7.42 (m, 1H), 7.51 (t, J=1.69 Hz, 1H).
A microwave tube was charged with tris(dibenzylideneacetone)dipalladium(0) (5.4 mg, 0.006 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (5.4 mg, 0.01 mmol), EXAMPLE 103 (50 mg, 0.16 mmol), azetidin-2-one (53 mg, 0.62 mmol) and Cs2CO3 (70 mg, 0.21 mmol). Anhydrous dioxane was added, and the suspension was heated in a CEM Explorer® microwave reactor (Matthews, N.C.) at 200° C. for 30 minutes. After concentration, the residue was partitioned between ethyl acetate and brine. The organic phase was concentrated. The residual solid was separated by flash chromatography on silica gel (100% ethyl acetate) to provide the title compound. MS (DCI/NH3) m/z 311 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 101, substituting pyrroline-2-one for azetidin-2-one. MS (ESI) m/z 339 (M+H)+.
The title compound was prepared as described in EXAMPLE 66B. MS (DCI/NH3) m/z 321 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 72 for EXAMPLE 103, and pyrroline-2-one for azetidin-2-one. MS (ESI) m/z 325 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 72 for EXAMPLE 103. MS (ESI) m/z 311 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 72 for EXAMPLE 103, and benzamide for azetidin-2-one. MS (ESI) m/z 361 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.48-1.70 (m, 4H), 2.41 (d, J=17.29 Hz, 4H), 3.92 (s, 2H), 7.86 (t, J=1.86 Hz, 3H), 7.86-7.90 (m, 2H), 7.99-8.06 (m, 1H), 8.12 (d, J=8.48 Hz, 1H), 8.24 (d, J=2.37 Hz, 1H), 10.72 (s, 1H) 12.60 (s, 1H).
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 72 for EXAMPLE 103, and isonicotinamide for azetidin-2-one. MS (ESI) m/z 362 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.65 (d, J=5.09 Hz, 4H), 2.41 (d, J=16.28 Hz, 4H), 3.93 (s, 2H), 7.68 (dd, J=8.48, 2.37 Hz, 1H), 7.90-8.00 (m, 2H), 8.11 (d, J=8.48 Hz, 1H), 8.27 (d, J=2.03 Hz, 1H), 8.76-8.82 (m, 2H), 11.12 (s, 1H), 12.60 (s, 1H).
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 72 for EXAMPLE 103, and nicotinamide for azetidin-2-one. MS (ESI) m/z 362 (M+H)+.
The title compound was a side-product of EXAMPLE 108. MS (ESI) m/z 481 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 67, substituting EXAMPLE 92 for 66. MS (ESI) m/z 304 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.63 (d, J=3.05 Hz, 4H), 2.29-2.46 (m, 4H), 2.72 (d, J=—4.41 Hz, 3H), 4.09 (s, 2H), 6.88 (d, J=3.73 Hz, 1H), 7.51 (d, J=3.73 Hz, 1H), 8.31 (d, J=4.41 Hz, I H), 12.66 (s, 1H).
A solution of EXAMPLE 89 (50 mg, 0.2 mmol) and 2,5-dioxopyrrolidin-1-yl 2-(tert-butoxycarbonylamino)acetate 59 mg, 0.22 mmol) in anhydrous tetrahydrofuran (4 mL) was stirred at room temperature for 16 hours, and concentrated. The residual solid was dissolved in dichloromethane (4 mL) and treated with trifluoroacetic acid (2 mL) at room temperature for 1 hour. The reaction mixture was concentrated and the residue was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 313 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.64-1.75 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.54 (m, 2H), 3.80 (s, 2H), 3.98 (s, 2H), 7.00 (d, J=7.80 Hz, 1H), 7.28 (t, J=7.97 Hz, 1H), 7.37-7.40 (m, 1H), 7.42-7.47 (m, 1H).
The title compound was prepared according to procedure for EXAMPLE 98, substituting 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid for 3-(piperidin-1-yl)propanoic acid. MS (DCI/NH3) m/z 439 (M+H)+.
A solution of EXAMPLE 112A (64 mg) in dichloromethane (4 mL) was treated with trifluoroacetic acid (2 mL) at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 339 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.64-1.73 (m, 4H), 2.36-2.44 (m, 2H), 2.46-2.53 (m, 2H), 2.57-2.69 (m, 1H), 2.81-2.93 (m, 1H), 3.94-4.04 (m, 1H), 3.98 (s, 2H), 4.08-4.20 (m, 1H), 5.07 (dd, J=9.49, 7.80 Hz, 1H), 7.03 (d, J=8.14 Hz, 1H), 7.30 (t, J=7.80 Hz, 1H), 7.41 (t, —1.70 Hz, 1H), 7.49 (dd, J=7.97, 1.53 Hz, 1H).
The title compound was prepared according to procedure for EXAMPLE 112, substituting 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid for 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid. MS (DCI/NH3) m/z 339 (M+H)+; 1H NMR (300 MHz, CD3OD): δ1.62-1.75 (m, 4H), 2.36-2.44 (m, 2H), 2.46-2.54 (m, 2H), 3.69-3.83 (m, 1H), 3.97 (s, 2H), 4.17-4.33 (m, 4H), 7.00 (dd, J=7.14, 1.19 Hz, 1H), 7.27 (t, J=7.93 Hz, 1H), 7.40 (t, J=1.59 Hz, 1H), 7.45-7.51 (m, 1H).
The title compound was prepared according to the procedure for EXAMPLE 97, substituting methanesulfonyl chloride for dimethylsulfamoyl chloride. MS (DCI/NH3) m/z 334 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.53-1.67 (m, 4H), 2.29-2.42 (m, 4H), 2.95 (s, 3H), 3.88 (s, 2H), 6.92 (d, J=7.63 Hz, 1H), 7.00 (s, 1H), 7.06 (dd, J=7.93, 1.22 Hz, 1H), 7.26 (t, J=7.78 Hz, 1H), 9.68 (br s, 1H), 12.63 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 97, substituting propane-2-sulfonyl chloride for dimethylsulfamoyl chloride. MS (DCI/NH3) m/z 362 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.19 (d, J=7.02 Hz, 6H), 1.53-1.66 (m, 4H), 2.25-2.33 (m, 2H), 2.34-2.41 (m, 2H), 3.08-3.22 (m, 1H), 3.87 (s, 2H), 6.88-6.91 (m, 1H), 7.01 (s, 1H), 7.08 (dd, J=8.24, 1.22 Hz, 1H), 7.23 (t, J=7.78 Hz, 1H), 9.68 (br s, 1H), 12.64 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 97, substituting benzenesulfonyl chloride for dimethylsulfamoyl chloride. MS (DCI/NH3) m/z 396 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.48-1.60 (m, 4H), 2.10-2.21 (m, 2H), 2.29-2.39 (m, 2H), 3.78 (s, 2H), 6.83-6.87 (m, 2H), 6.92 (dd, J=8.09, 1.37 Hz, 1H), 7.15 (t, J=7.78 Hz, 1H), 7.48 (t, J=7.78 Hz, 2H), 7.58 (t, J=7.48 Hz, 1H), 7.64-7.69 (m, 2H), 10.24 (br s, 1H), 12.64 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 97, substituting pyridine-3-sulfonyl chloride hydrochloride for dimethylsulfamoyl chloride. MS (DCI/NH3) m/z 397 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.50-1.61 (m, 4H), 2.12-2.21 (m, 2H), 2.33-2.40 (m, 2H), 3.80 (s, 2H), 6.85 (s, 1H), 6.92 (d, J=7.63 Hz, 1H), 6.96 (dd, J=7.93, 1.22 Hz, 1H), 7.19 (t, J=7.78 Hz, 1H), 7.55 (dd, J=8.09, 4.73 Hz, 1H), 8.02-8.06 (m, 1H), 8.75 (dd, J=4.88, 1.53 Hz, 1H), 8.77 (d, J=1.83 Hz, 1H), 10.43 (br s, 1H), 12.63 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 97, substituting furan-2-sulfonyl chloride for dimethylsulfamoyl chloride. MS (DCI/NH3) m/z 386 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.52-1.63 (m, 4H), 2.19-2.28 (m, 2H), 2.32-2.40 (m, 2H), 3.82 (s, 2H), 6.57 (dd, J=3.66, 1.83 Hz, 1H), 6.89 (d, J=1.53 Hz, 1H), 6.91 (d, J=7.63 Hz, 1H), 6.95-6.99 (m, 1H), 7.04 (d, J=3.36 Hz, 1H), 7.20 (t, J=7.78 Hz, 1H), 7.90 (dd, J=1.83, 0.92 Hz, 1H), 10.60 (br s, 1H), 12.65 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 97, substituting 1-methyl-1H-imidazole-4-sulfonyl chloride for dimethylsulfamoyl chloride. MS (DCI/CH3) m/z 400 (M+H)+. 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.55-1.61 (m, 4H), 2.24-2.32 (m, 2H), 2.32-2.40 (m, 2H), 3.63 (s, 3H), 3.80 (s, 2H), 6.80 (d, J=7.93 Hz, 1H), 6.92 (s, 1H), 6.99 (dd, J=8.09, 1.37 Hz, 1H), 7.13 (t, J=7.78 Hz, 1H), 7.70 (d, J=1.22 Hz, 1H), 7.73 (d, J=1.22 Hz, 1H), 10.15 (br s, 1H), 12.64 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 97, substituting thiophene-2-sulfonyl chloride for dimethylsulfamoyl chloride. MS (DCI/NH3) m/z 402 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.41-1.64 (m, 4H), 2.18-2.24 (m, 2H), 2.34-2.40 (m, 2H), 3.82 (s, 2H), 6.90-6.94 (m, 2H), 6.97 (d, J=7.93 Hz, 1H), 7.06 (dd, J=5.03, 3.81 Hz, 1H), 7.17-7.24 (m, 1H), 7.45 (dd, J=3.81, 1.37 Hz, 1H), 7.85 (dd, J=5.03, 1.37 Hz, 1H), 10.36 (br s, 1H), 12.65 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 97, substituting 4-cyanobenzene-1-sulfonyl chloride for dimethylsulfamoyl chloride. MS (DCI/NH3) m/z 421 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.49-1.62 (m, 4H), 2.14-2.20 (m, 2H), 2.31-2.39 (m, 2H), 3.80 (s, 2H), 6.84 (s, 1H), 6.90 (d, J=7.63 Hz, 1H), 6.94 (dd, J=7.93, 1.22 Hz, 1H), 7.19 (t, J=7.93 Hz, 1H), 7.83 (d, J=8.85 Hz, 2H), 8.00 (d, J=8.54 Hz, 2H), 10.52 (br s, 1H), 12.65 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 97, substituting naphthalene-1-sulfonyl chloride for dimethylsulfamoyl chloride. MS (DCI/NH3) m/z 421 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d): δ 1.41-1.47 (m, 2H), 1.47-1.56 (m, 2H), 2.00-2.10 (m, 2H), 2.30-2.39 (m, 2H), 3.71 (s, 2H), 6.75-6.80 (m, 2H), 6.83-6.89 (m, 1H), 7.07 (t, J=7.78 Hz, 1H), 7.50-7.56 (m, 1H), 7.64 (t, J=7.02 Hz, 1H), 7.67-7.72 (m, 1H), 8.04 (d, J=7.63 Hz, 1H), 8.06-8.10 (m, 1H), 8.18 (d, J=8.24 Hz, 1H), 8.67 (d, J=8.54 Hz, 1H), 10.65 (br s, 1H), 12.64 (br s, 1H).
The title compound was prepared as described in EXAMPLE 74B. MS (DCI/NH3) m/z 321 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 123 for EXAMPLE 103, and pyrroline-2-one for azetidin-2-one. MS (ESI) m/z 325 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 123 for EXAMPLE 103, and benzylamide for azetidin-2-one. MS (ESI) m/z 361 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d): δ 1.63 (m, 4H), 2.40 (m, 4H), 4.02 (s, 2H), 6.95 (d, J=7.46 Hz, 1H), 7.38-7.54 (m, 2H), 7.50-7.62 (m, 1H), 7.67-7.84 (m, 1H), 7.90-8.12 (m, 3H), 10.69 (s, 1H), 12.61 (s, 1H).
A suspension of EXAMPLE 90 (500 mg, 1.57 mmol), 3-formylphenylboronic acid (352 mg, 2.35 mmol), dichlorobis(triphenylphosphine)palladium(II) (112 mg, 0.16 mmol) and sodium carbonate (2M solution, 3.13 mmol, 1.6 mL) in a 7/3/3 mixture of 1,2-dimethoxyethane/water/ethanol (23 mL) was purged with nitrogen, and heated at 70° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator. The crude solid was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound. MS (DCI/NH3) m/z 345 (M+H)+.
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 65, substituting EXAMPLE 127A for formaldehyde, and propan-2-amine for EXAMPLE 56. MS (DCI/NH3) m/z 388 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.41 (d, J=6.71 Hz, 6H), 1.64-1.76 (m, 4H), 2.43-2.48 (m, 2H), 2.48-2.53 (m, 2H), 3.42-3.52 (m, 1H), 4.06 (s, 2H), 4.27 (s, 2H), 7.22 (d, J=7.93 Hz, 1H), 7.41 (t, J=7.63 Hz, 1H), 7.45-7.50 (m, 2H), 7.51-7.56 (m, 2H), 7.64-7.69 (m, 1H), 7.71-7.74 (m, 1H).
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 65, substituting EXAMPLE 127A for formaldehyde, and cyclopentanamine for EXAMPLE 56. MS (DCI/NH3) m/z 414 (M+H)+.
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 65, substituting EXAMPLE 127A for formaldehyde and 2-methylpyrrolidine for EXAMPLE 56. MS (DCI/NH3) m/z 414 (M+H)+.
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 65, substituting EXAMPLE 127A for formaldehyde, and cyclopropanamine for EXAMPLE 56. MS (DCI/NH3) m/z 386 (M+H)+.
The title compound was prepared as a trifluoroacetic acid salt according to procedure for EXAMPLE 65, substituting EXAMPLE 127A for formaldehyde, and cyclobutanamine for EXAMPLE 56. MS (DCI/NH3) m/z 400 (M+H)+.
A solution of EXAMPLE 103 (100 mg, 0.31 mmol) in dichloromethane (15 ml) was treated with meta-chloroperoxybenzoic acid (100 mg, 0.58 mmol) at room temperature overnight, and concentrated. The residue was dissolved in methanol, and separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid, CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 336 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 132, substituting EXAMPLE 102 for EXAMPLE 103. MS (ESI) m/z 341 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 5-bromothiophene-2-carbaldehyde for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH4) m/z 312 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C substituting EXAMPLE 134A for EXAMPLE 2B. MS (DCI/NH3) m/z 326 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 66, substituting EXAMPLE 134B for EXAMPLE 66B. MS (DCI/NH3) m/z 305 (M+H)+.
To a solution of 2-(2-(-t-Boc-aminoethoxy)ethoxy)ethyl bromide (Toronto, 137 mg, 0.44 mmol) in N,N-dimethylformamide (4 mL) was added EXAMPLE 5 (84 mg, 0.22 mmol) and potassium carbonate (91 mg, 0.66 mmol). The reaction mixture was heated at 35° C. overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The residue was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 250×2.54 column, mobile phase A: 0.1% trifluoroacetic acid in H2O: B: 0.1% trifluoroacetic acid in CH3CN; 0-100% gradient) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 612 (M+H)+.
To a suspension of EXAMPLE 135A (43 mg, 0.06 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The solution remained at room temperature for 1 hour, and was concentrated. The residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 250×2.54 column, mobile phase A: 0.1% trifluoroacetic acid in H2O; B: 0.1% trifluoroacetic acid in CH3CN; 0-100% gradient) to provide the title compound as a trifluoroacetic acid salt. The trifluoroacetic acid salt was dissolved in a mixture of methylene chloride and methanol, and was treated with 1M solution of HCl in ether. Removal of the volatiles afforded the title compound as a HCl salt. MS (DCI/NH3) m/z 338 (M+H)+.
A solution of EXAMPLE 89 (20 mg, 0.08 mmol), 1-methylcyclopropanecarboxylic acid (10 mg, 0.096 mmol), HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium) (38 mg, 0.1 mmol) and triethylamine (20 mg, 0.2 mmol) in dimethylacetamide (2.5 mL) was stirred at room temperature for 18 hours, and concentrated. The residue was dissolved in a 1:1 mixture of dimethylsulfoxide/methanol, and separated by HPLC (Waters Sunfire® C-8 analytical column [Milford, Mass.], 0.1% trifluoroacetic acid/water/CH3CN) to provide the title compound. MS (DCI/NH3) m/z 338 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 0.57-0.69 (m, 2H), 1.02-1.10 (m, 2H), 1.38 (s, 3H), 1.57-1.65 (m, 4H), 2.29-2.44 (m, 4H), 3.87 (s, 2H), 6.89 (d, J=7.63 Hz, 1H), 7.23 (t, J=7.93 Hz, 1H), 7.42 (s, 1H), 7.46 (d, J=8.24 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-methylcyclopropanecarboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 338 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3-ethoxypropanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 356 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1H NMR (500 MHz, Solvent) δ 1.08 (t, J=7.02 Hz, 3H), 1.54-1.64 (m, 4H), 2.32-2.42 (m, 4H), 2.51 (t, J=6.26 Hz, 2H), 3.43 (q, J=7.02 Hz, 2H), 3.64 (t, J=6.26 Hz, 2H), 3.88 (s, 2H), 6.90 (d, J=7.63 Hz, 1H), 7.24 (t, 7.78 Hz, 1H), 7.36 (s, 1H), 7.48 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting (S)-5-oxopyrrolidine-2-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 367 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1H NMR (500 MHz, Solvent) δ 1.56-1.66 (m, 4H), 1.93-2.03 (m, 1H), 2.14-2.27 (m, 2H), 2.32-2.43 (m, 5H), 3.96 (s, 2H), 4.19 (dd, J=8.70, 4.42 Hz, 1H), 6.94 (d, J=7.63 Hz, 1H), 7.27 (t, J=7.93 Hz, 1H), 7.40 (s, 1H), 7.49 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting (R)-5-oxopyrrolidine-2-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 367 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56-1.66 (m, 4H), 1.93-2.02 (m, 1H), 2.13-2.25 (m, 2H), 2.32-2.42 (m, 5H), 3.89 (s, 2H), 4.18 (dd, J=8.70, 4.42 Hz, 1H), 6.94 (d, J=7.63 Hz, 1H), 7.27 (t, J=7.93 Hz, 1H), 7.39 (s, 1H), 7.49 (d, J=8.24 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 1-carbamoylcyclopropanecarboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 367 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.35-1.44 (m, 4H), 1.55-1.67 (m, 4H), 2.31-2.44 (m, 4H), 3.88 (s, 2H), 6.91 (d, J=7.63 Hz, 1H), 7.26 (t, J=7.78 Hz, 1H), 7.40 (s, 1H), 7.43 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-(benzyloxy)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 404 (M+H)+. 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56-1.64 (m, 4H), 2.32-2.42 (m, 4H), 3.89 (s, 2H), 4.06 (s, 2H), 4.60 (s, 2H), 6.93 (d, J=7.63 Hz, 1H), 7.26 (t, J=7.78 Hz, 1H), 7.31-7.34 (m, 1H), 7.36-7.42 (m, 5H), 7.50 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3-phenylpropanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 388 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.55-1.65 (m, 4H), 2.32-2.42 (m, 4H), 2.60 (t, J=7.63 Hz, 2H), 2.89 (t, J=7.63 Hz, 2H), 3.87 (s, 2H), 6.89 (d, J=7.63 Hz, 1H), 7.18 (t, J=7.17 Hz, 1H), 7.21-7.26 (m, 3H), 7.28 (t, J=7.48 Hz, 2H), 7.32 (s, 1H), 7.45 (d, J=8.24 Hz, 1H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting 3-(2,5-dimethoxyphenyl)propanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 448 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 1-phenylcyclopropanecarboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 400 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting (S)-2-phenylbutanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 402 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 4-phenylbutanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 402 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-(m-tolyloxy)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 404 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-(o-tolyloxy)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 404 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 2-(p-tolyloxy)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 404 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56-1.65 (m, 4H), 2.23 (s, 3H), 2.33-2.44 (m, 4H), 3.89 (s, 2H), 4.61 (s, 2H), 6.88 (d, J=8.54 Hz, 2H), 6.94 (d, J=7.63 Hz, 1H), 7.11 (d, J=8.24 Hz, 2H), 7.27 (t, J=7.78 Hz, 1H), 7.41 (s, 1H), 7.50 (d, J=8.24 Hz, 1H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting (R)-2-methoxy-2-phenylacetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 404 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.53-1.66 (m, 4H), 2.29-2.44 (m, 4H), 3.35 (s, 3H), 3.87 (s, 2H), 4.81 (s, 1H), 6.91 (d, J=7.63 Hz, 1H), 7.25 (t, J=7.93 Hz, 1H), 7.33-7.36 (m, 1H), 7.39 (t, J=7.17 Hz, 2H), 7.45-7.49 (m, 3H), 7.52 (d, J=8.24 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting (S)-2-methoxy-2-phenylacetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 404 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.53-1.66 (m, 4H), 2.30-2.42 (m, 4H), 3.34 (s, 3H), 3.87 (s, 2H), 4.81 (s, 1H), 6.91 (d, J=7.63 Hz, 1H), 7.25 (t, J=7.93 Hz, 1H), 7.32-7.36 (m, 1H), 7.39 (t, J=7.17 Hz, 2H), 7.44-7.49 (m, 3H), 7.51 (d, J=8.24 Hz, 1H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting 3-phenoxypropanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 404 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 4-(thiophen-2-yl)butanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m z 408 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 1-acetylpiperidine-4-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 409 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.36-1.46 (m, 1H), 1.52-1.67 (m, 5H), 1.79 (t, J=14.19 Hz, 2H), 2.02 (s, 3H), 2.30-2.43 (m, 4H), 2.56-2.63 (m, 1H), 3.06 (t, J=12.97 Hz, 1H), 3.85-3.90 (m, 2H), 3.97 (s, 2H), 4.39 (d, J=13.43 Hz, 1H), 6.89 (d, J=7.63 Hz, 1H), 7.24 (t, J=7.78 Hz, 1H), 7.38 (s, 1H), 7.48 (d, J=8.24 Hz, 1H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting 2-(3,5-difluorophenyl)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 410 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.53-1.67 (m, 4H), 2.31-2.42 (m, 4H), 3.67 (s, 2H), 3.88 (s, 2H), 6.91 (d, J=7.63 Hz, 1H), 7.04 (d, J=6.41 Hz, 1H), 7.07-7.13 (m, 1H), 7.25 (t, J=7.93 Hz, 1H), 7.36 (s, 1H), 7.46 (d, J=8.24 Hz, 1H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting (S)-2-acetamido-4-methylpentanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 411 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 0.88 (d, J=6.71 Hz, 3H), 0.90 (d, J=6.71 Hz, 3H), 1.43-1.53 (m, 2H), 1.56-1.66 (m, 5H), 1.87 (s, 3H), 2.29-2.43 (m, 4H), 3.88 (s, 2H), 4.39 (dd, J=9.61, 5.34 Hz, 1H), 6.91 (d, J=7.63 Hz, 1H), 7.25 (t, J=7.78 Hz, 1H), 7.38 (s, 1H), 7.49 (d, J=8.24 Hz, 1H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting (S)-2-(dipropylamino)propanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 411 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 4-oxo-4-phenylbutanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 411 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.55-1.66 (m, 4H), 2.31-2.42 (m, 4H), 2.70 (t, J=6.26 Hz, 2H), 3.32 (t, J=6.26 Hz, 2H), 3.87 (s, 2H), 6.88 (d, J=7.63 Hz, 1H), 7.23 (t, J=7.93 Hz, 1H), 7.37 (s, 1H), 7.45 (d, J=8.24 Hz, 1H), 7.55 (t, J=7.63 Hz, 2H), 7.66 (t, J=7.32 Hz, 1H), 7.99 (t, J=6.41 Hz, 2H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting 2-benzamidoacetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 417 (M+H)+. 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.55-1.66 (m, 4H), 2.31-2.40 (m, 4H), 3.89 (s, 2H), 4.04 (s, 2H), 6.92 (d, J=7.93 Hz, 1H), 7.26 (t, J=7.93 Hz, 1H), 7.38 (s, 1H), 7.47 (d, J=8.24 Hz, 1H), 7.49-7.54 (m, 2H), 7.58 (t, J=7.32 Hz, 1H), 7.85-7.90 (m, 2H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting 3-(3-methoxyphenyl)propanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 418 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 3-(4-methoxyphenyl)propanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH4) m/z 418 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 2-(3,4-dimethylphenoxy)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 418 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting (R)-2-hydroxy-4-phenylbutanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 418 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.55-1.65 (m, 4H), 1.80-1.90 (m, 1H), 1.95-2.03 (m, 1H), 2.31-2.44 (m, 4H), 2.69 (t, J=7.93 Hz, 2H), 3.88 (s, 2H), 3.96 (s, 1H), 4.01 (dd, J=8.09, 4.12 Hz, 1H), 6.91 (d, J=7.63 Hz, 1H), 7.17-7.23 (m, 3H), 7.25 (t, J=7.78 Hz, 1H), 7.29 (t, J=7.48 Hz, 2H), 7.49 (s, 1H), 7.53 (d, J=7.93 Hz, 1H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting 4-phenoxybutanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 418 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.55-1.67 (m, 4H), 1.96-2.06 (m, 2H), 2.31-2.42 (m, 4H), 2.47 (t, J=7.48 Hz, 2H), 3.88 (s, 2H), 3.99 (t, J=6.26 Hz, 2H), 6.87-6.91 (m, 2H), 6.91-6.96 (m, 2H), 7.24 (t, J=7.78 Hz, 1H), 7.26-7.30 (m, 2H), 7.36 (s, 1H), 7.48 (d, J=8.24 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-oxo-4-(thiophen-2-yl)butanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 422 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.55-1.65 (m, 4H), 2.32-2.42 (m, 4H), 2.69 (t, J=6.41 Hz, 2H), 3.26 (t, J=6.41 Hz, 2H), 3.87 (s, 2H), 6.88 (d, J=7.63 Hz, 1H), 7.23 (t, J=7.93 Hz, 1H), 7.25-7.29 (m, 1H), 7.37 (s, 1H), 7.44 (d, J=8.24 Hz, 1H), 7.97 (d, J=4.88 Hz, 1H), 7.99 (d, J=2.75 Hz, 1H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting 2-(4-methylpyrimidin-2-ylthio)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 422 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 3-(2-chlorophenyl)propanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 422 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 3-(4-chlorophenyl)propanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 422 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 3-methyl-2-phenylpentanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 430 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 2-(4-chloro-2-methylphenoxy)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 438 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 5-oxo-5-(phenylamino)pentanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 445 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.55-1.65 (m, 4H), 1.84-1.94 (m, 2H), 2.31-2.42 (m, 8H), 3.87 (s, 2H), 6.89 (d, J=7.63 Hz, 1H), 7.05 (t, J=7.32 Hz, 1H), 7.24 (t, J=7.93 Hz, 1H), 7.30 (t, J=8.09 Hz, 2H), 7.36 (s, 1H), 7.48 (d, J=8.24 Hz, 1H), 7.57 (d, J=7.63 Hz, 2H).
The title compound was prepared according to procedure for EXAMPLE 136, substituting 4-(4-methoxyphenyl)-4-oxobutanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 446 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 2,2-diphenylacetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 450 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 136, substituting 3-(phenylsulfonyl)propanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 452 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.52-1.70 (m, 4H), 2.29-2.42 (m, 4H), 2.66 (t, J=7.32 Hz, 2H), 3.59 (t, J=7.32 Hz, 2H), 3.87 (s, 2H), 6.90 (d, J=7.32 Hz, 1H), 7.20-7.26 (m, 2H), 7.37 (d, J=8.54 Hz, 1H), 7.66 (t, J=7.63 Hz, 2H), 7.74 (t, J=7.48 Hz, 1H), 7.91 (d, J=7.32 Hz, 2H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-(3-phenoxyphenyl)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 466 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.54-1.65 (m, 4H), 2.29-2.42 (m, 4H), 3.60 (s, 2H), 3.87 (s, 2H), 6.86-6.92 (m, 2H), 6.98-7.03 (m, 3H), 7.10 (d, J=7.93 Hz, 1H), 7.16 (t, J=7.48 Hz, 1H), 7.24 (t, J=7.78 Hz, 1H), 7.32-7.37 (m, 2H), 7.38-7.42 (m, 2H), 7.46 (d, J=8.24 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-ethylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 388 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3-fluoro-2-methylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 392 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 5-fluoro-2-methylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 392 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3-fluoro-4-methylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 392 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2,3-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH4) m/z 396 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2,4-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 396 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2,5-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 396 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3,5-difluorobenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m z 396 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-propylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 402 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-isopropylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 402 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-ethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 404 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-isopropoxybenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 418 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.30 (d, J=6.10 Hz, 6H), 1.53-1.67 (m, 4H), 2.33-2.46 (m, 4H), 3.91 (s, 2H), 4.67-4.80 (m, 1H), 6.94 (d, J=7.63 Hz, 1H), 7.02 (d, J=8.85 Hz, 2H), 7.29 (t, J=7.78 Hz, 1H), 7.55 (s, 1H), 7.62 (d, J=8.24 Hz, 1H), 7.89 (d, J=8.85 Hz, 2H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-(diethylamino)benzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 431 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.1 (t, J=7.02 Hz, 6H), 1.57-1.66 (m, 4H), 2.34-2.44 (m, 4H), 3.45 (q, J=7.02 Hz, 4H), 3.91 (s, 2H), 6.87 (d, J=8.85 Hz, 2H), 6.91 (d, J=7.63 Hz, 1H), 7.27 (t, J=7.93 Hz, 1H), 7.55 (s, 1H), 7.62 (d, J=8.24 Hz, 1H), 7.85 (d, J=8.85 Hz, 2H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-butoxybenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 432 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-fluoro-5-(trifluoromethyl)benzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 446 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-chloro-5-(trifluoromethyl)benzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 461 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting furan-2-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 350 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting furan-3-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 350 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2,5-dimethylfuran-3-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 378 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting thiophene-2-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 366 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting thiophene-3-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 366 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.54-1.66 (m, 4H), 2.32-2.44 (m, 4H), 3.92 (s, 2H), 6.96 (d, J=7.63 Hz, 1H), 7.30 (t, J=7.93 Hz, 1H), 7.53 (s, 1H), 7.59-7.65 (m, 3H), 8.31 (dd, J=2.75, 1.53 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3-methylthiophene-2-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 380 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 5-methylthiophene-2-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 380 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting pyrrole-3-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 349 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56-1.66 (m, 4H), 2.33-2.44 (m, 4H), 3.91 (s, 2H), 6.18 (dd, J=3.51, 2.29 Hz, 1H), 6.92 (d, J=7.63 Hz, 1H), 6.98 (d, J=1.53 Hz, 1H), 7.03-7.07 (m, 1H), 7.27 (t, J=7.93 Hz, 1H), 7.53 (s, 1H), 7.60 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 1-methyl-1H-pyrrole-2-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 363 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2,5-dimethyl-1H-pyrrole-3-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 377 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 1-methyl-1H-pyrrole-3-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 363 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting thiazole-2-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 367 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting thiazole-4-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 367 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting thiazole-5-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 367 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.54-1.67 (m, 2H), 2.32-2.44 (m, 2H), 3.92 (s, 2H), 7.00 (d, J=7.63 Hz, 1H), 7.32 (t, J=7.93 Hz, 1H), 7.49 (s, 1H), 7.59 (d, J=8.24 Hz, 1H), 8.66 (s, 1H), 9.27 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting isoxazole-5-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 351 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.54-1.68 (m, 4H), 2.33-2.45 (m, 4H), 3.93 (s, 2H), 7.03 (d, J=7.63 Hz, 1H), 7.22 (d, J=2.14 Hz, 1H), 7.34 (t, J=7.93 Hz, 1H), 7.54 (s, 1H), 7.63 (d, J=7.93 Hz, 1H), 8.77 (d, J=1.83 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3,5-dimethylisoxazole-4-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 379 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting nicotinic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 361 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting isonicotinic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 361 (M+H)1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.57-1.68 (m, 4H), 2.33-2.45 (m, 4H), 3.94 (s, 2H), 7.04 (d, J=7.63 Hz, 1H), 7.36 (t, J=7.78 Hz, 1H), 7.56 (s, 1H), 7.66 (d, J=8.24 Hz, 1H), 8.10 (d, J=6.41 Hz, 2H), 8.90 (d, J=6.10 Hz, 2H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3-hydroxypicolinic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 377 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-hydroxynicotinic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 377 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 6-hydroxynicotinic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 377 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.53-1.65 (m, 4H), 2.32-2.43 (m, 4H), 3.91 (s, 2H), 6.45 (d, J=10.07 Hz, 1H), 6.95 (d, J=7.63 Hz, 1H), 7.29 (t, J=7.93 Hz, 1H), 7.46 (s, 1H), 7.57 (d, —=8.24 Hz, 1H), 7.98 (dd, J=9.76, 2.75 Hz, 1H), 8.16 (d, J=2.14 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-(pyridin-2-yl)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 375 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-(pyridin-3-yl)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 375 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.54-1.66 (m, 4H), 2.30-2.42 (m, 4H), 3.88 (s, 2H), 3.98 (s, 2H), 6.94 (d, J=7.32 Hz, 1H), 7.27 (t, J=7.93 Hz, 1H), 7.38 (s, 1H), 7.46 (d, J=8.85 Hz, 1H), 8.04 (dd, J=7.93, 5.80 Hz, 1H), 8.52 (d, J=8.24 Hz, 1H), 8.81 (d, J=5.49 Hz, 1H), 8.85 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 5-methylpyrazine-2-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 376 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.54-1.69 (m, 4H), 2.34-2.46 (m, 4H), 2.63 (s, 3H), 3.93 (s, 2H), 7.00 (d, J=7.63 Hz, 1H), 7.33 (t, J=8.09 Hz, 1H), 7.68-7.74 (m, 2H), 8.68 (s, 1H), 9.13 (d, J=1.22 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 1H-indole-3-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH4) m/z 399 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 440 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 6-chloro-2H-chromene-3-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 448 (M+H)+.
N3,N3-dimethyl-N1-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-beta-alaninamide
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3-(dimethylamino)propanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH4) m/z 355 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.55-1.66 (m, 4H), 2.30-2.43 (m, 4H), 2.77-2.93 (m, 100H), 3.93 (s, 2H), 6.74 (s, 1H), 6.90 (dd, J=8.09, 1.37 Hz, 1H), 7.06 (d, J=—7.63 Hz, 1H), 7.37 (t, J=7.78 Hz, 1H).
To a solution of 2-(3-bromophenyl)acetic acid (4.4 g, 20.56 mmol) in N,N-dimethylformamide (125 ml) was successively added N,O-dimethylhydroxyamine (4.5 g, 46.26 mmol), triethylamine (10 ml), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (8.9 g, 46.26 mmol) and 1-hydroxybenzotriazole (6.24 g, 46.26 mmol). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The residue was purified by flash chromatography on silica gel (50% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 258 (M+H)+.
A solution of EXAMPLE 222A (2.5 g, 9.7 mmol) in anhydrous tetrahydrofuran (50 ml) was treated with LiAlH4 (0.37 g, 9.7 mmol) at 0° C. for 10 minutes, and quenched with water. The mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was washed with water and concentrated. The residue was purified by flash chromatography on silica gel (20% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 199 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting EXAMPLE 222B for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 319 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 222C for EXAMPLE 2B. MS (DCI/NH3) m/z 333 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 222, substituting 2-(3-bromo-4-fluorophenyl)acetic acid for 2-(3-bromophenyl)acetic acid in EXAMPLE 223B. MS (DCI/NH3) m/z 216 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting EXAMPLE 223A for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 351 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 2,2,2-trifluoro-1-phenylethanone for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 295 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 224A for EXAMPLE 2B. MS (DCI/NH3) m/z 309 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-hydroxy-4-methylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 390 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-acetylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 402 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-(d6): δ 1.54-1.69 (m, 4H), 2.34-2.46 (m, 4H), 2.64 (s, 3H), 3.93 (s, 2H), 6.99 (d, J=7.63 Hz, 1H), 7.32 (t, J=7.93 Hz, 1H), 7.57 (s, 1H), 7.65 (d, J=7.93 Hz, 1H), 8.01-8.05 (m, 2H), 8.05-8.10 (m, 2H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3-methoxy-4-methylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 404 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-ethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 404 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3-fluoro-4-methoxybenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH4) m/z 408 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 1-naphthoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 410 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-naphthoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 410 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-hydroxy-5-methylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 390 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-tert-butylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 416 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-acetamidobenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 417 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.53-1.68 (m, 4H), 2.10 (s, 3H), 2.33-2.44 (m, 4H), 3.92 (s, 2H), 6.95 (d, J=7.93 Hz, 1H), 7.30 (t, J=7.93 Hz, 1H), 7.56 (s, 1H), 7.63 (d, J=7.63 Hz, 1H), 7.70 (d, J=8.85 Hz, 2H), 7.90 (d, J=8.85 Hz, 2H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-propoxybenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH4) m/z 418 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 1-hydroxy-2-naphthoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 426 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-chloro-5-(methylthio)benzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 440 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3,4-diethoxybenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 448 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-benzoylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 450 (M+H)+.
The title compound was prepared as a trifluoroacetic acid salt according to the procedure for EXAMPLE 136, substituting 2-(phenylamino)benzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 451 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.55-1.68 (m, 4H), 2.31-2.45 (m, 4H), 3.91 (s, 2H), 6.91-6.99 (m, 3H), 7.13 (d, J=7.63 Hz, 2H), 7.27-7.34 (m, 4H), 7.38-7.42 (m, 1H), 7.49 (s, 1H), 7.58 (d, J=8.85 Hz, 1H), 7.71-7.75 (m, 1H).
The title compound was prepared as according to the procedure for EXAMPLE 136, substituting 2-benzoylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 464 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-phenethylbenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 464 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 5-bromo-2-chlorobenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m z 472 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-(4-methylbenzoyl)benzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 478 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 2-iodobenzoic acid for 1-methylcyclopropaneccarboxylic acid. MS (DCI/NH3) m/z 486 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 3-iodobenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 486 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 136, substituting 4-iodobenzoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 486 (M+H)+.
The title compound was prepared as a free base according to the procedure for EXAMPLE 39, substituting 3-acetamidophenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step. MS (DCI/NH3) m/z 392 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.58-1.67 (m, 4H), 2.05 (s, 3H), 2.33-2.39 (m, 2H), 2.40-2.46 (m, 2H), 3.95 (s, 2H), 7.16 (d, J=7.02 Hz, 1H), 7.18-7.21 (m, 1H), 7.22-7.27 (m, 1H), 7.30 (dd, J=7.63, 2.14 Hz, 1H), 7.38 (t, J=7.93 Hz, 1H), 7.59 (d, J=7.32 Hz, 1H), 7.76 (s, 1H), 10.04 (br s, 1H), 12.61 (br s, 1H).
The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3-(methylsulfonyl)phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step. MS (DCI/NH3) m/z 413 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.57-1.73 (m, 4H), 2.34-2.41 (m, 2H), 2.41-2.48 (m, 2H), 3.28 (s, 3H), 3.98 (s, 2H), 7.24-7.28 (m, 1H), 7.28-7.33 (m, 1H), 7.47 (dd, J=7.63, 2.14 Hz, 1H), 7.77 (t, J=7.78 Hz, 1H), 7.90 (d, J=7.93 Hz, 1H), 7.96-8.00 (m, 1H), 8.04 (s, 1H), 12.61 (br s, 1H).
The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3-(pyrrolidine-1-carbonyl)phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step. MS (DCI/NH3) m/z 432 (M+H)+.
The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 4-(pyrrolidine-1-carbonyl)phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step. MS (DCI/NH3) m/z 432 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.57-1.68 (m, 4H), 1.78-1.93 (m, 4H), 2.32-2.39 (m, 2H), 2.40-2.47 (m, 2H), 3.39-3.53 (m, 4H), 3.95 (s, 2H), 7.21-7.24 (m, 1H), 7.24-7.31 (m, 1H), 7.39 (dd, J=7.63, 1.86 Hz, 1H), 7.55-7.59 (m, 2H), 7.60-7.64 (m, 2H), 12.60 (br s, 1H).
The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 3-carbamoylphenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step. MS (DCI/NH3) m/z 378 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.55-1.72 (m, 4H), 2.33-2.41 (m, 2H), 2.41-2.47 (m, 2H), 3.97 (s, 2H), 7.19-7.24 (m, 1H), 7.24-7.30 (m, 1H), 7.42 (dd, J=7.63, 2.14 Hz, 1H), 7.44 (s, 1H), 7.56 (t, J=7.78 Hz, 1H), 7.68 (d, J=7.63 Hz, 1H), 7.88-7.92 (m, 1H), 8.02 (s, 1H), 8.07 (s, 1H), 12.61 (s, 1H).
The title compound was prepared as free base according to the procedure for EXAMPLE 39, substituting 4-(dimethylcarbamoyl)phenylboronic acid for 3-pyridineboronic acid, but eliminating the last HCl salt formation step. MS (DCI/NH3) m/z 406 (M+H)+. 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.56-1.69 (m, 4H), 2.31-2.40 (m, 2H), 2.40-2.47 (m, 2H), 2.95 (s, 3H), 3.00 (s, 3H), 3.96 (s, 2H), 7.20-7.24 (m, 1H), 7.24-7.30 (m, 1H), 7.40 (dd, J=7.48, 1.98 Hz, 1H), 7.49-7.52 (m, 1H), 7.56-7.59 (m, 2H), 7.60-7.65 (m, 1H), 12.61 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 1,1,1-trifluoro-3-phenylpropan-2-one for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 309 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 254A for EXAMPLE 2B. MS (DCI/NH3) m/z 323 (M+H)+.
The title compound was prepared as a side product according to the procedure for EXAMPLE 101, substituting EXAMPLE 222 for EXAMPLE 103. MS (DCI/NH3) m/z 255 (M+H)+.
A solution of EXAMPLE 222A (3.5 g, 13.56 mmol) in anhydrous tetrahydrofuran (50 ml) was treated with 1N sodium dicyanamide v solution in tetrahydrofuran (16 ml, 16.27 mmol) at −78° C. for 1 hour. Iodomethane (3.85 g, 27.1 mmol) was added through a syringe, and the mixture was allowed to warm up to room temperature for 2 hours. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic phase was concentrated, the residue was purified by flash column chromatography (30% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 273 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 222B, substituting EXAMPLE 256A for EXAMPLE 222A. MS (DCI/NH3) m/z 214 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 256B for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 334 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 256C for EXAMPLE 2B. MS (DCI/NH3) m/z 348 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 222A, substituting 4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid for 2-(3-bromophenyl)acetic acid. MS (DCI/NH3) m/z 408 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 222B, substituting EXAMPLE 257A for EXAMPLE 222A. MS (DCI/NH3) m/z 349 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting EXAMPLE 257B for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 469 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 257C for EXAMPLE 2B. MS (DCI/NH3) m/z 483 (M+H)+.
A solution of EXAMPLE 257D (0.77 g, 1.6 mmol) in tetrahydrofuran (100 ml) was treated with 10% palladium on carbon (85 mg, 0.8 mmol) at room temperature under hydrogen (balloon) overnight. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by flash chromatography (0-15% gradient of methanol in CH2Cl2) to provide the title compound. MS (DCI/NH3) m/z 349 (M+H)+.
The title compound was prepared as described in EXAMPLE 257D. MS (DCI/NH3) m/z 483 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 222A, substituting 3-nitrobenzoic acid for 2-(3-bromophenyl)acetic acid. MS (DCI/NH3) m/z 225 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 222B, substituting EXAMPLE 259A for EXAMPLE 222A.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting EXAMPLE 259B for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 286 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 259C for EXAMPLE 2B. MS (DCI/NH3) m/z 300 (M+H)+.
A suspension of EXAMPLE 259 (110 mg, 0.17 mmol) in methanol (20 ml) was treated with Raney Nickel (20 mg) at room temperature under hydrogen (balloon) overnight. The solid material was filtered off, and the filtrate was concentrated to give the title compound. MS (DCI/NH3) m/z 270 (M+H)+.
A solution of EXAMPLE 258 (35 mg, 0.1 mmol) in trifluoroacetic acid (5 ml) was stirred at room temperature for 1 hour, and was concentrated. The residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 249 (M+H)+.
To a solution of EXAMPLE 260 (100 mg, 0.37 mmol) in methylene chloride (5 mL) was added 4-chlorobutyrlchloride (52.3 mg, 0.37 mmol) and triethylamine (0.12 mL, 0.45 mmol). The mixture was stirred at room temperature overnight, and was concentrated. The residue was dissolved in absolute ethanol (5 mL), and was treated with sodium ethoxide (0.2 mL, 21 wt % in ethanol) at room temperature for 16 hours. 1 mL of 2N HCl was added, and the mixture was concentrated. The residue was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 338 (M+H)+.
A solution of 2-phenoxyacetic acid (28 mg, 0.186 mmol) in anhydrous dichloromethane (3 ml) was treated with oxalyl chloride (35.3 mg, 0.186 mmol) and a drop of N,N-dimethylformamide at room temperature for 1 hour, and was concentrated. The residue was re-dissolved in anhydrous dichloromethane (5 ml). A suspension of EXAMPLE 260 (50 mg, 0.186 mmol) in anhydrous tetrahydrofuran (2 ml) was then added. The reaction mixture was stirred at room temperature overnight, and was concentrated. The residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid, CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 404 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.60-1.70 (m, 4H), 2.35-2.39 (m, 2H), 2.42-2.50 (m, 2H), 2.66-2.93 (m, 4H), 4.68 (s, 2H), 6.82-7.09 (m, 4H), 7.23 (t, J=7.80 Hz, 1H), 7.24-7.38 (m, 2H), 7.40-7.60 (m, 2H), 10.01 (s, 1H) 12.54 (s, 1H).
A microwave vial charged with EXAMPLE 223 (50 mg, 0.14 mmol), dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.014 mmol), 3-(morpholine-4-carbonyl)phenylboronic acid (40 mg, 0.17 mmol), a mixture of DME(7)/water(3)/ethanol(2) (3 ml), and sodium carbonate solution (2M, 0.1 ml) was heated in a CEM Explorer® microwave reactor (Matthews, N.C.) at 150° C. for 15 minutes. After cooling, the reaction mixture was diluted with methanol (20 ml), and filtered. The filtrate was concentrated, and the residue was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound. MS (DCI/NH3) m/z 462 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.60-1.67 (m, 4H), 2.35-2.39 (m, 2H), 2.44-2.50 (m, 2H), 2.75-3.01 (m, 4H), 3.44-3.73 (m, 8H), 7.17-7.28 (m, 1H), 7.27-7.34 (m, 1H), 7.38-7.47 (m, 1H), 7.50-7.67 (m, 4H), 12.55 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 66, substituting EXAMPLE 222 for EXAMPLE 66B. MS (DCI/NH3) m/z 313 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 66, substituting EXAMPLE 256 for EXAMPLE 66B. MS (DCI/NH3) m/z 237 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 264, substituting 4-(morpholine-4-carbonyl)phenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 462 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 264 substituting 2-(pyrrolidine-1-carbonyl)phenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 446 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 264, substituting 3-(pyrrolidine-1-carbonyl)phenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 446 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.64-1.81 (m, 4H), 1.83-2.03 (m, 4H), 2.43-2.47 (m, 2H), 2.56-2.59 (m, 2H), 2.76-2.88 (m, 2H), 2.93-3.06 (m, 2H), 3.48 (t, J=6.54 Hz, 2H), 3.67 (t, J=6.74 Hz, 2H), 7.01-7.11 (m, 1H), 7.11-7.21 (m, 1H), 7.29 (dd, J=7.54, 2.38 Hz, 1H), 7.39-7.54 (m, 2H), 7.55-7.62 (m, 1H), 7.69 (s, 1H), 10.10 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 264, substituting 3-(cyclopropylcarbamoyl)phenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 432 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 264, substituting 3-(2-(dimethylamino)ethylcarbamoyl)phenylboronic acid for 3-(morpholine-4-carbonyl)-phenylboronic acid. MS (DCI/NH3) m/z 463 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.28-2.39 (m, 2H), 2.35 (m, 3H), 2.45 (s, 6H), 2.60-2.69 (m, 2H), 2.73-2.82 (m, 2H), 2.87 (t, J=7.14 Hz, 2H), 3.01 (t, J=7.14 Hz, 2H), 3.54-3.64 (m, 1H), 3.69 (q, J=5.29 Hz, 2H), 6.95-7.10 (m, 1H), 7.10-7.20 (m, 1H), 7.35-7.53 (m, 2H), 7.65-7.80 (m, 2H), 7.79-7.88 (m, 1H).
The title compound was prepared according to the procedure for EXAMPLE 264, substituting 3-carbamoylphenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 392 (M+H)+; 1H NMR (500 MHz, pyridine-d5): δ 1.54 (s, 4H), 2.27 (s, 2H), 2.70 (s, 2H), 2.76-2.95 (m, 2H), 2.98-3.21 (m, 2H), 7.19-7.27 (m, 2H), 7.31 (s, 1H), 7.49 (d, J=7.02 Hz, 1H), 7.82 (d, J=7.32 Hz, 1H), 8.42 (d, J=7.63 Hz, 1H), 8.47 (s, 1H), 8.68 (s, 1H), 9.02 (s, 1H), 14.05 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 264, substituting 3-(methylsulfonamido)phenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 442 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.31-2.48 (m, 4H), 2.59 (m, 4H), 2.77-2.96 (m, 4H), 3.02 (t, J=7.80 Hz, 3H), 6.92-7.03 (m, 1H), 7.02-7.12 (m, 1H), 7.10-7.22 (m, 2H), 7.27-7.33 (m, 1H), 7.32-7.47 (m, 2H), 10.96 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 264, substituting 3-acetamidophenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 406 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.06-2.21 (m, 4H), 2.25 (s, 3H), 2.34 (m, 2H), 2.58 (m, 2H), 2.80-2.94 (m, 2H), 2.92-3.06 (m, 2H), 6.93-7.10 (m, 2H), 7.10-7.19 (m, 1H), 7.23 (d, J=4.36 Hz, 1H), 7.27-7.33 (m, 1H), 7.38 (t, J=7.73 Hz, 1H), 7.67-7.76 (m, 1H), 11.25 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 264 substituting EXAMPLE 293 for EXAMPLE 223. MS (DCI/NH3) m/z 476 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 264 substituting EXAMPLE 293 for EXAMPLE 223, and 3-(pyrrolidine-1-carbonyl)phenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 460 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.36 (d, J=6.74 Hz, 3H), 1.61-1.78 (m, 4H), 1.76-2.06 (m, 4H), 2.26-2.45 (m, 2H), 2.49-2.67 (m, 2H), 2.84 (m, 2H), 3.21-3.36 (m, 1H), 3.40-3.57 (m, 2H), 3.59-3.83 (m, 2H), 7.13-7.23 (m, 1H), 7.36 (t, J=7.93 Hz, 1H), 7.40-7.51 (m, 3H), 7.55-7.64 (m, 1H), 7.73 (s, 1H) 9.98 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 264, substituting EXAMPLE 293 for EXAMPLE 223, and 3-(cyclopropylcarbamoyl)phenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 446 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-chloro-3-nitrobenzaldehyde for 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 290 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-methoxy-3-nitrobenzaldehyde for 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 286 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-hydroxy-3-nitrobenzaldehyde for 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 272 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2, substituting 4-methyl-3-nitrobenzaldehyde for 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 270 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 264, substituting EXAMPLE 256 for EXAMPLE 223, and 3-(2-(dimethylamino)ethylcarbamoyl)phenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 459 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 264, substituting EXAMPLE 256 for EXAMPLE 223, and 3-carbamoylphenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 388 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.40 (d, J=7.14 Hz, 3H), 1.53-1.81 (m, 4H), 2.25-2.59 (m, 4H), 2.91 (d, J=7.14 Hz, 2H), 3.31-3.41 (m, 1H), 7.23 (d, J=7.54 Hz, 1H), 7.36 (t, J=7.93 Hz, 1H), 7.42-7.51 (m, 2H), 7.50-7.59 (m, 1H), 7.73 (d, J=7.93 Hz, 1H), 7.79-7.91 (m, 1H), 8.09 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 264, substituting EXAMPLE 256 for EXAMPLE 223, and 3-acetamidophenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 402 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.40 (d, J=7.12 Hz, 3H), 1.50-1.78 (m, 4H), 2.16 (s, 3H), 2.36-2.53 (m, 4H), 2.83 (m, 1H), 2.88 (d, J=7.46 Hz, 2H), 7.16-7.23 (m, 1H), 7.22-7.29 (m, 1H), 7.29-7.36 (m, 2H), 7.36-7.45 (m, 2H), 7.47-7.67 (m, 1H), 7.72 (t, J=1.86 Hz, 1H).
A solution of 3-bromoethyl benzene (2 g, 11 mmol). N-bromosuccinimide (91.9 g, 11 mmol) and azobisisobutyronitrile (10 mg, 0.06 mmol) in chloroform (30 ml) was stirred at 65° C. under nitrogen for 18 hours. After cooling, the reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, and was concentrated. The residue was separated by flash chromatography on silica gel (10% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 262 (M+H)+.
A solution of EXAMPLE 285A (1.0 g, 3.8 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) in toluene (15 ml) was heated at 120° C. under nitrogen for three days. After cooling to room temperature, the solid material was collected by filtration, washed with toluene, and dried to provide the title compound.
A suspension of EXAMPLE 285B (1.88 g, 3.4 mmol) in tetrahydrofuran (100 ml) was treated with potassium t-butoxide (1N solution in tetrahydrofuran, 3.4 ml, 3.4 mmol) at −78° C. for 1 hour, and was allowed to warm up to 0° C. over 30 minutes. A solution of 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (0.54 g, 3.4 mmol) in tetrahydrofuran (10 ml) was then added. The reaction mixture was warmed up to room temperature, and stirred at room temperature for additional 4 hours. After quenching with water, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The residue was separated by flash chromatography (20% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 320 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 285C for EXAMPLE 2B. MS (DCI/NH3) m/z 334 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 264, substituting EXAMPLE 285D for EXAMPLE 223, and 3-carbamoylphenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 374 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.59 (d, J=7.12 Hz, 3H), 1.61-1.81 (m, 4H), 2.10-2.22 (m, 1H), 2.39-2.55 (m, 2H), 2.61-2.73 (m, 1H), 4.32 (q, J=6.78 Hz, 1H), 7.08-7.21 (m, 1H), 7.35-7.43 (m, 1H), 7.48-7.59 (m, 3H), 7.75 (d, J=7.80 Hz, 1H), 7.80-7.87 (m, 1H), 8.06-8.11 (m, 1H).
The title compound was prepared according to the procedure for EXAMPLE 264, substituting EXAMPLE 285D for EXAMPLE 223, and 3-acetamidophenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 388 (M+H)+; 1H NMR (300 MHz, CD OD): δ 1.58 (d, J=7.12 Hz, 3H), 1.60-1.82 (m, 4H), 2.14 (s, 3H), 2.10-2.23 (m, 1H), 2.47-2.55 (m, 2H), 2.60-2.73 (m, 1H), 4.30 (q, J=6.78 Hz, 1H), 7.15 (d, J=7.46 Hz, 1H), 7.23-7.30 (m, 1H), 7.31-7.40 (m, 2H), 7.41-7.47 (m, 1H), 7.47-7.56 (m, 1H), 7.56-7.69 (m, 1H), 7.77 (t, J=1.86 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 264, substituting EXAMPLE 285D for EXAMPLE 223, and 3-(2-(dimethylamino)ethylcarbamoyl)phenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 445 (M+H)+.
A solution of EXAMPLE 266 (50 mg, 0.16 mmol) in tetrahydrofuran (10 ml) was treated with a solution of LiOH.H2O (100 mg, 4 mmol) in water (4 ml) at 50° C. overnight. The mixture was concentrated, and the residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound. MS (DCI/NH3) m/z 313 (M+H)+.
To a solution of 4-(4-methoxyphenyl)-4-oxobutanoic acid (29 mg, 0.14 mmol) in dioxane (1.5 mL) was added 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (42 mg) and N,N′-diisopropylethylamine (32 μL). The mixture was stirred at room temperature for 15 minutes, and EXAMPLE 2 (25 mg, 0.091 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, and was concentrated. The crude was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 464 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.53-1.66 (m, 4H), 2.29-2.40 (m, 4H), 2.74 (t, J=6.41 Hz, 2H), 3.25 (t, J=6.56 Hz, 2H), 3.84 (s, 2H), 3.85 (s, 3H), 6.88-6.96 (m, 1H), 7.05 (d, J=8.85 Hz, 2H), 7.12-7.20 (m, 1H), 7.74 (d, J=6.41 Hz, 1H), 7.97 (d, J=9.15 Hz, 2H), 9.75 (br s, 1H), 12.60 (br s, 1H).
To a solution of EXAMPLE 2 (100 mg, 0.37 mmol) in acetic acid (8 mL) was added 3,4-dimethylfuran-2,5-dione (46 mg, 0.37 mmol). The reaction mixture was heated at 80° C. for 16 hours, and concentrated. The residue was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CNH2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 382 (M+H)+; 1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.56-1.68 (m, 4H), 1.98 (s, 6H), 2.30-2.43 (m, 4H), 3.93 (s, 2H), 7.18 (dd, J=7.02, 1.53 Hz, 1H), 7.31-7.35 (m, 2H), 12.63 (br s, 1H).
To a suspension of EXAMPLE 2 (210 mg, 0.77 mmol) in acetonitrile (8 mL) was added 3-oxabicyclo(3.1.0)hexane-2,4-dione (95 mg, 0.85 mmol) and stirred at 80° C. for 16 hours. The reaction mixture was cooled and concentrated on a rotary evaporator. The residual solid was dissolved in dioxane (4 mL), and treated with O-(benzotriazol-1-yl, N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 0.99 mmol) and N,N′-diisopropylethylamine (0.3 mL, 1.69 mmol) at room temperature for an additional 16 hours. The reaction mixture was concentrated, and separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 368 (M+H)+; 1H NMR (400 MHz, dimethylsulfoxide-d6): δ 1.57-1.64 (m, 4H), 1.66-1.72 (m, 2H), 2.32-2.41 (m, 4H), 2.75 (dd, J=7.82, 3.22 Hz, 2H), 3.91 (s, 1H), 7.16 (d, J=7.36 Hz, 1H), 7.27-7.29 (m, 1H), 7.29-7.32 (m, 1H), 12.61 (br s, 1H).
A solution of EXAMPLE 258 (138 mg, 0.29 mmol) in methylene chloride (10 ml) was treated with trifluoroacetic acid (2 ml) at 40° C. for 2 hours, and concentrated. The residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as TFA salt. MS (DCI/NH3) m/z 383 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 222A, substituting 2-(3-bromo-4-fluorophenyl)acetic acid for 2-(3-bromophenyl)acetic acid. MS (DCI/NH3) m/z 276 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 256A, substituting EXAMPLE 293A for EXAMPLE 222A. MS (DCI NH3) m/z 291 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 256B, substituting EXAMPLE 293B for EXAMPLE 256A. MS (DCI/NH3) m/z 232 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 1C, substituting 293C for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH3) m/z 352 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 293D for EXAMPLE 2B. MS (DCI/NH3) m/z 366 (M+H)+.
A mixture of 4-oxo-4-phenylbutanoic acid (50 mg, 0.28 mmol), 2-(3H-(1,2,3)triazolo(4,5-b)pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate (V) (106 mg, 0.28 mmol) and Hunig's base (120 mg, 0.9 mmol) in anhydrous N,N-dimethylformamide (0.5 ml) was stirred at room temperature for 10 minutes, and EXAMPLE 260 (50 mg, 0.18 mmol) was added in one portion. The reaction mixture was stirred at room temperature for another 1 hour, and was diluted with 5 mL of methanol. The solid material was collected by filtration, washed with methanol, and dried to provide the title compound. MS (DCI/NH3) m/z 430 (M+H)+. 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.54-1.77 (m, 4H), 2.30-2.42 (m, 2H), 2.42-2.49 (m, 2H), 2.65-2.79 (m, 4H), 2.79-2.89 (m, 2H), 3.30-3.38 (m, 2H), 6.90 (d, J=7.80 Hz, 1H), 7.19 (t, J=7.80 Hz, 1H), 7.38-7.49 (m, 2H), 7.54 (t, J=7.46 Hz, 2H), 7.61-7.69 (m, 1H), 7.99 (t, J=6.61 Hz, 2H), 9.96 (s, 1H), 12.52 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 264, substituting EXAMPLE 293 for EXAMPLE 223, and 3-carbamoylphenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 406 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 264, substituting EXAMPLE 293 for EXAMPLE 223, and 3-acetamidophenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 420 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 264, substituting EXAMPLE 293 for EXAMPLE 223, and 3-(methylsulfonamidomethyl)phenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 470 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 291, substituting hexahydroisobenzofuran-1,3-dione for oxabicyclo(3.1.0)hexane-2,4-dione. MS (DCI/NH3) m/z 410 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.31-1.53 (m, 5H), 1.57-1.68 (m, 4H), 1.66-1.78 (m, 3H), 1.76-1.92 (m, 2H), 2.29-2.43 (m, 4H), 3.93 (s, 2H), 7.12-7.17 (m, 1H), 7.28-7.33 (m, 1H), 7.33-7.37 (m, 1H), 12.63 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 291, substituting 3,3-dimethyldihydrofuran-2,5-dione for oxabicyclo(3.1.0)hexane-2,4-dione. MS (DCI/NH3) m/z 384 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.31 (s, 6H), 1.54-1.70 (m, 4H), 2.30-2.44 (m, 4H), 2.78 (s, 2H), 3.94 (s, 2H), 7.19 (d, J=7.46 Hz, 1H), 7.30-7.33 (m, 1H), 7.35 (s, 1H), 12.62 (br s, 1H).
A 100 mL round bottom flask was charged with 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.93 mmol), tris(dibenzylideneacetone)dipalladium(0) (450 mg, 0.493 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (428 mg, 0.739 mmol), and cesium carbonate (2.4 g, 7.39 mmol). The mixture was purged with nitrogen, and anhydrous dioxane (15 mL), and 5-methylpyrrolidinone (0.586 g, 5.91 mmol) were added. The reaction mixture was purged with nitrogen again, and heated at 100° C. for 20 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was separated by flash chromatography (50% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 222 (M+H)+.
A solution of EXAMPLE 1B (486 mg, 1.16 mmol), EXAMPLE 300A (265 mg) and triethylamine (0.16 mL) in dichloromethane (8 mL) was stirred at room temperature for 16 hours, and concentrated. The residue was dissolved in ethanol (5 mL) and treated with hydrazine monohydrate (0.11 mL) at 80° C. for 2 hours. The mixture was allowed to cool and the precipitated solid was filtered and dried to provide the title compound. MS (DCI/NH3) m/z 356 (M+H)+; 1H NMR (400 MHz, dimethylsulfoxide-d6): δ 1.02 (d, J=6.14 Hz, 3H), 1.57-1.63 (m, 4H), 1.64-1.72 (m, 1H), 2.27-2.34 (m, 1H), 2.34-2.40 (m, 4H), 2.41-2.46 (m, 2H), 3.90 (s, 2H), 4.08 (q, J=6.44 Hz, 1H), 7.10-7.14 (m, 1H), 7.14-7.18 (m, 1H), 7.20-7.27 (m, 1H), 12.61 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting oxazolidin-2-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 210 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 301A for EXAMPLE 300A. MS (DCI/NH3) m/z 344 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.55-1.75 (m, 4H), 2.30-2.45 (m, 4H), 3.90 (s, 2H), 3.98 (t, J=7.93 Hz, 2H), 4.45 (dd, J=8.72, 7.14 Hz, 2H), 7.11-7.17 (m, 1H), 7.25 (dd, J=10.91, 8.53 Hz, 1H), 7.36 (dd, J=7.54, 2.38 Hz, 1H), 12.61 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting azepan-2-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 236 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 302A for EXAMPLE 300A. MS (DCI/NH3) m/z 370 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.54-1.65 (m, 4H), 1.65-1.80 (m, 6H), 2.32-2.45 (m, 4H), 2.54-2.63 (m, 2H), 3.57-3.72 (m, 2H), 3.88 (s, 2H), 7.04-7.12 (m, 2H), 7.13-7.22 (m, 1H), 12.61 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 291, substituting dihydro-2H-pyran-2,6(3H)-dione for oxabicyclo(3.1.0)hexane-2,4-dione. MS (DCI/NH3) m/z 370 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.53-1.69 (m, 4H), 1.84-1.97 (m, 1H), 1.98-2.11 (m, 1H), 2.29-2.42 (m, 4H), 2.75 (t, J=6.44 Hz, 4H), 3.90 (s, 2H), 7.04 (d, J=7.80 Hz, 1H), 7.24 (s, 1H), 7.26 (d, J=1.36 Hz, 1H), 12.63 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting imidazolidin-2-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 209 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 304A for EXAMPLE 300A. MS (DCI/NH3) m/z 343 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d): δ 1.55-1.69 (m, 4H), 2.31-2.44 (m, 4H), 3.39 (t, J=7.97 Hz, 2H), 3.75-3.83 (m, 2H), 3.86 (s, 2H), 6.86 (br s, 1H), 6.94-7.03 (m, 1H), 7.16 (dd, J=1.19, 8.48 Hz, 1H), 7.31 (dd, J=7.63, 2.20 Hz, 1H), 12.61 (br s, 1H).
To a solution of EXAMPLE 2 (150 mg, 0.55 mmol) in dichloromethane (5 mL) was added 3-chloropropane-1-sulfonyl chloride (97 mg, 0.55 mmol), and the mixture stirred for 16 hours. The reaction mixture was concentrated, and the residual solid was dissolved in dioxane (3 mL). Sodium ethoxide (0.14 mL, 21 wt % in ethyl alcohol) was then added, and the solution was heated at 80° C. for 16 hours. After cooling, the reaction mixture was concentrated. The residue was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as free base. MS (DCI/NH3) m/z 378 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.56-1.70 (m, 4H), 2.33-2.47 (m, 6H), 3.40 (t, J=7.29 Hz, 2H), 3.72 (t, J=6.44 Hz, 2H), 3.90 (s, 2H), 7.09-7.16 (m, 1H), 7.23 (d, J=8.48 Hz, 1H), 7.25-7.28 (m, 1H), 12.61 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting azetidin-2-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 194 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 306A for EXAMPLE 300A. MS (DCI/NH3) m/z 328 (M+H)+. 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.55-1.68 (m, 4H), 2.31-2.43 (m, 4H), 3.11 (t, J=4.58 Hz, 2H), 3.82 (q, J=4.41 Hz, 2H), 3.86 (s, 2H), 6.86-6.94 (m, 1H), 7.18 (dd, J=11.87, 8.48 Hz, 1H), 7.74 (dd, J=7.63, 2.20 Hz, 1H), 12.60 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting piperidin-2-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 222 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 307A for EXAMPLE 300A. MS (DCI/NH3) m/z 356 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.54-1.67 (m, 4H), 1.77-1.93 (m, 4H), 2.31-2.44 (m, 6H), 3.44-3.53 (m, 2H), 3.88 (s, 2H), 7.10-7.14 (m, 1H), 7.15 (d, J=6.35 Hz, 1H), 7.17-7.23 (m, 1H), 12.62 (s, 1H).
A solution of EXAMPLE 1B (25.8 g, 61.5 mmol), methyl-3-formylbenzoate (10.01 g, 61.0 mmol), and triethylamine (8.7 mL, 62.4 mmol) in dichloromethane (125 mL) was stirred at room temperature for 16 hours, and concentrated. The residue was stirred with a mixture of ethyl acetate and water. The precipitated solid was filtered, washed with water, and dried to provide the title compound. MS (DCI/NH3) m/z 285 (M+H)+.
A solution of EXAMPLE 308A (9.9 g, 35 mmol) in 1:1 mixture of tetrahydrofuran/water (100 mL) was treated with lithium hydroxide monohydrate (2.93 g, 70 mmol) at room temperature for 16 hours. Ethyl acetate was added (100 mL) and the mixture washed with 2M HCl (100 mL). The combined organics were concentrated and dried under vacuum to provide the title compound. MS (DCI/NH3) m/z 271 (M+H)+.
A solution of EXAMPLE 308B (9.0 g, 33.33 mmol) in absolute ethanol (120 mL) was heated with hydrazine monohydrate (3.3 mL, 66.66 mmol) at 80° C. for 16 hours. After cooling to room temperature, the precipitated solid was filtered, and dried to provide the title compound. MS (DCI/NH3) m/z 285 (M+H)+.
A solution of EXAMPLE 308C (2.73 g, 9.6 mmol) in anhydrous tetrahydrofuran (30 mL) was treated with oxalyl chloride (1.3 mL, 14.4 mmol) and a couple of drops of N,N-dimethylformamide at room temperature for 10 minutes and at 50° C. for 1 hour. The reaction mixture was concentrated and dried to provide the title compound. MS (DCI/NH3) m/z 303 (M+H)+.
A solution of EXAMPLE 308D (19 mg, 0.06 mmol), furan-3-ylmethanamine (0.07 mmol) and triethylamine (14.6 mg, 0.14 mmol) in tetrahydrofuran (1.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The residue was dissolved in 1:1 mixture of dimethylsulfoxide/methanol and purified by HPLC (Waters Sunfire® C-8 analytical column [Milford, Mass.]/0.1% trifluoroacetic acid/water/100% CH3CN) to provide the title compound. MS (DCI/NH3) m/z 363 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.54-1.69 (m, 4H), 2.32-2.45 (m, 4H), 3.96 (s, 2H), 4.29 (s, 2H), 6.41-6.49 (m, 1H), 7.32-7.37 (m, 1H), 7.41 (t, J=7.63 Hz, 1H), 7.52-7.60 (m, 2H), 7.64-7.72 (m, 2H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting thiophen-2-ylmethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 380 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56-1.70 (m, 4H), 2.32-2.43 (m, 4H), 3.97 (s, 2H), 4.61 (s, 2H), 6.97 (dd, J=5.03, 3.51 Hz, 1H), 7.02 (d, J=2.44 Hz, 1H), 7.34-7.39 (m, 2H), 7.42 (t, J=7.63 Hz, 1H), 7.67 (s, 1H), 7.70 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting thiophen-3-ylmethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 380 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting pyridin-3-ylmethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 375 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.53-1.70 (m, 4H), 2.31-2.45 (m, 4H), 3.98 (s, 2H), 4.61 (s, 2H), 7.37-7.41 (m, 1H), 7.45 (t, J=7.63 Hz, 1H), 7.69 (s, 1H), 7.74 (d, J=7.63 Hz, 1H), 7.91 (dd, J=7.93, 5.49 Hz, 1H), 8.37 (d, J=7.93 Hz, 1H), 8.72 (d, J=5.19 Hz, 1H), 8.78 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting pyridin-4-ylmethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 375 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N1,N1-dimethylethane-1,2-diamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 355 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56-1.66 (m, 4H), 2.33-2.44 (m, 4H), 2.84 (s, 6H), 3.26 (t, J=5.95 Hz, 2H), 3.60 (t, J=5.95 Hz, 2H), 3.98 (s, 2H), 7.38-7.41 (m, 1H), 7.45 (t, J=7.63 Hz, 1H), 7.67 (s, 1H), 7.71 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N1,N1-dimethylpropane-1,3-diamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 369 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-(pyrrolidin-1-yl)propan-1-amine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 395 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-(piperidin-1-yl)propan-1-amine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 409 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-morpholinopropan-1-amine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 411 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56-1.68 (m, 4H), 1.87-1.97 (m, 2H), 2.31-2.45 (m, 4H), 3.08 (t, J=12.05 Hz, 2H), 3.11-3.17 (m, 2H), 3.33 (t, J=6.71 Hz, 2H), 3.42 (d, J=12.51 Hz, 2H), 3.65 (t, J=12.05 Hz, 2H), 3.96-4.02 (m, 2H), 3.97 (s, 2H), 7.35-7.39 (m, 1H), 7.43 (t, J=7.63 Hz, 1H), 7.65 (s, 1H), 7.69 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(1H-indol-3-yl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 427 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting thiazol-2-amine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 367 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.59-1.68 (m, 4H), 2.35-2.46 (m, 4H), 4.01 (s, 2H), 7.28 (d, J=3.66 Hz, 1H), 7.45-7.48 (m, 1H), 7.50 (t, J=7.48 Hz, 1H), 7.56 (d, J=3.66 Hz, 1H), 7.87 (s, 1H), 7.93 (d, J=7.63 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 294, substituting 2-(benzyloxycarbonylamino)acetic acid for 4-oxo-4-phenylbutanoic acid. MS (DCI/NH3) m/z 461 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 294, substituting 4-oxo-4-(4-phenoxyphenyl)butanoic acid for 4-oxo-4-phenylbutanoic acid. MS (DCI/NH3) m/z 522 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 294, substituting 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid for 4-oxo-4-phenylbutanoic acid. MS (DCI/NH3) m/z 515 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 294, substituting 2-(p-tolyloxy)acetic acid for 4-oxo-4-phenylbutanoic acid. MS (DCI/NH3) m/z 418 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 294, substituting 2-(4-methoxyphenoxy)acetic acid for 4-oxo-4-phenylbutanoic acid. MS (DCI/NH3) m/z 434 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting 1-methylimidazolidin-2-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 223 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 325A for EXAMPLE 300A. MS (DCI/H3) m/z 357 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.54-1.69 (m, 4H), 2.32-2.43 (m, 4H), 2.74 (s, 3H), 3.39-3.44 (m, 2H), 3.67-3.76 (m, 2H), 3.86 (s, 2H), 6.97-7.05 (m, 1H), 7.17 (dd, J=1.19, 8.48 Hz, 1H), 7.31 (dd, J=7.63, 2.20 Hz, 1H), 12.60 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting tetrahydropyrimidin-2(1H)-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 223 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 326A for EXAMPLE 300A. MS (DCI/NH3) m/z 357 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.57-1.68 (m, 4H), 1.87-2.00 (m, 2H), 2.33-2.43 (m, 4H), 3.23 (t, J=5.76 Hz, 2H), 3.44-3.52 (m, 2H), 3.86 (s, 2H), 6.60 (s, 1H), 7.00-7.07 (m, 1H), 7.09-7.18 (m, 2H), 12.61 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting 1-tert-butylimidazolidin-2-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 265 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 327A for EXAMPLE 300A. MS (DCI/NH3) m/z 399 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.3 (s, 9H), 1.53-1.68 (m, 4H), 2.31-2.45 (m, 4H), 3.43-3.48 (m, 2H), 3.58-3.69 (m, 2H), 3.86 (s, 2H), 6.95-7.02 (m, 1H), 7.15 (dd, J=11.36, 8.31 Hz, 1H), 7.28 (dd, J=7.46, 2.03 Hz, 1H), 12.59 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting (1S,4R)-2-azabicyclo(2.2.1)heptan-3-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 234 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 328A for EXAMPLE 300A. MS (DCI/NH3) m/z 368 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.49-1.56 (m, 2H), 1.57-1.65 (m, 4H), 1.69-1.76 (m, 1H), 1.79-1.86 (m, 1H), 1.89-1.96 (m, 1H), 1.97-2.03 (m, 1H), 2.32-2.45 (m, 4H), 2.74-2.82 (m, 1H), 3.87 (s, 2H), 4.25 (s, 1H), 7.01-7.08 (m, 1H), 7.16-7.23 (m, 1H), 7.23-7.28 (m, 1H), 12.59 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-ethylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 388 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-ethylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 388 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-ethylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 388 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-propylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 402 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-isopropylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 402 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-isopropylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 402 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.20 (d, J=7.02 Hz, 6H), 1.55-1.72 (m, 4H), 2.34-2.47 (m, 4H), 2.82-2.96 (m, 1H), 4.01 (s, 2H), 7.23 (d, J=8.24 Hz, 2H), 7.39 (d, J=7.63 Hz, 1H), 7.47 (t, J=7.63 Hz, 1H), 7.63 (d, J=8.54 Hz, 2H), 7.74 (s, 1H), 7.80 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-tert-butylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 416 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-tert-butylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 416 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting biphenyl-4-amine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 436 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.57-1.70 (m, 4H), 2.34-2.48 (m, 4H), 4.02 (s, 2H), 7.36 (t, J=7.32 Hz, 1H), 7.42 (d, J=7.93 Hz, 1H), 7.45-7.48 (m, 2H), 7.49-7.52 (m, 1H), 7.66-7.71 (m, 4H), 7.78 (s, 1H), 7.81-7.87 (m, 3H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-fluoro-4-methylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 392 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-fluoro-4-methylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 392 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-fluoro-2-methylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m z 392 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-fluoro-3-methylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 392 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-chloro-4-methylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 408 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-chloro-3-methylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 408 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-bromo-4-methylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 452 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-bromo-3-methylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 452 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-fluoro-4-methoxyaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 408 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.55-1.69 (m, 4H), 2.33-2.49 (m, 4H), 3.83 (s, 3H), 4.01 (s, 2H), 7.16 (t, J=9.31 Hz, 1H), 7.40 (d, J=7.93 Hz, 1H), 7.44-7.50 (m, 2H), 7.69 (dd, J=13.58, 2.59 Hz, 1H), 7.73 (s, 1H), 7.79 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-methoxy-5-(trifluoromethyl)aniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 458 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-amino-3-methylphenol for furan-3-ylmethanamine. MS (DCI/NH3) m/z 390 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-amino-2-methylphenol for furan-3-ylmethanamine. MS (DCI/NH3) m/z 390 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-amino-5-methylphenol for furan-3-ylmethanamine. MS (DCI/NH3) m/z 390 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-methoxy-5-methylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 404 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 5-methoxy-2-methylaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 404 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 5-amino-2-methoxyphenol for furan-3-ylmethanamine. MS (DCI/NH3) m/z 406 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-ethoxyaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 404 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-propoxyaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 418 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 5-tert-butyl-2-methoxyaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 446 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N-(3-amino-4-methoxyphenyl)acetamide for furan-3-ylmethanamine. MS (DCI/NH3) m/z 447 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2,3-dihydrobenzo(b)(1,4)dioxin-6-amine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 418 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.56-1.68 (m, 4H), 2.34-2.48 (m, 4H), 4.00 (s, 2H), 4.15-4.32 (m, 4H), 6.84 (d, J=8.85 Hz, 1H), 7.16 (dd, J=8.85, 2.44 Hz, 1H), 7.34 (d, J=2.44 Hz, 1H), 7.38 (d, J=7.93 Hz, 1H), 7.46 (t, J=7.63 Hz, 1H), 7.72 (s, 1H), 7.77 (d, J=7.63 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 5-chloro-2,4-dimethoxyaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 454 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-(methylthio)aniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 406 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-(methylthio)aniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 406 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-(piperidin-1-yl)aniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 443 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-morpholinoaniline for furan-3-ylmethanamine. MS (DCI/NH3) m/z 445 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.57-1.68 (m, 4H), 2.34-2.46 (m, 4H), 3.15-3.23 (m, 4H), 3.79-3.82 (m, 4H), 4.01 (s, 2H), 7.10 (d, J=9.15 Hz, 2H), 7.39 (d, J=7.63 Hz, 1H), 7.45-7.50 (m, 1H), 7.66 (d, J=9.15 Hz, 2H), 7.72-7.77 (m, 1H), 7.80 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N1-phenylbenzene-1,2-diamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 451 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.54-1.69 (m, 4H), 2.31-2.44 (m, 4H), 3.95 (s, 2H), 6.78 (t, J=7.32 Hz, 1H), 6.86 (d, J=7.63 Hz, 2H), 7.02-7.09 (m, 1H), 7.15-7.23 (m, 3H), 7.28-7.32 (m, 1H), 7.35-7.39 (m, 1H), 7.42 (t, J=7.63 Hz, 1H), 7.59 (d, J=7.32 Hz, 1H), 7.63 (s, 1H), 7.69 (d, J=7.63 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N1-(4-methoxyphenyl)benzene-1,2-diamine for furan-3-ylmethanamine. MS (DCI/NH4) m/z 481 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting quinolin-7-amine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 411 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.57-1.72 (m, 4H), 2.36-2.49 (m, 4H), 4.04 (s, 2H), 7.44-7.50 (m, 1H), 7.54 (t, J=7.63 Hz, 1H), 7.82 (s, 1H), 7.88 (dd, J=8.24, 5.19 Hz, 2H), 8.19 (d, J=9.15 Hz, 1H), 8.27 (dd, J=9.15, 2.14 Hz, 1H), 8.74 (d, J=2.44 Hz, 1H), 8.88 (d, J=7.93 Hz, 1H), 9.04 (d, J=4.88 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 5-aminonaphthalen-1-ol for furan-3-ylmethanamine. MS (DCI/NH3) m/z 426 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1H-indazol-6-amine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 400 (M+H)+.
To a solution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) was added (4-fluorobenzyl)magnesium chloride (0.25 M in tetrahydrofuran, 20 ml, 5.1 mmol) through a syringe at −78° C. The reaction mixture was stirred at the same temperature for 30 minutes and was quenched with addition of water. After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to give the title compound. MS (DCI/NH3) m/z 274 (M+H)+.
A solution of EXAMPLE 369A (0.46 g, 1.68 mmol) in ethanol (20 ml) was treated with hydrazine (108 mg, 3.37 mmol) at room temperature for 5 hours. The reaction mixture was concentrated to about 5 mL. The solid was collected by filtration, washed with ethanol and dried to provide the title compound. MS (DCI/NH3) m/z 256 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 369A, substituting (2-chloro-4-fluorobenzyl)magnesium chloride for (4-fluorobenzyl)magnesium chloride. MS (DCI/NH3) m/z 308 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 369B, substituting EXAMPLE 370A for EXAMPLE 369A. MS (DCI/NH3) m/z 290 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting (R)-5-(hydroxymethyl)pyrrolidin-2-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 232 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 371A for EXAMPLE 300A. MS (DCI/NH3) m/z 352 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.54-1.63 (m, 4H), 1.64-1.72 (m, 1H), 2.13-2.22 (m, 1H), 2.23-2.31 (m, 1H), 2.33-2.44 (m, 4H), 2.54-2.64 (m, 1H), 3.72 (t, J=10.17 Hz, 1H), 3.78-3.84 (m, 2H), 3.91-4.05 (m, 1H), 4.48 (dd, J=10.51, 3.05 Hz, 1H), 6.77-6.82 (m, 1H), 6.84-6.89 (m, 1H), 8.26 (d, J=2.03 Hz, 1H), 12.58 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting N-methylmethanesulfonamide for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 232 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 372A for EXAMPLE 300A. MS (DCI/NH3) m/z 366 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.57-1.71 (m, 4H), 2.34-2.47 (m, 4H), 3.13 (s, 6H), 3.93 (s, 2H), 7.25 (dd, J=8.33, 1.98 Hz, 1H), 7.51 (d, J=7.93 Hz, 1H), 7.58 (d, J=1.98 Hz, 1H), 12.62 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting 5,5-dimethyloxazolidine-2,4-dione for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 226 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 373A for EXAMPLE 300A. MS (DCI/NH3) m/z 360 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.34 (s, 6H), 1.53-1.70 (m, 4H), 2.29-2.45 (m, 4H), 3.87 (s, 2H), 6.85-7.02 (m, 1H), 7.20 (dd, J=10.91, 8.53 Hz, 1H), 7.91 (dd, J=7.54, 1.98 Hz, 1H), 9.24 (s, 1H), 12.62 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting (S)-5-(hydroxymethyl)pyrrolidin-2-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 232 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting EXAMPLE 374A for EXAMPLE 300B. MS (DCI/NH3) m/z 352 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.54-1.62 (m, 4H), 1.63-1.76 (m, 1H), 2.13-2.22 (m, 1H), 2.23-2.31 (m, 2H), 2.32-2.40 (m, 4H), 3.72 (t, J=10.31 Hz, 1H), 3.81 (s, 2H), 3.90-4.04 (m, 1H), 4.48 (dd, J=10.71, 3.17 Hz, 1H), 6.77-6.83 (m, 1H), 6.84-6.91 (m, 1H), 8.26 (d, J=1.98 Hz, 1H), 12.58 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-phenylethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 388 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.56-1.69 (m, 4H), 2.33-2.45 (m, 4H), 2.84 (t, J=7.48 Hz, 2H), 3.43-3.51 (m, 2H), 3.96 (s, 2H), 7.21 (t, J=7.17 Hz, 1H), 7.23-7.26 (m, 2H), 7.27-7.32 (m, 2H), 7.32-7.36 (m, 1H), 7.40 (t, J=7.63 Hz, 1H), 7.60 (s, 1H), 7.64 (d, J=7.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-o-tolylethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 402 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-o-tolylethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 402 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-p-tolylethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 402 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(pyridin-2-yl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 389 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.57-1.68 (m, 4H), 2.31-2.43 (m, 4H), 3.24 (t, J=6.56 Hz, 2H), 3.69 (t, J=6.41 Hz, 2H), 3.95 (s, 2H), 7.33-7.37 (m, 1H), 7.40 (t, J=7.63 Hz, 1H), 7.53 (s, 1H), 7.57 (d, J=7.63 Hz, 1H), 7.86-7.89 (m, 1H), 7.90-7.94 (m, 1H), 8.40-8.49 (m, 1H), 8.75 (d, J=4.88 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-(pyridin-2-yl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 389 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-(pyridin-2-yl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 389 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2-methoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 418 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 3-(2-methoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 418 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 4-(2-methoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 418 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.55-1.68 (m, 4H), 2.32-2.45 (m, 4H), 2.77 (t, J=7.48 Hz, 2H), 3.37-3.47 (m, 2H), 3.71 (s, 3H), 3.96 (s, 2H), 6.83-6.88 (m, 2H), 7.14-7.20 (m, 2H), 7.32-7.36 (m, 1H), 7.40 (t, J=7.63 Hz, 1H), 7.61 (s, 1H), 7.64 (d, J=7.63 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2-fluorophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 406 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(3-fluorophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 406 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(4-fluorophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 406 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2-chlorophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 422 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(3-chlorophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 422 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(4-chlorophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 422 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(3-bromophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 467 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(4-bromophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 467 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(biphenyl-4-yl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 464 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.54-1.67 (m, 4H), 2.30-2.44 (m, 4H), 2.89 (t, J=7.48 Hz, 2H), 3.52 (t, J=7.32 Hz, 2H), 3.96 (s, 2H), 7.33-7.37 (m, 4H), 7.41 (t, J=7.63 Hz, 1H), 7.44-7.50 (m, 2H), 7.59 (d, J=8.24 Hz, 2H), 7.64 (d, J=8.24 Hz, 2H), 7.64-7.68 (m, 2H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(3-(trifluoromethyl)phenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 456 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(4-(trifluoromethyl)phenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 456 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(4-phenoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 480 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.55-1.66 (m, 4H), 2.32-2.43 (m, 4H), 2.83 (t, J=7.32 Hz, 2H), 3.48 (t, J=7.32 Hz, 2H), 3.96 (s, 2H), 6.91-6.94 (m, 2H), 6.96 (d, J=7.63 Hz, 2H), 7.12 (t, J=7.48 Hz, 1H), 7.26 (d, J=8.54 Hz, 2H), 7.32-7.35 (m, 1H), 7.35-7.38 (m, 2H), 7.38-7.43 (m, 1H), 7.62 (s, 1H), 7.64 (d, J=7.63 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(3,4-dimethylphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 416 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2,4-dimethylphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 416 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2,5-dimethylphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 416 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(3-ethoxy-4-methoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 462 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(4-ethoxy-3-methoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 462 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2,3-dimethoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 448 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2,4-dimethoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 448 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2,5-dimethoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 448 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(3,4-dimethoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 448 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(3,5-dimethoxyphenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 448 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(benzo(d)(1,3)dioxol-5-yl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 432 (M+H)+; 1H NMR (500 MHz, D2O/DMSO-d6): δ 1.54-1.72 (m, 4H), 2.32-2.44 (m, 4H), 2.75 (t, J=7.32 Hz, 2H), 3.43 (t, J=7.32 Hz, 2H), 3.96 (s, 2H), 5.94 (s, 2H), 6.70 (dd, J=7.93, 1.53 Hz, 1H), 6.80 (s, 1H), 6.81-6.83 (m, 1H), 7.32-7.36 (m, 1H), 7.40 (t, J=7.63 Hz, 1H), 7.61 (s, 1H), 7.64 (d, J=17.93 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2,3-dichlorophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 457 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(3,4-dichlorophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 457 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2,6-dichlorophenyl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 457 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting (1S,2R,6S,7R)-4,4-dimethyl-3,5-dioxa-8-azatricyclo(5.2.1.0(2,6))decan-9-one for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 306 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 411A for EXAMPLE 300B. MS (DCI/NH3) m/z 440 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.29-1.34 (m, 3H), 1.42 (s, 3H), 1.55-1.67 (m, 4H), 2.01-2.11 (m, 1H), 2.12-2.21 (m, 1H), 2.32-2.45 (m, 4H), 2.77-2.84 (m, 1H), 3.88 (s, 2H), 4.16-4.24 (m, 1H), 4.58-4.64 (m, 1H), 4.64-4.69 (m, 1H), 7.02-7.09 (m, 1H), 7.22 (dd, J=11.19, 8.48 Hz, 1H), 7.31 (dd, J=7.46, 2.03 Hz, 1H), 12.59 (s, 1H).
A solution of 1-(3-bromo-4-fluorophenyl)ethanone (15.0 g, 69 mmol) in tetrahydrofuran (200 mL) was treated with sodium borohydride (5.3 g, 138 mmol) at 0° C.
After the addition, the ice bath was removed, and the mixture was stirred at room temperature for 30 minutes and at reflux overnight. After cooling, 1N HCl (10 mL) was slowly added and the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with water, and concentrated. The residue was purified by flash chromatography (30% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 220 (M+H)+.
To a solution of EXAMPLE 412A (1.5 g, 6.8 mmol) and triphenyl phosphine (1.9 g, 7.2 mmol) in dimethylformamide (20 ml) was added bromine (1.1 g, 6.8 mmol) through a syringe. After the addition, the reaction mixture was stirred at room temperature for additional 15 minutes, and partitioned between water (100 ml) and ethyl acetate (200 ml). The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (2.6% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH4) m/z 282 (M+H)+.
(1-(3-bromo-4-fluorophenyl)ethyl)triphenylphosphonium bromide
The title compound was prepared according to the procedure for EXAMPLE 285B, substituting EXAMPLE 412B for EXAMPLE 285A.
The title compound was prepared according to the procedure for EXAMPLE 285C, substituting EXAMPLE 412C for EXAMPLE 285B. MS (DCI/NH3) m/z 338 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 2C, substituting EXAMPLE 412D for EXAMPLE 2B. MS (DCI/NH3) m/z 352 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 412 for EXAMPLE 103, and pyrroline-2-one for azetidin-2-one. MS (ESI) m/z 356 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.42 (d, J=6.74 Hz, 3H), 1.46-1.70 (m, 4H), 1.93-2.16 (m, 4H), 2.29-2.67 (m, 6H), 4.25 (q, J=6.74 Hz, 1H), 7.07-7.15 (m, 1H), 7.18 (s, 1H), 7.19-7.29 (m, 1H), 12.70 (s, 1H).
A mixture of EXAMPLE 369 (150 mg, 0.6 mmol), 5% platinum on carbon (30 mg), concentrated aqueous HCl (50 μL) and dimethylformamide (5 ml) in a pressure vessel was stirred at room temperature under 50 psi of hydrogen for 16 hours. The mixture was filtered, and the filtrate was concentrated. The residual solid was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies. Santa Clara, Calif.], 0.1% TFA/CH3CNH2O) to provide the title product as TFA salt. MS (EST) m/z 260 (M+H)+.
A mixture of magnesium turnings (880 mg, 37 mmol) and 2-bromo-4-(bromomethyl)-1-fluorobenzene (1.0 g, 3.7 mmol) in anhydrous diethyl ether (15 ml) was treated with a piece of iodine. The mixture was then heated to gentle reflux until the color of the mixture disappeared, after which the heating continued for additional hour. The suspension was cooled to room temperature, and cannulated into a solution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) at −78° C. The reaction mixture was maintained at the same temperature for 30 minutes, and was quenched with addition of water. After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 353 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 369B substituting EXAMPLE 415A for EXAMPLE 369A. MS (DCI/NH3) m/z 335 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N1-ethyl-N2,N2-dimethylethane-1,2-diamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 383 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N1,N1-diethyl-N2-methylethane-1,2-diamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 397 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N-benzylethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 402 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 0.97-1.11 (m, 3H), 1.36-1.57 (m, 4H), 2.22-2.30 (m, 2H), 2.50-2.66 (m, 2H), 3.27-3.45 (m, 2H), 3.98 (s, 2H), 4.61-4.74 (m, 2H), 7.26-7.31 (m, 1H), 7.32-7.40 (m, 6H), 7.42-7.47 (m, 1H), 7.52 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N-benzylpropan-2-amine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 416 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N-benzylbutan-1-amine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 430 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting dibenzylamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 464 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(benzylamino)ethanol for furan-3-ylmethanamine. MS (DCI/NH3) m/z 418 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.40-1.54 (m, 4H), 2.21-2.33 (m, 2H), 2.50-2.61 (m, 2H), 3.62-3.78 (m, 2H), 3.89-4.02 (m, 2H), 3.96 (s, 2H), 4.82-4.97 (m, 2H), 7.25-7.29 (m, 1H), 7.30-7.36 (m, 5H), 7.36-7.43 (m, 1H), 7.43-7.47 (m, 1H), 7.50 (d, J=7.32 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting N-methyl-2-(pyridin-2-yl)ethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 403 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.42-1.52 (m, 4H), 2.24-2.34 (m, 2H), 2.51-2.62 (m, 2H), 2.97 (s, 3H), 3.07-3.21 (m, 2H), 3.83-3.94 (m, 2H), 3.99 (s, 2H), 7.12 (dd, J=7.32, 5.49 Hz, 1H), 7.14-7.20 (m, 1H), 7.28-7.32 (m, 2H), 7.32-7.37 (m, 1H), 7.37-7.45 (m, 1H), 7.57 (t, J=7.63 Hz, 1H), 8.55 (d, J=3.66 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(3,4-dimethoxyphenyl)-N-methylethanamine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 462 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting piperidin-4-ol for furan-3-ylmethanamine. MS (DCI/NH3) m/z 368 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.42-1.52 (m, 4H), 1.63-1.75 (m, 2H), 1.87-1.98 (m, 2H), 2.27-2.35 (m, 2H), 2.54-2.62 (m, 2H), 3.25-3.40 (m, 2H), 4.01 (s, 2H), 4.01-4.04 (m, 2H), 4.05-4.07 (m, 1H), 7.35 (t, J=7.17 Hz, 1H), 7.37-7.40 (m, 1H), 7.40-7.44 (m, 1H), 7.51 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting piperidine-3-carboxamide for furan-3-ylmethanamine. MS (DCI/NH3) m/z 395 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting piperidine-4-carboxamide for furan-3-ylmethanamine. MS (DCI/NH3) m/z 395 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.41-1.55 (m, 4H), 1.82-1.97 (m, 4H), 2.27-2.37 (m, 2H), 2.54-2.61 (m, 2H), 2.63-2.73 (m, 1H), 2.94-3.06 (m, 2H), 4.00 (s, 2H), 4.16-4.32 (m, 2H), 7.32-7.36 (m, 1H), 7.36-7.40 (m, 2H), 7.48-7.51 (m, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1-(piperidin-4-yl)-1H-benzo(d)imidazol-2(3H)-one for furan-3-ylmethanamine. MS (DCI/NH3) m/z 484 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1-methylpiperazine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 367 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.46-1.52 (m, 4H), 2.24 (s, 3H), 2.29-2.34 (m, 2H), 2.37-2.42 (m, 4H), 2.54-2.62 (m, 2H), 3.61-3.73 (m, 4H), 4.02 (s, 2H), 7.35-7.39 (m, 1H), 7.39-7.43 (m, 2H), 7.51 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1-ethylpiperazine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 381 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting piperazine-1-carbaldehyde for furan-3-ylmethanamine. MS (DCI/NH3) m/z 381 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1-(piperazin-1-yl)ethanone for furan-3-ylmethanamine. MS (DCI/NH3) m/z 395 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.44-1.57 (m, 4H), 2.09 (s, 3H), 2.28-2.39 (m, 2H), 2.51-2.66 (m, 2H), 3.39-3.73 (m, 8H), 4.03 (s, 2H), 7.36-7.39 (m, 1H), 7.43 (t, J=7.02 Hz, 2H), 7.54 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(piperazin-1-yl)ethanol for furan-3-ylmethanamine. MS (DCI/NH3) m/z 397 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.42-1.55 (m, 4H), 2.27-2.37 (m, 2H), 2.50-2.62 (m, 6H), 2.69 (t, J=5.80 Hz, 2H), 3.54-3.75 (m, 4H), 3.89 (t, J=5.80 Hz, 2H), 4.02 (s, 2H), 7.35-7.38 (m, 1H), 7.39-7.43 (m, 2H), 7.50 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1-phenylpiperazine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 429 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.44-1.57 (m, 4H), 2.27-2.42 (m, 2H), 2.52-2.66 (m, 2H), 3.08-3.20 (m, 4H), 3.68-3.83 (m, 4H), 4.04 (s, 2H), 6.91 (t, J=7.32 Hz, 1H), 6.98 (d, J=7.93 Hz, 2H), 7.28-7.34 (m, 2H), 7.37-7.41 (m, 1H), 7.44 (t, J=7.48 Hz, 1H), 7.46-7.49 (m, 1H), 7.57 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1-(pyridin-2-yl)piperazine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 430 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.46-1.55 (m, 4H), 2.29-2.40 (m, 2H), 2.52-2.65 (m, 2H), 3.53-3.63 (m, 4H), 3.64-3.78 (m, 4H), 4.03 (s, 2H), 6.66 (dd, J=6.71, 4.58 Hz, 1H), 6.73 (d, J=8.54 Hz, 1H), 7.37-7.41 (m, 1H), 7.43 (d, J=7.63 Hz, 1H), 7.45-7.48 (m, 1H), 7.49-7.54 (m, 1H), 7.57 (s, 1H), 8.29 (dd, J=4.88, 1.22 Hz, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(piperazin-1-yl)pyrimidine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 431 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.42-1.59 (m, 4H), 2.26-2.40 (m, 2H), 2.50-2.66 (m, 2H), 3.62-3.74 (m, 4H), 3.82-3.91 (m, 4H), 4.03 (s, 2H), 6.55 (t, J=4.73 Hz, 1H), 7.38 (d, J=5.80 Hz, 1H), 7.40-7.45 (m, 1H), 7.45-7.49 (m, 1H), 7.57 (s, 1H), 8.38 (d, J=4.88 Hz, 2H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 2-(2-(piperazin-1-yl)ethoxy)ethanol for furan-3-ylmethanamine. MS (DCI/NH3) m/z 441 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1-(2-fluorophenyl)piperazine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 447 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1-(4-fluorophenyl)piperazine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 447 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.44-1.56 (m, 4H), 2.30-2.39 (m, 2H), 2.53-2.63 (m, 2H), 3.02-3.12 (m, 4H), 3.68-3.81 (m, 4H), 4.05 (s, 2H), 6.93-6.97 (m, 2H), 7.04-7.09 (m, 2H), 7.37-7.41 (m, 1H), 7.44 (t, J=7.32 Hz, 1H), 7.46-7.51 (m, 1H), 7.57 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1-(2-chlorophenyl)piperazine for furan-3-ylmethanamine. MS (DCI/NH3) m/z 463 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 308, substituting 1-methyl-4-(piperazin-1-yl)azepane for furan-3-ylmethanamine. MS (DCI/NH3) m/z 381 (M+H)+; 1H NMR (500 MHz, D2O/pyridine-d5): δ 1.44-1.48 (m, 1H), 1.48-1.51 (m, 4H), 1.92-2.01 (m, 2H), 2.28-2.36 (m, 2H), 2.51-2.55 (m, 2H), 2.58 (s, 3H), 2.64 (t, J=5.65 Hz, 1H), 2.84-2.94 (m, 2H), 3.64-3.71 (m, 3H), 3.88-3.92 (m, 1H), 4.01 (s, 2H), 7.33-7.39 (m, 1H), 7.39-7.41 (m, 1H), 7.41-7.45 (m, 1H), 7.51 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 300A, substituting 1,4-butanesultam for 5-methylpyrrolidinone. MS (DCI/NH3) m/z 258 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 448A for EXAMPLE 300A. MS (DCI/NH3) m/z 392 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.57-1.71 (m, 4H), 1.75-1.87 (m, 2H), 2.13-2.24 (m, 2H), 2.34-2.46 (m, 4H), 3.16-3.28 (m, 2H), 3.46-3.58 (m, 2H), 3.92 (s, 2H), 7.23 (dd, J=8.13, 2.18 Hz, 1H), 7.48 (d, J=7.93 Hz, 1H), 7.57 (d, J=1.59 Hz, 1H), 12.61 (br s, 1H).
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 415 for EXAMPLE 103. MS (ESI) m/z 325 (M+H)+.
The title compound was prepared as TFA salt according to procedure for EXAMPLE 414, substituting EXAMPLE 370 for EXAMPLE 369. MS (ESI) m/z 294 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 412 for EXAMPLE 103. MS (ESI) m/z 342 (M+H)+; 1H NMR (300 MHz, DMSO-d6): 1.41 (d, J=7.12 Hz, 3H), 1.44-1.67 (m, 4H), 1.84-2.08 (m, 1H), 2.34 (m, 2H), 2.53-2.74 (m, 1H), 3.11 (t, J=4.58 Hz, 2H), 3.72-3.88 (m, 2H), 4.22 (q, J=6.78 Hz, 1H), 6.81-6.95 (m, 1H), 7.18 (dd, J=11.87, 8.48 Hz, 1H), 7.76 (dd, J=7.46, 2.37 Hz, 1H), 12.70 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLEs 2, 3 and 4, substituting 3-nitrobenzaldehyde for 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 256 (M+H)+.
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 2 for EXAMPLE 89, and 2-(2-oxopyrrolidin-1-yl)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 356 (M+H)+. MS (DCI/NH3) m/z 399 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.53-1.67 (m, 4H), 1.89-2.06 (m, 2H), 2.26 (t, J=7.97 Hz, 2H), 2.31-2.43 (m, 4H), 3.39-3.47 (m, 2H), 3.86 (s, 2H), 4.07 (s, 2H), 6.93-6.99 (m, 1H), 7.18 (dd, J=10.85, 8.48 Hz, 1H), 7.71 (dd, J=7.46, 2.03 Hz, 1H), 9.82 (br s, 1H), 12.61 (br s, 1H).
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 2 for EXAMPLE 89, and 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 356 (M+H)+. MS (DCI/NH3) m/z 458 (M+H)+.
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 2 for EXAMPLE 89, and 5-oxohexanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 386 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.53-1.65 (m, 4H), 1.67-1.80 (m, 2H), 2.08 (s, 3H), 2.28-2.34 (m, 2H), 2.34-2.41 (m, 4H), 2.42-2.49 (m, 2H), 3.85 (s, 2H), 6.82-6.96 (m, 1H), 7.15 (dd, J=10.85, 8.48 Hz, 1H), 7.67 (dd, J=7.46, 1.70 Hz, 1H), 9.60 (br s, 1H), 12.61 (br s, 1H).
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 2 for EXAMPLE 89, and 3-methoxypropanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 360 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.55-1.66 (m, 4H), 2.30-2.43 (m, 4H), 2.60 (t, J=6.10 Hz, 2H), 3.23 (s, 3H), 3.59 (t, J=6.27 Hz, 2H), 3.86 (s, 2H), 6.85-6.99 (m, 1H), 7.16 (dd, J=10.85, 8.48 Hz, 1H), 7.74 (dd, J=7.46, 1.70 Hz, 1H), 9.64 (br s, 1H), 12.61 (br s, 1H).
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 2 for EXAMPLE 89, and 5-oxo-5-(phenylamino)pentanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH3) m/z 463 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.55-1.67 (m, 4H), 1.83-1.94 (m, 2H), 2.31-2.40 (m, 6H), 2.40-2.45 (m, 2H), 3.85 (s, 2H), 6.89-6.96 (m, 1H), 6.98-7.06 (m, 1H), 7.15 (dd, J=10.85, 8.48 Hz, 1H), 7.24-7.32 (m, 2H), 7.59 (d, J=7.46 Hz, 2H), 7.71 (dd, J=7.97, 1.53 Hz, 1H), 9.67 (br s, 1H), 9.88 (br s, 1H), 12.62 (br s, 1H).
To a solution of 4-fluoro-3-nitrobenzoic acid (5 g, 27.0 mmol) in dimethylformamide (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (5.93 g, 60.8 mmol) and triethylamine (17.0 mL, 122 mmol). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (11.65 g, 60.8 mmol) and hydroxybenzotriazole (9.31 g, 60.8 mmol) were added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated and partitioned between ethyl acetate (150 mL) and brine (150 mL). The organics were concentrated on rotary evaporator and the crude was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to provide the title product. MS (DCI/NH3) m/z 254 (M+H)+.
A solution of EXAMPLE 458A (2.34 g, 9.24 mmol) in tetrahydrofuran (40 mL) was treated with Raney Ni (2.0 g, Raney 2800, slurry in water) at room temperature under a hydrogen (balloon) for 16 hours. The catalyst was filtered off, and the filtrate was concentrated. The residue was used the subsequent step without further purification.
To a solution of EXAMPLE 458B in a mixture of tetrahydrofuran (20 mL) and water (20 mL) was added cesium carbonate (6.02 g, 18.58 mmol) and benzyl chloroformate (1.5 mL, 10.16 mmol). The reaction mixture was stirred at room temperature for 16 hours, and concentrated. The residue was partitioned between ethyl acetate (100 mL) and brine (75 mL). The organic layer was washed with brine, and concentrated. The residual oil was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to provide the title product. MS (DCI/NH3) m/z 358 (M+H)+.
A solution of EXAMPLE 458C (2.89 g, 8.1 mmol) in anhydrous tetrahydrofuran (20 mL) was treated with lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 8.1 mL, 8.1 mmol) at 0° C. for 10 minutes. The reaction was quenched with water, and the mixture was partitioned between ethyl acetate and diluted HCl solution. The organic layer was washed with brine, and concentrated on a rotary evaporator. The residual oil was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to provide the title product. MS (DCI/NH3) m/z 299 (M+H)+.
The title compound was prepared according to the procedure for EXAMPLE 300B, substituting EXAMPLE 458D for EXAMPLE 300A. MS (DCI/NH3) m/z 433 (M+H)1.
The title compound was prepared according to procedure for EXAMPLE 414, substituting EXAMPLE 449 for EXAMPLE 369. MS (EST) m/z 329 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.61-1.76 (m, 2H), 2.33 (t, J=6.35 Hz, 2H), 3.12 (t, J=4.56 Hz, 2H), 3.17 (m, 2H), 3.77 (s, 2H), 3.81 (q, J=4.36 Hz, 2H), 6.32 (s, 1H), 6.87-7.01 (m, 1H), 7.17 (dd, J=11.90, 8.33 Hz, 1H), 7.78 (dd, J=7.54, 2.38 Hz, 1H), 11.80 (s, 1H).
To a solution of 2-bromo-1-fluoro-4-iodobenzene (13.23 g, 44 mmol) in anhydrous tetrahydrofuran (30 mL) was added isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 24.18 mL, 48.4 mmol) at −20° C. After the addition, the reaction mixture was stirred at 0° C. for 3 hours, and was added to a solution of 3,4,5,6-tetrahydrophthalic anhydride (6.08 g, 40 mmol) in anhydrous tetrahydrofuran (60 mL) at −78° C. The mixture was stirred for 2 hours, and a saturated aqueous ammonium chloride solution was added to the reaction mixture, which then was stirred at room temperature for 30 minutes. Anhydrous magnesium sulfate was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated. Thionyl chloride (10.4 mL, 142 mol) was added dropwise to methanol (40 mL) at −10° C., and the solution was stirred at 0° C. for 30 minutes. To the thionyl chloride solution was then added the residue from the filtrate in anhydrous methanol (15 mL). The reaction mixture was stirred at room temperature overnight, and was concentrated. The residue was dissolved in methylene chloride (40 mL), and was treated with triethylamine (5.58 mL) at 0° C. for 1 hour. Water was added, and the mixture was washed with sodium bicarbonate, brine and water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was separated by flash chromatography (10-35% gradient ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 341, 343 (M+H)+.
A solution of EXAMPLE 460A (9.5 g, 27.8 mmol) and hydrazine monohydrate (1.76 mL, 36.2 mmol) in ethanol (70 mL) was heated under reflux for 4 hours. After cooling to room temperature, the solids were collected by filtration, washed with ethanol and dried to provide the title compound. MS (DCI/NH3) m/z 323, 325 (M+H)+; 1H NMR (300 MHz, DMSO-D6): δ 1.57-1.65 (m, 2H), 1.66-1.74 (m, 2H), 2.34 (t, J=5.75 Hz, 2H), 2.45 (t, J=6.15 Hz, 2H), 7.45 (t, J=8.72 Hz, 1H), 7.49-7.55 (m, 1H), 7.80 (dd, J=6.74, 2.38 Hz, 1H), 12.85 (br s, 1H).
To a solution of EXAMPLE 460 (2.0 g, 6.19 mmol) in anhydrous dimethylformamide (30 mL) was added potassium t-butoxide (1 M solution in tetrahydrofuran, 6.50 mL, 6.5 mmol). The solution was stirred at room temperature for 30 minutes, and benzyl chloromethylether (1.163 g, 7.43 mmol) was added. The reaction mixture was stirred at room temperature overnight. After quenching with water, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, and concentrated. The residue was separated by flash chromatography (20-60% gradient ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 443 (M+H)+.
A microwave reactor tube was charged with EXAMPLE 461A (137 mg, 0.309 mmol), tris(dibenzylideneacetone)dipalladium(0) (28.3 mg, 0.031 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (26.9 mg, 0.046 mmol), 2-azetidinone (44 mg, 0.619 mmol), and potassium phosphate tribasic (98 mg, 0.464 mmol). Anhydrous dioxane (3 mL) was added. The suspension was purged with nitrogen, and was capped with a microwave septum. The reaction mixture was heated in a CEM Explorer® microwave reactor (Matthews, N.C.) at 200° C. for 50 minutes. After cooling, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with water, and concentrated. The residue was separated by flash chromatography (20-70% gradient ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 434 (M+H)+.
To a solution of EXAMPLE 461B (140 mg, 0.323 mmol) in methanol (10 mL) was added 20% palladium hydroxide on carbon (80 mg) under nitrogen. This suspension was purged with hydrogen, and stirred under hydrogen (balloon) at 50° C. for 4 hours. The mixture was filtered, and the filtrate was concentrated. The residue was recrystallized from methanol (4 mL) to provide the title compound. The mother liquor was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies. Santa Clara, Calif.), 250×2.54 column. Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in CH3CN; 0-100% gradient) to provide additional title compound. MS (DCI/NH3) m/z 314 (M+H)+; 1H NMR (400 MHz, DMSO-d6), δ 1.57-1.63 (m, 2H), 1.67-1.74 (m, 2H), 2.33 (t, J=5.83 Hz, 2H), 2.45 (t, J=6.14 Hz, 2H), 3.14-3.18 (m, 2H), 3.86-3.90 (m, 2H), 7.16-7.21 (m, 1H), 7.34 (dd, J=11.66, 8.59 Hz, 1H), 7.93 (dd, J=7.52, 2.30 Hz, 1H), 12.89 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 66C, substituting EXAMPLE 415 for EXAMPLE 66B. MS (DCI/NH3) m/z 314 (M+H)+.
A solution of EXAMPLE 462A (1 g, 3.2 mmol) in 7N ammonia in methanol (5 ml) was heated at 70° C. overnight, and cooled to room temperature. The solid was collected by filtration, washed with methanol and dried to provide the title compound. MS (DCI/NH3) m/z 299 (M+H)+.
A mixture of 1.5 N aqueous KOH solution (2 ml) and 3 g of ice was treated with bromine (80 mg, 0.5 mmol) at −10° C. for 10 minutes. EXAMPLE 462 (100 mg, 0.3 mmol) was added. The reaction mixture was stirred at −10° C. for an additional 10 minutes, and was then allowed to warm up to 65° C. for 1 hour. After cooling, the mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated to about 10 mL. The solid was collected by filtration, washed with methanol, and dried to provide the title compound. MS (DCI/NH3) m/z 271 (M+H)+.
A solution of EXAMPLE 415 (1 g, 3 mmol) in anhydrous dimethylformamide (100 ml) was treated with potassium t-butoxide (1N solution in tetrahydrofuran, 3 mL, 3 mmol) at room temperature for 30 minutes. Benzyloxychloromethane (0.6 g, 3.6 mmol) was then added, and the mixture was stirred at room temperature overnight. After quenching with water, the reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine, and concentrated. The residue was purified by flash chromatography (85% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 454 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 101, substituting EXAMPLE 464A for EXAMPLE 103. MS (ESI) m/z 459 (M+H)+.
A mixture of EXAMPLE 464B (130 mg, 0.28 mmol), 5% platinum on carbon (25 mg), 5% Pd(OH)2 on carbon (25 mg), concentrated aqueous HCl (66 μL) and dimethylformamide (10 ml) was stirred in a pressure vessel at room temperature under 40 psi of hydrogen for 48 hours. The volatiles were removed, the residue was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% TFA/CH3CN/H2O) to provide the title product as TFA salt. MS (ESI) m/z 343 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.57-1.81 (m, 2H), 2.01-2.18 (m, 2H), 2.26-2.46 (m, 4H), 3.17 (m, 2H), 3.72 (t, J=6.94 Hz, 2H), 3.84 (s, 2H), 6.39 (s, 1H), 7.16-7.19 (m, 1H), 7.18-7.25 (m, 1H), 7.29 (dd, J=7.54, 1.98 Hz, 1H), 11.89 (s, 1H).
The title compound was prepared as TFA salt according to procedure for EXAMPLE 414, substituting EXAMPLE 462A for EXAMPLE 369. MS (EST) m/z 318 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.61-1.75 (m, 2H), 2.34 (t, J=6.15 Hz, 2H), 3.17 (m, 2H), 3.44 (s, 3H), 3.84 (s, 2H), 6.39 (s, 1H), 7.27 (dd, J=10.91, 8.53 Hz, 1H), 7.46-7.56 (m, 1H), 7.76 (dd, J=7.14, 2.38 Hz, 1H), 11.84 (s, 1H).
The title compound was prepared as TFA salt according to procedure for EXAMPLE 414, substituting EXAMPLE 463 for EXAMPLE 369. MS (ESI) m/z 275 (M+H)+; 1H NMR (300 MHz, DMSO-d6): 1.62-1.74 (m, 2H), 2.35 (t, J=6.27 Hz, 2H), 3.10-3.23 (m, 2H), 3.69 (s, 2H), 4.91 (s, 2H), 6.25 (s, 1H), 6.45-6.54 (m, 1H), 6.64 (dd, J=8.82, 2.03 Hz, 1H), 6.92 (dd, J=11.53, 8.48 Hz, 1H), 11.93 (s, 1H).
The title compound was prepared according to procedure for EXAMPLE 288, substituting EXAMPLE 465 for EXAMPLE 266. MS (EST) m/z 304 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.61-1.77 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 3.06-3.25 (m, 2H), 3.84 (s, 2H), 6.36 (s, 1H), 7.22 (dd, J=10.85, 8.48 Hz, 1H), 7.39-7.52 (m, 1H), 7.73 (dd, J=7.12, 2.37 Hz, 1H), 11.82 (s, 1H) 13.19 (s, 1H).
The title compound was prepared as TFA salt according to procedure for EXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and ethylamine for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 331 (M+H)+; 1H NMR (300 MHz, DMSO-d6): 1.09 (t, J=7.14 Hz, 3H), 1.58-1.74 (m, 2H), 2.34 (t, J=6.15 Hz, 2H), 3.12-3.20 (m, 2H), 3.20-3.29 (m, 2H), 3.82 (s, 2H), 6.39 (s, 1H), 7.19 (dd, J=10.31, 8.33 Hz, 1H), 7.30-7.38 (m, 1H), 7.47 (dd, J=6.74, 2.38 Hz, 1H), 8.17-8.29 (m, 1H), 11.88 (s, 1H).
The title compound was prepared as TFA salt according to procedure for EXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and cyclobutanamine for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 357 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.56-1.77 (m, 4H), 1.90-2.10 (m, 2H), 2.12-2.28 (m, 2H), 2.33 (t, J=6.35 Hz, 2H), 3.05-3.25 (m, 2H), 3.81 (s, 2H), 4.27-4.45 (m, 1H), 6.35 (s, 1H), 7.18 (dd, J=10.31, 8.33 Hz, 1H), 7.26-7.37 (m, 1H), 7.42 (dd, J=6.74, 2.38 Hz, 1H), 8.49 (d, J=7.54 Hz, 1H), 11.84 (s, 1H).
The title compound was prepared as TFA salt according to procedure for EXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and 2-(pyrrolidin-1-yl)ethanamine for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 400 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.63-1.76 (m, 2H), 1.76-1.93 (m, 2H), 1.93-2.10 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 2.61-2.76 (m, 2H), 2.96-3.12 (m, 2H), 3.12-3.22 (m, 2H), 3.25-3.40 (m, 2H), 3.52-3.68 (m, 2H), 3.84 (s, 2H), 6.35 (s, 1H), 7.25 (dd, J=10.85, 8.48 Hz, 1H), 7.33-7.49 (m, 1H), 7.57 (dd, J=7.12, 2.37 Hz, 1H), 8.31-8.50 (m, 1H), 11.84 (s, 1H).
The title compound was prepared as TFA salt according to procedure for EXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and morpholino(piperazin-1-yl)methanone for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (EST) m/z 485 (M+H)+; 1H NMR (300 MHz, DMSO-d): δ 1.60-1.78 (m, 2H), 2.35 (t, J=6.15 Hz, 2H), 3.05-3.28 (m, 12H), 3.51-3.58 (m, 4H), 3.60-3.70 (m, 2H), 3.82 (s, 2H), 6.41 (s, 1H), 7.16-7.29 (m, 2H), 7.29-7.37 (m, 1H), 11.92 (s, 1H).
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and 5-oxo-5-(phenylamino)pentanoic acid for 1-methylcyclopropanecarboxylic acid. MS (ESI) m/z 464 (M+H)+; 1H NMR (300 MHz, DMSO-d): δ 1.62-1.75 (m, 2H), 1.81-1.96 (m, 2H), 2.34 (t, J=7.12 Hz, 4H), 2.42 (t, J=8.14 Hz, 2H), 3.09-3.22 (m, 2H), 3.77 (s, 2H), 6.30 (s, 1H), 6.93-7.07 (m, 1H), 7.14 (dd, J=10.85, 8.48 Hz, 1H), 7.22-7.34 (m, 3H), 7.59 (d, J=7.80 Hz, 2H), 7.68-7.77 (m, 1H), 9.62 (s, 1H), 9.87 (s, 1H), 11.82 (s, 1H).
The title compound was prepared according to procedure for EXAMPLE 3, substituting EXAMPLE 463 for EXAMPLE 2. MS (ESI) m/z 371 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 4, substituting EXAMPLE 475A for EXAMPLE 3. MS (ESI) m/z 353 (M+H)+.
The title compound was prepared according to procedure for EXAMPLE 414, substituting EXAMPLE 475B for EXAMPLE 369. MS (ESI) m/z 357 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.58-1.78 (m, 2H), 2.33 (t, J=6.27 Hz, 2H), 2.72-2.90 (m, 4H), 3.07-3.23 (m, 2H), 3.84 (s, 2H), 6.34 (s, 1H), 7.13 (dd, J=6.95, 2.20 Hz, 1H), 7.27-7.37 (m, 1H), 7.37-7.43 (m, 1H), 11.83 (s, 1H).
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and 3-methoxypropanoic acid for 1-methylcyclopropanecarboxylic acid. MS (ESI) m/z 361 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.63-1.74 (m, 2H), 2.33 (t, J=6.15 Hz, 2H), 2.60 (t, J=6.15 Hz, 2H), 3.09-3.21 (m, 2H), 3.24 (s, 3H), 3.59 (t, J=6.15 Hz, 2H), 3.77 (s, 2H), 6.33 (s, 1H), 6.93-7.05 (m, 1H), 7.14 (dd, J=10.91, 8.53 Hz, 1H), 7.69-7.80 (m, 1H), 9.63 (s, 1H), 11.85 (s, 1H).
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and 5-oxohexanoic acid for 1-methylcyclopropanecarboxylic acid. MS (ESI) m/z 387 (M+H)+; 1H NMR (300 MHz, DMSO-d6): 1.64-1.80 (m, 4H), 2.08 (s, 3H), 2.27-2.39 (m, 4H), 2.42-2.50 (m, 2H), 3.10-3.23 (m, 2H), 3.77 (s, 2H), 6.34 (s, 1H), 6.94-7.04 (m, 1H), 7.13 (dd, J=10.85, 8.48 Hz, 1H), 7.66-7.71 (m, 1H), 9.58 (s, 1H), 11.86 (s, 1H).
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and 3-phenoxypropanoic acid for 1-methylcyclopropanecarboxylic acid. MS (ESI) m/z 423 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.55-1.74 (m, 2H), 2.33 (t, J=6.15 Hz, 2H), 2.84 (t, J=6.15 Hz, 2H), 3.08-3.21 (m, 2H), 3.78 (s, 2H), 4.24 (t, J=6.15 Hz, 2H), 6.36 (s, 1H), 6.88-6.96 (m, 3H), 6.97-7.05 (m, 1H), 7.16 (dd, J=10.91, 8.53 Hz, 1H), 7.25-7.31 (m, 2H), 7.77 (dd, J=7.54, 1.98 Hz, 1H), 9.79 (s, 1H), 11.89 (s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and 4-oxo-4-phenylbutanoic acid for 1-methylcyclopropanecarboxylic acid. MS (ESI) m/z 435 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.63-1.73 (m, 2H), 2.32 (t, J=5.95 Hz, 2H), 2.75-2.79 (m, 2H), 3.08-3.19 (m, 2H), 3.27-3.36 (m, 2H), 3.75 (s, 2H), 6.27 (s, 1H), 6.91-7.04 (m, 1H), 7.14 (dd, J=10.91, 8.53 Hz, 1H), 7.54 (t, J=7.54 Hz, 2H), 7.59-7.69 (m, 1H), 7.70-7.77 (m, 1H), 7.94-8.03 (m, 2H), 9.74 (s, 1H), 11.78 (s, 1H).
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and 2-(4-(benzyloxy)phenoxy)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (ESI) m/z 515 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.53-1.81 (m, 2H), 2.22-2.39 (m, 2H), 3.07-3.21 (m, 2H), 3.78 (s, 2H), 4.66 (s, 2H), 5.04 (s, 2H), 6.34 (s, 1H), 6.83-6.99 (m, 4H), 7.02-7.10 (m, 1H), 7.14-7.23 (m, 1H), 7.30-7.37 (m, 2H), 7.37-7.46 (m, 3H), 7.65 (dd, J=7.54, 1.98 Hz, 1H), 9.77 (s, 1H), 11.84 (s, 1H).
The title compound was prepared as TFA salt according to the procedure for EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and 2-(4-methoxyphenoxy)acetic acid for 1-methylcyclopropanecarboxylic acid. MS (ESI) m/z 438 (M+H)+; 1H NMR (300 MHz, DMSO-d6): 1.63-1.75 (m, 2H), 2.33 (t, J=6.27 Hz, 2H), 3.08-3.24 (m, 2H), 3.70 (s, 3H), 3.79 (s, 2H), 4.66 (s, 2H), 6.35 (s, 1H), 6.84-6.96 (m, 4H), 7.01-7.11 (m, 1H), 7.18 (dd, J=10.85, 8.48 Hz, 1H), 7.66 (dd, J=7.63, 2.20 Hz, 1H), 9.73 (s, 1H), 11.85 (s, 1H).
The title compound was prepared as TFA salt according to procedure for EXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and cyclopropanamine for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 343 (M+H)+; 1H NMR (300 MHz, DMSO-d6): 0.44-0.59 (m, 2H), 0.63-0.76 (m, 2H), 1.60-1.78 (m, 2H), 2.34 (t, J=6.35 Hz, 2H), 2.74-2.90 (m, 1H), 3.09-3.22 (m, 2H), 3.81 (s, 2H), 6.39 (s, 1H), 7.03-7.25 (m, 1H), 7.25-7.37 (m, 1H), 7.42 (dd, J=6.74, 2.38 Hz, 1H), 8.33 (d, J=3.97 Hz, 1H), 11.89 (s, 1H).
The title compound was prepared as TFA salt according to procedure for EXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and 1-(2-ethoxyethyl)piperazine for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 444 (M+H)+; 1H NMR (300 MHz, DMSO-d6): 1.09 (t, J=9.0 Hz, 3H), 1.61-1.76 (m, 2H), 2.56-2.69 (m, 2H), 3.01-3.11 (m, 2H), 3.11-3.24 (m, 4H), 3.35-3.43 (m, 4H), 3.43-3.61 (m, 4H), 3.82 (s, 2H), 6.35 (s, 1H), 7.18-7.26 (m, 1H), 7.28-7.34 (m, 1H), 7.34-7.41 (m, 1H), 11.84 (s, 1H).
The title compound was prepared according to procedure for EXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and 2-(piperidin-1-yl)ethanamine for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 414 (M+H)+; 1H NMR (300 MHz, DMSO-d6): 1.33-1.49 (m, 2H), 1.50-1.64 (m, 4H), 1.62-1.75 (m, 2H), 2.33 (t, J=6.35 Hz, 2H), 2.54-2.82 (m, 4H), 3.10-3.20 (m, 2H), 3.20-3.35 (m, 2H), 3.37-3.55 (m, 2H), 3.82 (s, 2H), 6.35 (s, 1H), 7.20 (dd, J=10.51, 8.53 Hz, 1H), 7.33-7.44 (m, 1H), 7.53 (dd, J=7.14, 2.38 Hz, 1H), 8.51 (dd, J=4.36, 1.59 Hz, 1H) 11.83 (s, 1H).
The title compound was prepared according to procedure for EXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and 2-amino-1-(piperidin-1-yl)ethanone for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 428 (M+H)+; 1H NMR (300 MHz, DMSO-d6): 1.44 (m, 2H), 1.48-1.65 (m, 4H), 1.65-1.79 (m, 2H), 2.33 (t, J—=6.27 Hz, 2H), 3.10-3.24 (m, 2H), 3.34-3.42 (m, 2H), 3.41-3.50 (m, 2H), 3.84 (s, 2H), 4.13 (d, J=5.09 Hz, 2H), 6.00-6.50 (m, 1H), 7.05-7.28 (m, 1H), 7.32-7.53 (m, 1H), 7.63 (dd, J=7.12, 2.37 Hz, 1H), 8.17 (q, J=5.09 Hz, 1H), 11.82 (s, 1H).
To a solution of EXAMPLE 1 (100 mg, 0.33 mmol) in dimethlyacetamide (5 mL) was added 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (126 mg, 0.33 mmol) and triethylamine (92 μL, 0.66 mmol) and stirred for 20 minutes at room temperature. (Piperazin-1-yl)pyrimidine dihydrochloride (78 mg, 0.33 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. After concentration, the residual oil was purified by HPLC (Zorbax®J C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% TFA/CH3CN/H2O) to provide the title product. MS (DCI/NH3) m/z 449 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.53-1.71 (m, 4H), 2.32-2.44 (m, 4H), 3.24-3.39 (m, 2H), 3.67-3.78 (m, 4H), 3.79-3.88 (m, 2H), 3.93 (s, 2H), 6.67 (t, J=4.75 Hz, 1H), 7.21-7.23 (m, 1H), 7.24-7.28 (m, 1H), 7.30-7.35 (m, 1H), 8.39 (d, J=4.75 Hz, 2H), 12.62 (br s, 1H).
The title compound was prepared according to the procedure for EXAMPLE 461, substituting 2-pyrrolidinone for 2-azetidinone in EXAMPLE 461B. MS (DCI/NH3) m/z 328 (M+H)+; 1H NMR (400 MHz, CD2OD): δ 1.73-1.79 (m, 2H), 1.83-1.90 (m, 2H), 2.22-2.29 (m, 2H), 2.55-2.60 (m, 4H), 2.69 (t, J=5.83 Hz, 2H), 3.91 (t, J=7.06 Hz, 2H), 7.35-7.41 (m, 1H), 7.48-7.52 (m, 1H), 7.60-7.64 (m, 1H).
To a solution of 1-cyclohexene-1,2-dicarboxylic anhydride (25.2 g, 165.6 mmol) in tetrahydrofuran (125 mL) placed in an ice bath was added sodium borohydride (1.51 g, 39.97 mmol). The ice bath was removed and the mixture was stirred at room temperature for 30 minutes, and under reflux for 5 hours. After cooling to room temperature, 1N HCl was added, and the reaction mixture concentrated. The residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, water and concentrated. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes to provide the title compound. MS (ESI) m/z 155 (M+H)+.
tributyl(3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-1-yl)phosphonium bromide
To a flask charged with EXAMPLE 1A (3.0 g, 19.5 mmol) in acetic acid (10 mL) was added tri-n-butyl phosphine (4.81 mL, 19.5 mmol) and a 33% solution of HBr in acetic acid (3.34 mL, 13.65 mmol). The reaction mixture was refluxed for 21 hours, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane to provide the title compound. MS (DCI/NH3) m/z 420 (M+H)+.
To a solution of EXAMPLE 492B (27.3 g, 65 mmol) in anhydrous dichloromethane (200 mL) was added 3-bromo-4-fluorobenzaldehyde (13.2 g, 65 mmol) and triethylamine (9.0 mL, 65 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, and concentrated. The residue was partitioned between ethyl acetate and brine. The organics were concentrated, and purified by flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes to provide the title compound. MS (DCI/NH3) m/z 325 (M+H)+.
A solution of EXAMPLE 492C (16 g, 49.5 mmol) in ethanol (200 mL) was treated with hydrazine monohydrate (4.8 mL, 99 mmol) at 80° C. for 2 hours, and cooled to room temperature. The mixture was filtered and the solid was dried to provide the title compound. MS (DCI/NH3) m/z 339 (M+H)+.
A 250 mL pressure bottle was charged with EXAMPLE 492D (7.3 g, 21.65 mmol), a mixture of methanol (60 mL) and N,N-dimethylformamide (5 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.317 g, 0.433 mmol), and triethylamine (6.04 ml, 43.3 mmol). The mixture was purged, and pressurized with carbon monoxide (60 psi), and stirred at 110° C. for 16 hours. Solid material was filtered off, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes to provide the title compound. MS (DCI/NH3) m/z 317 (M+H)+.
A solution of EXAMPLE 492E (5.7 g, 18 mmol) in 1:1 tetrahydrofuran/water (100 mL) was treated with lithium hydroxide monohydrate (1.5 g, 36 mmol) at ambient temperature for 16 hours. The reaction mixture was acidified with 2 N HCl to a pH 3, and concentrated. The residue was partitioned between ethyl acetate and brine. The organics were concentrated and dried to provide the title compound. MS (DCI/NH3) m/z 303 (M+H)+.
To a solution of EXAMPLE 492F (390 mg, 1.3 mmol) in dimethylacetamide (10 mL) was added 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) and triethylamine (0.36 mL, 2.6 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and concentrated. The residue was partitioned between ethyl acetate and brine. The organics were concentrated, and the residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to provide the title compound as the TFA salt. The TFA salt was dissolved in a mixture of methylene chloride and methanol, and treated with 1M HCl in ether. Concentration of the mixture yielded the title compound as the HCl salt. MS (DCI/NH3) m/z 439 (M+H)+; 1H NMR (CD3OD) δ 0.79-0.93 (m, 4H), 1.70-1.76 (m, 4H), 1.86-2.05 (m, 1H), 2.46-2.57 (m, 4H), 3.33-3.45 (m, 2H), 3.52-3.64 (m, 2H), 3.65-3.78 (m, 2H), 3.80-3.93 (m, 2H), 4.03 (s, 2H), 7.17 (t, J=8.92 Hz, 1H), 7.24-7.29 (m, 1H), 7.33-7.40 (m, 1H).
To a solution of 3-amino-4-fluorobenzoic acid (30 g, 193 mmol) in a mixture of tetrahydrofuran (300 mL) and water (300 mL) was added cesium carbonate (157 g, 483 mmol) and benzyl chloroformate (30.4 mL, 213 mmol). This mixture was stirred at ambient temperature for 16 hours, and was concentrated to about 200 mL. The residue was acidified with 2N HCl to a pH 3, and was partitioned between ethyl acetate and brine. The precipitated solid was collected by filtration, washed with ethyl acetate and water, and dried to provide the title compound. MS (DCI/NH3) m/z 290 (M+H)+.
To a solution of EXAMPLE 493A (38.4 g, 133 mmol) in a mixture of dioxane (500 mL) and dichloromethane (200 mL) was added N,O-dimethylhydroxylamine hydrochloride (29.2 g, 299 mmol) and triethylamine. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (57.3 g, 299 mmol) and N-hydroxybenzotriazole (HOBt) (40.4 g, 299 mmol) were added. The reaction mixture stirred at room temperature for 16 hours and concentrated. The crude mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and concentrated. The residue was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to provide the title compound. MS (DCI/NH3) m/z 333 (M+H)+.
To a solution of EXAMPLE 493B (27 g, 81 mmol) in anhydrous tetrahydrofuran (100 mL) was added lithium aluminum hydride solution (1M) in tetrahydrofuran (41 mL) at 0° C. After stirring at 0° C. for 15 minutes, the reaction was quenched with water. The mixture was partitioned between ethyl acetate and dilute aqueous HCl solution. The organics were washed with water and concentrated. The residue was purified by flash chromatography eluting with 25% ethyl acetate in hexanes to provide the title compound. MS (DCI/NH3) m/z 274 (M+H)+.
To a solution of EXAMPLE 492B (25.2 g, 60.2 mmol) in dichloromethane (200 mL) was added EXAMPLE 493C (16.5 g, 60.2 mmol) and triethylamine (8.3 mL, 60.2 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and concentrated. Ethyl acetate was added and the mixture washed with water and brine. The organics were concentrated and dried to provide the title compound. MS (DCI/NH3) m/z 394 (M+H)+.
To a solution of EXAMPLE 493D (14.6 g, 37.1 mmol) in ethanol (150 mL) was added hydrazine monohydrate (3.6 mL, 74.2 mmol) and the mixture was heated at 80° C. for 16 hours. The mixture was cooled and the precipitated solid was filtered and dried to provide the title compound. MS (DCI/NH3) m/z 408 (M+H)+.
To a solution of EXAMPLE 493E (1.65 g, 4.05 mmol) in tetrahydrofuran (100 mL) was added 20% Pd(OH)2/C (0.32 g) under nitrogen. The suspension was purged, and pressurized with hydrogen at 30 psi with stirring for 1 hour. The solid material was filtered off and the filtrate concentrated to provide the title compound. MS (DCI/NH3) m/z 274 (M+H)+.
To a solution of EXAMPLE 493F (1.1 g, 4 mmol) in a mixture of acetonitrile (20 mL) and dioxane (20 mL) was added succinic anhydride (800 mg, 8 mmol). The mixture was stirred at 80° C. for 18 hours, and concentrated. The crude solid was triturated from methanol to provide the title compound. MS (DCI/NH3) m/z 374 (M+H)+.
To a solution of EXAMPLE 493G (230 mg, 0.6 mmol) in N,N-dimethylformamide (8 mL) was added potassium bicarbonate (123 mg, 1.23 mmol) and iodomethane (0.08 mL, 1.23 mmol). The mixture was stirred at room temperature for 16 hours and was concentrated. The residue was purified by flash chromatography on silica gel eluting with 8% methanol in dichloromethane to provide the title compound. MS (DCI/NH3) m/z 388 (M+H)+; 1H NMR (DMSO-d6) δ 1.52-1.69 (m, 4H), 2.27-2.43 (m, 4H), 2.53-2.61 (m, 2H), 2.61-2.68 (m, 2H), 3.59 (s, 3H), 3.85 (s, 2H), 6.89-6.96 (m, 1H), 7.15 (dd, J=11.10, 8.33 Hz, 1H), 7.72 (d, J=7.54 Hz, 1H), 9.72 (s, 1H), 12.61 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 442 (M+H)+; 1H NMR (CD3OD) δ 1.67-1.76 (m, 4H), 2.41-2.48 (m, 2H), 2.48-2.55 (m, 2H), 2.86 (s, 6H), 3.17-3.23 (m, 2H), 3.32-3.40 (m, 4H), 3.75-3.82 (m, 2H), 3.99 (s, 2H), 7.12-7.18 (m, 1H), 7.23 (dd, J=6.29, 2.30 Hz, 1H), 7.32-7.37 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 482 (M+H)+; 1H NMR (CD3OD) δ 1.52-1.59 (m, 4H), 1.60-1.67 (m, 2H), 1.69-1.77 (m, 4H), 2.41-2.47 (m, 2H), 2.48-2.54 (m, 2H), 3.18-3.22 (m, 2H), 3.23-3.28 (m, 4H), 3.33-3.40 (m, 4H), 3.75-3.80 (m, 2H), 3.99 (s, 2H), 7.15 (t, J=8.90 Hz, 1H), 7.23 (dd, J=6.44, 2.15 Hz, 1H), 7.32-7.37 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 449 (M+H)+; 1H NMR (CD3OD) δ 1.69-1.78 (m, 4H), 2.42-2.48 (m, 2H), 2.49-2.57 (m, 2H), 3.44-3.51 (m, 2H), 3.61-3.69 (m, 2H), 3.74-3.80 (m, 2H), 3.87-3.92 (m, 2H), 4.00 (s, 2H), 7.13-7.21 (m, 1H), 7.26 (dd, J=6.29, 2.30 Hz, 1H), 7.34-7.39 (m, 1H), 7.83 (d, J=2.46 Hz, 1H), 8.16 (dd, J=2.61, 1.38 Hz, 1H), 8.25 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 448 (M+H)+; 1H NMR (CD3OD) δ 1.67-1.77 (m, 4H), 2.42-2.49 (m, 2H), 2.49-2.55 (m, 2H), 3.55-3.64 (m, 2H), 3.71-3.77 (m, 2H), 3.86-3.92 (m, 2H), 3.92-3.97 (m, 2H), 4.01 (s, 2H), 7.14-7.18 (m, 2H), 7.18-7.22 (m, 1H), 7.29 (dd, J=6.44, 2.46 Hz, 1H), 7.36-7.43 (m, 1H), 8.17 (d, J=7.67 Hz, 2H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 413 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the free base? according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 463 (M+H)+; 1H NMR (CD3OD) δ 1.68-1.77 (m, 4H), 2.38 (s, 3H), 2.43-2.49 (m, 2H), 2.49-2.56 (m, 2H), 3.43-3.51 (m, 2H), 3.58-3.66 (m, 2H), 3.73-3.78 (m, 2H), 3.88 (dd, J=6.44, 3.99 Hz, 2H), 4.00 (s, 2H), 7.14-7.21 (m, 1H), 7.26 (dd, J=6.44, 2.15 Hz, 1H), 7.34-7.40 (m, 1H), 7.73 (s, 1H), 8.02 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 413 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 442 (M+H)+; 1H NMR (CD3OD) δ 1.69-1.76 (m, 4H), 2.42-2.47 (m, 2H), 2.48-2.53 (m, 2H), 2.56-2.62 (m, 2H), 2.68-2.75 (m, 2H), 2.84 (t, J=6.14 Hz, 2H), 2.93 (s, 6H), 3.31-3.36 (m, 2H), 3.38-3.45 (m, 2H), 3.79-3.88 (m, 2H), 3.99 (s, 2H), 7.13-7.19 (m, 1H), 7.21 (dd, J=6.29, 2.30 Hz, 1H), 7.33-7.39 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 399 (M+H)+; 1H NMR (CD3OD) δ 1.67-1.77 (m, 4H), 2.11-2.33 (m, 2H), 2.41-2.48 (m, 2H), 2.49-2.56 (m, 2H), 2.90-2.95 (m, 1H), 2.98 (s, 3H), 3.34-3.43 (m, 1H), 3.44-3.58 (m, 3H), 3.61-3.70 (m, 1H), 3.71-3.78 (m, 1H), 3.82-3.91 (m, 1H), 4.00 (s, 2H), 7.15-7.20 (m, 1H), 7.26-7.30 (m, 1H), 7.36-7.41 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 386 (M+H)+; 1H NMR (CD3OD) δ 1.39-1.49 (m, 1H), 1.50-1.59 (m, 1H), 1.69-1.74 (m, 4H), 1.77-1.85 (m, 1H), 1.90-1.98 (m, 1H), 2.41-2.47 (m, 2H), 2.48-2.55 (m, 2H), 3.12-3.23 (m, 1H), 3.33-3.41 (m, 1H), 3.45-3.55 (m, 1H), 3.83-3.93 (m, 1H), 3.99 (s, 2H), 4.13-4.22 (m, 1H), 7.11-7.17 (m, 1H), 7.18-7.22 (m, 1H), 7.30-7.36 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 387 (M+H)+; 1H NMR (CD3OD) δ 1.69-1.76 (m, 4H), 2.42-2.47 (m, 2H), 2.48-2.54 (m, 2H), 2.99 (s, 3H), 3.01 (s, 6H), 3.45 (t, J=6.26 Hz, 2H), 3.91 (t, J=6.26 Hz, 2H), 4.00 (s, 2H), 7.15-7.20 (m, 1H), 7.28 (dd, J=6.41, 2.44 Hz, 1H), 7.37-7.41 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 469 (M+H)+.
To a mixture of magnesium turnings (1.36 g, 56 mmol) and 2-bromo-4-(bromomethyl)-1-fluorobenzene (5.0 g, 18.6 mmol) in diethyl ether (100 mL) was added a granule of iodine. The slightly purple suspension was stirred at ambient temperature for 5-10 minutes, and the color of the mixture disappeared. The exothermic mixture was refluxed with stirring for an additional 1 hour, and cooled to room temperature. The formed Grignard reagent was directly used in the next step without further purification.
To a solution of dimethylpyridine-2,3-dicarboxylate (5.45 g, 19 mmol) in tetrahydrofuran (200 mL) was added a suspension of 506A (19 mmol) at −78° C. The mixture was stirred at −78° C. for 30 minutes, and warmed to room temperature and quenched with water. This mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to give the title compound. MS (DCI/NH3) m/z 353 (M+H)+.
A solution of EXAMPLE 506B (3.2 g, 9.1 mmol) in ethanol (50 mL) was treated with hydrazine (455 mg, 9.1 mmol) at 90° C. for 5 hours. Solid precipitated, and after cooling to room temperature, was collected by filtration, washed with ethanol, and dried to give the title compound. MS (DCI/NH3) m/z 335 (M+H)+.
A 250 mL high pressure vessel was charged with EXAMPLE 506C (4.5 g, 13.47 mmol), methanol (50 mL), N,N-dimethylformamide (50 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.099 g, 0.135 mmol) and triethylamine (3.75 ml, 26.9 mmol). The mixture was purged and pressurized with carbon monoxide (60 psi), and stirred at 100° C. for 5 hours. Solid material was filtered off and the filtrate was concentrated. The solid was collected by filtration, washed with methanol, and dried to give the title compound. MS (DCI/NH3) m/z 314 (M+H)+.
In a 250 mL high pressure vessel, EXAMPLE 506D (3.3 g, 10.53 mmol) and 5% Pt/C (0.330 g, 1.692 mmol) were suspended in 30 mL of acetic acid. This suspension was purged and pressurized with 30 psi of hydrogen, and stirred at ambient temperature for 32 hours.
Solid material was filtered off and the filtrate concentrated. The formed solid was collected by filtration, washed with methanol and dried to give the title compound. MS (DCI/NH3) m/z 318 (M+H)+.
A solution of EXAMPLE 506E (2.8 g, 8.8 mmol) in tetrahydrofuran (150 mL) was treated with LiOH (253 mg, 10.6 mmol) in water (20 mL) at 50° C. overnight. After cooling to room temperature, the mixture was acidified with dilute HCl to pH 4, and concentrated to about 10 mL. The solid material was collected by filtration, washed with water and dried to provide the title compound. MS (DCI/NH3) m/z 305 (M+H)+.
To a solution of EXAMPLE 506F (100 mg, 0.33 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added cyclopropyl(piperazin-1-yl)methanone (66 mg, 0.43 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (82 mg, 0.43 mmol), N-hydroxybenzotriazole (HOBT) (66 mg, 0.43 mmol) and triethyl amine (44 mg, 0.43 mmol). The reaction mixture was warmed until homogeneous. The solution was stirred at ambient temperature for 16 hours and concentrated. The residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to provide the title compound as the TFA salt. MS (DCI/NH3) m/z 440 (M+H); 1H NMR (DMSO-d6) δ 0.60-0.82 (m, 4H), 1.59-1.79 (m, 2H), 1.94 (m, 1H), 2.34 (t, J=6.27 Hz, 2H), 3.00-3.35 (m, 4H), 3.38-3.79 (m, 2H), 3.82 (s, 2H), 3.83-4.11 (m, 4H), 6.37 (s, 1H), 7.15-7.27 (m, 1H), 7.24-7.30 (m, 1H), 7.30-7.40 (m, 1H), 11.87 (s, 1H).
EXAMPLE 506D (1.5 g, 4.8 mmol) was suspended in a solution of NH3 in methanol (7N, 50 mL) in a pressure tube. The tube was sealed and heated at 110° C. for 48 hours. After cooling to room temperature the precipitate was collected by filtration, washed with methanol, and dried to give the title compound. MS (DCI/NH3) m/z 299 (M+H)+.
To a mixture of ice (30 g) and solution of KOH (1.7 g, 30.2 mmol) in water (2 mL) was added bromine (0.17 ml, 3.35 mmol) at −10° C. After stirring at −10° C. for 10 minutes, EXAMPLE 507A (1.0 g, 3.35 mmol) was added. The mixture was stirred at −10° C. for an additional 10 minutes and at 65° C. for 1 hour. After cooling, the mixture was acidified with HCl to pH 7, and partitioned between brine and ethyl acetate. The organic phase was washed with brine, and concentrated. The residue was purified by flash chromatography (70% ethyl acetate in hexane) to give the title compound. MS (DCI/NH3) m/z 299 (M+H)+.
To a solution of EXAMPLE 507B (200 mg, 0.74 mmol) in acetonitrile (20 mL) was added dihydro-2H-pyran-2,6(3H)-dione (84 mg, 0.74 mmol). The mixture was stirred at 80° C. for 6 days and concentrated. The residue was dissolved in dichloromethane (20 mL) and treated with 1,1′-carbonyldiimidazole (CDI) (104 mg, 0.74 mmol) at ambient temperature for 5 days. The mixture was concentrated and the residue partitioned between ethyl acetate and brine. The organic phase was washed with brine, and was concentrated. The residue was purified by flash chromatography (2%-15% gradient methanol in ethyl acetate) to provide the title compound. MS (DCI/NH3) m/z 367 (M+H)+.
To a solution of EXAMPLE 507C (200 mg, 0.546 mmol) in N,N-dimethylformamide (20 mL) in a 100 mL pressure bottle was added 5% Pt/C (60.0 mg, 0.308 mmol) and concentrated HCl (55 μl, 1.2 eq). The reaction mixture was purged and pressurized with hydrogen (30 psi), and stirred at ambient temperature for 3 days. An additional 60 mg of 5% Pt/C and 40 μL of concentrated HCl were added and the mixture stirred at ambient temperature for 3 days. Solid material was filtered off and the filtrate was concentrated. The residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to provide the title compound as the TFA salt. MS (DCI/NH3) m/z 371 (M+H)+; 1H NMR (DMSO-d6) δ 1.58-1.78 (m, 2H), 1.82-2.10 (m, 2H), 2.34 (t, J=6.15 Hz, 2H), 2.76 (t, J=6.35 Hz, 4H), 3.81 (s, 2H), 3.79-4.01 (m, 2H), 6.37 (s, 1H), 7.07 (dd, J=7.14, 2.38 Hz, 1H), 7.18-7.28 (m, 1H), 7.28-7.38 (m, 1H), 11.88 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 371 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 400 (M+H)+
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 449 (M+H)+; 1H NMR (DMSO-d6) δ 1.60-1.82 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.09-3.25 (m, 2H), 3.43 (m, 2H), 3.68 (m, 2H), 3.74-3.88 (m, 4H), 3.84 (s, 2H), 6.38 (s, 1H), 7.17 (d, J=7.12 Hz, 2H), 7.21-7.29 (m, 1H), 7.28-7.33 (m, 1H), 7.34-7.42 (m, 1H), 8.30 (d, J=7.46 Hz, 2H), 11.86 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 450 (M+H)+; 1H NMR (DMSO-d6) δ 1.61-1.76 (m, 2H), 2.34 (t, J=6.15 Hz, 2H), 3.10-3.24 (m, 2H), 3.34 (m, 2H), 3.54 (m, 2H), 3.67 (m, 2H), 3.74 (m, 2H), 3.83 (s, 2H), 6.43 (s, 1H), 7.20-7.27 (m, 1H), 7.28 (dd, J=6.54, 2.18 Hz, 1H), 7.31-7.38 (m, 1H), 7.87 (d, J=2.78 Hz, 1H), 8.10 (d, J=2.78 Hz, 1H), 8.32 (s, 1H), 11.95 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 443 (M+H)+; 1H NMR (DMSO-d6) δ 1.37-1.52 (m, 2H), 2.09 (t, J=6.15 Hz, 2H), 2.17-2.29 (m, 2H), 2.75-2.85 (m, 2H), 2.91 (m, 6H), 2.91-3.01 (m, 4H), 3.38 (m, 2H), 3.56 (s, 2H), 6.17 (s, 1H), 6.91-6.99 (m, 1H), 6.97-7.03 (m, 1H), 7.04-7.10 (m, 1H), 11.68 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 388 (M+H)+; 1H NMR (DMSO-d6) δ 1.57-1.77 (m, 2H), 2.33 (t, J=6.15 Hz, 2H), 2.74-2.97 (m, 1H), 2.85 (s, 3H), 2.86 (s, 3H), 2.87 (s, 3H), 3.16 (m, 2H), 3.24-3.40 (m, 1H), 3.74-3.82 (m, 2H), 3.82 (s, 2H), 6.36 (s, 1H), 7.17-7.30 (m, 2H), 7.32-7.44 (m, 1H), 11.85 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 495 (M+H)+; 1H NMR (DMSO-d6) δ 1.55-1.73 (m, 4H), 2.33-2.44 (m, 4H), 3.03-3.24 (m, 2H), 3.35-3.55 (m, 2H), 3.64-3.90 (m, 6H), 4.29 (s, 2H), 7.21-7.24 (m, 1H), 7.24-7.29 (m, 1H), 7.31-7.37 (m, 1H), 7.41-7.46 (m, 1H), 7.47-7.52 (m, 1H), 7.52-7.55 (m, 1H), 7.59 (s, 1H), 12.61 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 447 (M+H)+; 1H NMR (DMSO-d6) δ 1.55-1.69 (m, 4H), 2.31-2.43 (m, 4H), 3.03-3.13 (m, 2H), 3.18-3.27 (m, 2H), 3.31-3.40 (m, 2H), 3.73-3.82 (m, 2H), 3.92 (s, 2H), 6.82 (t, J=7.21 Hz, 1H), 6.92-6.95 (m, 1H), 6.95-6.98 (m, 1H), 7.20-7.25 (m, 3H), 7.26 (d, J=6.14 Hz, 1H), 7.28-7.33 (m, 1H), 12.60 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 386 (M+H)+; 1H NMR (DMSO-d6) δ 1.52-1.78 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 2.84 (s, 3H), 2.92-3.25 (m, 6H), 3.39 (m, 2H), 3.57 (m, 2H), 3.83 (s, 2H), 6.37 (s, 1H), 7.06-7.36 (m, 2H), 7.33-7.51 (m, 1H), 11.86 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 481 (M+H)+; 1H NMR (DMSO-d6) δ 1.55-1.70 (m, 4H), 2.33-2.43 (m, 4H), 2.87-2.96 (m, 2H), 2.99-3.06 (m, 2H), 3.33-3.42 (m, 2H), 3.76-3.85 (m, 2H), 3.93 (s, 2H), 7.04-7.10 (m, 1H), 7.16 (dd, J=7.98, 1.53 Hz, 1H), 7.23 (d, J=2.76 Hz, 1H), 7.24-7.27 (m, 1H), 7.28-7.30 (m, 1H), 7.30-7.34 (m, 1H), 7.43 (dd, J=7.98, 1.53 Hz, 1H), 12.61 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 495 (M+H)+; 1H NMR (DMSO-d6) δ 1.54-1.70 (m, 4H), 2.32-2.43 (m, 4H), 3.08-3.29 (m, 2H), 3.36-3.52 (m, 2H), 3.96-4.20 (m, 6H), 4.32 (s, 2H), 7.23-7.29 (m, 2H), 7.31-7.37 (m, 1H), 7.43-7.50 (m, 2H), 7.55-7.60 (m, 1H), 7.63-7.68 (m, 1H), 12.61 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 414 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 413 (M+H)+; 1H NMR (DMSO-d6) δ 1.56-1.68 (m, 4H), 2.00 (s, 1.5H), 2.02 (s, 1.5H), 2.32-2.41 (m, 4H), 3.14-3.21 (m, 1H), 3.21-3.27 (m, 1H), 3.35-3.43 (m, 2H), 3.48-3.55 (m, 2H), 3.55-3.62 (m, 1H), 3.63-3.70 (m, 1H), 3.92 (s, 2H), 7.20-7.27 (m, 2H), 7.28-7.32 (m, 1H), 12.63 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 465 (M+H)+; 1H NMR (DMSO-d6) δ 1.55-1.70 (m, 4H), 2.31-2.43 (m, 4H), 3.28-3.37 (m, 2H), 3.56-3.66 (m, 2H), 3.69-3.80 (m, 4H), 3.92 (s, 2H), 6.63 (dd, J=3.38, 1.84 Hz, 1H), 7.02 (d, J=3.38 Hz, 1H), 7.21-7.27 (m, 2H), 7.28-7.35 (m, 1H), 7.84 (s, 1H), 12.61 (br s, 1H)
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 465 (M+H)+; 1H NMR (DMSO-d6) δ 1.56-1.69 (m, 4H), 2.31-2.44 (m, 4H), 2.90-2.98 (m, 2H), 3.02-3.10 (m, 2H), 3.32-3.38 (m, 2H), 3.75-3.83 (m, 2H), 3.93 (s, 2H), 6.97-7.02 (m, 1H), 7.02-7.08 (m, 1H), 7.08-7.13 (m, 1H), 7.14-7.18 (m, 1H), 7.20-7.23 (m, 1H), 7.23-7.27 (m, 1H), 7.28-7.33 (m, 1H), 12.61 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 483 (M+H)+; 1H NMR (DMSO-d6) δ 1.56-1.71 (m, 4H), 2.32-2.43 (m, 4H), 2.86-2.94 (m, 2H), 2.97-3.06 (m, 2H), 3.31-3.42 (m, 2H), 3.74-3.83 (m, 2H), 3.92 (s, 2H), 6.96-7.03 (m, 1H), 7.05-7.13 (m, 1H), 7.17-7.21 (m, 1H), 7.22-7.23 (m, 1H), 7.24-7.27 (m, 1H), 7.28-7.33 (m, 1H), 12.61 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 475 (M+H)+; 1H NMR (DMSO-d6) δ 1.54-1.69 (m, 4H), 2.31-2.44 (m, 4H), 3.21-3.35 (m, 2H), 3.39-3.52 (m, 2H), 3.52-3.63 (m, 2H), 3.66-3.78 (m, 2H), 3.91 (s, 2H), 7.19-7.26 (m, 2H), 7.27-7.33 (m, 1H), 7.39-7.49 (m, 5H), 12.60 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 483 (M+H)+; 1H NMR (DMSO-d6) δ 1.36-1.58 (m, 6H), 1.62-1.79 (m, 2H), 2.34 (t, J=0.10 Hz, 2H), 2.98-3.10 (m, 2H), 3.10-3.27 (m, 10H), 3.64 (m, 2H), 3.82 (s, 2H), 6.37 (s, 1H), 7.17-7.24 (m, 1H), 7.23-7.28 (m, 1H), 7.28-7.37 (m, 1H), 11.88 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 465 (M+H)+; 1H NMR (DMSO-d6) δ 1.57-1.70 (m, 4H), 2.32-2.45 (m, 4H), 3.09-3.16 (m, 2H), 3.23-3.29 (m, 2H), 3.30-3.37 (m, 2H), 3.71-3.79 (m, 2H), 3.92 (s, 2H), 6.55-6.61 (m, 1H), 6.72-6.76 (m, 1H), 6.76-6.79 (m, 1H), 7.19-7.25 (m, 2H), 7.25-7.28 (m, 1H), 7.28-7.34 (m, 1H), 12.60 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 465 (M+H)+; 1H NMR (DMSO-d6) δ 1.55-1.70 (m, 4H), 2.31-2.44 (m, 4H), 2.97-3.06 (m, 2H), 3.10-3.20 (m, 2H), 3.29-3.38 (m, 2H), 3.72-3.83 (m, 2H), 3.92 (s, 2H), 6.95-7.00 (m, 2H), 7.04-7.10 (m, 2H), 7.20-7.24 (m, 1H), 7.23-7.28 (m, 1H), 7.28-7.34 (m, 1H), 12.61 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 448 (M+H)+; 1H NMR (DMSO-d6) δ 1.55-1.70 (m, 4H), 2.31-2.44 (m, 4H), 3.33-3.43 (m, 2H), 3.52-3.59 (m, 2H), 3.64-3.73 (m, 2H), 3.74-3.82 (m, 2H), 3.93 (s, 2H), 6.80-6.86 (m, 1H), 7.09 (d, J=8.59 Hz, 1H), 7.22-7.29 (m, 2H), 7.30-7.37 (m, 1H), 7.76-7.84 (m, 1H), 8.10 (dd, J=5.52, 1.84 Hz, 1H), 12.61 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 470 (M+H)+; 1H NMR (DMSO-d6) δ 1.04 (t, J=7.06 Hz, 6H), 1.57-1.67 (m, 4H), 2.32-2.42 (m, 4H), 2.99-3.06 (m, 2H), 3.10-3.17 (m, 6H), 3.19-3.26 (m, 2H), 3.57-3.66 (m, 2H), 3.91 (s, 2H), 7.19-7.22 (m, 1H), 7.22-7.25 (m, 1H), 7.26-7.32 (m, 1H), 12.60 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 413 (M+H)+; 1H NMR (DMSO-d6) δ 1.26 (d, J=6.75 Hz, 6H), 1.54-1.69 (m, 4H), 2.32-2.43 (m, 4H), 2.87-3.01 (m, 1H), 3.05-3.23 (m, 2H), 3.29-3.45 (m, 2H), 3.48-3.63 (m, 3H), 3.93 (s, 2H), 4.64 (d, J=6.44 Hz, 1H), 7.23-7.30 (m, 2H), 7.32-7.38 (m, 1H), 12.62 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 483 (M+H)+; 1H NMR (DMSO-d6) δ 1.60-1.75 (m, 2H), 1.77-1.86 (m, 2H), 1.89-1.94 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 3.08-3.25 (m, 4H), 3.26-3.45 (m, 6H), 3.56 (m, 4H), 3.83 (s, 2H), 4.21 (s, 2H), 6.36 (s, 1H), 7.13-7.33 (m, 2H), 7.32-7.51 (m, 1H), 11.85 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 484 (M+H)+; 1H NMR (DMSO-d6) δ 1.56-1.67 (m, 4H), 2.30-2.41 (m, 4H), 3.11 (dd, J=6.14, 3.38 Hz, 2H), 3.13-3.17 (m, 4H), 3.19-3.25 (m, 4H), 3.53-3.57 (m, 4H), 3.59-3.66 (m, 2H), 3.91 (s, 2H), 7.19-7.22 (m, 1H), 7.22-7.25 (m, 1H), 7.27-7.32 (m, 1H), 12.60 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 414 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 416 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 450 (M+H)+; 1H NMR (DMSO-d6) δ 1.39-1.85 (m, 2H), 2.33 (t, J=6.10 Hz, 2H), 3.06-3.21 (m, 2H), 3.24-3.35 (m, 2H), 3.55-3.96 (m, 8H), 6.40 (s, 1H), 6.67 (t, J=4.75 Hz, 1H), 7.16-7.26 (m, 1H), 7.24-7.30 (m, 1H), 7.30-7.39 (m, 1H), 8.38 (d, J=4.75 Hz, 2H), 11.91 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH3) m/z 482 (M+H)+; 1H NMR (CD3OD) δ 1.69-1.76 (m, 4H), 1.93 (q, J=6.55 Hz, 2H), 2.01 (q, J=6.55 Hz, 2H), 2.42-2.48 (m, 2H), 2.49-2.56 (m, 2H), 3.34-3.41 (m, 2H), 3.43 (t, J=6.75 Hz, 4H), 3.49 (t, J=6.90 Hz, 4H), 3.67-3.77 (m, 2H), 4.00 (s, 2H), 4.19 (s, 2H), 7.19 (dd, J=9.51, 8.59 Hz, 1H), 7.29 (dd, J=6.29, 2.30 Hz, 1H), 7.38-7.43 (m, 1H).
To a solution of EXAMPLE 493F (75 mg, 0.27 mmol) in N,N-dimethylformamide (8 mL) was added isopropyl isocyanate (23 mg, 0.27 mmol) and triethylamine (0.12 mL, 0.81 mmol). The reaction mixture was stirred at 70° C. for 16 hours and was concentrated. The residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to provide the title compound. MS (DCI/NH3) m/z 359 (M+H)+.
The title compound was prepared, using the appropriate reagents, according to the procedure for EXAMPLE 538. MS (DCI/NH3) m/z 359 (M+H)+.
The title compound was prepared, using the appropriate reagents, according to the procedure for EXAMPLE 538. MS (DCI/NH3) m/z 385 (M+H)+.
The title compound was prepared, using the appropriate reagents, according to the procedure for EXAMPLE 538. MS (DCI/NH3) m/z 429 (M+H)+.
The title compound was prepared, using the appropriate reagents, according to the procedure for EXAMPLE 538. MS (DCI/NH3) m/z 373 (M+H)+.
To a solution of EXAMPLE 492F (1.5 g, 5 mmol) in N,N-dimethylformamide (20 mL) was added benzylpiperazine-1-carboxylate (1.09 g, 5 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (1.9 g, 10 mmol), N-hydroxybenzotriazole (HOBt) (1.34 g, 10 mmol), and triethylamine (1.4 mL, 10 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and was concentrated. The residue was diluted with ethyl acetate and washed with brine. The organic layer was concentrated and the residue purified by flash chromatography on silica gel eluting with 60% ethyl acetate in hexanes to provide the title compound. MS (DCI/NH3) m/z 505 (M+H)+; 1H NMR (CD3OD) δ 1.67-1.77 (m, 4H), 2.39-2.56 (m, 4H), 3.33-3.37 (m, 2H), 3.42-3.54 (m, 2H), 3.54-3.65 (m, 2H), 3.71-3.80 (m, 2H), 3.98 (s, 2H), 5.14 (s, 2H), 7.11-7.19 (m, 1H), 7.23 (dd, J=6.35, 2.38 Hz, 1H), 7.29-7.32 (m, 1H), 7.33-7.38 (m, 5H).
The title compound was prepared, using the appropriate reagents, as a free base according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 519 (M+H)+.
The title compound was prepared, using the appropriate reagents, as TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 449 (M+H)+; 1H NMR (DMSO-d6) δ 1.60-1.80 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.10-3.24 (m, 2H), 3.39 (m, 2H), 3.55 (m, 2H), 3.68 (m, 2H), 3.73-3.81 (m, 2H), 3.84 (s, 2H), 6.41 (s, 1H), 6.78-6.88 (m, 1H), 7.09 (d, J=8.81 Hz, 1H), 7.20-7.28 (m, 1H), 7.26-7.32 (m, 1H), 7.32-7.42 (m, 1H), 7.79 (t, J=7.29 Hz, 1H), 8.00-8.14 (m, 1H), 11.90 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 448 (M+H)+; 1H NMR (DMSO-d6) δ 1.52-1.78 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 3.09 (m, 2H), 3.13-3.26 (m, 4H), 3.35 (m, 2H), 3.68-3.85 (m, 2H), 3.83 (s, 2H), 6.36 (s, 1H), 6.82 (t, J=7.29 Hz, 1H), 6.96 (d, J=7.80 Hz, 2H), 7.22 (d, J=8.48 Hz, 2H), 7.24-7.30 (m, 2H), 7.30-7.39 (m, 1H), 11.85 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 466 (M+H)+; 1H NMR (DMSO-d6) δ 1.55-1.87 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.07-3.22 (m, 4H), 3.21-3.30 (m, 2H), 3.34 (m, 2H), 3.76 (m, 2H), 3.83 (s, 2H), 6.41 (s, 1H), 6.49-6.70 (m, 1H), 6.69-6.86 (m, 2H), 7.12-7.25 (m, 1H), 7.22-7.31 (m, 2H), 7.31-7.45 (m, 1H), 11.91 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 466 (M+H)+; 1H NMR (DMSO-d6) δ 1.53-1.86 (m, 2H), 2.35 (t, J=6.15 Hz, 2H), 3.03 (m, 2H), 3.09-3.24 (m, 4H), 3.36 (m, 2H), 3.78 (m, 2H), 3.83 (s, 2H), 6.43 (s, 1H), 6.94-7.02 (m, 2H), 7.02-7.12 (m, 2H), 7.19-7.31 (m, 2H), 7.30-7.40 (m, 1H), 11.94 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 466 (M+H)+; 1H NMR (DMSO-d6) δ 1.61-1.81 (m, 2H), 2.34 (t, J=6.15 Hz, 2H), 2.96 (m, 2H), 3.00-3.12 (m, 2H), 3.13-3.22 (m, 2H), 3.38 (m, 2H), 3.80 (m, 2H), 3.83 (s, 2H), 6.38 (s, 1H), 6.96-7.05 (m, 1H), 7.06-7.13 (m, 2H), 7.13-7.19 (m, 1H), 7.19-7.30 (m, 2H), 7.30-7.38 (m, 1H), 11.87 (s, 1H).
The title compound was prepared, using the appropriate reagents, according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 466 (M+H)+; 1H NMR (DMSO-d6) δ 1.62-1.77 (m, 2H), 2.34 (t, J=6.35 Hz, 2H), 2.90 (m, 2H), 2.96-3.06 (m, 2H), 3.17 (m, 2H), 3.29-3.48 (m, 2H), 3.79 (m, 2H), 3.82 (s, 2H), 6.35 (s, 1H), 7.02 (dd, J=7.93, 2.78 Hz, 1H), 7.08 (dd, J=9.12, 5.95 Hz, 1H), 7.16-7.22 (m, 1H), 7.22-7.30 (m, 2H), 7.30-7.38 (m, 1H), 11.85 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 476 (M+H)+; 1H NMR (DMSO-d6) δ 1.57-1.78 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 3.17 (m, 4H), 3.21-3.37 (m, 2H), 3.45 (m, 2H), 3.69 (m, 2H), 3.82 (s, 2H), 6.40 (s, 1H), 7.18-7.30 (m, 2H), 7.29-7.38 (m, 1H), 7.39-7.50 (m, 5H), 11.92 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 466 (M+H)+; 1H NMR (DMSO-d6) δ 1.59-1.79 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.06-3.25 (m, 2H), 3.33 (m, 2H), 3.65 (m, 2H), 3.68-3.81 (m, 4H), 3.83 (s, 2H), 6.43 (s, 1H), 6.63 (dd, J=3.56, 1.86 Hz, 1H), 7.03 (dd, J=3.39, 0.68 Hz, 1H), 7.18-7.31 (m, 2H), 7.31-7.39 (m, 1H), 7.83-7.86 (m, 1H), 11.93 (s, 1H).
The title compound was prepared, using the appropriate reagents, (as a TFA salt?) according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 482 (M+H)+; 1H NMR (DMSO-d6) δ 1.56-1.80 (m, 2H), 2.34 (t, J=6.27 Hz, 2H), 2.75-2.98 (m, 2H), 2.96-3.09 (m, 2H), 3.17 (m, 2H), 3.35 (m, 2H), 3.74-3.83 (m, 2H), 3.83 (s, 2H), 6.36 (s, 1H), 7.02-7.10 (m, 1H), 7.17 (dd, J=8.14, 1.36 Hz, 1H), 7.20-7.31 (m, 2H), 7.30-7.38 (m, 2H), 7.43 (dd, J=7.97, 1.53 Hz, 1H), 11.85 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 482 (M+H)1.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 450 (M+H); 1H NMR (DMSO-d6) δ 1.63-1.81 (m, 2H), 2.35 (t, J=6.27 Hz, 2H), 2.91 (m, 3H), 3.09 (m, 2H), 3.12-3.24 (m, 4H), 3.32 (m, 2H), 3.74 (m, 2H), 3.82 (s, 2H), 6.38 (s, 1H), 7.17-7.29 (m, 2H), 7.31-7.39 (m, 1H), 11.89 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 471 (M+H)+; 1H NMR (DMSO-d6) δ 1.04 (t, J=6.95 Hz, 6H), 1.51-1.85 (m, 2H), 2.35 (t, J=6.27 Hz, 2H), 3.04 (m, 2H), 3.07-3.38 (m, 10H), 3.64 (m, 2H), 3.82 (s, 2H), 6.39 (s, 1H), 7.02-7.28 (m, 2H), 7.26-7.45 (m, 1H), 11.90 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 412 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 457 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 492 (M+H)+; 1H NMR (DMSO-d6) δ 1.61-1.84 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.17 (m, 6H), 3.58 (s, 4H), 3.83 (s, 2H), 4.19-4.53 (m, 4H), 6.37 (s, 1H), 6.94-7.06 (m, 3H), 7.21-7.45 (m, 5H), 11.86 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 512 (M+H)+; 1H NMR (DMSO-d6) 1.54-1.73 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 2.88 (m, 2H), 2.92-3.03 (m, 2H), 3.07-3.18 (m, 2H), 3.30 (m, 2H), 3.66-3.77 (m, 2H), 3.83 (s, 2H), 6.32 (s, 1H), 6.94-7.23 (m, 2H), 7.22-7.44 (m, 1H), 7.44-7.87 (m, 5H), 11.84 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 429 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 440 (M+H)+; 1H NMR (DMSO-d6) δ 1.29-1.86 (m, 8H), 2.01 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 2.98 (m, 1H), 3.03-3.29 (m, 4H), 3.43 (m, 2H), 3.56 (m, 4H), 3.83 (s, 2H), 6.38 (s, 1H), 7.04-7.34 (m, 2H), 7.34-7.54 (m, 1H), 11.86 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 442 (M+H)+; 1H NMR (DMSO-d6) δ 0.99 (d, J=4.41 Hz, 6H), 1.61-1.78 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 2.88 (m, 1H), 3.07-3.32 (m, 4H), 3.45 (m, 2H), 3.58 (m, 4H), 3.82 (s, 2H), 6.40 (s, 1H), 7.04-7.31 (m, 2H), 7.29-7.50 (m, 1H), 11.90 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 485 (M+H)+; 1H NMR (DMSO-d6) δ 1.61-1.78 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 2.73 (m, 2H), 2.81-2.92 (m, 2H), 2.99 (m, 2H), 3.17 (m, 6H), 3.25 (t, J=5.93 Hz, 2H), 3.35 (m, 2H), 3.73-3.82 (m, 6H), 3.83 (s, 2H), 6.39 (s, 1H), 7.09-7.32 (m, 2H), 7.29-7.54 (m, 1H), 11.88 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 468 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 482 (M+H)+; 1H NMR (DMSO-d6) δ 1.04-1.42 (m, 5H), 1.47-1.81 (m, 6H), 2.35 (t, J=6.10 Hz, 2H), 3.08-3.29 (m, 6H), 3.43 (s, 2H), 3.57 (s, 4H), 3.82 (s, 2H), 6.39 (s, 1H), 7.09-7.31 (m, 2H), 7.28-7.46 (m, 1H), 11.90 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 470 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 483 (M+H)+; 1H NMR (DMSO-d6) 1.53 (m, 2H), 1.72 (m, 6H), 2.34 (t, J=6.27 Hz, 2H), 2.64 (m, 2H), 2.69-2.85 (m, 2H), 2.92 (m, 2H), 3.11-3.23 (m, 4H), 3.23-3.41 (m, 4H), 3.59-3.78 (m, 2H), 3.83 (s, 2H), 6.38 (s, 1H), 6.99-7.31 (m, 2H), 7.28-7.52 (m, 1H), 11.86 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 484 (M+H)+; 1H NMR (CD3OD) δ 1.68-1.77 (m, 4H), 2.41-2.47 (m, 2H), 2.49-2.55 (m, 2H), 2.60-2.70 (m, 2H), 2.74-2.82 (m, 2H), 2.92 (t, J=5.95 Hz, 2H), 3.32-3.36 (m, 6H), 3.40-3.48 (m, 2H), 3.82-3.87 (m, 2H), 3.89-3.95 (m, 4H), 3.99 (s, 2H), 7.14-7.19 (m, 1H), 7.21 (dd, J=6.41, 2.14 Hz, 1H), 7.35-7.39 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 387 (M+H)+; 1H NMR (DMSO-d6) δ 1.15-1.44 (m, 2H), 1.56-1.86 (m, 4H), 2.34 (t, J=6.10 Hz, 2H), 2.94-3.11 (m, 1H), 3.11-3.24 (m, 3H), 3.25-3.41 (m, 1H), 3.61-3.79 (m, 1H), 3.82 (s, 2H), 3.92-4.14 (m, 1H), 6.40 (s, 1H), 6.89-7.25 (m, 2H), 7.24-7.45 (m, 1H), 11.90 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 464 (M+H)+; 1H NMR (DMSO-d6) δ 1.64-1.78 (m, 2H), 2.31 (s, 3H), 2.35 (t, J=6.27 Hz, 2H), 3.11-3.26 (m, 2H), 3.35 (m, 2H), 3.52 (m, 2H), 3.67 (m, 2H), 3.74 (m, 2H), 3.84 (s, 2H), 6.44 (s, 1H), 7.20-7.31 (m, 2H), 7.31-7.39 (m, 1H), 7.78 (s, 1H), 8.12 (s, 1H), 11.95 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 511 (M+H)+; 1H NMR (CD3OD) δ 1.64-1.75 (m, 4H), 2.37-2.44 (m, 2H), 2.45-2.54 (m, 2H), 2.94-3.01 (m, 2H), 3.04-3.16 (m, 2H), 3.39-3.46 (m, 2H), 3.83 (t, J=5.03 Hz, 2H), 3.95 (s, 2H), 7.08-7.13 (m, 1H), 7.15 (dd, J=6.41, 2.14 Hz, 1H), 7.30-7.35 (m, 1H), 7.63 (t, J=7.63 Hz, 2H), 7.71 (t, J=7.32 Hz, 1H), 7.77 (d, J=1.53 Hz, 1H), 7.79 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 439 (M+H)+; 1H NMR (CD3OD) δ 1.65-1.80 (m, 8H), 1.80-1.90 (m, 2H), 2.10-2.25 (m, 2H), 2.41-2.47 (m, 2H), 2.49-2.56 (m, 2H), 3.03-3.24 (m, 3H), 3.48-3.64 (m, 4H), 3.70-3.86 (m, 2H), 4.00 (s, 2H), 7.17-7.21 (m, 1H), 7.30 (dd, J=6.41, 2.14 Hz, 1H), 7.39-7.42 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 468 (M+H)+; 1H NMR (CD3OD) δ 1.69-1.77 (m, 4H), 1.82-1.89 (m, 4H), 2.42-2.47 (m, 2H), 2.48-2.55 (m, 2H), 3.23-3.27 (m, 2H), 3.34-3.39 (m, 8H), 3.39-3.44 (m, 1H), 3.76-3.81 (m, 2H), 3.99 (s, 2H), 7.13-7.19 (m, 1H), 7.24 (dd, J=6.26, 2.29 Hz, 1H), 7.32-7.37 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 491 (M+H)+; 1H NMR (CD3OD) δ 1.66-1.79 (m, 4H), 2.39-2.47 (m, 2H), 2.48-2.55 (m, 2H), 3.35-3.48 (m, 2H), 3.48-3.61 (m, 4H), 3.64-3.69 (m, 2H), 3.69-3.78 (m, 2H), 4.00 (s, 2H), 4.34-4.44 (m, 2H), 6.99-7.00 (m, 1H), 7.01-7.03 (m, 2H), 7.17-7.23 (m, 1H), 7.28-7.31 (m, 1H), 7.30-7.35 (m, 2H), 7.38-7.44 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 428 (M+H)+; 1H NMR (CD3OD) δ 1.66-1.78 (m, 4H), 2.38-2.46 (m, 2H), 2.46-2.56 (m, 2H), 2.81-2.87 (m, 3H), 2.89 (s, 3H), 2.94-3.07 (m, 3H), 3.33-3.44 (m, 4H), 3.58 (t, J=6.26 Hz, 2H), 4.00 (s, 2H), 7.16 (dd, J=10.83, 8.39 Hz, 1H), 7.38-7.42 (m, 1H), 7.59 (dd, J=6.87, 2.29 Hz, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 441 (M+H)+; 1H NMR (CD3OD) δ 1.04-1.17 (m, 6H), 1.67-1.79 (m, 4H), 2.41-2.48 (m, 2H), 2.49-2.57 (m, 2H), 2.85-3.03 (m, 1H), 3.32-3.45 (m, 2H), 3.54-3.63 (m, 2H), 3.66-3.73 (m, 2H), 3.73-3.86 (m, 2H), 3.99 (s, 2H), 7.14-7.20 (m, 1H), 7.22-7.29 (m, 1H), 7.34-7.38 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/H3) m/z 399 (M+H); 1H NMR (CD3OD) δ 1.37 (t, J=7.32 Hz, 3H), 1.67-1.81 (m, 4H), 2.41-2.48 (m, 2H), 2.48-2.57 (m, 2H), 2.98-3.22 (m, 2H), 3.26 (q, J=7.32 Hz, 2H), 3.40-3.87 (m, 6H), 4.00 (s, 2H), 7.17-7.22 (m, 1H), 7.29 (dd, J=6.41, 2.14 Hz, 1H), 7.38-7.44 (m, 1H).
To a solution of EXAMPLE 493F (200 mg, 0.732 mmol) in a mixture of dioxane (6 mL) and acetonitrile (2 mL) was added N-(carbobenzyloxy-L-aspartic anhydride (365 mg, 1.464 mmol). The mixture was heated at 80° C. for 24 hours, cooled to ambient temperature and concentrated. The residue was dissolved in anhydrous methylene chloride (10 mL) and was treated with 1,1′-carbonyldiimidazole (CDI) (356 mg, 2.195 mmol) at ambient temperature overnight. The mixture was directly purified by flash chromatography [0-15% methanol in 2:1 ethyl acetate/hexane] to give a mixture of two major products. The slower diluting fraction was further purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in CH3CN; 0-100% gradient) to provide the title compound as the TFA salt. MS (DCI/NH3) m/z 399 (M+H)+.
A solution of EXAMPLE 506D (1 g, 3.2 mmol) in methanol (20 mL) was treated with 7N ammonia in methanol (15 mL) in a pressure tube at 90° C. overnight. After cooling to room temperature, the white solid material was collected by filtration, washed with methanol, and dried to give the title compound. MS (DCI/NH3) m/z 299 (M+H)+.
To a mixture of ice (50 g) and a solution of KOH (2 g, 36 mmol) in 8 mL of water was added bromine (0.2 mL, 4 mmol) at −10° C. The mixture was stirred at −10° C. for 10 minutes, and EXAMPLE 582A (1.2 g, 0.4 mmol) was added. This mixture was stirred at −10° C. for an additional 10 minutes and at 65° C. for 1 hour. After cooling to room temperature, the mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic phase was washed with brine, water and concentrated to about 10 mL. The formed solid material was washed with methanol and dried to give the title compound. MS (DCI/NH3) m/z 271 (M+H)+.
A mixture of EXAMPLE 582B (1.3 g, 4.8 mmol), 5% Pt/C (650 mg), concentrated HCl (0.8 mL) and N,N-dimethylformamide (150 mL) in a pressure vessel was purged and pressurized with hydrogen at ambient temperature for 16 hours. Solid material was filtered off and the filtrate concentrated. The residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to provide the title compound as the TFA salt. MS (ESI) m/z 275 (M+H)+.
A suspension of EXAMPLE 582C (50 mg, 0.18 mmol) in CH3CN (15 mL) was heated until homogeneous. After cooling, methyl 2-isocyanato-3-methylbutanoate (32 mg, 0.18 mmol) was added, and the mixture stirred at 65° C. overnight. The mixture was concentrated and the residue dissolved in N,N-dimethylformamide (10 mL), 2N NaOH (1 mL) was added, and the mixture stirred at room temperature overnight. Solvent was removed and the residue purified by HPLC (Zorbax C-8, 0.1% TFA/CH3CN/H2O) to provide the title compound as the TFA salt. MS (DCI/NH3) m/z 416 (M+H)+; 1H NMR (DMSO-d6) δ 0.88 (d, J=6.74 Hz, 3H), 0.92 (d, J=6.74 Hz, 3H), 1.56-1.75 (m, 2H), 1.98-2.19 (m, 1H), 2.34 (t, J=6.15 Hz, 2H), 3.01-3.27 (m, 2H), 3.74 (s, 2H), 4.10 (dd, J=8.53, 4.56 Hz, 1H), 6.34 (s, 1H), 6.67-6.86 (m, 1H), 6.93 (d, J=8.72 Hz, 1H), 7.08 (dd, J=11.50, 8.33 Hz, 1H), 8.48 (d, J=2.78 Hz, 1H), 11.90 (s, 1H).
To a solution of EXAMPLE 581 (150 mg, 0.297 mmol) in methanol (10 mL) was added 10% palladium on carbon (30 mg) under nitrogen. This suspension was purged with hydrogen, and stirred under hydrogen (balloon) for 1.5 hours. Solid material was filtered off and the filtrate concentrated. The residue was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in CH3CN; 0-100% gradient) to provide the title compound as the TFA salt. MS (DCI/NH3) m/z 371 (M+H)+; 1H NMR (CD3OD) δ 1.62 (m, 4H), 2.33-2.40 (m, 4H), 2.84-2.93 (m, 1H), 3.18-3.30 (m, 1H), 3.96 (s, 2H), 4.56-4.65 (m, 1H), 7.09 (d, J=5.83 Hz, 1H), 7.36-7.44 (m, 2H), 8.71 (s, 2H) 12.64 (s, 1H).
To a solution of EXAMPLE 493F (75 mg, 0.27 mmol) in 1:1 tetrahydrofuran/acetonitrile (6 mL) was added 4-methylpiperazine-1-carbonylchloride (179 mg, 1.1 mmol) and triethylamine (56 mg, 0.55 mmol). The mixture was heated at 70° C. for 18 hours and was concentrated. The residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to provide the title compound as a free base. MS (DCI/NH3) m/z 400 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 427 (M+H)+; 1H NMR (CD3OD) δ 1.06-1.15 (m, 3H), 1.67-1.75 (m, 4H), 2.40 (q, J=7.63 Hz, 2H), 2.43-2.48 (m, 2H), 2.48-2.55 (m, 2H), 3.32-3.43 (m, 2H), 3.51-3.59 (m, 2H), 3.62-3.71 (m, 2H), 3.73-3.83 (m, 2H), 3.99 (s, 2H), 7.14-7.19 (m, 1H), 7.23-7.28 (m, 1H), 7.33-7.38 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18. 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 463 (M+H)+; 1H NMR (DMSO-d6) δ 1.21 (t, J=7.48 Hz, 3H), 1.55-1.72 (m, 4H), 2.32-2.43 (m, 4H), 3.08 (q, J=7.53 Hz, 2H), 3.11-3.18 (m, 2H), 3.23-3.32 (m, 4H), 3.64-3.79 (m, 2H), 3.92 (s, 2H), 7.20-7.23 (m, 1H), 7.23-7.27 (m, 1H), 7.29-7.33 (m, 1H), 12.63 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 455 (M+H)+; 1H NMR (CD3OD) δ 1.28 (s, 9H), 1.68-1.77 (m, 4H), 2.42-2.48 (m, 2H), 2.48-2.55 (m, 2H), 3.34-3.39 (m, 2H), 3.60-3.67 (m, 2H), 3.73-3.81 (m, 4H), 4.00 (s, 2H), 7.14-7.19 (m, 1H), 7.25 (dd, J=6.26, 2.29 Hz, 1H), 7.33-7.38 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 505 (M+H)+; 1H NMR (CD3OD) δ 1.67-1.76 (m, 4H), 2.42-2.48 (m, 2H), 2.47-2.53 (m, 2H), 3.33-3.45 (m, 2H), 3.54-3.62 (m, 2H), 3.66-3.73 (m, 2H), 3.74-3.86 (m, 2H), 3.99 (s, 2H), 4.79 (s, 2H), 6.92-7.00 (m, 3H), 7.16 (t, J=9.00 Hz, 1H), 7.23-7.30 (m, 3H), 7.33-7.39 (m, 1H).
The title compound was prepared, using the appropriate reagents, as TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 506 (M+H)+; 1H NMR (DMSO-d6) δ 1.58-1.78 (m, 2H), 2.34 (t, J=6.27 Hz, 2H), 3.06-3.34 (m, 4H), 3.44 (m, 2H), 3.56 (m, 2H), 3.66 (m, 2H), 3.83 (s, 2H), 4.84 (d, J=16.95 Hz, 2H), 6.39 (s, 1H), 6.84-6.99 (m, 3H), 7.16-7.31 (m, 4H), 7.31-7.39 (m, 1H), 11.90 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 456 (M+H)+; 1H NMR (DMSO-d6) δ 1.19 (s, 9H), 1.50-1.80 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 2.97-3.32 (m, 4H), 3.47-3.58 (m, 2H), 3.62 (s, 4H), 3.83 (s, 2H), 6.42 (s, 1H) 7.10-7.28 (m, 2H), 7.29-7.46 (m, 1H) 11.93 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 464 (M+H)+; 1H NMR (DMSO-d6) δ 1.21 (t, J=7.46 Hz, 3H), 1.63-1.77 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.08 (q, J=7.23 Hz, 2H), 3.13-3.22 (m, 4H), 3.21-3.35 (m, 4H), 3.71 (s, 2H), 3.82 (s, 2H), 6.40 (s, 1H), 7.08-7.28 (m, 2H), 7.29-7.47 (m, 1H), 11.91 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 428 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 442 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 428 (M+H)+; 1H NMR (DMSO-d6) δ 0.99 (t, J=6.95 Hz, 3H), 1.58-1.82 (m, 2H), 2.22-2.44 (m, 4H), 3.04-3.31 (m, 4H), 3.41 (m, 2H), 3.52 (m, 2H), 3.56-3.72 (m, 2H), 3.83 (s, 2H), 6.45 (s, 1H), 7.05-7.28 (m, 2H), 7.28-7.50 (m, 1H), 11.96 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 582. MS (DCI/NH3) m/z 372 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 478 (M+H)+; 1H NMR (DMSO-d6) δ 1.62-1.79 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.02 (m, 2H), 3.07-3.24 (m, 4H), 3.39 (m, 2H), 3.70 (s, 3H), 3.81 (m, 2H), 3.84 (s, 2H), 6.46 (s, 1H), 6.89 (d, J=8.48 Hz, 2H), 7.00 (d, J=8.81 Hz, 2H), 7.18-7.31 (m, 2H), 7.31-7.40 (m, 1H), 11.99 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 542 (M+H)+; 1H NMR (DMSO-d6) δ 1.55-1.77 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 2.74-2.89 (m, 2H), 2.94 (m, 2H), 3.09-3.19 (m, 2H), 3.24-3.36 (m, 2H), 3.71 (m, 2H), 3.78 (s, 2H), 3.87 (s, 3H), 6.34 (s, 1H), 7.17 (d, J=8.81 Hz, 2H), 7.16-7.23 (m, 2H), 7.23-7.37 (m, 1H), 7.67 (d, J=9.15 Hz, 2H), 11.87 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 506 (M+H)+; 1H NMR (DMSO-d6) δ 1.57-1.80 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.09-3.22 (m, 2H), 3.29 (m, 2H), 3.48 (m, 2H), 3.55 (m, 2H), 3.69 (m, 2H), 3.79 (s, 3H), 3.83 (s, 2H), 6.43 (s, 1H), 6.98 (d, J=8.48 Hz, 2H), 7.16-7.30 (m, 2H), 7.28-7.36 (m, 1H), 7.40 (d, J=8.81 Hz, 2H), 11.94 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 516 (M+H)+; 1H NMR (DMSO-d6) δ 1.55-1.83 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.09-3.26 (m, 4H), 3.27-3.43 (m, 4H), 3.79 (m, 2H), 3.83 (s, 2H), 6.41 (s, 1H), 7.11 (d, J=7.80 Hz, 1H), 7.17-7.32 (m, 4H), 7.31-7.39 (m, 1H), 7.44 (t, J=7.80 Hz, 1H), 11.91 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m z 542 (M+H)+; 1H NMR (DMSO-d6) 1.41 (s, 9H), 1.59 (m, 2H), 1.63-1.78 (m, 2H), 2.33 (t, J=5.43 Hz, 2H), 3.14-3.22 (m, 2H), 3.21-3.38 (m, 1H), 3.43-3.54 (m, 2H), 3.62-3.78 (m, 1H), 3.71-3.83 (m, 2H), 5.11 (s, 2H), 6.38 (d, J=2.03 Hz, 1H), 7.00-7.29 (m, 2H), 7.29-7.59 (m, 1H), 11.89 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 457 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 582. MS (DCI/NH3) m/z 448 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 582. MS (DCI/NH3) m/z 372 (M+H)+; 1H NMR (DMSO-d6) δ 1.68 (m, 2H), 2.27-2.37 (m, 2H), 2.40 (t, J=6.27 Hz, 2H), 3.17 (m, 2H), 3.33 (m, 2H), 3.73 (s, 2H), 6.24 (s, 1H), 6.66-6.82 (m, 2H), 7.05 (dd, J=11.36, 8.31 Hz, 1H), 8.31 (s, 1H), 11.79 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 386 (M+H)+; 1H NMR (DMSO-d6) 1.47-1.78 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 3.07-3.24 (m, 2H), 3.39 (m, 2H), 3.69-3.81 (m, 2H), 3.83 (s, 2H), 4.11 (s, 2H), 6.38 (s, 1H), 7.04-7.30 (m, 2H), 7.31-7.41 (m, 1H), 8.13 (s, 1H), 11.89 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 475 (M+H)+; 1H NMR (DMSO-d6) δ 1.38-1.58 (m, 2H), 1.59-1.74 (m, 2H), 1.70-1.81 (m, 1H), 1.91 (m, 1H), 2.33 (t, 0.1=6.10 Hz, 2H), 2.90-3.08 (m, 1H), 3.13-3.21 (m, 2H), 3.21-3.29 (m, 1H), 3.45 (m, 1H), 3.65-3.83 (m, 1H), 3.82 (s, 2H), 4.52 (m, 1H), 6.39 (s, 1H), 7.14-7.28 (m, 2H), 7.28-7.35 (m, 1H), 7.55 (t, J=7.29 Hz, 2H), 7.60-7.70 (m, 1H), 7.95-8.04 (m, 2H), 11.88 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 505 (M+H)+; 1H NMR (DMSO-d6) 1.38-1.58 (m, 2H), 1.60-1.74 (m, 3H), 1.81-1.88 (m, 1H), 2.33 (t, J=6.10 Hz, 2H), 2.91-3.06 (m, 1H), 3.17 (m, 2H), 3.19-3.30 (m, 1H), 3.45 (m, 1H), 3.72 (m, 1H), 3.82 (s, 2H), 3.85 (s, 3H), 4.52 (m, 1H), 6.41 (s, 1H), 7.06 (d, J=9.15 Hz, 2H), 7.13-7.26 (m, 2H), 7.27-7.36 (m, 1H), 7.99 (d, J=9.15 Hz, 2H), 11.89 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 515 (M+H)+; 1H NMR (DMSO-d6) δ 1.60-1.74 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 3.17 (m, 2H), 3.30 (m, 2H), 3.52 (m, 2H), 3.57-3.66 (m, 2H), 3.69 (m, 2H), 3.82 (s, 2H), 6.48 (s, 1H), 7.06 (m, 2H), 7.16-7.30 (m, 2H), 7.30-7.38 (m, 1H), 7.47 (dd, J=4.92, 2.20 Hz, 2H), 7.58 (d, J=8.14 Hz, 1H), 11.30 (s, 1H), 11.91 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 510 (M+H)+; 1H NMR (DMSO-d6) δ 1.36-1.55 (m, 2H), 1.61-1.74 (m, 3H), 1.81-1.88 (m, 1H), 2.33 (t, J=6.10 Hz, 2H), 2.91-3.09 (m, 1H), 3.12-3.20 (m, 2H), 3.20-3.32 (m, 1H), 3.44 (m, 1H), 3.69-3.81 (m, 1H), 3.82 (s, 2H), 4.51 (m, 1H), 6.41 (s, 1H), 7.13-7.27 (m, 2H), 7.26-7.36 (m, 1H), 7.58 (t, J=7.80 Hz, 1H), 7.73 (dd, J=7.46, 1.70 Hz, 1H), 7.90-8.04 (m, 2H), 11.90 (s, 1H).
The title compound was prepared, using the appropriate reagents, according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 506 (M+H)+; 1H NMR (DMSO-d6) δ 1.51-1.76 (m, 2H), 2.33 (t, J=6.10 Hz, 2H), 3.17 (m, 2H), 3.24 (m, 2H), 3.35-3.44 (m, 2H), 3.48 (m, 2H), 3.64 (m, 2H), 3.81 (s, 2H), 5.10 (s, 2H), 6.34 (s, 1H), 7.17-7.28 (m, 2H), 7.29-7.36 (m, 1H), 7.34-7.40 (m, 5H), 11.83 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 548 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 490 (M+H)+.
The title compound was prepared, using the appropriate reagents, as TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 372 (M+H)+.
N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N-methyl-N-phenylurea
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 584. MS (DCI/NH3) m/z 407 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 441 (M+H)+; 1H NMR (DMSO-d6) δ 0.89-1.15 (m, 3H), 1.52-1.65 (m, 4H), 1.90-2.00 (m, 2H), 2.01-2.16 (m, 3H), 2.27-2.40 (m, 4H), 3.18-3.32 (m, 4H), 3.35-3.43 (m, 2H), 3.60-3.74 (m, 1H), 3.90 (s, 2H), 7.17-7.25 (m, 2H), 7.25-7.32 (m, 1H), 12.60 (br s, 1H).
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 541 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 515 (M+H)+; 1H NMR (CD3OD) δ 1.68-1.77 (m, 4H), 2.43-2.48 (m, 2H), 2.49-2.55 (m, 2H), 3.16-3.24 (m, 2H), 3.32-3.36 (m, 2H), 3.46-3.55 (m, 2H), 3.90-3.95 (m, 2H), 4.00 (s, 2H), 7.11 (d, J=7.63 Hz, 1H), 7.17 (t, J=8.85 Hz, 1H), 7.19-7.24 (m, 2H), 7.26 (dd, J=6.41, 2.14 Hz, 1H), 7.34-7.38 (m, 1H), 7.41 (t, J=7.78 Hz, 1H).
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 505 (M+H)+; 1H NMR (CD3OD) δ 1.66-1.77 (m, 4H), 2.41-2.47 (m, 2H), 2.47-2.53 (m, 2H), 3.37-3.48 (m, 2H), 3.55-3.67 (m, 2H), 3.67-3.77 (m, 2H), 3.77-3.82 (m, 2H), 3.83 (s, 3H), 3.99 (s, 2H), 7.00 (d, J=8.85 Hz, 2H), 7.14-7.19 (m, 1H), 7.25 (dd, J=6.10, 2.14 Hz, 1H), 7.33-7.38 (m, 1H), 7.42 (d, J=8.54 Hz, 2H).
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 477 (M+H)+; 1H NMR (CD3OD) δ 1.67-1.77 (m, 4H), 2.42-2.48 (m, 2H), 2.49-2.56 (m, 2H), 3.19-3.27 (m, 2H), 3.33-3.41 (m, 2H), 3.56-3.65 (m, 2H), 3.78 (s, 3H), 3.96-4.07 (m, 4H), 6.93-6.94 (m, 1H), 6.95-6.97 (m, 1H), 7.16-7.18 (m, 2H), 7.19-7.21 (m, 1H), 7.28 (dd, J=6.41, 2.14 Hz, 1H), 7.35-7.41 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 481 (M+H)+; 1H NMR (CD3OD) δ 1.19-1.29 (m, 1H), 1.30-1.40 (m, 2H), 1.41-1.49 (m, 2H), 1.65-1.74 (m, 7H), 1.76-1.84 (m, 2H), 2.41-2.48 (m, 2H), 2.48-2.56 (m, 2H), 2.58-2.73 (m, 1H), 3.33-3.43 (m, 2H), 3.52-3.62 (m, 2H), 3.64-3.72 (m, 2H), 3.72-3.85 (m, 2H), 3.99 (s, 2H), 7.14-7.20 (m, 1H), 7.22-7.28 (m, 1H), 7.33-7.39 (m, 1H).
To a solution of EXAMPLE 493F (100 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added ethyl-2-isocyanoacetate (47 mg, 0.37 mmol). The solution was stirred at room temperature for 16 hours and sodium hydroxide (15 mg, 0.37 mmol) was added. The mixture was heated at 70° C. for 2 hours and was concentrated. The residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to provide the title compound. MS (DCI/NH3) m/z 375 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 625. MS (DCI/NH3) m/z 431 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 625. MS (DCI/NH3) m/z 389 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 625. MS (DCI/NH3) m/z 465 (M+H)+.
To a solution of EXAMPLE 493F (2.0 g, 7.3 mmol) in a mixture of tetrahydrofuran (25 mL) and N,N-dimethylformamide (2 mL) was added ethyl-2-isocyanoacetate (0.95 g, 7.3 mmol). The mixture was stirred at room temperature for 16 hours and was concentrated. The residue was partitioned between ethyl acetate and brine and the organic layer was washed with brine and concentrated. The residue was purified by flash chromatography on silica gel eluting with 70% ethyl acetate in hexanes to provide the title compound. MS (DCI/NH3) m/z 403 (M+H)+; 1H NMR (DMSO-d6) δ 1.19 (t, J=7.17 Hz, 3H), 1.52-1.63 (m, 4H), 2.29-2.40 (m, 4H), 3.81 (s, 2H), 3.86 (d, J=5.80 Hz, 2H), 4.10 (q, J=7.12 Hz, 2H), 6.69-6.77 (m, 1H), 6.88-6.97 (m, 1H), 7.09 (dd, J=11.29, 8.54 Hz, 1H), 7.94 (dd, J=7.93, 1.83 Hz, 1H), 8.56 (br s, 1H), 12.60 (br s, 1H).
To a solution of EXAMPLE 629 (650 mg, 1.6 mmol) in 1:1 chloroform/ethanol (40 mL) was added 10N HCl (20 mL). The mixture was heated at 80° C. for 2 days and was concentrated. The residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to yield the title compound as a free base. MS (DCI/NH3) m/z 357 (M+H)+; 1H NMR (CD3OD) δ 1.69-1.75 (m, 4H), 2.43-2.48 (m, 2H), 2.48-2.54 (m, 2H), 4.01 (s, 2H), 4.15 (s, 2H), 7.18-7.20 (m, 1H), 7.21-7.25 (m, 1H), 7.31-7.35 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 478 (M+H)+; 1H NMR (DMSO-d6) δ 1.48-1.83 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 2.93 (m, 2H), 2.99-3.09 (m, 2H), 3.09-3.26 (m, 2H), 3.37 (m, 2H), 3.76 (m, 2H), 3.79 (s, 3H), 3.84 (s, 2H), 6.46 (s, 1H), 6.84-6.96 (m, 2H), 6.94-7.05 (m, 2H), 7.18-7.30 (m, 2H), 7.30-7.38 (m, 1H), 11.97 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 451 (M+H)+; 1H NMR (DMSO-d6) δ 1.62-1.82 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.10-3.23 (m, 2H), 3.30-3.39 (m, 2H), 3.75 (m, 2H), 3.76-3.82 (m, 2H), 3.84 (s, 2H), 3.86-3.94 (m, 2H), 6.45 (s, 1H), 7.16-7.31 (m, 2H), 7.32-7.40 (m, 1H), 8.64 (s, 2H), 11.96 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 451 (M+H)+; 1H NMR (DMSO-d6) δ 1.61-1.79 (m, 2H), 2.34 (t, J=6.27 Hz, 2H), 3.11-3.22 (m, 2H), 3.28 (m, 2H), 3.65 (m, 6H), 3.83 (s, 2H), 4.06-4.39 (m, 2H), 5.23 (m, 1H), 6.39 (s, 1H), 6.85 (s, 4H), 7.17-7.32 (m, 2H), 7.30-7.41 (m, 1H), 11.89 (s, 1H).
To a solution of EXAMPLE 544 (584 mg, 1.13 mmol) in 1:1 dichloromethane/methanol (20 mL) was added 10% Pd/C (150 mg) under nitrogen. The suspension was purged with hydrogen, and stirred under hydrogen at room temperature for 18 hours. Solid material was filtered off, and the filtrate was concentrated to provide the title compound. MS (DCI/NH3) m/z 385 (M+H)+.
To a solution of EXAMPLE 634A (30 mg, 0.08 mmol) in N,N-dimethylformamide (2 mL) was added cyclopropanecarboxylic acid (6.7 mg, 0.08 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (30 mg, 0.16 mmol), N-hydroxybenzotriazole (HOBt) (24 mg, 0.16 mmol) and triethylamine (0.02 mL, 0.16 mmol). The mixture was stirred at room temperature for 16 hours, filtered, and concentrated. The residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to yield the title compound as a TFA salt. MS (DCI/NH3) m/z 453 (M+H)+; 1H NMR (CD3OD) δ 0.77-0.85 (m, 4H), 0.85-0.96 (m, 1H), 1.67-1.78 (m, 4H), 1.86-2.10 (m, 2H), 2.39-2.47 (m, 2H), 2.47-2.56 (m, 2H), 3.34-3.50 (m, 2H), 3.54-3.68 (m, 2H), 3.74-3.79 (m, 1H), 3.79-3.88 (m, 2H), 3.99 (s, 2H), 3.99-4.04 (m, 1H), 7.09-7.14 (m, 1H), 7.14-7.19 (m, 1H), 7.30-7.37 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634. MS (DCI/NH3) m/z 467 (M+H)+; 1H NMR (CD3OD) δ 0.56-0.66 (m, 2H), 0.83-0.96 (m, 2H), 1.26-1.32 (m, 3H), 1.53-1.66 (m, 1H), 1.67-1.78 (m, 4H), 1.95-2.06 (m, 1H), 2.38-2.47 (m, 2H), 2.48-2.56 (m, 2H), 3.33-3.41 (m, 1H), 3.43-3.50 (m, 1H), 3.57-3.69 (m, 2H), 3.75-3.86 (m, 2H), 3.89-3.97 (m, 2H), 3.98 (s, 2H), 7.01-7.10 (m, 1H), 7.11-7.19 (m, 1H), 7.31-7.37 (m, 1H).
The title compound was prepared, using the appropriate reagents, according to the procedure for EXAMPLE 634. After HPLC purification, the compound was treated with 1M HCl in ether to give the HCl salt. MS (DCI/NH3) m/z 493 (M+H)+.
The title compound was prepared, using the appropriate reagents, according to the procedure for EXAMPLE 634. After HPLC purification, the compound was treated with 1M HCl in ether to give the HCl salt. MS (DCI/NH3) m/z 493 (M+H)+.
A solution of EXAMPLE 614 (60 mg, 0.1 mmol) in tetrahydrofuran (10 mL) was treated with trifluoroacetic acid (5 mL) at room temperature for 3 days and was concentrated. The residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to provide the title compound as the TFA salt. MS (DCI/NH3) m/z 448 (M+H)+; 1H NMR (DMSO-d6) δ 1.48-1.86 (m, 2H), 2.14-2.42 (m, 2H), 3.02-3.37 (m, 2H), 3.40-3.73 (m, 2H), 3.87 (m, 4H), 3.84 (s, 2H), 4.63 (m, 1H), 6.37 (s, 1H), 7.20-7.37 (m, 3H), 7.37-7.47 (m, 2H), 7.48-7.63 (m, 3H), 9.56 (s, 1H), 11.86 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 484 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 468 (M+H)+; 1H NMR (DMSO-d6) δ 1.42-1.63 (m, 4H), 1.64-1.85 (m, 6H), 2.35 (t, J=0.10 Hz, 2H), 2.82-3.08 (m, 1H), 3.12-3.30 (m, 4H), 3.35-3.52 (m, 2H), 3.50-3.71 (m, 4H), 3.83 (s, 2H), 6.41 (s, 1H), 7.10-7.28 (m, 2H), 7.28-7.51 (m, 1H), 11.92 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 511 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 559 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 469 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 527 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 511 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 626 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 493 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 527 (M+H)+; 1H NMR (DMSO-d6) δ 1.60-1.79 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 3.11-3.23 (m, 2H), 3.27 (m, 2H), 3.48 (m, 2H), 3.58 (m, 2H), 3.63-3.73 (m, 2H), 3.82 (s, 2H), 6.43 (s, 1H), 7.18-7.29 (m, 2H), 7.30-7.39 (m, 1H), 7.64 (d, J=2.03 Hz, 1H), 7.80 (d, J=2.37 Hz, 1H), 11.92 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 530 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 516 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 527 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 511 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 520 (M+H)+; 1H NMR (DMSO-d6) δ 1.51 (m, 1H), 1.69 (m, 2H), 1.74-1.86 (m, 1H), 2.22-2.40 (m, 2H), 3.17 (m, 2H), 3.22-3.42 (m, 2H), 3.46 (m, 4H), 3.51-3.68 (m, 1H), 3.67-3.79 (m, 1H), 3.81 (s, 2H), 5.09 (s, 2H), 6.43 (s, 1H), 7.07-7.43 (m, 8H), 11.68-12.04 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 477 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 477 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 478 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 516 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 478 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 477 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 444 (M+H)+; 1H NMR (DMSO-d6) δ 1.19 (t, J=7.14 Hz, 3H), 1.52-1.78 (m, 2H), 2.35 (t, J=6.15 Hz, 2H), 3.08-3.29 (m, 4H), 3.33 (m, 2H), 3.45 (m, 2H), 3.62 (m, 2H), 3.82 (s, 2H), 4.06 (q, J=7.14 Hz, 2H), 6.41 (s, 1H), 6.99-7.46 (m, 3H), 11.93 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 414 (M+H)+; 1H NMR (DMSO-d6) δ1.68 (s, 6H), 1.71 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 3.17 (m, 4H), 3.30 (m, 2H), 3.81 (s, 2H), 6.42 (s, 1H), 7.16-7.34 (m, 3H), 8.15 (s, 1H), 11.90 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18. 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 489 (M+H)+; 1H NMR (CD3OD) δ 1.17-1.33 (m, 2H), 1.64-1.80 (m, 4H), 2.38-2.56 (m, 4H), 2.98-3.13 (m, 1H), 3.16-3.27 (m, 1H), 3.34 (s, 3H), 3.39-3.59 (m, 1H), 3.63-3.86 (m, 1H), 3.99 (s, 2H), 4.41-4.60 (m, 1H), 7.10-7.18 (m, 1H), 7.19-7.27 (m, 1H), 7.29-7.39 (m, 1H), 7.41-7.55 (m, 5H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 450 (M+H)+; 1H NMR (CD3OD) δ 1.68-1.77 (m, 4H), 2.43-2.48 (m, 2H), 2.49-2.56 (m, 2H), 3.44-3.52 (m, 2H), 3.86-3.90 (m, 2H), 3.92-3.97 (m, 2H), 4.01 (s, 2H), 4.05-4.10 (m, 2H), 7.15-7.22 (m, 1H), 7.27 (dd, J=6.41, 2.14 Hz, 1H), 7.33-7.42 (m, 1H), 8.61 (s, 1H), 8.63 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the free base according to the procedure for EXAMPLE 630. MS (DCI/NH3) m/z 441 (M+H)+; 1H NMR (CD3OD) δ 1.61-1.77 (m, 4H), 2.38-2.46 (m, 2H), 2.47-2.55 (m, 2H), 3.03 (dd, J=13.73, 7.32 Hz, 1H), 3.19 (dd, J=13.73, 5.19 Hz, 1H), 3.90 (s, 2H), 4.57-4.66 (m, 1H), 6.74-6.80 (m, 1H), 6.99 (dd, J=10.98, 8.54 Hz, 1H), 7.19-7.25 (m, 3H), 7.25-7.32 (m, 2H), 7.85 (dd, J=7.63, 2.14 Hz, 1H).
The title compound was prepared, using the appropriate reagents, according to the procedure for EXAMPLE 634A substituting EXAMPLE 543 for EXAMPLE 544. MS (DCI/NH3) m/z 371 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634B substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 510 (M+H)+; 1H NMR (CD3OD) δ 1.65-1.78 (m, 4H), 2.39-2.55 (m, 4H), 3.37-3.44 (m, 1H), 3.46-3.52 (m, 1H), 3.53-3.59 (m, 1H), 3.63-3.70 (m, 1H), 3.73-3.78 (m, 1H), 3.79-3.84 (m, 1H), 3.88 (s, 2H), 3.95-4.03 (m, 2H), 7.11-7.21 (m, 1H), 7.22-7.30 (m, 1H), 7.31-7.43 (m, 1H), 7.64-7.70 (m, 1H), 7.95-8.04 (m, 1H), 8.55-8.66 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 482 (M+H)+; 1H NMR (CD3OD) δ 1.66-1.80 (m, 4H), 2.41-2.55 (m, 4H), 3.37-3.54 (m, 2H), 3.71-3.81 (m, 2H), 3.83-3.95 (m, 4H), 4.00 (s, 2H), 7.13-7.22 (m, 1H), 7.23-7.30 (m, 1H), 7.31-7.43 (m, 1H), 8.13 (s, 1H), 9.00-9.10 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 482 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 514 (M+H)+; 1H NMR (CD3OD) δ 1.38-1.46 (m, 3H), 1.61-1.76 (m, 7H), 2.41-2.47 (m, 2H), 2.49-2.57 (m, 2H), 3.36-3.49 (m, 2H), 3.53-3.64 (m, 2H), 3.66-3.77 (m, 1H), 3.84-3.93 (m, 1H), 4.00 (s, 2H), 4.05-4.15 (m, 1H), 4.43-4.55 (m, 2H), 4.80-4.95 (m, 2H), 7.15-7.21 (m, 1H), 7.23-7.29 (m, 1H), 7.36-7.40 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 465 (M+H)+; 1H NMR (CD2OD) δ 1.66-1.77 (m, 4H), 2.39-2.48 (m, 2H), 2.48-2.58 (m, 2H), 3.37-3.52 (m, 2H), 3.68-3.79 (m, 1H), 3.79-3.93 (m, 3H), 3.92-3.99 (m, 1H), 4.00 (s, 2H), 4.04-4.16 (m, 1H), 6.63-6.71 (m, 1H), 7.13-7.21 (m, 1H), 7.23-7.29 (m, 1H), 7.32-7.39 (m, 1H), 7.67-7.74 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 477 (M+H)+; 1H NMR (CD3OD) δ 1.67-1.77 (m, 4H), 2.42-2.55 (m, 4H), 3.39-3.46 (m, 1H), 3.47-3.55 (m, 1H), 3.57-3.63 (m, 1H), 3.69-3.75 (m, 1H), 3.76-3.81 (m, 1H), 3.81-3.87 (m, 1H), 3.90 (s, 2H), 3.96-4.04 (m, 2H), 7.12-7.21 (m, 1H), 7.22-7.32 (m, 1H), 7.31-7.40 (m, 1H), 8.58-8.76 (m, 2H), 8.89 (d, J=6.10 Hz, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 515 (M+H)+.
To a solution of EXAMPLE 493F (2.0 g, 7.3 mmol) in dichloromethane (15 mL) was added 2,4-dinitrobenzene-1-sulfonyl chloride (1.95 g, 7.3 mmol) and pyridine (0.7 mL, 8.8 mmol). The mixture was stirred at room temperature for 16 hours and was concentrated. The residue was partitioned between ethyl acetate and water and the organic layer collected and concentrated. The residue was purified by flash chromatography eluting with 60% ethyl acetate in hexanes to provide the title compound. MS (DCI/NH3) m/z 504 (M+H)+.
To a solution of EXAMPLE 681A (1.4 g, 2.8 mmol) in N,N-dimethylformamide (8 mL) was added methyl iodide (0.21 mL, 3.3 mmol) and potassium carbonate (1.92 g, 13.9 mmol). The mixture was stirred at room temperature for 16 hours and was concentrated. The residue was partitioned between ethyl acetate and water and the organic layer concentrated. The residue was purified by flash chromatography eluting with 60% ethyl acetate in hexanes to provide the title compound. MS (DCI/NH3) m/z 518 (M+H)+.
To a solution of EXAMPLE 681B (940 mg, 1.8 mmol) in dichloromethane (15 mL) was added thioglycolic acid (0.16 mL, 2.4 mmol) and triethylamine (0.5 mL, 3.6 mmol). The mixture was stirred at ambient temperature for 5 minutes and washed with brine. The organic layer was concentrated and the residue purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane to provide the title compound. MS (DCI/NH3) m/z 288 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 491 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 491 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 491 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 492 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 530 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 541 (M+H)+; 1H NMR (DMSO-d6) δ 1.56-2.00 (m, 4H), 2.27-2.42 (m, 2H), 3.10-3.25 (m, 2H), 3.30-3.45 (m, 1H), 3.44-3.67 (m, 3H), 3.67-3.93 (m, 6H), 6.47 (m, 1H), 6.97-7.43 (m, 3H), 7.49-7.72 (m, 3H), 7.71-8.00 (m, 1H), 7.96-8.12 (m, 1H), 8.29-8.73 (m, 1H), 11.93 (s, 0.5H), 11.99 (s, 0.5H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 541 (M+H)+; 1H NMR (DMSO-d6) δ 1.51-1.81 (m, 4H), 2.21-2.42 (m, 2H), 3.04-3.26 (m, 3H), 3.39 (m, 2H), 3.49 (m, 2H), 3.60-3.70 (m, 1H), 3.75 (m, 2H), 3.84 (s, 1H), 3.87 (s, 1H), 6.49 (s, 1H), 7.07-7.41 (m, 3H), 7.60-7.77 (m, 1H), 7.78-7.97 (m, 1H), 7.97-8.16 (m, 2H), 8.48 (s, 0.5H), 8.50 (s, 0.5H), 8.92 (s, 0.5H), 8.94 (s, 0.5H), 11.97 (s, 0.5H), 11.99 (s, 0.5H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 544 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 573 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 493 (M+H)+; 1H NMR (DMSO-d6) δ 1.35-1.59 (m, 2H), 1.60-1.81 (m, 3H), 1.91 (m, 1H), 2.33 (m, 2H), 2.90-3.07 (m, 1H), 3.07-3.31 (m, 3H), 3.45 (m, 1H), 3.65-3.82 (m, 1H), 3.82 (s, 2H), 4.52 (m, 1H), 6.41 (s, 1H), 6.89-7.32 (m, 3H), 7.37 (t, J=8.92 Hz, 2H), 8.10 (dd, J=8.72, 5.55 Hz, 2H), 11.89 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 515 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 492 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 480 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 449 (M+H)+; 1H NMR (DMSO-d6) δ 1.52-1.80 (m, 2H), 2.35 (t, J=6.10 Hz, 2H), 3.18 (m, 2H), 3.39 (m, 4H), 3.47-3.61 (m, 2H), 3.76-3.84 (m, 2H), 3.84 (s, 2H), 6.44 (s, 1H), 7.05-7.33 (m, 2H), 7.30-7.48 (m, 1H), 7.82 (dd, J=8.98, 5.26 Hz, 1H), 8.02 (dd, J=8.81, 2.37 Hz, 1H), 8.24 (d, J=5.42 Hz, 1H), 8.46 (d, J=2.71 Hz, 1H), 11.92 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 450 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 400 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 500 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 486 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 486 (M+H)+)+; 1H NMR (DMSO-d6) 1.20-1.30 (m, 1H), 1.38 (s, 9H), 1.59-1.74 (m, 3H), 1.78 (m, 1H), 2.34 (t, J=6.10 Hz, 2H), 2.85-2.99 (m, 2H), 3.03-3.12 (m, 1H), 3.17 (m, 2H), 3.35 (m, 1H), 3.50 (m, 1H), 3.81 (s, 2H), 4.33 (m, 1H), 6.42 (s, 1H), 7.13-7.26 (m, 2H), 7.26-7.38 (m, 1H), 7.95 (s, 1H), 11.90 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m z 501 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 480 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 497 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 466 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 483 (M+H)+)+; 1H NMR (DMSO-d6) δ 1.71-1.92 (m, 2H), 2.53 (t, J=6.10 Hz, 2H), 3.46 (m, 2H), 3.70-3.83 (m, 4H), 3.88 (m, 4H), 3.93 (s, 2H), 7.16 (t, J=8.98 Hz, 1H), 7.29 (dd, J=6.27, 1.86 Hz, 1H), 7.32-7.46 (m, 1H), 8.13 (d, J=1.70 Hz, 1H), 9.05 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 638. MS (DCI/NH3) m/z 400 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 638. MS (DCI/NH3) m/z 466 (M+H)+; 1H NMR (CD3OD) δ 1.71-1.91 (m, 4H), 2.20 (dd, J=14.07, 3.22 Hz, 2H), 2.51 (t, —6.27 Hz, 2H), 3.07-3.22 (m, 2H), 3.22-3.30 (m, 2H), 3.37-3.49 (m, 4H), 4.03-4.29 (m, 1H), 7.14 (dd, J=10.51, 8.48 Hz, 1H), 7.33-7.48 (m, 1H), 7.51 (dd, J=6.78, 2.37 Hz, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 638. MS (DCI/NH3) m/z 386 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 401 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 505 (M+H)+.
To a solution of EXAMPLE 492F (500 mg, 1.654 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added N-Boc-N′-ethyl-1,2-ethylene diamine hydrochloride (446 mg, 1.985 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC) (476 mg, 2.481 mmol), 1-hydroxybenzotriazole monohydrate (380 mg, 2.481 mmol), and triethylamine (0.807 mL, 5.79 mmol). The mixture was stirred at ambient temperature overnight and was partitioned between ethyl acetate and brine. The organic phase was washed with brine and water and concentrated. The residue was purified by flash chromatography (ethyl acetate) to give the title compound. MS (DCI/NH3) m/z 473 (M+H)+; 1H NMR (CDCl3) δ 1.07 (t, J=7.21 Hz, 3H), 1.45 (s, 9H), 1.71 (m, 4H), 2.33-2.42 (m, 2H), 2.55-2.62 (m, 2H), 3.17-3.29 (m, 2H), 3.38-3.45 (m, 2H), 3.58-3.64 (m, 2H), 3.87-3.91 (m, 2H), 5.06 (s, 1H), 6.98-7.05 (m, 1H), 7.13-7.19 (m, 2H), 11.34 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 505 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 530 (M+H)+.
To a solution of EXAMPLE 492F (102 mg, 0.337 mmol) in anhydrous N,N-dimethylformamide (8 mL) was added 1-(2-aminoethyl)pyrrolidin-2-one hydrochloride (83 mg, 0.506 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC) (97 mg, 0.506 mmol), 1-hydroxybenzotriazole monohydrate (78 mg, 0.506 mmol), and triethylamine (0.165 mL, 3.5 mmol). The mixture was stirred at ambient temperature overnight, and was partitioned between ethyl acetate and brine. The organic phase was washed with brine and water and concentrated. The residue was purified by flash chromatography (15% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. MS (DCI/NH3) m/z 413 (M+H)+; 1H NMR (CD3OD) δ 1.71 (t, J=2.90 Hz, 4H), 1.99-2.05 (m, 2H), 2.33 (t, J=8.09 Hz, 2H), 2.44 (m, 2H), 2.50 (m, 2H), 3.49 (t, J=5.49 Hz, 2H), 3.52-3.57 (m, 4H), 3.99 (s, 2H), 7.13 (dd, J=10.37, 8.54 Hz, 1H), 7.33-7.38 (m, 1H), 7.51 (dd, J=6.71, 2.14 Hz, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 494 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 515 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 511 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 494 (M+H)+.
A solution of EXAMPLE 711 (662 mg, 1.40 mmol) in 20 mL of methylene chloride was treated with trifluoroacetic acid (5 mL) at ambient temperature for 1 hour. Toluene (10 mL) was added and the solution concentrated. The residue was dissolved in methylene chloride and methanol, and treated with an access of 2M HCl in ether. Concentration provided the title compound as the HCl salt. MS (DCI/NH3) m/z 373 (M+H)+; 1H NMR (CD3OD) δ 1.10 (t, J=7.02 Hz, 3H), 1.71-1.78 (m, 4H), 2.47-2.50 (m, 2H), 2.55 (m, 2H), 3.24 (t, J=6.41 Hz, 2H), 3.29-3.33 (m, 2H), 3.80 (t, J=6.41 Hz, 2H), 4.08 (s, 2H), 7.19 (t, J=9.00 Hz, 1H), 7.29-7.32 (m, 1H), 7.36-7.40 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 476 (M+H)+; 1H NMR (CD3OD) δ 1.66-1.79 (m, 4H), 2.41-2.55 (m, 4H), 3.34-3.41 (m, 2H), 3.46-3.56 (m, 2H), 3.74-3.83 (m, 2H), 3.85-3.93 (m, 2H), 3.95-4.05 (m, 2H), 7.11-7.21 (m, 1H), 7.22-7.30 (m, 1H), 7.32-7.44 (m, 1H), 7.75-7.81 (m, 1H), 7.82-7.91 (m, 1H), 8.76-8.89 (m, 2H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m z 505 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 476 (M+H)+; 1H NMR (CD3OD) δ 1.66-1.79 (m, 4H), 2.40-2.47 (m, 2H), 2.48-2.57 (m, 2H), 3.38-3.51 (m, 2H), 3.51-3.63 (m, 2H), 3.75-3.84 (m, 2H), 3.85-3.95 (m, 2H), 4.00 (s, 2H), 7.11-7.22 (m, 1H), 7.22-7.29 (m, 1H), 7.30-7.42 (m, 1H), 7.71-7.85 (m, 1H), 8.17-8.30 (m, 1H), 8.72-8.87 (m, 2H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 526 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 491 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 625 (M+H)+; 1H NMR (CD3OD) δ 1.65-1.73 (m, 4H), 1.74 (d, J=7.02 Hz, 6H), 2.39-2.47 (m, 2H), 2.47-2.57 (m, 2H), 3.40-3.70 (m, 4H), 3.73-3.95 (m, 4H), 3.99 (s, 2H), 4.93-5.17 (m, 1H), 7.13-7.21 (m, 1H), 7.22-7.29 (m, 1H), 7.31-7.39 (m, 1H), 7.55 (d, J=8.54 Hz, 1H), 7.92 (s, 1H), 8.00 (d, J=8.54 Hz, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 480 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 486 (M+H)+; 1H NMR (CD3OD) δ 1.68-1.77 (m, 4H), 2.42-2.48 (m, 2H), 2.48-2.54 (m, 2H), 3.12-3.23 (m, 1H), 3.37-3.50 (m, 2H), 3.54-3.64 (m, 2H), 3.65-3.73 (m, 3H), 3.77-3.95 (m, 3H), 4.36-4.43 (m, 1H), 4.44-4.51 (m, 1H), 4.89-5.01 (m, 2H), 7.15-7.20 (m, 1H), 7.23-7.28 (m, 1H), 7.36-7.40 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 558 (M+H)+; 1H NMR (CD3OD) δ 1.65-1.75 (m, 4H), 1.73 (d, J=6.71 Hz, 6H), 2.41-2.47 (m, 2H), 2.48-2.54 (m, 2H), 3.43-3.67 (m, 4H), 3.69-3.94 (m, 4H), 3.99 (s, 2H), 5.21-5.30 (m, 1H), 7.12-7.20 (m, 1H), 7.23-7.29 (m, 1H), 7.31-7.40 (m, 1H), 7.63 (d, J=8.85 Hz, 1H), 7.93 (d, J=8.54 Hz, 1H), 8.12 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 501 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 476 (M+H)+; 1H NMR (CD3OD) δ 1.64-1.78 (m, 4H), 2.39-2.56 (m, 4H), 3.36-3.43 (m, 1H), 3.46-3.55 (m, 2H), 3.57-3.67 (m, 1H), 3.72-3.85 (m, 2H), 3.90 (s, 2H), 3.96-4.05 (m, 2H), 7.09-7.20 (m, 1H), 7.22-7.30 (m, 1H), 7.31-7.41 (m, 1H), 7.49-7.59 (m, 1H), 7.68 (t, J=8.70 Hz, 1H), 7.94-8.07 (m, 1H), 8.61 (dd, J=27.46, 3.97 Hz, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 497 (M+H)+; 1H NMR (DMSO-d6) δ 1.34-1.59 (m, 2H), 1.62-1.75 (m, 2H), 1.89 (m, 2H), 2.33 (t, J=6.10 Hz, 2H), 2.92-3.10 (m, 1H), 3.10-3.22 (m, 2H), 3.20-3.31 (m, 1H), 3.81 (s, 2H), 3.93-4.21 (m, 2H), 4.35 (d, J=1.70 Hz, 1H), 6.38 (s, 1H), 7.19 (dd, J=10.17, 8.48 Hz, 1H), 7.24-7.38 (m, 1H), 7.36-7.54 (m, 1H), 8.14 (d, J=1.70 Hz, 1H), 8.32 (d, J=7.46 Hz, 1H), 9.17 (d, J=2.03 Hz, 1H), 11.85 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 477 (M+H)+; 1H NMR (CD3OD) δ 1.66-1.78 (m, 4H), 2.40-2.48 (m, 2H), 2.48-2.55 (m, 2H), 3.41-3.53 (m, 3H), 3.58-3.66 (m, 1H), 3.77-3.91 (m, 4H), 4.00 (s, 2H), 7.10-7.20 (m, 1H), 7.23-7.31 (m, 1H), 7.31-7.42 (m, 1H), 8.85-8.95 (m, 2H), 9.24 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 480 (M+H)+; 1H NMR (DMSO-d6) δ 1.31-1.56 (m, 2H), 1.60-1.75 (m, 2H), 1.77-1.96 (m, 2H), 2.24-2.39 (m, 2H), 3.00-3.23 (m, 6H), 3.82 (s, 2H), 4.17-4.62 (m, 1H), 6.40 (s, 1H), 6.54 (d, J=2.37 Hz, 1H), 6.97 (d, J=3.39 Hz, 1H), 7.14-7.25 (m, 1H), 7.28-7.39 (m, 1H), 7.44 (dd, J=6.95, 2.20 Hz, 1H), 7.78 (d, J=2.03 Hz, 1H), 8.30 (d, J=7.46 Hz, 1H), 11.87 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 492 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 491 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 491 (M+H)+; 1H NMR (DMSO-d6) δ 1.44-1.74 (m, 2H), 1.75-1.89 (m, 2H), 1.97 (m, 1H), 2.02-2.21 (m, 1H), 2.51 (t, J=6.27 Hz, 2H), 3.01-3.21 (m, 1H), 3.22-3.32 (m, 3H), 3.58 (m, 1H), 3.92 (s, 2H), 4.03-4.28 (m, 1H), 4.57 (m, 1H), 7.14 (dd, J=10.34, 8.65 Hz, 1H), 7.26-7.45 (m, 1H), 7.53 (dd, J=6.78, 2.03 Hz, 1H), 7.82 (d, J=6.44 Hz, 2H), 8.84 (d, J=5.76 Hz, 2H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 526 (M+H)+; 1H NMR (CD3OD) δ 1.61-1.78 (m, 4H), 2.38-2.56 (m, 4H), 3.41-3.48 (m, 1H), 3.50-3.57 (m, 1H), 3.57-3.62 (m, 1H), 3.66-3.74 (m, 1H), 3.82-3.90 (m, 2H), 3.95 (s, 2H), 3.96-3.99 (m, 1H), 4.00-4.05 (m, 1H), 7.09-7.22 (m, 1H), 7.23-7.30 (m, 1H), 7.31-7.43 (m, 1H), 7.64-7.76 (m, 2H), 7.79-7.90 (m, 1H), 7.96-8.03 (m, 1H), 8.04-8.13 (m, 1H), 8.46-8.55 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 400 (M+H)+.
To a suspension of EXAMPLE 719 as the HCl salt (65 mg, 0.134 mmol) in a mixture of tetrahydrofuran (2 mL) and acetonitrile (2 mL) was added 2,5-dioxopyrrolidin-1-yl benzoate (44 mg, 0.201 mmol) and triethylamine (0.056 mL, 0.403 mmol). The solution was heated at 60° C. overnight. After concentration, the residue was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in CH3CN: 0-100% gradient) to provide the title compound as the TFA salt. MS (DCI/NH3) m/z 477 (M+H)+; 1H NMR (CD3OD) δ 1.08 (t, J=7.20 Hz, 3H), 1.66-1.72 (m, 4H), 2.32-2.40 (m, 2H), 2.43-2.51 (m, 2H), 3.27-3.32 (m, 2H), 3.38-3.45 (m, 2H), 3.68-3.72 (m, 2H), 3.94 (s, 2H), 7.01-7.30 (m, 5H), 7.11-7.15 (m, 1H), 7.43-7.47 (m, 1H), 7.80-7.83 (m, 1H).
To a suspension of EXAMPLE 719 as the HCl salt (65 mg, 0.134 mmol) in a mixture of tetrahydrofuran (2 mL) and acetonitrile (2 mL) was added triethylamine (0.056 mL, 0.403 mmol) and 1-pyrrolidinecarbonyl chloride (0.030 mL, 0.269 mmol). The solution was heated at 60° C. overnight. After concentration, the residue was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in CH3CN; 0-100% gradient) to provide the title compound. MS (DCI/NH3) m/z 470 (M+H)+; 1H NMR (CD3OD) δ 1.05 (t, J=7.02 Hz, 2H), 1.24 (t, J=7.17 Hz, 1H), 1.69-1.74 (m, 4H), 1.88-1.92 (m, 4H), 2.42-2.46 (m, 2H), 2.49-2.52 (m, 2H), 3.17-3.26 (m, 4H), 3.28-3.35 (m, 2H), 3.45 (t, J=6.26 Hz, 2H), 3.65 (t, J=6.26 Hz, 2H), 3.98 (s, 1H), 3.99 (s, 1H), 7.11 (t, J=9.00 Hz, 1H), 7.15-7.20 (m, 1H), 7.27-7.35 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH3) m/z 463 (M+H)+; 1H NMR (DMSO-d6) δ 1.56 (q, J=10.5 Hz, 2H), 1.65-1.74 (m, 2H), 1.95 (dd, J=13.09, 3.17 Hz, 2H), 2.34 (t, J=6.15 Hz, 2H), 2.75 (d, J=4.36 Hz, 1H), 3.26 (t, J=11.70 Hz, 2H), 3.82 (s, 2H), 4.07-4.21 (m, 3H), 6.38 (s, 1H), 6.83 (t, J=6.35 Hz, 1H), 7.15-7.29 (m, 2H), 7.32-7.39 (m, 1H), 7.44 (dd, J=6.94, 2.18 Hz, 1H), 7.85 (t, J=7.73 Hz, 1H), 8.04 (dd, J=5.75, 1.78 Hz, 1H), 8.28 (d, J=7.54 Hz, 1H), 11.86 (s, 1H).
To a solution of EXAMPLE 506F (400 mg, 1.32 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added tert-butyl piperidin-4-ylcarbamate (264 mg, 1.32 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC) (327 mg, 1.72 mmol), 1-hydroxybenzotriazole monohydrate (264 mg, 1.72 mmol), and triethylamine (173 mg, 1.72 mmol). The reaction mixture was stirred at ambient temperature overnight, and partitioned between methylene chloride and brine. The organic phase was washed with brine, water, and concentrated. The residue was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in H2O: B: 0.1% TFA in CH3CN; 0-100% gradient) to provide the title compound as TFA salt. MS (DCI/NH3) m/z 486 (M+H)+.
A solution of EXAMPLE 746A (1.5 g) in tetrahydrofuran (15 mL) was treated with trifluoroacetic acid (2 mL) at 60° C. overnight and concentrated. The residue was purified by HPLC (Zorbax, C-18, 250×2.54 column. Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in CH3CN; 0-100% gradient) to provide the title compound as TFA salt. MS (DCI/NH3) m/z 386 (M+H)+.
To a solution of EXAMPLE 746B (50 mg, 0.13 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added picolinic acid (20 mg, 0.17 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC) (32 mg, 0.17 mmol), 1-hydroxybenzotriazole monohydrate (26 mg, 0.17 mmol), and triethylamine (17 mg, 0.17 mmol). The mixture was heated until homogeneous and stirred at ambient temperature overnight. The mixture was partitioned between methylene chloride and brine. The organic phase was washed with brine, water, and concentrated. The residue was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in CH3CN; 0-100% gradient) to provide the title compound. MS (DCI/NH3) m/z 491 (M+H)+; 1H NMR (DMSO-d6) δ 1.53-1.78 (m, 5H), 1.84-1.92 (m, 1H), 2.35 (t, J=6.27 Hz, 2H), 2.88-2.99 (m, 1H), 3.11-3.24 (m, 4H), 3.42 (d, J=13.90 Hz, 1H), 3.83 (s, 2H), 4.05-4.14 (m, 1H), 4.49 (d, J=13.22 Hz, 1H), 6.42 (s, 1H), 7.18-7.35 (m, 2H), 7.56-7.63 (m, 1H), 7.95-8.06 (m, 2H), 8.64 (d, J=4.07 Hz, 2H), 11.91 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH3) m/z 491 (M+H)+; 1H NMR (DMSO-d6) δ 1.41-1.60 (m, 2H), 1.65-1.75 (m, 2H), 1.83 (d, J=10.31 Hz, 1H), 1.94 (d, J=11.90 Hz, 1H), 2.35 (t, J=6.15 Hz, 2H), 2.99 (t, J=11.30 Hz, 1H), 3.13-3.23 (m, 3H), 3.44 (d, J=13.48 Hz, 1H), 3.84 (s, 2H), 4.05-4.15 (m, 1H), 4.46 (d, J=13.48 Hz, 1H), 6.42 (s, 1H), 7.18-7.27 (m, 2H), 7.30-7.36 (m, 1H), 7.59 (dd, J=7.93, 5.16 Hz, 1H), 8.28 (d, J=8.33 Hz, 1H), 8.58 (d, J=7.54 Hz, 1H), 8.75 (dd, J=5.16, 1.59 Hz, 1H), 9.03 (d, J=11.98 Hz, 1H), 11.92 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH3) m/z 491 (M+H)+; 1H NMR (DMSO-d6) δ 1.40-1.60 (m, 2H), 1.66-1.73 (m, 2H), 1.78-1.85 (m, 1H), 1.93 (d, J=10.51 Hz, 1H), 2.35 (t, J=6.27 Hz, 2H), 2.93-3.03 (m, 1H), 3.12-3.23 (m, 3H), 3.43 (d, J=13.56 Hz, 1H), 3.83 (s, 2H), 4.04-4.15 (m, 1H), 4.46 (d, J=12.89 Hz, 1H), 6.40 (s, 1H), 7.19-7.25 (m, 2H), 7.31-7.35 (m, 1H), 7.82-7.88 (m, 2H), 8.68 (d, J=7.46 Hz, 1H), 8.74-8.80 (m, 2H), 11.91 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH3) m/z 530 (M+H)+; 1H NMR (DMSO-d6) δ 1.45-1.59 (m, 2H), 1.65-1.73 (m, 2H), 1.78-1.87 (m, 1H), 1.94 (d, J=10.17 Hz, 1H), 2.34 (t, J=6.10 Hz, 2H), 2.91-3.03 (m, 1H), 3.15-3.22 (m, 3H), 3.45 (d, J=13.22 Hz, 1H), 3.83 (s, 2H), 4.07-4.18 (m, 1H), 4.50 (d, J=12.88 Hz, 1H), 6.41 (s, 1H), 7.18-7.27 (m, 2H), 7.33 (dd, J=5.26, 1.86 Hz, 1H), 7.82 (d, J=8.81 Hz, 1H), 7.96 (dd, J=8.48, 1.36 Hz, 1H), 8.26 (s, 1H), 8.50-8.57 (m, 1H), 9.23 (s, 1H), 11.89 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH3) m/z 480 (M+H)+; 1H NMR (DMSO-d6) δ 1.40-1.58 (m, 2H), 1.66-1.77 (m, 3H), 1.86 (d, J=10.51 Hz, 1H), 2.34 (t, J=6.10 Hz, 2H), 2.86-2.96 (m, 1H), 3.09-3.22 (m, 3H), 3.41 (d, J=12.54 Hz, 1H), 3.83 (s, 2H), 3.99-4.08 (m, 1H), 4.48 (d, J=13.22 Hz, 1H), 6.43 (s, 1H) 6.61 (dd, J=3.39, 1.70 Hz, 1H), 7.10 (d, J=3.73 Hz, 1H), 7.18-7.27 (m, 2H), 7.29-7.36 (m, 1H), 7.83 (s, 1H), 8.28 (s, 1H), 11.92 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH3) m/z 497 (M+H)+; 1H NMR (DMSO-d6) δ 1.50-1.62 (m, 1H), 1.63-1.78 (m, 3H), 1.86 (d, J=10.31 Hz, 1H), 2.35 (t, J=6.15 Hz, 2H), 2.87-2.97 (m, 1H), 3.11-3.22 (m, 2H), 3.41 (d, J=13.09 Hz, 1H), 3.83 (s, 2H), 4.04-4.13 (m, 1H), 4.49 (d, J=13.09 Hz, 2H), 6.40 (s, 1H), 7.17-7.25 (m, 2H), 7.28-7.36 (m, 1H), 8.32 (d, J=1.98 Hz, 1H), 8.37 (s, 1H), 9.17 (d, J=1.98 Hz, 1H), 11.90 (s, 1H).
To a solution of EXAMPLE 681C (40 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was added (cyclobutanecarboxylic acid (14 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (53 mg, 0.28 mmol). N-hydroxybenzotriazole (HOBt) (38 mg, 0.28 mmol), and triethylamine (28 mg, 0.28 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and was concentrated. The residue was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to provide the title compound (13 mg, 25%). MS (DCI/NH3) m/z 370 (M+H)+.
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 529 (M+H)+; 1H NMR (CD3OD) δ 1.64-1.80 (m, 4H), 2.40-2.47 (m, 2H), 2.47-2.56 (m, 2H), 2.88 (s, 3H), 3.39-3.68 (m, 4H), 3.71-3.94 (m, 4H), 3.99 (s, 2H), 7.12-7.21 (m, 1H), 7.22-7.27 (m, 1H), 7.34-7.41 (m, 1H), 7.64 (d, J=8.24 Hz, 1H), 7.82 (d, J=8.54 Hz, 1H), 7.84 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 510 (M+H)+; 1H NMR (CD3OD) δ 1.65-1.81 (m, 4H), 2.39-2.56 (m, 4H), 3.22-3.28 (m, 1H), 3.35-3.46 (m, 2H), 3.46-3.54 (m, 1H), 3.73-3.86 (m, 2H), 3.90 (s, 2H), 3.95-4.04 (m, 2H), 7.10-7.22 (m, 1H), 7.26 (d, J=9.76 Hz, 1H), 7.30-7.40 (m, 1H), 7.44-7.54 (m, 1H), 7.82-7.92 (m, 1H), 8.42-8.52 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 448 (M+H)+; 1H NMR (CD3OD) δ 1.67-1.79 (m, 4H), 2.41-2.49 (m, 2H), 2.49-2.57 (m, 2H), 3.41-3.50 (m, 2H), 3.52-3.63 (m, 4H), 3.91-3.98 (m, 2H), 4.01 (s, 2H), 7.19 (t, J=9.00 Hz, 1H), 7.27 (dd, J=6.26, 2.29 Hz, 1H), 7.36-7.42 (m, 1H), 7.85 (dd, J=9.00, 5.34 Hz, 1H), 8.08-8.13 (m, 1H), 8.16 (d, J=5.49 Hz, 1H), 8.39 (d, J=2.75 Hz, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 543, but was purified by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) instead of flash chromatography. MS (DCI/NH3) m/z 449 (M+H)+; 1H NMR (CD3OD) δ 1.66-1.80 (m, 4H), 2.41-2.48 (m, 2H), 2.48-2.56 (m, 2H), 3.33-3.39 (m, 2H), 3.41-3.50 (m, 2H), 3.50-3.67 (m, 2H), 3.90-3.98 (m, 2H), 4.00 (s, 2H), 7.13-7.23 (m, 1H), 7.24-7.31 (m, 1H), 7.34-7.43 (m, 1H), 8.52 (s, 2H), 8.61 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH3) m/z 480 (M+H)+; 1H NMR (DMSO-d6) δ 1.43-1.59 (m, 2H), 1.65-1.77 (m, 3H), 1.83-1.90 (m, 1H), 2.34 (t, J=6.27 Hz, 2H), 2.87-2.97 (m, 1H), 3.10-3.22 (m, 2H), 3.40 (d, J=13.22 Hz, 1H), 3.83 (s, 2H), 4.00-4.10 (m, 1H), 4.47 (d, J=13.22 Hz, 1H), 6.39 (s, 1H), 6.67 (d, J=2.03 Hz, 1H), 7.17-7.26 (m, 3H), 7.29-7.34 (m, 1H), 7.74 (d, J=2.03 Hz, 1H), 8.04 (s, 1H), 11.89 (s, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH3) m/z 399 (M+H)+; 1H NMR (CD2OD) δ 1.66-1.78 (m, 4H), 2.39-2.48 (m, 2H), 2.48-2.56 (m, 2H), 2.99 (d, J=5.49 Hz, 3H), 3.39 (t, J=5.19 Hz, 1H), 3.49 (t, J=5.49 Hz, 1H), 3.60 (t, J=5.19 Hz, 1H), 3.91-4.00 (m, 2H), 4.00 (s, 2H), 4.27-4.36 (m, 1H), 7.14-7.21 (m, 1H), 7.25-7.29 (m, 1H), 7.36-7.40 (m, 1H).
To a suspension of EXAMPLE 719 as the HCl salt (59 mg, 0.134 mmol) in anhydrous pyridine (2 mL) was added cyclopropanecarbonyl chloride (0.018 mL, 0.20 mmol). This solution was stirred at ambient temperature overnight and concentrated. The residue was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in CH3CN; 0-100% gradient) to provide the title compound as the TFA salt. MS (DCI/NH3) m/z 441 (M+H)+; 1H NMR (CD3OD) δ 0.72-0.77 (m, 3H), 0.81-0.85 (m, 1H), 1.05 (t, J=7.02 Hz, 2H), 1.24 (t, J=7.17 Hz, 1H), 1.52-1.57 (m, 1H), 1.71 (t, J=2.75 Hz, 4H), 2.43-2.47 (m, J=1.83 Hz, 2H), 2.48-2.52 (m, J=1.53 Hz, 2H), 3.24 (t, J=7.17 Hz, 2H), 3.29-3.34 (m, 2H), 3.49 (t, J=6.56 Hz, 1H), 3.63 (t, J=6.41 Hz, 2H), 3.99 (s, 2H), 7.10-7.20 (m, 2H), 7.28-7.33 (m, 1H).
The title compound was prepared, using the appropriate reagents, as the TFA salt according to the procedure for EXAMPLE 761. MS (DCI/NH3) m/z 513 (M+H)+; 1H NMR (CD3OD) δ 1.03-1.10 (m, 2H), 1.22-1.29 (m, 1H), 1.66-1.73 (m, 4H), 2.44 (d, J=2.44 Hz, 2H), 2.47-2.51 (m, 2H), 3.26 (q, J=7.32 Hz, 1H), 3.30-3.35 (m, 2H), 3.38-3.47 (m, 1H), 3.58-3.62 (m, 1H), 3.69-3.73 (m, 2H), 3.99 (s, 2H), 7.00-7.07 (m, 1H), 7.12-7.18 (m, 2H), 7.24 (dd, J=6.10, 2.14 Hz, 1H), 7.28-7.35 (m, 1H), 7.44-7.51 (m, 1H).
To a suspension of EXAMPLE 719 as the HCl salt (59 mg, 0.134 mmol) in a mixture of anhydrous tetrahydrofuran (2 mL) and acetonitrile (2 mL) was added triethylamine (0.056 mL, 0.403 mmol) and 2,5-dioxopyrrolidin-1-yl nicotinate (44 mg, 0.201 mmol). This suspension was heated at 60° C. overnight and concentrated. The residue was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in H2O: B: 0.1% TFA in CH3CN; 0-100% gradient) to provide the title compound as the TFA salt. MS (DCI/NH3) m/z 478 (M+H)+; 1H NMR (CD3OD) δ 1.08 (t, J=7.17 Hz, 3H), 1.67-1.72 (m, 4H), 2.39-2.43 (m, 2H), 2.46-2.51 (m, 2H), 3.27-3.32 (m, 2H), 3.44-3.53 (m, 1H), 3.73 (t, J=5.95 Hz, 1H), 3.79-3.84 (m, 2H), 3.97 (s, 2H), 7.09-7.16 (m, 2H), 7.29-7.35 (m, 1H), 7.84 (dd, J=7.93, 5.49 Hz, 1H), 8.51-8.57 (m, 1H), 8.81 (dd, J=10.99, 4.88 Hz, 1H), 9.08 (s, 1H).
The foregoing is meant to be illustrative of the invention and not meant to limit it to disclosed embodiments. Variations and changes obvious to one skilled in the art are intended to be within the scope and nature of the invention as defined in the appended claims.
This application is a continuation application of U.S. patent application Ser. No. 12/138,168, filed Jun. 12, 2008, now U.S. Pat. No. 8,466,150, which is a continuation-in-part of U.S. patent application Ser. No. 11/964,822, filed Dec. 27, 2007, which claims priority from Provisional U.S. patent application Ser. No. 60/882,317, filed Dec. 28, 2006, all of which are incorporated by reference in their entireties.
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| Number | Date | Country | |
|---|---|---|---|
| 20140212509 A1 | Jul 2014 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60882317 | Dec 2006 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12138168 | Jun 2008 | US |
| Child | 13902055 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11964822 | Dec 2007 | US |
| Child | 12138168 | US |
