The present invention concerns antiviral compounds, their methods of preparation and their compositions, and use in the treatment of viral infections. More particularly, the invention provides imidazopyridine and imidazopyrimidine derivatives (Formula I) for the treatment of respiratory syncytial virus infection.

1. Field of the Invention
The present invention concerns antiviral compounds, their methods of preparation and their compositions, and use in the treatment of viral infections. More particularly, the invention provides imidazopyridine and imidazopyrimidine derivatives (Formula I) for the treatment of respiratory syncytial virus infection.
2. Background Art
Respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory tract infection in infants, children, elderly and immunocompromised persons. Severe infection of the virus may result in bronchiolitis or pneumonia which may require hospitalization or result in death. (JAMA, 1997, 277, 12). Currently only Ribavirin is approved for the treatment of this viral infection. Ribavirin is a nucleoside analogue which is administered intranasally as an aerosol. The agent is quite toxic, and its efficacy has remained controversial. Other than Ribavirin, RespiGam and Synagis are an immunoglobulin and monoclonal antibody, respectively, that neutralize RSV. They are the only two biologics that have been approved for prophylactic use in high risk pediatric patients for RSV infection. Both RespiGam and Synagis are very expensive and require parental administration.
Many agents are known to inhibit respiratory syncytial virus (De Clercq, Int. J. Antiviral Agents, 1996, 7, 193). Y. Tao et al. (EP 0 058 146 A1, 1998) disclosed that Cetirizine, a known antihistamine, exhibited anti-RSV activity. Tidwell et al., J. Med. Chem. 1983, 26, 294 (U.S. Pat. No. 4,324,794, 1982), and Dubovi et al., Antimicrobial Agents and Chemotherapy, 1981, 19, 649, reported a series of amidino compounds with the formula shown below as inhibitors of RSV.
Hsu et al., U.S. Pat. No. 5,256,668 (1993) also disclosed a series of 6-aminopyrimidones that possess anti-viral activity against RSV.
In addition, Y. Gluzman, et al., (AU Patent, Au-A-14,704, 1997) and P. R. Wyde et al. (Antiviral Res. 1998, 38, 31) disclosed a series of triazine containing compounds that were useful for the treatment and/or prevention of RSV infection.
Another series of compounds structurally related to this invention are pyrido[1,2-a]benzoazoles and pyrimidio[1,2a]benzimidazoles disclosed by S. Shigeta et al in Antiviral Chem. and Chemother. 1992, 3, 171. These compounds have demonstrated inhibition of orthomyxovirus and paramyxovirus replication in HeLa cells. The structures of these compounds are shown in formulas Id and Ie, in which Fxe2x95x90NH, S, or O; Qxe2x95x90xe2x80x94NHCOPh, xe2x80x94COOH, COOEt, or CN; Txe2x95x90COMe, CN, or COOEt; Gxe2x95x90O or NH.
A bis-benzimidazole with an ethylenediol linker shown below has also been reported as a potent inhibitor of rhinoviruses (Roderick, et al. J. Med. Chem. 1972, 15, 655).
Other structurally related compounds are bis-benzimidazoles which possess antifungal activity (B. Cakir, et al. Eczacilik Fak. Derg. 1988, 5, 71).
Most recently Yu et al. have discovered a series of benzimidazoles (Formula II) for the treatment and prevention of RSV infection (WO 00/04900). In addition, Theodore Nitz has also found a series of compounds with Formula III that inhibit RSV in Hep-2 cell tissue culture assay (WO 99/38508). Although many other agents are known to inhibit respiratory syncytial virus (De Clercq, Int. J. Antiviral Agents, 1996, 7, 193) none of them have been used in human clinical trials. Thus, there is a medical need for a convenient and less expensive anti-viral agent for the treatment and prevention of RSV infection.
This invention relates to compounds having the Formula I, and pharmaceutically acceptable salts thereof
wherein:
W is O or S;
R1 is xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x94X;
X is H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionally substituted with one to six of the same or different halogen atoms; halogen, CN, ORxe2x80x2, OCORxe2x80x3xe2x80x3, NRxe2x80x2Rxe2x80x3, NRxe2x80x2CORxe2x80x3, NRxe2x80x2CONRxe2x80x3Rxe2x80x2xe2x80x3, NRxe2x80x2SO2Rxe2x80x3, NRxe2x80x2COORxe2x80x3, CORxe2x80x2, CRxe2x80x2xe2x80x3NNRxe2x80x2Rxe2x80x3, CRxe2x80x2NORxe2x80x3, COORxe2x80x2, CONRxe2x80x2Rxe2x80x3, SOmRxe2x80x2, PO(ORxe2x80x2)2, aryl, heteroaryl or non-aromatic heterocycle;
m is 0-2; n is 2-6;
R2 is
(i) H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, xe2x80x94(CH2)t, C3-7 cycloalkyl, xe2x80x94(CH2)t, C4-7 cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionally substituted with one to six of the same or different halogen atoms; SO2Rxe2x80x3, SO2NRxe2x80x2Rxe2x80x3 or CN; wherein t is 1-6;
(ii) xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x2xe2x80x94Y, wherein Y is CN, ORxe2x80x2, OCONRxe2x80x2Rxe2x80x3, NRxe2x80x2Rxe2x80x3, NCORxe2x80x2, NRxe2x80x2SO2Rxe2x80x3, NRxe2x80x2COORxe2x80x3, NRxe2x80x2CONRxe2x80x3Rxe2x80x2xe2x80x3, CORxe2x80x2, CRxe2x80x2xe2x80x3NNRxe2x80x2Rxe2x80x3, CRxe2x80x2NORxe2x80x3, COORxe2x80x2, CONRxe2x80x2Rxe2x80x3, SOmRxe2x80x2, SO2NRxe2x80x2Rxe2x80x3 or PO(ORxe2x80x2)2; wherein
m is 0-2 and nxe2x80x2 is 1-6;
(iii) xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x3xe2x80x94C6H4xe2x80x94Z, wherein the Z group may be in the ortho, meta or para position relative to the xe2x80x94(CH2)nxe2x80x3 group; Z is CN, ORxe2x80x2, OCONRxe2x80x2Rxe2x80x3, NO2, NRxe2x80x2Rxe2x80x3, NCORxe2x80x2, NRxe2x80x2SO2Rxe2x80x3, NRxe2x80x2COORxe2x80x3, NRxe2x80x2CONRxe2x80x3Rxe2x80x2xe2x80x3, CORxe2x80x2, CRxe2x80x2xe2x80x3NNRxe2x80x2Rxe2x80x3, CRxe2x80x2NORxe2x80x3, COORxe2x80x2, CONRxe2x80x2Rxe2x80x3, SOmRxe2x80x2, SO2NRxe2x80x2Rxe2x80x3 or PO(ORxe2x80x2)2;
m is 0-2; nxe2x80x3 is 0-6; or
(iv) xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x2xe2x80x3-heteroaryl, wherein nxe2x80x2xe2x80x3 is 0-6;
(v) xe2x80x94(CRxe2x80x2Rxe2x80x3)nxe2x80x2xe2x80x3-non-aromatic heterocycle, wherein nxe2x80x2xe2x80x3 is 0-6;
R3, R4, R5 and R6 are each independently hydrogen, halogen, C1 6 alkyl, C1-6 alkyl substituted with one to six of the same or different halogen atoms, ORxe2x80x2, CN, CORxe2x80x2, COORxe2x80x2, CONRxe2x80x2Rxe2x80x3, or NO2;
A, B, E, D are each independently Cxe2x80x94H, Cxe2x80x94Qxe2x80x94, N, or Nxe2x80x94O; provided at least one of A, B, E or D is not Cxe2x80x94H or Cxe2x80x94Q; wherein Q is halogen, C1-3 alkyl or C1-3 alkyl substituted with one to three of the same or different halogen atoms; and
Rxe2x80x2, Rxe2x80x3, Rxe2x80x2xe2x80x3 are each independently H, C1-6 alkyl, C26 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionally substituted with one to six of the same or different halogen atoms; or Rxe2x80x2 and Rxe2x80x3 taken together form a cyclic alkyl group having 3 to 7 carbon atoms; benzyl or aryl;
Rxe2x80x3xe2x80x3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, NRxe2x80x2Rxe2x80x3, CRxe2x80x2NRxe2x80x3Rxe2x80x2xe2x80x3, aryl, heteroaryl, non-aromatic heterocycle; and
Non-aromatic heterocycle is a 3-7 membered non-aromatic ring containing at least one and up to 4 non-carbon atoms selected from the group consisting of O, S, N, and NRxe2x80x2;
Aryl is phenyl, naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl;
Heteroaryl is a 4-7 membered aromatic ring which contains one to five heteroatoms independently selected from the group consisting of O, S, N or NRxe2x80x2, wherein said aromatic ring is optionally fused to group Bxe2x80x2;
Bxe2x80x2 is an aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl;
Aryl, Bxe2x80x2, said 4-7 membered aromatic ring, and said 3-7 membered non-aromatic ring may each independently contain one to five substituents which are each independently selected from R7, R8, R9, R10 or R11; and R7, R8, R9, R10 and R11 are each independently
(i) H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl being optionally substituted with one to six of the same or different halogen atoms; and
(ii) halogen, CN, NO2, ORxe2x80x2, NRxe2x80x2Rxe2x80x3, CORxe2x80x2, COORxe2x80x2, CONRxe2x80x2Rxe2x80x3, OCORxe2x80x2, NRxe2x80x2CORxe2x80x3, SOmRxe2x80x2, SO2NRxe2x80x2Rxe2x80x3, PO(ORxe2x80x2)2.
A preferred embodiment includes compounds of Formula I wherein heteroaryl is selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazol-5-one, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, tetrazole and phenoxazinyl.
Another preferred embodiment includes compounds of Formula I wherein:
R1 is xe2x80x94(CH2)nxe2x80x94X;
X is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionally substituted with one to six of the same or different halogen atoms; halogen, CN, ORxe2x80x2, OCORxe2x80x3xe2x80x3, NRxe2x80x2Rxe2x80x3, NRxe2x80x2CORxe2x80x3, NRxe2x80x2COORxe2x80x3, CORxe2x80x2, CRxe2x80x2xe2x80x3NNRxe2x80x2Rxe2x80x3, CRxe2x80x2NORxe2x80x3, COORxe2x80x2, CONRxe2x80x2Rxe2x80x3, SOmRxe2x80x2, aryl or heteroaryl;
m is 0-2; n is 2-4;
R2 is
(i) H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, xe2x80x94(CH2)t C3-7 cycloalkyl, xe2x80x94(CH2)t C4-7 cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionally substituted with one to six of the same or different halogen atoms; SO2Rxe2x80x3, SO2NRxe2x80x2Rxe2x80x3 or CN; wherein t is 1-6;
(ii) xe2x80x94(CH2)nxe2x80x2xe2x80x94Y, wherein Y is CN, ORxe2x80x2, CORxe2x80x2, COORxe2x80x2, CONRxe2x80x2Rxe2x80x3, SOmRxe2x80x2, SO2NRxe2x80x2Rxe2x80x3, PO(ORxe2x80x2)2 wherein m is 0-2 and nxe2x80x2 is 1-6; or
(iii) xe2x80x94(CH2)nxe2x80x3xe2x80x94C6H4xe2x80x94Z, wherein the Z group may be in the ortho, meta or para position relative to the xe2x80x94(CH2)nxe2x80x3 group; Z is CN, ORxe2x80x2, CORxe2x80x2 or SOmRxe2x80x2; m is 0-2; nxe2x80x3 is 0-3;
R3, R4, R5, and R6 are each independently hydrogen, halogen, C1-6 alkyl, optionally substituted with one to six of the same or different halogen atoms; and
A, B, E, D are each independently Cxe2x80x94H or N; provided at least one of A, B, E or D is not Cxe2x80x94H.
Another preferred embodiment includes compounds of Formula I wherein:
R3, R4, R5 and R6 are each H;
A, B and D are each Cxe2x80x94H; and
E is N.
Another preferred embodiment includes compounds of Formula I wherein:
R3, R4, R5 and R6 are each H;
A, B and E are each Cxe2x80x94H; and
D is N.
In another embodiment of the invention there is provided a method for treating mammals infected with RSV, and in need thereof, which comprises administering to said mammal a therapeutically effective amount of one or more of the aforementioned compounds of having Formula I, including pharmaceutically acceptable salts thereof.
Another embodiment includes a pharmaceutical composition which comprises a therapeutically effective amount of one or more of the aforementioned anti-RSV compounds having Formula I, including pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
The term pharmaceutically acceptable salt includes solvates, hydrates, acid addition salts and quarternary salts. The acid addition salts are formed from a compound of Formula I and a pharmaceutically acceptable inorganic or organic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, citric, malonic, fumaric, maleic, oxalic acid, sulfamic, or tartaric acids. Quaternary salts include chloride, bromide, iodide, sulfate, phosphate, methansulfonate, citrate, acetate, malonate, fumarate, oxalate, sulfamate, and tartrate. Halogen means bromine, chlorine, fluorine and iodine.
The following definitions apply unless indicated otherwise:
An xe2x80x9carylxe2x80x9d group refers to an all carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, napthalenyl and anthracenyl.
As used herein, a xe2x80x9cheteroarylxe2x80x9d group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups are furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzthiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, and pyrazinyl.
As used herein, a xe2x80x9cnon-aromatic heterocyclexe2x80x9d group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Examples, without limitation, of non-aromatic heterocycle groups are azetidinyl, piperidyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, oxazolidonyl, oxazolonyl, 2-pyrrolidinonyl, hydantoinyl, meleimidyl and oxazolidinedionyl.
An xe2x80x9calkylxe2x80x9d group refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g., xe2x80x9c1-20xe2x80x9d, is stated herein, it means that the group, in this case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. For example, the term xe2x80x9cC1-6 alkylxe2x80x9d as used herein and in the claims (unless specified otherwise) mean straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and the like.
A xe2x80x9ccycloalkylxe2x80x9d group refers to a saturated all-carbon monocyclic or fused ring (i.e., rings which share and adjacent pair of carbon atoms) group wherein one or more rings does not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and adamantane.
A xe2x80x9ccycloalkenylxe2x80x9d group refers to an all-carbon monocyclic or fused ring (i.e., rings which share and adjacent pair of carbon atoms) group wherein one or more rings contains one or more carbon-carbon double bonds but does not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkenyl groups are cyclopentene, cyclohexadiene, and cycloheptatriene.
An xe2x80x9calkenylxe2x80x9d group refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond.
An xe2x80x9calkynylxe2x80x9d group refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
A xe2x80x9chydroxyxe2x80x9d group refers to an xe2x80x94OH group.
An xe2x80x9calkoxyxe2x80x9d group refers to both an xe2x80x94O-alkyl and an xe2x80x94O-cycloalkyl group as defined herein.
An xe2x80x9cO-carboxyxe2x80x9d group refers to a Rxe2x80x3C(O)O-group, with Rxe2x80x3 as defined herein.
An xe2x80x9caminoxe2x80x9d group refers to an xe2x80x94NH2 group.
A xe2x80x9cN-amidoxe2x80x9d group refers to a RxC(xe2x95x90O)NRyxe2x80x94 group, with Rx selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and heteroalicyclic and Ry selected from hydrogen or alkyl.
A xe2x80x9ccyanoxe2x80x9d group refers to a xe2x80x94CN group.
It is known in the art that nitrogen atoms in heteroaryl systems can be xe2x80x9cparticipating in a heteroaryl ring double bondxe2x80x9d, and this refers to the form of double bonds in the two tautomeric structures which comprise five-member ring heteroaryl groups. This dictates whether nitrogens can be substituted as well understood by chemists in the art. The disclosure and claims of the present invention are based on the known general principles of chemical bonding. It is understood that the claims do not encompass structures known to be unstable or not able to exist based on the literature.
Compounds of Formula I can be prepared either by coupling 2-substituted-benzimidazoles (II), where X is a halide or sulfonate such as mesylate or tosylate, with 2-oxo-imidazopyridines or 2-oxo-imidazopyrimidines (III) in the presence of base, preferably phosphazene bases such as t-butylimino-tri(pyrrolidino)phosphorane (BTPP), cesium carbonate or sodium hydride (Scheme I-A) or by reacting Ia with a R2-LG, where LG is a leaving group, preferably a halide or sulfonate such as mesylate or tosylate (Scheme I-B). Alternatively, compounds of Formula I can be synthesized according to the procedure described in Scheme I-C. Coupling of 2-substituted-benzimidazoles (IV) containing protecting groups (P) such as p-methoxybenzyl, mesyl, or 2-cyanoethyl with 2-oxo-imidazopyridines or 2-oxo-imidazopyrimidines in the presence of base is followed by removal of the protecting group using appropriate conditions. Deprotection can be accomplished by treatment with ceric ammonium nitrate (CAN), treatment with hydrazine or tetrabutylammonium fluoride (TBAF), or treatment with potassium tert-butoxide to respectively remove p-methoxybenzyl, mesyl, or 2-cyanoethyl groups and give intermediates V. Compounds of Formula I can then be prepared by reacting V with R1-LG where LG is a leaving group preferably a halide or sulfonate such as mesylate or tosylate.
The synthesis of 2-substituted-benzimidazoles (IIa) is shown in Schemes II A-C. Treatment of substituted or unsubstituted 2-hydroxymethylbenzimidazole (VI) with 1.05 equivalents of base, preferably sodium hydride or cesium carbonate, followed by the addition of R1-LG, where LG is a leaving group such as halide or sulfonate, gives compound VII. Treatment of the alcohol with thionyl chloride provides 2-chloromethyl-benzimidazole Ia (Scheme II-A). In a separate synthetic route, depicted in Scheme II-B, 2-fluoro-nitrobenzene (VIII) reacts with an amine to afford compound IX. Reduction of the nitro group provides a phenylenediamine derivative X which is cyclized with glycolic acid in 4-6 N HCl to give alcohol VII. Alternatively, 2-amino-nitrobenzene (IX) is acylated with 2-benzyloxyacetyl chloride to provide XI (Scheme II-C). Reduction of the nitro group followed by ring closure in ethanol in the presence of catalytic amount of acetic acid provides XII. Removal of the benzyl group using boron tribromide or palladium hydroxide on carbon and cyclohexene yields VII.
Preparation of compounds IVa-IVd containing protecting groups is depicted in Schemes IID-F. In Scheme II-D, 2-chloromethylbenzimidazole reacts with methane sulfonyl chloride (Ms-Cl) and triethylamine to give compound IVa. The chloride can be refluxed with potassium iodide in acetone to produce compound IVb. A p-methoxybenzyl protecting group is installed in Scheme II-E. Reaction of 4-methoxybenzyl chloride with 2-hydroxymethyl benzimidazole (VI) in the presence of base, preferably sodium hydride, gives compound of Formula XIV. Treatment of alcohol XIV with (bromomethylene)dimethylaiimonium bromide provides compound IVc. Compound IVd can be prepared as described in Scheme II-F. Michael addition of 2-hydroxymethylbenzimidazole (VI) with acrylonitrile yields compound XV which is then converted to the chloride IVd by treatment with thionyl chloride.
2-Oxo-imidazopyridines and 2-oxo-imidazopyrimidines can be synthesized using the procedure depicted in Scheme III. Displacement of Z, which is a halide, preferably chlorine, or an alkoxy group, preferably methoxy, of nitropyridines XVI (2-chloro-3-nitro-pyridine, 4-alkoxy-3-nitropyridine and 3-alkoxy-2-nitropyridine) with an amine gives XVII (Scheme III-A). Reduction of the nitro group and cyclization of the resulting diamine (XVIII) using phosgene/polyvinylpyridine, carbonyldiimidazole or urea provides N3-substituted 2-oxo-imidazopyridine III. N-substituted 2-oxo-5-imidazo-pyridines IIIa are prepared from known compound XIX by N-alkylation and deprotection of the t-butoxycarbonyl with aqueous sodium hydroxide (Scheme III-B). On the other hand, N-alkylation of XX and acid hydrolysis of the isopropenyl group gives 2-oxo-imidazo-6-pyridine IIIb (Scheme III-C). 2-Oxo-imidazopyrimidines (IIIc) can be prepared directly by reacting 2-oxo-imidazopyrimidine (XXI) with R2-LG where LG is a leaving group as described above, to give IIIc, as illustrated in Scheme III-D. Alternatively, 4,6-dichloro-5-nitropyrimidine (XXII) is treated with an amine to generate XXIII (Scheme III-E). Catalytic reduction of both the nitro group and the carbon-chlorine bond, and cyclization of the resulting diamine (XIV) with phosgene provides IIId.
Experimental Section
Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker Avance 500, AC-300, Bruker DPX-300 or a Varian Gemini 300 10 spectrometer. All spectra were determined in CDCl3, CD3OD, or DMSO-d6 and chemical shifts are reported in xcex4 units relative to tetramethylsilane (TMS). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; b, broad peak; dd, doublet of doublets; dt, doublet of triplets. Mass spectroscopy was performed on a Finnigan SSQ 7000 quadrupole mass spectrometer in both positive and negative electrospray ionization (ESI) modes or on a LC-MS using Shimadzu LC-10AS with micromass platform LC single quadrupole mass spectrometer in positive electrospray ionization. High resolution mass spectroscopy was recorded using a Finnigan MAT 900. Infrared (IR) spectra were recorded on a Perkin-Elmer system 2000 FT-IR. Elemental analysis was performed with a Perkin-Elmer series II, model 2400 CHN/O/S analyzer. Column chromatography was performed on silica gel from VWR Scientific. Preparative HPLC was performed using a Shimadzu LC-8A on a C18 column eluted with mixture of MeOH in water with 0.1% trifluoroacetic acid.
Abbreviations used in the experimental section:
BEMP: 2-t-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine
BTPP: t-butylimino-tri(pyrrolidino)phosphorane
CAN: ceric ammonium nitrate
DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene
DIEA: N,N-diisopropylethylamine
DMF: dimethylformamide
DMSO: dimethyl sulfoxide
Et2O: diethyl ether
EtOAc: ethyl acetate
EtOH: ethyl alcohol
MeOH: methanol
Prep HPLC: preparative high performance liquid chromatography
Prep TLC: preparative thin layer chromatography
TBAF: tetrabutylammonium fluoride
TFA: trifluoroacetic acid
THF: tetrahydrofuran
I. Preparation of Benzimidazoles:
Compounds 1-25, 59-111, and 138-143 are benzimidazole intermediates synthesized according to the procedures described in Scheme II.
To a solution of 2-hydroxymethylbenzimidazole (29.63 g, 200 mmol) in a mixture of DMF/THF (150 mL, 1:1) was added sodium hydride (60% in mineral oil, 8.4 g, 210 mmol) in several portions at room temperature. After stirring for 1 hour, 4-bromobutyronitrile (29.6 g, 200 mmol) was added and the resulting solution was stirred at 80xc2x0 C. for 16 hours. The solvent was evaporated and the residue diluted with water and extracted with EtOAc. The combined extracts were dried over MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, EtOAc/hexane, 1:1 to 2:1, then EtOAc/MeOH, 10:1) to give 22.11 g (51% yield) of 1 as a white solid.
1H NMR (CDCl3) xcex4 2.27-2.32 (m, 2 H), 2.41 (t, J=6.0 Hz, 2 H), 4.41 (t, J=7.2 Hz, 2 H), 7.26-7.38 (m, 3 H), 7.67-7.70 (m, 1 H); MS m/e 216 (MH+).
General Procedure for Converting 2-Hydroxymethyl-benzimidazoles to 2-Chloromethyl-benzimidazoles.
The procedure described below was used for the synthesis of compounds 2, 4, 9, 11A+11B, 15, 19, 23, 25, 70, 72, 76, 81, 88, 92, 94, 96, 98, 100, 102, 108, and 111 and 143.
To alcohol 1 (22 g, 102.2 mmol) suspended in CH2Cl2 (100 mL),thionyl chloride (15.81 g, 132.9 mmol) was slowly added with ice-water bath cooling. The ice bath was removed. The solution was stirred at room temperature for 1 hour and then evaporated. The residue was triturated with EtOAc to give a nearly quantitative yield of 2 as light gray powder.
1H NMR (CDCl3) xcex4 2.32-2.38 (m, 2 H), 2.70 (t, J=7.3 Hz, 2 H), 4.69 (t, J=7.6 Hz, 2 H), 5.33 (s, 2 H), 7.69-7.74 (m, 2 H), 7.85-7.87 (m, 1 H), 8.00-8.02 (m, 1 H); MS m/e 234 (MH+). Anal. Calcd for C12H12N3xe2x80xa2HClxe2x80xa20.25 H2O: C, 52.48; H, 4.95; N, 15.30 Found: C, 52.52; H, 4.88; N, 15.26
Compound 3 was prepared using the same procedure described for compound 1, except that 4-bromobutyronitrile was replaced with 3-methylbutylbromide.
1H NMR (CDCl3) xcex4 1.71-1.78 (m, 3 H), 4.28 (t, J=7.5 Hz, 2 H), 5.02 (s, 2 H), 7.33-7.41 (m, 3 H), 7.75 (d, J=7.9 Hz, 2 H); MS m/e 219 (MH+).
Compound 4 was prepared according to the same procedure described for compound 2.
1H NMR (CDCl3) xcex4 1.08 (d, J=6.4 Hz, 6 H), 1.83-1.89 (m, 3 H), 4.57-4.60 (m, 2 H), 5.30 (s, 2 H), 7.68-7.73 (m, 2 H), 7.84-7.86 (m, 1 H), 7.93-7.95 (m, 1H); MS m/e 237 (MH+).
A solution of 2,5-difluoronitrobenzene (15.4 g, 96.8 mmol), 4-aminobutyronitrile (7.4 g, 88 mmol) and diisopropylethylamine (23 ml, 132 mmol) in DMF (250 ml) was stirred at room temperature for 32 hours. After filtration, the solvent was evaporated and the orange solid was recrystallized from MeOH (250 ml) to afford 5 (14 g, 65% yield) as orange crystals.
1H NMR (CDCl3) xcex4 2.06-2.12 (m, 2 H), 2.54 (t, J=7.0 Hz, 2 H), 3.48-3.53 (m, 2 H), 6.85-6.88 (m, 1 H), 7.27-7.31 (m, 1 H), 7.89-7.92 (m, 1 H); MS m/e 224 (MH+).
To a suspension of nitrile 5 (10.8 g, 48.4 mmol) and potassium carbonate (20.1 g, 145 mmol) in CH3CN (200 ml) was added benzyloxyacetyl chloride (7.64 ml, 48.4 mmol) dropwise. After stirring at room temperature for 12 hours, the mixture was diluted with EtOAc (500 ml) and filtered. The filtrate was washed with 1 N HCl, brine, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, EtOAc/hexane, 1:2 to 1:1) to yield 6 (7.5 g, 42% yield) as a viscous pale yellow oil.
1H NMR (CDCl3) xcex4 1.86-1.98 (m, 2 H), 2.38-2.51 (m, 2 H), 3.34-3.39 (m, 1 H), 3.80-3.87 (m, 2 H), 4.06-4.14 (m, 1 H), 4.40-4.48 (m, 2 H), 7.18-7.19 (m, 1 H), 7.26-7.40 (m, 5 H), 7.72-7.74 (m, 1 H); MS m/e 394 (MH+).
In a flask equipped with a mechanical stirrer, a suspension of compound 6 (6.40 g, 17.25 mmol), iron powder (2.89 g, 51.8 mmol) and ammonium chloride (4.61 g, 86.2 mmol) in a mixture of MeOH and H2O (200 ml, 1:1) was stirred at reflux for 4 hours. The mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was evaporated and the residue was taken up in EtOAc (500 ml), washed with brine, dried over MgSO4, and evaporated. To the residue was added CH3CN (100 ml) and acetic acid (1 ml), and the mixture was stirred at reflux for 4 hours. The solvent was evaporated and the residue was purified by flash chromatography (gradient, EtOAc/hexane, 1:2 to 2:1) to give 7 (4.42 g, 75% yield) as a viscous oil which solidified upon standing.
1H NMR (CDCl3) xcex4 2.15-2.20 (m, 2 H), 2.31 (t, J=7.0 Hz, 2 H), 4.35 (t, J=7.2 Hz, 2 H), 4.62 (s, 2 H), 4.83 (s, 2 H), 7.07-7.11 (m, 1 H), 7.29-7.38 (m, 6 H), 7.43-7.46 (dd, J=2.4, 9.2 Hz, 1 H); MS m/e 324 (MH+).
To a solution of 7 (3.23 g, 10 mmol) in CH2Cl2 (100 ml) at 0xc2x0 C. was added boron tribromide (2.84 ml, 30 mmol). After stirring for 1 hour, the mixture was quenched with saturated NaHCO3 solution with ice bath cooling and extracted with EtOAc. The combined extracts were dried over MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, CH2Cl2/MeOH, 40:1 to 20:1) to give 8 (1.68 g, 72% yield) as an off-white solid.
1H NMR (CDCl3) xcex4 2.25-2.30 (m, 2 H), 2.43 (t, J=7.1 Hz, 2 H), 4.41 (t, J=7.1 Hz, 2 H), 4.85 (s, 2 H), 7.04-7.081 (m, 1 H), 7.29-7.34 (m, 2 H); MS m/e 234 (MH+).
Compound 9 was prepared according to the same procedure described for compound 2.
1H NMR (CD3OD) xcex4 2.30-2.36 (m, 2 H), 2.70 (t, J=7.2 Hz, 2 H), 4.67 (t, J=7.6 Hz, 2 H), 5.30 (s, 2 H), 7.49-7.54 (dt, J=2.4, 9.2 Hz, 1 H), 7.62-7.64 (dd, J=2.4, 8.0 Hz, 1 H), 8.01-8.04 (dd, J=2.0, 9.2 Hz, 1 H); MS m/e 252 (MH+).
A mixture of 10A and 10B was prepared from 5-fluoro-2-hydroxymethyl-benzimidazole using the same procedure described for compound 1.
1H NMR (CDCl3) xcex4 2.26-2.30 (m, 2 H), 2.42-2.46 (m, 2 H), 4.36-4.42 (m, 2 H), 4.87 (s, 2 H), 7.03-7.07 (m, 1.5 H), 7.30-7.32 (m, 1 H), 7.60-7.63 (m, 0.5 H); MS m/e 234 (MH+).
Compounds 11A and 11B were prepared according to the same procedure described for compound 2.
1H NMR (CDCl3) xcex4 2.24-2.30 (m, 2 H), 2.44-2.47 (m, 2 H), 4.32-4.39 (m, 2 H), 4.829 (s, 1 H), 4.831 (s, 1 H), 7.01-7.11 (m, 1.5 H), 7.30-7.33 (dd, J=4.4, 8.8 Hz, 0.5 H), 7.40-7.42 (dd, J=2.3, 9.0 Hz, 0.5 H), 7.66-7.68 (dd, J=4.8, 8.8 Hz, 0.5 H); MS m/e 252 (MH+).
2-Fluoronitrobenzene (35.4 g, 250.9 mmol), 3-(methylthio)propylamine (24.0g, 228.1 mmol) and potassium carbonate (47.3 g, 342 mmol) were stirred in CH3CN (100 mL) at room temperature overnight. After stirring for an additional hour at reflux, the mixture was cooled to room temperature and filtered. The filtrate was evaporated. To the residue in DMF (150 mL), magnesium monoperoxyphthalate hexahydrate (MMPP, 168 g, 340 mmol) was added in several portions with ice-water cooling. The mixture was stirred at room temperature for 3 hours and the solvent was evaporated. The residue was dissolved in CH2Cl2 and washed with 1 N NaOH, water, brine, dried over MgSO4 and evaporated. The residue was triturated with hot EtOAc to give 12 (48.7 g, 75% yield) as an orange solid.
1H NMR (CDCl3) xcex4 2.25-2.35 (m, 2 H), 2.97 (s, 3 H), 3.17 (t, J=7.2 Hz, 2 H), 3.59 (t, J=6.9 Hz, 2 H), 6.68-6.74 (m, 1 H), 6.89 (d, J=8.1 Hz, 1 H), 7.45-7.51 (m, 1 H), 8.20 (dd, J=1.5, 8.7 Hz, 1 H); MS m/e 259 (MH+); Anal. Calcd for C10H14N2O4S: C, 46.50; H, 5.46; N, 10.84 Found: C, 46.53; H, 5.54; N, 10.90.
To a suspension of 12 (48.5 g, 187.8 mmol) in a mixture of CHCl3 and MeOH ( 150 mL, 1:3) was added 10% palladium on carbon (6 g) under nitrogen. The reduction was carried out in a Parr shaker with hydrogen pressure maintained between 40 and 60 psi for 25 minutes. The catalyst was removed by filtration through a pad of Celite and the filtrate was evaporated to give crude 13.
1H NMR (CD3OD) xcex4 2.11-2.21 (m, 2 H), 2.98 (s, 3 H), 3.28-3.36 (m, 4 H), 6.75 (dt,J=0.9, 7.2 Hz, 1 H), 6.85 (d,J=7.5 Hz, 1 H), 7.06-7.12 (m,2 H); MS m/e 229 (MH+).
The crude diamine 13 obtained above was stirred at reflux overnight with glycolic acid (15.7 g, 207 mmol) in 6 N HCl (150 mL). The solution was cooled in an ice bath and neutralized with concentrated NH4OH solution, extracted with EtOAc, dried over MgSO4 and evaporated. The residue was purified by chromatography (gradient, EtOAc/hexane, 1:1 to EtOAc/MeOH, 10:1) to give a product which crystallized from EtOAc/MeOH to afford 25.7 g (51% yield in two steps) of 14.
1H NMR (CD3OD) xcex4 2.38-2.44 (m, 2 H), 2.97 (s, 3 H), 3.24 (t, J=7.6 Hz, 2 H), 4.54 (t, J=7.6Hz, 2 H), 7.27 (t, J=1.1, 8.1 Hz, 1 H), 7.33 (dt, J=1.1, 8.0Hz, 1 H), 7.62 (d, J=8.1 Hz, 1 H), 7.64 (dd, J=1.0, 8.0 Hz, 1 H); MS m/e 269 (MH+).
Compound 15 was prepared according to the same procedure described for compound 2.
1H NMR (CD3OD) xcex4 2.46-2.52 (m, 2 H), 3.03 (s, 3 H), 3.37 (t, J=7.1 Hz, 2 H), 4.77 (t, J=7.8 Hz, 2 H), 5.31 (s, 2 H), 7.68-7.73 (m, 2 H), 7.86 (dd, J=2.8, 6.9 Hz, 1 H), 8.03 (dd, J=1.7, 6.1 Hz, 1 H); MS m/e 287 (MH+).
To a solution of 2,5-difluoronitrobenzene (15.1 g, 95.06 mmol) in CH3CN (150 mL) was added potassium carbonate (26.3 g, 190.11 mmol) and 3-(methylthio)propylamine (10.0 g, 95.06 mmol). The mixture was stirred vigorously with the aid of a mechanical stirrer for 16 hours at room temperature. The solid was filtered and the filtrate was evaporated. The residue was diluted with EtOAc (600 mL) and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to give crude 16 as an orange solid (25 g, 70% pure).
1H NMR (CDCl3) xcex4 1.97-2.01 (m, 2 H), 2.11 (s, 3 H), 2.62 (t, J=6.9 Hz, 2 H), 3.43 (q, J=6.3 Hz, 2 H), 6.87 (dd, J=4.6, 9.3 Hz, 1 H), 7.22-7.24 (m, 1 H), 7.85 (dd, J=3.1, 9.3 Hz, 1 H), 7.95 (bs, 1 H); MS m/e 245 (MH+).
A solution of 16 (25 g) in MeOH (300 mL) was added to a mixture of iron powder (12.0 g, 214.9 mmol) and ammonium chloride (19.2 g, 358.2 mmol) in water (100 mL). The reaction mixture was vigorously stirred with a mechanical stirrer and heated at 90xc2x0 C. for 16 hours. The mixture was filtered through a plug of Celite which was rinsed with hot methanol. The solvent was evaporated to give the crude diamine. LC-MS m/e 215 (MH+).
The diamine (500 mg crude, 2.33 mmol) and glycolic acid (266 mg, 3.50 mmol) were heated at reflux in 4 N hydrochloric acid (15 mL) for 16 hours. The aqueous solution was cooled and neutralized with concentrated NH4OH (15 mL). The aqueous solution was then extracted with EtOAc. The organic extracts were dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography (gradient, EtOAc/hexanes, 2:1 to EtOAc/MeOH, 10:1) to give 17 (150 mg, 25% yield).
1H NMR (CD3OD) xcex4 2.08 (s, 3 H), 2.12-2.20 (m, 2 H), 2.53 (t, J=6.9 Hz, 2 H), 4.43 (t, J=6.3 Hz, 2 H), 4.85 (s, 2 H), 7.07 (dt, J=2.4, 9.2 Hz, 1 H), 7.30 (dd, J =2.4, 9.3 Hz, 1 H), 7.53 (dd, J=4.6, 8.9 Hz, 1 H); MS m/e 255 (MH+).
To a solution of sulfide 17 (150 mg, 0.59 mmol) in DMF (5 mL) was added magnesium monoperoxyphthate hexahydrate (MMPP, 583 mg, 1.18 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the residue was diluted with water and extracted with EtOAc. The combined extracts were washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography (gradient, straight EtOAc to EtOAc/MeOH, 10:1) to give 18 (129 mg, 76% yield) as a white solid.
1H NMR (CD3OD) xcex4 2.37-2.47 (m, 2 H), 3.00 (s, 3 H), 3.26 (t, J=7.4 Hz, 2 H), 4.55 (t, J=7.5 Hz, 2 H), 7.14 (dt, J2.4, 9.4Hz, 1 H), 7.34 (dd, J=2.4, 9.2 Hz, 1 H), 7.62 (dd, J=4.5, 8.9 Hz, 1H); IR (KBr, cmxe2x88x921) 3139, 1624, 1591, 1489, 1478, 1446, 1416, 1308, 1270, 1143, 1134, 1047, 951, 859, 802, 527, 500; MS m/e 287 (MH+); Anal. Calcd for C12H15FN2O3S: C, 50.33; H, 5.28; N, 9.78 Found: C, 50.17; H, 5.17; N, 9.57.
Compound 19 was prepared according to the same procedure described for compound 2.
1H NMR (DMSO-d6) xcex4 2.15-2.20 (m, 2 H), 3.00 (s, 3 H), 3.26 (t, J=7.2 Hz, 2 H), 4.47 (t, J=7.8 Hz, 2 H), 5.11 (s, 2 H), 7.27 (dt, J=2.4, 9.4 Hz, 1 H), 7.51 (dd, J =2.4, 9.0Hz, 1 H), 7.76 (dd, J=4.8, 9.0 Hz, 1 H); IR (KBr, cmxe2x88x921) 3429, 2577, 1635, 1536, 1496, 1290, 1277, 1130, 962, 927, 784; MS m/e 305 (MH+).
To a solution of 2,5-difluoronitrobenzene (45 g, 282.86 mmol) in CH3CN (500 mL) was added potassium carbonate (78 g, 565.72 mmol) and isoamylamine (25 g, 282.86 mmol). The reaction mixture was stirred at room temperature for 18 hours with the aid of a mechanical stirrer. The potassium carbonate was filtered and the filtrate was evaporated to give an orange oil. The oil was diluted with EtOAc, washed with water and brine, dried over MgSO4, and evaporated. Purification by flash column chromatography (hexanes/EtOAc, 20:1) gave 53 g (83% yield) of compound 20.
1H NMR (CDCl3) xcex4 0.98 (d, J=6.5 Hz, 6 H), 1.61-1.65 (m, 2 H), 1.74-1.78 (m, 1 H), 3.30 (t, J=7.3 Hz, 2 H), 6.83 (dd, J=4.6, 9.5 Hz, 1 H), 7.23-7.27 (m, 1 H), 7.85 (dd, J=3.1, 9.2 Hz, 1 H).
To a solution of compound 20 (53 g, 235.14 mmol) and concentrated HCl (15 mL) in MeOH (200 mL) was added 10% palladium on carbon (5 g) and the mixture was agitated under H2 at 55 psi for 1.5 hours. The catalyst was removed by filtration through a pad of Celite and the filtrate was concentrated to give 47 g (87% yield) of diamine 21 as the HCl salt.
1H NMR (CDCl3) xcex4 0.97 (d, J=6.2 Hz, 6 H), 1.65-1.77 (m, 3 H), 3.36 (t, J=8.0 Hz, 2 H), 6.50-6.57 (m, 1 H), 6.71 (dd, J=2.7, 10.5 Hz, 1 H), 7.28 (dd, J=5.5, 8.8 Hz, 1 H); MS m/e 197 (MH+).
A mixture of diamine 21 (47 g, 200.66 mmol) and glycolic acid (16 g, 210.70 mmol) in 4 N HCl (500 mL) was stirred at reflux for 18 hours. The reaction mixture was cooled first to room temperature and then to 0xc2x0 C. The reaction was diluted with concentrated ammonium hydroxide (200 mL) until the pH was adjusted to approximately 8. The product was extracted with EtOAc, dried over MgSO4, and evaporated. The crude product was recrystallized with EtOAc/hexanes to give 27 g (37% yield) of compound 22 as brown crystals.
1H NMR (CDCl3) xcex4 1.02 (d, J=6.0 Hz, 6 H), 1.68-1.75 (m, 3 H), 3.19 (bs, 1 H), 4.22 (t, J=7.7 Hz, 2 H), 4.93 (s, 2 H), 7.06 (dt, J=2.2, 9.1 Hz, 1 H), 7.26-7.28 (m, 1 H), 7.37 (dd, J=2.1, 8.9 Hz, 1 H); MS m/e 237 (MH+).
Compound 23 was prepared according to the same procedure described for compound 2.
1H NMR (CDCl3) xcex4 1.08 (d, J=6.4 Hz, 6 H), 1.79-1.90 (m, 3 H), 4.44 (bt, J=8.2 Hz, 2 H), 5.32 (s, 2 H), 7.36 (dt, J=2.2, 8.9, 1 H), 7.54-7.59 (m, 2 H); MS m/e 255 (MH+).
Compound 24 was prepared using the same procedure described for compound 1, except that 4-biomobutyromitrile was replaced with 4-bromobutyl acetate.
1H NMR (CDCl3) xcex4 1.68-1.72 (m, 2 H), 1.91-1.94 (,2 H), 2.03 (s, 3 H), 4.07 (t, J=6.4 Hz, 2 H), 4.26 (t, J=7.5 Hz, 2 H), 4.86 (s, 2 H), 6.86 (bs, 1 H), 7.20-7.29 (m, 3 H), 7.65 (dd, J=1.8, 6.7 Hz, 1 H); MS m/e 263 (MH+).
Compound 25 was prepared according to the same procedure described for compound 2.
1H NMR (CDCl3) xcex4 1.80-1.86 (m, 2 H), 2.03 (s, 3 H), 2.06-2.12 (m, 2 H), 4.14 (t, J=6.1 Hz, 2 H), 4.55 (t, J=8.1 Hz, 2 H), 5.42 (s, 2 H), 7.48 (t, J=7.3 Hz, 1 H), 7.55 (t, J=7.3 Hz, 1 H), 7.64 (d, J=8.5 Hz, 1 H), 7.78 (d, J=8.2 Hz, 1 H); MS m/e 281 (MH+).
Compound 59 was prepared using the same procedure described for compound 1, except that 4-bromobutyronitrile was replaced with 4-methoxybenzyl chloride.
1H NMR (CDCl3) xcex4 3.77 (s, 3 H), 4.99 (s, 2 H), 5.45 (s, 2 H), 6.84 (d, J=8.6 Hz, 2 H), 7.11 (d, J=8.6 Hz, 2 H), 7.28-7.34 (m, 3 H), 7.75 (d, J=6.8, 1 H); MS m/e 269 (MH+).
Compound 59 (4,75 g, 17.7 mmol) was combined with CH2Cl2 (100 mL) and the mixture was treated with (bromomethylene)dimethylammonium bromide (5.25 g, 23.0 mmol). The reaction was stirred at room temperature for 30 minutes and then filtered to isolate a white solid. The solid was rinsed with CH2Cl2, then with diethyl ether. The solid was triturated with water (50 mL), isolated by filtration, rinsed with water, then with acetone, and finally with Et2O. The white powder was labeled crop 1 and set aside. All liquids were combined and concentrated in vacuo to give an off-white solid which was triturated with a mixture of acetone (50 mL) and Et2O (300 mL). The liquid was decanted and the solid was suspended in acetone and isolated by filtration to give crop 2. Crops 1 and 2 were determined to be spectroscopically identical and were combined to give 6.65 g (91% yield) of compound 60 as a white powder.
1H NMR (DMSO-d6) xcex4 3.72 (s, 3 H), 5.18 (s, 2 H), 5.68 (s, 2 H), 6.92 (d, J=8.7 Hz, 2 H), 7.29 (d, J=8.7 Hz, 2 H), 7.44-7.47 (m, 2 H), 7.62-7.63 (m, 1 H), 7.78-7.80 (m, 1 H); MS m/e 332 (MH+).
Compound 61 was prepared according to the same procedure described for compound 16 using 3-methoxypropylamine instead of 3-(methylthio)propylamine.
1H NMR (CDCl3) xcex4 1.95-2.00 (m, 2 H), 3.37 (s, 3 H), 3.39-3.43 (m, 2 H), 3.52 (t, J=5.7 Hz, 2 H), 6.61 (t, J=8.2 Hz, 1 H), 6.86 (d, J=8.8 Hz, 1 H), 7.41 (t, J=7.9 Hz, 1 H), 8.14 (dd, J=1.4, 8.7 Hz, 1 H), 8.26 (bs, 1 H); MS m/e 211 (MH+).
Compound 62 was prepared from compound 61 according to the same procedure described for compound 13 and was used immediately upon isolation.
MS m/e 181 (MH+).
Compound 63 was prepared from compound 62 according to the same procedure described for compound 14.
1H NMR (CDCl3) xcex4 2.09-2.14 (m, 2 H), 3.30 (t, J=5.7 Hz, 2 H), 3.33 (s, 3 H), 4.35 (t, J=6.9 Hz, 2 H), 4.89 (s, 2 H), 7.22-7.26 (m, 2 H), 7.35-7.37 (m, 1 H), 7.69-7.70 (m, 1 H); MS m/e 221 (MH+).
A solution of compound 63 (1.50 g, 6.81mmol) in CH3CN (20 mL) was treated with (bromomethylene)dimethylammonium bromide. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with H2O (3 mL) and the solvent was evaporated and dried under vacuum to give compound 64 which was used immediately upon isolation.
MS m/e 283, 285 (MH+).
Compound 65 was prepared according to the same procedure described for compound 1, except that 4-bromobutyronitrile was replaced with benzyl 4-bromobutylether.
1H NMR (CD3OD) xcex4 1.65-1.71 (m, 2 H), 1.94-1.99 (m, 2 H), 3.52 (t, J=6.2 Hz, 2 H), 4.36 (t, J=7.7 Hz, 2 H), 4.47 (s, 2 H), 4.84 (s, 2 H), 7.22-7.27 (m, 3 H), 7.27-7.31 (m, 4 H), 7.48 (d, J=7.4 Hz, 1 H), 7.61 (dd,J=1.4, 7.1 Hz, 1 H); MS m/e 311 (MH+).
Compound 66 was prepared according to the same procedure described for compound 64.
MS m/e 373, 375 (MH+).
To a suspension of 1,2-phenylenediamine (50 g, 462 mmol) in THF (150 mL) cooled at 0C was slowly added a solution of benzyloxyacetyl chloride (171 g, 924 mmol) in THF (100 mL). The reaction mixture was stirred for 3 hours. The reaction mixture was cooled to 0xc2x0 C. with an ice bath and 4N HCl (300 mL) was slowly added to the reaction mixture. The ice bath was removed and the mixture was heated at reflux for 18 hours. The majority of the THF was evaporated. The aqueous material was neutralized with 10 N NaOH, extracted with EtOAc, dried over MgSO4, and evaporated to give a tan solid. The solid was recrystallized from EtOAc to give 45 g (41% yield) of compound 67. 1H NMR (CD3OD) xcex4 4.65 (s, 2 H), 4.77 (s, 2 H), 7.22-7.41 (m, 7 H), 7.56 (dd, J 3.2, 6.1 Hz, 2 H); MS m/e 239 (MH+).
To a solution of compound 67 (6.00 g, 25.18 mmol) in DMF (50 mL) was added sodium hydride (60% dispersion in mineral oil, 1.46 g, 36.52 mmol). The reaction mixture was cooled to 0xc2x0 C. and stirred for 30 minutes. To the cooled mixture 1 -bromo-3 -chloropropane (5.3 5 g, 3 2.99 mmol) was added and the reaction mixture was stirred for 4.5 hours. The mixture was diluted with H2O (75 mL) and extracted with Et2O (3xc3x97300 mL). The combined organic extracts were dried over MgSO4 and evaporated. Purification by flash column chromatography on silica (gradient, hexanes/FtOAc 2:1 to 1:1) gave 6.86 g (87% yield) of compound 68.
1H NMR (CDCl3) xcex4 2.22-2.36 (m, 2 H), 3.53 (t, J=6.0 Hz, 2 H), 4.45 (t, J=7.0 Hz, 2 H), 4.62 (s, 2 H), 4.90 (s, 2 H), 7.28-7.44 (m, 7 H), 7.42-7.48 (m, 1 H), 7.79-7.82 (m, 1 H); MS m/e 315, 317 (MH+).
A solution of compound 68 (4.00 g, 12.71 mmol) in CH2Cl2 (75 mL) was cooled to 0xc2x0 C. with an ice bath. To this solution was added boron tribromide (0.99M in CH2Cl2, 20 mL, 19.76 mmol) slowly via syringe. The reaction mixture was stirred at 0xc2x0 C. for 2 hours. The reaction was quenched at 0xc2x0 C. with MeOH (75 mL). The solvent was evaporated with a room temperature rotary evaporator bath. More MeOH was added and was again evaporated. The resulting solid was dried under high vacuum for 48 hours to give 3.70 g (95% yield) of compound 69.
1H NMR (CD3OD) xcex4 2.39-2.44 (m, 2 H), 3.72 (t, J=6.0 Hz, 2 H), 4.61 (t, J7.2 Hz, 2 H), 5.19 (s, 2 H), 7.62-7.68 (m, 2 H), 7.80-7.82 (m, 1 H), 7.93-7.95 (m, 1 H); MS m/e 225, 227 (MH+).
Compound 70 was prepared according to the same procedure described for compound 2.
MS m/e 244 (MH+).
Compound 71 was prepared according to the same procedure described for compound 1 using 1,4-dibromobutane and the reaction was carried out at 0xc2x0 C.
1H NMR (CD3OD) xcex4 1.91-1.95 (m, 2 H), 2.01-2.08 (m, 2 H), 3.48 (t, J=6.6 Hz, 2 H), 4.38 (t, J=7.4 Hz, 2 H), 4.86 (s, 2 H), 7.23-7.27 (m, 1 H), 7.29-7.32 (m, 1H), 7.54 (d, J=8.0 Hz, 1 H), 7.62 (d, J=8.0 Hz, 1 H); MS m/e 282, 284 (MH+).
Compound 72 was prepared according to the same procedure described for compound 2 and was used immediately upon isolation.
Compound 73 was prepared according to the same procedure described for compound 1 using 1,3 dibromopropane and the reaction was carried out at 0xc2x0 C.
1H NMR (CDCl3) xcex4 2.42-2.47 (m, 2 H), 3.43 (t, J=6.1 Hz, 2 H), 4.43 (t, J=7.0 Hz, 2 H), 4.94 (s, 2 H), 7.25-7.32 (m, 2 H), 7.42-7.44 (m, 1 H), 7.68-7.70 (m, 1 H); MS m/e 268, 270 (MH+).
2-Propanethiol (305 mg, 4.00 mmol) and sodium hydride (60% dispersion in mineral oil, 240 mg, 6.00 mmol) were stirred together in DMF (20 mL) and then cooled to 0xc2x0 C. To this mixture was added compound 73 (542 mg, 2.00 mmol) and the reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, and evaporated. Purification by column chromatography (gradient, CH2Cl2/MeOH, 40:1 to 20:1) gave 310 mg (59% yield) of compound 74 as an off-white oil.
1H NMR (CD3OD) xcex4 1.22 (d, J=6.7 Hz, 6 H), 2.10-2.18 (m, 2 H), 2.58 (t, J=7.0 Hz, 2 H), 2.90-2.93 (m, 1 H), 4.45 (t, J=7.3 Hz, 2 H), 4.87 (s, 2 H), 7.23-7.32 (m, 2 H), 7.55 (d, J=8.0 Hz, 1 H), 7.62 (d, J=7.9 Hz, 1 H); MS m/e 265 (MH+).
Compound 75 was prepared from compound 74 according to the same procedure described for compound 18.
1H NMR (CD3Cl) xcex4 1.32-1.36 (m, 6 H), 2.44-2.50 (m, 2 H), 3.00-3.02 (m, 2 H), 3.06-3.10 (m, 1 H), 4.48 (t, J=7.3 Hz, 2 H), 4.87 (s, 2 H), 7.23-7.30 (m, 2 H), 7.42 (d, J=7.7 Hz, 1 H), 7.65 (d, J=7.8 Hz, 1 H); MS m/e 297 (MH+).
Compound 76 was prepared according to the same procedure described for compound 2 and was used immediately upon isolation.
To a solution of compound 67 (18.25 g, 76.59 mmol) in DMF (85 mL) was added sodium hydride (60% dispersion in mineral oil, 3.37 g, 84.25 mmol). The reaction mixture was stirred for 30 minutes and then cooled to 0xc2x0 C. 1,3-Dibromopropane was slowly added to the cooled solution. The temperature was raised to room temperature after 20 minutes as no starting material remained. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc, 2:1) gave 5.2 g of a 60/40 mixture of the desired bromide compound 77A (8% yield) and an undesired elimination product 77B. This mixture was used in the next step without further purification.
Bromide 77A: MS m/e 360, 361 (MH+);
Elimination product 77B: MS m/e 279 (MH+).
To a solution of ethanethiol (1.04 g, 16.77 mmol) in DMF (60 mL) was added sodium hydride (60% dispersion in mineral oil, 670 mg, 16.77 mmol). The mixture was stirred for 15 minutes at room temperature and then cooled to 0xc2x0 C. In a separate flask, the mixture containing compounds 77A and 77B (5.2 g mixture, 3.0 g, 8.3 8 mmol) as dissolved in DMF (10 mL), cooled to 0xc2x0 C. and added slowly to the ethanethiol mixture. The reaction mixture was stirred for 1 hour while the temperature was slowly allowed to rise to room temperature. The DMF was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with H2O. The organic layer was dried over MgSO4 and evaporated. This material containing compound 78 was used immediately as a mixture without further purification.
Compound 79 was prepared from crude 78 according to the same procedure as compound 18 and was purified by flash column chromatography on silica (gradient, EtOAc/hexanes, 2:1 to straight EtOAc).
1H NMR (CDCl3) xcex4 1.21 (t, J=7.5 Hz, 3 H), 2.35-2.42 (m, 2 H), 2.73 (q, J=7.5 Hz, 2 H), 2.84-2.88 (m, 2 H), 4.43 (t, J=7.2 Hz, 2 H), 4.60 (s, 2 H), 4.87 (s, 2 H), 7.27-7.34 (m, 5 H), 7.42 (dd, J=1.5, 7.0Hz, 1 H), 7.77 (dd, J=1.6, 6.9Hz, 1 H), 8.00(s,2H); MS m/e 373 (MH+).
A solution of compound 79 (1.95 g, 5.24 mmol) in CH2Cl2 (50 mL) was cooled to 0xc2x0 C. with an ice bath. To this solution was added boron tribromide (0.99 M in CH2Cl2, 9.0 mL, 9.00 mmol) slowly via syringe. The reaction mixture was stirred for 40 minutes at 0xc2x0 C. before quenching at 0C by cautious addition of anhydrous MeOH (50 mL). The solvent was evaporated with a room temperature rotary evaporator bath. More anhydrous MeOH was added and the solvent was again evaporated. The resulting solid was dried under high vacuum for 48 hours to give 1.82 g (96% yield) of compound 80.
1H NMR (DMSO-d6) xcex4 1.22 (t, J=7.4 Hz, 3 H), 2.23-2.89 (m, 2 H), 3.11 (q, J 7.4 Hz, 2 H), 3.29 (t, J=7.7 Hz, 2 H), 4.53 (t, J=7.5 Hz, 2 H), 5.08 (s, 2 H), 7.58-7.65 (m, 2 H), 7.80 (dd, J=1.0, 7.3 Hz, 1 H), 8.04 (d, J=7.75 Hz, 1 H); MS m/e 283 (MH+).
Compound 81 was prepared according to the same procedure described for compound 2.
MS m/e 301 (MH+).
To a solution of compound 67 (1.43 g, 6.00 mmol) in DMF (25 mL) was added sodium hydride (60% dispersion in mineral oil, 260 mg, 6.60 mmol) and the mixture was cooled to 0xc2x0 C. To the mixture was added 4-bromo-1-1-butene (972 mg, 7.20 mmol) and the mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was quenched with H2O and extracted with EtOAc. The organic extracts were washed with water and then brine, dried over MgSO4, and evaporated. Flash column chromatography (gradient, hexanes/EtOAc, 4:1 to 1: 1) gave 5 80 mg (33% yield) of compound 82 as a viscous oil.
1H NMR (CDCl3) xcex4 2.55-2.59 (m, 2 H), 4.31 (t, J=7.5 Hz, 2 H), 4.59 (s, 2 H), 4.88 (s, 2 H), 5.01 (d, J=7.8 Hz, 1 H), 5.04 (d, J=10.4 Hz, 1 H), 5.71-5.80 (m, 1 H), 7.26-7.39 (m, 8 H), 7.79 (d, J=7.6 Hz, 1 H); MS m/e 293 (MH+).
To a solution of compound 82 (468 mg, 1.92 mmol) and water (71 mg, 3.93 mmol) in DMSO (5 mL) was added N-bromosuccinimide (NBS, 700 mg, 3.93 mmol) at room temperature and the mixture was stirred for 1 hour. The resulting solution was diluted with EtOAc and washed with H2O. The organic extracts were dried with MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, hexane:EtOAc 3:1 to 1:2) to give 214 mg (56% yield) of compound 83 as a off-white viscous oil.
1H NMR (CDCl3) xcex4 1.90-1.97 (m, 1 H), 2.12-2.18 (m, 1 H), 3.22-3.30 (m, 2 H), 3.61-3.66 (m, 1 H), 4.38-4.50 (m, 2 H), 4.59-4.64 (m, 2 H), 4.87-4.92 (m, 2 H), 7.28-7.37 (m, 7 H), 7.42-7.46 (m, 1 H), 7.78-7.80 (m, 1 H); MS m/e 389, 391 (MH+).
A mixture of compound 83 (214 mg, 0.55 mmol) and sodium azide (107 mg, 1.65 mmol) in DMF (5 mL) was stirred at 50xc2x0 C. for 1 hour. The resulting solution was diluted with EtOAc and washed with water. The organic extracts were dried with MgSO4 and evaporated to give 190 mg (98% yield) of compound 84 as a off-white viscous oil.
1H NMR (CDCl3) xcex4 1.84-1.91 (m, 1 H), 2.02-2.09 (m, 1 H), 3.08-3.14 (m, 2 H), 3.52-3.56 (m, 1 H), 4.36-4.41 (m, 1 H), 4.44-4.50 (m, 1 H), 4.60-4.67 (m, 2 H), 4.88-4.93 (m, 2 H), 7.26-7.38 (m, 7 H), 7.42-7.44 (m, 1 H), 7.79-7.81 (m, 1 H); MS m/e 352 (MH+).
Compound 85 was prepared from compound 84 according to the same reduction procedure described for compound 13.
1H NMR (CD3OD) xcex4 1.86-1.94 (m, 1 H), 2.03-2.10 (m, 1 H), 2.70-2.74 (m, J=3.2, 12.8 Hz, 1 H), 2.84-2.88 (dd, J=3.2, 12.8 Hz, 1 H), 3.70-3.75 (m, 1 H), 4.44-4.54 (m, 2 H), 4.60-4.65 (m, 2 H), 4.88-4.93 (m, 2 H), 7.27-7.38 (m, 7 H), 7.59 (d, J=8.0 Hz, 1 H), 7.65 (d, J=8.0 Hz, 1 H); MS m/e 326 (MH+).
A solution of compound 85 (162 mg, 0.50 mmol), carbonyldiimidazole (89 mg, 0.55 mmol) and pyridine (198 mg, 2.50 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 2 hours. The mixture was diluted with CH2Cl2 and washed with water. The organic extracts were dried over MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, CH2Cl2:MeOH, 40:1 to 20:1) to give 130 mg (74% yield) of compound 86 as a off-white viscous oil.
1H NMR (CD3OD) xcex4 2.16-2.21 (m, 2 H), 3.06-3.09 (m, 1 H), 3.52-3.59 (m, 1 H), 4.41-4.50 (m, 2 H), 4.58-4.65 (m, 3 H), 4.80-4.84 (m, 2 H), 7.26-7.38 (m, 6 H), 7.55-7.58 (m, 1 H), 7.82-7.85 (m, 1 H), 8.51-8.53 (m, 1 H); MS m/e 352 (MH+).
Compound 86 (130 mg, 0.37 mmol), palladium hydroxide on carbon (Pearlman""s catalyst, 50 mg), EtOH (2 mL) and cyclohexene (1 mL) were stirred at reflux for 1 hour. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated and purified by flash column chromatography (gradient, CH2Cl2/MeOH, 30:1 to 10:1) to give 20 mg (21% yield) of compound 87 as a viscous white oil.
1H NMR (CD3OD) xcex4 2.26-2.33 (m, 2 H), 3.21-3.24 (m, 1 H), 3.65 (t, J=8.8 Hz, 1 H), 4.50-4.54 (m, 2 H), 4.67-4.70 (m, 1 H), 4.89-4.92 (m, 2 H), 7.24-7.34 (m, 2 H), 7.57 (d, J=8.0 Hz, 1 H), 7.63 (d, J=7.9 Hz, 1 H); MS m/e 294 (MH+).
Compound 88 was prepared according to the same procedure described for chloride 2 and was used immediately upon isolation.
To a solution of 2-(chloromethyl)benzimidazole (80 g, 0.48 mol) and methanesulfonyl chloride (58.3 mL, 0.75 mol) in CH2Cl2 (0.5 L), triethylamine (136 mL, 0.97 mol) was added dropwise under nitrogen. The resulting mixture was stirred at room temperature for 6 hours. The mixture was filtered and the filtrate was evaporated. The residue was triturated with MeOH and filtered to afford 74.9 g (64% yield) of compound 89 as a brown solid.
1H NMR (CDCl3) , 3.44 (s, 3 H), 5.11 (s, 2 H), 7.40-7.49 (m, 2 H), 7.76-7.82 (m, 1 H), 7.85-7.91 (m, 1H); IR (KBr, cmxe2x88x921) 3027, 2920, 1371, 1349, 1177, 1144, 1059; MS m/e 245 (MH+); Anal. Calcd for C9H9ClN2O2S: C, 44.18; H, 3.71; N, 11.45 Found: C, 44.09; H, 3.57; N, 11.49.
A solution of potassium iodide (206 g, 1.24 mol) and compound 89 (74.8 g, 0.414 mol) in acetone (1 L) was stirred at reflux under nitrogen for 4 hours. The solid was filtered and the filtrate was evaporated. The crude product was triturated in MeOH and filtered to give 83 g (60% yield) of compound 90 as a solid.
1H NMR (CDCl3) xcex4 3.48 (s, 3 H), 4.97 (s, 2 H), 7.40-7.50 (m, 2 H), 7.75-7.85 (m, 2 H); IR (KBr, cmxe2x88x921) 3022, 2916, 1366, 1173, 1055, 966, 763, 745; MS m/e 336 (MH+); Anal. Calcd for C9H9IN2O2S: C, 32.16; H, 2.70; N, 8.33 Found: C, 32.05; H, 2.63; N, 8.22.
Compound 91 was prepared according to the Michael addition procedure described by Popov, I. I. in Khim Geterotskl. Soedin. 1996, 6, 781-792.
1H NMR (CDCl3) xcex4 3.08 (t, J=6.8 Hz, 2 H), 4.63 (t, 3 6.8 Hz, 2 H), 4.77 (d, J 5.7 Hz, 2 H), 5.73 (t, J=5.7 Hz, 1 H), 7.17-7.28 (m, 2 H), 7.64 (d, J=1.2 Hz, 1 H), 7.70 (d, J=1.2 Hz, 1H);
MS m/e 202 (MH+); Anal. Calcd for C11H11N3O: C 65.66; H, 5.51; N, 20.88 Found: C, 65.94; H, 5.57; N, 21.08.
Compound 92 was prepared according to the same procedure described for compound 2.
1H NMR (CDCl3) xcex4 3.02 (t, J=7.0Hz, 2 H), 4.65 (t, J=7.0 Hz, 2 H), 4.99 (s, 2 H), 7.34-7.44 (m, 3 H), 7.79-7.82 (m, 1 H); MS m/e 220 (MH+); Anal. Calcd for C11H10ClN3: C, 60.09; H, 4.65; N, 19.13 Found: C, 60.09; H,4.65; N, 19.11.
Compound 93 was prepared according to the same procedure described for compound 1 except that 4-bromobutyronitrile was replaced with ethyl 4-bromobutyrate.
1H NMR (CDCl3) 5 1.24 (t, J=7.0 Hz, 3 H), 2.15-2.22 (m, 2 H), 2.38-2.42 (m, 2 H), 4.12 (q, J=7.1 Hz, 211), 4.29-4.34 (m, 211), 4.96 (s, 211), 7.22-7.30 (m, 2 H), 7.38-7.43 (m, 1 H), 7.66-7.70 (m, 1 H); MS m/e 250 (MH+).
Compound 94 was prepared according to the same procedure described for chloride 2 and was used immediately upon isolation.
Compound 95 was prepared according to the same procedure described for compound 1 except that 4-bromobutyronitrile was replaced with 1-bromo-4-fluorobutane.
1H NMR (DMSO-d,) 8 1.65-1.75 (m, 2 H), 1.85-1.90 (m, 2 H), 4.32 (t, J=7.5 Hz, 2 H), 4.41 (t, J=6.0 Hz, 1 H), 4.51 (t, J=6.0 Hz, 1H), 4.71 (d, J=5.8 Hz, 2 H), 5.62 (t, J=5.8 Hz, 1 H), 7.18 (t, J=7.0 Hz, 1 H), 7.23 (t, J=6.3 Hz, 1 H), 7.56-7.60 (m, 2 H); MS m/e 222 (MH+).
Compound 96 was prepared according to the same procedure described for chloride 2 and was used immediately upon isolation.
Compound 97 was prepared according to the same procedure described for compound 1 except that 4-bromobutyronitrile was replaced with 1 -bromo-4,4,4-trifluorobutane.
1H NMR (DMSO-d6) xcex4 1.99-2.05 (m, 2 H), 2.34-2.40 (m, 2 H), 4.35-4.38 (m, 2 H), 4.73 (s, 2 H), 7.20 (t, J=7.2 Hz, 1 H), 7.26 (t, J=7.4 Hz, 1 H), 7.60-7.63 (m, 1 H), 7.96 (s, 1 H); MS m/e 258 (MH+).
Compound 98 was prepared according to the same procedure described for chloride 2 and was used immediately upon isolation.
Compound 99 was prepared according to the same procedure described for compound 1 except that 4-bromobutyronitrile was replaced with 4-methylsulfonylbenzyl bromide.
1H NMR (DMSO-d6) 3.16 (s, 3 H), 4.75 (d, J=5.6Hz, 2 H), 5.70 (s, 2 H), 5.73-5.75 (m, 1 H), 7.17-7.21 (m, 2 H), 7.36-7.38 (m, 1 H), 7.42 (d, J=8.2 Hz, 2 H), 7.64-7.65 (m, 1 H), 7.87 (d, J=8.2 Hz, 1 H); MS m/e 316 (MH+).
Compound 100 was prepared according to the same procedure described for chloride 2 and was used immediately upon isolation.
Compound 101 was prepared according to the same procedure described for compound 1 except that 4-bromobutyronitrile was replaced with 4-fluorobenzyl bromide.
1H NMR (DMSO-d6) xcex4 4.74 (s, 2 H), 5.55 (s, 2 H), 7.13-7.18 (m, 3 H), 7.28-7.30 (m, 2 H), 7.38-7.40 (m, 1 H), 7.59-7.63 (m, 1 H); MS m/e 256 (MH+).
Compound 102 was prepared according to the same procedure described for chloride 2 and was used immediately upon isolation.
Compound 103 was prepared according to the same procedure as compound 1 except that 4-bromobutyronitrile was replaced with 4-trifluoromethylbenzyl bromide.
1H NMR (DMSO-d6) xcex4 4.74 (s, 2 H), 5.68 (s, 2 H), 7.11-7.20 (m, 2 H), 7.35-7.39 (m, 2 H), 7.62-7.64 (m, 1 H), 7.64-7.72 (m, 2 H); MS m/e 369 (MH+).
Compound 104 was prepared according to the same procedure described for compound 64 and was used immediately upon isolation.
Compound 105 was prepared according to the same procedure described for compound 16 using 1-(3-aminopropyl)-2-pyrrolidinone instead of 3-(methylthio)propylamine.
1H NMR (CDCl3) xcex4 1.93 (m, 2 H), 2.02-2.07 (m, 2 H), 2.39 (t, J=8.05 Hz, 2 H), 3.32-3.36 (m, 2H), 3.36-3.45 (m, 4 H), 6.64 (t, J=7.0 Hz, 1 H), 6.83 (d, J=8.7 Hz, 1 H), 7.42 (t, J=8.7 Hz, 1 H), 8.07 (bs, 1 H), 8.16 (d, J=7.0 Hz, 1 H); MS in/e 263 (MH+); Anal. Calcd for C13H17N3O3xe2x80xa20.24 H2O: C, 58.34; H, 6.58; N, 15.70 Found: C, 58.05; H, 6.20; N, 11.41.
Compound 106 was prepared according to the same reduction procedure described for compound 13.
1H NMR (CDCl3) xcex4 1.83-1.88 (m, 2 H), 1.99-2.05 (m, 2 H), 2.41 (t, J=8.0 Hz, 2 H), 3.16 (t, J=6.5 Hz, 2 H), 3.33-3.43 (m, 4 H), 6.63-6.65 (m, 2 H), 6.70 (d, J=7.1 Hz, 1 H), 6.78 (t, J=7.5 Hz, 1 H), 7.26 (s, 1 H); MS m/e 233 (MH+).
Compound 107 was prepared according to the same procedure described for compound 14.
1H NMR (DMSO-d6) xcex4 1.87-1.92 (m, 2 H), 1.95-2.00 (m, 2 H), 2.21 (t, J=8.0 Hz, 2 H), 3.25-3.34 (m, 4 H), 4.26 (t, J=7.6 Hz, 2 H), 4.72 (s, 2 H), 5.65 (bs, 2 H); MS m/e 273 (MH+).
Compound 108 was prepared according to the same procedure described for chloride 2 and was used immediately upon isolation.
A mixture of 2,3-diaminotoluene (10.21 g, 83.57 mmol) and glycolic acid (9.5 3 g, 125.3 6 mmol) in 6 N HCl (1 00 mL) were stirred at I100xc2x0 C. for 14 hours. The reaction mixture was cooled and made basic (pH 7-8) with ammonium hydroxide. A dark brown solid was collected by filtration, washed with H2and dried to give 12.47 g (92% yield) of compound 109.
1H NMR (DMSO-d6) xcex4 2.50 (s, 3 H), 4.70 (s, 2 H), 6.93 (d, J=7.3 Hz, 1 H), 7.04 (t, J=7.6Hz, 1 H), 7.31 (d, J=7.9Hz, 1 H).
Compound 110 was prepared according to the same procedure described for compound 24 except that the base employed was cesium carbonate.
1H NMR (CDCl3) xcex4 1.67-1.73 (m, 2 H), 1.89-1.96 (m, 2 H), 2.02 (s, 3 H), 2.59 (s, 3 H), 4.05-4.10 (m, 2 H), 4.27 (t, J=7.5 Hz, 2 H), 4.89 (s, 2 H), 7.01-7.03 (m, 1 H), 7.12-7.15 (m, 2 H); MS m/e 277 (MH+).
Compound 111 was prepared according to the same procedure described for chloride 2 and was used immediately upon isolation. MS m/e 295 (MH+).
To a solution of 2-hydroxymethylbenzimidazole (5.92 g, 40.0 mmol) and imidazole (6.81 g, 100.0 mmol) in THF (100 mL) was added t-butyldimethylsilyl chloride (12.65 g, 84.0 mmol) in several portions. The resulting mixture was stirred at room temperature for 2 hours and filtered. The filtrate was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over MgSO4 and evaporated. The residue was recrystallized from hexanes/EtOAc to give 8.50 g (81%) of compound 138 as white needles.
1H NMR (CDCl3) xcex4 0.15-0.16 (m, 6 H), 0.95-0.97 (m, 9 H), 5.02-5.03 (m, 2 H), 7.24-7.27 (m, 2 H), 7.59 (bs, 2 H); MS m/e 263 (MH+).
Compound 139 was prepared according to the same procedure described for compound 68 except that cesium carbonate was used instead of sodium hydride as the base.
1H NMR (CDCl3) xcex4 0.13-0.14 (m, 6 H), 0.91-0.92 (m, 9 H), 2.35-2.37 (m, 2 H), 3.58 (t, J=6.0 Hz, 2 H), 4.50 (t, J=7.0 Hz, 2 H), 5.01 (s, 2 H), 7.26-7.32 (m, 2 H), 7.44 (d, J=8.0 Hz, 1 H), 7.77 (d, J=10.0 Hz, 1 H); MS m/e 339 (MH+).
Compound 140 was prepared through the coupling of compound 139 and cyclopropylsulfide according to the same procedure described for compound 74 except using cesium carbonate instead of sodium hydride as the base. The cyclopropylsulfide was prepared according to a literature procedure by E. Block, A. Schwan, and D. Dixon in Journal of the American Chemical Society, 1992, 114, 3492-3499.
1H NMR (CDCl3) xcex4 0.12-0.13 (m, 6 H), 0.54-0.56 (m, 2 H), 0.84-0.86 (m, 2 H), 0.90-0.91 (m,9 H), 1.87-1.92 (m, 1 H), 2.20-2.25 (m,2 H), 2.62 (t, J=7.0 Hz, 2 H), 4.43 (t, J=7.4 Hz, 2 H), 5.00 (s, 2 H), 7.26-7.32 (m,2 H), 7.44 (d, J=8.0 Hz, 1 H), 7.77 (d, J=10.0 Hz, 1 H); MS m/e 377 (MH+).
Compound 141 was prepared from compound 140 by the same procedure described for compound 18.
1H NMR (CDCl3) xcex4 0.13-0.14 (m, 6 H), 0.91-0.92 (m, 9 H), 1.01-1.03 (m, 2 H), 1.23-1.24 (m, 2 H), 2.31-2.34 (m, 1 H), 2.48-2.52 (m, 2 H), 3.07 (t, J=7.2 Hz, 2 H), 4.51 (t, J=7.1 Hz, 2 H), 5.00 (s, 2 H), 7.26-7.32 (m, 2 H), 7.44 (d, J=8.0 Hz, 1 H), 7.77 (d, J=10.0 Hz, 1 H); MS m/e 409 (MH+).
To solution of compound 141 (27 mg, 0.07 mmol) in THF (0.5 ml) was added TBAF (1 M THF solution, 0.13 mL, 0.13 mmol) at 0xc2x0 C. and the mixture was stirred for 10 minutes. The solvent was evaporated and the residue was passed through a short plug of silica (CH2Cl2/MeOH, 10:1) to give crude compound 142 which was used immediately upon isolation.
Compound 143 was prepared according to the same procedure described for compound 2 and was used immediately upon isolation.
II. Preparation of 2-Oxo-imidazopyridines and 2-Oxo-imidazopyrimidines:
Compounds 26-58 and 112-126 are intermediates prepared according to the procedures depicted in Scheme III.
3,4-Diaminopyridine (30 g, 274.9 mmol), ethyl acetoacetate (53.66 g, 412 mmol) and DBU (1 mL) were stirred at reflux in xylene (300 mL) under a Dean-Stark trap. After stirring for 3.5 hours, the solvent was evaporated and the residue was purified by flash chromatography (EtOAc; EtOAc:MeOH =10:1) to give a solid which was recrystallized from CH2Cl2/EtOAc to afford 26 (21.45 g, 45% yield) as white crystals.
1H NMR (CDCl3) xcex4 2.19 (s, 3 H), 5.22 (s, 1 H), 5.46 (s, 1 H), 7.19 (d, J=5.4 Hz, 1 H), 8.20 (d, J=5.4 Hz, 1 H), 8.23 (s, 1 H); MS m/e 176 (MH+).
Compound 26 (1.0 g, 5.71 mmol) in the presence of 10% palladium on carbon (0.1 g) in MeOH (10 mL) was hydrogenated in a Parr shaker at 40 psi for 2 days. The catalyst was removed by filtration and the filtrate was evaporated to give compound 27 as a white solid.
1H NMR (CDCl3) xcex4 1.57 (d, J=7.0 Hz, 6 H), 4.72-4.76 (m, 1 H), 7.19 (d, J=5.8 Hz, 1 H), 8.30 (d, J=5.8 Hz, 1 H), 8.58 (s, 1 H); MS m/e 178 (MH+).
The same procedure described for compound 26 was carried out using 2,3-diaminopyridine to give 28A and 28 B which were separated by flash chromatography (gradient, CH2Cl2/acetone,5:1 to 4:1).
Compound 28A
1H NMR (CD3OD) xcex4 2.31 (s, 3 H), 5.40 (s, 1 H), 5.51 (s, 1 H), 7.04 (dd, J=5.2, 7.7 Hz, 1 H), 7.38 (dd, J=1.4, 7.7 Hz, 1 H), 8.09 (dd, J=1.4, 5.2 Hz, 1 H); MS m/e 176 (MH+).
Compound 28B
1H NMR (CD3OD) xcex4 2.26 (s, 3 H), 5.21 (s, 1 H), 5.38 (s, 1 H), 7.11 (dd, J=5.5, 7.9 Hz, 1 H), 7.40 (dd, J=1.3, 7.9 Hz, 1 H), 8.09 (dd, J=1.3, 5.5 Hz, 1 H); MS m/e 176 (MH+).
2-Chloro-3-nitropyridine (7.0 g, 50.0 mmol), cyclopropylamine (3.71g, 65 mmol) and potassium carbonate (13.82 g, 100 mmol) were stirred in CH3CN (100 mL) at room temperature overnight and at reflux for an additional hour. The solid was filtered and the filtrate was evaporated. Water was added to the residue and the mixture was extracted with EtOAc. The combined extracts were dried over MgSO4 and filtered. Evaporation of the solvent gave 29 (8.40 g, 94% yield) as a dark brown solid.
1H NMR (CD3OD) xcex4 0.63-0.69 (m, 2 H), 0.93-0.97 (m, 2 H), 3.01-3.06 (m, 1 H), 6.70-6.72 (dd, J=4.5, 8.3 Hz, 1 H), 8.24 (bs, 1 H), 8.42 (dd, J=1.7, 8.3 Hz, 1 H), 8.52 (dd, J=1.7, 4.5 Hz, 1 H); MS m/e 180 (MH+).
Compound 29 (8.29 g, 46.28 mmol) was reduced with iron using the procedure described for compound 7. To the crude diamine in THF (50 mL) was added 1 equivalent of carbonyldiimidazole and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was diluted with CH2Cl2; washed with water, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, EtOAc/hexane, 1:1 to EtOAc/MeOH, 10: 1) to give 30 (1.93 g, 24% yield over two steps) as a light orange solid.
1H NMR (CDCl3) xcex4 1.19 (d, J=3.4 Hz, 2 H), 1.20 (s, 2H), 3.01-3.04 (m, 2 H), 7.02 (dd, J=5.3, 7.7 Hz, 1 H), 7.32 (dd, J=1.4, 7.7 Hz, 1 H), 8.12 (dd, J=1.4 Hz, 5.3 Hz, 1 H), 9.61 (bs, 1 H); MS m/e 176 (MH+).
A mixture of 26 (2.0 g, 11.4 mmol), Cs2CO3 (5.58 g, 17.1 mmol) and p-methylsulfonylbenzyl chloride (2.34 g, 11.4 mmol) in acetone (50 mL) was stirred at reflux for 2 hours. The solid was removed by filtration and the filtrate was evaporated. The residue was purified by flash chromatography (gradient, CH2Cl2/MeOH, 40:1 to 20:1) to afford 31 ( 3.24 g, 83% yield) as a white solid.
1H NMR (DMSO-d6) xcex4 2.18 (s, 3 H), 3.20 (s, 3 H), 5.23 (s, 2 H), 5.26 (s, 1 H), 5.45 (d, J=1.2 Hz, 1 H)), 7.21 (d, J=5.3 Hz, 1 H), 7.63 (d, J=8.4 Hz, 2 H), 7.92 (d, J=8.4 Hz, 2 H), 8.25 (d, J=5.1 Hz, 1H), 8.41 (s, 1 H); MS m/e 344 (MH+).
Compound 32 was prepared using the same procedure for compound 31, except that methylsulfonylbenzyl chloride was replaced with methyl p-bromomethylbenzoate.
1H NMR (DMSO-d6) xcex4 2.05 (s, 3H), 3.70 (s, 3H), 5.06 (s, 2H), 5.12 (s, 1H), 5.32 (d, J=1.4 Hz, 1H), 7.07-7.09 (dd, J=0.45, 5.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.80-7.82 (m, 2H), 8.11 (d, J=5.3 Hz, 1H), 8.23 (s, 1H); MS m/e 324 (MH+).
A solution of 31 (3.24 g, 9.45 mmol) in concentrated HCl (5 ml) and MeOH (50 ml) was stirred at reflux for 2 hours. The solvent was evaporated and the residue was triturated in hot MeOH to yield 33 (2.80 g, 87% yield) as a white solid as the HCl salt.
1H NMR (DMSO-d6) xcex4 3.18 (s, 3 H), 5.17 (s, 2 H), 7.07 (d, J=5.2 Hz, 1 H), 7.58 (d, J=8.0 Hz, 2 H), 7.91 (d, J=8.2 Hz, 2 H), 8.17 (d, J=5.0 Hz, 1 H), 8.29 (s, 1 H); MS m/e 304 (MH+).
A solution of 32 (1.30 g, 4.02 mmol) in concentrated HCl (10 ml) and MeOH (10 ml) was stirred at reflux for 1 hour. The solution was neutralized with K2CO3 to pH 6, and extracted with EtOAc. The organic layer was dried and evaporated to dryness. The crude product was triturated with hot CH2Cl2 to yield 34 (0.85 g, 75% yield) as off-white solid.
1H NMR (DMSO-d6) xcex4 3.90 (s, 3 H), 5.20 (s, 2 H), 7.13 (d, J=5.2 Hz, 1 H), 7.53 (d, J=8.2 Hz, 2 H), 8.00 (d, J=8.2 Hz, 2 H), 8.22 (d, J=5.2 Hz, 1 H), 8.31 (s, 1 H); MS m/e 284 (MH+).
A solution of 4-methoxy-3-nitro-pyridine (7.71 g, 50 mmol) and cyclopropylamine (7.14g, 125 mmol) in EtOH (20 mL) was stirred at reflux under a dry-ice trap condenser for 2 hours. The solvent was evaporated to give 35 as a yellow solid.
1H NMR (CD3OD) xcex4 0.72-0.75 (m, 2 H), 0.99-1.03 (m, 2 H), 2.63-2.68 (m, 1 H), 7.19 (d, J=6.2 Hz, 1 H), 8.26 (bs, 1 H), 8.35 (d, J=6.2 Hz, 1 H), 9.22 (s, 1 H); IR (KBr, cm1) 3369, 1613, 1560, 1515, 1406, 1254, 1195, 1039, 881, 846, 769, 545; MS m/e 180 (MH+).
To a solution of 35 (12.28 g, 68.6 mmol) in anhydrous MeOH (120 mL) was added 10% palladium on carbon (3 g) in several portions under nitrogen. The reduction was carried out using a balloon containing hydrogen (1 atm) for 16 hours. The catalyst was removed by filtration through a pad of Celite and rinsed with MeOH. The filtrate was concentrated to a slurry and Et2O was added to precipitate the diamine product as a light yellow solid (10.1 g, 99% yield).
To a slurry of the diamine and polyvinylpyridine (22.0 g) in acetonitrile (70 mL) of a 20% phosgene solution in toluene was added dropwise (70 mL, 135.4 mmol). After stirring at room temperature for 2 hours, the reaction was quenched with water. Polyvinylpyridine was removed by filtration and rinsed with MeOH. The filtrate was concentrated and Et2O was added to precipitate product 36 (15.5g, 98% yield) as a light brown solid.
1H NMR (CD3OD) xcex4 0.95-0.98 (m, 2 H), 1.07-1.14 (m, 2 H), 2.91-2.96 (m, 1 H), 7.32 (dd, J=0.5, 5.3 Hz, 1 H), 7.18 (s, 1 H), 8.21 (d, J=5.3 Hz, 1 H); MS m/e 176 (MH+).
2-Oxo-imidazopyridine 39 was prepared using the same procedure described for the preparation of 36, except that cyclopropylamine was replaced with 2 equivalents of trifluoroethylamine hydrochloride and diisopropylethylamine, and the reaction was carried out in a sealed tube at 120-130xc2x0 C. for 2 days.
1H NMR (CDCl3) xcex4 4.02 (q, J=7.9 Hz, 2 H), 6.83 (d, J=5.5 Hz, 1 H), 8.43 (d over bs, 2 H), 9.28 (s, 1 H); IR (KBr, cmxe2x88x921): 3287, 3241, 1629, 1611, 1363, 1254, 1150, 1047, 870; MS m/e 222 (MH+); Anal. Calcd for C7H6F3N3O2: C, 38.02; H, 2.73; N, 19.00 Found: C, 38.00; H, 2.69; N, 19.19.
1H NMR (CD3OD) xcex4 4.23 (q, J=9.0 Hz, 2 H), 7.05 (d, J=6.6 Hz, 1 H), 7.74 (d, J=1.1 Hz, 1 H), 7.84 (d, J=1.1, 6.6 Hz, 1 H); IR (KBr, cm1): 3343, 3202, 3062, 1625, 1578, 1529, 1257, 1154, 949; MS m/e 192 (MH+); Anal. Calcd for C7H8F3N3xe2x80xa2HCl: C, 36.94; H, 3.99; N, 18.46 Found: C, 37.19; H, 3.86; N, 18.79.
1H NMR (DMSO-d6) xcex4 4.99 (q, J=9.2 Hz, 2 H), 7.90 (d, J=6.3 Hz, 1 H), 8.61 (d, J=6.3 Hz, 1 H), 8.63 (s, 1 H); IR (KBr, cmxe2x88x921): 3423, 2994, 1744, 1517, 1347, 1254, 1263, 1173, 1000, 811; MS m/e 218 (MH+).
2-Oxo-imidazopyridine 41 was prepared using the same procedure described for compound 36, except that cyclopropylamine was replaced with t-butylamine and the reaction was carried out in a sealed tube at 80xc2x0 C. This compound was used as a crude intermediate for the coupling reaction.
1H NMR (CDCl3) xcex4 1.54 (s, 9 H), 7.21 (d, J=6.3 Hz, 1 H), 8.17 (d, J=6.3 Hz, I H), 9.08 (s, 1 H); MS m/e 196 (MH+).
A mixture of 1,2-dihydro-2-oxo-3H-imidazol[4,5-c]pyridine-3-carboxylic acid, 1,1-dimethyl ethyl ester (470 mg, 2.0 mmol) (prepared according to the procedure described by N. Meanwell et al. in J. Org. Chem. 1995, 60, 1565), Cs2CO3 (978 mg, 3.0 mmol) and p-methylsulfonylbenzyl chloride (451 mg, 2.2 mmol) in acetone (10 mL) was stirred at reflux for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by flash chromatography (gradient, CH2Cl2/MeOH, 40:1 to 20 :1) to afford 42 (500 mg, 62% yield) as a white solid.
1H NMR (CDCl3) xcex4 1.71 (s, 9 H), 3.04 (s, 3 H), 5.15 (s, 2 H), 6.90 (m, 1 H), 7.54 (m, 2 H), 7.93 (m, 2 H), 8.40 (m, 1 H), 9.01 (m, 1 H); MS m/e 404 (MH+).
A mixture of 42 (260 mg, 0.64 mmol) and 1 N NaOH (3.22 ml) in THF (5 ml) and water (1 ml) was stirred at the ambient temperature overnight. The mixture was diluted with saturated NH4Cl and extracted with CH2Cl2. The combined extracts were dried over MgSO4 and evaporated. The residue was triturated with EtOAc to produce 43 (180 mg, 93% yield) as a white solid.
1H NMR (DMSO-d6) xcex4 3.34 (s, 3 H), 5.16 (s, 2 H), 7.19 (d, J=5.2 Hz, 1 H), 7.56 (d, J=8.4Hz, 2 H), 7.89 (d, J=8.4Hz, 2 H), 8.15 (d, J=5.2Hz, 1 H), 8.22 (s, 1 H), 11.34 (s, 1 H); MS m/e 304 (MH+).
2-Oxo-imidazopyridine 45 was prepared using the same procedure for compound 43, except that p-methylsulfonylbenzyl chloride was replaced with cyclopropylmethyl bromide. This compound was used as a crude intermediate for the coupling reaction.
1H NMR (CD3OD) xcex4 0.44-0.45 (m, 2 H), 0.56-0.58 (m, 2 H), 1.21-1.25 (m, 1 H), 1.69 (s, 9 H), 3.79 (d, J=7.1 Hz, 2 H), 7.35 (d, J=5.4Hz, 1 H), 8.34 (d, J5.4 Hz, 1 H), 8.84 (s, 1 H); MS m/e 290 (MH+).
1H NMR (CD3OD) xcex4 7.54 (d, J=1.2 Hz, 1 H), 8.19 (d, J=1.2 Hz, 1 H), 8.23 (s, 1 H), 8.67 (s, 1 H); MS m/e 137 (MH+).
To a solution of 3-hydroxy-2-nitropyridine (100 g, 0.71 mol) in acetone (800 mL) was added potassium carbonate (148 g, 1.07 mol) followed by dimethyl sulfate (99 g, 0.79 mol). The reaction mixture was stirred vigorously using a mechanical stirrer and heated to 60xc2x0 C. for 4.5 hours. The mixture was filtered while still warm. The filtrate was stripped of solvent to give a crude brown solid. The solid was diluted with water and extracted with EtOAc. The organic extracts were dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography (CH2Cl2/EtOAc, 1:1) to give 46 as a bright yellow solid (81 g, 74% yield).
1H NMR (CDCl3) xcex4 3.98 (s, 3 H), 7.51-7.57 (m, 2 H), 8.10 (dd, J=1.5, 7.5 Hz, 1 H); MS m/e 155 (MH+).
Compound 47 was obtained from 46 using the same procedure for the preparation of 35 except that the reaction was carried out with 1.5 equivalents of cyclopropylamine in a sealed tube at 120xc2x0 C. for 2 days.
1H NMR (CDCl3) xcex4 0.67-0.72 (m, 2 H), 0.89-1.00 (m, 2 H), 2.58-2.65 (m, 1 H), 7.50 (dd, J=4.0, 8.6 Hz, 1 H), 7.82 (J=8.6 Hz, 1 H), 7.83 (d, J=8.6 Hz, 1 H), 7.97 (dd, J=1.4, 4.0 Hz, 1 H); MS m/e 155 (MH+).
A solution of 47 (300 mg, 1.67 mmol) in MeOH (25 mL) was agitated under H2 (10 psi) in the presence of 10% palladium on carbon (60 mg) for 15 min. The catalyst was removed by filtration through a pad of Celite. To the filtrate was added urea (402 mg, 6.70 mmol), and the mixture was evaporated. The solid residue was then heated at 170xc2x0 C. for 16 hours. The resulting black solid was heated in boiling ethanol and filtered. The filtrate was evaporated and the residue was purified by flash chromatography (gradient, straight CH2Cl2 to CH2Cl2/MeOH, 20:1) to give compound 48 as a yellow solid (82 mg, 28% yield). 1H NMR (CDCl3) xcex4 0.99-1.04 (m, 2 H), 1.12-1.15 (m, 2 H), 2.89-2.93 (m, 1 H), 7.05 (dd, J=5.3, 7.8Hz, 1 H), 7.41 (dd, J=1.3; 7.8Hz, 1 H), 8.05 (d, J=5.3Hz, 1 H); MS m/e 176 (MH+).
Compound 49 was prepared from 4,5-diaminopyrimidine and urea using the same procedure described for compound 48.
To a slurry of 49 (136 mg, 1.0 mmol) in THF (5 mL) was added BTPP (946 mg, 3.0 mmol) and p-methylsulfonylbenzyl chloride (205 mg, 1.0 mmol) at ambient temperature. After stirring overnight, the solution was diluted with EtOAc, washed with water, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, CH2Cl2/MeOH, 40:1 to 20:1) to afford compound 50 (52 mg, 34% yield) as a white solid.
1H NMR (CD3OD) xcex4 3.08 (s, 3 H), 5.26 (s, 2 H), 7.67 (d, J=8.4 Hz, 2 H), 7.91-7.93 (m, 2 H), 8.34 (s, 1 H), 8.74 (s, 1 H); MS m/e 305 (MH+).
To a suspension of 4,6-dichloro-5-nitropyrimidine (3.88 g, 20.0 mmol) and triethylamine (4.05 g, 40.0 mmol) in THF (50 ml) was added cyclopropylamine (1.14 g, 20.0 mmol) dropwise at 0xc2x0 C. After stirring at 0xc2x0 C. for 2 hours, the slurry was filtered. The filtrate was diluted with EtOAc, washed with water, dried over MgSO4, and evaporated. The residue was purified by flash chromatography (gradient, CH2Cl2/MeOH, 100:1 to 40:1) to afford compound 51 (2.75 g, 64% yield) as a yellow solid.
1H NMR (DMSO-d6) xcex4 0.61-0.64 (m, 2 H), 0.74-0.78 (m, 2 H), 2.92 (bs, 1 H), 8.43 (bs, 1 H), 8.51 (s, 1 H); MS m/e 215 (MH+).
Pyrimidine 51 was reduced using catalytic hydrogenation with 10% palladium on carbon in MeOH at 40 psi (Parr shaker) for 1 hour to afford compound 52.
1H NMR (DMSO-d6) xcex4 0.74-0.76 (m, 2 H), 0.79-0.83 (m, 2 H), 3.06-3.11 (m, 1 H), 6.17 (bs, 2 H), 7.47 (d, J=1.5 Hz, 1 H), 8.37 (d, J=1.0 Hz, 1 H), 9.09 (d, J 3.8 Hz, 1 H); MS m/e 151 (MH+).
Compound 53 was obtained by cyclization of diamine 52 according to the same procedure described for compound 36 using phosgene and polyvinylpyridine.
1H NMR (CD3OD) xcex4 1.14-1.19 (m, 2 H), 1.20-1.27 (m, 2 H), 3.11-3.18 (m, 1 H), 8.47 (d, J=0.45 Hz, 1 H), 9.01 (s, 1 H); MS m/e 177 (MH+).
2-Oxo-imidazopyrimidine 56 was prepared using the same procedure for compound 53, except that cyclopropylamine was replaced with t-butylamine. The compound was used as a crude intermediate for the coupling reaction without further purification.
1H NMR (CDCl3) xcex4 1.52 (s, 9 H), 7.26 (bs, 1 H), 8.37 (s, 1 H); MS m/e 231 (MH+).
1H NMR (CD3OD) xcex4 1.57 (s, 9 H), 7.49 (d, J=1.3 Hz, 1 H), 8.27 (d, J=1.3 Hz, 1 H); MS m/e 167 (MH+).
2-Oxo-imidazopyrimidine 58 was prepared according to the same procedure described for compound 53, except that cyclopropylamine was replaced with 2,2,2-trifluoroethylamine. The crude intermediate was used in the coupling reaction without further purification.
1H NMR (CD3OD) xcex4 4.30-4.36 (m, 2 H), 8.46 (s, 1 H); MS m/e 226 (MH+).
2-Oxo-imidazopyridine 113 was prepared according to the same procedure for the preparation of 36, except that cyclopropylamine was replaced with 2 equivalents of 3-amino-5-methylisoxazole, and the reaction was carried out in MeOH at 100xc2x0 C. for 18 hours in a sealed pressure tube.
1H NMR (CD3OD) xcex4 0.88 (s, 3 H), 4.71 (s, 1 H), 6.79 (d, J=6.2 Hz, 1 H), 6.95 (d, J=6.2 Hz, 1 H), 7.69 (d, 1 H); IR (KBr, cmxe2x88x921) 3323, 3125, 3097, 1604, 1581, 1521, 1499, 1228, 1179; MS m/e 221 (MH+); Anal. Calcd for C9H8N4O3: C, 49.09; H, 3.66; N, 25.44 Found: C, 49.04; H, 3.63; N, 25.06.
1H NMR (CD3OD) xcex4 2.50 (s, 3 H), 6.94 (s, 1 H), 7.95 (dd, J=0.6, 6.55 Hz, 1 H), 8.31 (s, 1 H), 8.32 (d, J5.5 Hz, 1 H); IR (KBr, cmxe2x88x921) 3546, 3463, 2679, 1744, 1720, 1596, 1474, 1457, 1193, 1129, 809, 633; MS m/e 217 (MH+).
A mixture of compound 26 (400 mg, 2.28 mmol) and BTPP (1.57 g, 5.02 mmol) in THF (10 mL) was stirred for 20 minutes after which 2,2,2-trifluoroethyl p-toluenesulfonate (605 mg, 2.40 mmol) was added to the mixture. The reaction mixture was stirred at 45xc2x0 C. for 18 hours and then at 60xc2x0 C. for an additional 24 hours. The solvent was evaporated and the residue was diluted with H2O and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and evaporated. Purification by flash column chromatography (EtOAc/MeOH, 20:1) gave 295 mg (50% yield) of 114 as a white solid.
1H NMR (CDCl3) xcex4 2.24 (s, 3 H), 4.51 (q, J=8.6 Hz, 2 H), 5.24 (s, 1 H), 5.43 (d, J=1.1 Hz, 1 H), 7.10 (d, J=5.5Hz, 1 H), 8.39 (s, 1 H), 8.40 (d, J=5.5 Hz, 1 H); IR(KBr,cm1)3026, 1727, 1605, 1503, 1169, 1156, 1126, 827; MS m/e 258 (MW+).
Compound 114 (272 mg, 1.06 mmol) and concentrated HCl (12 mL) in MeOH (20 mL) were refluxed for 72 hours. The solvent was evaporated and the residue was dried under vacuum to give 263 mg (99% yield) of compound 115 as the HCl salt.
1H NMR (DMSO-d6) xcex4 4.93 (q, J=9.2 Hz, 2 H), 7.61 (d, J=6.3 Hz, 1 H), 8.54 (d, J=6.3 Hz, 1 H), 8.89 (s, 1 H); MS m/e 218 (MH+).
Compound 28B (1.2 g, 6.86 mmol) and BTPP (3.21 g, 10.28 mmol) in CH2Cl2 were mixed together in a sealed flask and cooled to -78xc2x0 C. Chlorodifluoromethane (gas, approximately 2 g, 23.26 mmol) was bubbled into the solution in the sealed flask. The flask was sealed and the temperature was raised to 0xc2x0 C. for 10 minutes and then to room temperature for 3 minutes. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined extracts were dried over MgSO4 and evaporated. To the residue was added 6 N HCl in MeOH (1 :1 mixture, 10 mL). The mixture was stirred at reflux for 6 hours. The reaction was neutralized with solid Na2CO3. The solvent was concentrated and the resulting aqueous solution was extracted with CH2Cl2. The combined extracts were dried over MgSO4 and evaporated. Purification by flash column chromatography (gradient, straight EtOAc to EtOAc/MeOH, 5:1) gave 398 mg (31% yield) of 116.
1H NMR (CDCl3) xcex4 7.14 (dd, J=5.7, 7.4 Hz, 1 H), 7.36 (t, J=58.7 Hz, 1 H), 7.62 (d, J=7.8 Hz, 1 H), 8.21 (d, J=5.3 Hz, 1 H), 9.40 (bs, 1 H); MS m/e 186 (MH+).
Compound 119 was prepared using the same procedure described for the preparation of 36, except that cyclopropylamine was replaced with 2 equivalents of cyclopentylamine, and the reaction was carried out in a sealed pressure tube at 120xc2x0 C. for 2 hours.
1H NMR (CDCl3) xcex4 1.62-1.69 (m, 2 H), 1.70-1.76 (m, 2 H), 1.79-1.85 (m, 2 H), 2.10-2.16 (m, 2 H), 3.96-4.01 (m, 1 H), 6.76 (d, J=6.2 Hz, 1 H), 8.23 (bs, 1 H), 8.27 (d, J=6.2 Hz, 1 H), 9.21 (s, 1 H); MS m/e 208 (MH+).
1H NMR (CDCl3) xcex4 1.48-1.53 (m, 2 H), 1.61-1.64 (m, 2 H), 1.69-1.74 (m, 2 H), 2.00-2.06 (m, 2 H), 3.12 (bs, 2 H), 3.77-3.83 (m, 1 H), 4.22 (bd, J=4.5 Hz, 1 H), 6.47 (d, J=5.4 Hz, 1 H), 7.85 (s, 1 H), 7.92 (d, J=5.4 Hz, 1 H); MS m/e 178 (MH+).
1H NMR (DMSO-d6) xcex4 1.61-1.68 (m, 2 H), 1.85-1.95 (m, 4 H), 1.97-2.02 (m, 2 H), 4.11 (bs, 1 H), 4.67-4.74 (m, 1 H), 7.20 (d, J=5.3 Hz, 1 H), 8.16 (d, J=5.4 Hz, 1 H), 8.19 (s, 1 H); MS m/e 204 (MH+).
Compound 122 was prepared using the same procedure described for the preparation of 36, except that cyclopropylamine was replaced with 2 equivalents of cyclobutylamine, and the reaction was carried out in a sealed pressure tube at 100xc2x0 C.
1H NMR (CDCl3) xcex4 1.89-1.97 (m, 2 H), 2.05-2.09 (m, 2 H), 2.50-2.56 (m, 2 H), 4.06-4.13 (m, 1 H), 6.56-6.62 (m, 1 H), 8.23 (s, 1 H), 8.27 (d, J=5.6 Hz, 1 H), 9,21 (s, 1 H); MS m/C 194 (MH+).
1H NMR (DMSO-d6) xcex4 1.70-1.79 (m, 2 H), 1.83-1.91 (m, 2 H), 2.32-2.50 (m, 2 H), 3.85-3.91 (m, 1 H), 4.59 (s, 2 H), 5.49 (d, J=6.2 Hz, 1H), 6.22 (d, J=5.3 Hz, 1 H), 7.55 (d, J=5.2 Hz, 1 H), 7.63 (s, 1 H); MS m/e 164 (MH+).
1H NMR (CD3OD) xcex4 1.92-2.04 (m, 2 H), 2.43-2.49 (m, 2 H), 2.88-2.97 (m, 2 H), 4.93-4.98 (m, 1 H), 7.83 (d, J=6.6 Hz, 1 H), 8.41-8.43 (m, 2 H); MS m/e 190 (MH+).
To a solution of 4-chloro-3-nitropyridine (4.9 g, 30.80 mmol) and 2-(3-aminopropyl)-2-pyrrolidinone (4.4 g, 30.80 mmol) in CH3CN (50 mL) was added K2CO3 (4.25 g, 30.8 mmol) and the mixture was stirred for 8 hours. Additional 1-(3-aminopropyl)-2-pyrrolidinone (0.2 g, 1.41 mmol) was added and the mixture was stirred for 24 hours at room temperature. The mixture was filtered and concentrated to give 8.0 g (98% yield) of the compound 123 as an orange oil.
1H NMR (CDCl3) xcex4 1.89-1.99 (m, 2 H); 2.02-2.15 (m, 2 H), 2.35 (t, J=8.05 Hz, 2 H); 3.36-3.47 (m, 6 H), 6.70 (d, J=6.2 Hz, 1 H), 8.28 (d, J=6.27 Hz, 1 H), 8.37-8.40 (s, 1 H), 9.20 (s, 1 H); MS m/e 264 (MH+).
A mixture of 123 (2.0 g, 7.6 mmol) and 10% palladium on carbon (200 mg) in EtOH (50 mL) was hydrogenated at 50 psi for 18 hours, filtered and concentrated to give 1.6 g (90% yield) of the diamine as a black oil. The oil was dissolved in CH2Cl2 (40 mL), treated with carbonyl diimidazole (1.22 mg, 7.5 mmol) and stirred for 12 hours at room temperature. The solvent was evaporated and the residue was subjected to flash column chromatography (gradient, 3% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) to give 1.09 g (62% yield) of compound 124 as an orange gum.
1H NMR (CDCl3) 5 2.01-2.05 (m, 4 H), 2.39 (t, J=7.9 Hz, 2 H) 3.37-3.43 (m, 4 H), 3.90 (t, J=7.2 Hz, 2 H), 7.01 (d, J=5.4 Hz, 1 H), 8.29 (d, J=5.4 Hz, 1 H), 8.37 (s, 1 H); MS m/e 260 (MH+).
A mixture of 28A (1.00 g, 5.71 mmol), o-fluoronitrobenzene (0.88 g, 6.28 mmol) and Cs2CO3 (5.58 g, 17.1 mmol) in DMF was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over MgSO4, and concentrated. Purification by flash chromatography (gradient, CH2Cl2/hexane, 40:1 to 20:1) gave 1.10 g (65% yield) of 125 as a yellow foam.
1H NMR (CDCl3) xcex4 2.28-2.32 (m, 3 H), 5.45-5.49 (m, 2 H), 7.01-7.05 (m, 1 H), 7.11-7.15 (m, 1 H), 7.62-7.68 (m, 2 H), 7.80-7.84 (m, 1 H), 8.14-8.22 (m, 2 H); MS m/e 297 (MH+).
Compound 126 was prepared from compound 125 according to the same procedure described for compound 115.
1H NMR (DMSO-d6) xcex4 7.06-7.09 (m, 1 H), 7.33-7.34 (m, 1 H), 7.75-7.79 (m, 1 H), 7.85-7.87 (m, 1 H), 7.94-7.98 (m, 1 H), 8.04-8.05 (m, 1 H), 8.21-8.23 (m, I H); MS m/e 257 (MH+).
III. Preparation of R1-LGs:
Compound 127 was prepared according to the procedure described by A. Yebga et al. in Eur. J Med. Chem., 1995, 30, 769-777.
Compound 128 was prepared according to the procedure described by J. C. Heslin and C. J. Moody in J. Chem. Soc. Perkins Trans. I, 1988, 6, 1417-1423.
Compound 129 was prepared according to the same procedure described for compound 127.
1H NMR (CDCl3) xcex4 1.22 (s, 6 H), 1.57-1.60 (m, 2 H), 1.92-1.98 (m, 3 H), 3.42 (t, J=6.7 Hz, 2 H).
To neat 2,6-lutidine (11.42 g, 106.60 mmol) cooled with an ice bath to 0xc2x0 C. was added t-butyldimethylsilyltrifluoromethane sulfonate (16.91 g, 63.96 mmol). After 30 minutes, a solution of compound 129 (7.72 g, 42.64 mmol) in CH2Cl2 (15 mL) was added. The resulting brown reaction mixture was stirred at 0xc2x0 C. for 2.5 hours. The reaction mixture was poured onto ice (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL) and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4 and evaporated. The crude brown oil was purified by flash column chromatography (pentane:Et2O, 15:1) to give compound 130 as a colorless oil.
1H NMR (CDCl3) xcex4 0.07 (s, 6 H), 0.85 (s, 9 H), 1.21 (s, 6 H), 1.52-1.55 (m, 2 H), 1.93-1.99 (m, 2 H), 3.42 (t, J=6.7 Hz, 2 H).
Compound 131 was prepared according to the procedure described by O Kulinkovich et al. in Tetrahedron Letters, 1996, 37, 1095-1096. To a solution of ethyl-4-bromobutyrate (16.36 g, 83.85 mmol) in Et2O (200 mL) was added titanium (IV) isopropoxide (2.38 g, 8.39 mmol). Ethylmagnesium bromide (3.0 M in Et2O, 58.7 mL, 176.09 mmol) was added to the mixture slowly via addition funnel over 30 minutes maintaining the temperature between 10-20xc2x0 C. The reaction mixture was stirred for 6 hours at room temperature and then poured slowly into chilled 10% aqueous H2SO4 (300 mL) and stirred. The layers were separated and the aqueous layer was further extracted with Et2O. The combined organic extracts were dried over MgSO4 and evaporated. The crude oil was purified by flash column chromatography (gradient, hexanes/Et2O 3:1 to 1:1) to give 10.3g (67% yield) of compound 131 as a yellow oil.
1H NMR (CDCl3) xcex4 0.42-0.48 (m, 2 H), 0.69-0.76 (m, 2 H), 1.63-1.70 (m, 2 H), 2.05-2.14 (m, 2 H), 3.45-3.50 (m, 2 H);
Compound 132 was prepared from compound 131 according to the same procedure described for compound 130 and was used immediately for coupling upon isolation.
Compound 133 was prepared according to the same procedure described for compound 131 using ethyl 3-bromopropionate.
1H NMR (CDCl3) 60.51 (t, J=6.1 Hz, 2 H), 0.76 (t, J=6.2Hz, 2 H), 2.07 (t, J=7.3 Hz, 2 H), 3.57 (t, J=7.3 Hz, 2 H).
Compound 134 was prepared from compound 133 according to the same procedure described for compound 130.
1H NMR (CDCl3) xcex4 0.10 (s, 6 H), 0.50 (t, J=6.3 Hz, 2 H), 0.74 (t, J=6.3 Hz, 2 H), 0.85 (s, 9 H), 2.03 (t, J=8.0 Hz, 2 H), 3.56 (t, J=8.0 Hz, 2 H).
A solution of 4-(trifluoromethylthio) benzoic acid (5.00 g, 22.50 mmol) and triethylamine (2.36g, 23.40 mmol) in THF (50 mL) was cooled to 0xc2x0 C. and to the solution was added ethyl chloroformate (2.53 g, 23.40 mmol). The mixture was filtered and the added dropwise to a cooled solution of sodium borohydride (3.54 g, 93.38 mmol) in a mixture of H2O and THF (1 :1 ratio, 50 mL). The reaction mixture was stirred for 2 hours keeping the temperature below 15xc2x0 C. and then for 18 hours at room temperature. The reaction was quenched with IN HCl and the organic layer was separated. The aqueous layer was extracted with Et2O and all organic layers were combined, dried over Na2SO4, and evaporated. The resulting solid was dissolved in EtOAc and was washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated to give 3.53 g (75% yield) of compound 135 as a white solid.
1H NMR (DMSO-d6) xcex4 4.57 (d, J=5.7 Hz, 2 H), 5.38 (t, J=5.7 Hz, 1 H), 7.48 (d, J=7.3 Hz, 2 H), 7.68 (d, J=7.3 Hz, 1 H).
A mixture of compound 135 (3.50 g, 16.81 mmol), hydrogen peroxide (30%, 19.05 g, 168.10 mmol) and glacial acetic acid (40 mL) was stirred at 80xc2x0 C for several minutes and then at 50xc2x0 C. for 48 hours. The solution was poured into H2O and extracted with Et2O. The combined extracts were washed with aqueous 10% NaHCO3, dried over Na2SO2, and evaporated to give 3.6 g (89% yield) of compound 136 as a white solid.
1H NMR (DMSO-d6) xcex4 4.70 (d, J=7.1 Hz, 2 H), 5.61 (bs, 1 H), 7.78 (d, J=7.2 Hz, 2 H), 8.10 (d, J=7.2 Hz, 2 H).
A solution of alcohol 136 (2.0 g, 8.32 mmol) in Et2O (50 mL) was cooled to xe2x88x925xc2x0 C. with an ice/salt bath. To this solution was added phosphorous tribromide and the resulting mixture was stirred at xe2x88x925xc2x0 C. for 5 hours and then at room temperature for 18 hours. The reaction mixture was poured into ice water and the aqueous layer was extracted with Et2O. The combined organic layers were washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4, and evaporated to give 1.45 g (56% yield) of 137 as a clear oil.
1H NMR (DMSO-d6) xcex4 4.87 (s, 2 H), 7.91 (d, J=8.5 Hz, 2 H), 8.15 (d, J=8.4 Hz,2H).
IV. Preparation of Examples of Formula I:
Unless a specific procedure is described, Examples 1-166 are prepared according to the general coupling procedures described below:
General Coupling Procedure of 2-Chloromethyl-benzimidazoles (II) and 2-Oxo-imidazopyridines or 2-Oxo-imidazopyrimidines in Scheme I-A.
Examples 1-3, 8-12, 14-16, 23-46, 65, 69-70, 72, 90, 94, 102, 104, 111-113, 120, 122, 126, 128-131, 135-136, 140-151, 156-157, 154-155, 157 and 160-163, and 166 were prepared according to the following procedure:
To a solution of II and 2-oxo-imidazopyridine or 2-oxo-imidazopyrimidine (1 equivalent of each) in THF or CH2Cl2 or DMF is added 3-4 equivalents of BTPP or Cs2CO3. The mixture is stirred at 0xc2x0 C. or room temperature for 1-16 hours. The solvent is evaporated, and the residue is diluted with water and extracted with EtOAc. The crude product is then purified by chromatography on silica gel or by reverse phase preparative HPLC.
General Procedure of Reacting Ia with R2-LG in Scheme I-B.
Examples 5-7, 18, 100, and 138 were prepared according to the following procedure:
To a solution of Ia and 1.5-3 equivalents of BTPP, Cs2CO3, or BEMP on polystyrene resin in THF or DMF is slowly added R2-LG at room temperature. When the reaction is completed, the solvent is evaporated or resin is filtered and filtrate is evaporated. The residue is purified by dissolving in EtOAc or CH2Cl2 and washing with water followed by flash chromatography, or by trituration of the solid collected from the reaction in solvents such as MeOH, or by reverse phase preparative HPLC.
General Procedure of Reacting V with R1-LG in Scheme I-C.
Examples 48, 67-68, 76, 78, 80, 82, 84, 88, 124, and 152-153 were prepared according to the following procedure.
To a mixture of V and 1.5-3 equivalents of sodium hydride or BEMP on polystryrene resin in THF, DMF or CH3CN is added R1-LG. The reaction is stirred at temperatures ranging from 0xc2x0 C. to 80xc2x0 C. for 30 minutes to 18 hours In examples where BEMP on polystyrene resin is utilized, the resin is filtered. The filtrate is evaporated and the residue is purified by flash column chromatography on silica or reverse phase preparative HPLC. In examples where sodium hydride is used as base, the reaction mixture is diluted with water, extracted with EtOAc or CH2Cl2, and purified by flash column chromatography on silica or reverse phase preparative HPLC.

Imidazopyridine and imidazopyrimidine antiviral agents


An airbag module (10) with a housing (11) accommodating a gas generator (12) and a folded airbag (13) whose deployment opening (14) is closed before activation of the airbag (10) by a cover (15) fixed on the housing (11) by at least one predetermined breaking point (18) and to secure the opened cover (15) on the housing (11). An arrester strap (20) is positioned in a displaceable manner between the cover (15) and the housing (11). The cover (15) bearing a manufacturer emblem (17) on its exterior is secured on the housing (11) by means of a hinge (19) and the arrester strap (20) is attached by its one end (22) to a part affixed to the housing and encloses at least an area of the cover (15) or the manufacturer emblem (17) in a loop (27).

An airbag module of a type related to the present invention is known from DE 196 17 758 C1. A deployment opening is thereby constructed in a covering forming a component part of the housing which is closed before activation of the airbag module by a cover formed therein. The cover is constructed as one-piece with the covering but is defined in its contour by the predetermined break point, so that the cover upon activation of the airbag module by the pressure of the inflating airbag is separated out of the covering and releases the deployment opening. In order that the vehicle passengers are thus not injured by the cover separated from the covering, the cover is fixed on the housing by means of an arrester strap which is secured on one end to the inside of the covering an on the other end to the inside of the housing.
To the extent that emblems of the manufacturer of the vehicle equipped with the airbag module are frequently attached to such covers of airbag modules, EP 1 091 865 B1 describes how to secure the manufacturer emblem to the cover with a clip in addition to an arrester strap whose one end is fixed on the cover and whose other end on the emblem.
The known securing of the cover by the arrester strap is associated with the disadvantage that especially with an increase of the weight of a cover by the emblem attached thereon, the simple fixing of an arrester strap on the cover is not secure enough to provide for a sufficiently safe attachment of the cover to the housing after activation of the airbag module.
The object of the invention therefore is to provide in an airbag module with the characteristic features generally described previously having a more secure attachment of the airbag cover on the airbag module housing after its release.
The attainment of the object including advantageous designs and embodiments is indicated from the contents of this description.

Airbag module with a cover bearing a manufacturer emblem


A chair having an adjustable seat pan is disclosed. The chair includes a seat frame having a front end and a rear end, a seat back attached to the rear end of the seat frame, a seat pan pivotally connected to the seat frame, and a seat drop down link having a first end attached to the seat frame and a second end in contact with a catch member located beneath the seat pan so that the seat pan can be raised and lowered from a flat position to approximately a 6° angle with respect to the seat frame.

Traditional seats were designed so that the seating portion of the seat was at a right angle to the backrest. These seats, however, proved to be uncomfortable to sit in during long trips or flights. In an effort to improve the comfort level of seats, manufactures have tried various designs including increased padding in the seat and backrests as well as installing lumbar cushions in the lower portion of the back rest in an attempt to relieve pressure in the lower back of the seat occupant.
Another way of making seating more comfortable was to incline the seat with respect to the backrest. The inclination of the seat by approximately 2-6° allows the weight of the occupant to be transferred toward the intersection of the seat bottom with the back rest. This reduces the fatigue on the gluteus maximus that results from sitting directly on one's bottom for extended periods of time.
Although the angling of the seat bottom with respect to the back rest provides for greater comfort over an extended period of time, such an arrangement is not always possible or practicable. For example, in an aircraft passenger seat the seat bottom or pad is angled at between 2-6° for taxi, take-off, and landing (TTOL). The seat could remain at this angle throughout the flight, however, should one attempt to work at a desk or tray table, or eat sitting at this angle they would have to move up to the edge of the seat or lean forward so as to be able to write or avoid dropping food down the front of themselves. This type of seating is not necessarily desirable, particularly for executive style seating on private or VIP aircraft.
It would be much easier and comfortable to work or eat in a chair in which the seat bottom was flat, as opposed to being oriented at approximately a 2-6° angle. For this reason, a seat having a drop down seat pan for which the position could be either flat or angled approximately 2-6° from the horizontal would be an important improvement in the art.